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PMC10388536_01

Male

A 56-year-old man presented at our institution in March 2017 with altered mental status and diaphoresis, which was believed to be a myocardial infarction. The cardiac workup was negative. However, examination revealed manifestations of hypogonadism and a serum prolactin level of approximately 200 ng/mL. A brain MRI was ordered and revealed a 2 x 2 cm pituitary mass ( Figures 2A, B ). He was diagnosed with a prolactinoma and initiated on cabergoline but experienced gastrointestinal disturbances and was subsequently switched to bromocriptine. The bromocriptine dose was gradually increased to 20mg/day. The tumor size stabilized, and serum prolactin levels decreased ( Figure 3 ). In December 2020, the patient presented with three days of new-onset diplopia, blurry vision in the left eye, and headache. Physical examination showed a left eye adduction deficit with anisocoria, consistent with left cranial nerve (CN) III palsy. The neurological exam also revealed a subtle left CN VI palsy. His serum prolactin level at admission was 330 ng/mL. A brain MRI showed progression of the mass with suprasellar extension, left cavernous sinus invasion, and evidence of apoplexy ( Figures 2C, D ). Surgical resection was recommended, and the tumor was debulked through a transsphenoidal approach ( Figures 2E, F ). Pathological analysis of the resected tissue showed positive immunohistochemical (IHC) staining for prolactin and PIT-1 and a 30% MIB1/Ki-67 proliferation index with increased mitotic activity and nuclear atypia. Postoperatively, the patient's CN III palsy improved, and serum prolactin level decreased to 166 ng/mL. The patient was prescribed cabergoline 1 mg twice a week and subsequently underwent adjuvant fractionated radiotherapy (total dose 30 Gy), which was completed 2 months later. In November 2021, the patient reported significant decrease in vision of the left eye; follow-up MRI revealed progression of the residual tumor with bilateral invasion of the cavernous sinuses and compression of the left optic nerve ( Figures 2G, H ). The serum prolactin was elevated at approximately 500 ng/mL despite an increase in cabergoline dosage. Clinically, his visual acuity was significantly decreased in both eyes, with only light perception in the left eye. He was prescribed two courses of TMZ; however, his vision deteriorated and the tumor continued to grow ( Figures 4A, B ). In January 2022, he underwent a second operation through a transcranial approach and subtotal resection was achieved, decompressing the optic nerves ( Figures 4C, D ). The resected tumor tissue was sent for detailed histopathological and genetic analysis, and the findings are discussed in the section below. Postoperatively, vision partially improved, but then started deteriorating again two months later to complete blindness. Follow-up MRI revealed progression of tumor size, and the serum prolactin level continued to increase (730 ng/mL). Based on the tumor aggressiveness and resistance to all standardized lines of therapy, a novel approach was explored. The multi-kinase inhibitor, pazopanib, showed promising results in patients with neuroendocrine carcinomas of gastrointestinal, lung, and pancreatic origins. The patient was subsequently started on pazopanib (800 mg daily). His symptoms gradually improved, and after 3 months, there was an improvement in vision in the right eye with partial restoration of visual fields bilaterally. Additionally, serum prolactin decreased to 122 ng/mL, and MRI showed a reduction in tumor size along with a decrease in the cystic and necrotic components of the tumor ( Figures 4E, F ). The patient remained progression-free for six months. However, after 7 months of starting pazopanib treatment, MRI revealed tumor progression ( Figures 4G, H ). Based on PD-L1 positive staining of the tumor tissue ( Figure 5 ), the PD-L1 inhibitor pembrolizumab was added to the patient's treatment regimen, however, the tumor continued to progress. The patient was prescribed a combination therapy of pazopanib and TMZ, yet the tumor still continues to grow. Histopathological examination of the resected tumor tissue revealed pituitary adenoma with foci of necrosis and hemorrhage. IHC staining was positive for PIT-1 and prolactin but negative for FSH, LH, SF1, GH, TSH, ACTH, and TBX19. IHC results were also strongly positive for PD-L1, MLH1, MSH2, MSH6, and PMS2. The MIB1/Ki-67 proliferation index was 30%, mitotic figures were up to 18 per 10 HPF, and nuclear atypia was moderate to severe. Genome sequencing by microarray analysis of the tumor specimen revealed numerous acquired copy number abnormalities, including focal amplification of chromosome 3q, complex aberrations consistent with chromothripsis in two regions of chromosome 1p, regional loss of chromosome 9p (with a portion of focal homozygous loss breaking within the CDKN2A gene), and regional loss of chromosome 17p (containing the TP53 gene). Other abnormalities detected via microarray analysis included regional chromosomal gain(s) in chromosomes 1, 3, 5, 7, 8, 9, 12, 14q, 16, 17p, 18p, and 19; regional chromosomal loss(es) in chromosomes 1p, 4, 9p, 12p, 17p, 18q, and Yq; and copy neutral loss of heterozygosity in chromosomes 8p, 9p, 13q, 15q, 19p, 20, and 21q ( Figure 6 ). Genomic DNA sequencing also revealed low-level microsatellite instability, low tumor mutational burden, and low (7%) genomic loss of heterozygosity. HLA sequencing detected A*26:01, A*31:01, B*38:01, B*40:01, C*03:04, and C*12:03 genotypes. Details of the methodology of analysis is present in the supplementary material.

aggressive, atypical, molecular biomarkers, pazopanib, prolactinoma pituitary adenomas

PMC9067377_01

Male

A 31-year-old man presented to the emergency department with a 3-day history of headache along with nausea and vomiting, 5 h of confusion followed by generalized tonic-clonic seizures and fevers to 38.9 C. His seizures occurred twice within an hour, lasting about 5 min and 2 min each and resolving spontaneously. The patient did not have personal or family history of seizures. His past medical history was significant for an AML with t (8; 21) (q22; q22.1)/RUNX1-RUNX1T1 6 months prior. Meanwhile, when he was first diagnosed with AML, he also had a widespread papular rash with vesicles in the lip, trunk, and extremities, which suggested varicella with VZV infection. With the diagnosis of AML, the patient received a standard 7 + 3 IA regimen (idarubicin 10 mg/m2 for 3 days, cytarabine 100 mg/m2 for 7 days) as induction chemotherapy which achieved complete remission. Considering the VZV infection, the patient simultaneously received intravenous acyclovir and foscarnet sodium, after which the skin lesions were fully recovered. During regular chemotherapy, although the CSF pressure and routine analysis were normal, the intrathecal chemotherapy with cytarabine, methotrexate, and dexamethasone was prophylactically given. Consolidation chemotherapy with another cycle of IA and 2 cycles of high dose cytarabine was administered, and he remained in complete remission. An outline of the episodes is described in Figure 1. On admission, his vital signs included a temperature of 37.5 C. A skin examination revealed a few scattered erythematous rash and varicella in the lip and extremities. In the neurologic examination, the patient was confused and unable to follow complicated commands. Withdrawal reflex response was elicited by noxious stimuli to the upper and lower extremities. Pupils were reactive, but he displayed impaired left eye adduction and right eye abduction. He had signs of meningeal irritation in the form of neck stiffness, positive Kernig's, and Lesage's sign. Movement and sensory examination were unreliable due to the patient's altered level of consciousness. He had a palpable bladder. The Babinski sign was positive bilaterally. CT scans of the head showed no acute abnormalities. Considering the skin varicella, intravenous acyclovir (at a dose of 10 mg/kg q8 h) therapy was instituted on day 1 after admission. However, it is doubtful whether the skin varicella on admission was the reactivation of VZV. Based on the initial presentation, a broad differential diagnosis was considered. First, we should consider the localization for his presentation. The symptoms of headache, confusion, and seizures clinically suggested a central rather than peripheral etiology. Neck stiffness indicates involvement of the meninges, and generalized tonic-clonic seizures suggest diffuse cortical involvement. The urinary retention suggests either bi-hemispheric lesions or a spinal cord lesion; Second, we should consider the etiology of his presentation. The differential etiology included infection (e.g., meningoencephalitis, meningomyelitis, and progressive multifocal leukoencephalopathy), intracranial malignancy (e.g., CNS leukemia, leptomeningeal carcinomatosis, and paraneoplastic syndromes), toxic encephalopathy (e.g., chemotherapy-induced), inflammatory etiologies (e.g., autoimmune encephalitis and acute disseminated encephalomyelitis), and vascular (e.g., cerebral venous sinus thrombosis). On day 2 after admission, the lumbar puncture revealed xanthochromic CSF with a slow flow rate. The patient's CSF opening pressure was normal (140 mm H2O). CSF analysis showed pleocytosis (630 total nucleated cells/mul with 70% mononuclear cells), marked elevation in protein at 10.326 g/L, normal glucose/chloride, negative Gram stain, negative Cryptococcal antigen, negative PCR for Mycobacterium tuberculosis, and negative bacterial cultures. Immunoglobulin M (IgM) antibodies for herpes simplex virus, Epstein-Barr virus, and cytomegalovirus were negative. On day 5 after admission, the cytology testing of CSF revealed 4% lymphocytes, 2% monocytes, and 94% atypical cells (Figure 2A). Brain MRI with contrast was reported as multiple abnormal signals in the cortex, extensive pachymeningeal enhancement, and irregular thickening (Figure 3A). The Magnetic resonance venography and diffusion-weighted imaging were normal. MRI of the cervical and thoracic spine showed T2 hyperintense lesions located at C2-C3 and T6-T9, with partial enhancement (Figure 3E). Based on the above examinations, we have a debate about the diagnosis. The fever and apparent immunocompromise support infectious causes. CSF profile of pleocytosis, high protein level, and normal glucose/chloride helped to confine the differential diagnosis to virus, bacteria, tuberculosis, and fungi. The serum and CSF screens for bacteria, tuberculosis, and fungi were normal. Thus, we excluded the CNS infections with bacteria, tuberculosis, and fungi. The varicella infection supported the suspicion of meningoencephalitis associated with VZV. However, brain MRI of our patient showed obvious enhancement and thickening of pachymeninges. The pachymeningeal enhancement was different from the typical MRI imaging of viral meningitis, which often presented with diffuse enhancement along the leptomeninges. Furthermore, his CSF analysis showed marked elevation in protein at 10.326 g/L, which is rare in viral infections. Moreover, CSF cytology suggested 94% atypical cells. Based on his past medical history, the suspected presence of atypical cells in CSF raised the concern for CNS leukemia. The above diagnostic workup was unable to differentiate between VZV infections and CNS leukemia. Thus, additional testing should be performed. The flow cytometric analysis was proved to be a sensitive test for detecting CNS involvement when compared to traditional CSF cytology. On day 7 after admission, cell phenotypes of immune cells were detected by flow cytometry from CSF. The cell-surface markers used in flow cytometry include CD45, CD14, CD64, CD117, CD3, CD4, and CD19, which showed a predominance of mature lymphocytes (93.6%) and rare monocytes (0.7%). No myeloblasts and no cells of the prior leukemic immunophenotype were identified. Thus, we speculated that the atypical cells in CSF cytology do not belong to the malignant clone but are reactive. Furthermore, the AML1-ETO fusion gene in CSF and bone marrow was also negative. The negative results of flow cytometry and AML1-ETO fusion gene from CSF should cast doubt on the diagnosis of CNS leukemia. Given the strong suspicion for viral meningoencephalitis, other CSF tests were also conducted on day 7 after admission. On this set of CSF studies, metagenomic next-generation sequencing (mNGS) and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to further assess for an infectious cause. The mNGS has the capability of rapid, sensitive, and accurate pathogen identification. The sequencing detection identified 15,281 (out of 16,544) sequence reads uniquely aligned to the VZV genome, and these reads covered a high percentage (92.37%) of the VZV (Figure 4). The presence of VZV DNA in CSF was further verified by VZV-specific qRT-PCR. The CSF qRT-PCR was positive for VZV. Based on the positive mNGS and confirmatory qRT-PCR test, a final diagnosis of VZV meningoencephalitis with meningomyelitis was made. The patient received an additional foscarnet sodium (3g q12 h) on day 7 after admission. The combined use of acyclovir and foscarnet sodium resulted in a steady improvement in symptoms. After combination therapy, repeated CSF studies on day 19 after admission revealed 95% lymphocytes and 5% monocytes. Meanwhile, no atypical cells were found in the cytology testing of CSF (Figure 2B). On day 7 after admission, the skin varicella showed gradual recovery. A repeated MRI on day 29 after admission showed less meningeal enhancement (Figures 3B,F). During the entire treatment course of hospitalization, we did not use steroids. By the time of discharge (hospital day 62), the patient was conscious, and denied headache fever. No fever and seizure occur during hospitalization. Examination revealed normal eye movements, normal strength/sensation, normal coordination/gait testing, and no nuchal rigidity. But the Kernig's sign and left-sided Babinski's sign were still positive. Repeated CSF studies revealed a clear appearance, pleocytosis (18 total nucleated cells/mul), and elevated protein (1.2 g/L). Compared with the CSF on admission, the pleocytosis and elevated protein were significantly alleviated. A repeated brain MRI revealed obvious resolution of the previous abnormal pachymeningeal enhancement (Figure 3C). At the 6-month follow-up visit, he denied headache, nausea, vomiting, diplopia, and confusion. Repeated CSF studies revealed normal cell count and protein (Table 1). The repeated brain MRI revealed no abnormal meningeal enhancement (Figure 3D).

varicella-zoster virus, acute myelogenous leukemia, case report, central nervous system infections, metagenomic next-generation sequencing

PMC9816133_01

Male

Patient: Mr. Niu; gender: male; age: 70 years old; occupation: retired medical staff. The chief complaint was intermittent facial and bilateral lower extremity edema. The patient developed facial and bilateral lower limb edema without any known cause one year ago. Increased nocturia was reported, although there was no hematuria, no fever, no malaise, no skin rash, and no photosensitivity. The patient was found to be positive for proteinuria several times. The patient was administered "Bailing Capsules and Shenyankangfu Tablets" orally, but the edema varied between mild and (at times) severe. The outpatient examination results were as follows (2021-10-13): urine protein quantification 5.54 g/24 h/2300 ml, blood glucose (BG) 7.5 mmol/L, glycosylated albumin 21.3%. The patient had a previous history of DM for 26 years with a maximum BG of 16 mmol/L. The patient was treated with Novolin 16 U bid and glargine insulin 12 U qn, together with oral administration of "Metformin". Fasting BG (FBG) was within the range of 10-15 mmol/L with basically normal postprandial blood glucose (PBG). The patient had a 20-year history of hypertension with maximum blood pressure (BP) of 160/90mmHg. He was medicated with oral administration of Norvasc 5 mg QD and BP was maintained at around 140/80 mmHg. He had a 20-year history of coronary heart disease (CHD) with long-term oral administration of Atorvastatin. A pacemaker had been implanted for eight months due to bradycardia. Patient had undergone cataract surgery in the right eye six months earlier, and suffered from blurred vision in both eyes at time of examination. Personal history: reported no history of smoking and drinking. Marital history: patient married at 29 years of age; spouse had hypertension and DM. Patient had one son, who was healthy. Family history: patient's father died of unknown cause; mother died of cerebral hemorrhage. Patient's two brothers died of renal failure and esophageal cancer, respectively. Patient's two sisters had DM and hypertension respectively before death. Results of physical examination at admission: T 36.5C, P 66/min, R 18 times/min, BP 153/92 mmHg. The patient was conscious and communicated fluently. The bilateral breath sound was clear without dry and moist rales. The pacemaker rate was 66 times/min. The abdomen was flat, and the liver and spleen were impalpable. Mild pit edema of both lower extremities was observed. Ultrasonography results: normal size of both kidneys, sclerosis plaque formation in the bilateral carotid artery. Chest computed tomography (CT) results: multiple micronodules in both lungs with partial calcification, which were considered to be benign. Post cardiac surgery, aortic and coronary artery sclerosis. No significant changes compared to the examination results on 3 Mar 2021. Electrocardiography (ECG) results: dual-chamber pacing rhythm with normal electrical axis. Routine blood test results: white blood cell (WBC) 5.78x109, red blood cell (RBC) 4.62x1012, platelet (PLT) 154x109, Neutrophil (N) 65%. Routine urine test results: urine protein 3+, occult blood, RBC 0.61/Hp, glucose (GLU)2+. Renal function test results: blood urea nitrogen (BUN) 7.63 mmol/L, creatinine (Cr) 57 mumol/L, uric acid (UA) 336 mumol/L. Liver function test results: albumin (ALB) 30 g/L, lipid:total cholesterol (TCH) 5.60 mmol/L, triglyceride (TG) 2.13 mmol/L. The levels of serum albumin, serum creatinine, and urine protein of this patient on different dates are show in Table 1 . Glycosylated hemoglobin (HBA1c) 7.2%; albumin creatinine ratio (ACR) 5871.94 mg/g. No abnormalities in the following: four items of coagulation, three items of cardiac enzymes, eight items of infection, antineutrophil cytoplasmic antibody (ANCA), anti-phospholipase A2 antibody (PLA2R), antinuclear antibody profile, autoantibodies, blood and urine immunofixation electrophoresis, immunoglobulins, and complements. Impressions at admission: 1. nephrotic syndrome (NS); 2. hypertension, grade 2 with very high risk; 3. DM; 4. CHD; 5. post-pacemaker implantation; 6. post-operation of right cataract surgery. The treatments administered were as follows: 1. monitoring of BP and BG, with a low-salt, low-fat diabetic diet; 2. Atorvastatin for lipid-lowering, Novolin + glargine insulin + Metformin for BG lowering and amlodipine besylate for BP lowering; 3. plan to conduct a renal biopsy to confirm the pathological diagnosis. On 10 Nov 2021, following the completion of relevant examinations, a renal biopsy was conducted. On 12 Nov 2021, the T cell results for tuberculosis were found to be positive, and the department of tuberculosis was consulted. The suggestions were as follows: taking into account the calcific density nodule in the right middle lobe in lung CT and TB-IGRA (+), the status of tuberculosis infection should be considered, and old tuberculosis of the right lung could not be excluded; prophylactic anti-tuberculosis therapy should be conducted through the administration of hormones or immunosuppressants. Results following consultation with the department of ophthalmology were as follows: macular degeneration in both eyes, cataract in the left eye, post-operation of cataract surgery in the right eye. Calcium hydroxybenzene sulfonate was recommended along with regular review. Immunofluorescence (IF): IgA+ IgG+- IgM- C3+ C1q- FRA- Alb+- kappa+- lambda+- IgG1- IgG2- IgG3- IgG4-; Light microscopy showed moderate to severe diffuse proliferation of mesangial cells and stroma. The periodic acid-Schiff staining showed moderate to diffuse proliferation of mesangial cells and stroma ( Figure 1A ), and the periodic acid silver methenamine staining and Masson's staining showed severe diffuse proliferation of mesangial cells and stroma ( Figure 1B ). It was accompanied by diffuse thickening of the basement membrane, small eosinophilic deposits in the subendothelial segment, and microangioma-like expansion of segmental capillary loops. There were vacuoles and granular degeneration of renal tubular epithelial cells, focal atrophy, and a few protein casts were observed in the lumen. Renal interstitial focal lymphocyte and monocyte infiltration with fibrosis, wall thickening of small arteries, intimal fibrosis and sclerosis, and lumen stenosis were also observed. Electron microscopy examination showed mild to moderate proliferation of glomerular mesangial cells, mostly homogeneous thickening of the glomerular basement membrane (GBM), occasional small deposits of electron-dense material in the mesangial region, and segmental fusion of epithelial foot processes. The renal tubular epithelial cells exhibited vacuolar degeneration with increased lysosomes and partial atrophy. The renal interstitium was infiltrated by a small number of lymphoid mononuclear cells with collagen fiber proliferation. These results were consistent with mild to moderate mesangial proliferative IgAN (Type IIa), as shown in Figure 2 . Hormones (methylprednisolone: 32 mg, q.d.) and prophylactic (isoniazide: 0.3 g, q.d.) anti-tuberculosis therapy were conducted for three months, after which NS was found to be partially relieved. The patient is currently undergoing treatment.

