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Screen speed is a factor determining the sensitivity (or speed) of a radiographic receptor. It is the Screen film amount of exposure required to form an image. Two screen (Diagnostic Radiology) A screen film radiographic receptor con- speeds are illustrated on Figure S.21. A low-speed screen is sists of a film in direct contact with either one or two intensifying generally thin to reduce blurring and absorbs only a fraction of Screen unsharpness 838 Secondary collimator Image blurring Screen-film contact screen thickness (Diagnostic Radiology) See Film-screen contact ‘Detail screen’ ‘Fast screen’ South-East Asia Federation of Organizations for Medical Physics (SEAFOMP) (General) The South-East Asia Federation of Organizations for Medical Physics (SEAFOMP) was founded in 2000 as a regional organisation of the International Organization for Medical Physics (IOMP). As of 2019 the Federation consists of six national member organisations (plus three affiliated members), represent- ing about 1,400 physicists and engineers working in the field of medical physics. FIGURE S.20 Effect on two types of screens on image resolution. Since its inauguration the main objective of SEAFOMP has (Courtesy of Sprawls Foundation, www .sprawls .org) been to harmonise and promote the best practice of medical phys- ics in the South-East Asian region. SEAFOMP includes the medical physics societies from the Receptor sensitivity following countries: Indonesia, Malaysia, Philippines, Singapore, (speed) Thailand and Vietnam. affected by Hyperlink: www .seafomp .org screen thickness Low exposure Sealed source High exposure (Nuclear Medicine) A sealed, or closed source, refers to an encap- sulated or otherwise contained radioactive source. From a radio- 100% protection point of view, a sealed source is defined as a source that 50% is unlikely to cause contamination. Related Article: Unsealed source ‘Fast screen’ ‘Detail screen’ Secondary barrier (Radiotherapy) The design of a radiotherapy treatment depends on adequate shielding if the radiation exposure to those outside FIGURE S.21 Effect of screen speed on radiation exposure. (Courtesy S of the room is to be kept below the regulatory requirements. That of Sprawls Foundation, www .sprawls .org) part of the room that the primary beam falls on directly is called the primary barrier and will be the most heavily shielded part of the room (e.g. for a 10 MV linear accelerator this will be of the Intensifying screen order of 2.5 m of regular concrete). image blurring Outside of this is a region where lower intensity radiation aris- ing from scattered or leakage radiation falls needs less in the way Image of shielding and the barrier here is known as the secondary bar- rier. The thickness of the wall in this region is of the order of Small object 1–1.5 m depending on beam energy. See Figure S.23. Related Article: Maze Secondary circuit (General) A secondary circuit is a circuit or winding (e.g. of a transformer) in which a current is produced by the electromag- netic induction of a current in a neighbouring circuit or winding called the primary circuit or winding. The primary circuit sup- FIGURE S.22 Screen unsharpness and image blurring. (Courtesy of plies the power that is ultimately used by the secondary circuit. Sprawls Foundation, www .sprawls .org) Related Articles: Transformer, High-voltage transformer, High-voltage circuit, Three-phase transformer the x-radiation. Therefore, a higher exposure to and through a Secondary collimator patient must be used to form an image. Often the relative speed (Radiotherapy) Within the head of a linear accelerator once the between various screen-film combinations can be expressed as electrons have impinged on the target and generated the x-rays to 100, 200, 400, etc. be formed into the treatment beam, a primary collimator is used to initially form a beam which may be used to treat a patient. Screen unsharpness Once the beam has been through the flattening filter a useable (Diagnostic Radiology) Blurring occurs within the thickness of treatment field must be created. This typically takes the form of intensifying screens, as illustrated on Figure S.22. This is some- squares or rectangles which may be created by the secondary times referred to as ‘screen unsharpness’ although unsharpness collimator. This secondary collimator is also commonly called is just one of the effects of screen blurring. Two other effects are the field-forming jaws, and the jaws are commonly termed x- and a reduction in visibility of anatomical detail and the other is a y-jaws. The four blocks consist of two to form the upper jaws, and reduction in spatial resolution. two to form the lower jaws. Secondary electron spectrum 839 Secondary ionising radiation Typically the collimator is made from tungsten and is approxi- given a range or spectrum of kinetic energies dependent on the mately 7 cm in thickness which attenuates the x-rays to the order energy and angle of the incident radiation, with some electrons of 1%–3%. Field sizes can be anything from a few millimetres having enough kinetic energy to cause further ionisations in the up to a 40 × 40 cm2 field as defined at the isocentre plane. It is medium. The range of electron energies is referred to as the sec- important that the position of each jaw is known to within 1 mm ondary electron spectrum, and will be characteristic of the type at the isocentre plane. In older linacs the jaws only moved in pairs and energy of the incident radiation, and of the composition of symmetrically about the central axis. However all modern linacs the medium. now allow each of the four collimator blocks to be moved inde- Related Articles: Secondary ionising radiation, Secondary pendently. In this scenario at least one pair can then cross beyond electron the central axis by up to 10 cm in the isocentre plane. This allows so-called asymmetric treatments, where one of the beam edges Secondary electrons is positioned coincident to the central axis. These are known as (Radiation Protection) Secondary electrons are electrons given half-blocked treatments and are most commonly used in breast kinetic energy and liberated from atomic orbits as a result of cancer treatments. interactions between incident photonic or charged particle radia- It is important that the secondary collimator provides a sharp tion and the medium. These secondary electrons may be given beam penumbra irrespective of the field size. To achieve this linear enough kinetic energy to cause further ionisations in the medium. accelerator manufacturers have created two options: (a) a straight Related Articles: Secondary ionising radiation, Secondary edge is moved on an arc so that the collimator always presents the electron spectrum full surface to the diverging beam edge or (b) a curved edge is moved on a straight line (Figure S.24). Related Articles: Collimation, Collimator, Dynamic wedge, Secondary ionisation Treatment head, Penumbra, Asymmetric jaws (Radiation Protection) When secondary ionising radiation (photonic and/or charged particles) resultant from an interac- Secondary electron spectrum tion between an incident photon or particle of ionising radiation (Radiation Protection) Secondary electrons are electrons given and the medium carries on to cause further ionisations in the kinetic energy and liberated from atomic orbits as a result of medium, these further interactions are referred to as secondary interactions between incident photonic or charged particle radia- ionisations. tion and the medium. These secondary electrons will have been Secondary ionising radiation may travel in any direction away from the initial site of interaction. Therefore secondary ionisa- tions and subsequent energy deposition in the medium may occur outside the primary radiation beam. Primary barrier Related Articles: Secondary radiation, Secondary ionising radiation S Secondary barrier ~2.5 m Concrete 2350 kg/m3 Secondary ionising radiation (Radiation Protection) Secondary ionising radiation refers to all photons and charged particles resultant from an interaction Treatment between an incident photon or particle of ionising radiation and machine the medium, which still have enough energy to cause further ioni- sations. Therefore secondary ionising radiation does not include any secondary photons or charged particles which are non-ionis- ing, e.g. ultraviolet radiation. ~1.5 m Secondary ionising radiation may travel in any direction away Maze entrance from the site of interaction. Therefore further ionisations and energy deposition in the medium may occur outside the primary radiation beam. Such secondary interactions are important for radiation protection purposes – they are important in radiother- apy treatment planning when attempting to deliver the prescribed dose to the target volume (tumour) while minimising the periph- eral dose to surrounding healthy tissues. FIGURE S.23 Treatment room showing secondary and primary barri- Related Articles: Secondary radiation, Secondary electron, ers and maze corridor. Peripheral dose (a) (b) FIGURE S.24 Illustrations of the possible solutions for providing a sharp beam penumbra. (a) A straight edge is moved on an arc so that the collima- tor always presents the full surface to the diverging beam edge or (b) a curved edge is moved on a straight line. Secondary malignancies 840 Segmentation Secondary malignancies Sector image (Radiotherapy) A secondary malignancy is a new cancer that (Ultrasound) Sector image is an image formed by a convex ultra- occurs in an individual as a result of previous treatment with radi- sound transducer in the form of a pie slice. Typically, the ultra- ation or chemotherapy. Secondary cancers may occur months or sound beam is swept in an angular manner in order to form the years after the treatment and are a consequence or side effect of image. The advantage of a sector image is that it allows a wider the initial cancer treatment. ‘window’ of the internal anatomy. The disadvantage of a sector See Radiation-induced secondary malignancies. image is that at areas far away from the face of the transducer (deeper within the body) the lateral resolution is lower due to lower Secondary radiation line density as compared to areas closer to the transducer face. (Radiation Protection) See Radiation, secondary ionising Secondary standard (Radiation Protection) A radiation detector (whether an ionisation chamber or solid state-based detector) used for day-to-day mea- surements of radiation output or dose is called a field instrument. The displayed reading on the instrument must have a traceable calibration such that it can be compared to any other instrument making the same measurement. While the response of the field instrument may be checked regularly using a simple radiation check source of known output to ensure that the instrument is functioning correctly, it must be calibrated at less regular intervals (e.g. annually) against a primary standard held at a national institute such as the National Physical Laboratory (NPL) in the UK, or the National Institute of Standards and Technology (NIST) in the USA. The primary standard used by such national institutes will be a radiation detector that is only used for calibration purposes, and is kept and used in a way to ensure that it has a very well-controlled and precisely defined response to given quantities of radiation. Related Article: B-mode It is not practicable for all field instruments used nationally Further Reading: Bushberg, Seibert, Leidholdt and Boone. S to be sent to a single institute for direct comparison and calibra- 2012.The Essential Physics of Medical Imaging, 3rd edn., tion against the primary standard. Therefore, an intermediate step Lippincott Williams and Wilkins. is introduced – the use of secondary standard calibration instru- ments. Such instruments are more widely available for calibration Sector integration work, while not being used for day-to-day work as field instru- (Radiotherapy) Sector integration is a method of determining ments. A field instrument will be calibrated against the secondary dosimetric parameters for an irregular field from data for circular standard which itself has already been calibrated against the pri- beams. It was first proposed by Clarkson (1941) and developed by mary standard, thus providing the necessary traceability to future Cunningham (1972) to calculate scatter air ratios for rectangular readings on the field instrument. fields. In this method an irregular field is approximated by a num- Related Article: Reference ionisation chamber ber of circle segments as shown in the example in Figure S.25. Further Reading: Graham, D. T. and P. Cloke. 2003. The contribution from each sector is then integrated to give the Principles of Radiological Physics, Elsevier Science Ltd., total contribution at a point. Edinburgh, London, UK. Further Readings: Clarkson, J.R. 1941. A note on depth doses in fields of irregular shape. Br. J. Radiol. 14:265; Cunningham, J.R. 1972. Scatter-air ratios. Phys. Med. Biol. 17(1):42–51. Secular equilibrium (Nuclear Medicine) Transient equilibrium refers to the activ- ity equilibrium that occurs in a decay series when the half-life of the parent nucleus is so long that

the decay is negligible over the course of the observation period. The activity of the daugh- ter nucleus is increased until it reaches an equilibrium state with the same activity as the parent nucleus. After a time period of 5 daughter half-lives the two activities can be said to be in equilib- rium since Ad = 0.98Ap (Ad and Ap is the activity of the daughter and parent nucleus, respectively) (Figure S.26). Related Articles: Transient equilibrium, Bateman equation for secular equilibrium, Bateman equation for transient equilibrium Segmentation FIGURE S.25 Simple approximation of an irregular field using circle (Nuclear Medicine) Segmentation is an image processing tool sectors. used to reduce an image to its base components or objects. This Segmentation 841 Selenium detector is achieved by grouping all pixels that have certain defined char- Segmented imaging acteristics. In nuclear medicine, for example image segmenta- (Magnetic Resonance) Segmented imaging refers to imaging tion can be used to classify different types of tissue according to k-space in parts or segments to create a cine image. their tracer uptake. It is also useful in the automatic definition of Related Article: Cine MRI regions of interest. Selective excitation slice selection (Magnetic Resonance) See Slice selection Segmentation (Radiotherapy) Segmentation is a tissue structure contouring pro- cess in treatment planning. Normal organs of interest and target Selenium detector volumes are identified and outlined either automatically or manu- (Diagnostic Radiology) The selenium detector or amorphous- ally on CT, MR and/or PET images for treatment planning and selenium (a-Se) detector is an example of a direct conversion, dose calculation. flat panel detector used in medical imaging (x-ray) radiography. Selenium detectors can be used for both static radiography and real-time fluoroscopic imaging. It is referred to as a direct detec- tion method as the image information is transferred from the inci- dent x-rays directly to electrical charge with no intermediate stage 1.2 via photoconductive detection. Figure S.27 shows a typical pixel of a selenium detector: It is formed from a continuous photocon- 1 ductive layer, which is electronically coupled to an active matrix 0.8 array. The active matrix array consists of a two-dimensional array of thin-film transistors (TFTs) which act like switches to read out 0.6 the signal from each pixel. This detection method is in contrast to indirect detection where the incident x-rays are first converted 0.4 into visible light wavelength photons by a phosphor screen prior 0.2 to detection. Parent The top surface of the detector is constructed out of a continu- 0 ous high-voltage electrode that allows the application of an elec- 0 5 10 15 20 tric field across the photoconductor, with the pixel elements held Number of daughter half-lives at a positive potential in relation to the top electrode. Detection occurs because x-rays that are absorbed by the photoconductor FIGURE S.26 The graph shows the build-up to a secular equilibrium. form electron-hole pairs, which are separated and migrated across The half-life of the daughter is negligible compared to the half-life of the the photoconductor to the opposite electrodes by the applied elec- S parent. tric field. The electrons move towards the pixel electrode at the Incident x-ray Electrode + Electron hole pair – Electric field Amorphous selenium S G D Storage capacitor Adjacent gate line TFT Detector element Glass substrate FIGURE S.27 A direct selenium photoconductor detector pixel, the incoming x-ray creates an electron-hole pair and the liberated electron is then detected and stored by the detector element and storage capacitor. Activity (a.u.) Self-absorption 842 Semiconductor detector bottom of the detector and are stored as charge in the capacitor. Related Articles: Amorphous selenium, active matrix array, The amount of stored charge is proportional to the energy of the thin film technology, electron-hole pair x-rays incident to the detector. Further Readings: Kasap, S. O., C. Haugen, M. Nesdoly, J. The photoconductive layer is usually constructed out of a thick A. Rowlands. 2000. Properties of a-Se for use in flat panel x-ray layer of amorphous selenium (Z = 34), as it is easily deposited image detectors. J. Non-Cryst. Solids 266–269(Part 2):1163– over large areas via traditional plasma deposition, has a low dark 1167; Kasap, S. O., M. Z. Kabir and J. A. Rowlands. 2006. Recent current, and good electron and hole transportation properties. The advances in x-ray photoconductors for direct conversion x-ray thickness of the selenium used in the photoconductor is dependent image detectors. Curr. Appl. Phys. 6:288–292; Rowlands, J. A. on the x-ray absorption depth (δ), the imaging application and the and J. Yorkston. 2000. Flat panel detectors for digital radiography. K and L edge energies. For mammography with mean peak energy In J. Beutel, H. L. Kundel and R. L. Van Metter (eds.), Handbook 20 keV, the a-Se thickness required is 2δ, about 100 μm while for of Medical Imaging, Volume 1. Physics and Psychophysics, SPIE chest and general radiography with 60 keV it is 2000 μm. Press, Bellingham, WA, pp. 223–313. To detect an image, many pixels form an active matrix array shown in Figure S.28. In this each pixel is formed by a charge Self-absorption collection electrode, a storage capacitor and a thin film transistor (Radiation Protection) Self-absorption is the absorption of radia- switch/gate. To detect the image signal, the charge stored in each tion (emitted by radioactive atoms) by the material in which the pixel’s capacitor is drained by the charge collector electrode and atoms are located; in particular, the absorption of radiation within read out row by row. The gate line driver controls this readout a sample being assayed. process by applying a switching voltage to the transistor gates in The scattered radiation produced when a radiation beam each row. The signal stored within the capacitance of individual impinges on a medium is partially absorbed within the medium. pixels in each row is then drained and travels down the data line This phenomenon may be described as self-absorption as well. where the signal is amplified and read out by the multiplexer. A third example of self-absorption occurs in scintillation The resolution of direct conversion detectors is almost entirely detectors. The incident ionising radiation is converted to light dependent on the pixel aperture and has a higher resolution than photons within the scintillator; however a fraction of these light indirect-conversion detection for the equivalent pixel size as the photons are absorbed within the scintillator itself and are not electric field forces the electrons to travel directly to the electrode detected by the photomultiplier optically coupled to it. without lateral diffusion. Another important advantage of direct Related Articles: Radiation absorption, Scattered radiation over indirect detection is the pixel fill factor, that is the percentage of the pixel that is sensitive to incident x-rays, defined as Self-shielded cyclotron Light sensitivearea (Nuclear Medicine) A self-shielded cyclotron is a low-energy Fill factor = (S.5) cyclotron in which the steel frame or yoke serves as primary radi- S Fullarea of pixel ation shield. Additionally hydraulically driven movable blocks made of specially formulated concrete surround the cyclotron and By appropriate design of the electrode the electric field can be add more radiation shielding. adjusted to increase the effective fill factor of each pixel as elec- trons that are liberated above insensitive areas of the pixel can be redirected to active region. This allows fill factors of 85%–95% Semiconductor detector to be common. (Radiation Protection) A semiconductor detector of ionising Abbreviation: TFT = Thin film transistor. radiation is a solid state detector in which electron-hole pairs are created when charged particles (e.g. alpha) or photons (gamma, x-rays) pass through the detector. Figure S.29 shows the electron energy band structure for: (a) intrinsic, (b) p-type and (c) n-type Multiplexer ADC semiconductors. The density of solid state semiconductors is more than 1,000 Charge amplifier times greater than that of a gas, and the energy needed for the cre- G ation of one pair electron-hole (an electric charge carrier) is not S Charge collector greater than 3 eV (very small in comparison with the 100 eV which D electrode is needed for some scintillation detectors or with the approximately 35 eV needed for gas counters). Most often, the semiconductor detector is a reverse biased diode. The semiconductor detector is more efficient for x- and gamma-rays as well as for α-particles detection than the gas or the scintillation counters. Its energy reso- lution is also better, but the thermal noise at room temperature is TFT Conduction band Conduction band Conduction band Energy Donor levels Gate line gap Acceptor levels Valence band Valence band Valence band (a) (b) (c) Data line FIGURE S.29 Band structure in: (a) intrinsic semiconductor, (b) p-type FIGURE S.28 An active matrix array and peripheral electronics. semiconductor, (c) n-type semiconductor. Gate line driver Semiconductors 843 Sensitivity high and usually the semiconductor detector must be operated at peripheral electron (z) of the semiconductor used. So, an N-type low temperature, e.g. at liquid nitrogen temperature of 77°K. semiconductor carries current mainly in the form of negatively Examples of semiconductor detectors are Ge(Li), Si(Li), HPGe charged electrons. A P-type semiconductor carries current pre- (to be kept at room temperature when not used) and Cd-Zn-Te, dominantly as positive electric charge–holes. with an efficiency of about 100% for 100 keV photons. Some of the most widely used materials for manufacturing of Silicon-based diode detectors, which can operate at room semiconductors are antimony, arsenic, carbon, germanium, sele- temperature, are used as personal dose monitors for measuring nium, silicon, gallium arsenide. either dose rate or integrated dose. Hyper-pure Germanium detec- tors have excellent energy resolution (used for spectrometry), but Semiflex chamber require liquid nitrogen cooling. (Radiation Protection) The semiflex chamber is a cylindrical ion- Figure S.30 shows an example of a semiconductor detector isation chamber used for in vivo dose measurements in external (diode in reversed bias) in a circuit with 1.5 V power supply and beam radiotherapy and brachytherapy. The chamber can be used 1 MΩ resistor. Radiation with increasing intensity (from 10–100 for absorbed dose to water, air kerma and exposure measurements. mGy) creates increasing reversed current through the diode (of Related Articles: Absorbed dose, Air Kerma, Exposure, the order of 0.1–1 μA). This respectively creates a voltage drop Cylindrical ionisation chamber over the resistor, proportional to the radiation dose. The dotted Further Reading: PTW, 2008/2009. Ionizing Radiation ‘load line’ shows the maximum dose which can be measured with Detectors, p. 22. this diode in this circuit. Related Articles: Cumulative dose, Dose rate, Gas detector, Sensitivity Ionising radiation, Scintillation counter (General) See Receiver operating characteristic (ROC) Further Readings: Knoll, G. F. 2000. Radiation Detection and Measurement. 3rd edn. New York, Chichester, Weinheim, Sensitivity Brisbane, Toronto, Singapore: John Wiley & Sons, Inc., pp. 354– (Nuclear Medicine) The sensitivity is a measure of how many of 376; Dendy, P. P. and B. Heaton. 1999. Physics for Diagnostic the emitted photons are being detected by the PET system. This Radiology. 2nd edn. Bristol and Philadelphia: Institute of sensitivity is determined by a number of factors, primarily the Physics Publishing, pp. 149–151; Saha, G. B. 2001. Physics and attenuation efficiency of the scintillation material and the geomet- Radiobiology of Nuclear Medicine. 2nd edn. New York, Berlin, ric parameters. For a source located inside an absorbing medium, Heidelberg: Springer-Verlag, pp. 87–88; Hobbie, R. K. 1997. the true coincidence rate Rtrue, for two coincidence detectors is Intermediate Physics for Medicine and Biology. 3rd ed. New given by York, Berlin, Heidelberg: Springer-Verlag, p. 425. R E 2g -mT true = e ADCe (S.6) Semiconductors S (General) A semiconductor is a substance that can conduct elec- where tricity under some conditions but not others. These properties of E is the source emission rate such substances turn them into a good medium for the control of ɛ is the intrinsic efficiency of the detectors (the fraction of inci- electrical current. Conductance varies depending on the current dent photons detected) or voltage applied to a control electrode, or on the intensity of μ and T are the linear attenuation coefficient and the thickness radiation. of the patient, respectively The specific properties of a semiconductor depend on the gADC is the geometrical efficiency of the detector, that is the impurities, or dopants, added to it. Two types of dopants can be number of annihilation events where both photons are used having either an extra peripheral electron (z + 1) for N-type emitted in a

direction where they can be detected by or a lack of one electron (z − 1) for P-type regarding the number of two opposite detectors FIGURE S.30 Indicative example of radiation dose measurement with scintillation detector. Left: A Block diagram showing the circuit in which a semiconductor detector (diode) is connected. Right: A diagram of a diode current, where the reverse diode current increases from about 0.1–1 μA, with the increase of radiation dose from 10–100 mGy. The voltage drop, created by the reversed diode current over the resistor, is calibrated to measure the radiation dose through the diode. Sensitivity profile 844 Serial organs The geometrical efficiency is maximised if the source is Sentinel lymph node located at the middle of a centreline between two detectors. When (Radiotherapy) A sentinel lymph node is the hypothetical first the source is moved away from the centre point the efficiency lymph node reached by metastasising cancer cells from a pri- decreases. A more appropriate measure for distributed sources is mary tumour. Biopsy, which entails injecting a radioactive tracer the average geometric efficiency, given by and dye near the tumour, detects the first draining lymph node(s) which is then pathologically sampled. 2A g det ACD = (S.7) 3pD2 Septal penetration (Nuclear Medicine) Photons emitted with an oblique angle rela- where tive to the collimator holes can penetrate the septal wall before D is the distance between the detectors being detected. This problem is referred to as septal penetration Adet is the area of the individual detector and it gives rise to degradation in spatial resolution. The probability of septal penetration is proportional to pho- Related Articles: PET, Beta decay ton energy and inversely related to atomic number of the col- Further Reading: Cherry, S. R., J. A. Sorenson and M. E. limator material and septa wall thickness. For a parallel-hole Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, collimator a registered photon is assumed to have been emit- Philadelphia, PA, pp. 337–338. ted somewhere along an event line perpendicular to the detector surface. If the photon has penetrated the septa the event will be Sensitivity profile misplaced. The misplacement is relatively short since the prob- (Nuclear Medicine) In nuclear medicine, sensitivity profiles are ability of a photon penetrating multiple septa walls is relatively used to evaluate different parameters in imaging equipment. In small. PET imaging the sensitivity, i.e. events per unit time, depends on Septal penetration leads to a degradation in spatial resolution the PET scanner, the data acquisition type (2D or 3D acquisition) but the effect is only prominent when using high-energy γ emit- and the source position along the axial direction. The sensitivity ters and high-resolution collimators with thin septa walls. can be measured by acquiring images of a line source oriented Related Articles: Collimators, Parallel-hole collimator along the central axis. Further Reading: Cherry, S. R., J. A. Sorenson and M. E. Another example of a sensitivity profile is the spectral sen- Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, sitivity of the photocathode in a photomultiplier tube. The pho- Philadelphia, PA, p. 223. tocathode spectral sensitivity must have an overlap with the corresponding scintillation light emission spectra in order to give Septum a signal enhancement. (Nuclear Medicine) A barrier consisting of a high attenuating S material used to shield detectors or attenuate radiation with an Sensitometer oblique angle of incidence. (Diagnostic Radiology) A sensitometer is a light-emitting One example of septa are the walls separating the holes in a instrument for exposing areas on a film to a range of exposure collimator. The thickness of the wall is designed for a certain pur- values, usually in a step pattern as illustrated in Figure S.31. pose, i.e. thick walls for high-energy photons and thinner walls The colour of the light has to match the sensitivity spectrum for low-energy photons. Another use for septa walls is when sepa- of the film. rating detector rings in a PET scanner. Films exposed with a sensitometer can be used to determine the characteristics of both the film and the film processing. Sequestration targetting (Nuclear Medicine) Sequestration refers to the process where the spleen identifies and removes damaged red blood cells. This is Sensitometry used when studying the spleen. Small portions of the patients’ (Diagnostic Radiology) See Sensitometer blood are removed and labelled with radioisotopes. Before the cells are reintroduced into blood circulation they are heated to cause cell damage so that the spleen will gather the radiolabeled cells. Sensitometer Serial exposures (Diagnostic Radiology) Serial exposures (also known as image Light sequences) are images obtained in a rapid succession (series). These are used for recording dynamic processes in rapidly mov- ing organs (for example in the heart). The series can be with speed Film from 2–8 images/s (when using record on x-ray film) to 25–30 or more fps (in digital x-ray systems). See the articles on Image sequences and Pulsed fluoroscopy. Related Articles: Image sequences, Pulsed fluoroscopy Processed film Serial organs (Radiotherapy) Radiation treatment inevitably affects normal tis- FIGURE S.31 Principle of sensitometer. (Courtesy of Sprawls sue and so may cause radiation-induced adverse effects. The toler- Foundation, www .sprawls .org) ance of normal tissues to radiation depends on the ability of the Servobrake 845 Set-up error clonogenic cells to maintain a sufficient number of mature cells used to drive the system in the direction necessary to reduce or suitably structured to conserve organ function. The tissue archi- eliminate the error. tecture is thought to be important in determining the tolerance Related Article: Voltage regulation dose for partial organ irradiation. In radiotherapy, it is generally the case that the total dose that Set-up error can be tolerated depends on the volume of tissue irradiated – the (Radiotherapy) The set-up error accounts for the variability in dose-volume effect. It has been suggested that groups of cells positioning the patient with respect to the treatment beams. Errors within an organ are organised into collective bodies called func- are either systematic, geometric errors that arise during treatment tional subunits (FSU). The arrangement of the FSUs within the preparation and are effectively ‘frozen’ into the patient’s treat- tissue is thought to be an important factor in determining the ment, or random treatment execution errors. volume dependence of an organ. In serial organs, the FSUs are Causes of systematic error include arranged in series, like the links of a chain, and the integrity of each is critical to organ function. Damage to a single FSU is • Linac geometry error (laser error, collimator axis error, sufficient to cause a complication. Radiation damage to such tis- or beam alignment error) sues is expected to show a binary response: normal function for • Treatment planning system error (volume growing, doses below a threshold dose above which there is loss of func- image transfer) tion. For these tissues, the greater the volume of tissue irradiated, • Geometric imaging error (CT couch indication, CT the steeper the sigmoid dose–response curve becomes and the laser error) threshold dose decreases. The effect of increasing the irradiated • Delineation uncertainty volume is greatest with changes to small volumes: Once a large • Systematic set up error (patient position) number of FSUs are irradiated any further increase in volume • The random variability in patient positioning inherent has little effect on the threshold or slope of the sigmoid dose– in the scanning process used to prepare the treatment response curve. The steepness of this curve for serial organs means that they are sensitive to small increases in ‘biologically effective’ dose. Therefore administering large dose fractions to the spinal cord, for example will increase the biological effec- EXAMPLE: MARGIN FORMULAE tiveness per unit of dose so that using a large volume together with large dose fractions, as occurs in palliative treatments, Stroom et al. derived the following margin formula for could augment the danger of myelitis. 99% of the CTV to receive 95% dose: When planning radiotherapy treatment, assessment is always made of the dose to normal tissues and modern commercial treat- M = 2S + 0.7s ment planning systems have a number of tools to aid this process S including dose-volume histograms (DVH). For serial organs, seri- Van Herk et al. calculated margins for a minimum CTV ous complications are likely to be dominated by small-volume, dose of 95% in 90% of patients: high-dose effects so particular attention is paid to the maximum dose they receive. Examples of serial organs are spinal cord, optic chiasm, optic M = 2.5S + 0.7s lens, small bowel. It should be noted however that most real nor- mal tissues have a mixed parallel and serial architecture. where Abbreviations: FSU = Functional sub-unit and DVH = Dose- M is the margin size volume histogram. Σ is the size of the systematic error and Related Articles: Adverse events, Biological effective dose, σ is the random error Dose response model, Dose volume histogram, Parallel organs, Sigmoid dose–response curve, Tolerance It is also important to remember that set-up error will also Further Readings: Hall, E. J. and A. J. Giaccia. 2006. affect the position of organs at risk. Radiobiology for the Radiologist, 6th edn., Lippincott Williams & Wilkins, Philadelphia, PA; Withers, H. R., J. M. G. Taylor and B. Maciejewski. 1988. Treatment volume and tissue tolerance. Int. All the above errors should be minimised as much as possible J. Radiat. Oncol. Biol. Phys. 14:751–759. with regular QA and training. Additionally, the extent of system- atic errors can be limited by setting an action level for correcting Servobrake discrepancies revealed by portal imaging. The remaining error (General) See Servomotor must be accounted for by the use of planning margins. Margins can be quantified by multiplying the variance of Servomotor the error distribution by a multiplication factor according to (General) Servomotor is the motive element in a servomecha- the level of confidence required to encompass the entire CTV. nism. A servomechanism (or servo) is an automatic device that The variance of the error distribution should include contri- uses error-sensing feedback to correct the performance of a mech- butions from all the above sources, combined in quadrature anism. A common type of servomechanism provides position if Gaussian. Breathing positional errors are not Gaussian in control using an electric servomotor. Usually, servomechanisms nature. operate on the principle of negative feedback, where the control Various numerical simulations have been carried out to deter- input is compared to the actual position of the mechanical system mine the multiplication factors and treatment margins necessary as measured by some kind of transducer at the output. Any dif- to achieve a certain probability of target coverage as a function ference between the actual and expected values is amplified and of the size of the two types of error. These reveal the effects of Set-up margin 846 Shadowing systematic errors to be of order 3 times more important than ran- parameters for assessment and management of coronary artery dom errors. disease (CAD). Abbreviations: IM = Internal margin, SM = Set up margin Related Article: Extent and EPID = Electronic portal imaging device. Related Articles: IM internal margin, SM set up margin, SFO (Single field optimisation) Electronic portal imaging device EPID (Radiotherapy) See Single field optimisation (SFO) Further Readings: Stroom, J. C., H. C. J. de Boer, H. Huizenga and A. G. Visser. 1999. Inclusion of geometrical uncertainties in SFUD (Single field uniform dose) radiotherapy treatment planning by means of coverage probabil- (Radiotherapy) See Single field uniform dose (SFUD) ity. Int. J. Radiat. Oncol. 43:905–919; van Herk, M., P. Remeijer, C. Rasch and J.V. Lebesque. 2000. The probability of correct tar- Shading artefact get dosage: Dose-population histograms for deriving treatment (Magnetic Resonance) The shading artefact appears as a variation margins in radiotherapy. Int. J. Radiat. Oncol. 47:1121–1135. in signal intensity on the image. The main cause of this artefact is the uneven excitation of nuclei due to an RF pulse with a flip angle Set-up margin other than 90° or 180°. Other causes of shading are the uneven (Radiotherapy) A margin needs to be added to the clinical tar- loading of the coil, which could occur if the patient is touching get volume (CTV) to form the planning target volume (PTV) to the coil or inhomogeneities within the magnetic field, which can account for any positional errors from the planning information. be improved with shimming. The

ICRU Report 62 (ICRU 1999) divided this margin into the Abbreviation: RF = Radiofrequency. set up margin (SM) and internal margin (IM), in order to separate out the contributory sources of positional error into set up error Shadowing and physiological error, respectively. The SM accounts for varia- (Ultrasound) Shadowing is an artefact effect where the region tions in patient positioning and alignment of the treatment beams. behind a structure with high attenuation is interrogated with a Immobilisation devices and portal imaging help to reduce the SM beam with decreased intensity, with the consequence that, in by improving the reproducibility of patient position. Regular QA B-mode (imaging) ultrasound the tissue deep to this appears with helps to reduce the SM by improving the precision and accuracy reduced brightness compared to adjacent similar tissue (Figure of the treatment beam motion. S.32). In colour Doppler flow imaging the consequence of shad- The remaining source of error, i.e. the physiological varia- owing is that colour signal is lost for regions deep to highly tion of the tumour size and shape is accounted for by the inter- attenuating or highly reflecting tissue such as calcified plaques. nal margin. The CTV plus the IM defines the internal target The combination of bright echoes with corresponding shadow- volume (ITV). The total required margin (SM + IM) can be S ing is useful for detection of gallstones and arterial plaques, for quantified from the standard deviations (σ) of the associated instance. probability distributions. If the error distributions can be treated Shadowing might also occur due to scattering by gas bubbles as Gaussian and independent, then their standard deviations which, in turn, might have been created by cavitation due to the should be combined in quadrature (i.e. sum of variances), with high-intensity interrogating ultrasound itself (Leighton, in Duck a multiplication factor according to the level of confidence, as et al. 1998). shown in Equation S.7. In transverse section on Figure S.32 there is strong reflec- In other words, the total margin would be proportional to the tion from the graft surface (grey arrow). There is little or no combined standard deviation. Combining margins for set up error and physiological (inter- nal) error: Total marginµ sSM + sIM (S.8) However this approach is not commonly used in practice to cal- culate margins. A more practical method is to decompose the margin into random and systematic components as explained in Set-up error. Abbreviation: SM = Set up margin. Related Articles: IM internal margin, Set up error Further Readings: ICRU (International Commission on Radiation Units & Measurements, Inc.) 1993. Prescribing, reporting and recording photon beam therapy. ICRU Report 50, Washington, DC; ICRU (International Commission on Radiation Units & Measurements, Inc.) 1999. Prescribing, recording and reporting photon beam therapy (Supplement to ICRU Report 50), ICRU Report 62, Washington, DC. Severity (Nuclear Medicine) The severity of the abnormality indicates how low the tracer uptake with the abnormality is and usually is expressed as the sum of SD (standard deviation) below the lower limit of normal. Extent and severity are two important FIGURE S.32 Shadowing caused by high attenuation through a graft. Sharpness 847 Shim coils transmission onwards through to deep tissue and there is a cor- Nuclear Shell Model: The atomic nucleus is a quantum responding dark shadow in the image (white arrow). n-body system, where the nucleons are bound together by the Related Articles: Attenuation, Acoustic Impedance residual strong force, the nuclear force. The nucleons are fermions Further Reading: Duck, F. A., A. C. Baker and H. C. Starritt. and they obey the Pauli exclusion principle stating that two fer- 1998. Ultrasound in Medicine, Medical Science Series, Institute mions cannot occupy the same quantum state. The nucleons are of Physics Publishing, Bristol, UK. according to this principle not interacting even if they are closely packed, as there are no states available for the collision processes. Sharpness Experimental evidence, like magic atomic numbers, suggests (Diagnostic Radiology) Sharpness is a visual characteristic of a nuclear shell structure, as mentioned above. In other words, an image where objects and structures appear to not be blurred. each nucleon seems to move inside a potential well created by Unsharpness is when there is a perceived effect of blurring. Better the forces from all the other nucleons in the nucleus. The nuclear image sharpness assumes better spatial resolution. n-body problem is thus replaced by n single-body problems. This independent particle model, based on the concept of a mean field, Shear waves has been very successful in explaining nuclear structure. (Ultrasound) Shear waves, or transverse waves, are characterised In order to solve the single-body problem, the potential of the by particle motion perpendicular to the direction of propagation. mean field must be defined. A historically successful phenomeno- These can propagate easily through some solid materials, such logical method was proposed by S. G. Nilsson (Nilsson 1969), as steel and bone, but they do not effectively travel in soft tissue. where a deformed harmonic oscillator together with an empirical Some applications however have been reported where transverse spin-orbit coupling was used to characterise the nuclear potential. waves are generated, and then detected, but normally, only Today, with powerful computers available, self-consistent meth- longitudinal waves are considered in ultrasound imaging. ods (Hartree-Fock methods) are used to deduce the nuclear poten- tial from the nucleon-nucleon interactions. The nuclear shell model, correctly describing magic numbers, Shear wave elastography has been able to predict nuclear properties based on the single (Ultrasound) A shear wave is a slow longitudinal wave (1–10 m/s) particle energy level scheme. and propagates by creating a tangential ‘sliding’ force between Further Readings: Bohr, A. and B. Mottelson. 1969–1975. tissue layers. Shear waves are explicitly correlated to tissue stiff- Single Particle Motion, Vol. 1, Nuclear Deformations, Vol. 2, ness. To quantify tissue stiffness, Young’s modulus E is calculated World Scientific Publishing Company, Singapore; Cook, N. using the following equation, where Vs is the shear wave velocity 2006. Models of the Atomic Nucleus, Springer, Berlin, Germany; and ρ is tissue density: Nilsson, S. G., C. F. Tsang, A. Sobiczewski, Z. Szymanski, S. E = 3rV 2 s Wycech, C. Gustafsson, I.-L. Lamm, P. Möller and B. Nilsson. 1969. On the nuclear structure and stability of heavy and super- S Ultrasound-based elastographic techniques are divided into strain heavy elements. Nucl. Phys. A 131(1):1–66. techniques and shear wave elastography techniques. There are three types of shear wave elastography: transient elastography, Shielded gradients point shear wave elastography (pSWE) and two-dimensional (Magnetic Resonance) Switching of gradients induces voltages shear wave elastography (2D SWE) (Sporea et al., 2014) and currents in conducting material throughout the system, called Further Reading: Sporea, I., S. Bota, O. Gradinaru-Tascau, eddy currents. These eddy currents produce fields that oppose the R. Sirli and A. Popescu. 2014. Comparative study between two applied gradients. In order to minimise eddy currents, gradient point Shear Wave Elastographic techniques: Acoustic Radiation coils can be shielded by means of applying a secondary coil pair Force Impulse (ARFI) elastography and ElastPQ. Med Ultrason, at a larger radius than the main gradient coil. Current flows in the 16(4):309–314. opposite direction to the gradient coils which produces fields that counteract the primary fields. The shielding leads to a reduction Shell model of nucleus of the primary field, thus a larger current is needed to obtain the (General) desired gradient field. Nuclear Structure: The atomic nucleus consists of neutrons Related Articles: Eddy currents, Shielding and protons commonly referred to as nucleons. The nucleons Further Reading: Haacke, E. M., R. W. Brown, M. R. belong to the family of baryons, composite particles made of Thompson and R. Venkatesan. 1999. Magnetic Resonance three quarks, and the baryons belong to the hadrons, i.e. all parti- Imaging, Physical Principles and Sequence Design, John Wiley cles made of quarks. The hadrons are bound states of quarks, held & Sons, Inc., Hoboken, NJ. together by the strong force. The nucleons in the atomic nucleus are bound together by the nuclear force (the residual strong force), Shim coils which is the residue strong interaction between the quarks that (Magnetic Resonance) The purpose of shimming is to compen- constitute the nucleons. sate minor spatial inhomogeneities in the B0 magnetic field in In order to describe nuclear structure, a number of models the imaging object. This is done by imposing B0 fields of spe- have been developed. The liquid drop model, where the nucleus cific spatial dependence, each of which is created by a shim coil. is regarded as a drop of neutrons and protons, was one of the first These are either superconducting (static) or resistive (mounted models that successfully described the basic principles of the within the magnet bore). Common in MRI systems is a set of 9 nuclear binding energy (semi-empirical mass formula). However, coils creating spherical harmonic dependence of linear and qua- there were systematic deviations not accounted for in this model. dratic order. The shorthand X, Y, Z, Z2 ≈ Z2 − (x2 + y2)/2, XZ, These deviations could be explained if the nucleons in the atomic YZ, X2 − Y 2, 2XY denotes the spatial dependence in Cartesian nucleus exhibited a shell structure ‘similar’ to the situation for the coordinates. atomic electron. Related Article: Shimming Shimming 848 Short tau inversion recovery (STIR) Further Reading: Haacke, E. M., R. W. Brown, M. R. Short tau inversion recovery (STIR) Thompson and R. Venkatesan. 1999. Magnetic Resonance (Magnetic Resonance) Short inversion time (TI) or short tau (τ) Imaging, Physical Principles and Sequence Design, John Wiley inversion recovery, STIR, is a signal suppression or nulling tech- & Sons, Inc., Hoboken, NJ. nique with a specific inversion time, giving zero signal for compo- nents with longitudinal relaxation time T1. Usually this technique Shimming is applied to suppress the fat signal, whereas for nulling of water/ (Magnetic Resonance) Even at the isocentre of the magnet, the CSF (fluid attenuated inversion recovery [FLAIR]) a long TI is static field (B0) is not perfectly homogeneous. The term ‘shimming’ required. denotes the process of reducing the spatial inhomogeneities over a The concept of nulling can be understood by inspection of the certain region of interest. These are given in ppm units and form signal curves obtained as function of the selected TI value in an part of the system specification. IR sequence (see Figure S.33 and Inversion recovery). At a spe- Passive shimming is performed during installation by distrib- cific TI value, which depends upon T1 of the tissue as well as uting pieces of iron in the bore of next to the cryostat. Active the selected TR, the signal will be zero for phase representation shimming involves adjusting DC currents in a set of (up to 18) as well as for magnitude (or modulus) representation of the IR shim coils creating additional B image. For very long TR values, TInull ≈ 0.69T1 indicating TI 0 fields of linear or quadratic null spatial dependence. These fields conform to spherical harmonic values between 150 and 200 ms for STIR and above 2000 ms for functions, which are adjusted automatically before every exami- FLAIR. nation, because the shape and dielectric properties of the body/ In the diagrams to the left in Figure S.33, signal (arbitrary sample impose distortions of the B0 field. units) is plotted against inversion time (ms) for three different Related Article: Shim coils tissue types having low T1 (green lines), medium T1 (red lines) Further Reading: Haacke, E. M., R. W. Brown, M. R. and high T1 (blue lines). In the images to the right, brain images Thompson and R. Venkatesan. 1999. Magnetic Resonance from a healthy volunteer at 1.5 T are shown for three selected TI Imaging, Physical Principles and Sequence Design, John Wiley values. & Sons, Inc., Hoboken, NJ. Note specifically the modulus representation at TI = 150 ms, where TI is close to the value optimal for nulling of fat (STIR) Shock absorber and at TI = 2200 ms which illustrates a FLAIR type sequence. (General) The function of a shock absorber or ‘damper’ is to Note also that, neglecting transverse relaxation effects, optimisa- reduce or minimise sudden mechanical movement or vibration of tion of TI for STIR and FLAIR depends upon field strength (via a device which may otherwise cause the device to malfunction or T1 dependence) and the selected TR. Furthermore the inversion sustain physical damage. times

given above assume that the longitudinal magnetisation Shock absorbers are usually mechanical in form, based on fully recovers before applying the next inversion rf-pulse. S absorbing the energy of an applied impulse by gradual dissipa- The STIR sequence is often combined with a fast spin echo tion through friction between surfaces or by viscous flow of some (FSE) imaging sequence (see Figure S.34). This combination is enclosed fluid such as oil or air within a piston. called fast inversion recovery or turbo inversion recovery. Fast IR sequences have opened the possibility to perform the inversion recovery experiment (see Inversion recovery) within reasonable Shock waves acquisition times, since in this case Tacq will be reduced by the (Ultrasound) A shock wave is an abrupt increase in acoustic pres- echo train length (ETL) factor as in FSE. sure, which is built up as a result of non-linear propagation. The Additional contrast can be obtained in STIR and FLAIR by limiting case of an N-shaped waveform is termed a shock wave, combining a high TR value and an adequately chosen TI value and here the harmonic components in the spectrum have ampli- with a relatively long TE. As an example, in the modulus rep- tudes that fall off by 1/n, where n is the nth harmonic. The higher resentation of STIR, the low inversion time chosen for nulling harmonics are quickly attenuated, however, and the N-shaped of fat enforces mirroring of signal values for most tissue types waveform cannot be sustained. After some additional distance, in the brain. Hence, tissue with high-T1 values will have higher the waveform will resemble a sinusoid but with much smaller signal than tissue with lower T1. In cases where the high-T1 tis- amplitude than it originally had. sue also has higher T2 than the low-T1 tissue, the choice of a long The underlying mechanisms are, first, a convection effect, echo time will further enhance image contrast (Figure S.34). In and second, an effect of nonlinear compressibility. Both of Figure S.35a, the vertical dashed line shows the selected TI value these effects have the result that pressure peaks travel faster for nulling of fat. Using this TI, a tissue type with high T1 (blue) than rarefactions, and will thereby eventually encroach upon will give higher potential signal intensity than a tissue type with them. The effect is more pronounced the higher the acoustic medium T1 (red). If the transverse relaxation time T2 is higher pressure. for the ‘blue’ tissue than for the ‘red’ tissue, the T2 decay dur- The generation of harmonics generated from a shocked wave- ing TE will give a measured signal that further enhances signal form are used in harmonic imaging, for instance. Shocked wave- intensity differences between the two tissue types. A selection of forms are also encountered in lithotriptors for the disintegration TE/TR/TI as described can be used to enhance signal differences of kidney stones. Here, the peak acoustic pressures can reach 100 between liquid and brain matter, but also to enhance the more MPa. subtle signal differences between grey and white matter. In Figure S.35b, a fast IR sequence with parameters TE = 60 Short circuit ms, TR = 4,900 ms and TI = 150 ms (STIR type with additional (General) A short circuit is a condition in the electrical system T2 contrast) is shown. where energised conductors come in contact (or generate an arc Related Articles: Echo train length, Fluid attenuation inver- by coming in close proximity) with each other or with ground, sion recovery (FLAIR), Inversion recovery, Inversion time, RF allowing (typically large) fault currents to flow. pulse Shortest exposure time 849 Shrapnel TI = 150 ms TI = 350 ms TI = 2200 ms Phase 1 0.5 0 0 250 500 750 1000 1250 1500 1750 2000 2250 2500 2750 3000 3250 –0.5 –1 Modulus 1 0.5 0 0 200 450 700 950 1200 1450 1700 1950 2200 2450 2700 2950 3200 –0.5 –1 FIGURE S.33 Illustration of the concept of nulling. (Figure courtesy of Sara Brockstedt, University of Lund, Sweden.) TI Fast inversion recovery INV 90° SE1 SE2 SE3 SE4 SE5 S RF G TR slice Gphase Gread ADC TEeff FIGURE S.34 Conceptual illustration of a fast inversion recovery pulse sequence. Shortest exposure time the patient’s body. The internal presence of metallic fragments in (Radiotherapy) See Exposure time patients is an exclusion criterion for the MR safety before the MRI examination, even if the fragment is small in dimension. Patients Shrapnel who have been injured by bullets or shrapnel or who work with (Magnetic Resonance) The term ‘shrapnel’ is often used to metals could have internal metallic fragments. The main concern describe fragments or shot intentionally included in an explosive is fragments located in or around eyes as the static magnetic field device but in an MR shrapnel is indicated a metallic fragment in exerts a force on ferromagnetic objects and the metal fragment Shunt 850 Side lobes 1 S HI MED T2 0.5 0 0 2 503200 TE TI –0.5 –1 Short TI chosen for STIR ETL 7, TE/TR/TI = 60/4900/150 ms (a) Short TI + long TE enchances contrast (b) FIGURE S.35 Illustration of a modulus representation of a STIR sequence, where additional contrast is allowed by using a long TE: (a) Variation of signal with echo time for STIR pulse sequence and (b) fast inversion recovery of the brain (TR = 4900 ms, TI = 150 ms, TE = 60 ms) (STIR type with additional T2 contrast). (Figure courtesy of Sara Brockstedt, University of Lund, Sweden.) in the eye could move or be displaced and could result in injury to the eye or the surrounding tissues. If the patient works or has worked with sheet metal or as a welder it is probable that he has metallic fragments or slivers placed in or around the eye and his line of work should be specifically questioned to determine S if an MRI examination is possible. The presence of small for- eign bodies could be assessed by a plain film radiography that is considered an acceptable standard in screening for intra-ocular metallic foreign bodies with sufficient size to cause ocular dam- age. Furthermore, a CT scan of the orbits could determine more accurately the presence of smaller fragments. Shunt (General) In electronics, a shunt is a device having appreciable impedance connected in parallel across another device and allow- ing some part of the current to pass around to another point in FIGURE S.36 Theoretically calculated beam profile of a circular trans- the circuit. An ammeter shunt allows the measurement of current ducer. The plane shown includes the central axis of the circular aperture. values too large to be directly measured by a particular ammeter. The aperture is actually located a small distance to the left of the fig- The term shunt is used in filter circuits to refer to the compo- ure for computational reasons. The aperture width is approximately four nents connected between the line and common. Capacitors can be wavelengths. The main lobe is directed to the right, and side lobes can be seen above and below the main lobe at increasing angles. used as shunts to redirect high-frequency noise to ground. Where devices are particularly sensitive to reverse polarity of signal or power supply, a Zener diode may be used as a shunt to protect the Late side effects can happen months or years after treatment. Side circuit. effects depend on the type of radiation therapy, the part of body Related Articles: Zener diode, Voltage limiter being treated, the delivered dose of radiation, treatment schedule, patient radiosensitivity and patient overall health. Shutter Related Articles: Late reaction toxicity, Adverse effects (Diagnostic Radiology) See Cineradiography (Radiotherapy), Repair SID (source-to-image distance) Side lobes (Radiotherapy) See Source-to-image distance (SID) (Ultrasound) Due to interference, sound is emitted in a number of principal directions from a disc source. Perpendicular to the Side effects disc, along the central axis, is the main lobe, which contains the (Radiotherapy) Damage to healthy cells during radiotherapy most energy. However, in the direction that corresponds to the causes side effects. Side effects can happen any time during, imme- divergence angle, destructive interference causes a minimum. At diately after, or a few days or weeks after radiation therapy. Most increasing angles to the main lobe, alternate maxima and minima side effects disappear within two months of finishing treatment. are formed, as can be seen in Figure S.36. The regions containing Sievert (Sv) 851 Sigmoid dose–response curve these maxima are referred to as side lobes. In Figure S.36, three general, it has a sigmoid (S) shape with the probability of effect side lobes can be seen aside from the main lobe. tending to zero as the dose tends to zero and tending to 100% at very large doses. This applies to both tumour control and nor- Sievert (Sv) mal tissue complications, although the curve is often steeper for (Radiation Protection) Sievert (Sv) is the unit given to the radia- normal tissue damage than for tumour control such as in the tion protection quantities equivalent dose, and effective dose, case of a large inhomogeneous tumour containing sub-volumes as defined by the International Commission on Radiological with considerably different radiation sensitivities (e.g. hypoxic Protection (ICRP 2007). It is also used for derived dose quanti- areas). ties such as committed equivalent dose and committed effective In the case of tumour control, the sigmoid shape can be dose, and for ‘operational quantities’ defined by the International explained from the random nature of cell killing after irradia- Commission on Radiation Units and Measurements (ICRU 1998) tion and the need to kill every cell (see article on Tumour con- such as ambient dose equivalent and directional dose equivalent. trol probability). However, for most normal tissue end-points, the In SI units, 1 Sv is equivalent to 1 J of energy from incident biological interpretation of the sigmoid shape of the relationship ionising radiation absorbed in each kilogram of human tissues, is not obvious (see article on Normal tissue complication prob- that is: ability). Some authors have suggested a hypothetical tissue res- cue unit (TRU), arguing that tissue breakdown occurs when the 1Sv = 1J kg-1 number of TRUs falls below a critical level. A TRU is defined as the minimum number of functional sub-units (FSU) required In base SI Units, this can be more properly defined as to maintain tissue function (see articles on Parallel organs and Serial organs for more on FSUs). However, this explanation for 1Sv = 1m2s-2 the sigmoid shape of the curve is questionable. Many authors have proposed mathematical models to describe where dose response and most have used one of three mathematical m is metres forms: the Poisson, the logistic or the probit model. The posi- s is seconds tion of the dose–response curve is usually quantified by the dose required to obtain a specified level of response. The most frequently used position parameter is the D50, i.e. the radiation Sievert was named after the Swedish medical physicist Rolf dose for 50% response. In the case of normal tissue complica- Maximilian Sievert (1896–1966). For further information on use tions, the D5, that is the dose producing a 5% incidence of com- of the Sievert, see Related Articles detailed below. plications, is often quoted since this is typically the acceptable Related Articles: International Commission for Radiological incidence level for complications in patients receiving radiation Protection, International Commission on Radiation Units and therapy. Various measures have been used to quantify the steep- Measurements, Equivalent dose, Effective dose, Committed S ness of the curve but the most commonly used is the normalised equivalent dose, Committed effective dose dose response gradient, denoted by γ, introduced by Brahme in Further Readings: ICRP (International Commission on 1984. In this formalism, γ represents the increase in response, in Radiological Protection). 2007. The 2007 Recommendations percentage points, for a 1% increase in dose and its definition is of the International Commission on Radiological Protection. given in Equation S.9. Thus γ is the product of slope and dose and Annals of the ICRP Publication 103, 2007; ICRU (International is a dimensionless quantity. Commission on Radiation Units and Measurements). 1998. The normalised dose-response gradient, γ Fundamental quantities and units for ionising radiation. ICRU Report 60, Bethesda, MD. DP(D) g = D (S.9) DD Sigmoid dose–response curve (Radiotherapy)

The relationship between dose and radiation where P(D) is the probability of incidence with respect to dose D. effect, i.e. the dose–response curve, is shown in Figure S.37. In This equation is useful in practical calculations where an esti- mate is required of the effect of a change in dose on the response of a tumour or normal tissue. However, since Equation S.9 cor- responds to approximating the S-shaped dose–response curve to 1 a straight line, the value of γ will depend on the response level at 0.9 which it is evaluated. Clearly, evaluation at the bottom or top of 0.8 the curve will produce a smaller increment in response for a given 0.7 increase in dose than if it is evaluated on the steep part of the curve. Generally, the value of γ is written with an index indicating 0.6 the response level at which it is defined, for example γ 0.5 50 refers to the γ-value at a 50% response level. 0.4 For both tumours and normal tissues, the position and steep- 0.3 ness of the dose–response curve will vary within a population 0.2 due to their heterogeneous nature. They will also depend on the 0.1 volume of tissue irradiated (dose–volume effect) and the frac- 0 tionation scheme. Dose-response data are usually obtained from Dose (Gy) changing the total dose by one of two methods: either by increas- ing the dose delivered per fraction while maintaining the same FIGURE S.37 The dose–response relationship is sigmoid in shape. This number of fractions or by increasing the number of fractions applies to both tumour control and normal-tissue damage. while maintaining the same dose per fraction. However, for a Probability Signal aliasing 852 Signal-to-noise ratio (SNR) specific end-point, the steepness of the dose response depends on In diagnostic radiography the signal is typically a measurement of which method is used. If the dose per fraction is increased, the x-rays which are transmitted through a patient and attenuated by dose–response curve is steeper than if the number of fractions various anatomical structures. is increased since this will result in an increase in the biological All radiographic images contain noise. In an ideal system this effectiveness per Gy. noise is due to the stochastic fluctuation of the x-ray quanta, σ, Abbreviations: TRU = Tissue rescue unit, FSU = Functional which is described by Poisson statistics so that the maximum sub-unit, D50 = Dose producing 50% response, D5 = Dose produc- SNR available is ing 5% response and γ50 = The normalised dose-response gradient defined at the 50% response level. N Related Articles: Dose response model, Fractions, SNR = = N N Fractionation, Normal tissue control probability, Normal tissue dose response, Parallel organs, Serial organs, Therapeutic effect, where N is the number of x-ray quanta incident upon the detec- Tumour control probability tor. This relationship assumes that the detector is ideal and thus Further Readings: Bentzen, S. M. and S. L. Tucker. 1997. only quantum noise is present. In real systems there are many Quantifying the position and steepness of radiation dose-response additional sources of noise such as structural or inherent detector curves. Int. J. Radiat. Biol. 71:531–542; Brahme, A. 1984. noise which is due to the structure of the detector components Dosimetric precision requirements in radiation therapy. Acta such as the film granularity of screen-film systems or the density Radiol. Oncol. 23:379–391; Hall, E. J. and A. J. Giaccia. 2006. and dimensions of the phosphor screen used in indirect digital Radiobiology for the Radiologist, 6th edn., Lippincott Williams detectors. & Wilkins, Philadelphia, PA; Steel, G. G. 2002. Basic Clinical The above description assumes that both the signal and Radiobiology, 3rd edn., Arnold Publishers, London, UK. noise are scalar quantities. Both signal and noise can be treated as spatial frequency dependent, in this case the signal is S( f ) and the noise becomes the noise power spectrum NPS( f ). For Signal aliasing more complex assessment of system performance, detective (Magnetic Resonance) Signal aliasing occurs in MRI when an quantum efficiency DQE( f ) can be calculated using the modu- error in the spatial encoding of objects occurs. This is due to the lation transfer function MTF( f ), and the noise power spectrum anatomy being scanned exceeding the FOV in the phase encoding NPS( f ). direction. Objects outside the FOV cannot be distinguished from Related Articles: Rose model, Noise equivalent quanta objects inside the FOV and this leads to a spatial mismapping of (NEQ), Noise power spectrum (NPS), Detective quantum effi- the area outside the FOV to the opposite side of the image. This ciency (DQE), Modulation transfer function (MTF) causes problems when viewing the images as structures of interest Further Reading: Beutel, J., H. L. Kundel and R. L. van S are often obscured. Metter. 2000. Handbook of Medical Imaging, Vol. 1, Physics and Abbreviation: FOV = Field of view. Psychophysics, SPIE, Bellingham, WA. Related Article: Wrap-around artefact Signal-to-noise ratio (SNR) Signal amplification technique (SAT) in PET (Magnetic Resonance) Signal-to-noise ratio is used to describe (Nuclear Medicine) See Photomultiplier (PM) tubes the relative contributions to a detected signal of the true signal received from the coils and random background noise. This is Signal processor used as an image quality parameter to ensure that the system is (Nuclear Medicine) Signal processing deals with the analysis working correctly. If the SNR is found to be reduced, this could and manipulation of signals. These signals can be of a variety of indicate one of a number of problems with the system including types: sound, images, electrical signals, etc. In nuclear medicine system calibration, gain, coil tuning, RF shielding, coil loading the signals of interest are invariably images. and image processing. Image processing techniques in nuclear medicine include Improving the SNR will generally improve the quality of the image subtraction, spatial filtering, image reconstruction and the image. There are several common methods used to increase the production of time activity curves. SNR. The first is to average several measurements of the signal, These tasks are all performed by microprocessors. For very with the expectation that random noise will be reduced. The specific tasks an applications-specific integrated circuit (ASIC) is SNR can also be improved by sampling larger volumes. This is used. These devices are used in applications such as analogue-to- achieved by increasing the field of view, which will increase the digital conversion and pulse height analysis. size of the pixels and therefore the signal in each, and by increas- Another type of microprocessor called a digital signal proces- ing the slice thickness, which will decrease problems caused by sor can be used to perform very fast real-time signal processing the partial volume effect. The amount of noise can be reduced such as 3D image rotation. by reducing the bandwidth and/or by applying a pre-processing filter. SNR will also be improved by increasing the strength of the magnetic field used. Signal-to-noise ratio (SNR) Choosing the most appropriate coil will also affect the SNR. (Diagnostic Radiology) The signal-to-noise ratio of a detector is a The receiver coil should encompass the whole anatomical area of measure of the detector’s performance. It is defined by the ratio of interest to obtain the best SNR possible. Surface coils will pro- the total measured signal, S, and the total system noise (standard vide the best SNR but can only be used to image structures close deviation of the measured signal), σ: to the surface of the patient. The SNR of a system is measured using a uniform phantom. S SNR = An image is acquired and five small ROIs are drawn on the image. s One is placed in the centre and the rest at 3, 6, 9 and 12 o’clock Signal-to-noise ratio (SNR) 853 Silicon diode detector around the edge of the image. In each ROI the mean pixel value an alloying element, particularly in combination with aluminium and the standard deviation are recorded: to produce a casting alloy. Silicon is also the base material for the vast range of useful compounds with oxygen and/or carbon SNRof the ROI = Mean pixelvalue/Standarddeviation known as silicones. In recent times, the ability of silicon to act as The SNR over the whole image is the average of the five SNRs the basis for semiconductors and computer chips has had a mas- measured. sive impact on modern life. Absolute SNR: It is also possible to measure absolute signal- Medical Applications: Imaging panels – Silicon-charged to-noise ratio to give SNR in Hz1/2mL−1 instead of as a relative particle detectors have good energy and spatial resolution and ratio. The principle of the method is to create a single gradient an excellent signal-to-noise ratio. Thus silicon is widely used in along a small tube of pure water. This produces a simple projec- diagnostic imaging, most notably in amorphous silicon flat panel tion from which a basic signal to noise for 1 mL of water in a 1 Hz detectors. bandwidth may be calculated. Biomedical engineering – Silicon is used in the design of tem- Abbreviations: RF = Radiofrequency, ROI = Region of inter- porary therapeutic scaffolds (support structures) which assist or est and SNR = Signal-to-noise ratio. even promote the body’s natural healing processes. When con- structed from silicon such scaffolds are biodegradable and do not Signal-to-noise ratio (SNR) require surgical removal. Devices that rely on an electrical impulse to stimulate the (Ultrasound) The signal-to-noise ratio (SNR) in an ultrasound body’s natural rehabilitative functions (e.g. defibrillators, pace- imaging system can be defined as the maximum instantaneous makers and cochlear implants) are silicon-based. Silicone rub- received signal power divided by the noise power. The received ber is found in mammary prostheses, finger joint prostheses and signal strength from a scatterer is dependent on attenuation of catheters. both the incident and the scattered sound wave, and consequently Related Article: Imaging the SNR is depth dependent. The noise may arise from the trans- ducer, preamplifier and A/D-converter. To optimise the SNR an optimal reception filter is chosen to be equal to the bandwidth of Silicon diode detector the receiver system (mainly the transducer). In other words this (Diagnostic Radiology) The silicon diode detector is an exam- filter should match the bandwidth of the received signal, and is ple of an indirect digital detector system used in medical imag- therefore called a matched filter. ing (x-ray). In its simplest form, it consists of a phosphor screen The term SNR can also be used in connection with speckle coupled to an amorphous silicon photodiode. The incoming statistics, where it is defined as the mean received signal ampli- x-rays interact with phosphor screen which absorbs the incident tude divided by its standard deviation. Since the signal received radiation, and converts it to visible wavelength light photons. The from a large number of point scatterers is Rayleigh distributed, wavelength of the radiation detected is dependent on the mate- this relation is equal to rial used for in the phosphor screen. The use of a scintillation S crystal is what makes it an indirect method. Although detectors based upon silicon diode technology can be used to detect almost p(4 - p) any wavelength of radiation, in diagnostic radiology the detectors are most used to detect x-ray wavelength radiation and a digital as a consequence of the definition of mean and standard deviation radiographic image is produced by the use of an array of pixels for this distribution. This number approximately equals 1.91 or each formed by an individual diode, a pixel for which is shown in 5.6 dB. Figure S.38. Silicon (General) Symbol Si Element category Metalloid Mass number A 28 Atomic number Z 14 Incident x-rays Atomic weight 28.085 kg/kg-atom Visible light Electronic configuration 1s2 2s2 2p6 3s2 3p2 Phosphor screen Melting point 1687 K Boiling point 3538 K ITO Density near room temperature 2330 kg/m3 n Amorphous silicon photodiode a-Si:H i History: Silicon was first identified by Lavoisier in 1787 and first isolated in reasonably pure amorphous form by Berzelius G S D in 1824. It is the second most abundant element by mass in the p Earth’s crust after oxygen. It is found as silicon dioxide (silica) which occurs in many different mineral forms, and as silicates TFT Glass substrate which are minerals containing silicon, oxygen and one or more metals. Its main use is as a

major constituent of construction mate- FIGURE S.38 The typical pixel construction of an amorphous silicon rials such as stone, concrete, cement and glass. Silicon is used as diode image detector. Silicon diode detector 854 S ilicon-controlled rectifiers (SCRs) In x-ray image detection the scintillation crystal is typically Silicon diode detector made of caesium iodine most commonly doped with thallium. (Radiotherapy) The irradiation of a semiconductor material can There are several reasons why this is used; firstly the k edges of result in the creation of an electron-hole pair, provided enough CsI are at 33 and 36 keV which gives a high absorption probability energy is given to the electron to raise it into the conduction band. of the x-ray energies generally used in radiography. The second Therefore a semiconductor detector can be considered to be the advantage of using a CsI phosphor over the traditional phosphor solid state analogue of an ionisation chamber. Semiconductors material is that it can be grown in columnar crystals, which act can be used in the form of a silicon diode which is a p–n junction like fibre optics. This allows a minimal level of lateral spread of diode. The dosimeters are produced by taking n type or p type light, and thus a high spatial resolution when coupled to photodi- silicon and counter-doping the surface to produce the opposite ode pixels. This columnar structure also permits the application of type material. These diodes are referred to as n-Si or p-Si dosim- relatively thick layers of CsI which increases the probability that eters, depending upon the base material. N-type or p-type diodes an incoming x-ray photon will interact with the detector without behave differently because their minority carriers are holes or loss of spatial resolution. Unlike the conventional powdered phos- electrons, respectively. phors, spatial resolution is less limited by the diffusion of light. Due to its high density, the sensitivity of a diode detector These fluorescent light photons emitted by the phosphor exceeds that of similar gaseous detectors by a factor of several screen are then converted into electric charge by a photodiode tens of thousands, which implies that a point-like detector can which stores the charge in the diode’s intrinsic capacitance. The be designed with a sensitive volume of less than 1 mm3. In the photodiodes are constructed out of amorphous silicon, usually boundary between two regions one of p-type and another of in the form of n-i-p diodes (although schottky and metal-insu- n-type silicon there is a depletion layer which is free of charge lator-semiconductor [MIS] structures are also used); the capaci- carriers. When the detector is operating with zero external volt- tance of the n-i-p structure can be described by the parallel plate age, a potential difference of about 0.7 V exists over this depletion formula with a 100 × 100 μm photodiode having a capacitance area, causing the charge carriers created by the radiation to be of ≈1 pF. The diodes are very thin (0.5–0.8 μm) and have high swept away into the body of the crystal. The sensitivity of the quantum efficiency. detector depends on the lifetime of the charge carriers and con- To detect an image, many pixels form an active matrix sequently on the amount of recombination centres in the crystal, array, with each pixel formed by a photodiode and a thin film which is determined by the diode type, the doping level and the transistor switch/gate, Figure S.28. To detect the image signal, accumulated dose. Diode sensitivity decreases with accumulated the charge stored in each pixel is drained by the charge col- dose as radiation induces recombination centres into the lattice. lector electrode and read out row by row. The gate line driver The effect of radiation damage represents the main limitation of controls this readout process by applying a switching voltage silicon diodes. Other effects related to the detector material have to the transistor gates in each row. The signals associated with also to be considered. The output signal of the diode depends on S individual pixels in each row are amplified and read out by the the photon energy because of the higher atomic number of silicon multiplexer. (Z = 14) compared to soft tissue (Z ∼ 7) and the resultant higher An important aspect in pixel structure and detector sensitiv- contribution to the signal from the photoelectric effect. The diode ity is the fill factor of each pixel, Equation S.10. This is due to signal is also dose rate dependent because at high dose rates the the placement of the TFT within the pixel as it uses some of the recombination centres will be occupied resulting in a relatively active detection area that the photodiode cannot utilise and thus lower rate of recombination. Moreover the radiation damage may any radiation incident on this area will not be detected: change the dose rate dependence of diode. The thickness and the shape of the build-up cap will influence Light sensitivearea the angular response of the diode. Diodes are also temperature Fill factor = (S.10) Fullarea of pixel dependent. Diodes can be used both for in vivo measurements and those inside phantoms. Diodes are particularly useful for Although some research is currently investigating pixel arrange- measurements in high-dose gradient areas such as the penumbra ments with 100% fill factor, most current medical imaging silicon region and in small field dosimetry. They are also often used for diode detectors have a fill factor of approximately 70%. measurements of depth-dose curves in electron beams. Diodes A modern example of an indirect x-ray system uses a cae- are also widely used in routine in vivo dosimetry. To determine sium iodide scintillator doped with thallium (CsI:Tl) with an the diode calibration factor for in vivo dosimetry, a set of cor- amorphous silicon photodiode matrix panel (which is often made rection factors has to be established to account for variations of 4 single panels, what is technologically cheaper). The panel in diode response in situations different from the reference includes 3,000 × 3,000 pixel array (each pixel being 143 μm). This condition. way the total active area is 43 × 43 cm, with 12-bit greyscale reso- lution (4,096 levels) and a maximum detective quantum efficiency Silicon-controlled rectifiers (SCRs) of approximately 70%. (General) Silicon-controlled rectifier (SCR) is a type of thyristor. Abbreviations: MIS = Metal-insulator-semiconductor and This four-layer, three-terminal solid state rectifier is controlled TFT = Thin film transistor. by gate signal. Related Articles: Indirect digital radiography, Storage phos- The SCR is made up of four layers of semiconductor mate- phor, Dark current, Flat panel detector, Active matrix array, rial arranged PNPN. The function of the SCR is similar to the Detector quantum efficiency (DQE) diode, but its operation is best explained in terms of transistors. Further Readings: James, J., A. G. Davies, A. R. Cowen and The anode is attached to the upper P-layer; the cathode, C, is part P. J. O’Connor. 2001. Developments in digital radiography: an of the lower N-layer; and the gate terminal, G, goes to the P-layer equipment update. Eur. Radiol. 11: 2616–2626; Beutel, J., H. L. of the NPN triode (Figure S.39). Kundel, R. L. van Metter. 2000. Handbook of Medical Imaging, SCR’s main application is as a fast switch that can turn on Vol. 1, Physics and Psychophysics, SPIE, Bellingham, WA. or off any amount of power without involving any moving parts. Silver 855 Simulated annealing algorithm G • When a light (or x-ray) photon excites a bromine atom it loses an electron. • These free electrons are trapped into crystal defects of the photographic emulsion. • The (+) silver ions are attracted into these negative K A defects, where they are neutralised and become Ag atoms (sensitised grains). FIGURE S.39 Silicon-controlled rectifier (SCR). • The combination of areas in the film with different number of sensitised grains forms a LATENT IMAGE. • During the process of film development the sensitised The SCR can often replace much slower and larger mechanical grains are stabilised (the exposed AgBr crystals being switches. reduced to stable Ag atoms). • During the next process of film fixing the remaining un- Silver sensitised grains (which had not been exposed to light (General) photons) are removed and washed out. • The final visible image contains areas with various darkness (optical density) depending on the concentra- Symbol Ag tion of Ag atoms, which in turn is proportional to the Element category Transition metal intensity of light or x-ray beam. Mass number A 108 Atomic number Z 47 Simulated annealing algorithm Atomic weight 107.87 kg/kg-atom (Radiotherapy) Simulated annealing is an optimisation technique Electronic configuration 1s2 2s2 2p6 3s2 3p6 3d10 4s2 4p6 4d10 5s1 used for inverse radiotherapy treatment planning. Melting point 1,235 K In inverse planning a map of the desired distribution is speci- Boiling point 2,435 K fied. This may be the dose, a function of dose such as tumour Density near room temperature 10,500 kg m−3 control probability (TCP), dose volume histogram, or dose lim- its. The dose is then calculated for the desired beam orientations (in external beam radiotherapy) or source positions (in brachy- History: Silver has been known since ancient times because, therapy) and a cost function (C) constructed describing the dif- like gold, it sometimes occurs as a native metal. It is commer- ference between the prescribed (Dpres) and calculated (Dcalc) dose cially extracted from ores containing various combinations of distributions: copper, nickel, lead and zinc. Peru and Mexico have been pro- S ducing silver since the sixteenth century and are still the two top C = silver-producing nations. In addition to its use as a precious metal, å ( 2 Dpres - Dcalc ) x,y,z silver has many applications in the electrical industry, photogra- phy, optics and medicine. x, y, z describes summation over 3D space. The weights (i.e. Medical Applications: X-ray film emulsion – Silver’s main intensities) of the beams or sources are then adjusted iteratively to application in medicine is as a component of x-ray film emulsion. minimise this cost function. X-ray films are similar to those used for normal photography, The simulated annealing aspect is in the adjustment of the except that the emulsion (containing silver bromide attached to beam weights. A beam element is chosen at random and inten- a gelatin base) is about ten times thicker. The thicker emulsion sity added or subtracted from it. If it reduces the cost function increases the probability of interaction between the x-rays and then the change is kept. If it increases the cost function then silver bromide. it is kept with a probability, P, depending on the size of that The interaction process within film can be summarised change, ΔC, and a parameter called the temperature, T, via the as follows: an incident x-ray is absorbed by a silver bromide equation: crystal (usually via the photoelectric process) and its energy is transferred to an electron. This electron goes on to produce P = exp(-DC /kT ) other free electrons (by ionisation) which can become trapped in faults in the crystal lattice referred to as ‘sensitivity specks’ or ‘sensitivity centres’. The trapped electrons attract positive where k is a constant. The temperature is decreased as the opti- silver ions and separate them from the bromine ions. The bro- misation progresses. Allowing changes which increase C allows mine atoms escape into the gelatin, while the silver atoms are the optimisation to escape from local minima in the cost func- left behind, forming a latent (invisible) image of trapped silver tion. Decreasing T with time ensures the optimisation settles to atoms. Chemical processes can then be applied to the film to a solution. create a visible image. Simulated annealing has the advantage over most other inverse Related Articles: Film emulsion, Emulsion layer, Latent image planning optimisation methods, such as gradient descent, in that it avoids trapping of the problem in local minima. Local minima Silver bromide may exist if the optimisation allows beam angles to vary or the (Diagnostic Radiology) Silver bromide (AgBr) is a photosensitive cost function is expressed in terms of a non-linear function of compound that is the typical active element in a photographic/x- dose, such as TCP. ray film (the photographic emulsion). Abbreviation: TCP = Tumour control probability. A brief explanation of the AgBr photographic image formation Related Articles: Inverse radiotherapy planning,

Interactive is as follows: planning Simulator 856 Simultaneous multi-slice (SMS) excitation Simulator (Radiotherapy) Simulators provide the ability to reproduce the treatment set up and mimic most treatment configurations attain- able on megavoltage treatment units. It is then possible to visualise the resulting treatment fields on radiographs or under fluoroscopic examination as though the observer were looking along the beam, that is ‘a beam’s eye view’. This view can be used to check the geometrical accuracy of the set up before treatment. Simple treat- ments such as parallel pairs can also be planned on a simulator when CT or other images are not required. Simulators consist of a gantry and table arrangement as simi- lar as possible to that found on isocentric megavoltage treatment units, with the exception that the radiation source in a simulator is a diagnostic quality x-ray tube rather than a high-energy linac or a cobalt source. Some simulators have a special attachment that allows them to collect patient cross-sectional information simi- larly to a CT scanner; the combination is referred to as a simu- lator CT. Figure S.40 shows a conventional treatment simulator. The photons produced by the x-ray tube are in the kilovoltage FIGURE S.41 A modern simulator unit has the capability to screen range and are preferentially attenuated by higher Z materials such the patient in fluoroscopic mode and produce digital images of the treat- as bone through photoelectric interactions. The result is a high- ment area with field margins and multi-leaf collimator shapes and other shielding. quality diagnostic radiograph with limited soft tissue contrast but with excellent visualisation of bony landmarks and high Z con- trast agents. A fluoroscopic imaging system may also be included and would be used from a remote console to view the patient’s anatomy and to modify beam placement in real time. Figures S.40 through S.42 show a simulator, the console moni- tors and a radiograph showing the treatment field and areas of shielding. Simultaneous multi-slice (SMS) excitation S (Magnetic Resonance) Simultaneous multi-slice (SMS) excitation is a method to use composite RF pulses to excite several slices at a time. The signals from the different excitations are phase shifted from each other to distinguish the two signals for image recon- struction. SMS excitation done in this phase shift manner does not result in the SNR reduction seen with other image accelera- tion techniques, but it does make the imaging more susceptible to phase-based artefacts and does not tolerate image foldover FIGURE S.42 A typical simulator radiograph for a head and neck patient. The field limits and shielding are clearly indicated on the radiograph. suppression techniques. SMS excitation can also be done at dif- ferent frequencies, and the spatial sensitivity differences of RF receiver coils are used to distinguish the signal for image recon- struction. This frequency-based method is sometimes referred to as multi-band imaging. The advantage of SMS excitation is a FIGURE S.40 A conventional treatment simulator has the capability to reduction in acquisition time with less geometric SNR penalty reproduce most treatment geometries available on radiotherapy treatment than is seen with other parallel acquisition techniques. SMS exci- units. Simulators use a diagnostic x-ray tube and fluoroscopic system to tation is also sometimes referred to as ‘multiband imaging’, but image the patient. this term is less frequency used in recent publications. Sinc filter 857 S ingle field uniform dose (SFUD) Related Articles: Radiofrequency pulse, Parallel acquisition height (V) intervals, called channels, is achieved by energy dis- techniques (PAT) criminators: lower level (LLD) and upper level (ULD) or the base- Further Reading: Feinberg, D. A. and K. Setsompop. 2013. line (E) and window (∆E). Ultra‐fast MRI of the human brain with simultaneous multi‐slice For more information see Pulse-height analysers (PHAs) for imaging. J. Magn. Reson. 229:90–100. radiation detectors. Related Articles: Proportional counter, Pulse-height analysers Sinc filter (PHAs) for radiation detectors, Scintillation detector (General) The Fourier transform of the sinc function is a rectan- gular function (‘top-hat’ function). Hence the application of a sinc Single element transducer filter in the time domain, would theoretically give the ‘ideal’ low- (Ultrasound) Single element transducers can be used for A-mode, pass filter, eliminating all frequencies above the cut-off frequency, B-mode and pulsed Doppler imaging. Therapeutic ultrasound while leaving those below the cut-off frequency preserved. devices use single element transducers. However, implementation of the ideal sinc filter is impossible, For diagnostic ultrasound, the single element is used for trans- since the function has infinite extent. Hence it is often truncated mit and receive. The pulse echo technique is used in: for real signals – the windowed sinc filter. A-mode scanning: The echo back shows the range of ampli- The sinc function is also used commonly as RF pulse wave- tudes from the beam direction. An A-line transducer is shown in forms in MRI for obtaining sharp slice profiles. Figure S.45. Related Article: Fourier transform B-mode imaging: The single element has to be swept or rotated about an axis to provide the sweep of echoes to recon- Sinc function struct the B-mode. These mechanical scanners were the first (General) The sinc (sine cardinal, sinus cardinalis) function can used for B-mode imaging and can still be found today but are no be seen in Figure S.43. There are two commonly used versions of longer used for high-end scanners where array transducers now the function: the normalised sinc function and the unnormalised dominate. sinc function. Pulsed Doppler: Single element transducers can be used for The sinc-normalised function is defined as follows and is pulsed Doppler. An intravascular 20 MHz transducer is shown in plotted with the dotted line in Figure S.43. The function crosses Figure S.46. zero at integer values. This version is commonly used in signal Related Articles: Mechanical transducers, A-mode scanning, processing: Pulsed wave Doppler sin(px) sinc(x) = Single exposure px (Diagnostic Radiology) The most often used radiographic opera- tion mode of an x-ray equipment. It produces only one x-ray expo- S The sinc unnormalised function is defined as follows and is plot- sure per examination (e.g. one chest radiograph) using the preset ted with the solid line in Figure S.43. The function crossed zero at parameters (kV, mA, ms, or mA s). This mode differs from the multiples of pi. This is historically used in mathematics: multiple exposure mode, used most often in x-ray angiography, where a pre-planned sequence of x-ray exposures is performed sin(x) sinc(x) = during the examination. x For both forms, the value of sinc at x = 0 is unity. Single field optimisation (SFO) (Radiotherapy) Single field optimisation (SFO) is also known as Single-channel analysers (SCAs) single field uniform dose (SFUD). (Radiation Protection) A single-channel analyser is a pulse height This is an optimisation technique, where each beam will analyser used for only a single energy. The selection of the pulse deliver a fraction of the total dose to the entirety of the treatment volume. This means that if only one of the beams is delivered, the entire target would be covered by that beam to some fraction of the dose (see Figure S.44). 1.2 Each beam is optimised individually and does not take into sin(x)/x 1 account the contribution from other beams. It is possible to have sin(pi * x)/(pi * x) multiple dose levels using SFO (for example a simultaneous inte- 0.8 grated boost, or sparing an overlapping organ at risk). In these cases, however, the beams are still completely independent of 0.6 each other in the optimisation. 0.4 SFO is a very robust method of delivery as all beams cover the entire target: it is irradiated multiple times. 0.2 SFO has limited benefit in cases where the target wraps around an organ at risk (e.g. volumes wrapping around the spinal cord) or 0 –10 –8 –6 –4 –2 0 2 4 6 8 10 where a single beam angle is inappropriate for the entire extent of –0.2 the volume (e.g. in a head and neck plan). Abbreviation: SFO = Single field optimisation –0.4 Related Article: Multifield optimisation (MFO) FIGURE S.43 Graphical representation of the sinc function (solid line: Single field uniform dose (SFUD) unnormalised sinc function, dotted line: normalised sinc function). (Radiotherapy) See Single field optimisation (SFO) Single phase generator 858 Single photon emission computed tomography (SPECT) FIGURE S.46 Intravascular (R) 20 MHz transducer seen next to a cur- vilinear array for comparison. The transducer element is annular so that the catheter slides over a guide wire. Single phase transformer FIGURE S.44 Single field optimisation (SFO): (a) combined dose, (b) (Diagnostic Radiology) See Transformer dose from left lateral field and (c) dose from right lateral field. Single photon emission computed tomography (SPECT) (Nuclear Medicine) Single photon emission computed tomog- S raphy (SPECT) is a tomographic imaging method/system. A SPECT system typically consists of one or two scintillation cam- eras. The scintillation cameras will measure the distribution of administered activity from different angles to obtain projections. The scintillation cameras are mounted on a rotating gantry so that the cameras can be rotated around the patient in order to attain all projections. Acquiring two projections simultaneously will speed up the acquisition by a factor of two or more. This is of great use in dynamic studies. The 2D image projections acquired are used to reconstruct a 3D image volume. There are a number of different algorithms used for image reconstruction which are described in separate articles. The spatial resolution in the resulting image depends on FIGURE S.45 Single element transducer for A-mode scanning of skin. the source-to-detector distance. Scintillation cameras in newer The plastic stand-off fitting (L) is filled with water so that the far field is SPECT systems are designed to orbit close to the patient in order used for imaging. to minimise the source-to-detector distance. The cameras can fol- low the contour of the patient which will result in an improved spatial resolution. Single phase generator SPECT is most frequently used to study myocardial perfusion. (Diagnostic Radiology) Less powerful x-ray equipment with clas- The studies provide information about a possible coronary artery sical high voltage generator use single-phase mains supply. Most disease or myocardial damage following infarction. The myocar- often this type of generator is used for dental and mobile x-ray dial perfusion study is performed twice, once while the patient is equipment. This high voltage generator uses single phase high resting and once while the patient exercises to see differences in voltage transformer. The rectifiers deliver mainly two-pulse kV cardiac perfusion. Sometimes the SPECT system is gated to map waveform (100% pulsations). See typical circuit of this generator a certain part of the cardiac cycle. This is usually done with an in the article High-voltage generator. electrocardiogram. Usually most contemporary medium frequency generators use Another area in which SPECT is commonly used is cerebral also single-phase mains supply, but the term single phase genera- perfusion. Important information about diseases like Alzheimer’s, tor is used only for the older classical generators. seizure disorders and cerebrovascular diseases is gained by using Related Articles: High-voltage generator, Voltage waveform SPECT. Single room particle therapy system 859 Sinogram Further Readings: Contreras, J., T. Zhao, S. Perkins, B. Sun, S. Goddu, S. Mutic, B. Bottani, S. Endicott, J. Michalski, C. Robinson and C. Tsien. 2017. The world’s first single- room proton therapy facility: Two-year experience. Practical Radiation Oncology 7(1):e71–e76; Aitkenhead, A. H., D. Bugg, C. G. Rowbottom, E. Smith and R. I. Mackay. 2012. Modelling the throughput capacity of a single-accelerator multitreatment room proton therapy centre.The British Journal of Radiology 85(1020):e1263–e1272. Single tank generator (Diagnostic Radiology) See Mono block generator Single voxel spectroscopy (a) (b) (Magnetic Resonance) Single voxel spectroscopy (SVS) is the term used to describe a class of magnetic resonance spectroscopy FIGURE S.47 (a) Normal patient bone uptake in a bone scintigraphy. (MRS) techniques in which signal is acquired from a localised The high uptake in the patient’s left arm is due to an ‘extravasal’ injection volume (usually of cuboidal shape). when administering the radioactive tracer. (b) Pathological uptake in a Localised signal acquisition is an important prerequisite for bone scintigraphy. Patient demonstrates an increased relative uptake of in vivo MRS, since otherwise the spatial extent of the region the tracer in metastases from a prostate cancer. from which signal is acquired is limited only by the sensitivity of the RF coil. SVS has for some years been the most

widespread approach to this, although it has now been eclipsed to some extent Another application is in oncology. Some radiotracers accu- by chemical shift imaging (CSI). mulate in cancer cells. SPECT images will therefore show an The localisation pulse sequence typically consists of a number increase in uptake in regions with a high concentration of can- of pulses applied along each of the three Cartesian axes in turn, so cer cells. This technique can find metastases at an early stage that the intersection of the three selected slices selects a volume of and make the treatment more effective. Displayed in Figure S.47 interest (VOI). Depending on the specific technique, signal may are anterior (Figure S.47a) and posterior (Figure S.47b) views be acquired from this region directly (e.g. STEAM, PRESS), or of two bone scans. The patient in Figure S.47a demonstrates no post-processing may be required (chiefly ISIS and its variants). pathological uptake of the radiopharmaceutical. The patient in The VOI selected using SVS is often only an approximation to Figure S.47b shows an increased uptake of radioactive tracer in the shape of most anatomical structures (although in some tech- S metastases originating from a prostate cancer. niques, slices may be made oblique or a more elaborate pattern of The SPECT system can be combined with other imaging intersecting slices may be employed to sculpt the selected volume techniques such as computed tomography (CT) and magnetic more precisely to the anatomical region of interest). However, the resonance tomography (MRT). This combined image system ability to position and size the VOI freely by manipulating the RF can provide both functional and morphological information. and gradient pulses was a major advance over previous techniques Consider trying to locate metastases using only images pro- when SVS was first developed in the 1980s. In commercial imple- vided by SPECT. The resulting images could prove occurrence mentations, the user is able to prescribe the VOI graphically at the of metastases but not yield any precise information about the MR scanner console (Figure S.48). metastases location. Using a combined image system the mor- The aim of SVS is to collect as much signal as possible from phologic and functional images can be matched to provide both within the VOI, while eliminating signal from outside this region functional and positional information. These combined images entirely. Unfortunately, there is inevitably some signal loss and can help increase the accuracy of the diagnosis and treatment. a degree of contamination with extraneous signal. Protocols and The CT images can also be used in the SPECT reconstruction to phantoms have been developed to assess the performance of SVS correct for attenuation. techniques in this regard. Related Article: Scintillation camera An important issue with most SVS techniques is that the use Further Reading: Cherry, S. R., J. A. Sorenson and M. E. of frequency selectivity to achieve slice selection means that each Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders. resonance peak within the spectrum originates from a slightly Philadelphia, PA, pp. 299–303, 322–324. different spatial location. This chemical shift offset is minimised by using high switched gradient amplitude. Single room particle therapy system Related Articles: Chemical shift imaging, ISIS, PRESS, (Radiotherapy) Single room particle therapy systems are also STEAM, Magnetic resonance spectroscopy, MRS voxel called compact particle therapy systems. A single room particle contamination therapy system may be chosen over a multi-room treatment cen- Further Reading: Keevil, S. F. 2006. Spatial localization in tre for reasons such as limited space and/or budget. Single room nuclear magnetic resonance spectroscopy. Phys. Med. Biol. 51: systems typically use compact superconducting cyclotrons. The R579–R636. beamline is much shorter than in a multi-room system, with fewer magnetic components and so a reduced cost. At the time Sinogram of writing (2020), Hitachi, Varian (ProBeam Compact), Mevion (Nuclear Medicine) In SPECT and PET, images are acquired from (S250) and IBA (ProteusONE) all provide single room treatment different angles and they produce a 2D projection of the radionu- solutions. clide distribution. One can assume that a single trans-axial row Skin cancer 860 Skin sparing 5 Gy, and effects become progressively worse with higher dose. Skin dose is calculated additively for all exposures in a single procedure. However, effects are localised to the area of exposure, so an individual may incur separated exposures that contribute to a total skin dose in excess of 5 Gy without actually causing erythema because the total dose was not delivered to the same area of skin. Skin dose calculations therefore also need to take into account the area of exposure in order to assess the risk of erythema. The skin dose limit defined by ICRP is an equivalent dose of 500 mSv averaged over an area of no greater than 1 cm2. Repeated expo- sures to the same area will combine additively towards the ery- thema risk, while exposures to different areas will not (although all exposures contribute towards a calculation of overall skin dose). In radiotherapy skin dose is one of the limiting factors affect- ing the treatment plan. Rotational geometries spread the exposure over circumference of the patient, reducing the erythema risk (and dose to other radiosensitive organs near the tumour site), while still delivering the prescribed target dose to the tumour. Related Articles: Equivalent dose, Deterministic effects Further Reading: Martin, C. J. and D. G. Sutton. 2002. Practical Radiation Protection in Health Care, Oxford Medical FIGURE S.48 Graphical prescription of a VOI to collect a proton MRS Publications, Oxford, UK. signal from the pons in a healthy volunteer. (From Keevil, S.F., Phys. Med. Biol. 51, R579, 2006.) Skin reference marks (Radiotherapy) In external beam radiotherapy treatment it is in such a projection would be 1D representation of the activity important to relate the internal treatment target to the treatment distribution in that cross section. A 1D distribution from all pro- room and hence the delivery system. A key component of this is jections is used to reconstruct a cross-section image. A common to mark the patient’s skin with reference marks. These are usually S way to represent these distributions is in a sinogram, which is a tattoos and are aligned to the treatment room using localisation 2D matrix where the successive rows represent successive pro- lasers. jection angles. If a source is located off centre the source traces The first stage of the treatment process involves imaging the a sinusoidal track along the matrix; hence the name sinogram. patient, for example with CT. The skin reference marks are often A sinogram is a convenient way to represent data collected from drawn at this point. At treatment simulation and each treatment different projection angles and sinograms are often used to deter- visit, the skin reference marks are used to set the patient up. mine the cause of image artefacts. See article CT reconstruction. Related Articles: Localisation lasers, Treatment verification, Further Reading: Cherry, S. R., J. A. Sorenson and M. E. Radiotherapy Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, Philadelphia, PA, p. 276. Skin sparing (Radiotherapy) One of the advantages of megavoltage photon Skin cancer radiotherapy is the ability to treat deep-seated malignancies (Non-Ionising Radiation) This is cancer that forms in the skin, with relative skin sparing. This is a consequence of the low and it is one of the most common types of tumours. surface dose from the relatively long range of the secondary There are several forms of skin cancer according to the por- electrons, which carry energy deeper into the medium. Typical tion of the skin mostly affected. The deadliest form of skin surface doses are ∼20% for an MV photon beam, (Figure S.49) cancer, melanoma, generates from melanocytes (the skin cells and increase with increasing field size and decreasing energy of responsible for pigment). The second most common type of skin beam. Orthovoltage/superficial photon beams do not exhibit skin cancer, and less deadly than melanoma is basal cell carcinoma, sparing, and hence are used for shallow lesions where a high skin which affects the basal cell layer of the skin. dose is beneficial. In cases where a thermoplastic shell is used for Related Articles: AORD, Basal cell carcinoma, Melanoma, immobilisation, it is common for the shell to be cut out around UV light hazard, UV dosimetry critical structures so that the full effect of the skin sparing can Further Reading: Blumenberg, M. 2018. Human Skin be utilised. Cancers: Pathways, Mechanisms, Targets and Treatments. MeV electron beams display a limited amount of skin spar- London. ing, with the surface dose typically 80%. In the case where skin sparing is not desired, to obtain a more uniform depth dose dis- Skin dose tribution within the tissue, wax bolus can be placed on the skin as (Radiation Protection) Skin dose is the absorbed dose, in Gray tissue substitute. (Gy), incurred by an irradiated area of skin. Skin dose is calculated Related Article: Percentage depth dose by using exposure factors (e.g. x-ray kVp and dose-area-product). Further Reading: Podgorsak, E. B. 2003. Review of Radiation Of particular concern with skin irradiation is the risk of caus- Oncology Physics: A Handbook for Teachers and Students. ing erythema. There is a threshold for causing erythema of about International Atomic Energy Agency (IAEA), Vienna, Austria. Slant-hole collimator 861 Slice profile Slant-hole collimator In Equation S.11, dB/dt denotes the magnetic field variation over (Nuclear Medicine) A slant-hole collimator is basically a parallel- time, dB/dr is the intended gradient strength in the r direction hole collimator with angled holes, typically 25°. Due to the design after ramping up, Lr is the effective length of the gradient coil in the collimator can be positioned closer to the patient in some the r direction and Δt is the ramp time for the gradient to reach patient studies, for example left anterior oblique cardiac views. the value dB/dr. The slew rate (SR) is, with the notation according When the source to collimator distance decreases the spatial reso- to Equation S.11, defined as the ratio between dB/dr and Δt and lution increases, which is why it is desirable to get as close to the hence a direct multiplication between SR and Lr/2 gives the bio- patient’s body as possible. The collimator characteristic is similar logically important parameter dB/dt at position Lr/2 (Figure S.50). to those of the parallel-hole collimator (see separate article). In modern MRI scanners, minimum ramp times are of the Related Articles: SPECT, Collimator, Parallel-hole collima- order of a few hundred microseconds. Using Equation S.10 above, tor, Diverging collimator, Converging collimator, Collimator SR can be calculated for any gradient applied. As an example, design, Collimator parameters consider a gradient coil with an effective length of 0.5 m in the Further Reading: Cherry, S. R., J. A. Sorenson and M. E. z direction, a desired gradient in the same direction of dB/dz = Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, 30 mT/m and a ramp time of 300 μs. Insertion of these values in Philadelphia, PA, p. 220. Equation S.11 gives: Slew rate SR = (dB/dr)/Dt = 30mT/m/0.3ms = 100(T/m)/s (S.12) (Magnetic Resonance) In MRI, the term slew rate denotes the ratio between a magnetic field gradient (often measured in mT/m, Related Articles: Ramp time, Gradients millitesla per meter) and the ramp time (see also Ramp time), for example the time it takes for the gradient to build up by driving Slice position a current through one or more of the gradient coils (see Magnetic (Magnetic Resonance) Errors in slice position can be very impor- field gradients). tant in a clinical context. If measurements from MR images are to The parameters minimum ramp time and maximum gradient be used in radiotherapy or surgical planning, then slice position strength are governed by health aspects, since when a magnetic accuracy is vital. field variation dB/dr is built up or turned off a temporally varying The main factors which affect slice position accuracy are magnetic field dB/dt interacts with the body according to 1. Calibration of the slice select gradient dB/dt = (dB/dr)* Lr /2/Dt = SR * Lr /2 (S.11) 2. Frequency settings 3. Misadjustment of the measurement system on the scan- ning couch Measurement of Slice Position: The standard test object used S Source Patient to measure slice position accuracy is EuroSpin Test Object 3: a Perspex cylinder filled with copper sulphate solution and 16 pairs of

crossed rods (MR cold targets). Each pair of rods intersects midway through the test object in the axial direction. D The simplest test to perform is a single slice calibration test. max = 100 Here the centre point of TO3 is accurately aligned with the light 0 zmax zex beams, such that a slice midway through the test object can be acquired. For perfect slice position, the rod separation in the resulting image would be zero. Any increased rod separation D would be indicative of slice position error. ex Further Reading: Lerski, R. et al. 1998. Quality control Ds in magnetic resonance imaging. IPEM Report 80, Institute of Physics and Engineering in Medicine (IPEM), York, UK. 0 zmax Depth z zex Slice profile FIGURE S.49 A typical dose deposition curve in a patient from a MV (Diagnostic Radiology) In computed tomography, the slice pro- photon beam. Note the significant skin sparing effect. file is also referred to as the slice sensitivity profile, z-sensitivity Bz (r)/T G(r)/ mT/m t/ms r/m Ramp time FIGURE S.50 During the ramp time, the gradient amplitude G(r), measured in mT/m, is increased/decreased to the intended value prescribed by the pulse sequence code. Slice profile 862 S lice selection profile or slice width profile. It is a measure of the sensitivity of Related Article: Slice thickness a detector to objects at different positions along the scan axis Further Reading: Edyvean, S., M. A. Lewis, N. Keat and A. P. (z-axis), and is obtained by plotting of CT number against z-axis Jones. 2003. Measurement of the Performance Characteristics of position (Figure S.51). The full width at half maximum of the Diagnostic X-ray Systems Used in Medicine. Part III. Computed slice sensitivity profile defines the slice thickness. Tomography X-ray Scanners, Institute of Physics and Engineering The slice sensitivity profile can be measured using a thin in Medicine (IPEM), York, UK. angled plate in axial (sequential) or a thin disc in helical scanning (Edyvean et al. 2003). Slice profile Axial (sequential) scanning results in the most ideal slice sen- (Magnetic Resonance) A slice profile is a plot of signal intensity sitivity profile. In helical scanning, the slice sensitivity profile along a line that perpendicularly bisects a slice (Figure S.53). broadens if the pitch is increased (Figure S.52). The ideal slice profile would be a top hat function with con- stant signal intensity over the slice width and zero signal from outside the slice of interest. In practice, slice profiles are imper- fect, typically being more rounded (as in Figure S.53). Problems Associated with Poor Slice Profiles: Clinically, slices with poor profiles are undesirable: if a small region of pathol- ogy were to coincide with the edge of such a slice it could be hard to detect. Furthermore in multi-slice acquisitions with small slice spacing, poor slice profiles can lead to interference between adja- z-axis cent slices (additional saturation and cross talk), which can reduce image SNR and uniformity. Two methods to reduce such inter- ference can be adopted: firstly, the slice spacing can be increased (in which case small pathologies within the inter-slice gap may be missed); secondly, slices can be acquired in a non-consecutive (interleaved) order, for example odd slices and then even slices. Factors Affecting Slice Profile: RF pulse envelope: ideally the RF pulse would have a sinc envelope extending infinitely throughout time – this would Fourier transform to give the perfect (top hat) slice profile. In practice, the sinc has to be truncated in FWHM time, giving a rounded slice profile. The more truncated the sinc, the worse the slice profile: S 1. Gradient linearity and gradient gain 2. Main magnetic field inhomogeneity z-axis distance 3. TR/T1 ratio FIGURE S.51 A slice sensitivity profile of a CT scanner. (Courtesy of Measuring Slice Profile: Typically test objects contain- ImPACT, UK, www .impactscan .org) ing angled plates/wedges are used to measure slice profile (see Figure S.54). Further Reading: Lerski, R. et al. 1998. Quality control in magnetic resonance imaging, IPEM Report 80, Institute of Physics and Engineering in Medicine (IPEM), York, UK. Related Article: Slice thickness Slice selection (Magnetic Resonance) Slice selection is one of the principal methods used for spatial localisation in MRI. It is used to restrict Slice Slice profile FIGURE S.52 Slice sensitivity profiles for an axial scan and helical scans of varying pitch. FIGURE S.53 Diagram of slice profile relative to an ideal slice. CT number Slice selective 863 S lice thickness Glass plate 90° 180° Slice RF A Slice width Slice (a) FIGURE S.56 Slice selection gradients and RF pulses from a conven- tional spin echo pulse sequence. FWHM close to rectangular as possible within the pulse length constraints imposed by the remainder of the pulse sequence. (b) Because nutation occurs over the duration of the RF pulse, the resulting transverse magnetisation is dephased by the slice selec- FIGURE S.54 Diagram to show how a slice profile can be obtained tion gradient. A rephasing gradient is applied immediately after- from imaging an angled plate. In the volume where the glass plate enters wards to compensate for this, although perfect rephasing is not the slice (a), the ‘MR cold’ plate causes a reduction in signal (b), corre- possible. The properties of this additional gradient are determined sponding to an inverted slice profile. empirically or by modelling, but its area (amplitude × duration) is usually approximately half that of the slice selection gradient. In a spin echo sequence, the refocusing pulse is usually also ω made slice selective, but no rephasing gradient is needed as long as the pulse and gradient are arranged symmetrically (Figure S.56). Related Articles: B0 gradients, Frequency encoding, Phase encoding, Multislice Further Reading: McRobbie, D. W. et al. 2007. MRI from Picture to Proton, Cambridge University Press, Cambridge, UK. δω Slice selective (Magnetic Resonance) ‘Slice selective’ is a term used to describe MRI pulse sequence elements that are designed to affect only magnetisation lying within a discrete slice of the object being S imaged. Examples include slice selective excitation, refocusing δz z and saturation pulses. Related Articles: Slice selection FIGURE S.55 Linear relationship between location and frequency in the presence of a gradient. Slice sensitivity (Diagnostic Radiology) See Slice thickness Related Articles: Computed tomography, Multislice scanner, spin excitation to one or more two-dimensional slices within the Helical pitch, Helical interpolation, Partial volume effect object or person being imaged. Other techniques are then used to localise signal within the selected slice. Slice thickness Slice selection is normally achieved using a frequency-selec- (Diagnostic Radiology) In computed tomography, the slice thick- tive RF pulse in combination with a static field gradient. This ness is the thickness of the data volume imaged along the scan approach is based on the resonant frequency of a nucleus being axis (z-axis). It is also referred to as the slice width, the slice proportional to the strength of the magnetic field in which it sensitivity or the z-sensitivity. The slice thickness is defined as is situated. Thus application of a linear magnetic field gradient the full width at half maximum (FWHM) of the slice sensitivity results in linear variation in frequency along the direction of profile (Figure S.51). field variation (Figure S.55). An RF pulse with bandwidth δω On single slice scanners the slice thickness is determined by can then be applied in the presence of the gradient to nutate the z-axis x-ray beam collimation. Slice thicknesses of between 1 magnetisation into the transverse plane only within a predeter- and 10 mm can be achieved. mined slice of material of thickness δz, within which the reso- On multislice scanners the minimum slice thickness is deter- nant frequencies of spins correspond to the frequency content mined by the data acquisition width, which is governed by the of the pulse. z-axis detector, or detector grouping, dimension (see Multislice It is desirable to select a slice with a rectangular profile, so that CT scanner). For the same data acquisition width different slice there is uniform excitation of material within the desired slice thicknesses can be reconstructed by altering the filter width used and none outside. This would require application of a sinc-shaped (see Helical interpolation). RF pulse, since a sinc function is the Fourier transform of a rect- Selection of slice thickness is determined by the clinical appli- angular, ‘top hat’ function and the pulse would therefore have cation. Narrow slices result in an improved z-axis spatial resolu- the required frequency profile. Since a sinc function is of infinite tion and enable equal resolution in all planes, so-called ‘isotropic extent, a compromise is necessary and it is usual to use truncated resolution’ (Figure S.57). Isotropic resolution enables high-quality sinc pulses with Gaussian smoothing or, increasingly, numerically multiplanar and 3D reconstructions. Another advantage of nar- tailored ‘designer’ pulses. The aim is to achieve a slice profile as row slices is a decrease in partial volume effect, so that contrast Slice thickness 864 Slice thickness Pixel size < 1 × 1 mm2 Pixel size < 1 × 1 mm2 Slice width > 1 mm Slice width < 1 mm Resolution in scan plane Isotropic resolution better than z-axis FIGURE S.57 Improved z-axis spatial resolution for narrow slice thickness. z-axis Images in scan (x–y) plane S (a) (b) FIGURE S.58 Improved contrast resolution for narrow slice thickness. (a) Contrast reduced due to partial volume effect with wide slice, and (b) contrast optimised with narrow slice. resolution is optimised (Figure S.58). Use of narrow slices also Slice thickness reduces partial volume artefacts which cause streaking in the CT (Magnetic Resonance) In MRI slice profiles may not be perfect image. However, one disadvantage of using narrow slice widths (see Slice profile). For this reason the full width half maximum is that image noise (standard deviation of CT numbers) increases (FWHM) of the slice profile is used to define the slice thickness. inversely with the square root of the slice thickness (Equation FWHM: The full width at half maximum (FWHM) is defined S.13). Halving the slice thickness therefore increases noise by a as the distance between the points where the intensity is half of factor of 1.41: the maximum value (see Figure S.59). Clinically, the slice thickness used depends upon the anatomic 1 s= (S.13) region being imaged. Typically, a large organ such as the liver T will be imaged with relatively thick slices (∼7 mm), the brain will where be imaged with medium slices (∼5 mm), and small joints will be σ is the standard deviation of CT numbers or image noise imaged with thin slices (∼3 mm). T is the slice thickness Related Article: Slice profile Further Reading: Lerski, R. et al. 1998. Quality control Related Articles: Computed tomography, Multislice scanner, in magnetic resonance imaging, IPEM Report 80, Institute of Helical pitch, Helical interpolation, Partial volume effect Physics and Engineering in Medicine, York, UK. Slice thickness 865 Slip ring technology Slice Slice thickness–5 MHz linear array with ATS 539 phantom Imax End view of transducer Slice profile Imax/2 D FWHM FIGURE S.59 Diagram of FWHM as a measure of slice thickness. > FIGURE S.61 The effect of variation in slice thickness in an ultrasound phantom. Transducer elements Lens Variable thickness transducer elements: Differences in A transducer element thickness lead to differences in resonant fre- quency across the elevation plane with high frequencies used in the centre of the elements for superficial structures and low fre- B quencies applied over a wider aperture for use at greater depths. Harmonic imaging: It is postulated that because harmonics FIGURE S.60 Diagrammatic image of slice thickness variation in a are generated in the highest intensity region of the beam, har- linear array. monic images inherently show echoes from the centre of the beam with a possible reduction in effective slice thickness. Figure S.60 shows an image of slice thickness variation in S Slice thickness a linear array. The width of the beam in the elevation plane is (Ultrasound) The slice thickness of an ultrasound image is the dependent on the transducer elements and the lens. In the dia- distance in the elevation plane from which echoes arise. In most gram, the slice thickness (arrows) is optimised at depth A and is systems, the slice thickness varies with depth. poor at depth B. The impression of a 2D ultrasound image is that it is from a Figure S.61 shows the

effect of variation in slice thickness in thin slice. However, in conventional transducers the thickness is an ultrasound phantom. The tubes are 2 mm diameter and are governed by the width of the active elements and an acoustic lens imaged along their length by a 5 MHz linear array transducer. The (Figure S.60). The element/lens combination is chosen to opti- diagram shows the end view of the transducer. At D, depth 2 cm mise slice thickness at a depth appropriate to the frequency of the the tube is clearly displayed. At larger depths, the slice thickness transducer and at which it will be used. A high-frequency trans- encompasses the tube and surrounding material (diagram). The ducer (e.g. 10 MHz) optimised for 1–2 cm depth has narrower image of the tube is less clear and the edges less clearly displayed. elements than a transducer operating at 3 MHz optimised for 6–10 cm which requires a larger aperture in the elevation plane. Slice warp For more superficial tissue, the 3 MHz transducer may have slice (Magnetic Resonance) Slice warp is defined as the shift of the mid- thickness of several mm. point of a slice in the slice select direction from its true orthogonal Slice thickness is usually the worst of the three planes of spa- plane. This effect is rarely seen with modern-day scanners but can tial resolution (link) in ultrasound images but is often overlooked be caused by main field non-uniformity. The Eurospin test object by users since, unlike axial (link) and lateral resolution (link), TO3 can be used to look for slice warp. TO3 is made up of a series its effects are not always obvious in the displayed image. Poor of pairs of rods perpendicular to each other spaced throughout the control of slice thickness can adversely affect contrast resolution phantom. A variation in the separation of rod pairs over the image (link) as shown in Figure S.61. For objects smaller than the slice plane indicates a warping of the slice, with the degree of variation thickness, the ultrasound characteristics of the object are com- indicating the degree of warping present. bined with adjacent tissue within the slice thickness at the same depth, so reducing contrast. Slip ring technology Slice thickness can be improved by (Diagnostic Radiology) Slip ring technology removes the need for Annular arrays: Mechanically swept annular arrays permit cables to be connected to the rotating gantry and so enables con- focussing in the transverse and elevation plane by using timing tinuous gantry rotation. Before the introduction of slip rings in CT differences in transmission and reception. Annular arrays are no design, the power from the generator to the tube was supplied by longer commonly available. high-tension cables. Cables were also required to transfer power 2D arrays: Rows of elements can be used to provide dynamic to other components, such as the collimators, and also to transmit focussing in transmission and reception in the elevation plane. the signal from the detectors. The gantry therefore had to stop Sm-153-EDTMP [Lexidronam] 866 S m-153-EDTMP [Lexidronam] and reverse direction after each rotation in order to unwind these With low-voltage slip rings the high-voltage generator plus cables. This resulted in long acquisition times and limited the use x-ray tube are located on board the rotating gantry, so a low-volt- of CT in many clinical applications. age signal is transferred across the slip rings. Slip rings consist of electrical conducting rings located on the Modern, clinical CT scanners all employ low-voltage slip ring stationary part of the gantry (Figures S.62 and S.63). The cables technology. are connected to these stationary rings, while ‘brushes’ on the Related Article: Helical scanning rotating part of the gantry ‘slip’ round the rings and transfer the electrical power to the gantry components and signal from the Sm-153-EDTMP [Lexidronam] detectors. In this way the gantry can rotate continuously. Slip ring (Nuclear Medicine) Sm-153 Lexidronam or Quadramet© (CIS technology, coupled with a continuously moving table during data Bio International, France) is a therapeutic radiopharmaceutical acquisition, results in helical or spiral CT, an acquisition mode for palliation of bone pain from metastatic prostate carcinoma. which has revolutionised CT scanning by allowing much shorter 153Sm-lexidronam consists of 153Sm labelled with ethylenedi-ami- scan times. netetramethylenephosphonic acid (EDTMP). Quadramet is for- The first slip ring CT scanner was launched in 1988. In the mulated as a sterile, non-pyrogenic, clear, and colourless to light early days of adoption of this technology, two different types of amber isotonic solution of 153Sm-lexidronam for slow IV admin- slip ring systems were employed: high voltage and low voltage. istration (infusion). The 153Sm-EDTMP activity recommended With high-voltage slip rings, the generator is located in the for therapy of bone pain is 37 MBq kg−1 body weight. Thirty-five scanner room and the high-voltage signal supplied to the slip rings percent of the patients obtain pain relief after one week, rising to is transferred to the x-ray tube via the ‘brushes’. 70% within a month. Samarium-153 is produced in high yield and purity by neutron irradiation of isotopically enriched samarium: Brushes transfer power b,g from slip rings to x-ray Sm-oxide : 152Sm (n,g) 153Sm ® 153Eu tube, collimators, etc. 46.28h 153Sm is a mixed beta emitter with max beta energies of 640 (30%), 710 (50%) and 810 keV (20%), and a gamma energy of 103 keV (29%). It has an average (CSDA) and maximum beta particle ranges in water of 0.5 and 3.0 mm, respectively. The half-life of 89Sr is 46.28 h. After an IV injection the 153Sm-EDTMP is rapidly elimi- S Power unit nated from the blood and avidly localises in reactive bone metastasis similar to 99Tcm-diphosponates, but 153Sm under- goes a hydrolysis reaction at the bone surface. After 4–6 h 35% Detector signals has been excreted by the urine. The bone uptake is about 65% Brushes transfer of the administered activity and related to the extent of the signal from metastasis. detectors via slip The mean absorbed dose to bone metastasis from an IV rings to computer injection of 153Sm-EDTMP has been estimated to be 33 mGy MBq−1. The organ most exposed is not unexpectedly the bone FIGURE S.62 Diagramatic illustration of slip rings on CT gantry. surface and red bone marrow, which receive an absorbed dose (Courtesy of ImPACT, UK, www .impactscan .org) of 6.8 and 1.5 mGy MBq−1, respectively. The effective dose for 153Sm-lexidronam is approximately 0.31 mSv MBq−1. Thus, a typical total activity of 2590 MBq, divided in several fractions, gives an average absorbed dose to the metastasis of approxi- mately 86 Gy, 18 Gy to the bone surface and 4 Gy to the red bone marrow. Further Readings: Bartlett, M. L., M. Webb, S. Durrant, A. J. Morton, R. Allison and D. J. Macfarlane. 2002. Dosimetry and toxicity of Quadramet for bone marrow ablation in multiple Slip ring myeloma and other haematological malignancies. Eur. J. Nucl. Med. 29: 1470–1477; Eary, J. F., C. Collins, M. Stabin, C. Vernon, S. Petersdorf, M. Baker, S. Hartnett, C. Ferency, S. J. Addisib, Brush F. Appelbaum and E. E. Gordon. 1993. Samarium-153-EDTMP biodistribution and dosimetry estimation. J. Nucl. Med. 34: 1031– 1036; Firestone, R. B. 1999. Table of Isotopes, 8th edn., Update with CD-ROM. http://ie .lbl .gov /toi .html (Accessed date 18 July 2012); Kowalsky, R. J. and S. W. Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine, 2nd edn., American Pharmacists Association, Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear Pharmacy, 5th edn., Springer, New York. FIGURE S.63 Photograph of slip rings and brushes on CT gantry. Related Articles: Sr-89-Chloride [Metastron], Re-186-HEDP Small animal CT 867 Snell’s law Small animal CT Technical Reports Series No.483) was published covering all (Diagnostic Radiology) CT scanners with small gantry aper- the aspect of dosimetry for small fields. First an overview of tures have been used for many years for in vivo imaging of the physics of small field dosimetry is presented, followed by small animals. The geometry of these scanners allows a high a general formalism for reference dosimetry in small fields. density of the projections in the small scanning area, hence high Guidelines for its practical implementation using suitable resolution scans of the small animals (mostly laboratory mice). detectors and methods for the determination of field output fac- These small CT scanners are also used for scanning of biologi- tors are also given for specific clinical machines that use small cal specimens. static fields. Guidance for relative dosimetry including detec- Such small CT scanners are often named micro-CT (the name tors, procedures, uncertainties and data is also provided. has been introduced initially associated with the small cone-beam Further Reading: Wuerfel, J. U. 2013. Dose measurements in CT scanners). Some novel micro-CT systems use carbon nano small fields. J. Med. Phys. International 1(1):81–90. tube (CNT) x-ray sources. The detector area of micro-CT is smaller than 10 × 10 cm and Snell’s law the pixel size is below 50 microns. (Ultrasound) Snell’s law describes the change in wave path direc- Related Article: Micro CT tion due to refraction as it passes between different media where Further Reading: Badea, C. T. 2017. Small animal X-ray com- there is a change in wave velocity. Snell’s law applies to light, puted tomography. In P. Russo (ed.), Handbook of X-ray Imaging: sound and other wave phenomena, the law is named after the Physics and Technology, CRC Press. Dutch scientist Willebrord Snellius (1580–1626). For ultrasound, the law describes the transmission angle when Small-animal SPECT imaging an ultrasound wave encounters tissue boundaries with differing (Nuclear Medicine) Imaging the internal distribution of radio- propagation speed in the case of oblique incidence (Figure S.64). pharmaceuticals in small animals using dedicated SPECT In the diagram, θi is the incident angle, θt the transmitted angle systems with high resolution. Different detectors and collima- and θr the reflected angle. θr is equal to θi. c1 and c2 are the speeds tors are used. Most common is scintillation detectors and pin- of sound in two tissue types: hole collimators. In some literature the instruments used are named micro-SPECT. This implies that the spatial resolution is c1 /c2 = sinqt /sinqi submillimeter. Related Article: Micro-SPECT In ultrasound scanning, refraction leads to registration errors Further Reading: Kupinski, M. A. and H. H. Barret, eds. since the scanner assumes a straight path in transmission and 2005. Small-Animal SPECT Imaging, Springer, New York. reception of echoes. Refraction also leads to loss of signals and changes in contrast resolution as a result of variation in ultra- Small field dosimetry sound intensity. In soft tissue there is generally little relative dif- S (Radiotherapy) In conventional radiotherapy, dosimetry is ference in speed of sound and refraction is not a severe problem. based on the application of codes of practice. These are based Refraction is more of a problem if ultrasound strikes bone at an on measurements using an ionisation chamber with a calibra- oblique angle since there is a greater disparity between the speeds tion coefficient in terms of absorbed dose to water, traceable of sound. If ultrasound meets an interface at an angle exceeding to a primary standards dosimetry laboratory under reference the critical angle, then it is reflected from the interface and there conditions, such as a conventional field size of 10 cm × 10 is no onward transmission. cm. In radiotherapy practice there has been an escalation in Related Articles: Speed of sound, Reflection coefficient the use of small fields due to the use of multileaf collimators (MLCs). Moreover, measurement procedures for determination of absorbed dose to water in small and composite fields are not standardised. Three physical conditions have to be fulfilled for an external photon beam to be designated as small field: (1) there is a loss of lateral charged particle equilibrium on the beam axis; (2) there is partial occlusion of the primary photon Incident source by the collimating devices on the beam axis; and (3) the wave θi θr size of the detector active volume is similar to the beam dimen- sions. The first two characteristics are beam related, while the C Reflected third one is detector related for a given field size. All three of 1 wave these conditions result in overlap between the field penumbrae and the detector volume. Standardised guidance for dosimetry C2 Transmitted wave procedures and detectors was introduced by the IAEA in coop- eration

with the AAPM. In 2008, an IAEA/AAPM working group published a formalism for the dosimetry of small and θt composite fields introducing the concept of two new interme- diate calibration fields: (1) a static machine specific reference (msr) field for those modalities that cannot establish conven- tional reference conditions; and (2) a plan-class specific refer- ence field that is closer to the patient-specific clinical fields and thereby facilitates standardisation of composite field dosimetry. In 2017, an international code of practice for the dosimetry of FIGURE S.64 Incident, reflected and transmitted wave. The angles are small static fields used in external beam radiotherapy (IAEA determined by the propagation speeds of the two media. SNR 868 Software phantom SNR to be evenly distributed in a compartment. A compartment is typi- The term is an abbreviation for signal-to-noise ratio. For more cally an organ or part of an organ assumed to have the same size information see the relevant articles in Diagnostic radiology, and location in every patient. It is also assumed that the attenu- Magnetic resonance imaging and Ultrasound. ation coefficient is constant for the whole compartment. These SOBP (Spread-out Bragg peak) assumptions are not true because the activation tends to accu- (Radiotherapy) See Spread-out Bragg peak (SOBP) mulate unevenly over the compartment, patients are not all alike and the attenuation coefficients do change within the organ. Even Sodium though the limitations to the MIRD formalism are well known, it (General) is still in use when calculating organ doses in nuclear medicine examinations. In the future more complex models with patient specific photons will be available as computer power increases. Symbol Na Related Articles: Physical phantom, MIRD formalism Element category Alkali metal Mass number A 23 Soft x-ray tomography Atomic number Z 11 (Diagnostic Radiology) Soft x-ray tomography is an analytical Atomic weight 22.99 kg/kg-atom technique used for three-dimensional imaging of tissue cells and Electronic configuration 1s2 2s2 2p6 3s1 sub-cellular structures. Melting point 371 K It is a CT modality featuring sub-micron spatial resolution and Boiling point 1156 K x-ray energies in the range between the K-edges of carbon (284 Density near room temperature 970 kg/m3 eV) and oxygen (543 eV) – the so-called ‘water window’. The strong x-ray absorption for carbon resulting from the proximity of the K-edge (mass attenuation coefficient µ/ρ= at the History: The compound sodium chloride, common salt, K-edge) gives high contrast even for sub-cellular structures. has been a valuable commodity since ancient times. The reac- Soft x-ray tomography systems are present at synchrotron tive nature of sodium results in the formation of very strongly facilities worldwide. Soft x-rays from a synchrotron beam are bonded compounds, and it was not until 1807 that Humphry Davy focussed onto the sample by means of x-ray optics, and then used electricity to obtain sodium metal by electrolysis of molten detected by a direct-detection CCD camera. sodium hydroxide. Elemental sodium is a soft metal which reacts Typical resolutions are in the range 25–50 nm (McDermott et violently with water, limiting its practical uses. It does find appli- al., 2009; Harkiolaki et al., 2018). cations in sodium vapour lamps commonly used for street light- To prevent cell degradation from x-ray exposure, most sys- ing, and liquid sodium has been employed as a coolant in nuclear tems include a cryogenic stage, leading to the term cryo-soft x-ray S reactors and as a reducing agent in the production of titanium. tomography (cryo-SXT). Compounds such as sodium carbonate and sodium hydroxide are Figure S.65 (Bertilson et al., 2011) shows an example of data employed in many industrial processes. Sodium ions are impor- reconstructed from a cryo-SXT of a kidney cell. tant in many physiological processes and sodium levels must be Abbreviations: CT = Computed tomography. regulated at the cellular level within animals to maintain health. Related Articles: CCD, Synchrotron Medical Applications: Scintillation counters – The very early Further Readings: McDermott, G. et al. 2009. Soft X-ray workers with radioactivity were aware that some substances, such tomography and cryogenic light microscopy: the cool combina- as zinc sulphite and diamond, are luminescent when exposed to tion in cellular imaging. Trends Cell Biol. 19(11) (November): x-rays. In modern times sodium iodide (activated by the introduc- 587–595; Harkiolaki, M. et al. 2018. Cryo-soft X-ray tomogra- tion of small amounts of thallium) is commonly used as a lumi- phy: using soft X-rays to explore the ultrastructure of whole nescent scintillator in x-ray/γ detectors. Sodium iodide is ideal for cells. Emerg. Top Life Sci. 2(1):81–92; Bertilson, M. et al. 2011. this purpose as it is highly absorbing of x- and γ−rays, transparent Laboratory soft X-ray microscope for cryotomography of biologi- (so that the flashes of scintillation light can escape to be counted) cal specimens. Optics Letters 36(14):2728–2730. and it can be grown as large crystals. Related Articles: Scintillator, Scintillation camera, Scintilla- Software phantom tion detector (Diagnostic Radiology) Software phantoms are used in conjunc- tion with Monte Carlo simulations in the study of radiation expo- Software phantom sure. Applications include the calculation of radiation dose to a (Nuclear Medicine) Software phantom is a term used for com- patient or specific organ, image reconstruction algorithm testing puter-made phantoms. These phantoms are used to gather infor- and the theoretical study of imaging instrumentation. mation about the imaging system. The advantage of software Initial anthropomorphic software phantoms, termed as ‘styl- phantoms is that the user knows (sets) all parameters and can ised’ or ‘mathematical’, consisted of mathematically defined adjust them in order to detect the influence of each parameter in and generalised organ geometries, compositions and positions. a controlled environment. Software phantoms are used in Monte Early examples include the original MIRD phantoms, consist- Carlo simulations. Monte Carlo programs can then be used to cal- ing of ellipsoids, cylinders and rectangular volumes to repre- culate radiation dose to a patient or specific organ when assuming sent organs for the purpose of estimating doses from internal a certain distribution and radiation behaviour (interactions prob- or external sources of radioactivity. These phantoms can also ability distributions, organ attenuation coefficients, etc.). be defined to incorporate motion, such as cardiac or respiratory. An obvious disadvantage with software phantoms is the dif- Given the methods of their creation, they are approximate as ferences between the clinical situations and the simulated ones. opposed to realistic representations. However, they are still used Conclusions drawn from simulated data are not always valid on to date due to their simplicity, particularly when only estimates patients. For example, in the MIRD formalism, activity is assumed are required. Mathematical software phantoms may also take a Solar simulator 869 Solar simulator FIGURE S.65 Cross-sectional slices at different heights and three-dimensional rendering of a kidney cell. (Reprinted with permission from © The Optical Society.) non-anthropomorphic form, exhibiting structured details for the semi-quantitative or quantitative study of an MC simulated imag- ing system. With the development of tomographic scanning, three-dimen- sional datasets of the human body could be transformed into voxel-based phantoms, permitting a greater realism in compari- son to the previous stylised phantoms. By utilising tomographic scans for a range of human forms, these phantoms have been developed for a range of cases, including paediatrics, pregnancy FIGURE S.66 Schematic of a solar simulator. and race-specific phantoms. Examples include the ICRP refer- ence phantoms, REGINA and REX, used to update organ dose S coefficients for internal and external exposure. However, the pro- dosimetry. J. Appl. Clin. Med. Phys. 15(5) (September):246–256; cess of converting these datasets into phantoms requires time- Lee, C. 2014. Monte Carlo calculations in nuclear medicine sec- consuming delineation of the organs and the rigidity brought ond edition: applications in diagnostic imaging. Health Physics. about by the fixed anatomy means that it can be difficult to vary 106(3):431–432; Xu, X.G. 2014. An exponential growth of com- the model, specifically redefining organ sizes or introducing putational phantom research in radiation protection, imaging, and motion. radiotherapy: a review of the fifty-year history. Phys. Med. Biol. The latest advancement in software phantom development 59(18):R233. is the use of boundary representation (BREP) methods to cre- ate hybrid phantoms. Typically, segmented data from three- dimensional patient datasets are fitted with non-uniform rational Solar simulator b-splines or polygon meshes consisting of control or vertex points, (Non-Ionising Radiation) A solar simulator is a specialist photo- respectively. By modifying these points, BREP-based phantoms biological source which can emit broadband light which repro- are deformable. They can therefore adjust into existing phantoms duces the solar light spectrum. or the anatomy of a patient. The core elements of the monochromator (Figure S.66) are: Both physical and software phantoms allow for experiments that cannot be easily carried out on humans, in particular the • A broadband source emitting in the 200-1000nm range determination of dose deposition in organs. As with physical • Optical filters to cut the UVC emissions and part of the phantoms, software phantoms exhibit drawbacks as a result of infrared their simplification and standardisation, particularly where styl- • Output optics ised software phantoms are concerned. In contrast to a physical phantom, software phantoms and the corresponding simulated In terms of the resulting output spectrum most research group source have the advantage of being highly adjustable, as well as will refer to the COLIPA standards, although they have been pri- the ability to circumvent certain practical constraints (e.g. place- marily established for testing of sun screens. ment of TLDs within a physical phantom). Solar simulators are Risk Group 3 optical sources, as even Related Articles: Computational phantom, MIRD formalism, a short unprotected exposure to some of the emissions can be Limitations to the MIRD formalism, Monte Carlo calculation hazardous. Further Readings: Kobayashi, M., Y. Asada, K. Matsubara, Related Articles: COLIPA, Monochromator, Photobiological Y. Matsunaga, A. Kawaguchi, K. Katada, H. Toyama, K. lamp safety, Spectroradiometer Koshida, and S. Suzuki. 2014. Evaluation of organ doses and Further Reading: Sayre, R. M. et al. 1990. Spectral com- effective dose according to the ICRP Publication 110 reference parison of solar simulators and sunlight. Photodermatol, male/female phantom and the modified ImPACT CT patient Photoimmunol. Photomed. 7(4):159–165. Solenoid 870 Sonography Solenoid The concept of solubility is used to quantify the amount of solute (General) A solenoid is a helical (spiral) coil of wire that pro- that is soluble in a given volume of solvent at a given temperature. duces a magnetic field when carrying electrical current (see also There are two main types of solvent, polar and organic. A useful the article Electro-magnet). When a current is passed through the way to remember which type of solvent dissolves which type of coil, the magnetic field within the coil is relatively uniform. In solute is ‘like-dissolves-like’ that is a polar solute dissolves well engineering, the term solenoid may also refer to a variety of trans- in a polar solvent. ducer devices that convert magnetic energy into linear motion. Polar: Polar solvents are made up of polar molecules. A mol- Related Articles: Electro-magnet, Stator ecule is described as polar if the atoms that make it up have dif- fering electronegativities. The most common polar solvent in use Solid state detectors is water. (Diagnostic Radiology) Solid state detectors use a crystalline Organic: Organic solvents are made up of molecules that con- semiconductor material (e.g. silicon, germanium) as a detecting tain carbon, they are non polar; common examples include ace- medium. It consists of a p–n junction across which a pulse of cur- tone, ethanol and hexane. It should be noted that organic solvents rent develops when a particle of ionising radiation traverses it. are often highly flammable. Organic solvents are used in paint See Semiconductor detector. thinners, nail polish removers, perfumes and detergents. Related Articles: Solution, Atom Solid state rectifier (General) Solid state rectifiers are a type of rectifiers based on Sonogram solid state (semiconductor) diodes. The main characteristics of (Ultrasound) Velocity data in pulsed Doppler measurements (or such a rectifier are low voltage drop, quick response, low cost. continuous-wave Doppler) is usually presented as a sonogram, Related Article: Rectifier where time is represented on the horizontal axis, and velocity (or Doppler shift) on the vertical. The brightness represents the Solid water phantom received Doppler power at a given velocity. Figure S.67 shows (Radiotherapy) The use of epoxy resin-based substances (aka a so-called triplex image where the anatomical greyscale image solid water) as a substitute for water is common in radiation is shown

with the velocity information in colour overlaid on the dosimetry. Solid water has radiation characteristics very close to greyscale image. In the bottom part of the image is shown the those of water, and when used as a phantom for radiation in the sonogram. This gives a time-velocity representation of the veloc- radiotherapy energy range, any phantom-water corrections can ity distribution within the range gate, which is indicated by the be eliminated. The use of solid water phantoms is advantageous small lines perpendicular to the line indicating the insonation over traditional water phantoms, as they avoid the possibility of angle for the pulsed Doppler beam. S immersing chambers in water, reduce the reproducibility errors Sometimes a sonogram is also referred to as a spectrogram. and are more convenient to use. Solid water is available in slabs of varying thicknesses that can be used to create specific depths of Sonography required build-up or to provide backscatter, as well as inserts to (Ultrasound) Sonography describes the use of ultrasound, spe- hold specific chambers, such as parallel plate chambers. cifically medical diagnostic ultrasound. It is an abbreviation of Further Readings: Christ, G. 1995. White polystyrene as a ultrasonography. The term ultrasound describes sound frequen- substitute for water in high energy photon dosimetry. Med. Phys. cies which are inaudible to the human ear, that is above 20 kHz. 22(12):2097–2100; Constantinou, C., F. H. Attix, B. R. Paliwal. Typically the frequencies used range from 1 to 20 MHz. An 1982. A solid water phantom material for radiotherapy x-ray advantage of ultrasound over other diagnostic imaging modalities and gamma-ray beam calibrations. Med. Phys. 9(3):436–441; is that it is relatively inexpensive and is safe; it does not use ion- McEwen, M. R. and D. Niven. 2006. Characterization of the ising radiation and does not usually require contrast agents. An phantom material Virtual Water™ in high-energy photon and elec- tron beams. Med. Phys. 33(4):876–887. Solution (General) Solutions are homogeneous mixtures that are com- posed of two or more substances. They contain a solute which is dissolved in a solvent. A solution is characterised by interactions between the solvent and solute which results in a reduction in free energy. An everyday example of a solution of a solid in liquid is sugar dissolved in water. It is also possible to dissolve a gas in a liquid, for example carbonated drinks in which carbon dioxide is dissolved in water. Furthermore the definition of solutions extends to solids, for example a metal alloy is described as a solid solution. Concentration is a measure used to quantify the amount of solute dissolved in a solvent which can be expressed in parts per million (ppm) or molarity. Related Article: Solvent Solvent FIGURE S.67 Triplex image of the carotid artery. In the upper part of (General) Solvents are fluids (liquids or gases) that can dissolve the image is the greyscale image with velocity information in colour over- solutes in solid, liquid, or gaseous form, to produce a solution. laid on the greyscale data. In the bottom the sonogram is shown. Sound attenuation 871 Source loading in brachytherapy often quoted disadvantage is that it is user-dependent meaning the X = K(X + - X - )/Z (S.15) acquisition and interpretation of ultrasound images depends upon the training and skill of the operator. Y = K(Y + - Y - )/Z (S.16) The term sonographer is used to describe practitioners of med- ical ultrasound. The term sonologist has also been used to denote medical doctors using ultrasound but is less commonly used. In the newer cameras, the output signal from each PMT is digi- tised. This is often analogous to the signals described above and Sound attenuation the same equations are used. Because the positional information (Ultrasound) See Attenuation is determined using software, accuracy can be improved by incor- porating weighting factors which take into account any non-lin- Source axis distance (SAD) earity in PMT response. (Radiotherapy) This describes the distance from the target Related Articles: Scintillation camera, PMT source to the isocentre of the machine. Commonly it is 100 cm. It is widely used in radiotherapy for dosimetry and patient set-up. Source diaphragm distance (SDD) Linacs are isocentrically calibrated when the reference point is (Radiotherapy) This describes the distance from the source to the located at the reference depth at a distance from the source, equal forward part of the secondary collimators. It can also be called to the SAD. Equivalently, cobalt units are normally calibrated ‘in- the source to collimator distance (SCD). air’, with the reference point again located at the isocentre, equal Related Articles: Source axis distance (SAD), Source surface to the SAD. distance (SSD) Abbreviation: SAD = Source axis distance. Related Article: Source surface distance (SSD) Source loading in brachytherapy (Radiotherapy, Brachytherapy) The brachytherapy source/s must Source block distance (SBD) be handled and loaded into the applicators for treatment, and (Radiotherapy) This describes the distance from the target source many methods have been used over the time. These methods have to the block tray, either to the upper side or in rare cases to the been developed primarily to reduce the dose to the personnel, but lower side as seen from the source. also to improve the quality of the treatment itself: Related Articles: Source axis distance (SAD), Source surface distance (SSD) 1. Manual loading a. Historical method, for example handling of radium Source coordinates sources, which were manually introduced and (Nuclear Medicine) In nuclear medicine imaging this refers to the removed; treatment times from a number hours to process by which a gamma ray entering the gamma camera is several days: S represented at the appropriate x–y position on the image. i. Speedy insertion techniques were mandatory. When a scintillation event reaches the crystal, the light pro- ii. The patient was a radiation source during the duced is distributed among a number of adjacent photomultiplier long treatment. tubes (PMTs). The PMT closest to the event receives the maxi- 2. Manual afterloading mum amount of light, so this represents its approximate position. a. Still used: A more accurate X–Y coordinate is obtained by considering the i. Applicators, needles, catheters, etc. are relative response of the other PMTs. The amount of light detected inserted. by a PMT is inversely related to the distance between its centre ii. Correct applicator positions are verified using and the site of the interaction (Figure S.68). dummy sources. In the older style analogue cameras, the position of an event is iii. Improves the accuracy in applicator position- determined by splitting the signal from each PMT into four output ing, as there is no risk of dose to staff. lines known as X+, X−, Y+, Y−. The positioning voltages X and Y iv. Finally, the sources are inserted into the appli- and the energy Z are determined using the following equations (K cators manually. is a constant): 3. Remote afterloading a. Recommended method: Z = X + + X - + Y + + Y - (S.14) i. Applicators, needles, catheters, etc. are inserted. ii. Correct positions are verified using dummy sources. iii. The source is loaded into the applicator(s) Electronic using a remote-controlled afterloading unit. signal Relevant personnel operate the afterloading unit from the operator’s room close to the treat- PMT ment room (compare ‘linac’ treatments). Light Note! Today, many permanent prostate implants are performed Light guide with manual loading and manual afterloading techniques, using Scintillation low-energy sources. During these procedures, dose to staff from the crystal sources used is very low; if fluoroscopy is used during the implant Scintillation procedure, the dose to staff comes mainly from the fluoroscopy. event Related Articles: Brachytherapy, Afterloading, Manual load- ing, Manual afterloading, Remote afterloading, Remote after- FIGURE S.68 X–Y positioning of a scintillation event. loading unit Source localisation 872 Source strength (brachytherapy) Source localisation When brachytherapy was introduced as a treatment modality, the (Nuclear Medicine) In nuclear medicine imaging this refers to only sources available were radium sources. Source strength was the process by which a gamma ray entering the gamma camera is given as the mass of the radium contained in the encapsulated represented at the appropriate point on the image. Please see the source. The filtration of the encapsulation was also given; usu- article Source coordinates for more information. ally 0.5 mm Pt for needles and 1–2 mm Pt for tubes. (The UK’s Related Articles: Source coordinates, Scintillation camera National Physical Laboratory [NPL], a standards/measurement institute established at the turn of the last century, acquired its Source models first radium standard in 1913, made by Marie Curie, and specified (Radiotherapy, Brachytherapy) A source model is used in a in terms of mass of radium.) treatment planning system for dose distribution calculations. The Contained activity is a quantity that can be used for all types source model describes the dose distribution around a source and of brachytherapy sources. But, for brachytherapy dosimetry, the is specific for the isotope and also for the design of the source, quantity of interest is the output of the encapsulated source, not that is its size and shape and the materials used for the source the contained activity. (Sources are encapsulated, and it is thus encapsulation. difficult to determine the contained activity.) The quantity appar- Both point and line source models have been used in treat- ent activity, which is an output specification, has been used as an ment planning systems. Point source models are spherically sym- alternative to contained activity and it is still used, especially for metric and can be described by a one-dimensional dose or dose radiation protection applications. rate table. Linear source models are symmetric about their linear The apparent activity of an encapsulated photon emitting central axis, and can be described by a two-dimensional dose/ source is the activity of a hypothetical unfiltered point source of dose rate table. Note that tables using Cartesian coordinates are the same nuclide that gives the same air kerma rate or exposure different from tables using cylindrical polar coordinates and that rate at the same distance from the centre of the source. it is possible to extend a point source model to reflect a cylindrical When artificial radionuclides became available, the brachy- dose distribution by introducing a second function describing the therapy community aimed at specifying source strength for these anisotropy. ‘radium substitutes’ in a radium-like manner. The new sources Source Model Recommendations (2009): As per 2009 the were similar in shape and strength to the old ones, and thus all source models based on the AAPM TG43 Formalism are rec- the experience gained from the earlier radium treatments could ommended for use in treatment planning systems. Recognised easily be transferred. published ‘best source data’ should always be used, and data are The equivalent mass of radium, the mgRaEq, for an encapsu- available from the AAPM and from ESTRO. lated photon emitting source is the mass of Ra-226 filtered by 0.5 It is of the utmost importance that the user of a treatment mm Pt that gives the same air kerma rate or exposure rate at the same distance from the centre of the source. (Note that this could S planning system understands the model used and how it is implemented. lead to interpretation problems for Ra sources! Consider an Ra Abbreviations: AAPM = American Association of Physicists tube with strength 20 mg and filtered by 1 mm Pt, not 0.5 mm Pt; in Medicine and ESTRO = European Society for Therapeutic the strength of the tube will correspond to 18.7 mgRaEq!) Radiology and Oncology. The ICRU Report 38 – Dose and Volume Specification for Related Articles: Treatment planning systems– Reporting Intracavitary Therapy in Gynecology – contains the Brachytherapy, AAPM TG32 formalism, Point source calcula- following statement: tions, Meisberger polynomial ‘It is recommended that radioactive sources be specified in terms of “reference air kerma rate”. The reference air kerma rate of a source is the kerma rate to air, in air, at a reference Source–skin distance (SSD) distance of 1 meter, corrected for air attenuation and scattering. (Radiotherapy) See Source surface distance For this purpose, the quantity is expressed in mGy * h−1 at one metre.’ Source strength (brachytherapy) Task Group 43 of the AAPM defines ‘air-kerma strength’: (Radiotherapy, Brachytherapy) Calibration of source strength is ‘Air-kerma strength’ has units of μGy * m2 * h−1 and is numeri- a very important

part of a comprehensive brachytherapy quality cally identical to the quantity Reference Air Kerma Rate rec- system. The instruments, ion-chambers and electrometers, used ommended by ICRU 38 and ICRU 60 (ICRU 1985, 1998). For for source strength determinations, should have calibrations that convenience these unit combinations are denoted by the symbol are traceable to national and international standards. U where U = 1 μGy * m2 * h−1 = 1 cGy * m2 * h−1. The National Specification of Source Strength for Photon Emitting Institute of Science and Technology (NIST) maintains the US Sources: Source strength for a photon-emitting source can be primary air-kerma standards for x-rays in the energy range of given as a quantity describing the radioactivity contained in the 10–300 keV and for photon-emitting radionuclides such as 137Cs, source or as a quantity describing the output of the source: 192Ir, 103Pd and 125I. Air-kerma strength, SK, is the air-kerma rate, K˙δ(d), in vacuo and due to photons of energy greater than, δ at a 1. Specification of contained activity distance d, multiplied by the square of this distance, d2: a. Mass of radium; mg Ra b. Contained activity; Ci, Bq SK = K d(d)* d2 2. Specification of output a. Equivalent mass of radium; mg Ra eq In modern brachytherapy dosimetry, reference air kerma rate or b. Apparent activity air kerma strength is the quantity used to calculate absorbed dose. c. Reference exposure rate Abbreviations: ICRU = International Commission on d. Reference air kerma rate Radiation Units and Measurements and AAPM = American e. Air kerma strength Association of Physicists in Medicine. Source–surface distance (SSD) 873 S patial compounding Related Articles: Mass of radium, Contained activity, Anode Equivalent mass of radium, Apparent activity, Reference air kerma rate, Air kerma strength Further Readings: ICRU (International Commission on Radiation Units & Measurements, Inc.). 1985. Dose and vol- Actual ume specification for reporting intracavitary therapy in gyne- focus cology. ICRU Report 38, Washington, DC; ICRU (International Commission on Radiation Units & Measurements, Inc.). 1998. Fundamental quantities and units for ionizing radiation. ICRU W target Report 60, Washington, DC; Nath, R. et al. 1995. Dosimetry of interstitial brachytherapy sources: Recommendations of the AAPM Radiation Therapy Committee, Task Group No. 43. Med. Phys. 22:209–234; Rivard, M. J., B. M. Coursey, L. A. DeWerd, α α–Anode W. F. Hansson, M. S. Huq, G. S. Ibbott, M. S. Mitch, R. Nath and J. F. Williamsson. 2004. Update of AAPM Task Group No 43 Cathode angle with focusing cup Report: A revised AAPM protocol for brachytherapy dose calcu- lation. Med. Phys. 33:633–674. Effecive Source–surface distance (SSD) focus (Radiotherapy) This describes the distance from the target source to the surface of the phantom (or patient). It is widely used in X-ray towards the patient radiotherapy for photon beam calculations and patient set-up. It is historically used for when treatments are delivered at a fixed source to surface distance SSD, often as the distance was fixed FIGURE S.69 Space-charge effect in front of the cathode filament. The focusing cup (Wehnelt electrode) around the cathode filament controls by the use of an applicator. Standard SSD calibration uses a refer- the cloud of thermal electrons. ence depth located at 10 cm depth in a phantom with a standard SSD equal to the source axis distance (SAD). The distance from the source to the reference point is thus equal to SAD + 10 cm. Spatial average intensity I(SA) The term is also used widely now for isocentric treatments to aid (Ultrasound) The spatial average intensity is the intensity aver- patient set up. aged over a cross-sectional area within a transmitted ultrasound This term can be described as source skin distance (SSD). It field that may contain variations in intensity from point to point can be measured using the optical distance indicator (ODI) on within the measured cross section. For example, the average S linear accelerators. intensity across a whole beam width may be measured, including Abbreviations: SSD = Source surface distance and SSD = the central peak intensity and the low-intensity side lobes. Source skin distance. The area of averaging is either (a) determined by the area of Related Articles: Optical distance indicator, SAD source axis the measuring device, for example a wide hydrophone, or (b) from distance an integration of measurements made over a defined cross-sec- tional area of the transmitted field. Source-to-image distance (SID) Related Articles: Time average intensity, Intensity, Beam (Radiotherapy) This is used in portal imaging, and describes width/area, Side lobe, Hydrophone the distance from the source to the plane of the image. This is equivalent to source-to-film distance before the advent of portal Spatial compounding imaging. (Ultrasound) Spatial compounding refers to the technique of Related Articles: Source axis distance (SAD), Source surface acquiring an ultrasound image by directing the beams from indi- distance (SSD) vidual transducer elements in several different angles, and form- ing the final image by combining the reflected echoes from all Space-charge effect the angles. By averaging the data from the different angles, the (Diagnostic Radiology) The electrons emitted from the heated resultant compound image has a better image quality. cathode filament form an electron cloud around it. This cloud is called space-charge. When the electrons leave the filament the cathode loses part of its negative charge and becomes more ‘posi- tive’. This attracts back some of the electrons. Normally an equi- librium state exists between the number of electrons emitted and these attracted back. The electron cloud remains near the filament until high voltage (from 20 to 150 kV) is applied between the cath- ode and the anode. This effect is the main reason for saturation of the anode current at lower kV (usually below 50 kV), known as ‘space-charge limited’ operation of the x-ray tube (see article on Filament current). The space-charge effect (Figure S.69) can be regulated by the Wehnelt electrode in grid-controlled x-ray tube, thus allowing the creation of very short x-ray pulses. Related Articles: Cathode, Filament circuit, Filament heating, Filament current, Tube current, Wehnelt electrode Related Article: B-mode Spatial filtering 874 Spatial resolution Further Reading: Bushberg, Seibert, Leidholdt and Boone. Spatial pulse length 2012.The Essential Physics of Medical Imaging, 3rd edn., (Ultrasound) Spatial pulse length is the distance that a pulse occu- Lippincott Williams and Wilkins. pies in space. The spatial pulse length is equal to the number of cycles in the pulse multiplied by their wavelength. It determines Spatial filtering axial resolution, which can be said to be approximately half the (Nuclear Medicine) Spatial filtering is an image processing spatial pulse length due to tapering of the pulse. The spatial pulse tool used to enhance the appearance of an image. In nuclear length is inversely proportional to the frequency and directly pro- medicine, for example images have a grainy appearance portional to the number of cycles in the pulse. Tapering of the because of the statistical nature of the acquisition. A type of pulse edges makes it necessary to determine a criterion, for exam- spatial filtering called smoothing can be used to reduce this ple a −3 dB limit, to compare pulses. effect, although it does adversely affect the spatial resolution of the image. Spatial resolution Mathematically, a filter is a matrix which is applied to all pix- (Diagnostic Radiology) Spatial resolution is the ability of an els in the image using an operation known as convolution. It is imaging system to resolve, or see, the separation between two rel- defined as follows: atively small and closely spaced objects. This resolving is reduced by blurring. Resolution test objects consisting of adjacent lines ¥ separated by spaces (line pairs – spatial frequency) are used to g(x) = òI(x¢)h(x - x¢)dx¢ evaluate the effect of blurring in imaging procedures. -¥ The best quantitative descriptor of spatial resolution is the where Modulation Transfer Function (MTF). I(x) is the input image The limiting spatial resolution of one system is normally taken g(x) is the result at MTF = 0.1 (10%), which is also known as cut-off frequency. h(x) is the convolution kernel which represents the filter This way the limiting spatial resolution of a typical x-ray radio- graphic film is 8–10 lp/mm (the same figure for a typical fluoro- The convolution operation is usually denoted by *: scopic system can be 4–6 lp/mm). As spatial resolution in x-ray imaging is measured by test g(x) = I(x)* h(x) = h(x)* I(x) objects with high absorption line pairs. In some cases (as with CT scanners), spatial resolution can also be named high-contrast Instead of using convolution to apply a filter to an image, it is resolution (as opposed to low-contrast resolution, what is just con- much easier to use Fourier transforms. This is because the Fourier trast resolution). Related Articles: Modulation transfer function, Line pairs, S transform of the convolution of two functions is equal to the prod- uct of their individual Fourier transforms: Unsharpness, Contrast resolution FT {I(x)* h(x)} = FT {I(x)}´ FT {h(x)} Spatial resolution (Nuclear Medicine) Spatial resolution refers to the detector sys- tems’ ability to provide sharpness and details in an image. Related Articles: Filtering, Kernel The spatial resolution in most nuclear medicine images is somewhat limited; at least compared to the resolution in radio- Spatial frequency graphic images. The spatial resolution depends on a number of (Magnetic Resonance) Spatial frequencies are the elements of the parameters which differ between SPECT and PET. Fourier domain of a spatial distribution of signals. These are vec- Single Photon Imaging: The gamma camera spatial resolu- tors representing plane waves in space. They carry the unit of a tion is mainly limited by the collimator resolution and intrinsic wave number, that is of inverse distance. In the context of MRI resolution. The collimator resolution is dependent on the width this Fourier domain is called k-space. High spatial frequencies and length of the collimator holes and the intrinsic resolution is correspond to fine detail in an image (like sharp edges). Thus, the affected by crystal properties and the electronics. The spatial maximum spatial frequency is often used as a measure of spatial resolution of an object is also dependent on its distance from the resolution. collimator face. See articles on k-space, Bar phantom and Line pair. PET: In PET there are three different factors that contribute to the spatial resolution degeneration. The positron (β+-particle) is Spatial linearity emitted and it does not annihilate immediately. Since the positron (Magnetic Resonance) See Gradient linearity path before the annihilation is not known, the spatial resolution can never be less than the positron range. Spatial peak intensity ISP An assumption in PET is that when the positron annihilates (Ultrasound) The point in the ultrasound field where the highest the positron has no momentum, hence the annihilation photons intensity is measured. It may be measured in one instant in time are emitted with a 180° opposite angle. This is untrue because in or averaged over time. general the positron is only slowed down to thermal speeds before The time average value (spatial peak time average intensity annihilation. As a result the positron annihilation angle deviates ISPTA) is an important quantity to know because in an attenuating (∼0.5°) from 180°. medium that is the point where the maximum ultrasound power Due to the depth of interaction effect the spatial resolution in is being deposited and where heating from the ultrasound will PET is degraded when the source is moved further away from the therefore be greatest. It will usually be found at transmit focal centre of rotation. point. To read more about the spatial resolution in PET and scintilla- Related Articles: Intensity, Heating, Time average intensity tion camera please read Related Articles. Spatial resolution 875 Spatial resolution in a scintillation camera Axial Lateral Lateral Elevation Axial (slice thickness) FIGURE S.70 Spatial resolution in the three planes (L) of an ultrasound image (R). The axial and lateral resolution are evident from the image; the effect of changes in slice thickness, which is usually the worst plane for resolution is not apparent. Abbreviation: SPECT = Single photon emission computed tomography and PET = Positron emission tomography. Related Articles: Annihilation, Annihilation coincidence detection, Beta decay, Compton effect, PET, Spatial resolution PET, Spatial resolution SPECT, SPECT Further Reading: Cherry, S. R., J. A. Sorenson and M. E. Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, Philadelphia, PA, pp. 253–259, 319–320,