iga nephropathy, case report, diabetes mellitus, diabetes mellitus combined with iga nephropathy, nephrology

PMC9134426_01

Female

The first patient we present is a 2-year-old girl with an early, isolated bone marrow (BM) relapse of B-cell precursor (BCP)-ALL after allogeneic HSCT (Figure 1 and Table 1). The girl was diagnosed with an KMT2A-rearranged BCP-ALL (KMT2A-AFF1 gene fusion positive) at the age of 7 weeks. She received treatment according to the Interfant-2006 protocol for high-risk patients (Clinicaltrials.gov registration number: NCT00550992) and underwent an allogeneic HSCT in first complete remission (CR1). At that time, she was negative for minimal residual disease (MRD) as measured by polymerase chain reaction (PCR) of immunoglobulin/T-cell receptor and KMT2A rearrangements. During front-line therapy, the patient had considerable treatment-related toxicity, including an episode of respiratory failure that required mechanical ventilation, repeated septicaemias and hepatopathy with pronounced hyperbilirubinaemia. After chemoconditioning with fludarabine, treosulfan, and thiotepa, the girl received a BM graft from a human leukocyte antigen (HLA)-matched unrelated donor, matched at 10 out of 10 loci. Graft-versus-host disease (GvHD) prophylaxis consisted of anti-thymocyte globulin, cyclosporine A and methotrexate. Further serious infectious complications occurred in the pre-engraftment phase, including an extensive soft tissue infection at the implantation site of her percutaneous endoscopic gastrostomy tube. This required broad-spectrum antibiotics and granulocyte transfusions. Neutrophil engraftment in the peripheral blood (PB) was documented on Day + 19. BM puncture on Day + 26 revealed molecular remission (MRD negative by both immunoglobulin/T-cell receptor- and KMT2A-based targets) with full donor chimerism. The patient had a CD19+ (>99% CD19 expression), isolated BM relapse on Day + 180 after allogeneic HSCT. After having a multidisciplinary leukaemia and cellular therapy board session, we opted for tisagenlecleucel as remission induction therapy followed by allogeneic HSCT. Given the patient's body weight (10 kg), apheresis was performed via the AMICUS system using allogeneic donor erythrocytes for machine priming. 148 x 106/kg CD3+ cells were harvested, resulting in a final product of 3.26 x 106/kg CAR T-cells. As bridging therapy prior to tisagenlecleucel, the patient received F1 and F2 courses according to the ALL-relapse study of the Berlin-Frankfurt-Munster Group (ALL-Relapse BFM 2002) (Clinicaltrials.gov registration number: NCT00114348) with adjacent lymphodepletion (fludarabine, cyclophosphamide). During bridging therapy, the patient had another soft tissue infection. Nevertheless, she remained MRD positive by PCR at a level of 7 x 10-1. Tisagenlecleucel was tolerated well; the patient did not develop cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Molecular remission in the BM was achieved on Day + 21. The patient proceeded to a second allogeneic HSCT using PB stem cells from her mother (who was HLA matched at 9 out of 10 loci) after fractionated total body irradiation (TBI) to a total dose of 8 Grey (Gy) and etoposide (60 mg/kg). GvHD prophylaxis consisted of post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil. Toxicities of the second allogeneic HSCT included another soft tissue infection and mild veno-occlusive disease. Engraftment in the PB was achieved on Day + 23. BM on Day + 32 showed complete donor chimerism with negative MRD by PCR. Immunosuppression was tapered and withdrawn on Day + 39 at complete absence of acute GvHD. Molecular remission and complete donor chimerism were confirmed on Day + 60, and Day + 100, and day +180.

acute lymphoblastic leukaemia, allogeneic haematopoietic stem cell transplantion, immunotherapy, relapse

PMC9134426_02

Female

The second case we present is a 16-year-old girl with a late, isolated BM ALL relapse after allogeneic HSCT (Figure 2 and Table 1). The patient was initially treated according to the Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP)-BFM ALL 2009 protocol (Clinicaltrials.gov registration number: NCT01117441) and was transplanted from an unrelated donor matched at 9 out of 10 loci in CR1 after administration of blinatumomab. The latter was used to lower her pre-transplant MRD and led to an MRD load of 2 x 10-4 prior to allogeneic HSCT. Conditioning consisted of 12 Gy TBI in combination with etoposide (60 mg/kg). BM was used for the graft. Pre- and post-transplant organ toxicities included severe necrotic pancreatitis with concomitant stomach perforation and polyomavirus BK-associated haemorrhagic cystitis requiring prolonged antiviral treatment. After allogeneic HSCT, the patient developed acute GvHD of the skin (grade IV), which responded well to multimodal immunosuppressive therapy. Nephrotoxic side effects of both immunosuppressive and antiviral treatment resulted in stage IV renal insufficiency (glomerular filtration rate 20 mL/min/1.73 m2; serum creatinine 2.0-2.5 mg/dL). After successful haematopoietic engraftment with full donor chimerism at Day + 28, the BM at 21 months after allogeneic HSCT revealed a late, isolated BM relapse (partially CD19 +, CD22 +). Despite the CD19- subclone (49% of the cells), the multidisciplinary leukaemia and cellular therapy board opted for CAR T-cell therapy with tisagenlecleucel as an attempt for remission induction therapy followed by allogeneic HSCT. While awaiting CAR T-cell production, the patient received bridging chemotherapy derived from the ALL-BFM protocol III variant (Clinicaltrials.gov registration number: NCT00430118) under continuous veno-venous haemodiafiltration (CVVHDF). MRD as measured by PCR remained at a level of 1 x 10-1. During chemotherapy, the patient developed multiple pulmonary lesions with pleural effusion and both hepatic and intracerebral lesions, which were considered of fungal origin and finally treated with isavuconazole. Due to rapid deterioration of the patient's general condition, tisagenlecleucel was given without prior lymphodepleting chemotherapy. It was well-tolerated with only grade I CRS and no neurotoxicity. Follow-up imaging showed clearance of the hepatic and pulmonary lesions; the intracerebral lesions remained unchanged. BM puncture on Day + 28 showed molecular remission of the CD19+ clone; however, as expected, the CD19- clone persisted with an MRD level of 2 x 10- by PCR. The presence of the CD19- clone led us perform the second allogeneic HSCT very soon after tisagenlecleucel infusion (Day + 59), using the patient's haploidentical mother. Due to stage IV renal insufficiency, the patient received a reduced-intensity dose-adjusted chemoconditioning with fludarabine, treosulfan and thiotepa under concomitant CVVHDF. Chemoconditioning was a reduced-toxicity regimen based on the For Omitting Radiation Under Majority age (FORUM) study in paediatric ALL. Post-transplant cyclophosphamide, mycophenolate mofetil and tacrolimus were used as GvHD prophylaxis. Overall, the second allogeneic HSCT was well-tolerated. BM on Day + 28 showed full donor chimerism; however, the CD19- leukaemic clone persisted with an MRD level of 1 x 10- by PCR. Thus, immunosuppression was reduced to the lowest possible level. Three months after allogeneic HSCT, MRD by PCR in the BM was negative for the first time. Secondary graft failure prompted us to administer a stem cell boost (CD3/19 and alpha/beta depleted PB stem cells) on Day + 107, leading to stable engraftment. Unfortunately, a second isolated BM relapse of the patient's CD19+ BCP-ALL occurred on Day + 180. After a profound discussion with the patient and her family regarding her dismal prognosis, a mutual decision for another CAR T-cell infusion, using allogeneic T-cells transplanted at the second HSCT, was reached and induced a third CR at the time of writing.

acute lymphoblastic leukaemia, allogeneic haematopoietic stem cell transplantion, immunotherapy, relapse

PMC6186962_01

Female

A 36-year-old female was referred to our hospital for further evaluation on abnormal finding in the computed tomography (CT). The patient had chest discomfort and mild dyspepsia for 3 months but otherwise healthy. She never smoked, had no previous medical history including trauma or pulmonary disease including tuberculosis. Her blood laboratory tests were unremarkable. In the primary clinic, chest imaging evaluation was done. On axial image of chest CT, there was a chain of non-enhancing small nodules in the left hemi-diaphragmatic pleura with fat containing lesion (Fig. 1A and B). The chest magnetic resonance imaging (MRI) also showed similar findings from chest CT without chest wall invasion (Fig. 1C). On positron emission tomography-computed tomography (PET-CT) represented pleural based lesions without significant FDG uptake in left lower lobe of the lung (Fig. 1D). The leading initial radiographic impression was pleural lipomatosis and was referred to thoracic surgeon to evaluate the necessity of surgical resection. Due to patient's symptom and growing rate of tumor, the patient underwent video assisted thoracotomy (VATS) of pleural exploration. During the operation, a total of twenty-five smooth glossy white round-shaped, pearl-like lesions were observed in the pleura (Fig. 2A and B). The largest thoracolithiasis found in was 20mm. Most nodules were freely movable and discovered around the dependent position of the lung. There were some nodules that seemed to be originating from visceral & parietal pleura. There was no adhesion between the nodules and the organs around, and all the nodules were completely removed. Around the diaphragmatic pleura and nearby parietal pleura showed inflammatory change with minimal amount of serous effusion but otherwise no other abnormality was detected. Histopathological examination showed extensive necrotic fatty tissue at its center surrounded by fibrosis, as assumed from the thoracic image findings (Fig. 2C). The postoperative recovery was uneventful. The patient was symptom free after the surgical removal, suggesting thoracolithiasis was associated with chest discomfort. She is still being followed up for about two years after the surgical removal with chest CT every year and the last CT scan showed no remarkable finding in the pleural cavity, lungs or mediastinum.

intrapleural loose body, intrathoracic calculus, pleural stone, pleurolith, thoracolithiasis

PMC3885781_02

Male

An 83-yr-old man was referred to a tertiary hospital because of the increased sputum with dyspnea. He had a history of pulmonary tuberculosis in his 20s. Fasting blood glucose was 210 mg/dL, and hemoglobin A1c was 8.4% on initial laboratory tests. He was newly diagnosed with diabetes mellitus. His chest computed tomography (CT) scan revealed large cavitary lesions in the upper lungs (Fig. 1). Acid-fast staining and bronchoalveolar lavage fluid culture yielded negative results. On the fifth day of hospitalization, the serum Aspergillus galactomannan index value was slightly increased at 0.87 (threshold, 0.5). With a diagnosis of suspected pulmonary aspergillosis, itraconazole therapy (400 mg bid) was initiated. Fungus culture of bronchoalveolar lavage fluid was performed on Sabouraud dextrose agar at room temperature. After 3 days of incubation, white, aerial, cotton candy-like colonies appeared and quickly covered the agar surface (Fig. 2). These colonies turned pale brownish gray and light yellow reverse with time. Sputum culture on Sabouraud dextrose agar revealed the same colonies. Microscopic examination showed broad, unseptated hyphae. Sporangiophores were unbranched and arose singly or in groups from above rhizoids. Sporangia were spherical, brown, and filled with sporangiospores (Fig. 3). The organism was provisionally identified as a Rhizopus species on the basis of colony morphology and microscopic features. Antifungal therapy was switched to intravenous amphotericin B. For further identification, the ITS region (including the 5.8S ribosomal DNA gene) of the 28S ribosomal DNA was sequenced with primer ITS1: 5'-TCCGTAGGTGAACCTGCGG-3' and primer ITS4: 5'-TCCTCCGCTTATTGATATGC-3'. The isolate was identified as either Rhizopus microsporus or R. azygosporus by GenBank's Basic Local Alignment Search Tool (accession numbers GQ328854.1 and DQ119008.1) with 99.5% homology to both species. Sequencing of the D1/D2 regions yielded the same result. The isolate grew at 37C, 40C, and 45C, but did not grow at 50C, and its sporangiospores were striated. On the basis of these phenotypic characteristics, the isolate was finally identified as R. microsporus. The patient died of respiratory insufficiency on the 35th day after admission. Mucormycosis is an emerging infectious disease and represents the second leading cause of invasive mold infection, following aspergillosis. It is reported mainly in patients with hematologic malignancy, organ transplantation, immunosuppressive therapy, and diabetes. Diabetes is the most common underlying condition, and Roden et al. reported that 36% of patients with mucormycosis had diabetes at the time of infection, and mucormycosis led to the diagnosis of diabetes in 16% of these patients. In this case, the patient was newly diagnosed with diabetes at admission. Ketoacidosis and uncontrolled hyperglycemia may be related to mucormycosis acquisition in patients with diabetes. Pulmonary mucormycosis is a rapidly progressive disease. The overall mortality rate is above 70%. The clinical findings and chest imaging features are not specific, and it is often difficult to differentiate between aspergillosis and mucormycosis. Unfortunately, the therapeutic regimens for these 2 diseases are different. Azole, used for invasive aspergillosis, has limited activity for mucormycosis. Moreover, mucormycosis has been recently reported in patients receiving voriconazole for prophylaxis or for treatment of invasive aspergillosis. A delay in administering the appropriate therapy often leads to poor outcomes. Thus, rapid diagnosis is very important for optimal therapeutic management. Fungus culture is the primary method for the diagnosis of mucormycosis. Mucorales are easily recognized by their grayish, fluffy colonies that rapidly fill the culture media. The differentiation of the various genera is based on the presence and location of rhizoids, the branching nature of the sporangiophores, the shape of the columella, the size and shape of the sporangia, and the maximum growth temperature. However, the identification of Mucorales species based on morphological features alone can be difficult. It is time-consuming and requires experience in the recognition of microscopic differences. Kontoyiannis et al. reported that approximately 21% of Rhizopus species were erroneously identified by morphology, compared with ITS sequencing. To overcome the limitations of morphology-based identification, molecular identification is applied. Ribosomal DNA sequences including the V9 region of the 18S ribosomal RNA, the D1/D2 domains of the 28S ribosomal DNA, and the ITS region are used for fungal identification. The ITS region, including 5.8S ribosomal DNA, is recommended as the standard choice for identification of human pathogenic Mucorales to the species level. The ITS sequences of most Mucorales are highly variable and species-specific. R. oryzae and R. microsporus show only 70% similarity between their ITS sequences, allowing for clear differentiation. Most Mucor spp. possess 79-96% sequence similarity, allowing for good species identification. Although ITS sequencing is reliable for identification of Mucorales species, a few closely related species have nearly 100% identical ITS regions. The sequences of R. microsporus are nearly identical to those of R. azygosporus. The sequences of M. circinelloides demonstrate a 99-100% match with those of M. rouxii or Rhizomucor variabilis var. regularior. For differentiation of these species, sequencing of the ITS region alone is inadequate. Alternative DNA targets such as the D1/D2 domains of the 28S ribosomal DNA may be needed for differentiation. We present a case of fulminating pulmonary mucormycosis by R. microsporus in a patient with diabetes mellitus. We emphasize the importance of rapid and accurate identification of the pathogen by both morphology and molecular techniques for appropriate treatment.

Computed tomography of chest showed traction bronchiectasis, fibrosis, and large cavitary lesion in both upper lobes.

PMC7857119_01

Male

A 46-year-old male with past medical history of hypertension presented with two-month history of cervical adenopathy. His family members had no history of genetic diseases and similar diseases. Physical examination revealed bilateral multiple enlarged lymph nodes in his neck and axillae. The largest lymph node was located in the left side of the neck (3.0 cm * 3.0 cm), which was firm, fixed, and non-tender. On admission, his complete blood count and metabolic panel were normal. Positron emission tomography (PET) showed the presence of fluorodeoxyglucose avid uptake in multiple parts, including the posterior peritoneum, pelvis, groin, bilateral submaxillary, cervical, and axillary lymph nodes, along with a similar uptake in the 6th anterior rib on the right and the left iliac bone, which was considered as likely lymphoma infiltration. In addition, there was no mediastinal mass or involvement of the central nervous system (CNS) in this patient at diagnosis. The biopsy of the left cervical lymph node (biopsy was completed in other hospital before admission) showed diffuse infiltration with TdT-positive lymphoblasts expressing CD3, BCL2, MYC, and Ki-67. Myeloperoxidase (MPO) and CD20 were negative. Bone marrow (BM) aspiration and flow cytometry analysis revealed a 15.5 and 22% infiltration of immature T-lineage lymphoblastic cells, respectively. Immunophenotype showed a T-lineage phenotype (CD7, CD34, cCD3, CD5), which was similar to that of the lymph node tissue (Figure 1). TCR beta (TRB), TRD, TCR gamma (TRG), immunoglobulin heavy (IgH), light chains kappa (IgK), and lambda (IgL) rearrangement were negative. Cytogenetic analysis was implemented with R-banding showed a noncomplex karyotype: 46XY, (9:22) (q34;q11) [1]/46, XY, [19] (Figure 2), and fluorescence in situ hybridization (FISH) confirmed the presence of a translocation of 9q34 (ABL1) to 22q11 (BCR) in 18% of the nuclei (300 nuclei were analyzed) (Figure 3). Multiplex polymerase chain reaction (PCR) showed the e1a2 BCR-ABL1 fusion transcript. Next-generation sequencing (NGS) revealed DNA methyltransferase 3 alpha (DNMT3A c.2645G>C p.Arg882Pro, mutation rate is 2.3%) and mediator complex subunit 12 (MED12 c.4278G>A p.Trp1426, mutation rate is 4.3%) gene mutation. Diagnosis of T-cell lymphoblastic lymphoma was made based on his clinical presentation, histological and immunological evaluation of lymph node specimens and bone marrow. He was in stage IV according to the Ann Arbor system. The patient received initial induction with hyper CVAD regimen: hyper-fractionated cyclophosphamide (CTX) given 300 mg/m2 intravenously over 2 h every 12 h for 6 doses on days 1 to 3 with 600 mg/m2 Mesna per day intravenously via continuous infusion on days 1 to 3 beginning 1 h prior to CTX and completed by 12 h after the last dose of CTX; 2.5 mg/m2 vincristine intravenously on days 4 and 11; 50 mg/m2 doxorubicin intravenously over 24 h via central venous catheter on day 4; and 40 mg dexamethasone daily intravenously on days 1 to 4 and days 11 to 14. In addition, dasatinib 100 mg daily was started as soon as cytogenetic analysis and FISH examination verified the existence of Ph chromosome. Complete hematological and cytogenetic remission was achieved after the induction chemotherapy, but nested real time-polymerase chain reaction (RT-PCR) was still positive for the BCR-ABL1 (ela2) transcript. The enlarged lymph nodes located at groins and posterior peritoneal resolved, but adenopathy still existed in the cervical and axillary regions after the induction chemotherapy. Later, the patient achieved complete molecular remission (CMR) after the first consolidation therapy. Meanwhile, the patient underwent CNS prophylaxis with the triple intrathecal therapy (methotrexate, cytarabine, dexamethasone). He then underwent an allogeneic hematopoietic stem cell transplantation (allo-HSCT) from a HLA-haploidentical daughter with the improved TBI/CY conditioning regimen (total body irradiation 8 Gy on days -8 to -6, 2g/m2 cytarabine intravenously over 3 h on day -5, CTX was given 1.8 g/m2 intravenously over 3 h on days -4 to -3 with 600 mg/m2 Mesna per day intravenously via continuous infusion on days -4 to -3 beginning 1 h prior to CTX and completed by 12 h after the last dose of CTX). There were no major complications, and he is currently alive in continuous CMR 2 years after allo-HSCT.

philadelphia chromosome, t-cell lymphoblastic lymphoma, clinical characteristics, managements, prognosis

PMC9852703_01

Male

A 40-year-old adult male labourer, who was a construction worker mainly engaged in the handling of construction materials, presented with a more than 4-month history of low back pain, pain radiating to the left limb (visual analogue scale score of 9; Oswestry Disability Index score of 70%), and left limb numbness, without symptoms of tuberculosis, such as fever, night sweats, or cough. A physical examination revealed weakness of the left limb of approximately grade IV, sensory disturbance in the left L4 and L5 area, and difficulty in stretching the left hip. The bilateral Achilles tendon and knee jerk reflexes were normal. There was localised tenderness in the lower lumbar spine. The patient had no medical history of tuberculosis, tumour, AIDS, operations, sarcoidosis, treatment with corticosteroids, or organ transplantation. His close relatives had no history of cancer, tuberculosis, Cryptococcus, or other diseases. He denied a past exposure to bird droppings or decaying wood. Therefore, we did not find the source of infection. Lumbar x-ray was performed, which showed that the left pedicle of L4 was unclear and was suspected to be bone destruction. Computed tomography (CT) revealed a lytic lesion at the L4 vertebrae. The entire left half of the vertebral body was involved. The left side of the L4 vertebral body was obviously damaged, and the lesion involved the paravertebral soft tissue. A single photon emission computed tomography (SPECT) scan showed increased uptake in the L4 vertebrae. SPECT did not find any further lesions except the L4 vertebra. Magnetic resonance imaging (MRI) revealed bone destruction in the L4 vertebral body and a portion of the spinal column enclosure. Sagittal T1-weighted MRI of the lumbar spine demonstrated areas of diffuse low signal intensity in L4. Sagittal T2-weighted MRI of the lumbar spine showed a high-intensity zone of oedema around the areas of isointensity in L4. The endplates of the L4 vertebral body were involved, and the upper and lower discs of the L4 vertebra were normal. A transverse MRI scan showed a paraspinal soft tissue lesion that looked like a tumour in L4 (Figure 1). Laboratory investigations revealed that the erythrocyte sedimentation rate (ESR) was 57 mm/h. C-reactive protein (CRP) and procalcitonin were normal. Blood counts, liver and renal function, and other serum chemistries were also normal. The enzyme linked immunosorbent assay (ELISA) test for AIDS was negative. We performed a needle biopsy surgery to identify the nature of the lesion. The pathologist found Cryptococcus in the lesion; thus, the pathological examination suggested cryptococcal infection. After needle biopsy surgery, we drew a sample of the patient's blood for cryptococcal antigen detection, which was positive. At the same time, the patient was examined by chest CT and brain MRI, and no abnormality was found. We suggested surgical treatment for the patient, but he was concerned about the risk of surgery, refused the operation, and required conservative treatment. The patient was referred to the infection department for antifungal therapy. However, in the course of antifungal treatment with oral fluconazole (400 mg/day) for approximately 2 weeks, the lower limb pain symptoms continued to worsen, so the patient returned to our department for surgical treatment. We performed a posterior approach surgery to remove the lesion and relieve spinal nerve compression. This study was performed according to the guidelines of the Declaration of Helsinki and its amendments. Written informed consent was obtained from the patient for the publication of this study and any accompanying images. Under general endotracheal anaesthesia, the patient was placed on the operating table in a prone position. At the affected section of the spine, a standard posterior middle approach was made. Through lateral subperiosteal dissection, the resected levels were exposed to the facet joints in the lumbar region. Pedicle screws were inserted one level above and below the lesion by the freehand technique. When inserting pedicle screws into the L4 vertebra, we found that the accessory structure of the left vertebral body had been destroyed so that pedicle screws could not be placed. Therefore, pedicle screws were not placed on the left side of the L4 vertebral body. After all pedicle screws had been inserted into the centre of the pedicles, the laminae, articular processes, and spinous processes at the level of the lesions were resected. The dura and L4 and L5 nerve roots were then carefully exposed. Then, the lesions were debrided by bone curettes and pituitary rongeurs. The lesions looked like jelly (Figure 2). Simultaneously, 360 decompression around the canal and roots was completed. We filled the lesion with a fluconazole-soaked gelatine sponge to provide local antifungal therapy and used longitudinal beams to connect with the pedicle screws to build a complete internal fixture. The resected lesions were histopathologically examined (Figure 3). Mannitol (125 ml/day) and dexamethasone (10 mg/day) were administered intravenously for 3 days following surgery to relieve nerve root oedema and inflammation. The patient was administered oral fluconazole (400 mg/day) as an antifungal treatment. The patient left the hospital approximately 1 week after surgery. Three months following the spinal surgery, the patient reported relief of his symptoms and had returned to his normal preoperative activities. Physical examination revealed that the left limb strength, sensation in his left L4 and L5 areas, and left hip activity had returned to normal. His erythrocyte sedimentation rate was 41 mm/h, which is higher than normal. Twelve months postoperatively, follow-up MRI images of the lumbar spine showed a significant reduction of the lesion (Figure 4).

cryptococcus, case report, lumbar vertebral cryptococcosis, spinal infection, surgery

PMC7708850_01

Female

A 68-year-old woman was referred to our hospital due to a growing shadow in the right paratracheal and hilar area on the chest X-ray performed during the medical examination. She was a non-smoker and had a history of tuberculosis (TB) 40 years ago. A CT scan revealed two lobulated masses with homogeneous contrast enhancement in the right paratracheal and hilar area; however, no lung lesions were observed. EBUS-TBNA of the lesion was performed under deep sedation by a well-trained bronchoscopist. The patient was discharged without complications 1 day after the procedure. The amount of specimen was sufficient to analyze histological results, and no evidence of malignancy was found. Eight days after the EBUS-TBNA, the patient was admitted to our emergency room due to chest discomfort and high fever. The vital signs were: systolic blood pressure (BP) 100 mm Hg, diastolic BP 60 mm Hg, heart rate 82/min, respiratory rate 16/min, and peak fever 38.4 C. The blood test results revealed a white blood cell count of 12110/muL and C-reactive protein of 25.3 mg/dL. On a chest X-ray, pleural effusion of both lung fields and enlarged heart margin were revealed, in addition to a previously observed shadow in the right hilar area that had increased in size (Fig. 1A). A portable cardiac echocardiogram was performed. Although the ejection fraction of the left ventricle was within the normal range, a large pericardial effusion was observed. Pig tail catheter was inserted through percutaneous pericardiocentesis and 400 mL of fluid was drained, and symptoms were slightly improved. On a chest CT, enlargement of the right lower paratracheal lymph nodes and a multiloculated mediastinal abscess with gas formation (Fig. 1B, C) were observed. The patient underwent surgery for debridement and drainage along with lymph node dissection on the same day. The operation was initiated with VATS under general anesthesia; adhesion of the whole lung and severe adhesion of the target lesion to surrounding structures were revealed; therefore, we converted to thoracotomy. Purulent fluid was contained in the thoracic cavity when we approached the target lesion, and a thick layer was found around the swollen lymph node; therefore, dissection was performed using surgical electrocautery and energy devices. Upon detachment, a large amount of pus-like fluid was secreted, and cytologic examination and culture were performed. Conglomerated and necrotic lesions seen on the CT were removed as much as possible, and biopsy was performed to confirm the pathology. The surgery was completed after massive saline irrigation, a 28-French chest tube was inserted into the thoracic cavity, and a 28-French right-angled chest tube was inserted into the pericardial space for effective drainage of the pericardial effusion. After the operation, the patient had stable vital signs without fever and gradually recovered. The pathological examination of the biopsy obtained during the surgery revealed inflammation, without other abnormal findings. During the hospitalization period, additional CT performed to check the changes of lesion revealed reduction in size, and the blood test results were within the normal range. The patient was discharged without any complications.

abscess, case report, endobronchial ultrasound guided transbrochial needle aspiration, mediastinitis

PMC7708850_02

Male

A 54-year-old man was referred to the otorhinolaryngology department in our hospital for examination due to voice change that started 6 months ago. The patient had a history of TB 30 years ago and was taking medication for arterial hypertension and diabetes. CT scan of both sides confirmed multiple lymphadenopathies with calcific foci in the mediastinum, and EBUS-TBNA was performed for biopsy. Target lesions were the right paratracheal and subcarinal lymph nodes. The patient was discharged the day after the procedure without complications, and histological examination revealed few lymphoid cells with necrotic debris. The patient was admitted to the emergency room of our hospital 21 days after the EBUS-TBNA due to general weakness, chills, and high fever of 39.3 C. Systolic BP was 107 mm Hg, diastolic BP was 67 mm Hg, heart rate was 82/min, and respiration rate was 18/min. The blood test results revealed a white blood cell count of 7720/muL, C-reactive protein of 26.4 mg/dL, and procalcitonin of 58.89 ng/dL. On chest CT scan, enlargement of the lymph node accompanied by the intranodal necrotic portion was found (Fig. 2A, B). The patient underwent surgery for debridement on the same day. The operation was performed with VATS under general anesthesia. A layer accompanied by calcification was formed around the swollen lymph node, and a small amount of fluid was observed during the dissection. Cytology, culture, and biopsy were performed, and the 28-French chest tube was inserted, and the operation was completed. After the operation, the patient had stable vital signs, with mild fever, and broad-spectrum antibiotics were administered intravenously. On the 5th postoperative day, the fever persisted and the chest x-ray showed an increase in shadow around the surgical site; therefore, the chest CT scan was re-evaluated. A loculated effusion with newly generated gas formation was observed, and empyema was suspected; therefore, the patient underwent a reoperation (Fig. 2C). In the previous lymph node enlargement site, a space with a large amount of pus was found without inflammatory findings. All fluid was removed, and massive irrigation was performed using saline. After the operation, the patient had no additional fever and blood test results also normalized. The pathological examination of the biopsy obtained during the first surgery revealed mature adipose tissue with focal fat necrosis, without other malignant or abnormal findings. The patient was discharged 8 days after the second surgery without any clinical signs of fever or inflammation.

abscess, case report, endobronchial ultrasound guided transbrochial needle aspiration, mediastinitis

PMC5686471_01

Male

A 40-year-old obese man with a history of hypertension, methamphetamine use, and heart failure presented to an outside ED with chest discomfort and shortness of breath. A chest x-ray revealed a right paratracheal mass measuring 6 cm which was confirmed on follow-up CT. CT also showed a small right-sided pleural effusion and moderate hilar, mediastinal, mesenteric and pelvic lymphadenopathy (Fig. 1). The initial outside radiographic read considered these imaging findings concerning for lymphoma vs. metastatic primary lung malignancy. The Hounsfield Units of the initial scan were 17.8. The patient was initially referred to thoracic surgery, but given the proximity of the lesion to the trachea, thoracic surgery referred the patient for consultation by interventional pulmonary with endobronchial ultrasound (EBUS) guided transbronchial needle aspiration (TBNA). Bronchoscopy with EBUS guided FNA was performed in the operating room under general anesthesia using a laryngeal mask airway (LMA). To our surprise, the mass was hypoechoic, yet Doppler US (Fig. 2a) did not suggest any blood flow through the lesion. A 22 gauge EBUS needle was inserted into the lesion under direct US guidance. On aspiration, the syringe filled with a serous fluid (Fig. 2b). Cytologic analysis of the sample showed a paucicellular proteinaceous fluid with occasional foamy macrophages and no evidence of malignancy. Further review of the outside pulmonary embolism (PE) protocol CT taken in conjunction with the biopsy results confirmed the clinical picture was most consistent with a bronchogenic cyst. In addition, re-read of the outside CT suggested the presence of a PE, which helped explain the hilar and mediastinal adenopathy and pleural effusion. Due to concern for PE, a repeat PE protocol CT was performed showing no evidence of a current PE; furthermore, it showed resolution of the ipsilateral pleural effusion and hilar and mediastinal lymphadenopathy. The cyst was reduced to from 6 cm to 3 cm following drainage (Fig. 3). Since undergoing EBUS guided TBNA, our patient has reported a good functional outcome with total resolution of his symptoms and greatly improved exercise tolerance.