328–337. S Spatial resolution (Ultrasound) The spatial resolution of an ultrasound system describes the ability to separate objects in the display. Spatial resolution (Figure S.70) is usually best in the axial direction (link–axial resolution); resolution is dependent on the pulse length. Lateral resolution is dependent on beam width and var- ies within the image. Resolution in the elevation plane is usu- ally referred to as slice thickness, and in conventional systems FIGURE S.71 Image of an ultrasound phantom. is controlled by the design of the transducer elements and the lens. This also varies in the image. An example of the changes in spatial resolution in an image of an ultrasound phantom is shown overall resolution which is called the system resolution Rsys. The in Figure S.71. system resolution, in FWHM is given by Improved spatial resolution often results in improvements in contrast resolution. In Figure S.72, images of a popliteal fossa Rsys = R2 2 Int + Rcoll (S.20) from two scanners show the effect of improvements in axial and lateral resolution with sharper boundaries and less noise in the The collimator resolution is determined by the width and length image from the newer scanner. of the collimator holes. For example, the lowest principal spatial On Figure S.71 the targets are groups of nylon wires. There resolution can never be lower than the hole width. The hole can- are five wires in a horizontal line in each group but lateral resolu- not be made too small if one expects to attain reasonable col- tion is inadequate to resolve the three closest together and they limator efficiency. Collimators with high resolution have many merge into one echo in the top group (A). In the middle and low- small holes with thinner septa (or longer holes), but a low effi- est groups, resolution is notably worse with less clear separation ciency. Since Rcoll depends on the source to detector distance of the targets. (Figure S.73) so does the system resolution. Figure S.72b shows more detail of small structures; larger Spatial resolution is dependent on the distance between the structures have improved edge definition. source and the detector. The collimator will always allow photons with an angle of incidence lower than a certain angle threshold Spatial resolution in a scintillation camera to pass. In the left example the organs will overlap whereas in (Nuclear Medicine) Spatial resolution in single photon emission the right example when the sources are closer to the detector the computed tomography (SPECT) is determined by a number of images do not overlap. factors. The two most important are the intrinsic resolution Rint, When the distance between the source and the detector and the collimator resolution Rcoll. These two factors affect the increases the spatial distribution of the photons is also increased. Spatial resolution PET 876 Spatial resolution PET (a) (b) FIGURE S.72 The effects of improved spatial resolution is displayed in these two images of an older scanner (a) and a newer scanner (b) with improved axial and lateral resolution. Detector Collimator Point source in S patient FIGURE S.73 Scintillation camera spatial resolution at two different distances between source and detector. This can be seen in Figure S.73. Photons with an angle of inci- dence lower than a threshold angle will pass through the colli- mator no matter what the distance between the source and the detector is. At organ depths (5–10 cm) the Rsys is primarily deter- mined by Rcoll since the Rsys is much poorer than RInt. Another process that has a degenerative effect on the spatial resolution is scattered photons or photons that pass right through the collimator. These photons, if registered, are interpreted as FIGURE S.74 Example of speckle as seen in an ultrasound image. true events when in fact they are false. False events will cause blurriness and a lower SNR. Other factors that have a degenerative effect on spatial resolu- (ACD) is used for spatial localisation. The PET system resolution tion are patient movement during image acquisition and image is dependent upon smoothing in the preprocessing stage. Related Articles: Annihilation, Annihilation coincidence 1. Positron physics detection, Beta decay, Compton effect, Depth-of-interaction, 2. Detector properties Intrinsic resolution, PET, SPECT 3. Source location relative centre of rotation Further Reading: Cherry, S. R., J. A. Sorenson, M. E. Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, The limiting physical factor for the spatial resolution in PET is the Philadelphia, PA, pp. 319–320. distance travelled by the positron before annihilation. One can never attain images with lower resolution since one does not know the actual Spatial resolution PET path travelled by the positron before annihilation. The maximum (Nuclear Medicine) PET spatial resolution refers to the PET detec- energy of the beta particle emitted from 18F is 635 keV which cor- tor system’s ability to provide sharpness and details in an image. responds to a mean range Rrange, in water of approximately 0.2 mm. The parameters affecting the spatial distribution in PET differ In addition to the degenerative effects of positron range, the from SPECT. For example, the collimator resolution is not a fac- positron is seldom brought to a full stop before annihilation, lead- tor in PET imaging since the annihilation coincidence detection ing to a small deviation (±0.23°) from an 180° opposite emission Spatio-temporal contrast sensitivity 877 S pecific absorption rate (SAR) Line of d response Detector x ring θ Point of annihilation FIGURE S.75 Non-collinearity of the annihilation photons because of residual momentum of the positron and electron at annihilation. The actual angle deviation range is ±0.23°. angle. The ACD will incorrectly assign such a coincidence as a FIGURE S.76 Graphical view of the parameters used to calculate the system resolution for an off-centre source. straight line of response as displayed in Figure S.75. The effect on spatial resolution, expressed in terms of FWHM, is dependent on the distance between the detectors, D and is given by True coincidence Random coincidence Scattered coincidence R180° = 0.0022 ´ D (S.17) For a PET system with discrete detector elements the effect on the spatial resolution, Rdet, is primarily determined by the width of the detector element, d. Rdet is equal to the full width at half maximum (FWHM) for a point source on a line be two opposite detector element. When the point source approaches a detector element FWHM increases hence the best resolution for a PET system is in (a) (b) (c) the centre of rotation (COR). In COR Rdet equals half the detector Line of Point of Detector element width. response annihilation ring S The system resolution for a source at COR (Rdet = d/2) is given by FIGURE S.77 Three types of events, true coincidence (a), random coin- cidence event (b) and scattered coincidence (c). The two latter cases will Rsys = R2 R2 2 range + 180° + Rdet (S.18) provide false coincidences that will lower the signal-to-noise ratio, hence resulting in a loss of contrast. If the point of annihilation is not in the centre of rotation the two photons might enter the crystal at an oblique angle. In such a case the photons can penetrate one or more adjacent crystals and inter- Abbreviation: PET = Positron emission tomography. act in another crystal. Again the line of response will be mis- Related Articles: Annihilation, Annihilation coincidence placed and as a result the spatial resolution will decrease. This is detection, Beta decay, Depth-of-interaction, PET, SPECT called the depth-of-interaction (DOI) effect. For a source located Further Reading: Cherry, S. R., J. A. Sorenson and M. E. off-centre the DOI degeneration of spatial resolution is given by Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, Philadelphia, PA, pp. 328–337. é x ù R ’det = Rdet ´ æ ö êcosq + ç ÷sinq (S.19) Spatio-temporal contrast sensitivity ë è d ú ø û (General) Spatio-temporal contrast sensitivity refers to the per- where ception of images which change intensity across space and over d and x is the width and the length of the detector time. The effects can be demonstrated by observing a flickering θ is the angle indicated in Figure S.76 grating which shows that the contrast required to detect the grat- ing is dependent on the relationship between its spatial and tem- Another degenerative effect is false coincidences. Two exam- poral frequency. ples are shown in Figure S.77. Random and scattered coinci- Related Article: Perception dences will yield false positional information. These random Further Reading: http: / /www .psyp ress. com /m ather /reso coincidences will contribute to the overall background thus lead- urces / ing to a loss of contrast. While reconstructing image data it is common to use some Specific absorption rate (SAR) kind of smoothing filter. This procedure can also reduce the spa- (Magnetic Resonance) The specific absorption rate is defined as tial resolution. the radio frequency (RF) power absorbed per unit of mass of an Patient’s movement can obviously lead to a blurring of other- object, and is measured in watts per kilogram (W/kg). The SAR wise sharp edges. Therefore it is important to minimise patient describes the potential for heating of the patient’s tissue due to the movement during image acquisition. application of the RF fields necessary for the MR measurement. Specific activity 878 S peckle The interactions of RF fields with the biological tissues and bod- on the production method. An example of a radioisotope that is ies depend on many parameters in a very complex way. The radio never carrier free is 99mTc because the decay product is the long- waves in free space are characterised by the intensity of the elec- lived 99Tc. tric (E) and magnetic (H) fields and by their frequency, direction If a large quantity of an element is injected, there might be a and polarisation. Inside the body the interaction with the inter- pharmacologic response to the specific isotope. For example, too nal RF field depends on the parameters of the external RF field much iodine can cause a reaction. But a sample of 0.4 MBq of as well as the electromagnetic properties of the exposed body. carrier-free 131I only contains 10−10 g of element iodine, which is Since a detailed analysis of this interaction is very complex, usu- not by far enough to cause an iodine reaction. ally simple interaction models are analysed. SAR is defined as Radioactive isotopes are often attached to biological com- the time derivative of the incremental energy (dW) absorbed by pounds in order to trace (study) a certain biological process. or dissipated in an incremental mass (dm) contained in a volume These compounds could be protein, glucose or antibodies. In such element (dV) of a given density (ρ): situations the specific activity is given by the activity per labelled substance mass (Bq/g). d æ dW ö d é dW ù Further Reading: Cherry, S. R., J. A. Sorenson and M. E. SAR = = ( dt ç è dm ÷ ê ú W/kg) ø dt ërdV û Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, Philadelphia, PA, pp. 38–40, 59–60. The equation indicates the rate at which the RF energy is con- verted into heat and provides a quantitative measure of all the Specifications of a medical device interaction that depends on the intensity of the internal electric (General) A detailed list of the working characteristics of a field. In MR imaging RF absorption causes tissue heating. The medical device. The specifications are usually defined during the patient’s ability to dissipate excess heat is an important safety conceivement phase of the design and followed during the devel- issue. The temperature rise in patient resulting from a given SAR opment and implementation phases of a medical device. depends mostly on the blood flow and the volume of tissue receiv- They can originate from technical requirements and different ing radiation energy and to a lesser extent on thermal conduction. standards or from the needs of users, stakeholders, policymakers SAR also depends on the pulse duty cycle, tissue density conduc- or the context in which the medical device will be operationalised. tivity, patient size, and the type and shape of the coil. Therefore The specifications can foster the safety, quality and efficacy the patient’s weight and the selected pulse sequence parameters of medical devices along with the adequate planning of the finan- are

important factors to be taken into account to ensure that the cial, infrastructure and human resources to be considered during SAR does not exceed the permitted levels. For safety reasons, the the implementation, functioning and decommissioning phases of RF power emitted by the system into the body is monitored and the devices. the respective SAR values are limited accordingly. The IEC limit The new European Commission Medical Devices Regulation S values are 4 W/kg (whole body) as well as 8 W/kg (spatial peak). (MDR) 2017/745 and In Vitro Diagnostic Medical Device The FDA has established different SAR limits: 4 W/kg averaged Regulation (IVDR) 2017/746 are introducing the concept of over the whole body for any 15-min period; 3 W/kg averaged over common specifications, i.e. ‘a set of technical and/or clini- the head for any 10-min period or 8 W/kg in any gram of tissue cal requirements, other than a standard, that provides a means in the extremities for any period of 5 min. The guidelines limits of complying with the legal obligations applicable to a device, for the RF patient exposure are only based upon the assumption process or system’. Such specifications could be adopted by the of heating effects. If the receiving RF coil is in resonance with European Commission (EC), after consulting the Medical Device the transmitter, it may act to increase the RF field close to the Coordination Group, when no harmonised standards exist or coil. This increase in field strength is of particular concern when when they are insufficient or when there is the need to deal with it occurs near the eyes. To eliminate this effect, the receive coil public health concerns. To this end, the EC should respect the is decoupled during transmission. The SAR is highest with pulse general safety and performance requirements specified in Annex sequences that require large flip angles such as 180° RF pulses in I, the technical documentation specified in Annexes II and III, the fast spin echo sequences. MR systems calculate the SAR as its clinical evaluation and post-market clinical follow-up set out in measurements are not trivial. The standard IEC 60601-2-33 estab- Annex XIV or the requirements regarding clinical investigation lishes three modes of operation: level 0 (normal operating mode) specified in Annex XV. with a SAR less than or equal to 1.5 W/kg; level I (first level- Related Articles: Standards, Medical device controlled operating mode) with a SAR greater than 1.5 W/kg but Further Reading: Medical Device Regulations 2017/745, less than 4 W/kg and level II (second level-controlled operating In-Vitro Diagnostics Regulations 2017/746, FDA Regulation mode) with the SAR greater than 4 W/kg. The limits are applied of Medical Devices. WHO. WHO Technical Specification for to normal environment conditions in temperature and humidity Medical Devices. and for patient lightly clothed and resting. Hyperlink: www .w ho .in t /med ical_ devic es /ma nagem ent _u se / md e _tec h _spe c /en/ Specific activity (Nuclear Medicine) Specific activity is the amount of activity Specificity per gram of the radioisotope of interest (Bq/g) in a sample or (General) See Receiver Operating Characteristic (ROC) a radioactive compound. A radioactive sample seldom or never consists of single particular isotope. Instead the sample contains Speckle a mixture of radioactive and stable isotopes. If a one or a number (Ultrasound) of stable isotopes are present in the sample, they are called car- Background: Ultrasound images of tissues show a granu- riers. A sample containing carriers is said to be with carriers. lar appearance, which is called ‘speckle’ after a similar effect If the sample does not contain any stable isotopes the sample is in laser optics. The granular appearance can be interpreted as carrier free. Whether or not the sample is carrier free depends noise, but is deterministic, that is if the transducer is returned to Speckle decorrelation 879 SPECT clinical applications the exact same location, the exact same image will be produced. Speckle decorrelation The effect can be explained as an interference phenomenon: tis- (Ultrasound) Speckle is the granular appearance in an ultra- sue can be modelled as a collection of scatterers which are so sound image and is the result of constructive or destructive inter- small that a large number of them occupies one resolution cell, ference of echoes emanating from the same resolution cell. As and all scattered wavelets from this resolution cell will interfere long as the positions of all scattering objects are the same, the constructively or destructively. As high amplitude of the return- same ultrasound image will result. As the scatterers start to move ing echoes is represented by white in the ultrasound image (and relative to one another, the speckle pattern changes its appear- low by black), the result is a granular texture of the image, which ance, or decorrelates. Conversely, the speckle pattern will also notably has no correlation to the microstructure of tissue – see decorrelate if the scatterers are stationary, but the transducer is Figure S.74. translated. The rate of decorrelation of the ultrasound amplitude Speckle Statistics, First Order: The speckle noise obeys a at a certain location for a given translation is described by a cor- Rayleigh probability density function if the phases are uniformly relation function in the axial, lateral, and elevational directions, distributed between 0 and 2π and the number of scatterers is large respectively. The derivation of these correlation functions is within a resolution cell. Under those conditions, the ratio between rather laborious, but is basically the result of a convolution of the the mean amplitude level and the standard deviation of the ampli- point spread function and the distribution of point scatterers, fol- tude (commonly referred to as signal-to-noise ratio [SNR]) will lowed by translations of the point spread function as the depen- be 1.91 for the received signal. Note that this is valid only for data dent variable. To obtain practically independent amplitudes at a that has not undergone any form of logarithmic or other form of certain location, the displacement of two apertures needs to be nonlinear processing. 0.4–0.5 aperture widths. For a displacement of 0.5, the ampli- Speckle Statistics, Second Order: The size of the speckle tude correlation coefficient will be 0.25. Decorrelation may be granules is in the same order as the resolution of the imaging obtained for even smaller displacements if the area is far from system, both in the lateral and the axial direction, determined the focal region. by beam width and pulse length, respectively. The mathematical procedure to describe this is in terms of a correlation function, SPECT (single-photon emission computed tomography) and the more mathematically stringent way to describe this is that (Nuclear Medicine) See Single photon emission computed tomog- the effective width of the correlation function corresponds to the raphy (SPECT) axial and lateral resolutions. The derivation of these correlation functions is rather laborious, but is basically the result of a con- SPECT clinical applications volution of the point spread function and the distribution of point (Nuclear Medicine) The clinical uses of single photon emission scatterers, followed by translations of the point spread function as computed tomography (SPECT). SPECT is the most widely the dependent variable. used nuclear medicine technique for clinical imaging. The Speckle Reduction: In order to reduce the speckle noise, radionuclides used for SPECT images typically have half-lives S statistically uncorrelated images of the same area can be inco- ranging from 6 h to 8 days. Such radionuclides can be manu- herently added (compounding). Uncorrelated images can be factured at a remote facility and then transported to the users obtained either by changing the centre frequency of the transmit- location, thus there is no need for expensive radionuclide pro- ted pulse, or by a given translation of the ultrasound beam. Both duction equipment, for example cyclotrons. The table outlines approaches have the effect of changing the interference pattern radionuclides used for SPECT imaging and their clinical appli- from the scatterers, while specular echoes will remain unaf- cation (Table S.2). fected. It can be shown that if N images, that are independent in Abbreviation: SPECT = Single photon emission computed terms of the random speckle process, are averaged, the SNR will tomography. increase by a factor of square root of N. To obtain practically Further Reading: Miller, J. and J. Thrall. 2003. Clinical independent images the displacement of two apertures needs to molecular imaging. J. Am Coll. Radiol. 1(1):4–23. be 0.4–0.5 aperture widths. For a displacement of 0.5, the ampli- tude correlation coefficient will be 0.25. Decorrelation may be obtained for even smaller displacements if the area is far from the focal region. The first approach is used in beam formers, which sometimes TABLE S.2 are designed to form at least two beams of different sub-bands Common Radionuclides in SPECT Imaging and Their within the usable bandwidth of the transducer, which are then subsequently summed. Applications At least one manufacturer is known to use speckle reduction Radionuclide Half-Life Molecular Imaging Applications by phasing beams in different directions from a linear array, thus 99m imaging the same area from different angles, and thereby dif- Tc 6 h Tumour detection and characterisation, ferent effective apertures. However, the number of beams used cardiac infarction detection and seems to exceed the necessary number for independent images, monitoring thrombolytic therapy, renal thus resulting in ‘redundant’ beams. This may however be neces- function studies 131 sary due to the slight distortions in tissue: if there are regions with I 8 days Thyroid function and tumour detection, different sound speed, sound waves are refracted. This degrades renal function studies, receptor binding the quality of the compounded image due to angular distortion studies, transporter function and a shift of sampling points in the individual scans. Ideally, 111In 2.8 days Inflammatory disease detection, some sort of geometric correction of individual images would neuroendocrine tumour detection, thus be desirable, but the compounding seems to work well even receptor binding studies without such correction. SPECT-CT scanner 880 Spectral broadening SPECT-CT scanner otherwise appear as a zero-frequency spike in the frequency (Nuclear Medicine) A combination of a single photon emission domain spectrum. computed tomography (SPECT) scanner and a computed tomog- Sensitivity Enhancement/Line Broadening: The time domain raphy (CT) scanner. The SPECT scanner acquires images of the in signal is multiplied by a decaying function, frequently an exponen- vivo radiotracer distribution while the CT scanner provides mor- tial, in order to weight out later data points that contribute to noise phological images. The combination of these two scanners allows but not to signal. An undesirable, but inevitable, consequence is accurate localisation of abnormalities imaged by the SPECT. that lines in the spectrum are broadened, so there is a trade-off The CT data can also be used to correct for photon attenuation between improvement in signal-to-noise and loss of resolution. in the patient’s body. Resolution Enhancement: This can be achieved either by mul- Further Reading: Wernick, M. N. and J. N. Aarsvold. 2004. tiplying the time domain signal by a rising function (e.g. a nega- Emission Tomography: The Fundamentals of PET and SPECT, tive exponential), at the cost of reduced signal-to-noise, or by zero Elsevier, London, UK, pp. 142–143. filling the data up to the next power of two. This can allow previ- ously unresolved multiplet structure to be recovered. Spectra Baseline Correction: Some baseline correction methods oper- (Magnetic Resonance) The term spectra (singular spectrum) ate on time domain data. Please refer to article Baseline correc- refers to signals that have been decomposed into components with tion for details. different frequencies, often specifically to a two-dimensional plot Frequency Domain Processing: These steps are applied in of signal intensity against frequency. the frequency domain, after Fourier transformation. In the present context, an NMR spectrum is obtained by Fourier Baseline Correction: Some baseline correction methods oper- transformation of the time-domain NMR signal (Figure .78). ate on frequency domain data. Please refer to article Baseline cor- Related Article: Magnetic resonance spectroscopy, MRS rection for details. Phasing: The delay between nuclear excitation and signal Spectral analysis acquisition allows the development of both frequency-inde- (Magnetic Resonance) This term refers to the steps that are pendent and frequency-dependent phase. These effects can be applied to analyse in vivo NMR spectra in order to yield qualita- eliminated by manual adjustment of phase, achieved while view- tive or quantitative results. ing the

spectrum at the spectrometer console, or increasingly by In vivo spectra present a number of challenges in this regard, less onerous, automated means. The latter can include correc- as compared to in vivo data. Peaks are generally broad and fre- tions derived from the unsuppressed water peak, or calculated by quently overlap: it may be impossible to resolve closely spaced numerical optimisation. peaks due to different compounds, and multiplet structure that Quantification: Measurement of the areas of the resonance is well resolved in vivo is often lost. In phosphorus (31P) spectra peaks in a spectrum may be achieved using a number of time- S in particular, there are often broad baseline features due to mem- domain and frequency-domain techniques. See article Peak areas brane phospholipids. for details. This article presents an overview of the main stages of spec- Peak areas may be converted into absolute concentrations by tral analysis. Certain key stages are described in more detail in comparison with an ‘internal standard’ (a compound within the dedicated articles. tissue of known or assumed concentration), by using an external Time Domain Processing: These steps are applied to raw data standard placed adjacent to the subject’s body or studied in a sepa- in the time domain, prior to Fourier transformation. rate experiment, or by using an external standard to determine the DC Correction: The mean value of a section of the spectrum concentration of an internal marker (often water) which can then well away from any resonance peaks is subtracted from all of itself be used as an internal standard. If separate experiments are the data points. This eliminates any offset voltage that would performed, great care is needed to ensure that parameters such as receiver gain are properly accounted for. Relaxation correc- tion, using either literature values or values measured in situ, is a requirement of absolute quantification. Related Articles: Baseline correction, Peak areas, Peak 0.8 assignment Spectral broadening 0.6 (Ultrasound) The frequency shift due to the Doppler effect is given by the Doppler equation. Clearly, if all targets (red blood cells) within the ultrasound beam have the same velocity (a situ- 0.4 ation that occurs in plug flow) and if the angle is fixed (a single value for θ) then the spectrum of the Doppler signal will be a single spectral line. Spectral broadening will occur if either the beam is wide, so that the angle subtended by the beam is not a 0.2 single value (the so-called geometrical spectral broadening), or if the distribution of velocities of the red blood cells within the beam is wide (i.e. there is a statistical blood velocity distribution 0.0 different from that of plug flow). The beam can be made narrow, ppm so the geometrical factor can be controlled. If that is done, then 4 3 2 1 spectral broadening is an indication of a broad profile of blood velocities. FIGURE S.78 Proton NMR spectrum of the human brain. Spectral display 881 Spectroradiometer Spectral broadening is associated with turbulence in arterial information of optical sources, and they measure the light output sites just distal from plaques, for instance, and this is used in (irradiance) at the different wavelengths in the spectrum. clinical practice: At the site of the plaque, the stenosis results Spectroradiometers can be single monochromators, like in the in an increased blood velocity and at sites just distal from the schematic below (Figure S.79), or double monochromators. Double plaque, spectral broadening occurs as a consequence to the dis- (or more chamber) monochromators are considered the gold stan- turbance in the flow – which might include reverse flow in cer- dard, as they are able to eliminate more of the out-of-band light, tain areas. also known as stray light, by a sequential filtering of light. The most commonly employed single monochromators are Spectral display charge-coupled device (CCD) spectroradiometers (such those (Ultrasound) See Sonogram produced by Ocean Inside, Florida https://www .oceaninsight .com/), where light diffracted by a fixed grating is focused on an Spectral matching array of CCD elements (Figure S.80). (Magnetic Resonance) This term refers to the identification of Double monochromator spectroradiometers (such as those resonance peaks in an NMR spectrum. It is a synonym for peak produced by Bentham Ltd, Reading www .bentham .co .uk/) gen- assignment. erally exploit a rotating diffraction grating or a prism to extract Related Article: Peak assignment a narrowband component around a selected central wavelength, and reconstruct a whole spectrum by mechanically changing the wavelength section at each step. Spectral width Double monochromators systems show a better rejection of (Magnetic Resonance) This term refers to the range of frequen- stray light (light outside the band measured), whilst CCDs have cies present in a spectrum. The spectral width required in a par- the advantage of being faster and more portable, and are very use- ticular experiment is determined by the range of frequencies over ful for environmental measurements. which spectral peaks are expected to occur. The NMR signal induced in the receive coil is sampled and converted by an analogue-to-digital converter. According to the Nyquist theorem, the ADC sampling rate must be at least twice the highest frequency present in the signal if aliasing is to be avoided. In order to satisfy the Nyquist theorem, the sampling rate, f, must be set so that f = 2Dw S where Δω is the spectral width. Filters are normally used to ensure that noise (and any unan- ticipated signals) outside the spectral width are not aliased back into the spectrum. Related Article: Nyquist theorem Spectroradiometer (Non-Ionising Radiation) A spectroradiometer is a light measure- ment instrument made of a combination of light separation optics and light sensors. Spectroradiometers are used to gather spectral FIGURE S.80 Picture of an Ocean Inside spectroradiometer. FIGURE S.79 Schematic of a single grating monochromator. Spectroscopic imaging 882 Speed displacement artefact Related Articles: Irradiance, Monochromator, Solar simulator In the production of x-rays from an x-ray tube the spectrum Further Reading: Matts, P. J. et al. 2010. The COLIPA in vitro will contain both a continuous and a discrete component. The dis- UVA method: a standard and reproducible measure of sunscreen crete part of the spectrum arises due to electrons having sufficient UVA protection. Int. J. Cosmet. Sci 32(1):35–46. energy to remove inner shell electrons from the atom. As a result Hyperlink: www .e esc .e uropa .eu /e n /pol icies /poli cy -ar eas /e of a gap in the inner shell, electrons from the higher energy outer nterp rise/ datab ase -s elf -a nd -co -regu latio n -ini tiati ves /1 27 shells will fill the gap and as a result the residual energy will be emitted in the form of an x-ray photon. The energy of the x-ray Spectroscopic imaging photon is dictated by the difference in energy between the two (Magnetic Resonance) See Chemical shift imaging (CSI) electron shells, and is a characteristic of the atom. The discrete spectrum is composed of spectral (or characteristic) lines and Spectrum, continuous these depend on the atomic composition of the target in the x-ray (General) A continuous spectrum is a spectrum where energy is tube into which the electrons are accelerated. produced at all possible wavelengths between certain specified An illustration of an x-ray spectrum is given on Figure S.82. The minimum and maximum values. The most common example spectrum contains both a continuous component (Bremsstrahlung of a continuous spectrum (or thermal spectrum) is blackbody production) and discrete components. radiation where the spectrum from an ideal radiator or absorber Related Article: Spectrum, continuous depends only on temperature. The continuous spectrum is also sometimes known as a thermal spectrum as hot, dense objects Specular reflection will emit electromagnetic radiation at all wavelengths. Examples (Ultrasound) Specular reflection is the reflection of ultrasound of a continuous spectrum are the Sun and a rainbow. waves from a smooth boundary in a single direction. This type Another source of a continuous spectrum, not associated with of reflection occurs when the dimensions of the boundary are heat, is x-ray production through the rapid deceleration of elec- much larger than the wavelength of the ultrasound beam. When trons (also known as bremsstrahlung or braking radiation). In an the dimensions of the boundary/scatterer are comparable to the x-ray tube electrons are accelerated by a voltage and strike a metal wavelength, sound is scattered in multiple directions and leads to target with the x-rays produced over a range in energy from zero non-specular reflections. Image formation in ultrasound imaging up to a maximum corresponding to the tube voltage. depends on specular reflections from boundaries of organs and An illustration of a continuous x-ray spectrum is given on tissues. Figure S.81. Related Articles: B-mode, Non-specular Related Articles: Spectrum, Discrete Further Readings: Bushberg, Seibert, Leidholdt and Boone. 2012. The Essential Physics of Medical Imaging, 3rd edn., Lippincott Williams and Wilkins; Kremkau, F. W. 2006. S Spectrum, discrete (General) A discrete spectrum is a spectrum where energy is only Sonography, Principles and Instruments, 8th edn., Elsevier produced at certain wavelengths which are characteristic of the Saunders. system. Familiar examples of discrete spectra are neon advertis- ing signs (filled with different fluorescent gases), coloured street Speed displacement artefact lamps and the specific colours of lasers. (Ultrasound) Speed displacement artefact is a common artefact This discrete spectrum arises due to the structure of atoms encountered in B-mode ultrasound imaging. It occurs due to the where internal energy can only be changed by certain set (dis- variability of sound in different tissues. The speed of sound in fat crete) amounts, and these discrete energies are known as quantum is about 1450 m/s, while that in soft tissue is 1540 m/s. However, states. When changing between these quantum states a certain the software assumes a speed of 1540 m/s during processing of amount of electromagnetic radiation will be emitted (known as ultrasound images. If part of the ultrasound beam encounters a a quantum), which is equal to the energy difference between the patch of fatty tissue, the returning echoes take longer to reach two states. Therefore different chemical elements within the peri- the transducer. As a result, the software interprets this as the odic table will produce different discrete spectra. Therefore it is tissue boundary posterior to the fatty patch being further away possible to identify the chemical composition of a material emit- from the transducer. Thus, the posterior boundary of the organ ting or absorbing radiation by measuring the spectrum of light is ‘displaced’ to a deeper location on the display and is seen as being emitted or absorbed. Discrete spectrum Continuous spectrum Photon energy (or wavelength) Photon energy (or wavelength) FIGURE S.82 An illustration of an x-ray spectrum containing both con- FIGURE S.81 An illustration of a continuous spectrum. tinuous and discrete components. Relative intensity of x-rays Relative intensity of x-rays SPGR 883 Spencer Attix theory a discontinuity. In the clinical image, the discontinuity at the liver boundary, shown by the yellow arrow, is an example of this artefact. FIGURE S.83 A material can be described as masses, which are con- nected to each other with springs, the springs represent the stiffness of the material and the masses represent the density. If the material is stiff the sound wave travels rapidly from one side to the other; if the material is dense then it is more resistant to movement by the sound wave. be transferred through the material. If the springs are very stiff (high k) the movement of all masses will be almost simultaneous, thus generating very high speed of sound. If the springs are weak (low k) the movement of the adjacent mass will be time shifted thus generating a lower speed of sound. A similar observation Related Articles: B-mode, Image artefact with large and small masses shows that it is easier to move small Further Reading: Bushberg, Seibert, Leidholdt and Boone. masses than large masses and that small masses will generate 2012. The Essential Physics of Medical Imaging, 3rd edn., higher speed of sound. Lippincott Williams and Wilkins. Material with high stiffness and low density gives a higher speed of sound compared to a material with low stiffness and Speed of film high density. Normally materials with high stiffness have high (Diagnostic Radiology) Speed is a term used for both photo- density, for example metal, and materials with low stiffness have

graphic and radiographic film describing the amount of exposure, low density, for example gas. However, the increase in stiffness is at least in relative values, required to produce an image. Film normally greater than the increase in density so that the speed of S sensitivity is an alternative quantity for film speed and is usually sound is higher in a metal than in a gas. Speed of sound is tem- expressed in actual exposure values. perature dependent. Generally speaking the thicker the emulsion of the x-ray film In diagnostic imaging the speed of sound is normally deter- and the larger the AgBr crystals in it, the less radiation is neces- mined as an average speed of 1540 m/s. Some examples of speed sary for producing a specific radiographic optical density on the of sound are given as follows: film. Such film is referred to as more sensitive, or with higher speed (as it will produce the image for shorter time). However, due to the larger crystals, such film will produce a courser image, that Material c (m s−1) is with lower spatial resolution. Aluminium 5100 Film speed is measured with ASA or DIN, or ISO. For exam- Fat 1430 ple, a film ASA 400 is more sensitive (with higher speed, but with Water 1480 lower resolution) than film ASA 100, etc. Air 333 Related Articles: ASA, Film type Liver 1578 Kidney 1560 Speed of sound Bone 3190–3406 (Ultrasound) A sound wave travels with a specific speed depen- dent on the density and stiffness of the medium through which it is travelling. The speed of sound, c, is given by: Related Articles: Acoustic impedance, Reflection k Spencer Attix theory c = r (Radiotherapy) The cavity theory is used to relate the radia- tion dose deposited in the sensitive volume of a detector to c = Speed of sound that in the surrounding medium. The size of the cavity is defined relative to the range of the electrons set in motion k = Stiffness in the medium. When the detector is small compared to the r = Density electron range and cavity is filled with air, Dm absorbed dose to medium, is given by Consider a material consisting of particles with mass m linked together with springs with stiffness k, Figure S.83. If the parti- W S m = æ öæ ö D Jair ç è e ÷ç ÷ cles to the left are displaced (by a transducer) this movement will øè r øm,air SPGR (spoiled gradient recalled acquisition) 884 Spin where Abbreviation: RF = Radiofrequency. Jair is the ionisation charge per unit mass of air in the cavity Related Article: Herring bone artefact (S/ρ)m,air is the ratio of the mean collision mass stopping power of material m to that of air Spin W/e is the quotient of the average energy expended to produce (Magnetic Resonance) Spin is a purely quantum mechanical an ion pair by the electronic charge form of angular momentum, arising out of the Dirac equation for relativistic quantum mechanics. The closest analogy in classical To estimate the mass stopping power ratio required in the physics is the ‘spin’ of a top. equation, it is necessary to calculate the mean collision stopping Each elementary particle, such as the electron or photon, and powers for the appropriate materials averaged over the spectrum every atomic nucleus can be associated with a spin quantum num- of all the electrons crossing the cavity taking into account the ber I, such that the magnitude of its spin angular momentum is polarisation effect and considering the effect of large discrete given by energy transfer with the production of δ-rays. Spencer and Attix theory made allowance for δ-rays by including into the so-called restricted mass collision stopping powers only energy transfers P = I(I +1) below some selected maximum Δ in the energy transfer. Electron collisions in which the energy transfer exceeds Δ are not con- The value of I is an intrinsic property of the elementary particle, sidered dissipative and these electrons are added to the elec- similar to its electric charge or rest mass. Composite particles, tron energy spectrum. The difference between unrestricted and such as the proton, are also described as having a fixed value of restricted collision mass energy stopping powers is small, less I, where this refers to the spin of the lowest energy state of the than 1%, for all materials of low atomic number for electron ener- composite particle. gies below 1 MeV but is significant at higher energies. Unlike the orbital angular momentum quantum number, which Consequently the Spencer Attix cavity theory relates the dose may only take integer values, I may also take half integer values. delivered to the gas in the ionisation chamber Dgas to the dose in This leads to the classification of two types of particle, those with the surrounding medium Dmed by the relationship integer I values, called bosons, and those with odd half-integer values, called fermions. An example of a boson is the photon, med æ L ö Dmed = Dgas ç ÷ with I = 1, while both the electron and the proton are fermions è r ø with I = 1/2. gas A particle with spin angular momentum P also has a corre- where the mass stopping power ratio (L /r)med gas is the ratio of the sponding intrinsic magnetic moment given by spectrum averaged mass collision stopping powers for the medium S to that for the gas where the averaging extends from a minimum m = gP energy Δ to the maximum electron energy in the spectrum. The fundamental assumptions of the theory are that the cavity does where γ is a particle specific quantity called the gyromagnetic not change the electron energy spectrum in the medium, all the ratio. Thus, only nuclei with non-zero spin exhibit magnetic dose in the cavity comes from electrons entering the cavity and resonance. that electrons with energy below Δ are in charged particle equi- For a particle placed in a magnetic field, this magnetic moment librium. The theory applies where charged particle equilibrium of will lead to an interaction energy (E = −μ⃗ · B ⃗) dependent on the the electrons above Δ does not exist which is generally the case projection of the spin angular momentum vector onto the mag- near an interface between media or at the edge of a beam. netic field direction. The magnetic field is usually considered to Related Articles: Bragg–Gray cavity theory, Charge particle define the z-axis, so this projection is labelled by the Pz quantum equilibrium number. The possible values of Pz are given by SPGR (spoiled gradient recalled Pz = mI acquisition in the steady state) (Magnetic Resonance) See Spoiled gradient recalled acquisition where in the steady state (SPGR) mI = I,(I -1),(I - 2),¼- I Spikes (Magnetic Resonance) Magnetic resonance images are recon- For spin 1/2 particles like the proton, there are two possible values structed from data in k-space. If one or more of the data points in for Pz : ±ħ/2. This means that there are two possible stationary k-space becomes corrupt then a spike occurs. The corrupt points states, one with a lower energy of interaction than the other (see in k-space are referred to as spikes due to the fact that corrupted Figure S.84). This leads to a preference for the spin to be aligned data points have a high signal magnitude. These spikes in the data lead to an image artefact called a herring bone artefact, where, when Fourier transformed, the spikes are convolved with the mI = + 1 image information providing a regular series of high- and low- 2 intensity stripes in one or more directions across the image. ΔE = γћB0 There are many possible sources that will lead to the corrup- mI = – 1 tion of the data. These are static discharge caused by synthetic 2 fibres near the receiver coil, mechanical stress on gradient coils, hardware, such as the RF amplifier and the gradient amplifier, FIGURE S.84 The energy of a spin-1/2 magnetic moment μ split by a failing and leaks in the shielding around the magnet. B-field as seen in quantum mechanics. Spin density 885 S pin warp imaging in the lower energy configuration, although thermal effects mean influence of T2 on the signal in Equation S.21, a low value of TE that at room temperature the difference in number between spins relative to T2, giving a low TE/T2 ratio, is chosen. The following at the two different energies is only about 1/106 spins. ‘rules of thumb’ are frequently used: Spin density (Magnetic Resonance) In MRI, spin density refers to the number PDW (PD-Weighted) T1W (T1-Weighted) T2W (T2-Weighted) of hydrogen nuclei per unit volume, precessing at the Larmor fre- TR ‘High’ ‘Low’ ‘High’ quency. The spin density (ρ0) is proportional to the magnetisation ∼2000 ms ∼500 ms ∼2000 ms along the external magnetic field (M0). TE ‘Low’ ‘Low’ ‘High’ Related Articles: Proton density ∼20 ms ∼20 ms ∼100 ms Spin echo (Magnetic Resonance) One of the most robust and frequently It must be emphasised, that the values given above are only valid used pulse sequences in MRI is the spin echo (SE) sequence, for a certain interval of relaxation times in the object and tissue introduced by Hahn long before the advent of MRI itself (Hahn with extreme relaxation times obtain signal values that depend 1950). In this sequence, two RF pulses are used (Figure S.85). significantly upon several parameters in the equation. Shaded areas in the slice and read gradient directions are refocus- The SE pulse sequence has the advantage of robustness and it ing pulses (see Pulse sequence). In the phase direction, different gives large possibilities to vary object contrast by simple changes values of the gradient are used after each repetition interval in of system parameters. However, one of the drawbacks is long order to cover k-space. acquisition times. The total acquisition time of an SE sequence The first RF pulse (90°) is used to flip the longitudinal mag- can be calculated by the formula netisation (Mz) into the transverse plane. The amplitude of the resulting transversal magnetisation Mxy is rapidly reduced by spin Tacq,SE = Nave × Nphase ×TR dephasing due to the combined effects of T2 decay and influence of magnetic field inhomogeneities. Such inhomogeneities can, where for example be caused by field variations in interfaces between Nave denotes number of execution averages tissues with different magnetic field susceptibility, by metal- Nphase denotes number of repetitions required for the different lic implants and by imperfections in the main magnetic field. In the phase encoding steps (number of k-space lines) order to reduce effects of field inhomogeneity, a second RF pulse (180°) is applied at time interval (TE/2) to reverse the order of From this formula, it can easily be seen that a PD or T2W the dephased spins. At a time interval TE the spins are refocused image with 256 phase steps and 2 averages takes over 17 min with respect to the field inhomogeneity effects and thus the ampli- to acquire. Therefore much effort has been put down to further S tude of Mxy will depend only upon T2 relaxation. After a given reduce acquisition times, for example by using fast spin echo repetition time TR, when Mz is recovering due to T1 relaxation, sequences. the sequence is repeated with a new value of the phase encoding Related Articles: Pulse sequence, RF pulse, T1, T1-weighted, gradient amplitude to obtain data of the complete k-space. T2, T2-weighted, Fast spin echo The pause created by the repetition time is normally used to Further Readings: Hahn, E. L. 1950. Spin echoes. Phys. Rev. excite slices at other positions, in order to facilitate multislice 80:580–594; Hendrick, R. E., P. D. Russ and J. H. Simon, eds. imaging. When using the SE sequence, the signal amplitude 1993. MRI: Principles and Artifacts, Raven Press, New York, depends upon three object parameters (proton density (PD), T1 pp. 64–82. and T2) and two acquisition parameters (TE and TR) and if TE ≪ TR the signal can be approximated by Equation S.21: Spin temperature (Magnetic Resonance) The spin temperature is used to charac- S ~ PD × (1 - eTR /T1 ) × e-TE /T 2 SE (S.21) terise a spin population

of the various energy states of the spin system that follows a Boltzmann distribution with this particular In standard MRI, the acquisition parameters are used to manip- temperature, that is the spin temperature is the Boltzmann tem- ulate the image contrast. For example, in order to reduce the perature that corresponds to the observed distribution of the spins. The spin temperature provides a convenient way to describe the orientational order in the spin system even when it is not in ther- RF 90° 180° mal equilibrium with the lattice. Related Articles: Boltzmann distribution, Relaxation Gslice TR Further Reading: Slichter, C. P. Principles of Magnetic Resonance, Springer-Verlag, Berlin, Heidelberg, Germany, 1990. Gphase Spin warp imaging Gread TR (Magnetic Resonance) In conventional Fourier transform imaging techniques, spatial information is encoded into the NMR signal ADC by means of frequency encoding and phase encoding, producing a two-dimensional array of data in k-space from which the image TE can be recovered by Fourier transformation. Acquisition of this array involves repetition of the pulse sequence a number of times, FIGURE S.85 An example of a spin echo pulse sequence diagram. with each repetition utilising a different displacement of the data Spine coil 886 Spin-spin relaxation acquisition trajectory along the phase encoding axis in k-space. The method of incremental displacement in almost universal use today is that known as spin warp imaging. In the original implementation of this technique, due to Kumar et al., incrementation of data acquisition along the phase encoding axis was achieved by altering the duration of the phase encoding gradient, so that in each repetition magnetisation evolved in the presence of the gradient for a different period of time and hence acquired a different phase distribution, corresponding to a dif- ferent value of k. The drawback of this technique was that the interval between excitation and signal detection varied between repetitions as well, leading to image degradation due to variations in T2 relaxation and field inhomogeneity effects. The solution, proposed by Edelstein et al. (1980) and known as spin warp imaging, was to increment the amplitude of the phase FIGURE S.87 Spine coil. encoding gradient, rather than its duration. Because the phase accumulated by magnetisation at a given location along the gradi- ent depends on the product of the gradient amplitude and dura- tion, this has the same effects as the original technique of Kumar et al. (1975) while avoiding the disadvantages (Figure S.86). Related Articles: Frequency encoding, k-space, Phase encoding Further Readings: Edelstein, W. A., J. M. S. Hutchison, G. Johnson and T. W. Redpath. 1980. Spin warp NMR imaging and applications to human whole-body imaging. Phys. Med. Biol. 25:751–756; Kumar, A., D. Welti and R. R. Ernst. 1975. NMR Fourier zeugmatography. J. Magn. Reson. 18:69–83. Spine coil (Magnetic Resonance) A spine coil is used in MRI as the dedi- cated receive RF coil for spinal imaging. The spine coil fits to or S forms part of the MRI patient table (Figures S.87 and S.88). The FIGURE S.88 Spine coil in position on patient table in MRI. patient lies supine on the coil for imaging. A spine coil is a type of surface coil, providing good SNR for structures close to the coil but a limited field view in the anterior-posterior direction but Spin-spin relaxation large field of view along the feet-head direction. (Magnetic Resonance) This term refers to the stochastic dephas- ing phenomenon whereby transverse magnetisation undergoes Spin-lattice relaxation exponential decay. Transverse magnetisation is composed of (Magnetic Resonance) When an RF excitation pulse is switched nuclei that have been put into phase coherence by a radiofre- off, nuclei start to dissipate energy to their surroundings (mainly quency (RF) pulse. via thermal mechanisms): this is spin-lattice relaxation. Spin-spin relaxation occurs when a nucleus in the higher Related Article: Relaxation energy level releases energy, thus moving to the lower energy level, and this quantum of energy is absorbed by another nucleus Spin-spin coupling which is thus promoted to the higher energy level. The two nuclei (Magnetic Resonance) Two nuclei with non-zero spin can interact have in effect ‘swapped’ energy levels, but the newly excited to cause further energy-level splitting in the presence of an exter- nucleus is out of phase with those that were excited by the initial nal magnetic field: this is spin-spin coupling. RF pulse, and as a consequence the net transverse magnetisation Related Article: Magnetic coupling is smaller. This energy-level transition does not in general occur spon- taneously, but rather is induced by time-varying electromagnetic fields. For the hydrogen nuclei (protons) in a water molecule RF (almost exclusively the target of conventional MRI), these fields Slice arise as a result of thermal motion of the molecule, mainly in the form of rotation, sweeping each hydrogen nucleus through the FE spatially inhomogeneous magnetic field generated by the other one. These are known as intramolecular dipole-dipole interac- PE tions, and fall into two categories in terms of their impact on nuclear relaxation. Signal Dynamic dipole-dipole effects relate to magnetic field varia- tion which is at the Larmor frequency of the nucleus, and there- fore induces energy-level transitions. The emitted energy may be FIGURE S.86 Two-dimensional spin echo pulse sequence using spin- absorbed by another nucleus or lost to the lattice, and so these warp imaging. effects contribute to both spin-spin and spin-lattice relaxation. Spiral (helical) interpolation 887 Spiral imaging Static dipole-dipole effects relate to magnetic field variations The freedom of molecules to move, and hence the proportion of that are slow on the NMR timescale (<100 kHz) and so gener- molecules contributing to dynamic and static dipole-dipole inter- ate quasi-static inhomogeneities that cause irreversible dephasing actions, depends on the physicochemical environment of the mol- of transverse magnetisation. These effects contribute to spin-spin ecules. The resulting difference in T2 relaxation times between relaxation only. Thus, large quasi-stationary molecules experi- water protons in different body tissues is one of the principal ence a high degree of static dephasing and have very short T2, sources of contrast in MRI. Additional dephasing due to static rendering them ‘MRI-invisible’. field inhomogeneities (see T2*) can be reversed by acquiring The gross effect of spin-spin relaxation is exponential decay of a spin echo. By varying the interval after the excitation pulse at transverse magnetisation (Mxy) at a rate determined by the spin- which the NMR signal (spin echo) is collected, one can achieve spin or transverse relaxation time, T2: different degrees of T2 weighting in the resulting image. Related Articles: Spin-lattice relaxation, T2-weighted, T2* Mxy = M0 exp( - t /T2 ) Spiral (helical) interpolation (Diagnostic Radiology) Spiral or helical interpolation is the pro- cess by which the data required to reconstruct an axial, planar image is obtained from a helical CT scan. When scanning in heli- Helical path of beam cal mode the attenuation data acquired at different angles in a rotation is non-planar (Figure S.89). It is therefore necessary to interpolate the acquired data in order to obtain a planar data set for image reconstruction. Different types of interpolation can be used. On single slice scanners, the simplest is the so-called 360° linear interpolation (Figure S.90), where attenuation data at each angular position Direction of couch movement is obtained by interpolation of the two nearest measurements, obtained at the same angular tube position, on each side of the Axial slice reconstruction plane. The measured data is weighted linearly with distance from the reconstruction point. More commonly on single FIGURE S.89 Helical path of x-ray beam around patient. slice systems, 180° linear interpolation is used. This utilises the concept of complimentary projections, where attenuation data from opposing projections (e.g. anterior-posterior and posterior- anterior are regarded as equivalent). This reduces the interpola- tion distance and results in less broadening of the slice profile. S On multislice scanners different helical interpolation approaches are used in helical scanning. For each rotation a number of data points are available for interpolation at each angle (Figure S.91a). By selecting a filter width and only using the points within this width, different slice widths can be recon- structed from a given acquired data set. A wide filter width will result in a wider reconstructed slice (Figure S.91b), whereas a nar- rower filter width will give a narrow slice (Figure S.91c) Related Articles: Helical scanning, Helical pitch, Slice pro- Measured data file, Multislice CT Recon plane Interpolated data Spiral imaging FIGURE S.90 Obtaining an axial (planar) slice from a helical data set (Diagnostic Radiology) Spiral imaging (or scanning) is also by interpolation. (Courtesy of ImPACT, UK, www .impactscan .org) known as Helical scanning – see the article Helical scanning. Filter width Filter width (a) (b) (c) FIGURE S.91 Helical interpolation on a multislice scanner with variable filter width. (a) Multiple number of data points available for interpolation at each projection angle. (b) Wide filter width selected for wide reconstructed slices. (c) Narrow filter width selected for narrow reconstructed slices. (Courtesy of ImPACT, UK, www .impactscan .org) Spoiled gradient recalled acquisition in the steady state 888 Spiral sampling Related Articles: Helical pitch, Helical interpolation, Slip Further Reading: Bernstein, M. A., K. F. King and X. J. rings, Image artefact, CT reconstruction, Slice thickness Zhou. 2004. Handbook of MRI Pulse Sequences, Elsevier, San Diego, CA. Spiral imaging (Magnetic Resonance) In MR imaging, the acquired data is col- Spiral sampling lected in the Fourier domain, or the so-called k-space. In order to (Diagnostic Radiology) Spiral sampling, or z-sampling, refers to form an image all data points in this k-space have to be obtained the sampling of data along the scan axis, or z-axis, of a CT scan- (e.g. sampled). The traditional way to collect data is to traverse ner in spiral (helical) scanning. Figure S.93 is an example on a k-space line by line on a Cartesian grid. However, it is also pos- 4-slice CT scanner. The solid lines show the central ray paths sible to collect data on other trajectories, for example by starting from the four detector rows. The dashed lines are the complemen- in the centre of k-space and collect outwards in k-space in a spiral tary data sets for each row, synthesised from the opposing pro- manner. This is done by oscillating the gradient waveforms in x- jections principle (see Spiral (helical) interpolation). By utilising and y-direction simultaneously (Figure S.92). these complementary data sets, the sampling interval may be With a spiral acquisition scheme, the effective echo time reduced and image quality improved. On multislice CT scanners becomes short since k-centre is acquired first. Spiral imaging can different z-sampling patterns arise depending on pitch employed. be used when fast collection of data is necessary, for example in For integer pitch values the complementary data overlap with the dynamic MR sequences. direct data and no improvement in z-sampling is achieved (Figure With spiral acquisitions, the data is usually resampled on a S.93a). For non-integer pitch values the distance between the data Cartesian grid and performing a fast Fourier transform subse- points is decreased (Figure S.93b), resulting in reduced helical quently. Spiral acquisitions are often sensitive to off-resonance interpolation artefacts. effects, causing blurring in the resulting MR images. Another approach to increasing z-sampling is through the use Related Article: Spiral scanning of a z-flying focal spot (Figure S.94). The use of a flying focal spot in the scan plane to improve spatial resolution has been explained elsewhere (see Flying focal spot). In a similar way, by electromag- netically switching the position of the focal spot in the z-direc- tion everytime the detectors are sampled, each detector row is z-flying focal spot d = detector width S d/2 = sampling distance z-axis kx FIGURE S.92 Readout scheme in k-space during a spiral acquisition. FIGURE S.94 Diagram showing the principle of the z-flying focal spot. The spiral readout scheme collects data along a spiral trajectory. (Courtesy of Siemens.) Rotation 1 Rotation 2 Rotation 1 Rotation 2 0° 0° 180° 180° (a) Pitch 1 (b) Pitch 0.875 FIGURE S.93 Effect of pitch on spiral sampling: example for 4-slice CT scanner. (a) Pitch 1: For integer pitch values complementary projection data overlaps with actual projection data. (b) Pitch 0.875: For non-integer pitch values improved z-sampling can be achieved. (Courtesy of ImPACT, UK, www .impactscan .org) ky Spiral scanning 889 Spot film camera double-sampled, halving the sampling distance and giving rise to manufacturer, that is SPGR (General Electric),

spoiled fast low- twice the number of ‘slices’ as there are detector rows. angle shot FLASH (Siemens) and T1 fast field echo T1-FFE Related Articles: Helical pitch, Helical interpolation, Image (Philips) and RF-spoiled field echo (Toshiba). A steady state artefact, Flying focal spot acquisition means that the longitudinal magnetisation Mz is equal in value before each excitation pulse after a sufficient number of Spiral scanning repetitions. The required number of start-up cycles to reach the (Diagnostic Radiology) Spiral CT scanning is also known as steady state depends on TR, the longitudinal relaxation time T1 Helical CT scanning – see the article Helical scanning. and applied flip angle θ. The spoiling is introduced to force trans- Related Articles: Helical pitch, Helical interpolation, Slip verse magnetisation Mxy to be equal to zero prior to the applying rings, Image artefact, CT reconstruction, Slice thickness of each new excitation pulse by applying radio frequency (RF) spoiling. That is done by linearly varying the phase of the RF Spiral scanning pulse in each cycle depending on RF pulse number n. The phase (Magnetic Resonance) During MR imaging, data is collected in φrf of RF pulse must be of the form Fourier space (often called k-space). The information in k-space is most often collected by acquiring the data in one or more rows jrf (n) = jrf (n -1) + njrf (0) n = 1,2,3,. during a repetition time (depending on pulse sequence), until all data in k-space is collected. The start phase value φ(0) is recommended by Zur et al. (1991) However, there is also a possibility to collect the data using to be 117°; this value makes the RF spoiled signal similar to the a spiral trajectory through k-space, i.e. to collect data beginning ideal incoherent (non-naturally) spoiled steady state, and is valid from the centre of k-space and spiralling outwards instead of col- for all values of T1, T2, TR, and flip angle θ of practical interest. lecting the data row by row. In this so-called spiral scanning, the Related Articles: Gradient spoiling, Steady-state traditional phase- and frequency-encoding gradients are replaced Further Readings: Bernstein, M. A., K. F. King and X. by two oscillating read-out gradients during data collection (see J. Zhou. 2004. Handbook of MRI Pulse Sequences, Elsevier Figure S.95). Academic Press, Amsterdam, the Netherlands.; Haacke, E. M., R. Spiral scanning can be used in most of the MR applications in W. Brown, M. R. Thompson and R. Venkatesan. 1999. Magnetic which fast acquisition of the data is desirable, for example in dif- Resonance Imaging. Physical Principles and Sequence Design, fusion imaging, flow imaging, and imaging of dynamic processes. Wiley-Liss (John Wiley & Sons, Inc.), New York; Zur, Y., M. L. Another advantage of spiral scanning is the more effective tra- Wood and L. J. Neuringer. 1991. Spoiling of transverse magnetiza- versal of k-space, as the inner parts of k-space can be sampled tion in steady-state sequences. Magn. Reson. Med. 21(2):251–263. denser. However, spiral scanning is sensitive to off-resonance effects, causing the resulting images to be blurred. For image Spontaneous discharge reconstruction, the obtained data is usually resampled onto a (General) Spontaneous discharge is the rapid and chaotic trans- S Cartesian grid in order to perform a fast Fourier transform for fer of electrical charge between two objects at high potentials. the final image formation. This results in a higher computational Some electronic devices are very susceptible to damage by elec- effort for the image reconstruction. trostatic discharge. Keypads, buttons, and other user interfaces Related Articles: k-space, Spiral imaging on electronic devices provide a possible vulnerable entry point Further Reading: Bernstein, M. A., King, K. F. and Zhou, X. for electrostatic charges to reach electronic device components. J. 2004. Handbook of MRI Pulse Sequences, Elsevier Academic Electrostatic discharge can occur also through a conducting path Press, San Diego, CA. between two pins of an IC. Circuits located at the inputs and out- puts of ICs can protect the internal devices from the discharge Spoiled gradient recalled acquisition events. in the steady state (SPGR) In gas-filled radiation detectors increasing the voltage higher (Magnetic Resonance) Spoiled gradient echo is a steady-state than that of the Geiger region we reach the continuous discharge sequence that goes by a variety of names depending on the region, where the spontaneous discharge occurs, which may dam- age the detector. Related Articles: Voltage limiter, Gas-filled radiation detectors Gx Spontaneous emission (Non-Ionising Radiation) Process involved in the production of a G laser beam. See Laser. y Spot film camera (Diagnostic Radiology) Spot film camera is used to take quick Gz static images from the output of an image intensifier (II). Usually the camera is connected to the II through special optics (tandem RF lenses or fibre optic) – see the article on Cinefluoroscopy. The spot camera uses either special x-ray films, which are either 100 mm cut film, or 105 mm roll film. The film exposure requires quick Data switching of the x-ray generator from fluoroscopic mode to radio- collection graphic mode of operation. This is necessary as more radiation is required for the quick exposure of the spot film. For example, a 23 FIGURE S.95 A simple gradient echo sequence with spiral acquisition. cm image intensifier would need entrance exposure of the order of Spot size 890 Spot spacing FIGURE S.97 Line profile from scintillator detector. FIGURE S.96 Two-dimensional image of a proton spot profile acquired with a scintillator detector. 75–100 μR/s. The exposed film is collected in special magazine, which is developed after the examination. The speed of spot film camera is 4–8 fps (much lower than cineradiography). Contemporary digital spot cameras use CCD sensor and record directly the digital image into memory. These systems require a different adjustment of the x-ray generator exposure in order to avoid over saturation of the camera. Related Articles: Fluoroscopy, Cinefluoroscopy, Cineangio- S graphy, Cine radiography, Spot film Further Reading: Bushberg, J. T., J. A. Seibert, E. M. Leidholdt and J. M. Boone. 2002. The Essential Physics of Medical Imaging, 2nd edn., Lippincot Williams & Wilkins, FIGURE S.98 Comparison of two different sigmas, x-axis in mm. Philadelphia, PA. Spot size points that lie at 50% of the maximum intensity, shown by the (Radiotherapy) The spot size is a property of a proton beam (in horizontal line in Figure S.97. pencil beam scanning). It can be described in several ways, but This type of measure could also be taken at, for example, generally is a way of quantifying the lateral fall-off, i.e. dose fall- 80% or 90% of the dmax and will provide information about the off perpendicular to the beam direction. lateral fall off of dose. It should be noted that the spot size may Spot sizes can be measured in air using film or with detectors differ between the x and y direction, indicating non-symmetri- such as an ion-chamber array or scintillator. The signal will be cal spots. highest at the centre of the spot and fall off quickly (see Figure Abbreviation: FWHM = Full width half maximum. S.96). If you take a profile along the central axis, represented by Related Article: Spot spacing, Pencil beam scanning the black line, a bell-shaped curve known as the spot profile (see Figure S.97) will be acquired. Spot spacing Often, these profiles are modelled using a Gaussian equation: (Radiotherapy) In order to produce a homogenous dose distribu- tion in pencil beam scanning, individual proton spots are deliv- (x-m )2 - ered at a given distance from each other. The distance between 2s 2 e each spot and the spot size will have an effect on the homogene- ity. If the spots are too far apart, the dose distribution becomes where non-uniform. If spots are placed closer together, the weighting x represents the lateral position of each spot gets smaller. Hardware will have limits on how low μ is the x-position at the middle of the curve the weight of each spot can be: below a certain limit spots are σ represents the broadness of the curve. undeliverable so the spacing must balance these two factors (see Figure S.99). Sigma therefore gives a quantitative measure of the spot size The spacing can be defined by a fixed distance between the (see Figure S.98). centre of each spot, or as a function of the spot size (e.g. 0.5 times Another method of defining spot size is by measuring the lat- the spot sigma) and can be arranged in various patterns in any eral distance between two equal intensities, for example, the full given layer, for example square or hexagonal (see Figure S.100). width half maximum (FWHM) is the distance between the two Related Article: Spot size, Pencil beam scanning Spot test 891 SPR (scatter phantom ratio) FIGURE S.99 Left hand figure: spot spacing that is too large results in a non-uniform dose profile. Right hand figure: suitable spot spacing. S FIGURE S.100 Examples of spot grid patterns. Left = square, right = hexagonal. Spot test applied to the strip and the obtained colour of the strip is com- (Nuclear Medicine) Spot test can be used to investigate the pared with a test with the reference solution. A more dense colour presence of aluminum in the 99Tcm-eluate. Aluminum cations of the test solution indicates too high amount of aluminium. are formed during the production of the 99Mo/99Tcm-generator Related Articles: TLC, Rf-value and may be found in the eluate. The aluminum breakthrough Further Readings: Kowalsky, R. J. and S. W. Falen. 2004. may interfere with the 99Tcm-labelling procedure and, for Radiopharmaceuticals in Nuclear Pharmacy and Nuclear example cause agglutination of red blood cells during the Medicine, 2nd edn., American Pharmacists Association, 99Tcm-labelling of the cells, precipitation of phosphate buf- Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear fer in colloid preparations and 99Tcm-MDP may form colloids Pharmacy, 5th edn., Springer, New York; Zolle, I., ed. 2007. with liver and spleen uptake and particles can be trapped in the Technetium-99m Pharmaceuticals – Preparation and Quality lungs as a result. Control in Nuclear Medicine, Springer, Heidelberg, Germany. The presence of aluminium can be detected using test kits consisting of a strip impregnated with a colour complexing agent SPR (scatter phantom ratio) and a reference aluminium solution. A small drop of the eluate is (Radiotherapy) See Scatter phantom ratio (SPR) Sprawls Resources 892 Spurious echoes Sprawls Resources (General) The Sprawls Resources are a comprehensive collection Line of of educational materials developed by Prof. Perry Sprawls and response provided as an open and free resource to support medical phys- Point of ics education around the world. In addition to online textbooks annihilation and modules, a major feature is the extensive collection of high- quality visuals. These are used by educators in classrooms and Detector conferences to enhance the development of highly effective con- ring ceptual visual mental knowledge structures that can support the application of physics to clinical imaging procedures. The objec- tive is to visually connect class and conference rooms to medical imaging methods and procedures where educators can lead and FIGURE S.101 Schematic representation of a spurious coincidence. direct interactive learning activities. The resources are based on the concept of collaborative teaching in which resources, espe- cially visuals, developed by some teachers are freely shared with seldom coplanar or have a 180° correlation to the annihilation pho- other teachers. The collaboration increases both the effectiveness ton, hence leading to a misplaced line of response. These events and efficiency of the learning and teaching process. can be falsely interpreted as true coincidences, that is provide false Hyperlink: www .sprawls .org /resources/ spatial information which degrades the spatial resolution. A PET system operating in 3D mode is more sensitive to spurious coinci- Spread-out Bragg peak (SOBP) dences than while running in a 2D mode. (Radiotherapy) The depth-dose distribution of high-energy x-rays One of the two annihilation photons in Figure S.101 is attenu- shows a build-up region from the surface to the depth of maxi- ated in the object while the other is detected. The dashed arrow mum dose, which results in skin sparing. Beyond the depth of represents the γ-photon direction. If the γ-photon is detected the maximum dose, the percentage depth dose decreases almost expo- line of response will be misplaced. nentially with depth. The depth-dose characteristics of protons Spurious effects can be avoided by using a narrow

energy are very different. Protons are charged particles and lose energy window because the γ-photon energy often differs from 511 keV. mainly due to inelastic Coulomb interactions with atomic elec- The energy window in PET is typically set to 300–700 keV and trons causing ionisation and excitation of atoms in the medium events of an energy outside that window are discriminated. High- until they reach the end of their range. At this point the rate of energy γ-photons (over 700 keV) can Compton scatter prior to energy loss per unit of path length or linear energy transfer (LET) detection and therefore avoid being discriminated by the energy reaches its maximum and the protons come to rest, depositing thresholds. However a narrow energy window will also result in S the highest radiation dose. This sharp radiation dose deposition is a low sensitivity. called the Bragg peak (Khan and Gibbons, 2014). Related Articles: Dirty radionuclides, PET The sharp Bragg peak of a mono-energetic proton beam is called the pristine peak. However, the high radiation dose region Spurious echoes of a pristine Bragg peak is too narrowly-spread in depth to treat (Magnetic Resonance) The term ‘echo’ in MRI refers to a signal a tumour, which can extend several cm in depth. In practice, the that has been delayed (or recalled) in order to allow time for addi- dose distribution is spread out by using a combination of mono- tional pulse sequence elements prior to data acquisition, and/or energetic proton beams. The resulting total dose distribution has to introduce signal weighting. Echoes may be obtained by using a spread-out Bragg-peak (SOBP), which is more suitable for the RF pulses to flip magnetisation that is dephasing because of static treatment of most tumours, offering better coverage (Boyer et al., field inhomogeneity to the opposite side of the transverse plane (a 2002). The SOBP can be achieved by using a range modulation spin echo, usually obtained using a 90° and 180° pulse combina- system in the treatment head or nozzle that combines pristine tion). Alternatively, signal may be deliberately dephased using a peaks of different energies and ranges. switched gradient, the effect of which is reversed by a gradient Beyond the SOBP, the depth dose distribution drops off of opposite polarity at the desired later point in time (a gradient sharply to zero, although with a slight reduction in slope. This is echo). due to energy loss straggling of the particles approaching the end In addition to intentional generation of spin and gradient of their range (Khan and Gibbons, 2014). echoes, the extensive use that is made of RF pulses and switched Related Articles: Bragg peak spreading, Beam modulation, gradients in MRI pulse sequences means that echoes may some- Modulation wheel, Range modulation times be generated unintentionally due to inopportune combi- Further Readings: Boyer, A. L., M. Goitein, A. J. Lomax and nations of gradients or RF pulses. For example, a train of any E. S. Pedron. 2002. Radiation in the treatment of cancer. Phys. three RF pulses with flip angles other than 180° will generate a Today 55(9):34–36; Khan, F. M., and J.P. Gibbons. 2014. Khan’s type of spin echo known as a stimulated echo. An MRI experi- the Physics of Radiation Therapy, 5th edn., Wolters Kluwer ment consisting of repetitive application of a sequence containing Health. several RF pulses will therefore unintentionally generate many stimulated echoes as well as the intended signal. Similarly, the Spurious coincidence cumulative effect of a train of gradient pulses will in general lead (Nuclear Medicine) This refers to the coincidence between either to inadvertent rephasing of magnetisation, generating unwanted a γ-photon and an annihilation photon or two γ-photons. Spurious gradient echoes. coincidences occur when imaging radionuclides which emit both These unintentional echoes may collectively be termed spuri- positrons and high energy prompt cascade γ-rays. Such radionu- ous echoes. The phenomenon can become problematic if spuri- clides are referred to as dirty radionuclides. These γ-photons are ous echoes, which may not have experienced the same history of Square wave oscillation 893 Stabiliser spatial encoding as the intended signal and may have different Stabilisation contrast properties, fall within the data acquisition window and (General) In radiology this term refers to the process of stabilising hence contribute to the acquired image. For example, stimulated or regulating the output of a power supply which can be subjected echoes can give rise to inverted ghosts overlying the main image. to changes in both input supply voltage and output power demand. Elimination of spurious echoes and the resulting artefacts In order to provide proper regulation of the output of x-ray requires careful pulse sequence design, particularly in terms of generators and other high-power electrical devices, it is necessary the phase encoding gradients since magnetisation retains memory to stabilise the mains power supply to these devices. of previous phase encoding episodes while stored along the lon- Two techniques are used – the constant voltage transformer gitudinal axis and this may later contribute to stimulated echo (CVT) and the automatic voltage stabiliser (AVS). Both are based artefacts. Spoiler gradients may also need to be added to elimi- around the use of a power transformer, and so are usually bulky nate unwanted coherences, as is done routinely in the STEAM devices. sequence. The constant voltage transformer has a special ferromagnetic Related Articles: Gradient echo (GE), Spin echo, Spoiling, core which when operating normally is fully ‘saturated’ each half STEAM (stimulated echo acquisition mode), Stimulated echo cycle by the induced field of the primary or input winding. Thus the output winding receives a magnetic field of constant maxi- Square wave oscillation mum value independent of the input supply and therefore provides (General) See Saw-tooth voltage an output as though from an unfluctuating source. This type of transformer is good at absorbing large input voltage spikes, but is Sr-89-strontium chloride [Metastron™] not as efficient as the AVS. (Nuclear Medicine) Strontium-89 chloride, commonly known as The automatic voltage stabiliser is a variable (auto) transformer Metastron™ (GE Healthcare) is a bone-seeking radiopharmaceuti- controlled electronically or electromechanically to maintain a cal used for pain palliation and is considered a clinically effec- constant output voltage. The transformer output is converted to tive and cost-effective treatment in patients with advanced cancer a DC value and compared to a preset reference voltage. When metastatic to bone. Patients can often obtain pain relief for up to the output sags or rises due to a line or load change, the number 6 months after a single injection of 89Sr-chloride, resulting in a of turns in one transformer winding is altered to compensate – significant improvement in quality of life. either by a motor-driven contactor or by electronic semiconductor 89Sr is a beta-emitter with maximum beta energy of 1495 keV switching. This is a much more power efficient technique but may and a maximum range of the beta particles in tissue of 8 mm. The not be able to react instantaneously to changes, and will not be half-life of 89Sr is 50.53 days. The 89Sr-chloride activity recom- able to absorb large input voltage spikes. mended for therapy of bone pain is 1.5–2.22 MBq kg−1 with mean Related Articles: Stabilisation, Variable transformer activity of 150 MBq given intravenously. After an IV injection of 89Sr-SrCl2 it localises in reactive bone Stabilised amorphous selenium (a-Se) S and 80% is excreted in the urine and 20% in feces with a biologi- (Diagnostic Radiology) Selenium (Se) is a non-metal chemical cal half-life of 4–5 days. It is assumed that approximately 30–35% element with an atomic number (Z) of 34. Stabilised amorphous of the administered activity retains in normal bone for 10–14 selenium (stabilised a-Se) is the most widely used photocon- days. However, it has been reported that the retention could be as ductor in medical imaging. Amorphous selenium is stabilised high as 85%–90% in osteoblastic areas 3 months after injection. by alloying it with 0.2%–0.5% arsenic (As) and doping with Initial pain relief may be noticed already after 3–5 days, and the chlorine (Cl) in 10–20 ppm range. The arsenic is introduced to mean duration is of the order of 3–6 months. prevent the structure from re-crystallising while the Cl com- The mean absorbed dose to vertebral metastasis from an pensates for the hole traps introduced by the As. The amor- IV injection of 89Sr-chloride has as an average value been esti- phous nature of selenium is advantageous in the manufacture mated to be 230 mGy MBq−1 (interval 60–610 mGy MBq−1). The of flat panel detectors as it can be easily deposited on a suit- absorbed dose is 17 mGy MBq−1 to bone surfaces and 11 mGy able substrate by conventional vacuum deposition techniques MBq−1 to the red bone marrow. Other organs receive less than 5 to form large area photoconductive film of thicknesses up to mGy MBq−1. The effective dose for 89Sr-chloride is approximately 1000 μm. 2.9 mSv MBq−1. Related Articles: Amorphous selenium, a-Se photoconductive Related Articles: Sm-153-EDTMP [Lexidrom], Rhenium- layer, Selenium detector, TFT (thin-film technology). 186-hydroxyethylidene diphosphonate Further Readings: Belev, G. and S. O. Kasap. 2004. Further Readings: Annals of the ICRP. 1992. Amorphous selenium as an x-ray photoconductor. J. Noncryst. Radiological Protection in Biomedical Research. Addendum Solids 345: 484–488; Kasap, S. O., C. Haugen, M. Nesdoly and J. 1 to ICRP Publication 53. Radiation Dose to Patients from A. Rowlands. 2000. Properties of a-Se for use in flat panel x-ray Radiopharmaceuticals, Vol. 22, ICRP Publication 62, image detectors, J. Noncryst. Solids 266–269(Part 2):1163–1167; Pergamon Press, Oxford, UK; Firestone, R. B. 1999. Table of Kasap, S. O., M. Z. Kabir and J. A. Rowlands. 2006. Recent Isotopes, 8th edn., Update with CD-ROM. http://ie .lbl .gov /toi advances in x-ray photoconductors for direct conversion x-ray .html (Accessed date 18 July 2012); Kowalsky, R. J. and S. W. image detectors. Curr. Appl. Phys. 6:288–292; Rowlands, J. A. Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and and J. Yorkston. 2000. Flat panel detectors for digital radiog- Nuclear Medicine, 2nd edn., American Pharmacists Association, raphy, Handbook of Medical Imaging, Volume 1. Physics and Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear Psychophysics, eds., J. Beutel, H. L. Kundel and R. L. van Metter, Pharmacy, 5th edn., Springer, New York. SPIE Press, Washington, DC, pp. 223–313. SSFP Stabiliser (Magnetic Resonance) See Steady state free precession (SSFP) (General) See Stabilisation Stable nuclei 894 Standards Stable nuclei regulatory or competent authorities so that the design and proposed (General) Stable nuclei are nuclei that require the addition of practices can be considered to be ‘approved’ by the authorities. energy to transform them into other nuclei. Stable nuclei do not All groups affected by the proposal to implement such prac- spontaneously decay and can only be transformed by being bom- tices involving potential exposure to ionising radiation (the staff, barded by particles or photons under specific conditions. All the patients, the public and the regulatory or competent authori- radioactive decay processes eventually result in a stable nuclide, ties) may be called ‘stakeholders’ and the process of allowing although there may be a number of intermediate radionuclides. dialogue and consultation with these groups towards the imple- Stable nuclides with low mass (apart from hydrogen) have sim- mentation of the practices is termed ‘stakeholder involvement’ (or ilar number of neutrons and protons but with increasing atomic ‘stakeholder engagement’). number there is an increasing excess of neutrons over neutrons Related Articles: Radiation protection ethics, Justification, and the ‘line of nuclear stability’ deviates from the N = Z line Optimisation, Regulatory or competent authority (Figure S.102). The reason for this lies in the characteristics of the nuclear force and the electrostatic repulsion between protons. Standard man The nuclear force has a very short range, less than that of a large (Radiation Protection) ‘Standard man’ was originally presented nucleus, so additional neutrons are required in large nuclei to in 1949 at the Chalk River Conference on Permissible Dose. In overcome the electrostatic repulsion between the protons. 1963 the International Commission on Radiological Protection A nuclide which does not have a stable combination of neu- (ICRP) requested the revision and extension of standard man and trons and protons (nucleons) transforms spontaneously into a recommended that the name be changed to ‘reference man’. stable (or more stable) nuclide through the process of radioactive The need to establish a reference man arose due to a require- decay.

ment to Related Articles: Nuclear force, Nuclear instability, Nucleons, Nuclide, Radioactive decay a. Represent a typical radiation worker b. Indicate some of the factors such as age and sex on Stakeholder involvement (or Stakeholder engagement) which estimating dose to individuals depends (Radiation Protection) Whenever there is a proposal to build a facility and/or to implement new practices involving the use of The full specification of reference man is given in ICRP a source of ionising radiation, such as in diagnostic radiology, Publication 23, Report of the Task Group on Reference Man nuclear medicine or radiotherapy departments, decisions will have (ICRP 1974). Many characteristics are defined in this publication to be made on the justification of the use of radiation, and on the including weight, length and surface area of the whole body for radiation protection design of the facility and implementation of males and females of different ages. the practices that have a consequential impact on staff, patients S Related Article: International Commission on Radiation and the public to ensure any doses received are minimised (opti- Protection mised). Such decisions have a potential ethical dimension and Further Reading: ICRP (International Commission on should always be made in an open manner to ensure transparency Radiological Protection). 1974. Report of the task group on refer- and inclusiveness with those persons potentially affected. It is ence manual, ICRP Publication No. 23, Ottawa, Ontario, Canada. also important to ensure that there has been a dialogue with the Standards (General) A standard is a norm, model or a type that specifies the normal (standard) condition or properties of a specific product, process or service. Standards are usually published as formal tech- 120 nical documents with international validity and are compiled by a committee of experts of a regulatory body or a corporation. Geographically, there are three levels of standards: interna- 100 tional, regional and national. International standards, which are valid worldwide and can 80 be adopted by any country, are compiled by international stan- dards organisations (e.g. the International Organization for Standardization [ISO] and the International Electrotechnical 60 Commission) with contributions from all the country members of such organisations. Regional standards, which are applied at a regional level (e.g. 40 within Europe), are compiled by appropriate bodies (e.g. the European Committee for Standardization [CEN] in Europe, the African Organisation for Standardisation [ARSO] or the Arabic 20 Industrial Development and Mining Organization [AIDMO]). National standards, which are applied at a national level (e.g. within the UK), are compiled by a single recognised national stan- dards body (e.g. the British Standards Institution [BSI] or Ente 20 40 60 80 Nazionale Italiano di Unificazione [UNI]) that is the only mem- Number of protons (Z) ber from that country in ISO. The technical content of national standards is usually compiled by national technical societies. FIGURE S.102 Schematic diagram showing the relative number of pro- Sometimes international standards can also be adopted at a tons and neutrons of stable nuclides. regional and national level, bypassing the respective regional and Number of neutrons (Z) Standard uptake value (SUV) 895 S tarling equation national standards, which, however, should be prepared based on Standing wave the ISO/IEC Directives (Part 2) to foster universality and world- (Radiotherapy) See Wave guide wide uniformity. Regarding medical devices, different standards should be Stannous chloride (Sn2+Cl2) taken into account and met while designing medical devices (Nuclear Medicine) Stannous chloride, Sn2+ Cl2, is the preferred according to their type, intended use and risk. reducing agent for 99Tcm–radiopharmaceuticals that need to be The standards taken into account during medical device labelled by a simple procedure shortly before use. The 99Tcm– design include: pertechnetate ion (No99TcmO- 4) is in the oxidation state +VII and must be reduced to +I, +III, +IV or +V in order to give 99Tcm–com- • ISO 14630: Non-active surgical implants plexes with high labelling efficiency, shelf-life and purity. • IEC 60601: Medical electrical equipment and systems Prefabricated 99Tcm–kits offering labelling in isotonic solu- • EN 62304: Medical device – Software life cycle tions simply by adding pertechnetate in the evacuated vial. processes Stannous salts are reliable reducing agent used in all kit for- • EN 80001: Application of risk management for IT net- mations. SnCl is nontoxic and stable during lyophilisation (i.e. works incorporating medical devices freeze drying). • ISO 14708: Implants for surgery – Active implantable Tin forms compounds in the oxidation states +II and +IV. The medical devices Tc-chemistry is difficult and not known in detail, but the first step • EN ISO 11607: Packaging for terminally sterilized is the reduction of Tc to (+V) from Tc (+VII), followed by two suc- medical devices cessive complementary reactions: • EN ISO 11135: Sterilization of health-care products – Ethylene oxide – Requirements for the development, Tc(VII) + Sn(II) ® Tc(V) + Sn(IV) validation and routine control of a sterilization process Tc(V) + Sn(II) ® Tc(III) + Sn(IV) for medical devices • ISO 11137: Sterilization of health-care products – Radiation The reduced technetium is chemical reactive and can be labelled • ISO 17665: Sterilization of health-care products – to different chemical molecules, for example chelates: Moist heat Reduced 99Tcm + chelating substance ↔ 99Tcm − chelate. • ISO 20857: Sterilization of health-care products – Dry Although Sn is the reducing agent of choice there are some heat problems. The chemistry of stannous compounds is complex and • ISO 10993-1: Biological evaluation of medical devices the Sn is difficult to purify. Thus, the labelled product contains • ISO 22442-1: Medical devices utilizing animal tissues Sn(IV). Sn is easily oxidised to Sn(IV) by the oxygen in air. The and their derivatives shelf-life of the preparation is dependent on the Sn concentration. The amount of Sn2+ is optimised for each pre-fabricated Tc-kit, S • EN ISO 13485: Medical devices – Quality management systems in order to maintain that the amount is large enough to ensure • EN ISO 14971: Risk management for medical devices reduction of both 99Tcm and its daughter 99Tc, and conversely to be • IEC 62366-1: Medical devices low enough in order to avoid further reduction of the TcmO4 to a lower oxidation state. The SnCl amount in a pre-fabricated 99Tcm • EN ISO 15223-1 – ISO 15223-1:2016: Medical devices – Symbols to be used with medical device labels, label- kit ranges from 0.76 to 500 μg, corresponding to a Sn/Tc–ratio ling and information to be supplied 103–105. Since oxygen for most of the 99Tcm radiopharmaceutical kits Regarding medical locations, there are standards that regulate may oxidise the Sn ions, an air-valve cannula should not be used them, but they depend on the national level. For example, in the during the labelling. UK there are the health building notes which contain best practice Related Article: Tc-99m – sodium pertechnetate guidance for designing and planning new healthcare buildings or Further Readings: Kowalsky, R. J. and S. W. Falen. 2004. adapting existing facilities (e.g. the recommended standard size Radiopharmaceuticals in Nuclear Pharmacy and Nuclear for all in-patient operating theatres is of 55 m2). Medicine, 2nd edn., American Pharmacists Association, Related Articles: Medical device, Medical equipment man- Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear agement, Specifications of a medical device Pharmacy, 5th edn., Springer, New York; Zolle, I., ed. 2007. Further Readings: Technical Standard. 2019. Wikipedia, Technetium-99m Pharmaceuticals – Preparation and Quality Wikimedia Foundation, en .wi kiped ia .or g /wik i /Tec hnica l _sta Control in Nuclear Medicine, Springer, Heidelberg, Germany. ndard ; Regional or National Adoption of International Standards and Other International Deliverables. 2005. ISO, International Star pattern Organization for Standardization; Almir, B. and L. G. Pokvić. (Diagnostic Radiology) The star pattern is a test device used to 2020. Legal metrology framework for medical devices. Clinical determine the effective size of an x-ray tube focal spot. It consists Engineering Handbook. Academic Press. of a star-shaped pattern as illustrated below. When a magnified x-ray image is formed the amount of blurring produced by the Standard uptake value (SUV) focal spot can be measured. This is then used to calculate the (Nuclear Medicine) The standard uptake value (SUV) is the ratio focal spot size as illustrated in Figure S.103. of the radionuclide concentration in the volume of interest to the mean radionuclide concentration throughout the body. Starling equation (Nuclear Medicine) The Starling equation relates the net fluid flux Standby position (due to filtration), Jv, across the capillary wall to the net driving (Diagnostic Radiology) See Parking position pressure and reads as follows: Starter 896 Static field In some materials separation of charges can be generated also by mechanical pressure (piezoelectric materials) or by heating (pyroelectric materials). Image (magnified) The feeling of a static electric shock is caused by the stimula- Effective tion of nerves as the electrostatic discharge current flows through blur size the human body. Usually the accumulated charge is generally not enough to cause a hazardously high current. The spark associ- ated with static electricity is caused by electrostatic discharge as excess charge is neutralised by a flow of charges from or to the F surroundings. Star Despite the apparently harmless nature of static electricity as test pattern Blur pattern we generally experience it, there can be significant risks where Dimension Calculate large charges may accumulate in the presence of sensitive materi- als or devices. FIGURE S.103 The steps in using a star test pattern to determine the Related Articles: Spontaneous discharge, Voltage limiter effective size of a focal spot. (Courtesy of Sprawls Foundation, www Further Reading: http://en .wikipedia .org /wiki /Static .sprawls .org) electricity Static field J (Magnetic Resonance) v = K f (éëPc - Pi ùû-séëpc - pi ùû) Introduction: Magnetic resonance imaging makes use of three types of magnetic field: a static field, a pulsed field vary- In the equation, Kf is the filtration coefficient (constant of propor- ing linearly in space (the imaging gradients) and a radiofrequency tionality) and is the product of the capillary hydraulic conduc- (RF) field. Of these, the static field is the most conspicuous, and tance and the capillary surface area. Pc and Pi are the hydrostatic arguably of overriding importance in determining the quality pressure in the capillary and interstitial space, respectively. πc and π of images obtained and the range of techniques that can be per- i are the colloid osmotic pressure in the capillary and interstitial formed on a given MR imaging system. It is also the most prob- space. The capillary wall is fairly, but not totally, impermeable to lematic from a safety perspective. large molecular weight proteins. σ is a reflection coefficient, and The purpose of the static magnetic field is to cause magnetic is used to correct for this effect. nuclei in the imaged object to align with a component of their angular momentum either parallel or antiparallel to the field S Starter direction, corresponding to two different energy levels and hence (Diagnostic Radiology) See Starting device endowing the object as a whole with a small net longitudinal mag- netisation because of the difference in population of these two Starting device levels determined by the Boltzmann distribution. Because the net (Diagnostic Radiology) This device (anode starting device) sup- magnetisation is proportional to the strength of the static field, plies the stator of the induction electrical motor of a rotating and because it is this magnetisation that determines the amount of anode x-ray tube. Its prime role is to accelerate it to reach quickly signal available for image formation and hence is the limiting fac- the necessary revolutions per minute (rpm) for particular x-ray tor for image resolution in space and time, much effort has been exposure. Usually this device uses initially triple frequency to expended in the development of whole-body MRI devices with quickly rotate the anode, and after this switches to its normal fre- ever-increasing static field strengths. This requirement, in turn, quency for the exposure. has been a major driver in the development of superconducting Related Articles: Anode, Rotation anode, Anode rotation magnet technology. speed, Anode acceleration, Medium frequency generator, High- Historical Aspects: Early MRI researchers made use of resis- frequency generator. tive electromagnets with field strengths of up to about 0.15 T. At higher field strengths, these magnets required water cooling Static electricity to dissipate heat generated by the considerable electrical cur- (General) Static electricity refers to the accumulating of electric rents flowing through the magnet windings.

The development of charges on the surfaces of objects. The static charges remain on whole body superconducting magnets in the mid-1980s allowed an object until they either bleed off to ground or are rapidly neu- construction of scanners with static field strengths of up to 1.5 T tralised by an electrostatic discharge. or more, without resistive heating. However, these systems intro- The phenomenon of static electricity requires a separation of duced the new problem of fringe fields extending to a considerable positive and negative charges of the contacting objects. Electrons distance from the magnet with concomitant difficulties in siting can be exchanged between materials on contact: materials with (either because of the field itself or the tonnes of steel shielding weakly bound electrons tend to lose them, while materials with required to contain it). Introduction of active shielding did much sparsely filled outer shells tend to gain them. This is known as the to alleviate this situation, but arguably has exacerbated the safety triboelectric effect and results in one material becoming positively problems around static fields, in that it introduces a very steep charged and the other negatively charged. Separation of charge static field gradient close to the scanner with little prior warning. within the conductor can occur when a charged object is brought The Market Today: Today, whole body superconducting into the vicinity of an electrically neutral object. Charges of the magnets (usually based on niobium-titanium (NbTi) wire) are in same polarity are repelled and charges of the opposite polarity are use with field strengths of up to 9.4 T, with yet higher field sys- attracted. tems under rapid development. Scanners at 7 T are becoming an Stationary anode 897 Stationary anode established feature of major MRI research centres, while 3 T is almost commonplace. Ultrahigh field machines have undoubted benefits in areas such as functional MRI and perfusion imaging, as well as opening up new contrast mechanisms for exploitation. However, these benefits are offset by a worsening of problems such as magnetic field inhomogeneity, susceptibility artefacts, RF penetration and specific absorption rate (SAR). There is certainly still a place in the market for lower field scanners, today usually based around permanent magnets, which have lower operating costs than resistive electromagnets. This is particularly so for open architecture scanners, which are better suited to obese and paediatric patient populations and for many types of interventional MRI. Performance Specification: The most important performance parameter related to the static field, apart from the field strength itself, is the uniformity of the field. This determines the useful field of view (FOV) of the scanner, and is often specified in terms of the field variation (in ppm) over a spherical volume of a specific diameter (DSV) at the scanner isocentre. For example, a modern 1.5 T superconducting system might have field homogeneity of 0.2–0.4 ppm over a 40 cm DSV, while for a lower field open sys- tem this might be 2–4 ppm over a 20 cm DSV. From a practical point of view, the extent of the fringe field will have a major impact on ease of siting and operation, and FIGURE S.104 X-ray tube with stationary anode (dental x-ray tube). potentially on interference with other activities in the vicinity. (Courtesy of EMERALD project, www .emerald2 .eu) The 0.5 mT isocontour is often taken to define the extent of the fringe field for safety purposes. However, it is important to recog- nise that some devices, such as PET scanners, may be affected at significantly lower field strengths. Safety Aspects: The static field presents the greatest safety 2 challenge in MRI, since ferromagnetic objects brought close to 1 the magnet are subject to considerable force and torque and can be S turned into high-speed projectiles. Death and serious injury have resulted from accidents of this sort. There is also a risk that the field may cause malfunction of implanted active medical devices (IAMDs) or injury due to the force exerted on IAMDs or ferrous foreign bodies such as shrapnel. Most safety precautions in place in MRI units are designed to ameliorate this hazard. In terms of direct biological effects, the phenomenon most 4 3 frequently reported is vertigo and related symptoms when mov- ing the head in a strong static field, usually 3 T or above. These transient effects are increasingly well understood. Measurable changes in blood pressure have occasionally been reported, prob- ably related to induction of electrical potentials due to movement FIGURE S.105 X-ray tube with static anode (low power): (1) Anode of charged ions in blood through the magnetic field. These are stem; (2) Electron capture hood; (3) Beryllium window over the anode; physiologically negligible at least up to 8 T. (4) Metalisation of the glass envelope. (Courtesy of EMERALD -project, Related Articles: Boltzmann distribution, Longitudinal mag- www .emerald2 .eu) netisation, Magnet, Magnet(s) superconducting, Nuclear mag- netic resonance (NMR), Tesla scattered backwards from the target, enter again the accelerat- Stationary anode ing field and fall again to the anode, but this time outside their (Diagnostic Radiology) X-ray tubes with stationary anode are used original target place. This creates extrafocal radiation (generated for low power (usually up to 2 kW) x-ray equipment – for example outside the focal spot), also called off-focus radiation or stem some small mobile and dental x-ray equipment (Figure S.104). radiation. This off-focus radiation effectively enlarges the focal The simplest construction of stationary anode is large copper spot and leads to blurred image. The scattered electrons can also stem with a small tungsten plate (2–3 mm thick) embedded at its hit the glass, which can not only metalise it but even rupture it target side (exactly opposite the cathode). The thermal conductiv- and affect the vacuum in it. A metal ‘electron-capture’ hood is ity of the copper is sufficient to remove the heat from the target placed over the anode in order to retain these electrons. The anode to the surrounding space. For tubes used for frequent exposures hood is made of copper with an opening at the side of the cathode. the copper end of the anode can be cooled with non-conducting At the path of the useful radiation the copper is replaced with mineral oil (see the article Anode). Beryllium plate which can pass the x-rays with minimal absorp- Some undesirable effects happen during the bombardment of tion (Z = 4 for Be). Beryllium ‘window’ is widely used in many the anode. First, some of the bombarding electrons are elastically contemporary x-ray tubes (Figure S.105). Stationary grid 898 Steady state condition in tracer kinetic modelling Because historically the first x-ray tubes had stationary anode Stationary grid we can use them for easier explanation of the line focus prin- (Diagnostic Radiology) A stationary grid is not moved (as in a ciple. In the early x-ray tubes the angle between the target plate Bucky device) during an x-ray exposure. Often it leaves over the and the electron beam was 45°. In 1918 German scientist Goetze film undesired image of the grid strips/lines. patented a tube with much smaller anode angle α, thus increasing Related Articles: Grid, Bucky the area bombarded by the electrons – the actual focus AF (or the thermal focus, Ft, also called actual focus Fa) and decreasing the Stator size of the effective focus EF (Fe, also called optical focus). This (Diagnostic Radiology) The x-ray tubes with rotating anode use allowed increasing of x-ray tube power (due to increasing the an induction electrical motor. The copper rotor of this motor is anode heat capacity) and increasing the sharpness of x-ray image inside the glass envelope of the tube and rotates the anode disk. (the smaller optical focus acts as smaller point source of ‘light’). The stator consists of a number of electromagnets (solenoids) In fact this new design affected the length of the actual focus placed outside the glass envelope. These are switched on and (proportional to the length of the filament spiral coil) while the off in a rapid sequence, thus creating a rotating electromagnetic width of the actual focus (equal to the width of the filament spiral field, which drags the rotor to turn in the same direction. The coil) remained unchanged. Due to this reason the principle for mechanical speed of rotation of the rotor (rpm) can never reach enlarging the area of the actual focus, while keeping the effective the speed of magnetic field change in the stator (due to mechani- focus small is called the line focus principle (or Goetze prin- cal slipping). All control of acceleration, speed of anode rotation ciple). From Figure S.106 one can see that the relation between and deceleration (stopping) of a rotating anode is done through the actual focus and the effective focus depends on the sine of variation of the stator electrical supply. See the model of a stator the anode angle: in the article Rotating anode. Related Articles: Anode, Rotation anode, Anode rotation Fe = sinaFa speed, Starting device, Bearing Further Reading: Thompson, M., M. Hattaway, D. Hall and There are two stationary anodes on Figure S.106 – with anode S. Dowd. 1994. Principles of Imaging Science and Protection, angle α of 20° (Figure S.106a) and with 10° anode (Figure S.106b). W.B. Saunders Company, Orlando, FL. On the diagram, a is the projection of the cathode filament over the anode target. It is obvious that the size of Fa corresponds to Steady state the width of the filament spiral coil. Both x-ray tubes have similar (Magnetic Resonance) The term steady state is generally used to effective focus (Fe) but the tube with smaller anode angle (Figure describe a situation where a given property of a system does not S.106b) has larger actual focus (Fa) and this way the heat is dis- change over time. In MRI, steady state typically refers to a period tributed over larger area of the target. of time during which the magnetisation is stable. For example, S The anode angle of most contemporary diagnostic x-ray tubes longitudinal steady state requires that the longitudinal magnetisa- varies between 10° and 20° and for the therapeutic x-ray tubes it is tion is unchanging over time while a transverse steady-state con- still 45°. The increase of the thermal focus allows better heat dis- dition implies that the transverse magnetisation attains a non-zero tribution over the anode target, but the need for further increase steady state. In practice, the term steady state is typically used in x-ray tube power led to the development of the x-ray tubes with for the case when the transverse magnetisation at each radiofre- rotating anode. quency (RF) pulse in a sequence, or at a given time after it, is the Related Articles: Anode, Rotating anode, Target same as at the corresponding point at, or after, the next RF pulse Hyperlink: EMERALD (DR module), www .emerald2 .eu in the sequence. Related Articles: CISS constructive interference in the steady state, Dual echo steady state (DESS), Fast imaging with steady state precession (FISP), Spoiled gradient recalled acquisition in the steady state (SPGR), SSFP steady state free precession 10° Steady state condition in tracer kinetic modelling (Nuclear Medicine) A steady state system refers to a system in Fe Fe which a process, parameter or variable is not changing with time. A biochemical flux is said to be in a steady state when the con- centrations of reactants and products are steady over time. Such a system seldom exists because different systems have different biorhythms, for example the vascular system flux varies with heartbeats. However if the experimental sampling rate is slow in Ft comparison to the biorhythm, for example the sample is collected Ft over a series of heartbeats, the sample represents the mean flux of blood, and thus the steady state assumption is valid. In an oppo- site situation where the experiment sample rate is faster than the biorhythm the sample seldom represents a steady state condition. (a) (b) It is important not to confuse the steady state of a process with the steady state of a tracer. Measurements are often made while FIGURE S.106 Effective focus (Fe) and actual focus (Ft or Fa) for two the tracer is distributing within the process under study. Tracer x-ray tubes with stationary anode (a) anode angle of 20°; (b) 10° anode kinetic models that measure the desired function while both

the angle. The size of Fa corresponds to the size (length and width) of the tracer and process are in a steady state are usually referred to as filament spiral coil. equilibrium models. a Steady state free precession (SSFP) 899 Stepping motor Related Articles: Analogue tracer, Distribution volume, Steel Partition coefficient (General) Further Reading: Cherry, S. R., J. A. Sorenson, M. E. Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, Molar mass ∼0.056 kg mol−1 Philadelphia, PA, pp. 383–384. Density at STP 7000–8200 kg m−3 Melting point 1500–1800 K Steady state free precession (SSFP) Boiling point 3000–3500 K (Magnetic Resonance) Steady state free precession refers to the use of steady state gradient echo sequences (GRE) using short Tensile strength 200–2000 MPa repetition and short echo times. Due to the rapid repetition of excitation pulses, the intensity of the MR-signal (the amplitude of the magnetisation vector) will initially fluctuate before eventually Steel is an alloy consisting predominantly of iron with 0.2%– reaching a steady state in the longitudinal direction. For the very 2.14% carbon and other elements including chromium, manga- short repetition times even the T2*-decay is not complete at the nese and tungsten. The purpose of the alloying elements is to end of each sequence repetition (i.e. at the next excitation pulse) improve the properties of steel, such as tensile strength and hard- and there remains a residual component of the transversal magne- ness, by preventing the movement of dislocations in the crystal tisation vector before the next excitation. Part of this transversal lattice. However, as hardness increases the steel becomes more component will be refocused by the next excitation rf-pulse. The brittle and so a compromise is made. overall transversal magnetisation is the sum of different trans- Steel is classified by a number of grades defined by standards versal magnetisation components, which can cause coherently or organisations. There are several types of steel, such as carbon destructively interferences Therefore steady state gradient echo steel, stainless steel (includes chromium to increase corrosion sequences are divided into two groups; steady state incoherent resistance) and maraging steel (includes nickel making it mallea- (SSI) sequences, where the remaining transverse magnetisation is ble). Iron alloys have various phases, such as austenite, cementite spoiled, and steady state coherent (SSC) sequences, where the use and cast iron, which have a lower melting point than steel and of balanced gradients is introduced. The latter is accomplished good castability. through the use of rewinding/refocusing gradient pulses, added Steel became common when efficient production methods so that the gradient scheme becomes balanced over one repetition were invented in the seventeenth century and became relatively time, that is the gradient area is summing up to zero. Therefore cost-effective when the Bessemer process was devised in the the latter group is also denoted as balanced steady state free pre- nineteenth century. Today steel is widely used in construction, cession (bSSFP) sequences, which results in a high SNR. vehicles and many appliances. The rapid repetition of excitation pulses in an SSC sequence Medical Applications: Because of its strength, steel is used will also lead to the generation of several different signal compo- extensively for medical applications from surgical instruments S nents since any rapid repetition of three or more RF pulses will (normally stainless steel to prevent corrosion) to components in fact generate at least five different echo signals. Depending of medical equipment. Steel can be non-magnetic, making it upon the timing of the SSFP pulse sequence, the MR signal will suitable for use in MRI controlled areas. In magnetic form it is build from several different components and it is crucial to keep widely used in permanent magnetic cores used in MRI scanners. track of which signal is actually collected. The SSFP-FID sig- However superconducting magnets are most commonly used in nal is the gradient refocused echo which is collected immedi- modern machines, due to the higher magnetic field strengths ately after an excitation pulse, whereas the SSFP-echo signal achievable. is generated after two consecutive RF pulses, where the second Related Articles: Magnetic resonance imaging, Controlled area pulse is seen upon as a refocusing pulse (similar to the 180° in the SE case) for the spins which were excited by the preceding Step wedge RF pulse. This leads to the somewhat confusing consequence (Radiotherapy) A step wedge was originally a concept used for that the SSFP-echo sequence has a TE which is longer than the testing the contrast and brightness performance of display moni- TR. Since the SSFP-echo sequence collects the phase coherent tors, and consists of a set of 11 squares ranging from 0% (black) to signal just prior to an RF pulse, the pulse sequence structure 100% (white) in steps of 10% (see Attenuation steps). An equiva- is a time-reversed SSFP-fid sequence. The SSFP sequences are lent to this can be delivered on a linac (typically by delivering a designed to collect signals which are generated through many series of fields by moving the MLC leaves) where the steps relate different coherence pathways and the contrast is thus a com- to different doses and this is used for calibration of film or some bination of both T1 and T2 relaxation effects. A pulse sequence other dosimeter. can be designed to look at either one (see FISP and PSIF), or Abbreviation: MLC = Multi leaf collimator. both (see CISS and DESS), of the two signal components and depending upon which signal is detected different contrasts will Step-down transformer be obtained. (Diagnostic Radiology) Transformer producing lower output Related Articles: CISS, Constructive interference in the voltage. steady state, Dual echo steady state (DESS), Fast imaging with See article on Transformer steady state precession (FISP), Gradient echo (GRE), PSIF (FISP reversed), T2 Stepping motor Further Readings: Scheffler, K. 1999. A pictorial descrip- (General) A stepping motor operates in a different mode to a nor- tion of steady-states in rapid magnetic resonance imaging. mal DC electric motor in that when energised it does not move its Concept. Magnetic Res. 11(5):291–304; Nitz, W. 2002. Fast and rotor automatically but holds it at a specific position. To produce ultrafast non-echoplanar MR imaging techniques. Eur. Radiol. stepping of the rotor, a microprocessor controller may selectively 12:2866–2882. energise electromagnets within the static housing of the motor in Step-up transformer 900 Stereotactic ablative radiotherapy (SABR) an ordered fashion to cause the rotor to step sequentially in the beam radiation treatments. Furthermore, the SABR treatment can selected direction. be delivered from a specific beam angle allowing for the possibil- Such motors may have rotors with any number of poles from ity of re-irradiation using an alternative beam angle if it is required four upward, resulting in stepping from one quarter turn for a four (see spine example in Table S.3). pole motor through to a maximum typically of 1024 steps per These treatment techniques are delivered using either a rotation for more complex motors. Cyberknife or linear accelerator and require a baseline level of Stepper motors are useful in situations where known precise achievable set-up accuracy and imaging. Typically, you would position and movement are required, such as in mechanical posi- want systematic set-up uncertainties <3 mm, but this should be tioning devices, linear actuators, goniometers, computer scan- evaluated locally. Therefore, a large aspect of planning to deliver ners, disc drives and printers. SABR treatment is finding and commissioning the immobilisation Further Reading: http: / /en. wikip edia. org /w iki /S teppe r _mot or techniques you plan to use. For some treatment sites, patients will be required to be on the bed and/or immobilised for significantly Step-up transformer longer, so additional consideration should be given to patients’ (Diagnostic Radiology) Transformer producing higher output comfort and the reproducibility of a given set-up. Motion during voltage. treatment should be mitigated to reduce the required treatment See article on Transformer volume expansions and the possibility of under-dosing. Motion amplitude is assessed for each patient using either kV fluoroscopy, Stereotactic ablative radiotherapy (SABR) 4D-CT or 4D-MRI. The motion should then either be controlled (Radiotherapy) Stereotactic ablative radiation therapy (SABR) and (e.g. abdominal compression) or mitigated (e.g. passive respira- stereotactic body radiation therapy (SBRT) can be interchangeably tory gating). A minimum standard set by the UK SABR consor- used to refer to the stereotactic coordinate system being applied to tium is that mitigation of respiratory motion should be attempted treatment sites outside of the brain. The technique can be used for when the known amplitude for a patient exceeds 10 mm for lung either primary tumour cancers or oligometastatic cancers, where or 5 mm for liver or abdominal sites (see Further Reading section). the latter refers to metastatic disease which has derived from a The SABR guidelines are usually set nationally. Below are a primary cancer elsewhere in the body. An overview of the spe- few examples of national guidelines for further reading: cific treatment sites is shown in Table S.3. The technique differs to standard external beam radiation therapy as the doses are higher, • United Kingdom: UK SABR consortium which is where the ‘ablative’ term in the treatment name origi- • North America: ASTRO nates and will consist of a small number of fractions (typically 1–5 • Australia and New Zealand: RANZCR fractions). This results in a much higher dose per fraction than is traditionally given in external beam radiation therapy (typically Related Articles: Stereotactic body radiation therapy, S around 1.5–2 Gy per fraction). The good conformity and high dose Stereotactic radiosurgery, Hypofractionation, Fractionation, of SABR treatment will usually result in a very steep dose gradi- Alpha beta ratio ent. When treating metastases this dose gradient can be extremely Further Reading: Stereotactic Ablative Body Radiation useful in minimising healthy tissue irradiation, reducing the likeli- Therapy (SABR): A Resource (version 6.1). The Faculty of hood of crossover exposure with any prior or concurrent external Clinical Oncology of The Royal College of Radiologists. TABLE S.3 Overview of Stereotactic Ablative Radiotherapy Treatment Sites Primary or Treatment Site Secondary Description Lung Both Treatment method for early-stage non-small cell lung cancer. Generally used for smaller tumours positioned towards the edges of the lung. Furthermore, SABR treatment is also a possible treatment for patients with a small amount of metastatic disease in the lung. Prostate Primary Treatment method of localised prostate cancer. A growing body of evidence is supporting the use of SABR techniques for patients with low- and intermediate-risk prostate cancer. Severe toxicity rates are reported as similar to other types radiotherapy at much shorter treatment durations. Spine Secondary Treatment modality for patients with oligo-metastases of the spine. Typically, patients should have little systemic disease or at least controlled disease elsewhere with a reasonable duration prognosis (at least three months). Treatment is also suited to trying to gain control of progressing oligo-metastases, whilst the systemic disease has been controlled, to avoid changing the currently beneficial systemic treatment. Finally, SABR treatment can also be used in the event of persistent progression following an attempted previous external beam radiotherapy treatment (at least three months prior). Liver Both Possible treatment for both primary liver cancer (e.g. hepatocellular carcinoma) and for metastatic liver cancer. The latter being the most prominent as many cancers metastasise to the liver. This is due to the liver’s pivotal role in our circulatory (blood) and lymphatic systems making it susceptible to circulating cancer cells from other primary tumours. The sharp dose gradients in SABR techniques can often help avoid giving large doses to the healthy liver whilst achieving radical doses to the target cancer. Stereotactic frame 901 Stimulated echo Stereotactic body radiotherapy (SBRT) to using moulds (e.g. thermoplastic) along with optical methods to (Radiotherapy) See Stereotactic ablative radiotherapy track the patient’s head position. Related Articles: SABR, SBRT, Hypofractionation, Stereotactic frame Fractionation, Alpha beta ratio, Immobilisation (Radiotherapy) A stereotactic frame is used to enable highly Further Reading: Scorsetti et al. 2017. OS03.4 Gammaknife accurate patient set-up for stereotactic radiosurgery. Such a device versus Linac based (EDGE) radiosurgery (SRS) for patients with is often used in conjunction with a gamma knife or a conven- limited brain metastases (BMS) from different solid tumor: a tional linear accelerator. The frame is attached to the patient’s phase III randomized trial. Neuro-Oncology. head, often using bite blocks and screw fixation. The frame gener- ally has a pattern of radio-opaque markers to enable localisation Stimulated acoustic emission during CT

imaging to plan the treatment and/or contrast markers (Ultrasound) This is a phenomenon discovered during the early to enable location of the frame in an MR scan. Two approaches clinical use of contrast agents. After a period of not transmit- to attaching the frame to the treatment room are used: pedestal ting ultrasound (i.e. the system in ‘freeze’-mode) a short-lived mounting and couch mounting. A common example is the Gill– ‘mosaic’ of colours would be seen in colour Doppler mode, as the Thomas–Cosman frame. system was activated. The phenomenon was explained as a result Abbreviations: CT = Computed tomography and MR = of rupturing contrast agent particles (microbubbles) that caused Magnetic resonance. a random pseudo Doppler shift: microbubbles with a stabilising Related Articles: Gamma knife, Robotic linac, Arc therapy, shell, as used in contrast agents, behave differently in an acoustic Stereotactic radiosurgery field, depending on the transmitted power. At low emission power, Hyperlinks: Gill–Thomas–Cosman frame, http: / /www .radi the bubbles act as linear backscatters, but with increasing power, onics .com/ produ cts /r t /rel ocata ble .s html they start to respond non-linearly, which results in harmonic fre- quencies. At high power levels, as used in colour flow imaging, Stereotactic radiosurgery they disintegrate, and the free gas that is released is rapidly dis- (Radiotherapy) The term ‘stereotactic’ refers to a three-dimen- solved. As colour Doppler systems detect if there has been a phase sional coordinate system which is related to a fixed, external shift between consecutive pulses, the sudden disappearance of an reference frame. It is then assumed that the object within the echo will be interpreted as a phase shift of random magnitude. stereotactic coordinate remains fixed relative to the external In fact the phase shift is not entirely random, but will on aver- reference frame, allowing precise localisation. Introduced in age have a slight negative bias, depending on acoustic power and the 1950s the technique of stereotactic radiosurgery (SRS) was microbubble concentration. The phenomenon has been suggested adopted by neurosurgeons for the treatment of brain lesions. for clinical use in a more formal way according to a scheme called Originally, this was done using collimated beams of cobalt-60 sono-scintigraphy. gamma-rays. Whilst cobalt-60 is still used in some delivery S methods (Gamma Knife), in the 1980s methods for adapting the Stimulated echo linear accelerator arose to produce similarly suited generated (Magnetic Resonance) A stimulated echo is a type of spin echo mega-voltage beams. signal produced by a series of three RF pulses rather than from The clinical indications for SRS treatment are wide due to its the combination of a 90° and 180° pulse as in a conventional spin versatility in the attainable dose distributions. Examples of use echo sequence. include benign arteriovenous malformations, small benign brain The process by which a stimulated echo is formed is illustrated tumours (vestibular schwannomas and meningiomas), small brain below for the case of a train of three 90° pulses, although in gen- metastases, re-treatment of small tumours and treatment of some eral any train of pulses with flip angles other than 180° can pro- primary tumours. Patients who have brain metastases can some- duce a stimulated echo (Figure S.107). times receive SRS instead of whole-brain radiotherapy; this will The initial RF pulse generates transverse magnetisation. It is usually depend on the number of tumours or total target volume to assumed in this example that this magnetisation is fully dephased establish if SRS is suitable. Typically, treatment will be delivered by the time the second RF pulse is applied (a spoiler gradient can in either single- or hypo-fractionated regimens, with some debate be employed to ensure that this is the case), so that transverse still present for the optimal number of fractions. magnetisation is distributed isotropically in the x–y plane before Delivery of SRS can be achieved using purpose-built equip- the second RF pulse is applied. The y-component of each mag- ment, such as the Gamma Knife, or using modified linear acceler- netisation isochromat will be rotated to the z-axis by this second ators. Whilst the Gamma Knife boasts slightly better dosimetric pulse. The longitudinal magnetisation generated in this way is accuracy, at present there is no significant evidence for clinically ‘stored’ along the z-axis until application of the final pulse, while observable differences between the delivery techniques (Scorsetti remaining transverse magnetisation dephases (again with the aid et al., 2017). During the treatment, the patient is required to be of a spoiler gradient if needed). Application of the third RF pulse immobilised. The stringent coordinate system of stereotactic returns stored magnetisation to the transverse plane where it refo- treatment was made possible through the use of physical ste- cuses as a ‘stimulated echo’. This process results in loss of 50% reotactic frames. Originally, this was done using neurosurgical of the potential signal, assuming an isotropic spin distribution, frames which were fixed to the patient's head by means of steel so a stimulated eco has at most only 50% of the amplitude of the pins inserted into the patient’s skull. Whilst, this provided the corresponding spin echo. desired effect of immobilising the patient it meant that the treat- Stimulated echoes may be a source of ghosting artefacts in ment procedure usually had to be carried out in a single day. For some MRI pulse sequences. However, they are put to beneficial fractionated SRS relocatable fixations were designed which used use in the STEAM sequence (primarily for spectroscopy). things like the mouth, ears and nose to perform daily immobilisa- Related Articles: Spin echo, STEAM (stimulated echo acqui- tion. More recently, immobilisation techniques have progressed sition mode) Stimulated echo acquisition mode (STEAM) 902 Stochastic effects z 90° Dephasing 90° Dephasing M pulse pulse y΄ x΄ 90° pulse Rephasing FIGURE S.107 Formation of a stimulated echo. 90° 90° 90° and each pair of pulses a two-dimensionally selective echo; these unwanted signals are dephased using spoiler gradients (see RF Figure S.108). The use of a stimulated echo, rather than a spin echo as in PRESS, results in loss of 50% of the available signal. The effects Gs of J-modulation can be minimised in STEAM by using a short echo time (TE). STEAM is a popular technique because the VOI is well defined and contamination with extraneous signal is minimal. Gy Related Articles: ISIS, PRESS, Magnetic coupling, Magnetic S resonance spectroscopy, Mixing time, Single voxel spectroscopy Gx Further Readings: Frahm, J., K.-D. Merboldt and W. Hänicke. 1987. Localized proton spectroscopy using stimulated echoes. J. Echo Magn. Reson. 72: 502–508; Keevil, S. F. 2006. Spatial localiza- tion in nuclear magnetic resonance spectroscopy. Phys. Med. TE/2 TM TE/2 Biol. 51:R579–R636. FIGURE S.108 STEAM pulse sequence. (From Keevil, S. F., Phys. Stimulated emission Med. Biol., 51, R579, 2006.) (Non-Ionising Radiation) Process involved in production of a laser beam. See Laser. Stimulated echo acquisition mode (STEAM) STIR (short TI/tau inversion recovery) (Magnetic Resonance) STEAM is a common spatial localisation (Magnetic Resonance) See Short tau inversion recovery (STIR) technique used for single voxel spectroscopy (SVS). Because it involves acquisition of a stimulated echo signal some time after Stochastic effects excitation, it is particularly suited to nuclear species with long T2 (Radiation Protection) There are two types of biological effects relaxation times, such as hydrogen (1H) nuclei (protons). (Bioeffects) of ionising radiation on human tissues categorised by STEAM is a ‘single shot’ technique, in that it requires a single the risk of the effects being observed. These two categories are acquisition of the pulse sequence to achieve localisation, and is stochastic and non-stochastic or deterministic effects. not dependent on post-acquisition signal combination (as is the Effects, which are statistically detectable only in populations case with, e.g. ISIS). are termed ‘stochastic effects’ because of their random nature. The STEAM pulse sequence uses three selective 90° pulses in Stochastic effects may occur if an irradiated cell is modified turn, each applied with a gradient along a different Cartesian axis, rather than killed. and hence selecting orthogonal planes of spins (Figure S.108). The Modified abnormal cells may, after a prolonged process, first pulse and gradient combination is used to excite a plane of develop into a cancer. Because the body’s defences are not com- spins, and when the second is applied, spins at the intersection of pletely effective, the smallest number of modified cells may the two selected slices are returned to the z-axis during the ‘mix- develop into a cancer and there is assumed to be no threshold ing time’ TM, when the magnetisation experiences T1-relaxation. below which effects do not occur. Furthermore, since the prob- The third pulse brings magnetisation within the volume of inter- ability of developing a cancer is partly dependent on the initial est at the intersection of all three slices back into the transverse number of modified cells, these so-called stochastic effects occur plane, where it forms a so-called stimulated echo. The individual with the probability rather than the severity of the effect being a pulses generate slice-selective free induction decay (FID) signals, function of radiation dose. Stoichiometric calibration 903 S topping power If the cell damaged by radiation exposure is a germ cell, whose Formulae based on the HU and elemental composition of the function is to transmit genetic information to progeny, it is con- materials are used to predict the electron densities for photon ceivable that hereditable effects of various types may develop in therapy or stopping power ratios for proton/ion therapy. (These the descendants of the exposed individual. can then be verified experimentally.) As shown on Figure S.109, the current internationally accepted A linear regression fit based on the calculated values for framework for radiation protection assumes a linear relationship biological tissues is then used to create the calibration curve. between the risk (probability) of a stochastic effect, and the dose Generally, three linear fits are used for three different regions of received, with no threshold – that is the linear non-threshold the curve representing air (0–800 HU), soft tissues (800–1200 model. HU) and bone (>1200 HU). Stochastic effects are restricted to cancers and hereditary dis- Abbreviations: HU = Hounsfield units, SPR = Stopping power ease only and are normally expressed as a risk of the effect occur- ratio and CT = Computed tomography ring per unit dose. Current values taken from ICRP 103 (2007) Further Reading: Schneider, U., E. Pedroni and A. Lomax. are shown in Table S.4. 1996. The calibration of CT Hounsfield units for radiotherapy It is important to note that malignancies induced as a result of treatment planning. Phys. Med. Biol. 41:111–124. radiation damage are not distinguishable from those induced by other causes. It must also be remembered that the time interval Stopping power between exposure and the manifestation of the leukaemia or solid (Radiation Protection) The energy lost from a beam of charged tumour – the so-called latent period – may be tens of years: particle (e.g. alpha or beta) ionising radiation as it travels through a medium is known as the stopping power of the material tra- • Leukaemia: latent period of 5–10 years versed. This loss of energy for alpha particles, and protons (but • Solid cancers: latent period 20–30 years not electrons) is described by the Bethe–Bloch Equation. The stopping power can be described in terms of distance trav- Related Articles: Bioeffects, LNT Model elled through the medium (linear stopping power), or in terms of Further Reading: ICRP. 2008. Recommendations of the the atomic mass of the medium (collisional mass stopping power). International Commission on Radiological Protection. ICRP The term ‘stopping power’ is used to imply that the particles Annual Report, ICRP Publication 103, Vol. 37, pp. 2–4. will have a finite range in matter whereby all incident and second- ary particles have been totally absorbed within the medium (as Stoichiometric calibration opposed to x- or γ-radiation that is attenuated exponentially with (Radiotherapy) Stoichiometric calibration is a method of convert- at least some transmission through the material and out the other ing the attenuation information obtained from a computed tomog- side). raphy (CT) scan – scaled to Hounsfield units (HU) – into electron Related Articles: Linear stopping power, Collision mass stop- densities for photon therapy or stopping power ratios (SPRs) for ping power, Collisional energy loss, Bethe–Bloch equation S proton/ion therapy. Materials of known elemental composition that relate to clini- Stopping power cally relevant tissues (such as

muscle, bone and water) are CT (Radiotherapy) As a fast charged particle passes through matter scanned. it interacts with elastic and inelastic collision with atomic elec- trons and nuclei. The various types of interactions produce a loss of energy bringing the charged particle eventually to rest. The evaluation of the energy loss should include energy losses due to all types of interactions but the predominant mode of energy loss is the ionisation of the medium atoms. The average linear rate of energy loss per unit of path length x by a charged particle with a kinetic energy E in a medium of Linear, no threshold atomic number Z is called stopping power. Common units for (LNT) model the stopping power are MeV cm−1. Using the relativistic quantum mechanics the following expression for the stopping power can be derived: Dose dE 4pk2z2e4n é mc2 2 0 2 b 2 ù - = 2 êl - b2 n b ú dx mc ë I(1 - b2 ) û FIGURE S.109 Dose–response curve for stochastic effects. where k0 is the 8.99 109 N m2 C−2 z is the atomic number of the heavy particle TABLE S.4 e is the magnitude of the electron charge n is the number of electrons per unit volume in the medium ICRP Detriment-Adjusted Nominal Risk Coefficients m is the electron rest mass (CRP 2013) (10-2 Sv-1 – Percent per Sievert) c is the speed of light in vacuum β = v/c is the speed of the particle relative to c Exposed Population Cancer Introduction Hereditable Effects I is the mean excitation energy of the medium Whole 5.5 0.2 Adult 4.1 0.1 At low energies (β → 0) the factor in front of the bracket increases while the logarithmic term increases the stopping Probability of effect Storage phosphor 904 Storage phosphor power at very high energies (β → 1). Nevertheless the logarithm electron as it has the same mass and also because the two elec- term then decreases causing a peak called Bragg peak where the trons are identical and in quantum mechanics the identity of par- linear rate of energy loss is a maximum. ticles implies that they cannot be distinguished. In the cavity theory the stopping power ratio, a dimensionless The collision stopping power for electron can be written as quantity, is used to describe the rate of energy loss of the charged particles in one medium in relation with another. dE 4pk2z2e4n é c2 0 m t t + 2 ù When a charged particle suffers an acceleration it radiates - = 2 2 êln + F (b) - dú dx mc b electromagnetic energy and the intensity of the emitted radiation ëê 2I ûú is proportional to the acceleration times the charge. For a par- ticle of mass M and charge z being accelerated by a charge Ze where the acceleration is proportional to zZe2/M and the intensity of the τ is the E/mc2 with E kinetic energy of the electron emitted radiation is therefore proportional to (zZe2/M)2. A light δ is the density effect correction particle such as an electron is therefore more efficient to produce bremsstrahlung than a heavy particle of the same energy. 1 - b2 é t2 ù F(b) = 1 + - (2t +1)ln2 e stopping power could be subdivided into a collision stop- 2 ê ú Th ë 8 û ping power Scol and a radiative stopping power Srad. The collision stopping power, due to inelastic collisions with atomic electrons The following approximate formula gives the ratio of the radiative of the medium, results in excitation and ionisations. The radiative and collision stopping power for an electron: stopping power, due to the particle interaction with the electric field of the nucleus, results in the production of bremsstrahlung radiation. (-dE / dx) (Z +1.2)E rad @ The total stopping power is the sum of the two given by the (-dE / dx)col 800 following equation: where æ dE E is the electron total energy expressed in MeV ç - ö ÷ = Scol + Srad Z is the atomic number of the target material è dx ø E E = æ d - ö + æ d ö Storage phosphor ç dx ÷ ç - ÷ è ø Radiology) Storage phosphors are phosphors that are col è dx ø (Diagnostic rad designed to trap x-ray energy until the energy is released by laser This separation emphasises the difference between the two readout. They are the basis for computed radiography systems. components as the energy lost in ionisations and excitations is These phosphors were patented by Kodak but the first com- S absorbed close to the charge particle track while the energy car- mercial systems were introduced by Fuji. The storage phosphor is ried as form of bremsstrahlung travels far before being absorbed. usually made from BaFX:Eu2+ (X = Cl, Br, I). It is a thin flat sheet The collisional stopping power for electrons is different from contained within a cassette, similar in appearance to the x-ray that of heavy charged particles because an electron can lose a cassettes used in film-screen radiography. large fraction of its energy in a single collision with an atomic Figure S.110 shows the basis of a storage phosphor. Trap Conduction band τtunnelling τ Phonon Relax recombination 4f6 Laser F/F+ stimulation 2.0 eV 8.3 eV PSL 3.0 eV τE 47 E3/E2 e Valence band Incident x-rays FIGURE S.110 Principle of photostimulated luminescence. (Drawing courtesy of J. A. Seibert.) Strain imaging 905 S train imaging The incident x-ray energy moves an electron from the Eu2+, shortening in the longitudinal dimension (assessed from apical converting it to Eu3+ + free electron. This electron is captured by views) or percent thickening in the radial dimension from a the bromine energy traps. sequence of images. The technique provides a 2D represen- The number of produced free electrons is proportional to the tation of the tissue stiffness and facilitates visualisation of energy and intensity of the incident x-ray beam. This way the deep lying tumours, which are difficult to locate with palpa- areas of the storage phosphor, where electrons are captures, and tion alone. The technique has been developed into ultrasound the number of these electrons, correspond to the area of the x-ray elastography. fields with varying intensity – that is a latent image of trapped In cardiology the use of strain imaging combined with routine electrons is formed. B-mode and M-mode assessment increases sensitivity compared In the absence of other external energy (e.g. heat) the captures with the use of visual assessment alone for determination of myo- electrons can stay long time into these f-trapping centres – that is cardial viability or regional myocardial function. the latent image is stored in the phosphor. Related Article: Elastography When the storage phosphor is scanned with external laser (usually Infrared, e.g. He-Ne 632 nm) the trapped electrons gain sufficient energy to be move out of the trap. The released elec- trons during this process (reading) return to the Europium. During this process it returns back to its original Eu2+ state and releases characteristic quant with 390 nm (photostimulated luminescence, PSL). Figure S.111 shows the process of reading the storage phos- phor. A reading laser scans the whole storage phosphor plate and the released PSL is read by a photomultiplier (through a light channelling guide). The intensity of the read light is proportional to the number of released electrons (from the traps) and hence to the intensity of the x-ray beam radiated the scanned area. As the laser and PSL lights are with different wavelength the reading laser does not interfere with the PSL light. The read information from the phosphor plate enters the image processor, where it is arranged in a digital image matrix (thus forming the visual image of the radiograph). After the reading process the storage phosphor plates are erased by exposing them to a bright light. This way the storage S phosphor returns into its original state and is ready to be used again. The number of uses of a storage phosphor is more than 10,000 (Figures S.112 and S.113). Strain imaging (Ultrasound) Strain imaging assesses the tissue stiffness by FIGURE S.112 Typical storage phosphor reader (CR unit). The laser compressing the tissue (with the ultrasound probe) and obtain- scanner is seen through the open door. The unit opens the cassette, reads ing the local tissue deformation, which translates to percent the plate, erases it and returns it to the cassette. Reference f-theta Cylindrical lens Beam Light channelling Laser source Output Beam PM AD Laser beam: Amplifier scan To image processor Plate translation: FIGURE S.111 Principle of the CR laser reader. (Drawing courtesy of J. A. Seibert.) Straton 906 Strontium-82 FIGURE S.114 Streamlines and the enclosed streamtube. A pathline shows the path of an individual particle over time. Streaklines show the position of all particles that have passed a particular point; for example if dye is injected from a point, the resulting pattern is the streakline. In constant laminar flow, the streamline, particle path and streakline coincide. For unsteady flow they differ. The term streamline flow is used to describe steady flow with- out turbulence. Related Article: Laminar flow Stress echocardiography (Ultrasound) Stress echocardiography is echocardiography that FIGURE S.113 Storage phosphor plate in a cassette. it is performed both at rest and after increased cardiac work, or stress. This is invoked in the patient by exercise either on a bicy- Straton cle or treadmill or by using a drug to increase heart rate. After (Diagnostic Radiology) Straton is a vendor name (SIEMENS) of a myocardial infarction some of the heart muscle contracts less a specific x-ray tube used in computed tomography. The tube uses efficiently. In coronary artery disease, narrowed arteries restrict special focusing and deflection coils to form the beam of thermal blood flow to the heart muscle. These effects may be minimal or electron bombarding the anode. This way the shape of this metal undetected at rest but become significant and evident when the S x-ray tube is unusual and allows variable focal spot. The station- heart performs more work – hence the clinical need to perform ary round anode of Straton is sealed with the tube metal envelope the investigation after exercise. and rotates with it. This design allows for the back side of anode Related Article: Echocardiography to be in direct contact with the cooling oil, hence increased power of the x-ray tube (see the article CT x-ray tube). Stripping foil Related Article: CT x-ray tube (Nuclear Medicine) A stripping foil is used to convert H− ions to protons by stripping it of two electrons in a negative ion cyclotron. Stray magnetic field In modern negative ion cyclotrons two foils are used to gradually (Magnetic Resonance) The stray field, called also fringe field, is extract the beam to two separate targets. When the H− ion beam the magnetic field outside the magnet of an MR system. Its strength passes the foil the two electrons are stripped from the atom leav- depends on the magnet type and the magnetic field strength. The ing nothing but a proton with an opposite charge. Since the proton higher the field strength, the larger the fringe field. The stray field has positive charge it will bend outwards where it can be focused can be reduced through the use of a high permeability material on a target. that provides a return path of the magnetic flux with a significant Related Article: Cyclotron decrease in the flux away from the magnet (passively shielded magnet). An alternative and more diffused method to control the Strontium-82 stray field is to use an active shielding which consists of adding (Nuclear Medicine) A radionuclide used in Strontium-82/ appropriate additional superconducting coils to superconducting Rubidium-82 generators for the production of Rubidium-82, a magnets thus resulting in a significant reduction of the extent of tracer used in myocardial perfusion imaging. As Rubidium-82 the stray fields (actively shielded magnets). However the strength has a very short half-life of 75 seconds, it is essential to produce of the stray magnetic field of actively shielded magnets usually it on-site and the use of a Strontium-82/Rubidium-82 generator rises very rapidly. The stray magnetic field constitutes one of the removes the necessity for an on-site cyclotron. major hazards of MR scanners as

these fields acting over extended distances outside the magnet produce strong attractive forces Half-life Decay mode Daughter upon magnetic objects. 25.35 days Electron capture Rubidium-82 Streamline (Ultrasound) Streamlines are curves that show the instantaneous Strontium-82 is accelerator produced either by proton spallation direction of velocity of every particle along its line. There is no or using a Rubidium-85 target via a (p,4n) reaction. Similar to a flow across the streamline. A bundle of streamlines enclosing a Molybdenum-99/Technetium-99m generator, the Strontium-82 is volume of fluid is known as a streamtube and no flow crosses this placed on ion exchange columns in the generator. Rubidium-82 (Figure S.114). is obtained by eluting the Strontium-82/Rubidium-82 generator. Structured noise 907 Summed scoring Related Articles: Positron emission tomography, Perfusion is the difference in the object area and background density values imaging, Radionuclide generators (DBg and Do). Further Readings: Sharp, Gemmell and Murray. 2005. Practical Nuclear Medicine, 3rd edn., Springer; Yano. Essentials Subtraction of a rubidium-82 generator for nuclear medicine, International (Diagnostic Radiology) See Digital subtraction angiography Journal of Radiation Applications and Instrumentation. Part A. (DSA) Applied Radiation and Isotopes, 38(3):205–211; Alvarez-Diez, deKemp, Beanlands and Vincent. 1999. Manufacture of stron- Subtense angle tium-82/rubidium-82 generators and quality control of rubid- (Non-Ionising Radiation) This is the angle subtended by the ium-82 chloride for myocardial perfusion imaging in patients actual source at the position of the eye. This is estimated by divid- using positron emission tomography. Appl. Radiat. Isotopes ing the source diameter (or average dimension) by the distance 50(6):1015–1023. between the source and the observer. Subtense angles are usually measured in steradiants. Structured noise Related Articles: AORD, Blue light hazard, Infrared light (Nuclear Medicine) Image noise can take the form of either ran- hazard, Radiance dom noise or structured noise. In nuclear medicine, random noise Further Readings: Council Directive 2006/25/EC on the refers to the mottled appearance of the images due to the statisti- minimum health and safety requirements regarding the exposure cal nature of the acquisition. Structured noise refers to non-ran- of workers to risks arising from physical agents (artificial optical dom variations in counts which interfere with the structures of radiation) (19th individual Directive within the meaning of Article interest within the image. 16(1) of Directive 89/391/EEC) [2006] OJ L 114; A Non-Binding Structured noise can be caused by the distribution of the Guide to the Artificial Optical Radiation Directive 2006/25/EC, tracer. An example of this might be activity in the gut masking Radiation Protection Division, Health Protection Agency, https the myocardium in myocardial perfusion imaging. It can also be :/ /os ha .eu ropa. eu /en /legi slati on /gu ideli nes /n on -bi nding -guid e -to- the result of imaging system problems such as artefacts caused by good- pract ice -f or -im pleme nting -dire ctive -2006 -25 -e c -201 aar ti camera non-uniformity. ficia l -opt ical- radia tion2 019 (Accessed January 2020); Related Article: Noise ICNIRP. 2013. Guidelines on limits of exposure to incoher- ent visible and infrared radiation, Health Physics 105(1):74–91; Subject contrast BS EN 62471. 2008. Photobiological safety of lamps and lamp (Diagnostic Radiology) The formation of an x-ray image is systems. the transfer and conversion of different types of contrast. If Subtractive colour model an object in the body is to be visible it must have some form (General) See Red green blue (RGB) of physical contrast in relation to its surrounding background. S This can be in the form of a difference in density or atomic Summed scoring number (Z). (Nuclear Medicine) This is a scoring system used in the interpre- As an x-ray beam passes through the body section the object tation of myocardial perfusion SPECT scans. The myocardium is will attenuate either more or less than the surrounding tissue and divided into 20 segments and each is given a score of 0–4 where will form an image where the contrast is in the form of exposure 0 represents normal uptake and 4 no uptake at all. This 5-point differences as shown in Figure S.115. The contrast in the x-ray scoring system leads to the derivation of three global summed beam coming from the patient’s body and exposing the receptor is scoring indices of perfusion. These are as follows: designated as the subject contrast. For an object that is being imaged the subject contrast can be 1. The summed stress scoring SSS expressed as the ratio of the difference in the object area exposure 2. The summed rest scoring SRS (Eo) and the background area exposure (EBg) to the background 3. The summed difference scoring SDS exposure (EBg). When the image is recorded on film the contrast The SSS and SRS are defined as the sum of stress scores for the 20 segments and the sum of rest scores for the 20 segments, respec- Object contrast tively. Moreover, the SDS is defined as the difference between the SSS and SRS. The SSS can be interpreted as follows: Receptor • A SSS of less than 4 is considered normal or nearly exposure E EBg – E normal o Bg C = • A SSS of 4–8 is considered mildly abnormal E E o Bg • A SSS of 9–13 is considered moderately abnormal • A SSS greater than 13 is considered severely abnormal D Related Article: Scoring Film C = D density Bg – Do Further Readings: Germano, G. and D. S. Berman. 1999. D An approach to the interpretation and reporting of gated myo- Bg cardial perfusion SPECT. In: Clinical Gated Cardiac SPECT, eds., G. Germano, D. S. Berman, Futura Publishing Co., New FIGURE S.115 Three types of contrast that are present in the forma- York, pp. 155–158; Silberstein, E. B. and D. F. DeVries, July 1985. tion of a radiograph. (Courtesy of Sprawls Foundation, www .sprawls .org) Reverse redistribution phenomenon in thallium-201 stress tests: Superconducting magnet 908 Superficial therapy Angiographic correlation and clinical significance. J. Nucl. Med. the critical temperature can be explained by the energy gap ΔE, see 26(7):707–710. above, but in the type-2 superconductor there is no explanation (yet) to why the critical temperature appears. In Figure S.116 the resistiv- Superconducting magnet ity, ρ, and the specific heat at constant volume, cv, are plotted as a (Magnetic Resonance) A superconducting magnet is a type function of the temperature normalised to the critical temperature. of electromagnet that is built of superconducting coils and can Related Article: Superconductive magnet reach much higher magnetic field strength than conventional electromagnet or permanent magnets. The coil is made up of Superficial radiation tiny filament (∼20 μm) made of a type two superconductor (e.g. (Radiotherapy) Superficial radiation falls in the range 50–160 kV niobium-titanium, Nb3Ti). The type two superconductors become (1.0–8.0 mm Al half value layer [HVL]). Table S.5 shows its rela- superconducting at a very low temperature (<10 K) and cooling is tionship to other radiation ranges. therefore required. Therefore the superconducting coil is inside a Further Reading: Bomford, C. K. and I. H. Kumkler, eds. cryostat filled with liquid helium with a temperature at 4.2 K. The 2003. Walter and Miller Textbook of Radiotherapy, 6th edn., magnetic field intensity of a superconducting magnet with Nb3Ti Churchill, Livingstone, Zambia, p. 143. coils can reach up to about 15T but is clinically used up to 3 T. A more expensive material for the coils is niobium-tin (Ni3Sn) Superficial therapy that reaches superconductivity at 18 K. This superconductor can (Radiotherapy) Superficial therapy describes treatment with low- reach magnetic field intensities of up to 25–30 T at 4.2 K. It is energy kilovoltage x-ray beams (accelerating potential 50–160 more difficult to make the coil filament of this material, hence a kV, 1.0–8.0 mm Al half value layer [HVL]). combination of both materials is used and the Ni3Sn is only used There is no sharp division between the various voltage ranges in a small part of the magnet. and they can vary slightly in different documents. The magnetic field of the superconductor is always on and the Abbreviation: HVL = Half-value layer. only controlled way to remove the magnetic field is to slowly ramp Further Reading: Bomford, C. K. and I. H. Kumkler, eds. down the power in the superconducting coils, which is a time con- 2003. Walter and Miller Textbook of Radiotherapy, 6th edn., suming process. The power consumption of the magnet is neg- Churchill, Livingstone, Zambia, p. 143. ligible in the steady field state. The magnetic field can also be shut down by allowing some part of the coil to become resistive. This more rapid procedure is called quenching and can be used in emergencies. It can, although rarely, also occur accidentally, for example during refilling of the cryostat. Quenching results in heat development and boil-off of the helium, hence the cryostat in cv ~ T S superconducting magnets is always connected to outer air using a ρ ~ T3 so-called quench pipe. Furthermore, a quench may be associated cv ~ e–Δ/kTc with significant damage to the magnet. Related Articles: Electro-magnet, Magnet, Permanent mag- net, Quenching, Resistive magnet, Superconductivity Superconducting material (Magnetic Resonance) See Superconducting magnet ρ = 0 Superconductivity (Magnetic Resonance) Superconductivity occurs in certain mate- 0 1 2 3 rials at extremely low temperature. The effect is characterised T/Tc by close to zero electrical resistance and exclusion of the interior magnetic field. FIGURE S.116 The resistivity and the specific heat at constant vol- Superconductivity occurs in some simple elements such as tin ume plotted as a function of temperature normalised to the critical or aluminium, in various metallic alloys and in heavily doped temperature. semiconductors. In a conventional superconductor (type-1 super- conductor) the electrons in the electron fluid form pairs, known as Cooper pairs. The Cooper pair possesses an energy gap, ΔE, that is the minimum amount of energy that has to be applied to TABLE S.5 excite the Cooper pair. If the energy gap is larger than the thermal energy of the lattice the electrons will move through the lattice HVL and Energy Ranges for Grenz, Superficial and without scattering. Orthovoltage Radiation In the type-2 superconductor (including all known high- Half Value Layer (HVL) Energy (kV) temperature superconductors) a small resistance, negligible in comparison with an ordinary conductor, is created by vortices in Very low energy x-rays 0.035–1.0 mm aluminium 8–50 the electron fluid. When the vortices move they use some of the (Grenz rays) energy from the electron fluid and that creates the resistance. If Low-energy x-rays 1.0–8.0 mm aluminium 50–160 the temperature is lowered the vortices becomes stationary and (superficial) the resistance disappears. Medium energy 0.5–4.0 mm copper 160–300 The superconductivity appears when the temperature is below (orthovoltage) the critical temperature, Tc. In an ordinary (type-1) superconductor Resistivity ρ (a.u.) Specific heat cv (a.u.) Superior (cephalic) 909 Supervised area Superior (cephalic) • Ultrasmall superparamagnetic iron oxide preparations (General) Directional anatomical terms describe the relationship (USPIOs) and monocrystalline iron oxide preparations of structures relative to other structures or locations in the body. (MIONs), consisting of smaller (<30 nm) particles. ‘Superior’ or ‘cephalic’ means above, over or towards the head They leave the vascular system slowly, often taken up (e.g. the elbow is superior to the hand). by macrophages in the lymph nodes, spleen and bone Related Article: Anatomical relationships marrow. • Receptor-directed iron oxides, which are iron cores Superorthicon bound to receptor-specific carbohydrates. (Diagnostic Radiology) One of the first sensitive TV camera tubes • Antibody-labelled iron oxides, usually MION deriva- was Orthicon (successor of the Iconoscope and Emitron). This tives attached to antibodies or antibody fragments. An tube was more sensitive but still not suitable for the low light example is MION-antimyosin, which is taken up spe- intensity of the fluoroscopic phosphor screen (before the use of cifically by infarcted myocardium. image intensifier). The improved TV camera tube Superorthicon • Bowel suppression agents to eliminate signal from was able to directly convert this low light into video signal. This bowel which may otherwise obscure diagnosis, particu- camera was used in the first x-ray fluoroscopic systems where larly in the presence of peristalsis. the image was observed on a TV monitor, and not directly from the phosphorescence panel. The x-ray fluoroscopic system with These agents produce negative contrast by shortening the T2 or T * Superorthicon was the first improvement of the systems with 2 of hydrogen nuclei (protons) in tissue water. As

the particles direct phosphorescence screen/panel. This way the x-ray fluoro- become larger, it is a matter of semantics as to whether the effect scopic system with Superorthicon appeared as predecessor of the is regarded as a shortening of the relaxation time or irreversible image intensifier. dephasing due to an increase in local field inhomogeneity – i.e. a The Orthicon uses photosensitive plate (photocathode) which susceptibility effect. emits photoelectrons and a system of electrodes to accelerate Smaller superparamagnetic particles have a prominent T1 these towards the target. The scanning beam reads the image effect as well, although this is rarely exploited in MRI. directly from the target. The result is a high-resolution image. Related Articles: Negative contrast media, Ultrasmall par- This camera has a logarithmic characteristic curve, which is well ticles of iron oxide (USPIO), Superparamagnetic iron oxide accepted by the human eye. These cameras have not been used after the 1960s, being replaced by the newer TV camera tubes Supervised area Vidicon and Plumbicon (used in the x-ray fluoroscopy systems (Radiation Protection) with Image Intensifier). Classification of Areas: There are two types of areas where Related Articles: Video camera tube, Vidicon, Plumbicon ionising radiation may be used: controlled and supervised. The Further Readings: Karadimov, D. 1978. Roentgen Equipment, responsibility of designating an area as controlled or super- S Technika, Sofia, Bulgaria; Tabakov, S. and A. Litchev. 1998. vised is attributed to the registrants and licensees, who shall Diagnostic Radiology–Physics and Equipment, Inter-University appoint a qualified expert, usually the radiation protection offi- Centre, Plovdiv, Bulgaria. cer, to deal with the practical work. He/she shall designate as Hyperlink: The Cathode Ray Tube site, http://members .chello supervised any area (not already designated as controlled area) .nl/∼h.dijkstra19/page4 .ht ml where occupational exposure conditions need to be reviewed, even though specific protection measures are not normally Superparamagnetic iron oxide needed. (Magnetic Resonance) Superparamagnetism is a phenomenon in In determining the boundaries of any supervised area, the which sufficiently small particles of magnetic material behave as qualified expert (appointed by the registrants and licensees) shall a single magnetic domain. In an aggregate of such particles, ran- take into account the magnitude of the expected normal expo- dom orientation of the magnetic moments of the single domain sures, the likelihood and magnitude of potential exposures and particles leads to cancelling out of magnetisation in the aggregate the nature and extent of the required protection and safety proce- as a whole, but in the presence of an applied magnetic field the dures. As an example, in a radiology facility, all x-ray rooms shall individual moments align to generate a large magnetisation. be controlled area while internal corridors may be a supervised In MRI, particles of superparamagnetic iron oxide (usually area. Rooms where mobile x-ray equipment is used may also be iron (II, III) oxide, Fe2O3, or magnetite) are used as negative con- considered a supervised area. trast agents. Operational Conditions: As the working conditions might Related Articles: Negative contrast media, Ultrasmall par- change, it should be determined whether an area will be main- ticles of iron oxide (USPIO), Superparamagnetic particles tained as supervised or public area; the evaluation being made on the basis of regular, routine, safety assessment (including the Superparamagnetic particles planned use of each area) and the evaluation of shielding. (Magnetic Resonance) Small particles of superparamagnetic Registrants and licensees are also responsible for ensuring material, normally iron oxide, are a common form of negative that: the supervised area be delineated by physical (or other suit- contrast agent in MRI. able) means; and that warning signs and warning lights symbols Agents in this category include the following: (such as those recommended by International Organization for Standardization) be displayed. • Large superparamagnetic iron oxide preparations Further Readings: IAEA (International Atomic Energy (SPIOs), which consist of polycrystalline particles of Agency). 1996. International Basic Safety Standards for Protection varying size. Administered intravenously, they have a against Radiation and for the Safety of Radiation Sources, Safety short half life in blood and undergo phagocytosis in the Series No. 115, International Atomic Energy Agency, Vienna, liver and spleen. Austria; ICRP. 1991. 1990 Recommendations of International Supine 910 Surface dose Commission on Radiological Protection, ICRP Annual Report, Many surface coils can be combined to cover large parts of ICRP Publication 60, Pergamon Press, Oxford, UK. the body and, depending on the number of receiver channels on the MR-scanner, they can even be used to cover the entire body. Supine Related Article: Magnetic resonance imaging (MRI) (General) There are a series of terms used to describe the position of an individual when undertaking different imaging examination. Surface contours Supine: Lying on the back. For example, the position for (Magnetic Resonance) Surface contour plots are used to repre- supine abdominal imaging. sent distributions of scalar data. They can be created, for exam- Related Article: Patient position ple from 3D matrices, in which there is information both about intensity (1D) and position (2D). An example is three-dimensional Suppressing filter datasets describing temperature distributions in space, or air pres- (General) A suppressing filter is an electric component designed sure on different locations, in which information exist both about to reduce electronic transients which may be generated within the value of a parameter and its spatial distribution. electronic devices or may be carried via the mains power lines Surface contours are created by assigning matrix elements into a device. with identical values a specific colour while other matrix ele- Contact suppressor: When an inductive load is switched ments are transparent, thus creating a surface of points in which OFF it produces a large voltage spike which can be damaging. the values are identical (iso-surfaces). These can be overlaid as To suppress these spikes, ‘snubbers’ or contact suppressors are contour lines onto 2D images (like on maps) or contour surfaces used, which usually are made up of a single unit containing both onto 3D images. capacitor and a series resistor (e.g. 100 Ω and 0.1 μF) which may be connected across the switching device or load. Surface dose Motor suppressor: Motors are inductive and may have com- (Radiotherapy) When exposed to ionising radiation the skin is mutators (effectively switches), and so are a source of voltage prone to damage and an important parameter quoted in relation spikes which often contain considerable energy at radio frequen- to this is surface dose which is commonly regarded as the dose to cies – likely to cause interference in nearby circuitry. Motor sup- the surface of the skin. pression may also be performed by use of a suitable RC filter Megavoltage external beam therapy with high-energy x-rays combination. sets in motion electrons which interact with tissue over a range EMI filters: Modern electronic circuitry is inherently sus- of several millimetres. As a result of this a dose maximum, dmax, ceptible to sharp electrical transients and electro-magnetic inter- is produced at some depth around 1–2 cm or more below the skin ference (EMI). Recent legislation requires all new devices to be surface depending on the energy of the radiation beam. capable of proper operation when subject to a certain amount To understand the significance of surface dose it is important S of external interference, and also to operate without generating to know the processes involved in the interaction of radiation with such interference themselves. It is therefore common to have an the structures that lie between the point of the dose maximum and ‘EMI filter’ built into the power input circuitry to reduce incom- the skin surface. ing electrical interference, and also prevent any backward flow Early radiation damage can manifest itself in the basal layers of interference into the mains supply. This is usually a module where the dose gradient is steep. These layers lie at about 0.07 made of inductors and capacitors designed to block and absorb mm below the skin surface. Because of the steep dose gradient such signals. the surface dose does not give a reliable estimate of the skin dose. Surge suppressors: where very short and very high voltage Late radiation damage is thought to arise from the dermis which spikes might be expected, surge suppressors, usually semiconduc- lies about 0.05–3 mm below the skin surface where blood vessels tor materials with programmed ‘breakdown voltages’, are fitted to lie which are sensitive to damage. Therefore, knowledge of dose prevent thin parallel with any load. These devices react extremely from the surface down to a depth of 3 mm is important in clinical quickly and short out any overvoltage spike. Examples include situations. varistors (MOVs), discharge tubes, and specialised diodes. Measurement of surface dose requires detectors which are Related Articles: Inductor, Capacitor capable of high special resolution. Metal oxide semiconductors field effect transistors (MOS-FETs) can be used which are physi- Surface coil cally small in size. Carbon loaded thermoluminescent dosimeters (Magnetic Resonance) The term surface coil refers to a type of (TLDs) can also be used which have an effective measurement receive coil used in magnetic resonance imaging. These coils depth of 0.07 mm which corresponds to the depth of the basal may consist of one or several loop shaped elements and are layers. applied close to the surface of the part of the body that is to be In practice several things can contribute to surface dose; one of examined. Contrary to a so called volume coil, such as the stan- these could be the use of immobilisation devices which effectively dard body coil in the MR-scanner, a surface coil has a more lim- add a layer of tissue equivalent material and push dmax towards the ited region of sensitivity. It ‘sees’ only the volume that is closest skin surface. Other contributions come from electrons generated to each of the elements. The sensitivity is also highly dependent in the treatment machine. These are typically generated in the on the distance from the coil element and decreases as the dis- flattening filter, ionisation chamber, jaws, blocking tray and in the tance increases. air between the machine head and the patient. Surface dose also Surface coils are typically more flexible than volume coils and increases with increasing field size. Typical values are shown in can be applied close to the body, for example around joints, and Table S.6. thereby provide much better signal-to-noise ratio (SNR) than a Related Article: Build up volume coil would do. The limited region of sensitivity also con- Further Reading: Metcalfe, P., Korn, T. and Hoban, P. 1997. tributes to the increased SNR since the coil covers a smaller tissue The Physics of Radiotherapy X-rays from Linear Accelerators, volume from which it can pick up thermal noise. Medical Physics Publications, New York. Surface guided radiation therapy (SGRT) 911 Susceptibility Dose (Gy) TABLE S.6 0 10 20 30 40 Typical Surface Doses for a 10 × 10 cm Open Field Energy Surface Dose % of dmax 1.25 MeV γ-rays 23 4 MV 18 6 MV 15 Surface guided radiation therapy (SGRT) (Radiotherapy) Surface guided radiation therapy (SGRT) uses non-ionising imaging techniques to accurately set-up the patient and/or monitor their position throughout treatment. The position of the patient’s external surface is compared to a reference model FIGURE S.118 Shape of survival curve for mammalian cells exposed to that is either derived during treatment planning or from internal radiation. The fraction of cells surviving is plotted on a logarithmic scale images obtained during treatment. All six spatial degrees of free- against the radiation dose on a linear scale. dom plus the motion time-course are considered. Related Article: Image guided radiotherapy the form shown in Figure S.118 for x- and γ-rays, with dose plotted Surface wave on a linear scale and surviving fraction on a logarithmic scale. (Ultrasound) When an ultrasound wave propagates in a medium, A cell’s radiosensitivity can be determined from cell survival the particles within the medium will start oscillating. In gases, curves. The shape of survival curves is commonly described by liquids and soft tissue this oscillation is always in the same direc- the linear-quadratic model with the ratio of its two parameters, tion as the ultrasound wave, giving rise to longitudinal wave α and β, often used as a measure of a cell’s radiosensitivity. An propagation. However, in solid materials both longitudinal (com- alternative parameter of radiosensitivity relevant to the doses pressional) and transverse (shear) wave propagation are possible. used in fractionated radiotherapy is

the surviving fraction at the In a transverse wave the particles oscillate perpendicular to the 2 Gy level (SF2). This has the advantage of only requiring mea- wave propagation direction. Surface (Rayleigh) waves are a com- surement at one point on the survival curve, useful for human bination of longitudinal and transverse waves and can propagate tumours/tissues where samples are often small and difficult to at the boundary between a liquid and a solid, Figure S.117. Ocean obtain. S waves are surface waves. Abbreviation: SF2 = Surviving fraction at 2 Gy level. Related Articles: Longitudinal wave, Transverse wave, Lamb Related Articles: Alpha beta ratio, Cell proliferation, Cell sur- wave vival, Cell survival curve, Dose response model, Linear quadratic (LQ) model, Linear quadratic dose–response curve, Probability Survey meter of cell survival, Radiosensitivity. (Radiation Protection) A calibrated radiation detection instru- Further Readings: Hall, E. J. and A. J. Giaccia. 2006. ment used to make accurate measurements of radiation fields in Radiobiology for the Radiologist, 6th edn., Lippincott Williams & order to make dose assessments of the output of clinical equip- Wilkins, Philadelphia, PA; Nias, A. H. W. 1998. An Introduction ment, or to describe the hazard to persons present in the area. to Radiobiology, 2nd edn., John Wiley & Sons Ltd., Chichester, UK. Surviving fraction (Radiotherapy) The surviving fraction is the proportion of cells Susceptibility that survive irradiation. A plot of surviving fraction against radia- (Magnetic Resonance) The degree of magnetisation of a material tion dose is called a cell survival curve and is usually presented in in an applied magnetic field is called magnetic susceptibility, χ. The magnetic field is strengthened, χ positive, by a paramagnetic material but it is weakened, χ negative, by a diamagnetic material. Susceptibility effect can be advantageous in the following Surface wave cases: Displacement 1. Detection of haemorrhage due to the paramagnetic properties of deoxyhemoglobin. 2. Dynamic susceptibility contrast MRI, where measure- ment of perfusion can be assessed using a paramagnetic contrast agent (gadolinium chelate). The contrast agent is injected intravenously and followed through rapid imaging. The dynamic time curve describing suscep- tibility-induced signal drop during first passage of the contrast agent can then be used to calculate perfusion FIGURE S.117 Surface (or Rayleigh) wave. The particles move in a cir- parameters such as cerebral blood flow (CBF) using cular pattern. (Courtesy of EMIT project, www .emerald2 .eu) tracer kinetics. Surviving fraction Susceptibility-weighted imaging (SWI) MRI 912 Symmetric energy window Related Articles: Dynamic susceptibility contrast MRI, depths will produce spikes of identical amplitude on the cathode Ferromagnetism, Paramagnetism ray tube screen irrespective of depth of the interface that pro- duced the echo. Susceptibility-weighted imaging (SWI) MRI Related Articles: Depth gain control, Time gain control (Magnetic Resonance) In susceptibility-weighted imaging (SWI), susceptibility differences between tissues are exploited as a con- SWI (Susceptibility-weighted imaging) trast mechanism. It is well-known that susceptibility differences (Magnetic Resonance) See Susceptibility-weighted imaging (SWI) between two adjacent structures lead to a magnetic field spatial deviation within and around the interface, which is a function of Switch off their geometries. Consequently, MR signals from substances with (General) See Switch on different magnetic susceptibilities compared to their neighbour- ing tissue are out-of-phase with these tissues. In SWI, phase infor- Switch on mation is used to enhance the contrast of the magnitude image. (General) Switching on means turning on (energising) an electri- The SWI datasets are obtained by flow-compensated three- cal device (or vice versa–off) by allowing current to flow through dimensional gradient-echo sequences and both magnitude and the circuit and the switch when closed (or by providing isolation phase images are reconstructed. The echo time is optimised when opened). to exploit the dephasing associated with susceptibility. As spin In IEC-60601-1 compliant medical electrical equipment the dephasing is faster, increasing the field strength, the optimal switches used to control power to medical electrical equipment echo time decreases, increasing the magnetic field strength. or its parts, including mains switches, have their ‘on’ and ‘off’ Consequently, the acquisition time of SWI sequences is shorter at positions marked with symbols corresponding to IEC 60417- high field compared to lower field (i.e. TE = 40 ms, TR = 60 ms at 5007 (I) and IEC 60417-5008 (O), or indicated by an adjacent 1.5 T; TE = 10 ms, TR = 25 ms at 7 T). indicator light, or indicated by other unambiguous means The SW image is obtained by multiplication of the magni- (Figure S.119). tude image with a phase mask designed to weight the pixels of Related Articles: Switch off, Switch, Toggle switch, Dead the magnitude image according to their phases. However, the man’s switch, Exposure switch, Foot switch acquired phase image contains information about all magnetic fields (due to local susceptibility, chemical shift, global patient Symmetric energy window geometry and scanner main field) while only the local infor- (Nuclear Medicine) In a symmetric energy window, the photo- mation on tissue susceptibility is of interest in SWI. To remove peak is located in the centre of the window. For example, 99mTc the low-spatial frequency components of the background field, has a photopeak at 140 keV. A symmetric energy window with a high-pass filter is applied to the phase image as the first step 20% would result in a 140 ± 14 keV window. Changing the width S of the SWI image processing. In the second step, the processed of the energy window to a narrower window will degenerate the phase image, with the background field changes removed, is detector uniformity. In SPECT and planar scintillation camera used to create the phase mask. As an example, a negative phase imaging an appropriate energy width is decided with a uniformity mask set equal to zero pixels with phase −π, applies a weight quality control provided by the manufacturer. A correct and stable smaller than 1 to pixels with negative phase and does not affect energy window is crucial for accurate data acquisition. the signal intensity of pixel with positive phase. Similarly, a pos- Further Reading: Graham, L S., A. Todd-Pokropek and itive mask can be defined. Diamagnetic and paramagnetic struc- E. Busemann Sokole. 2003. IAEA Quality Control Atlas for tures are differentiated according to the positive or negative Scintillation Camera Systems, International Atomic Energy phase shifts, i.e. ferritin molecule is highly paramagnetic and Agency, Vienna, Austria. calcium in tissue acts as a diamagnetic substance. Moreover, the Hyperlink: www .IAEA .org repeated application of the phase mask modulates contrast and noise. In SWI, the highest visibility is obtained by structures with largely different susceptibilities compared to their surrounding tissues, such as deoxygenated blood in veins, hemosiderin and methemoglobin in haemorrhage or iron-rich brain nuclei. The clinical application of SWI is increased with the diffusion of MRI scanner with 3 T magnetic field or higher. Related Articles: Magnetic susceptibility, Susceptibility, Phase angle, Gradient echo Further Reading: Haacke, E.M. et al. 2009. Susceptibility- weighted imaging: technical aspects and clinical applications, Part 1. Am. J. Neuroradiol. 30:19–30. https://doi .org /10 .3174 /ajnr .A1400 Swept gain (Ultrasound) Swept gain control, sometimes called ‘depth-cor- rected gain control’, ‘time-corrected gain control’ or ‘distance amplitude-correction gain control’, is a scheme designed for increasing the gain of the receiver system the later the ultrasound echoes are received. By adjusting this gain properly, echoes FIGURE S.119 On-off switch of a mammographic equipment marked from acoustic mismatches of the same magnitude but at different with relevant symbols. Synchrocyclotron 913 Synthesised 2D mammography Synchrocyclotron circular accelerators. As the particle energy increases in synchro- (Radiotherapy) Synchrocyclotrons combine the features of syn- trons, it takes less time for the particles to traverse one orbit, so chrotrons and cyclotrons. Synchrocyclotrons are like cyclotrons the magnetic field strength must increase in sync with the par- in that particles are accelerated between D-rings and travel along ticles’ increase in speed. As a result, the radii of the particle orbit circular orbits outwards. Synchrocyclotrons are like synchrotrons stay roughly the same for different energies, unlike in fixed-field in that the time for particles to complete a half orbit in a D-ring alternating gradient accelerators where the orbit radius increases (for two-D-ring cyclotrons) increases with radius, so the radiofre- with increasing speed. quency (i.e. the frequency to switch the electric field between the The size of a synchrotron is about 8 m for proton acceleration, D-rings) must decrease with radius, i.e. the radiofrequency must and about 25 m for heavier ions. Since the magnets must be in be in sync with the particle speed. sync with the particle speed, synchrotrons can only accelerate one Related Articles: Synchrotron, Cyclotron ‘bunch’ of particles at one time. As a result, synchrotrons have low average dose rate and limited average intensity. Advantages Synchronisation of synchrotrons are they can output variable energies (unlike (General) Synchronisation is a situation when two or more cyclotrons which output fixed beam energy) and they can accel- processes coordinate their activities based upon a condition. erate any particle (they just need to adjust the field strengths of Synchronisation is also the process of determining (usually chan- the synchrotron components). Another advantage is that if higher nel) parameters from a received signal (e.g. carrier frequency energy is required, an additional linear accelerator can be con- offset, carrier phase, or symbol timing), or timekeeping, which nected to the entrance of the synchrotron. requires the coordination of events to operate a system in unison Related Articles: Fixed field alternating gradient accelerators, (based on GPS and network time protocol (NTP) timekeeping Cyclotrons, Linear accelerator systems). In diagnostic radiology, reduction of breathing motion arte- Synthesised 2D mammography facts can be achieved by using respiration synchronised gating (Diagnostic Radiology) Also known as synthetic mammog- techniques. The latter use external devices to predict the phase of raphy (SM). It consists of two-dimensional images recon- the respiration cycle while the patient breathes freely. structed from digital breast tomosynthesis (DBT) data. DBT is Cardiac synchronisation methods (see the article Cardiac gat- both a diagnostic and screening modality. In DBT, the images ing) used to synchronise with cardiac motion essentially rely on are acquired at multiple angles and are viewed as a series of the electrocardiogram (ECG). The peripheral pulse is only used sequential sections. DBT is usually used in combination with as a last resort. Cardiac synchronisation limits the artefacts linked two-dimensional full-field digital mammography (FFDM) to to the motion of the heart and blood flow, thus enabling the differ- compare it with previously acquired two-dimensional images ent phases of the cardiac cycle to be sampled. (Figure S.120). Related Article: Cardiac gating However, the introduction of the DBT/FFDM combination S results in increased radiation dose and increased acquisition time. Synchrotron for particle therapy This has led to the development of SM where DBT data are pro- (Radiotherapy) Synchrotrons accelerate charged particles in an cessed to reconstruct FFDM lookalike images. Some clinical data annular ring of radiofrequency chambers and magnetic compo- have demonstrated that SM images are comparable to FFDM in nents (dipoles, quadruples). Synchrotrons are within the class of cancer detection positive predictive values and recall rates. It is FIGURE S.120 Two-dimensional full-field digital mammography and two-dimensional synthesised mammogram. (Images courtesy of Dr W. Y Chan, University of Malaya.) Syringe shield 914 S ystem of work anticipated that with the advancement of technology SM will for reading syringe markings. Another syringe shield is made completely replace FFDM. entirely of leaded glass facilitating the reading of the syringe Synthesised 2D mammography is called C-View by Hologic, marks. A thickness of 3 mm lead reduces the 99Tcm-exposure rate V-preview by GE and Insight 2D by Siemens. by a factor of 1000. Tungsten is 50% denser than lead thus reduc- Related Articles: Digital breast tomosynthesis, Full-field digi- ing the syringe shield thickness. The relative absorbed dose to the tal mammography fingers is also dependent on the position on the shield and on the Further Reading: Ratanaprasatporn, L., S. A. Chikarmane, filling volume of the syringe (Figures S.121 and S.122). and C. S. Giess. 2017. Strengths and weaknesses of synthetic Further Readings: Kowalsky, R. J. and S. W. Falen. 2004. mammography in screening. RadioGraphics 37:1913–1927. Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine, 2nd edn., American Pharmacists Association, Syringe shield Washington, DC; Zolle, I., ed. 2007. Technetium-99 m (Nuclear Medicine) Syringe shields are used in nuclear medicine Pharmaceuticals–Preparation and Quality Control in Nuclear and nuclear pharmacy to reduce the absorbed dose to fingers

and Medicine, Springer, Heidelberg, Germany; Saha, G. B. 2004. hands of the persons working with both preparation and patient Fundamentals of Nuclear Pharmacy, 5th edn., Springer, New injections of the radiopharmaceuticals. One type of syringe York. shield is a tungsten shield with a leaded-glass viewing window System of work (Radiation Protection) A ‘system of work’ is a term used in cer- tain countries to describe radiation protection procedures regard- ing access to designated radiation areas, to minimise the risk of staff and other persons receiving significant radiation exposure. Systems of work contain detailed information and instructions for any worker not designated as a classified worker, and for con- tractors and visitors who are required to enter a controlled area, such that their radiation doses received are kept below 3/10 of any dose limit. In principle classified workers, who are by definition expected to receive more than 3/10 of a dose limit, cannot be following the system of work for the controlled area because if they did then they would not have to be classified. They will still be expected to follow the more general requirements set out in the local rules S document. Information on any safety requirements, time restrictions, use of personal protective equipment and devices, shielding etc. should be specified in the systems of work. Usually the local radiation protection supervisor, with support from the head of department and radiation protection adviser is given the duty of preparing the system of work, which will be tailored to vari- ous functions and situations. It is a further requirement that all involved individuals must receive adequate training in the proce- dures set out in the document. Finally, there may be contingencies described in the local rules FIGURE S.121 Typical syringe shields for 5 and 10 mL syringes. document for the controlled area that are used for emergency 7 7 6 1 6 With syringe shield 5 5 4 2 4 3 5 3 2 9 2 1 18 1 0 0 1 2 5 9 % of max dose rate 0 75 15 2 0.4 % of max dose rate 4 0.5 0.09 0 0.4 without syringe shield (a) (b) FIGURE S.122 Dose rates around a 2 mL syringe filled with 1 mL 99mTc. (a) Unshielded syringe. (b) Shielded syringe and the dose rates are nor- malised to the maximum dose rate in an unshielded syringe. (cm) (cm) Systemic chemotherapy 915 System resolution in a scintillation camera situations (fire alarm, etc.), and for which in the interests of the which result from fast-dividing cells of the body, such as hair immediate danger to staff and other persons, the normal systems cells, blood cells and bowel lining cells. Toxicities can be acute of work will not therefore apply. occurring within hours or days, or chronic occurring in weeks Related Articles: Classified worker, Controlled area, Local to years of administration. Due to the systemic nature of chemo- rules, Radiation protection supervisor, Radiation protection adviser therapy, almost all regimes can cause impairment of the immune system. This impairment can result in the patient catching infec- Systemic chemotherapy tions from others, or developing infections due to naturally occur- (Radiotherapy) Chemotherapy is a cytotoxic (toxic to living ring micro-organisms already found within the patient. cells) drug which can be given with curative or palliative intent. As with all cancer treatment modalities, chemotherapy has Chemotherapy can be given with surgery or radiotherapy as its limitations. Chemotherapeutic agents are limited in treating either neoadjuvant treatment (chemotherapy is used to shrink the brain cancers as the agents are often not able to pass the blood- tumour) or adjuvant treatment (following the primary treatment brain barrier, which is designed to protect the brain from harmful to address the risk of subclinical metastatic disease). The use of chemicals. However, this is an active field of research and some chemotherapy is usually referred to as systemic as many of the agents such as lomustine or temozolomide are able to cross the toxic agents used are circulated throughout the body using the blood-brain barrier. Furthermore, chemotherapy is often deliv- bloodstream. This can be beneficial as it can treat cancer cells ered through the blood vessels; tumours, which often have poorly almost anywhere in the body. However, the downside of this sys- formed vasculature, may have areas at which are not accessible by temic approach is that the toxic agents are indiscriminately lethal the cytotoxic agent. Cancers may also be chemo-resistant, mak- to both normal and cancerous cells, so the normal tissue toxicity ing them resilient to the chemotherapy agent and therefore either must be managed carefully. limiting or entirely negating the therapeutic window. Some can- Broadly speaking, most chemotherapy agents function through cers may have gene amplification which can result in increased the impairment of cells to undergo cellular mitosis (cell division). DNA repair activity or defective cell death pathways response. The DNA damage which is inflicted by the cytotoxic agent will Alternatively, cancer cells may produce a large number of p-gly- often trigger a cellular death pathway at the point of mitosis, such coprotein pumps on the cell surface, which effectively help cancer as apoptosis (programmed cell death), and die. This is beneficial cells remove chemotherapy molecules from inside the cell to the when treating cancer as typically cancer cells will be proliferating outside. frequently, whilst a lot of normal cells may be non-proliferating, Related Articles: Adverse effect, Cell cycle, Cell prolifera- resulting in a therapeutic window of preferentially treating cancer tion, Cell survival, Probability of cell survival (Figure S.123). Further Reading: Corrie, P.G. 2008. Cytotoxic chemother- With chemotherapy biological mechanisms revolving around apy: clinical aspects. MEDICINE 10.1016/j.mpmed.2007.10.012 mitosis, the tumour which has high proliferation rates (which cor- respond to growth rates in the context of tumours), are more sensi- System resolution in a scintillation camera S tive to chemotherapy. As an example, this is why chemotherapy is (Nuclear Medicine) A gamma camera’s ability to depict sharp more suitable to treat aggressive lymphomas (e.g. high-grade non- edges and point sources is referred to as the system resolution. Hodgkin’s lymphoma) rather than indolent lymphomas. There is a There are two main factors affecting the system resolution Rsys in wide range of cancers which chemotherapy can be used for which a gamma camera, namely the intrinsic resolution Rint and the col- have been covered in the literature (Corrie, 2008). limator resolution Rcoll. The intrinsic resolution includes the spa- Chemotherapeutic side-effects can depend on the type of agent tial degenerative properties of the electronics and detector crystal. used. However, generally, the most common effects are those The combination of these two factors is Rsys = R2 2 int + Rcoll (S.22) Since the collimator resolution depends on the source to collima- tor distance so does the system resolution. At typical organ depths (5–10 cm) the system resolution is much poorer than the intrin- sic resolution which means that it is primarily determined by the collimator resolution. Differences in intrinsic resolution between camera systems might appear when imaging superficial structures but is not a dominating factor when imaging organs and structures at greater depths. The system resolution is also degraded by scattered radia- tion and septal penetration. The fraction of scattered radiation increases with photon energy and distance travelled through an absorbing medium before detection. The effects of scattered radi- ation can be limited using pulse height analysis and dual energy window techniques so that the degeneration of system resolution is small. The fraction of septal penetration increases with photon energy. This contribution to resolution degeneration can be lim- ited using a collimator appropriately designed for the specific photon energy. FIGURE S.123 Dose-response curved for a chemotherapy drug for kill- Related Articles: SPECT, Spatial resolution, Spatial resolu- ing cancer and normal cells. tion SPECT Système International (SI) 916 Système International (SI) Further Reading: Cherry, S. R., J. A. Sorenson and M. E. tera T 1012 piko p 10−12 Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, giga G 109 nano n 10−9 Philadelphia, PA, pp. 244–245. mega M 106 micro μ 10−6 kilo k 103 milli m 10−3 Système International (SI) hecto h 102 centi c 10−2 (General) The International Bureau of Weights and Measures deca da 101 deci d 10−1 (Bureau International des Poids et Mesures–BIPM) during sev- eral General Conferences on Weights and Measures (Conference Generale des Poids et Mesures–CGPM) adopted the International The SI consists of the coherent-derived units expressed in terms System of Units (SI) (Système International) based on the seven of base units, e.g. velocity (m s−1), acceleration (m s−2) and coher- units: metre (m) for length, kilogram (kg) for mass, second (s) for ent derived units with special names, e.g. hertz (Hz) for fre- time, ampere (A) for electric current, kelvin (K) for thermody- quency, newton (N) for force, joule (J) for energy, becquerel (Bq) namic temperature, candela (cd) for luminous intensity and mole for activity, gray (Gy) for absorbed dose, sievert (Sv) for equiva- (mol) for amount of a substance, and on two supplementary units: lent dose, effective dose, ambient dose equivalent and directional radian (rad) for plane angle and steradian (sr) for solid angle. dose equivalent. The SI introduced the names of multiples and submultiples of Abbreviations: BIPM = Bureau International des Poids the units which are formed by means of the following prefixes: et Mesures and SI = International System of Units (Système International). Hyperlink: http://www .bipm .org /en /home/ yotta Y 1024 yocto y 10−24 Further Reading: International Committee for Weights zetta Z 1021 zepto z 10−21 and Measures. 2006. The International System of Units (SI) exa E 1018 atto a 10−18 Organisation Intergouvernementale de la Convention du Mètre. peta P 1015 femto f 10−15 www .bipm .fr /en /si /si _brochure (accessed on 18 July 2012). S T T1 In the T1-weighted image fat has a strong signal due to its short (Magnetic Resonance) See Relaxation time T1 constant, since a larger percentage of fat spins will relax before the next excitation RF pulse. Water has a rather long T2 constant T1 rho (T1ρ) and will therefore have more signal left and appear white in the (MRI) T1 rho (T1ρ) describes a relaxation mechanism that is image. Cerebral white matter has a shorter T1 than grey matter related to T1 (spin-lattice) relaxation in the transverse plane under and will therefore be more intense (Figure T.2). the presence of an RF pulse. After an initial RF pulse, T1ρ relax- In spoiled gradient echo MRI strong T1-weighting can be ation effects are created applying a second RF pulse applied in achieved by using a large flip angle (e.g. >50°) to avoid the pos- line (or parallel) to the magnetisation vector. The second pulse sibility for the excited spins to have time to return to the longitu- ‘locks’ the magnetisation vector into the transverse plane, causing dinal direction. transverse magnetisation to decay with the surrounding spin-lat- Related Articles: Echo time (TE), Relaxation, Relaxation tice (T1) effect rather than spin-spin (T2) effects. T1ρ depends on time (T1), Repetition time (TR), T1 a tissue’s T1 and T2 values and the power of the spin-lock pulse. Further Reading: McRobbie, D. W., E. A. Moore, M. J. The sequence increases image sensitivity to interaction between Graves and M. R. Prince. 2003. MRI: From Picture to Proton, large molecules and water protons. The major current clinical Cambridge University Press, Cambridge, UK. indication is for use in cartilage imaging (Figure T.1). Related Articles: Relaxation time, Radiofrequency T2 Further Reading: Wang, Y. X., Q. Zhang, X. Li, W. Chen, A. (Magnetic Resonance) T2 denotes the transverse relaxation time, Ahuja and J. Yuan. 2015. T1ρ magnetic resonance: Basic physics that is the time constant for the irreversible decay of the magne- principles and applications in knee and intervertebral disc imag- tisation vector M component that is perpendicular to the main ing. Quant. Imaging Med. Surg. 5(6):858–885. magnetic field B0 after RF excitation. See Relaxation time. Related Articles: Relaxation, Relaxation time, Relaxation T rate, T2-weighted 1-weighted (Magnetic Resonance) In a T1-weighted MR image the difference in T1-relaxation time is the main parameter of the image contrast. T2-shine through However the proton density (PD) will always contribute to the (Magnetic Resonance) The T2-shine through effect is especially image intensity and thus also influence image contrast. important when diagnosis is based on diffusion weighted (DW)

T In spin echo MRI T1-weighting can be achieved by using a images, that is if ADC maps are not calculated. In diffusion imag- short repetition time (TR) and a short echo time (TE), typically ing, the basic protocol uses spin echo (SE) pulse sequence with TR < 700 ms and TE < 30 ms. With the short TR the spins in the long echo times (TE) and long repetition times (TR), a combi- tissues with a long T1 will not have time to fully relax back to the nation that normally constitutes a T2-weighted image. On top of longitudinal direction (z-direction). This leads to a reduction in this, the diffusion encoding gradients are added, (requiring sub- signal for tissues with long T1 because there are not so many spins stantially long TEs) and thus the signal decay is influenced by in the longitudinal direction that can be excited. The short TE will the combined effects of T2-relaxation and long TEs as well as the reduce the influence of T2 relaxation. diffusion coefficient (D) and the diffusion sensitivity (b-value). In spin echo MRI the transversal magnetisation can be The signal decay is given by described by S = S e-T2 /TEe-bD 0 M = M ( - e-TR /T 0 1 1 ) -TE /T2 xy e where If TE is much shorter than T2, the equation can be reduced to S0 is the initial signal amplitude S is the measured signal affected by the imaging protocol M » M (1 - -TR /T1 xy 0 e ) parameters TE and b-value as well as the intrinsic object parameters T2 and D For small TR the equation can be reduced further (ignoring the higher order terms of a Taylor series representation of the expo- The equation implies that for low diffusion sensitivities the nential term): T2 effect will dominate. The actual crossing point where the T2- weighted contrast will no longer dominate the image depends on TR the T2 and D values of the tissue. An intense signal area can for Mxy » M0 an image acquired with a low b-value indicate either a long T2 T1 or decreased diffusion. Examining for instance a patient with an The last equation shows that the transversal magnetisation (sig- ischemic stroke (Figure T.3) in the acute phase and who has a his- nal) depends on the T1 and the spin density (M0) of the tissue. tory of earlier strokes, lesions corresponding to the ‘old infarct’ 917 T2-weighted 918 T2-weighted will also appear bright in images of low diffusion sensitivity due to its high water content. In the upper row a high signal lesion is marked with an arrow in the b = 0 s/mm2 image. A similar- looking lesion marked with an arrow, is also present in the bottom row. Following the lesions for increasing b-values shows that for a b-value of 1000 s/mm2 the lesion corresponding to a chronic lesion, (bottom row) is no longer visible. Examining the ADC maps gives a correct representation of the lesions where the acute lesion shows a low ADC value whereas the chronic lesion appears bright due to increased water content. For ischaemic stroke it is considered safe to use b-values above 1000 s/mm2 in order to avoid effects from T2-shine through (Figure T.3). Related Articles: b-value, Diffusion imaging T2-weighted (Magnetic Resonance) In a T2-weighted MR image differences in T2-relaxation times are the main source of image contrast. FIGURE T.1 Images made with T1ρ contrast. An intervertebral disk However the proton density (PD) will always contribute to the (IVD) with normal collagen (top) and an IVD with deteriorated collagen. image intensity and thus strongly influence image contrast. T FIGURE T.2 PD-, T1- and T2-weighted transverse spin echo image of the head (TR = 3000/630/3000 ms, TE = 20/17/80 ms). b = 0 b = 400 b = 600 b = 1000 ADC FIGURE T.3 Images obtained from a patient with an ischemic stroke in the acute phase. Similar looking lesions are marked with arrows in b = 0 s/ mm2. Increasing b-values show that the bottom row lesion corresponds to a stroke lesion in the chronic phase. T2-weighted 919 Tantalum In a conventional spin echo sequence this can be achieved with Table top a long repetition time (TR > 1500 ms) and an appropriate long (Diagnostic Radiology) The top of the patient table of any imag- echo time (TE > 75 ms). With a long TR the excited spins in all ing equipment has to be not only capable of supporting the tissues will have time to relax back to the longitudinal direction patient, but also have minimal influence on the image, that is be (z-direction). Therefore, image contrast is based on differences in almost ‘invisible’. For example, the patient table in x-ray imaging T2-relaxation and spin density M0, see Figure T.2. has to be with minimal absorption, as it stays between the patient In spin echo MRI, the transversal magnetisation (excited and the detector (usually the cassette holder and anti-scatter grid spins) can be described by are under the table top). In contemporary x-ray equipment this is achieved by using table top made of special carbon fibre materi- M = M ( - e-TR /T 0 1 1 )e-TE /T2 xy als. However even such a table top would absorb 30%–50% of the radiation exiting the patient (the modulated x-ray beam), thus If TR is much longer than T1 the equation is reduced to reducing significantly the amount of modulated radiation reach- ing the detector. To reduce this effect (as well as the magnifica- M = M e-TE /T2 xy 0 tion), some x-ray radiography procedures require the detector (or film) to be as close as possible to the patient (e.g. typically The signal in the xy-direction is only dependent on the spin den- in mammography). In this case the detector (or film cassette) is sity M0 and the T2 of the tissue. placed below the patient – directly on the top of the table. This In the T2-weighted image fat, that has a short T2 constant so radiographic method is known as ‘table top examination’. that signal (Mxy) drops off faster after the RF-excitation, has a weak signal on T2-weighted image with longer TE and will appear TADR (Time-averaged dose rate) with less signal intensity. Water has a rather long T2 constant (Radiation Protection) See Time-averaged dose rate (TADR) and will therefore have much signal left and appear white in the image. Cerebral white matter is less intensive than grey matter. Tangent fields In a spoiled gradient echo there is no refocusing of the spins (Radiotherapy) This is the most common field arrangement (see Spin echo), which leads to the effect that inhomogeneities used for breast radiotherapy. An illustration of this is given in in the magnetic field will reduce the transversal relaxation rate. Figure T.4. In this technique the diverging posterior beam edges Hence, true T2-weighting is not achieved in this type of sequence of two fields are matched together along a single line to minimise but rather so-called T * 2 -weighting (see Relaxation). the dose to the lung tissue, by careful selection of gantry angle. Related Articles: Echo time (TE), Flip angle, Relaxation, Related Articles: Beam arrangement, Beam divergence Relaxation time, Spin echo, Repetition time (TR), T2 Further Reading: McRobbie, D. W., E. A. Moore, M. J. Graves and M. R. Prince. 2003. MRI: From Picture to Proton, Tantalum Cambridge University Press, Cambridge, UK. (General) T * 2 Symbol Ta (Magnetic Resonance) Transverse magnetisation generated by Element category Transition metal T an RF pulse undergoes exponential decay because of spin–spin Mass number A 181 relaxation. However, in practice it is found that the free induc- Atomic number Z 73 tion decay (FID) or echo signal decays more rapidly than T2 alone Atomic weight 180.948 g/mol would suggest. The actual rate of decay is known as T * 2 , such that Electronic configuration 1s2 2s2 2p6 3s2 3p6 3d10 4s2 4p6 4d10 4f14 5s2 5p6 5d3 6s2 Mxy = M0 exp(-t / T * 2 ) Melting point 3290 K Boiling point 5731 K This phenomenon occurs because of inhomogeneities on a micro- Density near room temperature 16.4 g/cm3 scopic scale in the static magnetic field. Even if a magnet could be constructed with a perfectly uniform field, this would be distorted by placing an object in the field for imaging, and specifically by differences in magnetic susceptibility between components of the object (different tissues and anatomical structures in the case of in vivo imaging). The resulting effective relaxation time is given by 1 1 Dw Beam 2 = T * + 2 T2 2 where Δω = γΔB and ΔB is the magnetic field inhomogeneity. A spin echo can be used to reverse the effects of field inho- mogeneity and recover a true T2-weighted signal. Alternatively, a sequence using gradient echo acquisition alone will result in a T * 2 weighted image. Beam 1 Related Articles: Free induction decay (FID), Gradient echo (GE), Magnetic susceptibility, Spin echo, Spin–spin relaxation, Static field, Transversal magnetisation, T2-weighted FIGURE T.4 An illustration of a tangential field arrangement. Tantalum filter 920 Target volume History: Tantalum was first discovered in 1802, but it was only Target dose distribution in 1907 that a sample of the relatively pure metal was produced. (Radiotherapy) The distribution of dose within a target is called It is usually extracted along with niobium from minerals such as the target dose distribution. Knowledge of this allows the degree columbite and tantalite. It is a strong ductile metal with excep- of conformity and the homogeneity of the dose distribution pat- tional resistance to chemical attack. It is therefore used to make tern inside the radiotherapy target volume to be evaluated. components that need to operate in aggressive environments where corrosion is not acceptable. Target film distance (TFD) Medical Applications: Instruments and implants – The pas- (Diagnostic Radiology) The term target film distance (TFD) is sive nature and corrosion resistance of tantalum make it a suitable used in planar x-ray radiology to describe the distance between material for surgical instruments and implants. In particular it is the x-ray target or focal spot in the x-ray tube, and the surface regarded as a favourable material for implants in bone, where it of the film. It is sometimes referred to as the focal film distance has been reported to display osseointegration. (FFD). In modern digital radiology where film is no longer used, the distance between the target and detector is called the focal Tantalum filter detector distance (FDD) which is also known as the target detec- (Diagnostic Radiology) The shaping of the x-ray spectrum in tor distance (TDD), the focal image receptor distance (FID), or diagnostic radiology requires specific filtering of the x-ray beam the target image receptor distance (TID) (Figure T.5). with various metal filters with different photon energy attenuation Related Articles: Focal film distance (FFD), Object film dis- characters. The most often used filters are aluminium and copper tance (OFD), Object image receptor distance (OID), Magnification which selectively absorb the low-energy (soft) radiation reducing the absorbed patient dose. Other metal filters are gadolinium and Target localisation tantalum which are mainly used in fluoroscopic examinations. (Radiotherapy) The first stage in planning radiotherapy treatment Gadolinium filters (with K-edge 50.2 keV) are useful for is to determine the location of the tumour/target. This is generally examinations with iodine-based contrast media (iodine K-edge is achieved using imaging of soft tissue to establish the location and 33.17 keV). visible extent of the tumour. This is known as the GTV (gross Tantalum filter (most often used by the manufacturer Toshiba) tumour volume). Margins are grown around this to account for has a K-edge 67.4 keV and is useful for examinations using metal uncertainties in the treatment process. catheters and needles. This filter has significantly more absorp- Localisation for Planning: CT and MRI are the imaging tion of low-energy radiation, compared with the usual copper techniques used most commonly for target localisation in radio- filter. Tantalum filters attenuate significant radiation above its therapy planning. The location of the tumour and critical normal K-edge and reduce the scatter radiation from the metal catheters tissues is outlined on the images and dose calculations carried out and needles. Some examinations show up to

30% decrease of monitoring the doses each are expected to receive. effective patient dose in such examinations. Tantalum filters are Localisation for Verification: Soft tissue imaging may be very thin (e.g. of the order of 0.05 mm), compared with copper used during each treatment fraction to locate the tumour position filter (e.g. between 0.1 and 0.5 mm thickness). and correct set-up before irradiation starts. A common technique Related Articles: Aluminium, Copper, X-ray beam filtration, to achieve this is conebeam CT on the treatment machine. T Added filtration, Beam spectrum See also all other articles on volumes and margins Further Reading: Rossi, P. L. et al. 2009. Decrease in patient Abbreviation: GTV = Gross tumour volume. radiation exposure by a tantalum filter during electrophysiological procedures. Pacing Clin. Electrophysiol. 32(Suppl 1):S109–S112. Target organ Hyperlinks: https :/ /us .medi cal .c anon/ produ cts /x -ray/ ultim ax - (Radiotherapy) Radiotherapy treatments may target a particular i/ benefi ts/ organ; however, it is more common for them to be described in terms of target volumes – for example the clinical target vol- ume (CTV) describes the full extent of malignant growth that Taper is grossly visible, plus subclinical microscopic growth which is (Diagnostic Radiology) See Fibre optic taper based not just on anatomy but biological considerations. The CTV often includes regional lymph nodes. TAR (tissue air ratio) Related Articles: Target volume, Clinical target volume (Radiotherapy) See Tissue air ratio (TAR) Target volume Target angle (Radiotherapy) This is a generic term for the volume containing (Diagnostic Radiology) See Anode angle malignancy that is targeted by radiotherapy or brachytherapy in order to eliminate the cancerous cells. More specific descriptors Target cooling are given in ICRU 60, specifying distinct components of the tar- (Diagnostic Radiology) See Anode-cooling curve get volume as the gross tumour volume (GTV), clinical target vol- ume (CTV), and planning target volume (PTV). See individual Target dose articles for more information. (Radiotherapy) This could refer to many different aspects such as Related Articles: Gross tumour volume (GTV), Planning tar- mean target dose, maximum target dose, minimum target dose, get volume (PTV), Clinical target volume (CTV) modal target dose. The target dose would be considered along Further Readings: ICRU (International Commission on with dose–volume constraints. Radiation Units and Measurements, Inc.). 1993. Prescribing, Related Articles: Mean target absorbed dose, Maximum tar- reporting and recording photon beam therapy. ICRU Report 50, get absorbed dose, Minimum target absorbed dose, Modal target Washington, DC; ICRU (International Commission on Radiation absorbed dose Units and Measurements, Inc.). 1999. Prescribing, recording and Target of x-ray tube 921 Target of x-ray tube X-ray tube housing Focal spot Target Internal collimators Focal film distance (FFD) or Target film distance (TFD) Focal object distance (FOD) Object Object film Ant-scatter grid distance (OFD) Film or detector surface FIGURE T.5 Distance metrics in planar radiography. reporting photon beam therapy (Supplement to ICRU Report 50). ICRU Report 62, Washington, DC. T Target of x-ray tube (Diagnostic Radiology) The small region of the anode, which is bombarded by the thermal electrons and produces x-rays is called the target. In stationary anode x-ray tubes it is a small Tungsten plate (∼1 mm thick). Almost 99% from the energy imparted to the target by the electrons is converted to heat and generation of sec- ondary electrons (strictly speaking the thermal energy converted directly to heat is ∼75%). Due to this reason the material of the target is normally tungsten – a material with a very high melting point (3410°C) and high atomic number. The latter is important for the effective conversion of the energy of electrons to x-rays. The ‘Bremsstrahlung generation efficiency’ (η) is the ratio of the intensity of x-ray radiation (W) and the energy flux of the electron beam (E ∼ I U). The intensity of x-ray radiation W (x-ray energy flux density) FIGURE T.6 Tungsten target of tube with stationary anode (a plate with round or rectangular shape). Note the melted area of the actual focal spot. is W ∼ I U2 Z, where W is the intensity of x-ray radiation, I is the (Courtesy of EMERALD project, www .emerald2 .eu) anode current, Z is the atomic number of anode, U is the acceler- ating high voltage (anode tension – kV), from what follows that η ∼ W/E ∼ k U Z. The constant k is experimentally established as 1.1 × 10−9. For is converted to useful radiation. Due to this reason a very high tungsten Z = 74. Thus for 100 kV the bremsstrahlung generation electron beam energy is necessary for production of useful x-rays. efficiency is approximately 0.8%. But the x-rays are spread in dif- As a result the target of the anode heats up to very high tempera- ferent directions (isotopic x-ray emission) and just a small propor- tures during the exposure (Figure T.6 – the photograph shows the tion of them leave the tube in the direction of the patient. This anode removed from the tube). radiation is additionally absorbed in the tube housing and added The other reason for choosing tungsten for the anode material filtration. Thus less than 0.1% of the energy imparted to the anode is its high thermal conductivity. One disadvantage of tungsten is Targeted alpha therapy 922 Tc-99m albumin microspheres (HAM) thermo-mechanical stress due to high thermal gradients, which most important of these would be the 225Ac: 213Bi generator. With leads to cracks on the tungsten surface. The cracks not only a half life of 10 days, 225Ac can be delivered around the world and decrease the life of the x-ray tube (damaging the anode), but eluted (milked) to produce 213Bi. This is chelated to the monoclo- also make the target surface uneven. The cracked anode surface nal antibody specific for the targeted cancer to form the alpha- causes scattering or absorbing (in the cracks) of some of the x-ray immunoconjugate (AIC). 213Bi has a 46 min half life, so patients quanta, and so decreases the tube efficiency. In order to minimise are treated as outpatients. this effect rhenium is added to the tungsten target (approximately The key requirement is to achieve disease regression within 2%–10% Re/W alloy) and special care is taken to remove the heat the maximum tolerance dose (MTD). This has been achieved in accumulated in the anode. The x-ray tubes with rotating anode the majority of trials. have all their front surfaces covered with this alloy, although only Comment: TAT was indicated for micrometastases or subclin- part of it is bombarded – the thermal path (Figure T.7 – the photo- ical cancer, for which targeting would be swift and the short alpha graph shows the anode removed from the x-ray tube, only part of range effective in killing the cancer cells. Liquid cancers such as the broken glass envelope is seen). leukaemia are also indicated as the uptake of short-lived radioiso- Some x-ray tubes use an anode target made from other materi- tope in the cancer mass is achieved within 5 min. However, TAT als (e.g. molybdenum or rhodium, used for mammographic tubes). was not indicated for solid tumours, where only a heterogeneous These types of target produce significant percentage of charac- distribution would be achieved. The short alpha range would pro- teristic radiation, which forms part of the mammographic x-ray hibit effective cross fire, as is the case for beta rays. In the case of spectrum. GBM, the AIC is injected into the post-surgical cavity, so shallow Related Articles: Anode, Rotating anode, Stationary anode, diffusion of the conjugate can be readily achieved. Filament heating Abbreviations: AIC = Alpha-immunoconjugate, AML = Hyperlinks: EMERALD (DR module), www .emerald2 .eu. Acute myelogenous leukaemia, GBM = Glioblastoma multiforme, LET = Linear energy transfer, MTD = Maximum tolerance dose Targeted alpha therapy and TAT = Targeted alpha therapy. (Radiotherapy) Related Article: Alpha-immunoconjugate Background: Radioisotopes (radionuclides) are used in nuclear medicine procedures for imaging and therapy. Imaging Tc-99m albumin microspheres (HAM) isotopes emit gamma rays; therapeutic isotopes emit low energy (Nuclear Medicine) Tc-99m-labelled human albumin micro- gamma rays or high energy beta radiation. Cancer is the main tar- spheres (HAM) are albumin spheres normally with an average get for therapeutic nuclear medicine. A new approach to therapy diameter of 40 μm (range 10–50 μm). It is used clinically for scin- is emerging where radioisotopes that emit very short range (80 tigraphy of pulmonary perfusion and determination of right-to- μm) alpha particles are tagged onto monoclonal antibodies for left shunt after an intravenous injection. After an arterial injection targeted alpha therapy (TAT). The alpha radiation is high linear microspheres may be used for regional perfusion in other organs. energy transfer (LET) radiation and transfers ∼100 keV/μm to A kit contains human serum albumin (HSA) microspheres, the targeted cells, causing increased double strand breaks in the stannous chloride and surfactants to avoid aggregation. nuclei of the targeted cancer cells. The radiation weighting factor Different labelling techniques may be used. The specific activity T for alphas is 20 and the relative biological effectiveness (RBE) for of 99Tcm-HAM should be higher than 185 MBq per 106 micro- tumour regression is ∼3–5. spheres and the number of 99Tc-atoms in the 99Tcm-elute should As of 2009, clinical trials are in progress for acute myelogenous be minimised. leukaemia (AML), metastatic melanoma, lymphoma, glioblastoma The number of microspheres can be determined by Coulter multiforme (GBM), and breast and prostate bone metastases. counter measurements. The 99Tcm-HAM microspheres should Methods: There are a number of suitable alpha emitting radio- be homogenously suspended to avoid in vivo aggregates when isotopes, viz 149Tb, 211At, 212Bi, 213Bi, 223Ra, 224Ra, 225Ac but the injected intravenously. Thus, no blood aspiration into the syringe is allowed. The radiochemical purity of 99Tcm-HAM microspheres can be determined using membrane (Millipore) filtration with a pore diameter of 3 μm. Less than 5% of the activity should be measured on the Millipore filter. It is also possible to measure the 2 radiochemical purity by centrifugation, or more conveniently by 1 paper or thin-layer chromatography. 99Tcm-HAM microspheres are trapped by the capillary bed, that is the lung after an I.V. injection where they later are metab- olised – larger microspheres are removed more slowly than the small ones. The organs that are most exposed to radiation are the lungs (mGy/MBq) and bladder wall (mGy/MBq). The retention in the lung can be modelled using a double exponential, 1.8h (60%) and 1.5d (40%). The microspheres are primarily excreted by the kidneys. The effective dose is 11 μSv/MBq – one of the lowest in diagnostic imaging. Normally the administered activity to an adult patient is 185 MBq. Abbreviations: HAM = Human albumin microspheres, HSA FIGURE T.7 Tungsten target of tube with rotating anode (the bom- = Human serum albumin and IV = Intravenous injection. barded target area is the visible ring 1, where two spots have been melted Related Articles: Tc-99m-sodium pertechnetate, – 2). (Courtesy of EMERALD project, www .emerald2 .eu) Tc-99m- HMPAO. Tc-99m SestaMIBI (methoxyisobutyl isonitrile) 923 Tc-99m-albumin (HSA) Further Readings: Annals of the ICRP. 1987. Radiation dose Tc-99m tetrofosmin to patients from radiopharmaceuticals, biokinetic models and (Nuclear Medicine) Technetium-99m-tetrofosmin, Myoview™ data, ICRP Publication 53, Vol. 18, Pergamon Press, Oxford, (GE Healthcare) is used for myocardial perfusion studies in UK; Annals of the ICRP. 1998. Radiation dose to patients from patients with coronary artery disease to diagnose ischemic heart radiopharmaceuticals, Addendum to ICRP Publication 53. ICRP disease and reduced regional perfusion and to localise myocar- Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; Council dial infarction and perfusion defects. The uptake of the lipophilic of Europe, European pharmacopeia (founded 1964), http://www 99mTc-tetrofosmin complex in the heart muscle is proportional .edqm .eu /en /Homepage -628.–html; Kowalsky, R. J. and S. W. to the blood flow. Uptake is due to diffusion and the complex is Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and retained by the viable myocytes. Nuclear Medicine, 2nd edn., American Pharmacists Association, Two injections are usually required to distinguish between a Washington, DC; Saha, G. B. 2003. Fundamentals of Nuclear transient and a permanent perfusion defect. One examination is Pharmacy, 5th edn., Springer, New York; Zolle, I. (ed.). 2007. performed after maximum exercise or pharmacological stress Technetium-99m Pharmaceuticals – Preparation and Quality and the other one at rest. The examinations are performed using Control in Nuclear Medicine, Springer, Heidelberg, Germany. SPECT or a planar technique and commence at 15–30 min

but the delay can be up to 4 h. Stress-rest imaging can be performed using Tc-99m SestaMIBI (methoxyisobutyl isonitrile) either 1- or 2-day protocols. (Nuclear Medicine) Technetium-99m-SestaMIBI, MIBI, Cardio- The tetrofosmin kit contains lyophilised, sterile, pyrogen-free, lite® (Bristol-Myers Squibb) is used for myocardial perfusion substance in nitrogen atmosphere, prepared for labelling with 4–8 studies in patients with coronary artery disease to diagnose mL of 99mTc–sodium pertechnetate not exceeding 1.11 GBq/mL ischemic heart disease and reduced regional perfusion and to and 8.88 GBq. The radiopharmaceutical is ready for use after 15 localise myocardial infarction and perfusion defects. The radio- min reaction in room temperature and should be used within 8 h pharmaceutical can also be used for breast imaging (Miraluma®, after preparation. The preparation should be stored at 2°C–8°C. Bristol-Myers Squibb) and parathyroid imaging in patients with Small amounts of 99mTc impurities may be formed during hyperfunctioning adenoma. labelling, which is taken up, for example in the thyroid and the The uptake of the lipophilic 99mTc-MIBI complex in the heart liver. The radiochemical purity shall be at least 90% and may be muscle by passive diffusion is proportional to the regional myo- checked using instant thin-layer chromatography (ITLC). cardial blood flow. Two injections are usually required to distin- The injected activity is rapidly eliminated from the circulating guish between a transient and a permanent perfusion defect. One blood with less than 5% of injected activity remaining 10 min examination is performed after maximum exercise or pharma- after injection. Tetrofosmin is mainly accumulated in muscle cological stress and the other one at rest. The examinations are tissue. The maximum uptake in heart muscle is approximately performed using SPECT or a planar technique and commence at 1.2% slowly decreasing to about 0.7% at 4 h p.i. The excretion via 15–30 min after injection but the delay can be up to 4 h. Stress- the hepatobiliary tract and the faeces is 34% in 48 h and via the rest imaging can be performed using either 1- or 2-day protocols. urinary tract 39%. The MIBI kit contains lyophilised, sterile, pyrogen-free, sub- The highest absorbed doses are received by the gallbladder stance in nitrogen atmosphere, prepared for labelling with 1–3 wall, the intestinal tract, the urinary bladder wall and the kid- mL of 99mTc–sodium pertechnetate (0.925–5.55 GBq). The vial neys. The calculated effective dose is 0.0089 mSv/MBq at rest T should be agitated vigorously to dissolve the material and then and 0.0071 mSv/MBq at stress. be placed in a boiling water bath for 10 min. The preparation is Abbreviation: p.i. = Post-injection. ready for after being cooled at room temperature at about 15 min Related Articles: Radionuclide generator, Tc-99m SestaMIBI and should be stored at room temperature (15°C–25°C) for up to (methoxyisobutyl isonitrile) 6 h protected from light. Further Readings: Kowalsky, R. J. and S. W. Falen. 2004. Small amounts of 99mTc – impurities may be formed during Radiopharmaceuticals in Nuclear Pharmacy and Nuclear labelling, which is taken up, for example in the thyroid and the Medicine, 2nd edn., American Pharmacists Association, liver. The radiochemical purity shall be at least 94% and may be Washington, DC; Zolle, I. (ed.). 2007. Technetium-99m checked using instant thin-layer chromatography (ITLC). Pharmaceuticals – Preparation and Quality Control in Nuclear The injected activity is rapidly eliminated from the circulat- Medicine, Springer, Heidelberg, Germany. ing blood with 2.5% of injected activity 10 min after injection. Technetium-99m-MIBI is mainly accumulated in muscle tissue Tc-99m-albumin (HSA) and the myocardial uptake is 1.0%–1.4%. The initial high liver (Nuclear Medicine) Technetium-99m-albumin, 99mTc-HSA, is uptake the radiopharmaceutical excreted via the hepatobiliary used for static or gated cardiac blood pool imaging, first-pass tract and the faeces is 37% in 24 h and via the urinary tract 29%. studies, or regional circulatory imaging. The time of examination The highest absorbed doses are received by the gallbladder is immediately or shortly after IV administration. Recommended wall, the kidneys and the intestinal tract. The calculated effective activity is 111–185 MBq for blood pool imaging, 370–450 MBq dose is 0.0085 mSv/MBq at rest and 0.0075 mSv/MBq at stress. for angiocardiography, 185–925 MBq for gated ventriculography, Related Articles: Radionuclide generator, Tc-99m tetrofosmin and 18.5–185 MBq for blood flow studies. Further Readings: Kowalsky, R. J. and S. W. Falen. 2004. Human serum albumin, HSA kits contain HSA and Sn2+. HSA Radiopharmaceuticals in Nuclear Pharmacy and Nuclear is the most common protein in the blood and is isolated from Medicine, 2nd edn., American Pharmacists Association, donor blood. Several methods for labelling have been derived Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear and commercial products available are Albumoscint (Nordion), Pharmacy, Springer Science + Business Media, New York; Zolle, TechneScan (Mallinckrodt/Tyco) and VesculoCis TCK-2 (CIS I. (ed.). 2007. Technetium-99m Pharmaceuticals – Preparation Bio). and Quality Control in Nuclear Medicine, Springer, Heidelberg, The kit contains lyophilised, sterile, pyrogen-free, substance Germany. in nitrogen atmosphere, prepared for easy labelling with 99mTc Tc-99m-albumin macroaggregates (MAA) 924 Tc-99m-albumin millimicrospheres – sodium pertechnetate by adding 1–8 mL with an activity up to radiopharmaceuticals. Addendum to ICRP Publication 53. ICRP 2.22 GBq. After preparation, the injection solution should be used Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; Council within 6 h. The radiochemical purity can be tested by paper or of Europe, European pharmacopeia (founded 1964), http://www thin-layer chromatography (recommended), and the purity should .edqm .eu /en /Homepage -628 .html; Kowalsky, R. J. and S. W. not be less than 95%. Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and 99mTc-HSA is distributed homogenously in the vascular com- Nuclear Medicine, 2nd edn., American Pharmacists Association, ponent following an IV injection. It accumulates in the kidneys Washington, DC.; Saha, G. B. 2004. Fundamentals of Nuclear and an increased uptake can also be seen in stomach and gut. Pharmacy, 5th edn., Springer, New York; Zolle, I. (ed.). 2007. The absorbed dose estimation is carried out assuming a multiple- Technetium-99m Pharmaceuticals – Preparation and Quality exponential elimination from the blood compartment, that is 3 Control in Nuclear Medicine, Springer, Heidelberg, Germany. half-times, 6.8 h (40%), 1.28d (22%) and 19.4d (38%). Any 99mTc- HSA outside the blood compartment is assumed to be eliminated Tc-99m-albumin microcolloid quickly through the kidneys. The effective dose has been calcu- (Nuclear Medicine) Technetium-99m-albumin microcolloids are lated to 7.8 μSv/MBq. The absorbed dose to the heart wall is esti- used for liver and spleen scintigraphy. The time of examination mated to 20 μGy/MBq, spleen 14 μGy/MBq and kidneys 8 μGy/ performed is 15–60 min after an IV injection. Common trade MBq. names are ALBURES (Solco) and Microlite (DuPont Merck). The Abbreviation: HSA = Human serum albumin. kit contains sterile, lyophilised, preformed HSA-microcolloids Related Articles: Tc-99m-albumin macroaggregates (MAA), with a size distribution of 0.2–2.0 μm, stannous chloride · Tc-99m-albumin microspheres (HAM) 2H2O, and a stabilising agent. Preformed albumin colloid is eas- Further Readings: Annals of the ICRP. 1992. Radiological ily labelled with reduced 99mTc. No heating or pH adjustment is protection in biomedical research. Addendum 1 to ICRP needed. More than 90% of the colloids have a size distribution Publication 53. Radiation dose to patients from radiopharmaceu- between 0.2 and 2.0 μm. ticals, ICRP Publication 62, Vol. 22, Pergamon Press, Oxford, 99mTc-albumin microcolloids are removed from circulation by UK; Annals of the ICRP. 1998. Radiation dose to patients from phagocytosis in the RES. The biodistribution of colloid particles radiopharmaceuticals. Addendum to ICRP Publication 53. ICRP is influenced by their particle sizes; with 0.3–0.6 μm 80%–90% Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; Council of the colloids are trapped in the liver, 4%–8% by the spleen, and of Europe, European pharmacopeia (founded 1964), http://www less than 1% in the bone marrow. Larger particles tend to accumu- .edqm .eu /en /Homepage -628 .html; Kowalsky, R. J. and S. W. late in the spleen, while for smaller particles 10%–15% localise Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and in the bone marrow. Nuclear Medicine, 2nd edn., American Pharmacists Association, For quality control of radiochemical purity the manufacturer Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear recommends thin-layer chromatography, using 85% methanol as Pharmacy, 5th edn., Springer, New York; Zolle, I. (ed.). 2007. solvent. The purity should be above 95%. Technetium-99m Pharmaceuticals – Preparation and Quality About 95% of IV injected particles are rapidly removed from Control in Nuclear Medicine, Springer, Heidelberg, Germany. the blood and accumulated in the liver by phagocytosis. The rest is trapped by the spleen and bone marrow 15 min post-injection, and T Tc-99m-albumin macroaggregates (MAA) less than 1% remains in the blood at that time. These organs are the (Nuclear Medicine) Technetium-99m-macroaggregated albumin, most exposed, with an absorbed dose to the liver, spleen and red bone 99mTc-MAA, is used for lung perfusion scintigraphy for diagno- marrow of 71, 75, and 11 μGy/MBq respectively. The effective dose sis of pulmonary emboli. The distribution of MAA is related to is approximately 10 μSv/MBq. Normally 40–150 MBq is adminis- regional pulmonary blood flow. tered IV for planar imaging, whereas 200 MBq is used for SPECT. MAA is human serum albumin (the most common protein in Abbreviations: IV = Intravenously and RES = Reticuloendo- the blood) that has been denatured by heat in an agitated aqueous thelial system (of the liver). solution to form microaggregates with particle size of 10–90 μm. Related Articles: Tc-99m tin colloids, Tc-99m albumin A kit contains about 1.5–2 million albumin particles (2 mg) of nanocolloid which 90% have a size distribution of 10–50 μm. Labelling is per- Further Readings: Annals of the ICRP. 1992. Radiological formed by adding 2–10 mL 99mTc-pertechnetate with an activity protection in biomedical research. Addendum 1 to ICRP up to 3.7 GBq. After preparation, the injection solution should be Publication 53. Radiation dose to patients from radiopharmaceu- used within 6 h. The radiochemical purity can be tested by paper ticals, ICRP Publication 62, Vol. 22, Pergamon Press, Oxford, or thin-layer chromatography (recommended), and the purity UK; Annals of the ICRP. 1998. Radiation dose to patients from should not be less than 90%. radiopharmaceuticals. Addendum to ICRP Publication 53. ICRP After IV injection 90% of the 99mTc-MAA is extracted during Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; Council the first pass and sequestrated in the lung capillaries (8.2 ± 1.5 of Europe, European pharmacopeia (founded 1964), http://www μm) and arterioles (25 ± 10 μm). Particles smaller than the capil- .edqm .eu /en /Homepage -628 .html; Kowalsky, R. J. and S. W. laries are trapped by the RES in the liver. Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and The effective dose of IV administered 99mTc-MAA is 12 μSv/ Nuclear Medicine, 2nd edn., American Pharmacists Association, MBq and the organs that receive highest absorbed dose is lungs Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear (66 μGy/MBq), liver (16 μGy/MBq) and bladder (8.7 μGy/MBq). Pharmacy, 5th edn., Springer, New York; Zolle, I. (ed.) 2007. Abbreviation: MAA = Macroaggregated albumin. Technetium-99m Pharmaceuticals – Preparation and Quality Related Articles: Radiochemical purity, Technetium-99m Control in Nuclear Medicine, Springer, Heidelberg, Germany. Further Readings: Annals of the ICRP. 1987. Radiation dose to patients from radiopharmaceuticals, biokinetic models and Tc-99m-albumin millimicrospheres data, ICRP Publication 53, Vol. 18, Pergamon Press, Oxford, (Nuclear Medicine) 99mTc-albumin millimicrospheres (99mTc- UK; Annals of the ICRP. 1998. Radiation dose to patients from milli-HAM) is used for liver and spleen scintigraphy, regional Tc-99m-albumin nanocolloid 925 Tc-99m-arcitumomab liver perfusion and RES function, and bone marrow scintigraphy. 99mTc-nanocolloids may be tested using paper chromatog- In these applications the radiopharmaceutical is administered raphy, for example Whatman 31 ET paper and saline as solvent intravenously. It may also be used for pulmonary ventilation stud- or thin-layer chromatography with Gelman silica gel fibreglass ies when the substance is inhaled as an aerosol (nebulisation). sheets and acetone as solvent. The radiochemical purity should The time of examination is 10–60 min post-injection for liver and be at least 95%. spleen imaging and 45–60 min for bone marrow imaging. For 99mTc-albumin nanocolloid is removed from circulation by pulmonary ventilation scintigraphy is performed immediately phagocytosis. More than 95% of an IV injected preparation is after inhalation. accumulated in the liver, spleen and bone marrow 15 min post- A kit contains sterile, lyophilised, preformed HSA millimicro- injection. These are the most exposed organs, with an absorbed spheres with a 90% size distribution 0.3–0.8 μm. 99mTc-pertech- dose to the liver, spleen and red bone marrow of 74, 77 and 15

netate is simple added in a volume of 1–5 mL (max 3 GBq) and μGy/MBq respectively. The effective dose is 10 μSv/MBq. the reaction is left in room temperature for 15 min. No heating is Abbreviations: IV = Intravenous and SC = Subcutaneous. needed. Commercial kits available are Nanotec (Sorin). For QC Related Articles: Tc-99m albumin microspheres, Tc-99m of 99mTc-milli-HAM thin-layer chromatography (TLC) with 85% HSA, Tc-99m microcolloids methanol as solvent is recommended. The radiochemical purity Further Readings: Annals of the ICRP. 1987. Radiation dose should be at least 95%. The preparation is stable for 6 h. to patients from radiopharmaceuticals, biokinetic models and Small amounts of IV administered 99mTc-milli-HAM are data, ICRP Publication 53, Vol. 18, Pergamon Press, Oxford, quickly cleared from the blood in the first minutes. About 85% UK; Annals of the ICRP. 1998. Radiation dose to patients from is phagocyted by RES with a maximum uptake 5–10 min post- radiopharmaceuticals. Addendum to ICRP Publication 53. ICRP injection, and the retention reflects the function of the Kupffer Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; Council cells. Plasma clearance rate depends on particle size of colloids. of Europe, European pharmacopeia (founded 1964), http://www As for most colloids, the liver, spleen and bone marrow are the .edqm .eu /en /Homepage -628 .html; Kowalsky, R. J. and S. W. most exposed organs. Absorbed doses have been estimated to be Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and 71, 75, and 11 μGy/MBq, respectively. The effective dose is esti- Nuclear Medicine, 2nd edn., American Pharmacists Association, mated to be 10 μSv/MBq. Normally 40–150 MBq is administered Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear IV for planar imaging, whereas 200 MBq is used for SPECT. Pharmacy, 5th edn., Springer, New York; Zolle, I. (ed.). 2007. Abbreviation: HSA = Human serum albumin. Technetium-99m Pharmaceuticals – Preparation and Quality Related Articles: Tc-99m-labelled microcolloids, Tc-99m- Control in Nuclear Medicine, Springer, Heidelberg, Germany. albumin microcolloid, Tc-99m-labelled nanocolloids, Tc-99m- albumin nanocolloid Tc-99m-arcitumomab Further Readings: Annals of the ICRP. 1992. Radiological (Nuclear Medicine) 99mTc-arcitumomab is a carcinoembryonic protection in biomedical research. Addendum 1 to ICRP Publication antigen complex, used for scintigraphic studies of malignan- 53. Radiation dose to patients from radiopharmaceuticals, cies in patients with colorectal carcinoma and with recurrence ICRP Publication 62, Vol. 22, Pergamon Press, Oxford, UK; or metastasis. An example of a commercial product is CEA- Annals of the ICRP. 1998. Radiation dose to patients from Scan (Immunomedics Europe). A 99mTc-CEA-Scan kit contains radiopharmaceuticals. Addendum to ICRP Publication 53. ICRP lyophilised, sterile 1.25 mg arcitumomab IMMU-4 Fab’ anti- Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; Council T CEA MABf in argon atmosphere, ready for labelling with 99mTc- of Europe, European pharmacopeia (founded 1964), http://www pertechnetate. The radiopharmaceutical is given IV in an activity .edqm .eu /en /Homepage -628 .html; Kowalsky, R. J. and S. W. of 740–1110 MBq (in 2 mL). Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and The radiochemical purity should be at least 90%, and is tested Nuclear Medicine, 2nd edn., American Pharmacists Association, for free 99mTc-pertechnetate before administration. Thin-layer Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear chromatography (instant (I)TLC-silica gel fibreglass sheets) and Pharmacy, 5th edn., Springer, New York; Zolle, I. (ed.). 2007. acetone as solvent is recommended. Technetium-99m Pharmaceuticals – Preparation and Quality 99mTc-arcitumomab is excreted by the kidneys; thus, together Control in Nuclear Medicine, Springer, Heidelberg, Germany. with the urinary bladder, liver and spleen are the most exposed organs: 89, 10, 8.7 and 14 μGy/MBq respectively. The effective Tc-99m-albumin nanocolloid dose is estimated to 11 μSv/MBq. (Nuclear Medicine) 99mTc albumin nanocolloids are used for Abbreviations: CEAf = Carcinoembryonic antigen fragments imaging of the bone marrow or inflammatory processes after an and IV = Intravenous. IV injection. It can also be used for lymphoscintigraphy or visu- Further Readings: Annals of the ICRP. 1992. Radiological alisation of lymphatic flow, regional lymph nodes in the extremi- protection in biomedical research. Addendum 1 to ICRP ties and the trunk, and sentinel lymph node (SLN) scintigraphy. Publication 53. Radiation dose to patients from radiopharmaceu- Technetium-99m albumin nanocolloids are available in ticals, ICRP Publication 62, Vol. 22, Pergamon Press, Oxford, different sizes of the colloid particles. A common trade name is UK; Annals of the ICRP. 1998. Radiation dose to patients from Solco Nanocoll (GE Healthcare). A preformed 99mTc-kit contains radiopharmaceuticals. Addendum to ICRP Publication 53. human albumin nanocolloid (0.5 mg), stannous chloride (0.2 mg), ICRP Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; and is easily labelled at room temperature. More than 95% of the Council of Europe, European pharmacopeia (founded 1964), nanocolloids lay between 10 and 80 nm. http://www .edqm .eu /en /Homepage -628 .html; Kowalsky, R. The kit contains lyophilised, sterile, pyrogen-free, substance J. and S. W. Falen. 2004. Radiopharmaceuticals in Nuclear in nitrogen atmosphere, prepared for easy labelling with 99mTc – Pharmacy and Nuclear Medicine, 2nd edn., American sodium pertechnetate, normally 1–5 mL with a maximum activity Pharmacists Association, Washington, DC; Saha, G. B. 2004. of 5500 MBq. 99mTc-HSA nanocolloid is pyrogen free, sterile, and Fundamentals of Nuclear Pharmacy, 5th edn., Springer, New a clear solution ready for IV or SC injection. York; Zolle, I. (ed.). 2007. Technetium-99m Pharmaceuticals Tc-99m; Ceretec 926 Tc-99m-DTPA – Preparation and Quality Control in Nuclear Medicine, Hydroxy ethylidiene diphosphonate and MDP = Methylene Springer, Heidelberg, Germany. diphosphonate. Related Article: Tc-99m-pyrophosphate (PYP) Tc-99m; Ceretec Further Readings: Annals of the ICRP. 1992. Radiological (Nuclear Medicine) This is 99mTc D,L-HMPAO, hexamethylpro- protection in biomedical research. Addendum 1 to ICRP pylene amine oxime, also called exametazime. The commer- Publication 53. Radiation dose to patients from radiopharmaceu- cial product is Ceretec (GE Healthcare). For further details see ticals, ICRP Publication 62, Vol. 22, Pergamon Press, Oxford, Tc-99m HMPAO. UK; Annals of the ICRP. 1998. Radiation dose to patients from radiopharmaceuticals. Addendum to ICRP Publication 53. ICRP Tc-99m-diphosphonates (DPD, HDP, MDP, HEDSPA) Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; Council (Nuclear Medicine) 99mTc-diphosphonates are available as differ- of Europe, European pharmacopeia (founded 1964), http://www ent complexes. Phosphonate and phosphate complexes are both .edqm .eu /en /Homepage -628 .html; Kowalsky, R. J. and S. W. taken up in the bone to a high extent. Phosphonates are more sta- Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and ble in vivo than phosphates because the P-O-P bond in the latter Nuclear Medicine, 2nd edn., American Pharmacists Association, is easily broken down by phosphatase enzyme, whereas the P-C-P Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear bond in diphosphonate is not. Thus, 99mTc-diphosphonates can be Pharmacy, 5th edn., Springer, New York; Zolle, I. (ed.) 2007. used for skeletal imaging with great advantages. Examples are Technetium-99m Pharmaceuticals – Preparation and Quality diagnosis of primary or metastatic bone tumours, osteomyelitis, Control in Nuclear Medicine, Springer, Heidelberg, Germany. localisation of fractures and evaluation of pain in the skeleton in patients with negative x-rays. Tc-99m-DMSA (dimercaptosuccinic acid) 99mTc-disphophonates of frequent occurrence are 1-hydroxy- (Nuclear Medicine) 99mTc-DMSA is used for planar or tomographic ethylidene diphosphonate (HEDP), methylene diphosphonate imaging of renal cortex function and morphological studies of (MDP), and hydroxymethylene diphosphonate (HDP or HMDP). lesions and areas with reduced function. The radiopharmaceutical Commercial kits are available from different manufacturers: can also be used for detection of metastasis of medullary thyroid carcinoma. In the kidney 99mTc-DMSA is retained in the renal • 99mTc-DPD (dicarboxypropane diphosphonate) – Teceos parenchyma by tubular fixation and indicates its function. (CIS Bio International) Tumours, cysts and abscesses appear as cold spots. The time of • 99mTc-HDP (hydroxymethylene diphosphonate) – examination for renal imaging is 1–3 h post-IV administration. TechneScan HDP (Mallinckrodt Medical) Radiochemical purity of 99mTc-DMSA should not be less than • 99mTc-MDP (methylene diphosphonate) – MedroCis 95%, which is tested by thin-layer chromatography (TLC) on TCK-14 (CIS Bio International) silica gel fibreglass sheets with methyl ethyl ketone (MEK) and • 99mTc-HEDSPA (hydroxyethylidiene diphosphonate) – saline as solvents. HEDSPA (Union Carbide) The uptake of 99mTc-DMSA is related to the renal cortical per- fusion. One hour after an IV injection 24% of 99mTc-DMSA has Independent of the manufacturer, the kit contains lyophilised, taken up in the renal parenchyma. The complex is excreted with T sterile, pyrogen-free diphosphonate in nitrogen atmosphere, pre- the urine with significant uptake in the bladder as well. Most of pared for easy labelling with 2–10 mL 99mTc – sodium pertechne- the circulating 99mTc-DMSA is loosely bound to plasma proteins, tate with an activity up to 6.6–18.5 GBq, depending on labelling and no other organs show any uptake. Thus, the organs receiving efficiency, number of patients and scheduled time of administra- largest absorbed dose are kidneys, bladder wall and adrenals, 180, tion. After a few minutes at room temperature the preparation is 18 and 12 μGy/MBq respectively. The effective dose is 8.8 μSv/ ready for use with an expiry time of 6–8 h. The time of examina- MBq. tion for bone imaging is 2 h post-administration. Abbreviation: IV = Intravenous. Historically HEDSPA was the first 99mTc-disphosphonate Related Article: Tc-99m-MAG3 complex used in the early 1970s. MDP was for long the Further Readings: Annals of the ICRP. 1992. Radiological diphosphonate complex of choice. Later both HMDP and HDP protection in biomedical research. Addendum 1 to ICRP were introduced with similar good characteristics, followed Publication 53. Radiation dose to patients from radiopharmaceu- by DPD also with excellent merits. The signals for detection ticals, ICRP Publication 62, Vol. 22, Pergamon Press, Oxford, of lesions are an increased blood flow to the skeleton and an UK; Annals of the ICRP. 1998. Radiation dose to patients from increased regional uptake in bone metastasis. The detection rate radiopharmaceuticals. Addendum to ICRP Publication 53. ICRP is mainly independent of the diphosphonate complex (DPD, HDP Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; Council or MDP). of Europe, European pharmacopeia (founded 1964), http://www The radiochemical purity can be tested by thin-layer .edqm .eu /en /Homepage -628 .html; Kowalsky, R. J. and S. W. chromatography (recommended), and the purity should not be Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and less than 95%. Nuclear Medicine, 2nd edn., American Pharmacists Association, After an IV administration 45%–50% of 99mTc-diphosphonates Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear accumulate in the skeleton, while the rest is excreted in the urine. Pharmacy, 5th edn., Springer, New York; Zolle, I. (ed.). 2007. Maximum bone uptake is 1 h post-administration and remains Technetium-99m Pharmaceuticals – Preparation and Quality constant for 72 h. The most exposed organs are bone surfaces (63 Control in Nuclear Medicine, Springer, Heidelberg, Germany. mGy/MBq), urinary bladder (48 mGy/MBq), red bone marrow (9 mGy/MBq), kidneys and the heart wall (7.3 mGy/MBq). The Tc-99m-DTPA effective dose is estimated at 6 μSv/MBq. (Nuclear Medicine) Technetium-99m Diethylenetriamine penta- Abbreviations: DPD = Dicarboxypropane diphospho- acetic acid, 99mTc-DTPA, together with EDTA is the most com- nate, HDP = Hydroxymethylene diphosphonate, HEDSPA = mon chelating agent used in nuclear medicine pharmacy. DTPA Tc-99m-EC (ethylene dicysteine) 927 T c-99m-ECD has eight possible complexing sites, three nitrogen and five car- complex is excreted by tubular secretion in the kidneys. The dif- boxylic sites. The DTPA-chelate binds to Tc(IV), and other metals ference between 99mTc-EC and 99mTc-MAG3 is a higher plasma very tightly. It can be used as a detoxification agent for lead, for clearance and lower uptake in liver, bowel and gallbladder for example it chelates the metal and speeds up the excretion through 99mTc-EC. the kidneys. Kidneys, bladder wall and adrenals are the organs that show 99mTc-DTPA is efficiently transferred from the blood to highest absorbed doses. For normal kidney function the effective the urine and used for renal studies. The complex may also be dose is 6.3 μSv/MBq, the absorbed dose to kidney 3.4 μGy/MBq utilised for regional lung ventilation studies as an aerosol that is and bladder wall 9.4 μGy/MBq. For reduced kidney function the inhaled (e.g. TechneScan DTPA/Aerosol kit). Using an ultrasonic effective dose is 4.6 μSv/MBq, the absorbed dose to kidney 1.2 nebulisation aqueous 99mTc-DTPA complex forms aerosol μGy/MBq and bladder wall 4.3 μGy/MBq. particles with a diameter of 500 nm. Abbreviation: IV = Intravenous. Other clinical applications are localisation of inflammatory Related Articles: Tc-99m-MAG3 (mercaptoacetyltriglycine), bowel disease and cerebral scintigraphy at suspected blood–brain Tc-99m-DTPA) barrier leakage. Further Readings: Annals of the ICRP. 1992. Radiological After IV injection, 99mTc-DTPA passes capillary walls to enter protection in biomedical research. Addendum 1 to ICRP Publication

the extravascular space within 4 min. The complex is hydrophilic 53. Radiation dose to patients from radiopharmaceuticals, and negatively charged and thus stays in the extravascular space. ICRP Publication 62, Vol. 22, Pergamon Press, Oxford, UK; The kidneys alone are responsible for the removal of the complex Annals of the ICRP. 1998. Radiation dose to patients from and the renal transit time is 5 min. The plasma clearance is radiopharmaceuticals. Addendum to ICRP Publication 53. ICRP described by a double-exponential function, 99% is excreted with Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; Council a biological half-life of less than 2 h, the remaining 1% with a of Europe, European pharmacopeia (founded 1964), http://www half-life of 7 days. .edqm .eu /en /Homepage -628 .html; Kowalsky, R. J. and S. W. The effective dose of IV administration of 99mTc-DTPA is 5 Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and μSv/MBq and the organ that receive highest absorbed dose is the Nuclear Medicine, 2nd edn., American Pharmacists Association, bladder with 62 μGy/MBq. Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear Abbreviation: IV = Intravenous injection. Pharmacy, 5th edn., Springer, New York; Zolle, I. (ed.). 2007. Related Articles: Chelates, Tc-99m Technetium-99m Pharmaceuticals – Preparation and Quality Further Readings: Annals of the ICRP. 1987. Radiation dose Control in Nuclear Medicine, Springer, Heidelberg, Germany. to patients from radiopharmaceuticals, biokinetic models and data, ICRP Publication 53, Vol. 18, Pergamon Press, Oxford, Tc-99m-ECD UK; Annals of the ICRP. 1998. Radiation dose to patients from (Nuclear Medicine) 99mTc-ECD, ethyl cysteinate dimer (also radiopharmaceuticals. Addendum to ICRP Publication 53. ICRP called bicisate), is a substance for brain perfusion imaging. Its Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; Council trade name is Neurolite (Bristol-Myers Squibb). The Neurolite kit of Europe, European pharmacopeia (founded 1964), http://www consists of two vials, one with the lyophilised, sterile, pyrogen- .edqm .eu /en /Homepage -628 .html; Kowalsky, R. J. and S. W. free, ECD-substance in nitrogen atmosphere, in which 3 mL of Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and saline is added and inverted to dissolve the content. After 30 s 1 Nuclear Medicine, 2nd edn., American Pharmacists Association, T mL is withdrawn. The other vial contains 1 mL phosphate buffer, Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear in which 2 mL Na 99 TcmO- 4 with an activity of 925–3700 MBq is Pharmacy, 5th edn., Springer, New York; Zolle, I. (ed.) 2007. added. Labelling is performed by adding 1 mL from the first vial Technetium-99m Pharmaceuticals – Preparation and Quality (ECD-vial) to the second vial and allowing it to react for 30 min. Control in Nuclear Medicine, Springer, Heidelberg, Germany. The 99mTc- ethyl cysteinate dimer is a clear, colourless and sterile solution for IV injection. It is stable for 8 h after preparation. Tc-99m-EC (ethylene dicysteine) A radiochemical purity test should be performed before (Nuclear Medicine) 99mTc-EC, ethylene dicysteine, is used for injection and if the labelling efficiency is below 90% the dynamic examination of renal function, determination of the preparation should be discarded. The manufacturer recommends tubular extraction rate, and study of the function of a transplanted thin-layer chromatography (TLC) using Baker-flex silica gel kidney. Gamma camera acquisition should start immediately strips and an organic solvent. after an IV administration of the 99mTc-EC, and continue for 99mTc-ECD is used in brain scintigraphy for diagnosis of focal approximately 20 min. Recommended activity administered is perfusion abnormalities; stroke, inflammatory processes in the 90–120 MBq. brain, abnormal focus in patients with head trauma (accidents), A 99mTc-EC kit consists of 3 vials containing the lyophilised differentiation of focal abnormalities in CBF for multi-infarct components. The first vial contains ethylene-l, l dicysteine and dementia and degenerative dementia. The optimal time of ingredients to facilitate labelling with 99mTc-pertechnetate at examination is after 30–60 min post-injection, but imaging can alkaline pH. Labelling is started by adding Sn2+ as reducing agent be done from 10 min to 6 h after injection. 99mTc-ECD uptake from the second vial, and left for 15 min incubation. The third is linear with blood flow values up to 20 mL/100 g/min, but vial contains a buffer as a stabilising agent, which is added to the underestimates higher flow rates. A disadvantage is the clearance 99mTc-EC. rate which is 3%–4% h−1. The radiochemical control is performed by thin-layer chroma- The effective dose for 99mTc-ECD is 7.7 μSv/MBq. The organs tography using a solvent system to separate 99mTc and reduce it most exposed are bladder wall (49 μGy/MBq), gall bladder (29 from the 99mTc-EC complex. The purity should exceed 95%. The μGy/MBq) and the large intestine (21 μGy/MBq). complex is stable for 3–8 h and sufficient for three patients. See also Tc-99m-HMPAO, which is a similar radiopharmaceu- The blood clearance of 99mTc-EC complex is rapid, 2–3 min tical used for brain perfusion imaging. after IV injection no activity is seen in heart and liver. The Abbreviation: CBF = Cerebral blood flow. Tc-99m-HMPAO 928 Tc-99m-IDA (iminodiacetic acid) Related Articles: Radiochemical purity, Tc-99m-HMPAO, Further Readings: Annals of the ICRP. 1992. Radiological TLC protection in biomedical research. Addendum 1 to ICRP Further Readings: Annals of the ICRP. 1987. Radiation dose Publication 53. Radiation dose to patients from radiophar- to patients from radiopharmaceuticals, biokinetic models and maceuticals, ICRP Publication 62, Vol. 22, Pergamon Press, data, ICRP Publication 53, Vol. 18, Pergamon Press, Oxford, Oxford, UK; Costa, D. C., P. J. Ell, I. D. Cullum and P. H. UK; Annals of the ICRP. 1998. Radiation dose to patients from Jarritt. 1986. The in vivo distribution of Tc-99m -HM-PAO radiopharmaceuticals. Addendum to ICRP Publication 53. ICRP in normal man. Nucl. Med. Comm. 7:647–658; Kowalsky, R. Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; Council J. and S. W. Falen. 2004. Radiopharmaceuticals in Nuclear of Europe, European pharmacopeia (founded 1964), http://www Pharmacy and Nuclear Medicine, 2nd edn., American .edqm .eu /en /Homepage -628 .html; Kowalsky, R. J. and S. W. Pharmacists Association, Washington, DC; Saha, G. B. 2004. Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and Fundamentals of Nuclear Pharmacy, 5th edn., Springer, New Nuclear Medicine, 2nd edn., American Pharmacists Association, York; Zolle, I. (ed.). 2007. Technetium-99m Pharmaceuticals Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear – Preparation and Quality Control in Nuclear Medicine, Pharmacy, 5th edn., Springer, New York; Zolle, I. (ed.). 2007. Springer, Heidelberg, Germany. Technetium-99m Pharmaceuticals – Preparation and Quality Control in Nuclear Medicine, Springer, Heidelberg, Germany. Tc-99m-IDA (iminodiacetic acid) (Nuclear Medicine) 99mTc-IDA, iminodiacetic acid, is a hepa- Tc-99m-HMPAO tobiliary radiopharmaceutical for imaging and evaluation of (Nuclear Medicine) 99mTc D,L-HMPAO, hexamethylpropylene hepatocyte function, obstruction of the cystic duct, examina- amine oxime, also called exametazime. The commercial product tion of acute cholecystitis, and common bile duct obstruction. is Ceretec (GE Healthcare). A Ceretec-kit contains lyophilised, For hepatobiliary scintigraphy, 150 MBq of activity is recom- sterile, pyrogen-free substance in nitrogen atmosphere, prepared mended. The examination is started 5 min post-IV adminis- for labelling with 99mTc – sodium pertechnetate. Five microlitres tration, and the scintigrams are taken at 10 min intervals for of Na 99 TcmO- 4 with an activity of 370–1100 MBq is added to the normally 1 h. vial, which should be gently inverted for 10 s and the reaction The 99mTc-IDA kit contains sterile, lyophilised, preformed allowed to proceed at room temperature for 5 min. A mixture of ingredients. Labelling is simple performed with 1–5 mL 99mTc- methylene blue in phosphate buffer may be used for stabilisation pertechnetate (300–1500 MBq) added to the vial. The complex is of the preparation. stable for 6 h after preparation. The radiochemical purity is tested When fresh 99mTc is reduced with Sn2+, the 99mTc d,l-HMPAO with thin-layer chromatography, TLC, with two different solvent complex is formed rapidly. Any oxidant should be avoided. The systems: (1) using saline for control of unbound 99mTc at the sol- preparation should normally be used within 1 h after labelling. vent front and the sum of reduced, hydrolysed technetium and With the stabiliser (methylene blue) the preparation is stable for the 99mTc-IDA at the start, and (2) using Gelman ITLC-SG and 4 h. acetonenitrile/water as solvent, where reduced, hydrolysed tech- 99mTc-HMPAO is used for brain scintigraphy, normally netium is identified separately at the start. The labelling efficiency SPECT, for the diagnosis of perfusion defects of regional cerebral should be at least 95%. T blood flow (rCBF); focal perfusion abnormalities, stroke, and Following IV administration 99mTc-IDA is bound to plasma multi-infarct and degenerative dementia. The complex can also proteins and transported to the liver. In the liver the complex be used for labelling of leukocytes. is dissociated to facilitate active transport of the 99mTc-IDA 99mTc-exametazine is lipophilic and can cross the blood–brain complex into hepatocytes. In patients with normal liver function, barrier (BBB) with high efficacy. Due to the in vivo instability of the maximum uptake is at 12 min, and the gallbladder is clearly the complex, the secondary 99mTc-HMPAO formed cannot pass visible within 20 min post-injection. the BBB and is trapped inside the brain. The effective dose for 99mTc-IDA is 17 μSv/MBq. The most The labelled 99mTc-HMPAO must be tested for radiochemical exposed organs are gallbladder (110 μGy/MBq), the wall of the purity before being injected to the patient, and the labelling guts, that is ULI (86 μGy/MBq), LLI (59 μGy/MBq), SI (44 μGy/ efficiency should be at least 80%, that is lipophilic 99mTc-HMPAO. MBq), and the liver (14 μGy/MBq). It is normally checked using thin-layer chromatography (TLC) Abbreviations: IV = Intravenous, LLI = Lower large intestine, on Gelman ITLC silica gel sheets and paper chromatography on SI = Small intestine and ULI = Upper large intestine. Whatman 1 strips, using three solvent systems for the analysis Further Readings: Annals of the ICRP. 1992. Radiological of lipophilic 99mTc-HMPAO, secondary hydrophilic complex, protection in biomedical research. Addendum 1 to ICRP unbound 99mTc and reduced, hydrolysed 99mTc. Publication 53. Radiation dose to patients from radiopharmaceu- After 5 min, the 99mTc-HMPAO has disappeared from the ticals, ICRP Publication 62, Vol. 22, Pergamon Press, Oxford, blood and the distribution of activity in the brain represents the UK; Annals of the ICRP. 1998. Radiation dose to patients from true image of the initial blood flow. It remains constant for about radiopharmaceuticals. Addendum to ICRP Publication 53. 24 h, and the elimination rate is very slow (1% per hour). ICRP Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; The effective dose for 99mTc-HMPAO is 9.3 μSv/MBq. The Council of Europe, European pharmacopeia (founded 1964), organs most exposed are kidneys (32 μGy/MBq), bladder wall (22 http://www .edqm .eu /en /Homepage -628 .html; Kowalsky, R. μGy/MBq) and lungs (11 μGy/MBq). J. and S. W. Falen. 2004. Radiopharmaceuticals in Nuclear See also Tc-99m ECD, which is a similar radiopharmaceutical Pharmacy and Nuclear Medicine, 2nd edn., American used for brain perfusion imaging. Pharmacists Association, Washington, DC; Saha, G. B. 2004. Abbreviations: ECD = Ethyl cysteinate dimmer and HMPAO Fundamentals of Nuclear Pharmacy, 5th edn., Springer, New = Hexamethylpropylene amine oxime. York; Zolle, I. (ed.). 2007. Technetium-99m Pharmaceuticals Related Articles: TC-99m ECD, Tc-99m-labelled leukocytes, – Preparation and Quality Control in Nuclear Medicine, TLC, Radiochemical purity Springer, Heidelberg, Germany. Tc-99m-labelled bone imaging agents 929 Tc-99m-labelled leukocytes Tc-99m-labelled bone imaging agents Tc-99m-labelled leukocytes (Nuclear Medicine) See Tc-99m-pyrophosphate (PYP), (Nuclear Medicine) Labelled leukocytes or white blood cells Tc-99m-diphosphonates (WBC) can be used for abdominal scintigraphy to locate sites of focal infection, that is abdominal abscess, sepsis, or examination Tc-99m-labelled colloids of fever of unknown origin. It can also be used for detection of (Nuclear Medicine) See Tc-99m-labelled microcolloids, Tc-99m- osteomyelitis in children offering superior information compared tin colloids, Tc-99m-rhenium sulphide colloid, Tc-99m-albumin with 99mTc-pyrophosphates. Leukocytes can be labelled either microcolloid, Tc-99m-albumin millimicrospheres, Tc-99m- with 99mTc or 111In. Imaging is normally performed at 1, 2 and/or labelled nanocolloids, Tc-99m-albumin nanocolloid 24 h post-administration. The lipophilic 99mTc-exametazime (HMPAO) can be used to Tc-99m-labelled erythrocytes label leukocytes without affecting cell viability. The activity used (Nuclear Medicine) Imaging-labelled erythrocytes, or red blood for abdominal scintigraphy is 185–370 MBq. cells (RBC), can be used clinically for radionuclide angiography, For description of the kit and for detailed procedure of for example regional imaging of blood pools, ejection fraction and the biological labelling of leukocytes, see 99mTc-HMPAO. wall motion, gastrointestinal haemorrhage and blood loss through Published and approved descriptions should carefully be fol- determination of erythrocyte mass or blood volume. After heat lowed. Briefly, labelling of

the leukocytes includes withdrawing treatment at 49.5°C erythrocytes will get damaged (become dena- of the patient’s blood into syringes with ACD-solution, allow- tured) and can be used for spleen scintigraphy. ing the syringe to stand for 30–40 min at room temperature Erythrocytes can be labelled, using in vitro, in vivo, or modified for erythrocytes to sediment. The leukocyte- and platelet-rich in vivo methods. Each technique has its own advantage and plasma is drawn into a sterile tube for gentle centrifugation. disadvantage, but since the in vitro technique has best labelling Removal of the supernatant platelet-rich plasma leaves a pel- efficiency, 98%, it is often the preferred technique although being let of mixed leukocytes on the bottom of the tube, in which 1 more time consuming. mL 99mTc-HMPAO is added and the white blood cells are incu- The basic principle of 99mTc-labelling of erythrocytes involves bated for 10 min. After incubation, cell-free plasma is added mixing the cells with Sn2+ (stannous chloride) ions followed and the cell mixture washed by gentle centrifugation. Finally, by addition of 99mTc-pertechnetate. The Sn2+ enters into the new cell-free plasma containing ACD is added to the pellet erythrocytes and afterwards 99mTc-pertechnetate diffuses into it. of leukocytes and made ready for reinjection into the patient The pertechnetate with oxidation state 7+ is reduced by the Sn2+ without delay. to a lower oxidation state and nearly 80% binds to the beta-chain The labelled 99mTc-HMPAO-leukocytes should be tested of the globulin part of the haemoglobin molecule and the rest to before reinjection into the patient. The radiochemical purity the heme molecule. should be at least 95%, and tested by TLC similar to the control For in vivo labelling Sn-PYP kit is diluted with saline and of 99mTc-HMPAO. Free 99mTc-pertechnetate and unbound 99mTc- a sufficient volume is injected IV into the patient. After 20–30 HMPAO are the impurities to be measured. The viability of the min 99mTc-pertechnetate is injected which tags the erythrocytes cells is normally not tested. immediately. Labelling efficiency is 80%–90%. In the modified 99mTc-labelled leukocytes show an initial transitory uptake in in vivo method the patient blood is labelled in vivo with Sn-PYP, the lung, followed by an accumulation in liver, spleen and bone marrow. Kidneys and the gall bladder may also be seen. The 99mTc T but blood is redrawn and labelled in a sterile vial with 99Tcm- pertechnetate and injected back into the patient following flushing complex is slowly released from the leukocytes, and excreted by with saline. Labelling efficiency is above 95%. the urine and faeces. The most exposed organs are the heart, lungs, kidneys and The absorbed doses for 99mTc-labelled leukocytes are liver with absorbed doses of 23, 18, 18 and 13 μGy/MBq respec- 150 μGy/MBq for the spleen, 20 μGy/MBq for the liver, and tively. The effective dose for 99Tcm-labelled erythrocytes is 7 μSv/ 23 μGy/MBq for the red bone marrow. The effective dose is MBq. 11 μSv/MBq. Abbreviation: RBC = Red blood cells. Abbreviations: ACD = Acid-citrate-dextrose, IV = Intravenous, Related Articles: Tc-99m-labelled leukocytes, Tc-99m- RBC = Red blood cells (erythrocytes), TLC = Thin-layer chroma- diphosphonates, Tc-99m-PYP tography and WBC = White blood cells (leukocytes). Further Readings: Annals of the ICRP. 1992. Radiological Related Article: Tc-99m-HMPAO protection in biomedical research. Addendum 1 to ICRP Publication Further Readings: Annals of the ICRP. 1992. Radiological 53. Radiation dose to patients from radiopharmaceuticals, protection in biomedical research. Addendum 1 to ICRP ICRP Publication 62, Vol. 22, Pergamon Press, Oxford, UK; Publication 53. Radiation dose to patients from radiopharmaceu- Annals of the ICRP. 1998. Radiation dose to patients from ticals, ICRP Publication 62, Vol. 22, Pergamon Press, Oxford, radiopharmaceuticals. Addendum to ICRP Publication 53. ICRP UK; Annals of the ICRP. 1998. Radiation dose to patients from Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; Council radiopharmaceuticals. Addendum to ICRP Publication 53. of Europe, European pharmacopeia (founded 1964), http://www ICRP Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; .edqm .eu /en /Homepage -628 .html; Kowalsky, R. J. and S. W. Council of Europe, European pharmacopeia (founded 1964), Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and http://www .edqm .eu /en /Homepage -628 .html; Kowalsky, R. Nuclear Medicine, 2nd edn., American Pharmacists Association, J. and S. W. Falen. 2004. Radiopharmaceuticals in Nuclear Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear Pharmacy and Nuclear Medicine, 2nd edn., American Pharmacy, 5th edn., Springer, New York. Pharmacists Association, Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear Pharmacy, 5th edn., Springer, New Tc-99m-labelled human serum albumin York; Zolle, I. (ed.). 2007. Technetium-99m Pharmaceuticals (Nuclear Medicine) See Tc-99m-albumin (HSA), Tc-99m-albumin – Preparation and Quality Control in Nuclear Medicine, macroaggregates (MAA), Tc-99m-albumin microspheres (HAM) Springer, Heidelberg, Germany. Tc-99m-labelled microcolloids 930 Tc-99m-pyrophosphate (PYP) Tc-99m-labelled microcolloids www .edqm .eu /en /Homepage -628 .html; Kowalsky, R. J. and S. (Nuclear Medicine) See Tc-99m tin colloids, Tc-99m rhenium sul- W. Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy phide colloid, Tc-99m-albumin microcolloid and Nuclear Medicine, 2nd edn., American Pharmacists Association, Washington, DC; Saha, G. B. 2004. Fundamentals Tc-99m-labelled monoclonal antibodies of Nuclear Pharmacy, 5th edn., Springer, New York; Zolle, I. (Nuclear Medicine) See Tc-99m-arcitumomab (ed.). 2007. Technetium-99m Pharmaceuticals – Preparation and Quality Control in Nuclear Medicine, Springer, Heidelberg, Germany. Tc-99m-labelled nanocolloids (Nuclear Medicine) See Tc-99m-rhenium sulphide nanocolloid, Tc-99m MIBI Tc-99m-albumin nanocolloid (Nuclear Medicine) See Tc-99m sestaMIBI Tc-99m-labelled red blood cells (RBC) Tc-99m-Myoview (Nuclear Medicine) See Tc-99m-labelled erythrocytes (Nuclear Medicine) See Tc-99m tetrofosmin Tc-99m-labelled white blood cells Tc-99m-pyrophosphate (PYP) (Nuclear Medicine) See Tc-99m-labelled leukocytes (Nuclear Medicine) 99mTc-(Sn)-pyrophosphate was introduced in the early 1970s for skeletal imaging and has also been dem- Tc-99m-MAG3 (mercaptoacetyltriglycine) onstrated to be useful for imaging of myocardial infarction. The (Nuclear Medicine) Technetium-99m mercaptoacetyltriglycine, PYP compound can be used as a stannous agent for in vivo label- MAG3, is used for renal imaging, that is renography. Using MAG3 ling of RBC with 99mTc-pertechnetate, for 99mTc-RBC radionuclide information may be obtained of renal anatomy and function, for angiography (deep vein visualisation, ejection fraction and wall example to demonstrate satisfactory renal perfusion, renal tubular motion of the ventricle, detection of GI haemorrhage, RBC mass function, and determination of the excretion rate. and blood volume, spleen scintigraphy with denatured RBCs). The MAG3 kit contains lyophilised, sterile, pyrogen-free Because of instability in vivo 99mTc-PYP is not used for skeletal substance in nitrogen atmosphere, prepared for labelling with imaging any more (diphosphonate complexes are preferable). 99mTc – sodium pertechnetate. The commercial product is called A kit contains lyophilised, sterile, pyrogen-free PYP and Sn2+ Technescan MAG3 (Mallinckrodt). in nitrogen atmosphere, prepared for easy labelling with 1–5 Small amounts of 99mTc – impurities may be formed during mL 99mTc – sodium pertechnetate. After a few minutes in room labelling, which is taken up in the liver. The radiochemical purity temperature the preparation is ready for use within 6–8 h. The shall be at least 90% and may be checked using thin-layer chro- time of examination for bone imaging is 2 h post-administration. matography (TLC). Activities recommended are 555–740 MBq for myocardial infarct 99mTc-MAG3 is quickly distributed in the extracellular fluid imaging and blood pool imaging and 37–75 MBq for spleen scin- and excreted solely by the kidneys after IV injection with a tigraphy with heat denatured 99mTc-RBC. plasma elimination described by two biological half-lives, 3.2 The radiochemical purity of 99mTc-(Sn)-pyrophosphate T and 16.9 min. The maximal uptake in the renal system is seen should be at least 90%. The recommended test method is thin- after 3–4 min, and 3 h post-injection the blood activity is less layer chromatography (TLC) or instant TLC-silica gel fibreglass than 1%. sheets, using methyl ethyl ketone (MEK) as solvent. Renal clearance is dependent on the function of the kidneys 99mTc-(Sn)-pyrophosphate accumulates temporarily in regions and the urogenital system. The mechanism of excretion is pre- of osteogenesis and a few percent uptakes in injured myocardium. dominately based on renal tubular secretion, and glomerular fil- The effective dose for 99mTc-(Sn)-pyrophosphate administered tration rate accounts for less than 2% of the total clearance. intravenously is 8.5 μSv/MBq. The most exposed organs are the kidneys and bladder wall. For heat denatured 99mTc-RBCs for spleen scintigraphy the Normally the renal transit time is about 4 min. Depending on the effective dose is approximately 4 μSv/MBq. function of the kidneys the radiation doses are as follows: Abbreviations: GI = Gastrointestinal and RBC = Red blood cell. • Normal function: Effective dose 7.3 μSv/MBq (kidneys Related Articles: Tc-99m-diphosphonates, Tc-99m-RBC 3.4 μGy/MBq) Further Readings: Annals of the ICRP. 1992. Radiological • Abnormal function: Effective dose 6.3 μSv/MBq (kid- protection in biomedical research. Addendum 1 to ICRP neys 10 μGy/MBq) Publication 53. Radiation dose to patients from radiopharmaceu- • Acute unilateral blockage: Effective dose 10 μSv/MBq ticals, ICRP Publication 62, Vol. 22, Pergamon Press, Oxford, (kidneys 56 μGy/MBq) UK; Annals of the ICRP. 1998. Radiation dose to patients from radiopharmaceuticals. Addendum to ICRP Publication 53. Related Articles: Radiochemical purity, Technetium-99m, ICRP Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; Tc-99m DTPA Council of Europe, European pharmacopeia (founded 1964), Further Readings: Annals of the ICRP. 1987. Radiation http://www .edqm .eu /en /Homepage -628 .html; Kowalsky, R. dose to patients from radiopharmaceuticals, biokinetic mod- J. and S. W. Falen. 2004. Radiopharmaceuticals in Nuclear els and data, ICRP Publication 53, Vol. 18, Pergamon Press, Pharmacy and Nuclear Medicine, 2nd edn., American Oxford, UK; Annals of the ICRP. 1992. Radiological protection Pharmacists Association, Washington, DC.; Saha, G. B. 2003. in biomedical research. Addendum 1 to ICRP Publication 53. Fundamentals of Nuclear Pharmacy, 5th edn., Springer, New Radiation dose to patients from radiopharmaceuticals, ICRP York; Zolle, I. (ed.). 2007. Technetium-99m Pharmaceuticals Publication 62, Vol. 22, Pergamon Press, Oxford, UK; Council – Preparation and Quality Control in Nuclear Medicine, of Europe, European pharmacopeia (founded 1964), http:// Springer, Heidelberg, Germany. Tc-99m rhenium sulphide colloid 931 Tc-99m-sodium pertechnetate Tc-99m rhenium sulphide colloid nanocolloid is used for imaging of motility disorder or the esoph- (Nuclear Medicine) Technetium-99m-labelled rhenium sul- agus or gastroduodenal motor function. phide colloid is a sterile, pyrogen free, light brown solution for 99mTc-rhemium sulphide nanocolloid is commercially avail- IV administration. The radiopharmaceutical is used for liver able as NanoCis TCK-17 (CIS Bio) or Lymphoscint Solco (GE and spleen imaging, and occasionally for bone marrow imaging. Healthcare). A preformed 99mTc-kit consists of two vials. One After oral administration it can be used for imaging of digestive contains sterile, pyrogen-free solution of rhenium sulphide and transport and transit time, and for gastroduodenal motor activ- other ingredients. The second vial contains sodium pyrophos- ity. The time of examination is 15–20 min post-injection for liver phate and stannous chloride. The two constituents are mixed and and spleen scintigraphy, 1 h for bone marrow, and for digestive 99mTc-pertechnetate is added. The mixture is placed in a boiling dynamic imaging (transit time) immediately after administration. water bath for 15–30 min. After cooling, the radiopharmaceutical A 99mTc-(Re) sulphide colloid kit contains lyophilised, ster- is ready for use. ile, pyrogen-free, substance in nitrogen atmosphere, prepared for Several factors affect the labelling efficiency, that is low labelling with 99mTc – sodium pertechnetate. The basic principle colloid formation and thus low specific activity are principally for preparation of 99mTc –(Re) sulphide colloid is in principle the related to pH, wrong mixing order, low heating temperature, too same as for 99mTc- sulphur colloid, that is colloidal sulphur and large volume at heating, incorrect boiling time, or a failing kit. technetium heptasulphide are formed at acidic pH in a water bath The 99mTc-(Re) sulphide nanocolloid kit is normally stable for 4 h at 100°C. Commercial kits listed are HepatoCis (TCK-1) and after preparation. Sulfotec Sorin. 99mTc-(Re)-sulphide nanocolloid labelling efficiency can be The particle size distribution is 0.3 and 0.8 μm. Paper chro- tested using paper chromatography, for example. Whatman 31 matography using saline as solvent is recommended for the paper using methyl ethyl ketone (MEK) as solvent. TLC may also radiochemical control (yield) of the preparation. Labelling effi- be used for quality control in which acetone is used as a solvent. ciency in a good preparation should not be less than 92%. Factors The radiochemical purity should be at least 95%. affecting the yield are mostly related to pH, wrong mixing order, After subcutaneous administration 99mTc-(Re)-sulphide low heating temperature, too large volume at heating, or incor- nanocolloid is transported with the interstitial fluid through the rect boiling time. The 99mTc-(Re) sulphide colloid kit is

normally lymphatic capillaries into the lymph ducts, and retained by the stable for 6 h. regional lymph nodes. Clearance is slow and depends on the With a particle size of 0.3–0.8 μm 80%–90% are rapidly motion of the patients’ extremities. removed from the blood and accumulated in the liver by phagocy- Dosimetric evaluation after subcutaneous administration is tosis (RES), 4%–8% in the spleen, and 3%–5% in the bone mar- based on the assumption that about 5%–15% of the activity is dis- row. Larger colloids show increased uptake in the spleen, while tributed among 10–20 lymph nodes. The highest absorbed dose smaller colloidal particles localise in the bone marrow. may be received at the site of injection and could be 10–20 mGy/ The most exposed organs are the spleen, liver and red bone MBq and to a 5g lymph node 0.5–0.7 mGy/MBq. The effective marrow, which result in absorbed doses of 75, 71 and 11 μGy/ dose has been estimated to be approximately 5 μSv/MBq. MBq respectively. The effective dose is approximately 10 μSv/ Abbreviation: SC = Subcutaneous. MBq. Normally 75–150 MBq is administered IV for planar imag- Related Articles: Tc-99m nanocolloid, Tc-99m sulphur colloid ing, whereas 200 MBq is used for SPECT. Further Readings: Annals of the ICRP. 1987. Radiation Related Articles: Tc-99m sulphur colloids, Tc-99m tin dose to patients from radiopharmaceuticals, biokinetic mod- T colloids, Tc-99m albumin microcolloids, Stannous chloride els and data, ICRP Publication 53, Vol. 18, Pergamon Press, Further Readings: Annals of the ICRP. 1992. Radiological Oxford, UK; Bergvist, L., S.–E. Strand, B. Persson, L. Hafström protection in biomedical research. Addendum 1 to ICRP and P.–E. Jönsson. 1982. Dosimetry in lymphoscintigraphy of Publication 53. Radiation dose to patients from radiopharmaceu- Tc-99m antimony sulfide colloid. J. Nucl. Med. 23:298–705; ticals, ICRP Publication 62, Vol. 22, Pergamon Press, Oxford, Bergvist, L. 1987. Radioactive colloids – Particle characteriza- UK; Annals of the ICRP. 1998. Radiation dose to patients from tion, experimental studies, clinical and dosimetric consider- radiopharmaceuticals. Addendum to ICRP Publication 53. ICRP ations. Doctoral dissertation, Lund University, Sweden; Council Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; Council of Europe, European pharmacopeia (founded 1964), http://www of Europe, European pharmacopeia (founded 1964), http://www .edqm .eu /en /Homepage -628 .html; Kowalsky, R. J. and S. W. .edqm .eu /en /Homepage -628 .html; Kowalsky, R. J. and S. W. Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine, 2nd edn., American Pharmacists Association, Nuclear Medicine, 2nd edn., American Pharmacists Association, Washington, DC; Zolle, I. (ed.). 2007. Technetium-99m Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear Pharmaceuticals – Preparation and Quality Control in Nuclear Pharmacy, 5th edn., Springer, New York; Zolle, I. (ed.). 2007. Medicine, Springer, Heidelberg, Germany. Technetium-99m Pharmaceuticals – Preparation and Quality Control in Nuclear Medicine, Springer, Heidelberg, Germany. Tc-99m-sodium pertechnetate (Nuclear Medicine) Chemical name: Sodium pertechnetate 99mTc Tc-99m-rhenium sulphide nanocolloid Abbreviated name: Na 99m TcO- 4 (Nuclear Medicine) 99mTc-rhenium sulphide nanocolloid is used Examples of commercial products: 99Mo/99mTc-generators; for imaging of lymphoscintigraphy, imaging of lymphatic flow Ultra-Teknekow® DTE (COVIDEN – Mallinckrodt); DRYTEC and regional lymph nodes in torso and extremities after subcu- (GE Healthcare); TechneLite® (Bristol-Myers Squibb). taneous or interstitial administration. It is also used for sentinel Sodium pertechnetate, Na 99m TcO- 4 is eluted carrier-free from lymph node (SLN) scintigraphy in which the radiopharmaceuti- a 99Mo/99mTc-generator with sterile 0.9% saline solution in a vol- cal is administered subdermally or peritumourally. Imaging of ume of about 10–20 mL. The activity of the elute depends on the the SLN can detect the first lymph node of a primary tumour size of the generator, that is the 99Mo column activity, which var- before surgery. After oral administration, 99mTc-rhenium sulphide ies normally between 37 GBq (1 Ci) and 370 GBq (10 Ci) at the Tc-99m-Sulesomab 932 Tc-99m-tin colloids day of reference. Since the activity of the 99mTc elute relates to the chromatography (instant (I)TLC-silica gel fibreglass sheets) and time between elutions, daily elution of the generator at an interval acetone as solvent is recommended. of 24 h will give the best quality of the elute. 99mTc-Sulesomab is excreted by the kidneys; thus, they are the Sodium pertechnetate is a highly water soluble product but most exposed organs together with the urinary bladder, liver and when reduced it loses its water solubility and forms relatively spleen: 89, 10, 8.7 and 14 μGy/MBq respectively. The effective stable bonds to chelates, proteins and cells. When it is reduced dose is estimated to be 11 μSv/MBq. several redox states are possible, making the technetium chemis- Abbreviation: IV = Intravenous. try quite complex, but at the same time many possibilities to label Further Readings: Annals of the ICRP. 1992. Radiological to different substances. protection in biomedical research. Addendum 1 to ICRP Publication The oxidation state of TcO- 4 is +VII and it is the most stable 53. Radiation dose to patients from radiopharmaceuticals, form of Tc in water and air. The radiopharmaceutical chemis- ICRP Publication 62, Vol. 22, Pergamon Press, Oxford, UK; try involves the reduction of pertechnetate to an oxidation state Annals of the ICRP. 1998. Radiation dose to patients from between +VI and +III for labelling of different compounds. The radiopharmaceuticals. Addendum to ICRP Publication 53. ICRP reducing agent of choice is Sn2+ (see Stannous chloride). Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; Council Sodium pertechnetate, 99mTc(+VII) may be administered of Europe, European pharmacopeia (founded 1964), http://www intravenously as it is for scintigraphy of the thyroid, salivary .edqm .eu /en /Homepage -628 .html; Kowalsky, R. J. and S. W. glands, gastric mucosa, brain lesions (defective BBB), and for in Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and vivo labelling of red blood cells (RBC). Nuclear Medicine, 2nd edn., American Pharmacists Association, However, the main use of the pertechnetate is ad hoc labelling Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear of pre-fabricated kits, available for a number of clinical applica- Pharmacy, 5th edn., Springer, New York; Zolle, I. (ed.). 2007. tions in nuclear medicine. 99mTc is used in about 95% of all nuclear Technetium-99m Pharmaceuticals – Preparation and Quality medicine examinations. Control in Nuclear Medicine, Springer, Heidelberg, Germany. The organs that receive the highest absorbed doses after an IV administration of Na 99m TcO- 4 are the thyroid (0.022 mGy/MBq), Tc-99m-sulphur colloid gastrointestinal tract, that is the walls, (0.16–0.42 mGy/MBq) (Nuclear Medicine) Technetium-99m-labelled sulphur colloid and the bladder (0.018 mGy/MBq). The effective dose is 0.013 is a classical radiopharmaceutical for liver and spleen imaging, mSv/MBq. If a blocking agent (stable iodine) has been given the and occasionally for bone marrow imaging. It can also be used absorbed doses will reduce a factor of 10, and the effective dose for scintigraphy of GI blood loss and for gastric emptying using to 0.0042 mSv/MBq. 99mTc-labelled scrambled eggs. Today, this radiopharmaceutical Abbreviation: IV = Intravenously. is rarely used. Related Articles: Radionuclide generator, Stannous chloride, The basic principle of 99mTc sulphur colloid labelling is to add Kits, Blocking agent an acid to a mixture of 99mTc-pertechnetate and sodium thiosul- Further Readings: Annals of the ICRP. 1987. Radiation phate and then heat it at 95°C–100°C in a water bath for 5–10 min. dose to patients from radiopharmaceuticals, biokinetic mod- The pH (6–7) is adjusted with a suitable buffer. Labelling effi- els and data, ICRP Publication 53, Vol. 18, Pergamon Press, ciency is normally close to 100%. Commercial kits are available. T Oxford, UK; Annals of the ICRP. 1992. Radiological protection The particle size is 0.1–1 μm with a mean of 0.3 μm. Using a in biomedical research. Addendum 1 to ICRP Publication 53. membrane filter (0.1 or 0.2 μm), small particle size sulphur colloid Radiation dose to patients from radiopharmaceuticals, ICRP may be used for lymphoscintigraphy as well. Publication 62, Vol. 22, Pergamon Press, Oxford, UK; Council The most exposed organs are the liver, spleen and red bone of Europe, European pharmacopeia (founded 1964), http:// marrow, which result in absorbed doses of 71, 75 and 11 μGy/ www .edqm .eu /en /Homepage -628 .html; Kowalsky, R. J. and S. MBq respectively. The effective dose is approximately 10 μSv/ W. Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy MBq. Normally 40–150 MBq is administered IV for planar imag- and Nuclear Medicine, 2nd edn., American Pharmacists ing, whereas 200 MBq is used for SPECT. Association, Washington, DC; Saha, G. B. 2004. Fundamentals Related Articles: Tc-99m tin colloids, Tc-99m albumin of Nuclear Pharmacy, 5th edn., Springer, New York; Zolle, I. microcolloids, Stannous chloride (ed.). 2007. Technetium-99m Pharmaceuticals –Preparation Further Readings: Annals of the ICRP. 1992. Radiological and Quality Control in Nuclear Medicine, Springer, Heidelberg, protection in biomedical research. Addendum 1 to ICRP Germany. Publication 53. Radiation dose to patients from radiopharmaceu- ticals, ICRP Publication 62, Vol. 22, Pergamon Press, Oxford, Tc-99m-Sulesomab UK; Annals of the ICRP. 1998. Radiation dose to patients from (Nuclear Medicine) 99mTc-Sulesomab is antigranulocyte mono- radiopharmaceuticals. Addendum to ICRP Publication 53. ICRP clonal antibody fragment complex, used for scintigraphic studies Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; Council of infection and inflammation in patients with suspected osteo- of Europe, European pharmacopeia (founded 1964), http://www myelitis, joint infection involving implants, inflammatory bowel .edqm .eu /en /Homepage -628 .html; Kowalsky, R. J. and S. W. disease, and foot ulcers in diabetic patients. An available com- Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and mercial kit is LeukoScan from Immunomedics Europe. Nuclear Medicine, 2nd edn., American Pharmacists Association, A LeukoScan kit contains lyophilised, sterile sulesomab Washington, DC; Zolle, I. (ed.) 2007. Technetium-99m (IMMU-MN3 Fab’-SH antigranulocyte antibody fragments) in a Pharmaceuticals – Preparation and Quality Control in Nuclear nitrogen or argon atmosphere, ready for labelling with 1100 MBq Medicine, Springer, Heidelberg, Germany. 99mTc-pertechnetate. The radiopharmaceutical is given IV for planar or SPECT imaging. Tc-99m-tin colloids The radiochemical purity should be at least 90%, and is tested (Nuclear Medicine) Technetium-99m-labelled tin colloids are in for free 99mTc-pertechnetate before administration. Thin-layer the range of 0.2–0.8 μm particle size. The radiopharmaceutical is TD (time delay) 933 Technetium-99m [99Tcm] 180° inversion α excitation pulses 180° inversion pulse pulse pulse RF transmit TI TR TR TR TD Slice acquisition FIGURE T.8 TD in a multislice, single shot turboFLASH sequence. used for liver and spleen scintigraphy. IV injected 99mTc tin col- slice (or segment). To allow adequate longitudinal recovery after loids localise within the liver due to phagocytosis of the reticulo- each inverting pulse, a delay TD is introduced from the end of endothelial system (RES). The time of examination is performed each slice or segment acquisition to the acquisition of the next. 10–15 min after an IV injection. Common trade names are Similarly TD is implemented in MP-RAGE, the 3D variant of Amerscan Heptate II (GE Healthcare) and Livoscint (Bristol- turboFLASH (Figure T.8). Myers Squibb). TD contributes to overall scan time. In turboFLASH the scan A kit contains sterile, lyophilised, preformed tin-II-fluoride time is as follows: with a size distribution of 0.2–0.8 μm, sodium fluoride and a sta- bilising agent (Poloxamer 188). Preformed tin colloid is easily Scan time = No.of slice labelled with reduced 99mTc. Maximum activity is 3.7 GBq per vial. The radiochemical purity should at least be 95%, for example æ ö ´ ç TI + No. of lines in phase tested with TLC. encode direction ´ TR + TD÷ è ø With a particle size of 0.2–0.8 μm, 80%–90% are rapidly removed from the blood and accumulated in the liver by phago- Note that in MR literature the term time delay (TD) is used quite cytosis, 5%–10% in the spleen, and 5%–9% in the bone mar- arbitrarily to denote a delay between events in an acquisition or row. These organs are the most exposed, with an approximate sequence and its meaning is not limited to the definition given absorbed dose to the liver, spleen and red bone marrow of 71, here. 75 and 11 μGy/MBq respectively. The effective dose is approxi- Further Reading: McRobbie, D. W., E. A. Moore, M. J. Graves mately 10 μSv/MBq. Normally 75–185 MBq is administered IV and M. R. Prince. 2006. From Picture to Proton, Cambridge for planar imaging, and 200 MBq for SPECT imaging. University Press, Cambridge, UK. Abbreviation: IV = Intravenously. Related Articles: Tc-99m albumin microcolloids, Tc-99m T albumin nanocolloid, Stannous chloride TE (echo time) Further Readings: Annals of the ICRP. 1992. Radiological (Magnetic Resonance) See Echo time (TE) protection