bronchogenic cysts, endobronchial ultrasound, hounsfield units

PMC5491827_01

Female

A 28-year-old woman developed SLE in 2005, with symptoms of a high fever and arthritis. She had lupus manifestations in the central nervous system with disturbance of consciousness and multiple intracranial lesions, as well as proliferative lupus nephritis (Class IV-G[A/C]+V, ISN/RPS classification). She was treated with high-dose corticosteroid therapy, intravenous injection of high-dose cyclophosphamide (4 g total), tacrolimus, and plasmapheresis. Her symptoms improved, and clinical remission was maintained with daily administration of 11 mg prednisolone and 100 mg azathioprine. In August 2014, she experienced pain of the left buttock and a high temperature of 38.8C; she was admitted to our hospital with a diagnosis of cellulitis. Palm-sized redness, swelling, and partial induration were observed on the left buttock. A laboratory examination revealed mild cytopenia: white blood cell count, 4.57x103/muL; hemoglobin, 8.4 g/dL; and platelet count, 10.5x104/muL. Blood cultures were negative, with normal procalcitonin levels; however, C-reactive protein (12.5 mg/dL) levels were elevated. In addition, anti-DNA antibody was not elevated (9.7 IU/mL), and hypocomplementemia was not evident (CH50, 70.6 IU/mL). Despite administering 3 g cefozopran, no therapeutic efficacy was noted, and a fever of 39C persisted. The antibiotics were then changed to 3 g cefazolin plus 1,800 mg clindamycin in addition to 3 g meropenem plus 2 g vancomycin. However, the local redness and pain extended further (Fig. 1a). To distinguish between an infectious disease and skin lesion due to SLE, we performed a skin biopsy. The histopathological findings revealed inflammatory cell infiltrates that were mainly composed of lymphocytes and plasma cells extending from the dermis into the subcutaneous fat as well as granuloma formation (Fig. 2a). Furthermore, a microscopic examination of a direct smear showed slight positivity for acid-fast bacilli (+/-, equivalent to Gaffky scale of 1) (Fig. 2b). The polymerase chain reaction test was negative for tubercle bacillus. Accordingly, this patient was diagnosed with cutaneous nontuberculous mycobacteriosis, although the strain was unknown at this point. She was administered 4-drug combination therapy with isoniazid, rifampicin, ethambutol, and 800 mg clarithromycin daily to cover M. avium complex (MAC) and M. kansasii, which are the most common causes of nontuberculous mycobacteriosis. Her fever was immediately alleviated, and the skin findings improved. One week later, M. abscessus was detected from a Mycobacterium culture of the tissues and was considered to be the pathogenic bacteria. Although remission was maintained until the end of September, relapse occurred with a fever and a painful new cutaneous lesion consisting of redness and swelling at the initial infection site on her foot. Based on the possible emergence of resistant bacterium, the antituberculosis drugs were discontinued, except for clarithromycin, and amikacin and imipenem/cilastatin were additionally administered in accordance with the guidelines (ver. 2) of the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA). However, a fever of 39C persisted, and her general condition gradually worsened. A second skin biopsy, which was performed to clarify either the deterioration of SLE or relapse of M. abscessus, indicated similar histopathological findings to the previous results but showed stronger positivity for acid-fast bacilli (2+; equivalent to Gaffky scale of 5) on the smear specimen; cultivation later also showed M. abscessus. Because of concerns about resistance to clarithromycin, clarithromycin was changed to azithromycin, which contributed to the immediate alleviation of the fever. The drug susceptibility test results, which were obtained 4 weeks later, revealed resistance; the minimal inhibitory concentration of clarithromycin was 0.25 mug/mL at the first biopsy and >32 mug/mL at the second biopsy (Table). Subsequently, azathioprine was reduced to 50 mg daily. A three-drug combination of azithromycin, amikacin, and imipenem/cilastatin was continued for one month, and her symptoms were stable; therefore, we switched the treatment to oral antibiotics consisting of azithromycin, faropenem, and levofloxacin at the beginning of November. However, she experienced a relapse three weeks later, and cutaneous redness and induration occurred at a new lesion on the wide area of the inside of the left thigh and on the right buttock (Fig. 1b). By switching amikacin and levofloxacin to kanamycin and moxifloxacin, respectively, therapeutic efficacy was achieved. Accordingly, a four-drug combination of macrolide, carbapenem, aminoglycoside, and a new quinolone was continued for four months. The cutaneous lesion gradually improved, and her general condition was stable; however, the subcutaneous induration partially remained (Fig. 1c). She developed high tone deafness during treatment and was diagnosed with auditory nerve disorders because of long-term aminoglycoside use. Therefore, aminoglycoside was switched to minocycline. Although linezolid was also temporarily used, it was discontinued because she developed malaise and thrombocytopenia. Finally, a three-drug combination of azithromycin, moxifloxacin, and minocycline was administered, and she was discharged in the tenth month after hospitalization (Fig. 3). She was then continuously treated in the outpatient department for 12 months and showed no recurrence of skin lesions; in addition, her SLE was stable.

mycobacterium abscessus, clarithromycin, cutaneous lesion, resistance, systemic lupus erythematosus

PMC8376431_01

Female

A 37-year-old Bangladeshi woman with Cushingoid face presented with complaints of inflammatory low back and several large and small joint pain and swelling that affected symmetrically the upper extremities involving both the wrists and bilateral 2nd and 3rd metacarpophalangeal (MCP) joint and asymmetrically in the lower limbs involving the right knee and both ankle joints with significant morning stiffness longer than one hour for the last four years. Pain aggravated during inactivity and rest and partially relieved with activity and steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and naproxen. Moreover, she complained of headaches, shortness of breath (exertional and lying bed), malaise, and anorexia; however, the patient had no leg swelling. There was a history of repeated spontaneous miscarriage at the first trimester of pregnancy, itching, and foreign-body sensation in the eyes and alopecia, though the history of photosensitivity, rash, reddening of the eye, oral ulcer, tingling and numbness of both the upper and lower limbs, and loss of weight or contact with a TB patient was insignificant. She had a positive family history of RA and AS in her 1st-degree relatives. AS and RA was diagnosed: AS in an elder brother and nephew and RA in a younger sister. Painless mouth ulcer involved the tongue, soft palate, and gum. She was anemic (hemoglobin 8.7 gram/dl, range 13.5-16.00), and she had a puffy face. She neither had cough, palpitation, vomiting of blood, or chest pain. Her bowel and bladder habits were also normal. Her vital signs were stable, though her breathing pattern was reversed (abdominothoracic). Besides, grade II tenderness elicited over sacroiliac joints. Modified Schober's test and chest expansion and occiput-wall distance were recorded as 4, 2, and 1 cm, respectively. However, the Owen Thomas test was negative. She neither had a rounded shoulder, protruded abdomen, flat chest, or stooping forward posture while standing or walking, typical AS phenotype. Examination of higher psychic function and cranial nerves unveiled no abnormality. Biochemical investigations unveiled low hemoglobin, microcytic hypochromic anemia, low hematocrit (30%), thrombocytopenia, leucopenia, and raised ESR (40 mm in 1st hour, range 0-10), raised CRP (24 mg/dl, reference value >3), and mild proteinuria were seen. Schirmer's test was positive. She was positive for RA (test value 41.4 U/ml, reference value <16), anti-CCP (test value 42.5 U/ml, reference value-<5 U/ml), ANA (performed in indirect immunofluorescence on Hep-2 cell and titer was 1 : 320), anti-Sm antibody, anti-SSA, anti-SSB, antiphospholipid IgG/IgM (anticardiolipin and anti-b2glycoprotein1), and HLA B27, but prothrombin time (PT), partial thromboplastin time (PTT), and dilute Russell viper venom test (DRVVT) were normal. She was negative for anti-dsDNA, anti- RNP, anti-Jo-1 (antibody is directed against the histidyl-tRNA synthetase), anti- Scl70 (antitopoisomerase antibody type of ANA), antineutrophil cytoplasmic antibodies (p-ANCA and c-ANCA), and Coomb's test (used to detect antibodies that act against the surface of red blood cells). Screening for quantiferon TB gold, ICT for malaria, and ICT for filarial was uneventful. Her serum thyroid status and complements (C3 and C4) levels were within normal values; however, she had elevated serum basal cortisol level (1203 nmol/L (reference range 140-690 nmol/L), and IgE was 175.4 IU/ml (cut off value <100)). Radioimaging included X-ray sacroiliac joint that revealed grade II bilateral sacroiliitis (grade III right side, grade II left side) (Figure 1(a)). MRI also confirmed bilateral sacroiliitis (Figures 1(b) and 1(c)). CXR showed cardiomegaly; echocardiography unveiled atrial regurgitation and ascending aorta aneurysm, with an ejection fraction of 62%. CT angiogram of the heart and great vessels further explored a large aneurysm with thrombus at the aortic root (Figure 2). High-resolution computed tomography (HRCT) depicted scattered fibrosis at the inferior segment of the left upper lobe favoring interstitial lung disease (ILD). RA (ACR 2010 score was 8), AS (according to modified New York criteria), SLE (according to ACR and SLICC criteria), SS (according to 2002 American-European criteria, score 4/6, including serology for anti-SSA/SSB), and APS (based on clinical and immunology profile) were the ultimate diagnosis. Her disease activity score (DAS28), ASDAS, SLE disease activity index (SLEDAI), and Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) scores was 3.46, 2.36, 23, and 5, respectively. A multidisciplinary approach was made to treat the patient. The patient is under hydroxychloroquine 200 mg daily, prednisolone 20 mg in the morning, and naproxen 500 mg twice daily with omeprazole and calcium supplementation. Pulsed cyclophosphamide (CYC) was given. Unfortunately, we lost the patient due to a massive hemorrhagic stroke from ruptured aneurysm after two weeks of the 1st dose of CYC; at that time, she developed thrombocytopenia (130 thousand/mm3 (reference value 150-450)).

PMC6416525_01

Female

A 49-year-old woman was admitted to hospital with an elevated white blood cell (WBC) count and platelet count but without any other symptoms. The initial peripheral blood laboratory evaluation revealed a WBC count of 27,500 cells/microL (neutrophils 77.6%, lymphocytes 13.6%, monocytes 2.2%, eosinophils 1.9%, basophils 4.7%), hemoglobin of 12.7 g/dL, and platelet count of 174.9 x 104 cells/muL. No coagulopathy was observed. Bone marrow examination showed a total nucleated cell count of 43.5 x 104 cells/microL. Karyotype analysis revealed 46, XX, t(9;22)(q34;q11.2) in 20/20 cells, and fluorescence in situ hybridization of BCR/ABL was 98% positive. Sokal risk stratification was high. The patient was diagnosed with CML in the chronic phase, and treatment with 100 mg dasatinib once daily was initiated. Three months after the diagnosis, the patient achieved a complete cytogenetic response (CCyR), but complained of various indefinite symptoms in the interim. One week after starting dasatinib therapy, the patient complained of myodesopsia, although a physical examination and non-contrast computed tomography revealed no abnormalities. The myodesopsia persisted for 1 month and subsequently resolved. The patient then started to complain of headache, which was atypical and difficult to describe (the patient used expressions such as: 'I feel that metal is squished in my head', or, 'I feel a strange feeling like graveling'). Contrast magnetic resonance imaging (MRI) was performed, but revealed no abnormality. After these symptoms resolved, the patient began to complain of throat constriction and difficulty in swallowing. At the same time, she experienced edema in the face and extremities. We considered these symptoms to be adverse events of dasatinib, and discontinued the patient from dasatinib therapy at 1 year after the diagnosis of CML. At this point, the patient was in MR4 (real-time quantitative polymerase chain reaction [RT-PCR]; international scale, BCR-ABL IS), considered an optimal response under the European Leukemia Net criteria, and was switched to nilotinib 400 mg/day. The patient was still in MR4 at 18 months after diagnosis. From 12 months to 18 months after diagnosis, the patient again complained of various indefinite symptoms, such as heartburn, cough, and unexplained headache. All examinations to determine the cause of these symptoms were negative. Nineteen months after diagnosis, the patient experienced molecular failure, with an increase in IS from 0.0073% to 0.0163%. The patient was switched to 100 mg/day bostinib, and simultaneously complained of myodesopsia of the left eye. The symptom worsened and vision in both eyes gradually diminished until the patient was diagnosed with bilateral optic neuritis using contrast MRI (Fig. 1a). Steroid therapy and plasma exchange were initiated, but without a successful outcome. Because the patient's bilateral optic neuritis was refractory to the treatment, we examined the cerebrospinal fluid (CSF) and found an increased WBC count (1636 cells/mm3), indicative of myeloid immature blasts (Fig. 1b). BCR-ABL mRNA levels in CSF were determined by RT-PCR and found to be 3.0 x 106 copy/mug RNA. The patient was therefore diagnosed as having CNS BC of CML. However, peripheral blood testing revealed no elevation of IS, bone marrow examination remained normal, and the patient remained in MR4. Thus, the patient was diagnosed with isolated CNS BC and was treated with intrathecal methotrexate, cytarabine, dexamethasone, and whole brain irradiation. Despite the MR4 stage of the patient, bostinib therapy was switched to 30 mg/day ponatinib, which is currently ongoing.

blast crisis, central nervous system, chronic myeloid leukemia, myodesopsia, tyrosine kinase inhibitor

PMC8416249_01

Male

A young male teacher who visited our hospital in November 2017 has complained of recurrent jaundice and severe pruritus experienced for more than 15 years. His symptoms first occurred in 2002 while he was still 19 years old. He denied experiencing fever, chills, vomiting, abdominal pain, and weight loss. He also denied history of similar episodes among his family members. Thus, he visited a local hospital. His liver functional test showed total bilirubin (TB) level of over 50.0 mumol/L and slightly elevated transaminase level. Computed tomography of the abdomen showed no remarkable findings. His TB level increased gradually, reaching a maximum of 500.0 mumol/L during hospitalization. His condition improved gradually, and liver function tests normalized after 4 months. He experienced seven similar episodes over a span of 15 years, which sometimes aggravated after administering penicillin and ibuprofen for treating common cold. Two weeks before visiting our hospital, he took "Vitamin C Yinqiao Tablets," which is a traditional Chinese medicine for cold, for sore throat for 3 days. Further, he developed itchy skin (pruritis), his skin and sclera became increasingly yellow, and his urine and stool turned dark brown. On his visit to the local hospital, his liver functional tests revealed alanine aminotransferase (ALT) of 242.0 U/L, aspartate aminotransferase (AST) of 102.0 U/L, TB of 73.2 mumol/L, and direct bilirubin (DB) of 59.4 mumol/L. On admission, physical examination showed his skin and sclera were moderately yellow. His entire abdomen was soft and nontender. He neither had hepatomegaly nor splenomegaly. No spider angiomas or palmar erythema was observed on his skin. Dynamic changes of his liver test are shown in Table 1. Although his blood ammonia level was 104.0 mumol/L (normal range, 9.0-33.0 mumol/L), he did not show signs of central nervous system involvement or hepatic encephalopathy. His urine tested positive for bilirubin. Results of blood and fecal routine examination and coagulation functions were within normal ranges. The alpha-fetoprotein level was normal. Serum makers were negative for hepatitis A, B, C, D, and E viruses. The screening for toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus infections was negative. Deoxyribonucleic acid detection of Epstein-Barr virus and human cytomegalovirus were both negative. Autoimmune antibodies including anti-mitochondria antibody, anti-hepatorenal microsomal antibody, anti-hepatocyte solute antibody, and anti-soluble liver antigen antibody were negative. Serum levels of copper and ceruloplasmin were normal. Serum levels of thyroid hormones were normal. Ultrasonography revealed a normal liver echo texture and non-dilated biliary system. Magnetic resonance cholangiopancreatography confirmed the absence of dilatation of any intrahepatic or extrahepatic bile duct, except for mild splenomegaly. With the collected evidence, common liver diseases causing jaundice were excluded. However, the cause of his obstructive cholestasis still remained unclear. After obtaining his consent, liver biopsy was performed. The result of biopsy reported mostly normal liver lobule structures and extensive cholestasis of hepatocytes in zone 3 accompanied by the formation of bile embolism; few lymphocytes, monocytes, and neutrophils were found infiltrating the portal areas. Positive cytokeratin 7 staining indicated slight proliferation of small bile ducts and cholestatic state in a part of the hepatocytes. Immunohistochemical staining of hepatitis B surface antigen and hepatitis B core antigen, periodic acid-Schiff staining, copper staining, and iron staining were negative (Figure 1). On further molecular analysis of whole-exome sequencing for the ATP8B1 gene, homozygous variants, including c.1817T>C and p.I606T were revealed. This is a novel variant site that has been searched on certain databases including Genome Aggregation Database (gnomAD), Human Gene Variant Database, and Clinvar of NCBI. A familial genetic testing by sanger sequencing showed heterozygosity in his parents' ATP8B1 genes (Figure 2). The diagnosis of intrahepatic cholestasis was made with total evaluation of case history, clinical features, examination, and liver biopsy as per the criteria proposed by Luketic and Shiffman. The patient was finally diagnosed with BRIC-1. The patient was prescribed with ursodeoxycholic acid (UDCA). His symptoms relieved, and his liver function recovered 1 month after his discharge from the hospital. During the follow-up period of about 2 years (January 2020), the patient did not show any signs of jaundice or pruritus, and liver function tests were always normal (ALT, 31 U/L; AST, 25 U/L; TB, 14.3 mumol /L; DB, 4.2 mumol/L; gamma glutamyl transpeptidase [GGT], 14 U/L). His liver function tests in May 2021 were normal.