in biomedical research. Addendum 1 to ICRP Publication 53. Radiation dose to patients from radiopharmaceu- Technetium ticals, ICRP Publication 62, Vol. 22, Pergamon Press, Oxford, (Nuclear Medicine) Technetium is a chemical element with atomic UK; Annals of the ICRP. 1998. Radiation dose to patients from number 43 and is commonly used in medicine (in particular 99mTc) radiopharmaceuticals. Addendum to ICRP Publication 53. ICRP because of its favourable physical characteristics. Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; Council Technetium does not occur naturally in nature since none of of Europe, European pharmacopeia (founded 1964), http://www the isotopes are stable. The presence of technetium was predicted .edqm .eu /en /Homepage -628 .html; Kowalsky, R. J. and S. W. by Dmitri Mendeleev because of the gap in the periodic system. Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and The most commonly used technetium isotope in medical imaging Nuclear Medicine, 2nd edn., American Pharmacists Association, is 99mTc because of its favourable physical decay properties: Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear Pharmacy, 5th edn., Springer, New York; Zolle, I. (ed.). 2007. • Low radiation dose per decay Technetium-99m Pharmaceuticals – Preparation and Quality • Convenient half-life (6.01 h) Control in Nuclear Medicine, Springer, Heidelberg, Germany. • γ-rays are suitable for imaging (140 keV) TD (time delay) 99mTc can be labelled to different compounds that target specific (Magnetic Resonance) Time delay (TD, also called ‘intersegment physiological bio-processes and it is used to study the functional- delay’) is a delay introduced between successive slice acquisitions ity of a number of organs and bio-systems, for example brain, in multislice scanning (or between successive partitions in 3D myocardium, thyroid, lungs, liver, gallbladder, kidneys and skel- scanning) in some fast imaging techniques. eton. 99mTc can also be used to locate tumours. For example, in turboFLASH imaging the sequence begins with a preparatory, non-selective 180° inverting pulse. Slice Technetium-99m [99Tcm] acquisition then follows, either in a single shot, filling all of (Nuclear Medicine) Element: technetium k-space, or in segments, filling many lines of k-space. The pro- Isotopes: 45 < N < 69 cess then repeats, with a preparatory pulse and filling of the next Atomic number (Z): 43 Technetium generator 934 Techniques to improve radionuclide uptake Neutron number (N): 56 Publication 80, Vol. 28(3), Pergamon Press, Oxford, UK; Chu, S. Symbol: 99mTc Y. F., L. P. Ekström and R. B. Firestone. 1999. The Lund/LBNL - Production: Generator 98 IT Mo(n, f )99 Mo ®b 99 Tcm ® 99 Tc Nuclear Data Search, Lund University, Sweden, http: / /nuc leard 65,9h 6.01h ata .n uclea r .lu. se /nu clear data/ toi/; Firestone, R. B. 1999. Table of Mother: 99Mo (reactor/fission produced) Isotopes, 8th edn., Update with CD-ROM, John Wiley & Sons, Daughter: 99Tc Inc., New York, http://ie .lbl .gov /toi .html; Kowalsky, R. J. and S. Half-life: 6.01 h W. Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and Decay mode: IT Nuclear Medicine, 2nd edn., American Pharmacists Association, Radiation: gamma, internal conversion electrons, Auger Washington, DC. electrons, characteristic x-ray photons Gamma energy: 140.5 keV (89.1%) Dose rate from 1 MBq: 0.26 μSv/h at 1 cm (point source); Technetium generator 0.022 μSv/h at 30 cm (10 mL vial) (Nuclear Medicine) A radionuclide generator with the 99Mo – Absorption (HVL): 0.27 mm lead 99mTc parent daughter couple. 99mTc is used worldwide in many Absorption (range of electrons): 0.2 mm glass clinical radionuclide imaging applications. The parent 99Mo is in Biological half-life: 3–5 h (45%), 45 h (55%) the form of the molybdate ion, MoO4 which is bound to an alu- Critical organ: thyroid gland, gastrointestinal walls mina column. 99mTc is not as strongly bound to the column and it ALImin (50 mSv): 3000 MBq is therefore possible to elute 99mTc from the column. The eluate contains 99m Effective dose: 0.020 mSv/MBq (oral); 0.016 mSv/MBq TcO4 (pertechnetate) and normal saline. The saline (inhalation) is used to filter the column. As much as 75%–85% of the avail- able 99mTc is extracted in a single elution. Maximum activity is available again some 24 h after the previous elution when a new 6 99 S Mo – 99mTc equilibrium is reached; but it is also possible to elute 5/2 usable quantities after 3–6 h. The generator must be recharged on 1/2+ 65.94 h 43 a weekly basis because of the parent decay. Tc 99 3% 42 Mo β– 6 .99 A small fraction of 99Mo will always be eluded with the 99mTc. This is called 99Mo breakthrough. The radiation dose per disinte- IT 99 Technetium 0.0037% gration for 99Mo is higher than for 99mTc and there is no γ-radiation (98) 1/2– 6.01 h 142.6833 β– suitable for imaging from the 99Mo decay so in regard to patient 9/2+ 0 2.111 × 105 y safety the fraction of 99Mo should be kept to a minimum. [Kr]4d55s2 99 7.28 43Tc β– Related Article: Molybdenum breakthrough Qβ–1357.2 Further Reading: Cherry, S. R., J. A. Sorenson and M. E. Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, Philadelphia, PA, pp. 52–53. Clinical Applications: Technetium-99m was introduced in T the early 1960s and is nowadays used in over 90% of all nuclear Technique projections medicine examinations. It is very simply labelled to a number of (General) There is a convention where the radiographic technique pre-fabricated kits. 99mTc has advantageous decay characteristics projection is identified by the direction of the x-ray beam. For for imaging with scintillation cameras, as well as from a radiation example, for the chest x-ray the projection can either be posterior- dosimetry point of view. anterior or antero-posterior. Related Articles: Tc-99m-pertechnetate, Tc-99m-generator, Antero-Posterior Projection (AP): The x-ray tube produces Kits an x-ray beam which passes through the back to the front of the patient to produce an image. Posterior-Anterior Projection (PA): The x-ray tube produces 99Mo 65.94 h an x-ray beam which passes through the front to the back of the patient to produce an image. β– Techniques to improve radionuclide uptake in tumour cells (Nuclear Medicine) These are techniques that intend to maximise 99Tcm 6.01 h 142.68 keV the accumulation of the targeting agent in tumour cells. 140.51 keV There are a number of approaches suggested on how to increase the radionuclide uptake in tumour cells, four of them being hν = 140.51 keV 1. Changes of receptor and antigen expression 2. Increased binding affinity 99Tc 0 keV 3. Increased cellular retention and internalisation 4. Nuclear localisation Further Readings: Annals of the ICRP. 1987. Radiation dose The first approach aims to up- or down-regulate receptors and to patients from radiopharmaceuticals, biokinetic models and antigens on the cell surface by using substances like cytokines, data, ICRP Publication 53, Vol. 18, Pergamon Press, Oxford, hormones or other biological response modifiers. By regulating UK; Annals of the ICRP. 1998. Radiation dose to patients from the receptors and antigens it is possible to improve the target agent radiopharmaceuticals. Addendum to ICRP Publication 53. ICRP uptake. Technologist 935 Temperature control The second approach aims to increase the binding affinity of Teleradiography is a radiographic technique where the dis- the target agent to disseminated tumour cells. If one increases the tance from the x-ray tube to the detector is about 2 m. The advan- binding affinity in bulky tumours this might lead to an uneven tages of this geometrical solution are distribution in the tumour and the method is therefore mainly considered for locating and eliminating disseminated cells. • Reduction of the penumbra due to the focal spot dimension The third approach aims to increase the retention and inter- • Minimisation of the geometric distortion nalisation of the target agent. The longer the radiolabelled tracer • Almost total elimination of the ‘Heel effect’ stays in or near the targeted cell the greater is the radiation dose given to the tumour cell and subsequently greater chance of suc- The overall effect on image quality is improved radiographic cessful therapy results. In the case of internalisation, the targeting sharpness. Teleradiography is often used for chest radiography agent is situated closer to the most radiosensitive part of the cell, and orthodontics. namely the nuclear DNA. However there may be other problems arising with internalisation, for example a quicker degeneration of the targeting agent followed by a fast diffusion and clearance of Teletherapy the radionuclide. One alternative to prevent intracellular degrada- (Radiotherapy) Radiotherapy, radiation therapy, is the treatment tion of the targeting agent is dextranation. of a disease with ionising radiation. Nuclear localisation aims to trap the targeting agent inside the Depending on the distance between the radiation source and cell nucleus, close to the radiosensitive DNA. If possible nuclear the target volume, that is the tissues to be treated, radiotherapy is localisation therapy would allow the use of much lower activi- divided into two categories: teletherapy and brachytherapy. ties of β- and α-emitters since the therapeutic effect per decay increases. One principle of nuclear localisation is the use of radio- • In teletherapy the source is far from the target (Greek labelled steroids which binds to steroid-receptor-rich tumour word tele, distant, far away). cells. The downside is that conventional steroids have a low resi- • In brachytherapy the source is placed close to or inside dence time inside the cell nucleus, hence not producing the high the target (Greek word brachys, short). therapeutic effect desired. Related Articles: Radionuclide uptake in tumour cells, External beam therapy is ordinarily regarded to be identical with Extracorporeal elimination teletherapy. Further Reading: Carlsson, J., E. F. Aronsson, S.-O. Hietala, It is to be noted though, that there are external beam tech- T. Stigbrand and J. Tennvall. 2003. Tumour therapy with radionu- niques with very short source-skin distances, such as contact clides: Assessment of progress and problems. Radiother. Oncol. therapy using kilovoltage x-ray equipment. 66(1):107–117. Related Articles: External beam therapy, Radiotherapy equip- ment, Dosimetry, Treatment planning Technologist (Nuclear Medicine) Technologist is a profession for people edu- Temperature coefficient cated in the field of technology. In some countries technologist is (Radiation Protection) See Pressure and temperature correction a certified profession and only students who have graduated from factor T an accredited institution/university are certified. Temperature control Teleradiology (General) Temperature control is common both within equipment (Diagnostic Radiology) Teleradiology is the practice of transmis- and in the local environment. Temperature control requires some sion, usually via the internet, of radiological images for remote form of sensor – either a simple on–off device, a thermostat, or reporting or as part of a consultation between radiologists for the more complex sensors or probes which have an output propor- purposes of making a diagnosis and producing a report. Images tional to temperature. stored electronically, usually within a PACS system, can be trans- On–Off Control: The simpler devices use a heater or cooler mitted almost instantaneously to another remote image handling wired via a thermostat which turns them on/off when a preset system or software package from where they can be reported. This temperature is reached. Thermostats have inbuilt hysteresis or allows for radiological imaging to operate in a small or remote a ‘dead band’ so that, once switched, they require a significant location, even without the presence of a radiologist, whilst still difference in temperature before they will switch back. This pre- having the capability of providing a relatively prompt report turn vents any race condition where the thermostat and cooler/heater around with access to a wider pool of trained and often specialist can reach an equilibrium temperature where the thermostat would radiologists only available in larger populated areas. International flutter on and off, and could result in damage to the heater/cooler. arrangements could even be made to lower the costs of radiologi- Proportional Control: More complex temperature control sys- cal reporting out of hours by sending images to radiologists in tems use sensors which can measure the ambient temperature and different time zones rather than employing radiologists to work coolers/heaters which can either provide varying thermal output outside of normal hours. or be switched on/off frequently. A microprocessor or analogue The specialist software packages allow for image handling filter circuit is used to amplify the sensor signal, compare it with and manipulation and visualisation of images from a number of the required temperature value and drive the thermal output in the different specialities and to produce verbally recorded or writ- most efficient manner to minimise the difference. Proportional ten reports, possible using

voice recognition tools, which can be controls need to be used where thermal tolerances are low or large relayed back to the referring centre. variations in temperature must be corrected in the shortest time. As teleradiology refers to electronic transfer of radiographs, Control of Temperature in X-Ray Generators: Temperature it can be confused with a specific method of x-ray radiography control of the anode of an x-ray tube is very important for the – Teleradiography. correct and safe use of an x-ray generator. The whole tube is Temperature correction 936 T emporary implant immersed in oil (in the tube housing). The simplest temperature Related Articles: Persistence, Colour flow imaging, Doppler control uses a rubber membrane which opens a switch (i.e. inter- ultrasound rupts the power supply) when the oil expands due to high tempera- ture of the tube. The most sophisticated one is a microprocessor Temporal (instantaneous) peak intensity ITP or I system which models the tube temperature and controls the expo- IP (Ultrasound) This is the maximum instantaneous intensity. It is the sure parameters (kV, mA, length of exposure) according to the highest intensity to be found anywhere within an ultrasound field. tube thermal load characteristic. It is determined directly from p Related Articles: Thermostat, Thermal probe, X-ray generator, + or p−, whichever has the largest value. It is usually found within a pulse at a transmit focal point. Temperature probe Related Articles: Intensity, Focal point, Spatial peak intensity, Pressure parameters Temperature correction (Radiation Protection) See Pressure and temperature correction factor Temporal resolution (Ultrasound) The term temporal resolution refers to the fre- Temperature probe quency with which the image is updated. It applies to B-mode, (General) A general term for any temperature sensor mounted in colour flow and spectral Doppler imaging. a long thin housing. For B-mode and colour flow imaging, the image is updated at Depending on the temperature range to be monitored, the a frame rate indicated on the screen. Each individual frame takes environment in which it will be used, and the accuracy required, a finite time so that an individual image is not an instantaneous a large number of options are available, among which are as snapshot of the area under investigation. This may be important follows: for fast moving structures such as the foetal heart and rapidly changing flow where different parts of the image show different • Thermocouple – It uses wires of dissimilar metals parts of the cardiac cycle. Temporal resolution is dependent on the which, if connected to form a pair of junctions in series, size of the image and the line density; there is often a compromise will generate an electro chemical potential across the to be made between temporal and spatial resolution, especially in pair related to the temperature difference (small signal, colour flow imaging. wide operating range). For spectral Doppler, the temporal resolution in the sono- • Thermostat – A mechanical switching device which gram is several hundred Hz, dependent on the processing used, uses the thermal expansion of some material to toggle the PRF used and whether B-mode and colour flow are deployed an electric switch when a preset temperature is reached concurrently. (usually range −40°C to +150°C). Related Articles: Frame rate, Spatial resolution, Resolution • Thermistor – A temperature dependent resistor. Resistance usually drops as temperature increases. Must Temporal resolution be calibrated and only linear over a short temperature (Diagnostic Radiology) Just as the spatial resolution of an imag- range. Usually range within band and −20°C to +100°C. ing system describes its ability to distinguish objects in space, T • Diode – All semiconductor diodes have a precise nega- the temporal resolution of a system describes its ability to distin- tive temperature coefficient of current when reverse guish events in time. Specifically, temporal resolution describes biased (−20°C to +140°C). the time taken for an imaging system to respond to a change in • Optical fibre – Various designs use the reflection of exposure. light from the tip of a fibre optic cable as a method of Fluoroscopy systems sacrifice the excellent signal to noise safe monitoring temperature in high magnetic, radia- ratio performance seen in standard radiography for a superior tion or electric fields. Among temperature sensitive temporal resolution. This temporal resolution will depend on both properties that tips may have are thermo-optical, and the parameters by which imaging is undertaken and the intrinsic thermo-mechanical. limits of the imaging equipment used. For example, if undertaking • IR Optical sensor – Non-contacting sensor relying on pulsed fluoroscopy, an increasing pulse rate (whilst maintaining a infra-red spectrum emitted from the object being mea- constant pulse width) will increase temporal resolution whereas a sured. Often requires input of some emissive property decreasing pulse rate will reduce temporal resolution. Image lag, of the object being measured. when an image is not completely extracted between two frames of a fluoroscopic acquisition (due to the limits of the detector sys- Related Articles: Thermostat, Fluoroptic probe tem), reduces temporal resolution (as displayed in Figure T.9). Related Articles: Fluoroscopy, Digital fluoroscopy Temperature sensor Further Readings: Dowsett, D. J. 2006. The Physics of (General) See Temperature probe Diagnostic Imaging, Oxford University Press, p. 368; Maher, K. P. Diagnostic Radiology Physics: A Handbook for Teachers and Temporal filtering Students – Chapter 8. (Ultrasound) Temporal filtering is a general term in imaging whereby time-changing features in a signal or image are used to Temporary implant improve image resolution and feature detection. An example of (Radiotherapy, Brachytherapy) There are two different types of this is recursive filtering in ultrasound images, where frame aver- brachytherapy, considering the duration of the treatment: aging is used to reduce the effect of speckle. Another implemen- tation is the subtraction of successive images such that images of 1. Permanent implants stationary images are removed and images from moving targets, a. The sources are placed in the target volume by an most commonly blood, are emphasised. interstitial technique. Tendering 937 Tendering FIGURE T.9 Image lag as an object moves across detector face, reduc- ing temporal resolution. b. The sources are then left permanently in the target to decay. FIGURE T.10 Temporary interactive prostate implant showing all c. The total dose is delivered over a long time with needles placed in the prostate, the ultrasound transducer and the Foley decreasing dose rate. catheter in the bladder with contrast in the balloon, marker wires in three d. There is just ONE implant procedure for the whole needles. treatment. e. This is a low dose rate technique. 2. Temporary implants a. The sources are placed in the target volume by either interstitial or intracavitary techniques. b. The sources stay in the target volume until the cor- rect dose is delivered. c. Fixation of applicators can be used for the short HDR treatments, with good control of both total dose and dose distribution. d. The treatment is often delivered in several fractions, that is several implant procedures are required. e. Temporary implants are suitable for all dose rates, high dose rate, low dose rate and pulsed dose rate. T Temporary implants are often used as a boost treatment together with external beam radiotherapy. A combination of brachyther- apy and external beam radiotherapy is for instance the ‘stan- dard radical radiotherapy’ for cervical cancer (see Intracavitary FIGURE T.11 Template for HDR needles with locking mechanism (double template system; screw on top displacing one template) to hold all brachytherapy). the needles stably in place during the treatment. Temporary high dose rate interstitial implants can be used also for the treatment of prostate tumours, either as brachyther- apy alone or as a boost together with external beam radiother- It is a tool used by the public administration or by private apy (mostly for the ‘higher risk’ tumours). The basic procedure structures and companies to express their need for procuring ser- is similar to the permanent prostate implant; needles are placed vices, products or works. in the prostate according to a planned pattern under transrectal The legislation varies from country to country. In the European ultrasound -guidance, using a template to position the interstitial Union the directives 2014/23/EU, 2014/24/EU and 2014/25/EU needles (Figures T.10 and T.11). set the legislative framework. A remotely controlled afterloading unit with a high intensity The contracting authority issues an invitation to tender, defin- 192Ir-source is used for the treatment. Fluoroscopy is used to ing both the general and special requirements for participation position the needles to the correct depth, see Figure T.10. Marker (such as economic and technical capabilities). wires are inserted into three of the needles, indicating stop The procedures for conducting the tendering process can vary positions for the source in the applicators. according to the nature of goods and services as well as to the Related Articles: Brachytherapy, Intracavitary brachyther- overall cost. apy, Interstitial brachytherapy, Remote afterloading, Permanent Related Articles: Bidding process, Procurement, Disposal implant, Iridium-192 Further Readings: Iadanza, E. 2019. Clinical Engineering Handbook, 2nd edn., Academic Press, Elsevier, ISBN: Tendering 9780128134672; Miniati, R., E. Iadanza and F. Dori. 2016. (General) A process for realising constructions or for acquiring Clinical Engineering: From Devices to Systems, Academic goods and services. Press, Elsevier, ISBN 9780128037676; Willson, K., K. Ison and Tensor 938 Tertiary collimator S. Tabakov. 2014. Medical Equipment Management, Taylor & used as image intensifying screens in x-ray imaging. Such phos- Francis Group, ISBN: 9780429130373. phors luminesce in green and have a relatively high rate of conver- sion between absorbed x-rays and emitted visible photons. Tensor Related Articles: Phosphor, Phosphorescence, X-ray image (Magnetic Resonance) A tensor is a mathematical idealisation intensifier of a geometric or physical quantity that is invariant to transfor- mations, such as rotations. This allows the writing of equations TERMA independently of a given coordinate system so that observables do (Radiotherapy) TERMA is an acronym for total energy released not depend on the chosen frame of reference. Three examples of per unit of mass and represents the energy that is imparted to the tensors are a scalar representing the mass of a particle, a vector secondary charged particles and retained by the scatter photon describing the force on an object or the stress tensor that describes when the primary photons interact in a unit mass. The TERMA the stress in a small volume. A tensor is commonly represented distribution differential in energy TE(r), that is the total radiant as an array of numbers or a matrix, where the numbers transform energy released per unit mass by primary photons of energy E appropriately under change of basis. The rank of a tensor can with energy fluence ΨE(r) in a medium of density ρ(r) is given by intuitively be described as the number of array indices required to describe the quantity. r m E,r é ù In diffusion tensor imaging (DTI), a model based on a diffu- TE (r ) = (r )2 ( ) / r ê 0 ( ) YE (r r 0 )exp -òm(E,l )dlú sion tensor is used to describe the diffusion of water in varying r ê ú ë r0 û directions. DTI of the brain visualises white matter fibres and can where map changes associated with diseases. When the diffusion tensor μ(E, r) is the linear attenuation coefficient of the medium at r is estimated over a larger volume, the diffusion tensors of differ- Ψ ent voxels can be used to perform fibre tractography. E(r0) is the energy fluence differential in energy on a refer- ence plane on which the ray from the source to r inter- DTI of the brain enables visualisation of white matter fibres sects at r and can map changes associated with diseases. 0 Related Articles: Tractography, Trace, Diffusion tensor imag- ing (DTI) The TERMA, which can be thought of as the energy lost out by the primary photon beam in a unit mass, is always larger than Tenth value layer (TVL) the Kerma by a factor μ/μtr. (General) The tenth value layer (TVL) is the thickness of a mate- The TERMA is generally used as a factor that modulates the rial required to reduce the intensity of a particular type and qual- energy deposition kernel in the convolution method to calculate ity of radiation to one-tenth. It is expressed in units of distance the photon beam dose distribution. referred to the specific material (e.g. mm Al). It is used as an

The dose in a homogenous phantom is obtained by convolv- alternative to the half value layer (HVL) to indicate the quality ing the TERMA distribution with the kernels. The convolution or penetrating ability of the radiation. The HVL and TVL are integral assumes that the kernel is spatially invariant and the proportional to both the penetrating ability of the radiation and integration is carried out over all space, although in practice the T the attenuation coefficient of the material. integration need only be done in regions where the product of Related Articles: Half value layer (HVL), Beam quality, TERMA and photon density is reasonable large. Beam energy If the total energy imparted to a unit of mass at r′ is the TERMA T(r′), the energy deposited in a unit volume at another point r due to this energy imparted is given by T(r′)H(r − r′) where H(r − r′) Terbium is the kernel value for a displacement r − r′ from the kernel origin. (General) The kernel value can be separated into its primary and scattered components, respectively HP and HS. The total dose at r is given Symbol Tb by integrating over all unit masses in the irradiated volume. The Element category Transition metal dose at r is therefore given by Mass number A 159 Atomic number Z 65 D (r ) = òT (r ’) éëHP (r - r ’) + HS (r - r ’)ùû dr ’3 Atomic weight 158.92 g/mol r ’ Electronic configuration 1s2 2s2 2p6 3s2 3p6 3d10 4s2 4p6 4d10 4f9 5s2 5p6 6s2 Terminal voltage Melting point 1629 K (General) A term describing the potential difference measured Boiling point 3503 K between two specified ‘terminals’ or connections to the output of Density near room temperature 8.2 g/cm3 a power supply or electrical circuit. Where only one terminal is specified, the second is assumed to be the reference zero voltage point, commonly the chassis or ‘ground’ potential. History: Terbium was discovered in 1843 by Carl Gustaf Usually the terminal voltage is specified for a particular situ- Mosander as one component of the mineral gadolinite. It is cur- ation such as ‘no load’, ‘open circuit’ or ‘full load’ state, so that a rently obtained mainly from monazite sand using an ion exchange check can be made against some operational specification. process which yields a mixture rich in lanthanide elements. It is used as a doping agent for certain types of solid-state devices and Tertiary collimator as a stabiliser in high temperature fuel cells. (Radiotherapy) This is an additional collimator beyond the main Medical Applications: X-ray phosphor – rare-earth phosphors jaws (secondary collimators) on the beam path towards the patient. such as terbium-activated gadolinium oxysulphide are sometimes The tertiary collimator can be permanently mounted within the Tesla 939 T he European pharmacopeia head of the linac (e.g. MLCs) or externally mounted as and when Background: Thallium bromide is a crystalline semiconduc- required (e.g. micro-MLCs). tor made of thallium and bromine atoms. Although its use has Related Articles: Collimation, Collimator, Multileaf col- previously been limited due to relatively poor chemical purity, limator, Secondary collimator, Treatment head, Conformal new purification methods have improved gamma and x-ray detec- radiotherapy tion performance. Manufacture: Crystals of thallium bromide can be grown Tesla using the travelling solvent floating zone technique, whereby (Magnetic Resonance) Tesla is the SI (Système International) unit sections of a mixed thallium and bromine rod are melted using used to express the strength of a magnetic field. In everyday life, focused infrared heat as the rod travels through the focus. It 1 T is a very large unit. The typical strength of the earth’s mag- can also be formed by the cooling of molten thallium bromide netic field is 50 μT, and fields in the mT range are relatively rare. from a region containing a seed crystal, a method known as the However, the magnets used in MRI have static fields with flux Bridgman-Stockbarger technique. densities of the order of tesla. The switched gradient field used for Use in Medicine: Ionising radiation detectors – Thallium bro- imaging have amplitudes of the order of mT, while the radiofre- mide has a high atomic number (Z = 81 and Z = 35 for thallium quency magnetic field is measured in fractions of a μT. and bromine, respectively) and a high radiation stopping power. In common with all common nouns, including eponymous SI This property, combined with a wide band gap of 2.68 eV, makes units, ‘tesla’ should be written with a lower case initial letter, even it useful as an x- and gamma-ray photon detector, which has low though its symbol is capitalised, ‘T’. noise at room temperature. The older CGS unit, the gauss, is still sometimes encountered. Thallium bromide semiconductor crystals can be used as a The conversion factor is 1 T = 104 G. Strictly speaking, both tesla detection material in digital radiography applications, and thin and gauss are units of ‘magnetic flux density’, but this quantity is films of the material may also have a role in xeroradiography, commonly referred to as ‘magnetic field strength’ in the context whereby an x-ray image is printed onto paper with toner which of MRI. has been attracted to the charges created by excitation of semi- The tesla is named in honour of Nikola Tesla (1856–1943), a conductor electrons. Serbian-American electrical engineer who invented numerous Infrared detectors – Thallium bromide and thallium iodide devices and laid the foundations for the electrical power industry. can be combined to form a crystal (thallium bromide-iodide) that performs as an infrared radiation detector. Due to its transmission Test object of infrared light up to wavelengths of around 50 μm, it is also (Nuclear Medicine) See Physical phantom commonly found in optical lenses and other optical instruments. Test voltage The European pharmacopeia (General) A term describing the potential difference to be pro- (Nuclear Medicine) The European pharmacopeia (Greek: phar- vided to the input of a device or circuit section in order that fur- makon = drug and poeioo = to work or manufacture) is an official ther measurements may be made on the device with a known reference book from the Council of Europe, with a set of stan- input state. Such a test voltage must usually be provided by an dardised specifications that define the quality of pharmaceutical external voltage source such as a DC power supply. preparations and their components. The Ph.Eur. states neces- T In some situations the test voltage will represent a specific sary characteristics of medical products described, and includes voltage to be selected by the operator from a range of voltages monographs on the methods of analysis, reagents, chemical and already available within a device under test (e.g. the kV setting for pharmaceutical forms. It defines requirements for purity and an x-ray exposure). activity for an about 60 radiopharmaceuticals for diagnostic or therapeutic purposes. Texture There are two general monographs on radiopharmaceutical (General) This is a term used in image processing. An object preparations, describing principles and methods to be applied, can have a smooth or coarse texture depending on its spatial fre- and several monographs on specific radiopharmaceuticals; quency content. A smooth object has only low frequency compo- common photon and particle emitting radiopharmaceuticals, nents whereas a coarse object has high frequency components. A 99mTc preparations, Iodine-labelled radio-pharmaceuticals, and high-pass filter or a Fourier transform operation will identify the on PET-radiopharmaceuticals. spatial frequencies of the objects within an image. The monographs of the Ph.Eur. are mandatory in all European Union countries, and constitute the basis for the national version TFD (target film distance) of the pharmacopeia and legislations in some countries or is used (Diagnostic Radiology) See Target film distance (TFD) as such in other countries. Monographs for radiopharmaceutical preparations are elaborated by the Expert Group 14 (on radioactive Thallium bromide compounds) of the European Pharmacopeia Commission. (General) The sixth edition (2008) of the European pharmacopeia is available online. Symbol TlBr Abbreviations: EDQM = European directorate for the quality of medicines and Ph.Eur. = European pharmacopeia Family Metal halide Related Articles: GMP, Quality control, Radiochemical Molecular weight 284.31 purity, Radionuclide purity, Biological purity Boiling point Around 1088 K Further Reading: Council of Europe, European pharmaco- Melting point Around 753 K peia (founded 1964), European Directorate for the Quality of Density 7.5 × 106 g/m3 Medicines (EDQM), Council of Europe, Maisonneuve, Sainte- Ruffine, France, http://www .edqm .eu /en /Homepage -628 .html The 5 Rs of radiobiology 940 Thermal index (TI) The 5 Rs of radiobiology The therapeutic index or therapeutic ratio is often used as a (Radiotherapy) The 5 Rs of radiobiology are the biological factors measure of the efficacy of treatment. It is the ratio of the tumour that influence the response of tumours and normal tissues to response for a fixed level of normal-tissue complication. In radiation and account for the efficacy of fractionated treatment. Figure T.12, the therapeutic ratio for the situation represented by They are radiosensitivity, repair, repopulation, redistribution the solid-line curves (Case A) is better than that for the dashed- and reoxygenation. line curves (Case B). In Case A, 95% probability of tumour con- The basis of fractionation in radiotherapy can be understood trol is possible for a 5% incidence of complications (the level by consideration of these factors. Dividing the radiotherapy dose generally regarded as acceptable in clinical radiotherapy for radi- into fractions spares normal tissues since the cells can repair some cal treatment) but in Case B this complication level only gives a of the radiation damage in the time between fractions and cell 12% probability of tumour control. The therapeutic window is repopulation will occur provided the overall time is sufficiently the horizontal distance between the normal tissue dose–response long. Conversely, fractionating the dose increases the damage to curve and the tumour control dose–response curve for a fixed the tumour due to reoxygenation and the redistribution of cells level of normal-tissue complication. This defines the range of into radiosensitive phases of the cell cycle between fractions. treatment doses that can be delivered without inducing an unac- Generally, repair and repopulation will tend to make the tissue ceptable level of normal tissue damage. In Figure T.12, the thera- more resistant to a second dose of radiation; redistribution and peutic window is the horizontal distance between the NTCP reoxygenation tend to make it more sensitive. Although the repop- curve and TCP curve this is clearly larger for Case A than for ulation of normal tissues is a benefit of fractionation, it should be Case B. noted that excessive prolongation of the overall treatment time Both the solid and dashed curves may represent the same can adversely affect local tumour control due to tumour cell tumour and normal tissue combination but under different con- repopulation. This has been observed in a number of tumour sites ditions, for example different fractionation regimes. Generally, including squamous cell cancers of the head and neck region, non- the prolongation of treatment by the use of fractionation has been small cell lung cancer and cervix carcinoma. It is recommended shown to be beneficial in many cases (for more details see the that interruptions in treatment are avoided for such patients and article on Fractionation). The use of a radiosensitiser or radiopro- that corrections are considered should a gap in treatment occur to tector may improve the therapeutic ratio if it produces a favour- minimise any prolongation of the overall treatment time. able differential effect (for more information see the article on Some publications discuss the 4 Rs of radiobiology, excluding Radiosensitisers). radiosensitivity. Related Articles: Dose–response model, Fractionation, Related Articles: Alpha beta ratio, Fractionation, Interruption Normal tissue control probability, Radiosensitisers, Sigmoid of treatment, Radiosensitivity, Repair, Repopulation, Redistribu- dose–response curve, Tumour control probability tion, Reoxygenation Further Reading: Hall, E. J and A. J. Giaccia. 2006. Radiobiology for the Radiologist, 6th edn., Lippincott Williams Therapeutic effect & Wilkins, Philadelphia, PA. (Radiotherapy) The effectiveness of a radiotherapy treatment is measured by its ability to obtain tumour control without induc- Therapeutic efficacy T ing serious complications due to the irradiation of normal tissues. (Radiotherapy) The therapeutic efficacy of a radiotherapy treat- In general, the relationship between dose and radiation effect, ment is measured by its ability to obtain tumour control without that is the dose–response curve, is sigmoid (S) in shape for both

inducing serious complications due to the irradiation of normal tumour control and normal tissue complications although the curve tissues. For more information, see the article on Therapeutic is often steeper for normal tissue damage than for tumour control. effect. For the treatment to be effective, the response curve of normal Related Articles: Adverse effect, Therapeutic effect, Tumour tissues must lie to the right of the tumour response. Figure T.12 control illustrates such a situation if the blue curves represent the tumour response and the red curves represent normal tissue. Thermal index (TI) (Ultrasound) The thermal index is an indicator of the relative risk of thermal bio-effects resulting from diagnostic ultrasound. 1 Case A 1 Ultrasound may be converted to heat in tissue though absorp- 0.9 0.9 tion processes. Heating is dependent on the ultrasound power and 0.8 0.8 intensity which in turn are dependent on the mode used – B-mode, 0.7 0.7 colour flow, PW spectral Doppler and M-mode – and the scanner 0.6 0.6 settings including power output, focal depth and frequency. The 0.5 0.5 heating is also dependent on the tissue type and the proximity of 0.4 0.4 the transducer face which can itself be a source of heat. The thermal index is defined by 0.3 0.3 0.2 0.2 Case B 0.1 0.1 W TI = p 0 0 Wdeg Dose where FIGURE T.12 Dose–response curves for tumour control (tumour con- Wp is the power output trol probability, TCP) and normal tissue damage (normal-tissue compli- Wdeg is the estimated power necessary to raise the target tissue cation probability, NTCP). by 1°C TCP NTCP Thermal light hazard 941 Thermal stress TI is calculated based on modelling of three different scan- In radiotherapy, thermal neutrons are produced from repeated ning conditions: scanning soft tissue which is described by TIS, photon scatter down the bunker maze: polythene-loaded boron or scanning where there is bone in the focal region of the scan, TIB, lithium maze linings are often used to provide thermal neutron and scanning where bone is close to the surface TIC, used in tran- capture. scranial imaging, for example. Models have been produced to Related Article: Neutron capture cross section account for scanning (B-mode and colour flow) and nonscanning (M-mode and spectral Doppler) modes. Thermal printing The output display standards (ODS) were put forward by the (Diagnostic Radiology) The laser film printer (also known as American Institute of Ultrasound in Medicine (AIUM) and the dry laser imager or laser camera) uses different types of films to National Electrical Manufacturers Association (NEMA) in 1992 record the image from a digital x-ray detector. The printer uses a as a guide for users to monitor the output level, and by association, laser beam which exposes the film by scanning it. The pixel val- relative risk of ultrasound scanners. These have been adopted by ues of the digital image modulate the intensity of the laser beam. the Food and Drug Administration (FDA). There is a requirement One of these printing methods uses thermal film (hence the to display TIs greater than 1 on the system with the onus on the thermal printing). The film emulsion is a combination of silver operator to keep within safe limits. No limits have been set by the behenate and silver halide coated onto polyester. The scanning FDA but several bodies have recommended upper limits for use laser beam (modulated with the intensities of the digital radio- in various clinical examinations. graph) triggers a ‘thermal developing process’ producing a ‘true’ Abbreviation: TI = Thermal index greyscale. However, there is no fixer after the ‘dry-development’ Further Readings: Abbott, J. G. 1999. Rationale and derivation process – i.e. the undeveloped silver halide crystals remain on of MI and TI – A review. Ultrasound Med. Biol. 25:431–441; Ter the film, which makes it thermally unstable. This way the ther- Haar, G. and F. A. Duck. 2000. The Safe Use of Ultrasound in mal film could lose its original contrast after a certain period of Medical Diagnosis, BMUS/BIR Publications, London, UK. time (even at normal room temperature). The film could also lose its original contrast when exposed to bright light for a long time. Thermal light hazard Sometimes the films are covered with a protective transparent (Non-Ionising Radiation) Visible light around the blue region layer in order to extend the preservation of the original contrast. (400–450 nm) and infrared radiation can cause heating of either This printing is suitable for digital radiography, as before the skin or the eye which can cause temporary or permanent dam- the printing the image has been windowed in order to visualise age. The nature of the damage depends on the energy absorbed, the important anatomical features with the necessary contrast. and its distribution which is linked to the possibility and speed to In such cases an indicative window width between 100 and 200 dissipate the heating. would deliver sufficient image contrast. For this reason, the small The International Commission on Non-Ionizing Radiation contrast dynamics of the thermal film (only 256 grey levels) is Protection (ICNIRP) refers to a thermal action spectrum to take adequate for diagnosis. Thermal printing is often used in dental into account the thermal hazard of non-laser optical radiation (see radiography and in ultrasonography. Action spectra). Typical parameters of a small direct thermal printer will Related Articles: AORD, Action spectra, ICNIRP, Eye, Skin, present resolution of 300 dpi (i.e. about 6 lp/mm); 256 grey lev- Cornea, Lens, Skin cancer els (memory: 16 MB); effective print pixels: c. 2500 × 2500 (i.e. T Further Readings: Coleman, A., F. Fedele, M. Khazova, about 200 × 200 mm). The printing process requires about 45 P. Freeman and R. Sarkany. 2010. A survey of the optical haz- seconds. ards associated with hospital light sources with reference to the Related Articles: Laser film printer, Adherographic printing, Control of Artificial Optical Radiation at Work Regulations 2010. Window J. Radiol. Prot. 30(3):469; ICNIRP. A closer look at the thresholds of thermal damage: Workshop report by an ICNIRP task group. Thermal stress Health Phys. 111(3):300–306; ICNIRP. 2013. Guidelines on limits (Diagnostic Radiology) The reason for thermal stress of the of exposure to incoherent visible and infrared radiation. Health anode of an x-ray tube is its rapid heating and cooling (during Phys. 105(1):74–91; ICNIRP. 2013. Guidelines on limits of expo- and after the x-ray exposure), which leads to rapid mechanical sure to laser radiation of wavelengths between 180 nm and 1,000 expansion and shrinking of the target material. This way after μm. Health Phys. 105(3):271–295; ICNIRP. 2004. Guidelines on time the thermo-mechanical stress causes cracks on the tungsten limits of exposure to ultraviolet radiation of wavelengths between surface (see Figure T.13). The cracks not only decrease the life of 180 nm and 400 nm (Incoherent Optical Radiation). Health Phys. the x-ray tube (damaging the anode), but also uneven the target 87(2):171–186; ICNIRP. 2000. Revision of the guidelines on limits surface. The cracked anode surface causes scattering or absorbing of exposure to laser radiation of wavelengths between 400 nm and (in the cracks) of some of the x-ray quanta, and thus decreases the 1.4 μm. Health Phys. 79(4):431–440; Sihota, R. and R. Tandon. tube efficiency. 2011. Parsons’ Diseases of the Eye, Elsevier, India. In order to minimise this effect rhenium is added to the tung- sten target (approximately 2%–10% Re/W metal alloy) and spe- Thermal neutrons cial care is taken for removing the heat accumulated in the anode. (General) A thermal neutron is a free neutron (one that is not The x-ray tubes with rotating anode have all their front surface bound within an atomic nucleus) that exists in thermal equilib- covered with this alloy, although only part of it is bombarded – the rium with its surrounding material. thermal path. Thermal neutrons are relatively slow and have a large cross- Another way to deal with the thermal stress is to manufacture sectional area for fission interaction, making them desirable in the anode with radial slits, which allow the thermal expansion certain nuclear chain reactions. They are also used in production of the target without causing cracks (see the diagram in article of radionuclides through neutron activation of or neutron capture Rotating anode). by the target material, typically in a nuclear reactor. Related Articles: Rotating anode, Target Thermionic emission 942 Thermoluminescent dosimeter (TLD) Conduction band Electron trap Hole trap Valence band (a) (b) FIGURE T.14 (a) Formation of electron-hole pair and its trapping. (b) Emission of a thermoluminescence photons. PC (output date presentation) FIGURE T.13 A section form x-ray tube rotating anode with cracked Electronic processing surface due to thermal stress. of data Thermionic emission PM tube (Diagnostic Radiology) Thermionic emission is emission of elec- trons or ions from the surface of a material, due to thermal energy greater than the electrostatic forces keeping these charges bound Optical filters with the material. This effect is used in the x-ray tube cathode filament to produce thermal electrons. The density of the therm- ionic (thermal) emission current is described with the Richardson Thermoluminscent detector (TLD) equation (called also Richardson–Dushman equation): J = A T 2e-w / kT Electric hot plate 0 0 with temperature regulation and timer where J is the density of the emission current T 0 FIGURE T.15 Overall scheme of an equipment for thermoluminescent T is the temperature of the emitter (in Kelvin) dosimetry. k and w are constants (k, Boltzmann constant, w, work func- tion, for tungsten = 4.5 eV) A0 is the constant depending on the material of the emitter (for of the trap, the trapped electrons can move back to the conduction tungsten = 60 A/cm2/K2) band and then recombine with the emitted visible radiation. At a temperature lower than that required to free the trapped holes, the Related Articles: Cathode, Filament heating, Filament cur- electrons may migrate from their trap to a near trapped hole and rent, Tube current recombine with the emitted visible photons (Figure T.14b). The Hyperlinks: Thermionic emission (Wikipedia): http: / /en. amount of light released is proportional to the energy of ionising wikip edia. org /w iki /T hermi onic_ emiss ion radiation absorbed by the thermoluminescent (TL) detector, which is often formed as a chip/tablet of TL material (see Figure T.17). Thermoluminescent dosimeter (TLD) The thermoluminescent dosimeter equipment includes a tray (Radiation Protection) Thermoluminescence is the physi- where the TLD detector is placed and can be heated, a photomul- cal phenomenon of emission of optical radiation in the form of tiplier tube (PM) to measure the light emitted as the temperature prompt fluorescence when a material is heated. Many crystals, is gradually increased, and associated electronics (Figure T.15). for example diamonds and chemical compounds such as lithium An oven to anneal the TLD detectors in between irradiations and fluoride (LiF), can absorb ionising radiation and store it by mov- restore their original sensitivity is also needed. ing electrons from the valence band to the conduction band and The emitted light as a function of the detector temperature then capturing them at the trapping centres (metastable states) may be graphically represented as a glow curve (Figure T.16). The within the bandgap, below the bottom of the conduction band. radiation dose is proportional to the area under the glow curve. Holes, created in the valence band, can move through the crystal The TLDs can be used to measure absorbed doses in the range of and be trapped by the trapping centres situated above the top of 10−7 to 103 Gy. the valence band (Figure T.14a). The probability that an electron The loss of trapped electrons at room temperature is called escapes from the trap is proportional to the Boltzmann constant: ‘fading’ and appears if the energy levels of the traps are very near exp(−E/kBT), where E is energy, kB is the Boltzmann’s constant to the edge of the band gap. and T is temperature. The life time of the trapped state can be long The choice of TLD detector should take into account the (up to hundreds of years) if E is large. atomic number of the thermoluminescent material, the fading The trapped electrons can be detected through heating. When characteristics and the relation between the measured signal and the temperature reaches the value determined by the energy level the absorbed energy of radiation. TLDs based on LiF are mostly Thermostat 943 Thimble chamber

Thermostat (General) A thermostat is an on–off electrical temperature sensor which may be used in a thermal control process. The thermostat is placed in the area where temperature is to be measured or clamped directly to the object being monitored. Both preset and adjustable thermostats act to sense temperature and compare it against a predefined value, switching an electrical circuit when that temperature is exceeded. Typically the thermostat has a ‘hysteresis region’, such that once switched in one direction, it will not switch back until a pre- 100 200 300 400 defined change in temperature has occurred. This prevents a race Temperature (°C) condition of ‘chatter’ of the electrical contacts when the threshold temperature is reached. Thermostats are used as control sensors in both cooling FIGURE T.16 Example of a thermoluminescent glow curve for LiF. and heating systems, and also on occasion as safety cut-outs. Thermostats only allow for on–off control, while more sophis- ticated control systems may use proportional sensors (see Temperature control). Related Articles: Temperature control, Thermal probe, Temperature probe Thimble chamber (Radiotherapy) Gas-filled detectors represent probably the most widely used class of radiation detectors. The detection is based on the collection of ions produced in the sensitive volume of the detector as the radiation interacting in a gas-filled volume produces ion pairs in the volume through the process called ionisation. The essential parts of an ionisation chamber are two electrodes kept at different potentials. The electrode to which the measuring instru- ment is attached is called the collecting electrode. The collecting electrode is ordinarily but not necessarily at a potential close to ground potential while the other electrode, which is ordinarily kept at a constant voltage of several hundred volts, is called the high- FIGURE T.17 Examples of TLD detectors in Poland, in a cassette and in voltage electrode. A number of commercially available ionisation a card. (Photo courtesy of Maciej Budzanowski, PhD, Institute of Nuclear chambers are generally used in radiotherapy dosimetry having air Physics, Polish Academy of Sciences, Krakov, Poland.) as a filling gas. An ionisation chamber is intended to measure the absorbed dose in a point in a medium and this requirement imposes T an upper limit on the chamber dimension while its sensitivity and used because of their good energy response, due to the fact that limitation in the mechanical design impose a lower limit. As the the average atomic number of lithium fluoride is 8.2, very close to ionisation methods depend on the Bragg–Gray cavity theory and soft tissue, which has a value of 7.5. LiF may be doped with Cu, its extension by Spencer and Attix there is no explicit restriction on Mg, P and Ti. the geometrical shape of the cavity while the choice of the materials TLDs are produced in the form of powder, discs (Figure T.17), for wall, gas and electrodes as well the chamber wall thickness are chips, rings, rods and plates. LiF detectors enriched with Li-6 can governed by the cavity theory requirements. Generally the ionisa- be used to measure thermal (slow) neutron doses through the (n, tion chambers are divided into three geometrical shapes: cylindrical alpha) reaction. or thimble, parallel plane and spherical. The shape of the ionisation The thermoluminescent dosimeters work in passive mode but chamber influences its spatial resolution when the spatial gradi- can be used many times because of their recyclability. However, ent of the radiation field is large. Figure T.18 shows the schematic they require individual or batch calibration against a standard. The diagram of a thimble chamber with the indication of the specific TLDs are frequently used to monitor the dose of radiation workers materials used for the chamber construction. However a variety of and to measure patient doses undergoing radiological procedures. materials can be used requiring different correction factors. The TLD readout has normally only one reading (after reading The characteristics of some thimble ionisation chambers are all trapped electrons are released). In comparison, the film badge given in Table T.1. keeps the record over the film, and also some readouts of opti- cally stimulated luminescence (OSL) extract the necessary signal, without exhausting all trapped electrons, which could ensure a consecutive OSL reading. PTCFE Graphite Central electrode Insulator Outer electrode Abbreviation: TLD = Thermoluminescent dosimeter. Related Articles: Dose, Radiation dosimetry, Radiation expo- sure, Film badge, Personnel dosimetry, Optically stimulated Aluminium luminescence dosimeter (OSLD), Pulsed OSL readout Further Readings: Knoll, G. F. 2000. Radiation Detection and Measurement, John Wiley & Sons, Inc., New York; Graham, Dural D. T. and P. Cloke. 2003. Principles of Radiological Physics, Elsevier Science Limited, Edinburgh, UK. FIGURE T.18 Cross sectional view of a thimble chamber. Relative intensity Thimble chamber 944 Thimble chamber TABLE T.1 Characteristics of Some Thimble Ionisation Chambers Cavity Cavity Cavity Radius Wall Wall Thickness Central Electrode Ionisation Chamber Type Volume (cm3) Length (mm) (mm) Material (g/cm2) Material Capintec PR-05P mini 0.07 5.5 2.0 C-552 0.220 C-552 Capintec PR-05 mini 0.14 11.5 2.0 C-552 0.220 C-552 Capintec PR-06C/G Farmer 0.65 22.0 3.2 C-552 0.050 C-552 Capintec PR-06C/G Farmer 0.65 22.0 3.2 C-552 0.050 C-552 Capintec PR-06C/G Farmer 0.65 22.0 3.2 C-552 0.050 C-552 Exradin A2 Spokas (2 mm cap) 0.53 11.4 4.8 C-552 0.176 C-552 Exradin T2 Spokas (4 mm cap) 0.53 11.4 4.8 A-150 0.113 A-150 Exradin A1 mini Shonka (2 mm cap) 0.05 5.7 2.0 C-552 0.176 C-552 Exradin T1 mini Shonka (4 mm cap) 0.05 5.7 2.0 A-150 0.113 A-150 Exradin A12 Farmer 0.65 24.2 3.1 C-552 0.088 C-552 Far West Tech IC-18 0.1 9.5 2.3 A-150 0.183 A-150 FZH TK 01 0.4 12.0 3.5 Delrin 0.071 Nuclear Assoc. 30–750 0.03 3.6 2.0 C-552 0.068 C-552 Nuclear Assoc. 30–749 0.08 4.0 3.0 C-552 0.068 C-552 Nuclear Assoc. 30–744 5.8 3.0 C-552 0.068 C-552 Nuclear Assoc. 30–716 0.25 10.0 3.0 C-552 0.068 C-552 Nuclear Assoc. 30–753 0.25 9.0 3.1 C-552 0.068 C-552 Farmer shortened Nuclear Assoc. 30–751 Farmer 0.69 23.0 3.1 Delrin 0.056 Aluminium Nuclear Assoc. 30–752 Farmer 0.69 23.0 3.1 Graphite 0.072 Aluminium NE 2515 0.2 7.0 3.0 Tufnol 0.074 Aluminium NE 25 15/3 0.2 7.0 3.2 Graphite 0.066 Aluminium NE 2577 0.2 8.3 3.2 Graphite 0.066 Aluminium NE 2505 Farmer 0.6 24.0 3.0 Tufnol 0.075 Aluminium NE 2505/A Farmer 0.6 24.0 3.0 Nylon 66 0.063 Aluminium NE 2505/3, 3A Farmer 0.6 24.0 3.2 Graphite 0.065 Aluminium NE 2505/3, 3B Farmer 0.6 24.0 3.2 Nylon 66 0.041 Aluminium T NE 2571 Farmer 0.6 24.0 3.2 Graphite 0.065 Aluminium NE 2581 Farmer (PMMA cap) 0.6 24.0 3.2 A-150 0.041 A-150 NE 2581 Farmer (polystyrene cap) 0.06 24.0 3.2 A-150 0.041 A-150 NE 2561/2611 Sec. Std 0.33 9.2 3.7 Graphite 0.090 Aluminium (hollow) PTW 23323 micro 0.1 12.0 1.6 PMMA 0.197 Aluminium PTW 23331 rigid 1.0 22.0 4.0 PMMA 0.060 Aluminium PTW 23332 rigid 0.3 18.0 2.5 PMMA 0.054 Aluminium PTW 23333 (3 mm cap) 0.6 21.9 3.1 PMMA 0.059 Aluminium PTW 23333 (4.6 mm cap) 0.6 21.9 3.1 PMMA 0.053 Aluminium PTW 30001 Farmer 0.6 23.0 3.1 PMMA 0.045 Aluminium PTW 30010 Farmer 0.6 23.0 3.1 PMMA 0.057 Aluminium PTW 30002/30011 Farmer 0.6 23.0 3.1 Graphite 0.079 Graphite PTW 30004/30012 Farmer 0.6 23.0 3.1 Graphite 0.079 Aluminium PTW 30006/30013 Farmer 0.6 23.0 3.1 PMMA 0.057 Aluminium PTW 31002 flexible 0.13 6.5 2.8 PMMA 0.078 Aluminium PTW 31003 flexible 0.3 16.3 2.8 PMMA 0.078 Aluminium SNC 100730 Farmer 0.6 24.4 3.5 PMMA 0.060 Aluminium SNC 100740 Farmer 0.6 24.4 3.5 Graphite 0.085 Aluminium Victoreen Radocon III 550 0.3 4.3 2.5 Delrin 0.529 Victoreen Radocon II 555 0.1 23.0 2.4 Polystyrene 0.117 Victoreen 30–348 0.3 18.0 2.5 PMMA 0.060 Victoreen 30–35 1 0.6 23.0 3.1 PMMA 0.060 Victoreen 30–349 1.0 22.0 4.0 PMMA 0.060 Victoreen 30–361 0.4 22.3 2.4 PMMA 0.144 Scdx-Wellhöfer IC 05 0.08 4.0 3.0 C-552 0.068 C-552 Scdx-Wellhöfer IC 06 0.08 4.0 3.0 C-552 0.068 C-552 (Continued) Thimble ionisation chamber 945 Thin-film technology (TFT) TABLE T.1 (CONTINUED) Characteristics of Some Thimble Ionisation Chambers Cavity Cavity Cavity Radius Wall Wall Thickness Central Electrode Ionisation Chamber Type Volume (cm3) Length (mm) (mm) Material (g/cm2) Material Scdx-Wellhöfer IC 10 0.14 6.3 3.0 C-552 0.068 C-552 Scdx-Wellhöfer IC 15 0.13 5.8 3.0 C-552 0.068 C-552 Scdx-Wellhöfer IC 25 0.25 10.0 3.0 C-552 0.068 C-552 Scdx-Wellhöfer IC 28 0.3 9.0 3.1 C-552 0.068 C-552 Farmer shortened Scdx-Wellhöfer IC 69 Farmer 0.67 23.0 3.1 Delrin 0.056 Aluminium Scdx-Wellhöfer IC 70 Farmer 0.67 23.0 3.1 Graphite 0.068 Aluminium Source: Adapted from Absorbed dose determination in external beam radiotherapy, An International Code of Practice for Dosimetry Based on Standards of Absorbed Dose to Water, TRS No. 398, IAEA, Vienna, Austria, pp. 32–34, 2000. Data courtesy to the manufacturers listed in the first column. 0 2 4 6 8 10 12 14 dmin Chamber wall thickness (mm) FIGURE T.20 0.6 cm3 thimble chamber. T (a) (b) plastic). A variety of smaller chambers are available for mea- surement of field size factors with small fields. Miniature ioni- sation chambers with volumes less than 0.01 cc have also been (c) developed. Some typical thimble ionisation chambers are shown in Figures T.20 and T.21. FIGURE T.19 Variation of the thimble chamber response with the wall thickness. (a) Thimble chamber; (b) build-up cap; (c) cap fitted the chamber. Thimble ionisation chamber (Radiation Protection) See Thimble chamber A thimble ionisation chamber type may be used for the cali- bration of beams of medium energy x-rays above 80 kV and an Thin-film technology (TFT) HVL of 2 mm aluminium, 60Co gamma radiation, high energy (General) The advent of thin-film technology has allowed the photon beams, electron beams with energy above 10 MeV approx- development of all modern computing and therefore all digital imately, and therapeutic proton and heavy ion beams. Generally medical imaging modalities. Thin films are fabricated by the the calibration of all the high energy photon and electron beams deposition of individual atoms onto the substrate. A thin film is are performed in a phantom as stated in the dosimetry protocols. categorised as a low dimensional material produced by condens- In case of measurement in air the thimble chamber wall must be ing atoms or molecules individually, with a final thickness of sufficient to provide electronic equilibrium and this condition is usually less than a few microns. Thin films are deposited onto a obtained adding a build-up cap to reach a wall thickness at least substrate by thermal evaporation, chemical decomposition (chem- equal to dmin (Figure T.19a through c). ical vapour deposition CVD) and/or the evaporation of source Depth dose measurements usually require thimble-type material by irradiating it with energetic species or photons (sput- chambers with active volumes ranging from 0.1 to 1.0 cm3. Their tering). The properties of thin films are governed by the deposi- walls are most often made from graphite or plastic (nylon, A-150 tion process. Instrument reading Thin-layer chromatography (TLC) 946 Thorium solvent tank. The case of prolonged air contact, however, may cause oxidation of the 99mTc-chelate and technetium components may also bind to the solid phase. Related Articles: Gelchromatography, Rf-value Further Readings: Kowalsky, R. J. and S. W. Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine, 2nd edn., American Pharmacists Association, Washington, DC; Saha, G. B. 2004. Fundamentals of Nuclear Pharmacy, 5th edn., Springer, New York; Zolle, I. (ed.). 2007. Technetium-99m Pharmaceuticals – Preparation and Quality Control in Nuclear Medicine, Springer, Heidelberg, Germany. Thiosulphate in film processing (Diagnostic Radiology) Compounds of thiosulphate (S2O3), such as sodium thiosulphate (also known as hypo) or ammonium thio- sulphate, are used as the fixer in the film processing cycle. After a film is removed from the developer it is then passed through FIGURE T.21 Microchamber. the fixing solution. The fixer performs several actions including neutralising and stopping the development process, removing the undeveloped silver halide grains from the film, and hardening the emulsion. Thin-layer chromatography (TLC) (Nuclear Medicine) Thin-layer chromatography, TLC, is a method used for determination of radiochemical purity and of various Thomson scattering radiochemical impurities in radiopharmaceutical preparations, (Radiation Protection) Thomson scattering named after J. J. especially for 99mTc-radiopharmaceuticals. This method is based Thomson is the scattering of electromagnetic radiation by charged on two phases, a stationary phase placed on glass plates or on particles, mainly electrons. When an electromagnetic wave passes aluminium or plastic foils and a mobile phase (solvent). near an electron, the electron is momentarily accelerated by the A small aliquot of the radiopharmaceutical

is placed at least electric field of the wave and, as a consequence, it radiates energy. 1 cm from the end of the plate (application point). The plate is The cross section of this process, called the Thomson classical dipped in a covered tank containing the mobile phase, keeping scattering coefficient, may be derived from classical physics and the application point above the solution, and the solvent front has the same value for all photon energies. In this type of scatter- is allowed to migrate a certain distance from the application ing, the incident photon interacts with a free electron but the inter- point. Different components of the radiopharmaceutical will action is elastic and the electron is given no energy; it is merely distribute themselves along the plate depending on the station- scattered from the beam. T ary phase, the solvent and on the solubility of the component. Related Article: Elastic scattering The application point and solvent front should carefully be marked to be able to calculate the Rf value. The plate is dried Thorium and the activity distribution is measured either by scanning (General) of the plate with a collimated NaI(Tl)-detector or by cutting the foil into small segments and measuring the activity with a NaI(Tl)-well counter. The distance each component migrates Symbol Th is characterised by the Rf (retention factor) value. For com- Element category Transition metal ponents migrating with the solvent front the Rf value is 1 and Mass number A 232 for the components remaining at the application point the Rf Atomic number Z 90 value is 0. Atomic weight 232.04 g/mol The stationary phase is available as, for example silica gel, Electronic configuration 1s2 2s2 2p6 3s2 3p6 3d10 4s2 4p6 4d10 reversed-phase silica and aluminium oxide. Most used are instant 4f14 5s2 5p6 5d10 6s2 6p6 6d2 7s2 TLC (ITLC) plates made of fibreglass sheets impregnated with, Melting point 2023 K for example silica gel. The advantage of ITLC is that it is rapid Boiling point 5061 K and accurate due to a fine mesh material that increases the migra- Density near room temperature 11.72 g/cm3 tion properties. Whereas standard TLC takes more than 30 min to develop, ITLC may take less than 5 min. Commonly used solvents are, for example 85% methanol, History: Thorium was discovered in 1828 by Berzelius from acetate, methyl ethyl ketone (MEK), acetone and 0.9% NaCl. The a sample of a previously unknown ore now known as thorite chromatographic separation of the components depends on the (ThSiO4). It is found in small amounts in most rocks and soils, but system and several stationary and mobile phases can be combined is usually commercially obtained from monazite along with other to not only obtain the radiochemical purity but also the amount of rare-earth metals. The element has limited applications as an the various impurities in the preparation. alloying addition to magnesium and to tungsten. It has potential To avoid artefacts the TLC plates must be handled carefully uses as a fertile material in nuclear fuels. There are several uses and test conditions must be as similar as possible between mea- for the very high melting point thorium oxide (ThO2), including surements. It is important that the solid phase is dry and that the gas mantles, high temperature crucibles and high refractive index sample spot is small and should dry before being placed in the glass for lenses. Three-dimensional (3D) conformal dose distribution 947 Three-dimensional ultrasound imaging (3D imaging) Medical Applications: Disused contrast agent – Thorium More details including references can be found under Kernel- oxide was used as Thorotrast (a contrast agent) in x-ray diagnos- based treatment planning. tics. This was discontinued due to its carcinogenic nature. Convolution equation to determine dose at a point is Related Article: Contrast agent D ( r ) m j× ( r × K r r d r ) ( = ò - × ) 3r × Three-dimensional (3D) conformal dose distribution (Radiotherapy) A 3D conformal dose distribution is a dose distri- bution generated by a specific beam arrangement to treat a target Abbreviation: TERMA = Total energy released per unit mass. structure whilst minimising the dose to any region outside of that Related Article: Kernel-based treatment planning target. This dose distribution is typically shown on a CT dataset so that it can be visualised against the patient anatomy. By contour- Three-dimensional ultrasound imaging (3D imaging) ing structures in the CT dataset it is possible to report on the dose (Ultrasound) Three-dimensional (3D) ultrasound imaging is the statistics to the structure which has been outlined, either target or acquisition and display of ultrasound from a volume of tissue. organ at risk. Conventional B-mode and colour flow imaging obtains data from As treatment techniques improve, so does the conformality of a plane of thin slice thickness, essentially a 2D image. The opera- the plans. Sequential transitions from simple 3D conformal radio- tor moves the transducer to obtain a series of real-time images therapy, to intensity-modulated radiotherapy (IMRT) to volume- from different positions in the elevation plane. In practice free modulated arc therapy (VMAT) all brought improvements in movement of the transducer by rotation and translation are used conformality. to build up an overall picture of the tissue under investigation. High dose conformality allows for dose escalation to targets. In 3D imaging the acquisition of echoes from a tissue volume A plan with high conformality means that the high prescription is used to provide a volume of data which can be viewed and ana- dose is shaped around the target shape tightly with minimal pre- lysed at the time of the scan of after data acquisition. The terms scription dose outside the target. 3D and 4D are used to describe volume imaging of ultrasound. In Conformality can be quantified using a conformity index. The general, 3D encompasses static and dynamic 3D acquisition and conformity index is the ratio of the reference isodose volume to display; 4D refers to specifically dynamic 3D imaging. the treatment target volume. The equation is shown below. 3D imaging can be thought of as having three distinct stages: V CI = iso 1. Data acquisition Vtarget 2. Image processing and segmentation 3. Presentation/display where CI = conformity index There are currently three different methods for 3D acquisition Viso = volume of reference isodose line which are commercially used (Figure T.22): Vtarget = volume of treatment target Freehand movement in the elevation plane. This provides a 3D volume set but without spatial measurement of movement and dis- Abbreviations: VMAT = Volume-modulated arc therapy, tance in the elevation plane. IMRT = Intensity-modulated radiation therapy. T ‘Wobbling’ or mechanically rotated arrays are usually curvi- Related Articles: Intensity-modulated radiotherapy (IMRT), linear arrays which are swept in the elevation plane. This tech- Arc therapy nique can be used at frame rates of a few Hz to provide moving Further Reading: Zhang, T. et al. 2015. Double-arc volumet- images, most commonly foetal movement. Distances in the eleva- ric modulated therapy improves dose distribution compared to tion plane are known from the angle at which individual images static gantry IMRT and 3D conformal radiotherapy for adjuvant are obtained. therapy of gastric cancer. Radiat. Oncol. 10, Article number: 114, 2D arrays insonate a volume of tissue from plane surface. open access from: https :/ /do i .org /10 .1 186 /s 13014 -01 5- 0420- x Frame rates of >15 Hz are possible and the technique is also used for 3D colour flow imaging. The location of all points in the axial, Three-dimensional scatter convolution lateral and elevation planes are established allowing measurement (Radiotherapy) In radiotherapy, many dose calculation algo- of linear, area and volume dimensions. rithms are based on the convolution-superposition approaches. In Other 3D techniques include external location of transducer these, the dose is calculated from first principles by separating position including optical and magnetic methods. the primary and scatter dose contributions. The primary dose is Processing can be real-time or following data capture, includ- calculated using a ray tracing approach to determine TERMA at ing off-line processing. Segmentation can be difficult for ultra- a point. The total dose at that point is then calculated by convolu- sound since echo levels from surfaces are dependent on the beam/ tion of this TERMA with a pre-calculated scatter kernel, usually interface angle. The most common surface rendering images are generated by Monte Carlo techniques. This approach inherently of the heart and foetus where there is a strong fluid/tissue interface. includes radiation transport of scattered photons and electrons set The display of 3D ultrasound can be of a surface (Figure T.23) in motion at the primary photon interaction site and is inherently or by examining different planes within a block of data The latter 3D in nature since the kernels represent the 3D dose spread pat- allows imaging in the C-plane, which has been shown to be ben- tern arising from a photon interaction at a point. eficial in coronal imaging of breasts. In surface and planar imag- The convolution approach works provided the scatter kernel ing, the operator has a range of tools to alter the planes imaged is assumed to be spatially invariant throughout the volume of and the post-processing of images. Surface rendered images can interest. If this is not the case, for example in calculation of dose similarly be viewed from different angles and with different ren- in a heterogeneous medium, then a more general superposition dering parameters (Figure T.24). approach is required. Related Article: Matrix arrays Three-phase AC 948 Three-phase generator Matrix array (a) (b) (c) FIGURE T.22 Three different types of transducer formats for data acquisition. (a) Conventional array moved manually in the elevation plane. (b) Mechanically rotated curvilinear array. (c) 2D matrix array. T FIGURE T.23 Surface views of 3D volume set of an aorta. Three-phase AC There are two types of electrical circuits – asymmetric (3 sec- (Diagnostic Radiology) A continuous series of three overlapping ondary windings and 6 diodes) and symmetric (6 secondary AC cycles offset by 120°. Three-phase power is used for all large windings and 12 diodes). The six-pulse waveform ensures kV scale electrical distribution systems. pulsations of the order of 14%. This is far less than the 100% pulsations of the 2 pulse generator using single-phase mains Three-phase generator supply. (Diagnostic Radiology) Power x-ray equipment with classical Further reduction of kV pulsations is achieved by the 12-pulse high voltage generator use three-phase mains supply. This ensures classical high voltage generator. In this case the secondary wind- sufficient power and produces kV with less pulsation (this way ing of the high voltage transformer is normally with star-delta reducing both – the absorbed dose and image noise). The high connection (Figure T.26). This ensures kV pulsations of the order voltage transformer of these generators requires different types of of 3%–4%. The electrical circuits of these generators (transformer secondary winding connections. and rectifiers) are also two types – asymmetric (6 secondary The three phase generator producing kV with six-pulse windings and 12 diodes) and symmetric (12 secondary windings waveform uses high voltage transformer with secondary wind- and 12 diodes). ing, which is normally with star type connection (Figure T.25). Related Articles: High voltage generator, High frequency gen- The rectifiers in this case are usually in bridge-type connection. erator, High voltage circuit, voltage waveform Three-phase rectifier 949 Threshold contrast detail detectability (TCDD) 1 R S 2 T 0 4 3 FIGURE T.24 3D image of an ultrasound phantom. The data has been acquired by an elevation sweep from a linear array (see Figure T.21a). The data can be viewed in a surface rendered images (main picture L) where the low echoes of the fluid allow visualisation of the wall of the FIGURE T.26 Twelve-pulse generator with star-delta-type secondary tube in this oblique view. Data in three orthogonal planes is shown in the winding connection (asymmetric circuit with 6 secondary windings and three small images on the right. The top image shows a transverse view, 12 diodes). the middle image shows the long view of the centre cylinder cyst, slightly oblique. The lower image shows a C-plane cut along the line shown in the transverse (top R) scan. In each image the two planes for the other views are displayed as horizontal and vertical lines. Related Articles: High voltage generator, Three-phase gen- erator,

High voltage circuit Three-phase transformer (Diagnostic Radiology) Powerful equipment (e.g. power x-ray generators) use three-phase power supply as opposed to the nor- mal mains 220 V supply. The transformers used with three-phase mains are normally with three primary coils (for each phase) and a number of secondary coils. The most often used connection of the secondary coils is star, delta or star-delta. For illustration of these connections see the diagrams in the article Three-phase generator. T R Threshold contrast detail detectability (TCDD) (Diagnostic Radiology) Threshold contrast detail detectability S (TCDD) is a characteristic used to describe physical image qual- ity by assessing the visibility of low contrast details. The use of T TCDD tests in conjunction with DQE analysis has proved a prac- tical and effective method for evaluating the performance of the O whole digital x-ray imaging system. The results of a TCDD test can be presented as a contrast detail diagram, or more conveniently as a threshold detection index HT(A), defined by the following formula: HT ( A) = 1 / (C A A 2 T ( )´ 1/ ) where CT(A) is the threshold contrast corresponding to the last vis- ible image detail of area A. Threshold contrast CT(A) is determined FIGURE T.25 Six-pulse generator with star type secondary winding by the image taken of the contrast-detail test phantom, for example connection (symmetric circuit with 6 secondary windings and 12 diodes). by CDRAD (Artinis Medical Systems, the Netherlands) or TO12 or TO20 (Leeds Test Objects Ltd, United Kingdom). An accepted protocol for the use of these test phantoms in routine testing has Further Reading: Karadimov, D. 1978. Roentgen equipment, been in widespread use and is recommended in IPEM Report 32 Technika, Sofia, Bulgaria. (2010). The threshold detection index is usually plotted against the square root of detail area on double logarithmic axes (Figure T.27). Three-phase rectifier The observer views the image under a set of standard condi- (Diagnostic Radiology) The type of rectifying circuitry of an tions, and counts the number of details visible in each row. The x-ray three-phase generator (classical type) – see typical circuits viewing results are then compared with tabulated data, relating in the article Three-phase generator. the number of details seen to threshold contrast, for given x-ray Threshold detection 950 Thulium 100 IPEM (Institute of Physics and Engineering in Medicine). 2010. CDRAD Measurement of the performance characteristics of diagnostic TO12 Reference x-ray systems: Digital imaging systems. IPEM Report 32, Part VII. IPEM, York, UK. 10 Hyperlinks: IPEM, KCARE Threshold detection (General) A threshold value refers to a particular level of a parameter (usually a voltage) which has been defined so as to dis- 1 criminate between signals above and below that value. The result 0.1 1.0 10.0 is therefore a binary logical one (above threshold versus below). Square root of detail area (mm) FIGURE T.27 TCDD test results (by using CDRAD and Leeds TO12) presented as the threshold detection index (HT(A)) values with the fitted curve (data from Scottish CR Group). (Adapted from IPEM, Measurement of the performance characteristics of diagnostic x-ray systems: Digital Input reshold imaging systems, IPEM Report 32, Part VII, IPEM, York, UK, 2010.) signal value Time beam quality. Alternatively, the contrast of the image details can Logic be calculated for various thicknesses of the PMMA using the output x-ray spectral and attenuation data derived from IPEM Report 78. Also software is available for automated scoring of CDRAD – this is more consistent and removes the subjectivity of the human In ionising radiation detectors, the output signal usually consists observer from the evaluation process. of many short pulses of varying height each related to the incident TCDD scores are dependent on detector air kerma (DAK) and energy of individual particles or rays. It is therefore possible to set therefore it is important to choose such a receptor dose for testing a threshold voltage related directly to a specific particle or ray’s that allows a valid comparison with the reference data. For exam- energy, the threshold energy, and only count those signal events ple, a DAK of 4 μGy is assumed to allow comparison with type which exceed this threshold. In this way it is possible to make a test data from KCARE and a receptor dose of 3 μGy is assumed selective detector only counting particles above a certain energy. for direct comparison with the reference curves from the Scottish It is also possible to specify multiple threshold energies or val- CR Group (Figure T.27). ues and, by combining the outputs of a parallel group of threshold At commissioning, the TCDD results are compared to those detectors with some basic logic, provide information in the form from other similar systems, if available, and are used to set a base- of count number against energy band or pulse height – a pulse line (reference TCDD curve) for future quality control tests. height discriminator. T Figure T.27 presents threshold detection index curve mea- Related Article: Pulse height discriminator sured by using test phantoms CDRAD and TO12. Alternatively, a single image quality factor can be used to track changes in image quality over a range of all detail sizes (Cowen Threshold energy and Workman 1992; Gallacher et al. 2003). This factor shows less (Diagnostic Radiology) See Threshold detection variability than the scores for individual detail sizes. The image Related Articles: Pulse height discriminator, Threshold quality figure (IQF) is calculated by using the following formula: energy n 1 Threshold value å HT ( A ) 0.5 IQF = i é Kref ù ref (Diagnostic Radiology) See Threshold detection n HT ( A ) ëêi K ûúi=t Related Articles: Pulse height discriminator, Threshold where detection HT(A) is the threshold contrast detail index value for the image of interest Thulium H ref T (A) is the threshold contrast detail index value for the ref- (General) erence image K is the DAK at the image plate Symbol Tm Kref is the DAK at the image plate for the reference image n is the number of different detail diameters visible in the Element category Lanthanoid metal image Mass number A 169 Atomic number Z 69 Related Articles: Contrast detail (C-D) studies, Contrast detail Atomic weight 168.93 kg/kg-atom Further Readings: Cowen, A. R. and A. Workman. 1992. Electronic configuration 1s2 2s2 2p6 3s2 3p6 3d10 4s2 4p6 4d10 4f13 5s2 5p6 6s2 A physical image quality evaluation of a digital spot fluorogra- phy system. Phys. Med. Biol. 37(2):325–342; Gallacher, D. J., Melting point 1818 K A. Mackenzie, S. Batchelor, J. Lynch and J. E. Saunders. 2003. Boiling point 2223 K Use of a quality index in threshold contrast detail detection mea- Density near room temperature 9320 kg/m3 surements in television fluoroscopy. Br. J. Radiol. 76:464–472; Threshold detection index Thyratron 951 Time average intensity (ITA) History: Thulium was discovered in 1879 by Per Theodor Cleve when he extracted holmium and thulium oxides from impu- rities in erbium oxide. It is now obtained along with many other rare-earth elements by chemical separation using an ion exchange process applied to monazite sand ((Ce, La, Th, Nd, Y)PO4). It is the least abundant of the naturally occurring rare-earth elements and has no significant commercial uses. Medical Applications: Radiation source – Radioactive isotopes of thulium (such as thulium-171) have been used as brachytherapy seed sources. Another isotope, thulium-169, has a potential use as a radiation source for portable x-ray machines. Lasers – Thulium lasers are often high power and well suited for use in medicine. Related Articles: X-ray, Brachytherapy, Brachytherapy sources Thyratron (Diagnostic Radiology) Thyratron is a gas filled electronic tube, mainly used as high voltage switching device or controlled recti- fier. The thyratron includes a cathode (more often hot filament FIGURE T.28 Digital radiography detector, made of four plates tiled cathode), control grid(s) and anode. The gas type varies and together. The upper-left plate has a problem (possibly related to power often includes xenon, neon and hydrogen. The electrical current supply) and does not show this part of the radiograph. through the device is controlled by varying the potential of the control grid. Thyratron is especially useful for fast commutation of high voltage. One of its many uses is for kV rectifiers and stabi- detector plates (named ‘tiles’ in professional jargon). A detector lisers (see the article about x-ray Pulse-less generator). According with good tiling will present the combined digital image as one to the number and type of the control grids the thyratron can be image, without visualising the areas where the composite detec- triode, tetrode or pentode. The thyratron was one of the most tor plates are ‘stitched together’. Using a very narrow visualising commonly used switches/rectifiers in x-ray classical high voltage window might show faint lines at the places between the separate generators, but is now replaced by semiconductor elements as thy- detector plates. Visualising these areas with normal (diagnostic) ristor and triac. However it is still very good for fast kV commuta- window parameters is considered an artefact (Figure T.28). tion due to its very short switching time. Related Articles: Digital detector; Digital detector arrays, Related Article: Pulse-less generator Window Thyroid radioiodine uptake measurements Tilting table (Nuclear Medicine) The determination of the uptake of radioac- (Diagnostic Radiology) A table, typically for fluoroscopy, that can tive iodine by the thyroid gland was the first radioisotope test that be tilted to raise the head of the patient during some procedures. T required in vivo measurements. A certain amount of radioactive In some countries the tilting table position with patient head lower iodine, usually 123I or 131I, is administered to the patient. The test than his feet is called Trendelenburg position. consists of the determination of the fraction of the activity present in the thyroid at a later time. The test has to consider the following parameters: (1) the Time activity curve amount of radioactivity present in the thyroid has to be deter- (Nuclear Medicine) When calculating the radiation dose to a spe- mined accurately, thus the detector has to calibrated and the cific organ or a patient one of the important parameters is the thyroid position and volume determined to account for the tissue kinetics of the radio-compound in the patient (i.e. delivery, uptake attenuation and self attenuation and (2) at the time of measure- (accumulation), metabolism, clearance in the specific organ). ment only a fraction of the iodine is present in the thyroid and it After injection different organs are studied to determine the spa- is important to correct for the background signal (meaning the tial and temporal distribution of the administered activity. The activity in the extrathyroidal tissue in the detectors field of view). spatial and temporal distribution for an individual compartment The instruments used are either single collimated probes or is called the time activity curve. dedicated scintillation cameras. The measurements have to be In the MIRD formalism the time activity curve is used to deter- calibrated with a standard activity and a proper phantom (neck mine the cumulated activity which is an integration over the time phantom). activity curve from injection (t = 0) to total radionuclide clearance. Related Articles: Iodine, Thyroid, Probe Thus the cumulated activity is the total number of disintegrations Further Reading: Hine, G. J. and J. B. Williams. 1967. In: in the organ from initial uptake to total clearance. Instrumentation in Nuclear Medicine, Vol. 1, ed., G. Hine, Related Articles: MIRD formalism, Cumulated activity Academic Press, New York, Chapter 14, pp. 327–350. Further Reading: Cherry, S. R., J. A. Sorenson and M. E. Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, TI (inversion time) Philadelphia, PA, p. 408. (Magnetic Resonance) See Inversion time (TI) Time average intensity (ITA) Tiling of digital detector (Ultrasound) Time average intensity is the intensity measured (Diagnostic Radiology) Large digital detectors (e.g. in radiog- over a given cross-sectional area, averaged over time. The raphy) are usually manufactured as an array of several smaller time average is taken over an integral number of pulse or field Time-averaged dose rate (TADR) 952 Time delay circuit repetition periods. It will average out the variation in intensity account the occupancy of the area where the person is exposed resulting from the pulse-space ratio in pulsed ultrasound beams – i.e. what proportion or percentage of the time the person may and give the average intensity at a field point insonated

by mul- be standing there during a normal working year (which is taken tiple beams when in a scanning mode. to be 8 hours per day × 5 days per week × 50 weeks per year = Related Articles: Intensity, Spatial average intensity, Pulse 2000 hours). average intensity For more details see articles on Instantaneous dose rate (IDR) and Time-averaged dose rate (TADR). Time-averaged dose rate (TADR) Related Articles: Instantaneous dose rate (IDR), Workload (Radiation Protection) When determining the radiation protec- factor, Time-averaged dose rate (TADR), Occupancy factor tion shielding and other features of a facility using a radiation source to ensure the safety of staff and the public, it is appropriate Time constant as a first step to consider the maximum instantaneous dose rate (General) A time constant is a measure of how quickly a system that the source is capable of delivering, and then to consider the can respond to a step change in input parameter. way in which the source is used to determine the radiation dose A time constant is usually used to describe the response a sys- that any person may receive over a longer period of time – by tem which is exponential in form, either when it is slow to change time-averaging the dose rate to which a person may be exposed. (a), or transient (b) (Figure T.29). For most radiation sources it will be this time-averaged dose rate The two forms have the mathematical expressions shown, (TADR) that will be of more importance in determining the radi- and in both cases they are fully defined by the time constant τ, ation protection design features and working practices that may the time it takes each circuit to reach 63% of its final value in be required to reduce the total dose received to acceptable and response to a step input change. optimised levels. In the simple electronic circuits given in the following, their An example of converting instantaneous dose rate (IDR) to responses can be described using the time constant, and addition- TADR is given in the article on Workload factor and is repro- ally can be shown to be related simply to the values of the circuit duced here: components shown (Figure T.30): Their frequency responses are also related directly to their • A CT scanner room has 15 patients during an 8-hour time constants, the low-pass filters cutting off signals higher than working day, and each scan involves a spiral scan (radi- 1/2πτ Hz, while the high-pass filters pass signals higher than this ation on) beam time of about 2 minutes. frequency. • Therefore, the ionising radiation is on for a total of 2 × The time constant is given in seconds when the electronic 15 minutes per 8-hour day. components are given in ohms, farads and henries. • That is 30/480 minutes – a workload factor of 0.0625. Further Reading: Horrowitz, P. and W. Hill. 2006. The Art of Electronics, Cambridge University Press, New York. Now, if we assume that the IDR at a given point where the operator sits is (say) 7.5 µSv/hr when the x-ray beam is on, then Time delay circuit the TADR over the working day will be: (General) A time delay circuit is designed to respond to a change T in input with a predefined delay. Both input and output are usually 7.5´ 0.0625 = 0.47 mSv/hr. (TADR) digital (on/off) and sometimes incorporate a relay in the output circuit to provide an electrically isolated but powerful switch. When considering the potential exposure of persons in areas adjacent to a radiation facility, the shielding calculations may also take into account not just the workload factor to convert IDR to TADR, but also then consider an occupancy factor to determine V Step input what proportion of the 2000-hour working year that a person may be present at that point in the adjacent area. For the operator of the Vo CT scanner in the example above, the occupancy factor is 1 – i.e. they work there all year long; however for other persons in areas such as public corridors near the CT Scanner room, the occu- pancy factor could be much less than 1 – down to 0.2 (i.e. they spend at most 20% of their time in that area). The adjusted TADR 63% t taking into account occupancy factor is called TADR2000. (a) Slow response Thus, in the example above, if a person standing at the same position as the operator was instead in a public corridor, then the V Step input TADR2000 at that point would be: 7.5´ 0.0625´ 0.2 = 0.094 mSv/hr. (TADR2000) Related Articles: Instantaneous dose rate (IDR), Workload fac- tor, Occupancy factor Time-averaged dose rate (TADR2000) 63% t (Radiation Protection) The time-averaged dose rate (TADR2000) (b) Transient response is a dose quantity related to occasional, frequent, or indeed con- tinuous radiation exposure from a source, but which takes into FIGURE T.29 Time constant graphs. Time delay integration 953 Time of flight L R C R Vin C Vo Vin R Vin V i n R V o Vin L Vo (a) T = RC (b) T = RC (c) T = L/R (d) T = L/R FIGURE T.30 Various filters. (a) LC low pass filter, (b) LC high pass filter, (c) LR low pass filter and (d) LR high pass filter. DC radiation from one fixed part of the patient continues to fall on power and integrate with the rest of the charge being detected from that part of the patient. R The TDI mode of operation of these systems improves sensi- tivity and reduces the influence of scattered radiation, but it takes cf Power on reset longer time. The spatial resolution of these systems depends on the accurate alignment of the signal gathering CCD columns of C the detector. 0 V Time distance shielding (TDS rules) (Radiation Protection) There are three means to protect people FIGURE T.31 Typical time delay circuit. against external radiation exposure: time, distance and shielding. That the time of permanence in the radiation field will propor- tionally reduce the exposure of the irradiated individual can be Time delay circuits can be complete modular units, usually grasped intuitively. To a certain extent, the same applies to the with a screw adjusted time delay given in seconds, and with speci- distance. In this case, however, there is no linear relationship, fied input and output properties. but an inverse square relation between the intensity of the radia- Time delay circuits can also be incorporated within more com- tion and the distance of the exposed individual from the source. plex circuits, and vary in design depending on the required accu- This means that when the distance from the radiation source is racy of the delay. The simplest type, often used in ‘power on reset’ doubled, there is one fourth of the exposure. Protection can also circuits, uses the slow rise of voltage when a capacitor is changed be achieved by shielding the radiation source with appropriate through a resistor attached to the circuit’s DC power input line. materials (see Lead content). The attenuation of the radiation by This is fed to a comparator whose output changes when the input this means follows an exponential relationship with the thickness voltage rises above a set reference level (Figure T.31). of the shielding material. More advanced circuits often use the ubiquitous ‘555 timer’ Hyperlink: http://IAEA .org T integrated circuit which incorporates all the necessary active components and requires only the odd resistor and capacitor to Time gain compensation produce a reliable and programmable delay. (Ultrasound) See Depth gain compensation Related Article: Time constant Further Reading: Horrowitz, P. and W. Hill. 2006. The Art of Time interval difference imaging Electronics, Cambridge University Press, New York. (Nuclear Medicine) A difference image is the result of the pixel by pixel subtraction of one image from another. In time interval dif- Time delay integration ference imaging, the two images are performed at different times. (Diagnostic Radiology) Time delay integration (TDI) is used in In nuclear medicine this can be used to look at the washout scanned-beam acquisition imaging systems (e.g. digital mam- of a tracer from a particular organ. An example of this is para- mography). The detector of these systems is a multilinear array thyroid imaging using Tc-99m MIBI. Over a period of time the with charge coupled devices (CCDs). The image is acquired by tracer washes out of the thyroid revealing the parathyroid gland. scanning the object with a narrow fan beam of x-rays. It can also be used to look at the uptake in a tumour pre- and post- CCDs develop a charge on their individual sensors which is therapy after registration and normalisation of the two images. proportional to both radiation intensity and time of exposure. Thus they can integrate the effects of exposure over a period of Time of flight time. In practice, this process may be taken further as the CCD (Nuclear Medicine) Time of flight is a technique used in PET to device has a method of readout which transfers the charge on indi- determine the position of positron annihilation. Ideally, the time vidual sensors in a linear fashion across the detector area, serially between two detected events can provide information about the outputting the results for each line of sensors as the charge pack- localisation of the event along the line of response (LOR). If the ets reach the edge. annihilation event is off centre one of the two photons will be In certain imagers with TDI the two processes are combined – detected earlier, less than a nanosecond, than the other photon. the detector and x-ray source jointly being moved linearly in one The principal limiting factor today is that the rise time of light direction while the charge packets move in the other direction. In output in the common scintillators is too slow (1 cm depth reso- this way, by clocking the charges across the sensors, whilst mov- lution requires 66 ps timing resolution). The position along the ing the detector at equivalent speed in the opposing direction, the LOR, Δd, is given by Time-of-flight (TOF) 954 Timer Dt ´ c phenomenon, which introduces a dependence upon flow direc- Dd = 2 tion, makes 2D inflow MRA more advantageous for low-velocity motion, since in 3D MRA, in this case a high signal is obtained where at the entrance side while at the exit side the signal is low. On the Δ t is the time difference between the two events other hand, the 3D technique gives better spatial resolution. c is the speed of light (3 × 108 m/s) The most common method for the calculation of MR angio- grams is the so-called ray-tracing technique. Using ray-tracing, Abbreviations: LOR = Line of response and PET = Positron a number of slices obtained in consecutive acquisitions of 2D emission tomography. images or a set of slices obtained in a 3D acquisition are stored in Related Article: PET a data set. By following rays through the data set the maximum Further Reading: Cherry, S. R., J. A. Sorenson and M. E. intensity is selected along that ray or projection (MIP). This value Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, is taken as the pixel value for that pixel hit by the ray in the pro- Philadelphia, PA, pp. 327–328. jected image plane. By rotating the projection angle it is possible to obtain a 3D visualisation in any direction. It is also possible to exclude parts of Time-of-flight (TOF) the 3D data set and to perform the computation of the projection (Magnetic Resonance) Time-of-flight (TOF) is MR angiography images through a selected subvolume of special interest. Vessels method that utilises the inflow effect (see Inflow effect). of minor interest can then be excluded and an enhanced image of In order to maximise signal enhancement from inflowing liq- interest may be obtained. A corresponding technique, more suit- uid and to reduce the signal from stationary tissue, a gradient echo able for the outflow effect, is ray-tracing using a minimum inten- (GRE) pulse sequence with a short TR is used. The strength of the sity projection (Figure T.32). signal is dependent on a number of parameters like slice thickness, Related Articles: Inflow effect, Maximum (minimum) inten- flow velocity, flip angle,

T1 relaxation time and TR. Normally, in sity projection order to avoid pulsation flow artefacts gradients are also designed to refocus spins with a constant velocity (flow compensation). Very often multiple two-dimensional (2D) inflow MRA, that Time of repetition is a number of thin contiguous 2D slices, are acquired with a (Magnetic Resonance) See Repetition time (TR) fast gradient echo sequence. Subsequently, the 2D data are col- lected in the computer and a three-dimensional (3D) data set is Time-of-flight techniques in PET formed and post-processed. In 3D inflow MRA, a thick slab or (Nuclear Medicine) See Time of flight a volume is excited and the spatial encoding is performed in all three dimensions. Timer The major difference between the 2D and the 3D inflow (Nuclear Medicine) A timer is used to set a time interval when a MRA methods lies in their difference in slab thickness, causing measurement is to be conducted. In radiology for x-ray exposure different signal behaviour due to progressive saturation of the the timing device functions as an automatic exposure timer and a inflowing spins as they move deeper into the imaging slab. This switch to control the current to the high-tension transformer and T (a) (b) FIGURE T.32 (a) Illustration of one slab from a 3D TOF data set (bright areas are vessels with prominent inflow effect). (b) Coronary MIP obtained from a 2D TOF sequence showing intracranial vessels. (Courtesy of Elna-Marie Larsson, Aalborg, Denmark.) Tin 955 Tissue air ratio (TAR) filament transformer. The face of the timer is calibrated in seconds of the heart. The central and peripheral nervous systems are com- and fractions of seconds. The timer controls the total time that the prised of nervous tissue, including the brain, spinal cord, nerves current passes through the x-ray tube and thus the time during and motor neurons. which the roentgen rays are emitted. In nuclear medicine a timer Related Articles: Bone soft tissue interface, CT Number, is used to measure the number of registered pulses (proportional Dose limiting tissue, Equivalent tissue air ratio (ETAR), Fat, Late to impinging particles of photons on a detector) during a certain response of normal tissue, Normal tissue complication probabil- time interval. Then also the count rate is easily determined. ity (NTCP), Normal tissue dose, Normal tissue dose–response, Normal tissue reaction, Normal tissue toxicity, Tissue air ratio Tin (TAR), Tissue compensation, Tissue contrast, Tissue deficit, (General) Tissue equivalent material, Tissue heterogeneity, Tissue maxi- mum ratio (TMR), Tissue phantom ratio (TPR), Tissue substitute, Tissue weighting factor, Water Symbol Sn Element category Metals Tissue air ratio (TAR) Mass number A 120 (Radiotherapy) The tissue air ratio was introduced for the dosi- Atomic number Z 50 metric calculations of firstly rotational radiotherapy, and more Atomic weight 118.710 kg/kg-atom latterly, isocentric treatments, in which the SAD remains constant Electronic configuration 1s2 2s2 2p63s23p63d104s24p64d105s25p2 with the SSD varying with the patient contour. Melting point 505.1 K It is the ratio of DQ, the absorbed dose in tissue at point Q on the Boiling point 2875 K central axis in a patient or phantom, to D* Q the absorbed dose to a Density near room temperature 7310 kg/m3 small mass of water in air at the same point Q on the central axis. The set-up is illustrated in Figure T.33. It is defined as follows: Tin (aka Stannum) is a ductile and malleable silvery-white metal with a highly crystalline structure. The major source of tin is the TAR (d A ) DQ (d, A,E ) , ,E = DQ * (air, A,E ) mineral cassiterite, in which tin is present as tin oxide, SnO2. Tin is used in alloys, such as bronze, and as a coating to prevent cor- In ICRU 24 the definition of TAR was given as follows: rosion of other metals. Medical Applications: In nuclear medicine, tin (II) fluoride The absorbed dose at a given point in a phantom (stannous agent) is used to bind 99mTc04− (pertechnetate) to red The absorbed dose which would be measured at the blood cells to allow multi-gated acquisition (MUGA) imaging same point in free air within a volume of the of the heart. The injected stannous agent binds with the patient’s phantom material just large enough to provide red blood cells in vivo; this then acts as a reducing agent on the electronic equilibrium at the point of reference injected technetium causing it to bind to the red blood cells. A The denominator can also be thought of as the absorbed dose due further use of tin in nuclear medicine is the imaging of sentinel to primary radiation only, and is normally measured with ionisa- nodes using a 99mTc-tin colloid radiopharmaceutical. tion chambers and build-up caps. However there are difficulties T Related Articles: Nuclear medicine imaging, Multi-gated with this definition when it comes to measurement: acquisition, Pertechnetate, Tc-99m-Tin colloids • At high energies, the build-up volume needed to com- Tissue pletely avoid scattered contribution is very large. (General) CT number: ∼ 0 HU (water), varies from −120 HU (fat) • Small field sizes below limit of build-up material diameter. to >400 HU (bone) • Readings must be free of scattered radiation from the Biological tissue is a cellular organisational level between walls or floor. cells and organs. It is defined as a group of cells of the same • The actual measurement set-up is cumbersome, com- origin, which provide a certain function. The functional group- pared to PDD measurements which can be automated ing of several tissues forms organs. The study of tissue is known more easily. as histology, or histopathology when in reference to disease. Tissues are studied by optical and electron microscopy as well as immunofluorescence. Animal tissues are categorised into four types based on their Source Source morphology, including connective, epithelial, muscle and ner- vous tissues. Connective tissue consists of cells separated by an SSD extracellular matrix that joins other tissues together and is flex- SAD ible. Bone (osseous tissue) and blood are examples of connective tissues. Epithelial tissues are layers of cells that cover organ sur- P P faces, such as the skin and the inner lining of the digestive tract. d The layer protects the underlying organ by providing a barrier to Q Q the external environment due to its semi-permeability. The epi- thelium also allows secretion and absorption. Muscle tissue is an A A active contractile tissue producing force to enable motion, either (a) (b) externally or internally. Muscle tissue is further subdivided into visceral/smooth muscle, in the inner linings of organs; skeletal FIGURE T.33 Set up for measuring the tissue air ratio (TAR). The field muscle, attached to bone for movement; and the cardiac muscle size A is defined at point Q, which is normally placed at the isocentre. Tissue compensation 956 Tissue phantom ratio (TPR) Compensator Radiation beam Wax bolus Tissue Patient contour deficit Patient Patient (a) (b) Point of interest FIGURE T.34 In (a) a wax bolus is placed on the skin, producing a flat radiation distribution. Skin sparing is lost with bolus. In (b) a compen- sator achieving the same dose distribution as in (a) is constructed and attached to the treatment unit. Due to the large air gap, skin sparing is FIGURE T.35 Irregular skin surface leading to tissue deficit. maintained. See also Bolus. the way of the beam. If bolus is used at the skin surface, the reduc- In practice, TARs are often derived from measured PDD curves, tion in skin sparing will need to be taken into account. as they can be related from first principles. The conversion pro- cess includes a Mayneord factor that is an inverse square law Tissue equivalent material correction. (Radiotherapy) A material that responds in the same way as tissue At d = dmax, the TAR becomes identical to the peak scatter does when irradiated is said to be tissue equivalent. For this to be factor (PSF). The TAR decreases as d increases further from dmax. the case the material has to have For constant depth and energy, TAR increases with increasing field size. For constant depth and field size, TAR increases with 1. An effective atomic number close to tissue so that the energy. photo-electric and pair production processes are con- Abbreviations: SAD = Source axis distance and SSD = Source tributing to absorption in the same way as tissue. surface distance. 2. An electron density close to that of tissue so that Related Articles: Peak scatter factor (PSF), Percentage depth Compton scatter and absorption is similar to that in dose (PDD), Scatter air ratio (SAR) tissue. 3. A density close to tissue so that any spatial measure- Tissue compensation ments made in the phantom will be relevant to those (Radiotherapy) To compensate for missing tissue or a sloping made in tissue. T surface, a custom made bolus arrangement can be made that conforms to the patient’s skin on one side and yields a flat per- Tissue heterogeneity pendicular incidence to the beam (see Figure T.34a). The result is (Radiotherapy) See Heterogeneity an isodose distribution that is identical to that produced on a flat Related Articles: Inhomogeneity correction factor, Heterogeneity phantom; however, skin sparing is not maintained. This can be overcome by retracting the bolus (taking divergence into account) Tissue maximum ratio (TMR) as in Figure T.34b. (Radiotherapy) The tissue maximum ratio (TMR) is a special A common material used for this kind of bolus is wax, which case of tissue phantom ratio (TPR) where the reference depth is is essentially tissue equivalent and when heated is malleable and chosen to be the depth of dose maximum d d can be fitted precisely to the patient’s contour. ref = max. See Tissue phantom ratio (TPR) for details of the set-up. Bolus can also be used to compensate for lack of scatter, such The TMR ranges between 0 and 1, where it equals 1 for d = as near the extremities or the head during total body irradiation d nergy, the TMR decreases with (TBI). Saline or rice bags can be used as bolus in these treatments. max. For constant field size and e increasing depth. The TMR increases with both increasing field Related Article: Bolus size and increasing energy, at constant depth. Related Article: Tissue phantom ratio (TPR) Tissue contrast (Diagnostic Radiology) See Chest radiography Tissue phantom ratio (TPR) (Radiotherapy) The tissue phantom ratio was introduced to cope Tissue deficit with the difficulties of measuring the tissue air ratio (TAR) in MV (Radiotherapy) Because of the variation in body shape, the skin set-ups, where the build-up required for the ‘in-air’ measurement can present a surface that is not flat with respect to the radiation becomes impractical. The TPR is defined as the ratio of the dose beam. At times there can be more or less tissue in the way of the in a phantom at point Q on the central axis, to the dose at the same beam and underlying treatment region (see Figure T.35). This will point Q in a phantom at a reference depth dref. It is equivalent to affect the dose distribution and the dose at the point of interest the ratio of the corresponding dose rates (Figure T.36): in Figure T.35. The situation can be regarded as one where there is a tissue deficit (i.e. missing tissue) and if the dose needs to be altered at the point of interest then some tissue equivalent mate- TPR ( D D d, A,E ) = Q = Q rial, bolus or a retractable compensator may have to be placed in D Q ref DQ ref Tissue substitute 957 Tissue weighting factor Source Source Usually MRI phantoms are fluid-filled plastic containers and fluids are selected free from susceptibility effects or signal dis- SSD ruption. Materials mimic conductivities found in the human body SAD and electrical loading of the coil. Related Articles: Tissue substitute, Tissue equivalent material P d Aref Further Readings: International Commission on Radiation Units and Measurements (ICRU). 1989. Tissue Substitutes Q Q dref in Radiation Dosimetry and Measurement ICRU Report 44, Washington, DC; International Commission on Radiation Units A AQ and Measurements (ICRU). 1992. Phantoms and Computational Models in Therapy, Diagnosis and Protection ICRU Report 48, AQ̋ Washington, DC; International Commission on Radiation Units and Measurements (ICRU). 1998. Tissue Substitutes, Phantoms and Computational Modelling in Medical Ultrasound ICRU FIGURE T.36 Set

up for measuring the tissue phantom ratio (TPR). Report 61, Washington, DC; Mastrogiacomo, S., W. Dou, J. Jansen and F. Walboomers. 2019. Magnetic resonance imaging of hard tissues and hard tissue engineered bio-substitutes. Mol. The measurement set-up is shown in Figure T.36. It is measured Imaging Biol. 21(6):1003–1019. in water or water substitute solid phantoms by keeping the detec- tor at a constant distance from the source and varying the depth of material. Tissue weighting factor When d (Radiation Protection) Tissue weighting factors are similar to ref is chosen to be dmax, the TPR becomes the tissue maximum ratio (TMR). the radiation weighting factors applied to convert absorbed dose Related Articles: Peak scatter factor (PSF), Percentage depth to equivalent dose. They are assigned to different body tissues dose (PDD), Scatter air ratio (SAR), Tissue air ratio (TAR) and are used to convert equivalent dose to effective dose using Equation T.1. The value of each weighting factor is based upon the radiosensitivity of different tissues and the probability of damage Tissue substitute should exposure to ionising radiation occur. Therefore effective (Radiotherapy) A tissue substitute is a material that can be used as dose is associated with stochastic effects: tissue equivalent in either in a phantom to make dosimetric mea- surements or to provide necessary build-up material on the skin Effectivedose while the patient is being treated. Materials such as wax and moist (T.1) gauze are often used. Barley and tissue equivalent gels, which are = S(Equivalentdose ´ Tissue weightingfactor)(Sv) commercially available, are also used. See also Tissue equivalent material. The tissue weighting factors are defined in the reports of the International Commission on Radiological Protection (ICRP). Tissue substitute material The most recent set of factors was published in ICRP Publication T (General) Tissue substitute materials are used in medical and 103 and is shown in Table T.2. health physics for various purposes, most often for preparation of The tissue weighing factor applied to the gonads has been phantoms. The materials of the phantoms should simulate human reduced in recent years. This is due to research showing that the tissues. In applications using ionising radiation the equivalence risk of hereditary disease from radiation of the gonads is not as between tissues and tissue equivalent materials is valid over a spe- high as was previously thought. cific photon energy range. This makes tissue substitute materials Related Articles: Absorbed dose, Radiation weighting factor, dependent on the type of ionising radiation being used. Equivalent dose, Effective dose, Stochastic effect, International ICRU Reports 44, 48 and 61 are a set of documents useful for Commission on Radiological Protection describing the physical and chemical characteristics of human tis- Further Reading: ICRP (International Commission on sues. ICRU Report 44 (1989) provides exhaustive tables of physi- Radiological Protection). 2007. The Recommendations of cal quantities that should be considered when tissue substitutes the International Commission Radiological Protection, ICRP are selected for dosimetry studies and other applications using Publication 103, Ottawa, Canada. photons (10 to 100 MeV), electrons (10 to 100 MeV), neutrons (25 to 100 MeV) and heavy charged particles (1 to 500 MeV). ICRU Report 48 (1992) identifies and characterises the body structures that are used to describe the variation within the human TABLE T.2 populations linked with body size and shape. ICRU 61 (1998) reviews the use of tissue substitutes represent- Tissue Weighting Factors as Defined in ICRP 103 ing human tissues in medical ultrasound. Water has been used as Weighting a tissue substitute in medical ultrasound measurements and cali- Tissue Factor (WT) Σ WT brations for several decades. A limitation is as a tissue substitute, Bone marrow, breast, colon, lung, stomach 0.12 0.60 its attenuation coefficient in the 1 to 15 MHz frequency interval, is smaller than the attenuation of soft tissue. Over 40 tissue sub- Bladder, oesophagus, gonads, liver, thyroid 0.05 0.25 stitutes have been developed for use in imaging. Doppler flow and Bone surface, brain, kidneys, salivary glands, skin 0.01 0.05 thermal measurements are described in ICRU 61 together with Remainder tissues 0.1 0.10 references that provide detailed information on their formulation, Total 1.00 physical properties, production and applications. TLD (thermoluminescent dosimeter) 958 Tolerance TLD (thermoluminescent dosimeter) irradiation. For example, re-epithelialisation of a denuded area (Radiation Protection) See Thermoluminescent dosimeter (TLD) of skin can occur either from surviving clonogens within the denuded area or by migration from adjacent areas. TOF (time-of-flight) In radiotherapy, it is generally the case that the total dose that (Magnetic Resonance) See Time-of-flight (TOF) can be tolerated depends on the volume of tissue irradiated – the dose–volume effect. The spatial arrangement of the FSUs in the Toggle switch tissue is critical. In serial organs, the FSUs are arranged in series, (General) A toggle switch is an electrical switch that is operated like the links of a chain, and the integrity of each is critical to by a mechanical lever. The lever usually has two separate stable organ function. Damage to a single FSU is sufficient to cause a positions and a snap action mechanism, so that a positive action complication. Radiation damage to such tissues is expected to occurs and it is easy to tell which position the switch is in. The show a binary response: normal function for doses below a thresh- switch is ‘toggled’ from one state to the other. old dose above which there is loss of function. For these tissues, Such switches may act simply to make or break one pair of the greater the volume of tissue irradiated, the steeper the sigmoid contacts (single pole, single throw), or switch between alternate dose–response curve becomes and the threshold dose decreases. contacts (single pole change over) – see Figure T.37. Multiple sets This explains the volume effect observed in spinal cord, a serial of contacts may be driven in concert to give a multi-pole switch. organ where the loss of any one FSU may result in myelopathy. In parallel organs, the FSUs are arranged in parallel so that the inactivation of a small number of FSUs does not lead to loss Tolerance of organ function. Inactivation of a critical number of FSUs is (Radiotherapy) Radiation treatment inevitably affects normal required for functional damage to occur meaning that there should tissue and so may cause radiation induced adverse effects. The be a threshold volume of irradiation below which no functional tolerance of normal tissues to radiation depends on the ability of damage will develop even after high-dose irradiation. Above this the clonogenic cells to maintain a sufficient number of mature threshold there is a graded rather than a binary response: func- cells suitably structured to conserve organ function. The tissue tional impairment increases in severity with increasing dose. architecture is thought to be important in determining the toler- Tissue with structurally undefined FSUs such as skin and mucosa ance dose for partial organ irradiation. Groups of cells within an respond in a similar way to tissues with a parallel FSU structure. organ may be thought of as organised into collective bodies called New knowledge of the dose–volume relationship for tissue tol- functional subunits (FSUs). If the integrity of a sufficient number erance is emerging from studies of patients who have received of FSUs is maintained, the function of the organ is preserved. IMRT treatment. Traditional radiotherapy treatments gener- In some tissues, the FSUs are discrete, anatomically delineated ally give high doses to relatively small volumes of normal tis- structures with a clear relationship to tissue function. Examples sue whereas the highly conformal nature of IMRT results in large of these structurally defined FSUs are the nephron in the kidney, volumes of normal tissue receiving a low dose. There is increas- the lobule in the liver, and the acinus in the lung. In other tissues, ing evidence that for some organs their tolerance to high doses the FSUs have no clear anatomic demarcation. Examples of these may be affected by the volume receiving a low dose. Reviews of structurally undefined FSUs include the skin, the mucosa and the data for patients who received IMRT treatment for mesothelioma spinal cord. These two types of tissue differ in their response to T and for non-small-cell lung cancer indicate that the risk of fatal radiation. pulmonary events after radiotherapy may be due to relatively For structurally defined FSUs their survival depends on that high lung doses (20 Gy) superimposed on extensive volumes of of one or more clonogenic cells within them and tissue survival lung exposed to low radiation doses. For example, Yorke et al. depends on the number and radiosensitivity of these clonogens. report pulmonary complications at the 20% level occurred when Such tissues are composed of a large number of FSUs but each is >50% of the lung volume received ≥10 Gy. Such findings are not considered a small self-contained entity independent of its neigh- confined to parallel organs; experiments on rat spinal cord have bours. Surviving clonogens cannot migrate from one to the other. shown that the radiation dose required to produce necrosis over Consequently, survival of the FSU after irradiation depends on short cord segments is significantly reduced if the adjacent tissue the survival of at least one clonogen within it. Taking the kidney is first exposed to sub-threshold doses of radiation as low as 4 Gy. and its FSU the nephron as an example, the survival of a neph- The suggested mechanism is that a negative effect is exerted by ron after irradiation depends on the initial number of renal tubule the low-dose bath on the regenerative capacity of neurons within cells per nephron and their radiosensitivity. Since this FSU is rela- the high-dose field. tively small, it is completely depleted of clonogens by low doses Curative radiotherapy usually involves treating the normal tis- which accounts for the low tolerance to radiation of the kidney. sues immediately surrounding the tumour to the limit of tolerance For structurally undefined FSUs the clonogenic cells are not and a much larger volume will receive a lower dose. Unfortunately, confined to one particular FSU but can migrate from one to a significant number of patients subsequently relapse or develop another allowing the repopulation of a depleted FSU following nodal disease or new tumours within the previously irradiated region. Decisions regarding re-treatment options require consid- eration of the dose received by normal tissues from the original treatment, the extent to which the normal tissues have regener- ated, and on the extent of any residual or latent damage present after regeneration. In general, acutely responding tissues, such as skin and intestine, recover from radiation injury rapidly and can Single pole Single pole Dual pole be re-irradiated to full tolerance within 1–3 months. However, for single throw change over single throw late toxicity endpoints tissues vary considerably in their recovery capability. The heart, bladder and kidney do not exhibit long-term FIGURE T.37 Various toggle switches. recovery at all. In contrast, the skin, mucosa, lung and spinal cord Tomography 959 Tomosynthesis are capable of limited long-term recovery and can be re-irradiated with partial tolerance doses. The extent of recovery is dependent on the organ type, magnitude of the initial radiation dose, and partly on the interval between radiation treatment courses. Abbreviations: FSU = Functional sub-unit and IMRT = Intensity- modulated radiotherapy. Related Articles: Adverse effect, Cell survival, Dose–response model, Intensity-modulated radiotherapy (IMRT), Normal tissue toxicity, Parallel organs, Serial organs, Sigmoid dose–response curve, Therapeutic ratio Further Readings: Bijl, H. P., P. van Luijk, R. P. Coppes, J. M. Schippers, A. W. T. Konings and A. J. van der Kogel. 2006. Influence of adjacent low-dose fields on tolerance to high doses of protons in rat cervical spinal cord. Int. J. Radiat. Oncol. Biol. Phys. 64:1204–1210; Emami, B., J. Lyman, A. Brown, L. Coia, M. Goitein, J. E. Munzenrider, B. Shank, L. J. Solin and M. Wesson. 1991. Tolerance of normal tissue to therapeutic irra- FIGURE T.38 Planar skull x-ray (projection). diation. Int. J. Radiat. Oncol. Biol. Phys. 21:109–122; Hall, E. J. and A. J. Giaccia. 2006. Radiobiology for the Radiologist, 6th images to be extracted from reconstructed 3D image volumes in edn., Lippincott Williams & Wilkins, Philadelphia, PA; Nieder, any orientation desired. C., L. Milas and K. K. Ang. 2000. Tissue tolerance to reirra- Positron Emission Tomography: Positron annihilation yields diation. Semin. Radiat. Oncol. 10:200–209; Rice, D. C., W. R. a pair of back-to-back 511 keV

photons which are registered in Smythe, Z. Liao, T. Guerrero, J. Y. Chang, M. F. McAleer, M. a pair of detectors, indicating a line along which the event took D. Jeter, A. Correa, A. A. Vaporciyan, H. H. Liu, R. Komaki, place (a line of response). Annihilation photons are collimated so K. M. Forster and C. W. Stevens. 2007. Dose-dependent pulmo- that only those travelling perpendicular to the patient axis reach nary toxicity after postoperative intensity-modulated radiother- detectors. Many such events build up projections of the distribu- apy for malignant pleural mesothelioma. Int. J. Radiat. Oncol. tion of radiotracer similar to the projections of x-ray absorption in Biol. Phys. 69:350–357; Stewart, F. A. and A. J. van der Kogel. CT. Similar reconstruction techniques are applicable, though the 1994. Retreatment tolerance of normal tissues. Semin. Radiat. higher noise characteristics of PET make iterative reconstruction Oncol. 4:103–111; Yorke, E. D., A. Jackson, K. E. Rosenzweig, with expectation-maximisation algorithms generally preferable to L. Braban, S. A. Leibel and C. C. Ling. 2005. Correlation of dosi- filtered back projection. metric factors and radiation pneumonitis for non-small-cell lung Magnetic Resonance Imaging: The term ‘tomography’ is cancer patients in a recently completed dose escalation study. Int. seldom used in MRI except as a synonym for imaging because J Radiat. Oncol. Biol. Phys. 63:672–682. nearly all methods yield sections and projections are rarely recon- structed. In most MR techniques two-dimensional or three-dimen- Tomography sional images are computed using Fourier transformation of data T (General) Tomography is the process of imaging sections through that is sampled in a Cartesian fashion from selectively excited 2D a three-dimensional object. It is distinct from projection methods sections or 3D volumes. In a small number of techniques such in which the effects of all tissue perpendicular to the imaging as projection-reconstruction imaging, the space of the measured plane accumulate, leading to the superposition of imaged tis- signal (k-space) is sampled radially rather than in a grid so as to sues. Tomography derives from the Greek word tomos (section) generate projections. These can be reconstructed into tomograms and came into use in the field of x-ray imaging in the 1930s. The with similar approaches to those used in CT and PET. means of acquiring sectional images (tomograms) differs widely Ultrasound Imaging: Ultrasound imaging is an inherently between imaging modalities, though there is substantial overlap tomographic method in which the profile of the ultrasound beam between reconstruction methods. from the probe defines the thickness of the imaged section. X-Ray: Whereas projection images such as the skull x-ray in Abbreviations: CT = Computed tomography, MRI = Magnetic Figure T.38 show the accumulated absorption of x-rays between resonance imaging and PET = Positron emission tomography. the source and the detector, tomograms show the absorption only of a slice of tissue of a specified thickness, allowing visualisation Tomosynthesis of structures in thin sections. At its inception, x-ray tomogra- (Diagnostic Radiology) Tomosynthesis is the process of using phy was achieved by moving the x-ray source and film in oppo- images of multiple projections of an object to construct images site directions. Signal from tissue outside the focal plane was of planes through that object. In conventional x-ray focal plane blurred, leaving a clear image of a section in the focal plane, the tomography a single exposure is taken while a tube and film move depth and thickness of which could be determined by the motion about a fulcrum in a chosen object plane. This produces a clear of source and film. In modern computed tomography (CT), sec- image only of that plane – all other planes are blurred in the film tions through the patient are reconstructed from a number of to some degree. The objective of tomosynthesis is to form an projections acquired by rotation of the x-ray gantry around the image of any plane in the object by processing images of multiple patient axis, as in the axial CT of the head in Figure T.39. A projections of the object. Grant (1972) was the first to adopt the number of reconstruction methods are available, including fil- term tomosynthesis and presented an analogue method of taking tered back projection and iterative reconstruction. CT tomog- and combining radiographs to view any plane through an object. raphy was originally used to yield axial sections from oblique While focal plane x-ray tomography was a routine, feasible exam- sagittal/coronal projections, as in the example in Figure T.39, ination with analogue techniques and detectors, multi-projection but the near-isotropic resolution of modern CT scanners allows tomosynthesis was not. Tomotherapy 960 Tomotherapy FIGURE T.39 CT tomogram of the head. T The introduction of flat panel detectors and digital image Tube motion processing techniques had led to a renewed interest in tomosyn- thesis. The low geometric distortion and high sensitivity of flat panel detectors have made tomosynthesis at relative low doses X-ray tube practicable. In mammography in particular the technique appears promising (Diekmann and Bick, 2007). In conventional mam- mography, evidence of pathology can be obscured, particularly in dense breast. In tomosynthesis, many projections (9–28) of the breast are taken (see Figure T.40). The resulting projection images are processed to produce multiple images of 1 mm slice thick- ness through the breast. Several reconstruction algorithms have been used, including matrix inversion, filtered backprojection and Compression plate maximum likelihood approaches (Rakowski and Dennis, 2006). The technique is also finding applications in musculoskeletal imaging and in chest imaging, clarifying pulmonary nodules that Breast may be obscured in a conventional chest x-ray (Vikgren et al., 2008), without the need to resort to a higher dose CT exam. Detector Further Readings: Diekmann, F. and U. Bick. 2007. Tomosynthesis and contrast enhanced digital mammogra- FIGURE T.40 Breast tomosynthesis. Multiple projections of the breast phy: Recent advances in digital mammography. Eur Radiol. are taken as the tube moves in an arc. 17(12):3086–3092; Grant, D. 1972. Tomosynthesis: A three dimensional radiographic imaging technique. IEEE Trans. Biomed. Eng. 19(1):20–28; Rakowski, J. and M. J. Dennis. 2006. Tomotherapy A comparison of reconstruction algorithms for C-arm mammog- (Radiotherapy) Tomotherapy is an external beam radiotherapy raphy tomosynthesis. Med. Phys. 33(8):3018–3032; Vikgren, J. et technique that delivers the dose distribution using similar geom- al. 2008. Comparison of chest tomosynthesis and chest radiogra- etry to a tomographic CT scanner (hence the name tomo). Two phy for detection of pulmonary nodules: Human observer study of variations on the geometry have been developed. The first is heli- clinical cases. Radiology 249:1034–1041. cal tomotherapy, which mimics a helical CT scanner’s geometry Tongue and groove leakage 961 Tongue and groove leakage and is a continuous irradiation with the linear accelerator revolv- ing round the patient, delivering a fan beam of radiation, as the Length patient position is slowly indexed. The second is slice-by-slice Height tomotherapy, in which a CT-image-like slice is irradiated with a fan of radiation from the linear accelerator, and then the patient position is indexed to treat the adjacent region. This is repeated until the whole target volume is irradiated. For both implementa- tions a one-dimensional binary collimator is used to shape the End dose distribution as the beam rotates. This binary collimator has a set of high attenuation collimating fingers which are either fully in or fully out of the beam. In the case of slice-by-slice tomo- Side therapy, two banks of binary collimators are used to allow two Width slices to be treated simultaneously. There are two main tomother- apy manufacturers. Tomotherapy inc. makes a helical tomother- apy system with the product name Tomotherapy. Nomos makes FIGURE T.41 A simple illustrative sketch of a single curved-end MLC leaf to demonstrate common terms used in describing MLC leaves. a slice-by-slice system with two banks of collimators called the MiMIC. Tomotherapy is often used as a specific product name for the helical system and as a general term for this class of tech- leakage). But when the adjacent leaves are not synchronised, irra- nology. Often tomotherapy is accompanied by megavoltage cone- diation occurs sequentially through the tongue of one leaf and beam CT (MVCT) using the treatment beam to enable imaging the groove of the adjacent leaf, whereby the dose in the region during treatment. between the adjacent pairs of leaves is less than that of the average Alternatives to tomotherapy for external beam treatment are of the two pairs of leaves (tongue-and-groove effect). the most common technique using a conventional set of fixed The amount of interleaf leakage can be easily measured using beam angles which are shaped in two dimensions, arc therapy some radiographic film, and should typically be less than 3% of with a conventional treatment unit and collimation system, and the dose in the beam. A film is placed at the isocentre on the intensity-modulated arc therapy (IMAT) which combines conven- couch and one field is delivered on each half of the film. Firstly tional arc therapy with beam shape and dose rate modulation. a rectangular open field is delivered to one side of the film with Abbreviations: CT = Computed tomography, IMAT = Intensity- a sufficient number of monitor units set to yield a useable optical modulated arc therapy and MVCT = Megavoltage CT. density. Then the couch is moved laterally to avoid overlap of the Related Articles: Linear accelerator, Computed tomography, two fields prior to the second field. This second field is the same Intensity-modulated radiotherapy, Image-guided radiotherapy, size but has one bank of MLC leaves covering the open portion Intensity-modulated arc therapy, Arc therapy of the field, with no additional shielding behind the MLCs. An Further Readings: Low, D. A., S. Mutic, J. F. Dempsey, J. illustration of the fields is shown in Figure T.42. A much larger Markman, S. M. Goddu and J. A. Purdy. 1999. Abutment region number of monitor units is set (approximately 25 times the first dosimetry for serial tomotherapy. Int. J. Radiat. Oncol. Biol. field) for this field to allow a sufficiently significant optical density Phys. 45:193–203; Mackie, T. R., T. Holmes, S. Swerdloff, T. P. Reckwerd, J. O. Deasy, J. Yang, B. Paliwal and T. Kinsella. 1993. T Tomotherapy – A new concept for the delivery of dynamic con- formal radiotherapy. Med. Phys. 20:1709–1719. Hyperlinks: The Nomos corporation: http://www .nomos .com/; Tomotherapy inc: http://www .tomotherapy .com/ Tongue and groove leakage (Radiotherapy) Adjacent MLC leaves must slide smoothly across each other with minimal gaps between leaves to reduce leakage and transmission radiation. This is accomplished by machining tongue-and-groove patterns into the sides of the leaves. The side of one leaf has an extended portion called the tongue, while the abutting side of the adjacent leaf has an indented portion called the groove. Two adjacent leaves are coupled together as the tongue of one leaf slides within the groove of the adjacent leaf. Each leaf has a tongue on one side and a groove on the opposite side. The manufacture of precise tongues and grooves into extremely small individual leaves is an exacting process that places a lower limit on the size of individual MLC leaves (Figure T.41). While this tongue-and-groove design reduces radiation leak- age, it also complicates treatment planning dose calculation because the transmission through any leaf depends on whether the beam passes through the tongue, the centre or the groove por- tion of the leaf. There are some interleaf effects falling into two categories: interleaf leakage and tongue-and-groove effect. When adjacent leaves travel in synchrony across the field, the transmis- FIGURE T.42 An illustration of the type of image acquired on a film for sion through the narrow gap between the adjacent leaves is larger testing MLC tongue and groove leakage. The dashed line indicates the than the transmission through the middle of the leaf (interleaf readout line for the MLC field. Topogram 962 Total body protein to be recorded on the film. The maximum optical density for each Whole Body Counting is the measurement of induced or natu- field is recorded (for the MLC field the transmission is measured rally occurring radiation in the body. It is performed in a shielded along a line approximately through the middle of the leaves – see room or chamber with low background radiation. The background the Figure T.42) and when the optical density of this field is read radiation is subtracted from the total radiation measured. A whole out the value is then divided by