atp8b1 gene, bric, case report, diagnosis, intrahepatic cholestasis, treatment

PMC8716732_01

Female

Secondly, risk perception was measured directly by asking participants whether they believed that the consumption of insects induces health risks for humans or animals. Responses were given as "Yes," "No," or "Don't know." A majority of 62.5% participants indicated their belief that consumption of insects does not induce health risks, while 26.1 and 19.7% of respondents believed consumption to pose a health risk to humans and animals, respectively. Respondents were less concerned about the use of insects as feed than as food, with 63.3% of respondents overall in favor of using insects as feed (27.1% were overall not in favor of this use) but only 46.6% overall in favor of using insects as food (47.6% were overall not in favor of this use). Insects as food were seen more favorably among those living in cities than those living in the countryside. Differences were observed between different age groups, with 18-29-year-olds most favorable and 14-17-year-olds and those aged 65+ least favorable. Individuals with lower levels of educational attainment also indicated less favorable views of insects as food than individuals with a high school or university degree. Respondents believing a health risk to be linked to consumption were asked to specify possible health risks in an open question. The transfer or outbreak of diseases was listed by 54.5% of respondents, followed by toxins (26%), and allergies/intolerances (16.8%). When asked to list possible reasons for consuming insects (N = 1,000), high protein content was the reason most frequently listed (33.7%), followed by providing additional sources of nutrition for the world population (17.1%), nutrition/vitamin content (14.2%), low costs and effort of husbandry (13.1%), high availability (12.3%), providing an alternative to presently available food (7.3%) or feed options (6.9%), sustainability of insect husbandry (5.2%), pleasant taste (4.6%), establishment as food in other cultures (2%), curiosity or interest in trying the novel consumption experience (1.8%), a view of insects as a normal food and edible animal species similar to others (1.7%), a healthy consumption choice (1.6%), or easy to prepare (0.6%), with 1.5% listing other reasons and 14.9% indicating they could not think of any possible reasons for consuming insects. Asked to list possible reasons for not consuming insects, disgust was listed by far the most frequently (45.7%), followed by concerns about hygiene and insects as carriers of diseases (14.9%), the lack of familiarity with insects as a food (13.4%), animal abuse concerns and lack of trust in suitable husbandry practices (11.8%), interference in natural ecosystems/threat of extinction or loss of species diversity (11.2%), avoidance of animal-based products or meat-free diets (4.4%), digestibility (4.0%), concerns over taste (3.4%), the availability of sufficient other foods (2.7%), concerns over preparation (1.3%), poisonous quality (0.9%), difficult husbandry (0.8%), and contaminants (0.7%), with 1.1% listing other reasons and 11.4% indicating they could not think of any possible reasons not to consume insects. Lombardi et al. conducted an experiment with 200 students at an Italian university which investigated the role of information and carriers (specific insect-containing products:pasta, cookies, and chocolate bars) on the willingness to pay for insect-based food. Different carriers generated different results in terms of willingness to pay for conventional and insect-based versions of the products. Food Neophobia and Beliefs and Attitudes toward insects negatively affected the willingness to pay. In the adapted version of the beliefs and attitudes toward insects scale used, several items relating to risk perception were assessed. Participants' belief that eating insects would increase risk of infectious disease was relatively low (M = 2.52, SD = 1.504, Range = 1-7). Relating to insects generally rather than as a food, participants' belief that insects carry harmful microbes (M = 3.09, SD = 1.642, Range = 1-7) or contain harmful toxins (M = 2.83, SD = 1.368, Range = 1-7) was also rather low than high (low ratings indicated low belief). Participants believed that insects are highly nutritious (M = 4.75, SD = 1.613, Range = 1-7), while fewer participants believed that humans eating insects is not natural (M = 2.97, SD = 1.842, Range = 1-7). A group comparison contrasted the impact of individual vs. community health benefit information on willingness to pay, showing a positive effect of either type of information with a slightly higher impact of individual benefits information. Meixner conducted a web-based survey with participants from Austria, Germany and Switzerland (n = 620). To measure risk perception, a scale consisting of four Items was used: (1) "Insects are unhygienic and dirty," (2) "The consumption of insects poses a hazard to human health," (3) "Insects are not suitable for human consumption," and (4) "The consumption of insects is fraught with risk." The consumption of insects was not perceived as particularly risky (M = 23.82, response scale 0-100). In the context of a master's thesis Manhartseder, risk perception relating to insects as food was measured in Austrian participants using a web-based survey. Participants rated their agreement with five statements relating to insects (1 = strongly disagree to 7 = strongly agree). Respondents were aged 16-65 (n = 164, M = 34.03, SD = 12.71) and 59.6 % of the sample were female; the sample was not population representative. Participants' relatively high agreement with "They are not presently part of our diets" (n = 164, M = 6.01, SD = 1.76) indicated insects were viewed as a novel food. "Insect products are identical to any other new, unfamiliar foodstuff introduced to the market" received much lower agreement (n = 144, M = 3.81, SD = 2.06), suggesting that insect-based foods may be considered a special case of novel food. If true, this could indicate that cognitive processes involved in the perception, acceptance and decision to consume relating to novel foods in general might not apply to insect-based foods and should thus not be generalized unless based on information about consumers' willingness to consume insects in particular. "Insects are not edible" received low agreement (n = 161, M = 2.86, SD = 1.92), indicating a tendency to view insects as edible rather than not. "Insects are horrible" was positively agreed with (n = 159, M = 5.34, SD = 1.98), but "Insects are hazardous and can transmit diseases" was barely agreed with (n = 135, M = 3.55, SD = 2.01). This indicates that factors other than attributions of hazard and disease contributed to the perception of insects as "horrible." Agreement with "Insects are not the solution to our environmental problems with respect to meat consumption" (n = 149, M = 5.52, SD = 1.96, Range = 1-7) may present a tentative indication that barriers to insect consumption in this sample outweighed any environmental motivations that might have incentivised consumption. A systematic literature review on the perception and acceptance of insects as food focuses on European willingness to consume insects and its predictors, and strategies to increase acceptance of edible insects. Europeans' willingness to consume insects is considered very low, with survey data indicating willingness to consume insects as a meat substitute in only 19% of the population. Higher willingness to consume was associated with male gender, but no other sociodemographic factors were identified as impacting the willingness to consume insects as food. No associations with food contamination, health risks or primitive diets were found in people's perception. A study conducted in the Netherlands explored the sensory perceptions of three unusual novel foods claimed to be present in beef burger patties. Participants consumed burger samples with different novel ingredient proportions. Taste expectations were more negative when a food had never been tested before. Consumption experience was determined mainly by the food's properties. Low willingness to eat was linked to food appropriateness more than the food's actual taste. Verneau et al. demonstrated that communication choices could positively impact willingness to consume insects in 282 university students (Denmark: n = 141; 65 Females, M = 23.35, SD = 3.40; Italy: n = 141; 74 females, M = 23.87, SD = 4.25). Highlighting (1) social benefits or (2) individual benefits of introducing insects' proteins into human diet (experimental groups) or (3) information irrelevant to insects (control group) affected participants' behavioral intentions and consumption behaviors. Highlighting consumption benefits impacted behavioral intention positively; this effect carried over to consumption behavior. The impact of information on social benefits on behavioral intention was more long-lasting than information on individual benefits. Increased familiarity and male gender positively affected intention to consume. Negative implicit attitudes toward insects were identified as a barrier to consumption, though this did not impede the positive impact of health information. Higher levels of consumption intention and behavior were found in the Danish than the Italian sample, indicating potential effects of food culture: the well-established Italian cuisine may reduce cultural openness to novel foods. Gere et al. conducted a study to understand the readiness of Hungarian consumers to adopt insects. Food neophobia was identified as the main barrier to insect consumption. A literature review on factors affecting entomophagy acceptance and adoption in Western food cultures provides a conceptual framework identifying key factors related to acceptance and adoption of insects and insects-based foods. Tan et al. explored the contribution of sensory-liking and food appropriateness to the willingness to eat unusual food among Dutch beef consumers. Food appropriateness, but not the experienced sensory-liking nor individual traits like food neophobia or gender, predicted willingness to eat unusual foods. Verbeke investigated Belgian consumers' readiness to adopt insects as a meat substitute. Gender, age, familiarity, food neophobia, convenience and environmental food choice motives, as well as meat-related attitudes and future meat consumption were identified as significant predictors. Food neophobia made the largest contribution to consumers' readiness to adopt insect substitution. De Boer et al. examined the relationship between motivational differences in food orientation and the choice of snacks made from "environmentally friendly proteins," including insects. The results indicate that there is potential for a dietary shift toward "environmentally friendly proteins" among Dutch consumers, but only 4% of participants chose insect-based snacks. A hybrid meat and meat-substitute snack was chosen most frequently, though consumers with high involvement in food, taste and reflection orientation and high levels of education and an urban background were more likely to choose plant-based alternative sources of protein (in this study, lentils, and seaweed). Kim et al. reviewed current trends related to insects as food resources among consumers, industry, and academia, revealing a steady increase in entomophagy worldwide. van Huis overview of edible insects as an alternative protein source for human food and animal feed discusses research pathways to make insects a viable sector in food and agriculture. Mancini et al.'s literature review on European consumers' readiness to adopt insects as food noted that acceptability of edible insects in European countries was the topic of very few publications. An entomophagy perception survey and hedonic test study among Belgian participants concluded that insect tasting sessions are important to decrease food neophobia and that insect integration into Western food culture will involve a transitional phase with minced or powdered insects incorporated into ready-to-eat preparations. An experiment with 26 Italian students found that insects were not easy to identify by taste alone. The authors suggest that consumer acceptance may be facilitated when insects are processed into flour or pastes and reduced when packaging displays insect images. A literature review on edible insects focusing on ecological and economical aspects provides insights into the rearing of insects and highlights the development of scientific research and its focus on ecological concerns and economical implementation in this field. Another literature review contrasts the perception and consumption of insects as traditional foods with the Western attitude toward edible insects. A web-based survey with 428 Swiss participants investigated willingness to eat insects. Participants made fewer positive evaluations and more negative evaluations of snacks containing insects than snacks not containing insects based on their images. Willingness to eat insects was predicted by disgust/uneasiness, inertia/dissatisfaction and positive emotional evaluations. The authors suggest the marketing of snacks containing processed insect ingredients. A study with 179 undergraduate students at a US university investigated factors influencing willingness to attend an insect tasting. Different aspects of disgust (animal reminder and core disgust) reduced willingness to taste insects. Following a priming to reflect on cooking processes, willingness to attend the tasting was less reduced in those with low sensitivity to animal remind disgust. An experiment with 231 young, Italian adults measured behavioral intention and action of eating novel food products containing insect flour in the following month. Beliefs in the positive effects on health and the environment positively impacted attitudes and intention to consume. Disgust, incompatibility with local food culture, and lack of products in the supermarket were barriers to consumption intentions. A field experiment in Kenya with a community sample of 432 participants investigated how consumers evaluated sensory attributes of buns blended with cricket flour. The effects of information on the evaluation, personal involvement and emotions were also tested. Providing product information affected sensory evaluation of the products' sensory attributes. In a sample of 887 participants from Finland, Sweden, Germany and the Czech Republic, Piha et al. compared how consumer knowledge influences willingness to buy insect food products in central and northern Europe. Distinct types of knowledge and food neophobia affected willingness to buy mainly indirectly, mediated by general attitudes. Subjective and objective knowledge predicted willingness to pay in northern but not central Europe, food neophobia in central more than in northern Europe. Product experience was a predictor in both regions. An online survey on Dutch consumer practices related to meat, meat substitution and meat reduction demonstrated the impact of meal formats, product familiarity, cooking skills, preferences for plant-based foods and motivational orientations toward food on the intention to prepare the presented meals at home (N = 1,083). An experiment in which 104 Swiss participants consumed traditional tortilla chips or cricket flour chips suggested that acceptance of insect consumption in unprocessed form might be increased after having consumed insect-based chips. Studying willingness to consume insects in American and Indian samples, Ruby et al. showed perceived benefits of eating insects were related to nutrition and environmental sustainability, and the most common risks related to risk of disease and illness (N = 399). In a combined experimental and web-based survey study using a Dutch sample, consumers evaluated appropriate and inappropriate mealworm products along with original mealworm-free products (N = 135 willing tasters for the sensory study; N = 79 unwilling tasters for the online study). Appropriate product context improved expected sensory-liking and willingness to buy mealworm products. Mealworm products were expected and experienced to taste different from original mealworm-free products, but taste preferences were similar to the original. Baker et al. investigated the role of contextual information on insect consumption, specifically the impacts of images and descriptions on risk perceptions and purchase intent (three experiments; N1 = 221; N2 = 200; N3 = 201). The results suggest that, in restaurant settings, risk perception may be increased when food images contain insects in animal form, though the difference was observed only in combination with a vague, not an explicit text description. In retail settings, packaging image (containing an insect or not) impacted risk perception; text description (vague or explicit) did so only when combined with an image. Explicit text descriptions increased risk perceptions. This study's results could indicate that visual or descriptive information elicit disgust responses, which may then sensitize consumers to potential consumption risks. In a web-based survey of German (n = 502; MAge = 44.3, SDAge = 14.2, RangeAge = 20-69; Proportion male = 0.48) and Chinese (n = 443; MAge = 44.2, SDAge = 13.1, RangeAge = 20-69; Proportion male = 0.49) samples, Chinese participants rated insect-based foods more favorably and indicated greater willingness to eat the tested food products than German participants, who also reported higher willingness to eat processed insect-based foods compared to the unprocessed foods. Disgust toward eating insects is a barrier to consumption. There is some evidence that this disgust does not relate to general pathogen disgust of perceived susceptibility to infection, which would suggest that fear of disease/contamination/illness is not the origin of disgust toward eating insects. Animal reminder disgust, one of the three main disgust domains alongside core and contamination disgusts, was highlighted as a barrier to willingness to taste insects. Participants less sensitive to animal reminder sensitivity were better able to overcome their disgust and consider that cooking transforms the insect-derived ingredients, classifying them as food and thus reducing the insects' "animalness." Animal reminder sensitivity was found to be greater in women than men, which could factor into gender differences in insect consumption readiness. The impact of animal reminder disgust may be reduced by processed or unprocessed state of the food and may explain some of the reduced willingness to consume unprocessed compared to processed state insect-based food. Animal reminder disgust may also contribute to the increased risk perception evoked by insect-containing food images and explicit text descriptions. Insect consumption or proxy measures (e.g., attitudes, behavioral intention) are higher among individuals with past consumption experience in some settings but not others, for example when food contained whole animals. The context of past consumption (a one-off novelty experience vs. cultural habits) may influence this relationship. The presence or absence of additional barriers or facilitating factors, such as processed vs. unprocessed state of insect-based food, may confound effects of familiarity. Individuals high in food neophobia, a general weariness of consuming novel foods, are less likely to consume insects as a novel food and less willing to pay for or consume insect-containing products. The stronger relationship between food neophobia and willingness to pay for insect-containing food in central compared to northern Europe indicates that this relationship is likely impacted by other barriers and facilitating factors. Several studies indicate that consumption of insect-based foods is more acceptable, in particular for individuals with low willingness to consume insects and those who have not tried insects before. Willingness to consume insects in unprocessed form may be increased in individuals who have consumed insects in the past, suggesting that introducing individuals to insect-based foods in processed form may increase the likelihood they will consume insects in unprocessed form in the future. Therefore, familiarity effects are likely to interact with the state of insect-based foods in their impact on individuals' willingness to eat insect-based foods and should be considered in future studies relating to the state of insect-based foods and their impact on willingness to eat. Unprocessed forms of insect-based food may also reduce animal reminder disgust and constitute an effective way to reduce this barrier to consumption as well as the barrier of novelty. Any effects of contextual information on insect consumption behavior and attitudes are likely to represent a complex interplay of factors. The degree of trust in the sources providing information may impact their effect, with some indication that scientific researchers, well-known relatives, the government, and persons using insect-based food products being trusted while food producers and famous persons may not be. There may however be cultural differences in the respective ratings of different informational sources; for example, consumer organizations may be more trusted by Dutch than Australian participants. Information given about products seems to have inconsistent effects on attitudes and behavior. Some evidence suggests that the choice to consume insects, willingness to pay, or consumption acceptance are not influenced by information received. Other findings indicate that information about social of individual benefits of introducing insects' proteins into human diet positively impacted intention to consume, with longer-lasting effects from information highlighting social benefits. In contrast, highlighting individual or community health benefits of insect consumption was found to impact willingness to pay positively, but with greater impacts from highlighting individual benefits. Underlying differences in the effect of individual vs. collective benefit perception may impact differently on investment choices (e.g., by measuring willingness to pay) than on other constructs related to insect consumption, such as intention to consume. Explicit product descriptions highlighting the animal content on the other hand may reduce purchase intent, though such effects may interact with the presence of visual stimuli. The visibility of insects as whole animal and visual animal reminders (e.g., images evoking thoughts of the live animals) may constitute a barrier to consumption. These findings are consistent with animal reminder disgust as a barrier to consumption and the facilitating effects of processed as opposed to unprocessed forms of insect-based foods. However, there is some evidence than the effects of insect images interact with contextual text information given. It is likely that information (visual or text) that evoke thought of the live animal elicit animal reminder disgust and/or increase risk perception, thus reducing consumption behaviors or proxy measures thereof. However, this effect may not be detectable when animal reminder disgust is evoked by other contextual sources (e.g., the impact of visual information may be detectable only when animal reminder disgust is not already evoked by text descriptions). The inconsistency in findings regarding contextual information seem to indicate a complex interplay of factors each associated with a comparatively low effect size. Large enough studies and samples to identify small effects, investigate the interactions between various contextual information factors, and account for the impact of other factors on consumption attitudes, intentions, and behaviors, would be needed to reliably investigate the relative roles of various contextual informational factors and their interactions. Insect consumption and related cognitions and intentions are affected by cultural and social context and norms. Individuals are more likely to consume insects when they believe many of those surrounding them to do so as well. This indicates that humans do not inherently fear or avoid insect consumption (e.g., based on biological instincts), but rather that avoidance is a result of not having experienced the food as safe to consume based on others' (social norm) and the individual's own (familiarity) experience. Cultural differences such as the lower willingness to consume insect-based foods in a German compared to a Chinese sample support this notion. Addressing social factors and perception could therefore be an effective strategy in promoting insect consumption. For example, consumption of insects or sharing of positive past consumption experiences by trusted persons in individuals' social circles (e.g., friends or family) might improve the perception of insect-based food consumption as a social norm and standard, rather than an exception. Positive consumption experiences among individuals low in barriers such as disgust would therefore be expected to positively influence the views and consumption behaviors of their social circles. There was a high degree of variability in the sociodemographic criteria of the samples of the studies reviewed. Given the likely impact of cultural influences on insect consumption perceptions, intentions, and behaviors, cross-cultural comparison studies conducted using samples representative of the respective populations would be required to reliably identify the role of sociodemographic criteria in diverse contexts. In particular, it is difficult to investigate the role of age on insect consumption behaviors and attitudes, partly because many of the above studies were conducted in disproportionately young populations due to the use of student samples or web-based methodologies. The identification of male gender as a facilitating factor for willingness to consume insects in a systematic literature review is a promising indicator that women may be less likely to consume insects than men. Such differences may be linked to increased animal reminder sensitivity sometimes shown in women compared to men. Regional differences in insect consumption behaviors, intentions, and attitudes have been identified in various studies and indicate that social and cultural contexts notably impact individuals' attitudes and behaviors. The literature search yielded 332 unique references; 12 publications were identified as most relevant from the article abstracts and included in the literature review (see Table 2). Key information extracted from each publication in order to inform the design of the communication strategy are summarized below. A population representative telephone survey in the Spanish population showed participants (n = 650) considered beef as one of the least safe products (M = 2.61, SD = 1.43, response scale = 1-5; higher scores indicating greater safety perception). Out of the 18 food products rated by participants, the items "beef" and "imported food" were joined for the second least safe food product, with only "ready-to-eat meals" perceived as less safe and thus the least safe item. Pork (M = 3.66, SD = 1.05, Range = 1-5) was perceived as notably safer, ranking 7th least safe out of the 18 food products. Standard deviation of safety perception ratings was greatest for beef, indicating great variability among consumers' risk perceptions. According to the authors, this pattern may result from differential impact of food scares on less experienced beef consumers who rely on mass media as an information source, which amplifies a negative perception of food safety in contrast with more experienced consumers who rely on other sources of information such as public authorities and whose food safety perceptions are less impacted by food scares and mass media. Angulo and Gil propose an economic framework for the relationship between food and beef safety perceptions, socioeconomic variables, beef safety incidents, risk retrievers and purchasing likelihood. Applying this framework, higher beef risk perception was linked to lower confidence in food safety in general as well as lower frequency of purchasing beef and lower per person consumption levels. The authors argue that more experienced beef consumers may draw information about the product from wider sources of information, resulting in greater trust in food safety information provided by public authorities. The price of beef products was also linked to beef risk perception, with higher prices linked to higher perceived risk. Though the relationships between beef risk perception and socioeconomic characteristics were not investigated in this study, general confidence in food safety was higher in individuals (1) with higher education levels, (2) less influenced by mass media in their purchasing decisions, and (3) paying more attention to food labels and more confident in the information included on them. Dwan and Miles report the findings of an experimental study performed on a community sample of 167 community-dwelling participants in the UK. The impact of health information about the link between red meat and cancer on participants' belief that red meat can cause cancer was measured. Attitudes toward red meat (including ratings of agreement relating to the nutritional properties and health benefits of red meat) were also assessed, but sample means were not reported in this study. Participants more ready to accept the link to cancer risk had more negative attitudes toward red meat (including, but not limited to, perceived health risks and benefits), evaluated the information provided more favorably, were lower in ambiguity aversion and meat consumption. However, because sample means of participants' attitudes toward red meat were not reported and acceptance of the risk associated with red meat consumption was only measured after exposure to specific health information, no inferences about population risk should be drawn. Gaspar et al. investigated changes in attitudes and perceived risk knowledge relating to red meat following exposure to health information and the role of information avoidance tendencies in British, Belgian and Portuguese participants (N = 174). Perceived knowledge and attitudes toward red meat were measured before as well as after exposure to health information. Overall sample means were not reported. Individuals low in information avoidance had less positive attitudes (M = 4.85, SD = 1.38, Range = 1-7) and higher perceived knowledge (M = 4.32, SD = 1.06, Range = 1-7) relating to red meat than individuals high in information avoidance (Attitudes: M = 5.51, SD = 1.19, Range = 1-7; Knowledge: M = 4.10, SD = 0.67, Range = 1-7). Exposure to health risk information about red meat led to a decrease in positive attitudes and an increase in perceived knowledge in both high and low information avoiders. This indicates that both groups' risk perception can be influenced by information, though it may constitute a challenge to engage high information avoiders in the risk communication process which would expose them to such information. A survey of 1,004 Polish participants assessed beef consumption habits and related motives and beliefs. The third most frequently stated reason for beef consumption was "It is healthy" (39% of respondents), with "Due to health-related reasons" the second least frequently stated (10% of respondents). The percentage of respondents between 26 and 40 years of age indicating health benefits as the reason for their beef consumption was higher than in other age groups. The relative importance of different factors or sources of information for consumers' decision to buy beef are reported, with press articles (7%), advertising (9%), labeling information (10%), seller's recommendation (10%), and exposition in the store (12%) receiving the lowest number of top ratings, while the desire to prepare a specific dish (44%), respondents' own expertise/wont (34%), medical advice (24%) and opinions of others, e.g., family, friends (19%) received the highest number of top ratings. However, medical advice also received the second highest number of lowest ratings (29%), indicating that some individuals are highly influenced by medical advice, while others are very little influenced by this factor. Hornibrook et al. conducted a survey on 687 Irish consumers who buy pre-packed beef in supermarkets to assess their perceived risk and risk reduction strategies. Risk perception was assessed only in relation to purchasing choices, with food safety being the most important factor in purchasing choices. When comparing the relative importance of risks relating to financial, time, psychosocial, physical and performance losses, the avoidance of physical risks (food poisoning and consuming meat from an animal with BSE) was rated most important. Individuals with children rated the avoidance of physical risks as more important than individuals without children. Participants also rate the usefulness of various information sources in relation to beef. Consumer-dominated sources of information (e.g., past experience, recommendations from family and friends, quality assurance symbols) were rated the most useful (M = 4.00, SD = 0.83, Range = 1-5; M = 3.94, SD = 0.85, Range = 1-5; M = 3.83, SD = 0.85, Range = 1-5, respectively). Information from consumer organisations (M = 2.78, SD = 0.83, Range = 1-5), the department of health (M = 2.89, SD = 0.75, Range = 1-5), and the Food Safety Authority of Ireland (M = 3.06, SD = 0.75, Range = 1-5) were rated as far less useful in contrast. Gender and age differences in the usefulness ratings of different sources of information were also detected; for example, older participants rated past experience as more useful. Van Wezemael et al. report findings from 8 focus group studies with 7-9 participants each conducted in Germany, Spain, France and the United Kingdom. All participants were beef eaters. Consumer perceptions of beef are reported on the basis of a qualitative analysis. The majority of participants considered beef as healthful and of positive nutritious value (specifically with respect to iron and proteins) resulting in positive health effects. High trust was expressed in food regulation. Few consumers worried about potential negative health effects of beef; carcinogenic, cardiovascular and other long-term effects were mentioned in this context, as well as possible disease transfer from animals to humans and obesity. Health risks were perceived to depend on consumption factors such as amount, type, preparation method and the presence of harmful residues in the beef. Participants associated unhealthfulness with cheap or low quality beef, beef with hormones or additives, packaged or canned beef or further processed beef products, beef sold or processed in unhygienic conditions, offals, expired beef, ready meals and BSE/food crises. Van Wezemael et al. collected data from 2,520 regular beef consumers (504 each from France, Germany, Poland, Spain and the United Kingdom) in an online survey. The study focused on assessing consumer acceptance of beef product and processing safety interventions, though various measures relating to safety perceptions are also reported. Results showed consumers to be overwhelmingly confident about purchased beef and beef product, though means and standard deviations were not reported. Schroeder et al. report results from an international survey with 4,005 participants from Canada, the US, Japan and Mexico aiming to better understand consumer perceptions relating to beef in target markets for Canadian beef. Beef safety perception was measured, showing that beef was considered very safe or somewhat safe by the majority of respondents in Canada and the US, while notably, most respondents in Japan and Mexico considered beef either mostly safe or neither safe nor unsafe. The product type was an important variable in safety perception, with organ meat considered the least safe across all consumer groups, while steak and roast were considered safest by all respondents. The study further queried participants' past experience with food-borne illnesses, with 18.4% (Japan) to 39.7% (Mexico) of respondents having a family member who had experienced food-borne illness. Branscheid et al. investigated consumers' sensory ratings in relation to sampled beef and lamb steaks; risk perception, knowledge or information requirements about beef were not measured. Branscheid discusses the quality of beef including the proportion of muscle to fatty tissue in a review paper. Risk perception relating to beef is not discussed. A tendency to avoid information may result in more positive attitudes toward and perceived knowledge about red meat, with forced engagement reducing positive attitudes and increasing perceived knowledge in individuals high and low in information avoidance. This would indicate that informational engagement, though not sought out voluntarily by information avoidant individuals, reduces positive attitudes toward red meat overall. This contrasts with other results indicating that individuals less likely to engage heuristic cognitive processing of food choices (higher educational attainments, less influenced by mass media, engaging with food label information) may have higher beef safety perceptions, indicating a latent presence of heuristic risk perception primes may boost everyday risk perception in the population (e.g., due to coverage of food scares). The distinct constructs of beef safety perception and attitudes toward red meat may be differently affected by informational engagement and availability. Information sources relied on to inform consumption behaviour vary between individuals are likely to vary across cultures. Many Polish consumers (N = 1,004) reported being influenced by own expertise, medical advice and opinions of others such as family and friends while other sources, such as press articles, advertising, labelling information, seller's recommendations, or exposition in the store were rated as little influential. Similarly, Hornibrook et al. find that consumer-dominated sources of information are rated as most useful by consumers, indicating the importance of personal experience for information sources to be considered trustworthy. Fears regarding beef safety, linked to confidence in production standards and regulation, are one of the key barriers to meat consumption. Such fears are linked to different information engagement strategies, with the types of information sources that are trusted and the readiness to engage with risk or health information affecting individuals' risk and safety perceptions. Positive health associations with beef consumption were found in Polish consumers, particularly in younger age groups; participants from Germany, Spain, France, and the United Kingdom [; eight focus groups, N = 65] also predominantly reported associations with positive health effects and nutritious value. There are some indications of low awareness of negative health impacts of beef with respect to carcinogenic and cardiovascular disorders from small samples across European nations, with some larger studies indicating an overall confidence in the safety of beef products on the market, although a population representative survey of Spanish consumers found low beef and moderate pork safety perceptions. Health risks may be perceived to depend on consumption factors such as amount, type, preparation method, and presence of harmful residues; variations in risk perception could therefore be a result of different assumptions made by participants regarding consumption factors. Given the link between beef safety perception, media reporting, and trust in production standards and food safety regulation, there are likely to be fluctuations in safety perceptions over time and across nations.