25. The procedure is repeated for body counter (WBC) is used to measure the total body potassium the opposite bank of MLC leaves. in human subjects, and radioactive contamination in accident Another means of reducing this leakage is to ensure that the conditions. back-up jaws (secondary collimators) are positioned as close as Potassium-40 has a half life of 1.3 × 109 years, and emits a possible to, but not within, the field edge. This will provide a fur- 1.46 MeV gamma ray on decay. 40K has an abundance of 0.0117% ther approximate ten-fold reduction in dose; therefore the shielded in natural potassium. The average potassium content of an adult areas should receive a dose of around 0.5% of the dose to the open male is ∼140 g, or about 15 mg of 40K. This translates to an emis- field area. sion rate of 30,000 photons/min. In adult females, the level is Abbreviation: MLC = Multileaf collimator. about 20,000 photons/min. Related Articles: Leakage radiation, Multileaf collimator A 1.46 MeV decay gamma ray is readily detected in supine Further Readings: AAPM (American Association of geometry by an array of NaI detectors. This measurement does Physicists in Medicine). July 2001. Basic applications of multileaf not give the body any additional radiation dose, as the activity collimators, Report of Task Group No. 50, AAPM Report No. 72, is already present in all cells in the FFM. A low background, Radiation Therapy Committee, Madison, WI; Memorial Sloan- shielded room is constructed with old steel, forged prior to the Kettering Cancer Center. 2003. A Practical Guide to Intensity- A-bomb testing program. The precision and accuracy of this Modulated Radiation Therapy, Department of Medical Physics, method, expressed as coefficients of variation, are 1.5% and 4.5% Medical Physics Publishing, Madison, WI. respectively. FFM is calculated from TBK on the basis that the potassium content of FFM is 2.26 g/kg in females and 2.52 g/kg Topogram in males. (Diagnostic Radiology) Topogram is a vendor name (Siemens) for Abbreviations: FFM = Fat free mass, TBK = Total body the scan projection radiograph used in computed tomography. potassium and WBC = Whole body counter. Related Article: Scan projection radiograph Related Articles: In vivo body composition, Total body pro- tein, Total body nitrogen, Total body water, Total body fat Total body irradiation Total-body PET (Radiotherapy) Total body irradiation (TBI), as its name implies, (Nuclear Medicine) Most of the currently available clinical is a radiotherapy technique that involves irradiation of the whole PET scanners typically have an axial coverage of 15 to 30 cm. body. It is often used prior to bone marrow or blood stem cell However, in order to study dynamic processes at high tempo- transplantation and its purpose is to suppress the recipient’s ral resolution occurring in the different anatomical regions of a immune system preventing rejection of the transplanted bone patient, the axial field of view needs to be greatly increased to marrow or blood stem cells. Doses used may be of the order cover the total body (100–200 cm). This increase in the field of T of 12 Gy. Treatments are often fractionated but may be single view requires many more detector elements and the associated fraction. electronics, greatly increasing the cost and technical complexity Further Readings: Gore, E. M., C. A. Lawton, R. C. Ash of the scanner. A team of scientists has worked with a consor- and R. J. Lipchik. 1996. Pulmonary function changes in long- tium to develop such a total-body PET scanner with an axial field term survivors of bone marrow transplantation. Int. J. Radiat. of view of 194 cm. This scanner offers a vastly increased effec- Oncol. Biol. Phys. 36(1):67–75; Walker, J. R. 1998. Citing serials: tive count rate (up to a factor of 40) for total-body applications Online serial publications and citation systems. Serials-Librarian compared to conventional scanners, which in turn can be used to 33(3/4):343–356. enhance image quality, reduce san time, reduce injected activity (reducing patient radiation dose) or a combination of these factors. Total body potassium The reference below describes the first human imaging studies (Nuclear Medicine) The human body comprises distinct and with this scanner. measurable body compartments. The status and rate of change Related Articles: Molecular Imaging, Positron emission of these compartments reflect the health of a person and the tomography (PET) response of treatment for a specific disease. While measure- Further Reading: Badawi, R. D., H. Shi, P. Hu, S. Chen, T. ment of body weight is a basic and useful parameter, it can Xu, P. M. Price, Y. Ding, B. A. Spencer, L. Nardo, W. Liu, J. Bao, be a misleading measure of disease status and response to T. Jones, H. Li and S. R. Cherry. 2019. First human imaging stud- treatment, which may increase oedema and fat while depleting ies with the EXPLORER total-body PET scanner. J. Nucl. Med. protein. 60(3):299–303. doi:0.2967/jnumed.119.226498. Epub 2019 Feb 7. Total body potassium (TBK) is one such compartment that provides information on the fat free mass (FFM), as potassium Total body protein is not found in adipose tissue and the fat-free tissues of the body (Radiotherapy) contain a constant proportion of potassium. Background: The body comprises distinct and measurable TBK is associated with the metabolising, oxygen-consuming body compartments. The status and rate of change of these com- portion of the body, so a decline in TBK is usually interpreted as partments reflect the health of a person and the response of treat- a loss of muscle mass due to a catabolic condition. However, TBK ment for a specific disease. Whereas measurement of body weight is not a gold standard for the measurement of fat free mass in sick (M) is a basic and useful parameter, it can be a misleading mea- subjects, as changes in TBK can reflect chemical changes in the sure of response to treatment, which may increase oedema and fat body and blood. while depleting protein. Total body water 963 Total skin irradiation An important compartment is the total body protein (TBP), Total brightness gain is one of the main parameters of II. It is which is a measure of muscle and visceral mass. It is determined defined as directly by measurement of the total body nitrogen (TBN): (Output light photons) TBP = 6.25*TBN Totalbrightnessgain = (Input x-ray photons) TBN is regarded as the superior measure of protein status in dis- Usually this figure is between 1000 and 6000. eased subjects. Another parameter of II is the minification gain (the ratio Methods: In vivo methods are used to obtain values of the between the input and output screens – area or diameter): body compartments. These might be done before and after ther- apy, to determine the effect of therapy. The measurement of nor- (Area of input screen) Minificationgain(Gm) = mal values is required so as to compare patient values, according (Area of output screen) to defined index. The nitrogen index NI = pTBN/nTBN where p designates the patient and n the normal values for healthy 2 = (Dinp Dout ) subjects. The importance of such indices relates to the impact on dis- This figure will depend on the diameters, for example 12 in image ease prognosis. intensifier with 1 in output screen diameter will have (12/1)2 = 144 In vivo interrogation techniques are used. These can give a minification gain. measure of the whole compartment, or in some cases the spatial Another parameter of an image intensifier is the flux gain, also distribution of the compartment. known as electronic gain (the ratio between the internal light pho- Nitrogen is measured in a body protein monitor (BPM) using tons in the image intensifier): a Cf252 or PuBe neutron source. The patient is moved over a col- limated neutron beam. The fast neutrons emitted by these radio- (Output screen light photons) active sources are moderated in tissue and captured by nitrogen Fluxgain(Gf) = (Input light photons to the photocathode) and hydrogen nuclei in the patient. The 11.4 MeV ground state gamma ray can be measured by NaI detectors, being of higher energy than all background radiations. The hydrogen gamma ray Usually this figure is between 30 and 60, most often around 50. is very intense and easily detected. The ratio of nitrogen to hydro- The product of Gm and Gf is known as total gain (G): gen yields eliminates the dependence of gamma ray attenuation on body habits. G = Gm ´ Gf Abbreviations: BPM = Body protein monitor, NI = Nitrogen (From the figures above G = 144 ´ 50 = 7200) index, TBN = Total body nitrogen and TBP = Total body protein. Related Articles: In vivo body composition, Total body nitro- gen, Total body potassium, Total body water, Total body fat A parameter which links the radiation dose used to produce the image and the output light is the conversion factor: Total body water (Output phosphor light) T (Radiotherapy) Conversionfactor = (Input screendose rate) Background: The body comprises distinct and measurable body compartments. The status and rate of change of these com- Usually this figure is between 100–1000 (cd/m−2 partments reflect the health of a person and the response of treat- /μGy/s). ment for a specific disease. Whereas measurement of body weight Further Reading: Hendee, W. R. and E. R. Ritenour. 2002. (M) is a basic and useful parameter, it can be a misleading mea- Medical Imaging Physics, Wiley-Liss, New York. sure of response to treatment, which may increase oedema and fat while depleting protein. Total scatter factor The mass of a subject is the sum of the defined compartments (Radiotherapy) The total scatter factor is the product of the col- in the four body compartment model: limator scatter factor (CF), and the scatter factor (SF). See related articles for more information. M = TBP + TBF + TBW + TBCa It is also known as the relative dose factor (RDF). It can be calculated directly as the ratio of the dose in a phantom, field size Methods: Analysis of blood and urine after ingestion of isoto- A, to the dose in a phantom for a 10 × 10 cm2 field. pically labelled molecules is used as the gold standard. Heavy Related Articles: Scatter factor, Collimator scatter factor water (D2O) is ingested and after 12 h nil by mouth, blood or urine samples are taken and analysed for deuterium by Fourier Total skin irradiation transform infrared analysis. This is a low-cost and accurate dilu- (Radiotherapy) Total skin irradiation (TSI) is an electron-based tion technique to determine total body water. treatment technique. It has been used since the 1950s and is Abbreviations: TBCa = Total body calcium, TBF = Total used to treat diseases including: mycosis fungoides, which is a body fat, TBP = Total body protein and TBW = Total body water. common chronic form of cutaneous T-cell lymphoma; leukemia Related Articles: In vivo body composition, Total body pro- cutis; Kaposi’s sarcoma and scleromyxoedema. This is a large tein, Total body nitrogen, Total body potassium, Total body fat SSD irradiation technique and often used electron energies of 3–10 MeV. Total brightness gain Abbreviations: SSD = Source to skin distance and TSI = Total (Diagnostic Radiology) There are a number of parameters used to skin irradiation. assess an image intensifier (II). Related Article: Electron therapy TR (repetition time) 964 Tracer delivery TR (repetition time) labelled compound. On the other hand these radionuclides might (Magnetic Resonance) See Repetition time (TR) have undesired physical characteristics or an expensive produc- tion cost, which limits their usefulness. Trace (of the diffusion tensor) When using analogue tracers it is possible to tailor the com- (Magnetic Resonance) The trace of the diffusion tensor (described pound so that the tracer only participates in chosen parts of the by a 3 × 3 square matrix) is the sum of its diagonal elements. biochemical sequence. This is a desired feature when trying to Equivalently, the trace can be defined as the sum of the eigenval- decrease the number of variables modelled in the activity time ues of the diffusion tensor. The trace is thus invariant with respect curve. One example of an analogue tracer is FDG (18F-2-fluoro-2- to a change of basis, that is the directions in which the apparent deoxy-d-glucose) which measures glucose metabolism. diffusion coefficients (ADC) are measured. Related Articles: Isotope effect, Analogue tracers The trace (of the diffusion tensor) can

be estimated as the sum Further Reading: Cherry, S. R., J. A. Sorenson and M. E. of the ADCs in three orthogonal directions. Moreover, the mean Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, diffusivity (MD) is a third of the trace of the diffusion, since MD Philadelphia, PA, pp. 378–380. is given by the average of the eigenvectors of the diffusion tensor. Related Articles: Apparent diffusion coefficients (ADC), Tracer delivery Eigenvalues, Mean diffusivity, Diffusion tensor (Nuclear Medicine) Tracer delivery refers to the process in which a tracer is extracted from a tracer transport system, for example Tracer the delivery of oxygen via the blood passing through the capillar- (Nuclear Medicine) Tracer is a common term to describe a sub- ies. A number of factors determine the magnitude of the extracted stance or compound that when injected into the body follows (or fraction, namely the blood flow F and the extraction and clear- ‘traces’) a certain chain of physiological or biochemical process. ance of tracer from the blood. In nuclear medicine such tracers are often labelled with radioiso- Blood flow can be measure as volume per unit time or as vol- topes and are referred to as radiotracers or radiopharmaceuti- ume per unit time per mass unit. The latter is referred to as perfu- cals. The temporal distribution of the radiotracer can be measured sion or blood flow per unit tissue mass. in a dynamic study. The extraction is defined as net and unidirectional extraction. There are three different types of tracers: (1) naturally occur- The net extraction depends on the difference in steady state tracer ring substances that are suitable for labelling; (2) substances that concentration in the blood entering the compartment (arterial) are analogues of natural substances, that is mimic the behaviour CA and the blood leaving the compartment (venous) CV. The net of naturally occurring substances and (3) compounds that par- extraction En is defined by ticipate and interact with different physiological or biochemical processes in the body. (C An ideal tracer should fulfil the following properties: = A - CV ) En (T.2) CA 1. Tracer behaviour should be identical or similar to the If there is no metabolism of the tracer, all of the tracer will be T natural substance. returned to the blood and the net extraction will equal zero. This 2. The mass of the tracer should be small relative to could be the case when using inert diffusible blood flow tracers the endogenous compound being traced. Typically when a steady state is reached. the tracer mass should be <1% of the endogenous The unidirectional extraction on the other hand refers only to compound. the tracer uptake to tissue from the blood and does not account for 3. A high specific activity is required to allow imaging the back-transfer of the tracer. and blood or plasma activity assays. The Fick principle is used to correlate the processes of blood 4. The consequence of the isotope effect (see Related flow, flux and extraction, and it states that, under steady state Article) should be negligible or quantitatively conditions, the extraction of tracer from the blood is equal to the predictable. difference in tracer concentration in blood input (arterial blood before the organ capillaries) and output (venous blood after the In some cases when the tracer is labelled with an element that organ capillaries). The uptake rate U (mg/min) is determined by is not originally present in the compound, the tracer must still the blood flow F (mL/min), the arterial tracer concentration CA behave in a way that is similar to the natural substance. 99mTc, and the venous tracer concentration CV. The uptake rate is 123I and 18F are examples of radioisotopes which are not normally present in biological systems but are commonly used when label- U = F ´ (CA - CV ) (T.3) ling compounds. Such radiotracers can be used to monitor simple parameters that are related to distribution, transport and excre- The Fick principle can only be applied on a steady state system. tion, but since they are not normally present in human biochem- The amount of tracer leaving the blood depends on the extrac- istry (iodine excepted, when studying thyroid metabolism), they tion through the capillary walls or membrane. The amount of are unsuited for tracing biochemical reactions in the body. These tracer extracted depends on the capillary surface area S, the cap- biochemical systems are more specific than the transport system. illary permeability for the tracer P, and the blood flow F. The When a foreign element is introduced into a compound, its bio- relationship between these quantities can be described by a simple chemical properties are likely to change. Such a radiotracer is not model proposed by Renkin and Crone. The model is based on a good representation of the biochemical processes it is required four assumptions; (1) an idealised capillary (i.e. rigid tube), (2) to study. Radionuclides which represent elements that normally tracer concentration is constant throughout the capillary, (3) the take part in biological processes, such as 11C, 13N and 15O, have extraction of tracer from the blood depends on the blood tracer the advantage that they generally do not alter the behaviour of the concentration and (4) there is no back-transfer of the tracer, that Tracer flux between compartments 965 Tracer transport is unidirectional blood flow. The extraction fraction for such a In most situations there is more than one potential pathway for a system is determined by tracer out from the compartment, each associated with an indi- vidual rate constant ki. The half time of the turnover in such a E = 1 - e-(P´S / F ) u (T.4) situation is the inverse of the sum of the rate constant The Renkin–Crone model is not completely realistic but it pro- 0.693 t1/2 = ( (T.7) vides instructive illustrations about the relationship between the k1 + k2 + + km ) extraction fraction and the blood flow, permeability of the capil- lary and the capillary surface area. The ratio (P × S/F) is called where m is the number of possible tracer pathways out of the the extraction coefficient. The permeability-surface product compartment. (P × S) can be considered as a representation of the tracer flow The most common compartment models are based upon the from the blood to the tissue through the capillaries, while F is assumption that the dynamics of the system are based upon first- considered the actual blood flow. Given by (P × S/F) is that the order kinetics, that is linear behaviour of the tracer kinetics. For extraction fraction can be increased by either reducing the blood example, when doubling the concentration the flux is also dou- flow through the capillaries (F) or by increasing the flow through bled. These models also adequately model compartments with the capillary walls (P × S). non-linear tracer kinetics. But at the same time the amount of tracer extracted to the Related Articles: Tracers, Analogue tracers, Distribution vol- tissue also depends on the product of the extraction fraction ume, Partition coefficient, Steady state condition in tracer kinetic E and the blood flow F. This product is also referred to as modelling clearance. For example, during exercise the heart beats faster, Further Reading: Cherry, S. R., J. A. Sorenson and M. E. that is increasing the blood flow, to provide the muscles with Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, more oxygen and nutrients. The extraction fraction decreases Philadelphia, PA, pp. 381–382. due to the increase in blood flow but at the same time more nutrients and oxygen reach the capillaries which allows for a Tracer kinetic modelling greater transport. This increase in capillary transport often (Nuclear Medicine) Tracer kinetic modelling uses mathemati- more than offsets the decrease in the extraction fraction. The cal models that describe the temporal behaviour and distribution tracer clearance from blood to tissue is used in tracer kinetic of radiopharmaceuticals. The modelled behaviour of a tracer is modelling. used to examine biological processes and determine radiation Related Articles: Tracers, Analogue tracers, Distribution vol- doses to specific organs. The temporal and spatial distribution ume, Partition coefficient of an injected radiotracer in any specific organ depends on the Further Reading: Cherry, S. R., J. A. Sorenson and M. E. tracer kinetic characteristics; tracer delivery, binding to cell sur- Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, face receptors, diffusion and transport through cell membranes, Philadelphia, PA, pp. 385–387. metabolism, clearance from cells, wash out from the tissue and excretion from the body. Tracer flux between compartments Tracer concentration in an organ is modelled over time by a (Nuclear Medicine) The amount of substance that crosses a time activity curve. Dynamic studies can provide information T boundary per unit time is referred to as flux. The boundary can be about the biological fate of the tracer after injection. The con- a membrane or a cross section of a blood vessel. Flux also refers clusions drawn from these studies can be used in mathematical to the transport of tracer between two compartments. The unit for models with a number of parameters explaining the time activity tracer flux is flux per unit volume or mass of tissue (e.g. mol/min/ curves. Some of these parameters can be directly related to bio- mL or mg/min/g). logical or physiological processes, for example tissue perfusion. Rate Constant: The substance flux between two compart- Related Article: Time activity curve ments is described by a number of rate constants ki. In a simple Further Reading: Cherry, S. R., J. A. Sorenson and M. E. first-order process the flux is the product of the rate constant Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, and the amount (e.g. concentration or mass) of a substance in a Philadelphia, PA, pp. 377–378. compartment: Tracer transport Flux = k ´ Amount of substance incompartment (T.5) (Nuclear Medicine) Tracer transport refers to the transport of tracer across barriers in a biological system. The unit of k is (time)−1. Depending on whether ‘amount’ refers There are three different ways of transporting a tracer across to mass or concentration the unit is mass/time (mg/mL) or mass/ a membrane or capillary wall, namely active transport and two time per unit of compartment volume (mg/min/mL) respectively. forms of passive transport: passive diffusion and carrier-mediated If the rate constant is 0.1 min−1 it would mean that 10% of the diffusion. substance is transported out or in per minute. The inverse of the Active transport involves a process that requires energy. rate constant is referred to as the turnover time or mean transit Substances in an active transport can move against concentration time τ(k = 0.1 min−1 ⇒ τ = 10 min). The turnover is described by gradients. The energy source for an active transport is often ade- an exponential function analogous to the radioactive decay factor, nosine triphosphate (ATP). The sodium-potassium pump and the and the time it takes for the original amount of tracer to decrease renal tubular reabsorption of glucose are two examples of active by 50% (assuming no back transfer), the halftime of turnover, is transport. given by Passive transport on the other hand does not require energy and will only move in the same direction as the concentration 0.693 t gradient. Passive diffusion through a membrane or a capillary is 1/2 = (T.6) k described by a diffusion constant D (cm2/min). The permeability Track structure 966 Tractography P (cm/min) of the membrane is related to the diffusion constant Related Article: Linear energy transfer (LET) according to D Tracking system P = (General) A tracking system is a device that determines and x tracks the position of a patient, organ or device within the patient where x is thickness of the membrane. A large D represents a rapid environment. clearance of tracer from the blood via passive diffusion mecha- This may be used for a variety of purposes, and forms the basis nisms. A large number of processes and substances depend on pas- of image-guided therapies and for automatic detection and correc- sive diffusion, for example water, oxygen, ammonia and carbon tion of patient movement in diagnostic imaging and therapy. dioxide. A wide range of tracking techniques are available, some Transport using carrier-mediated diffusion involves a carrier relying only on the patient’s

external features, others on pas- molecule C and a substrate molecule S, for example when trans- sive external markers, whilst more sophisticated devices may porting glucose and amino acid over the blood brain barrier. The rely on active external markers or even passive or active internal substrate, that is the tracer, is transported to the membrane via the markers. vascular system, and at the membrane it forms a carrier-substrate The common process is to detect known points or markers complex SC that moves across the barrier before it disassociates and determine their positions relative to a datum in the room, into its original compounds S and C again. and repeat the process often enough to accurately ‘track’ any The substrate transport rate is proportional to the amount of movement. substrate, but since there are only a limited number of carrier mol- Marker tracking systems include ecules available the transport can be saturated. A common carrier is a protein enzyme which is neither created nor destroyed in the • Passive – IR sensitive multi-camera detection of reflec- process but it works as a catalyst, that is speeding up the process. tive markers Related Articles: Analogue tracer, Distribution volume, • Active – fixed multi-sensor detection of IR light emit- Partition coefficient, Tracer flux between compartments, Tracer ting diode markers kinetic modelling • Fixed magnetic sensors detecting signals from Further Reading: Cherry, S. R., J. A. Sorenson and M. E. powered marker coils Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, • Fixed microphones detecting sounds from spark Philadelphia, PA, pp. 387–388. gap markers Track structure Surface tracking systems rely on computer image processing of (Radiotherapy) Track structure refers the pattern of energy one or more camera images of the patient by deposition around the path of a charged particle as it traverses a medium. This structure depends on the mass, velocity and charge • Projecting a complex pattern of light onto the patient’s of the particle. surface and analysing the observed images and calcu- T The track structure along the path of a charged particle can be lating the 3D surface that best fits the image observed split into two regions, the infra-track and ultra-track (as shown by one or more cameras in Figure T.43). The infra-track region encompasses the region • Comparing a 2D camera view image against a previ- where the electric field of the charged particle is sufficient to ously determined 3D dataset of the patient’s shape (e.g. directly cause ionisations. The ultra-track region encompasses from reconstructed MRI data) the infra-track and constitutes the region in which ionisations are caused by secondary electrons from the infra-track ionisations. Inherent tracker systems are also being developed which use the The size of the ultra-track depends on the maximum energy of the 3D medical imaging or therapy device itself to image the patient secondary electrons produced by the charged particle. and track the organ of interest or markers. In these cases, sophis- Linear energy transfer (LET) is commonly used to character- ticated fast image processing and segmentation algorithms are ise the track structure of a particle to allow relation to biological necessary to identify the organ boundary or marker positions and effectiveness. However, different particles of the same LET do not track movement. have the same track structure. Heavier particles with more charge and greater velocity typically create secondary particles with a Tractography greater range and thus deposit energy further away from the path (Magnetic Resonance) Tractography is a method used to con- of the particle. This lower ionisation density can cause a lower struct and visualise neuronal tracts or other fibre bundle. It is biological effect for the same LET. based on the main direction of the diffusion tensor derived from FIGURE T.43 Showing the infratrack and ultratrack regions surrounding a charged particles path. Training 967 Transducer DWI studies of the water self-diffusion in three dimensions. The from several countries, taking elements from most established method relies on the assumption that water diffusion is faster schemes. These are used in many countries. At international level along than perpendicular to the fibre bundles. By statistical analy- the IOMP runs a scheme for accrediting Master-level educational sis of the principal diffusional direction in adjacent image vox- programmes suitable for medical physics training, while IMPCB els 2D trajectories in 3D space are constructed. The analysis is a deals with international certification. seed-based tracking, where the fractional anisotropy value is used Related Articles: IAEA Guides for Medical Physics, IOMP, above a threshold for determining for how long the paths should EMERALD, EMIT, IMPCB, be followed, and the angle between adjacent principal eigenvec- Further Readings: International Atomic Energy Agency. tors is used to determine whether the path is proper or not. 2009. Clinical Training of Medical Physicists Specializing in The technique can be used for characterising nerve fibre dis- Radiation Oncology, Training Course Series 37, IAEA, Vienna, turbances diseases like tumours or neurodegenerative diseases Austria, www -p ub .ia ea .or g /boo ks /IA EABoo ks /82 22 /Cl inica l such as multiple sclerosis (MS), Parkinsonian disorders, or vari- -Tra ining -of -M edica l -Phy sicis ts -Sp ecial izin g -in -R adiat ion -O ous types of dementia. ncolo gy; International Atomic Energy Agency. 2010. Clinical In Figure T.44 a tractography projection is shown, indicating Training of Medical Physicists Specializing in Diagnostic the principal diffusion direction which is taken to correspond to Radiology, Training Course Series 47, IAEA, Vienna, Austria, the orientation of nerve fibres. www -p ub .ia ea .or g /boo ks /IA EABoo ks /85 74 /Cl inica l -Tra ining -of -M edica l -Phy sicis ts -Sp ecial izing -in -D iagno stic- Radio logy; Training International Atomic Energy Agency. 2011. Clinical Training of (General) Training is the activity leading to acquiring certain Medical Physicists Specializing in Nuclear Medicine, Training competencies (skills) necessary to practice a profession. While Course Series 50, IAEA, Vienna, Austria, www -p ub .ia ea .or g education equips the learner with the necessary academic knowl- /boo ks /IA EABoo ks /86 56 /Cl inica l -Tra ining -of -M edica l -Phy edge (most often through a university course), training equips the sicis ts -Sp ecial iz ing -in -N uclea r -Med icine ; International Atomic learner with the vocational knowledge (most often through a prac- Energy Agency. 2013. Postgraduate Medical Physics Academic tical course). Programmes, Training Course Series 56, IAEA, Vienna, Austria, Medical physics training follows specific rules and require- www -p ub .ia ea .or g /boo ks /IA EABoo ks /10 591 /P ostgr aduat e -Med ments, which can build certain listed competencies. This training ical- Physi cs -Ac ademi c -Pro gramm es. is normally combined with MSc-level education (through a paral- Hyperlinks: www .ipem .ac .uk; www .emerald2 .eu; www .aapm lel university course). Various countries have different require- .org ments for training (also known as residency). In many countries a post-education training course (which normally takes several Transducer years and is completed by examination) is the standard way for a (Ultrasound) An ultrasonic transducer acts as a transmitter, person to reach state registration/certification as suitable to per- receiver or, in pulse–echo systems, as both. It converts electrical form independently his/her professional tasks. energy to acoustical and acoustical energy to electrical. Large professional bodies have their own training require- A simple single element transducer is shown in Figure T.45 ments and schemes. For example, the UK Institute of Physics and with a circular piezoelectric disc, connected with electrodes on Engineering in Medicine (IPEM) has a training scheme which each flat end. A damping material can be mounted on the rear T is regularly updated. Elements of this scheme are used in other of the disc and a matching layer on the front side. The disc will countries. Similarly, elements of the residency programme (train- vibrate (produce sound) if an electrical pulse is applied between ing scheme) of the American Association of Medical Physics the wires and conversely an electrical signal will occur if a sound (AAPM) are used as a guide in some countries. The training wave hits the disc and makes it vibrate, Figure T.46. materials EMERALD and EMIT list specific training tasks, PZT, lead zirconate titanate, is the most commonly used trans- which will help the trainee to acquire specific competencies and ducer material. This material is a synthetic ceramic which can be vocational skills. These can be seen in the training tables of these produced in various versions for different applications requiring materials (available in each demo of the materials). The training particular properties. It consists of small crystals with separated guides of the IAEA have been developed by leading specialists Ultrasound generation Diagrammatic representation of a simple transducer Piezoelectric Damping material material Transducer element (e.g. PZT lead zirconate titanate) Matching layer Piezoelectric effect (discovered by Pierre and Jacques Curie in the 1880s) If a force is applied to the face of a piezoelectric material, then a charge is produced. ++++++ (In naturally occuring materials e.g. quartz, touramaline) –––––– FIGURE T.45 Principle design of a single element ultrasound trans- FIGURE T.44 Tractography. ducer. (Courtesy of EMIT project, www .emerald2 .eu) Transducer, linear array 968 Transformer Ultrasound generation Piezoelectric effect-II – + If a voltage is applied to the piezoelectric material then the material changes shape If an alternating voltage is applied then the transducer vibrates + – As well as axial displacement there is slight lateral displacement of the transducer when a charge is applied ickness chosen appropriate for the ultrasound frequency FIGURE T.46 Piezoelectric effect. (Courtesy of EMIT project, www .emerald2 .eu) Transducer elements Transducer elements-focusing Pulse excitation Displacement Unfocused Long pulse length Undamped transducer element poor axial resolution Pulse excitation Focused Lens T Displacement Curved transducer element Backing Short pulse length Focused Zone of best lateral resolution Damped transducer element good axial resolution FIGURE T.48 Focussing with acoustic lens or curved transducer ele- FIGURE T.47 The role of backing material to produce short ultrasound ment. (Courtesy of EMIT project, www .emerald2 .eu) pulses. (Courtesy of EMIT project, www .emerald2 .eu) Transducer, linear array positively and negatively loaded parts. When the material is com- (Ultrasound) See Linear array transducer pressed, this neutral load distribution is disturbed and a voltage across the flat ends occurs. Transformation ratio The transducer disc resonates best when applying a signal with (Diagnostic Radiology) Transformation ratio is the ratio of the a frequency corresponding to a wavelength of n × d/2, with d as number of windings (turns) in the primary coil to the number of the thickness of the disc, which means that it is more sensitive and windings (turns) in the secondary coil of one transformer. has a higher Q-value at these frequencies. This is due to multiple See Transformer reflections of the acoustical wave within the disc. For diagnostic applications, short acoustic pulses are needed Transformer for high resolution imaging. A damping backing material, with (Diagnostic Radiology) A transformer is used to transform input an acoustic impedance close to the acoustic impedance of the AC voltage into different (higher or lower) output voltage. A typi- disc material, will reduce the Q-value as well as the sensitivity, cal transformer for mono-phase electricity (for example from the Figure T.47. The most efficient way of reducing Q-value and keep- mains) will have ferromagnetic core with input winding (primary ing the sensitivity is to use matching layer at the front. coil) wrapped around it. This coil creates electromagnetic field If mechanical focusing is desired, this can be achieved using in the ferromagnetic core. This field induces voltage into the out- either a curved transducer disc or an acoustic lens, Figure T.48. put winding (secondary coil), also wrapped around the core. Both Related Articles: Backing material, Matching layer, PZT, coils are usually copper wires, electrically insulated both from Lens, Linear array, cMUT the core and between each other. Transformer core 969 Transient charged particle equilibrium The effectiveness of the transformer will depend on various Transformer core factors, but mainly in the magnetic permeability of the mate- (Diagnostic Radiology) The core of a transformer is made of rial of the transformer core. For example, ferrite materials have ferromagnetic material with specific magnetic permeability much higher magnetic permeability than iron and thus will μ (e.g. μ for

ferrite materials is a thousand times higher than μ produce electromagnetic induction into the secondary coil with for iron). fewer ‘losses’. For better effectiveness the loss of power due to The core can be of different shapes or sizes. For transformers Foucault’s current should be limited for by using a core of isolated with identical materials of the core, the larger is the required elec- sheets of ferrite material trical power, the larger is the core of the transformer. The most important parameter of one transformer is the trans- There is a known transformer relation between the transformer former ratio – the ratio between the input and output voltage. This core and the frequency of the AC electricity used: ratio is proportional to the number of windings (turns) in the pri- mary and secondary coils: U ~ An f Vp /Vs = N p /Ns , that isVs = Vp (Ns /N p ) where here(Ns /N p ) is the windings ratio A is the cross section of the transformer core (mm2) n is the transformer ratio (based on the number of secondary/ The transformer is Step-up if the windings of the secondary primary windings) coil are more than those of the primary (e.g. 50,000 turns in the f is the frequency of the secondary voltage U. secondary coil and 100 windings in the primary coil, producing windings ratio of 500). This ratio is typical for a high voltage This relation is in the base of the contemporary high frequency x-ray transformer and will produce 110 kV from a primary volt- x-ray generators. These use transformers with ferrite core, allow- age of 220 V (220 × 500 = 110,000). ing high frequencies to be used. Due to this reason the size of the The transformer is Step-down if the windings of the second- transformer core is approximately 25% of the size of similar high ary coil are less than those of the primary (e.g. 10 turns in the voltage step-up transformer with iron core (used in the classical secondary coil and 100 windings in the primary coil, producing x-ray generators). For more information see the article on High windings ratio of 1/10). This ratio is typical for the filament trans- frequency x-ray generators. former of an x-ray transformer and will produce 22 V from a pri- mary voltage of 220 V (220 × 0.1 = 22). Transformer oil See a diagram with both types of transformers in the article (Diagnostic Radiology) Special insulation oil in which high volt- High voltage generator. age transformers are usually immersed. The specific insulation There are various types of transformers according to the of the oil is normally more than 220 kV/cm. The same oil is used shape of the ferromagnetic core. Some more common types are inside the x-ray tube housing – both for insulation and cooling of as follows: the x-ray tube. • Air core transformer – This transformer has no iron T core. It consists of simply two insulated primary and Transformer winding secondary coils placed closely one to the other. (Diagnostic Radiology) See article on Transformer • Open core transformer – In this transformer the pri- mary and secondary coils are each separately wrapped Transient charged particle equilibrium around their own ferromagnetic cores. Again both (Radiation Protection) When a photon beam impinges on a coils + cores are placed close to each other. Some auto- medium, the transfer of energy from the beam to the electrons transformers are open-core type transformers (both does not lead to the absorption of energy exactly at the same loca- insulated coils are wrapped around a single iron core). tion where the photon interaction takes place. This is due to the • Closed core transformer (most often used) – In this finite range of the secondary electrons released. In an ideal situ- transformer the primary and secondary coils are ation inside a medium, losses of energy due to electrons which wrapped around an iron core with closed geometry leave the volume of interest are compensated by energy associ- (either a ring or square shape). ated with incoming charged particles from surrounding parts • Shell-type transformer – The iron core of this trans- of the medium. This is known as a charged particle equilibrium former has three columns (in an E shape), which form condition. two rectangular holes. The primary and secondary coils In a more realistic situation, that equilibrium is not gener- are wrapped around the central column. This way the ally achieved. At or near the entrance surface of the medium the core surrounds the coils. This design is used in some absorbed energy (absorbed dose) is smaller than the transferred power transformers. energy (kerma) because of the lack of equilibrium between the incoming and the exiting energy in the volume of interest. Transformers also vary according to the type of ferromagnetic At a certain depth both magnitudes become equal. After that material of the core – most often various types of iron core or fer- point where the maximum absorption is achieved, a transient rite core transformers. charged particle equilibrium condition occurs: attenuation of the Transformers also vary according to the phase of the AC beam reduces its intensity and absorbed energy (absorbed dose) current – most often single-phase transformers or three-phase becomes greater than energy transfer (kerma). Figure T.49 illus- transformers. trates those phenomena. Related Articles: Air core transformer, Open core trans- Related Articles: Charged particle equilibrium, Secondary former, Transformer core electrons, Absorbed dose, Kerma Transient equilibrium 970 Transmission coefficient Kerma Activity Maximum dose Absorbed dose Parent Daughter Time Transient equilibrium 1 Buildup region Transient charged particle equilibrium 0.8 0.6 Depth 0.4 Parent 0.2 Daughter FIGURE T.49 Transient charged particle equilibrium. 0 0 2 4 6 8 10 12 14 Number of daughter half lifes Transient equilibrium (Nuclear Medicine) Transient equilibrium refers to the activity FIGURE T.50 The graph illustrates the buildup phase to a transient equilibrium that occurs in a decay series when the half-life of the equilibrium. The dotted line and solid line represent the activity of the parent nucleus is approximately 10 times longer than the daughter parent and daughter nucleus respectively. A transient equilibrium occurs nucleus half-life. when the half-life of the parent nucleus is approximately ten times the This type of equilibrium occurs in the 99Mo-99mTc decay series. daughter half-life. In the case of a transient equilibrium the relationship between the number of parent and daughter atoms (N1 and N2 respectively) is described by the following equation: N 2 l = 1 N1 l2 - l1 where λ1 and λ2 are the decay constants of the parent and daugh- ter nucleus respectively. In a technetium generator 99Mo decays T to 99mTc which is extracted as technetium-pertechnetate. 99mTc is extracted when the 99mTc activity reaches its maximum at time point tmax: é1.44 ×T ×T ù T t p d æ p ö max = ê ê ( ln ë Tp - T ç ÷ d ) ú ûú è Td ø FIGURE T.51 Variable low-frequency pulse (10 to 500 Hz) is generated by the vibrator in the medium thus creating shear wave. (After Gennisson where Tp and Td are the half-lives of the parent and daughter et al., 2013.) nucleus respectively. tmax for 99mTc is 22.9 h (Figure T.50). Related Articles: Secular equilibrium, Bateman equation for secular equilibrium, Bateman equation for transient equilibrium estimated by correlating the diffused echoes recorded at a high framerate (1000 times per second) with an ultrasound transducer Transit time (5 MHz). (Magnetic Resonance) See Mean transit time (MTT) The FibroScan® that measures liver fibrosis and steatosis works on the principle of transient elastography. Transient elastography Further Reading: Sandrin, L., B. Fourquet, J. M. Hasquenoph, (Ultrasound) Transient elastography works by measuring the S. Yon, C. Fournier, F. Mal et al. 2003. Transient elastography: shear wave velocity. A transient elastography transducer gener- A new noninvasive method for assessment of hepatic fibrosis. ates a transient impulse on the medium. The system subsequently Ultrasound Med. Biol. 29(12):1705–1713. records the shear wave that propagates within the medium by using an ultrasound transducer. The surface of the transducer Transmission coefficient acts as a piston that vibrates and generates a low-frequency (Ultrasound) When a propagating ultrasound wave encounters a spherical compression wave as a spherical shear wave that trans- medium with different acoustic impedance (Z) part of it will be mits towards the surface of the medium (Sandrin et al., 2003) reflected and the other part will be transmitted. The definition of (Figure T.51). The shear wave propagation map is not an anatomi- the pressure transmission coefficient is (Figure T.52). cal image, rather it is the representation of the shear wave propa- Tp = pt/pi and can be expressed as Tp = 2Z2/(Z2 + Z1) for normal gation through the tissue as a function of depth and time. This is incident and as Tp = 2Z2 cos θi/(Z2 cos θi + Z1 cos θi) in the case of E/m Activity (a.u.) Transmission ionisation chamber 971 Transport index magnetisation in the patient in a prescribed manner. The time course and magnitude of flip angles applied is determined by the given sequence in use. The transmit coil is driven by an RF power amplifier. The output of the amplifier consists of RF pulses shaped to give the RF amplitude required to deliver a specific Incident Reflected flip angle over a specific bandwidth of resonant frequencies. The wave θ wave i θr transmit coil forms part of a tuned resonant circuit in order to minimise the driving power requirements of the coil. p p i r The transmit coil must produce uniform flip angles throughout Z the volume of interest. Reciprocity exists between transmit and 1 receive coils, in that a receive coil with good uniformity of sen- Z2 sitivity to signal throughout a volume will act as a transmit coil with an equivalent uniformity of flip angle throughout the same p volume. As such, volume coil designs are suitable as RF transmit t coils, whereas surface coil designs are not. θt Transmitted In many examinations in typical clinical imaging systems wave the body coil is used as the transmit coil with the body coil itself or other coils acting as the receiver(s). The bulk of coils used with clinical imaging systems are receive only. A coil that combines transmission and receive function is called a ‘trans- ceiver’ coil. Transmitter FIGURE T.52 Incident, reflected and transmitted pulse. The amplitudes (Ultrasound) An ultrasonic transducer acts most often both as are determined by the acoustic impedances of the two media. a transmitter and as a receiver. It converts electrical energy to acoustical and acoustical energy to electrical. However, in some ultrasound applications, separate transducers are used for trans- oblique incidence. The angles are related by Snell’s law. The cor- mission and reception. This is the case, for example for continu- responding equations expressing the intensity transmission coef- ous wave Doppler devices and ultrasound bone densitometry. ficient for plane waves are as follows: Related Articles: Transducer, CW doppler I Z 4Z Z T = t i = T 2 1 , 2 p Ti = 1 Transmutations of elements in radioactive decay Ii Z2 ( 2 Z2 + Z1 ) (Nuclear Medicine) The process of generating a new element via 4Z Z cos2q decay from an initial element. One way to achieve this is to irra- and T i i = 1 2 ( 2 diate a stable isotope with neutrons. Neutrons interact with the Z2cosqi + Z1cosqt ) nucleus increasing the mass number which yields a new radio- T which easily can be derived using the relationship I = p2/2Z (see active isotope. The radioactive isotope decays via alpha or beta Intensity). decay (decreases the atomic number) which yields a new element. Related Articles: Acoustic impedance, Intensity, Snell’s law, Related Articles: Mass number, Atomic number Reflection coefficient Transparency Transmission ionisation chamber (Diagnostic Radiology) See Opacity (Radiation Protection) The transmission ionisation chamber is used for verifying the configuration of the output beam of a linear accelerator in external beam radiotherapy, for example for inten- Transport index sity-modulated radiation therapy (IMRT). Transmission ionisa- (Radiation Protection) The transport index (TI) is a value attrib- tion chambers are also used in diagnostic radiology to measure uted to radioisotope packages in order to provide control over the dose-area

product of an x-ray beam to give a measure of the radiation exposure. The TI for packages, overpacks, freight con- total energy of the x-ray beam incident on the patient, and there- tainers, etc. shall be determined in the following way: fore to provide an indication of the patient dose. Usually the transmission ionisation chamber is a flat, multi- 1. The TI is the maximum radiation level in millisievert wire chamber which is fitted at the exit port/collimator of the lin- per hour (mSv/h) at distance 1 m from the external sur- ear accelerator or x-ray tube. face, multiplied by 100. For uranium and thorium ores A transmission ionisation chamber can also be used in conjunc- and their concentrates, the maximum radiation level at tion with other detectors in ionising particle identifier systems. 1 m from the external surface of the load might be taken Related Article: Ionisation chamber as: 0.4 mSv/h for ores or physical concentrates of ura- Further Reading: Knoll, G. F. 2000. Radiation Detection and nium and thorium; 0.3 mSv/h for chemical concentrates Measurement, 3rd edn., John Wiley & Sons, Inc., New York, pp. of thorium; 0.02 mSv/h for chemical concentrates of 396–398. uranium (except uranium hexafluoride). 2. For tanks, freight containers, etc., the aforementioned Transmit coil TI value shall be multiplied by appropriate factors (Magnetic Resonance) The transmit coil in MRI transmits depending on the dimension of the transport. Taking RF energy pulses. The purpose of the transmit coil is to flip into account the surface, in square meters, of the biggest Transrectal transducers 972 Transverse wave surface of the package, the multiplicative factors are: 1 pulse, longitudinal magnetisation is completely eliminated and for a surface of 1 m2; 2 for a surface between 1 and 5; 3 all of the magnetisation lies in the transverse plane. for a surface between 5 m2 and 20 m2; 10 for a surface Transverse magnetisation is composed of the individual mag- of more than 20 m2. netic moments of the coherent spins, and hence precesses about the static field direction at the Larmor frequency. It also decays The values of TI obtained earlier shall be always rounded up to due to spin–spin relaxation. This changing magnetisation induces the first decimal place. Values of 0.05 or less may be considered an electric current in a neighbouring receive coil according to as zero. Faraday’s law of induction, and it is this current that constitutes The transport index of overpacks, freight containers, and con- the NMR signal. veyance shall be the sum of the TIs of each package contained, or An NMR signal detected immediately after excitation is shall be determined by direct measurement of radiation level. In known as a free induction decay (FID) signal. More commonly, case of non-rigid overpacks the transport index shall be the sum however, signal acquisition is delayed using gradient echo and/ of the TIs of all packages. or spin echo techniques, both of which involve manipulation of transverse magnetisation to generate a signal later in time. The Transrectal transducers resulting echo signal is T2* or weighted, depending on the tech- (Ultrasound) Transrectal ultrasound is used for examining nique employed. the prostate. Imaging sections of the prostate should be ideally MRI data acquisition almost invariably requires repeated obtained in two planes for diagnostic: true transverse axial plane acquisition of a pulse sequence with excitation repeated at an and sagittal plane. For rectal ultrasound-guided biopsy, an end interval known as the repetition time (TR). Usually TR is long viewing sagittal section is needed and for perineal biopsy a sagit- enough that complete T2 decay of transverse magnetisation may tal plane view is best (Richards and Kelly, 1996). be assumed to have occurred before application of the next excita- Three types of transducers are used, depending on the tion pulse. However, in some instances, particularly fast gradient application, for transrectal examination: Single plane probes, echo sequences, this may not be the case, and it is then necessary with a linear array of elements; biplane probes with one lin- to consider the effect of excitation pulses on transverse magne- ear and one curved array set at a right angle to each other; tisation as well as longitudinal magnetisation, leading to much and multi-plane probes, with a single transducer orientated more complicated spin evolution and contrast properties. mechanically or as a phased array (McDicken, 1996; Richards Related Articles: Boltzmann distribution, Excitation, and Kelly, 1996). Flip angle, Free induction decay (FID), Gradient echo (GE), Most transrectal ultrasound transducers either have or can be Longitudinal magnetisation, Receive(r) coil, Repetition time fitted with a biopsy guide and needle. (TR), Spin echo, Spin–spin relaxation, T2-weighted, T2*. Further Readings: McDicken, W. N. 1996. Invasive ultra- sound transducers. In: Invasive Ultrasound, eds., W. R. Lees and Transversal plane E. A. Lyons, Martin Dunitz, London, UK, pp. 1–13; Richards, (General) See Anatomical body planes D. and I. Kelly. 1996. Transrectal ultrasound. In: Invasive Ultrasound, eds., W. R. Lees and E. A. Lyons, Martin Dunitz, Transverse wave T London, UK, pp. 15–16. (Ultrasound) When an ultrasound wave propagates in a medium, the particles within the medium will start oscillating. In gases, liq- Transversal magnetisation uids and soft tissue this oscillation is always in the same direction (Magnetic Resonance) Transversal magnetisation, otherwise as the ultrasound wave, giving rise to longitudinal wave propa- known as transverse magnetisation, refers to magnetisation lying gation. However, in solid materials both longitudinal (compres- in the transverse plane, defined as the plane perpendicular to the sional) and transverse (shear) wave propagation are possible. In a direction of the static magnetic field. It is changing transverse transverse wave the particles oscillate perpendicular to the wave magnetisation that leads to the generation of an NMR signal and, propagation direction, Figure T.53. This is due to the stronger hence, ultimately to the formation of MR images. bonds between atoms and molecules in solid materials compared When an object is placed in a static magnetic field, nuclei with to the much weaker bonds in liquids and gases. spin I = ½ occupy one of two energy levels, corresponding to ori- When a longitudinal wave crosses the boundary (at an angle) entation of the z-component of angular momentum parallel (lower between two solid materials, two different reflected waves and energy) or antiparallel (higher energy) to the static field direction. two different transmitted waves would occur (Figure T.54): one In this steady state condition, the greater population of the lower energy level (determined by the Boltzmann distribution) gener- ates a net longitudinal magnetisation along the direction of the field. Random precession of spins about the static field (or, in a Shear wave quantum mechanical model, Heisenberg’s uncertainty principle applied to angular momentum) ensures that there is no coherent magnetisation in the transverse plane. This situation is altered by the application of a radiofrequency (RF) magnetic field at the Larmor frequency of the spins. This results in promotion of spins from the lower to the higher energy level and brings these spins into phase coherence. Thus the lon- Displacement Direction of wave gitudinal magnetisation is decreased in size and a net transverse magnetisation is generated. The extent of these phenomena depends on the amplitude and duration of the RF field, commonly FIGURE T.53 Transverse (or shear) wave. (Courtesy of EMIT project, expressed as the flip angle or nutation angle. Following a 90° www .emerald2 .eu) Travelling wave 973 T reatment head P P iL rT PrL θ3 θ θ 1 1 Z1 Gross tumour volume Z2 Clinical target volume Planning target volume θ2 PtL Treated volume θ P 4 tT Irradiated volume FIGURE T.55 Definition of target volumes as in ICRU 50. FIGURE T.54 Incident (i), reflected (r) and transmitted (t) longitudi- nal (L) and transverse (T) waves at the boundary of two solid materials. (Courtesy of EMIT project, www .emerald2 .eu) Washington, DC; ICRU (International Commission on Radiation Units and Measurements). 1999. Prescribing, recording and reporting photon beam therapy (supplement to ICRU Report 50). longitudinal wave and one transverse wave. This is often called ICRU Report 62, Washington, DC. mode conversion. The transverse waves propagate at a slower speed of sound than the longitudinal, giving rise to the differ- Treatment head ent angles (by Snell’s law) of the transmitted and reflected waves. (Radiotherapy) The treatment head of a linear accelerator shapes This phenomenon is exploited in ultrasound-based non-destruc- and guides the electron beam exiting from the waveguide, to tive material testing. either form a clinically useful electron beam, or to bombard a Related Articles: Longitudinal wave, Surface wave, Lamb wave target to create a photon beam. The treatment head will contain (those in italic depend on the linac) Travelling wave (Radiotherapy) See Wave guide • Retractable targets and filters which are used in combi- nation to create the required energy and type of thera- Tray factor peutic beam (Radiotherapy) Tray factor is the ratio of the ionisation chamber • Collimators to achieve the required beam shape and signal with the tray in the beam to the signal without the tray for a penumbra T reference field 10 × 10 cm2 with ionisation chamber placed in the • Monitoring system to monitor beam dose, flatness and reference depth for current energy of photon beam. Some sources energy refer to the tray factor as tray attenuation factor. • Light field that matches the extent of the radiation field Related Articles: Block tray, Block design • Optical distance indicator to show the source-surface Further Reading: Podgorsak, E. B. 2005. Radiation Oncology distance Physics: A Handbook for Teachers and Students, International • Retractable wedges Atomic Energy Agency, Vienna, Austria. • Multileaf collimator Treated volume The target used to create a MV photon beam is normally made (Radiotherapy) The treated volume in radiotherapy is the volume from Tungsten, and is placed in the path of the electron beam. The enclosed by a specific isodose surface. The oncologist should have Bremstrahlung photons produced by the interactions in the target specified this isodose surface to be sufficient to achieve the pur- will be highly peaked along the central axis. Hence a flattening pose of treatment. In many cases, this will be 95% of the pre- conical filter is used to reduce the intensity in the centre. This scribed dose. The planning target volume (PTV) should always filter is energy specific. be fully enclosed by the treated volume. If this is not possible then The range of targets and filters are mounted on a rotating the plan needs re-evaluation. carousel or a sliding mechanism to enable automatic positioning The use of ‘treated volume’ as a planning volume was pro- within the beam. posed by the ICRU in Report 50 (with addendum 62). This report The treatment head also contains the primary pinhole colli- provides a common framework on prescribing, recording and mator, which defines a maximum circular field, and secondary reporting therapies, with the aim of improving the consistency adjustable rectangular collimators, which can be moved indepen- and inter-site comparability. It details the minimum set of data dently to create a rectangular field. The leakage through these col- required to be able to adequately assess treatments without having limators should be checked regularly as part of a quality control to return to the original centre for extra information (Figure T.55). program. Modern linacs may also incorporate multileaf collima- Related Article: Planning target volume (PTV) tor blocks within the treatment head; however, these can also be Further Readings: ICRU (International Commission on externally added. Radiation Units and Measurements). 1993. Prescribing, report- If an electron beam is required, the photon target is moved ing and recording photon beam therapy. ICRU Report 50, out of the path of the electron beam, and is replaced by a thin Treatment optimisation 974 Treatment planning system beryllium window and two scattering foils. These modify the Treatment phase shape and spectrum of the intense pencil beam of electrons to (Radiotherapy) Often radiotherapy treatments are delivered in a produce a clinically useful beam. Electron beams require addi- set of stages often referred to as phases. The use of several phases tional collimation called applicators to reduce the dose from the is often done to enable a sequential boost of the dose to the region high scatter that occurs in air. The beam current in electron mode closest to the centre of the target volume. Examples

include the must be reduced by a factor of 100 (along with the frequency of use of a boost phase in breast treatment to give more dosage to the the RF source) from that of x-ray mode to prevent dangerously tumour than to the surrounding region. high dose rates for electrons. Related Articles: Radiotherapy treatment planning, Boost Cobalt Unit: The treatment head of a cobalt unit consists of dose • Source housing (the source head) Treatment plan evaluation • Collimators (Radiotherapy) In radiotherapy a treatment plan is often evaluated • Light field to show the extent of the radiation field when in comparison with other competing plans to determine which is the source is in the OFF position the best plan with which to treat the patient. This evaluation may The source head consists of shielding whilst the source is in the be visual inspection of the isodose coverage of the plan on the OFF position (steel shell with lead), and a mechanism for mov- screen of the TPS or in a printout, or it may be a more quantitative ing the source from OFF to the ON position by the collimator evaluation based on dose–volume histograms (DVHs) or calcu- opening. This can either be achieved by moving the source to the lation of predicted tumour control probability (TCP) or normal treatment position, or moving attenuation material in front of the tissue complication probability (NTCP). source. Three methods are as follows: Abbreviations: DVH = Dose–volume histogram, NTCP = Normal tissue complication probability, TCP = Tumour control probability and TPS = Treatment planning system. 1. A rotating shutter to expose or shield the source Related Articles: Dose area histogram, Dose–volume histo- 2. A rotating heavy metal drum in which the source is gram, Dose–volume histogram differential (DVH), Dose–volume mounted histogram integral (cumulative) DVH, Probability of complica- 3. A sliding source bar tions, Tumour control probability (TCP), Normal tissue complica- tion probability (NTCP) Related Articles: Linear accelerator, Multileaf collimators, Cobalt unit Treatment plan normalisation Treatment optimisation (Radiotherapy) The process of normalising the treatment plan (Treatment Planning) Treatment optimisation is optimisation of dose distribution to achieve a result consistent with dose–volume the radiotherapy treatment plan, particularly in external beam constraints, on the target and organs at risk. x-ray planning. For each treatment beam, an optimisation algo- Related Article: Target dose rithm is used to generate the beam profile needed to deliver T the prescribed dose distribution using inverse planning. After Treatment planning system the plan has been optimised a second stage is often involved in (Radiotherapy) The treatment planning system consists of a num- which the constraints of the delivery system are modelled to pro- ber of computer workstations networked together and also with duce a deliverable beam plan. This is synonymous with fluence other equipment within the hospital (e.g. simulators, CT and MR optimisation. scanners, and linacs through a record and verify system, etc.). Related Articles: Fluence optimisation, Interactive planning, Associated with the workstations will be high resolution, large Inverse radiotherapy planning, Simulated annealing algorithm monitors for displaying images and graphics packages for visual- ising information in three dimensions. This has allowed the user Treatment parameters to view the dose coverage of tumours as a volume rather than (Radiotherapy) Treatment parameters determine the shape and on just one CT slice, to display the beam’s eye view of the treat- the size of treatment field, the use of wedges or any device for ment field, to calculate DVHs, and the ability to generate DRRs. beam modification, angles of beams and number of monitor The increased power and speed of computers has allowed com- units used to deliver the required radiation dose. They will vary plex dose calculations to be performed very rapidly and now even for individual patients and contain beam data including number more complex calculations (e.g. IMRT and electron Monte Carlo) and position of treatment beams relative to the patient’s contour are possible in a reasonable time. Other equipment associated and size, tumour size and location and the external reference with the treatment planning computer includes plotters, printers, points. film scanners and digitisers. The computer must also have suf- The treatment parameters are included in the radiotherapy ficient memory for storage of information, and this is becoming treatment chart which is an important working instrument, not more relevant with the rapid increase in additional imaging being only as a set of data but also as a method of communication performed. It is also essential that safety is built into the system among radiation oncologists, physicists and technicians. In addi- and it is robust to prevent problems such as viruses, power fail- tion to administrative and medical data, physical and simulation ures, etc. There should be a mechanism for a regular back-up or data that are indispensable for the daily accurate reproduction of archiving of the information stored on the system, and also regu- the therapy procedures should be recorded as well as accurate lar QA tests performed on the planning system. daily entries of the fractional and cumulative absorbed doses. Any Before using a planning system the user must input mechanical quality assurance programme must rely on the accessibility of the specifications and limits, naming conventions, and dosimetric data radiation treatment history and a correct record of the therapy relating to the linacs used, which can then be used as required when protocol in order to be verifiable. calculating a plan. There are a number of different calculation Treatment planning systems (brachytherapy) 975 Treatment planning systems (brachytherapy) algorithms which can be used for calculating the treatment plan. already mentioned, some dose optimisation algorithms and tools Further details on this are given in the following references. are specific to brachytherapy. Some tools are very useful but must Abbreviations: CT = Computed tomography, DRR = Digitally be used with care. An example is the ‘grab and drag’ tool which reconstructed radiograph, DVH = Dose–volume histogram, allows the user to move isodose lines and when used in this way IMRT = Intensity-modulated radiation therapy, MR = Magnetic has a profound effect on dwell times at the defined stop positions resonance and QA = Quality assurance. in the applicators. Related Articles: Kernel-based treatment planning, Pencil For specific brachytherapy applications, dedicated treatment beam planning systems are available. One such application is ultra- Further Readings: ICRU (International Commission on sound-guided interstitial permanent implantation of seeds for Radiation Units and Measurements). 1987. Use of computers in prostate cancer. The dedicated systems are streamlined for the external beam radiotherapy procedures with high-energy photons seed implantation process, and allow the user, for example to fol- and electrons. ICRU Report 42, Bethesda, MD; Podgorsak, E. B. low the implantation procedure interactively and continuously 2003. Review of Radiation Oncology Physics: A Handbook for update the seed positions and the resulting dose distribution. Teachers and Students, International Atomic Energy Agency, Treatment Planning Systems – Brachytherapy, Future Vienna, Austria. Developments: Traditionally, brachytherapy planning was based on ‘dosimetry systems and orthogonal radiographs’ without Treatment planning systems (brachytherapy) actual definitions of volumes of interest. Dose calculations were (Radiotherapy, Brachytherapy) A modern treatment planning based on point dose models in an infinite medium, and in prin- system for image-guided brachytherapy (BT) includes the same ciple no corrections were made for heterogeneities. type of basic modules and tools as an external beam radiotherapy With the development of image-based brachytherapy there (EBRT) treatment planning system for many planning tasks. The are now available 3D definitions of volumes of interest, informa- first tasks/modules encountered in the treatment planning process tion on tissue densities and on applicator/source positions. We are the modules for importing and registering 3D image volumes also have afterloading units, low energy sources, Monte Carlo and the modules for definition of tumour and target volumes and calculations, algorithms for the optimisation of physical dose organs at risk. Both EBRT and BT systems need tools to display and for radiobiological effects, etc. and there is a renewed inter- the 3D dose distributions in relation to anatomy, together with est in the development of brachytherapy source models and dose evaluation tools, for example based on dose–volume histograms. calculations. Algorithms for dose distribution optimisation are also needed, The treatment planning systems using the TG43 formalism even though they might be of different types for EBRT and BT. still have a number of limitations: Facilities for documentation of approved plans are also required, as well as access to appropriate archiving, information and com- • There are no heterogeneity corrections (water medium). munication systems. • There are no corrections for patient size (‘infinite’ Treatment Planning Systems – Brachytherapy: Specific medium). for a brachytherapy treatment planning system are modules for • There are in general no corrections for applicator com- definition of applicators and sources (source stop positions). For position and possible shields. image-guided brachytherapy the system should allow accurate • There are no intersource effects included. T interactive definition of applicators and source stop (dwell) • There are no transit dose corrections for remotely con- positions in the 3D volume. Radiograph-based applicator/source trolled afterloading units. definition is still used, and so this technique must also still be supported (use of digitisers, import of film). The availability of a In general, new algorithms based on Monte Carlo calculations are standard applicator library of ‘rigid’ applicators in the planning needed. system greatly assists the process. In the clinical setting, where you work with one or several Another brachytherapy specific module is the dose calcula- brachytherapy treatment planning systems, get to know your tion module, requiring a source model. Source models have been systems: based on point sources and line sources, and a popular source model is the model based on the AAPM TG43 formalism. In con- • Understand the source model/s used. trast to EBRT, where acceptance testing and commissioning of • Understand how source strength is defined. a treatment planning system requires a number of measurements • Understand the way source decay is handled. for the treatment units to be included, in BT this procedure con- • Understand how source positions are determined in the sists of a verification process. The important task of the physicist system. is not to make measurements around the brachytherapy source • Understand how the source actually moves in the appli- but to verify, first, which source model is used in the system, cator during treatment, in order to treat according to the and second, that this source model is implemented correctly for plan. the source used, where both the isotope and the source design • Get to know your applicators. must be correct. Verification is performed by comparing treat- • Understand how the system is ‘constructed’. ment planning system calculations with recognised published • Understand the limitations of the system. ‘best source data’. These data are available from the AAPM and • ‘Beware of updates’! They might change more than from ESTRO. they are supposed to change! ‘Improvements’ might not Brachytherapy dose distributions are characterised by large be improvements for you! dose variations inside the target volume. Besides the traditional cumulative and differential dose–volume histograms, the natu- Abbreviations: AAPM = American Association of Physicists ral dose–volume histogram is also used for evaluation purposes, in Medicine and ESTRO = European Society for Therapeutic where a point source is characterised by a horizontal line. As Radiology and Oncology. Treatment position 976 Treatment vault Related Articles: Source models, Point source calculation, In order for the treatment unit operator to observe the patient AAPM TG43 formalism, Dose–volume histograms – brachy- during treatment with an MV treatment unit, a CCTV system is therapy, Orthogonal films, Interactive implant technique, Dwell put in place. Other additional features of treatment rooms are door times, Intersource shielding interlocks (to turn the beam off immediately if someone attempts Further Readings: Dale Kubo, H. et al. 1998. High dose-rate to enter the room while the beam is on), air venting systems as brachytherapy treatment delivery: Report of the AAPM Radiation well as the capability to allow full movements of the treatment Therapy Committee, Task Group No. 59. Med. Phys. 25:375–403; machine, storage space for the associated accessories and suffi- Fraass, B. et al. 1998. AAPM Radiation Therapy Committee Task cient space for specialised treatments. Group No. 53: Quality assurance for clinical radiotherapy treat- Related Articles: Interlock; Interlocking device, Isocentre, ment planning. Med. Phys. 25:1773–1829; Nath, R. et

al. 1995. Leakage radiation, LINAC, Linear accelerator, Cobalt unit, Dosimetry of interstitial brachytherapy sources: Recommendations Maze, Kilovoltage (kV), Orthovoltage, Secondary barrier, Use of the AAPM Radiation Therapy Committee, Task Group No 43. factor, Total body irradiation. Med. Phys. 22:209–234; Nath, R. et al. 1997. Code of practice for brachytherapy physics: Report of the AAPM Radiation Therapy Treatment time Committee, Task Group No. 56. Med. Phys. 24:1557–1598; Rivard, (Radiotherapy) Treatment time in brachytherapy is the time dur- M. J. et al. 2004. Update of AAPM Task Group No. 43 Report: A ing which the radioactive sources are temporarily implanted into revised AAPM protocol for brachytherapy dose calculation. Med. or close to the tumour. They are removed once the desired radia- Phys. 33:633–674; Rivard, M. J. et al. 2007. Supplement to the tion dose has been delivered. Treatment time indicates also the 2004 update of the AAPM Task Group No. 43 Report. Med. Phys. time interval when the useful Co60 beam emerges from the treat- 34:2187–2205; Venselaar, J. and J. Pérez-Calatayud. (eds.). 2004. A ment head. Practical Guide to Quality Control of Brachytherapy Equipment, ESTRO Booklet No 8, Brussels, Belgium. Treatment vault (Radiation Protection) A shielded and secure area for the deliv- Treatment position ery of radiotherapy treatment. These facilities are designed to (Radiotherapy) This is the position in which the patient is treated, ensure that doses to persons beyond the vault are kept as low and is determined by practical constraints. It needs to be highly as reasonably practicable and within the relevant constraints. reproducible, and such that it is possible to treat the target. This During design, a realistic instantaneous dose rate (IDR) and is achieved by immobilisation devices and verification techniques workload are determined. In brachytherapy facilities, a patient such as image-guided radiotherapy (IGRT). transmission factor may be estimated. For linear accelera- Related Articles: Immobilisation, IGRT tors, barriers are classified as primary (i.e. those that a radia- tion beam can directly strike) or secondary (those that protect Treatment room against leakage and scattered radiation). In the case of primary (Radiotherapy) This is the location where the patient will receive barriers, a ‘use factor’ defined as the ‘fraction of the time dur- their radiotherapy treatment; it is also commonly known as a bun- ing which the radiation under consideration is directed at a ker. The design of the treatment room must be such that the level particular barrier’ is also determined (IAEA, 2006). In both T of dose outside the room is below that required by legislation. The cases, the distances to barriers are determined from floor plans room design will be dictated by the type of treatment machine and or measurements. the energy of the treatment beam. Once a machine is capable of From the parameters discussed above, a time-averaged dose producing a beam following installation, it is essential that a full rate incident on each of the barriers over the working year of radiation protection survey be carried out to confirm the integrity 2000 hours (TADR2000) is calculated. Following this, the required of the design. transmission, B, of the barriers for the relevant dose constraints In the case of a superficial unit (operating in the kV region, e.g. beyond the barrier to be met are then calculated: approximately 100 kVp), some additional protection such as lead lining around the door and leaded glass will be necessary. The D B = c leaded glass allows the operator to directly observe the patient TADR2000 ´T during treatment. For higher energy units in the MV region of operation (e.g. Where Dc is the annual dose constraint and T is the occupancy linear accelerators, cobalt units), a much higher level of protection factor (please see occupancy article). From the required transmis- is required. These rooms will either make use of a maze entrance sion, the number of tenth value layers (NTVL) required to achieve or a heavy lead-lined door (in situations where space is at a pre- this is calculated as below: mium) to ensure that the scattered dose at the entrance to the room 1 is low enough to meet the requirements. The room walls will con- NTVL = æ ö log10 ç ÷ è B sist of thicker portions of concrete (usually around 2.5 m thick- ø ness) known as the primary barrier where the beam can directly The thickness, x, of a given material can then be calculated with impinge onto the walls, ceiling and floor. Thinner portions of con- the following: crete (typically around 1.5 m thickness) known as the secondary barrier are used elsewhere where the beam cannot reach directly. x = TVLmaterial ´ NTVL When planning the thicknesses of material required, it is essen- tial to be aware of occupancy in the surrounding areas, as well as The main material of choice is often concrete, for further details above and below the treatment room. on shielding material, see Radiation shielding. When linear accelerators with x-ray beams of energy greater Note that additional safety requirements must be in place for than 10 MV are to be employed, the production of neutrons must treatment vaults, such as the provision of CCTV and a two-way be accounted for in the shielding design of the room. intercom system to the patient, emergency radiation off switches, Treatment verification 977 Trivial light source emergency releases for the heavy vault doors and in the case of Triggering brachytherapy, the provision of monitors and tools should the (General) In general, a ‘trigger’ is any event that initiates some source become lost or fail to retract. action. In electronics it refers to any electrical signal which causes Related Articles: Radiation shielding some event to occur in a synchronised manner. Further Readings: IPEM. 1997. Design of Radiotherapy It is common when some function is required to occur at a Treatment Room Facilities IPEM Report 75; IPEM. 2002. fixed time relative to another event, to derive some electrical sig- Medical and Dental Guidance Notes; IAEA. 2006. Radiation nal from this first event, and use it to ‘trigger’ the required func- Protection in the Design of Radiotherapy Facilities; ICRP. 2007. tion. It is particularly useful when multiple repeat events need to The 2007 Recommendations of the International Commission on be synchronised to external stimuli (e.g. x-ray exposures synchro- Radiological Protection; Sutton, J. M. 2015. Practical Radiation nised to the ECG). Protection in Healthcare. In cathode ray tube (CRT) displays, the short persistence of the display requires the trace of any signal to be repeatedly written Treatment verification across the screen. To produce a stable display where each trace (Radiotherapy) The purpose of radiation therapy is to deliver a reinforces previous ones, it is necessary to have the trace scan high, therapeutic dose to the tumour or target whilst constraining across the screen and then wait to an appropriate moment when it the dose to other, normal, tissues to be as low as possible. For can be retriggered so that following signals exactly overwrite the this reason verification of the treatment is carried out to ensure same part of a repeating waveform. that the radiation dose is delivered accurately with the high dose In a cathode ray oscilloscope (CRO) a ‘trigger circuit’ is pro- region closely matching the target position. vided, along with a variable ‘trigger level’ control which selects a Also in external beam radiotherapy, the dose is generally frac- particular input level or threshold for the incoming signal to ‘trig- tionated, that is delivered over several treatment sessions. The ger’ the trace to cross the screen. In this way the traces on the CRT verification process is important for each of these treatment ses- screen can be made to appear as one stationary trace (Figure T.56). sions to ensure that the combined dose distribution over the whole Related Article: Threshold detection treatment meets the required accuracy. Verification Methods: Verification of position has tradition- Triode tube ally been carried out using x-ray film to image the relationship (Diagnostic Radiology) The triode tube is a highly evacuated between the radiation portal and anatomy in two dimensions. electron tube containing an anode, a cathode and a control grid. This has been superseded by electronic portal imaging. More The principle of its operation is that, as with a thermionic recently three-dimensional verification has been used, based on diode, the heated filament causes a flow of electrons that are cone beam CT or CT on rails in the treatment room. Verification attracted to the plate and create a current flow. Applying a nega- of dose may be carried out using TLD (thermoluminescent dosim- tive charge to the control grid will tend to repel some of the (also etry), diodes, ionisation chambers, film, or EPID. negatively charged) electrons back towards the filament: the Abbreviations: CT = Computed tomography, EPID = larger the charge on the grid, the smaller the current flow to the Electronic portal imaging device and TLD = Thermoluminescent plate. If an AC signal is superimposed on the DC bias of the grid, dosimetry. an amplified version of the AC signal appears in the plate circuit. Related Articles: Target localisation, Film, Electronic portal Triode tubes are the predecessor of transistors and are used in T imaging, Computed tomography the control circuits of some high voltage equipment (Figure T.57). Hyperlink: http://en .wikipedia .org /wiki /Vacuum _tube Trendelenburg position (General) There are a series of terms used to describe the posi- Trivial light source tion of an individual when undertaking different imaging (Non-Ionising Radiation) An optical light source which is in the examinations. exempt category for photobiological lamp safety standards and ‘Trendelenburg’ means tipping the individual head down. whose emissions are below any limits specified by the ICNIRP Related Article: Patient position and in the AORD 2006 directive. Related Articles: AORD, Exposure limit values, ICNIRP, Trigger delay Photobiological lamp safety (Magnetic Resonance) In an ECG gated cardiac MRI, the trigger Further Readings: Coleman, A., F. Fedele, M. Khazova, delay TD is the time between detection of an R–wave trigger and P. Freeman and R. Sarkany. 2010. A survey of the optical haz- the start of the acquisition of lines in k-space. A TD can be used ards associated with hospital light sources with reference to the to ensure data acquisition occurs during diastole, when motion artefact will be reduced. R–R interval (a) (b) Data acquisition TD-delay time FIGURE T.56 CRO triggering examples. (a) Untriggered CRO trace and (b) triggered CRO trace. True coincidences 978 Tube current (mA) 3 = False negative (FN) 4 = True negative (TN) The fraction of true positive to all cases is called the sensitiv- ity, TP/(TP+FN), and the fraction true negative to all cases is called specificity TN/(TN+FP). A receiver-operator characteristic (ROC) analysis determines the fractions of 1–4. The result is usu- ally plotted as a ROC curve in the following Figure T.58 shows such a curve of two imaging systems where system B is better than system A. Related Articles: True positive, False positive, False negative, ROC True positive (General) See True negative FIGURE T.57 Symbol of triode tube. True non-contrast (TNC) image Control of Artificial Optical Radiation at Work Regulations 2010. (Diagnostic Radiology) Virtual non-contrast (VNC) image is an J. Radiol. Prot. 30(3):469; ICNIRP. A closer look at the thresholds image reconstructed by using an image post-processing technique of thermal damage: Workshop report by an ICNIRP task group. to create ‘non-contrast’ images of contrast-enhanced scans via Health Phys. 111(3):300–306; ICNIRP. 2013. Guidelines on limits the subtraction of iodine. On the other hand, a true non-contrast of exposure to incoherent visible and infrared radiation. Health image (TNC) is not an image reconstructed by using an image Phys. 105(1):74–91; ICNIRP. 2013. Guidelines on limits of expo- post-processing technique, but an image acquired without using sure to laser radiation of wavelengths between 180 nm and 1,000 contrast medium. μm. Health Phys. 105(3):271–295; ICNIRP. 2004. Guidelines on Related Articles: Virtual non-contrast (VNC) image limits of exposure to ultraviolet radiation of wavelengths between 180 nm and 400 nm (Incoherent Optical Radiation). Health Tube current (mA) Phys. 87(2):171–186; ICNIRP. 2000. Revision of the guidelines (Diagnostic Radiology) The thermal electrons, accelerated on limits of exposure to laser radiation of wavelengths between towards the anode by the electric field between the cathode and 400 nm and 1.4 μm. Health Phys. 79(4):431–440; International anode, form the anode current Ia (also known as x-ray

tube current Electrotechnical Commission: IEC 62471:2006 Photobiological – Ia). In practice it is expressed in mA, as it normally is within this safety of lamps and lamp systems. IEC 2006. range of current. The tube current is proportional to the produc- tion of thermal electrons (filament heating). At lower kV (usu- True coincidences ally below 50 kV) the tube current cannot increase with further T (Nuclear Medicine) True coincidences are used in PET imaging increase of the filament temperature (i.e. generation of more ther- and refer to registered coincidences where the two 511 keV pho- mal electrons). This is due to the Space charge effect, and in this tons originate from the same annihilation. The opposite of true case the tube current can be increased only by increasing the kV coincidences are false coincidences, that is where the two photons (see article on Filament current). generating a coincidence are either not from the same annihila- tion or one or both photons are scattered before registration. Abbreviation: PET = Positron emission computed tomography. Related Article: 1.0 Event type in PET True negative (General) The diagnosis of a disease using some kind of modal- Modality B ity, such as a scintillation camera, involves some kind of uncer- tainty in the decision of whether a patient has an abnormality or is normal. There can be four alternatives: Modality A 1. The diagnosis indicates a positive answer (disease) to a patient that has a disease. 2. The diagnosis indicates a positive answer (disease) to a patient that does not have a disease. 3. The diagnosis indicates a negative answer (no disease) to a patient that has a disease. 4. The diagnosis indicates a negative answer (no disease) to a patient that does not have a disease. The earlier situations are often labelled as follows: 0.0 0.0 1.0 False positive fraction 1 = True positive (TP) 2 = False positive (FP) FIGURE T.58 ROC curves comparing two imaging systems (A and B). True positive fraction Tube filament current 979 Tube load Tube current does not influence the contrast of the x-ray image kVp (in practice it is often referred to as just kV). Varying the tube (but changes its brightness). The operating mA depends on the kilovoltage varies the energy (keV) of the x-ray photons produced attenuation of anatomical region to be imaged. Due to this reason by the x-ray tube, thus forming the x-ray spectrum. The keV vary the radiographic tube current could vary significantly (e.g. from 5 from 0 to the applied tube kilovoltage (e.g. if Ua = 60, then photon to 1000 mA). The fluoroscopic tube current is usually very small energy varies from 0 to 60 keV). (e.g. from 1 to 4 mA), due to the high intensifying factor of the Tube kilovoltage determines the contrast of the x-ray image. image intensifier. Due to this reason the operating kV depends on the anatomical The intensity of x-ray radiation W (x-ray energy flux density) region to be imaged. The radiographic and fluoroscopic tube kilo- is W ∼ I U2 Z, where I is the anode current (Ia) Z is the atomic voltage is usually between 50 and 150 kV. Mammographic tube number of anode U is the accelerating high voltage (Ua). kilovoltage is between 20 and 35 kVp. From this is seen that the intensity of the x-ray radiation (hence The intensity of x-ray radiation W (x-ray energy flux density) the exposure) is in linear relation with the mA. is W ∼ I U 2 Z, where I is the anode current (Ia), Z is the atomic The tube current is usually measured with mA-meter placed number of anode, U is the accelerating high voltage (Ua). between ground and the middle point of the high voltage trans- From this is seen that the intensity of the x-ray radiation (hence former (see the article on High-voltage generator and its circuits). the exposure) is in quadratic relation with the kV. Similarly the Ua The variation of the Ia with changes of Ua (using the filament (kV) influences far more the contrast than the Ia (mA). current If as a parameter) is known as the anode characteristic of The tube kilovoltage is usually measured indirectly at the pri- the x-ray tube (Figure T.59). mary (low voltage) circuit of the high voltage transformer (based Related Articles: High voltage generator, High voltage circuit, on the fact that this transformer has fixed transformation ratio). Filament circuit, Filament current, Stationary anode, Rotating Another method to measure the kilovoltage indirectly is by the anode, Target kVp meter – effectively measuring the maximum photon energy Further Readings: Forster, E. 1993. Equipment for Diagnostic of the x-ray beam (peak kV, or kVp). Radiology, MTP Press, Lancaster, UK; Thompson, M., M. The variation of the Ia with the change of Ua (kVp), using the Hattaway, D. Hall and S. Dowd. 1994. Principles of Imaging Science filament current If as a parameter, is known as the Anode charac- and Protection, W.B. Saunders Company, Philadelphia, PA. teristic of the x-ray tube (Figure T.59). Related Articles: Tube current, High voltage generator, High Tube filament current voltage circuit, Filament circuit, Target (Diagnostic Radiology) See Filament current Further Readings: Forster, E. 1993. Equipment for Diagnostic Radiology, MTP Press, Lancaster, UK; Thompson, M., M. Hattaway, D. Hall and S. Dowd. 1994. Principles of Imaging Science Tube housing and Protection, W.B. Saunders Company, Philadelphia, PA. (Diagnostic Radiology) See X-ray tube housing Tube kilovoltage (kV) Tube load (Diagnostic Radiology) The accelerating voltage between the (Diagnostic Radiology) Tube load is a measure representing the anode and cathode of an x-ray tube is also known as tube kilovolt- energy imparted to the x-ray tube anode (kV mA). Approximately age (or anode voltage). In practice it is expressed as the peak kV 99% of this energy transforms to heat (strictly speaking the T energy converted directly to heat is ∼75%); hence, the maximum permissible tube load depends on the heat capacity of the anode heat units (HU). Tube load depends on the time (length) of the exposure – a single short exposure can impart much more energy to the anode, as after it will follow a long cooling period (during the time when the current patient leaves and a new patient arrives). Tube load for long exposures depends very much on the cooling effectiveness of the x-ray tube (e.g. fast rotating anode using oil cooling with external heat exchanger cools quickly the anode during the exposure, hence allows more energy to be imparted in it). Various x-ray tube operating charts can be used to determine the tube load at specific kV, mA and ms. Some high voltage gen- erators include a special calculator which estimates the tube load after each exposure and controls the cooling process. This auto- matic calculator rejects parameters which will overload the x-ray tube, and also ceases the current exposure(s) if the maximum tem- perature is exceeded (this way preventing the anode from thermal damage). A specific operating mode of the x-ray equipment (falling load mode) is sometimes used to allow the most effective use of the heat capacity of the anode and this way allows production of very FIGURE T.59 The graph shows the variation trend of the tube current powerful exposures for very short time. (Ia, mA) with changes of the anode voltage (Ua, kV) at three different (if Related Articles: Heat units, Heat capacity, Maximum load, three different increasing temperatures of the cathode filament). Falling load, Cooling curve, Tube rating charts Tube load time 980 Tumour antivascular alpha therapy Tube load time (limiting curves) represent the maximum permissible tube current (Diagnostic Radiology) Tube load time is a term associated with (Ia) for various length of exposures (ms). the time of the x-ray exposure. Sometimes the term can be used If such a graph is given for multiple exposures (e.g. when to specify the time for which an exposure reaches the peak power sequence of exposures is used in angiography), the chart would of the requested exposure (the front porch of the x-ray exposure represent the maximum permissible heat unit as a function of the pulse). Also sometimes the term can be used to specify the maxi- total number of exposures. In this case, the parameter will be the mal permissible time of the x-ray exposure (for which the tube number of exposures per second. Similarly, if the chart is for cine reaches its maximum load). use (again in cardiac angiography), then the maximum permis- Related Articles: Heat units, Heat capacity, Maximum load, sible heat units will be plotted against the number of cine frames Falling load, Cooling curve, Tube rating charts (in this case the parameters for the limiting curves will be the length of one cine frame). Tube rating charts (Diagnostic Radiology) Normally the manufacturers combine the heat loading characteristics and limitations in diagrams known EXAMPLES FROM FIGURE T.60 as tube rating charts, anode load charts, or other. These charts depend not only on the x-ray tube parameters, but also from the • Exposure with 100 mA and 50 ms is acceptable rectification and other specifics of the high voltage generator. The for all kVs, as it is below all limiting curves (i.e. charts are given according to the focal spot size, speed of anode the cross point of 100 mA and 50 ms is below rotation, kV waveform, etc. These charts are also given for dif- the all limiting curves). ferent modes of operation: single exposure, multiple exposures, • Exposure with 400 mA and 20 ms is not accept- cine-radiographic exposures, etc. able with 100 kVp, as it will impart too much Contemporary x-ray equipment have all these charts built energy to this particular anode, but the same in special automatic calculators. This way the equipment auto- matically rejects parameters, which will overload the x-ray tube exposure is acceptable with 80kVp. (and sometimes suggests other parameters). The design of this • Exposure with 500 mA and 30 ms is not automatic varies widely – from electronic analogous systems to acceptable even with 80 kVp, but if the speed of microprocessor programs. anode rotation increases from the normal 3000 Figure T.60 represents an example for a single exposure rat- to 9000 rpm, then the tube cooling is better and ing chart for low power rotating anode x-ray tube. The curves the exposure is acceptable (i.e. the cross point of 400 mA and 100 ms is above 80 kVp curve, but is below the dotted limiting curve for 80 kVp at 9000 rpm). • Exposure with 800 mA and 500 ms will not be permitted with any kVps, as it will overheat the T anode, hence destroy the x-ray tube. Related Articles: Heat units, Heat capacity, Maximum load, Falling load, Cooling curve, Tube rating charts Tube stand (Diagnostic Radiology) Tube stands and tube cranes are mechani- cal supports which hold the x-ray tube housing and its light beam diaphragm (with collimator). These supports can be floor or ceil- ing mounted. Tumour antivascular alpha therapy (Radiotherapy) Radioisotopes are used in nuclear medicine pro- cedures for imaging and therapy. Imaging isotopes emit gamma rays; therapeutic isotopes emit low energy gamma rays or high energy beta radiation. Cancer is the main target for therapeutic nuclear medicine. A new approach to therapy is emerging where radioisotopes that emit very short range (80 μm) alpha particles are tagged onto monoclonal antibodies for targeted alpha therapy (TAT). The alpha radiation is high linear energy transfer (LET) FIGURE T.60 The graph shows an approximate tube rate chart for single exposures – Ia (mA) = F(Exp. time, ms), with Ua (kV) as param- radiation and transfers ∼100 keV/μm to the targeted cells, causing eter. Note that all smooth line diagrams are for 3000 rpm anode speed increased double strand breaks in the nuclei of the targeted cancer rotation, while the dotted line (80 * kVp) is for 9000 rpm anode speed cells. The radiation weighting factor for alphas is 20 and the rela- rotation. tive biological effectiveness (RBE) for tumour regression is ∼3–5. Tumour control 981 T ungsten TAT was not indicated for solid tumour therapy, as the range than all of them as the body’s immune system will destroy those of alphas is too short, the diffusion time into the tumour too long remaining but there is no real evidence to support

this. and the uptake too heterogeneous. Taking the theory that radiation sterilisation of all clonogens Tumour anti-vascular alpha therapy (TAVAT) overcomes is required, the probability of tumour control as a function of the all these obstacles. The AIC can diffuse into the peri-vascular radiation dose can be derived by the application of Poisson statis- space through tumour capillary fenestrations, and target antigens tics to cell survival curves. Therefore, the probability of tumour expressed by pericytes and adjacent cancer cells. These antigens control may be described as in Equation T.8 where SF is the sur- will filter out the AIC and, on decay of the alpha radioisotope, viving fraction, obtained using the linear quadratic model, and N0 will set up a longitudinal alpha field, causing DSBs in the endo- is the original number of tumour clonogens in the target volume: thelial cell nuclei, apoptosis and closure of the tumour capillary. Oxygen and nutrient starvation will lead to tumour regression if TCP = e-SF.N0¥ (T.8) enough capillaries are shut down. Only alpha radiation can achieve this effect, the indirect An expression for tumour control probability can be obtained by killing of tumour capillary endothelial cells, and regression of the application of Poisson statistics to cell survival curves. tumours by antivascular therapy. It should be noted that this model describes the response of Abbreviations: AIC = Alpha-immunoconjugate, DSB = individual tumours and the dose–response curves obtained from Double strand break, LET = Liner energy transfer, MTD = it have particularly steep slopes. In reality, the position and steep- Maximum tolerance dose, RBE = Elative biological effectiveness, ness of the dose–response curve will vary within a tumour cell TAT = Talpha therapy and TAVAT = Tumour antivascular alpha population due to their heterogeneous nature and will depend therapy. on the volume of tissue irradiated (dose–volume effect), the Related Article: Targeted alpha therapy fractionation scheme and if the treatment includes concurrent chemotherapy. However, the Poisson method can be adapted to Tumour control incorporate such effects and many authors have suggested such (Radiotherapy) The aim of radiotherapy is to affect tumour con- models although there is not as yet a single, established model in trol without inducing serious complications due to the irradiation widespread use. A comprehensive review of TCP models can be of normal tissue. For tumour cure it is generally accepted that found in Chapter 10 of the book by Dale and Jones (2007). all clonogenic cells must have suffered reproductive death and so In clinical practice, the achievable level of tumour control will be incapable of further multiplication. For more details see the depend on the tolerance of neighbouring normal tissues. For more article on Tumour control probability. information see the article on Therapeutic effect. Related Article: Tumour control probability Abbreviation: TCP = Tumour control probability. Related Articles: Cell survival curves, Dose–response model, Tumour control probability (TCP) Linear quadratic (LQ) model, Radiosensitisers, Sigmoid dose– (Radiotherapy) The relationship between dose and tumour con- response curve, Surviving fraction, Therapeutic effect, Tolerance trol probability (TCP) is shown in Figure T.61. It has a sigmoid Further Readings: Dale, R. and B. Jones. 2007. Radiobiological (S) shape with the probability of tumour control tending to zero Modelling in Radiation Oncology, British Institute of Radiology, as the dose tends to zero and tending to 100% at very large doses. London, UK; Jones, B. and R. G. Dale. 1999. Mathematical T The sigmoid shape can be explained from the random nature models of tumour and normal tissue response. Acta Oncologica. of cell killing after irradiation and the need for all clonogenic 38:883–893. cells to have suffered reproductive death and so be incapable of further multiplication. There are those who believe tumour cure Tungsten can be obtained by sterilising most of the clonogenic cells rather (General) Symbol W 1 Element category Transition metal 0.9 Mass number A of stable isotopes 180 (0.12%), 182 (26.50%), 0.8 183 (14.31%), 184 (30.64%) 0.7 186 (28.43%) 0.6 Atomic number Z 74 0.5 Atomic weight 183.84 Electronic configuration 1s2 2s2 2p1 3s2 3p6 3d10 4s2 4p6 0.4 4d10 5s2 5p6 4f14 5d4 6s2 0.3 Melting point 3695 K 0.2 Boiling point 5828 K 0.1 Density near room temperature 19.25 × 103 kg/m3 (19.25 g/cm3) 0 Dose [Gy] History: Tungsten (aka Wolfram) was first isolated in 1783 FIGURE T.61 The relationship between the probability of tumour con- by the brothers José and Fausto Elhuyar, who used charcoal to trol and dose is sigmoid in shape. reduce tungstic acid. Tumour control probability Turbo factor 982 T winkle artefact Isotopes of Tungsten: There are five isotopes of tungsten that 180° rephasing pulses to form a series of spin echoes. Other names are considered stable, though they are in fact metastable isotopes for this type of sequence are fast spin echo (FSE), rapid acquisi- with extremely long half lives. These include the following: tion relaxation enhancement (RARE) and half-Fourier single shot turbo spin echo (HASTE). See Fast spin echo (FSE) for a more Isotope of tungsten 180 detailed description. W Related Articles: Echo train length, Fast spin echo (FSE), Half life 1.8 ± 0.2 × 1018 years Half acquisition single-shot turbo spin echo (HASTE), Rapid Natural abundance 0.12% acquisition relaxation enhancement (RARE) Isotope of tungsten 182W Half life >8.3 × 1018 years Turbulence Natural abundance 26.50% (Ultrasound) Turbulence describes a state of turbulent flow. (See Isotope of tungsten 183W Turbulent flow.) Half life >2.9 × 1019 years Related Article: Turbulent flow Natural abundance 14.31% Isotope of tungsten 184W Turbulent flow Half life >1.3 × 1019 years (Ultrasound) Turbulent fluid flow is characterised by random Natural abundance 30.64% irregular motion. In tubes, although the net flow is in the direc- Isotope of tungsten 186W tion of the tube, turbulence leads to local velocity vectors in Half life >2.7 × 1019 years several directions with fast changes of velocity in space and Natural abundance 28.45% time. There may also be non-random features such as vorti- ces and eddies. Turbulence can result spontaneously if the Reynolds number exceeds transition values and appears in the Medical Applications: X-ray tube filament and target – human circulation in arterial stenoses. The energy required for Tungsten compounds and alloys are widely used as both the turbulent flow is greater than for laminar flow, in arteries this electron-producing filament and the x-ray producing target in a results in increased pressure loss through the turbulent flow standard x-ray tube. The high atomic number of tungsten makes (Figure T.62). it a more efficient generator of x-ray radiation than many other Related Articles: Laminar flow, Reynolds number materials (although the bremsstrahlung process is still extremely inefficient) due to greater electrostatic forces between the tung- TVL (tenth value layer) sten atoms and the incident electrons. When tungsten is used as (Nuclear Medicine) See Tenth value layer (TVL) a filament, electrons are released by thermionic emission when a current is passed through the filament. Twinkle artefact Shielding of PET radionuclides – The high atomic number of (Ultrasound) The twinkle artefact is a common artefact encoun- tungsten allows it to be used to shield the high energy radiation tered in Doppler ultrasound imaging. It typically appears as a rap- produced by some PET radiopharmaceuticals, for example fluo- T idly fluctuating mixture of Doppler signals (red and blue pixels) rodeoxyglucose (FDG). The tungsten provides a large interaction that imitate turbulent flow and occurs behind a strongly reflecting cross section, enabling significant attenuation of the radiation granular interface such as urinary tract stones or parenchymal passing through it. calcification. In the clinical image here, the twinkle artefact is Scintillation detectors – Tungsten compounds in the form of shown by the yellow arrow. tungstate crystals are used as the scintillation material in some nuclear medicine imaging devices such as gamma cameras. Related Articles: Fluorodeoxyglucose (FDG), Target of x-ray tube, Radiation shielding, Scintillation camera Turbo factor (Magnetic Resonance) See Echo train length Turbo gradient spin echo (TGSE) (Magnetic Resonance) Turbo gradient spin echo (TGSE) is a hybrid pulse sequence that combines gradient echo and spin echo. The sequence is primarily used to obtain T2 weighted images. Compared to fast spin echo (FSE) TGSE has shorter acquisition time, decreased RF power deposition and more sensitivity to mag- netic susceptibility differences allowing improved visualisation of haemorrhage. TGSE is also called GRASE (gradient and spin echo). See GRASE for a more detailed description of the pulse sequence. Related Articles: Echo planar imaging (EPI), Fast spin echo (FSE), Gradient and spin echo (GRASE) FIGURE T.62 The image shows turbulent flow in a stream with high Turbo spin echo velocity disturbed flow through a high stream gradient. Downstream (Magnetic Resonance) Turbo spin echo (TSE) is a pulse sequence there is flow separation with foam accumulating close to the separation characterised by a 90° pulse followed by a series of rapidly applied point. Two-day protocol 98 3 Two-dimensional shear wave elastography (2D SWE) the first day (500–600 MBq) is administered to the patient at rest with an image acquisition starting 60–90 min post-injection. The advantage of a stress/rest combination compared to rest/stress is that if the first stress study is diagnosed as ‘normal’ then the rest of the study may be omitted. If the rest study, however, is performed as the first study, a dose of 500–600 MBq is administered and the image acquisition starts about 60–90 min after. The stress study is performed on the fol- lowing day with a 15–60 min time interval between the injection of 500–600 MBq and the imaging. From the logistic clinical viewpoint, having patients undergo- ing imaging on two separate days may sometimes be inconvenient and impractical, which results in increasing costs and a delay in the delivery of final information to be used in patient manage- ment. Acquiring information from both studies on a single day is therefore desirable in many cases. Example of a twinkle artifact (yellow arrow), represented here by the mix- Two-dimensional shear wave elastography (2D SWE) ture of red and blue pixels behind a strongly reflecting granular interface. (Ultrasound) In 2D SWE, acoustic radiation force impulse (ARFI) is used to induce tissue displacement in multiple focal Related Articles: Doppler imaging, Image artefact zones which are detected in rapid succession. Such a source, Further Reading: Bushberg, Seibert, Leidholdt and Boone. which moves faster than the shear waves, can be created by suc- 2012. The Essential Physics of Medical Imaging, 3rd edn., cessively focusing the ultrasonic push beam at different depths. Lippincott Williams & Wilkins. The different spherical waves generated for each focal beam inter- fere constructively along a Mach cone, creating two quasi plane Two-day protocol shear wavefronts propagating in opposite directions (Gennisson (Nuclear Medicine) The two-day stress/rest protocol is a proce- et al., 2013). This technique uses constructive interferences to dure for myocardial imaging starting with a 99mTc-sestamibi or increase their amplitude and propagation distance. When the 99mTc-tetrofosmin injection during cardiovascular stress follow- wave reaches the targeted tissue, the tissue is then pushed in the ing by a second injection of an equal activity 24 h later at rest. direction of propagation, causing the tissue to deform or displace. Alternatively, the two-day protocol can be conducted with the rest Since a shear wave is induced in the tissue with no external vibra- study as the initial study. If the stress study is performed as the tor required to generate it, SWE depends on the measurement first study then the image acquisition can start 15–60 min after of the shear wave propagation speed in tissue (Bercoff et al., the injection. On the next day, an injection of similar dose as in 2004). Based on Young’s modulus formula, assessment of tissue T FIGURE T.63 An example of 2D SWE of a right breast mass. The blue colour represents soft tissue, and the red colour represents stiff tissue. (Courtesy of Dr Sook Sam Leong, Department of Biomedical Imaging, University of Malaya Medical Centre.) Two-dimensional shear wave elastography (2D SWE) 984 Two-dimensional shear wave elastography (2D SWE) elasticity can be derived from shear wave propagation velocity, repetition for the entire displacement field. The Young’s modulus where elasticity is proportional to the square of shear wave propa- map is then reconstructed by estimating the speed of the shear gation velocity (Bercoff et al., 2004). wave between two points in the image, using a time of flight algo- The shear waves generated have to be tracked

by the ultra- rithm (Tanter and Fink, 2014) (Figure T.63). sound system. Typically, shear waves propagate in tissues at speed Related Articles: Shear wave elastography, Point shear wave between 1 and 10 m/s (corresponding to tissue elasticity from 1 elastography to 300 kPa) (Tanter and Fink, 2014). Consequently, shear waves Further Readings: Bercoff, J., M. Tanter and M. Fink. 2004. cross an ultrasound image plane of 3 to 6 cm width in 10–20 Supersonic shear imaging: A new technique for soft tissue elastic- milliseconds. Modern ultrasound systems generate only 50–60 ity mapping. IEEE Trans. Ultrason. Ferroelectr. Freq. Control images per second which is too slow for imaging, thus ultrafast 51(4):396–409; Gennisson, J. L., T. Deffieux, M. Fink and M. imaging is needed to display the entire imaging plane with high Tanter. 2013. Ultrasound elastography: Principles and techniques. temporal resolution in a single acquisition by reaching frame rates Diagn. Interv. Imaging 94(5):487–495; Tanter, M. and M. Fink. of up 5000 to 30000 images per second (Gennisson et al., 2013). 2014. Ultrafast imaging in biomedical ultrasound. IEEE Trans. This real-time technique facilitates complete acquisition without Ultrason. Ferroelectr. Freq. Control 61(1):102–119. T U Ultra-fine focus proportional to field strength, therefore MR spectroscopy pres- (Diagnostic Radiology) Some special x-ray tubes are produced ents better spectral resolution in UHF. Conversely, increasing the with very small focal spot. These tubes are either called ultra-fine field strength results in decreasing the RF wavelength and pres- focus tubes or microfocus tubes. They are mainly used in mam- ents challenges. mography, angiography or macroradiography (rarely used method At 7 T the 1H frequency is 300 MHz and the wavelength of these days). The ultra-fine focal spot of these tubes is normally the associated radiofrequency (RF) wave is 1 m, which is compa- equal or smaller than 0.1 mm effective focal spot size (also called rable with the body dimension. Consequently, non-uniform radio- 0.1 nominal in the IEC documents). These tubes produce sharp frequency fields, increased radiofrequency energy deposition in images with extremely high spatial resolution, but are only used the tissue, and enhanced susceptibility artefacts are observed. In for low-power exposures (otherwise the small focus will be over- UHF imaging, the SNR becomes a complex function of object loaded). Some contemporary x-ray tubes use electrical system size, object shape and object composition. The non-uniform that focuses the thermal electrons, thus producing variable focal radiofrequency field affects signal, contrast and local specific spot size, including ultra-fine sizes. absorption rate (SAR). Consequently, a number of coils and tech- Related Articles: Anode, Cathode, Focal spot, niques have been developed in order to reduce these problems. Macroradiography While good results have been obtained for head coil and brain imaging, the search for optimal UHF body imaging techniques is Ultrasmall particles of iron oxide (USPIO) still in progress (Ladd et al., 2018). (Magnetic Resonance) USPIOs are a widely used type of super- Possible adverse effects of UHF MRI are mainly unpleasant paramagnetic iron oxide contrast agent. sensory effects due to gradient switching, such as nerve stimula- The most commonly used form of USPIO is an agent with the tion, and tissue heating due to radiofrequency (RF) pulses. The generic name ferrumoxtran-10, which consists of <30 nm sized established limits on magnetic field gradient and RF fields are particles coated with dextran. These particles are taken up by the same as applied to low and high field systems (International macrophages in the lymph nodes, spleen and bone marrow. Their Electrotechnical Commission, 2015; United States Food and main emerging clinical application is in differentiating cancerous Drug Administration, 2014). There are specific issues in UHF from normal lymph nodes. Normal nodes take up the agent and primarily due to the shorter wavelength and the increased local hence appear dark on an MR image (since it is a negative contrast SAR. The sequence parameters are therefore optimised in order agent), while cancerous nodes remain bright allowing diagnosis to comply with the regulatory limits, resulting in longer repetition even if they are morphologically indistinguishable from healthy times, lower flip angles or reduced number of acquired slices. nodes. There is a potential role, for example in diagnosing lym- There is no evidence of long-term physiological effects of UHF phatic metastasis in breast cancer. In Figure U.1, signal loss fol- exposure (International Commission on Non-Ionizing Radiation lowing administration of ferrumoxtran-10 demonstrates uptake of Protection, 2017; European Parliament and Council, 2013). The the agent, indicating that the lymph node is healthy. transient effects are mainly nausea, dizziness, magnetophos- U Unlike larger superparamagnetic particles, USPIOs are gen- phenes, or a metallic taste; there is a large intersubjective vari- erally too small to accumulate in the reticuloendothelial system, ability of the reported discomfort. From a practical point of view, and so have a long half-life in blood. Consequently, they are it is important to report the distortion of the electrocardiogram, so promising candidates for intravascular (or blood pool) agents for that cardiac triggering is difficult to perform at UHF. use in MR angiography. The properties of UHF MR imaging create optimal conditions Related Articles: Negative contrast media, Superparamagnetic for the application of advanced MRI methods such as chemical iron oxide, Superparamagnetic particles, Magnetic resonance exchange saturation transfer (CEST), susceptibility weighted angiography (MRA) imaging (SWI), blood oxygenation level dependent (BOLD) con- trast and imaging with nuclei other than hydrogen, that are usually refereed as X-nuclei. In order to perform X-nuclei imaging, dedi- Ultra-high field (UHF) MRI cated hardware is necessary to be tuned to the Larmor frequency (Magnetic Resonance) MRI systems operating at static field of the nucleus under investigation (RF amplifiers, transmitter and strengths of 0.5 T or 1 T have been generally referred to as ‘low receiver coils). The low concentration and the low gyromagnetic field’ systems while MRI systems operating at field strengths of ratio of the X-nuclei result in reduced SNR and spatial resolution. 1.5 T or 3 T have been defined as ‘high field’ systems. Currently, 23Na MRI has been applied in brain and musculoskeletal clinical the majority of the clinical units are high field systems. In recent studies and MR images from 17O, 35Cl and 39K have been obtained years, human MRI systems are available operating at magnetic in acceptable acquisition time and including useful information fields of 7 T or higher, and they are referred to as ‘ultra-high field’ for clinical research. (UHF) systems. Sensitivity increases with field strength and con- The enhanced susceptibility artefacts in UHF result in sequently signal-to-noise ratio (SNR) increases in UHF images. increased blood oxygenation level dependent (BOLD) contrast High contrast and spatial resolution can be obtained, with (250 and consequently UHF produces high contrast functional MRI μm)3 isotropic pixel possible. Moreover, the chemical shift is (fMRI) studies with high spatial resolution. 985 Ultra-high field (UHF) MRI 986 Ultra-high field (UHF) MRI (a) (b) FIGURE U.1 Normal axillary lymph node before (a) and after (b) intravenous administration of ferrumoxtran-10 contrast agent. TABLE U.1 A Partial Overview of Potential Pros and Cons When Increasing the Magnetic Field Strength Characteristic Trend as B0 ↑ Pro Con SNR ↑ Higher resolution, shorter scan time, None X-nuclei feasible SAR ↑ None Fewer slices, smaller flip angle, longer TR, longer breathhold Physiological side-effects ↑ None Dizziness, nausea, metallic taste Relaxation times T1 ↑a TOF, ASL, cardiac tagging Longer scan time T2 ↓b DWI, DTI U T2*↓ SWI, BOLD RF field uniformity ↓ Parallel reception Position-dependent flip angle, poor inversion, unexpected Parallel transmission contrast Susceptibility effects ↑ BOLD, SWI, T2* Geometric distortions, intravoxel dephasing Chemical shift ↑ Fat saturation, CEST, MR spectroscopy Fat/water and metabolite misregistration Source: Reproduced from Ladd et al., 2018, under the licence http: / /cre ative commo ns .or g /lic enses /by -n c -nd/ 4 .0/ Note: A partial overview of potential pros and cons when increasing the magnetic field strength. Note that the consequences – pro or con – may depend on technical and anatomical details. a Although for most applications T1 increases with B0, an increasing contribution from chemical shift anisotropy can also result in a decrease in T1 relaxation times (e.g. in 31P MRS; cf. Section 6.1). b Although for most applications T2 decreases with B0, for quadrupolar nuclei T2 can also increase with field strength (cf. Section 6.1). In Table U.1, the UHF effects on some physical parameters of (ed.), Official Journal of the European Union, L 179/1, pp. 1–2; MR images are reported (Ladd et al., 2018). International Commission on Non-Ionizing Radiation Protection. Related Articles: Magnetic susceptibility, Image uniformity, 2017. ICNIRP statement on diagnostic devices using non-ionizing Susceptibility, Static field, SAR, Susceptibility weighted imaging radiation: Existing regulations and potential health risks. Health (SWI), Blood oxygenation level dependent contrast (BOLD) Phys. 112:305–321. doi:10.1097/HP.0000000000000654; Inter- Further Readings: European Parliament and Council. 2013. national Electrotechnical Commission. 2015. Medical electrical Directive 2013/35/EU of 26 June 2013 on the minimum health equipment Part 2–33: Particular requirements for the safety of and safety requirements regarding the exposure of workers to the magnetic resonance diagnostic devices, in: IEC (ed.), 60601-2-33, risks arising from physical agents (electromagnetic fields), in: EU Edition 3.2; Ladd, M. E. et al. 2018. Pros and cons of ultra-high- Ultrashort echo-time (UTE) 987 Ultrasonography field MRI/MRS for human application. Prog. Nucl. Magn. Reson. are broad [short T2]), dedicated pulse sequences have to be care- Spectrosc. 109:1–50. https :/ /do i .org /10 .1 016 /j .pnmr s .201 8 .06. 001; fully tuned to consider that off-resonance excitations and long RF United States Food and Drug Administration. 2014. Criteria for pulses may affect the long and short T2 components in different significant risk investigations of magnetic resonance diagnostic ways (Tyler et al., 2007). devices, in: FDA (ed.), Guidance for Industry and Food and Drug Finally, the exact gradient wave-form played out is important Administration Staff. in UTE, since any deviations from the planned k-space trajectory will negatively affect image quality. Ultrashort echo-time (UTE) The figure and the caption are reproduced from Fabich et al. (Magnetic Resonance Imaging) Ultrashort echo-time (UTE) (2014), an open access article under the CC BY license (http: / /cre pulse sequences are based on the free-induction-decay and enable ative commo ns .or g /lic enses /by /3 .0/). echo-time values in the range between 0.5 ms down to as short Related Articles: Relaxation times, k-space, k-space trajecto- as 5 μs, depending on the MR-system. There is a minimum time, ries, Saturation the so-called ‘deblank time’, just after signal excitation when no Further Reading: Du, J. and G. M. Bydder. 2013. Qualitative data sampling can be performed. The UTE sequences are used for and quantitative ultrashort-TE MRI of cortical bone. NMR imaging tissues or tissue components with very short T2s, such as Biomed. 26:489–506. doi:10.1002/nbm.2906; Fabich, H. T., M. cortical bone (T2 ~ 0.5 ms) or proteins (T2 ~ 0.1 ms) (Robson et Benning, A. J. Sederman and D. J. Holland. 2014. Ultrashort echo al., 2003). In order to minimise the nominal echo time, k-space time (UTE) imaging using gradient pre-equalization and com- can be sampled radially with signal acquisition starting immedi- pressed sensing. J. Magn. Reson. 245:116–124. http: / /dx. doi .o rg ately after the excitation pulse (see Figure U.2), without any phase /10 .1016 /j .jm r .201 4 .06. 015; Robson, M. D. et al. 2003. Magnetic encoding gradient between the excitation pulse and data sampling resonance: An introduction to ultrashort TE (UTE) imaging. J. (Fabich et al., 2014). Comput. Assist. Tomogr. 27:825–846; Tyler, D. J. et al. 2007. For very short T2 tissue components, decay will occur already Magnetic resonance imaging with ultrashort TE (UTE) PULSE during signal excitation, resulting in a lower than expected sequences: Technical considerations. J. Magn. Reson. Imaging observed magnetisation. In order to still observe these compo- 25:279–289. doi:10.1002/jmri.20851 nents, alternative techniques that suppress the signal of long T2 components can be employed. Dual echo acquisition with Ultrasonic field later echo subtraction is a simple and effective approach to sup- (Ultrasound) The ultrasonic field is the spatial extent of ultra- press long-T2 signals in UTE imaging (Du and Bydder, 2013). sound energy from a source. The transducer can be modelled as Furthermore, long-T2 saturation techniques can be applied. It a summation of an infinite number of point sources, and the total must be noted that since the line shapes of the components vary field is then the summation

of the field from all these sources. widely in width (i.e. components that are normally observed by Rather arbitrarily, the field is usually divided into a near and MRI are narrow [long T2], and those that are usually invisible a far field, separated at a distance, which corresponds to the position of the last maximum of the near field. For a circular plane transducer, this occurs at an axial distance of a2/λ from the surface (where a is the radius of the transducer and λ is the wavelength). Ultrasonic output (Ultrasound) Several parameters are commonly used to describe the ultrasonic output. For safety in diagnostic ultrasound, the two U indices mechanical index (MI) and thermal index (TI) are used to describe the risk with the chosen control settings. These two indices depend on the parameter’s frequency and peak negative acoustic pressure (MI) and acoustic power (TI). The parameters are most often adjusted automatically depending on which trans- ducer and which type of diagnostic measurement that have been chosen. However, the operator can affect the total power and the peak negative acoustic pressure with the output power control, which varies the amplitude of the electrical transmit signal to the transducer. If the electrical transmit signal is increased, the trans- ducer produces higher intensity sound waves, and the sensitivity of the scanner is increased. Related Article: Acoustic power Ultrasonography (Ultrasound) Ultrasonography describes the use of ultrasound, specifically medical diagnostic ultrasound. It is often abbrevi- ated to sonography. The term ‘ultrasound’ describes sound fre- quencies, which are inaudible to the human ear, that is above 20 FIGURE U.2 (a) Two-dimensional UTE imaging sequence. A ramped, half Gaussian, slice selective, soft pulse is used for excitation. Two excita- kHz. Typically, the frequencies used range from 2 to 20 mHz. An tions are used for each line acquired in k-space to produce a Gaussian- advantage of ultrasound over other diagnostic imaging modalities shaped slice selection. (b) k-space is mapped radially by varying the is that it is relatively inexpensive and is safe; it does not use ion- strength of the x and y gradients. (Reproduced from Fabich et al., 2014.) ising radiation and does not usually require contrast agents. An Ultrasound 988 Ultraviolet radiation often-quoted disadvantage is that it is user dependent, meaning For diagnostic ultrasound, the study of safety is broadly the acquisition and interpretation of ultrasound images depend divided into the following: upon the training and skill of the operator. • Understanding of mechanisms – predominantly heating Ultrasound (link) and cavitation (link) and their effects on tissue (Ultrasound) Ultrasound is sound above the threshold of human • Understanding of the likelihood of the mechanisms hearing. While this varies between individuals, ultrasound is gen- occurring in vivo and the relationship of output to heat- erally described as sound over 20 kHz, the upper limit of hearing ing and cavitation effects for healthy young adults. • Accurate measurement of ultrasound outputs (link) Ultrasound occurs in the natural world (bats use frequencies • Epidemiological studies of those undergoing ultrasound up to 100 kHz) and has extensive industrial applications including scans cleaning, flaw detection and sonochemistry. Diagnostic ultrasound uses frequencies from 1 to 20 MHz Ultrasound safety has been addressed by the US Food and Drug for imaging and Doppler applications although specialist single- Administration (FDA) in association with ultrasound manufac- element transducers have been used at frequencies up to 40 MHz. turers to give recommendations of maximum power and inten- Biomicroscopy transducers up to 75 MHz have been constructed sity for diagnostic applications. They have also implemented for imaging the anterior segment of the eye. the output display standards (ODS) of TI and MI (link) as a At higher power, ultrasound is also used for medical therapy: guide to users as to relative output and possible associated risk. National and international societies including the American • Physiotherapy ultrasound devices operate at higher Institute of Ultrasound in Medicine (AIUM) link, British intensities than diagnostic systems and at frequencies Medical Ultrasound Society (BMUS), European Federation of from approx. 0.8 to 3 MHz. Societies of Ultrasound in Medicine (EFSUMB) and the World • High-intensity focussed ultrasound (HIFU) uses focussed Federation of Ultrasound in Medicine and Biology (WFUMB) transducers operating from 0.5–3 MHz to destroy patho- have all issued guidelines for the duration and outputs used in genic tissue by heating and cavitation. Time-averaged diagnostic examinations. intensities are typically 5,000–25,000 W/cm2 (compared Further Reading: Ter Haar, G. and F. A. Duck. 2000. The with diagnostic ultrasound <1 W/cm2). Safe Use of Ultrasound in Medical Diagnosis, BMUS/BIR Publications, London, UK. Ultrasound, Doppler (Ultrasound) See Doppler ultrasound Ultrasound-guided brachytherapy (Ultrasound) Brachytherapy, used in the treatment of cancers, Ultrasound, pulsed involves the placement of small radioactive sources referred to (Ultrasound) See Pulsed ultrasound as seeds or pellets inside the body. The source may be introduced Ultrasound real time with a catheter, needle or special applicator. Ultrasound, x-ray or (Ultrasound) The term ‘real time’ refers to an ultrasound scan CT is used to position the seed accurately in the desired location. where the image is shown and updated as the scan is being Imaging may be subsequently used to verify the position of the performed. Early ultrasound scans were often obtained over source. Cancers throughout the body are treated in this fashion, several seconds or minutes from single transducers moved a typical example where ultrasound is used is in the treatment of slowly in relation to the target. With rotational swept trans- cancer of the prostate. U ducers and then array transducers, images that were updated several times a second were enabled. Modern ultrasound scan- Ultraviolet light (NIR) ners show tissue in real time and allow movement to be imaged See Ultraviolet radiation (RP) and measured. Related Articles: B-mode, Colour flow imaging, M-mode Ultraviolet radiation (Radiation Protection) Ultraviolet radiation is the part of the elec- Ultrasound safety tromagnetic spectrum between visible light and x-rays. The UV (Ultrasound) Ultrasound is widely used in healthcare for diag- spectrum ranges from 100–400 nm (Figure U.3). It is considered nostic and therapeutic applications. The term ‘ultrasound safety’ to be non-ionising radiation and is further split into different types encompasses the design and operation of ultrasound systems to of UV depending on the wavelength: ensure no or minimal adverse biological effects in clinical use. Some users and authors suggest that the term should include the • UVA ranges from 400–315nm scope of ultrasound practice and diagnostic competency and • UVB ranges from 315–280nm argue that the greatest risk from diagnostic ultrasound lies in its • UVC ranges from 280–100nm inappropriate use or errors of diagnosis. While this argument has merit, the term ‘ultrasound safety’ generally refers to issues of The major source of natural UV radiation is, of course, the sun. possible biological effects. UVA comprises 95% of solar UV that reaches the surface of the Ultrasound is a form of energy that causes thermal and Earth. UVB has a higher effective energy but only comprises 5% mechanical effects in tissue. There is no evidence that diagnos- of solar UVR reaching the Earth’s surface. The absolute amount tic ultrasound has been harmful to patients to date. Therapeutic of UVB reaching the Earth's surface varies considerably with alti- ultrasound has higher outputs, and physiotherapy systems may tude, latitude, and by the state of the ozone layer, cloud cover and use vibration or temperature to achieve its effects, but there is no pollution. UVC has the highest effective energy but does not reach evidence that this causes damage to tissue. At much higher out- the Earth’s surface and is therefore biologically irrelevant except puts, HIFU is used to destroy tissue by heating. when artificially produced. If an individual is exposed to UVC, Unblanking 989 Underexposure FIGURE U.3 Light spectrum. the radiation is absorbed in the keratin in the epidermis, and can Unblanking cause damage to DNA. (General) A cathode ray tube in a display monitor or oscilloscope When the solar spectrum is depicted in terms of the relative operates by repeatedly directing an electron beam onto the phos- ability of each UV band to cause erythema (sunburn), UVB is phor coating on the front inside of the screen. This causes light to responsible for 93% of the erythema and UVA for 7%, i.e. whilst be emitted through the front glass of the device. However, the per- UVB comprises only 5% of the solar spectrum, it is responsible sistence of the phosphor is generally short (a few milliseconds), for 93% of the erythema in sunburn. and so the device must rewrite the same or similar information UV radiation is produced artificially and used in industrial frequently (usually at least 25 times a second) to produce a stable applications, and medically in a dermatology department to treat image. a range of skin conditions. It is of course also used in sunbed tan- This requires the writing beam to retrace its position fre- ning units. quently so as to be ready to write the next trace. However, this Related Articles: AORD, ICNIRP, Light source, ‘retrace’ should NOT be visualised, so the electron beam must Electromagnetic radiation, Non-ionising radiation be blanked at all times except when relevant brightness signals Further Readings: ICNIRP website, www .i cnirp .org/ en are available to be written, and the beam is falling on the correct /fr equen cies/ infra red /i ndex. html; Ihrke, I., J. Restrepo, and screen area. L. Mignard-Debise (2016). Principles of light field imaging: Unblanking is the term used to describe this process and cor- Briefly revisiting 25 years of research. IEEE Signal Processing rectly implies that the natural, safe, standby position for a CRT is Magazine 33(5):59–69; Kitsinelis, S., Kitsinelis, S. (2015). Light the ‘blanked’ state. Sources: Basics of Lighting Technologies and Applications. CRC Press; Czapla-Myers, J. S., K. J. Thome, and S. F. Biggar Uncontrolled area (2008). Design, calibration, and characterization of a field radi- (Radiation Protection) An uncontrolled area (also known as ‘non- ometer using light-emitting diodes as detectors. Applied Optics designated area’) is an area that is undesignated, it has no dose 47(36):6753–6762. limit and is open for all to occupy and use. Some rooms require designation in order to ensure safety from radiation towards mem- Unblanking bers of the public or staff. (Diagnostic Radiology) Usually, the imaging chain of an x-ray Related Articles: Controlled area, Supervised area. video system (including image intensifier, optics, TV tube, moni- Hyperlink: https :/ /me dical -dict ionar y .the freed ictio nary. com / tor, etc.) displays some images with slight contrast degradation U u ncont rolle d +are a at the edge of the image. This effect is known as vignetting (see the eponymous article). Additionally to it, the stop of the scan- ning electron beam at the edge of the image creates a small white Underdevelopment line at this place. In order to reduce these distortions of image, (Diagnostic Radiology) There is an optimum level of chemical some manufacturers apply over the image a black circle, known development for each type of radiographic film that produces as blanking circle. This way only the signal inside this circle pres- the desired sensitivity (speed) and contrast. Underdevelopment ents an image, and the signal outside the circle is presented with 0 of film results in reduced sensitivity and usually a reduction in (i.e. total black). This way the blanking circle diameter is slightly contrast. An undeveloped film can appear to be underexposed as smaller than the image intensifier field size diameter. The blank- illustrated in Figure U.4. ing circle moves together with the zooming (field size). Part of Another undesirable consequence of underdevelopment is that the blanking circle is well seen at Figures H.14 and H.15 (down, the exposure might be increased in an attempt to compensate for middle-right) in the article High contrast. what is a processing problem. The level or degree of development Although the blanking circle presents an image well per- is determined by the design of the film, composition of the devel- ceived by the human eye, the area outside the circle (between the oper chemistry, development time and the developer temperature. outer edge of the circle and the outer edge of the filed size) still Quality assurance procedures are used to determine if a pro- receives radiation – that is small part of the patient is x-rayed but

cessor is producing the appropriate level of processing. not visualised. Due to this reason, the precise adjustment of the blanking circle is very important. Removing the blanking circle Underexposure (or ‘unblanking’) is necessary for adjustment and other techni- (Diagnostic Radiology) Underexposure is a condition in which an cal purposes, as well as for assessment of this irradiated, but not x-ray image receptor has received less than the exposure required imaged part of the patient. to produce an image with the desired quality. For most medical Related Articles: Video signal, Vignetting, Image intensifier procedures using radiation there is usually an optimum amount of Undersampling 990 Undertable cassette carriage exposure that produces the necessary image quality. In film radi- the Nyquist–Shannon theorem is violated, and undersampling ography underexposure results in reduced film density and a pos- occurs. The result is usually a lossy reconstruction of the signal in sible reduction in contrast. In digital radiography, underexposure the spatial domain. However, undersampling also allows for faster of the receptor (below the optimum value) results in increased acquisition and some sort of selective pre-filtering of unwanted image noise. frequencies; this is usually referred to as bandpass-sampling. Radiographs produced with three different exposures are com- Truncation artefacts like ghosting may appear as a conse- pared in Figure U.5. The one on the left appears to be over under- quence of undersampling. These are the results of discontinuities exposed. Compared to the optimally exposed one in the centre, of the spectrum acquired – if a discontinuity is encountered, for the underexposed radiograph has much less contrast and visibility instance, by cutting-off frequencies, or by limiting the domain of the anatomical structures. of the discrete Fourier transform, high-frequency artefacts show up; this is known in general as Gibbs phenomenon, which is well Undersampling known in MR imaging when dealing with anatomical areas where (Magnetic Resonance) According to the Nyquist–Shannon theo- sudden changes in contrast occur. In electronics, Gibbs phenom- rem, which is a fundamental principle of information theory, the enon is also known as ringing. Ring or ripple-like artefacts may sampling frequency of a signal to be discretised has to be twice also be observed in MRI (Gibbs ringing). the bandwidth (the difference between maximum and minimum frequency). It is therefore important to know the maximum fre- Undertable cassette carriage quency of the signal – which is, in medical imaging, usually given (Diagnostic Radiology) X-ray radiography systems using x-ray by the resolution of the image to be acquired since all transforms tube mounted above the patient table are equipped with an to k-space (i.e. the Fourier domain) are performed by means of undertable cassette carriage. This carriage is mounted under the a discrete Fourier transform. If an image signal is sampled with anti-scatter grid of the Bucky device. The carriage has a drawer- a readout frequency of less than the required double bandwidth, holder that moves in/out to load/remove the x-ray film cassette (Figure U.6). Related Articles: Radiography, Bucky table Under Correct U FIGURE U.4 Comparing an underdeveloped radiograph to one that has been correctly processed. There is a significant loss of contrast especially in the lighter areas. FIGURE U.6 Undertable cassette carriage. 70 kVp, 25 mA s 70 kVp, 50 mA s 70 kVp, 80 mA s FIGURE U.5 Radiographs produced with different exposures. Undertable fluoroscopy 991 Uniformity Related Articles: Radiography, Fluoroscopy, Undertable fluo- roscopy, Overtable radiography Unenhanced image (Magnetic Resonance) This term relates simply to an image that has not been enhanced by the use of an exogenous contrast agent. In clinical practice, it is common to collect an unenhanced ‘base- line’ image prior to administration of contrast agent. The flexibil- ity of MRI in terms of the information content of images and the ability to manipulate contrast through pulse sequence design also means that there is a greater role for unenhanced imaging than is the case with x-rays. Related Article: Contrast agent Ungrounded (General) Systems or devices that have no direct electrical con- nection to Earth. Related Article: Earthing Uniformity (Diagnostic Radiology) In a CT image, the term ‘uniformity’ refers to the scan plane variation of CT numbers in a homogenous object, usually a water phantom. There will be some inherent FIGURE U.7 Undertable fluoroscopy system. (Courtesy of EMERALD variation due to stochastic noise, but the mean CT number value project, www .emerald2 .eu) in regions of interest (ROIs), positioned at any point within the FOV, should be relatively constant. Uniformity can either be assessed by plotting a CT number Undertable fluoroscopy profile across the phantom diameter (Figure U.8) or by placing (Diagnostic Radiology) Undertable fluoroscopy x-ray systems ROI at the centre and peripheral regions and comparing the mean use x-ray tube mounted under the patient table and image inten- CT number in each ROI. sifier (II) above the patient table (Figure U.7). These are the The Institute of Physics and Engineering in Medicine (IPEM) most often used fluoroscopic systems, as the operation of the recommends that the variation in mean CT number between a fluoroscopy is conveniently placed over the II, what allows ROI at the centre, and one at the periphery, of a uniform phantom, the radiologist/radiographer to easily guide the investiga- should not be more than ±10 HU and ±20 HU in head-sized and tion. Another advantage of these systems is the fact that the body-sized phantoms, respectively. II absorbs most of the scatter radiation from the patient. This Poor uniformity is usually caused by artefacts such as beam way, the undertable fluoroscopy x-ray systems expose the staff hardening or ring artefacts. to much lower dose from scattered radiation. For example, in Related Articles: Beam hardening, Ring artefact such a system, the scattered radiation dose rate is of the order Further Reading: IPEM (Institute of Physics and Engineering of 1 μGy/min at 1 m from the patient. In comparison, an overt- in Medicine). 2005. Recommended standards for the routine able fluoroscopic system will have at the same place approx. 20 U times higher dose rate. In the case of overtable fluoroscopy, the x-ray tube is in front of the patient, and it is possible to have mounted in front of it a remote-controlled pressing device (also called palpator). This device is useful for some investigations, for example to move the barium meal in the stomach. Overtable fluoroscopy also allows for larger focus-patient distance. The multifunctional C-arm-mounted fluoroscopic systems move the x-ray tube at various positions around the patient. Related Articles: Radiography, Fluoroscopy Further Reading: Coulam, C., J. Erickson, D. Rollo and A. James eds. 1981. The Physical Basis of Medical Imaging, Appleton-Century-Crofts, New York. Undertable radiography (Diagnostic Radiology) Undertable (undercouch) radiography uses x-ray tube mounted under the patient table. This installation is usually associated with fluoroscopic units with overtable image intensifier. These systems produce considerable less scattered radiation (from the patient) in comparison with the systems where the image intensifier is below the patient table (see the article on FIGURE U.8 Image of homogenous water phantom showing good uni- Undertable fluoroscopy). formity. (Courtesy of ImPACT, UK, www .impactscan .org) Uniformity 992 United Nations Scientific Committee on the Effects performance testing of diagnostic x-ray imaging systems, IPEM V V Report 91, York, UK. Uniformity 0 0 (Magnetic Resonance) Uniformity can be used in a number of t t ways in magnetic resonance imaging. The first is the uniformity (a) (b) of the main magnetic field and the RF field. The uniformity of the main magnetic field is an important criterion of the quality of the magnet as non-uniformities will often lead to image arte- FIGURE U.9 Examples for (a) unipolar and (b) bipolar signals. facts. The main feature that affects RF uniformity is the RF coil. Structures close to the surface can be imaged with the use of a surface coil, which is not uniform, while internal structures often Related Article: Intrinsic flood field uniformity use a volume coil, which provides the most uniform RF field. Further Reading: Cherry, S. R., J. A. Sorenson and M. E. Signal and SNR uniformity measures are used in quality con- Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, trol tests to monitor scanner performance. Uniformity of image Philadelphia, PA, pp. 234–238. signal looks at the variation of image signal intensity over an image. Uniformity of SNR looks at the variation of SNR over Unipolar output an image. These tests ensure there is a constant signal and SNR (General) A unipolar output normally refers to an electronic across an image slice and that there are no image artefacts present. device capable of accepting or providing an output, which has one Abbreviations: RF = Radiofrequency and SNR = Signal to polarity (0 to +X volts or 0 to −X volts). This is a common form of noise ratio. output and is easy to understand and process when the parameter Related Articles: RF uniformity, Field uniformity it is representing is also unipolar (Figure U.9). When analogue-to-digital converters (ADC) are used, uni- polar ADCs accept only unipolar signals and output only an Uniformity unsigned binary number from zero to some predefined maximum. (Nuclear Medicine) Uniformity is an imaging detectors capabil- When a parameter to be represented electronically varies ity of depicting a homogenous distributed flood source. There are through both positive and negative values, a bipolar input and two primary causes for non-uniformity in a scintillation camera. output may be necessary, though this sometimes poses design The first one is non-uniform detection efficiency, which arises problems. from (1) the small difference in PM tube pulse height spectrum (or If a unipolar device (such as an amplifier or ADC) is to be used PM tube response) and (2) the position dependence of scintillation with a bipolar input signal, a reference voltage must be added to light collection efficiency, that is events occurring perpendicular ‘offset’ the signal prior to digitisation. A common standard is to to one of the gaps between two PM tubes will register a lower add a reference voltage equal to half the maximum input range of pulse than events originating perpendicular to the centre of a PM the ADC, thereby providing an output in ‘offset binary’. tube. The PM tube response can be tuned so the effect is mini- In digital electronics, the term ‘unipolar output’ may have a mised. The position-dependent efficiency is hard to compensate different meaning, referring to the inability of the logic device to for. The best way is to minimise the gap between the tubes and not both actively pull up and pull down any attached load, which may to use the FOV close to the physical PM tube edge. be connected. In such cases, it is important to make sure some The second cause for non-uniformity is image non-linearities, other method such as a ‘pull up’ or ‘pull down’ resistor is attached that is when straight line objects appear to be curved in the image. to that output to ensure that both logic states are detectable at the U They occur when the X- and Y-position does not change linearly output. with the position across the face of the detector. Nonlinearities can occur for a number of reasons, for example difference in sensitivity among the PM tubes, non-uniformity in optical light United Nations Scientific Committee on the guides and PM tube or electric malfunctions. Effects of Atomic Radiation (UNSCEAR) Another case of non-uniformity is a bright ring around the (General) The UNSCEAR is part of the United Nations (UN) and edge of the image. This characteristic artefact is called edge pack- reports directly to the General Assembly. ing and results from a small increase in light collection efficiency UNSCEAR was founded in 1955 with the mandate to assess for events originating close to the crystal edges. Light photons and report levels and effects of exposure to ionising radiation, can be reflected at the crystal edge surface and then registered in within the UN system. The UNSCEAR reports are considered one of the PM tubes. Regions demonstrating this effect are often as basis for the evaluation of radiation risk and therefore for the masked because they occur in the outer region of the FOV leaving implementation of adequate radiation protection. only the useful FOV. The UN General Assembly designates the countries from In planar emission imaging, the effect of detector non-unifor- where the scientists, who are going to be

members of the com- mity is relatively low (compared to tomographic emission imag- mittee, are coming from. The work program is also approved by ing). Acceptable variation in count rate in a flood-field image can the UN General Assembly and typically extends over a period of be ±10% or more. In tomographic imaging, non-uniformity can 4–5 years. lead to characteristic ring-artefacts. It is therefore customary to The secretariat is based in Vienna and is functionally linked use a uniformity correction on patient data. Uniformity should be to the United Nation Environmental Program (UNDP). The main measured as a part of the routine quality control. Data from the function of the secretariat is to organise the annual sessions and quality control are then used to update the uniformity correction. to prepare the documents for the committee scrutiny. The sec- An effective uniformity correction can justify the use of smaller retariat collects relevant data submitted by UN Member States, PM tubes and thinner light guides to improve the event localisa- international and non-governmental organisations and engages tion and intrinsic spatial resolution. specialists to analyse data, study the scientific literature and Universal wedge 993 Unsharp masking produce scientific reviews. The scientific reviews are then submit- Unsharp masking ted to each UNSCEAR session, and at the end of the process, the (Diagnostic Radiology) Unsharp masking is a software method substantive reviews are published. used in digital subtraction angiography (DSA). The method is The committee has published important scientific documents, specially useful for cardiac angiographic examinations. In this starting with the two reports produced in 1958 and 1962, which method, the mask image (the one to be subtracted from the image were the basis for the signature of the Partial Test Ban Treaty on with maximal contrast) is formed as a superimposed image. As this the prohibition of nuclear weapon tests in the atmosphere. Other mask is superimposed, it is with unsharp contours (over-smoothed important reports were published on the assessment of radiation image). On the contrary, the image with maximal contrast repre- exposures and health effects following the Chernobyl accident in sents the cardiac muscle at specific moments of the cardiac cycle – 1986. In fact, a first report was published in 1988 on acute radia- that is the contours of each image are different. When the unsharp tion effects in emergency workers and on the global exposures. mask is subtracted from these images with varying contours, the A more detailed assessment of radiation levels and effects was resultant subtracted images have similar blurring of their contours/ published in 2000. edges, which facilitates the visual representation of the movements The latest UNSCEAR program includes the evaluation of risk in the subtracted image. As a whole, the unsharp masking results from exposure to radon, epidemiological studies on radiation- in an overall image noise reduction. Different manufacturers apply induced cancer and non-cancer effects, radiation effects on the different image processing algorithms for unsharp masking. immune system, etc. The latest report will be published next year. An example is shown in the following. Figure U.11 shows a UNSCEAR is a member of the Inter-Agency Committee on DSA image of the heart (subtraction between the images from Radiation Safety (IACRS). exposure 40 and exposure 25). With this fixed subtraction, two Hyperlink: http://www .UNSCEAR .org images of one and the same vessel are presented (light and dark). Figure U.12 (from the same DSA examination) shows unsharp Universal wedge (Radiotherapy) A universal wedge is one of a given angle that is fixed in a beam for all beam widths up to a given size. See Figure U.10. When a small field is used, only a small thickness of wedge is needed to produce the tilt in the isodose plot. The remainder of the wedge thickness attenuates the beam and results in a reduction of dose rate. Unsealed source (Nuclear Medicine) Unsealed source, or open source, refers to a radioactive source, which is not encapsulated or otherwise con- tained. From a radioprotection point of view, an unsealed source can lead to contamination if not handled properly. In nuclear med- icine, radionuclide solutions and radiocompounds are unsealed sources. Radiotherapy when using an unsealed source is also referred to as unsealed source therapy. The opposite of an unsealed source is a sealed or closed FIGURE U.11 DSA image of the heart vessels without unsharp mask- U source. ing. (Courtesy of EMERALD project, www .emerald2 .eu) Related Article: Sealed source FIGURE U.10 A universal wedge where the wedge is fixed in the centre of the beam and the field can be opened to just about any size. The unused FIGURE U.12 DSA image of the heart vessels with unsharp masking. segment only serves to reduce the beam dose rate. (Courtesy of EMERALD project, www .emerald2 .eu) Unsharpness 994 UV radiation mask (subtraction between image 40 and an integrated sum of Further Readings: 2005. Structural Shielding Design and several other images). With this unsharp masking, the image of Evaluation from Megavoltage X- and Gamma-Ray Radiotherapy the vessels is clearly shown as one structure. Facilities, No. 151; IAEA. 2006. Radiation Protection in the Design of Radiotherapy Facilities, No. 47. IAEA, Austria; IPEM. Unsharpness 2017. Design and Shielding of Radiotherapy Treatment Facilities, (Diagnostic Radiology) Unsharpness is a characteristic of an IPEM Report 75. IOP Publishing. image resulting from blurring. In such an image, structures, Hyperlinks: Medical Radiology: https :/ /rr cmrt. wordp ress. objects and edges appear to be ‘unsharp’. com /2 011 /1 0 /27/ use -f actor -occu pancy -fa ct or -wo rkloa d/ Related Articles: Detail resolution, Geometric unsharpness Useful beam Use factor (Radiotherapy) The x-rays produced when the electron beam is (Radiotherapy) Radiotherapy facilities must be properly shielded incident on the target are predominantly in the forward direction in order to limit radiation exposures to members of the public and (towards the patient). However, while these x-rays are of benefit employees to an acceptable level. The NCRP Report No. 151 pro- in forming a beam (following some further modifications and vides technical data and recommendations regarding the design shaping), which may be of use for patient treatment, the x-rays and installation of structural shielding for high-energy x-ray and produced in the other directions are of no benefit. Therefore, a gamma-ray radiotherapy facilities. According to this report, for significant amount of shielding is in place in the head of a linac calculation of the design of primary and secondary barriers, it to reduce the dose from these other x-rays and provide a clearly is necessary to consider various factors such as workload W, use defined treatment field. This treatment field is known as the useful factor U and occupancy factors T. The barrier thickness (B) can beam, that is the beam that is used to irradiate the patient. be calculated as follows: Related Articles: Collimation, Collimator, Primary collimator Pd2 Useful field of view (UFOV) B = n = -log(B) t = TVL1 + (n -1)TVLeq (Nuclear Medicine) The FOV is the maximum image size that WUT the image system is capable of imaging. Only a portion of the FOV is suited for imaging or activity quantification. This por- P = shielding design goal (expressed as dose equivalent) tion is referred to as the useful field of view. The UFOV is deter- beyond the barrier mined by irradiating a detector with a uniform flood source. The d = distance from the x-ray target to the point protected (m) UFOV is the area where the uniformity does not deviate more U = use factor than 10% from a ROI placed in the central area of the image field. T = occupancy factor for the protected location of fraction of The UFOV is typically 80% of the total FOV. Using a scintilla- the worktime that a person is present beyond the barrier tion camera, artefacts close to the edges prevent any use of that W = workload or photon-absorbed dose delivered at 1 m from information. In PET, the UFOV is determined by the number of the x-ray target opposite elements used in the fan-beam acquisition. t = the barrier thickness During the quality control of the camera system, the resolu- TVL1 = first tenth-value-layer tion, linearity and uniformity are measured over the UFOV and/ TVLe = equilibrium tenth-value-layer or the central FOV. Further Reading: Cherry, S. R., J. A. Sorenson and M. E. The use factor U or beam direction factor is the fraction of Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, time during which the radiation under consideration is directed at Philadelphia, PA, pp. 411–412. U a particular barrier. The use factor is always equal to one for scat- Related Articles: Centre of field of view (CFOV), Field of tered and leakage radiation because these radiations impinge on view, PET, SPECT the barrier for all orientations of the primary beam. Typical use factors are US guidance (Radiotherapy) Ultrasound (US) guidance is the term indicating that ultrasound images and data are used as a tool for medical Full use U = 1 Floors of radiation rooms except dental procedures different from diagnostic purposes. installations, doors, walls and ceilings of radiation rooms exposed routinely to the User interface primary beam (Diagnostic Radiology) The user interface is a very broad term Partial use U = 1/14 Doors and walls of radiation rooms exposed associated with any human information exchange with a machine. routinely to the primary beam, also floors of In computers, the user interface is the way graphical, or other dental installations information is delivered by the software to the operator and, Occasional U = 1/16 Ceilings of radiation rooms not exposed respectively, the way the operator submits his commands to the use routinely to the primary beam. Because of software. Often the user interface is called also control panel the low use factor, shielding requirements (physical or software). for a ceiling are usually determined by secondary rather than primary beam USPIO considerations (Magnetic Resonance) See Ultrasmall particles of iron oxide (USPIO) Related Articles: Tenth-value layer (TVL) in shielding mea- UV radiation surements, Occupancy factor, Treatment room, Maze, Workload (Radiation Protection) See Ultraviolet radiation UTE (Ultrashort TE) 995 UV light hazard FIGURE U.13 Direct method measurement (a) indirect method measurement (b). UTE (Ultrashort TE) (UV), have enough energy to induce photochemical damage and/ (Magnetic Resonance) See Ultrashort TE (UTE) or mutations in the cells. The most common short-term effect of UV on the skin is ery- UV dosimetry, phototherapy thema, which is caused by a swelling of the skin capillaries. The (Non-Ionising Radiation) Ultraviolet (UV) dosimetry is the regu- UV damage is cumulative, and if not completely repaired by the lar practice recommended by NICE of measuring the light output skin repair mechanisms can lead with repetitive exposure to long- (irradiance) of a UV phototherapy unit by means of a calibrated term effects such as elastosis, or skin cancer. radiometer, whose calibration is traceable to a national standard. Whilst the typical short-term effects on the eye are photokera- There are two main methods of measurements: one direct titis which is a burning of the cornea and/or inside of the eyelid; method which consists in entering the phototherapy cabinet wear- and the most observed long-term effect is cataractogenesis (i.e. ing protective clothing and equipment, and one indirect method formations of cataracts). which exploits the use of a tripod. The cabin irradiance is not Related Articles: AORD, Eye, Lens, Skin cancer uniform and it changes with height and direction. Therefore, the Further Readings: Coleman, A., F. Fedele, M. Khazova, estimation of the dose is based on an average of a set of measure- P. Freeman and R. Sarkany. 2010. A survey of the optical haz- ments which can range to a minimum of 4 (one per each panel) to ards associated with hospital light sources with reference to the 24 or more (Figure U.13). Control of Artificial Optical Radiation at Work Regulations 2010. U Related Articles: Irradiance, Light Source, Photodiode, J. Radiol. Prot. 30(3):469; ICNIRP A closer look at the thresholds Phototherapy, Radiometer of thermal damage: Workshop report by an ICNIRP task group. Further Readings: Moseley, H. et al. 2015. Guidelines Health Phys. 111(3):300–306; 2013. ICNIRP Guidelines on limits on the measurement of ultraviolet radiation levels in ultravio- of exposure to incoherent visible and infrared radiation. Health let phototherapy: Report issued by the British