edible insects, food communication, food perception, health communication, novel foods, red meat substitute, risk communication, risk-benefit assessment (rba)

PMC10014732_01

Unknown

We reviewed the clinical data and pathological characteristics of the four cases(see Table 1 ). All of the four patients were men and they were aged 58-69 years. The clinical symptoms were not specific. Three cases were discovered during a health check-up (space-occupying lesion in the stomach), and one case manifested as gastric discomfort accompanied by an elevated serum CA19-9 level. The disease manifested endoscopically as SMTs ( Figures 1A. B ), with the lesion size ranging from 1.3 to 3.5 cm. Three lesions were located in the upper third of the stomach and one in the lower third of the stomach. No GC diagnosis was obtained after multiple gastroscopic biopsies. Three patients underwent local mass resection ( Figures 1C, D ), followed by radical gastrectomy for GC ( Figure 1E ), one underwent endoscopic submucosal dissection (ESD). The local mass resection specimens of the four cases, including the ESD specimens, were dissected along the largest lesion diameter perpendicular to the mucosal surface, to examine the lesions. Tumours were mainly located in the submucosa. The size of the tumours was in the 1.3-3.5 cm range, and they exhibited a greyish-white cut surface and unclear boundaries, and were mucinous in certain cases (75%, 3/4). For the three patients who underwent radical gastrectomy after local mass resection, specimens were collected using the routine procedure for radical gastrectomy specimen extraction, and the residual masses in the specimens were not observed by the naked eye. Three cases of mucinous adenocarcinoma were found, among which two were well-differentiated mucinous adenocarcinomas and one was a poorly differentiated mucinous adenocarcinoma. Another case had gastric carcinoma with lymphoid stroma (GCLS, i.e., lymphoepithelioma-like carcinoma). Under the microscope, the SMT specimen of the patient with a poorly differentiated mucinous adenocarcinoma exhibited a nodular distribution with copious extracellular mucin ( Figure 2A ). Tumour cells were epithelium-like, possessed a large nucleus and distinct nucleoli, and floated within mucin pools in small nest-like clusters ( Figure 2B ). Necrotic nuclear fragments were also observed. The microscopic examination of the well-differentiated mucinous adenocarcinoma specimens revealed the presence of dense hyperplasia of the submucosal glands, a large nucleus, distinct nucleoli, obvious nuclear division, and local glandular fusion. This was locally accompanied by the formation of mucin pools ( Figures 2C, D ). Certain regions exhibited glandular ulcerations with spill over of mucin into the fibrous mesenchyme, which was accompanied by hyperplasia of the fibrous granulation tissue. Histological examination of the SMT specimens of case 4 showed the presence of a nodular structure and a lymphocyte-rich mesenchyme, accompanied by lymphoid follicle formation ( Figure 2E ). At high magnification, the tumour cells exhibited a symplastic appearance with a dichroic cytoplasm, a large nucleus, distinct nucleoli, and an irregular nest- and sheet-like arrangement ( Figure 2F ). The involvement of the muscularis propria was found in certain cases (50%, 2/4). The tumor cells were found to have migrated to the epithelial cells of the mucosal layer in only two cases. Among the three patients who underwent extended resection, one exhibited a small amount of local residual mucinous adenocarcinoma in the submucosa and metastasis in one out of 18 lymph nodes. In the other two cases, no metastasis was found in lymph nodes dissected. The tumour cells of the four cases showed differing expression levels of the gastric mucins MUC1 (4/4), MUC5AC (2/4), MUC6 (2/4), CEA (4/4), CKpan (4/4)( Figure 2G ) and CK7 (3/4). The intestinal markers MUC2, CDX2 and CK20 were expressed in case 1, and EBER was expressed in the tumour cells of case 4 ( Figure 2H ). Ki-67 expression indicated that the tumour cell proliferation index was in the 20%-70% range. The tumor cells of four cases did not express CD10 and SATB2 proteins, no mutant expression of P53, and no deletion of mismatch repair proteins MLH1, PMS2, MSH2 and MSH6.

clinicopathological characteristics, differential diagnosis, gastric cancer, pathological diagnosis, submucosal tumour