Association of Phys. 105(1):74–91; 2013. ICNIRP Guidelines on limits of expo- Dermatologists and British Photodermatology Group 2015. Br. J. sure to laser radiation of wavelengths between 180 nm and 1,000 Dermatol. 173(2):333–350; Smith, C. H. et al. 2009. British asso- μm. Health Phys. 105(3):271–295; 2004. ICNIRP Guidelines on ciation of dermatologists’ guidelines for biologic interventions for limits of exposure to ultraviolet radiation of wavelengths between psoriasis 2009. Br. J. Dermatol. 161(5):987–1019. 180 nm and 400 nm (Incoherent Optical Radiation). Health Phys. 87(2):171–186; 2000. ICNIRP Revision of the guidelines on limits UV light hazard of exposure to laser radiation of wavelengths between 400 nm and (Non-Ionising Radiation) The shortest wavelengths in the opti- 1.4 μm. Health Phys. 79(4):431–440; Sihota, R. and R. Tandon. cal radiation (180–400 nm), also known as ultraviolet radiation 2011. Parsons’ Diseases of the Eye, Elsevier, India. V Vacuum focal plane. However, away from the focal zone, the decorrelation (Diagnostic Radiology) A vacuum is an empty space. The name is is more rapid. derived from the Latin, vacuus, meaning empty. Most electronic This theorem is useful for locating regions where the speckle tubes, including x-ray and image intensifier tubes, are evacuated, is well correlated for speckle-tracking applications. It can also be so there is no air or other gases to impede the passage of electrons. used in aberration correction as the coherence of the backscat- Vacuum is measured as pressure in pascals (SI unit, 1 Pa = 1 N/m2) tered field could be used to obtain information about the illumi- or in bars (1 bar = 100 kPa). For example, the vacuum in an x-ray nating beam width. tube is minimum 10−6 mbar. It is necessary so as not to impede the Further Reading: Liu, D.-L. and R. C. Waag. 1995. About flow of electrons, usually from a cathode to an anode. the application of the Van Cittert-Zernike theorem in ultrasonic There is never an absolute vacuum, and the quality of a spe- imaging. IEEE Trans. UFFC 42:590–601. cific vacuum is defined by the pressure of gases, such as air, that are in the space. Variable thickness transducer (Ultrasound) See Slice thickness Valence band (Nuclear Medicine) In semiconductors and isolators, the highest Variable transformer energy band with electrons present at absolute zero is called the (General) A variable transformer is a form of transformer where valence band. The bands are separated by regions with forbidden the number of windings associated with the output circuit can be energy states, which electrons cannot occupy. The band following varied with respect to the number associated with the input. the valence band (i.e. a band occupied by electrons with higher Such transformers are usually autotransformers, having only energy) is called the conduction band. As the name implies, elec- one common winding for both input and output, but with the out- trons in the conduction band take part in the conduction of elec- put connected via one of a selectable set of ‘taps’ or connections tricity. Electrons can be excited up to the conduction band via (Figure V.3). thermal excitation. In metals, these two bands are not separated, In this manner, an efficient device can be made that allows the and metals are therefore generally good conductors. selection of a wide range of AC output voltages for a given fixed Related Article: Conduction band AC input voltage. Most variable transformers are used in mains power circuits, Valve tube rectifier and it should be noted that being autotransformers, they provide (Diagnostic Radiology) Valve tube rectifier, also known as no electrical isolation between input and output. vacuum rectifier, is a rectification circuit that uses vacuum tube Related Article: Transformer diodes. Such rectifiers were often used in high-voltage generators of x-ray equipment, but nowadays are replaced by power semicon- Variable-aperture beam restrictor ductor diodes (Figures V.1 and V.2). (Diagnostic Radiology) See Beam restrictor Related Article: Rectifier Variance reduction techniques Van Cittert–Zernike theorem (Radiotherapy) Variance reduction techniques (VRTs) are (Ultrasound) As first applied in optics, the Van Cittert–Zernike employed in Monte Carlo (MC) modelling to improve the effi- theorem describes the spatial covariance of the field produced by ciency of simulations. Since MC is a numerical method based V an incoherent source. It states that the spatial covariance of the on statistical sampling, the accuracy of its calculations is limited field, sensed at two points X1 and X2 of an observation plane, is by their statistical uncertainty, as given by the (sample) vari- equal to the Fourier transform of the source aperture function. ance. Since the variance decreases with an increasing number of In ultrasound imaging, we may consider the sound scattered particle histories (N) sampled, the accuracy of MC calculations back from a multitude of scattering objects as the incoherent increases with N. source and our observation plane, the transducer face. The energy Simply increasing N in a simulation increases the required distribution radiated in the focal plane from a rectangular aper- computation time, often prohibitively if a useful level of accuracy ture is a sinc-function squared that is the Fourier transform of the is to be reached (increasing N is not considered to be a VRT). aperture function. Thus, sound scattered back from objects in the Rather, VRTs allow the same level of uncertainty to be reached focal plane will have an energy distribution in this form, so in a smaller calculation time, without introducing systematic the spatial coherence at the aperture is, according to the theorem, deviations from the result. VRTs in their common usage could the Fourier transform of this sinc2-distribution. This, in turn, will thus be more accurately referred to as efficiency enhancement be a triangular function with a base being twice the size of the techniques. aperture. This is equal to say that the spatial covariance of the Note that the condensed history approximation for charged backscattered field is proportional to the autocorrelation of the particles, as is employed in almost all modern MC implementa- transmitter aperture function. A consequence is thus that the lon- tions, is a VRT (see the related article for an in-depth description). ger the aperture, the wider the spatial covariance of speckle in the Some other VRTs can be listed and very briefly discussed here. 997 Vector array 998 Vector array U H L1 L2 – AC input AC output Selectable + FIGURE V.3 Variable transformer diagram. FIGURE V.1 Valve tube rectifier diagram. point (but still sampled over the angular and energy distribution of the interaction cross-section), each statistically weighted as 1/Nsplit. An example use of this would be when generating brems- strahlung photons from the target in a linac head. By generating multiple photons from a single electron interaction, the number of electrons which have to be tracked through the target is reduced. Since the vast majority of these electrons do not make it out of the target, the lower number sampled will have a negligible impact on any parameters of interest calculated beyond the target. Interaction Forcing: In photon tracking over a calculation grid of interest, there is no guarantee that any individual photon will interact inside that grid. Where no such interaction occurs, the computational power applied to the generation and tracking of that photon has been wasted. With the appropriate knowledge of mean free path lengths over the voxels of interest (as accounted for using their electron densities and the appropriate linear attenua- tion law), each photon can be forced to interact within the calcula- tion grid without biasing the final result, as long as an appropriate weighting is applied to each photon to account for the fact that the interactions are being oversampled. Electron History Repetition: Electron histories can be pre- FIGURE V.2 Valve tube rectifier from an x-ray generator. computed in a homogenous phantom, and the parameters (e.g. step lengths, multiple scattering angles, energy losses) of each history stored for later use. When later applied to a new simula- Range Rejection: For charged particles, which have a well- tion, these stored histories can be effectively overlayed on the new defined maximum range for a given energy, if that maximum geometry multiple times at different positions and attack angles. range falls below the distance required to reach the next volume Where this new geometry has heterogeneities, appropriate scaling V or sub-volume of interest (e.g. the next dose scoring voxel) within of the stored history parameters must, of course, be performed the simulation, then tracking of that particle can be terminated. dependent on local densities, stopping powers etc. The number Russian Roulette: For a chosen particle/interaction type, of repeats of a given history must also be appropriately limited to it can be decided to simulate only a small proportion of them. avoid too close of an average distance between them, which would When created, the individual particles face a high likelihood of introduce correlations and bias the result. being immediately killed-off from the simulation, with the sur- Related Articles: Condensed history technique, Monte Carlo vivors then carrying an enhanced weighting (in their contribu- method tion to whichever final parameters are being tracked) to account Further Reading: Seco, J. and F. Verhaegen. 2013. Monte for this. Tracking only a subset of particles in this manner frees Carlo Techniques in Radiation Therapy. CRC Press, Boca up a large amount of computation time and is useful where that Raton, FL. particle type can be predominantly ignored without a detrimental effect on the final result. For example, bremsstrahlung photons Vector array created within an electron beam will contribute little dose over (Ultrasound) A vector array is another term for phased array the planning region of interest (instead, contributing to a low- transducer, whereby scan lines are fired from a linear array in dif- level deep dose in tissue), and so can be safely approximated in ferent directions, allowing a sector to be imaged (Figure V.4). In this manner. some phased/vector arrays, the image at the transducer is depicted Particle Splitting: In almost the reverse of Russian roulette, as a point, in others a short straight line and in others a short where an interaction generates a new particle, it can instead be tightly curved line. forced to generate Nsplit such particles from the single interaction Related Article: Phased array transducer Veiling glare and contrast 999 V elocity mapping (a) (b) FIGURE V.4 (a) Diagram of a vector/phased array showing the beam directions and (b) a colour flow image showing the image format from a phased/ vector array. Veiling glare and contrast knowledge of expected maximum velocities in the studied ves- (Diagnostic Radiology) Veiling glare is observed in optical sys- sel is necessary to optimise contrast-to-noise (CNR) in the veloc- tems. It is caused by stray light reaching the sensor of an imaging ity maps. Selection of a too low VENC (a VENC lower than the system, causing distortions in imaging performance. The main actual maximum velocity encountered) results in phase wraps in source of veiling glare is reflections between the surfaces of the the velocity map, since the velocity-induced phase angle is only lens caused by reflections of the object itself or other out-of-field unambiguously defined in the interval [−180°, 180°]. objects. The resulting image is with decreased contrast in certain Conventionally, the VENC value (often in units of cm/s) is part areas affected by the veiling glare. of the sequence protocol at the scanner and can be chosen within Veiling glare in x-ray fluoroscopy is seen at the output window certain limits. A decrease in VENC (increase in velocity sensi- of the image intensifier (II). Part of the light emitted by the output tivity) requires higher velocity-encoding gradients for a fixed TE phosphor is reflected by the glass of the output window. This light and therefore the lower the VENC. bouncing reduces the overall contrast of the image. Other scat- Related Article: Velocity mapping tering effects in the input phosphor and the accelerated electron beam could also lead to reduced contrast due to veiling glare. Velocity mapping If a radio-opaque material (lead disk) is placed in front of the (Magnetic Resonance) Velocity mapping, also known as phase- II ideally, the light intensity of its image should be zero; however, contrast MRI (PC-MRI), is a MR technique for the measure- due to veiling glare, this intensity has some value. Contrast reduc- ment of the velocity (in one or more directions) of liquid or tissue

tion due to veiling glare can be measured by placing a lead disk motion. at the centre of the II (usually the diameter of the disk is 10% of When a spin moves with a constant velocity within a gradient V the diameter of the II). The light intensity at the centre of the II field, it will acquire a net phase offset equal to (behind the disk) is measured and is compared with the same light intensity without such lead disk. t¢ The ratio (light intensity without disk)/(light intensity with fmoving = òwdt = gG ( x,t )vòt dt¢ disk) gives indication about the veiling glare. The result of this 0 measurement is called contrast ratio and normally a good II should have contrast ratio >30. where Related Article: Image intensifier ω is the Larmor frequency of the spin γ is the gyromagnetic ratio Velocity encoding (VENC) Similarly, a non-moving spin will acquire a net phase offset of (Magnetic Resonance) In velocity encoding (also known as flow encoding), dedicated gradient waveforms are applied, which t¢ result in a velocity-induced phase shift ΔΦv. The design of the fstatic = gòG ( x,t ) x0 dt¢ gradient waveforms determines the maximal velocity that can be 0 encoded (the so-called VENC), which is defined as the velocity at which ΔΦv = 180°. Hence, v = VENC * Φv,net/180. If a subsequent gradient waveform of opposite polarity is applied In standard velocity mapping sequences, the VENC needs immediately after the first gradient, the net phase offset of the to be defined prior to sequence start, and therefore a general static spins will be zero, but the moving spin will end up with a net VENC (velocity encoding) 1000 Video camera tube for simulating radiotherapy/radiation therapy delivery equipment G and treatment rooms with the added advantages of simultaneously visualising internal anatomy and planned dose distributions for τ both simple and complex radiotherapy techniques. These could (a) be simple, applied treatment fields, multifield IMRT techniques or multi-arc VMAT treatments (IMRT, intensity-modulated Φ Spin with constant velocity radiation therapy; VMAT, volumetric-modulated arc therapy). Following a shortage of trained UK staff for the treatment of Static spin cancer (radiation therapists/therapeutic radiographers, medical (b) Time physicists, radiation oncologists/clinical oncologists), in 2007/8, the UK government provided VERTTM to all clinical radiotherapy departments and universities involved in radiotherapy education. FIGURE V.5 (a) A bipolar gradient with amplitude G. In practice, gradi- Since its introduction, VERTTM has developed internationally for ents have a trapezoid shape due to gradient rise times. The gradient lobes the highly successful training of student and qualified therapeutic can also be separated in time. (b) Corresponding phase shift of a moving and a stationary spin. radiographers/radiation therapists through a variety of software and hardware platforms. The system is available in large (rear projection screen), full phase offset proportional to its velocity. Such a gradient waveform room 3D immersive formats using real Linac hand pendants from is called a bipolar gradient and is often used in velocity mapping the main Linac manufacturers (Elekta Ltd. and Varian Medical (Figure V.5). Systems) and smaller desktop/laptop/tablet versions for demon- Phase offset of spins in velocity mapping can be caused by strating radiotherapy planning, anatomy, on-treatment verification other factors than the velocity of the spins, for example field (IGRT) and delivery to staff and patients alike using workbooks inhomogeneities and Eddy currents. These effects can be com- and other methods. Real CT datasets and associated computerised pensated by repeating the experiment with a bipolar gradient of treatment plans can be imported from all current treatment plan- opposite polarity or with another gradient strength of the bipolar ning platforms (e.g. Philips Pinnacle, Varian Eclipse, Raystation, gradient. The subtracted image will ideally only reflect a velocity- Elekta Monaco and many others). induced phase shift. The software and hardware are commercially available world- Further Readings: Lotz, J., C. Meier, A. Leppert and wide through Vertual, and has been expanded to include mod- M. Galanski. 2002. Cardiovascular flow measurement with ules dedicated to training in the physics aspects of radiotherapy/ phase-contrast MR imaging: Basic facts and implementations. radiation (VERT Physics); simulated proton beam therapy deliv- Radiographics 22:651–671; Ståhlberg, F., J. Mögelvang, C. ery (Proton VERT) and software optimised for display monitors Thomsen, B. Nordell, M. Stubgaard, A. Ericsson, G. Sperber, specifically to communicate the benefits and concepts of radio- D. Greitz, H. Larsson, O. Henriksen and B. Persson. 1989. A therapy/radiation therapy to patients and relatives (PEARL). It method for MR quantification of flow velocities in blood and CSF has been used for training therapeutic radiographers/radiation using interleaved gradient-echo sequences. Magn. Reson. Imag. therapists, medical physicists, clinical oncologists/radiation 7:655–667. oncologists and helping to inform patients, relatives, school and college students and the general public about radiotherapy/radia- tion therapy. VENC (velocity encoding) Abbreviation: VERTTM = Virtual Environment for (Magnetic Resonance) See Velocity encoding (VENC) Radiotherapy Training. Further Readings: Bridge, P., E. Giles, A. Williams et al. Venetian blind artefact 2017. International audit of virtual environment for radiotherapy (Magnetic Resonance) Venetian blind artefacts are artefacts training usage. J. Radiother. Pract. 16:375–382; Jimenez, Y., D. affecting magnetic resonance angiography. MRA visualises flow I. Thwaites, P. Juneja and S. J. Lewis. 2018. Interprofessional V in blood vessels with the blood flow imaged in sections called education: Evaluation of a radiation therapy and medical phys- slabs. Slowly flowing blood can become saturated and produce ics student simulation workshop. J. Med. Radiat. Sci. 65:106–113; signal drop-out, which increases with slab volume. One method Kirby, M. C. 2018. The VERTTM physics environment for teach- of improving problems found with this technique is to use mul- ing radiotherapy physics concepts – update of four years’ experi- tiple overlapping thin slab acquisition (MOTSA). This involves ence. Med. Phys. Int. J. 6(2):247–254. reducing the saturation effect seen in MRA by decreasing the Hyperlinks: www .vertual .co .uk; www .elekta .com; www .var- thickness of the slabs imaged, but maintaining the overall volume ian .com by increasing the number of slabs. The Venetian artefact occurs at the boundaries of these slabs, Video camera tube where they slightly overlap. The background tends to be brighter (Diagnostic Radiology) The video camera tube (VCT; also called at the top of the slab compared with the bottom due to an increased television pickup tube or TV camera tube) is an important element flip angle. A variation in signal response across the slab boundar- of the x-ray television (x-ray fluoroscopy). The VCT is a cylindri- ies can then be seen in the phase-encode direction. cal vacuum device with base approx. 3 cm (~1 in. diameter) and Abbreviations: MOTSA = Multiple overlapping thin slab length of approx. 15 cm. acquisition and MRA = Magnetic resonance angiography The front of the VCT is attached to the output optics of the II and takes directly the image from it. Figure V.6 shows a block dia- VERT training gram of VCT. The VCT front consists of glass entrance window, (Radiotherapy) VERTTM (Virtual Environment for Radiotherapy transparent conductive layer (signal plate) and photoconducting Training) provides a hybrid, virtual environment skills facility layer (target plate). When light from the II passes through the Video detector 1001 Video recorder Accelerating Target Signal electrodes plate plate Light Electron gun Steering system Video signal FIGURE V.6 Block diagram of video camera tube. glass and the transparent signal plate, it reaches the target plate. The material of the target plate is the most important element of the VCT and often the whole tube is named according to it (e.g. if the target is lead oxide, PbO, the camera type is plumbicon). The vidicon camera uses target of antimony sulphide (Sb2S3), which is suspended as microglobules over a matrix made of mica. This way, each microglobule (approx. 0.001 in. in diameter) is elec- trically isolated from the other. The target is an isolator if not lighted. When it is lighted, it reduces proportionally its electrical resistance. The cathode of the VCT is often a heated filament producing thermal electrons (electron gun). These electrons are accelerated through electrodes (approx. 250 V) towards the anode, which is in front of the target plate. A steering system of deflection coils moves the electron beam to scan the surface of the target plate. Different amounts of electrons pass through different micro- globules of the target plate, depending on their resistance – that is light level over these microglobules. This way, different cur- rents pass through the respective regions of the positive signal plate (which is a conductor). This current is proportional to the light levels over the target and forms the video signal from each FIGURE V.7 TV camera with removed video camera tube (vidicon). element of the surface of the target plate. The VCT is an ana- logue device, but the microglobules could be regarded as pixels V (what would be the case with a CCD camera). The amplified Using CCDs in small animal imaging gives the possibility of video signal is used to produce an analogue image over a TV building small scintillation cameras based on optical lens sys- monitor. tems projecting the scintillation light onto the CCD. Such sys- The VCT and its associated optics and electronics form the TV tems can also be used for optical imaging of bioluminescence or camera assembly (Figure V.7). fluorescence. Related Articles: Video signal, Plumbicon, Vidicon Abbreviation: CCD = Charge-coupled device Further Readings: Curry, T. S., J. E. Dowdey and R. C. Related Articles: CCD, Scintillation camera, Fluorescence, Murry. 1990. Christensen’s Physics of Diagnostic Radiology, Lea Bioluminescence and Febiger, Philadelphia, PA; Hendee, W. R. and E. R. Ritenour. Further Reading: Kupinski, M. A. and H. H. Barret eds. 2002. Medical Imaging Physics, Willey-Liss, New York. 2005. Detectors for small animal SPECT I. In: Small-Animal SPECT Imaging, p. 37, Springer, New York. Video detector (Nuclear Medicine) Charge-coupled devices (CCDs) have high Video recorder quantum efficiency for optical photons and are thus very well (Diagnostic Radiology) Video recorders were used in the past suited for detecting light from scintillators. When cooled, they to record analogue fluoroscopic information. The video signal have almost no dark current. Also, noise in the readout electron- from the x-ray TV camera was recorded either on tape (video- ics can be reduced by built-in electron magnification or parallel tape recorder) or on hard disk and from it to CD or DVD (video readout. recorder). These systems were used as replacement of cine film, Video signal 1002 Vidicon tube as video recording is made with significantly lower radiation (one for each horizontal line). The overall image of a normal reso- dose (direct recording of fluoroscopy requires approx. 10 less lution TV monitor has a number of horizontal lines (raster lines) dose than cinefluoroscopy). However, the resolution of the video depending on the standard (e.g. 625 lines in the European Union recording is significantly low. Contemporary digital fluoroscopic and 525 lines in the United States). Each horizontal video signal x-ray systems record directly on hard disk, the digitised signal ends with a horizontal sync pulse as on Figure V.8, which moves from the detector (TV camera with analogue to digital converter, the beam one step down and returns it at the beginning of the next CCD camera, flat panel detector, etc.). The fluoroscopic file is horizontal line. At the end of the last horizontal signal (down right then recorded on CD/DVD or other media to allow visualising at corner of the screen), a vertical sync pulse moves the beam back another place. at the upper left corner of the screen to start a new image. Not all Related Articles: Fluoroscopy, Digital fluoroscopy, Cinefluo- horizontal lines carry information. About 10% of those (mainly roscopy the most upper and most lower ones) are not used – for example in the United States, standard approx. 480 lines (from 525) are Video signal forming the image on the monitor. Increasing the number of raster (Diagnostic Radiology) The video signal from the TV camera of lines on the monitor leads to better image resolution (e.g. using a II chain represents important information for the II function and 1125 lines instead of 525). In digital LCD monitors, this resolu- the radiation dose during fluoroscopy. The video signal is directly tion depends on the pixel matrix. related to the II input dose rate (air kerma rate) and to the image Related Articles: Image

intensifier, Video camera tube, contrast. Unblanking The video signal is measured with a calibrated oscilloscope, usually connected directly to the output of the TV camera tube Vidicon tube (usually with 75 ohms terminating resistor). One video signal rep- (Diagnostic Radiology) The vidicon TV camera tube (also called resents one horizontal line from the TV raster. The signal is called hivicon) has been developed by the RCA. This camera has a tar- composite video signal as it includes elements related to the signal get with photoconductive layer of antimony sulphide (Sb2S3), sus- and to the synchronisation of the monitor. pended as globules on a mica matrix. Each globule is insulated Figure V.8 shows a typical composite video signal. It begins from its neighbours. These globules behave as tiny capacitors. with a synchronisation pulse (marking the beginning of the hori- This light-sensitive layer (usually with 1 in. diameter) is some- zontal raster line). The difference between the black level (dark times called retina. The operation of the camera is explained in screen) and the white level (full brightness) is related to image the article Video camera tube. According to the light intensity at contrast. The amplitude of the white is related to the II input the target of the camera, an electrical charge pattern is formed dose rate (at the end of the white signal is the effect of vignetting over the photoconductive layer. When the target is scanned by an associated with signal distortion). The blanking level is below the electron beam, the variously charged micro-areas are discharged, black level as it represents the completely black circle around the respectively, and the varying discharging current (proportional to image. The uneven parts of both black and white levels represent, the charge of the layer, hence to the intensity of the incoming respectively, the black noise and the white noise. light) forms the video signal. The image on the analogue TV monitor screen, carried by the The change of the discharge current is related to change of the video signal, consists of a number of such composite video signals resistance of the micro-areas on the target (when Sb2S3 is illumi- nated, it conducts electrons; when dark, it behaves as an insula- tor). This means that the amplitude of the signal is proportional to White level End of signal the intensity of the light. (image signal) and vignetting The sensitivity of the vidicon can be changed by changing the voltage applied to the target (in comparison, the plumbicon TV camera has fixed sensitivity). This way, TV systems using vidi- Black level con may have a circuit that monitors the light intensity level and, on this basis, operates automatic gain control. This means that V this TV tube can operate at various conditions of light. Also, this means that vidicon tubes can be used in system without automatic brightness control. Vidicon TV tubes have high dark current and are also more inert than plumbicon tubes. That is, they keep the old image for some time (what presents an effect of residual image, known as ghosting). This slow response is with time constant of the order of 1/5–1/10 s. This has two effects. From one side, the camera cannot be used to image rapid movement (i.e. heart movement), as it will blur the image. From another point of view, this inertia creates an averaging effect, which minimises the noise in the image. The vidicon camera has a characteristic curve with gamma 0.7. Blanking Sync pulse New sync pulse This means that the camera will have a wider contrast range (lati- tude), but the picture will be with lower contrast (contrast loss) than TV tubes with gamma 1 (as is plumbicon). However, vidicon Video signal and its visual presentation is less expensive than plumbicon. Vidicon is better suited for high-contrast fluoroscopic exami- nation of less dynamic objects (e.g. barium examination of FIGURE V.8 Composite video signal with its visual presentation. stomach). Viewing angle 1003 Viewing station CCD-type cameras and flat panel detectors gradually replace voltage applied to the electrodes on the glass plates. Furthermore, the fluoroscopic x-ray systems with TV camera tubes. the molecules have the property of absorbing light whose polari- Related Articles: Video camera tube, Superorthicon, sation is aligned to the long axis of the molecules. Plumbicon In the simplest twisted nematic (TN) liquid crystal, the mol- Further Readings: Coulam, C., J. Erickson, D. Rollo and A. ecules are initially twisted. The liquid crystal cells are backlit, James eds. 1981. The Physical Basis of Medical Imaging, Appleton- and the observed brightness of the cell is controlled by the level Century-Crofts, New York; Oppelt, A. ed. 2005. Imaging Systems of voltage placed across electrodes on the glass substrates. As an for Medical Diagnostics, Siemens, Erlangen, Germany. increasing voltage is applied, the molecules move in line with Hyperlink: The Cathode Ray Tube site: http: / /mem bers. chell o each other and become increasingly untwisted, eventually mov- .nl/ ~h .di jkstr a19 /p age4. html ing to allow no light to pass, and the pixel is viewed as black. As well as absorbing light, the molecules change the speed Viewing angle at which the light propagates through the crystal. In a property (Diagnostic Radiology) The viewing angle of an image display known as birefringence, light which is polarised along the short describes the ability of the device to be viewed at various angles axis of the molecules will travel through the material at a differ- by the observer without modification to the observed image. The ent speed to light polarised along the molecules’ long axis. The viewing angle is described as the angle at which the contrast ratio light source for the crystal will produce light with an orientation falls below 10:1, Figure V.9. The contrast ratio is defined as somewhere between these two directions. It is therefore possible to consider light as having components along each of these direc- Contrast ratio tions parallel and perpendicular to the molecules, each compo- nent travelling through the LC at a different speed. Brightnessat thescreencentre whenall pixelsare‘white’ = When the light exits the liquid crystal, the two light compo- Brightnessat thescreencentre whenall pixelsare‘black’ nents (ordinary and extraordinary) are out of phase with each other, and as they pass through the second (analysing) polariser of A large viewing angle is an important characteristic of modern the display, they constructively or deconstructively interfere with medical display technology. Although in some specific clinical each other. This interference will alter the viewed light inten- situation, a narrow viewing is desired for security reasons, when sity seen through the LC cell at different viewing angles as the a clinical radiographic image is being evaluated by more than one light passes through a greater length of liquid crystal at increased person, a wide viewing angle is desirable. angles, and thus, the phase difference of the two light components Modern display technology currently falls into two categories, will differ leading to a difference interference at the polariser, see cathode ray tubes (CRT) and flat panel technology, of which, flat Figure V.10. panel TFT LCD displays are most common in medical imaging. To reduce the effect that birefringence has on viewing angle, CRTs have a very large viewing angle of approx. 170°, due to the modern TN LCDs include a retardation film or discotic film. This isotropic nature of the emitted light. When flat panel TFT displays is placed between the LC cell and the analysing polariser, which were first developed, they had a viewing angle of as little as 90°, increases the viewing by rotating the angle of polarisation of light the low viewing angle being due to the birefringent properties of entering the polariser compensating for the retardance induced by the molecules in the liquid crystal material. Innovations in the the LCD through having the opposite birefringence. orientations of the molecules however have led to modern devices The use of the first type of liquid crystal displays was restricted having viewing angles comparable to CRTs. by low contrast ratio, narrow viewing angle and slow response Liquid crystal displays are constructed from two polarising time. To overcome these issues, different manufacturers have layers, with the angle of polarisation set to 90° from each other developed LCDs based upon several different molecular align- and a liquid crystal cell between them. The liquid crystal cell ment and electrode patterns. These are TN, in-plane switching consists of elongated molecules sandwiched between two glass (IPS) and vertically aligned (VA) LCD. plates. The orientation of the molecules is controlled through a Related Articles: Liquid crystal display (LCD), Active matrix flat panel liquid crystal display V Viewing station (Diagnostic Radiology) The workflow of PACS includes the viewing station (aka reading workstation), which includes a high- quality monitor (primary diagnostic digital display) and associ- ated keyboard and software. The viewing station design includes specific low-intensity ambient light and dictating equipment. The station has two main functions – user interface and display, and should be capable of displaying images from all imaging modali- ties (with different spatial resolution, dynamic range, etc) on the 140° Viewing angle: same screen, plus their manipulation and processing (windowing At 70° from normal monitor axis the contrast ratio drops to 10:1. and other image processing software). Related Articles: Digital display, Workstation Further Reading: Horii, S. C. and H. N. Horii. 1991. Reading room design for PACS. In: Picture Archiving and Communication Systems (PACS) in Medicine, eds., H. K. Huang, O. Ratib, A. R. Bakker, G. Witte and K. S. Chuang, NATO ASI Series (Series F: Computer and System Sciences), vol 74. Springer, ISBN FIGURE V.9 Illustration of 140° viewing angle for a flat panel screen. 978-3-642-76568-1. Vignetting 1004 Virtual learning environment (VLE) Viewing angle Normal Viewing angle at –30° viewing angle at +30° Observed brightness at each viewing angle Polariser Substrate Electrode TN molecules Electrode Substrate Polariser FIGURE V.10 The effect of viewing angle on the observed brightness of a TN LCD display. The liquid crystal cell has no voltage across and is in the ‘on’ or white state as viewed normally to the screen. Vignetting (Diagnostic Radiology) Vignetting is an optical term that refers to the gradual loss of brightness and/or saturation in the periphery of an image, compared to its centre. The resulting image is with dark corners, often showing the sides of the lens. Although con- sidered as a special effect in photography, vignetting has a nega- tive influence over the diagnostic image. Vignetting source could be mechanical, optical, natural or pixel. Vignetting in x-ray fluoroscopy is seen as brightness reduction at the periphery of the image. Its primary causes are the reduced precision of the lens-like effect of the accelerating electro-mag- netic field inside the II; the reduced light production at the periph- V ery of the slightly curved input screen of the II; the reflection of light around the output phosphor. Additionally, there may be vignetting due to the optical tandem optics between the II and the TV tube (if such optics is used). The summary effect of these is usually not more than 25% brightness reduction. Vignetting is FIGURE V.11 Old image intensifier with significant vignetting at the well seen at the graph of a video signal (see Figure V.8) and on periphery (and S-type distortion). Figure V.11. Related Articles: Video signal, Unblanking higher education institutions in the English-speaking world – the Virtual learning environment (VLE) most popular ones in this sector being (General) A virtual learning environment (VLE) is a web-based platform for the digital aspects of courses of study, usually within • WebCT, developed in 1996 by the University of British educational institutions. They present resources, activities and Columbia interactions within a course structure and provide for the differ- • Blackboard, developed in 1997 at Cornel University in ent stages of assessment. VLEs also usually report on participa- Washington tion and have some level of integration with other institutional • Moodle, which started its development in 1999 and systems. VLEs are becoming increasingly popular among higher exists in its present form (as at 2020) since 2001, devel- education institutions. They have been adopted by almost all oped in Perth, Australia, by Martin Dougiamas Virtual Library AAPM 1005 Visible light The main features of VLEs are as follows: • Content management (creation, storage, access to and use of learning resources) •

Facilitated assessment administration, providing authoring tools for creating the necessary documents by the instructor and, usually, submissions by the students and allowing tracking of progress • Support for communication between all autho- rised participants (i.e. chats, forums, video- and audio- conferencing) FIGURE V.12 Abdominal dual-energy CT images: (a) before iodine A VLE is normally capable of supporting multiple courses over subtraction (contrast-enhanced image) and (b) after iodine subtraction the full range of the academic programme, giving a consistent (VNC image). interface within the institution and – to some degree – with other institutions using the system. The virtual learning environment supports the worldwide exchange of information between a user An example of abdominal dual-energy CT images before and and the learning institute he or she is currently enrolled in through after iodine subtraction is shown in Figure V.12. It has been con- digital mediums like e-mail, chat rooms, web 2.0 sites or a forum. firmed that iodine is removed from contrast-enhanced CT images Similar terms, often used synonymously are learning manage- to obtain VNC images. VNC images provide reliable attenuation ment system (LMS), managed learning environments (MLEs) measurements for low, moderate and high iodine-induced attenu- and managed virtual learning environments (MVLEs). ations; however, for tissues with an extremely high iodine contrast VLEs do not provide participants with face-to-face interaction, agent load (e.g., excretory phase of CT urography), VNC values which can lead to lack of connection between them. In order to become less accurate and VNC attenuation increases over TNC mitigate this major disadvantage, it is recommended to use VLEs attenuation because of the beam hardening of x-rays. in combination with classical teaching to provide ‘blended learn- Related Articles: True non-contrast (TNC) image ing’ to provide an efficient and effective way to transfer knowledge. Further Reading: Tabakova, V. 2020. E-Learning in Virtual reality Medical Physics and Engineering, Series in Medical Physics and (General) See Augmented reality Biomedical Engineering. Hyperlink: https :/ /el itera te .us /acad emic- lms -m arket -shar e -vie Virtual source position w -acr oss -f our -g lobal -regi ons/ (Radiotherapy) Electron beams appear to originate from a Academic LMS Market Share: A view across four global point in space that does not coincide with the scattering foil or regions the accelerator exit window. The term virtual source position was introduced to indicate the virtual location of the electron Virtual Library AAPM source. (General) The Virtual Library of the American Association of Virtual source point or position is relevant to electron beams Physicists in Medicine (AAPM) is an online resource with pre- since they have passed through a scattering filter. This will change sentations (invited lectures, short courses, etc) from various the beam from its well-defined collimated shape to one which AAPM Annual Meetings, Spring Clinical Meetings, Summer diverges. The degree of divergence will be energy dependent and Schools and other selected programmes. The format is a combi- will mean that electron beams with different energies will appear nation of videos, slides with audio discussion and transcripts. It to have originated at different source positions. is provided without cost to AAPM members and to Developing Source position is an important factor when calculating the Country Educational Associates. change in output factor for extended FSD treatments. Presentations posted in the Virtual Library include: Virtual source position is also referred to as apparent or effec- V tive source position or point. • Streaming video and/or audio of the speakers Abbreviation: FSD = Focal to surface distance. • Transcription of the audio for numerous presentations Related Articles: Apparent source position, Effective source • Slides of the presentations point Hyperlink: www .aapm .org /education /VL/ Viscosity (Nuclear Medicine) Viscosity is a measure of the resistance of a Virtual non-contrast (VNC) image fluid when subjected to external stress, that is being deformed. (Diagnostic Radiology) Dual-energy CT allows the differentiation The higher the resistance to flow, the higher the viscosity. Oil for among multiple materials and the quantification of the mass density example has a higher viscosity than water. of two or three materials in a mixture with known elemental compo- sition. One of the examples that uses a three-material decomposition Visible light algorithm is a virtual non-contrast (VNC) image. This algorithm (Non-Ionising Radiation) It is the narrow region of light that is can remove iodine from contrast-enhanced CT images. If VNC visible to the human eye. The borders of this region are not well images can be used instead of true non-contrast (TNC) images, defined and there is some overlap with infrared and ultraviolet TNC acquisition can be omitted to reduce the total patient dose. light. Visual acuity 1006 Visual grading characteristics (VGC) FIGURE V.13 Light spectrum. The limits commonly used by the International Commission on Visual grading analysis (VGA) Non-Ionizing Radiation Protection are 400–780nm (Figure V.13). (Diagnostic Radiology) VGA is a method for evaluating clinical Related Articles: AORD, ICNIRP, Light source, Infrared image quality by assessing visibility of important anatomical or light, Ultraviolet light pathological structures. This method is characterised by simplic- Further Readings: Czapla-Myers, J. S., K. J. Thome and ity but enabling to quantify subjective opinions and to make them S. F. Biggar. 2008. Design, calibration, and characterization amenable to analysis. of a field radiometer using light-emitting diodes as detectors. VGA can be performed in two major ways: with relative or Appl. Opt. 47(36):6753–6762; ICNIRP website, www .i cnirp absolute grading. In relative VGA, the quality of an image or a par- .org/ en /fr equen cies/ infra red /i ndex. html; Ihrke, I., J. Restrepo ticular part of the image is compared with a reference image, and and L. Mignard-Debise. 2016. Principles of light field imaging: a grading is given depending on whether the quality of the image Briefly revisiting 25 years of research. IEEE Signal Process. is better or worse than the reference image. In absolute VGA, the Mag. 33(5):59-69; Kitsinelis, S. and S. Kitsinelis. 2015. Light scores are given on an absolute scale (i.e. fulfilment of image cri- Sources: Basics of Lighting Technologies and Applications. teria, e.g. European quality criteria), typically consisting of four to CRC Press. five scale steps ranging from ‘very bad’ to ‘very good’. In relative VGA, the observer compares an image with a refer- Visual acuity ence image and gives a statement of the relative visibility of the (General) As with all optical systems, the human eye has its structure. The scale typically consists of five steps ranging from modulation transfer function (MTF), contrast sensitivity, sub- ‘much worse’ to ‘much better’. Prior to analysis, the scale steps jective quality factor and other parameters. Visual acuity is in a VGA study are most often converted to numerical values. a parameter used to assess the limiting spatial resolution of For example, in an absolute VGA study with four scale steps, to human vision. Typically, it is measured as the resolution of the lowest scale step may be attributed the number 1 and to the the vision at the fovea (however, it is also a parameter used to highest scale step the number 4. In a relative VGA study with five assess peripheral vision as well). Opticians assess visual acuity scale steps, to the lowest scale step may be attributed the number by testing the ability to recognise various letters or symbols −2 and to the highest +2. (with maximal contrast – i.e. black/white) at specific distances. The results of a VGA study can be summarised in the VGA Vision acuity depends on the observation distance. Usually, score (VGAS) as follows: this parameter is expressed in cycles per degree (cpd), thus tak- ing into consideration the viewing angle to distinguish the test å Sc VGAS = O,I object. NiNo Using the familiar in medical physics measure for spatial V where resolution (line pairs per mm) to assess human vision, we can Sc are the given individual scores for observer (O) and image (I) present an indicative example (based on the size of the cones Ni is the total number of images and rods and some approximations). If reading a textbook from No is the total number of observers. 50 cm distance (book to eye lens) and assuming c. 2 cm distance from the eye lens to the retina (fovea), the observed text (image) VGA with reference images is very suitable for image quality will be minimised 25 times over the retina (fovea). Projecting studies with modern workstations, where two, three and some- the size of one cone (0.006mm) over the text, will present an times even more monitors are used. object of 0.006 × 25 = 0.150 mm (i.e. a pair will be 0.3 mm). Related Articles: Anatomical noise, Visual grading charac- This object size corresponds to 3.33 lp/mm (line pairs per mm). teristics (VGC) For printing, about 170 such objects will be displayed over 1 Further Reading: Månsson, L. G. 2000. Methods for the inch – i.e. 170 dots per inch (dpi). This indicative example gives evaluation of image quality: A review. Radiat. Protect. Dosim. an estimate of the minimal acceptable spatial resolution (with- 90(1–2):89–99. out zoom or optical magnification) of observed printouts or films with a normal eye at 50 cm. Related Articles: Retina, Cones, Rods, Visual perception Visual grading characteristics (VGC) Further Readings: Hecht, Eugene. 1987. Optics, 2nd edn., (Diagnostic Radiology) VGC analysis is a method for evaluat- Addison Wesley; https :/ /en .wiki pedia .org/ wiki/ Visua l _acu ity; ing clinical image quality, based on visual grading (e.g. image Tabakov, S. 2013. Introduction to vision, colour models and image criteria [IC] study or absolute VGA) data and similar concepts compression. J. Med. Phys. Int. 1:50–55. as developed for ROC analysis. VGC can be interpreted as a Visual perception 1007 Voltage limiter repeated image criteria scoring, where the observer changes The major property of the voltage divider is that in the fol- his threshold for the fulfilment of each criteria in a similar way lowing layout, the output voltage is directly related to the input as the scale steps in an ROC study are used by the observer to voltage by the ratio of impedances (Figure V.14). state the confidence of each positive/negative decision. So the Resistors are commonly used to provide a voltage divider as these probability distribution of the images from each modality is will precisely divide both DC and AC signals of all frequencies. sampled. The usual purpose is to attenuate an electrical signal by a VGC is conceptually different from VGA – VGC corresponds known amount prior to feeding on for further processing. to the observer grading his confidence in the fulfilment of an image A variable resistor or ‘potentiometer’ is often used as a vari- quality criterion whereas VGA corresponds to the observer grad- able voltage divider. This is made up of one long resistive winding ing his opinion about the visibility of a certain structure. or conductive track across, which the input voltage is applied. The VGC analysis can be used directly on the image quality crite- output is obtained using some form of electrical contact, which ria defined by the European Commission or on other radiographic can be moved anywhere along the track, thereby providing an quality criteria – giving statements of the required levels of repro- adjustable division ratio (Figure V.15). duction for certain anatomical landmarks – without the need for Related Articles: Resistor, Voltage extracting the relevant structures from the criteria and grading the visibility of these structures. Furthermore, the grading task in Voltage drop VGC is not limited to normal anatomy – grading of image criteria (Diagnostic Radiology) Due to the high electrical power of the based on pathology may also be used. x-ray exposure, the mains supplying the x-ray generator has to Related Articles: Receiver-operating characteristics (ROC), have a very low resistance. If this resistance is not low enough, the Anatomical noise electrical current passing through the cables will produce voltage Further Reading: Båth, M. and L. G. Månsson. 2007. Visual drop in the mains, what will lead to a decrement of the input volt- grading characteristics (VGC) analysis: A non-parametric rank- age, and from there a variation in the exposure kV. Voltage drop invariant statistical method for image quality evaluation. Br. J. is prominent in classical x-ray generators, and these have a whole Radiol. 80:169–176. circuitry (including the autotransformer), which is used to predict and

to compensate the voltage drop before the beginning of the Visual perception exposure. (General) While visual acuity is related to the resolution of the Related Articles: Anode, High-voltage generator, High- vision, visual perception refers to the ability of the brain to inter- voltage transformer pret what the eyes see. Visual perception is very important for medical physics and all areas of radiology. In medical imaging, it Voltage limiter is related to the interpretation of low contrast images (signals) on (General) A voltage limiter acts on an electrical signal to prevent the background of significant noise. it exceeding a preset maximum and/or minimum value, limiting Related Articles: Vision acuity, Contrast Detail the signal to a specific range of values. Further Reading: Bruce, V., P. Green and M. Georgeson. Many electronic circuits are susceptible static electricity and 2006. Visual Perception, 4th edn., Taylor and Francis; Morgan, signal exceeding their power supply values, so a voltage limiter R. 1966. Visual perception in fluoroscopy and radiography. circuit is commonly found at their input to avoid damage and Radiology 86(3):403-416. ensure safe operation (Figure V.16). VLE (Virtual learning environment) (General) See Virtual learning environment (VLE) Voltage (General) The voltage refers to the electrical potential of a point in a circuit with respect to some other reference level. Unless speci- V fied, the reference used is commonly taken to refer to ‘ground’, the earth potential provided by the mains supply or the chassis potential of a device. The units used are volts (V), plus their derivatives: megavolts (MV), kilovolts (kV), millivolts (mV) and microvolts (μV). FIGURE V.14 Voltage divider principle. The unit of 1 V is defined as the potential difference across a conductor when a current of 1 amp dissipates 1 W of power (BIPM 2006). In radiology, a similar sounding but separate unit, the electron Vin volt (eV), may be used to describe the energy of electrons, par- ticles, x- and gamma-rays. Related Article: Electron volt Vout Further Reading: BIPM. 2006. The International System of Units (SI), Stedi Media, France. Voltage divider 0 V 0 V (General) The voltage divider refers to a simple electrical circuit made up of two impedances (AC) or two conductors (DC). FIGURE V.15 The variable resistor. Voltage range 1008 Voltage waveform Input signal Output signal Voltage Constant voltage regulator Positive limit Varying load FIGURE V.19 Voltage regulation. FIGURE V.16 Voltage limiter principle. at some constant value when subject to varying input and output conditions. +ve supply A power source may be subject to varying input voltages and will certainly be subject to changing current demand by the cir- Input cuitry it feeds. Some form of regulation is therefore required to External 0 V make the supply maintain its output voltage as constant as pos- input sible. Electrical noise, mains ripple, etc. should also be minimised by the regulator circuitry. 0 V Voltage regulation is performed by either shunt or series reg- –ve supply ulation, though except for the Zener shunt regulator, nearly all are of the series regulation type, where some form of feedback or servo mechanism monitors the output voltage, compares it with FIGURE V.17 Diode voltage limiter maintains signal within =/− supply some internal standard voltage and automatically reacts to main- range. tain the output voltage constant (Figure V.19). More advanced regulators incorporate over-temperature shut- down, short-circuit protection and current limiting, which help to +ve protect itself and the circuitry it serves. However, this can cause supply problems and it may be necessary to test the regulator with a ‘dummy load’ to ensure it is functional. Input Related Articles: Zener, Voltage stabiliser External 0 V input Voltage stabiliser 0 V (General) See Stabilisation –ve Voltage supply supply (General) A voltage supply is the name given to a source of elec- trical power, which maintains its voltage whilst providing a vary- FIGURE V.18 Zener voltage limiter limits signal to +/− Zener values. ing current as required by the equipment or load attached. Two types of voltage supply are frequently referred to: the mains voltage supply and the DC power supply. Commonly used circuits shown in the following are designed Mains Voltage Supply: The ‘mains supply’ is an AC power to ‘shunt’ any excessive signal to ground whilst containing a resis- source with properties and limits specified nationally. Common tor to prevent excessive current and protect both source and lim- domestic and office supplies are single phase, 50 or 60 Hz fre- iter circuits (Figures V.17 and V.18). quency and 110–230 V rms depending on country, and the maxi- Related Articles: Diode, Zener, Static electricity, Suppressing mum current available from each outlet is limited (to protect filter V wiring etc.) to the range of 0–20 amp, again depending on country. Higher power (greater than about 3 kW) is usually only avail- Voltage range able where higher-rated cabling has been installed in the building, (General) The voltage range of a circuit represents that range of and nonstandard plug/socket arrangements are used. voltages over which the input (or output) of a device can function For high powers such as those required for CT, MR scanners correctly. and some x-ray sets, ‘three-phase’ supplies are used again spe- All electronic components will have specified operating cially cabled to the required equipment and usually hard wired to limits, outside which the devices will not function properly and equipment via mechanical circuit breakers. safely. As a complete unit, an electronic circuit will not usually DC Power Supply: DC power supplies are common in all operate correctly when the input voltages exceed the power sup- mains powered equipment and are nearly always ‘voltage sup- ply values, and the outputs are rarely capable of providing signals, plies’ – that is, they maintain their output at a constant volt- which swing as far as the power supply voltages. age, independent of changed to input voltage and output current Should circuits be driven past their operating voltage range, demand. their outputs usually ‘limit’ if designed well, but can on occasion Related Articles: Mains supply circuit, Mains voltage, Voltage swing violently in value or even latch up. regulation Related Article: Voltage limiter Voltage waveform Voltage regulation (Diagnostic Radiology) The voltage waveform of an x-ray genera- (General) Voltage regulation refers to the process by which a volt- tor is the variation of the kV value during the exposure. This is age source (usually a DC power supply) is regulated or maintained directly related to the type of x-ray generator (e.g. the rectification Voltmeter 1009 V oltmeter in classical x-ray generator; the frequency of medium frequency x-ray generator, etc.). These kV fluctuations are also called kVp ripple. The ripple factor represents the maximal variation of the kVp during the exposure. The voltage waveform is measured through oscil- loscope either directly (using high-voltage divider, connected directly to the generator) or indirectly (using special kVp meter). The kV voltage waveform is an important factor for the for- mation of the x-ray spectrum. The more and the higher are the kVp fluctuations, the greater is the proportion of the generated low energy x-rays (produced by the low kV components of the waveform). These low energy photons are anyhow absorbed by the tube housing filtration; hence the effectiveness of the x-ray tube is decreased. Contemporary medium frequency x-ray gener- ators produce smooth kV voltage waveform (with minimal ripple). Figures V.20 through V.25 present some typical kV voltage waveforms (all these are measured with Keithley kVp meter). Note the kV amplitude, compared with the amplitude of the x-ray dose (taken from the output of a dosimeter). Also note the front and back fronts of the whole x-ray exposure pulse. On all figures, the x-axis represents the exposure time (ms) while the y-axis is the kVp (and also the dose output on Figures V.22 and V.23). FIGURE V.21 kVp voltage waveform of single-pulse dental classical Related Articles: X-ray generator, Tube kilovoltage, Ripple x-ray generator. Note the initial pulses for pre-heating of the cathode with gradually increasing kV amplitude (1 division = 50 ms). Voltmeter (General) A voltmeter is a device used to measure the potential difference between two specified points, usually within an electri- TR2–180 mV: 118.0 ms cal circuit. A good voltmeter will be able to indicate the voltage accu- rately and without affecting the circuit under test. Both analogue and digital voltmeters are common, and apart from panel mounted meters, most are small portable devices capable of a wide range of electrical measurements – the multi-meter. Basic analogue voltmeters are either electrostatic or elec- tromagnetic in principle. The electrostatic meter relies on the force generated between two plates by the attraction of opposite FIGURE V.22 kVp waveform for two pulse classical x-ray generator – V below (1 division = 20 ms). The exposure time is 118 ms. The pulsations are 100%. The curve above the kVp waveform is the dose output wave- form – it follows the kVp waveform. charges, moderated by a fine spring. This force is so small that only high voltages (kV) can reliably be measured this way. This device does have a great advantage that it takes no current and so does not load the circuit being measured. The electromagnetic voltmeter relies on the applied voltage generating a proportional current in a small moving coil, which twists in reaction to a fixed magnetic field (DC meter) or attracts a piece of soft iron on a spring mount (AC and DC). Meter move- ments capable of full scale deflection with a current of only about 50 μA are common, and where this amount of current will not affect the real value of the circuit under test, this sort of movement FIGURE V.20 kVp voltage waveform of single-pulse classical x-ray with an appropriate series resistor provides an excellent method of generator. y-axis – kVp; x-axis exposure time (1 division = 20 ms). displaying voltage. The quality of these meters is defined by the Volume of interest (VOI) 1010 Volumetric-intensity-modulated arc therapy TR1–670 mV: 22.10 ms FIGURE V.25 kVp voltage waveform of capacity discharge x-ray gen- erator. Note the minimal ripple during the kV drop (1 division = 10 ms). The exposure time is 52.2 ms. FIGURE V.23 kVp waveform for six-pulse classical x-ray generator – below (1 division = 5 ms). The exposure time is 22.1 ms. The pulsations Volume of interest (VOI) are approx. 14%. The curve above the kVp waveform is the dose output (Nuclear Medicine) In planar scans, images are often evaluated waveform. by means of a region of interest (ROI) that is defined over the organ of interest using a pointing device. The area of the ROI is then determined by the number of pixels inside the ROI times TR2–380 mV: 11.50 ms the square of the pixel size. A three-dimensional (3D) image consists of a set of digital images, where each image is defined by a matrix of numbers that defines some estimate in a location corresponding to the pixel location in the image. For example, a pixel value in a digital image obtained from a SPECT scan reflects the activity concentration in that particular location. Usually, one defines a ROI using a track-ball or mouse that cal- culates, for example the sum of pixel values within a bound- ary, for example the kidney. Since each pixel defines an area and each image also defines a slice thickness, in the 3D space, this will be a voxel (volume element). By defining ROIs in con- secutive slices, a volume called VOI or volume-of-interest is obtained. The volume then will be Pixel size X * Pixel size Y * Slice thickness Z Abbreviations: ROI = Region of interest, VOI = Volume of inter- est and 2D = Two-dimensional. V FIGURE V.24 kVp voltage waveform medium frequency x-ray genera- tor (1 division = 2 ms). The exposure time is 1V.56 ms. The pulsations are below 3%. Note the very small ripple – 2 kV. Volume-modulated arc therapy (VMAT) (Radiotherapy) See Volumetric-intensity-modulated arc therapy ‘ohms/volt’ value of the movement. A value in the region of 50 kΩ Volumetric-intensity-modulated arc therapy makes for a good general-purpose device. (Radiotherapy) Volumetric-intensity-modulated arc therapy Digital voltmeters and multi-meters aim to mimic and improve (VIMAT sometimes known as IMAT) or volumetric-modulated on their analogue counterparts both in the accuracy possible by arc therapy (VMAT) is an advanced form of intensity-modulated multi-digit displays and in their ability

to operate whilst taking radiotherapy (IMRT) technique. The technique is based on a con- much smaller currents and hence having less effect on the circuit cept proposed by Cedric Yu. under test. This is possible by incorporating high-input-resistance Unlike step and shoot or dynamic MLC IMRT treatment amplifiers preceding the analogue-to-digital converters and dis- techniques, the gantry angle in a VMAT treatment varies con- play. Inexpensive multi-meters can be found with input imped- tinuously as in arc therapy, and, at the same time, the intensity ances in the megohm region. of the treatment beam is modulated with dynamic MLC motion. Specialist meters, which can take virtually no current, ‘elec- The technique can deliver highly conformal treatment faster and trometers’, are also available for measurement where the voltage with less machine monitor units than that as given by conven- to be determined is in a circuit where to take even a small current tional IMRT but with similar dose conformality. The VIMAT would affect the circuit under test. These are often used to mea- treatment mode is now commercially available and has been sure bio-potentials directly, such as from individual living cells. clinically implemented for routine clinical use. Volumetric prescribing (brachytherapy) 1011 Voxel Further Reading: Yu, C. X. 1995. Intensity-modulated arc is prescribed to a 3D image-based CTV taking into account dose therapy with dynamic multileaf collimation: An alternative to volume constraints for OAR. However, prospective use of these tomotherapy. Phys. Med. Biol. 40:1435–1449. recommendations in the clinical context is warranted, to further improve and develop the potential of image-based cervix cancer Volumetric prescribing (brachytherapy) brachytherapy’. (Radiotherapy, Brachytherapy) Abbreviations: CTV = Clinical target volume, ICRU = Inter- 3D Treatment Planning in Brachytherapy: Three- national Commission on Radiation Units and Measurements and dimensional images are used for both external beam and OAR = Organ at risk brachytherapy treatment planning, and acronyms like IGBT – Related Articles: Dose volume histograms – Brachytherapy, image-guided brachytherapy – and IGABT – image-guided Image-guided brachytherapy adaptive brachytherapy – have been used in the brachytherapy Further Readings: Haie-Meder, C. et al. 2005. community. Recommendations from Gynaecological/GYN) GEC-ESTRO With target volumes and organs at risk delineated, tools like working group (I): Concepts and terms in 3D image-based 3D dose volumes histograms are also available to evaluate dose dis- treatment planning in cervix cancer brachytherapy with empha- tributions in brachytherapy. sis on MRI assessment of GTV and CTV. Radiother. Oncol. ICRU Recommendations – Dose and Volume Specification 74:235–245; ICRU (International Commission on Radiation Units for Reporting: ICRU has published two brachytherapy reports; & Measurements, Inc.) 1985. Dose and volume specification for the ICRU Report 38: Dose and Volume Specification for reporting intracavitary gynecology, ICRU Report 38, Bethesda, Reporting Intracavitary Therapy in Gynaecology (1985), and the MD; ICRU (International Commission on Radiation Units & ICRU Report 58: Dose and Volume Specification for Reporting Measurements, Inc.) 1997. Dose and volume specification for Interstitial Therapy (1997). ICRU also recommends that the reporting interstitial therapy, ICRU Report 58, Bethesda, MD; same terms and concepts are used in brachytherapy as in external Kovács, G. et al. 2005. GEC/ESTRO-EAU recommendations beam radiotherapy, that is a consistent language used whenever on temporary brachytherapy using stepping sources for local- possible. ised prostate cancer. Radiother. Oncol. 74:137–148; Lang, S. et ICRU 58 also states that it is not the intention to ‘encourage al. 2006. Intercomparison of treatment concepts for MR image users to depart from their normal practice of brachytherapy and assisted brachytherapy of cervical carcinoma based on GYN dose prescription. The aim is to develop a common language GEC-ESTRO recommendations. Radiother. Oncol. 78:185–193; which is based on existing concepts. It should be usable to describe Pötter, R. et al. 2006. Recommendations from gynaecological what has been done in a way that can be more closely related to (GYN) GEC ESTRO working group (II): Concepts and terms the outcome of treatment and one that is generally understood’. in 3D image-based treatment planning in cervix cancer brachy- Developments: With the development of 3D treatment plan- therapy – 3D dose volume parameters and aspects of 3D image- ning, there are also developments in the recommendations on based anatomy, radiation physics, radiobiology. Radiother. Oncol. reporting brachytherapy, both for cancer of the cervix and for 78:67–77; Salambier, C. et al. 2007. Tumour and target volumes in prostate cancer. These new recommendations, both for intracavi- permanent prostate brachytherapy: A supplement to the ESTRO/ tary and interstitial brachytherapy, use dose-volume-histogram EAU/EORTC recommendations on prostate brachytherapy. information to evaluate dose distributions and relate dose-volume Radiother. Oncol. 83:3–10. histogram parameters to treatment results (see Salambier et al. and Kovács et al. for prostate brachytherapy and Haie-Meder et Voxel al., Pötter et al. and Lang et al. for cervix cancer brachytherapy). (General) A volume element in three dimensions. A voxel is the Volumetric Prescription: In the abstract of Haie-Meder et al., 3D analogue of the 2D pixel. Voxels are used to visualise 3D med- the authors state (cervix cancer brachytherapy), ‘It is expected ical data. Typically, a voxel contains no information regarding its that the therapeutic ratio including target coverage and sparing position in space. The position is derived from the position rela- of organs at risk can be significantly improved, if radiation dose tive to the other voxels in the data file. V W Wall filter is functioning in one room of the controlled areas. A green/red (Ultrasound) This is a high-pass filter that blocks low-frequency light above the door to the room housing the equipment should components of the Doppler signal. In Doppler measurements, the be green when it is possible to enter the room because the equip- Doppler shift frequency is detected. If however the target is sta- ment is ‘off’ and shall turn red when the equipment is ‘on’, that tionary, a DC-signal is received. This corresponds to the phase is emitting radiation. To see the red light should in fact prevent shift between the transmitted and received signals, which is people from accidentally entering the room. Standard warn- constant as the target is stationary. As tissue has on the order of ing lights should be used as recommended by the international 10–100 times higher scattering strength than blood, a high-pass organisations. Depending on the nature of the equipment and its filter must be inserted in order to eliminate this DC-component. applications, different systems shall be used. As an example, in Otherwise, the lower part of the power spectrum may be dis- radiotherapy, the system should be such that a teletherapy unit torted due to windowing and segmentation of the data. High must cease to operate when the entrance door is opened (there DC-components can also be a problem in the signal processing will also be other safety devices in addition to the light). On the due to clipping and thereby distorted results. other hand, in a diagnostic fluoroscopy room, the red light should The filter limits the lowest velocity that can be estimated, and only be a warning in order to avoid unnecessary entrance, but the limit has to be a trade-off between the desired lower veloc- opening the door shall not turn off the equipment. ity limit and tissue movements, transducer movements and set- Related Articles: Controlled area, Supervised area, Warning tling times for the filter. Moreover, as the blood signal is so much sign weaker than the tissue signal, the filter order has to be considered Further Reading: IAEA (International Atomic Energy so that there is sufficient suppression of the low-frequency tissue Agency). 1996. International basic safety standards for protection signal for the chosen −3 dB limit. against radiation and for the safety of radiation sources. Safety Series No. 115, International Atomic Energy Agency, Vienna, Warm-up Austria. (Diagnostic Radiology) Warming up of the x-ray tube is needed for two main reasons. First, the anode of a cool x-ray tube has to Warning sign be slowly heated, as very quick heating can lead to thermal stress (Radiation Protection) Warning signs shall be placed to clearly and cracks on its surface. Such warm-up can be performed at the indicate the demarcation of controlled and supervised areas. beginning of the working day (often done for CT scanners) or The warning signs to be used are those recommended by the before an examination with heavy exposures (often done before International Organization for Standardization (ISO). The signs QC tests). also give the possibility to indicate the nature of the radiation and Second, warm-up may be needed if the tube has not been used therefore of the related danger: only external irradiation (as, e.g. for a long period of time (several months or more). In this case, with x-ray diagnostic equipment) or internal contamination or it is possible that the x-ray tube vacuum has degreased (due to both (as, e.g. in nuclear medicine). internal ionisation), and a heavy exposure can lead to internal arc- Related Articles: Controlled area, Supervised area ing and destruction of the x-ray tube. In this case, the warm-up Further Reading: IAEA (International Atomic Energy uses exposures with gradually increasing power. These slowly Agency). 1996. International basic safety standards for protection consume the occasional ions in the tube, this way restoring the against radiation and for the safety of radiation sources. Safety vacuum (degassing of the x-ray tube). Series No. 115, International Atomic Energy Agency, Vienna, As an example for x-ray tube warm-up, at least three warming Austria. exposure have to be performed: Washing in film processing 1. Approximately 50 kV, 50 mA and 100 ms (Diagnostic Radiology) After going through the fixer solution W 2. Approximately 50 kV, 100 mA and 200 ms film is next passed through a water bath to wash the fixer solu- 3. Approximately 70 kV, 100 mA and 200 ms tion out of the emulsion. It is especially important to remove the thiosulphate. If thiosulphate (hypo) is retained in the emulsion, it The minimum interval between the exposures has to be at least will eventually react with the silver nitrate and air to form silver 1 min. sulphate, a yellowish brown stain. The amount of thiosulphate Related Articles: Anode, Cooling curve, Thermal stress retained in the emulsion determines the useful lifetime of a pro- cessed film. The American National Standard Institute recom- Warm-up time mends a maximum retention of 30 μg/in2. (Diagnostic Radiology) See Warm-up Waste disposal Warning lights (Radiation Protection) For the general definition, see Radioactive (Radiation Protection) Warning lights should be used to waste. In medical applications, it is often feasible to orga- clearly indicate when equipment that emits ionising radiation nise locally a system for waste disposal. Depending on the 1013 Waste, radioactive 1014 Water calorimeter characteristics of the radioisotopes used, it is important to evalu- water one of the highest specific heat capacities, allowing it to ate the possibility to store and sort out waste substances until the moderate the Earth’s climate. The van der Waals interactions level of radioactivity is below the limit allowed for general waste. between the molecules give water its characteristic property of In this case, it might also be possible to re-use some material, for high surface tension. Water exhibits capillary action, a tendency example the lead in the molybdenum generators used in nuclear to move up a narrow tube against gravity, which is vital in all vas- medicine. In case where local organisation of the waste disposal cular plants. Water is a strong universal solvent, essential for the would not be possible, it is advisable to make contracts with exter- transport of many substances in cells, such as DNA. Pure water nal companies (usually the same organisation that supplies the has a low electrical conductivity, but this increases considerably radioisotopes). with ionic solutes, such as sodium chloride. Water is unique in Related Article: Radioactive waste that it becomes less dense upon freezing, causing ice to float on water. Waste, radioactive Water is significant in the world economy, as it is extremely (Radiation Protection) See Radioactive waste versatile in its applications. It is used most extensively in agriculture for the irrigation of crops. Water is vital for drinking, Water as the human body is 55%–78% water and requires several litres (General) a day to function properly. It is useful as a solvent in industry, for cleaning and for the transportation of sewage waste. It is used for heat transfer for both heating and cooling, such as for

Molar mass 18.015 g/mol driving steam turbines in electric power plants. Water is effective Density at STP 998 kg/m3 at extinguishing fires (excluding electric and chemical fires) as it Melting point 273 K has a high heat of vaporisation and is relatively inert. Water is also Boiling point 373 K extensively applied in the chemical industry, power generation CT number 0 HU (hydroelectricity) and food processing. In a nuclear power plant, the reactor core is immersed in a suitable coolant. Fission occurs in the nuclear fuel, and the fis- Water is a common substance that covers 71% of the Earth’s sion energy in the form of kinetic energy of fission fragments and surface and which is essential for the existence of life. At room new neutrons is rapidly converted into heat. The coolant (usually temperature and pressure, it is in liquid form, but it is com- water) is used to maintain a stable temperature in the reactor core monly found in all three states, known as ice when solid and and exits the core either as steam or as hot pressurised water, steam when gaseous. Water exists in nature mostly in the oceans subsequently used to drive turbines connected to electric power (97%), rivers, aquifers, air, clouds, precipitation and glaciers. generators. Water is also contained within biological organisms. It moves In a nuclear reactor, moderators are used to slow down the continually through a hydrologic cycle of evaporation/transpira- newly produced fast neutrons through elastic scattering events tion, precipitation and runoff to the sea. Although fresh water is between neutrons and the nuclei of the moderator. Water serves essential for life, there is an increasing shortage in many parts as moderator material in most reactors; however, some reactors of the world. may use the so-called heavy water (deuterium based), graphite Pure water is a tasteless, odourless and has a very light blue or beryllium for the purposes of moderation. Heavy water has a colour. However, water readily dissolves many substances, giving smaller probability for neutron absorption through the (n,γ) reac- it various tastes and odours. Water is miscible with many sub- tion than water; however, it is much costlier. stances, except most oils. It is transparent, only absorbing strong Medical Applications: Water is applied widely in medicine, for UV light. Water is a polar molecule (Figure W.1) due to the dipole example for cleaning and as saline for intravenous use. It is often moment created by the oxygen and hydrogen atoms. This causes used as a scientific standard, such as for the Kelvin and Celsius the molecules to attract strongly via hydrogen bonding giving temperature scales and also the Hounsfield scale to quantify a material’s radiodensity in relation to water. Properties of human soft tissue are often approximated to that of water, due to its high water content. This makes water an effective and readily available H phantom material for medical physics applications. Related Articles: CT Number, De-ionised water, Solid water W phantom, Water calorimeter, Water cooling, Water suppression, Water tank 104.45° Water calorimeter (Radiation Protection) The absolute measurement of absorbed H dose in water can be performed using a sealed water calorimeter. The amount of heat ΔQ produced in the water by ionising radiation is equal to O DQ = cs ´ m ´ DT 0.9584 Å where cs is the water specific heat FIGURE W.1 Chemical structure of water (H2O) showing the bond m is the mass of water angle and bond length. ΔT is a change of temperature Water cooling 1015 W ater suppression The measurement of ΔT enables us to evaluate the absolute where CTDIvol(z) is the CTDIvol for that position and fDw(z) is the amount of energy absorbed by the water. The absorbed dose D is size-specific conversion factor as given by AAPM report 204 defined as energy absorbed per unit mass. The value of D can be (Boone et al., 2011). calculated from the equation Abbreviations: CT = Computed tomography. Related Articles: CTDI, Dose length product, CT number DD = cs ´ DT Further Readings: Boone, J. M. et al. 2011. Size-specific Dose Estimates in Pediatric and Adult Body CT examinations. Related Articles: Calorimeter, Calorimetry AAPM Report 204; McCollough, C. et al. 2014. Use of water Further Reading: Graham, D. T. and P. Cloke. 2003. equivalent diameter for calculating patient size and size-specific Principles of Radiological Physics, 4th edn., Elsevier Science dose estimates (SSDE) in CT. The report of AAPM task group Ltd., Edinburgh, UK, p. 331. 220. AAPM Rep. 2014:6–23. Water cooling Water equivalent path length (Diagnostic Radiology) X-ray tube with direct water cooling of (Radiotherapy) The water equivalent path length (WEPL) is the anode is rarely used these days. Such tube requires the anode defined as the radiological depth between a radiation source and to be grounded (0 V) and the cathode bears all the voltage (e.g. any other point of interest, as determined by the linear attenuation −100 kV). In this case, the stem of the anode has special construc- coefficient and thickness of each material in the path. In other tion, allowing running water to pass through and quickly cool it. words, for a single radiation ray traversing several materials of However, most often, the anode bears high positive voltage and different thicknesses and densities, the WEPL concept scales all is cooled by insulating oil, which oil is in turn cooled by running these materials to the depth of water which has the same attenuat- water (i.e. indirect water cooling). ing effects. Related Articles: Anode, Stationary anode, Rotation anode, Related Articles: Pathlength, Range Cooling curve, X-ray tube housing Water suppression Water cooling (Magnetic Resonance) A conventional MR image is essentially (Magnetic Resonance) Gradient systems dissipate a lot of heat a map of water distribution (spin density), and MRI would not due to the high current loads and heavy duty cycle. This can have be feasible at all, on the grounds of spatial resolution and imag- a detrimental effect on the magnet resonance imaging (MRI) ing speed, if it was not for the large amount of water present in system. Gradient coils are therefore equipped with closed-loop the body. In proton magnetic resonance spectroscopy (MRS), water-cooling systems. however, the desire is to detect proton-containing compounds Resistive magnets require large currents to generate the static (e.g. metabolites) at much lower concentration. Because the magnetic field, and significant water cooling of the magnet coils concentration of water in body tissues is around 10,000 times is required for such MRI units. that of metabolites, unless special measures are taken the water Related Articles: Duty cycle, Gradient coil, Magnet resistive peak dominates any in vivo proton spectrum to the extent that other signals are buried beneath it and occupy a tiny proportion Water equivalent area of the dynamic range of the analogue to digital converter. This (Diagnostic Radiology) Water equivalent area and water equiva- problem delayed the development of in vivo proton spectros- lent diameter are concepts used in CT dosimetry. copy until suitable water suppression techniques became avail- Concepts like CTDIvol, DLP provide an estimate of the tube able, a process that required pulse sequence development and in output needed for a certain scan; however, they don’t allow an many cases also hardware improvements that took some years estimate of a dose for a specific patient taking into account their to achieve. size. Today, a range of water suppression techniques is avail- The water-equivalent area, Aw, for a patient is defined as the able, and clinical MRI systems usually allow the user to choose cross-sectional area of a water cylinder giving the same attenua- between several methods. tion as the patient. It can be calculated as Frequency-Selective Excitation and Refocussing: Frequency selective RF-pulses can be used to selectively excite the frequency a range of metabolites whereas the water resonance remains unaf- åæ CT ( x, y) ö Aw = çç +1÷÷ ´ A fected. An alternative approach, frequency selective refocus- pixel 1000 x,y è ø ing, employs a spin-echo sequence designed to refocus only the W metabolite magnetisation, while dephasing that of water. where CT(x,y) is the CT number for a pixel with coordinates x,y, Frequency-Selective Saturation: A widespread approach to A water suppression in the context of in vivo MRS is the use of one pixel is the area of an image pixel and the exponent α is usually 1 (McCollough et al., 2014). or more frequency selective RF pulses, designed to tip water mag- From Aw, the water-equivalent diameter, Dw, can be calculated netisation into the transverse plane, followed by spoiler gradient as to dephase this magnetisation. Elimination of the water signal in this way is followed by a conventional MRS sequence, which A Dw = 2 detects only the remaining metabolite signals. p The most common implementation of this approach is the CHESS (chemical shift selective) sequence of Haase et al. In and the size-specific dose equivalent (SSDE) at a position z along practice, selective excitation is generally repeated two or three the longitudinal axis can be calculated as times to improve water suppression. Composite and Binomial Pulses: Both water suppression SSDE(z) = CTDIvol (z)´ fDw (z) techniques, frequency selective excitation and saturation require Water tank 1016 W aveguide frequency selective RF-pulses. Composite and binomial pulses Wave equation are often applied for this purpose. (Ultrasound) Any parameter Φ, being a function of time and posi- A composite pulse is a sequence of RF pulses designed to tion, that satisfies the equation emulate the behaviour of a simpler pulse, but with special fea- tures such as tailored off-resonance behaviour or insensitivity ¶2F 2 2 ¶ F 2 = c ¶t ¶x2 to magnetic field inhomogeneity. In the context of water sup- pression, composite pulses can be designed to generate a very can propagate as a wave at speed c in the positive or negative small flip angle at the resonance frequency of water, so that very direction. These functions generally have arguments of the type little water signal is collected relative to metabolites at other (ct − x) or (ct + x) respectively. frequencies. We can regard pressure as such a parameter, which propagate Binomial pulses are trains of RF pulses, with the flip angles due to the elasticity and density of the medium carrying the sound generated by successive pulses given by binomial coefficients. For wave. The elasticity (or compressibility) makes the medium return example, the ratios of the amplitudes of the pulses in the three to the state it had before the disturbance occurred. The mass of simplest binomial sequences are 1:1, 1:2:1 and 1:3:3:1. Phase alter- the medium (density) will give inertia to this returning motion so native between successive pulses may also be used. The usual that the movement will have an overshoot. If then the elements approach is to place water on resonance and choose the intervals of the medium are coupled, a wave can propagate. To describe between pulses, with respect to the frequencies of the metabolites this wave motion mathematically, one studies the small devia- of interest, so that off-resonance effects ensure that the sequence tions from equilibrium pressure: a small deviation in pressure as a whole places magnetisation from these metabolites into the will cause a corresponding deviation in density. Three equations xy-plane, while water signal is returned to the z-axis and produces (or relations) are needed: (1) the conservation of mass (the change no signal. It is possible to tailor the width of the spectral region in of mass in a volume must equal the difference between the mass which transverse magnetisation is generated and that of the null entering and leaving the volume), (2) conservation of momentum region, by using sequences of increasing complexity. (an equation of motion), and (3) that density can be expressed as a Further Reading: Haas, A., J. Frahm, W. Hanicke and D. function of pressure only (an equation of state). Relation (3) will Matthaei. 1985. 1H NMR chemical shift selective (CHESS) imag- be true under the assumption that the process is adiabatic, that is ing. Phys. Med. Biol. 30:341–344. that no heat transfer occurs between compressed and rarefracted regions. By combining these three statements, one arrives at the Water tank well-known wave equation given earlier. The derivation is based (Radiotherapy) A water tank is a large Perspex tank (typically at on small variations in density of

the medium caused by the pres- least 40 × 40 × 40 cm3), which is filled with water for dosimetric sure variations in the sound wave. The result is valid for a region work. An arm system allows a range of detectors to be positioned with homogeneous density and compressibility. very precisely throughout the volume to acquire detailed informa- tion such as beam profiles and percentage depth doses. Typically, Waveguide the water tank is used mainly at acceptance testing and commis- (Radiotherapy) A waveguide is an evacuated or gas-filled tube sioning, or whenever a major modification is made to the linac. structure that guides waves, transferring information or power. The time of set-up renders the water tank less useful for routine They are used in linear accelerators to accelerate the electrons to QC measurements, and so solid water materials are used for these high energy to form the therapy beam in radiotherapy (accelerat- measurements. ing waveguide) as well as coupling the microwave energy from the Abbreviation: QC = Quality control. klystron or magnetron source (power transmission waveguide). Related Article: Solid water phantom Accelerating Waveguide: There are two main types of accel- erating waveguide: standing wave or travelling wave, which refer Watt to the type of electromagnetic wave that is established within the (General) The watt (symbol W) is the Système International guide. The phase velocity of the electromagnetic wave can be (SI) unit of power (i.e. the rate of expenditure or transforma- adjusted by placing internal iris diaphragms within the circular tion of energy from one form to another). Therefore, in SI units, guide, creating internal cavities that form the basic structure. The 1 W = 1 J/s. electrons are injected into one end of the waveguide and ‘ride’ Similarly to joule, watt is a derived SI unit and may more prop- upon the crests of the electromagnetic wave. By increasing the erly be expressed in terms of base SI units as phase velocity of the electromagnetic wave, the electrons can be W accelerated up to MeV energies. kg × m2 1W = s2 • Travelling wave: In this type of waveguide, the elec- where tromagnetic wave enters the tube and propagates down kg is kilogram (mass) towards the end, where it is either absorbed or exits m is metre (distance) to be fed back into the input end. There is no reflec- s is second (time) tion of energy. These waveguides generally have two sections. In the first ‘buncher’ section, the cavities are The unit is named after James Watt, Scottish inventor and non-uniform (inner diameter, aperture diameter and mechanical engineer (1736–1819). axial spacing vary). This section groups the electrons Related Article: Système International together so they are all moving coherently in space, Further Reading: Benedek, G. B. and F. M. H. Villars. phase and velocity. The last section is the ‘accelerator’ 2000. Physics with Illustrative Examples from Medicine and section, which transfers energy to the electrons until Biology: Mechanics, 2nd edn., Springer-Verlag Inc., New York, they reach MeV energies. This structure can be seen pp. 354–355. in Figure W.2. Wavelength 1017 Wedge Electron gun Electron beam ‘Buncher’ section ‘Accelerator’ section RF power in RF power out RF power wave Force on electron FIGURE W.2 A schematic of the travelling wave waveguide. FIGURE W.4 A cut-away view of a standing waveguide. Note the side-coupled cavities. (From Podgorsak, E.B., ed., Review of Radiation Oncology Physics: A Handbook for Teachers and Students, International 1 2 3 4 5 6 Atomic Energy Agency, Vienna, Austria, 2003.) Wavelength (Ultrasound) Wavelength is the shortest distance between two points that are in phase on a sinusoidal wave, that is the distance of a complete cycle of the wave. The wavelength, λ, is related to FIGURE W.3 A schematic of the standing wave structure of a wave- the frequency by λ = c/f, where c is the wave propagation speed guide. See article for explanation. (or strictly phase speed, that of an infinitely long sinusoidal wave). Thus, it is somewhat difficult to talk about the wavelength for a broadband (i.e. short) pulse. • Standing wave: In contrast, a standing wave structure has conductive discs placed at each end that reflects Wax the electromagnetic power, so a standing wave is built (Radiotherapy) Wax can be used as bolus, which is a tissue-equiv- up. A schematic of the standing waveguide is shown in alent material placed directly on the skin surface to even out the Figure W.3. irregular patient contour and thereby provide a flat surface for The arrows show the axial electric field at an instant in time. An normal beam incidence. See article Bolus. electron in cavity 1 will receive acceleration at that instant. The Related Article: Bolus standing wave will then reverse the direction of the axial field at the oscillation frequency. If the speed of the electron is such that Weber it arrives in cavity 3 when the standing wave has reversed, then it (Magnetic Resonance) The Weber, abbreviated Wb, is the SI will receive acceleration again at that point. The electron injections unit of magnetic flux and is named after the German physicist are hence synchronised with the frequency of the RF power source Wilhelm Eduard Weber (1804–1893). so this occurs. Cavities 2, 4 and 6 are positioned at the nodes of The Weber is a large unit that is described as the amount of the standing wave and hence never transfer energy to electrons. magnetic flux that in 1 s produces 1 volt per turn of a linked circuit. This fact can be exploited to shorten the tube, by moving these Expressed in SI base units, the Weber is written as cavities to the sides – a side-coupled waveguide. A cut-away view can be seen in Figure W.4. This has advantages in that it produces kg × m2 a higher accelerating gradient per metre, and the reduced length s2 × A of the waveguide can be mounted directly in the gantry. However, they do also have greater lateral bulk, which forces everything fur- which is also equal to ther away from isocentre, hence needing a wider turning circle and W higher patient table. T × m2 Power Transmission Waveguide: Rectangular waveguides are used to transfer the microwave energy from the source to the Related Article: Flux accelerating waveguide. A circulator (or isolator) must be placed between the power source and the waveguide to protect the source Wedge from any reflected power travelling in the opposite direction. This (Radiotherapy) A wedge (or wedge filter, compensating wedge) allows radiation to pass through that is travelling from the source, is an external compensator that can be physically placed in the but blocks radiation travelling to the source. beam to create oblique dose profiles across the central axis of a Related Article: Linac beam, due to its tapering thickness in one dimension. They are Further Readings: Johns, R. C. and J. H. Cunningham. 1983. used to either compensate for an oblique surface (illustrated in In: The Physics of Radiology, ed., C. C. Thomas, Springfield, Figure W.6) or to correct for non-uniformities in multi-beam IL; Podgorsak, E. B., ed. 2003. Review of Radiation Oncology plans (illustrated in Figure W.7). Physics: A Handbook for Teachers and Students, International Figure W.5 shows a typical isodose distribution obtained from Atomic Energy Agency, Vienna, Austria. a wedge filter. The beam is attenuated greater at the thicker end Wedge angle 1018 W edge angle 110 100 90 80 70 60 50 FIGURE W.6 Using a pair of wedges (with thin edges nearest the 40 patient’s surface) to compensate for the breast’s varying thickness. 30 20 FIGURE W.5 A wedged isodose distribution. (From Podgorsak, E.B. (ed.) Review of Radiation Oncology Physics: A Handbook for Teachers and Students, International Atomic Energy Agency, Vienna, Austria, 2003.) of the wedge (the heel), leading to a higher dose at the thinner end of the wedge (the toe). Possible types of wedge filter are: physical, motorised and dynamic. A physical wedge is an angled piece of material (lead, brass or steel) that is placed in the beam to produce a gradient in radia- tion intensity. Manual intervention is required to place physical FIGURE W.7 Using a pair of wedges (with thick edges at the top) to wedges on the treatment unit’s collimator assembly. Historically, correct for non-uniformities in multi-beam plans. physical wedge filters were widely used in both cobalt units and linear accelerators. They were energy-specific. The wedge angles were limited to those available, often 15°, 30°, 45° and 60°. Example B: A three-field plan is often used for irradiation of However, intermediate angles could be effectively created over the pelvis, with two laterally opposed wedged fields and an ante- the whole treatment by swapping to an alternative wedge midway rior field. The wedges are necessary to balance the dose distribu- through treatment. tion within the target volume (Figure W.7). W A motorised wedge is a similar device, a physical wedge, Related Articles: Wedge angle, Wedge transmission factor, typically 60°, integrated into the head of the unit and controlled Dynamic wedge, Beam hardening remotely. Any wedge angle can then be created by combining Further Reading: Podgorsak, E. B., ed. 2003. Review of the wedged field with an open field of varying duration. The Radiation Oncology Physics: A Handbook for Teachers and advantages of this method over physical external wedges include Students. International Atomic Energy Agency, Vienna, Austria. greater flexibility, reduced manual handling risks for the radiog- rapher and reduced set-up time for the patient. Wedge angle A dynamic wedge produces a wedged intensity gradient by (Radiotherapy) The wedge angle of a wedged field can be defined moving one jaw across the field whilst keeping the other station- in two ways. The IEC standard defines the wedge angle as that of ary, which creates a wedged field since different parts of the field the isodose curve to a plane perpendicular to the central axis, at a are irradiated for different times. See article on Dynamic wedge depth of 10 cm. Alternatively, it is the angle that the 50% isodose for further information. line makes with the central axis of the beam. Example A: Wedge filters are routinely used in irradiation of The wedge angle required to act as a tissue compensator is the breast: two wedged (~15°) coaxially opposed beams are used normally between 50% and 75% of the angle of the surface obliq- to compensate for the oblique incidence (Figure W.6). uity depending on depth and energy. Wedge field 1019 Well-counter detector For treatments that combine the use of two wedges, the effec- Related Articles: Radiation weighting factor, Tissue weight- tive wedge angle of the combined fields is the weighted average of ing factor, Equivalent dose, Effective dose the tangents of the two wedges, weighted according to the relative Further Reading: ICRP Publication 103: Recommendations contribution to the dose at the depth of dose maximum: of the ICRP. w tan 1tanq1 + w2tanq q = 2 Wehnelt electrode 0 w1 + w2 (Diagnostic Radiology) Normally the beam of thermal electrons Wedge angle calculation, where w1 and w2 are weighting factors. produced by the cathode filament is quite spread, resulting in an For example, the motorised wedge uses a combination of a 60° increased area of the focal spot. This enlarged size of the source wedge and an open field. If equal weighting is given to each field, of radiation blurs the x-ray image. In order to focus the beam of then the effective wedge angle is given by thermal electrons and to decrease the space-charge effect, the cathode filament is placed in a focusing cup (a half-pipe groove, q0 = arctan (tan(60°)/2) = 41° known also as Wehnelt electrode or Wehnelt cylinder, named after its inventor). The focusing cap is specially shaped and is made of Abbreviation: IEC = International Electrotechnical Commission. molybdenum, nickel or steel, because of their poor thermionic Related Articles: Wedge filter, Wedge transmission factor, emission. The cup can be equipotential with the cathode. In this Dynamic wedge, Tissue compensation, Wedge case, placing the filament wire inner or outer in the cup changes the focusing of the electron beam (Figures W.8 and W.9). The cup can also be charged with slight negative potential Wedge field against the cathode (of the order of tenths of volts). Changing (Radiotherapy) See Wedge the negative charge of

the Wehnelt electrode leads to change in the focusing effect (Figure W.10). In this way, the electron flow Wedge filter (anode current) can be controlled (even stopped). Such x-ray (Radiotherapy) See Wedge tubes (known as grid-controlled) allow the creation of very short x-ray pulses (of the order of 1 ms), which are especially useful Wedge transmission factor for imaging of dynamic objects (e.g. the heart). Switching on/ (Radiotherapy) Wedge transmission factor (wedge factor, WF) is off the x-ray beam through the grid-control is technologically the ratio of the dose with the wedge in the beam to the dose in the easier and above all far quicker than switching on/off the high same conditions but without the wedge in the beam. This is gener- anode voltage. ally a function of both depth and field size and hence is normally Related Articles: Cathode, Focal spot, Space-charge effect, measured at a specified depth on the central axis for the reference Grid-controlled tube field size. Wedge factor measurements should be included in rou- Hyperlink: EMERALD (DR module), www .emerald2 .eu tine QA checks. When the wedge factor is measured, care must be taken to Well-counter detector place the ion chamber axis parallel to a constant thickness of (Nuclear Medicine) A counter system that consists of a single the wedge. The wedge factor is often compared to the oppos- crystal including a hole within it for insertion of radioactive ing wedge factor (by rotating wedge or collimator by 180°) to substances. The aim of the design is to surround the substance ensure that the position of the ion chamber/wedge is correct. with as much detector as possible (approaching a solid-angle of Rotation of the collimator verifies that the ionisation chamber 4π), increasing the efficiency of detection and pushing down the is positioned on the collimator axis of rotation. Rotation of the wedge itself reveals whether the side rails are symmetrically positioned about the collimator axis of rotation. The measured values should be within tolerance limit for the two wedge ori- entations. Usually, the average value of the two wedge orienta- tions is taken as the correct value of the wedge transmission factor. Abbreviation: WF = Wedge factor. Related Articles: Wedge filter, Wedge angle, Wedge Further Reading: Podgorsak, E. B., ed. 2005. Radiation W Oncology Physics: A Handbook for Teachers and Students, International Atomic Energy Agency, Vienna, Austria. Weighting Factor (Radiation Protection) Dimensionless factors developed by the International Commission on Radiological Protection (ICRP) for the determination of equivalent and effective dose. Radiation weighting factors reflect the ability of different types of ionising radiation to cause stochastic damage and are used to convert the absorbed dose to an organ into an equivalent dose. Tissue weight- ing factors reflect the varying sensitivities of different tissue types FIGURE W.8 Cathode assembly from x-ray tube with rotating anode. to radiation induced stochastic effects. They are applied to the The two filament wires in the focusing cup (Wehnelt electrode) are with equivalent doses for the defined organs and summed together to longitudinal positioning. (Courtesy of EMERALD project, www .emer- produce the effective dose. ald2 .eu) Well-counter detector efficiency 1020 W ell-type ion chamber Test tube containing radioactive sample Crystal Lead shielding PM tube FIGURE W.11 A schematic representation of an ordinary well-counter used to determine the activity in a sample. the detector efficiency is close to 1. The total efficiency is the product of the intrinsic and geometric efficiency. The detection efficiency of a well-counter for most typical γ-emitters is high. The primary reason is the high geometric effi- ciency g. A sample in a well-counter is almost entirely surrounded FIGURE W.9 Enlarged image from Figure W.8 showing that cath- by the crystal hence most of the emitted photons pass through the ode filaments can be placed at various depth inside the focusing cup. (Courtesy of EMERALD project, www .emerald2 .eu) crystal. The intrinsic efficiency ε depends on crystal thickness and γ-ray energy because a thick crystal increases the probability of photon attenuation in the same way as higher energy leads to higher photon penetration. The calculation of the intrinsic effi- 2 ciency is complicated because the crystal thickness is different for different emission angles, that is a photon with a perpendicular angle of incidence has less absorptive crystal to pass through than a photon with an oblique angle of incidence. In some well-counters, counts outside the photopeak are dis- criminated, which makes it necessary to account for the photo- fraction fp when calculating the efficiency. The photofraction is inversely proportional to the γ-ray energy and proportional to 1 the crystal thickness. The intrinsic photopeak efficiency εp is the product of photofraction and the intrinsic efficiency, and it is a more appropriate measure of the efficiency in a photopeak-only well-counter system: ep = e ´ fp (W.1) FIGURE W.10 Focusing effect of the cathode focusing cup – Wehnelt electrode (2) on the trajectories of electrons emitted from the cathode Related Article: Well-counter detector (filament – 1). Further Reading: Cherry, S. R., J. A. Sorenson and M. E. Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, Philadelphia, PA, pp. 186–188. minimum detectable activity (MDA). These simple detectors are W used to estimate the activity in a radioactive sample. Well-type ion chamber The common well-counter design consists of a single crystal (Radiotherapy, Brachytherapy) The well-type ion chamber, attached to a PM-tube sealed by a high attenuating material (lead designed for brachytherapy source calibrations, is the instru- shielding) as seen in Figure W.11. The crystal typically used for ment recommended for source strength measurements at the well-counter detectors is NaI (Tl). Lead shielding is employed to hospital level by the IAEA, see TECDOC-1274: ‘Calibration of reduce the background radiation contribution to the count rate. photon and beta ray sources used in brachytherapy. Guidelines Further Reading: Cherry, S. R., J. A. Sorenson and M. E. on standardised procedures at secondary standards dosim- Phelps. 2003. Physics in Nuclear Medicine, 3rd edn., Saunders, etry laboratories (SSDLs) and hospitals’. Well-type chambers, Philadelphia, PA, pp. 185–186. designed for brachytherapy, can in general be used both for high-dose and low-dose rate sources, as they have a large col- Well-counter detector efficiency lecting volume. (Nuclear Medicine) The ratio of the number of detected photons The well-type chamber is easy to use, fast and reliable; the to the total number of emitted photons from a sample is referred chamber is stable in response, and the measurement geometry is to as the well-counter detector efficiency. If a large fraction of the easy to reproduce. Special inserts are used for different types of emitted photons is detected and registered by the well-counter, sources; see the examples given in the following figures. WFUMB 1021 Whole-body dosimeters Figure W.12 shows the well-type chamber HDR 1000 from dosimetry laboratory is usually made with the source positioned Standard Imaging with an insert for high-dose rate sources. A at the point of maximum response. Source strength measurements needle is placed in the insert, which also guides the needle to a at the hospital must be made with the correct insert and with the position along the axis of the cylindrical chamber. (Notice the source at the same position as the one used for the calibration. plastic foam to minimise heating effects.) The insert to the right Verification of source strength is one of the most impor- is made of lead with a plastic slit in the middle, and this ‘QA tool’ tant parts of a quality assurance programme for brachytherapy. can be used to determine the source position for a stepping-source Aspects on quality assurance are presented in the ESTRO Booklet afterloading unit. (Radiochromic film is also used to verify source No. 8 and in the general references given in Brachytherapy. position and step size.) Abbreviations: ESTRO = European Society for Therapeutic Figure W.13 shows the well-type chamber HDR 1000 Plus from Radiology and Oncology and IAEA = International Atomic Standard Imaging with an insert for low-dose rate sources. This Energy Agency. insert is designed for stranded iodine-125 seeds (RAPID Strand, Related Article: Brachytherapy Oncura). A strand, consisting of 10 seeds in its amber coloured Further Readings: IAEA (International Atomic Energy holder, is placed in the insert. Two measurements are made; with Agency). 2002. Calibration of photon and beta ray sources the strand as shown, where the upper five seeds are blocked by the used in brachytherapy. Guidelines on standardized procedures cylindrical lead shield and with the strand inverted. The steel tube at Secondary Standards Dosimetry Laboratories (SSDLs) and used for transport of the strand in its holder is standing to the left. hospitals, IAEA-TECDOC-1274, Vienna, Austria; Venselaar, J. The well-type chamber must be calibrated, together with the and J. Pérez-Calatayud, eds. 2004. A Practical Guide to Quality corresponding insert, for each source and source design. The Control of Brachytherapy Equipment, ESTRO Booklet No. 8, sensitivity of the chamber with position of the source along the Brussels, Belgium. axis of the chamber usually varies slowly, displaying a broad maximum. Calibration of the chamber at a secondary standards WFUMB (Ultrasound) The World Federation of Ultrasound in Medicine and Biology is a federation of regional bodies covering • EFSUMB – Europe • AFSUMB – Asia • AIUM – North America • FLAUS – Latin America • ASUM – Australasia • MASU – Africa The Federation publishes a journal Ultrasound in Medicine and Biology (UMB) and hosts a website www .wfsumb .org. White noise (Nuclear Medicine) White noise is a random signal that in the fre- quency space has equal amplitude for all frequencies. The name comes from white light that contains all colours with the same FIGURE W.12 Well-type chamber with inserts for high-dose rate mea- intensity. surements. To the left, the standard insert for a HDR 192Ir source with a Related Article: Poisson noise needle, to the right the ‘QA tool’. Whole-body dosimeters (Radiation Protection) A device that allows the estimation of the whole-body effective dose incurred by the wearer. Whole-body dosimeters are either passive (the device must be processed, and the results returned to the wearer at a later date) or active (giving an immediate reading of the dose received by W the wearer). Passive devices, such as film-badges or thermoluminescent dosimeters (TLD), are often distributed to radiographic staff and allow monitoring over regular time periods (usually 1, sometimes 2 or 3 months). The original monitors developed for whole-body monitoring were small films placed in a holder, which provided different amounts of attenuation in different regions of the film to facilitate identification of the type and energy of the radiation, which caused the exposure. TLD materials are now more commonly used for whole-body monitoring than film, although these materials are less reliable at determining the source of the radiation exposure. More recently, one personnel dosimetry company has intro- FIGURE W.13 Well-type chamber with a special insert for stranded duced optically stimulated materials. These have much greater iodine-125 seeds. sensitivity than either film or thermoluminescent (TLD) materials. Whole-body magnet 1022 Window Active devices are based on semiconductor devices and may be referred to as electronic personal dosimeters. They are intended for situations where there is significant risk of exposure or where exposures are expected to be high. The original active devices were quartz-fibre electrometers. These were notoriously unreliable and have now been replaced by electronic devices using solid-state detectors. There are a variety of such solid-state devices, commonly referred to as ‘pocket dosimeters’. In addi- tion to displaying the cumulative dose at any instant, they also have the ability to set alarms to warn the wearer when a particular exposure has been reached. Related Articles: Personal dosimetry, Personnel dosimetry Whole-body magnet (Magnetic Resonance) The term whole-body magnet refers to an MRI system, which allows scanning of a whole human body, as opposed to specialised systems for brain or extremity scan- ning only. For whole-body MRI, the static magnetic field must be sufficiently uniform (homogeneous) in large volume allowing FIGURE W.15 Photograph of a whole-body radiation counters. MRI of different body parts (e.g. brain, spine, heart, abdomen, (Courtesy of Mr. Kamil Kisielewicz, M. Sklodowska-Curie Memorial extremities). Institute, Cracow, Poland.) Whole-body radiation counters (Radiation Protection) Whole-body radiation counting is used to Philadelphia, PA, pp. 183–184; Dendy, P. P. and B. Heaton. 1999. measure the uptake of an administered radiopharmaceutical by Physics for Diagnostic Radiology, 2nd edn., Institute of Physics

patient after a suitable interval of time. It is also applied for radia- Publishing, Philadelphia, PA, pp. 163–164. tion protection to estimate a total body activity of workers dealing with non-sealed radioactive sources as well as of a general public exposed to environmental radioactive contamination. Wiener spectrum In Figure W.14, a scheme of a whole-body counter is shown. (Diagnostic Radiology) See Noise power spectrum (NPS) The patient is placed between a set of some scintillation coun- ters located above and below him/her. The result of measurement Wilkinson converter presented as total example count is related to the total activity (Nuclear Medicine) See Analogue to digital converter (ADC) accumulated within the body. This system is called a ‘scanning shadow shield’ method. Window The photograph of a whole-body counter is presented in (Diagnostic Radiology) ‘Window’ is associated with the window- Figure W.15. ing technique used in the display of digital medical images. The The kind and the detailed distribution of radioisotope may be need for such a technique arose initially from the observations of explored with using a gamma camera. computed tomography (CT) images. Related Articles: Contamination, Gamma camera, CT images are generally displayed on a greyscale, where Radioactive source, Scintillation counter more attenuating materials are represented by pixels with lighter Further Readings: Brown, B. H. et al. 1999. Medical Physics grey shades and the less attenuating by darker ones. The stan- and Biomedical Engineering, Institute of Physics Publishing, dard Hounsfield scale of CT numbers ranges from approximately −1000 to +3000 HU and thus contains 212 (4096) levels of grey (Figure W.16a). The human eye however is only capable of distin- guishing about 16–100 levels of grey (depending on the person). Scintillation counters The windowing techniques allow for the display of a range of CT W numbers over the full greyscale. This way, it accommodates the limited contrast sensitivity of human eye to the high number of grey shades existing in the CT image. This technique uses two simple factors: Patient • Window level (WL) (or window centre) is the mid-point of the CT numbers displayed and is assigned the mean grey shade, visualising the CT number with mean grey shade (absolute grey, an analogue to optical density 1 of the characteristic film of an x-ray film) • Window width (WW) defines the range of CT numbers Scintillation counters around the WL, which are displayed over the greyscale For example, if in a CT imaging system WL = 0 and WW = 100, FIGURE W.14 Scheme of a whole-body radiation counters system. then the water (CT = 0 H) will be displayed by medium grey, Window fraction 1023 Window function –1000 0 1000 +3000 The windowing technique is now used in all types of digital WL = 1000 (a) WW = 4095 medical imaging systems. To obtain the best window parameters Fat Muscle Water (WL and WW), the observer must first measure the pixel value –1000 (e.g. the CT number or density value in digital radiography, etc.), 0 +1000 WL = 0 then adjust the WL to this pixel value and finally adjust the WW (b) WW = 2000 that best presents the diagnostic information. Although WW of Fat Muscle Air Water Bone the order of 100 will present a greyscale most suited to the human –200 0 +200 vision, many specialists prefer broad WW (say 400), as it dis- WL = 0 plays many tissues and gives a better overview of the anatomi- (c) WW = 400 Fat Water Muscle cal region. Once the specialist has seen the whole region with a broad window, he/she can concentrate on a specific organ with 800 1000 1200 WL = 1000 a narrower window. Some medical imaging systems can display (d) WW = 400 the scan with two (or more) window parameters. For example, Bone the image in Figure W.17a is presented with one set of window parameters (showing the lungs), but additionally, the mediasti- FIGURE W.16 The CT number scale in Hounsfield units (explanations num is selected as a region of interest, which is displayed over in the text). the image with second set of window parameters (showing only its structures). The figures for WW and WL used in the previous examples the less absorbent tissues with CT numbers from 0 to −50 will are related to CT; however, other digital medical imaging systems be presented with shades from medium grey to most dark grey may use various scales of its pixel values (e.g. −1000 to +3000 for (−50 H), and the more absorbent tissues with CT numbers from 0 most CT scanners and 0–512 for some digital fluoroscopy sys- to +50 will be presented with shades from medium grey to most tems). This will change the numbers for WL and WW. light grey (+50 H). All tissues with densities below −50 H will be When an image from a digital system is photographed (say seen as black on the monitor screen, and all tissues with densities with laser film printer), the WW and WL parameters have to be above +50 H will be seen as white. If the image is inverted (nega- shown, as otherwise the viewing conditions of this digital image tive), the greyscale is also inverted. cannot be reproduced correctly at a consecutive observation of The range of CT numbers displayed on the monitor can be this image on the monitor. varied by adjusting the WL and WW, according to the tissues Related Articles: CT number, Hounsfield scale of interest. Better differentiation between tissues (contrast) can be perceived if the window width is reduced, so that a smaller range of HU is displayed over the entire greyscale (Figure W.16b Window fraction through d). In the figure, (Nuclear Medicine) In nuclear medicine imaging, the energy sig- nal from each detected photon is passed through a pulse height a. The full range displayed over the greyscale analyser (PHA). Here, a window is set up around the photopeak b. WL changed and WW reduced energy so that photons outside that energy, which may have been c. WW reduced further to display a smaller range of CT scattered, are not included in the image. Most systems are set numbers over the greyscale up to accept photons whose energies are within a 20% window d. WL changed to display different range of CT number (10% each side of the photopeak). This is known as the window values fraction. Related Article: Gamma camera The WL can then be set to display the tissues of interest Figure W.17. Window function Figure W.17 shows a typical representation of a CT scan of the (Nuclear Medicine) A window function is used in signal process- lung, shown with two selections of window parameters. ing to limit data outside a certain interval. For example, an image 3000+ HU 3000+ HU W 0 HU WL WW WL WW –1000 HU WL–600, WW 500 WL–10, WW 400 –1000 HU (a) (b) FIGURE W.17 WL and WW set to display (a) lung tissue and (b) pulmonary metastases. Window width in single-channel analyser 1024 Workload factor (W) can be described by its frequencies and amplitudes by a Fourier transformation. Noise usually appears in the high frequency part Cross- Nearest of the Fourier spectrum. By applying a window function, all fre- Diameter Sectional Ohms per Nearest Metric quencies above a certain threshold are set to zero. This is com- AWG (mm) Area (mm2) Kilometre SWG (Whole) monly known as low-pass filtering. Often a window function used 10 2.59 10.53 3.3 12 26 in this way is rolled-off by a smoothing function in order to avoid ringing artefacts. 16 1.29 2.58 13.2 18 13 A window function can also mimic the limited field of view of 22 0.64 0.65 53 23 6 an imaging system such as a scintillation camera. This can then 28 0.32 0.16 213 30 3 address aliasing effects due to overlap of periodical functions. 34 0.16 0.04 856 38 2 40 0.08 0.01 3440 44 1 Window width in single-channel analyser (Nuclear Medicine) In single-channel analysers, the energy win- dow has to be selected to cover the region of the pulse height Other handy tips in working out physical wire size to gauge num- spectrum that should be analysed. The energy window is set over ber are as follows: the photo peak corresponding to the main energy of the emitted photons. • 36 AWG has diameter exactly 0.05 inch in diameter The energy range, the window is covering, is called ‘the win- • A change by 10 in AWG represents a 10X change in dow width’. In a scintillation camera, the energy width should be cross-sectional area narrow so that it excludes scattered photons to be measured. • As cross-section halves, SWG number decreases by 3 approximately • As diameter halves, SWG number increases by 6 Wipe test approximately (Radiation Protection) A wipe test is a form of monitoring for radioactive contamination, where the contamination is from Wisconsin test cassette a radionuclide of a type, quantity and/or energy that cannot (Diagnostic Radiology) The Wisconsin test cassette is cas- readily be detected by hand-held contamination monitors. sette using a single phosphor and optical attenuator. Penetration Wipe tests may be carried out on ‘clean’ surfaces (as part of through a copper step wedge is used as an indicator of effective contamination monitoring) or on sealed-sources (as part of kVp, half-value and x-ray generator output. The degree of penetra- leak-tests). tion is measured by noting the thickness of copper used over the A swab sample is taken over a surface. Radioactive particles unattenuated scintillator to produce a film equal in density to that may be extracted onto the swab material. These can be detected produced by a reference thickness of copper over the attenuated by sensitive counting equipment. If wipe-testing for gamma- scintillator. Typical such cassette is shown in Figure W.18. or high-beta-emitting radioisotopes, a scintillation counter is used. This device consists of a shielded well-counter, in which the sample exposes a scintillating crystal-photomultiplier tube Workload detector. (Radiation Protection) One prerequisite, when carrying out If wipe-testing for low-energy betas or alpha emitting shielding designs for any x-ray facility or a radiation risk assess- radioisotopes, the sample must be counted via liquid scintil- ment, is to have knowledge of the radiation beam on time (Sutton, lation. The sample is prepared with a solvent (which absorbs 2012). This includes which rooms and examinations are to be the emitted radiation) and a liquid scintillant (which re-emits it used and the no. of exams intended to be carried out for imaging as light) in a test-tube. Emitted light photons are then directly or treatment. The workload attempts to describe this. detected from the sample surface. In all cases, the samples will Dose metrics such as KAP, DAP; ESD, DLP (CT), MBq be counted for a time-period (from minutes to several hours) (Nuclear Medicine/PET) and monitor units, MU (Radiotherapy), in order to allow for detectable decays from any radionuclides can be used to describe the workload of a department over time. collected on the swab, since the activities involved may be Along with the frequency and type of scans conducted by a extremely low. department, this information can be used to calculate the typi- cal dose over a week, month or year for that department. This is W regarded as the workload. Wire cross section Related Articles: Occupancy factor, Use factor (General) The electrical properties of a copper wire are defined Further Reading: Sutton, D. G., C. M. 2012. Radiation mainly by its cross-sectional area. Whilst mostly round in cross Shielding for Diagnostic Radiology. The British Institute of section, all wires with equal cross-sectional area will have similar Radiology; rrcmrt. 2011, October 16. Use Factor, Occupancy resistance per unit length. If diameter is X mm, then cross sectional area is 1.57X2 mm2 Factor, Workload. Retrieved July 16, 2019, from Medical . Radiology Canada, Winnipeg: hhtp: //rrc mrt .w ordpr ess .c om /20 11 Standardly available copper wires are specified by a ‘wire /10 /27 /u se -fa ctor- occup ancy- f acto r -wor kload /. gauge’, of which there are many, the standard wire gauge SWG Hyperlink: Rrcmrt: https :/ /rr cmrt. wordp ress. com /2 011 /1 0 /27/ (Imperial), The American wire gauge AWG and the metric wire use -f actor -occu pancy -fa ct

or -wo rkloa d/ gauge. Wire tables are easily found in engineering texts and on the web. However, a simple ‘rule-of-thumb’ guide to gauges, the Workload factor (W) cross-sectional areas, and the resistance per unit length can be (Radiation Protection) Most radiation sources used in the work- given, based on the realisation that it is the cross-sectional area of place, especially those electrically produced such as diagnos- the wire that defines its resistance per unit length: tic x-ray units and linear accelerators do not produce ionising Workstation 1025 W orld Health Organization (WHO) 7.5´ 0.625 = 0.47 mSv/hr. If we were to assume that the radiation was on all the time, the operator could get a total annual radiation dose of 7.5 × 2000 hours in the working year = 15 mSv However, if we take into account the workload factor, the operator can be assumed to get a more realistic total annual radiation dose of 0.47 × 2000 = 0.94 mSv. Related Articles: IDR, TADR, TADR2000, Use factor (U), Orientation factor, Occupancy factor (T) Workstation (Diagnostic Radiology) The workstation is a main component of a PACS system (picture archiving and communication system), which includes the diagnostic screens to observe the images during the radiological evaluation of these. These screens are optimised and subject to regular quality control. These days the workstations use mainly liquid crystal display (LCD) flat screens with high resolution and contrast. For example, one such screen would have contrast ratio of the order of 700:1 and display at least 3000 grey levels. The resolution of the monitor is often presented with its pixels – for example 5 megapixels monitor (2048 × 2560). Usually, the workstation displays are in portrait mode. Related Articles: Liquid crystal display, Active matrix flat panel thin film transistor liquid crystal display FIGURE W.18 Wisconsin test cassette – open (above) and closed with indication of areas corresponding to various kVp (using various filters). World Health Organization (WHO) (General) The World Health Organization (WHO), the direct- radiation 8 hours a day, 5 days a week for 50 weeks a year (i.e. ing and co-coordinating agency for health in the United Nation 2000 hours per year). In most circumstances, the radiation is on System, became operative in 1948. Its responsibilities include for only a matter of tenths of a second up to several minutes at (1) providing leadership on global health matters, (2) shaping the a time, during which the instantaneous dose rate (IDR) that an health agenda, (3) setting norms and standards, (4) articulating individual might be exposed to could be significant. However, the evidence-based policy options, (5) providing technical support to time-averaged dose rate (TADR) over a longer period – a day, countries in need and (6) assessing health trends. week or a year – could be much lower. WHO’s headquarters is based in Geneva (Switzerland) and Hence the actual radiation dose that an individual person has an organisation of six regional offices. These are located might receive due to the use of such radiation equipment will on in Copenhagen (Denmark) for the European Region, in Cairo a factor describing the total time the ionising radiation is on as a (Egypt) for the Eastern Mediterranean Region, in Brazzaville proportion of the total working day/week/year. This factor is the (Republic of Congo) for the African region, in New Delhi (India) ’workload factor’ (assigned the letter W). for the South-East Asia region, in Manila (Philippines) for the Western Pacific region and in Washington, DC (United States) for the region of Americas. There are national offices in 147 counties. Over 8000 people including health experts, doctors, W EXAMPLE epidemiologists, scientists and administrators are employed. A CT scanner room has 15 patients during an 8-hour work- The budget in 2007 was about 3.3 billions USD; more than half ing day, and each scan involves a spiral scan (radiation on) of it coming from voluntary contribution from countries, agen- beam time of about 2 minutes. cies, etc. Therefore, the ionising radiation is on for a total of Representatives of the member states meet every year at the 2 × 15 minutes per 8-hour day. World Health Assembly in Geneva to set policies and approve the That is 30 minutes / 480 minutes = a workload factor budget. The work is supported by a 34-member executive board, of 0.0625. elected at the assembly. Now, if we assume that the IDR at a given point where WHO and its member states work in collaboration with partners the operator sits is (say) 7.5 μSv/hr when the x-ray beam is including other UN agencies, nongovernmental organisations and on, then the time-averaged dose rate over the working day donors. WHO guidelines and standards help countries to address will be: public health issues and tackle global health problems in order to improve people’s well-being. Wrap-around artefact 1026 Wrap-around artefact Since the beginning, WHO has played an essential role in pre- Wrap-around artefact paring the international classification of diseases and introduc- (Magnetic Resonance) Wrap-around artefact occurs when anat- ing the concept of ‘essential drugs’ and ‘national drug policy’. omy being scanned exceeds the FOV in the phase encoding direc- Another major activity has been the co-ordination of campaigns tion. The anatomy outside the FOV will experience a phase shift for the eradication of infectious diseases (e.g. the eradication of because the phase-encoding gradient is applied across the whole smallpox and the drastic reduction of polio). Major efforts aim to body. RF signals are then detected from outside the FOV and contain malaria, tuberculosis and HIV/AIDS. Chronic diseases incorrectly allocated to pixels within the FOV. also receive significant support. Reducing tobacco-related deaths To decrease or eliminate this artefact, there are several meth- and diseases, and the adoption of global strategies for diet, physi- ods that can be used. Increasing the FOV ensures that all of the cal activity and health rules are current objectives. anatomy is fully contained within the FOV. A smaller coil that In the radiation field, WHO is a member of the Inter-Agency more closely matches the FOV could be also used. Saturations Committee on Radiation Safety (IACRS) and a cosponsoring bands could be applied outside the desired FOV to suppress the organisation of the International Basic Safety Standards for signal from the anatomy outside this FOV and finally the data can Protection against Radiation and for the Safety of Radiation be oversampled, though this increases the acquisition time. Sources (IAEA, 1996). Abbreviation: FOV = Field of view. Hyperlink: http://www .who .org Related Article: Signal aliasing W X Xenon Xeroradiography (General) (Diagnostic Radiology) Xeroradiography uses a receptor consist- ing of an electrically charged semiconductor plate. The image is recorded by x-ray exposure as a pattern of varying degrees of Symbol Xe discharge on the plate. The electrostatic image is then printed Element category Non-metals onto paper similar to the process in a Xerox copy machine (pho- Mass number A 132 tocopier). A desirable characteristic of these images is that the Atomic number Z 54 process produces an edge enhancement effect and the dynamic Atomic weight 131.29 g/mol range of the radiograph is better than those of X-ray film. The Electronic configuration 1s2 2s2 2p6 3s2 3p6 3d10 4s2 4p6 4d10 method is not used anymore, but a similar effect is used in digital 5s2 5p6 radiography with amorphous selenium (Figure X.1). Melting point 161.4 K Boiling point 165.1 K X-ray Density near room temperature 5.89 kg/m3 (Diagnostic Radiology) X-ray is the name given by Wilhelm Roentgen to the ‘new kind of rays’ that he discovered, investi- gated and demonstrated the value of for imaging the internal Xenon is a colourless, odourless noble gas that is mostly un-reac- structures of the human body. Others suggested and promoted the tive. It was discovered by Sir William Ramsay and Morris Travers name Roentgen rays. in 1898 and is found in trace quantities in the earth’s atmosphere X-rays and gamma rays occupy the same portion of the elec- (0.087 parts per million). Xenon is used, in molecular form (Xe2), tromagnetic spectrum – approximately from 1 × 10−7 to 1.8 × in excimer lasers that emit ultraviolet light at 172 and 175 nm. 10−17 m wavelength. Such lasers are used both for eye surgery and for dermatological Related Articles: Bremsstrahlung, Characteristic radiation treatment. Isotopes of Xenon and Their Medical Applications: Xenon has nine stable isotopes; 124Xe is used in the production of 123I and X-ray beam filtration 125I, both of which are used extensively in nuclear medicine pro- (Diagnostic Radiology) Filtration of an x-ray beam occurs when- cedures. 123I is used to image the thyroid, dopamine transporters ever a beam passes through a material that has attenuation char- and neuroendocrine tumours, while 125I can be used to measure acteristics that depend on photon energies. This changes the blood plasma volume. Hyperpolarised 129Xe is used in magnetic spectrum by the selective attenuation. The common use of fil- resonance research to image ventilation in the lungs. tration is to remove the low-photon energy content of a beam to Related Articles: Iodine-123, Iodine-125, Isotope, Magnetic reduce patient exposure. resonance imaging, Nuclear medicine, Nuclear, Medicine imag- For energy spectrum filtering, materials are selected based ing, Radioactivity, Thyroid radioiodine uptake measurement on their attenuation characteristics in relation to photon energy. Most x-ray beams are filtered with a metal, usually aluminium, to attenuate the low photon energy end of the spectrum. The pur- Xenon-133 pose is to remove the low-energy photons that generally apply (Nuclear Medicine) A radionuclide used for in vivo gamma radiation to the patient’s body without penetrating to contribute imaging. to image formation. K-edge filters are used, especially in mam- mography, to attenuate the high-energy photons for the purpose Half-life Photon emission Common application of increasing contrast sensitivity. The section of the spectrum above the K-edge energies of the filter materials is removed by 5.2 days 81 keV Lung imaging (ventilation scan) the filter. Molybdenum and rhodium are the two most common filter materials used in mammography. In some applications, 133Xe gas is an agent used in lung ventilation imaging, typically in the spatial distribution or uniformity of an x-ray beam might planar gamma imaging. The gas freely exchanges between blood be adjusted with a filter that has a varying thickness across the and tissue. Most of the gas that enters the circulation returns to the beam. Related Article: Filtration total X lungs and is exhaled. This is one of the most common agents used in nuclear medicine for the assessment of pulmonary function. Related Articles: Gamma camera, Radionuclide imaging X-ray exposure Further Reading: Cherry, Sorenson and Phelps. 2012. Physics (Diagnostic Radiology) X-ray exposure is a term used in practice in Nuclear Medicine, 4th edn., Elsevier; Mettler, Guiberteau. to indicate either the production of an x-ray pulse (e.g. radiograph 2012. Essentials of Nuclear Medicine Imaging, 6th edn., Elsevier; with certain duration) or radiation exposure in air – roentgen (R) Zeissman, O’ Malley and Fahey Thrall. 2014. Nuclear Medicine, or coulomb/kg. 4th edn., Elsevier. Related Articles: Exposure, Exposure time, Exposure switch 1027 X-ray film 1028 X-ray television Typically, the horizontal image resolution depends on the step- ping motor moving the laser across the film (when a single light detector is used) or on the number of scanning elements (sensors – usually photodiodes) in the scanning array. Generally, the vertical image resolution depends on the stepping motor which moves the film in a Y direction over the scanning line. Example: If the necessary resolution is 300 × 300 dpi, and the scanner is digitising a part of the x-ray film with a dimension of 8.5 × 11-inch, then the CCD array will need to have 2550 sensors (8.5 × 300 = 2550), arranged in a horizontal row. The stepper motor in our example should be able to move the film in increments equal to 1/300ths of an inch. The final image quality also depends on the focussing of the laser spot, the calibrated intensity of the beam and the use of the automatic density control and image interpolation technology. The x-ray film scanner can be directly linked to PACS. Related Articles: Film digitisers, CCD array, Picture archiving and communication systems (PACS) X-ray generator (Diagnostic Radiology) This term is mainly used to describe the combination of the high voltage generator plus the x-ray tube. Related Articles: High voltage generator, X-ray tube FIGURE

X.1 Xeroradiography (xeromammography). X-ray image intensifier (Diagnostic Radiology) See Image intensifier X-ray film X-ray phase contrast (PhC) imaging (Diagnostic Radiology) One of the earliest detectors of x-rays is (Diagnostic Radiology) See Phase contrast imaging the x-ray film (also radiographic film). It is made of a thin clear polyester base covered with photographic emulsion. The base X-ray table exposure chamber is about 150 μm thick, and the emulsion (silver halide crystals (Diagnostic Radiology) X-ray table exposure chamber is the suspended in gelatin) is about 10 μm thick. The emulsion can be ionisation chamber used in automatic exposure control (AEC) placed either on one or on both sides of the film. systems. Usually, the x-ray film is placed in radiographic cassette with Related Article: Automatic exposure control phosphor screen (screen/film). Both are now replaced by digital detector. X-ray television When the x-ray film is exposed to radiation (and light from the (Diagnostic Radiology) The x-ray television of a fluoroscopic phosphor), the emulsion changes its chemical structure forming a system includes all parts of the imaging chain after the image latent image. After a process of film development, these changes intensifier. This way, the main components of the x-ray television form areas of the x-ray film, which have different opacity (or are: the video camera tube (transforming the visual information darkness) proportional to the intensity of the radiation. Following from the output of the image intensifier into an electrical video this, the film is observed on a view box. signal); the video amplifier; the TV diagnostic monitor (or flat The professional slang for x-ray (radiographic) film is simply monitor). film. For more details, see various articles describing elements of This system often includes also the automatic brightness the film, its processing, characteristics, types, etc. control system and/or the video gain control. As in all imaging Related Articles: Film (as in film base, film crystals, film chains, the composite (summary) modulation transfer function processing, characteristic curve, etc.) (MTF) of the x-ray television is the product of the MTFs of all X-ray film scanner its components: (Diagnostic Radiology) The x-ray film scanner (also known as film digitiser) is used to digitise x-ray films with diagnostic MTFsum =MTFcamera*MTFamplifier*MTFmonitor X images, thus allowing their storage in PACS. The scanner uses a focussed laser beam, which scans the transparent x-ray film. This way, the MTF of the worst element will define the final Passing through the film, the laser is modulated with the infor- summary MTF. Due to this reason, care should be taken for the mation in the film (areas with different opacity). The modulated MTF of each element to be good. For example, the analogue TV beam is detected by various light detectors, which transfer the diagnostic monitors of the x-ray television are made with high beam intensity after the film into digital values. resolution. This is achieved by using double horizontal lines (ras- The spatial resolution of the resulting digital image can be ter) – 1249 lines instead of the normal 625 lines (for 50 fps) or separated into horizontal and vertical resolution (i.e. in X and Y 1023 lines instead of the normal 525 lines (for 60 fps). This prob- directions). Usually, the initial measure of image resolution is dots lem does not exist in contemporary digital flat monitors (LCD per inch (DPI), or pixels per inch (PPI), which after this are trans- or other); however, the digitising presents another problem – see ferred into lp/mm. article Presampling MTF. X-ray tube 1029 X-ray tube housing Related Article: Presampling MTF X Further Reading: Krestel, E., ed. 1990. Imaging Systems for Medical Diagnostics, Siemens, Erlangen, Germany. X-ray tube (Diagnostic Radiology) The basic principle of x-rays production includes bombardment of a positively charged material (anode target) with electrons accelerated in a high voltage field (kV). Most conventional x-ray tubes consist of a glass envelope, which contains one negative and one positive electrode – a typi- cal ‘vacuum tube’. The negative cathode is heated in order to emit electrons (thermal electrons), which travel in the accelerat- ing electrical field (×10 kV) to the positive anode, collide with it and so produce x-ray stopping radiation (Bremsstrahlung in German). High vacuum is created in the glass envelope in order FIGURE X.2 Block diagram of an x-ray tube and associated high volt- to ensure uninterrupted fly of all emitted electrons to the anode age (kV) transformer. target (anode current, mA). The anode current does not depend on the high accelerating voltage (anode voltage, kV), and it depends only on the production of thermal electrons (i.e. the temperature of the cathode). Increasing the kV (anode voltage) leads to higher acceleration of the thermal electrons, which bombard the target, and thus produces x-ray quanta with higher energies (increased effective energy of the x-ray beam). At constant kV, increasing the mA (anode current) leads to the production of higher number of x-ray quanta (increased intensity of the x-ray beam). Changing both, kV and mA, leads to the production of x-ray spectrum with different penetrating power that produces x-ray images with dif- ferent contrast. The main parts of an x-ray tube are as follows: • Cathode – Cathode assembly that normally includes a focusing cup (Wehnelt electrode), where the heated tungsten wire (cathode filament) is placed, which pro- duces thermal electrons. The temperature of the cath- ode is proportional to the flux of thermal electrons. FIGURE X.3 Old-type x-ray tube with stationary anode. The whole cathode assembly is under high negative potential. • Anode – Anode assembly that includes anode stem with target plate (usually made of tungsten). There are Hyperlinks: Sprawls Foundation: http://www .sprawls .org / various anode constructions. The whole anode assem- resources; Toshiba x-ray tube history: http: / /www .e -ra diogr aphy. bly is under high positive potential. The potential net /h istor y /His tory% 20of% 20xra y %20t ubes % 20tos hiba. pdf between the cathode and anode (accelerating voltage) determines the energies of the created x-rays (the x-ray X-ray tube assembly spectrum). (Diagnostic Radiology) Technical term used to describe the x-ray • Glass envelope (or metal envelope) that keeps high vac- tube and its components. uum environment (minimum 10−6 mbar) in which the Related Article: X-ray tube thermal electrons fly undisturbed from the cathode fila- ment to the anode target. X-ray tube housing • The anode current has to depend only on the number (Diagnostic Radiology) The x-ray tube housing provides mechan- of thermal electrons. However, the high vacuum can ical support and protection for the tube (Figures X.4 and X.5). extract ions from the envelope or the other compo- Most housings are made of steel or aluminium alloy. As the high nents. Special care is taken for ‘degassing’ the x-ray voltage is supplied to tube through the cable sockets in the hous- tube, thus preventing eventual high current (arcing) ing, the latter must also provide good electrical insulation. For between the cathode and anode that can damage the this reason, the housing is grounded and is filled with special X x-ray tube. insulating oil (normally withstanding above 220 kV/cm), which provides the necessary insulation, but also assists in cooling the The x-ray tube is placed in an x-ray tube housing, which x-ray tube. assures cooling of the hot anode, electrical insulation, clear In stationary anode tube, the stem of the anode can be directly path of the x-rays towards the patient and absorption of the cooled in the oil. Often the end of the stem has attached a copper x-rays produced in directions other than towards the patient fins (radiator) for easier cooling. The low power of these tubes (Figures X.2 and X.3). permits cooling through simple convection. The powerful x-ray Related Articles: Anode, Cathode, X-ray tube housing, tubes with rotating anode require active cooling. For this purpose, Continuous spectrum, X-ray production the heated oil is moved by an oil pump through heat exchanger X-ray tube housing 1030 X-ray tube housing 2 1 FIGURE X.4 Cathode side of the x-ray tube housing: (1) lead shielded steel; (2) cathode bed with leads. FIGURE X.6 Thermal protection of the x-ray housing rubber mem- brane allowing expansion of the insulating/cooling oil to activate a cut-off switch (cathode side). 1 2 1 FIGURE X.5 Anode side of the x-ray tube housing: (1) lead shielded Alu 2 mm steel; (2) anode motor (stator winding). (normally cooled with running water). The temperature of the cir- culated oil is constantly monitored by a thermal sensor, and if it FIGURE X.7 Outside view of an x-ray tube housing. The inherent x-ray exceeds a certain degree (normally less than 90°C), it cuts off the tube filtration has been removed and is shown in the left segment of the tube power. Another (simpler) device is often fitted to the housing image. Note that through (1) – the radiolucent window – one can see the – an expansion diaphragm (rubber membrane). When the oil tem- anode disk. perature increases, it expands and moves the membrane, which in turn activates a switch cutting-off the power until the temperature drops down (Figure X.6). However good the lead shielding is, some radiation may escape The x-ray tube generates radiation in all directions. In order from the x-ray tube housing (leakage radiation). Measuring the to absorb this radiation, the housing is shielded inside with lead leakage radiation level of the x-ray tube housing is an important (3–4 mm). The x-ray tube housing has a small exit window cov- safety procedure. ered with aluminium plate (inherent Al filtration). Through this Related Articles: Anode, Cathode, Filament circuit, Filament window, the radiation is directed towards the patient (Figure X.7). current X Y Y-90-labelled ibritumomab tiuxetan (Zevalin®) Young’s modulus (Nuclear Medicine) Ibritumomab tiuxetan (Zevalin®, Schering (Ultrasound) The elasticity of materials is measured as Young’s AG) is a murine IgG1 kappa monoclonal antibody against the anti- modulus (E), named after the physicist Thomas Young. Young’s CD20 antigen. This antigen is found on the cell surface of normal modulus describes the material’s strain response to uniaxial stress and malignant B lymphocytes. The antibody is produced from in the direction of this stress CHO cells and is conjugated to an MX-DTPA linker that chelates 90Y or 111In with high affinity. E = (Stress) / (Strain) 90Y-labelled Zevalin is used for radioimmunotherapy of ritux- Young’s modulus is also known as the ‘Modulus of Elasticity’. It is imab-relapsed or -refractory CD20+ follicular non-Hodgkin’s measured in units for pressure (either Pascals or N/m2; 1 Pa = 1 N/ lymphoma (NHL). Pre-treatment with rituximab is performed, m2) and is a specific characteristic of materials/tissues examined which leads to an advantageous biodistribution due to blocking with ultrasound (e.g. E for muscles is 14–16 kPa). of accessible CD20 sites in the peripheral circulation and thus Young’s modulus is of particular importance in ultrasound elimination of B cells. elastography, and is related to the density () and shearwave veloc- The radionuclide, Yttrium-90, is a beta emitter, of which beta ity (cs) by the formula: particles have a maximum energy of 2.28 MeV and a maximum range of 11 mm soft tissue. The half-life is 64 h. Before treatment E = 3rc 2 s with 90Y-Zevalin, a pre-treatment diagnostic examination should be performed with 111Y-Zevalin, making an individual patient Related Articles: Shearwave elastography, Ultrasound imaging dose-planning possible. Further Reading: Taljanovic et al. 2017. Shear–wave elas- The radiochemical purity should be done before injection and tography: Basic physics and musculoskeletal applications. is assessed by instant thin-layer chromatography with silica gel Radiographics 37:855–870; Wells, T. and H.-D. Liang. 2011. (ITLC-SG) with saline as solvent. The purity should be at least Medical ultrasound: Imaging of soft tissue strain and elasticity. J. 95%. The recommended infused administered activity is 15 MBq/ R. Soc. Interface 8(64):1521–1549. kg body weight (maximum 1200 MBq) for patients with platelets >150 × 109/L and 11 MBq/kg for patients with platelet counts of Yttrium 100–150 × 109/L. (General) The mean effective half-life of 90Y-Zevalin in blood is 27 h, and the urinary excretion has been reported to be only 7% during the first week. Absorbed dose to the mostly exposed organs have Symbol Y preliminary been reported to be spleen 2–14 mGy/MBq, liver 2–8 Element category Transition metals mGy/MBq, lungs 1–3 mGy/MBq, red bone marrow 0.5–1 mGy/ Mass number (N) 89 MBq. The whole-body absorbed dose is estimated to 0.5 mGy/ Atomic number (Z) 39