PMC5943120_01

Male

A 21-year-old Japanese man visited a proctology clinic because of anal pain in July 2015. The patient was diagnosed as having anal fistulas, and was subsequently treated with seton drainage. He had been suffering from recurrent diarrhea and weight loss of 14 kg during the past 2 years. His father and one of his brothers had been diagnosed as having UC. In September 2015, the patient visited a gastroenterological clinic because of severe abdominal pain with high fever of 39 C. Colonoscopy showed longitudinal ulcers in the terminal ileum and aphthous erosions in the colorectum. Since he was suspected as having CD, 1.5 g/day of oral mesalazine was initiated and then he was referred to our hospital. At the time of the first visit, the patient presented with fever of 39 C, abdominal pain and recurrent stomatitis. His body mass index was 14.9 kg/m2. Physical examination revealed tenderness in his epigastrium. The laboratory data showed a white blood cell (WBC) count of 14,040/muL (neutrophils: 90.0%), serum C-reactive protein (CRP) 13.16 mg/dL, total protein 6.9 g/dL and albumin 3.8 g/dL. The interferon-gamma release assay (T-SPOT tuberculosis blood test) and cytomegalovirus antigenemia test showed negative results. The bacterial cultures from blood and fecal samples detected no infectious pathogens. Because of the possibility of mesalazine allergy, we ceased the medication of mesalazine. Three days later, however, both his fever and abdominal pain had resolved spontaneously with laboratory data of 4970/muL (neutrophils: 58.4%) in WBC count and 0.52 mg/dL in serum CRP value. Colonoscopy revealed longitudinal ulcers in the terminal ileum and multiple aphthous erosions in all areas of the colorectal mucosa (Fig. 1A, B). These endoscopic findings suggested a diagnosis of CD. Esophagogastroduodenoscopy (EGD) revealed multiple linear erosions in the gastric corpus (Fig. 1C) and circular erosions in the duodenal second portion. Although none of the biopsy specimens from these erosions, ulcerative lesions and normal-appearing mucosa revealed any evidence of epithelioid cell granulomas (Fig. 1D), we clinically diagnosed the patient as having CD, and intravenous administration of infliximab 5 mg/kg was started. However, his symptoms of fever and abdominal pain recurred 5 days after the start of infliximab. Both WBC count (38,800/muL and serum CRP level (6.56 mg/dL) further increased. Thereafter, we suspected the possibility of FMF because his symptoms met the Tel-Hashomer major criteria of 3 recurrent typical attacks. The patient was subsequently given 0.5 mg of colchicine per day. His fever and abdominal pain promptly subsided. We subsequently searched for mutations in exons 1-3, 5, and 10 in MEFV. As a result, he was found to have compound heterozygous mutations of E148Q/L110P in exon 2 of MEFV. Based on these findings, we finally made a definitive diagnosis of FMF in this patient. Oral administration of colchicine was continued, whereas infliximab was discontinued after 4 times administration (0, 2, 6, 14 weeks). Follow-up colonoscopy 6 months later demonstrated that both the longitudinal ulcers in the terminal ileum and aphthous lesions in the colorectum had completely disappeared (Fig. 2A, B).

PMC4877000_01

Unknown

During IFN-alpha monotherapy, the T315I mutation levels were reduced from 100% to 4% in patient no 5 (Fig 1), but two other mutations appeared (F317L and E255V). This 85-year old patient died of lung tuberculosis with an overall survival of 44 months. We observed a basic division of T-lymphocyte fractions during treatment management. The best IFN-alpha therapy outcome was described among others in patients younger than 60 years. The enhancing effect of IFN-alpha on the immune response was probably deficient in this elderly patient. In addition, the higher incidence of mutations may be related to advanced age. The concept of TKI cessation and IFN-alpha introduction did not contribute to the T315I reduction or to response improvement in patient no 6 (Fig 1). Recently, it was possible to switch therapy to ponatinib with a reduction of total BCR-ABL1 transcripts to MMR levels, which was associated with a simultaneous reduction of T315I.

PMC3988100_01

Unknown

Clinical studies suggest that antisocial behaviour, having fewer friends, aggressive tendencies, and an inability to tolerate frustration are common post-TBI consequences during childhood and adolescence, and that symptoms that often persist into adulthood could lead to vocational failure. For example, in a small cross-sectional investigation that compared 7-17 olds with moderate to severe TBI with age-matched youth who acquired orthopaedic injuries, found correlates of poor social cognition (below age expected social relations with peers, deficient social cognitive skills) at three months after the injury. Parents whose children (9 to 15 years old) had a TBI also reported that their children had greater peer relationship difficulties and also emotional distress, relative to parents whose children never acquired a TBI. We report here an investigation of the adverse mental health and behavioural correlates of lifetime TBI in a large representative sample of adolescents in grades 7-12 in the province of Ontario, Canada. This investigation provides the first population-level data on this association in a large adolescent sample of TBI with important measures including suicidality and other mental health measures, bullying, and conduct behaviors.

PMC6037862_01

Male

The patient was a 48 year old man who worked as a railway repair man. He presented to his general practitioner suffering from vomiting, genearl vagueness (which was confirmed by his wife) and loss of coordination. The general practitioner (GP) carried out some blood tests which showed that the patient's renal function tests were high. Within ten days of hid presentation he was referred to his local hospital. Here the GP's findings were confirmed. He had a lack of short-term memory, had suffered from frontal morning headaches for a month, he dropped things because of his poor coordination, and his blood pressure was 180/110 for which he was put onto atenolol. At this time his blood tests were as follows: - A chest x-ray showed no abnormalities, but a hint of prominent vasculature with upper lobe venous diversion. A CT scan of the head showed large ventricles, other CSF spaces not compressed, no focal lesions, and appearances consistent with communicating hydrocephalus. An MRI scan indicated some atrophy of white matter consistent with widespread ischaemic vascular disease. An electrocardiogram showed lateral T-wave inversion and left ventricular hypertrophy. Microbiological and immunological tests were normal. Ultrasound examination of the abdominal cavity showed that the liver, biliary system, spleen, bladder and prostate appeared to be normal, with no ascites and no lymphadenopathy. His kidneys appeared to be somewhat small (with a bipolar diameter of 9.0cm) by they were not hydonephrotic. His lumbar puncture pressure was high (38cm of water) and the protein content of the CSF was 1.28 g/L. He was treated with fluids, dextrose and saline, with insulin, glucose and calcium. This therapy brought his potassium level down from 7.8mm0l/L to 5.4mmol/L. He was also give frusemide, but this did not increase his urinary output to more than 30ml/hr. It was then decided to discharge him from the hospital, although his urea level had now risen to 41 mmol/L and his creatinine to 857 i mol/L; at the same time his bicarbonate level had fallen to 18mmol/L. However, on his way out of the hospital he fell badly and injured his head, face and right shoulder. He was therefore re-admitted. At this stage it was noticed that he had a skin rash in a "bathing-trunk" distribution. A dermatologist's advice was sought. The dermatologist's report stateed that "There are vascular lesions on the buttocks, groin, penis and scrotum. They are small angiomas, probably angiokeratomas-In this case this is either an incidental finding or an indication of Fabry's disease." The rash appeared like that in Fig.1. The patient was then transferred to the nearby teaching hospital, where a renal biopsy was performed. The histologist's report on the biopsy stated "the only glomerulus available for e.m. is rather collapsed and somewhat sclerosed; some of the podocytes contain numerous lipid rich vacuoles which have the striped appearance of 'zebra bodies' of Fabry's disease. The possibilty of Fabry;'s disease should be further investigated biochemically". This biochemical investigation showed an a-galactosidase-A activity of 3 units - the normal range being 16-64 units. This finding confirmed the views of the dermatologist and the histopathologist that this is a case of Fabry's disease. The patient was then transferred to the renal unit in order that he mightbenefit from renal dialysis. Fabry's disease is also known as the Anderson-Fabry disease as both Anderson and Fabry wrote papers about different aspects of the disease in the same year (1898). It is also know as "angiokeratoma corporis diffusum" - a description oif the dermatological symptoms - and a-galactosidase-A deficiency - a description of the inherited metabolic defect that causes the condition. It is now classed as a glycosphingolipid storage disorder. The inherited deficiency of a-galactosidase-A leads to an inability to break down glycosphingolipids with a terminal a-galactosyl moiety, mainly globotriaosylceramide (Gal-Gal-Glu-ceramide) or, sometimes, galabiosylceramide (Gal-Gal-ceramide). These glycosphingolipids are deposited in the lysosomes of many visceral tissues, especially in the vascular endothelium. The disorder is transmitted by an X-linked gene and is therefore more potent in male than in female subjects - but heterozygous female subjects can experience an attenuated form of the disease or they may be totally asymptomatic. Diagnosis is by means of the demonstration of a deficiency of the a-galactosidase-A enzymes. This deficiency can be observed in plasma cells, or white blood cells, but the accumulated glycosphingolipid can also be identified in plasma or urine sediment. The clinical features of the disease include pain which often occurs in chilhood or adolescence (but not apparently in the patient described above). Anaemia - very frequentCataract - very frequent Renal failure - very frequent Angiokeratoma - almost invariable Telangectasia mucous membranes / skin Hypertension - frequent Emphysema - frequent Mild mental retardation - sometimes Other clinical effects include: - Dermatologically, there are skin lesions with characteristic angiokeratoma lesions, especially in a "bathing-trunk" distribution - but there is wide variation between patients. There are cardiac and renal manifestations. These conditions are due to the build-up of glycosphingolipids in these tissues, causing abnormality of function. The renal manifestations are seen both in the renal tubules and in the glomeruli and often lead to renal failure. The cardiac manifestations are widespread, causing chest pain, cardiac enlargement and myocardial ischaemia, factors that may be complicated by systemic hypertension. In addition, other cardiovascular signs may be seen, including conduction defects; hypertension and its consequences; ischaemic heart attacks; mitral insufficiency; and thrombosis. There are ophthalmic complications such as: corneal opacities; cataracts; dilated and tortuous retinal vessels; and papilloedema +/- hypertensive changes Neurological complications include ischaemia and infarction in cortical and brainstem areas; strokes, seizures, personality changes and hemiplegia; mental retardation presents rarely and is often fairly minor. There can be gastrointestinal problems, including abdominal and flank pain; diarrhoea; hepatomegaly; and nausea and vomiting. Other clinical features include chronic chest problems, with dyspnoea and wheezing. Smokers are particularly prone to such effects. Lymphoedema of the legs and varicose veins can also occur, as can priapism. Patients may also suffer from anaemia due to shorter red-cell survival times. There are also effects on the musculo-skeletal system. If the disease is well-established there will be secondary problems, such as renal failure, cardiovascular problems, ocular complications and/or neurological disease. Clearly these must be treated by the standard methods for these conditions. Replacement of the abnormal gene or the abnormal enzyme is a topic that has been studied for some years and some workers believe that we are now at the stage when one or other of these replacement programmes can help the patients, particularly if diagnosed early in life. References to such work are given in the reference list. The treatment of the disease falls into two phases: In summary, Mendez, Stanley & Medel have stated that "Fabry's disease can present as an insidious dementia in middle or later life. It should be considered in the work-up of otherwise unexplained dementia in males of less than 65"

PMC8490161_01

Female

A 50-year-old female with no previous known medical history was transferred to our tertiary hospital for undiagnosed chronic abdominal pain, bloating, nausea, recurrent vomiting, and extreme unintentional weight loss ongoing for the past three years. During that time, she had many emergency department visits and evaluated by multiple specialists. Previous workups include numerous CT scans, MRIs, EGDs and colonoscopies without a clear clinical diagnosis. She had been prescribed multiple courses of PPIs and antibiotics. Also, she had undergone two abdominal surgeries for suspected bowel obstruction and pseudo-obstruction. Upon encounter, the patient was noted to be severely cachectic after being on TPN for the last three months due to severe esophageal reflux, heartburn, and food intolerance. A more careful history revealed symptoms of Raynaud s for the last 10 years. Also, when specifically asked and examined, the patient stated that her skin is hard and shiny, as if it was waxed. Based on the clinical presentation, diagnosis of CREST syndrome was suspected. That was further supported by a positive anti-centromere antibody test. Treatment options were limited due to the extent of disease progression by the time of diagnosis. Systemic sclerosis diagnosis can be challenging and requires a high level of suspicion. This case accents the gravity and value of a thorough history and physical examination as the prime foundation to reaching a diagnosis and it reminds us that sophisticated investigations are not a substitution for the essential skills of history taking and physical exam, especially in the setting of a long-standing undiagnosed illness.

rheumatology, abdominal pain and obstruction, clinical education

PMC8529303_01

Female

A previously healthy 55-year-old woman had a chest computed tomography (CT) scan showing mediastinal lymph node enlargement in September 2015. She denied any symptom of cough, hemoptysis, dyspnea, nasal congestion, wheezing, gastroesophageal reflux, fever and headache. Besides, she also denied being a smoker or drug user, bird or mold exposure, recent travel, or contact with tuberculosis or contagious water. Her family and psycho-social history are not specific. She had not been hospitalized in the past year. Six months later, without pharmacotherapy, she had an enhanced chest CT scan which revealed multiple mediastinal lymphadenopathy, the largest one being 17 mm x 14 mm (Figure 1(a)). Then, she was admitted into the Department of Thoracic Surgery in our hospital. On admission, her physical examination did not reveal any positive sign. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed to evaluate the mediastinal lymph node size. Furthermore, the biopsy result (Figure 2) revealed the enlarged lymph node was benign but contained non-caseating granulomas. Her brain CT scan was normal. Serological tests for human immunodeficiency virus, viral hepatitis, T cells enzyme-linked immunospot (T-SPOT) and purified protein derivative (PPD) for tuberculosis were all negative. Angiotensin-converting enzyme was 24 U/L. Mediastinoscopy was ordered to fetch biopsy of enlarged lymph nodes, and she was finally diagnosed with sarcoidosis by pathology (Figure 3). Then, she was treated with oral methylprednisolone 24 mg/d from 20 June 2016 to 1 March 2017. On 31 August 2016, another chest CT scan was performed which demonstrated multiple enlarged mediastinal lymph nodes were significantly smaller than before (the largest one was 7 mm x 10 mm). Six months later, she had a third chest CT scan which showed the lymph nodes had totally shrunk. However, multiple small nodules were found in the right upper lobe (Figure 1(b)). Given that she had been treated with glucocorticoid for over 7 months, we ordered a series of tests for opportunistic infections, among which the serum cryptococcal antigen was positive (the titer was 1:5) while her blood culture was negative and her lymphocyte subsets were normal. Since the diagnosis of cryptococcosis was probable which was the most likely cause of her pulmonary nodules, we suggested a lumbar puncture to rule out intracranial infection. However, she rejected it. Then, her corticosteroid was tapered off, and she was treated with oral fluconazole 400 mg/d according to the Chinese expert consensus. The whole clinical course was summarized in Table 1. During the follow-up, she underwent a fourth chest CT scan on 2 August 2017, which revealed that multiple nodules in the right upper lobe and the lymph nodes were both obviously shrunken. Due to the imaging improvement, she stopped fluconazole on her own terms which was against our recommendation of 6-month course. Since then, she had visited our hospital yearly with annual chest CT scans which indicated the original lesions turned to chronic inflammatory lesions gradually. Besides, she had never complained of any discomfort such as fever, headache, cough and so on during the follow-up.

cryptococcosis, glucocorticoid, sarcoidosis

PMC10362654_01

Female

Patient information: a young 30-year-old female complained of right-sided neck swelling for 4 years and intermittent pain over swelling for 4-5 months. No history of fever, cough, weight loss, or anorexia was present. No history of movement of swelling with deglutition was noted. No history of swelling on the left side of the neck, bilateral axillary region, ptosis, loss of sweating, hoarseness of voice, and syncopal attacks was present. The patient was not a known case of tuberculosis, hypertension, or diabetes mellitus. Clinical findings: on local examination, a relatively well-defined swelling of approximate size 2 x 2 cm is noted at the anteromedial aspect of the sternocleidomastoid (SCM) muscle, just below the angle of the mandible on the right side of the neck (Figure 1). The swelling was firm-hard in consistency, slightly tender, slightly pulsatile, and slightly ballotable on side-to-side movement. No evidence of a local rise in temperature was noted. Bilateral carotid arteries were palpable. On general examination, she was stable and afebrile with a pulse rate of 90 beats per minute and blood pressure (BP) of 120/80 mmHg. Breast examination and systemic examination were within normal limits. Laboratory investigations such as complete blood count (CBC), thyroid function test (TFT), kidney function test (KFT), and liver function test (LFT) were within normal limits. Diagnostic assessment: the patient has been further advised a neck ultrasound. On B mode ultrasonography neck, a well-defined ovoid homogenously isoechoic lesion of size 2.1 x 2.2 cm is noted just above the bifurcation of the right common carotid artery (CCA) causing splaying of the external carotid artery (ECA) and internal carotid artery (ICA). No evidence of calcification was noted within this lesion. No evidence of adjacent inflammatory changes is noted (Figure 2). On color Doppler, minimal vascularity is noted within this lesion (Figure 3). No evidence of lymph nodes is noted in the bilateral cervical region. Bilateral CCA S, bilateral ICA S, and bilateral ECA S show normal course and caliber with normal grey scale features. Duplex Doppler study shows normal laminar flow in bilateral CCA, ECA, and ICA with normal flow velocities and waveform patterns. A diagnosis of the well-defined isoechoic lesion at the bifurcation of the right CCA is likely a CBT was made. The patient was advised contrast-enhanced computed tomography (CECT) of the neck for further confirmation. On plain computed tomography (CT) sagittal (sag) section, an ill-defined soft tissue density mass lesion is noted on the right side of the neck anterior to the SCM muscle inferior to the angle of the mandible at the level of the hyoid bone extending superiorly up to suprahyoid space at C4-C6 vertebral level. No evidence of calcification was noted within (Figure 4). On the post-contrast study axial section, the bilobed mass lesion is noted in the carotid sheath on the right side of the neck at the bifurcation of the right CCA causing splaying of the ICA and ECA called Lyre s sign. It shows intense homogeneous enhancement. Multiple thin tortuous channels are noted around this lesion (Figure 5, Figure 6). According to the Shamblin group system, the tumor's circumferential angle of contact with ICA is a group I (<180 degrees of encasement). Diagnosis: a diagnosis of the well-defined homogeneously enhancing lesion at the bifurcation of the right CCA suggestive of carotid body tumor was made. Therapeutic interventions: the patient underwent surgical resection of a neck tumor. Post-operative image showing bilobed mass lesion. On histopathological examination, the definitive diagnosis came as carotid body paraganglioma. Follow-up and outcome of interventions: the patient returned to the clinic for follow-up but the further visits were inconclusive. Patient perspective: a patient was happy after receiving successful treatment. Informed consent: informed written consent was given by the patient.