MBq. Atomic weight 88.90585 g/mol Further Readings: Firestone, R. B. 1999. Table of Isotopes, Electronic configuration 1s2 2s2 2p6 3s2 3p6 3d10 4s2 4p6 4d1 5s2 8th edn., Update with CD-ROM, http://ie .lbl .gov /toi .html, Melting point 1799 K John Wiley & Sons, Inc., New York; Kowalsky, R. J. and S. W. Boiling point 3609 K Falen. 2004. Radiopharmaceuticals in Nuclear Pharmacy and Density near room temperature 4.472 g/cm3 Nuclear Medicine, 2nd edn., American Pharmacists Association, Washington, DC; Tennvall, J., M. Fischer, A. Bischof Delaloye, E. Bombardieri, L. Bodei, F. Giammarile, M. Lassmann, W. Oyen and B. Brans. 2007. EANM procedure guideline for radio- History: Yttrium was discovered by Gadolin in 1794. It was immunotherapy for B-cell lymphoma with 90Y-radiolabelled named after a small town called Ytterby in Finland, where a ibritumomab tiuxetan (Zevalin). Eur. J. Nucl. Med. Mol. Imag. quarry yielded many unusual minerals containing erbium, ter- 34:616–622; Wiseman, G. A., B. R. Leigh, W. L. Dunn, M. G. bium and ytterbium as well as yttrium. Stabin and C. A. White. 2003. Additional radiation absorbed dose Isotopes: Natural yttrium is found as 89Y with 100% abundance; estimates for Zevalin™ radioimmunotherapy. Cancer Biother. however, 19 other synthetic unstable isotopes have been character- ised. The isotope of interest in medicine is radioactive 90 Radiopharm. 18(2):253–258. Y. Y-90-Zevalin® Isotope 90Y (Nuclear Medicine) See Y-90-labelled ibritumomab tiuxetan Half-life 2.67 days Y Mode of decay Almost pure β− to 90Zr, some γ Yield, fluorescent Maximum decay energy, Emax β−: 2.28 MeV (γ: 1.83 MeV, 0.89 MeV) (General) See Fluorescent yield 1031 Yttrium-90 [90Y] 1032 Y voltage; star voltage 90Y is generator produced from its parent (90Sr) and is available Clinical Applications: Yttrium-90 is used for labelling of with high specific activity. therapeutic radiopharmaceuticals. It is used for labelling mono- The beta particles emitted from 90Y have a relatively high Emax clonal antibodies for radioimmunotherapy. One example is and a maximum range in water of 11 mm, making the isotope an 90Y-labelled Zevalin, which is used for radioimmunotherapy of attractive choice for therapeutic applications. rituximab-relapsed or -refractory CD20+ follicular non-Hodg- Medical Applications: Antibody therapy – Here, 90Y is kin’s lymphoma (NHL). attached to monoclonal antibodies, which bind to cancer cells Further Readings: Annals of the ICRP. 1987. Radiation dose and deliver lethal doses of β-radiation. This application is used to patients from radiopharmaceuticals, biokinetic models and data, to treat various cancers including lymphoma, leukaemia, ovarian, ICRP Publication 53, Vol. 18, Pergamon Press, Oxford, UK; Chu, colorectal, pancreatic and bone cancers. S.Y.F., L. P. Ekström and R. B. Firestone. 1999. The Lund/LBNL Hepatic microsphere therapy – Hepatic microsphere therapy: Nuclear Data Search, http: / /nuc leard ata .n uclea r .lu. se /nu clear data/ a novel approach to liver cancer therapy has been developed toi/; Firestone, R. B. 1999. Table of Isotopes, 8th edn., Update with that involves delivering synthetic microspheres loaded with 90Y CD-ROM, http://ie .lbl .gov /toi .html, John Wiley & Sons, Inc., New directly into the liver via a catheter placed in the hepatic artery. York; Kowalsky, R. J. and S. W. Falen. 2004. Radiopharmaceuticals The microspheres are designed to both embolise the tumour’s in Nuclear Pharmacy and Nuclear Medicine, 2nd edn., American blood supply and deliver a tumoricidal β-dose to the metastases Pharmacists Association, Washington, DC. while minimising the dose to normal liver tissue. Related Article: Y-90-labelled ibritumomab tiuxetan The relative lack of gamma emission allows treatment on an out-patient basis. Y voltage; star voltage (Diagnostic Radiology) These terms refer to the generation and Yttrium-90 [90Y] measurement of ‘three-phase’ electrical power. (Nuclear Medicine) Element: Yttrium Three-phase power is an efficient way to generate and trans- Isotopes: 42 < N < 60 fer large quantities of electrical energy. Typically, the generator Atomic number (Z): 39 is mechanical in form and contains three rotating coils in a fixed Neutron number (N): 51 magnetic field. When forced to rotate, each coil generates a sinu- Symbol: 90Y soidal potential, but at a phase dependent on the rotor’s physical Production: reactor (fission)/generator make up. If three coils are symmetrically mounted on the rotor, b- b- each output will be 120° different in phase to the other two: 235 U (n, f ) 90Sr ® 90 Y ® 90 Zr 28.79 d 64.8h or or A B C ree-phase rot b- 89 Y (n,g) 90 Y ® 90 Zr 64.8h Daughter: 90Zr Half-life: 2.7 days Decay mode: β−-decay Radiation: β− 2280 keV (max) ≈ 760 keV (mean) A Time Gamma energy: none (brehmsstrahlung) Skin dose rate from 1 MBq: 100 μSv/h at 30 cm (point source); 0.071 μSv/h at 1 m (10 mL glass vial) In connecting the individual coils to the supply, two different Maximum range: 11 m in air, 11 mm in water architectures are possible, the ‘Y’ formation or the star or delta Absorption shield: 9 mm lucite or 5 mm glass form: Biological half-life: bone Critical organ: liver, red bone marrow, bone surfaces ALImin (50 mSv): 20 MBq Effective dose: 2.7 mSv/MBq (ingestion); 1.41.5 mSv/MBq (inhalation) 2D Y or star form Delta form 3/2 % 82 99 39Y 99. 0.0018% 7+ IT 681.67 β– The Y form provides greater voltage but lower current, while 2– Yttrium 0 the delta form provides for higher current at lower voltage. Y 88.90585 90 In measuring three-phase AC voltages, it is common to mea- 39Y β– sure each voltage with respect to the common earth voltage [Kr]4d5s2 (Y-voltage). These should normally be equal, though with phases 6.2173 Q 120° apart. If they are not equal, it is usually due either a single- β–2280.1 phase load being much greater on one phase or to some inductive Voltage Y voltage; star voltage 1033 Y voltage; star voltage external load on the supply, which causes the phases to be unbal- each part of the load receiving a larger rms voltage (1.73×) and anced. Correction usually requires engineers to rebalance the hence power capability. Measuring between the phases should other connected to the supply. provide a higher voltage reading (for 230 V rms AC per phase, a Normal domestic single-phase supplies are taken from one of figure of 410 V rms will be found between any two phases). the three phases, with different buildings or areas connected to Three-phase power is usually only provided to high power different phases to balance the load. However, when three-phase loads such as motors, three-phase transformers and air-condition- supplies are used directly, the load can put across the phases, with ing units. Y Z Z number the other hand, it does not necessarily signify the most important (Nuclear Medicine) See Atomic number parts of the frequency spectrum and it is also vulnerable to noise. The zero-crossing count is a good estimate of the mean frequency Zebra stripe artefact for a very narrowband signal with little noise. However, the (Magnetic Resonance) The zebra stripe artefact appears as alter- Doppler signal from a vessel with a parabolic flow has a spectrum nating bright and dark bands in an MRI image. The term has been that is nearly rectangular distributed from zero up to the Doppler used to describe several different kinds of artefacts, causing some shift that corresponds to the maximum velocity. In that case, the confusion. Artefacts that have been described as a zebra artefact zero-crossing detector will overestimate the mean frequency by include the following: nearly 15% and is thus a biased estimator of the mean frequency. Moire fringes are a phase-based interference pattern most For a more plug-like flow profile, the mean frequency approaches commonly seen when acquiring gradient echo images using the the RMS frequency (as detected by the zero crossing detector), body coil. Because of imperfect magnetic field homogeneity at and the bias is then reduced. As noise inherently increases the the edges of the body, the superimposition of signals with differ- number of zero-crossings, it will introduce a bias. Practically, it ent phases alternatively add and cancel, creating bright and dark can be estimated that the error will be at least 10% for a parabolic bands. This causes the banding appearance, similar to the effect of flow measured with a signal-to-noise ratio of 40 dB. looking through two screened windows. Note these artefacts usu- Further Reading: Jensen, J. A. 1996. Estimation of Blood ally occur only at the edge of the images. They can also be caused Velocities Using Ultrasound, Cambridge University Press, New by a receiver picking up a stimulated echo (Figure Z.1). York, pp. 116–120. Spike in k-Space: More traditionally, zebra stripe artefacts are caused by one ‘bad’ data point in k-space. For example, a spike Zero filling in k-space as from an electrostatic spark causes stripes across the (Magnetic Resonance) Conversion of raw k-space data into images images. The spikes are due to overweighting of the frequency cor- is done with a fast Fourier transform (FFT). The FFT requires responding to the ‘bad’ data point in k-pace. The remedy is to that the raw data be in a matrix whose size is a power of two. If repeat the scan (Figure Z.2). the acquired k-space data matrix does not reach a power of two Related Articles: Artefacts in MRI (such as 128 or 256), one can fill in the missing phase encoding Further Readings: Krupa, K. and M. Bekiesińska-Figatowska. rows with rows of zeroes. This addition of rows of zeros is called Artifacts in magnetic resonance imaging; Zhuo, J. and R. P. zero filling. Gullapalli. MR artifacts, safety, and quality control. Zero filling can also be used in both the phase and frequency direction to double the acquisition matrix size; for example, going Zener diode from 128 × 128 to 256 × 256 by adding rows and columns of (Diagnostic Radiology) The Zener diode uses the Zener effect, zeros. Zero filling used in this manner is sometimes called ‘image which is a breakdown phenomenon, which holds the voltage close interpolation’ and appears to smooth the image appearance. It to a constant value called the Zener voltage. improves the reconstructed pixel resolution, but does not change Zener diode itself is a semiconductor with constant voltage, the acquired pixel resolution. used as a voltage regulator, to maintain fixed voltage, in discrete Related Articles: k-space, Phase encoding, Fourier transform components, within ICs, etc. because of its ability to maintain a constant voltage during fluctuating current conditions. It allows Zinc cadmium sulphide reverse bias current flow without damage to the avalanche region (Diagnostic Radiology) The output screen phosphor of an image (Figure Z.3). intensifier is often made from zinc cadmium sulphide (ZnS-CdS: Ag). This phosphorescence material has a broad spectrum of light Zero biased detector emission and some afterglow, but its wavelength matches with (Radiation Protection) Semiconductor radiation detectors are the sensitivity of the x-ray film (in case of spot camera film). In based on reversed biased p-n junction. Some new detectors are the past, materials on this base were also used for phosphors in based on the Schottky barrier inside the p-n junction. This means screen-film systems (cassettes). that that there is a zero bias (or very small bias) over the p-n junc- Further Reading: Thompson, M., M. Hattaway, D. Hall and tion without the need for external applied voltage. S. Dowd. 1994. Principles of Imaging Science and Protection, Related Articles: Semiconductor detector W.B. Saunders Company, Philadelphia, PA. Zero-crossing detector Zinc cadmium telluride (Ultrasound) A simple way of detecting the dominant Doppler (Diagnostic Radiology) Zinc cadmium telluride is a material used shift frequency is with a zero-crossing detector, whereby the num- in the detector of digital mammography systems. ber of times the oscillating demodulated Doppler signal changes Further Reading: Beutel, J., H. Kundel and R. Van Metter, sign, that is passes through zero volt (actually its mean value). eds. 2000. Handbook of Medical Imaging: Vol. 1 Physics and The advantage of this approach is that it can be easily built; but on Psychophysics, SPIE Press, Bellingham, WA. Z 1035 Zipper artefact 1036 z-Sensitivity Forward characteristic Current (mA) 300 200 Izk 100 –8 –6 –4 –2 0.5 1 1.5 Voltage (V) –25 –50 –75 Izmax (a) (b) FIGURE Z.3 (a) Symbol and (b) typical characteristic of a 5.6 V Zener diode. FIGURE Z.1 Moire fingers. FIGURE Z.2 Spike in k-space. FIGURE Z.4 Zipper artefact. Zipper artefact (Magnetic Resonance) The zipper artefact was one of the most common MRI equipment

artefacts. It can be caused by a break- through of radiofrequency from an external RF source, which is Zonography then picked up by the imaging coils. It can also be caused if the (Diagnostic Radiology) Zonography is a radiographic tomo- receive coil picks up part of the RF excitation pulse or with the graphic procedure (linear classical tomography) in which the use of stimulated echoes. angle of motion of the x-ray tube is set to a low value (like 10 The artefact will appear as an alternating dark and light line, angular degrees) to produce relatively thick image slices. two or three pixels in width, in the phase-encode direction. The See Linear (classical) tomography for details. position and width of the artefact is determined by the frequency Related Article: Linear (classical) tomography of the interfering RF source (Figure Z.4). If a zipper artefact occurs, it may be due to a leak in the z-Sensitivity Faraday cage surrounding the room. If equipment such as anaes- (Diagnostic Radiology) z-Sensitivity, also known as slice sen- thetic monitoring and pulse oximeters are being used, they may sitivity profile, is a term associated with the CT slice thickness cause a zipper artefact by allowing external RF waves to be trans- and image quality. For more detail, please see the article Slice mitted through the Faraday cage via leads going through the thickness. waveguides into the room. Related Articles: Computed tomography, Multislice scanner, Abbreviation: RF = Radiofrequency. Helical pitch, Helical interpolation, Partial volume effect Z Index 1.5 D array, 3 Acoustic radiation force impulse imaging AIF, see Arterial input function 2D arrays, 3 (ARFI), 16 Air, 30 3D imaging, 3 Acoustic streaming, 16 Air-cored transformer, see Transformer 3D printing, 3 Acoustic working frequency, 16 Air equivalent composition, 30 3D reconstruction, 3–4 Acoustics, 16–17 Air gap, 30 3D (three-dimensional), 4 Acquisition modes for digital image, 17 Air kerma, 31 4DCT, see Four-dimensional computed Acquisition time, 17 Air kerma strength, 31 tomography Acrylic, 17 AIUM, see American Institute for Ultrasound 4D dose calculation, 4 Action spectra (optical), AORD, 17–18 in Medicine 4D imaging, 4 Activation cross section, 18 Alanine, see Alanine dosimeter 90° pulse, 4 Activation cross sections in radionuclide Alanine dosimeter, 32 180° pulse, 4–5 production, 19 Alanine gel, 32 Activation formula, 19 ALARA, see As low as reasonably achievable A Activation formula thick target, 19 ALARP, see As low as reasonably practicable Activation formula thin target, 19–20 ALFIM, see Association of Latin American A number, see Mass number Activation rates in radionuclide production, see Physicists in Medicine AAPM TG43 formalism, 7 Activation formula Algebraic reconstruction technique (ART), 32 ABC, see Automatic brightness control Activators, 20 Algorithm, 32 Abdominal imaging, 7 Active breathing control, 20 ALI, see Annual limit of intake Aberration, 8 Active device, 20 Aliasing, 32–34 ABI, see Analyser-based imaging Active implant, 20 Alpha beta ratio, 34–35 Ablation, see Photoablative effects Active matrix array, 20–21 Alpha emission, 35 Absolute risk, 8 Active matrix liquid crystal flat-panel display, Alpha particle emitter, 35 Absorbed dose, 8 21–22 Alpha particles, 35 Absorbed dose conversion factor, 8–9 Active shielding, 22 Alpha radiation, 35 Absorbed dose distribution, 9 Active transport of tracers, 22 Alternating current (AC), 35–36 Absorbed fraction, 9 Activity, 22–23 Alternating voltage, 36 Absorbed radiation, 9 Actual focal spot, see Focal spot, actual Alumina (aluminium oxide), 36 Absorber, broad-beam geometry, 10 Actual pixel size, monitor, 23 Alum in film processing, 36 Absorber, linear attenuation coefficient, 10 Acute morbidity, 23 Aluminium, 36 Absorber, mass attenuation coefficient, 10 Adaptive collimation, 23 Aluminium equivalent, 36 Absorber, mean free path for photons, 10 Adaptive processing, 23 AMBER, see Advanced multiple-beam Absorber, narrow-beam geometry, 10 Adaptive radiotherapy, 24 equalisation radiography Absorber density, 10 Adaptive radiotherapy delivery, 24 Ambient lighting, 36–37 Absorption, 11 Adaptive responses and hormesis, 24–25 American Institute for Ultrasound in Medicine Absorption coefficients, 11 ADC, see Analogue-to-digital converter; (AIUM), 31 Absorption contrast tomosynthesis, 11–12 Apparent diffusion coefficient Americium, 37 Absorption cross section, 12 Added filtration, 25 A-mode, 37 Absorption efficiency, 12 Additive colour model, see Red, Green, Blue Amorphous selenium, 37–38 Absorptive backing, 12 Adenosine diphosphate (ADP), 25 Amorphous selenium photoconductive layer, AC generator, 12 Adenosine triphosphate (ATP), 25–26 38–39 AC motor, 12 Adherographic printing, 26 Ampere, 39 Accelerated partial breast irradiation Adhesive, 26–27 Ampere-second, 39 (APBI), 13 Adiabatic RF pulse, 27 Amplification factor, 39 Accelerating waveguide, see Wave guide Adjuvant therapy, 27 Amplifier, 39 Acceleration compensation, 13 Administration of Radioactive Substances Amplitude attenuation coefficient, 39–40 Accelerator, 13 Advisory Committee (ARSAC), Analogue image, 40 Accelerator-produced radionuclides, 13 27–28 Analogue signal, 40 Accelerators in film development, 13 ADP, see Adenosine diphosphate Analogue-to-digital converter (ADC), 40 Acceptance test, 13 Advanced multiple-beam equalisation Analogue tracer, 40 Accessible emission limit (AEL), 13 radiography (AMBER), 36–37 Analyser-based imaging (ABI), 40–41 Accessories, 13 Adverse effects, 28 Anatomical body planes, 42 Accidental coincidences of PET systems, 14 Adverse radiation effects, see Adverse effects Anatomical landmark, 42 Accumulator (storage battery), 14–15 AEC, see Atomic Energy Commission; Anatomical noise, 42 Accuracy, 15; see also Receiver Operating Automatic exposure control Anatomical reference point, 42 Characteristic ROC AEL, see Accessible emission limit Anatomical relationships, 42–43 ACD, see Annihilation coincidence detection Affinity, 29 Anechoic, 43 Acetic acid in film processing, 15 AFOMP, 29 Aneurysm, 43 Acoustic axis, 15 Afterglow, 29 Aneurysm clips, 43 Acoustic impedance, 15 Afterloading, 29 Anger logic, 43–44 Acoustic power, 15–16 Agatha phantom, 29–30 Anger scintillation camera, 44 Acoustic pressure, 16 AI, see Artificial intelligence Angiogram, 44 1037 Index 1038 Index Angle of beam incidence, see Oblique Artificial intelligence (AI), 58–59 Autotransformer, see High-voltage generator incidence Artificial neural networks, 59 Avalanche gain, 74 Angström, 44 Artificial optical radiation (AOR), 59 Avalanche ionisation in Geiger–Muller Angular anisotropy effect, see Anisotropy Artificial Optical Radiation Directive counter, 74–75 Angular sampling intervals in computed (AORD), 59 Avalanche photodiode, 75 tomography, 44 As low as reasonably achievable (ALARA), Average absorbed dose, 75 Anisotropy, 45 32, 59 Average dose, 75 Annealing, 45 As low as reasonably practicable (ALARP), 59 Average life, 75 Annihilation, 45 ASA (American Standards Association), 60 Average life time of atoms, 75 Annihilation coincidence detection (ACD), Asia-Oceania Federation of Organizations for Average mass energy absorption coefficient, 75 45–46 Medical Physics (AFOMP), 29 Avogadro’s number, 75 Annihilation photons in positron decay, see ASL, see Arterial spin labelling Axial (transverse) plane, 75–76 Annihilation radiation Asset depreciation, 60 Axial resolution, 76 Annihilation radiation, 46 Association of Latin American Physicists in Azimuthal, 76 Annual limit of intake (ALI), 46 Medicine (ALFIM), 32 Annular array, 46 Asymmetric energy window, 60 B Anode, 46 Asymmetric fields, 60–61 Anode acceleration, 47 Asymmetric jaws, 61 B0, 77 Anode angle, 47 Asymmetric screen film, 61 B0 gradients, 77 Anode cooling chart, see Anode cooling curve ATCM, see Automatic tube current modulation B0 homogeneity, 77–78 Anode cooling curve, 47–48 Atom, 62 B0 inhomogeneity, 78 Anode heel effect, 48–49 Atomic attenuation coefficient, 62 B1, 78 Anode (of an x-ray tube), 49 Atomic emissions, 62 B1 homogeneity, 78 Anode rotational speed, 50 Atomic Energy Commission (AEC), 62 B1 inhomogeneity, 78 Anode starting device, see Starting device Atomic excitation, 62–63 b-factor, 78 Antagonist, 50 Atomic mass, 63 B-lines, 78 Anterior, 50 Atomic mass unit, 63 B-scan, 78 Anteroposterior (AP) projection, 50 Atomic number, 63 Back pointer, 78–79 Anthropomorphic phantom, 50 ATP, see Adenosine triphosphate Background, 79 Antibodies, 50–51 Attenuation, 63–64 Background equivalent radiation time Anticoincidence circuit in single channel Attenuation coefficient, 64 (BERT), 79 analyser, 51 Attenuation correction, 65 Background radiation, 79 Antigen targeting, 51 Attenuation correction in PET, 65 Background signal, see Background Anti-aliasing filter, see Band limiting Attenuation correction in SPECT using Backing material, 80 Anti-idiotype antibody technique, 51 conjugate counting, 65–66 Back-projection, see Back-projection Antiscatter Grid see Grid, Bucky Attenuation correction in SPECT using the reconstruction AOR, see Artificial optical radiation Chang method, 66 Back-projection reconstruction, 80–81 AORD, see Artificial Optical Radiation Attenuation correction in SPECT using Backscatter, 81 Directive transmission scans, 66–67 Backscatter factor, 81–82 Aorta, 51 Attenuation depth, 67 Bad pixel, 82 APBI, see Accelerated partial breast Attenuation equation, 67 Baird-atomic system multi-crystal camera, 82 irradiation Attenuation factor, 67 Balanced FFE, see Fast imaging with steady Aperture, 51 Attenuation steps, 67–68 state precession Apex, 51 Attenuator, 68 Balanced gradients, 82 Apodization, 52 Audit, quality audit, 68 Ball bearing, see Bearing Apoptosis targeting, 53 Auger effect, 68 Band gap energy, 82 Apparent activity, 53 Auger electron, 68 Band limiting, 82–83 Apparent diffusion coefficient (ADC), 53 Augmented reality (AR), 68 Bandwidth, 83 Apparent focal spot, 53–54 Auto-contouring, 68 Bar pattern, see Bar phantom Apparent power, 54 Autocorrelation, 69 Bar phantom, 83–84 Apparent source position, 54 Autofluoroscope, 69 Barium, 84 Applicator, 54 Automatic brightness control (ABC), 69–70 Barium fluoride (BaF), 84 Applicator (brachytherapy), 54–55 Automatic circuit breaker, see Circuit breaker Barn, 84–85 Apron, lead, see Lead apron Automatic collimation control, 70 Barrel distortion, 85 AR, see Augmented reality Automatic control system, 70 Barrier, 85 Arcing of x-ray tubes, 55–56 Automatic dose rate control, 70 Barten contrast sensitivity model, see Barten Arc therapy, 56 Automatic exposure control (AEC), 70–72 model Ardran and Crooks cassette, 56 Automatic film processor, 72 Barten model, 85–86 ARFI, see Acoustic radiation force Automatic frequency control, 72 Basal cell carcinoma, 86 impulse imaging Automatic gain control, 72 Base layer, 86 Arithmetic mean of counts in attenuation Automatic kV reduction, see Radiographic kV Baseline, 86 correction in SPECT, 56 control Baseline correction, 86–87 Array coil, 56 Automatic line voltage regulation, 72 Basic safety standards (BSS), 87 ARSAC, see Administration of Radioactive Automatic multiple-sample systems of NaI(Tl) Bateman equation for secular equilibrium, 87 Substances Advisory Committee well counters, 72 Bateman equation for transient equilibrium, ART, see Algebraic reconstruction technique Automatic timer, 72–73 87–88 Artefact, 56–57 Automatic tube current modulation (ATCM), Bateman equation in parent–daughter Artefact reduction technique, see Metal 73–74 decay, 88 artefact Autoradiogram, 74 Bayonet catch, 88 Arterial input function (AIF), 57–58 Autoradiography, 74 Beam alignment, 88 Arterial spin labelling (ASL), 58 Autotimer, see Automatic timer Beam area, 88 Index 1039 Index Beam arrangement, 88 Blackening, see Film blackening Bucky diaphragm, 129 Beam attenuation, 88–89 Blank exposure, 110 Bucky table, 129 Beam collimator, 89 Bloch equations, 110–111 Bucky wall stand, 129–130 Beam divergence, 89–90 Block design, 111–112 Build-up, 130 Beam edge, 90 Block transmission factor, 112 Build-up cap, 130 Beam energy, 90–91 Block tray, 112 Build-up dose, 130 Beam flatness, 91 Blocking layer, 112 Build-up plates, 130–131 Beam former, 91 Blood–brain barrier, 112 Build-up region, 131 Beam hardening, 91–92 Blood–brain barrier leakage, 112–113 Bullseye image, 131–132 Beam kernel, 92–93 Blood oxygenation level–dependent (BOLD) Bus, 132 Beam limiting device, 93 contrast, 113 b-Value, 132–133 Beam modulation, 93–94 Blue light hazard, 113–114 Bystander effects, 133 Beam quality, 94–95 Blurring, see Detail resolution Beam reproducibility, 95 BMI, see Body mass index C Beam restrictor, 95–96 BMUS, see British Medical Beam spectrum, 96 Ultrasound Society CAD, see Computer-aided detection Beam steering, 96–97 Body coil, 114–115 Cadmium tungstate, 135 Beam symmetry, 97 Body contour, 115 CADx, see Computer-aided diagnosis Beam weight, 97 Body contouring orbit, 115 Caesium, 135 Beam width, 97 Body habitus, 115 Caesium fluoride (CsF), 135 Beamforming, 97–98 Body mass index (BMI), 115 Caesium iodide, 135–136 Beam-on time, 98–99 Body protein monitor, 115–116 Caesium unit, 136 Beam’s eye view, 99 BOLD contrast, see Blood oxygenation Calcium, 136–137 Bearing, 99 level–dependent contrast Calcium tungstate (CaWO4), 149 Becquerel, 99 Boltzmann distribution, 116 Calculation of absorbed dose, 137 BED, see Biological effective dose Boltzmann transport equation (BTE), 116 Calibration, 137 BEIR, see Biological effect of ionising Bolus, 116–117 Calibration curve, 137 radiation Bolus injection, 117 Calibration depth, 137–138 Bending magnet, 99–100 Bolus of tracer, 117 Calibration factor, 138 Bernoulli effect, 100 Bolus tracking, 117 Calibration source, 138 BERT, see Background equivalent Bone, 117–118 Calorimeter, 138–139 radiation time Bone densitometry, 118 Calorimetry, 139 Bessel function, 100 Bone–soft tissue interface, 118 CAP, see Computer-aided perception Beta decay, 100–101 Bonn Call for Action, 118–120 Capacitance, 139 Beta particle, 101 Boost (brachytherapy), 120 Capacitive micromachined ultrasound Beta radiation, 101–102 Boost dose, 120 transducer (cMUT), 139 Beta+ radiation, 102 Born approximation, 120 Capacitive reactance, 139–140 Betatron, 102 Boron, 120–121 Capacitor, 140–141 Bethe–Bloch equation, 102 Boron neutron capture, 121 Capacitor discharge generator, 141–142 BGO, see Bismuth germanate Boundary layer, 121–122 Capacity, 142 Biangular anode disc, 102–103 Bow-tie filter, 122 Capillary blockade imaging, 142 Bias, 103 Boxcar function, 122 Capillary flow heterogeneity, 142 Bidding process, 103 Brachytherapy, 122–123 Carbon, 142–143 Bidirectional, 103 Brachytherapy sources, 123–124 Carbon-11, 143 Big data, 103 Bragg peak, 124

Carbon-14 [14C], 143 Binary counter, 103 Bragg peak spreading, 124–125 Carbon dioxide as contrast agent, 143 Binding affinity, see Affinity Bragg–Gray cavity theory, 125 Carbon ion therapy (CIRT), 143–144 Binding energy, 104 Braking radiation, 125 Carcinogenesis, see Radiation-induced Binomial excitation, 104 Breakdown voltage, 125–126 secondary malignancies Binomials, 104 Breast, 126 Cardiac blood-pool imaging, 144 Bioeffects, 104–105 Breast coil, 126 Cardiac cineangiography, see Cineangiography Biological dosimeter, 105 Breast density, 126 Cardiac gating, 144–145 Biological effect of ionising radiation Breast phantom, see Mammographic Cardiolite, 145 (BEIR), 105 phantoms C-arm in fluoroscopy, 145 Biological effective dose (BED), 105–107 Bremsstrahlung, 126–127 Carr–Purcell (CP), 145 Biological half-life, 107 Bremsstrahlung contamination, 127 Carr–Purcell–Meiboom–Gill (CPMG), 145 Biological parameter, 107 Brick, see Radiation shielding Carrier-added radioisotope, 145 Biological purity, 107 Bridge circuit, 127–128 Carrier-free sample, 145–146 Biological response models, 108 Brightness, 128 Carrier-free specific activity (CFSA), 146 Biological target volume (BTV), 108 Brightness control, see Automatic Carrier-mediated diffusion of tracers, 146 Biplane cine system, 108 brightness control Cartesian coordinates, 146 Biplane imaging, 108 Brightness induction effect, 128 Cascaded imaging systems, 146 Bipolar gradient, 108 Brightness stabilisation, see Automatic Cassette, filmless, 146 Bipolar pulse in amplifier for radiation brightness control Cassette, Wisconsin, see Wisconsin test detector, 108–109 British Medical Ultrasound Society cassette Birdcage coil, 109 (BMUS), 114 Cassette carriage, 146 Bismuth germanate (BGO), 109 Broad-beam geometry, 128 Cassette changer, 146 Bit, 110 B-scanner, 128 Cassette, filmless, 146 Bit depth, see Matrix size BSS, see Basic safety standards Cassette size, 146 Bite-block, 110 BTE, see Boltzmann transport equation Cassette, Wisconsin, see Wisconsin Bitewing radiograph, 110 BTV, see Biological target volume test cassette Index 1040 Index Catapult bucky, 146 Chemical selective saturation Collimator rotation angle, see Collimation Cataracts (Eye), 146–147 (CHEMSAT), 164 Collimator scatter factor, 179 Cathode (of an x-ray tube), 147 Chemical shift, 164 Collision kerma, 179–180 Cathode ray tube, 148 Chemical shift artefact, 164–165 Collision mass stopping power, 180–181 Cathode rays, 148 Chemical shift imaging (CSI), 165 Collision sensor, 181 Catphan phantom, 148 Chemotaxis targeting, 165–166 Collisional energy loss, 181 Cavitation, 148–149 CHEMSAT, see Chemical selective saturation Colour Doppler, 181 Cavity-gas calibration factor, 149 Chest radiography, 166 Colour flow imaging (CFI), 181–182 CBF, see Cerebral blood flow Chirp, 166–167 Colour saturation, see Hue, saturation, CBV, see Cerebral blood volume Chi-square test, 167 luminance CCD, see Charge-coupled device Choline, 167 Colour sensitivity, 182 CCD array, scanner, 149 Chromium-51 [51Cr], 167–168 Columnar caesium iodide, see Caesium iodide CCD coupling (charge-coupled device CI, see Conformity index Combining cancer therapies, 182 coupling), 150 CIF, see Contrast improvement factor Comet tail, 182 CDMAM, 150–151 Cine film, 168 Comforters and carers, 182–183 CDRAD phantom, 151 Cine loop, 168 Commissioning, 183 Ceiling mount unit, 151 Cine MRI, 168–169 Committed dose, 183 Cell cycle, 151 Cineangiography, 169 Compartment, 183 Cell proliferation, 151 Cinefluoroscopy, 169 Compartment models, 183 Cell survival, 151 Cineradiography, 169–170 Compensating filters, 183 Cell survival curve, 152 Circuit breaker, 170 Compensating wedge, see Wedge CEM, see Contrast-enhanced mammography Circuit(s), electrical, 170 Compensation, 183–184 CEMA, see Converted energy per unit mass Circular orbit, 170 Compensator, 184 Centigray (cGy), 152 Circular polarisation, see Circularly polarised Competent or regulatory authority, 184 Central beam, see Central ray of x-ray beam Circularly polarised (CP), 170–171 Complex number, 184 Central field of view (CFOV), 152 Circularly polarised coil (CP coil), see Complication-free tumour control, 184 Central processing unit (CPU), 152 Quadrature coil Composite, 184 Central ray of x-ray beam, 152 CIRT, see Carbon ion therapy Composite transducer, 184 Central volume theorem, 152 CISS, see Constructive interference Compound filter, 184–185 Centre of rotation (COR), 152, 211 steady state Compound imaging, 185 Centric sampling, 153 Classic (coherent) scattering, see Coherent Compound nucleus, 186 Cephalometric radiography, 153 scattering Compound scan, 186 Ceramic capacitor, see Capacitor Classified workers, 171 Compounding, 186 Ceramic x-ray tube with double bearings, 154 Clearance of tracers, 171 Compressibility, 186 Ceramics, 154–155 Clinical engineering, 171 Compression, 186 Cerebral blood flow (CBF), 155 Clinical equipoise, 171 Compressed sensing (CS), 186 Cerebral blood volume (CBV), 155–156 Clinical target volume (CTV), 171–172 Compton effect, 186–187 Cerebrospinal fluid (CSF), 156 Clinical trial endpoints, 172 Compton electron, 187 Ĉerenkov effect, 156 Clock frequency, see Clock pulse Compton interaction, 187 Ĉerenkov radiation, 156 Clock pulse, 172 Compton scattering, 187 Cerrobend®, 156 Clutter, 172 Computational phantoms, see Software Certificate of conformity, 156–158 CMUT, see Capacitive micromachined phantom Certification, 158 ultrasound transducer Computed radiography (CR), 187 CEST, see Chemical exchange CNR, see Contrast to noise ratio Computed tomography (CT), 187–188 saturation transfer Coaxial cable, 172–173 Computer-aided detection (CAD), 188 CFI, see Colour flow imaging Cobalt, 173 Computer-aided diagnosis (CADx), 188–189 CFOV, see Central field of view Cobalt Gray Equivalent, 173 Computer-aided perception (CAP), 188–189 Chamber response, 158 Cobalt unit, 173 Computer-controlled accelerator, 189 Characteristic curve, 158–159 Coded aperture, 173–174 Concave target volume, 189–190 Characteristic function, see Coded aperture tomography, 174–175 Concomitant boost, 189 Characteristic curve Coded excitation, 175 Concrete, see Radiation shielding Characteristic radiation, 159 Coherence, 175 Concurrent therapy, see Combining cancer Characteristic x-ray, see Characteristic Coherent scattering, 175 therapies radiation Coherent source, 175 Condensed history technique, 190 Charge, 159 Coincidence circuit for liquid scintillation Condenser chamber, 191 Charge deposition effect, 159 counter, 175 Conduction band, 191 Charge measurement mode, 159 Coincidence detection in PET systems, true, Conductivity, 191–192 Charge-coupled device (CCD), 160 see True coincidences Cone, 192 Charge-sensitive preamplifier, 160 Coincidence imaging, 175 Cone beam artefact, 192 Charged particles, 160 Coincidence summing of pulse-height Cone beam CT, 192–193 Charged-particle disequilibrium, 160–161 spectrum, 175 Cones, retina, 193 Charged-particle equilibrium, 161 Coincidence timing window, 175–176 Cones and rods in vision, see Retina Charged-particle therapy, 161 Cold spot, see Hot and cold spots Confidence limit, 193–194 Chartered scientist, 161 COLIPA, 176 Conformal dose distribution, 194 Check source, 161–162 Collection efficiency, 176 Conformal radiotherapy, 194 Chemical dosimetry, 162–163 Collection region, 176–177 Conformity index (CI), 194 Chemical exchange, 163 Collective dose, 177 Consistency, 194–195 Chemical exchange saturation transfer College of Medical Physics (ICTP), 177 Constancy, 195 (CEST), 163 Collimation, 177–178 Constructive interference, 195 Chemical impurity, 163 Collimator, 178 Constructive interference steady state Chemical quenching, 164 Collimator design, 178–179 (CISS), 195 Index 1041 Index Contact therapy, 195 CPU, see Central processing unit Daughter nucleus, see Bateman equation in Contained activity, 195–196 CR, see Computed radiography parent–daughter decay Contamination, 196 Creatine, 214 Daughter radionuclides, 235 Contamination monitoring, 196 Critical structures, 215 DC, see Direct current Contingency plan, 196 Crookes tube, 215 DC offset artefact, 236 Continuous slowing down approximation, Cross section, 215 DCT, see Discrete cosine transform 196–197 Cross-correlation, 215 Dead man’s switch, 236 Continuous spectrum, 197 Cross-hairs, 215 Dead time, 236 Continuous wave laser, see Laser output mode Cross-line curves, 216 Deadtime losses, 236–237 Contract management, 197–198 Crossed grid, see Grids, crossed Decay, see Radioactive decay Contralateral, 198 Crosstalk, 216 Decay constant, 237 Contrast, 198 CR reader, 214 Decay factor, 237 Contrast agent, 198–199 CRT, see Cathode ray tube Decay scheme, 237 Contrast degradation factor, 199 Crusher gradient, 216 Decay series, 238 Contrast detail, 199–200 Cryogen, 216 Decibel (dB), 238 Contrast detail (C-D) studies, see Cryostat, 217 Decommissioning, 238 Contrast detail Cryotherapy, 217 Decontamination, 238 Contrast-enhanced angiography, 200 CS, see Compressed sensing Deconvolution, 238–239 Contrast-enhanced mammography (CEM), 201 C-scan, 217 Decoupling, 239 Contrast enhancement, 200–201 CSF, see Cerebrospinal fluid DECT, see Dual energy CT Contrast improvement factor (CIF), 201 CSI, see Chemical shift imaging Decubitus, 239 Contrast inversion, 201–202 CT, see Computed tomography Deep inspiration breath hold (DIBH) Contrast media, 202–203 CT detectors, 217 technique, 239 Contrast ratio of monitors, 203 CT dose index (CTDI), 223–224 Deep learning, 239–240 Contrast resolution, 203–204 CTF, see Contrast transfer function Deep therapy, 240 Contrast scale, 204 CT fluoroscopy, 217–218 Defective pixel, 240 Contrast sensitivity, 204 CT number, 218 Deflection electrode, see Deflection plates in Contrast threshold, 204–205 CT optimisation, 218–220 cathode ray tubes Contrast to noise ratio (CNR), 205 CT reconstruction, 220–221 Deflection plates in cathode ray tubes, 240 Contrast transfer function (CTF), 205–206 CT scanner, see Computed tomography Deformable image registration (DIR), 240–241 Control button, 206 CT simulator, 221–222 Degassing of x-ray tube, 241 Control of Artificial Optical Radiation at Work CTV, see Clinical target volume Degrader, 241 Regulations, 2010, 206 CT x-ray tube, 222–223 DEI, see Diffraction-enhanced imaging Control panel, see Control button Cumulated activity, 224–225 Deionised water, 241 Control rods of nuclear reactor, 206–207 Cumulative dose, 225 Delay relay, 241 Controlled area, 207 Cumulative dose volume histogram, see Dose Delta electrons, 241 Convection, 207 volume histogram Delta function, 241–242 Converging collimator, 207–208 Cupping artefact, 225 Delta rays, 242 Conversion efficiency of photocathodes, 208 Curie, 226 Demagnification factor, 242 Converted energy per unit mass (CEMA), 208 Current, eddy, see Eddy currents Demodulation, 242 Converter, 208–209 Current consumption, 226 Densitometer, 242–243 Convex array, see Curvilinear array transducer Current intensity, 226 Densitometry, 243 Convex target volume, 209 Current source, 226 Density correction, 243 Convolution, 209 Curvature correction, 226 Dental radiography, 243 Convolution integral, 209 Curvilinear array transducer, 226–227 Dephase, 243 Convolution kernel, see Convolution method Custom blocking, 227 Depletion layer, 243 Convolution method, 209–210 Cut film changer, 227 Deposition of dose, 243 Coolidge tube, 210 Cutoff frequency, 227 Depth dose curve, see Percentage depth dose Cooling curve, see Anode-cooling curve CW Doppler, 227–228 Depth dose distribution, 243–244 Coordinate system, 210 Cyberknife, 228–229 Depth gain compensation, 244–245 Coordinate transformation, 210 Cycles per degree, 229 Depth ionisation curve, 245 Copper, 210–211 Cyclotron, 229–230 Depth of interaction, 245–246 COR, see Centre of rotation Cyclotron electrodes (dees), 230 Depth of interaction effect, see Depth of Cornea (eye), 211–212 Cyclotron for proton therapy, 230 interaction Coronal plane, 212 Cyclotron target, 230 Depth of maximum dose, 246 Correction factor, 212 Cyclotron-produced radionuclides, Depth of penetration, 246–247 Correlation, 212 230–231 Dermis, 247 Correlation time, 212–213 Cylindrical ionisation chamber, 231 Design dose per week, 247 Cost/benefit analysis, 213 DESS, see Dual echo steady state Couch/patient, 213 D Destructive interference, 247 Coulomb, 213 Detail resolution, 247 Coulombs/kg, 213 DAC, see Digital-to-analogue converter Detection efficiency, 247–248 Count rate, 213 Damping, 233 Detective quantum efficiency (DQE), 248–249 Counting limitations, 213 Damping block, 233 Detector, 249–251 Counting systems, 213 DAP, see Dose area product Detector air kerma, 251 Counting times, see Acquisition time Dark blood, 233 Detector conversion efficiency, 251 Coupling efficiency, 213 Dark current, 233–235 Detector extrinsic efficiency, see Detector Coupling medium, 213 Darkroom, 235 conversion efficiency CP, see Circularly polarised Data acquisition PET, 235 Detector fill factor, 251 CPMG, see Carr–Purcell–Meibom–Gill Database, 235 Detector geometric efficiency, 251 sequence Data mining, 235 Detector intrinsic efficiency, 251–252 Index 1042 Index Detector PET, 252 Dirty radionuclides, 272 Dose volume histogram (DVH), differential, Detector quantum efficiency, 252 Discharge current, 272 see Dose volume histogram Detector scatter event, 252 Discrete cosine transform (DCT), 272 Dose volume histogram (DVH), integral Detector total efficiency, 253 Discrete Fourier transform (DFT), 272 cumulative, see Dose volume Deterministic effects, 253 Discrete wavelet transform, 272 histogram Detriment, 253 Discretisation, 272 Dose warping, 288 Deuterium, 253 Discriminator, 272–273 Dose width product (DWP), 288 Developer, 253 Disease-free survival, 273 Dosemeter, 288 Development time, 253 Disintegration, radioactive, 273 Dosimeter, 288–289 Dewar, 253 Displacement, 273 Dosimetry, 289 DEXA, see Dual energy x-ray absorptiometry Display quality control, 273 Dosimetry protocol, 289 DFT, see Discrete Fourier transform Disposal, 273 Dosimetry report, 289 Diagnostic radiology, 254 Distal, 273 Dosimetry systems, 289–290 Diagnostic reference level (DRL), 254 Distal edge tracking, 273–274 Double contrast, 290 Diagnostic x-ray, 254–255 Distance learning, 274 Double exposure radiograph, 290 Diamagnetic materials, 255 Distribution function method, 274 Double focus tube, 290–291 Diamond detector, 255–256 Distribution volume, 274 Double scattering, 291 Diaphragm (collimator), 256 Dithering, 274 Double-strand break, 291 DICOM, see Digital Imaging and Divergence, 274 Downscatter, 291 Communications in Medicine Divergent beam edge, 274–275 DQE, see Detective quantum efficiency DICOM-RT, 257–258 Diverging collimator, 275 Dragonfly CT, 291 Dielectric, 258 Dixon method, 275–276 DREF, see Dose rate effectiveness factor Dielectric constant, 258 DKI, see Diffusion kurtosis imaging Drift, 292 Differential absorption, 258 DNA targeting, 276 Drift mobility, 292 Differential cross section, 258 Doped, see Doping DRL, see Diagnostic reference level Differential scattering cross section, 258 Doping, 276 Dropping load, see Falling-load generator Differentiation, 258 Doppler angle, 276 DRR, see Digital reconstructed radiographs Diffraction, 259 Doppler effect, 276–277 Drying in film processing, 293 Diffraction-enhanced imaging (DEI), 259–260 Doppler equation, 277–278 Dry laser imager, see Laser film printer Diffraction imaging, 260–261 Doppler imaging modes, 278 DSA, see Digital subtraction angiography Diffusion, 261 Doppler phantom, 278 DSI, see Diffusion spectrum imaging Diffusion encoding, 262 Doppler sample volume, 278–279 DTI, see Diffusion tensor imaging Diffusion

imaging, 262 Doppler shift, see Doppler effect DTPA, see TC-99M-DTPA Diffusion kurtosis imaging (DKI), 261–262 Doppler ultrasound, 279 Dual echo steady state (DESS), 293 Diffusion spectrum imaging (DSI), 262–263 Dose, 279 Dual energy CT, 293 Diffusion tensor, 260–261 Dose accumulation, 279 Dual energy digital radiography, 293–294 Diffusion tensor imaging (DTI), 263 Dose area histogram, 279–280 Dual energy imaging, 294 Diffusion time, 263–264 Dose area product (DAP), 280 Dual energy index, 294 Diffusion weighting, 264 Dose calculation, 201 Dual energy subtraction, 294–295 Digital breast tomosynthesis, 264–265 Dose calibrator, 280 Dual energy x-ray absorptiometry (DEXA), 295 Digital detector array, 265 Dose conformity index, 280 Dual filament tube, 295–296 Digital detector with direct conversion, see Dose constraints, 280 Dual foil system, see Electron dual scattering foils Detector Dose conversion factors, 280 Dual source CT, 296 Digital detector with indirect conversion, see Dose distribution, 280–281 Dummy sources, 296 Detector Dose equivalent, 281 Duplex ultrasound, 296 Digital display, 266 Dose escalation, 281 Duplicating film, 297 Digital fluoroscopy, 266 Dose homogeneity, 281 Duty cycle, 297 Digital image, 266 Dose length product, 281–282 DVD, see Digital video disc Digital Imaging and Communications in Dose limiting tissue, 282 Dwell time, 297 Medicine (DICOM), 256–257, 266 Dose limits, 282 DWP, see Dose width product Digital industrial radiology, 266 Dose model evaluation, 282–283 Dynamic aperture, 297 Digital mammography, 266–267 Dose modulation, 283 Dynamic focusing, 297 Digital radiography, 267 Dose monitoring, 283 Dynamic imaging, 297 Digital reconstructed radiographs (DRR), Dose optimisation, 283–284 Dynamic jaw collimation, 298 267–268 Dose painting, 284 Dynamic multileaf collimation, see Multileaf Digital subtraction angiography (DSA), Dose profile, 284–285 collimator 268–269 Dose rate, 285 Dynamic radiography, 298 Digital-to-analogue converter (DAC), 269 Dose rate constant, 285 Dynamic radiosurgery, 298–299 Digital video disc (DVD), 269 Dose rate dependence, 285 Dynamic range, 299–300 Digital visual interface, 269 Dose rate distribution, 286 Dynamic receive focusing, 301 Dilution quenching, 269 Dose rate effectiveness factor (DREF), 286 Dynamic spatial reconstructor, 301 Dimensional metrology, 269 Dose reference point, 286 Dynamic susceptibility contrast MRI, 301–302 Diode, 269–270 Dose response curve, 286 Dynamic transmit focusing, 302–303 Diode detectors, 270 Dose response function, 286 Dynamic wedge, 303 Dipolar coupling, 270–271 Dose response model, 286 Dynode, 303 DIR, see Deformable image registration Dose tolerance, 286 Dirac d-function, see Delta function Dose-to-medium calculations, 286 E Direct current (DC), 271 Dose-to-water calculations, 287 Direct digital radiography, 271 Dose tracking software, 287 Ear protection, 305–306 Direct driven, 271 Dose verification, 287 Earth’s magnetic field, 306 Direct voltage (DC voltage), 271–272 Dose volume histogram, 287–288 Earthing, 306 Index 1043 Index Echo enhancing agent, 306 Electron beam dosimetry, 323 EPR, see Electron paramagnetic resonance Echo planar imaging (EPI), 306–307 Electron capture, 323 Equalisation, 338–339 Echo-planar imaging and signal targeting Electron capture (EC) decay, 323–324 Equilibrium absorbed dose constant, 339 with alternating radiofrequency Electron contamination, 324 Equilibrium dose distribution, 339 (EPISTAR), 307 Electron density, 324 Equivalent blur, 339–340 Echo ranging, 307 Electron dual scattering foils, 324–325 Equivalent dose (HT), 340 Echo spacing, 307 Electron field effective width, 325 Equivalent field size, 340 Echo time (TE), 307 Electron fluence, 325 Equivalent mass of radium, 340 Echo train length (ETL), 308 Electron gun, 325–326 Equivalent square, 340–341 Echocardiography, 308 Electron hole pair, 326 Equivalent tissue air ratio (ETAR), 341 Echogenic, 308 Electron maximum range, 326 Equivalent uniform dose (EUD), 341 ECT, see Emission computed tomography Electron Monte Carlo, 326 Erect, 341 Eddy currents, 308–309 Electron oblique incidence, 326 ERM project, 342 Edge artefact, see Edge shadow Electron off axis factor, 326–327 Ernst angle, 342 Edge detection, 309 Electron paramagnetic resonance (EPR), 327 Erythema, 342 Edge enhancement, 309 Electron positron pair, see Pair production ESAK, see Entrance surface air kerma Edge illumination, 309–311 Electron practical range, 327 Escape peak, 342 Edge shadow, 311 Electron ranges, 327 Escargot curves, 342 Edge spread, 311 Electron spin, 327–328 ETAR, see Equivalent tissue air ratio Edge spread function, 311 Electron spin resonance, see Electron Ethics of radiation protection, 342–343 Editing, spectral, 311–312 paramagnetic resonance ETL, see Echo train length Effective detective quantum efficiency, 313 Electron stopping power, 328 EUD, see Equivalent uniform dose Effective dose, 312–313 Electron therapeutic range, 328 EURATOM Treaty, 343 Effective dose equivalent, 313 Electron transport, 328 European Federation of Organisations Effective dynamic range, see Dynamic range Electron volt, 328–329 for Medical Physics (EFOMP), Effective echo time, 314 Electronic binding energy, 329 315–316 Effective energy, 314 Electronic equilibrium, 329–330 European Guidelines on Medical Physics Effective exposure, AORD, 314 Electronic focusing, 330 Expert project, 343 Effective focal spot, see Focal spot, effective Electronic generators, 330 The European pharmacopeia, 939 Effective half-life, 314 Electronic medical record (EMR), 330 Eurospin test objects, 344 Effective point of measurement, 314–315 Electronic paper (e-paper), 330 EUTEMPE Project (European Training and Effective source point, 315 Electronic portal imaging, 330–331 Education for Medical Physics Effective SSD, 315 Electronic portal imaging device, 331–332 Experts) Project, 344 Effective voltage value, 315 Electroscope, 332 Event-related design, 344 EFOMP, see European Federation of Electrostatic deflector, 332 Event type in PET, 344–345 Organisations for Medical Physics Elementary particles, 332 Event types in a scintillation camera, Eigenfunctions, 316 Elevation resolution, 332–333 345–346 Eigenvalues, 316 Embryo, 333 Evidence-based, 346 Elastic scattering, 316 EMERALD project, 333 Excess risk, 346 Elastography, 316 EMERALD II project, 333–334 Excitation, 346 e-Learning, 316–317 Emission computed tomography (ECT), 334 Exit dose, 346 Electrical charge, see Charge EMITEL project, 334 Exit window, 346 Electrical interlock, see Interlock; EMIT project, 334 Expert systems, 346 Interlocking device EMR, see Electronic medical record Exposure, 346 Electrical resistance, see Resistance, electrical Emulsion layer, see Film emulsion Exposure counter, 347 Electric arc, 317 End diastolic velocity, 334–335 Exposure index, 347 Electric current, 317 End of bombardment (EOB), 335 Exposure limit values, 347 Electric dipole, 317–318 Energy absorption coefficient, 335 Exposure point, 347–348 Electric field, 318 Energy deposition, 335 Exposure rate, 348 Electricity, static, see Static electricity Energy fluence, 335 Exposure switch, 348 Electric power, 318 Energy gap, see Band gap Exposure table, 348 Electrocardiographic triggering, see Energy loss rate, 336 Exposure time, 348 Cardiac gating Energy resolution, 336 Exposure time limit, 348 Electrode, 318 Energy selection system, 36 Extended field of view (FOV), 348 Electrolytic capacitor, see Capacitor Energy spectrum, 336 Extended source (optical), 348 Electromagnet, 318–319 ENETRAP project (European Network Extended SSD treatment, 349 Electromagnetic energy spectrum, 319 on Education and Training in Extension cylinder cone, 349 Electromagnetic field, 319–320 Radiological Protection project I, Extent, 349 Electromagnetic hyperthermia, 320 II, III), 336–337 External beam irradiation, 349–350 Electromagnetic spectrum, see Enhancing filter, 337 External beam therapy, 350 Electromagnetic energy spectrum Ensemble length, 337–338 External photoelectric effect, 350 Electrometer, 320 Entrance dose, 338 Extinction cross section, 350–351 Electron, 320–321 Entrance maze, 338 Extracorporal elimination, 351 Electron angular distribution, 321 Entrance surface air kerma (ESAK), 338 Extraction fraction, 351 Electron angular scattering power, 321–322 Entrance window, see Image intensifier Extrafocal radiation, 351 Electron applicator, 322 EOB, see End of bombardment Extraoral projection radiography, 351 Electron arc aperture, 322 EPI, see Echo planar imaging Extrapolated range of electrons, 351 Electron arc therapy, 322 Epidermis, 338 Extrapolation ionisation chamber, 351–352 Electron backscatter factor, 322–323 EPISTAR, see Echo-planar imaging and Extravascular, see Comet Tail Electron beam, 323 signal targeting with alternating Extremity coil, 352 Electron beam CT, 323 radiofrequency Extremity dosimeters, 352 Index 1044 Index F Filament current, 367 Fluoro-glass dosimeter, 384–385 Filament heating, 368 Fluoroptic® probe, 385 FAIR, see Flow-sensitive alternating Filament (of an x-ray tube), 368 Fluoroscopic dose rate, 385 inversion recovery Filament resistor, 368–369 Fluoroscopic portal imaging, 385–386 Falling-load generator, 353 Fill-in factor, see Detector fill factor Fluoroscopic timer, 386 False negative (FN), 353 Filling factor, 369 Fluoroscopy, 386 False positive (FP), ROC, see False negative Film badge, 369 Fluoroscopy, digital, see Digital fluoroscopy FAMPO, see Federation of African Medical Film base, 370 Fluoroscopy, mobile, see Fluoroscopy Physics Organizations Film blackening, 370 Flux, 386 Fan beam, 354 Film changer, see Cassette changer Flux density, 386 Fan beam collimator, 354 Film digitisers, 370 Flying focal spot, 386–387 Fano’s theorem, 354–355 Film dosimetry, see Film badge fMRI, see Functional magnetic Far zone, see Diffraction Film emulsion, 370 resonance imaging Farad, 355 Film fog, 370–371 FN, see False negative Faraday cage, 355 Film holder, 371 Focal film distance (FFD), 387 Faraday cup, 355–356 Film processing, 371 Focal plane tomography, 387 Faraday shield, 356 Film screen contact, 371 Focal point, 387–388 Farmer chamber, 356–357 Film transport, 371 Focal spot, 388 Fast CT, 357 Film type, 371 Focal spot, actual, 388 Fast field echo (FFE), 357 Filter, 371–372 Focal spot, apparent, see Focal spot, effective Fast Fourier transform (FFT), 357 Filter, compensating, 372 Focal spot, effective, 388–390 Fast imaging with steady state precession Filtered back projection, 372–373 Focal spot selection, 390–391 (FISP), 357–358 Filtration (of colloidal particles), 373 Focal spot selector, see Focal spot selection Fast kV switching, 358 Filtration, inherent, see Inherent filtration Focal zone, 391 Fast low angle shot (FLASH), 358 Filtration, total, 373 Focused collimator, see Diverging collimator Fast spin echo (FSE), 358 Filtration rate, 373 Focusing cup, 382 Fast timing techniques for single-channel Finger ring dosimeter, 373–374 Focussed grid, 391–392 analysers, 358–360 FISP, see Fast imaging with steady Foetus, 392 Fat, 360 state precession Fog, see Film fog Fat nulling, see Fat suppression The 5 Rs of radiobiology, 940 Foot switch, see Dead Man’s Switch FATSAT, see Fat saturation Fixation, see Immobilisation Forbidden energy gap, 392 Fat saturation (FATSAT), 360 Fixed aperture beam restrictors, see Beam Force balance, 392–393 Fat suppression, 360–361 restrictor Force, electrostatic, 393 Feature extraction, 361 Fixed field alternating gradient (FFAG) Forces, nuclear, see Nuclear forces FED, see Field emission display accelerator, 374 Forensic radiology, 393 Federation of African Medical Physics Fixer, 374 Forward treatment planning, 393 Organizations (FAMPO), 353–354 Fixing agent, 374–375 Four-dimensional computed tomography Feedback, 361 FLAIR, see Fluid attenuated inversion (4DCT), 4 Ferromagnetic materials, 361–362 recovery Four-dimensional (4D) dose calculation, see Ferromagnetism, 362 FLASH, see Fast low angle shot 4D dose calculation Ferrous sulphate dosimetry, see Fricke Flash artefact, 375 Four-rectifier circuit, 393 dosimeter Flat field image, 375 Fourier reconstruction, see Filtered back FET, see Field-effect transistor Flat panel array, see Flat panel detector projection F-factor, 362–363 Flat panel detector, 375–376 Fourier spectrum framework, 394 FFAG, see Fixed field alternating gradient Flattening filter, 376 Fourier transform, 394 accelerator Flattening filter free (FFF) beam, 377 FOV, see Extended field of view; Field of view FFD, see Focal film distance Flicker, 378 Fractional anisotropy (FA), 394 FFE, see Fast field echo Flip angle, 378 Fractionation, 394–395 FFF, see Flattening free filter beam Float value, 378 Fractions, 395 FFT, see Fast Fourier transform Flood field, 378 Frame mode, 395–396 Fibre optics, 363 Flood field image, 378–379 Frame mode for digital image acquisition, Fibre optic taper, 363 Flow compensation, 379 see Acquisition modes for Fibre tracking, 363 Flow effects, 379 digital image FibroScan®, 363 Flow encoding, 379 Frame rate, 396 Fick’s method, 363–364 Flow imaging, 380–381 Frames per second, 396 Fick’s principle, 364 Flow phantom, 381 Fraunhofer zone, see Diffraction FID, see Free induction decay Flow quantification, 381 Free-air ionisation chamber, 396–397 Field coverage, 364 Flow-sensitive alternating inversion recovery Free induction decay (FID), 397–398 Field echo, see Gradient echo (FAIR), 381 Free radicals, 398 Field emission display (FED), 364–365 Flow void, 381–382 Frequency, 398–399 Field emission x-ray tube, 365 Fluence optimisation, 382 Frequency encoding, 399 Field margin, 365 Fluid attenuated inversion recovery Frequency spectrum, 399 Field of view (FOV), 365–366 (FLAIR), 382 Frequency-tailored RF pulse, 399 Field selection, 365 Fluorescence, 382 Fresnel zone, see Diffraction Field size, 365 Fluorescent screen, 382–383 Fricke-based gel, 400 Field strength, 366 Fluorescent x-rays, 383 Fricke dosimeter, 400 Field uniformity, 366 Fluorescent yield, 383 Fringe field, 400–401 Field verification, 366 Fluorine, 383 Front pointer, 401 Field weight, see Beam weight Fluorine-18 (18F), 383–384 FSE, see Fast spin echo Field-effect transistor (FET), 366 Fluorine 19 (19F), 384 Full field digital mammography, 401–402 Filament circuit, 367 Fluorodeoxyglucose, 384 Full-wave rectification, see Rectifier Index 1045 Index Full width at half maximum (FWHM), 402 Geometric (g)-factor, 420 HAMA, see Human anti-mouse antibody Full width at one-tenth maximum Geometric unsharpness, 417 Hardening, beam, see Beam hardening (FWTM), 402 Germanium detector, 417–419 Hard pulses, 435–436 Functional magnetic resonance imaging Ghost artefact, 420 Hardening agent, 436 (fMRI), 402–403 Ghosting, 420 Harmonic imaging, 436 Fuse, 403 Gibb’s artefact, see Gibb’s ringing HASTE, see Half acquisition single-shot turbo FWHM, see Full width at half maximum Gibb’s ringing, 420–421 spin echo FWTM, see Full width at one-tenth maximum Glass envelope

(of an x-ray tube), 420–421 Hazard, 436 Gloves, lead, see Lead gloves Hazard distance (HD), 436 G Glow curve, 421 Hazard value (HV), 436 Glycolysis, 421 HC, see Homogeneity coefficient Gadolinium-153, 405 Glycolysis targeting, 421 HD, see Hazard distance Gadolinium chelate, 405 GMR, see Gradient motion rephasing HDR, see High dose rate Gadolinium orthosilicate (GSO), 405–406 Golay codes, 422 Head, pitch and roll, 436 Gadolinium oxysulphide, 406 Gonad shielding, 422 Head coil, 437 Gadopentetate dimeglumine (Gd-DTPA), see Good manufacturer practice, 422 Health hazard, 437 Gadolinium chelate Gradient and spin echo (GRASE), 422 Health Protection Agency (HPA), 437 Gafchromic film, 406 Gradient coils, 422–423 Heat unit (HU), 437 Gain, 407 Gradient echo (GE), 423 Heating, 437–438 Gain, amplification, see Amplification factor Gradient field, 424 Heating, radiofrequency, see Radiofrequency Gain correction, 407 Gradient linearity, 424–425 heating Gain factor, 407–408 Gradient motion rephasing (GMR), 425 Heating, resistive, see Filament Gallium-67 [67Ga], 408 Gradient spoiling, 425–426 Heavy charged particle stopping power, Gallium-68 [68Ga], 408 Grand-daughter radionucleus, 426 438–439 Gamma camera, see Scintillation camera Graphite, 426 Heavy ions, 439 Gamma camera SPECT systems, see Single GRASE, see Gradient and spin echo Heavy metal filter, 439 photon emission computed Grating interferometry, 426–427 Heavy particle beams, 439 tomography Grating lobes, 427 Heel effect, see Anode Heel effect Gamma correction tables, 409 Gray, 427 Helical artefact, 439–440 Gamma knife, 409 Green’s function, 427 Helical pitch (CT), 440 Gamma radiation, 409 Grenz rays, 427 Helical scanning, 440–441 Gamut, 409 Grey levels, 428 Helium, 441 Gantry, 409 Greyscale, 428 Helium, liquid, see Helium Gas amplification, 409–410 Greyscale Standard Display Function Helium-free magnet, 441 Gas flow counters, 410 (GSDF), 428 Helmholtz coil, 441 Gas-filled radiation detectors, 410 Grey values, 428–429 Herring bone artefact, 441 Gate, 410–411 Grid, Bucky, 429 Hertz (Hz), 442 Gated SPECT, 411 Grid, focussed, see Focussed grid Heterogeneity, 442 Gating, cardiac, see Cardiac gating Grid control, see Grid-controlled x-ray tube HIFU, see High-intensity focused ultrasound Gating, respiratory, 411 Grid-control, see Grid-controlled x-ray tube High activity sealed source, 442 Gauss, 411 Grid efficiency, 429 High contrast, 442–443 Gaussian distribution, 411 Grid ratio, 429–430 High counting rates, see Dead time Gaussian noise, 411 Grid-controlled x-ray tube, 430 High dose rate (HDR), 443–444 GE, see Gradient echo Grids, crossed, 430 High energy electrons, 444 Geiger–Muller (GM) counters, 411–412 Gross tumour volume (GTV), 430 High-frequency generator, 444–445 Gel, 412 Ground connection, see Grounding High-intensity focused ultrasound (HIFU), 445 Gel dosimetry, 413 Ground lead, 431 High kV technique, 445 General public exposure, 413–414 Grounding, 431 High-pass filter, 445 Generalised detective quantum efficiency, 414 GSD, see Genetically significant dose High-resolution CT (HRCT), 445 Generalised modulation transfer function, 414 GSDF, see Greyscale Standard Display High-voltage cable, 445–446 Generator, see AC generator Function High-voltage circuit, 446–447 Generator, battery powered, 414–415 GSO, see Gadolinium orthosilicate High-voltage control device, see Radiographic Generator, capacitor-discharge, see Capacitor GTV, see Gross tumour volume kV control discharge generator Gyromagnetic ratio, 431 High-voltage generator, 447–448 Generator, falling load, see Falling-load Gyroscopic radiosurgery ZAP-X, 431 High-voltage protection, 448 generator High-voltage transformer, 448 Generator, high-frequency, see High-frequency H HIS, see Hospital information systems generator Histogram, 449 Generator, single-phase, see Single phase H and D curve, 433 Histogram-based intensity windowing, 449 generator Hadron therapy, 433 HL-7, 449 Generator kV waveform, see Voltage waveform Haemodynamic response function, 433 Hogstrom algorithm, 449–450 Generators, radionuclide, see Radionuclide Half acquisition single-shot turbo spin echo Holmium, 450 generators (HASTE), 433 Holotomography, 450 Generator(s), three-phase, see Three-phase Half Fourier imaging (HFI), 433–434 Holt chamber, 450 generator Half Fourier turbo spin echo, see Half acquisition Homogeneity, 451 Genetically significant dose (GSD), 415 single-shot turbo spin echo Homogeneity coefficient (HC), 451 Geometric distortion, 415 Half value layer (HVL), 434 Homogeneity index, 451 Geometric efficiency, 415–416 Half wave rectification, see Rectifier Homogeneous field, 451 Geometric error, 416 Half-life of radionuclides, 434 Hormesis, 451–452 Geometric field separation, 416 Half-life of radionuclides in medicine, Hospital information systems (HIS), 452 Geometric field size, 416–417 434–435 Hot and cold spots, 452 Index 1046 Index Hot spot, see Hot and cold spots Image plane, 465 Input impedance, see Input circuit Hounsfield number, see CT number Image processing software, 465–466 Input screen in fluoroscopy, see Image Hounsfield scale, 452 Image quality, 466 intensifier Housing, see X-ray tube housing Image quality indicators, 466–468 Instantaneous dose rate (IDR), 481 HPA, see Health Protection Agency Image reconstruction, 468 Insulation resistance, 481–482 HRCT, see High-resolution CT Image registration, see Registration Integral dose, 482 HSL, see Hue, saturation, luminance Image retrieving, 468 Integrated backscatter, 482 HU, see Heat unit Image selected in vivo spectroscopy (ISIS), Integrated parallel acquisition technique HU calibration, 453 468–469 (iPAT), 512 Hue, see Hue, saturation, luminance Image sequences, 469 Integrating dosimeter, 482–483 Hue, saturation, luminance (HSL), 453 Image smoothing, 469 Integrating the healthcare enterprise Human anti-mouse antibody (HAMA), 435 Image storage, see Picture Archiving and (IHE), 483 Human visual response function, 453–454 Communication System Intelligent workstation, 483–484 Humidity correction factor, 454 Image uniformity, 469 Intense pulsed light source (IPL), 484 Huygens’ principle, see Diffraction Image-guided brachytherapy, 469–470 Intensification factor (IF), 484 HV, see Hazard value Image-guided radiotherapy, 470–471 Intensifying screen, 484 HVL, see Half value layer Imaging, 471 Intensifying screen(s), rare earth, see Rare Hybrid computation phantoms, 454 Imaging biomarkers, 471 earth screen Hydrogen, 454 Imaging system, 471 Intensity, 484 Hydrophone, 454–455 Imatron, 471 Intensity modulated proton therapy (IMPT), Hyperechoic, see Echogenic Immobilisation, 471–472 484–485 Hyperfractionation, 455–456 Immobilisation device, see Immobilisation Intensity-modulated radiotherapy (IMRT), 485 Hyperpolarised, 456 IMPCB, see International Medical Physics Intensity reflection coefficient, see Reflection Hyperthermia treatment, 456 Certification Board coefficient Hypoechoic, 456 Implant, 472 Intensity transmission coefficient, see Hypofractionation, 456–457 Implant dose distribution, 472 Transmission coefficient Hypothesis, 457 IMPT, see Intensity modulated proton therapy Intensity weighted mean, 485 Hypoxia, 457–458 Impulse response function, 473 Interaction, 485 Hypoxia targetting, 458 IMRT, see Intensity-modulated radiotherapy Interactive implant technique, 485–487 Hz, see Hertz In-111-labelled ibritumomab tiuxetan Interactive planning, 487 (Zevalin™®), see Y-90-labelled Interface, 487 I ibritumomab tiuxetan (Zevalin®) Interference, 487 In air calibration factor, 473 Interlacing monitors, see Acquisition modes IAEA, see International Atomic In silico, 473–474 for digital image Energy Agency In vitro, 474 Interleaved, 487–488 IAEA Guides for Medical Physics, 459 In vivo, 474 Interlock; interlocking device, 488 IAEA Handbooks for Medical Physics, 459 In vivo body composition, 474–475 Interlocking mechanism, see Interlock; ICNIRP, see International Commission In vivo dosimetry, 475 interlocking device on Non-Ionising Radiation; In vivo range verification, 475 Internal beam irradiation, 488 International Commission on Non- Inch, 475 Internal conversion, 488–489 Ionising Radiation Protection Incidence angle, see Oblique Incidence Internal margin, 489 ICRP, see International Commission on Incident air kerma, 475 Internal photoelectric effect, 489–490 Radiological Protection Incident analysis framework, 475–476 Internal radiation dosimetry, 490 ICRPM, see International Conference on Incident dose, 476 Internal reference point, 490–491 Radiation Protection in Medicine Incident energy fluence, 476 Internally deposited radionuclide, 491 ICRU, see International Commission on Incoherent light source, 476 International Atomic Energy Agency Radiation Units and Measurements Incoherent scattering, 476 (IAEA), 491 ICRU reference point, 459–460 Indirect detection, 476–477 International Centre for Theoretical Physics ICTP, see International Centre for Theoretical Indirect digital radiography, 477 (ICTP), 460 Physics Indium-111 [111In], 477 International Commission on Non-Ionising IDR, see Instantaneous dose rate Induced radioactivity, 478 Radiation Protection (ICNIRP), 491 IEC, see International Electrotechnical Industrial CT, 478 International Commission on Radiation Commission Industrial radiography, 478 Units and Measurements (ICRU), IF, see Intensification factor Inelastic scattering, 478 492–493 IFMBE, see International Federation Inferior; caudal, 478 International Commission on Radiological for Medical and Biological Inflow effect, 478 Protection (ICRP), 491–492 Engineering Informed Consent, 479 International Conference on Radiation IHE, see Integrating the healthcare enterprise Infrared light, 479 Protection in Medicine Image analysis, 460 Infrared light hazard, see Thermal Light (ICRPM), 492 Image artefact, 460–461 Hazard International Electrotechnical Commission Image compression, 461 Infrared radiation, 479 (IEC), 493 Image covariance, 461 Inherent contrast, 479 International Federation for Medical Image display, 461 Inherent filtration, 479 and Biological Engineering Image enhancement, 461 Inhomogeneity, 480 (IFMBE), 493 Image fusion, 462 Inhomogeneity correction factor, 480 International Medical Physics Certification Image Gently, 462 In-house service, 480 Board (IMPCB), 472 Image geometric distortion, 462–463 Inorganic phosphate, 480–481 International Organization for Medical Physics Image intensifier, 463–464 Inorganic scintillators, 481 (IOMP), 493–494 Image matrix, see Matrix size Input circuit, 481 International Radiation Protection Association Image noise, 464–465 Input curves on anode-cooling charts, see (IRPA), 494–495 Image perception, 465 Anode-cooling curve International Science Council (ISC), 495 Index 1047 Index International Union for Physical and Isodose shift method, 516 Laser beam, 536–537 Engineering Sciences in Medicine Isodose surface, 516 Laser beam delivery systems, 537 (IUPESM), 495 Isoeffect, 516–517 Laser classification, 537 Interpolation, 495 Isomeric transition (IT), 517 Laser film printer, 537–540 Interruption of treatment, 495–496 Isomers, 517–518 Laser interferometry, 540 Intersource shielding, 496 Isotones, 518 Laser localisers, 540 Interstitial, 496 Isotope, 518 Laser output mode, 540–541 Interstitial brachytherapy, 496–497 Isotropic, 518 Laser plasma particle accelerators (LPPAs), Interstitial implant, 497 Isotropic emission, 518 541–542 Interstitial therapy, 497 Isowatt circuit, see Automatic brightness Laser protection adviser (LPA), 542 Interventional MRI, 498 control Laser protection supervisor (LPS), 542 Intracavitary, 498 IT, see Isomeric transition Laser protective eyewear, 542–543 Intracavitary brachytherapy, 498–500 Iterative algorithm, see Iterative reconstruction Laser pumping methods, 543 Intracavitary therapy, 500 methods Lasing material, see Laser Intraluminary brachytherapy, 500 Iterative image reconstruction, 518 Late radiation toxicity, see Late response of Intraoperative radiation therapy (IORT), Iterative reconstruction methods, 519 normal tissue 500–501 IUPESM, see International Union for Physical Late reactions, 543 Intraoral radiography, 501–502 and Engineering Sciences in Late response of normal tissue, 543 Intravascular irradiation, 502 Medicine Latent image, 543–544 Intravascular ultrasound (IVUS), 502–503 IVIM, see Intravoxel incoherent motion Latent period, 544 Intravoxel incoherent motion (IVIM), 503 IVUS, see Intravascular ultrasound Lateral, 544 Intrinsic amplifier noise, 503 Lateral dose falloff, 544 Intrinsic efficiency, 503–504 J Lateral electronic equilibrium, 544–545 Intrinsic flood field uniformity, 504 Lateral penumbra, 545 Inverse Fourier transform, 504 J coupling, 521 Lateral position, 545 Inverse radiotherapy planning, 504 JND, see Just noticeable difference Lateral resolution, 545–546 Inverse square law, 504 Joule, 521 Latitude of film, 546 Inverse square law correction, 504–505 Justification, 521 Lattice, 546 Inversion recovery, 505–506 Just noticeable difference (JND), 521 LCD, see Liquid crystal display Inversion time (TI), 506 LDR, see Low dose rate Inversion time delay (TI delay), 506 K Lead, 547 Iodine, 506 Lead apron, 547 Iodine-123, 506–507 K absorption edges, 523 Lead content, 547 Iodine-124, 507 K-edge, see K absorption edges Lead drapes, 547 Iodine-125, 507–508 K-edge metal filter, 523 Lead equivalent, see Lead content Iodine-131, 508–509 Kerma, 523 Lead glass, 547–548 IOMP, see International Organization for Kernel, 523–524 Lead glasses (eyewear), 548 Medical Physics Kernel-based treatment planning, 524 Lead gloves, 548 Ion, 509 Keyhole imaging, 524–525 Lead protection, 548 Ion collection, see Ion pair Kit, 525 Lead zirconate titanate (PZT), 754 Ion pair, 509 Klein–Nishina differential cross section, 526 Leadership in medical physics, 548 Ion recombination, 509–510 Klein–Nishina equation, 526 Leak test, 548–549 Ion therapy, 510–511 KLM equivalent circuit model, 526 Leakage current, 549 Ionisation, 511 Klystron, 526–527 Leakage radiation, 549 Ionisation chamber, 511–512 Krypton-81m, 527 Lens, 549 Ionisation density, 512 k-space, 527 Lens (Eye), 550 Ionisation recombination loss, 512 k-space trajectories, 527–528 LET, see Linear energy transfer Ionising radiation, 512 kV meter, 528 Lethal dose, 550 IORT, see Intraoperative radiation therapy kVp, see Peak kilovoltage Life cycle of equipment, 551 iPAT, see Integrated parallel acquisition kV selector, 528–529 Lifetime attributable risk (LAR), 551–552 technique Kymography, 529 Light, 552 IPL, see Intense pulsed light source KZK equation, 529 Light field, 552 IPL classification, see Intense pulsed Light guide, 552 light source L Light localiser, 552–553 Ipsilateral, 512 Light radiometer, see Radiometer Iridium-192, 513 Labelling, 533 Light yield in scintillation detectors, 553 Iris diaphragm, 513–514 Labelling efficiency, 533 Limitation, 553 Iron-based contrast agents, 514 Labelling yield, 533 Limitations to the MIRD formalism, 553–554 IRPA, see International Radiation Protection Lactate, 533 Limited angle tomography, 554 Association Lamb wave, 533 Linac, see Linear accelerator Irradiance, 514–515 Lambert–Beer’s law, 533 Linac cone beam CT, 554 Irradiated volume, 514 Laminar flow, 533–534 Line artefacts, 554 Irregular field, 515 LAN, see Local area network Line density, 554 ISC, see International Science Council Lanthanides, 534 Line focus principle, 554 ISIS, see Image selected in vivo spectroscopy Lanthanum oxybromide in intensifying screen, Line of response (LOR), 554 Isobars, 515 see Rare earth screen Line pair, 554–555 Isocentre, 515 Laplace transform, 534 Line scanning, 555 Isocentric technique, 515 LAR, see Lifetime attributable risk Line

source model, 555 Isochromat, 515 Larmor equation, 534 Line spread function (LSF), 555 Isodose curve, 515–516 Laser, 534–536 Line voltage, 555 Isodose rate surface, 516 Laser aperture, 536 Linear accelerator, 555–556 Index 1048 Index Linear and shift-invariant systems, 556–557 Magnet, superconducting, see Superconducting Mayneord F factor, 596 Linear array, 557 magnet Maze, 596 Linear array transducer, see Linear array Magnetic beam steering, 574 MCO, see Multi-criteria optimisation Linear attenuation coefficient, 557 Magnetic coupling, 574–575 MDA, see Minimum detectable activity Linear Boltzmann transport equation (LBTE) Magnetic dipole, 575 MDCT, see Multidetector CT solver, 557–558 Magnetic dipole moment, 575 MDR, see Medium dose rate Linear (classical) tomography, 558–559 Magnetic field lines, 575 Mean absorbed dose to air, 596 Linear dose response curve, 559–560 Magnetic flux, 575 Mean dose per cumulated activity, 596–597 Linear energy transfer (LET), 560 Magnetic flux density, 575–576 Mean electron energy, 597 Linear gradient, see Gradient linearity Magnetic moment, 576 Mean energy imparted, 597 Linear no-threshold dose response, 560 Magnetic polarity, 576 Mean free path, 597–598 Linear no-threshold model, 560 Magnetic resonance angiography (MRA), 576 Mean glandular dose, 598 Linear quadratic (LQ) model, 560–562 Magnetic resonance imaging (MRI), 576–578 Mean life, see Average lifetime of atoms Linear-quadratic dose-response curve, 562 Magnetic resonance spectroscopy (MRS), Mean target absorbed dose, 598 Linear stopping power, 562 578–579 Mean transit time (MTT), 598–599 Linearly polarised (LP), 562 Magnetic susceptibility, 579–580 Measuring chamber, 599 Liquid chromatograph, 562–563 Magnetisation preparation, 580 Mebrofenin, 599 Liquid crystal display (LCD), 563–564 Magnetisation transfer contrast (MTC), Mechanical index (MI), 599–600 Liquid flow counting, 564 580–581 Mechanical interlock, see Interlock Liquid metal bearing, 564 Magnetisation transfer (MT), see Mechanical isocentre, 600 Liquid scintillation (LS) counting, 564–565 Magnetisation transfer contrast Mechanical locking system, 600 Liquid scintillators, 565 Magnetophosphenes, 581 Mechanical transducer, 600 List mode, 565 Magnetron, 581 Medial, 600 Lithotripter, 565 Magnification, 581–582 Median target absorbed dose, 600 Local area network (LAN), 565 Mains frequency, see Line voltage Medical device, 600–601 Local overdose, 565 Mains supply circuit, power supply, 582 Medical equipment management, 601–602 Local rules, 565–566 Mains voltage, see Mains supply circuit, Medical exposure, 602 Local underdose, 566 power supply Medical image display, 602 Localisation jig, 566 Mains voltage drop, see Voltage drop Medical Internal Radiation Dose (MIRD) Localisation radiograph, 566 Maintenance, 582 formalism, 602–604 Localiser, 566–567 mA-metre, 582 Medical lasers, 604–605 Logic analyser, 567 Mammographic phantoms, 582–583 Medical physics, 605–606 Longitudinal magnetisation, 567 Mammography (screen film), 583–584 Medical physics expert (MPE), 606 Longitudinal movement, 567–568 Mammography x-ray tube, 584–585 Medical Physics for World Benefit Longitudinal travel, see Longitudinal Man sievert, 585 (MPWB), 623 movement Manchester system, 585 Medical Radiation Protection Education Longitudinal wave, 568 Manganese, 585 and Training project Long-term morbidity, 568 Manual afterloading, 585–586 (MEDRAPET), 606 Lookup table, 568 Manual loading, 586 Medium dose rate (MDR), 606 LOR, see Line of response Markus chamber, 586 Medium frequency portable x-ray machine, see Lorentzian lineshape, 568 mAs selector, 586 High frequency generator Lossless compression, 568–569 Mask mode fluoroscopy, 586 MEDRAPET, see Medical Radiation Lossy compression, 569 mAs-metre, see mAs selector Protection Education and Low contrast, 569 Mass attenuation coefficient, 586 Training project Low contrast detectability, 569 Mass collision stopping power, 586 MEFOMP, 607 Low dose rate (LDR), 570 Mass defect, 586 Mega electron volt, see Electron volt Low melting point alloy, 570 Mass energy absorption coefficient, 586–587 Meisberger polynomial, 607 Low-pass filter, 570 Mass number, 587 Melanoma, 607 LP, see Linearly polarised Mass of radium, 587 MEP Workshop (Medical Physics and LPA, see Laser protection adviser Mass radiative stopping power, 587 Engineering Workshop), 602 LPPAs, see Laser plasma particle accelerators Mass stopping power, 587 Metal artefact, 607–608 LPS, see Laser protection supervisor Matching layer, 587–588 Metal-oxide–semiconductor field effect LQ model, see Linear quadratic model Matrix array, 588–590 (MOSFET) transistor, 608 LS counting, see Liquid scintillation counting Matrix depth, see Matrix size Metal x-ray tube, 608 LSF, see Line spread function Matrix size, 590–591 Metallic implant, 608–609 L-shell, 571 Maxillofacial cone beam CT, 591–592 Metastable nucleus, 609 Lubberts’ effect, 571 Maximum dose, 592 Metastable state, see Metastable nucleus Luminance, see Hue, saturation luminance Maximum exposure time, AORD, 592–593 Metastasis, 609 LUT, see Lookup table Maximum frequency follower, 593 MFO, see Multifield optimisation LYSO, 572 Maximum likelihood expectation maximum MI, see Mechanical index (MLEM), 593–594 Microbubbles, 609 M Maximum (minimum) intensity projection Micro CT, see Small animal CT (MIP), 594 Microdosimetry, 609–610 M-mode, 573 Maximum permissible concentrations, Micro-MLC, 610 mA selector, 573 594–595 Micron, 610 Machine learning, 573 Maximum permissible dose (MPD), 595 Micro-PET, 610 Macro CT, 573 Maximum permissible exposure (MPE), 595 Microprocessor, 610 Macroradiography, 573 Maximum target absorbed dose, 595 Micro-SPECT, 610 Magic angle, 573 Maximum velocity, see Maximum frequency Micro-switch, 610 Magnet, 574 follower Microwaves, 610 Magnet, permanent, see Permanent magnet Maxwell gradients, 595–596 Midpoint dose, 610–611 Index 1049 Index Minification gain, see Total brightness gain MR safety (new definitions), 625–626 Nerve stimulation, see Peripheral nerve Minimum detectable activity (MDA), 611 MRI safety, 626–627 stimulation Minimum target absorbed dose, 611 MRI transparent, 627 Net magnetisation, 641–642 MIP, see Maximum (minimum) intensity MRS, see Magnetic resonance spectroscopy Network architecture, 642 projection MRS voxel contamination, 627–628 Neuroreceptor targeting, 642 MIRD Committee, 611 MRT, see Magnetic resonance imaging Neutral conductor, 642 MIRD formalism, 611–612 MSAD, see Multiple scan average dose Neutrino, 642–643 Mirror image artefact, 612 MSCT, see Multislice CT scanner Neutron activation, 643 Misadministration, 612–613 ms selector, 628 Neutron capture cross section, 643 Misregistration, 613 MT, see Magnetisation transfer contrast Neutron capture therapy, 643 Mixed radionuclides, 613 MTC, see Magnetisation transfer contrast Neutron therapy, 643 Mixing time (TM), 613 MTF, see Modulation transfer function Neutrons, 643–644 MLC QA, 613 MTT, see Mean transit time NEX, see Number of excitations MLCs, 613 MUGA, see Multi-gated acquisition Nickel, 644 MLEM, see Maximum likelihood Multi-Band simultaneous Multislice Nit, see Brightness expectation maximum imaging, see Simultaneous Nitrogen, 644 Mobile shield, 613 multislice excitation Nitrogen-13, 644 Mobile target volume, 613–614 Multichannel analyser, 628 Nitrogen, liquid, see Nitrogen Mobile unit, 614 Multi-coil transmit, 628 NMR, see Nuclear magnetic resonance Modal target absorbed dose, 614 Multi-criteria optimisation (MCO), 629 NOHD, see Nominal ocular hazard distance Modalities, 614 Multicrystal scanners, 629 Noise, 645 Mode conversion, 614 Multidetector CT, 629–630 Noise equivalent quanta (NEQ), 645 Modulation factor, 614 Multi-echo, 630 Noise power spectrum (NPS), 645–647 Modulation transfer function (MTF), 614–615 Multi-gated acquisition (MUGA), 630 Nominal ocular hazard distance (NOHD), 647 Modulation wheel, 615–616 Multifield optimisation (MFO), 630 Nominal output, see Nominal value Modulator, 616 Multihole collimators for radioisotope Nominal pixel size, monitor, 647 Moiré patterns, 616 scanners, 630 Nominal value, 647 Molar mass, 616 Multihole focused collimators, see Diverging Non-coplanar beams, 647 Mole, 616 collimator Multileaf collimator, Non-designated (public) area, 647–648 Molecular excitation, 616 630–631 Non-homologous end-joining repair Molecular imaging, 616–617 Multimodality systems, 631 pathway, 648 Molecular mass, 617 Multi-pinhole collimator, 631–632 Non-ionising radiation, 648–649 Molecular targeting, 617 Multiplanar reconstruction (MPR), 632 Non-linear dose-response curve, 649 Molecular weight, see Molecular mass Multiple beams, 632 Non-linear propagation, 649 Molecule, 617 Multiple coulomb scattering, 632 Non-linearity parameter, 649 Molière scattering theory, 617 Multiple-image radiography, 632–633 Non-paralysable counting system, 650 Molybdenum, 617–618 Multiple isocentre treatment, 633 Non-scattering grid, 650 Molybdenum breakthrough, 618 Multiple reflection, see Reverberation Non-screen film, 650 Monitor chamber, 618 Multiple scan average dose (MSAD), 633 Non-specular, 650 Monitoring, 618 Multiple scattering, 633 Non-stochastic effects, 650–651 Monitor unit, 618 Multislice, 633–634 Non-threshold dose–response curve, 651 Mono-block generator, 618 Multislice CT scanner, 634–635 Non-transparent, see Opacity Monochromator, 618–619 Multi-vendor service, 635–636 Non-uniform activity distribution, 651 Monoclonal antibodies (mAb), 619 Mu-metal, 636 Non-uniformity, 651–652 Mono-energetic beam, 619 Muscle, 636 Normal database, 652 Monte Carlo calculations, 619 Myocardial perfusion imaging, 636 Normal distribution, 652 Monte Carlo method, 619–620 Myo-inositol, 636–637 Normalisation point, 655 Monte Carlo photon transport simulation, 620 Normalised noise power spectrum (NPS), Moodle, 620–621 N 652–653 MOS-FET detector, see Metal-oxide- Normalised treatment dose (NTD), 655 semiconductor field-effect transistor N/2 artefact, 639 Normal organ dose tolerance, 652 Most probable energy, 621 N-acetylaspartate (NAA), 639 Normal speed tube, 653 Motion artefacts, 621–622 NaI(Tl) detector crystal, 639 Normal tissue complication probability, Motion management, 622 Nanoparticles, 639 653–654 Motion unsharpness, 622 Narrow beam geometry, 639 Normal tissue dose, 654 Mottle, quantum, 622 National Council on Radiation Protection and Normal tissue dose–response, 654 Moving grid, 622–623 Measurements (NCRP), 640 Normal tissue reaction, 654–655 MPD, see Maximum permissible dose National Physical Laboratory (NPL), 655 Normal tissue toxicity, 655 MPE, see Maximum permissible exposure; National radiation authority (NRA), see Notification, 655 Medical physics expert Regulatory authority Nozzle, 655 MPR, see Multiplanar reconstruction National Radiological Protection Board NPL, see National Physical Laboratory MPWB, see Medical Physics for World Benefit (NRPB), 640 NPS, see Noise power spectrum; Normalised MRA, see Magnetic resonance angiography Navigator echo, 640–641 noise power spectrum MR elastography, 623 NCRP, see National Council on Radiation NRA, see Regulatory authority MRI, see Magnetic resonance imaging Protection and Measurements NRC, see Nuclear regulatory commission MRIgRT, see MRI-guided radiotherapy Near zone, see Diffraction NRPB, see National Radiological Protection MRI-guided radiotherapy (MRIgRT), 623–624 Negative contrast media, 641 Board MR-Linac, 624 Negative-ion cyclotron, 641 NTD, see Normalised treatment dose MR microscopy, 624–625 Negative pions, 641 Nuclear activation analysis, 655–656 MR-only treatment planning, 625 NEMA, 641 Nuclear binding energy, 656 MR safe, 625 NEQ, see Noise equivalent quanta Nuclear chain reaction, 656 Index 1050 Index Nuclear emissions, 656 Orthogonal pair of x-rays, 672 Patient-reported outcome measures Nuclear fission, 656 Orthovoltage radiation, 672 (PROMs), 688 Nuclear forces, 656 Oscillating gradient, 672 PBS, see Pencil beam scanning Nuclear instability, 657 Oscillator, 672 PCT, see Proton CT Nuclear interaction, 657 Oscilloscope, 672–673 PDE, see Phosphodiesters Nuclear magnetic resonance (NMR), Osmosis, 673 PDR, see Pulsed dose rate 657–658 Output factor, 673 Peak areas, 688 Nuclear medicine, 658 Output screen, see Image intensifier Peak assignment, 688–689 Nuclear medicine imaging, 658–659 Over-table radiography, 673 Peak kilovoltage (kVp), 689 Nuclear reactor, 659 Over-table tube, see Over-table radiography Peak scatter factor (PSF), 689 Nuclear regulatory commission (NRC), 659 Over voltage, see Overvoltage protection Peak systolic velocity, 689 Nuclear transformation, 659 Overall survival, see Clinical trial endpoints Peak voltage, 689 Nucleon, 659 Overbeaming, 674 Peaking, 689–690 Nucleus, 659–660 Overexposed, see Overexposure Pencil beam, 690 Nuclide, 660 Overexposure, 674 Pencil beam scanning, 690–691 Nude mouse, 660 Overload, see Overload protection Penetrating radiation, 692 Number of excitations (NEX), 660 Overload protection, 674–675 Penetration depth, 691–692 Nyquist frequency, 660 Oversampling, 675 Pentetreotide, 691 Nyquist limit, 660 Overscanning, 675 Penumbra, 692 Nyquist theorem, 660 Overshoot, 675 Penumbra effect, 692 Overvoltage protection, 675 Percentage depth dose, 692–693 O Oxine, 675 Perception, 694 Oxygen, 675–676 Perfusion imaging, 694 OAR, see Organ at risk Oxygen-15, 676 Periodic motion, 694–695 Object–film distance, 661 Oxygen enhancement ratio, 676 Periodic table, 695 Object image receptor distance, see Target– Oxyhaemoglobin, 676 Peripheral blurring, see Unblanking film distance Peripheral dose, 695 Object recognition, 661 P Peripheral nerve stimulation (PNS), 695–696 Object scatter events, 661 Permanent implant, 696 Oblique, 661 P-32-sodium orthophosphate, 677 Permanent magnet, 696 Oblique imaging, 661 PA (posteroanterior) projection, see Permeability-surface area product, 696–697 Oblique incidence, 661 Posteroanterior (PA) projection Personalised medicine, 697 Obliquity, 661 PACS, see Picture Archiving and Personal protective equipment (PPE), 697 Obliquity effect, see Oblique incidence Communication System Personnel dosimetry, 697 Occupancy factor, 661–662 Pair production, 677 Perspex characteristics, 698–699 Occupational dose limits, 662 Palliative treatment, 677 Pertechnetate, 699 Occupational exposures, 662–663 Paper and thin layer chromatography, 677 PET, see Positron emission tomography OER, see Oxygen enhancement ratio Paraffin phantom, 678 PET clinical applications, 699 Oersted, 663 Parallel acquisition technique (PAT), 678 PET/CT, 699 OFD, see Object–film distance Parallel connection, 678 PFI, see Partial Fourier imaging Off-resonance, 663 Parallel imaging, 678–680 Phagocytosis, 699 Offset, 663 Parallel opposed fields, 680 Phantom, 699 On-line portal imaging, 663–664 Parallel organs, 680 Phase angle, 699–700 One-day protocol, 664 Parallel plate ionisation chamber, 680–681 Phase coherence, 700–701 One-way rectifier, 664 Parallel-hole collimators, 681–683 Phase contrast, 701 Opacity, 664 Paralysable counting system, 683 Phase contrast angiography, 701 Open-core transformer, see Transformer Paramagnetic contrast agents, 683 Phase-contrast CT, see Phase-contrast Open field, 664 Paramagnetism, 683 tomography Open magnet, 665 Parent radionucleus, 683 Phase-contrast imaging, 701–704 Operating mode, see Acquisition modes for Parent–daughter decay, 683 Phase-contrast tomography, 704–705 digital image Pareto chart, 683 Phase-contrast tomosynthesis, 705–706 Operational amplifier, 665 Pareto surface, 683–684 Phase dispersion, 706 OPG, see Ortho pan tomography Paris system, 684 Phase encoding, 706–707 Optical density, 665–666 Parking position, 684 Phase image, 707 Optical distance indicator, 666 Partial Fourier imaging (PFI), 684–685 Phase

mapping, 707 Optical radiation hazard, 666 Partial parallel imaging (PPI), 685 Phase quadrature, 707 Optical transfer function, 666 Partial volume effect, 685 Phased array coil, 707–708 Optically stimulated luminescence, 666–667 Particle radiation, 686 Phased array transducer, 708 Optimal incident beam profile, 667 Particle therapy, 686 Phosphocreatine, 708 Optimisation, 667–668 Particle velocity, 686 Phosphodiesters (PDE), 708 Optimisation of, detector, 668 Partition coefficient, 686 Phosphomonoesters (PME), 708 Optocoupler, 668 Passive beam scattering, 686 Phosphor, 708–710 Ordered subset expectation maximum method, Passive device, 686–687 Phosphor layer, 710 668–669 Passive implant, 687 Phosphorescence, 710–711 Organ at risk (OAR), 669 Passive shielding, 687 Phosphorus, 711 Organ dose, 669 PAT, see Parallel acquisition technique Phosphorus-32 [32P], 711–712 Organic liquid scintillators, 669–670 Patch-field technique, 687 Phosphorus-33 [33P], 712 Organisational structure, 670 Path length, 687 Photic stimulation, 712 Orientation factor, 670 Patient position, 687 Photo peak, 712–713 Ortho pan tomography (OPG), 670 Patient radiation dose structured report Photoablative effects, 713 Orthogonal films, 670–671 (P-RDSR), 688 Photo-activation therapy, 713 Index 1051 Index Photobiological lamp safety, 713–714 Polarity effect, 728 Projectile, 741 Photocathode, 714 Polarity factor, 728–729 Prompt gamma, 741 Photocathode of photomultiplier tubes, 714 Polychromatic beam, 729 PROMs, see Patient-reported outcome Photoconductor, 714 Polycrystalline silicon (Si), 729 measures Photoelectric absorption, see Photoelectric Polyester in film base, see Film base Prone, 741 effect Polymer gel dosimetry, 730 Propagation, 741 Photoelectric effect, 714 Polymer gels, 730 Propagation-based imaging, 741–742 Photoelectric interaction, see Photoelectric Polymethyl methacrylate (PMMA), see Acrylic Propagation speed, see Speed of sound effect Polyvinylidene fluoride (PVDF), 754 Prophylactic irradiation, 742 Photoelectric relay, 715 Population inversion, 730 Proportional counter, 742–743 Photoelectron, 715 Porous medium, 730 Protective earth terminal, see Grounding Photographic detail, see Detail resolution Port film, 723 Protective grounding, see Grounding Photokeratitis (Eye), 715 Portal exit dosimetry, 730–731 Protocol, 744 Photomechanical effects, 715 Portal film digitisation, 731 Proton, 744 Photomultiplier (PM) tubes, 715–716 Portal image, 731–732 Proton arc therapy, 744–745 Photoretinitis (Eye), 716 Portal radiography, 732 Proton CT (pCT), 745 Photothermal effects, 716–717 Position-sensing photomultiplier tubes, 732 Proton density, 745 Photons, 717 Positive contrast media, 732–733 Proton radiography, 745 Photon beams, 717 Positive-ion cyclotron, 733 Proton therapy, 745 Photon fluence, 717 Positron decay, 733 Proximal, 745 Photon flux, 717–718 Positron emission tomography (PET), 733–734 Proximal inversion with a control for off- Photon scattering, 718 Post-processing, 734 resonance effects (PICORE), Photon(s): annihilation in positron decay, 718 Posterior, 734 745–746 Photon(s): interaction in matter, 718 Posterior enhancement, 734 Pseudo CT, 746 Photon(s): mean free path, 718 Posteroanterior (PA) projection, 735; see also Pseudoecho, 746 Photon(s): secondary, 718 Technique projection PSF, see Point spread function Photosensitivity, 718 Potential difference, 735 PSIF (a time reversed FISP), 746–747 Photostimulable phosphor plate, see Storage Potential energy, 735 PSWE, see Point shear wave elastography phosphor Power amplifier, 735 PTV, see Planning target volume Photostimulated luminescence, 718 Power breaker, see Circuit breaker Public exposure, 747 Physical penumbra, see Penumbra Power Doppler, 736 Pulsatile, see Pulsatility index Physical phantoms, 718–719 Power gain, see Power amplifier Pulsatility index (PI), 747 Physicochemical adsorption, 719 Power injector, 736 Pulse, 747–748 PI, see Pulsatility index Power spectrum, 736 Pulse average intensity (IPA), 748 PICORE, see Proximal inversion with a PPE, see Personal protective equipment Pulse duration, 748 control for off-resonance effects PPI, see Partial parallel imaging Pulse echo, 748 Picture Archiving and Communication System P-RDSR, see Patient radiation dose structured Pulse generator, 748 (PACS), 719 report Pulse inversion, 748–749 Piezoelectric crystal, 719 Preamplifier, 737 Pulse pileup, 749 Pincushion distortion, 719 Precession, 737 Pulse repetition frequency (PRF), see Pulse Pinhole collimator, 719–721 Precision, 737 repetition rate Pion therapy, 721 Pre-heating of cathode, 737 Pulse repetition period, see Pulse Piston, 721 Preparation (first trigger), 737 repetition rate Pitch, see Helical pitch Presampling MTF, 737–738 Pulse repetition rate, 749 Pixel, 721 Prescribed dose, 738 Pulse sequence, 749–751 Pixel value, 721–722 PRESS, see Point resolved surface coil Pulse sequence optimisation, 751 Plain film radiography, 722 spectroscopy Pulse shaping, 751 Planar imaging, 722 Pressure and temperature correction Pulsed cine, 751 Planning target volume (PTV), 722–723 factor, 738 Pulsed dose rate (PDR), 751–752 Plaque radiotherapy, 723 Pressure parameters, 738 Pulsed laser, see Laser output mode Plastic, 723 Pretargeting, 738–739 Pulsed mode, 752 Plates, deflection, see Deflection plates in PRF, see Pulse repetition rate Pulsed OSL readout, 752 cathode ray tubes Primary barrier, 739 Pulsed radiation, see Pulsed cine Platinum, 723–724 Primary collimator, 739 Pulsed ultrasound, 752 Plumbicon tube, 724 Primary colour, see Red, Green, Blue Pulsed wave Doppler, 752–753 PME, see Phosphomonoesters Primary display, see Digital display Pulse-height analysers (PHAs) for radiation PMMA (perspex, plexiglass, lucite), see Primary radiation, 739 detectors, 753–754 Perspex characteristics Primary standard, 739 Pulse-less generator, 754 PM tubes, see Photomultiplier (PM) tubes Primary tumour, 740 Pulse-pressure-squared integral, 754 PNS, see Peripheral nerve stimulation Pristine Bragg peak, 740 PVDF, see Polyvinylidene fluoride Pocket dosimeter, 724 Probability of cell survival, 740 PZT, see Lead zirconate titanate Point dose kernel, 724–725 Probability of complications, 740 Point resolved surface coil spectroscopy Procurement, 740 Q (PRESS), 725 Production of radiopharmaceuticals, 740 Point shear wave elastography (pSWE), 725 Production rate of radioactivity, see Activation Q factor, 755 Point source calculation, 726–727 formula Q-factor, 755 Point spread function (PSF), 727–728 Programmed radiographic technique, see Q-space (used in diffusion-MRI and Poiseuille’s law, 728 Automatic exposure control NMR), 755 Poisson distribution, 728 Progression-free survival, see Clinical trial Q-switching (Laser), 755 Poisson noise, 728 endpoints QALYs, see Quality-adjusted life years Polar coordinates, 728 Projected range, 740–741 QC, see Quality control Index 1052 Index QDE, see Detective quantum efficiency Radiation quality, 770 Radium, 783–784 QE, see Qualified expert Radiation safety instrument, 770 Radium substitute isotope, 784 Quadrature, see Phase quadrature Radiation safety officer (RSO), 770 Radon, 784–785 Quadrature artefact, 755 Radiation, scattered, 770 RAID technology, 785 Quadrature coil, 755–756 Radiation, secondary ionising, 770–771 RAKR, see Reference air kerma rate Quadrature detection, 756 Radiation shielding, 771 RAM memory, 785 Quadrature detector, 756–757 Radiation, ultraviolet, see Ultraviolet radiation Ramp converter, 785 Qualified expert (QE), 757 Radiation weighting factor, 771 Ramp filter, 785 Quality-adjusted life years (QALYs), 757–758 Radio waves, see also Electromagnetic energy Ramp time, 785–786 Quality assurance, 758–759 spectrum RANDO phantom, 786 Quality audit, 759 Radiation Protection of Patients (RPOP) Random coincidence, 786 Quality control, 759–760 website, 823–824 Random noise, see White noise Quality factor, 760 Radioactive decay, 771–772 Range, 786 Quality Index, 760–761 Radioactive materials, 772 Range compensator, 786 Quantitative imaging, 761 Radioactive series, see Parent–daughter decay Range energy relationship, see Electron Quantum detection efficiency (QDE), see Radioactive sources, 772 practical range Detective quantum efficiency Radioactive tracer, 772 Range modulation, 786–787 Quantum efficiency, 761 Radioactive waste, 772 Range shifter, 787 Quantum mottle, 761 Radiobiological models, 773 Range straggling, 787 Quantum noise, 761 Radiobiology, 772–773 Rapid acquisition relaxation enhancement Quantum number, 761–762 Radiochemical purity, 773–774 (RARE), 788 Quartz, 762 Radiochromic film, 774 Rare earth metals, 788 Quenching, 762 Radiofrequency (RF), 774 Rare earth screen, 788 Quench (quenching), 762 Radiofrequency absorption, see Specific Rarefaction, 788 QUIPSS-QUIPSS II-Q2TIPS, 762–763 absorption rate Ratemetre, 788 Radiofrequency heating, 774 Raw data, 788 R Radiofrequency screening, 774–775 Rayl, 788 Radiogenomics, 775 Rayleigh distribution, 788–789 RA, see Relative anisotropy Radiograph, 775 Rayleigh scattering, 789 Rad, see Radiation absorbed dose Radiographic accessories, 775 RBE, see Relative biological effectiveness Radial k-space sampling, 765 Radiographic contrast, 775 RC circuit, 789–790 Radiance, 765 Radiographic film dosimetry, 775–776 RC time constant, see RC circuit Radiant exposure, see Radiance Radiographic imaging chain, 776 RDSR, see Radiation Dose Structured Report Radiation, 765 Radiographic kV control, 776–777 Reaction time, 790 Radiation absorbed dose (Rad), 765 Radiographic mode, 777 Readout gradient, 790 Radiation, alpha, 765 Radiographic rating, 777 Readout period, 790 Radiation, beta, see Beta radiation Radiography, 777 Real-time imaging, 790 Radiation biology, 766 Radiography, digital, see Digital radiography Real-time portal imaging, 790–791 Radiation, bremsstrahlung, see Bremsstrahlung Radio-immunoconjugates, 777 Real-time tomography, 791 Radiation, Ĉerenkov, see Ĉerenkov radiation Radioisotope, 777 Receiver, 791–792 Radiation damage, 766 Radioisotope cameras, 777–778 Receiver coil, 792 Radiation detection systems, 766–767 Radioisotope scanner, 778 Receiver operating characteristic (ROC), Radiation dose, 767 Radioisotope scanner collimator, 778 792–793 Radiation Dose Structured Report Radioisotope scanner collimator line source Receptor targeting, 793 (RDSR), 767 response, 778 Recoil electron, 793 Radiation dosimetry, see Dosimetry Radiological technologist, see Radiographer Recombination correction, 793 Radiation, electromagnetic, 767 Radiologist, see Diagnostic radiology Recombination effect, 793 Radiation exposure, see Exposure Radiology information system (RIS), 778 Recombination factor, see Recombination Radiation field, 767 Radiolucent, 779 correction Radiation force, 768 Radiolysis, 779 Reconstruction kernels, 793–794 Radiation force balance, see Force balance Radiometer, light, 779 Recovery coefficient (RC) in emission CT, 794 Radiation, gamma, see Gamma radiation Radiomics, 779–780 Rectangular FOV, 794 Radiation hazard, 768 Radionuclide generators, 780 Rectangular pulse, 794 Radiation-induced secondary Radionuclide imaging, see Nuclear medicine Rectification, see Rectifier malignancies, 768 imaging Rectification, full-wave, see Rectifier Radiation, infrared, see Infrared radiation Radionuclide production, 780 Rectification, half-wave, see Rectifier Radiation, ionising, see Ionising radiation Radionuclide purity, 780–781 Rectifier, 795 Radiation isocentre, 768 Radionuclide therapy, 781 Rectilinear scanner, 795 Radiation monitoring, 768 Radionuclide uptake in tumour cells, 781 Red, Green, Blue (RGB), 795–796 Radiation, nuclear, 768 Radionuclides, 781 Redistribution, 796 Radiation, particle, see Particle radiation Radionuclides in radiotherapy, 781 Reducing agent, 796 Radiation, penetrating, see Penetrating Radiopacity, 782 Reference air kerma rate (RAKR), 796 radiation Radiopaque markers, 782 Reference depth, 796–797 Radiation, positron, see Positron decay Radiopharmaceuticals, 782 Reference ionisation chamber, 797 Radiation pressure, 769 Radiopharmacy, 782 Reference isodose, 797 Radiation, primary, see Primary radiation Radiosensitisers, 783 Reference levels, see Diagnostic reference level Radiation protection, 769 Radiosensitivity, 782–783 Reference volume, 798 Radiation protection adviser (RPA), 769 Radiosurgery, see Stereotactic radiosurgery Reflection, 798 Radiation protection officer (RPO), 769 Radiotherapy, 783 Reflection coefficient, 798–799 Radiation protection supervisor (RPS), Radiowaves, 783, see also Electromagnetic Refocusing, 799 769–770 energy spectrum Refraction, 799 Index 1053 Index Refresh rate, monitor, 800 Risk management, 819 Scattering, Thomson, see Thomson scattering Region of interest (ROI), 800 Risk perception, 819 Scattering cross section, 834 Registration, 800–801 Road mapping, 819 Scene-based registration, 834 Regulatory authority, 801 Roam and zoom, 819 Schlieren, 834 Reject film analysis, 801 Robotic linac, 819–820 Scintillation camera, 834–835 Rejection method, 801 ROC, see Receiver operating characteristic Scintillation detector, 835 Relative anisotropy (RA), 801 Rods, retina, 820 Scintillator, 835–837 Relative biological effectiveness (RBE), Roentgen (R), 820 Scoring, 837 801–803 ROI, see Region of interest Scout view, 837 Relative electron density, 803 Roos chamber, 820 SCR, see Silicon-controlled rectifiers Relative humidity, 803 Root mean square (RMS) voltage, 820 Screen film, 837 Relative risk, 803 Rose model, 820–821 Screen-film contact, see Film-screen contact Relaxation, 803–804 Rotating anode, 821–822 Screen selection, 837 Relaxation rate, 804 Rotating frame, 822–823 Screen speed, 837–838 Relaxation time, 804–805 Rotational 3-D scanning, 823 Screen unsharpness, 838 Relaxivity, 805 Rotor, 823 SCRs, see Silicon-controlled rectifiers Relaxometry, 805 RPA, see Radiation protection adviser SDD, see Source diaphragm distance Relay, 805–806 RPO, see Radiation protection officer SEAFOMP, see South-East Asia Federation of Remote afterloading, see Remote RPS, see Radiation protection supervisor Organizations for Medical Physics afterloading unit RSO, see Radiation safety officer Sealed source, 838 Remote afterloading unit, 806 Rubidium-82, 823 Secondary barrier, 838 Reorientation, 806–807 Rural centre, 823 Secondary circuit, 838 Reoxygenation, 807 Rural hospitals, 823 Secondary collimator, 838–839 Repair, 807–808 Secondary electrons, 839 Repair of radiation damage, 808 S Secondary electron spectrum, 839 Repetition time (TR), 808–809 Secondary ionisation, 839 Repopulation, 809–810 SABR, see Stereotactic ablative radiation Secondary ionising radiation, 839 Resistance, electrical, 810 therapy Secondary malignancies, 840 Resistance index, 810–811 Safelight filter, see Darkroom Secondary radiation, see Radiation, secondary Resistive magnet, 811 Safety culture (Radiation safety culture), 825 ionising Resistor, see Resistance, electrical Safety in Radiation Oncology (SAFRON) Secondary standard, 840 Resolution, 811–812 system, 825 Sector image, 840 Resonant frequency, 812 Sagittal plane, 825 Sector integration, 840 Respiratory gating, 812–813 Samarium-153, 825–826 Secular equilibrium, 840 Restricted area, 813 Sample volume, 826 Segmentation, 840–841 Restricted CEMA, 813 Sample volume effects in well-counter Segmented imaging, 841 Restricted collisional mass stopping detectors, 826–827 Selective excitation slice selection, see Slice power, 813 Sampling theorem, 827 selection Restricted stopping power, 813 SAR, see Scatter air ratio; Specific Selenium detector, 841–842 Retention fraction, 813 absorption rate Self-absorption, 842 Retina, 813–814 Saturation, 827 Self-shielded cyclotron, 842 Retinal hazard region, 814 Saturation activity, 827–829 Semiconductor detector, 842–843 Retrospective ECG gating, 814 Saturation curve, 829 Semiconductors, 843 Reverberation, 814 Saturation voltage, 829 Semiflex chamber, 843 Reynolds number, 814–815 Sawtooth voltage, 829 Sensitivity, 843–844 RF, see Radiofrequency SBD, see Source block distance Sensitivity profile, 844 RF coil, 815 SBRT, see Stereotactic body radiotherapy Sensitometer, 844

RF echo, 815 Scan converter, 829 Sensitometry, see Sensitometer RF pulse, 815 Scan line, 829 Septal penetration, 844 RF uniformity, 816 Scanned beams, 829–830 Septum, 844 Rf value, 816 Scan projection radiograph (SPR), 830 Sequestration targetting, 844 RGB, see Red, Green, Blue SCAs, see Single-channel analysers Serial exposures, 844 Rhenium, 816 Scatter, 830 Serial organs, 844–845 Rhenium-186-hydroxy-ethylidene Scatter air ratio (SAR), 830–831 Servobrake, see Servomotor diphosphonate, 816–817 Scatter coincidences, 831 Servomotor, 845 Rheostat, see Resistance, electrical Scatter correction, 831–832 Set-up error, 845–846 Rigid stem chamber, 817 Scatter correction in PET, 832 Set-up margin, 846 Ring artefact, 817–818 Scatter correction in SPECT, 832 Severity, 846 Ring down, 818 Scatter factor, 832–833 SFO, see Single field optimisation Ripple, see Voltage waveform Scatter phantom ratio (SPR), 833 SFUD, see Single field uniform dose Ripple factor, 818 Scatter subtraction, 833 SGRT, see Surface guided radiation therapy RIS, see Radiology information system Scatter to primary ratio (SPR), 833 Shading artefact, 846 Rise time, 818 Scattered radiation, 833 Shadowing, 846–847 RIS/HIS, see Hospital information systems; Scatterer, 823–834 Sharpness, 847 Radiology information system Scattering, classic (coherent), see Coherent Shear wave elastography, 847 Risk assessment, 818 scattering Shear waves, 847 Risk coefficient, 818 Scattering, coherent or Rayleigh, see Coherent Shell model of nucleus, 847 Risk communication, 818–819 scattering Shielded gradients, 847 Risk Group 1, 2, 3 (Photobiological optical Scattering, incoherent, see Incoherent Shim coils, 847–848 source), see Photobiological lamp scattering Shimming, 848 safety Scattering, Rayleigh, see Rayleigh scattering Shock absorber, 848 Index 1054 Index Shock waves, 848 Solid state rectifier, see Rectifier Spin-spin coupling, 886 Short circuit, 848 Solid water phantom, 870 Spin-spin relaxation, 886–887 Shortest exposure time, see Exposure time Solution, 870 Spiral (helical) interpolation, 887 Short tau inversion recovery (STIR), 848 Solvent, 870 Spiral imaging, 887–888 Shrapnel, 849–850 Sonogram, 870 Spiral sampling, 888–899 Shunt, 850 Sonography, 870–871 Spiral scanning, 889 Shutter, see Cineradiography Sound attenuation, see Attenuation Spoiled gradient recalled acquisition in the SI, see Systeme internationale Source axis distance (SAD), 871 steady state (SPGR), 889 SID, see Source-to-image distance Source block distance (SBD), 871 Spontaneous discharge, 889 Side effects, 850 Source coordinates, 871 Spontaneous emission, 889 Side lobes, 850–851 Source diaphragm distance (SDD), 871 Spot film camera, 889–890 Sievert (Sv), 851 Source loading in brachytherapy, 871 Spot size, 890 Sigmoid dose–response curve, 851–852 Source localisation, 872 Spot spacing, 890 Signal aliasing, 852 Source models, 872 Spot test, 891 Signal amplification technique (SAT) in PET, Source-skin distance (SSD), see Source SPR, see Scan projection radiograph; see Photomultiplier (PM) tubes surface distance Scatter phantom ratio; Scatter to Signal processor, 852 Source strength (brachytherapy), 872–873 primary ratio Signal-to-noise ratio (SNR), 852–853 Source-surface distance (SSD), 873 Sprawls Resources, 892 Silicon, 853 Source-to-image distance (SID), 873 Spread-out Bragg peak (SOBP), 892 Silicon diode detector, 853–854 South-East Asia Federation of Organizations Spurious coincidence, 892 Silicon-controlled rectifiers (SCRs), 854–855 for Medical Physics Spurious echoes, 892–893 Silver, 855 (SEAFOMP), 838 Square wave oscillation, see Saw-tooth voltage Silver bromide, 855 Space-charge effect, 873 Sr-89-strontium chloride [MetastronTM], 893 Simulated annealing algorithm, 855 Spatial average intensity I(SA), 873 SSD, see Source-surface distance Simulator, 856 Spatial compounding, 873–874 SSFP, see Steady state free precession Simultaneous multi-slice (SMS) excitation, Spatial filtering, 874 Stabilisation, 893 856–857 Spatial frequency, 874 Stabilised amorphous selenium (a-Se), 893 Sinc filter, 857 Spatial linearity, see Gradient linearity Stabiliser, see Stabilisation Sinc function, 857 Spatial peak intensity ISP, 874 Stable nuclei, 894 Single-channel analysers (SCAs), 857 Spatial pulse length, 874 Stakeholder involvement (or Stakeholder Single element transducer, 857 Spatial resolution, 874–875 engagement), 894 Single exposure, 857 Spatial resolution in a scintillation camera, Standard man, 894 Single field optimisation (SFO), 857 875–876 Standards, 894–895 Single field uniform dose (SFUD), see Single Spatial resolution PET, 876–877 Standard uptake value (SUV), 895 field optimisation Spatio-temporal contrast sensitivity, 877 Standby position, see Parking position Single phase generator, 858 Specific absorption rate (SAR), 877–878 Standing wave, see Wave guide Single phase transformer, see Transformer Specific activity, 878 Stannous chloride (Sn2+C12), 895 Single photon emission computed tomography Specifications of a medical device, 878 Star pattern, 895 (SPECT), 858–859 Speckle, 878–879 Starling equation, 895–896 Single room particle therapy systems, 859 Speckle decorrelation, 879 Starter, see Starting device Single tank generator, see Mono-block Speckle reduction, 879 Starting device, 896 generator SPECT, see Single photon emission computed Static electricity, 896 Single voxel spectroscopy, 859 tomography Static field, 896–897 Sinogram, 859–860 SPECT clinical applications, 879 Stationary anode, 897–898 Skin cancer, 860 SPECT-CT scanner, 880 Stationary grid, 898 Skin dose, 860 Spectra, 880 Stator, 898 Skin reference marks, 860 Spectral analysis, 880 Steady state, 898 Skin sparing, 860 Spectral broadening, 880–881 Steady state condition in tracer kinetic, Slant-hole collimator, 861 Spectral display, see Sonogram 898–899 Slew rate, 861 Spectral matching, 881 Steady state free precession (SSFP), 899 Slice position, 861 Spectral width, 881 STEAM, see Stimulated echo acquisition Slice profile, 861–862 Spectroradiometer, 881–882 mode Slice selection, 862–863 Spectroscopic imaging, see Chemical shift Steel, 899 Slice selective, 863 imaging Step wedge, 899 Slice sensitivity, 863 Spectrum, continuous, 882 Stepping motor, 899–900 Slice thickness, 863–865 Spectrum, discrete, 882 Step-down transformer, see Transformer Slice warp, 865 Specular reflection, 882 Step-up transformer, see Transformer Slip ring technology, 865–866 Speed displacement artefact, 882–883 Stereotactic ablative radiation therapy Sm-153-EDTMP [Lexidronam], 866 Speed of film, 883 (SABR), 900 Small animal CT, 867 Speed of sound, 883 Stereotactic frame, 901 Small-animal SPECT imaging, 867 Spencer Attix theory, 883–884 Stereotactic radiosurgery, 901 Small field dosimetry, 867 SPGR, see Spoiled gradient recalled Stimulated acoustic emission, 901 Snell’s law, 860–867 acquisition in the steady state Stimulated echo, 901 SNR, see Signal-to-noise ratio Spikes, 884 Stimulated echo acquisition mode SOBP, see Spread-out Bragg peak Spin, 884–885 (STEAM), 902 Sodium, 868 Spin density, 885 STIR, see Short tau inversion recovery Soft x-ray tomography, 868 Spin echo, 885 Stochastic effects, 902–903 Software phantom, 868–869 Spin temperature, 885 Stoichiometric calibration, 903 Solar simulator, 869 Spin warp imaging, 885–886 Stopping power, 903–904 Solenoid, 870 Spine coil, 886 Storage phosphor, 904–905 Solid state detectors, 870 Spin-lattice relaxation, 886 Strain imaging, 905 Index 1055 Index Straton, 906 Target localisation, 920 TE (echo time), see Echo time Stray magnetic field, 906 Target of x-ray tube, 921–922 Technetium, 933 Streamline, 906 Target organ, 920 Technetium-99m [99Tcm], 933–934 Stress echocardiography, 906 Target volume, 920–921 Technetium generator, 934 Stripping foil, 906 Targeted alpha therapy, 922 Technique projections, 934 Strontium-82, 906–907 Tc-99m; Ceretec, 922 Techniques to improve radionuclide uptake in Structured noise, 907 Tc-99m SestaMIBI (methoxyisobutyl tumour cells, 934–935 Subject contrast, 907 isonitrile), 923 Technologist, 935 Subtense angle, 907 Tc-99m tetrofosmin, 923 Teleradiology, 935 Subtraction, see Digital subtraction Tc-99m-albumin (HSA), 923–924 Teletherapy, 935 angiography Tc-99m-albumin macroaggregates Temperature coefficient, see Pressure and Summed scoring, 907–908 (MAA), 924 temperature correction factor Superconducting magnet, 908 Tc-99m-albumin microcolloids, 924 Temperature control, 935–936 Superconducting material, see Tc-99m albumin microspheres (HAM), Temperature correction, see Pressure and Superconducting magnet 922–923 temperature correction factor Superconductivity, 908 Tc-99m-albumin millimicrospheres, 924–925 Temperature probe, 936 Superficial radiation, 908 Tc-99m-albumin nanocolloids, 925 Temperature sensor, see Temperature probe Superficial therapy, 908 Tc-99m-arcitumomab, 925–926 Temporal filtering, 936 Superior (cephalic), 909 Tc-99m-diphosphonates (DPD, HDP, MDP, Temporal (instantaneous) peak intensity Superorthicon, 909 HEDSPA), 926 ITP/IIP, 936 Superparamagnetic iron oxide, 909 Tc-99m-DMSA (dimercaptosuccinic acid), 926 Temporal resolution, 936 Superparamagnetic particles, 909 Tc-99m-DTPA, 926–927 Temporary implant, 936–937 Supervised area, 909–910 Tc-99m-ECD, 927–928 Tendering, 937–938 Supine, see Patient position Tc-99m-EC (ethylene dicysteine), 927 Tensor, 938 Suppressing filter, 910 Tc-99m-HMPAO, 928 Tenth value layer (TVL), 938 Surface coil, 910 Tc-99m-IDA (iminodiacetic acid), 928 Terbium, 938 Surface contours, 910 Tc-99m-labelled bone imaging agents, TERMA, 938 Surface dose, 910 see Tc-99m-Diphosphonates; Terminal voltage, 938 Surface guided radiation therapy (SGRT), 911 Tc-99m-Pyrophosphate Tertiary collimator, 938–939 Surface wave, 911 Tc-99m-labelled colloids, see Tc-99m- Tesla, 939 Survey meter, 911 albumin microcolloids; Tc-99m- Test object, see Physical phantoms Surviving fraction, 911 albumin millimicrospheres; Test voltage, 939 Susceptibility, 911–912 Tc-99m-albumin nanocolloids; Texture, 939 Susceptibility-weighted imaging (SWI) Tc-99m-labelled microcolloids; TFD, see Target film distance MRI, 912 Tc-99m-labelled nanocolloids; TFT, see Thin film technology Swept gain, 912 Tc-99m-rhenium sulphide colloids; TGSE, see Turbo gradient spin echo SWI, see Susceptibility-weighted imaging Tc-99m-tin colloids Thallium bromide, 939 (SWI) MRI Tc-99m-labelled erythrocytes, 929 Therapeutic effect, 940 Switch on, 912 Tc-99m-labelled human serum albumin, see Therapeutic efficacy, 940 Symmetric energy window, 912 Tc-99m-albumin; Tc-99malbumin Thermal index (TI), 940–941 Synchrocyclotrons, 913 macroaggregates; Tc-99m-albumin Thermal light hazard, 941 Synchronisation, 913 microspheres Thermal neutrons, 941 Synchrotron for particle therapy, 913 Tc-99m-labelled leukocytes, 929 Thermal printing, 941 Synthesised 2D mammography, 913–914 Tc-99m-labelled microcolloids, see Thermal stress, 941 Syringe shield, 914 Tc-99malbumin microcolloids; Thermionic emission, 942 Systeme internationale (SI), 916 Tc-99mrhenium sulphide colloids; Thermoluminescent dosimeter (TLD), Systemic chemotherapy, 915 Tc-99m-tin colloids 942–943 System of work, 914–915 Tc-99m-labelled monoclonal antibodies, see Thermostat, 943 System resolution in a scintillation camera, Tc-99m-arcitumomab Thimble chamber, 943–945 915–916 Tc-99m-labelled nanocolloids, see Thimble ionisation chamber, see Thimble Tc-99malbumin nanocolloids; chamber T Tc-99mrhenium sulphide Thin film technology (TFT), 945 nanocolloids Thin-layer chromatography (TLC), 946 T1, see Relaxation time Tc-99m-labelled red blood cells (RBC), see Thiosulphate in film processing, 946 T1 rho (T1ρ), 917 Tc-99m-labelled erythrocytes Thomson scattering, 946 T1-weighted, 917 Tc-99m-labelled white blood cells, see Thorium, 946–947 T2, 917 Tc-99mlabelled leukocytes Three-dimensional (3D) conformal dose T2-shine through, 917–918 Tc-99m-MAG3 (mercaptoacetyltriglycine), 930 distribution, 947 T2-weighted, 918–919 Tc-99m MIBI, see Tc-99m SestaMIBI Three-dimensional scatter convolution, 947 Table top, 919 Tc-99m-Myoview, see Tc-99m-tetrofosmin Three-dimensional ultrasound imaging (3D TADR, see Time-averaged dose rate Tc-99m-pyrophosphate (PYP), 930 imaging), 947 Tangent fields, 919 Tc-99m rhenium sulphide colloids, 931 Three-phase AC, 948 Tantalum, 919–920 Tc-99m-rhenium sulphide nanocolloids, 931 Three-phase generator, 948–949 Tantalum filter, 920 Tc-99m-sodium pertechnetate, 931–932 Three-phase rectifier, 949 Taper, see Fibre optic taper Tc-99m-Sulesomab, 932 Three-phase transformer, 949 TAR, see Tissue air ratio Tc-99m-sulphur colloids, 932 Threshold contrast detail detectability Target angle, see Anode angle Tc-99m-tin colloids, 932–933 (TCDD), 949–950 Target cooling, see Anode-cooling curve TCDD, see Threshold contrast detail Threshold detection, 950 Target dose, 920 detectability Threshold energy, see Threshold detection Target dose distribution, 920 TCP, see Tumour control probability Threshold value, see Threshold detection Target film distance (TFD), 920 TD (time delay), 933 Thulium, 950–951 Index 1056 Index Thyratron, 951 Transformer winding, see Transformer Ultrasmall particles of iron oxide (USPIO), 985 Thyroid radioiodine uptake measurements, 951 Transient charged particle equilibrium, 969 Ultrasonic field, 987 TI, see Inversion time; Thermal index Transient elastography, 970 Ultrasonic output, 987 Tiling of digital detector, 951 Transient equilibrium, 970 Ultrasonography, 987–988 Tilting table, 951 Transit time, see Mean transit time Ultrasound, 988 Time activity curve, 951 Transmission coefficient, 970–971 Ultrasound, Doppler, see Doppler ultrasound Time average intensity (ITA), 951–952 Transmission ionisation chamber, 971 Ultrasound, pulsed, see Pulsed ultrasound Time-averaged dose rate (TADR), 952 Transmit coil, 971 Ultrasound-guided brachytherapy, 988 Time-averaged dose rate (TADR2000), 952 Transmitter, 971 Ultrasound real time, 988 Time constant, 952 Transmutations of elements in radioactive Ultrasound safety, 988 Time delay circuit, 952–953 decay, 971 Ultraviolet light (NIR), see Ultraviolet Time delay integration, 953 Transparency, see Opacity radiation Time distance shielding (TDS rules), 953 Transport index, 971–972 Ultraviolet radiation, 988–989 Time gain compensation, see Depth gain Transrectal transducers, 972 Unblanking, 989 compensation Transversal magnetisation, 972 Uncontrolled area, 989 Time interval difference imaging, 953 Transversal plane, see Anatomical body planes Underdevelopment, 989 Time-of-flight techniques in PET, see Transverse wave, 972–973 Underexposure, 989–990 Time-of-flight Travelling wave, see Wave guide Undersampling, 990 Time-of-flight (TOF), 953–954 Tray factor, 973 Undertable cassette carriage, 990 Time of repetition, see Repetition time Treated volume, 973 Undertable fluoroscopy, 991 Timer, 954–955 Treatment head, 973–974 Undertable radiography, 991 Tin, 955 Treatment optimisation, 974 Unenhanced image, 991 Tissue, 955 Treatment parameters, 974 Ungrounded, 991 Tissue air ratio (TAR), 955–956 Treatment phase, 974 Uniformity, 991–992 Tissue compensation, 956 Treatment plan evaluation, 974 Unipolar output, 992 Tissue contrast, see Chest radiography Treatment plan normalisation, 974 United Nations Scientific Committee on Tissue deficit, 956 Treatment planning system, 974–975 the Effects of Atomic Radiation Tissue equivalent material, 956 Treatment planning systems (brachytherapy), (UNSCEAR), 992–993 Tissue heterogeneity, see Heterogeneity 975–976 Universal wedge, 993 Tissue maximum ratio (TMR), 956 Treatment position, 976 Unsealed source, 993 Tissue phantom ratio (TPR), 956–957 Treatment room, 976 Unsharp masking, 993–994 Tissue substitute, 957 Treatment time, 976 Unsharpness, 994 Tissie substitute material, 957 Treatment vault, 976–977 Use factor, 994 Tissue weighting factor, 957 Treatment verification, 977 Useful beam, 994 TLC, see Thin-layer chromatography Trendelenburg position, 977 Useful field of view (UFOV), 994 TLD, see Thermoluminescent dosimeter Trigger delay, 977 User interface, 994 TMR, see Tissue maximum ratio Triggering, 977 US guidance, 994 TOF, see Time-of-flight Triode tube, 977 USPIO,

see Ultrasmall Particles of Iron Oxide Toggle switch, 958 Trivial light source, 977–978 UTE, see Ultrashort echo-time Tolerance, 958–959 True coincidences, 978 UV dosimetry, phototherapy, 995 Tomography, 959 True negative, 978 UV light hazard, 995 Tomosynthesis, 959–560 True non-contrast (TNC) image, 978 UV radiation, see Ultraviolet radiation Tomotherapy, 960–961 True positive, see True negative Tongue and groove leakage, 961–962 Tube current (mA), 978–979 V Topogram, 962 Tube filament current, see Filament current Total body irradiation, 962 Tube housing, see X-Ray tube housing Vacuum, 997 Total body potassium, 962 Tube kilovoltage (kV), 979 Valence band, 997 Total-body PET, 962 Tube load, 979 Valve tube rectifier, 997 Total body protein, 962–963 Tube load time, 980 Van Cittert–Zernike theorem, 997 Total body water, 963 Tube rating charts, 980 Variable-aperture beam restrictor, see Beam Total brightness gain, 963 Tube stand, 980 restrictor Total scatter factor, 963 Tumour antivascular alpha therapy, 980–981 Variable thickness transducer, see Slice Total skin irradiation, 963 Tumour control, 981 thickness TPR, see Tissue phantom ratio Tumour control probability (TCP), 981 Variable transformer, 997 TR, see Repetition time Tungsten, 981–982 Variance reduction techniques, 997–998 Trace (of the diffusion tensor), 964 Turbo factor, see Echo train length Vector array, 998 Tracer, 964 Turbo gradient spin echo (TGSE), 982 Veiling glare and contrast, 999 Tracer delivery, 964–965 Turbo spin echo, 982 Velocity encoding (VENC), 999 Tracer flux between compartments, 965 Turbulence, see Turbulent flow Velocity mapping, 999–1000 Tracer kinetic modelling, 965 Turbulent flow, 982 VENC, see Velocity encoding Tracer transport, 965–966 TVL, see Tenth value layer Venetian blind artefact, 1000 Track structure, 966 Twinkle artefact, 982–983 VERT training, 1000 Tracking system, 966 Two-day protocol, 983 VGA, see Visual grading analysis Tractography, 966–967 Two-dimensional shear wave elastography (2D VGC, see Visual grading characteristics Training, 967 SWE), 983–984 Video camera tube, 1000–1001 Transducer, 967–968 Video detector, 1001 Transducer, linear array, see Linear array U Video recorder, 1001–1002 Transformation ratio, see Transformer Video signal, 1002 Transformer, 968–969 Ultra-fine focus, 985 Vidicon tube, 1002–1003 Transformer core, 969 Ultra-high field (UHF) MRI, 985–987 Viewing angle, 1003 Transformer oil, 969 Ultrashort echo-time (UTE), 987 Viewing station, 1003 Index 1057 Index Vignetting, 1004 Water calorimeter, 1014–1015 X Virtual learning environment (VLE), Water cooling, 1015 1004–1005 Water equivalent area, 1015 Xenon, 1027 Virtual Library AAPM, 1005 Water equivalent path length, 1015 Xenon-133, 1027 Virtual non-contrast (VNC) image, 1005 Water suppression, 1015–1016 Xeroradiography, 1027 Virtual reality, see Augmented reality Water tank, 1016 X-ray, 1027 Virtual source position, 1005 Watt, 1016 X-ray beam filtration, 1027 Viscosity, 1005 Wave equation, 1016 X-ray exposure, 1027 Visible light, 1005–1006 Waveguide, 1016–1017 X-ray film, 1028 Visual acuity, 1006 Wavelength, 1017 X-ray film scanner, 1028 Visual grading analysis (VGA), 1006 Wax, 1017 X-ray generator, 1028 Visual grading characteristics (VGC), Weber, 1017 X-ray image intensifier, see Image Intensifier 1006–1007 Wedge, 1017–1018 X-ray phase contrast (PhC) imaging, see Phase Visual perception, 1007 Wedge angle, 1018–1019 contrast imaging VLE, see Virtual learning environment Wedge field, see Wedge X-ray table exposure chamber, 1028 VMAT, see Volume-modulated arc therapy Wedge filter, see Wedge X-ray television, 1028–1029 VOI, see Volume of interest Wedge transmission factor, 1019 X-ray tube, 1029 Voltage, 1007 Wehnelt electrode, 1019 X-ray tube assembly, 1029 Voltage divider, 1007 Weighting Factor, 1019 X-ray tube housing, 1029–1030 Voltage drop, 1007 Well-counter detector, 1019–1020 Voltage limiter, 1007–1008 Well-counter detector efficiency, 1020 Y Voltage range, 1008 Well-type ion chamber, 1020–1021 Voltage regulation, 1008 WFUMB, 1021 Y-90-labelled ibritumomab tiuxetan Voltage stabiliser, see Stabilisation White noise, 1021 (Zevalin®), 1031 Voltage supply, 1008 WHO, see World Health Organization Y-90-Zevalin®, see Y-90-labelled Voltage waveform, 1008–1009 Whole-body dosimeters, 1021–1022 ibritumomab tiuxetan Voltmeter, 1009–1010 Whole-body magnet, 1022 Yield, fluorescent, see Fluorescent yield Volume-modulated arc therapy (VMAT), 1010 Whole-body radiation counters, 1022 Young’s modulus, 1031 Volume of interest (VOI), 1010 Wiener spectrum, see Noise power spectrum Yttrium, 1031–1032 Volumetric-intensity-modulated arc therapy, Yttrium-90 [90 Wilkinson converter, see Analogue to digital Y], 1032 1010–1011 converter Y voltage; star voltage, 1032–1033 Volumetric prescribing (brachytherapy), 1011 Window, 1022–1023 Voxel, 1011 Window fraction, 1023 Z Window function, 1023–1024 W Window width in single-channel Z number, see Atomic number analyser, 1024 Zebra stripe artefact, 1035 Wall filter, 1013 Wipe test, 1024 Zener diode, 1035 Warm-up, 1013 Wire cross section, 1024 Zero biased detector, 1035 Warm-up time, see Warm-up Wisconsin test cassette, 1024 Zero-crossing detector, 1035 Warning lights, 1013 Workload, 1024 Zero filling, 1035 Warning sign, 1013 Workload factor (W), 1024–1025 Zinc cadmium sulphide, 1035 Washing in film processing, 1013 Workstation, 1025 Zinc cadmium telluride, 1035 Waste, radioactive, see Radioactive waste World Health Organization (WHO), Zipper artefact, 1036 Waste disposal, 1013–1014 1025–1026 Zonography, 1036 Water, 1014 Wrap-around artefact, 1025 z-Sensitivity, 1036

Bacteria and Cancer Abdul Arif Khan Editor Bacteria and Cancer Editor Abdul Arif Khan Microbiology Unit Department of Pharmaceutics College of Pharmacy King Saud University Riyadh, Saudi Arabia abdularifkhan@gmail.com ISBN 978-94-007-2584-3 e-ISBN 978-94-007-2585-0 DOI 10.1007/978-94-007-2585-0 Springer Dordrecht Heidelberg London New York Library of Congress Control Number: 2011944981 © Springer Science+Business Media B.V. 2012 No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfi lming, recording or otherwise, without written permission from the Publisher, with the exception of any material supplied specifi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Contents 1 Epidemiology of the Association Between Bacterial Infections and Cancer . 1 Christine P.J. Caygill and Piers A.C. Gatenby 2 Gastric Cancer and Helicobacter pylori . 25 Amedeo Amedei and Mario M. D’Elios 3 Streptococcus bovis and Colorectal Cancer . 61 Harold Tjalsma, Annemarie Boleij, and Ikuko Kato 4 Chlamydial Disease: A Crossroad Between Chronic Infection and Development of Cancer . 79 Carlo Contini and Silva Seraceni 5 Salmonella typhi and Gallbladder Cancer . 117 Catterina Ferreccio 6 Ocular Adnexal Lymphoma of MALT-Type and Its Association with Chlamydophila psittaci Infection . 139 Andrés J.M. Ferreri, Riccardo Dolcetti, Silvia Govi, and Maurilio Ponzoni 7 Possible Strategies of Bacterial Involvement in Cancer Development . 165 Puneet, Gopal Nath, and V.K. Shukla 8 Bacteria as a Therapeutic Approach in Cancer Therapy . 185 Sazal Patyar, Ajay Prakash, and Bikash Medhi 9 Targeting Cancer with Amino-Acid Auxotroph Salmonella typhimurium A1-R . 209 Robert M. Hoffman v vi Contents 10 Bacterial Asparaginase: A Potential Antineoplastic Agent for Treatment of Acute Lymphoblastic Leukemia . 225 Abhinav Shrivastava, Abdul Arif Khan, S.K. Jain, and P.K. Singhal 11 Can Bacteria Evolve Anticancer Phenotypes? . 245 Navya Devineni, Reshma Maredia, and Tao Weitao 12 Management of Bacterial Infectious Complications in Cancer Patients . 259 Kenneth V.I. Rolston Index . 275 Chapter 1 Epidemiology of the Association Between Bacterial Infections and Cancer Christine P. J. Caygill and Piers A. C. Gatenby Abstract The role of infectious agents such as bacteria, viruses, fungi etc. has been of interest for many years. Many studies have linked chronic bacterial infection with subsequent development of cancer at a number of different sites in the body. Most cancers have a multifactorial aetiology with a number of different steps between the normal and the malignant cell. One example of this is stomach cancer where it has been postulated that bacteria play a role at a number of stages but will also be true of cancers at other sites. This chapter summarises those situations where cancers occur as a possible result of bacterial infection and covers oesophageal, stomach, colorectal, gallbladder, pancreatic, bladder and lung cancer. Keywords Bacteria • Bacterial infections • Cancer • Epidemiology • Esophagus • Stomach • Colon • Rectum • Gallbladder • Pancreas • Bladder • Lung • Review • Cancer prevention • Infection 1.1 Introduction It has been postulated that over 80% of cancers are caused by environmental factors (Higginson 1 968 ) many of which factors are non-infectious such as diet and exposure to radiation. However the number of cancers caused by infectious agents is likely to rise with further research; for example until recently, it was thought that the acidic conditions of the stomach resulted in a sterile environment whereas in relatively C. P. J. Caygill (*) • P. A. C. Gatenby UK Barrett’s Oesophagus Registry, UCL Division of Surgery and Interventional Science , Royal Free Hospital , London NW3 2PF , UK e-mail: ccaygill@medsch.ucl.ac.uk A.A. Khan (ed.), Bacteria and Cancer, DOI 10.1007/978-94-007-2585-0_1, 1 © Springer Science+Business Media B.V. 2012 2 C.P.J. Caygill and P.A.C. Gatenby recent times one of the most important infectious agents found to increase the risk of cancer, H elicobacter pylori was identifi ed (Eslick 2 010 ) . Currently, more than 20% of cancer have been postulated to be linked to infectious agents (zur Hausen 2009 ) . Of these, the majority of the causative agents are viruses, which make up nearly two thirds of the infectious causes (human papilloma virus linked to squamous cell carcinoma of the ano-genital region and nasopharynx, Epstein Barr virus linked to Burkitt’s lymphoma and hepatitis B and C viruses linked to hepatocellular carcinoma) (zur Hausen 2 009 ) . Smaller numbers of tumours are related to infections from human herpes virus, liver fl ukes and schistosomes (Parkin 2 006 ) . Additionally, immuno-suppression caused iatrogenically, in patients with autoimmune disease and organ transplants, but also by HIV and HTLV results in higher rates of Kaposi’s sarcoma, lip, vulval and penile cancers as well as non-Hodgkin’s lymphoma compared to non-immuno-compromised subjects. Rates of salivary gland, eye, tongue, thyroid and cervical cancer are also higher than in non immuno-compromised controls (Ruprecht et al. 2 008 ) . Overall, if the infectious causes of cancer were prevented there would be 26.3% fewer cancers in developing countries and 7.7% in developed countries (Parkin 2 006 ) . The major bacterial cause of human cancer is H elicobacter pylori . This organism was classifi ed as being carcinogenic for humans in 1994 (IARC Working Group 1994 ) . It is causally associated with gastric carcinoma and gastric lymphoma as well as a number of other malignancies (Wu et al. 2 009b ) . Helicobacter pylori infection is generally acquired during childhood, with a gradual increase in preva- lence towards middle age (Parkin 2 006 ; Robins et al. 2 008 ) . Its prevalence varies globally and in some countries is greater than 75% with overall prevalence of 74% in developing countries and 58% in developed countries (Parkin 2 006 ) . This organ- ism has been implicated in one third of cancers caused by infective agents (including virus-caused cancers) and is found in 80% of patients with gastric cancer (zur Hausen 2009 ) . In 2002, there were estimated to be 592,000 cases of gastric adeno- carcinoma and 11,500 cases of gastric lymphoma attributable to H elicobacter pylori (Parkin 2 006 ) . There are a huge number of bacteria living symbiotically with the human host (10 15 in the alimentary tract fl ora (Ouwehand and Vaughan 2 006 ) ) and their pres- ence is crucial for normal human physiological function. The effects of bacteria are not ubiquitously harmful and the dichotomy of bacterial protection versus harm is illustrated by the relative protective effects of Helicobacter pylori infection of the stomach with regards to reduction of oesophageal cancer, but increased risk of gastric adenocarcinoma and lymphoma (Nakajima and Hattori 2 004) . Colonisation by bacterial species does not indicate a true infection and bacteria may colonise the abnormal host environment around a tumour. Additionally, some bacterial toxins have been used in anti-cancer therapy as chemotherapeutic agents (Patyar et al. 2 010 ) . 1 Epidemiology of t he Association Between Bacterial Infections and Cancer 3 1.2 Oesophageal Cancer The two major types of oesophageal cancer, squamous cell carcinoma and adeno- carcinoma have different aetiologies. Squamous cell carcinoma develops most fre- quently in patients who smoke and have high alcohol intake or long standing achalasia. Adenocarcinoma is associated with gastro-oesophageal refl ux and colum- nar metaplasia (“Barrett’s oesophagus”) (Allum et al. 2 002 ) . The oesophageal mucosa is continuously bathed in swallowed saliva and food boluses have a rapid transit time due to the organ’s coordinated peristalsis and appropriate lower oesophageal sphincter relaxation minimising the contact time of carcinogenic agents with the organ. In normal subjects a small volume of gastro- oesophageal refl ux occurs with low frequency, however in patients with defective antirefl ux mechanisms and inadequate lower oesophageal muscular clearance, the lower oesophagus may be bathed in swallowed boluses and gastric contents for more prolonged periods (Gatenby and Bann 2009 ) . The highest risk of oesophageal adenocarcinoma is seen in patients with the most frequent and prolonged refl ux symptoms (Lagergren et al. 1999 ) and those with metaplastic columnar-lined oesophagus (Barrett’s oesophagus) which has an annual incidence of adenocarci- noma of 0.69% per annum (Gatenby et al. 2 008 ) . There has been a worldwide increase in the incidence of oesophageal cancers over the last 50 years, the oesophagus being the eighth commonest site of primary carcinoma in 2000 (Parkin 2 001 ) . This increase has been demonstrated specifi cally in the United Kingdom (Newnham et al. 2 003 ; Kocher et al. 2 001 ; Powell and McConkey 1992 ; Johnston and Reed 1991 ; McKinney et al. 1995 ) as well as in other countries (Ries et al. 2 004 ; Daly et al. 1 996 ; Liabeuf and Faivre 1 997 ; Tuyns 1992 ; Moller 1992 ; Hansen et al. 1997 ) . The histological type of these tumours has changed, from historically a strong predominance of squamous cell carcinomata (Bosch et al. 1 979 ; Puestow et al. 1955 ; Turnbull and Goodner 1968 ; Webb and Busuttil 1 978 ) to the present time, when adenocarcinomata comprise the majority of oesophageal tumours in the United States and United Kingdom (Gelfand et al. 1992 ; Putnam et al. 1 994 ; Rahamim and Cham 1 993 ; Chalasani et al. 1 998 ; Johnston and Reed 1 991 ; Devesa et al. 1 998 ; Powell and McConkey 1 992 ) . Furthermore, current trends are predictive of a continued rise in oesophageal cancer in the UK (Gatenby et al. 2 011 ; Moller et al. 2 007 ) which is likely also to be seen in other countries, especially those with high proportions of adenocarcinoma (Curado et al. 2007 ) . However globally, squamous cell carcinoma is still the predominant histo- logical type (Curado et al. 2 007 ) . Swallowed bacteria from normal oral fl ora include S treptococcus , N eisseria , Veillonella , F usobacterium , Bacteroides , Lactobacillus , Staphylococcus and Enterobacteriaceae (Sjosted 1989 ) . A difference has been noted in the oesophageal fl ora in patients with oesophageal cancer compared to the normal oesophagus (Eslick 2 010 ) and Barrett’s oesophagus compared to the normal oesophagus 4 C.P.J. Caygill and P.A.C. Gatenby (MacFarlane et al. 2 007 ) . However it is likely that the majority of the changes in microbiological fl ora occurs due to opportunistic colonisation of the altered host environment of the cancer rather than earlier in the process of carcinogenesis as causative agents, with the exception of C ampylobacter concisus and C ampylobacter rectus which have been associated with the development of adenocarcinoma in patients with columnar metaplasia of the oesophagus via mutagenic effects including nitrite, N-nitroso and nitrous oxide mediated damage (MacFarlane et al. 2 007 ) . Streptococcus anginosus infection has been found in 44% of oesophageal cancer tissue samples (Morita et al. 2003 ) , but a role in the development of cancer has not been demonstrated. Treponema denticola , which is associated with gingivitis and periodontitis is frequently found in oesophageal cancer specimens. This was the most frequent organism found in resected oesophageal cancer specimens in one series (Narikiyo et al. 2 004 ) . Helicobacter pylori infection results in stomach infl ammation and reduced gastric acid production and its eradication has been shown to increase refl ux oesophagitis and metaplastic columnar-lined oesophagus (Labenz et al. 1 997 ; Corley et al. 2 008 ) . The EUROGAST group has demonstrated that the ratio of cases of squamous cell carcinoma of the oesophagus: adenocarcinoma of the oesophagus is higher in cen- tres with higher population prevalence of H elicobacter pylori infection (14 centres total), but that the strain of H elicobacter pylori did not have a clear relationship with histological type (Robins et al. 2 008 ) . The FINBAR study demonstrated that the rate of H elicobacter pylori positivity was lower in patients with refl ux oesophagitis (42.4% positive), Barrett’s oesophagus (47.4% positive) and adenocarcinoma (51.9% positive) compared to control subjects (59.3% positive). Cag A positivity (the strain most strongly associated with peptic ulcer disease and development of gastric tumours) was lower in Barrett’s oesophagus and oesophageal adenocarci- noma patients than in

patients with refl ux oesophagitis or control subjects. When the oesophageal cancer group was divided into those with true oesophageal tumours to tumours at the oesophagogastric junction, rates of H elicobacter pylori and the Cag A strain were similar in patients with junctional tumours and control subjects, but lower in true oesophageal tumours (Anderson et al. 2 008 ) . Three meta-analyses have been published on the relationship between Helicobacter pylori infection and the Cag A strain in the last 4 years. Rokkas et al. ( 2007 ) demonstrated an odds ratio of 0.52 (95% confi dence interval 0.37–0.73) for Helicobacter positive compared to negative patients in development of adenocarci- noma (with similar fi ndings for Helicobacter positivity and Barrett’s oesophagus). The odds ratio for Cag A positive H elicobacter pylori and development of adeno- carcinoma was 0.51 (95% confi dence limits 0.31–0.82). There was no signifi cant relationship between Helicobacter pylori positivity and squamous cell carcinoma (odds ratio 0.85, 95% confi dence limits 0.55–1.33). Zhuo et al . ( 2008 ) demonstrated that in 12 case-control studies, the odds ratio for development of oesophageal ade- nocarcinoma (9 studies, 684 cases oesophageal adenocarcinoma and 2,470 controls of which 259 cases and 1,287 controls were H elicobacter pylori positive) with 1 Epidemiology of t he Association Between Bacterial Infections and Cancer 5 Helicobacter pylori infection was 0.58 (95% confi dence interval 0.48–0.70) and for squamous cell carcinoma (5 studies, 644 cases squamous cell carcinoma and 2,021 controls of which 355 cases and 1,150 controls were Helicobacter pylori positive) was 0.80 (95% confi dence interval 0.45–1.43). For the Cag A strain-infected sub- jects compared to non-Cag A strain-infected subjects the odds ratio for development of adenocarcinoma was 0.54 (95% confi dence interval 0.40–0.73) and the odds ratio for development of squamous cell carcinoma was 1.20 (95% confi dence interval 0.45–3.18) (Zhuo et al. 2008 ) . Islami and Kamangar (2 008 ) demonstrated that in their meta-analysis of 13 studies (840 cases and 2,890 controls) that infection with the H elicobacter pylori was associated with reduced risk of oesophageal adenocar- cinoma odds ratio 0.56 (95% confi dence interval 0.45–0.69). The effect was also seen in the single study undertaken in a non-Western country (Iran), (but the result of this small study just fell short of statistical signifi cance). The odds ratio of devel- opment of oesophageal adenocarcinoma with the Cag A strain was 0.56 (95% con- fi dence interval 0.46–0.68) and no difference was seen between H elicobacter negative subjects and Cag A negative H elicobacter pylori positive subjects. No sig- nifi cant effect was seen with squamous cell carcinoma (Derakhshan et al. 2 008 ) . A further large case-control study from Taiwan (where squamous cell carcinoma accounts for 95% of oesophageal cancers) has demonstrated that the odds ratio of Helicobacter pylori infection with squamous cell carcinoma of the oesophagus was 0.470 (95% confi dence interval 0.340–0.648) and 0.375 (0.277–0.508) when com- pared to two hospital control groups and 0.802 (95% confi dence interval 0.591– 1.089) compared to a community control group (Wu et al. 2 009b ) . Within patients with established columnar-lined oesophagus there does not appear to be a difference in the risk of cancer development between those who had evidence of H elicobacter pylori infection and those who had not been infected (Ramus et al. 2 007 ) . Overall it is possible that the protective effects are secondary to Helicobacter pylori induced gastric atrophy and hypochlorhydria, both of which reduce acid exposure of the lower oesophagus (Blaser 2 008 ) and the overall results demonstrate that infection with Helicobacter pylori and particularly the Cag A strain are associ- ated with reduced risk of oesophageal adenocarcinoma development, but no clear effect is seen on the risk of squamous cell carcinoma development. Eradication of H elicobacter pylori would subsequently be likely to increase the risk of oesophageal adenocarcinoma, but eradication also reduces the risk of gastric cancers. Using an algorithm based on data from a systematic review, Nakajima and Hattori (2 004 ) estimated that in patients with atrophic gastritis (the macroscopic state most closely associated with development of gastric cancer), eradication of Helicobacter pylori would reduce the annual incidence of gastric adenocarcinoma by 5.9 times. The annual incidence of oesophageal cancer was modelled at 1% per annum with 16.5% of patients who had undergone eradication developing gastro- oesophageal refl ux disease and 12% of these patients developing columnar metapla- sia of the oesophagus. The overall risk of development of oesophageal adenocarcinoma was 0.18% per annum in patients who had undergone eradication. In the presence of atrophic gastritis and columnar metaplasia of the oesophagus, 6 C.P.J. Caygill and P.A.C. Gatenby there was still an overall benefi t seen in eradication with the combined incidence of gastric and oesophageal cancers being reduced from 1.4% to 1% per annum (Nakajima and Hattori 2 004 ) . Anand and Graham (1999) estimated that the risk of development of oesophageal adenocarcinoma following H elicobacter pylori eradi- cation was 10–60-fold lower than the risk of development of gastric adenocarci- noma if eradication was not undertaken. 1.2.1 Viral, Parasitic and Fungal Infection Expression of JC viral protein has been shown in a small study of oesophageal can- cer cells, but not in normal oesophageal cells (where viral DNA was also found). The authors suggest that JC virus may have a role in oesophageal cancer develop- ment (Del Valle et al. 2 005 ) . Studies have not shown a relationship between Epstein Barr Virus infection and risk of oesophageal cancer (Eslick 2 010 ) . No studies have examined the role of human herpes simplex virus in oesophageal cancer development (Eslick 2 010 ) . Human papilloma virus has been linked with squamous cell cancer of the oesophagus, with HPV 16 being the type most strongly associated and frequently studied (Eslick 2 010 ) . Chaga’s disease (protozoal infection with T rypanosoma cruzi ) has been associ- ated with both higher and lower rates of oesophageal cancer (Garcia et al. 2 003 ; de Rezende et al. 1 985 ) This occurs several decades after the initial infection with dysfunction of the nervous control of the gastrointestinal tract with development of a dilated mega-oesophagus with poor peristaltic function and oesophageal emptying (Matsuda et al. 2009 ) . However, there is a common fi nding of coinfection with Helicobacter pylori (Barbosa et al. 1 993 ; de Rezende et al. 1 985 ; Eslick et al. 1 999 ; El-Omar et al. 2000 ) and the overall number of cancers caused by this protozoan is likely to be small compared to the effects of H elicobacter pylori infection on oesophageal cancer development. The data on fungal causes of oesophageal cancer are largely circumstantial, with linkage of several mycotoxins to oesophageal cancer, but no good epidemiological studies (Eslick 2010 ) . 1.3 Gastric Cancer A hypothesis for the sequence of changes that lead from normal gastric mucosa to gastric cancer was fi rst proposed by Correa et al. (1 975 ) . Although this sequence has since been added to and changed, the essential hypothesis (shown in Fig. 1.1 ) remains the same. Bacterial colonisation/infection would appear to play a role by two different pathways. One pathway is normal mucosa progressing to gastric atrophy, at which stage the stomach would become hypochlorhydric resulting in chronic bacterial colonisation, and the production of N-nitroso compounds. The other pathway is as a result of H elicobacter pylori infection. 1 Epidemiology of t he Association Between Bacterial Infections and Cancer 7 Normal Gastric Mucosa Dietary factors Disruption of neuronal control and pylorus Increasing age Gastric Atrophy Bacterial Colonisation Helicobacter pylori Chronic inflammation Chronic atrophy Intestinal Metaplasia Production of N-nitroso compounds Dysplasia Gastric carcinoma Fig. 1.1 The pathogenesis of gastric cancer 1.3.1 Helicobacter pylori Infection Helicobacter pylori is a gram-negative bacterium which colonises gastric epithe- lium. It has evolved the ability to overcome the highly acidic environment of the stomach by metabolising urea to ammonia, thus generating a neutral environment (Wroblewski et al. 2 010 ) . Helicobacter pylori infection is associated with low socioeconomic status and crowded living conditions, especially in childhood (Malaty and Graham 1 994) . Approximately half the world’s population is infected (with most children in developing countries being infected by the age of 10) (Smith and Parsonnet 1 998 ) with the majority of these developing coexisting chronic infl ammation (Wroblewski et al. 2 010) . In contrast, in developed countries, infec- tion in children is uncommon and only 40–50% of adults are affected. There is a clear age-related increase in prevalence which is probably due to a cohort effect in that, H. pylori infection in childhood was more common in the past than it is today (Parsonnet et al. 1992 ; Banatvala et al. 1993 ) . The route of transmission of Helicobacter pylori remains controversial with circumstantial evidence suggesting it probably occurs through person to person transmission. 8 C.P.J. Caygill and P.A.C. Gatenby Studies comparing rates of H elicobacter pylori infection in different populations with rates of gastric cancer in the same populations have mostly correlated well (Forman et al. 1 993 ) . In addition, as H elicobacter pylori infection has declined over time so has the rate of gastric cancer incidence (Parsonnet et al. 1992 ; Banatvala et al. 1 993 ) . It is considered that the gastric infl ammatory response due to colonisa- tion by Helicobacter pylori is the single strongest risk factor for peptic ulceration and gastric cancer. However only a fraction of those colonised go on to develop cancer (Peek et al. 2 010 ) . Retrospective studies should be viewed with caution in view of the hypothesis that the cancerous stomach may lose its ability to harbour H elicobacter pylori (Osawa et al. 1996 ) but evidence from 2 meta-analyses of all case-control studies (Huang et al. 1 998 ; Eslick and Talley 1 998 ) indicate a 2-fold increase in the risk of gastric cancer in instances of Helicobacter pylori infection. Prospective case-control using stored serum from populations, and thus knowing that infection by H elicobacter pylori preceded gastric cancer, has provided more concrete evidence of a link (Parsonnet et al. 1991 ; Forman et al. 1991 ; Lin et al. 1995 ; Siman et al. 1 997 ) . It has also been shown that in those infected with Helicobacter pylori , and followed up for a period of 10 years or more, risk of gastric cancer was increased 8-fold (Forman et al. 1 994 ) . In a recent review of Helicobacter pylori infection and gastric cancer in the Middle East, Hussein (2 010 ) reported that although H elicobacter infection rates in childhood were high, gastric cancer rates differ markedly from very high in Iran (26.1/100,000) to low in Israel (12.5/100,000) and very low in Egypt (3.4/100,000). Atherton (2 006 ) concluded that H . pylori infection, distribution of virulence factors, diet and smoking could not explain the differences in gastric cancer rate even taking into account the accuracy of the data due to differences in diagnostic methods, limi- tations in medical services etc. Whether eradication of H elicobacter pylori is an effective strategy for prevention of gastric cancer is still controversial (Selgrad et al. 2 010 ) . Some studies show this to be the case (Malfertheiner et al. 2 005; Fry et al. 2007 ) but others do not (De Vries and Kuipers 2 007 ) . The effectiveness of H elicobacter pylori eradication as a means of protection against gastric cancer is dependant on the extent of preneoplastic changes (gastric atrophy, intestinal metaplasia etc.) at the time (Selgrad et al. 2 010 ) . Wu et al. ( 2009a ) reported that the earlier Helicobacter pylori is eradicated after peptic ulcer disease, the smaller the risk of gastric cancer. Development of a vaccine to be used as primary prevention, especially with infant vaccination was discussed (Selgrad et al. 2 010 ) . 1.3.2 Chronic Bacterial Overgrowth of the Stomach The normal stomach is acidic with a pH of 2. However in certain pathological conditions such as pernicious anaemia (caused by a lack of intrinsic factor and thus a failure to secrete gastric acid) and surgery for peptic ulcer,

or as part of the ageing 1 Epidemiology of t he Association Between Bacterial Infections and Cancer 9 process, the gastric pH may rise to 4.5 or above on a permanent basis. This would result in chronic bacterial overgrowth of the stomach. In the case of peptic ulcer, the aim of surgical treatment, either by gastrectomy or by vagotomy, was to decrease acid secretion in order to allow the ulcer to heal. In the case of gastrectomy the lower, acid secreting, part of the stomach was removed by a variety of procedures, and in vagotomy the vagal nerves, which control acid secretion, were severed. Both these procedures resulted in loss of gastric acidity within a year, and in both there was an increased risk of gastric cancer (Caygill et al. 1984, 1986 ) . 1.3.3 Pernicious Anaemia An increased risk of gastric cancer had been reported in several series of pernicious anaemia patients (Blackburn et al. 1968 ; Brinton et al. 1989 ) . A study by Caygill et al. (1 990 ) showed an overall 5-fold excess risk of gastric cancer in pernicious anaemia patients. It was not possible to ascertain the onset of pernicious anaemia accurately from patients records as it may be present for some years before diagno- sis, therefore the period after diagnosis was divided into 0–19 years and 20+ years and it was found that the excess risk of gastric cancer was 4-fold in the fi rst time period and 11-fold in the second time period. 1.3.4 Surgery for Peptic Ulcer Table 1 .1 is a summary of cohort studies which have shown an increased risk of gastric cancer in peptic ulcer patients who have undergone surgery to remove the ulcer, or in the case of vagotomy to stop secretion of stomach acid. In the study by Caygill et al. ( 1986 ) , cancer risk for those undergoing a gastrectomy for gastric ulcer was analysed separately from those who had the operation for duodenal ulcer. The risk was analysed by time interval. They found that in the case of duodenal ulcer there was a decrease in risk in the fi rst 19 years followed by an increase in risk thereafter. In contrast in the gastric ulcer patients there was a 3-fold increase in risk immediately after, and presumably prior to surgery, and this rose to over 5-fold 20 or more years after surgery. The pattern of an initial decrease in risk in those operated for duodenal ulcer has been confi rmed by Arnthorsson et al. (1 988 ) , Moller and Toftgaard (1 991 ) , Lundegardh et al. (1 988 ) and Eide et al. ( 1991 ) . This differ- ence in behaviour between duodenal ulcer and gastric ulcer patients needs to be rationalised. It was hypothesised that prior to surgery duodenal ulcer patients would have good acid secretion and the effect of surgery would be to induce hypochlohy- dric within a year of surgery. On the other hand many gastric ulcer patients would be hypochlorhydric for varying number of years prior to the operation. 10 C.P.J. Caygill and P.A.C. Gatenby Table 1.1 Cohort studies examining gastric cancer risk following surgery for peptic ulcer References Study population (n ) Excess risk Latency (years) Ross et al. (1 982 ) 779 None 19 Watt et al. (1 984 ) 735 3-fold 15 Tokudome et al. (1 984 ) 3,827 None – Caygill et al. ( 1986 ) 4,466 4-fold 20 Viste et al. (1 986 ) 3,479 3-fold 20 Arnthorsson et al. (1 988 ) 1,795 2-fold 15 Lundegardh et al. (1 988 ) 6,459 3-fold 30 Offerhaus et al. (1 988 ) 2,633 5-fold 15 females 3 males Toftgaard (1 989 ) 4,131 2-fold 25 (vagotomy cohort) 1,643 1.6 20 Caygill et al. (1 991 ) 1.3.5 Possible Mechanism for Gastric Carcinogenesis in Instances of Hypochlorhydria The histopathological seqence from the normal to the neoplastic stomach proposed by Correa et al. ( 1975 ) and reviewed by Correa (1 988 ) has been generally accepted. They postulated that the fi rst stage, gastric atrophy, progresses to chronic atrophic gastritis. Atrophic gastritis is at increased risk of developing intestinal metaplasia which in turn carries an elevated risk of progressing through increasingly severe dysplasia to cancer. It was suggested that this progression was a result of the action of carcinogenic N-nitroso compounds. Gastric atrophy results in the loss of gastric acid secretion allowing bacterial colonisation of the stomach. The bacteria react with nitrate, present in many foods and in drinking water, and convert it to nitrite. The nitrite further reacts with nitrosatable amines to form a variety of N-nitroso compounds. If this hypothesis is correct then the loss of gastric acidity, with conse- quent chronic bacterial overgrowth, from any cause (surgical, metabolic, clinical, genetic or environmental) should, after a latency period of 20 years or more, lead to an increased risk of gastric cancer as has been shown in patients with pernicious anaemia and those undergoing gastrectomy or vagotomy (see Fig 1.1 ). This also offers an explanation for the difference in cancer risk in those operated on for a gastric ulcer or for duodenal ulcer. Gastric ulcer patients, as a result of their hypoa- cidity prior to operation, will have bacterial overgrowth for variable lengths of time which would contribute to the latency period, whereas those with duodenal ulcer will only become hypochlorhydric after their operation, thus their increase in risk would only start to manifest itself 20 years later. 1 Epidemiology of t he Association Between Bacterial Infections and Cancer 11 1.4 Colorectal Cancer As in many cancers the progression from the normal epithelium to malignancy is a multi-stage process. There are at least three distinct histological stages prior to malignancy and metastatic disease. These are adenoma formation, adenoma growth and increasingly severe dysplasia (Hill et al. 1 978, 2001 ; Hill 1 991 ) . The evidence for this was reviewed by Morson (1 974 ) and Morson et al. (1 983 ) . Benign adenomas are very common in both men and women in western populations and their preva- lence has been found to be approximately 50% in males and 30% in females by the age of 70 in post mortem studies. Most are very small (around 3–5 mm) but some can be greater than 20 mm in diameter. The risk of fi nding malignant cells in a small adenoma is very small (less than 1 per 1,000 for those with a diameter less than 3 mm) but high in those with a diameter greater than 20 mm (Morson et al. 1983 ) . Thus one of the most important steps in the adenoma-carcinoma sequence is ade- noma growth. 1.4.1 Faecal Bacteria Present in the Colon There are differences within the colon in subsite distribution of small adenomas, large adenomas and colorectal cancers. A very large number of postmortem studies have shown that small adenomas are evenly distributed around the colon and rectum whereas large adenomas and cancers are concentrated in the distal colon and rec- tum, (Hill 1 986 ) . The implication being that the causal agents are delivered via the vascular system; and indeed the colon lumen is a rich source of potential carcino- gens, produced i n situ by bacterial action on benign substrates (Caygill and Hill 2005 ) . Although not proved, this is consistent with the hypothesis that the factors causing adenomas to increase in size and in severity of epithelial dysplasia are lumi- nal products of bacterial metabolism. There is further support for this by the fact that adenomas regress after diversion of the faecal stream. 1.4.2 Streptococcus bovis Several S treptococci have been linked to chronic infections of the colon and subsequent increased risk of colorectal cancer (Kim et al. 2 002 ; Siegert and Overbosch 1 995 ) . An association between Streptococcus bovis and colorectal cancer was fi rst reported by Roses et al. (1 974 ) and has been validated by more recent studies (Biarc et al. 2004 ; Gold et al. 2004 ) . The incidence of S treptococcus bovis associated with colorectal cancer has been determined as being between 18% and 62% (Zarkin et al. 1 990 ) . 12 C.P.J. Caygill and P.A.C. Gatenby 1.4.3 E. coli and Infl ammatory Bowel Disease The intestinal fl ora in patients with infl ammatory bowel disease (Crohn’s disease and ulcerative colitis) differs from control subjects with increased E . coli (Martin et al. 2 004 ) . These patients have a marked increase in rate of colorectal cancer development which is highest in those with chronic severe infl ammation (Munkholm 2 003 ) . Small studies have demonstrated increased mucosa-associated and intramu- cosal bacteria in Crohn’s disease (79% and 71% respectively) and colon cancer (71% and 57% respectively) compared to non infl amed controls (42% and 29% respectively), but no difference between controls and ulcerative colitis. These E . coli commonly expressed haemagglutinins (39% Crohn’s, 38% cancers, and 4% controls) and the resulting pro-infl ammatory cytokines may be implicated in car- cinogenesis (Martin et al. 2 004 ) . 1.5 Gallbladder Cancer Cancer of the gallbladder has a very poor prognosis. The highest incidence is in the Andean countries of South and Central America and in American Indian groups (Misra et al. 2003 ) but is rare in Western countries. The etiology is not well under- stood, but the major risk factor is the presence of gallstones which are involved in 70–80% of cases (Lazcano-Ponce et al. 2 001 ) . Risk factors include obesity, repro- ductive factors and environmental exposure to certain chemicals (Lazcano-Ponce et al. 2001 ; Wistuba and Gazdar 2 004 ) . However, the major risk factors are those which involve chronic bacterial infec- tion such are previous polya partial gastrectomy for peptic ulcer, gallstone carriage, chronic infection with S almonella typhi/paratyphi and with H elicobacter species . 1.5.1 Gallstones Although it has been known for some years that gallstones are the most important risk factor for gallbladder cancer (Devor 1 982 ; Zatonski et al. 1 997 ; Randi et al. 2006 ) , the nature of this association is not clear. Gallstones are, however associated with bacterial infection of the gallbladder (England and Rosenblatt 1977 ) . 1.5.2 Polya Partial Gastrectomy The routine treatment for persistent peptic ulcer, gastric or duodenal, was surgery using a variety of partial gastrectomy operations. These remove much of the lower part (including most of the acid secreting section) of the stomach. As a result, the stomach became hypochlorhydric attaining a pH of around 4.5. 1 Epidemiology of t he Association Between Bacterial Infections and Cancer 13 This is a perfect milieu for bacterial overgrowth and formation of N-Nitroso compounds (Hill 1 996 ) which have been shown to be carcinogenic in all species in which they have been studied. Polya partial gastrectomy is associated with a 10-fold excess risk of gallbladder cancer with a 20 year latency period (Caygill et al. 1988 ) . 1.5.3 Infection with Salmonella typhi/paratyphi There is a growing body of evidence that typhoid carriers are at an increased risk of biliary tract cancer. The New York City Health Department conducted a very large case–control study of 471 registered carriers and 942 age- and sex-matched controls which showed that chronic carriers were six times as liable to die of hepatobiliary cancer as controls (Welton et al. 1 979 ) . This fi nding has been confi rmed by others (Mellemgaard and Gaarslev 1 988 ; Caygill et al. 1994 ; Nath et al. 1997, 2008 ; Shukla et al. 2 000 ) . Caygill and co-workers studied long-term cancer risk in two Scottish cohorts – one a cohort of 386 acute typhoid cases from a single outbreak which occurred in Aberdeen in 1964 and the other 83 typhoid carriers from a number of different out- breaks (Caygill et al. 1994, 1995 ) . In case of acute infection in Aberdeen, there was neither excess risk for cancer of the gallbladder nor indeed for any other cancer. In the cohort of patients with chronic infection there was an almost 200-fold excess risk of cancer of the gallbladder and an excess risk of cancer of the pancreas (Table 1 .2 ). 1.5.4 Infection

with Helicobacter species Helicobacter species colonising the biliary tract have been associated with gallblad- der cancer (Leong and Sung 2 002 ; Kobayashi et al. 2 005 ) . There is no doubt that gallbladder cancer has a multi-factorial aetiology. Although a proportion of any risk may well be an individuals environmental and life style exposure, the most important risk factor appears to be exposure to chronic, but not acute bacterial infection. 1.6 Pancreatic Cancer Cancer of the pancreas has a relative low incidence but a very poor prognosis even if diagnosed early and ranks eighth in a world listing of cancer mortality. International incidence rates vary in different countries, implying that environmental factors are important. Smoking is the best documented etiologic agent and accounts for approx- imately about 25% of all cases. Little is known about dietary factors. The incidence 14 C.P.J. Caygill and P.A.C. Gatenby Table 1.2 Deaths from “cancer” in patients with chronic infection with typhoid/paratyphoid (Caygill et al. 1 994 ) Site of cancer ICD no Observed (O) Expected (E) O/E 95% CI Gallbladder 1,560 5 0.03 167* (54–391) Pancreas 157 3 0.37 8.1* (1.7–23.7) Colorectum 152–4 3 1.00 3.8 (0.6–8.8) Lung 162 5 1.98 2.5 (0.8–5.9) All neoplasms 140–208 20 7.80 2.6* (1.6–4.0) ICD International Classifi cation of Disease, O observed, E expected * P < 0.001 is strongly age dependent thus as the population of western countries ages we can anticipate an increasing number of cases (Lowenfels and Maisonneuve 2 006 ) . Cancer of the pancreas is also linked with bacterial infection. 1.6.1 Surgery for Peptic Ulcer Surgery for peptic ulcer with the resultant hypochlorhydria results in bacterial over- growth of the stomach. The bacteria thus formed react with ingested nitrates in food and converts them to nitrites. This is the perfect milieu for the formation of N-nitroso compounds which are formed when nitrite and nitrosatable amines are present together. These highly reactive compounds which can combine with nitrosatable amines, also present in food, and form a range of nitrosamines (Caygill et al. 1 984 ; Preussmann 1 984 ) . Nitrosamines have been found to be carcinogenic in a number of animals (Pour and Lawson 1 984 ) and are both species and target organ specifi c. This could well be the explanation for the fi nding of an excess risk for cancer of the pancreas after surgery for peptic ulcer (Caygill et al. 1 987 ; Mack et al. 1 986 ; Eide et al. 1991 ; Tersmette et al. 1990 ; Ross et al. 1982 ; Luo et al. 2007 ) , the excess risk being greater in gastric ulcer than in duodenal ulcer patients (Caygill et al. 1987 ) .It must be noted however that, Inokuchi et al. (1 984 ) , Watt et al. (1 984 ) and Moller and Toftgaard (1 991 ) did not fi nd an excess risk of cancer of the pancreas in patients who had undergone operations for peptic ulcer. 1.6.2 Helicobacter species Infection In recent years there have been a number of studies investigating a possible associa- tion between H elicobacter species infection and cancer of the pancreas. H elicobacter species ribosomal DNA was detected in the pancreas of 75% of pancreatic cancer patients (Nilsson et al. 2 006 ) and H elicobacter pylori was found to be associated with an increased risk of pancreatic cancer in studies by Raderer et al. (1 998 ) and 1 Epidemiology of t he Association Between Bacterial Infections and Cancer 15 Stolzenberg-Solomon et al. (2 001 ) . A study by Risch et al. (2 010 ) also found an association but only in individuals with non-O blood types. However studies by de Martel et al. ( 2008 ) and Lindkvist et al. (2 008 ) could fi nd no such association. Luo et al. (2 007 ) found a modest increased risk of pancreatic cancer in patients with gastric ulcer or gastric resection and hypothesised that colonisation of the corpus by H. pylori, together with atrophic gastritis resulting in bacterial overgrowth and nit- rosamine formation may contribute to pancreatic carcinogenesis. 1.6.3 Typhoid Carriage In a study examining cancer risk in those infected with typhoid and in typhoid car- riers, Caygill et al. (1 994 ) found a large excess (23-fold) in cancer of the pancreas in a cohort of 83 typhoid carriers, not in 386 acute cases of typhoid who did not become carriers. The mechanism is uncertain, but pancreatic cancer has been asso- ciated with bile refl ux from the common bile duct (Wynder 1 975 ) . 1.7 Bladder Cancer Industrial exposure to naphthylamines, benzidine and a range of aromatic amines, contained in chemical dyes, has long been known to be associated with cancer of the bladder and explained the reason why men in industrialised countries were most at risk. However, a proportion of bladder cancer cases do not have an industrial origin. Early anecdotal evidence suggested an excess risk of bladder cancer following chronic bladder infection and this was confi rmed by Radomski et al. (1 978 ) . Bladder infections are very common, and often asymptomatic (Sinclair and Tuxford 1 971 ) ; the data on cancer risk reported by Radomski et al. (1 978 ) concerns chronic symp- tomatic infection resistant to therapy, but many of his controls might have had asymptomatic bladder infections and so the magnitude of the excess risk would have been underestimated. There is copious evidence that carcinogenic N-nitroso compounds are produced in situ in the bladder by infecting organisms, which is to be expected since the urine is the route of excretion of the substrates for N-nitroso compounds production – nitrate and nitrosatable amines. Thus Radomski et al. (1 978 ) suggested that N-nitroso com- pounds, produced by bacterial action on these substrates were the cause of the cancer. 1.7.1 Schistosoma haematobium Bilharzial (S chistosoma haematobium) infection is a major risk factor for bladder cancer, and such infections are accompanied by a profuse secondary bacterial infection of the bladder. Hicks et al. (1 977 ) showed strong evidence that the 16 C.P.J. Caygill and P.A.C. Gatenby bladder cancer associated with bilharzial infection was in fact due to the N-nitroso compounds produced by the secondary bacterial infection. This has been supported by others who have shown a similar association (El-Mawla et al. 2 001 ; Bedwani et al. 1998 ; Saad et al. 2 006 ) . Hicks et al. (1 977 ) also produced evidence that the excess risk of bladder cancer in paraplegia was due to the same mechanism – N-nitroso compounds produced by a chronic bacterial infection of the bladder. 1.7.2 Tuberculosis Increased bladder cancer risk has also been found amongst tuberculosis sufferers in Korea, a country where the prevalence of tuberculosis is particularly high (Kim et al. 2 000 ) . 1.8 Lung Cancer The major risk factor for lung cancer is smoking, however infection by a number of bacteria also has a role. 1.8.1 Pulmonary Tuberculosis Before 1950 most TB patients died when relatively young, thus any risk of lung cancer would not have became manifest. It was not till TB treatment was suffi - ciently successful to give the patient a reasonable life-expectancy that the associa- tion was noted. Indeed, as a result of early studies there was a theory (Rokitansky 1854 ) that the two diseases were antagonistic. Since then there have been numer- ous reviews of the association between tuberculosis and subsequent lung cancer. Aoki (1 993) reviewed the epidemiological studies between 1960 and 1990 and confi rmed that patients with active pulmonary tuberculosis have an excess risk of dying of lung cancer even though they already had a high mortality from tubercu- losis. The excess was 5–10-fold depending on age, and was greater in women than in men. Patients with active disease were the most likely to develop lung cancer and he also found that they also had an excess risk of other cancers such as colon, lymphoma, myeloma etc. The mechanism for the association is not clear, and there are no good hypothe- ses to explain it. Attempts to stimulate the immune system in animal with BCG resulted in an increased, rather than decreased, cancer risk (Martin et al. 1977 ) . This may explain the reason for the increased risk of cancer at distant sites seen by Aoki ( 1993 ) . 1 Epidemiology of t he Association Between Bacterial Infections and Cancer 17 1.8.2 Chlamydia pneumonia There have been a number of reports of a connection between lung cancer and infec- tion with C hlamydia pneumonia (Laurila et al. 1 997 ; Kocazeybek 2 003 ; Littman et al. 2 004 ) . However accurate assessment of past C hlamydia pneumonia infection is diffi cult as there is no serological test to specifi cally identify persons with chronic infection (Littman et al. 2 005 ) . In 2 010 , Chaturvedi et al. evaluated the relationship of C hlamydia pneumoniae infection with prospective lung cancer risk using serologic markers for both chronic and acute Chlamydial infection and concluded that chronic infection 2–5 years before was associated with an increased risk of lung cancer. They highlight the potential for lung cancer reduction through treatments targeted towards C hlamydia pneumoniae infections. 1.8.3 Helicobacter pylori Infection Lung cancer has been associated with Helicobacter pylori infection in a number of studies (Gocyk et al. 2 000 ; Ece et al. 2 005 ; Zhou et al. 1 992 ) , however Philippou et al. (2 004 ) found no such association. The mechanism is unknown but H elicobacter pylori may contribute by upregulating gastrin and COX-2 thus stimulating tumour growth. Also increased plasma gastrin concentrations may increase the risk of lung cancer by inducing proliferation of mucosal cells in the bronchial epithelium (Kanbay et al. 2 007 ) . 1.9 Conclusion Bacteria play a signifi cant role in the aetiology of cancer development, but less than viral infection. The strongest association has been seen in gastric cancer with Helicobacter pylori and this bacterium has been associated with the development of other tumours as well as having an inverse association with the development of oesophageal cancer. Chronic infection with ongoing insult from the infecting bacte- rium has been most strongly demonstrated with typhoid infection and also Helicobacter pylori. Eradication of bacterial agents which are causes of cancer may result in a reduction in one quarter of cancers in developing countries and a smaller proportion in developed countries. 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D’Elios Abstract Helicobacter pylori ( H. pylori ) is a gram-negative bacterium that chronically infects the stomach of more than 50% of the human population and represents a major cause of gastric cancer, gastric lymphoma, gastric autoimmu- nity and peptic ulcer diseases. The International Agency for Research on Cancer classifi es H. pylori as a human carcinogen for gastric cancer. Eradicating the bac- terium in high-risk populations reduces the incidence of gastric cancer. Likewise, antibiotic treatment leads to regression of gastric mucosa-associated lymphoid tissue lymphoma. Gastric infl ammation induced by H. pylori is the main singular risk factor for gastric malignancies. This chapter outlines the bacterial and host factors involved in the genesis of gastric cancer and gastric lymphoma. Treatment options for patients with an advanced gastric malignancy are still limited, but the introduction of an effective vaccine will be the best tool for preventing both H. pylori infection, gastric cancer and gastric lymphoma. Keywords Helicobacter pylori • Gastric cancer • Gastric lymphoma • MALT • Mucosal immunity • T cells • T helper 1 • T helper 2 • T helper 17 • Cancerogenesis • Lymphoma genesis • Cytotoxicity • B-cell help • P erforin • Fas ligand • Antibiotic therapy • Vaccines A. Amedei • M. M. D’Elios (*) Department of Internal Medicine , University of Florence, viale Morgagni 85 , 50134 Florence , Italy Department of Biomedicine , Policlinico AOU Careggi, Florence , Italy e-mail: delios@unifi .it A.A. Khan (ed.), Bacteria and Cancer, DOI 10.1007/978-94-007-2585-0_2, 25 © Springer Science+Business Media B.V. 2012 26 A. Amedei and M.M. D’Elios Abbreviations AIG Autoimmune gastritis BER Base excision repair BMDC Normal bone marrow stem cells EGFR Epithelial Growth Factor Receptor GC Gastric Cancer HbEGF Heparin-binding EGF-like growth factor HP Helicobacter pylori IFNGR Interferon gamma receptor IL-1 b Interleukin-1 beta KO Knockout LPS Lipopolysaccharide MALT Mucosa-associated lymphoid tissue MALToma MALT lymphoma MBL2 Mannose binding lectin-2 gene mmP1 matrix metalloproteinase 1 MMR Mismatch repair pathway mtDNA mitochondrial DNA NFAT Nuclear factor of activated T cells NoD1 Nucleotide-binding oligomerization domain-containing protein 1 omP outer membrane proteins Pi3K Phosphotidyl inositol 3 kinase PTPRZ1 Protein receptor-type tyrosine protein phosphatase-z ROS Reactive oxygen species SHP-2 Src homology 2 domain–containing tyrosine phosphatase 2 T4SS Type 4 Secretion system TLR Toll-like receptor TNF Tumour Necrosis Factor TPM Tyrosine phosphorylation motifs TRAIL TNF-related apoptosis-inducing ligand VNTR Variable number of tandem repeats 2.1 Introduction Gastric cancer (GC) is currently the second leading cause of death due to cancer worldwide, with high incidence in China, South America, Eastern Europe, Korea, and Japan (Yao et al. 2003 ) . Surgical tumour resection remains the primary curative treatment for gastric cancer. Nevertheless, the overall 5-years survival rate remains poor, ranging between 15 and 35%. Among patients who relapse

after curative sur- gery, the 87% have locoregional recurrences (Roukos and Kappas 2 005 ) . These facts have prompted many studies addressing surgical issues, as well as exploring 2 Gastric Cancer and H elicobacter pylori 27 the role of adjuvant and neoadjuvant treatments, such as perioperative chemotherapy, which is associated with a 5 years overall survival benefi t in 13% cases for stages II or III operable GC patients (Cunningham et al. 2 006 ) . Despite the improvements in GC management, estimated cure rates for patients with advanced stages remain poor throughout the world (Liakakos and Roukos 2008 ) . These data highlight the urgent need of new therapeutic strategies to combat GC, such as Epithelial Growth Factor Receptor (EGFR) inhibitors (Vanhoefer et al. 2 004 ) , anti-angiogenetic agents (Shah et al. 2 006 ) , apoptosis promoters (Ocean et al. 2 006 ) and specifi c immuno- therapy (Elkord et al. 2 008 ; Amedei et al. 2009 ) . The mechanisms that account for the observed geographic and temporal incidence patterns have not yet been estab- lished and a number of factors are known to suppress or promote gastric cancer (Saikawa and Kitajima 2 009 ) . The intake of fruits and vegetables have a protective role, as well as modern food processing and storage, that had reduced both spoilage and the use of salt-curing and pickling also found to be protective for gastric cancer. Several gastric cancer promoting factors have been defi ned, such as natural carcino- gens or precursors (nitrates in food), carcinogens produced during the grilling of meats, and other carcinogens are synthesized from dietary precursors in the stom- ach. Helicobacter pylori (H . Pylori ) infection is the major GC-promoting factor. In 1994, the International Agency for Research on Cancer declared H . pylori to be a type I carcinogen, or a defi nite cause of cancer in humans (IARC Working Group 1994 ) and epidemiological studies have determined that the attributable risk for gastric cancer conferred by H . pylori is approximately 75% (Parkin 2 006 ) . If this is accurate, H . pylori would be responsible for as many as 5.5% of all cancers, making it the leading infectious cause of cancer worldwide and second only to smoking as a defi ned cause of malignancy. H. pylori is a gram negative, spiral-shaped, microaero- philic, urease-positive bacillus that is acquired during childhood, probably via the fecal/oral or gastric/oral routes. Once acquired, the infection persists throughout life unless treated with antibiotics. Common wisdom until 1980 suggested that the stomach, with its low pH, was a sterile environment. Then, endoscopy of the stom- ach became common and, in 1984, the Nobel Laureates Robin Warren and Barry Marshall found and cultured H . pylori from the gastric epithelium of patients with gastritis (infl ammation of the stomach) and ulcer disease (Marshall and Warren 1984 ) . Soon, the medical community understood that H . pylori is the major cause of stomach infl ammation, which, in some infected individuals, precedes peptic ulcer disease (10–20%), distal gastric adenocarcinoma (1–2%), and gastric mucosal- associated lymphoid tissue (MALT) lymphoma (<1%) (Kusters et al. 2 006 ) . Although, the bacteria mainly reside on the surface mucus gel layer with little inva- sion of the gastric glands, the host responds with an impressive humoral and cell- mediated immune response. Despite this sophisticated immune response, most infections become chronically established with little evidence that spontaneous clearance occurs (Amieva and El-Omar 2 008 ) . Two histologically distinct variants of gastric adenocarcinoma have been described, each with different pathophysio- logical features. D iffuse-type gastric adenocarcinoma more commonly affects younger people and consists of individually infi ltrating neoplastic cells that do not form glandular structures. The more prevalent form of gastric adenocarcinoma, 28 A. Amedei and M.M. D’Elios intestinal-type adenocarcinoma which progresses through a series of histological steps that are initiated by the transition from normal mucosa to chronic superfi cial gastritis, which then leads to atrophic gastritis and intestinal metaplasia, and fi nally to dysplasia and adenocarcinoma (Correa 1 992 ) . Although, H. pylori signifi cantly increases the risk of developing both dif- fuse-type and intestinal-type gastric adenocarcinoma, chronic infl ammation is not required for the development of diffuse-type cancers, suggesting that mech- anisms underpinning the ability of H. pylori to induce malignancy are different for these cancer subtypes. However, only a small proportion of HP-infected people ever develop neoplasia, and disease risk involves well-choreographed interactions between pathogen and host, which are in turn dependent on strain- specifi c bacterial factors and/or host genotypic traits. These observations under- score the importance and timelines of reviewing mechanisms that regulate the biological interactions of H . pylori with its hosts and that promote carcinogenesis. In this chapter we analyzed the role of H . pylori and host factors leading to gas- tric adenocarcinoma and gastric MALT lymphoma and discussed the epidemiologi- cal and pathophysiological data that led to the consensus that H . pylori is one of the world’s most important causes of cancer. 2.2 Pathophysiology of H. pylori Infection Helicobacter species inhabit the gastrointestinal tract of mammals and birds. These species are mostly host specifi c, implying coevolution of the bacteria with their hosts. By comparing nucleotide sequences of different strains, it is possible to deter- mine the minimal time that H. pylori and its host have shared a common ancestor. Genetic diversity among H. pylori strains diminish with distance from East Africa, just like genetic diversity decreases among humans (Atherton and Blaser 2 009 ) . Taken together these data show that H . pylori has coevolved with humans, at least since their joint exodus from Africa 60,000 years ago and likely throughout their evolution. In physiological terms, the stomach may be divided into two main compart- ments: an acidic proximal corpus that contains the acid-producing parietal cells and a less acidic distal antrum that does not have parietal cells but contains the endocrine cells that control acid secretion. Both animal and human ingestion stud- ies suggest that successful colonization of the gastric mucosa is best achieved with the aid of acid suppression (Danon et al. 1995 ) . Furthermore, the pharmacological inhibition of acid secretion in infected patients leads to the redistribution of the infection and its associated gastritis from an antral to a corpus-predominant pattern (Kuipers et al. 1996 ) . Thus, lack of gastric acid extends the colonization area and maximizes the tissue damage of colonization. The key pathophysiological event in H. pylori infection is the start of an infl ammatory response that is triggered by dif- ferent bacterial products, such as CagA, HP-NAP, VacA, lipopolysaccharide (LPS), 2 Gastric Cancer and H elicobacter pylori 29 urease with the ensuing infl ammatory response mediated by cytokines (D’Elios et al. 1 997b; Israel and Peek 2 001 ; Amedei et al. 2 006 ) . The cytokine repertoire comprises a multitude of pro- and anti-infl ammatory mediators whose function is to co-ordinate an effective immune response against invading pathogens without damage to the host (D’Elios et al. 2 005 ) . In addition to their infl ammatory proper- ties, some H . pylori -induced cytokines, such as interleukin-1 beta (IL-1b ), IFN-g , TNF- a , and IL-4 may exert a variety of effects on the gastric epithelial cells that might lead to gastric pH alterations or activation of oncogenes (El-Omar et al. 2000 ; El-Omar 2 001 ; Robert et al. 1 991 ) . Normal bone marrow stem cells (BMDCs) are frequently recruited to sites of tissue injury and infl ammation and a recent study (Houghton et al. 2 004 ) demonstrated that BMDCs might also represent a potential source of malignant cells in gastric cancer, while epithelial cancers are believed to originate from the transformation of tissue stem cells. They showed that chronic infection of C57BL/6 mice with H elicobacter induced repopulation of the stomach with BMDCs, and subsequently these cells progressed through meta- plasia and dysplasia to intraepithelial cancer. These fi ndings suggest that epithelial cancers can originate from marrow-derived sources. Subsequently, others studies demonstrated the possible relationship of BMDCs to carcinogenesis (Takaishi et al. 2008 ; Dittmar et al. 2 006 ) . Houghton et al. ( 2004 ) speculated that, the plastic- ity of BMDCs might contribute to epithelial cancers, particularly those associated with chronic infl ammation. The model of gastric cancer in H elicobacter felis infected C57BL/6 mice represents an ideal system for evaluating the effects of chronic infl ammation on BMDC recruitment and engraftment in the stomach. Infl ammation (maximal 2–3 months after infection) subsequently continues at a moderate level for the remainder of the life of the animal. In this model, chronic infl ammation and tissue injury may be associated with BMDC engraftment within the gastric epithelium, and the resulting microenvironment is strongly linked with the progression of infl ammation-associated cancer. BMDCs may also contribute to established cancers through cell mimicry or cell fusion as suggested for hepato- cytes or intestinal cells (Wang et al. 2003; Rizvi et al. 2006 ) , or they may initiate cancer directly. Interestingly, acute gastric infection with H elicobacter species, acute ulceration, or drug-induced parietal cell loss does not lead to the recruitment of BMDCs, while severe chronic infl ammation may lead to BMDC-related car- cinogenesis. The latter process probably upregulates proinfl ammatory cytokines such as IL-1 b, IL-6, and TNF (Tumour Necrosis Factor)- a , and chemokines such as CXCL12, contributing to the recruitment of progenitors. Therefore as result of chronic H . pylori infection there are three main gastric phenotypes: (a) the commonest by far is a mild pan-gastritis that is not associated with signifi cant human disease; (b) a corpus-predominant gastritis associated with progressive gastric atrophy and multifocal intestinal metaplasia and increased risk of gastric cancer (El-Omar et al. 1 997 ) ; and (c) an antral-predominant gastritis asso- ciated with high gastric acid secretion and increased risk of duodenal ulcer disease (El-Omar et al. 1 995 ) . It is fascinating to note that the determinants of these out- comes are the severity and extent of the gastritis, which in turn are determined by bacterial, host and environmental factors. 30 A. Amedei and M.M. D’Elios 2.3 H. pylori Factors That Interact with the Host and Mediate Carcinogenesis 2.3.1 CagA and the cag Pathogenicity Island The association of H . pylori infection with gastric cancer raises the interesting question of whether H . pylori encodes one or more oncogenes? Oncogenic viruses initiate and promote cellular transformation by integrating virally encoded onco- genes into the host genome (Maeda et al. 2008 ; Howley and Livingston 2009 ) . By contrast, H . pylori remains primarily extracellular and does not integrate its genome into the host DNA. However, the bacterium can still affect the function of host cells by translocating a bacterial protein, CagA, which is a component of the c ag patho- genicity island. c ag +strains signifi cantly augment the risk for distal gastric cancer compared with cag – strains (Peek and Blaser 2002 ) . In last few years, the research in this fi eld has advanced, particularly that concerning how effects are localized within the epithelial cell? (Kwok et al. 2 007 ; Higashi et al. 2 002a ; Amieva et al. 2003 ) ; how the CagA effector protein varies between strains? (Argent et al. 2 004 ; Basso et al. 2 008 ) , and how CagA can directly induce carcinogenesis? In H . pylori strains, the c ag PaI may be present, absent, or disrupted and thus nonfunctional. But, cag PaI is usually present and functional in H. pylori , it contains approximately 30 genes, including those that collectively encode a type IV secre- tion system (T4SS) – a conduit that connects the cytoplasm of the bacterial and host epithelial cells (Odenbreit et al. 2 000 ) . This is brilliantly designed for the human stomach: an antigenically variable, acid-stable structural protein (CagY) coats the “syringe,” conferring stability and allowing evasion from the host immune response (Algood et al. 2 007 ) . Subsequent contact of the tip protein (CagL) with the epithe- lial cell and delivery and activation of the effector protein (CagA) stimulate local signaling and effects at the site

of attachment (Backert and Selbach 2 008 ) (Fig. 2.1 ). CagA may also have more well-known cellular effects, including activation of NF-kB (Brandt et al. 2 005 ) (Fig. 2 .1 ). CagA is polymorphic and from different H. pylori strains has different numbers and types of activating tyrosine phosphory- lation motifs (TPMs), leading to different effects on cellular signaling and differing risks of disease; for example the D-type TPM found in East Asian strains binds to Src homology 2 domain–containing tyrosine phosphatase 2 (SHP-2) strongly and stimulates very marked cellular effects (Higashi et al. 2 002a, b ; Argent et al. 2008 ) . This may, in part explain the high rate of H . pylori associated disease in Japan and parts of China. In host cells, CagA interacts with a number of cellular complexes implicated in carcinogenesis (Bourzac and Guillemin 2 005 ; Hatakeyama 2 006 ) and appears to be very important in H . pylori induced gastric carcinogenesis, regardless of infl amma- tion status. Among transgenic mice engineered to express CagA constitutively, some developed B cell lymphomas and some developed gastric adenocarcinomas (Ohnishi et al. 2008 ) with no gastritis. This implies that the underlying mechanism 2 Gastric Cancer and H elicobacter pylori 31 Fig. 2.1 Local and whole-cell effects of the H . pylori protein CagA. H . pylori with an intact c ag PaI, forms a T4SS, which injects CagA into epithelial cells. The CagL protein of T4SS complex binds to and activates integrin a 5 b 1, resulting in local activation of focal adhesion kinase (F AK ) and then Src kinase. Activated kinases phosphorylate CagA, in turn activating local Src homology 2 domain–containing tyrosine phosphatase 2 (S HP-2 ) and therefore local signaling. A soluble component of bacterial peptidoglycan, g -D-glutamyl-m eso -diaminopimelic acid (i E-DAP ) also enters the cell and is recognized by the intracellular innate immune pattern-recognition receptor Nod1, leading to stimulation of NF-k B. In addition, phosphorylated CagA itself also may activate NF- k B and have other whole-cell effects. The b old text indicates cellular effects did not involve chronic infl ammatory damage, although early time points were not examined. The implications for human gastric intestinal-type carcinogenesis, which appears to arise on a background of infl ammation through a stepwise progression of gastritis-atrophy-metaplasia-carcinoma, remain to be fully elucidated. As the cag T4SS also induces proinfl ammatory cytokines via the intracellular bacterial peptidoglycan recognition molecule nucleotide-binding oligomerization domain- containing protein 1(NoD1). NoD1 activation by H . pylori peptidoglycan stimulates NF-k B, p38 and ERK, culminating in the expression of the chemokines CXCL2 and CXCL8 (Viala et al. 2004 ; Allison et al. 2009 ) . The delivery of peptidoglycan components into host cells induces additional epithelial responses with carcinogenic potential, such as the acti- vation of Pi3K and cell migration. The H . pylori gene s lt encodes a soluble lytic transglycosylase that is required for peptidoglycan turnover and release (Viala et al. 2004 ) , thereby regulating the amount of peptidoglycan translocated into host cells. Inactivation of slt has been shown to inhibit H . pylori induced Pi3K signalling and 32 A. Amedei and M.M. D’Elios cell migration (Nagy et al. 2 009 ) . The protein encoded by the H. pylori gene HP0310 deacetylates N -acetylglucosamine peptidoglycan residues and is required for nor- mal peptidoglycan synthesis (Wang et al. 2 009 ) . Loss of H P0310 , which leads to decreased peptidoglycan production, reciprocally augments the delivery of the other major cag secretion system substrate, CagA, into host cells. This suggests that func- tional interactions occur between H . pylori translocated effectors (Franco et al. 2009 ) . These fi ndings indicate that contact between c ag +strains and host cells acti- vates multiple signalling pathways that regulate oncogenic cellular responses, which may heighten the risk for transformation. Thus, while CagA may not promote cancer itself, exposure to CagA and infl am- matory insults may select for heritable host cell changes (genetic or epigenetic) that together contribute to cancer progression. Eradication of H . pylori in the human atrophic stomach does not greatly reduce the proportion of people who develop cancer over a 5-year time frame (Wong et al. 2004 ) , implying that CagA effects must be mediated relatively early in the carcinogenic process. 2.3.2 The H. pylori Vacuolating Cytotoxin The H. pylori gene vacA encodes a secreted protein (vacA) that was initially identifi ed on the basis of its ability to induce vacuolation in cultured epithelial cells (Telford et al. 1994 ) . However, vacA also exerts other effects on host cells (Boncristiano et al. 2003 ) , and vacA is a specifi c locus linked with gastric malignancy. All strains contain vacA , but there is marked variation in vacA sequences among strains with the regions of greatest diversity localized to the 5¢ signal terminus, the mid-region and the intermediate region (Rhead et al. 2 007 ) ; and vacA sequence diversity corresponds to variations in vacuolating activity. VacA is secreted and undergoes proteolysis to yield two fragments, p33 and p55 (Fig. 2 .2a ): the p33 domain contains a hydrophobic sequence that is involved in pore formation, whereas the p55 fragment contains cell-binding domains. VacA binds multiple epithelial cell-surface components, including the transmembrane protein receptor-type tyrosine protein phosphatase-z (PTPRZ1), fi bronectin, epidermal growth factor receptor (EGFR), various lipids and sphingomyelin, as well as CD18 (integrin b 2) on T cells (Polk and Peek 2 010 ) . The protein vacA not only induces vacuolation but also can stimulate apoptosis in gastric epithelial cells (Fig. 2 .2b ). Transient expression of p33 or full-length vacA induces cytochrome-c release from mitochondria, leading to the activation of cas- pase 3, and vacA proteins that contain a s1 signal allele induce higher levels of apoptosis than vacA proteins that contain a s2 allele or vacA mutants lacking the hydrophobic amino terminus region (Cover and Blanke 2 005 ) . In addition, vacA exerts effects on the host immune response that permit long- term colonization with an inherent increased risk of transformation. vacA binding to integrin b 2 blocks antigen-dependent proliferation of transformed T cells by 2 Gastric Cancer and H elicobacter pylori 33 a b H.pylori Secreted VacA VacAp88 Oligomerization Receptor p96 Apical surface Mitochondrion Endocytic compartment p88 p10 Epithelial Cytochrome c release cell Functional Vacuole Caspase 3 domains Apoptosis Basolateral surface p33 p55 Ca2+ Integrin b2 T cell NFAT P (Lamina propria) API NF-kB IL-2 Pore formation Cell binding IL-2receptor release Fig. 2.2 Constitution and functional effects of H . pylori Vaca protein. ( a ) VacA is secreted as a 96 kDa protein, which is rapidly cleaved into a 10 kDa passenger domain ( p10 ) and an 88 kDa mature protein ( p88 ). The p88 fragment contains two domains, designated p33 and p55, which are VacA functional domains. (b ) The p88 monomeric form of VacA binds to epithelial cells nonspe- cifi cally and through specifi c receptor binding. Following binding, VacA monomers form oligom- ers, which are then internalized and form anion-selective channels in endosomal membranes; vacuoles arise owing to the swelling of endosomal compartments. The biological consequences of vacuolation are currently undefi ned, but VacA also induces other effects, such as apoptosis, partly by forming pores in mitochondrial membranes, allowing cytochrome c release. VacA has also been identifi ed in the lamina propria, and probably enters by traversing epithelial paracellular spaces, where it can interact with integrin b 2 on T cells and inhibit the transcription factor nuclear factor of activated T cells (N FAT ), leading to the inhibition of IL-2 secretion and blockade of T cell activation and proliferation interfering with IL-2 (interleukin-2)-mediated signaling through the inhibition of Ca2 + mobilization and down regulation of the Ca2 + dependent phosphatase calcineu- rin (Boncristiano et al. 2003 ; Gebert et al. 2003 ) (Fig. 2.2 ). This in turn inhibits the activation of the transcription factor nuclear factor of activated T cells (NFAT) and its target genes I L2 and the high-affi nity IL-2 receptor-a (I L2RA ). vacA exerts effects on primary human CD4 + T cells that are different from its effects on trans- formed T cell lines by suppressing IL-2-induced cell cycle progression and prolif- eration in an NFAT-independent manner (Sundrud et al. 2 004 ) Collectively, these results suggest that vacA inhibits the expansion of T cells that are activated by bac- terial antigens, thereby allowing H . pylori to evade the specifi c immune response. Several epidemiological studies have evidenced linking vacA production to gastric cancer. H . pylori strains that express forms of vacA, that are active i n vitro are associated with a higher risk of GC than the strains that express inactive 34 A. Amedei and M.M. D’Elios forms of vacA (Gerhard et al. 1 999 ; Miehlke et al. 2000 ;). This relationship is consistent with studies that have examined the distribution of v acA genotypes throughout the world. In the regions that have high rate of distal gastric cancer, such as Colombia and Japan, most H. pylori strains contain vacA s1 and m1 alleles (Van Doorn et al. 1 999 ) . 2.3.3 Outer Membrane Proteins Generally, most H. pylori reside within the semi-permeable mucous gel layer of the stomach blanketing the apical surface of the gastric epithelium, but about 20% bind to gastric epithelial cells and genome analysis of H . pylori strains has revealed that an unusually high proportion of identifi ed open reading frames encode proteins that reside in the outer, as well as the inner, membrane of the bacterium (known as outer membrane proteins (omPs) (Oh et al. 2 006 ; McClain et al. 2 009 ) ). Consistent with genomic studies, H . pylori strains express multiple paralogous omPs, several of which bind to defi ned receptors on gastric epithelial cells, and strains differ in both expression and binding properties of certain omPs (Fig. 2 .3 ). A member of highly conserved omPs, the protein babA (encoded by the strain- specifi c gene b abA2 ), is an adhesin that binds the Lewis histo-blood-group antigen leb on gastric epithelial cells (Solnick et al. 2 004 ) . Gerhard et al. (1 999 ) have demonstrated that H. pylori babA2 + strains are associated with an increased risk of GC. SabA is an H. pylori adhesin that binds the sialyl-lewisx (lex) antigen, which is an established tumour antigen and a marker of gastric dysplasia that is up regulated by chronic gastric infl ammation (Mahdavi et al. 2 002 ) . Exploitation of host lewis antigens is further evi- denced by data demonstrating that the antigen of H . pylori lipopolysaccharide (LPS) contains various human lewis antigens (lex, ley, lea and leb); and the inactivation of lex and ley encoding genes prevents H . pylori from colonizing mice (Monteiro et al. 2 000 ) . Approximately 85% of H. pylori clinical isolates express lex and ley, and although both can be detected on individual strains but one antigen usually predominates (Wirth et al. 1999 ) . In vivo studies using mice have demonstrated that the lewis antigen expression pattern of colonizing bacteria is directly altered in response to the expression pattern of their cognate host. In leb expressing transgenic or wild-type control mice challenged with an H. pylori strain that expressed lex and ley, only bacterial populations recovered from leb positive mice expressed leb, and this was mediated by a putative galactosyl- transferase gene (b -(1,3)galT ) (Pohl et al. 2 009 ) . This suggests that lewis antigens facilitate molecular mimicry and allow H . pylori to escape host immune defenses by preventing the formation of antibodies against shared bacterial and host epitopes. Another differentially expressed omP of H . pylori is oipA that has been linked to disease outcome (Yamaoka et al. 2 002 ) . Expression of oipA is regulated by slipped strand mispairing within a CT-rich dinucleotide repeat region located in the 5 ¢ ter- minus of the gene. Several reports have demonstrated that the expression of proin- fl ammatory cytokines/chemokines (such as CXCL8, IL-6, CCL5) is co-regulated by oipA, as well as other effector proteins that may have a role in pathogenesis, such as matrix metalloproteinase 1

(mmP1) (Yamaoka et al. 2 002 ; Wu et al. 2006 ) . 2 Gastric Cancer and H elicobacter pylori 35 Fig. 2.3 Relations between gastric epithelial cells and H . pylori. Several adhesions (B abA, SabA and OipA ) mediate binding of H .pylori to gastric epithelial cells, probably through the apical sur- face. After adherence, H . pylori can translocate effector molecules such as CagA and peptidogly- can (P GN ) into the host cell. PGN is sensed by the intracellular receptor nucleotide-binding oligomerization domain-containing protein 1 (N OD1 ), which activates nuclear factor-k B (N F- k B ), p38, ERK and IRF7 to induce the release of pro-infl ammatory cytokines. After translocation, CagA is quickly phosphorylated (P ) by SRC and ABL kinases, leading to cytoskeletal rearrange- ments. Unphosphorylated CagA can trigger different signalling cascades such as the activation of NF- k B and the disruption of cell–cell junctions, which may contribute to the loss of epithelial bar- rier function. Injection of CagA seems to be dependent on basolateral integrin a 5 b 1. A J adherens junction, TJ tight junction, C SK c-src tyrosine kinase, I KK e Ik B kinase- e , IRF7 interferon regula- tory factor 7, R ICK receptor-interacting serine-threonine kinase 2, T BK1 TANK-binding kinase 1 2.4 Infl uence of Helicobacter pylori Infection on DNA Damage and Repair 2.4.1 DNA Repair Genetic instability is a hallmark of cancer. Therefore, one would expect that if H. pylori infection causes damage to DNA or decreases the activity of DNA repair pathways, it will allow accumulation of mutations that can cause inactivation of tumour suppressor genes or activation of oncogenes, which with time will increase the risk for growth of GC (Touati et al. 2 003 ) . MMR (Mismatch repair pathway) is one of the most studied DNA repair mech- anism. Human MMR is initiated by the binding of a heterodimeric protein com- plex, MutSa or MutS b to a mismatch. MutSa (formed by MSH2 and MSH6 proteins) binds preferentially to base-base mismatches and small insertion-deletion 36 A. Amedei and M.M. D’Elios loops. MutSb combines MSH2 an MSH3 proteins and binds to larger insertion- deletion loops. After the binding of one of these complexes to the mismatch, MutLa or MutLb is recruited. MutLa is formed by MLH1 and PMS2 proteins, and MutLb consists of the MLH1 and PMS1 proteins. These complexes signal downstream MMR com- ponents that proceed with the excision of the DNA containing the mismatch and resynthesis of the newly synthesized strand (Li 2 003 ) . Concerning the effect of H. pylori infection on the MMR pathway in GC, a recent study showed that, i n vitro expression of MLH1, PMS1, PMS2, MSH2 and MSH6 proteins decreased (dose- dependent) after H . pylori infection. Interestingly, the decrease in protein expres- sion correlated with mRNA down-regulation for MSH2 and MSH6. The levels of MLH1 in cells that had undergone H . pylori eradication, returned to values similar to the non-infected cells suggesting a reversible inhibition of MMR gene expression (Kim et al. 2 002 ) . To explore an association between H. pylori infection and decrease in MMR expression in vivo , Park et al. (2 005 ) studied H. pylori -infected gastritis and peptic ulcer disease tissue samples before and after eradication treatment. The results obtained elucidated that H . pylori eradication treatment increased MLH1 and MSH2 levels, suggesting that H. pylori gastritis might lead to a defi ciency of MMR in gas- tric epithelium that may increase the risk of mutation accumulation in the gastric mucosa cells during chronic H . pylori infection. In order to characterize the biological role of the bacteria-induced decrease in MMR gene/protein expression, Machado et al. (2 009 ) investigated the effect of H. pylori infection of gastric cells on major repair pathways. In AGS gastric epithe- lial cells as well as in C57BL/6 mice infected with H . pylori , MMR gene/protein expression decreased. This decrease regarding overall MMR is not dependent on the virulence factors of the bacteria and occurs during the early stages of infection. It was observed that MMR down-regulation in mice occurred after 3 months of infec- tion with H. pylori but not after 12 months. Another major repair pathway critical for the maintenance of genome stability is, Base excision repair (BER) that repairs a number of endogenously generated DNA lesions. BER removes various forms of base damage such as oxidation, methylation and deamination and is initiated by DNA glycosylases that recognize and cleave the damaged bases, creating abasic (AP) sites. The AP sites are cytotoxic and muta- genic, and therefore further processed by DNA glycosylases with AP-lyase activity or by APE1 (Guillet and Boiteux 2002 ; Fortini et al. 2003 ) . The single nucleotide gap is fi lled and the nick sealed to complete the repair reaction. APE1 expression was down-regulated in gastric cells infected with H . pylori , while OGG1 (a DNA glycosylase repairing oxidative DNA damage) remained constant. These results suggest that H. pylori infection causes an imbalance between generation and repair of AP sites, which is highly mutagenic (Machado et al. 2 009 ; Glassner et al. 1998 ) . All together the published literature suggests that increased levels of cellular dam- age and death due to for example reactive oxygen species (ROS) would lead to increased infl ammation and consequently to the production of more ROS and tumour-promoting 2 Gastric Cancer and H elicobacter pylori 37 cytokines. It also strongly indicates that one mechanism underlying genetic instability caused by H . pylori infection is deregulation of central DNA repair pathways. 2.4.2 DNA Damage H. pylori infection causes oxidative DNA damage of the host cells, which results in mutagenesis and disease development. Chronic infections that induce an infl amma- tory response are a great source of ROS. Various studies demonstrated an associa- tion between increased levels of oxidized bases and cancer or infl ammatory diseases including hepatitis, cirrhosis and H . pylori infection (Marnett 2 000 ) . The cellular consequences of DNA oxidation by ROS are several since it can lead to a number of different types of damage, such as oxidized bases, single and double-strand breaks (De Bont and van Larabeke 2 004 ) . Polyunsaturated fatty acid residues of phospho- lipids are also very sensitive to oxidation and the fi rst products derived from fatty acid oxidation can either be reduced into harmless fatty acid alcohols or react with metal, generating substances that damage DNA by forming exocyclic adducts that block the DNA base pairing region. The levels of DNA adducts are increased by chronic infections and infl ammation. Various studies have revealed a connection between H . pylori infection and oxidative DNA damage (De Bont and van Larabeke 2004 ) . It has been shown that the bacterial infection affects the antioxidant defenses of gastric cells, suggesting that this response is one of the cellular mechanisms to survive attack of ROS (Obst et al. 2 000 ; Khanzode et al. 2 003 ) . In vitro it was shown that H . pylori infection induced microsatellite instability (MSI), which correlated with a decrease in expression of the MMR proteins MLH1 and MSH2 (Yao et al. 2 006 ) . The decrease in MLH1 expression could be explained by the CpG methylation detected in the MLH1 promoter region from infected cells. It has been suggested that H. pylori is responsible for methylation of promoters in early steps of gastric transformation and eradication of infection may result in rever- sal of methylation (Perri et al. 2007 ; Leung et al. 2006 ) . In cancer, DNA methylation is often aberrant and methylation can lead to mutations due to the formation of mutagenic adducts (Stern et al. 2 000 ) . Alkylated DNA adducts can generate, for example, mutagenic AP sites and imidazole ring opening, which can be responsible for the blocking of DNA replication (Tudek et al. 1992 ) . With the purpose of eluci- date the nature of mutations introduced by H. pylori infection, Touati et al. ( 2003 ) used mice carrying the l phage shuttle vector containing a cII reporter to show that mutation frequencies increased after 6 months of infection. The mutation spectrum in infected mice was dominated by mutations that could be explained to originate from oxidative damage, supporting the idea that the bacterial infection induces oxi- dative DNA damage, which is associated with the host-infl ammatory response. These results add novelty to the fi eld of H. pylori pathogenesis by showing that H. pylori infection induces a decrease in repair activity and a transient mutator phe- notype, contributing to epithelial gastric genomic instability and to neoplastic transformation. 38 A. Amedei and M.M. D’Elios 2.4.3 mtDNA Instability and H. pylori Infection There is evidence that H . pylori plays a role in the appearance of mutations in mitochondrial DNA (mtDNA) (Hiyama et al. 2003 ; Lee et al. 2007 ) . In gastric cancer, mtDNA mutations occur both in the non coding D-loop region and the cod- ing genes (Wu et al. 2 005 ; Han et al. 2 003 ) . Recently it has been demonstrated, that H. pylori infection resulted in increased mutations in the non-coding D-loop as well as the coding genes ND1 and COI of mtDNA of gastric cells (Machado et al. 2009 ) . The increase in the number of mutations was mainly attributed to a rise of transitions, possibly a consequence of oxidative damage. The increase in mtDNA mutations was dependent on the bacterial virulence factors. H . pylori positive chronic gastritis patients also showed that transitions were the main mutational event and patients harboring mtDNA mutations were frequently infected by H. pylori with cagA+ and vacA s1/m1 genotype (Machado et al. 2 009 ) . In view of the studies cited, H. pylori infection is able to induce mtDNA muta- tions both i n vitro and i n vivo , suggesting that the mitochondrial genome is highly susceptible to bacterial infections. 2.5 Pro-tumorigenesis Host Factors 2.5.1 Human Gene Polymorphisms One of the paradoxes of H . pylori infection is its association with mutually exclu- sive clinical outcomes such as GC and duodenal ulcer disease. As we have already discussed previously, various bacterial virulence factors (e.g., cagA , vacA , BabA and OipA ) have an undoubted role in the pathogenesis of these diseases, but they do not readily distinguish between the two key outcomes of GC and duodenal ulcer. Also, hereditary factors clearly increase the risk of gastric cancer and this malig- nancy is part of a number of familial cancer syndromes. The most celebrated famil- ial case of gastric cancer is that of Napoleone Bonaparte (Marchall and Windsor 2005 ) . All these considerations prompted some researchers to consider the host genetic factors that may be relevant to this process. But what are the genes considered to be important and where to focus resources? Since H . pylori achieve most damage through induction of chronic infl ammation, it is reasonable to consider genes that control this process as appropriate candidates. 2.5.1.1 IL-1 Gene The IL-1 gene cluster on chromosome 2q contains three related genes within a 430 kb region: I L-1A , IL-1B and I L-1RN , which encode for the pro-infl ammatory cytokines IL-1a and IL-1 b , as well as their endogenous receptor antagonist IL-1ra, 2 Gastric Cancer and H elicobacter pylori 39 respectively (Dinarello 1 996 ) . IL-1 b is upregulated in the presence of H. pylori and plays a central role in initiating and amplifying the infl ammatory response to this infection (El-Omar 2 001 ) . Three diallelic polymorphisms in I L-1B have been reported, all representing C–T or T–C transitions, at positions−511, −31, and +3954 bp from the transcriptional start site (Bidwell et al. 2 001 ) . The I L-1RN gene has a penta-allelic 86 bp tandem repeat (VNTR) in intron 2, of which the less common allele 2 (I L-1RN *2) is associ- ated with a wide range of chronic infl ammatory and autoimmune conditions (Bidwell et al. 2001 ) . There are several epidemiologic studies that have tested the role of these candidate loci. El-Omar et al. (2 000 ) fi rst studied the correlation of

high IL-1b genotypes (two polymorphisms in the I L-1B and I L-1RN genes) with hypochlorhy- dria and gastric atrophy in a Caucasian population of gastric cancer. These relatives were known to be at increased risk of developing the same cancer and had a high prevalence of precancerous abnormalities (hypochlorhydria and gastric atrophy) but only in the presence of H . pylori infection (El-Omar et al. 2000 ) . The association between the same IL-1b genetic polymorphisms and gastric cancer itself was sub- sequently examined using two independent Caucasian case control studies from Poland and the USA (El-Omar et al. 2 000, 2003 ) . In the above studies the pro- infl ammatory IL-1 genotypes were associated with an increased risk of both intesti- nal and diffuse types of gastric cancer; however, the risk was restricted to the non cardia sub-site. Indeed, the IL-1 markers had no effect on risk of cardia gastric adenocarcinomas, esophageal adenocarcinomas or esophageal squamous cell carcinomas (El-Omar et al. 2 003 ) . The latter fi ndings are entirely in keeping with the proposed mechanism for the effect of these polymorphisms in gastric cancer, namely the reduction of gastric acid secretion. Thus, a high IL-1b genotype appears to increase the risk of non-cardia gastric cancer, a disease characterized by hypochlorhydria, while it has no effect on cancers associated with high acid exposure such as esophageal adeno- carcinomas and some cardia cancers. The association between I L-1 gene cluster polymorphisms and gastric cancer and its precursors has been confi rmed independently by other groups covering Caucasian, Asian and Hispanic populations (Rad et al. 2003 : Palli et al. 2005 ; Furuta et al. 2 002 ; Zeng et al. 2 003 ) . Machado et al. (2 001 ) were the fi rst to confi rm the association between I L-1 markers and gastric cancer in Caucasians and reported similar modest odds ratios to those reported by El-Omar (Machado et al. 2 001 ) Furthermore, the same group subsequently reported on the combined effects of pro- infl ammatory IL-1 genotypes and H . pylori bacterial virulence factors (c agA posi- tive, VacA s1 and VacA m1 ). This study on combined effects reported, that for each combination of bacterial and host genotype the odds of having a gastric carcinoma were greatest in those with both bacterial and host high-risk genotypes (Figueiredo et al. 2002 ) . This highlights a potentially important interaction between host and bacterium in the pathogenesis of gastric cancer. A decisive piece of evidence that confirmed the apparent role of IL-1b in H. pylori -induced gastric carcinogenesis came from a transgenic mouse model in which IL-1b over production was targeted to the stomach by the H+ /K + -ATPase beta 40 A. Amedei and M.M. D’Elios promoter (Tu et al. 2008 ) . With the over expression of IL-1 b confi ned to the stomach, these transgenic mice had a thickened gastric mucosa, produced lower amounts of gastric acid and developed severe gastritis followed by gastric atrophy, intestinal metaplasia, dysplasia and adenocarcinomas. Importantly, these IL-1b transgenic mice proceeded through a multistage process that mimicked human gastric neopla- sia. These changes occurred even in the absence of H . pylori infection, which, when introduced, led to an acceleration of these abnormalities. Most interestingly, the pathological changes, including the progression to gastric cancer were prevented by infusion of IL-1 receptor antagonist, proving beyond doubt that IL-1 b is responsible for the pathological effects. Another crucial piece of evidence came from well-designed recent study (Stoicov et al. 2009 ) : T-bet is a central regulator of the cytokine environment during Helicobacter infection and T-bet knockout (KO) mice maintain infection for 15 months at levels similar to wild type mice and develop signifi cant infl ammation with a blunted Th1 (T helper 1). Furthermore, this blunted response is associated with the preservation of parietal and chief cells and protection from the develop- ment of gastric cancer. Crucially however, T-bet KO mice respond to H elicobacter infection with a markedly blunted IL-1b and TNF-a and elevated IL-10 levels. This mirrors the situation in humans who are protected against gastric cancer, and merits further research. 2.5.1.2 TNF-a, IL-10 and CXCL8 Genes Soon after the identifi cation of IL-1 gene cluster polymorphisms as risk factors for gastric cancer, the proinfl ammatory genotypes of T NF- a and I L-10 were reported as independent additional risk factors for non cardia gastric cancer (El-Omar et al. 2000 ) . TNF- a is another powerful pro-infl ammatory cytokine that is produced in the gastric mucosa in response to H . pylori infection (D’Elios et al. 1 997a ) . The T NF- a -308 G>A polymorphism is known to be involved in a number of infl ammatory conditions. Carrying the pro-infl ammatory A allele increased the risk of non cardia gastric cancer. This association was independently confi rmed by a study from Machado et al. (2 003 ) . The same group also showed that the association between the T NF-a -308 G>A polymorphism and increased risk of gastric carcinoma is dependent on a linkage disequilibrium with an yet unidentifi ed locus (Canedo et al. 2008a, b ) . Another interleukin, IL-10, is an anti-infl ammatory cytokine that down regulates IL-1 b , TNF-a , interferon- g and other pro-infl ammatory cytokines. A rela- tive defi ciency of IL-10 may result in a Th1-driven hyper-infl ammatory response to H. pylori with greater damage to the gastric mucosa. A recent study reported that homozygosity for the low-IL-10 A TA haplotype (based on three promoter polymor- phisms at positions −592, −819 and −1,082) increased the risk of non cardia gastric cancer with an odds ratio of 2.5 (95% C I : 1.1–5.7) (El-Omar et al. 2 003 ) . Interestingly, there seems to be a cumulative effect in carrying more than one pro-infl ammatory cytokine gene polymorphism. The same authors studied the 2 Gastric Cancer and H elicobacter pylori 41 effect of having multiple pro-infl ammatory genotypes ( IL-1 b -511*T, IL-1RN *2*2, TNF- a -308*A and I L-10 ATA/ATA) on the risk of non-gastric cancer. With the addition of each relevant polymorphism the risk of non-gastric cancer increased progressively such that when three to four of these polymorphisms were present, the risk for gastric cancer was increased 27-fold (El-Omar et al. 2 003) . The fact that H. pylori is a prerequisite for the association of these polymorphisms with malig- nancy demonstrates that in this situation, infection−induced infl ammation may indeed be contributing to carcinogenesis. A chemokine that has an important role in the pathogenesis of H. pylori induced diseases is CXCL8. This chemokine is a potent chemoattractant for neutrophils and lymphocytes. It also has effects on cell proliferation, migration and tumour angio- genesis. The gene has a well established promoter polymorphism at position −251 (I L-8– 251 T>A). The A allele is associated with increased production of CXCL8 in H. pylori infected gastric mucosa (Smith et al. 2 004 ) . It has been reported to increase the risk of severe infl ammation and precancerous gastric abnormalities in Caucasian and Asian populations (Smith et al. 2 004 ; Taguchi et al. 2005 ) . 2.5.1.3 Immune Response Genes I n the last few years, association of other genes (particularly gene correlate with immune response) polymorphisms with the increased risk of GC have been studied vigorously. The seminal study by D’Elios et al. (1 997a ) demonstrated that H . pylori typically induces a Th1 response in infected individuals. A preferential activation of Th1 responses has been reported in different animal models, such as mice, beagle dogs, monkeys, and gerbils experimentally infected with H . pylori or H. felis (Mohammadi et al. 1997 ; Rossi et al. 2 000 ; Mattapallil et al. 2 000 ; Wiedemann et al. 2009 ) . A large number of studies agree that H . pylori elicits Th1 response and is associated with more severe disease, including precancerous and cancerous lesions (D’Elios et al. 1 997b ; Bamford et al. 1998 ; Sommer et al. 1 998 ; Fox et al. 2000 ; Lehmann et al. 2 002 ; Del Giudice et al. 2001 ; Tomita et al. 2001 ; de Jonge et al. 2004 ; Wen et al. 2 004 ) . The major Th1 promoting factor of H . pylori is HP-NAP that stimulates IL-12 production via TLR2 (Amedei et al. 2 006 ) . However, other Th1 driving factors also exist, such as products of c ag, as well as VacA, hsp90, outer membrane protein 18, cysteine-rich protein A, and lipopolysaccharide (D ’Elios et al. 1 997a ; Guiney et al. 2 003 ; Deml et al. 2 005 ; Voland et al. 2 006 ; Taylor et al. 2006 ; Takeshima et al. 2 011 ) . Hou et al. (2 007 ) studied the association between gastric cancer and several variants in genes responsible for Th1 cell-mediated response, that is typical in H . pylori infection, (D’Elios et al. 1 997a ; Amedei et al. 2006 ) , and in particular the results suggest that a polarized Th1 response may play a role in the genesis of severe clinical forms of disease (D’Elios et al. 1 997a, b ) , Hou et al. ( 2007 ) subsequently reported that carrying the C allele of the interferon gamma receptor 2 (I FNGR2 ) (Ex7–128) rs4986958 polymorphism was associated with an increased risk of gastric cancer compared with the TT genotype. Further more, there was an additive effect when the I FNGR2 polymorphism was combined with 42 A. Amedei and M.M. D’Elios the TNF-a- 308 TT genotype (O R 5.5, 95% C I 1.5–19.4). The interferon gamma receptor 1 (I FNGR1 ) –56C/T gene polymorphism was studied by Canedo et al. (2 008a, b ) in patients with early onset GC (less than 40 years of age at the time of diagnosis) there was a signifi cant over-representation of the I FNGR1 –56*T/*T homozygous genotype with an O R of 4.1 (95% CI 1.6–10.6). A recent study evaluated polymorphisms in the Th1 IL7R gene and one polymor- phism in the Th2 IL5 gene (Mahajan et al. 2008 ) . The OR for IL7R rs1494555 were 1.4 (95% C I 1.0–1.9) for A/G and 1.5 (95% C I 1.0–2.4) for G/G carriers compared with A/A carriers (P = 0.04). The O R for IL5 rs2069812 were 0.9 (95% CI 0.7–1.3) for C/T and 0.6 (95% CI 0.3–1.0) T/T carriers compared with C/C carriers ( P =0.03). These results suggest that I L5 rs2069812 and I L7R rs1389832, rs1494556 and rs1494555 polymorphisms may contribute to the risk of GC. Genetic polymorphisms of the cytokines and chemokines discussed above clearly play an important role in the risk of H. pylori -induced gastric adenocarcinomas. However, H . pylori is initially handled by the innate immune response and it is con- ceivable that functionally relevant polymorphisms in the genes of this arm of the immune system may affect the magnitude and subsequent direction of the host’s response against the infection. Most H . pylori cells do not invade the gastric mucosa but the inflammatory response against it is triggered through the attachment of H. pylori to the gastric epithelia, mainly via TLR2 or TLR4 (Amedei et al. 2006 ; Segal et al. 1 997 ) . Toll-like receptor 4 (TLR4) was initially identifi ed as the poten- tial signaling receptor for H. pylori on gastric epithelial cells (Su et al. 2 003 ) and recently, Hold et al. ( 2007 ) have shown that the TLR4 +896A>G polymorphism was associated with an exaggerated and destructive chronic infl ammatory phenotype in H. pylori infected patients. This phenotype was characterized by gastric atrophy and hypochlorhydria, the hallmarks of subsequent increased risk of gastric cancer. The association of T LR4 +896 A>G polymorphism with both GC and its precur- sor lesions implies that it is relevant to the entire multistage process of gastric car- cinogenesis that starts with the H . pylori colonization of the gastric mucosa. Patients with this polymorphism have an increased risk of severe infl ammation and subse- quent development of hypochlorhydria and gastric atrophy, which are regarded as the most important precancerous abnormalities. This severe infl ammation is

initi- ated by H . pylori infection but it is entirely feasible that subsequent co-colonization of an achlorhydric stomach by a variety of other bacteria may sustain and enhance the microbial infl ammatory stimulus and continue to drive the carcinogenic process. Recently another T LR4 polymorphism is associated to increase of the risk of intestinal type gastric cancer. The T LR4 Thr399Ile was linked with an increased hazard ratio of 5.38, (95% C I 1.652–8.145), P = 0.006 (Santini et al. 2 008 ) . There are other reports of innate immune response gene polymorphisms being associated with increased risk of gastric cancer: mannose binding lectin is an anti- gen recognition molecule involved in systemic and mucosal innate immunity. It is able to bind to a range of microbes and subsequently kill them by activating the complement system and promoting complement independent opsonophagocytosis. A latest work showed that polymorphisms in the mannose binding lectin-2 gene 2 Gastric Cancer and H elicobacter pylori 43 ( MBL2 ) were associated with increased risk of GC. In haplotype analysis, the HYD haplotype was associated with an increased risk of stomach cancer when compared with HYA, the most common haplotype (O R = 1.9, 95% C I 1.1–3.2; P = 0.02) (Baccarelli et al. 2 006 ) . 2.5.2 b -Catenin in H. pylori Carcinogenesis A specifi c host molecule that may infl uence carcinogenic responses in conjunction with H . pylori is b -catenin, a ubiquitously expressed protein that has distinct func- tions within host cells. Membrane bound b -catenin is a component of adherens junctions that link cadherin receptors to the actin cytoskeleton. Cytoplasmic b -catenin is a downstream component of the Wnt signal transduction pathway (Fig. 2.4a ). In the absence of Wnt ligand, the inhibitory complex induces the degra- dation of b -catenin and maintains low steady state levels of free b -catenin either in the cytosol or the nucleus. After binding of wnt to its receptor Frizzled, b -catenin translocate to the nucleus and activate the transcription of target genes that are involved in carcinogenesis (Fig. 2 .4b ). Increased b -catenin expression or A PC mutations are present in up to 50% of GC specimens when compared with non-transformed gastric mucosa (Tsukashita et al. 2003 ) , and the nuclear accumulation of b - catenin is increased in gastric adenomas and foci of dysplasia (Cheng et al. 2 004 ) , These studies suggest that, aberrant acti- vation of b -catenin precedes the development of GC. H . pylori increases the expres- sion of b -catenin target genes in colonized mucosa and during co-culture with gastric epithelial cells i n vitro. Therefore, it is likely that the activation of b -catenin signalling is a central component in the regulation of pre-malignant epithelial responses to H . pylori . H. pylori isogenic mutant studies have revealed that the translocation of CagA into gastric epithelial cells induces the nuclear accumulation and functional activa- tion of b -catenin (Cheng et al. 2 004 ; Franco et al. 2005 ) . Murata-Kamiya et al. ( 2007 ) demonstrated that intracellular CagA interacts with E-cadherin, disrupts the formation of E-cadherin–b -catenin complexes and induces nuclear accumulation of b- catenin, all of which are independent of CagA phosphorylation (Fig. 2 .4a ). Consequences of CagA-dependent b -catenin activation include the upregulation of target genes that infl uence GC, such as caudal type homeobox 1 ( CDX1 ), which encodes a transcription factor that is required for the development of intestinal metaplasia (Murata-Kamiya et al. 2 007 ) . Recently, additional pathways have been demonstrated to regulate b -catenin acti- vation in response to H . pylori . Activation of Pi3K and AKT leads to the phospho- rylation and inactivation of GSK3b , permitting b -catenin to accumulate in the cytosol and the nucleus. A recent study have shown that CagA Cm motifs interact with mET, leading to the sustained induction of Pi3K–AKT signalling in response to H. pylori and the subsequent activation of b -catenin i n vitro and i n vivo (Fig. 2.4b ) (Suzuki et al. 2 009 ) 44 A. Amedei and M.M. D’Elios a H.pylori Macrophage TNFa VacA E-catenin OipA Apical surface T4SS TNFR MET PGN CagA b-catenin CagA CagA CagA AKT AKT AKT b-catenin P13K P Axin b-catenin GSK3b b-catenin Target P APC APC LEF TCF genes GSK3b Ubiquitin-mediated Axin proteolysis Basolateral surface Hyperproliferation and aberrant differentiation b LRP5 LRP5 WNT E-cadherin FRZ LRP6 LRP6 FRZ b-catenin Ubiquitin-mediated a-catenin GSK3b Axin DSH proteolysis Axin APC b-catenin GSK3b Target b-catenin APC genes LEF TCF Ubiquitin-mediated b-catenin LEF TCF proteolysis Fig. 2.4 Aberrant b -catenin activation by H elicobacter pylori. ( a ) Membrane-bound b -catenin links cadherin receptors to the actin cytoskeleton, and in non-transformed epithelial cells b -catenin is primarily localized to E-cadherin complexes. Cytoplasmic b -catenin is a downstream compo- nent of the Wnt pathway; in the absence of Wnt, cytosolic b -catenin remains bound within a multi- protein inhibitory complex comprised of glycogen synthase kinase-3b ( GSK3b ), the adenomatous polyposis coli (A PC ) tumour suppressor protein and axin. Under unstimulated conditions, b -catenin is phosphorylated (P ) by GSK3b , ubiquitylated and degraded. (b ) Binding of Wnt to its receptor, Frizzled ( FRZ ; lower panel ), activates dishevelled (D SH ) and Wnt co-receptors, low density lipo- protein receptor-related protein 5 (L RP5 ) and LRP6, which then interact with axin and other mem- bers of the inhibitory complex, leading to the inhibition of the kinase activity of GSK3 b 141. These events inhibit the degradation of b -catenin, leading to its nuclear accumulation and formation of heterodimers with the transcription factor lymphocyte enhancer factor/T cell factor (L EF/TCF ), resulting in the transcriptional activation of target genes that infl uence carcinogenesis. Injection of CagA results in the dispersal of b -catenin from b -catenin–E-cadherin complexes at the cell mem- brane, allowing b -catenin to accumulate in the cytosol and nucleus. CagA, potentially by binding MET or other H . pylori constituents such as OipA, VacA and peptidoglycan (P GN ) as well as TNF a , which is produced by infi ltrating macrophages, can activate PI3K, leading to the phospho- rylation and inactivation of GSK3b . This liberates b -catenin to translocate to the nucleus and upregulate genes, leading to increased proliferation and aberrant differentiation; TNFR TNF receptor Studies focused on Pi3K and AKT have revealed that other H. pylori constituents may also infl uence b -catenin activation. Nakayama et al. ( 2009 ) reported that vacA can activate Pi3K-dependent b -catenin activation, and oipA has also been impli- cated in aberrant nuclear localization of b -catenin, although the specifi c mechanism underpinning this observation has not yet been delineated. 2 Gastric Cancer and H elicobacter pylori 45 H.pylori Ligand Cag Apical P P surface P P P P Transmembrane ADAMs P13K EGFR ligands AKT Cell polarity Lysosome BCL-2 BAX GSK3β Endocytosis Migration Caspase 3 β-catenin Target genes Apoptosis Basolatcral surface Gastric epithelial cell Fig. 2.5 eGFr transactivation by H. pylori and induced cellular effects with carcinogenic potential. H. pylori transactivates epidermal growth factor receptor (E GFR ) through cleavage, which is dependent on a disintegrin and metalloproteinase ( ADAM ) family proteinases, of EGFR ligands, such as heparin-binding EGF-like growth factor (H BEGF ) in gastric epithelial cells. One down- stream target of EGFR transactivation is PI3K–AKT, which leads to AKT-dependent cell migration, inhibition of apoptosis and b -catenin activation. B AX BCL-2-associated X protein, G SK3b glycogen synthase kinase-3b 2.5.3 Transactivation of EGFR by H. pylori EGFR is an important target for the treatment of several malignancies other than gastrointestinal cancers. Phosphorylation and activation of EGFR increases the transcriptional activity of b -catenin by the inactivation of GSK3b . H . pylori infec- tion, gastric epithelial hyperplasia and gastric atrophy are strongly linked to the dysregulation of EGFR and/or cognate ligands, such as heparin-binding EGF-like growth factor (HbEGF) in human animal and cell culture models (Romano et al. 1998 ; Wong et al. 2001 ) . The in vitro transactivation of EGFR by H. pylori is depen- dent on genes in the c ag pathogenicity island and secreted proteins as well as host factors such as TLR4 and NoD1 (Keates et al. 2 005 ; Basu et al. 2 008 ) . EGFR can be activated by direct interaction with ligands, which initiate dimerization and increased kinase activity (Fig. 2.5) . Cytokines, such as TNF a , and other stimuli are present in the gastric mucosa following H . pylori infection (D’Elios et al. 1 997a ) and transactivate EGFR in gastric epithelial cells (Pece and Gutkind 2 000 ) . EGFR transactivation by these elements is mediated through met- alloproteinase-dependent cleavage of EGFR (Erbb family) ligands in a manner 46 A. Amedei and M.M. D’Elios similar to H . pylori induced EGFR transactivation (Pece and Gutkind 2 000 ) . The required metalloproteinases are likely to be members of disintegrin and metallo- proteinase (ADAm) family. Given a requirement for metalloproteinase activity in H . pylori initiated HbEGF release, ADAm17, a multidomain type I transmembrane protein that contains an extracellular zinc-dependent protease domain is an ideal candidate enzyme for the regulation of this pathway (Pece and Gutkind 2 000 ) . ADAm17 was the fi rst ADAm to have a defi ned physiological substrate, the precursor transmembrane form of TNF a . In fact inhibitors of ADAm17 block the release of soluble TNFa . Although ADAm17 is ubiquitously expressed in the gastrointestinal tract and is a target of drug development for infl ammatory conditions, the disorganized and infl amed nature of the gastrointestinal tract that develops in ADAm17-defi cient mice suggests that this metalloproteinase may also have an important role in gut epithelial homeostasis, perhaps through the regulation of EGFR ligands (Sunnarborg et al. 2 002 ) . Therefore, a better understanding of the function of ADAm17 during H. pylori -induced gastric epithelial injury could provide insights into its potential role in gastric carcinogenesis. H. pylori specifi cally amplifi es EGFR signalling by both activating EGFR and decreasing EGFR degradation by blocking endocytosis (Bauer et al. 2 009 ) . The transactivation of EGFR by this pathogen mediates several cellular responses with pre-malignant potential (Fig. 2 .5 ). Alterations in apoptosis have been implicated in the pathogenesis of H. pylori induced injury before the development of GC and the ability of H . pylori to induce apoptosis in gastric epithelial cells has been well dem- onstrated i n vitro (Cover et al. 2003 ) However, chronically infected mongolian ger- bils harbouring c ag+ strains exhibit increased gastric epithelial cell proliferation without a concordant increase in apoptosis (Peek et al. 2 000 ) which may contribute to the augmented risk for gastric cancer that is associated with cag +strains. H. pylori has been shown to induce anti-apoptotic pathways in gastric epithelial cells through cag mediated EGFR transactivation (Maeda et al. 2 002 ) (Fig. 2.5 ). Altered cell polarity and migration are phenotypic responses to H . pylori infection. Although they may acutely promote gastric mucosal repair, long term stimulation of these responses has been linked to transformation and tumorigenesis (Nagy et al. 2009 ) . As the biological responses to EGFR activation include increased proliferation, reduced apoptosis, the disruption of cell polarity and enhanced migration, transacti- vation of EGFR by H. pylori is an attractive target for studying early events that may precede transformation. 2.5.4 H. pylori , Gastric Autoimmunity and Gastric Atrophy A strong association between H . pylori infection and gastric autoimmunity has been highlighted by a number of clinical and epidemiological studies indicating that most of patients with autoimmune gastritis (AIG) have or had H . pylori infection 2 Gastric Cancer and H elicobacter pylori 47 Fig. 2.6 Different effector functions of T cells in H . pylori -related gastric lymphoma and gastric autoimmunity. T cells are essential for defence against infection, but inappropriate Th responses can be harmful for the host. In H . pylori -infected patients with gastric lymphoma, gastric H . pylori - specifi c Th cells display defi cient cytotoxic control (both perforin and Fas-Fas-ligand mediated) of B-cell growth. Such cytolytic defects, associated with the chronic delivery of costimulatory signals by

Th cells and by the production of cytokines with B-cell growth factor activity, together with chronic exposure to H. pylori antigens, would result in overgrowth of B cells of gastric low-grade MALT B-cell lymphoma. Conversely, H. pylori induces gastric autoimmunity via molecular mim- icry by the expansion of H . pylori -specifi c T cells that cross-react with H+ ,K + -ATPase epitopes. Cross-reactive T cells would result in destruction of gastric mucosa, by the long-lasting activation of both Fas-ligand (F asL )-induced apoptosis and perforin-mediated cytotoxicity (D’Elios et al. 2 004 ) . H. pylori associated autoimmune gastritis is characterized by an infl ammatory infi ltrate of the gastric mucosa, including T cells, macrophages and B cells. It mainly affects the corpus and the fundus, and it is accompanied by loss of gastric parietal and zymogenic cells. We have characterized at molecular level the gastric T-cell mediated responses to H. pylori and to the H + , K+ -ATPase autoantigen in a series of H . pylori -infected patients with gastric autoimmunity (Amedei et al. 2 003 ) (Fig. 2 .6 ). Among gastric Th clones, a number proliferated to H . pylori, but not to the H. pylori proteins CagA, VacA, hsp, urease nor to H+ , K + -ATPase. Some other Th clones proliferated to H+ , K + -ATPase and not to H. pylori (autoreactive), and a third group of clones was found that proliferated to both H . pylori and H+ , K+ -ATPase (cross-reactive) (Amedei et al. 2 003 ) . All the Th clones able to proliferate to H + , K + -ATPase were studied for their ability to respond to the 261 overlapping 15-mer peptides covering the amino acid sequence of a and b chain of the human H + , K + - ATPase. In the series of cross-reactive Th clones 11 recognized their epitope in the 48 A. Amedei and M.M. D’Elios a chain and two clones in the b chain. In the subgroup of autoreactive Th clones 6 recognized their epitope in the a chain and 9 in the b chain of the proton pump. Therefore, some “shared” H+ , K+ -ATPase epitopes, mainly in the a chain, are cross- reactive with epitopes of H . pylori antigens, whereas others can be considered as “private” epitopes of H+ , K + -ATPase. A cross-reactive H . pylori peptide could be found for each of the 10 H+ , K + -ATPase/H . pylori cross-reactive gastric Th clones. Overall, that study led to the identifi cation of nine different H . pylori proteins (such as lipopolysaccharide biosynthesis protein, histidine kinase, porphobilinogen deam- inase, dimethyl-adenosine transferase, glucose-inhibited division protein A, VirB4 homolog, phosphoglucosamine mutase, acetate kinase, penicillin-binding protein-2) each harboring a T-cell peptide suitable for cross-reaction with T-cell epitopes of gastric H+ , K + -ATPase a chain. Interestingly, none of the bacterial epitopes recog- nized by cross-reactive Th clones belong to the known H. pylori immunodominant antigens, such as CagA, VacA and urease, which are major targets of gastric T-cell responses in H . pylori infected patients with peptic ulcer (D’Elios et al. 1 997a ) . Two possibilities can be considered: these peptides are implicated in cross-reactivity because of their structural properties or alternatively a physiological relevance implicating these particular nine proteins can be postulated. All the cross-reactive and autoreactive H+ , K + -ATPase-specifi c Th clones after activation were able to induce cell death via either Fas–Fas ligand-mediated apoptosis or perforin-mediated cytotoxicity against target cells (Amedei et al. 2 003 ) . This ability to induce apopto- sis in T cells might give a selective advantage that can promote survival and persis- tence of bacteria, allowing H . pylori to escape the host immune response. On the other hand, the relevance of cross-reactive and autoreactive cytolytic Th effector cells in the genesis of AIG is consistent with data in the mouse model that Fas- related death is required for the development of full-blown destructive autoimmune gastritis (Marshall et al. 2 002 ) . Based on these results, it is tempting to speculate that in the “gastric autoimmune infl ammatory scenario” in which cross-reactive and autoreactive Th clones are activated, parietal cells might become target of the pro- apoptotic and cytotoxic activity of cross-reactive and autoreactive gastric Th cells. The end point of this process would be gastric atrophy, which might lead to gastric cancer. 2.6 H. pylori and Immunity in MALT Lymphoma Extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) represents the third commonest form of non-Hodgkin lym- phoma (Armitage 1 997 ; Du 2007 ) . The most frequent site of MALT lymphomas is the stomach, where they were fi rst recognized as a distinct entity (Isaacson and Wright 1983 ) . A link of H. pylori infection with gastric MALT lymphoma was pro- vided by the identifi cation of H. pylori in the majority of the lymphoma specimens (Wotherspoon et al. 1 991 ) . H . pylori related low-grade gastric MALT lymphoma represents a model for studying the interplay between chronic infection, immune 2 Gastric Cancer and H elicobacter pylori 49 response, and lymphoma genesis (Fig. 2 .6 ). This lymphoma represents the fi rst described neoplasia susceptible of regression following antibiotic therapy resulting in H. pylori eradication (Wotherspoon et al. 1 991 ) . A prerequisite for lymphoma genesis is the development of secondary infl ammatory MALT induced by H. pylori . Tumour cells of low-grade gastric MALT lymphoma (MALToma) are memory B cells still responsive to differentiation signals, such as CD40 costimulation and cytokines produced by antigen-stimulated Th cells, and dependent for their growth on the stimulation by H. pylori specifi c T cells (Hussell et al. 1993, 1996 ; Greiner et al. 1997 ; D’Elios et al. 1999 ) . In early phases, this tumour is sensitive to with- drawal of H . pylori induced T-cell help, providing an explanation for both the tumour’s tendency to remain localized to its primary site and its regression after H. pylori eradication. The analysis of the antigen induced B-cell help exerted by H. pylori reactive gastric T-cell clones provided detailed information on the molecu- lar and cellular mechanisms associated with the onset of low-grade gastric MALToma. In the stomach of MALToma patients, a high percentage of Th cells were specifi c for H . pylori (between 3% and 20% in each case). In particular, 25% were specifi c for urease, 4% for VacA, and none for CagA or HSP; 71% of Th clones proliferated in response to H . pylori antigens, different from Urease, CagA, VacA, or HSP (D’Elios et al. 1 999 ) . Each H . pylori -specifi c Th clone derived from gastric MALToma produced IL-2 and a variety of B-cell-stimulating cytokines, such as IL-4 and IL-13 (D’Elios et al. 1999 ) . In vitro stimulation with the appropri- ate H . pylori antigens induced H . pylori specifi c Th clones derived from gastric MALToma to express powerful help for B-cell activation and proliferation (D’Elios et al. 1999 ) . B cells from MALToma patients proliferate in response to H . pylori , but the B-cell proliferation induced by H . pylori antigens was strictly T-cell-dependent because it could not take place with H . pylori and without T helper cells (D’Elios et al. 1999, 2003 ; Bergman and D’Elios 2 010 ) . In chronic gastritis patients, either with or without ulcer, the helper function towards B cells exerted by H. pylori anti- gen-stimulated gastric T-cell clones was negatively regulated by the concomitant cytolytic killing of B cells (D’Elios et al. 1 997a ) . In contrast, gastric T-cell clones from MALToma were unable to down modulate their antigen-induced help for B-cell proliferation. Indeed, none of these clones was able to express perforin- mediated cytotoxicity against autologous B cells. Moreover, the majority of Th clones from uncomplicated chronic gastritis induced Fas-Fas ligand mediated apop- tosis in target cells, whereas only a small fraction of H . pylori specifi c gastric clones from MALToma were able to induce apoptosis in target cells, including autologous B cells (D’Elios et al. 1 999 ) . Both defective perforin mediated cytotoxicity and poor ability to induce Fas-Fas ligand mediated apoptosis were restricted to MALToma- infi ltrating T cells, since H . pylori -specifi c Th cells derived from the peripheral blood of the same patients expressed the same cytolytic potential and proapoptotic activity as that shown by Th cells from chronic gastritis patients (D’Elios et al. 1 999 ) . Accordingly, mice lacking T cell and NK cell cytotoxic effector pathways have also been shown to develop spontaneous tumours (Swann and Smyth 2 007 ; Trapani and Smyth 2 002 ; Smyth et al. 2 000 ; Street et al. 2 001, 2002, 2004 ; Zerafa et al. 2005 ; Davidson et al. 1 998 ; Liu et al. 2004 ; Mitra-Kaushik et al. 2 004 ). 50 A. Amedei and M.M. D’Elios For example, mice that lack perforin, a cytotoxic molecule used by cytotoxic cells such as CD8+ T cells and NK cells to form membrane pores in target cells, develop lymphomas with age. These spontaneous lymphomas are of B cell origin, develop in older mice (>1 year of age) regardless of the mouse strain (Smyth et al. 2000 ; Street et al. 2002 ) , and when transplanted into WT mice, are rejected by CD8 + T cells (Smyth et al. 2000 ) . B cell lymphomas also arise in mice lacking both perforin and b m, and tumour onset is earlier and occurs with increased prevalence com- 2 pared with mice lacking only perforin. In addition, B cell lymphomas derived from mice lacking both perforin and b m are rejected by either NK cells or g d T cells 2 following transplantation to WT mice, rather than by CD8 + T cells (as in tumours derived from mice lacking only perforin), demonstrating that cell surface expres- sion of MHC class I molecules by tumour cells can be an important factor in deter- mining which effector cells mediate immune protective effects (Street et al. 2004 ) . Intriguingly, mutations in the gene encoding perforin have also been identifi ed in subsets of lymphoma patients (Clementi et al. 2 005 ) , although it is not clear whether this contributes to disease. Mice lacking the death-inducing molecule TNF-related apoptosis inducing ligand (TRAIL) or expressing a defective mutant form of the death- inducing molecule FasL have also been shown to be susceptible to spontaneous lymphomas that develop with late onset (Zerafa et al. 2005 ; Davidson et al. 1998 ) . These aging studies have clearly demonstrated a critical role for cytotoxic pathways in immunoregulation and/or immunosuppression of spontaneous tumour develop- ment in mice. The reason why gastric T cells of MALToma, while delivering power- ful help to B cells, are defi cient in mechanisms involved in the control of B-cell growth still remains unclear. It has been shown that VacA toxin inhibits antigen processing in APCs and T cells, but not the exocytosis of perforin-containing gran- ules of NK cells (Molinari et al. 1998 ; Boncristiano et al. 2003 ) . It is possible that, in some H . pylori -infected individuals, some bacterial components affect the devel- opment or the expression in gastric T cells of regulatory cytotoxic mechanisms on B-cell proliferation, allowing exhaustive and unbalanced B-cell help and lymphoma genesis to occur (D’Elios et al. 1999 ; Lehours et al. 2 004, 2009 ) . 2.7 Conclusion H. pylori is an important organism and, while it may not cause any clinical prob- lems in most infected patients, it has the potential to leave the host with devastat- ing consequences. Helicobacter pylori is able to induce a huge variety of responses in the stomach, due to host genetics, age, sex, different bacterial and environmen- tal factors, or other concomitant infections. Sporadic gastric cancer is a common cancer with a grave prognosis, particularly in China, South America, Eastern Europe, Korea, and Japan. A major advance in the fi ght against this global killer came with the recognition of the role of H . pylori infection in its pathogenesis and the acquisition of new techniques and

biological markers to identify high risk subpopulations. 2 Gastric Cancer and H elicobacter pylori 51 The cancer represents a classic example of an infl ammation induced malignancy. Host genetic factors interacting with bacterial virulence and environmental factors play an important role in the pathogenesis of cancer. In this chapter we have analyzed the different ways in which H . pylori can con- tribute to both gastric cancer, as the consequences of H . pylori infection on the integrity of DNA in the host cells, and gastric MALT lymphoma. By down-regulating major DNA repair pathways, H . pylori infection has the potential to generate mutations. In addition, H. pylori infection can induce direct changes on the DNA of the host, such as oxidative damage, methylation, chromo- somal instability, microsatellite instability, and mutations. It’s very interesting that H. pylori infection can generate genetic instability not only in nuclear but also in mitochondrial DNA. Based on the analyzed literature we can declare that H . pylori infection promotes gastric carcinogenesis by at least three different mechanisms: (I) a combination of increased endogenous DNA damage and decreased repair activities, (II) induction of mutations in the mitochondrial DNA, and (III) generation of a transient mutator phenotype that induces mutations in the nuclear genome. In addition, H . pylori can directly help the gastric carcinogenesis by some com- ponent such as CagA, that as mentioned previously in detail, may not promote can- cer itself, but the exposure to them and infl ammatory insults may select for heritable host cell changes (genetic or epigenetic) that together contribute to cancer progres- sion. Several epidemiological studies have evidenced that another H . pylori protein, vacA, is linking to gastric cancer. H . pylori strains that express forms of vacA that are active in vitro are associated with a higher risk of gastric cancer than the strains that express inactive forms of vacA and this relationship is consistent with studies that have examined the distribution of v acA genotypes throughout the world; in the regions that have high rate of distal gastric cancer, such as Colombia and Japan, most H. pylori strains contain v acA s1 and m1 alleles. Host factors in particular, genetic polymorphisms in the adaptive and innate immune response genes seem to increase the risk of gastric cancer, largely through induction of severe gastritis, which progresses to atrophy and hypochlorhydria. As noted previously, the most relevant and consistent genetic factors, among those considered and analyzed in the literature, uncovered thus far are in the IL-1 and TNF-A gene clusters. These cytokines appear to play a key role in the pathophysiology of gastric cancer and their roles have been confi rmed in animal models that mimic human gastric neoplasia. Furthermore, the cytolytic and helper effector functions of gastric H. pylori spe- cifi c T cells are extremely different between patients with autoimmune gastritis or MALT lymphoma. In some patients, due to genetic and environmental factors not yet fully elucidated, H. pylori infection triggers an abnormal activation at gas- tric level of cytotoxic, and proapoptotic cross-reactive T cells leading to gastric autoimmunity via molecular mimicry. Conversely in a minority of infected patients, H. pylori is able to induce the development of specifi c T cells defective of both perforin- and Fas ligand-mediated cytotoxicity, which consequently promotes both B-cell overgrowth and exhaustive B-cell proliferation, fi nally leading to the onset of low-grade gastric MALT lymphoma. 52 A. Amedei and M.M. D’Elios In conclusion, future research must focus on defi ning a more comprehensive genetic profi le (human and bacterial) that better predicts the clinical outcome of H. pylori infection, including gastric cancer and gastric lymphoma. Besides, the delineation of pathways activated by H . pylori -human interactions will not only improve our understanding of gastric carcinogenesis and lymphoma genesis, but will also facilitate identifi cation of potential therapeutic targets for prevention and more effective treatment of these malignant diseases. Acknowledgment T he authors thank Ente Cassa di Risparmio di Firenze and the Italian Ministry of University and Research, for support of their studies, and Dr. Chiara Della Bella for the artwork. Financial & Competing Interests Disclosure Mario M. D’Elios and Amedeo Amedei are applicants of the EU Patent 05425666.4 for HP-NAP as a potential therapeutic agent in cancer, asthma, allergic and infectious diseases. 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J Immunol 175(9):5586–5590 Chapter 3 Streptococcus bovis and Colorectal Cancer Harold Tjalsma , Annemarie Boleij , and Ikuko Kato Abstract The most salient feature of S treptococcus bovis (SB) is its clinical association with malignancy of the colon and rectum. The relationship between SB and colorectal cancer (CRC) was already recognized in the 1950s and many case reports and retrospective studies on this association have been published since then. SB is an opportunistic pathogen that normally resides asymptomatically in the human intestinal tract. In compromised individuals, however, this bacterium can cause systemic infections most often presenting as bacterial endocarditis. Investigators reported the presence of colorectal tumours in up to 60% of the cases in which a patient was diagnosed with SB endocarditis or bacteremia. Therefore, these infections are nowadays often regarded as indication for full bowel examina- tion in clinical practice. Importantly, recent studies have indicated that the associa- tion between S . gallolyticus subsp g allolyticus (previously called SB biotype I) with CRC seems much more pronounced than that of other known SB biotypes. Nevertheless, the question whether SB has a causal or predominantly incidental involvement with cancer of the colon remains to be answered. Furthermore, still little is known about the precise molecular mechanisms that determine this specifi c relationship. This chapter aims to summarize the literature on this subject and to illustrate possible mechanisms behind the association of SB with CRC. H. Tjalsma (*) • A. Boleij Department of Laboratory Medicine, Nijmegen Institute for Infection, Infl ammation and Immunity (N4i) & Radboud University Centre for Oncology (RUCO) , Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen , The Netherlands e-mail: H.Tjalsma@labgk.umcn.nl I. Kato Department of Pathology, Karmanos Cancer Institute , Wayne State University , Detroit , MI , USA A.A. Khan (ed.), Bacteria and Cancer, DOI 10.1007/978-94-007-2585-0_3, 61 © Springer Science+Business Media B.V. 2012 62 H. Tjalsma et al. Keywords Colon • Colorectal cancer • Tumour • Polyp • Carcinoma • Adenoma • Carcinogenesis • Streptococcus bovis • Streptococcus gallolyticus • Endocarditis • Bacteremia • Infl ammation • Intestine • Serology • Diagnosis • Biomarker Abbreviations CRC Colorectal cancer ELISA Enzyme-linked immunosorbent assay HP Helicobacter pylori IBD Infl ammatory bowel disease IC-TOF MS Immunocapture time-of-fl ight mass spectrometry MMP Matrix metalloproteinases NSAID Non steroidal anti infl ammatory drugs OR Odds ratio PAH Polycyclic aromatic hydrocarbons SB S treptococcus bovis SIC S . infantarius subsp . coli SGG S. gallolyticus subsp. gallolyticus SGM S. gallolyticus subsp. macedonicus SGP S. gallolyticus subsp. pasteurianus SII S . infantarius subsp . infantarius 3.1 Colorectal Cancer and Microbial Agents Colorectal cancer (CRC) is the third most common cancer for men and women in Western society. It is estimated that nearly 150,000 cases were newly diagnosed and 50,000 persons died of this disease in year 2009 in the USA (Horner et al. 2 009 ) . The temporal and geographic variations in CRC incidence in US whites and blacks (Horner et al. 2009 ) and among immigrants (Curado et al. 2007 ) are best explained by environmental factors rather than genetic predisposition. According to Dr. Parkin’s estimate (Parkin 2 006 ) , 17.8% of the worldwide cancer incidence is attributable to infectious agents, resulting in approximately 1.9 million cases per year. These include a variety of infectious agents: parasites such as S chistosoma haematobium and Opisthorchis viverrini , bacteria, such as H elicobacter pylori (HP), and, viruses, such as Epstein-Barr virus, Hepatitis virus, and Human herpes, papilloma (HPV), polyma and retro-viruses (IARC 1 994 ; Persing and Prendergast 1 999 ; Del Valle et al. 2002 ) . Several mechanisms have been proposed, including direct effects on host cell proliferation and communication pathways, impairment of host immune system, induction of genomic instability and chronic infl ammation (Herrera et al. 2 005 ) . Chronic infl ammation often accompanies increased host cell turnover, which increases the probability of mutagenic events, and enhanced formation of reactive 3 Streptococcus bovis and Colorectal Cancer 63 oxygen and nitrogen species that damage DNA and induce genomic instability (Coussens and Werb 2 002 ; Blaser 2 008 ; Hussain and Harris

2 007 ; Terzić et al. 2010 ) . Thus, infl ammatory responses play decisive roles at different stages of tumour development, including initiation, promotion, malignant conversion, inva- sion, and metastasis ( Grivennikov et al. 2 007 ) . Genomic instability may arise from inactivation of DNA mismatch repair (MMR) system (MSH1/2), which leads to the development of a specifi c molecular subtype of CRC termed microsatellite insta- bility high (MSI-H) (Jass 2007 ) . MSI has been observed frequently in long standing ulcerative colitis mucosa (Ishitsuka et al. 2 001 ) as well as in HP-positive gas- tric cancer (Li et al. 2 005 ) and MSH2 defi cient mice are susceptible to infl ammation associated colorectal tumours (Kohonen-Corish et al. 2 002 ) . In addition, overex- pression of a COX-2 receptor protein has been characterized for MSI-H tumours (Baba et al. 2 010 ) . The large bowel is indeed the natural habitat for a large, dynamic and highly competitive bacterial community, which is essential for the control of intestinal epithelial homeostasis and human health. Strikingly, the increase in bacte- rial colonization from the ileum to the colon (six orders of magnitude; Stone and Papas 1 997 ) , is paralleled by a marked difference in cancer incidence (by at least a factor of 30) between the small and large intestines. Although bacterial etiologies in sporadic CRC have never been fi rmly established in humans, studies in germ free mice suggest that intestinal bacteria are indeed required for colorectal carcinogen- esis in model systems (Hope et al. 2 005 ; Sinicrope 2 007 ) . Finally, there is good evidence that aspirin and non-steroidal anti-infl ammatory drugs (NSAIDs) reduce the risk of CRC and its precursor (Rostom et al. 2 007 ; Dubé et al. 2007 ) . 3.2 Microbiological Characteristics of Streptococcus bovis Streptococcus bovis (SB) is a gram-positive bacterium and lower-grade opportunis- tic pathogen that can cause systemic infections (endocarditis or bacteraemia) in humans. It is a group D streptococcus with the specifi c ability to grow in 40% bile (Moellering et al. 1 974 ; Roberts 1 992 ) . The classifi cation and identifi cation of SB has been problematic for a long time. Based on phenotypic diversity, three SB bio- types (I, II/1, and II/2) have been reported. Recently, based on biochemical traits, DNA homology and divergence in 16S rRNA sequences, Schlegel et al. ( 2004 ) sug- gested to rename SB I into S . gallolyticus subsp. gallolyticus (SGG), to divide SB biotype II/1 strains into (i) S . infantarius subsp . coli (SIC) and (ii) S . infantarius subsp . infantarius (SII) and to rename SB II/2 into S . gallolyticus subsp. p asteur- ianus (SGP; see Table 3.1 ). In addition, the closely related non-pathogenic strain Streptococcus macedonicus was reclassifi ed as S . gallolyticus subsp. m acedonicus (SGM). Earlier studies suggest that SGG and SII are the most commonly isolated pathogens from the SB group, with the former being the more virulent in humans and more often associated with endocarditis (Corredoira et al. 2 008a ) . In a recent reexamination of SB bacteremias in a 20-year period in France, the association of colon tumours with SGG was found to be ~50% versus 11% for SII. Strikingly, 64 H. Tjalsma et al. Table 3.1 Reappraisal of SB nomenclature New name Old name Association with CRC S. gallolyticus subsp. gallolyticus (SGG) S. bovis biotype I ++++ S. infantarius subsp. i nfantarius (SII) S . bovis biotype II/1 ++ S. infantarius subsp. c oli (SIC) S . bovis biotype II/1 ++ S. gallolyticus subsp. p asteurianus (SGP) S. bovis biotype II/2 + S. gallolyticus subsp. m acedonicus (SGM) S. macedonicus – however, for non-colonic cancer the association was 6% for SGG versus 57% for SII. Most of the non-colonic cancers associated with SII were of the pancreas and biliary tract (Corredoira et al. 2 008b ) . Because of the lack of unifi ed terminology informa- tion in literature, we refer to both SGG and SII as SB in the rest of this chapter. 3.3 Association of SB with Colorectal Disease Although SB is a member of normal gastrointestinal fl ora in ruminants, e.g., cattle, sheep, horses, pigs, camels and deers (Ghali et al. 2 004 ) , it can also found in human feces as well as gastric biopsy materials (Schlegel et al. 2 000 ; Ribeiro et al. 2 004 ) . Approximately 10% of healthy individuals have been estimated to carry this bacte- rium asymptomatically in their digestive tract (Schlegel et al. 2 000 ) . While fecal- oral or oral-oral is a possible transmission route between humans, it may be acquired through dietary intake of ruminant-derived foods, such as unpasteurized dairy prod- ucts (Randazzo et al. 2006 ) , red meat and animal organs (Schlegel et al. 2 000 ) . In fact SB is a frequently detected contaminant in commercially available meat (Knudtson and Hartman 1 993 ; Thian and Hartman 1 981 ) . The correlation between SB and colonic disease has long been recognized. Besides case-reports for the patients who were diagnosed with asymptomatic colorectal neoplasia simultane- ously with SB endocarditis or bacteremia (McMahon et al. 1991 ; Nielsen et al. 2007 ; Wentling et al. 2 006 ; Gupta et al. 2 010 ; Kahveci et al. 2 010 ; Kim et al. 2 010 ) , investigators have reported increased prevalence of colorectal tumours (cancer and polyps) among patients diagnosed with SB endocarditis or bacteremia. As summarized in the Table 3 .2 , the prevalence of colorectal tumours ranges from 10% to 60% (Corredoira et al. 2005, 2008a ; Murray and Roberts 1978 ; Klein et al. 1979 ; Reynolds et al. 1983 ; Pigrau et al. 1 988 ; Ruoff et al. 1 989 ; Clarridge et al. 2 001 ; Gonzlez-Quintela et al. 2 001 ; Gold et al. 2 004 ; Lee et al. 2 003 ; Zarkin et al. 1 990 ; Jean et al. 2 004 ; Alazmi et al. 2 006 ; Giannitsioti et al. 2007 ; Beck et al. 2008 ; Vaska and Faoagali 2009 ) , although these are based on diverse study populations in terms of patient demographics and colorectal surveillance methods. These variations may also be due to the heterogenous defi nition of the cases, as adenomas have been defi ned as dis- eased in some studies but not in others ( Boleij et al. 2009b ) . None of these studies, however, have evaluated their results in comparison with expected frequencies in the general population. The second set of evidence is derived from studies comparing 3 Streptococcus bovis and Colorectal Cancer 65 Table 3.2 Summary of studies among SB bacteremia patients Detected colorectal adenomas and carcinomas Author (year) Study location Patients (n) n % Murray and Roberts (1 978 ) USA 36 4 11% Klein et al. 1 979 USA 29 15 52% Reynolds et al. ( 1983 ) USA 19 7 37% Pigrau et al. (1 988 ) Spain 16 1 6% Ruoff et al. (1 989 ) USA 38 15 39% Zarkin et al. (1 990 ) USA 43 16 37% Clarridge et al. (2 001 ) USA 12 1 8% Gonzlez-Quintela et al. (2 001 ) Spain 20 6 30% Lee et al. (2 003 ) Hong Kong 37 4 11% Gold et al. (2 004 ) USA 45 17 38% Jean et al. (2 004 ) Taiwan 19 9 47% Corredoira et al. (2 005 ) Spain 124 54 44% Alazmi et al. (2 006 ) USA 46 6 13% Giannitsioti et al. (2 007 )a France 142 70 49% Corredoira et al. (2 008a ) Spain 107 42 40% Beck et al. (2 008 ) Germany 15 7 47% Vaska and Faoagali (2 009 ) Australia 20 12 60% a Include other benign lesions e.g., diverticulosis and colitis SB prevalence among various patient groups with or without colonic diseases (Table 3 .3 ) (Klein et al. 1 977 ; Burns et al. 1 985 ; Darjee and Gibb 1 993 ; Dubrow et al. 1 991 ; Potter et al. 1 998 ; Teitelbaum and Triantafyllopoulou 2 006 ; Tjalsma et al. 2 006 ; Abdulamir et al. 2 009 ) . While three small studies including 13–46 con- trols and corresponding 11 CRC, 47 pediatric infl ammatory bowel disease (IBD) and 56 polyp patients failed to show any association (Dubrow et al. 1991 ; Potter et al. 1 998 ; Teitelbaum and Triantafyllopoulou 2 006 ) , fi ve other studies found SB carriage (either in stool or antibodies) rates were signifi cantly higher in cancer patients than in controls. Interestingly, three studies also showed that patients with premalignant lesions (IBD or polyps) had intermediate SB carriage rate between cancer cases and controls (Klein et al. 1 977 ; Teitelbaum and Triantafyllopoulou 2006 ; Tjalsma et al. 2006 ) . For an update, see our recent literature-based meta- analysis on the association between S . bovis and CRC (Boleij et al. 2 011 ). 3.4 Potential Mechanisms in Carcinogenesis Despite observations discussed above, implications of SB infection on CRC remain largely elusive. There are several possible interpretations that are not necessarily mutually exclusive. First, it has been hypothesized that colorectal neoplastic sites provide a specifi c niche for SB resulting in sustained colonization, survival, and the 66 H. Tjalsma et al. Table 3.3 Summary of studies on SB prevalence by colonic disease status No. of subjects Author (year) Controls Premalignant Cancer SB detection Signifi cant results Klein et al. (1 977 ) 105 25 (IBD) 63 Fecal culture Cancer > controls Burns et al. (1 985 ) 216 62 (advanced polyps) 18 Fecal culture Cancer > controls Dubrow et al. (1 991 ) 46 56 (polyps) Fecal culture No signifi cant differences Darjee and Gibb ( 1 993 ) 16 – 16 Antibody titer Cancer > controls Potter et al. ( 1998 ) 13 – 11 Fecal culture No signifi cant differences Teitelbaum and 34 47(IBD) Fecal culture No signifi cant differences Triantafyllopoulou (2 006 ) Tjalsma et al. (2 006 ) 8 4 (polyps) 12 Antibody patterns Cancer/polyps > controls Abdulamir et al. (2 009 ) 50 14 60 Antibody titer C ancer/adenoma > controls 3 Streptococcus bovis and Colorectal Cancer 67 establishment of a local tumour-associated (clinically silent) infection. Second, silent SB infection itself possibly promotes colorectal carcinogenesis, which has been supported by several experimental studies. Administration of SB or SB wall extracted antigens in rodents increases the formation of colorectal precursor lesions in a chemical carcinogenesis model (Ellmerich et al. 2 000a ) . This was accompanied by increased expression of proliferative markers and enhanced interleukin IL-8 pro- duction in normal colonic mucosa of SB-injected animals. SB wall antigens are capable of adhering to various types of human cells, including GI-epithelial, endothelial and blood cells, as well as to extracellular matrix and induce IL-8 syn- thesis (Ellmerich et al. 2 000b ) . In fact, increased IL-8 positive cells have been reported in SB seropositive human CRC cases compared with SB-seronegative cases (Abdulamir et al. 2 009 ) . IL-8 is a pro-infl ammatory cytokine which also pos- sesses mitogenic and angiogenic properties. It increases oxidative/ nitrosative stress and mediate the formation of carcinogenic compounds in gastrointestinal mucosa/ lumen (Federico et al. 2 007 ; Vermeer et al. 2 004 ; Hussain and Harris 2 007 ) . IL-8 also leads to cyclooxygenase (COX)-2 overexpression (Biarc et al. 2 004 ) . COX-2 driven prostaglandin synthesis stimulates cell proliferation, motility and metastatic potential, promotes angiogenesis, and induces local immunosuppression (Harris 2007 ; Mutoh et al. 2 006 ) . On the other hand, selective and non-selective COX-2 inhibitors reduce the incidence and prevalence of colorectal polyps (Steinbach et al. 2000 ; Logan et al. 2 008 ) . Importantly, increased COX-2 expression has been demonstrated in rodent infectious colorectal carcinogenesis models (Skinn et al. 2006 ; Newman et al. 2 001 ; Balish and Warner 2 002 ; Wang and Huycke 2 007 ) . The induction of COX-2 by SB in colon tissue has been reported for a rat model (Biarc et al. 2004 ) and may also

occur in humans (Fig. 3 .1) . These enhanced COX-2 activi- ties may also exert synergistic effects with other enzymes sharing substrates (e.g., CYP1 family) in metabolic activation of diet-derived carcinogens, such as polycyclic aromatic hydrocarbons (PAH) found in cooked meat (Wiese et al. 2 001 ; Almahmeed et al. 2 004 ) . Such an enzyme, CYP1A1/B1, is indeed overexpressed in CRC and its precursors (McKay et al. 1 993 ; Kumarakulasingham et al. 2 005 ; Chang et al. 2 005 ) . This interplay is potentially important because meat consumption is one of the SB acquisition routes and because meat-derived PAH can induce intestinal CYP1A1/ B1 (Lampen et al. 2 004 ) . In addition, SB can induce matrix metalloproteinases (MMPs), e.g., MMP2 and MMP9 (Mungall et al. 2 001 ) , that play crucial roles in CRC growth and progression (Paduch et al. 2 010 ; Sinnamon et al. 2 008 ; Kim et al. 2009 ; Miyake et al. 2 009 ) . Furthermore, SB may also contribute to intra-colonic formation of potential carcinogens, e.g., nitroso-compounds (McKnight et al. 1999 ) . The human large intestine contains a large amount of nitrogenous residues and nitrosating agents from dietary protein, and enzymatic activities of intestinal bacteria, e.g., streptococci, mediate these reactions (Hughes et al. 2 001 ; Calmels et al. 1 996, 1988 ) . Intriguingly, consumption of red meat, a presumed route of SB acquisition, promotes colonic N-nitrosation via increasing supplies of colonic amine, nitrite and arginine (Hughes et al. 2 001 ; Bingham et al. 1 996, 2002 ; Silvester et al. 1 997 ) . Notably, large intestinal N-nitrosation does not occur in germ-free animals (Rowland et al. 1991 ) . 68 H. Tjalsma et al. Fig. 3.1 COX-2 induction by SB. (a ) The induction of COX-2 by SB was measured in HT-29 colorectal tumour cells i n vitro . SB and HT-29 cells were co-incubated for 0.5, 1, 2 or 4 h. Subsequently RNA was extracted for real-time PCR procedures. The relative expression of COX-2 was determined by real time PCR using GAPDH as endogenous internal control and considered to be induced at values greater than 1.5. The b ar graph shows that SB induces the expression of COX-2 after 2 and 4 h which is consistent with previously results in literature (Biarc et al. 2 004 ) . (b ) The correlation of COX-2 expression and the presence of SB in tumour tissue from 4 CRC patients was determined in parallel. The presence of SB was monitored by a nested PCR on the SB sodA gene. The results are suggestive for a correlation of SB and COX-2 expression i n vivo 3.5 SB Serology in CRC Patients Although infections have been recognized as a major preventable cause of human cancer (Kuper et al. 2 000 ) , bacterial etiologies in sporadic CRC have not been established in humans. Notably, SB has indeed been recognized as an infectious agent that fulfi lls the criteria for inferring causality to the highest extent among the four agents evaluated as a potential cause of CRC in a recent review (Burnett- Hartman et al. 2 008 ) . However, to our knowledge there have been no epidemiologic studies properly designed to address this issue. The lack of good serological assays for SB infection may have been one of the reasons for scarcity of epidemiologic data. Darjee and Gibb (1 993 ) were the fi rst to monitor increased SB antibody 3 Streptococcus bovis and Colorectal Cancer 69 responses in CRC patients by an ELISA approach. After that, Tjalsma et al. (2 006, 2007 ) established an SB antibody profi ling assay exploiting immunocapture time- of-fl ight mass spectrometry (IC-TOF MS) (Tjalsma et al. 2 008 ) , Abdulamir et al. ( 2009 ) also developed an ELISA to monitor SB antibodies in CRC patients and controls. As shown in Table 3 .3 , stronger associations observed by these approaches suggest that antibody assays may be a more powerful tool than fecal culture in assessing the associations between this bacterial infection and colorectal disease. Furthermore, as infectious agents in general induce a more pronounced immune response compared to tumour “self”-antigens, SB antigens could become instru- mental in the immunodiagnosis of CRC (Tjalsma 2 010 ) . 3.6 SB and CRC Risk To further investigate the exposure to SB in CRC patients, Boleij et al. ( 2010 ) , developed an ELISA based on SB antigen RpL7/L12, previously assigned as a diag- nostic antigen (Tjalsma et al. 2 007 ) . This assay was exploited for serological evalu- ation in Dutch (n = 209) and American (n = 112) populations. These analyses showed that an immune response against this bacterial antigen was increased in polyp patients and stage I/II CRC patients as compared to controls (Odds ratio (OR ) 1.50, 95% Confi dence Interval (CI) 0.48–4.62 in the Netherlands; OR 2.75, 95%CI 0.96– 7.88 in the US) . Notably, increased anti-RpL7/L12 levels were not or only mildly detected in late stage colorectal cancer patients having lymph node or distant metas- tasis (Fig. 3 .2 ). Increased anti-RpL7/L12 levels were not paralleled by increased antibody production to endotoxin, an intrinsic cell wall component of the majority of intestinal bacteria, which implicates that the humoral immune response against RpL7/L12 is not a general phenomenon induced by the loss of colonic barrier func- tion. The age-adjusted OR for all colorectal tumours combined was very similar in the US (2.30 95% CI 1.06–5.00) and Netherlands (1.90, 95% CI 0.49–2.84). Even a relatively modest increase should be relevant for the progression of colon adenomas to carcinomas (accumulation of mutations), a process which can take over a decade to take place. In this respect, it is interesting to note that the ORs of 1.5 and 2.8 for early stage CRC were within the range of those calculated for the serological response to a panel of H elicobacter pylori antigens in patients with early stage gas- tric precancerous lesions (ORs ranging from 1 to 9) (Gao et al. 2 009 ) . Unfortunately, no data are yet available (August 2010) that correlate SB colonization of tumour tissue with the humoral immune response to SB antigens. Nevertheless, our prelimi- nary studies suggest that tumour tissue provides a niche that allows increased SB colonization (Fig. 3 .3 ). Altogether, these fi ndings suggest that SB constitutes a risk factor for the development and/or progression of pre-malignant lesions into carcino- mas. Importantly, cross-sectional and retrospective studies, including the current study and others, are not able to address the temporal relationship between an expo- sure and a disease outcome directly. Thus, future prospective studies are essential to elucidate the etiological roles of SB in colorectal carcinogenesis. 70 H. Tjalsma et al. Fig. 3.2 Humoral immune response against SB antigen RpL7/L12. Serum anti-RpL7/L12 were determined in healthy control subjects (n = 60), “early stage CRC” (polyp and local tumours; n = 70) and “advanced CRC” (tumours with regional and distant metastases; n = 50) by an ELISA (Tjalsma et al. 2007 ) . The results are indicative for a moderate, but signifi cant (*), increased exposure to this antigen during the early stages of CRC. Median levels, second and third quartile (b oxes ), ad ranges (l ines ) are indicated. Relative anti-RpL7/L12 IgG levels were expressed as arbitrary optical density units 3.7 Model for the Association of SB with CRC Based on the current knowledge the following model for the association of SB with CRC can be envisaged (Fig. 3.4 ). Pre-malignant lesions are initiated by carcinogenic (dietary) factors that diffuse through the colonic mucus layer and induce mutations within the APC or B-catenin genes (Cho and Vogelstein 1 992 ) . These thereby immortalized epithelial cells are prone to the accumulation of other mutations and, as a side effect, the aberrant epithelial physiology disturbs the mucus layer covering the epithelial cells (Corfi eld et al. 2000 ) and makes it susceptible to bacterial infi l- tration. Such (pre-) malignant epithelial sites may also provide a selective bacterial microenvironment, for instance by the excretion of specifi c metabolites, recruitment of immune cells and/or production of selective anti-microbial substances. Bacteria, such as SB, which are unable to effectively colonize the healthy colon may have a competitive advantage in this microenvironment and survive for prolonged periods of time. Tumour infi ltration of SB may exert infl ammatory factors such as IL-8 and COX-2 and/or lead to increased levels of genotoxins and thereby promote intestinal carcinogenesis. These (pre-) malignant lesions also provide a portal of entry for SB which explains the increased anti-SB antibody titers and increased incidence of SB endocarditis in CRC patients. Late stage tumours entering the metastatic phase may change in such a way that bacterial survival on the tumour surface is diminished or 3 Streptococcus bovis and Colorectal Cancer 71 Fig. 3.3 SB detection in human colonic biopsy samples. The presence of SB in human biopsies from tumour tissue (T) and adjacent non-malignant mucosa (N) was monitored by a nested PCR on the SB sodA gene using biopsy- extracted DNA from 8 CRC patients as a template. CRC disease staging is indicated. A broad range 16S rRNA PCR was run in parallel to control for the presence of bacterial DNA and PCR inhibiting substances. The results are suggestive for a preferred colonization of tumour tissue by SB. The identity of the sodA PCR fragments was confi rmed by nucleotide sequencing, which showed that all products had the highest degree of similarity with SGG (SB biotype I) antibody expression due to bacterial interaction is reduced. The possibility that tumour progression may drive bacteria out of the cancerous tissue is similar to what has been reported for H . pylori during gastric cancer progression (Kang et al. 2 006 ; Brenner et al. 2 007 ) . If true, this phenomenon may partly account for a wide range of the prevalence of SB reported for CRC patients that is comprised of various stages of the disease. 72 H. Tjalsma et al. Fig. 3.4 Model for a temporal association between SB and CRC. The development of colorectal tumours is schematically depicted from l eft (healthy) to r ight (invasive and metastasizing carcino- mas). Initiation of carcinogenesis is a multi-factorial process in which dietary factor play an impor- tant role. It may be envisaged that adenomas and early carcinomas provide a preferred niche for SB, which leads to subclinical infection and an increased exposure to SB which can be measured by serological assays. Moreover, this could explain the increased incidence of SB bacteremia and endocarditis in CRC patients as these (pre-) malignant lesions can form a portal of entry into the human body. In addition, SB may interfere with colon carcinogenesis for instance by the induction of IL-8 and COX-2, whereas tumour progression may drive SB out of advanced cancerous tissue (see text for details) 3.8 Conclusion The clinical association between SB and CRC is widely acknowledged, and an SB infection is often regarded as an indication for full bowel examination in clinical practice. However, still little is known about the molecular mechanisms behind this association (Boleij et al. 2 009a, b ) . The recent deciphering of the SGG (SB biotype I) genome revealed unique features among streptococci, probably related to its adaptation to the intestinal environment (Rusniok et al. 2 010 ) . For instance, SGG has the capacity to use a broad range of carbohydrates of plant origin, in particular to degrade polysaccharides derived from the plant cell wall. Its genome encodes a large repertoire of transporters and catalytic activities, like tannase, phenolic com- pounds decarboxylase, and bile salt hydrolase, which should contribute to the detoxifi cation of the gut environment. Furthermore, SGG has the potential to syn- thesize all 20 amino acids and more vitamins than any other sequenced Streptococcus species (Rusniok et al. 2 010 ) . The surface properties (Fig. 3 .5 ) of this bacterium might be implicated in resistance to innate immunity defenses, and glucan muco- polysaccharides, three types of pili, and collagen binding proteins may play a role in adhesion to tissues in the course of endocarditis. Recent i n vitro studies revealed that SGG has a unique repertoire of

virulence factors that may facilitate infection through (pre-)malignant colonic lesions and subsequently can provide SGG with a 3 Streptococcus bovis and Colorectal Cancer 73 Fig. 3.5 SB surface structure. Electron microscopy picture of SGG cells (strain UCN34 (Rusniok et al. 2 010 ) ) showing the capsule of glucan mucopolysaccharides after polycationic ferritin labelling (Vanrobaeys et al. 1999 ) , which may be important for immune evasion in the course of endocardi- tis (The picture was kindly provided by Philippe Glaser and Nadège Cayet, Unité de Génomique des Microorganismes Pathogènes, Institute Pasteur, Paris, France) competitive advantage to evade the innate immune system and to form resistant vegetations at collagen-rich sites in susceptible CRC patients (Boleij et al. 2 011a ) . However, many questions on the relationship between SGG and CRC remain to be answered. Therefore, future studies should answer to which extent polyps and tumours actually provide a niche for SB colonization, and if so, which factors are involved in the adherence to, and/or survival in, the tumour microenvironment and how this increased colonization promotes carcinogenesis. In addition, improved (ELISA) assays are desirable to address the relationship between SB exposure and CRC directly in prospective and retrospective studies. Together, these molecular and epidemiological studies are essential for the full elucidation of the etiological roles of SB in colorectal carcinogenesis. Acknowledgements We thank all researchers for their valuable contributions to unravel the role of SB in CRC and we apologize for the fact that we could not mention all SB-related studies in this chapter. We especially thank Philippe Glaser, Albert Bolhuis, Julian Marchesi, Bas Dutilh, Dorine Swinkels and Rian Roelofs for their inspiring discussions on this subject. 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