paraganglioma, carotid body tumor, case report, chemodectomas, neck tumor

PMC3323202_01

Female

To the Editor: We report a case of a 36-year-old woman who sought treatment for 45 firm and erythematous nodular lesions on her face and neck. A physical examination showed no other abnormalities. Results of a chest x-ray and routine laboratory tests were normal. The patient tested negative for hepatitis B and HIV. Three weeks before she sought treatment, the patient reported receiving multiple intradermal microinjections in her face and neck for cosmetic purposes (mesotherapy) with an unlicensed product consisting of a solution of glycosaminoglycans. The injections had been administered by an unlicensed practitioner in a nonmedical office setting. The patient stated that 2 days after the therapy, a fever developed; it persisted for several days, along with redness at the inoculation sites, which gradually developed into nodules. Standard staining of a biopsied specimen from the lesion site was negative for bacteria, fungi, and mycobacteria. A histopathologic examination of a biopsy specimen showed an unspecific granulomatous infiltrate. Culture for common bacteria and fungi was negative, but culture of a sterile nodule aspirate on Lowenstein-Jensen medium was positive for acid-fast bacteria after 5 weeks. By using restriction endonuclease analysis of the 65-kDa heat shock protein gene, we found that the isolate showed a pattern compatible with Mycobacterium simiae. Identification was subsequently confirmed by high performance liquid chromatography of mycolic acids at the Centers for Disease Control and Prevention, Atlanta, Georgia. The isolate was tested for drug susceptibility against a panel of drugs and found to be resistant to most drugs tested (streptomycin, isoniazid, rifampin, ethambutol, ethionamide, rifabutin, ciprofloxacin, kanamycin, capreomycin, p-aminosalicylic acid, ofloxacin, and amikacin) and susceptible to clarithromycin at an MIC of 1 mug/mL. Treatment with clarithromycin was started, and the granulomas slowly cleared after 9 months of treatment. To our knowledge, this is the first reported case of an iatrogenic skin infection caused by M. simiae in an immunocompetent person. M. simiae is a species of nontuberculous mycobacterium commonly found in nature, but its role as a pathogen has been controversial. The slow-growing, photochromogenic mycobacterium has been isolated from both surface and tap water and has been associated with a nosocomial pseudo-outbreak suspected to have originated from a contaminated hospital water supply. M. simiae rarely causes disease in immunocompetent patients; most infections are associated with AIDS patients. Although this patient responded to treatment with clarithromycin, no established optimal therapeutic regimen exists against this species of Mycobacterium. M. simiae is often multidrug resistant, but successful therapy with clarithromycin in combination with ethambutol and ciprofloxacin has been reported in AIDS patients. We conclude that M. simiae can cause skin infections if injected directly into the dermis. Prolonged treatment is necessary to cure the patient of the infection. This report underscores the risk from alternative therapies performed with unlicensed products and by unlicensed practitioners. Unusual infectious agents should be considered when diagnosing skin infection in patients who have received injections for cosmetic purposes.

PMC3420481_01

Male

A 45-year-old man with no prior psychiatric history was brought to the emergency room for altered mental status and after initial assessment and work up, he was diagnosed with subarachnoid hemorrhage (SAH). The patient was hemodynamically stabilized for the next 2 days following which he underwent craniotomy and clipping of anterior cerebral communicating artery aneurysm. Following surgery, treatment was continued with labetalol to control elevated blood pressure, nimodipine to counteract cerebral vasospasm, and levetiracetam for seizure prophylaxis. Beginning postoperative day 4, the patient developed episodes of explosive outbursts of agitation and aggression. Patient was initially given lorazepam 2 mg IV Q 6 hrs by the primary team and a neurology consultation was requested concurrently. Neurologists noted that the CNS exam was unremarkable, but they expressed concern regarding possible worsening of agitated/aggressive behavior with use of levetiracetam. Based on the neurologist's recommendation, levetiracetam was switched to valproate sodium, starting with loading dose of 1000 mg IVPB, followed by 500 mg IVPB Q 12 hrs. Although the patient did not develop any seizure activity, his agitated behavior continued to be problematic. Three days after the switch, he continued to display episodic agitated behavior. At this stage the primary team requested psychiatry consultation for pharmaceutical management of agitation. The psychiatry team tried to manage the agitation/aggression with intense nursing intervention and various medications such as olanzapine (up to 10 mg IM Q 12 hrs), valproate (up to 1000 mg daily), lorazepam (2 mg IM Q 6 hrs), and haloperidol (10 mg IM Q 8 hrs). However, all the interventions were unsuccessful, and the patient continued to remain agitated and aggressive. We then considered beta blockers as a possible treatment for uncontrolled agitated and aggressive behavior. Although he was already on labetalol for the treatment of hypertension, since labetalol is hydrophilic and does not readily cross the blood brain barrier, we decided to switch to a lipophilic beta-blocker. We initiated treatment with metoprolol succinate at 50 mg po daily with close monitoring of his hemodynamic status (blood pressure and heart rate). The next day it was increased to 100 mg po daily. Within 3 days, the patient demonstrated significant decrease in agitation and aggression. The benefits were sustained up to a follow-up period of 2 weeks, and the patient was successfully discharged back to the community.

PMC2929619_01

Female

A 41-year-old female patient was referred to the ENT outpatient clinic with 5-month history of clear fluid discharging from the nose. Fluid samples were sent for tau protein analysis and outpatient imaging was requested. Prior to completion of skull base imaging, the patient was admitted in an acute confusional state, with a nonblanching rash, pyrexia, and signs of meningism. A diagnosis of streptococcal meningitis was made following lumbar puncture and she was commenced on appropriate antibiotics. Magnetic resonance imaging demonstrated an extensive skull base lesion involving the sphenoid and ethmoid sinuses, pituitary fossa, and suprasellar region (Figure 1). Computed tomography of the sinuses revealed bony destruction (Figure 2). An endonasal transethmoidal biopsy was undertaken, following which there was profuse CSF rhinorrhoea. Subsequently, the patient developed clinical signs of meningism with pyrexia, neck stiffness, photophobia, and deterioration in neurological status. CSF analysis revealed gram-negative coliforms and antibiotic treatment was commenced. The patient was transferred to the regional neuroscience centre for joint neurosurgical and ENT management. On recovery from the second episode of meningitis, she underwent an endoscopic endonasal biopsy and repair of the anterior pituitary fossa and planum sphenoidale using layered fat graft and artificial dural substitute sealed with Tisseel fibrin sealant (Baxter Healthcare, UK). Histological analysis of this biopsy specimen confirmed the tumour to be a prolactinoma. Although her initial serum prolactin level was only 451 miu/mL (normal range 102-496), it did rise to 953 miu/mL in the immediate postbiopsy period. Following endocrine review, she was commenced on cabergoline. Despite satisfactory intraoperative appearances, CSF rhinorrhoea recurred. A CT cisternogram was undertaken to further characterise the site of CSF leakage (Figure 3). Through a sublabial transphenoidal microsurgical approach, two further repairs of bony defects in the floor of the pituitary fossa and roof of the sphenoid sinus were undertaken using fascia lata and fat grafts sealed with Tisseel glue, along with a period of postoperative lumbar CSF drainage. Both attempts were unsuccessful and lumbar CSF drainage resulted in profound pneumocephalus (Figure 4). The patient suffered a rapid deterioration in clinical status, and following two generalised tonic-clonic seizures required intubation and ventilation in the neurointensive care unit. Once sufficient neurological recovery had occurred, a second CT cisternogram (Figure 5) was undertaken prior to a further endoscopic endonasal repair using fat graft and fascia lata. In this procedure, 0 and 30 endoscopes (Karl Storz, Germany) and the Stealth Station Tria neuro-navigation system (Medtronic, USA) were used to locate and visualise the bony defects through a right-sided sphenoidotomy. Despite postoperative lumbar CSF drainage, this procedure was also unsuccessful. Following the fourth unsuccessful attempt, the patient underwent a transcranial repair of the CSF leak through a right-sided pterional craniotomy. Intraoperatively, no dural defect was visible; however, bony defects in the anterior pituitary fossa floor were palpable and therefore sealed with layers of temporalis fascia and muscle grafts secured with Tisseel sealant. A prolonged post-operative period of lumbar CSF drainage (7 days) was also undertaken which resulted in a successful control of CSF rhinorrhoea.

PMC4062382_01

Male

A 64-year-old male, a current smoker with a wet cough and fever lasting for one week followed by the spontaneous resolution of symptoms, presented to the outpatient clinic for an evaluation of an abnormal shadow on a chest X-ray. The chest X-ray showed an area of consolidation in the apex of the right lung (Figure 1A). In addition, laboratory tests revealed an elevated CRP level(3.86 mg/L) and white blood cell count (8,980 ml), although the levels of serum tumor markers such as CEA, CYFLA, and ProGRP were within the normal range. Contrast-enhanced CT showed a low-density lesion with thick ring-enhanced irregular walls in the right upper lobe. The mass measured 53x43 mm, and had poorly defined margins. The interface between the lesion and surrounding organs was not clear. No gas collection or calcification was indicated. Enlarged lymph nodes were not detected in the mediastinum(Figure 1B). A PET/CT scan demonstrated a high uptake in the lesion, with a maximum SUV of 8.7, and the mediastinal lymph node, with a maximum SUV of 3.7, suspicious for both lung cancer and lung abscess formation (Figure 1C). An abscess was initially suspected based on the patient's symptoms, CT image findings and laboratory test results. Both a transbronchial lung biopsy (TBLB) and CT-guided fine-needle biopsy of the lesion showed inflammatory cells compatible with active inflammation, No malignant cells were seen, and all bacterial cultures were negative. The patient was referred to our institution for management of the mass one month later. We suspected that the lesion indicated malignancy, as a follow-up CT scan showed an increase in the lesion in size to 59x49 mm (Figure 2) despite the absence of symptoms, such as fever. Therefore, we planned to perform surgery because there were no other signs of distant metastasis based on a CT scan of the chest, abdomen and pelvis, brain MRI and PET/CT. Based on the intraoperative findings, the right middle lobe was found to be involved with the mass in the upper lobe. A pathological diagnosis of lung cancer was confirmed according to the results of a rapid frozen section biopsy of the lesion. Consequently, we performed the right upper and middle lobectomy. There were no intraoperative complications, and the patient had an uneventful recovery. The final results of the pathologic examination showed a pleomorphic carcinoma of pT2N0M0, stage A.

lung neoplasms – etiology, lung neoplasms – radiography, lung neoplasms – surgery

PMC5187466_01

Female

A 39-year-old Nigerian woman with history of sickle cell disease presented to our hospital with a chief complaint of increased swelling on her left flank for the past 2 years. She initially noticed the swelling "many years ago" as a 1 cm soft, painless mass. Over the years, the swelling progressively increased to the current size of approximately 10 cm on presentation. She reported no warmth, redness, or drainage of pus or fluid. Six months prior to presentation, the patient began experiencing a dull pain in the midline of her lower back, radiating laterally to the left lower quadrant. It fluctuated in severity but was aggravated with flexion of the back. She reported no recent fevers, fatigue, changes in weight, chills, sweats, hemoptysis, or dyspnea. She did not have any urinary or gastrointestinal symptoms nor did she experience weakness or sensory loss in her lower limbs. The patient immigrated to the United States from Nigeria one year ago. She has no known history of or exposure to TB but did receive the BCG vaccine as a child. On examination, she was a well appearing young female. Vital signs included BP 118/60 mmHg, HR 66/min, temperature 98.8 F, O2 saturation 97% on room air, and BMI 20.3. She was noted to have icteric sclera and multiple enlarged, nontender, soft, mobile cervical lymph nodes (LNs), the largest being a 2 cm right anterior cervical LN. Inspection of her back revealed a 10 cm x 16 cm well-demarcated fluctuant area without erythema or other skin changes. The area was not tender to palpation, nor were there any areas of focal tenderness at the spine. Range of motion of her back and hips was fully intact. The remainder of the examination including cardiopulmonary, abdominal, and neurologic examination was unremarkable. Review of her lab tests revealed hemoglobin of 94 g/L, MCV 92.5 fl, RDW 21.7%, reticulocyte count 0.08 of RBCs, leukocyte count 7.4 x 103/muL, and platelet count 317 x 103/muL. Other lab tests included blood urea nitrogen 2.86 mmol/L, serum creatinine 45 mumol/L, AST 65 U/L, ALT 29 U/L, alkaline phosphatase 19 U/L, total bilirubin of 148.8 mumol/L with indirect bilirubin 131.7 mumol/L, LDH 525 U/L, and ESR 28 mm/hr. Rapid HIV testing was negative. Blood cultures drawn at initial evaluation remained sterile after 48 hours. A computed tomography (CT) scan of the abdomen and pelvis revealed diskitis/osteomyelitis at the L4-L5 level with adjacent paraspinal and left retroperitoneal abscesses extending to the left lower back/flank subcutaneous tissue and into the epidural space. A follow-up magnetic resonance imaging (MRI) of the lumbar spine with and without contrast confirmed these findings of diskitis and osteomyelitis at L4-L5 with an expansile abscess within substance of the disk extending into ventral epidural space with involvement of left L5-S1 and right L4-L5 neural foramina (Figures 1 and 2). Ultrasound guided drainage of the abscess was attempted but only a small amount of thick tan fluid could be collected as the contents were extremely viscous. Fluid analysis showed glucose <10 mg/dL, protein 5 g/dL, and LDH 4872 U/L. Cell count was unable to be performed due to the fluid's viscosity but differential showed 82% neutrophils. Gram stain and acid-fast staining were negative for any organisms. Given her history and presentation, a tuberculous cold abscess was high on our differential and the patient was empirically started on the standard anti-TB regimen of isoniazid, rifampin, pyrazinamide, and ethambutol. Though she had no neurological symptoms, given the extension of the abscess, both orthopedic and neurosurgery specialists were consulted for surgical drainage of abscess. The patient and neurosurgeons were initially reluctant to perform the procedure and she was therefore discharged on anti-TB medications and pyridoxine. Upon follow-up at a local TB clinic, she complained of right upper quadrant pain and was found to have elevated transaminases. All of her medications were stopped and a week later she was restarted on rifampin and ethambutol. Four weeks from presentation, cultures from drained abscess revealed Mycobacterium tuberculosis. At this time, the patient was reevaluated by neurosurgery and underwent paraspinal abscess drainage through paravertebral muscles. Following the procedure, she was briefly treated with moxifloxacin as per instructions from the regional TB clinic. At her last clinic visit, six months into her treatment course, she was on isoniazid, rifampin, and pyridoxine without any complaints.

PMC5279080_01

Male

A 38-year-old man presented with an 8-day history of fever, myalgia, dry cough, dyspnea, and fatigue. He was a current smoker (10 cigarettes a day) and reported no occupational exposure. His medical history was unremarkable. Symptoms persisted despite antibiotic therapy with amoxicillin/clavulanic acid and roxithromycin. At admission, temperature was 38.5 C, respiratory rate was 24/minute, auscultation was normal and no extrathoracic signs were present. Chest X-ray showed diffuse micronodular opacities (Fig. 1A). High-resolution computed tomography (CT) demonstrated a profusion of well-delimited centrilobular micronodules, 2 mm in diameter, with subpleural sparing and a "bud in tree" pattern in some areas (Fig. 1B). Interbronchial lymph nodes were present (Fig. 1C). Arterial blood gases at 21% FiO2 showed PaO2 66 mm Hg, PaCO2 35 mm Hg, pH 7.44. Laboratory parameters were as follows: leukocyte count: 19.8 x 109/L (85% polymorphonuclear cells), C-reactive protein: 305 mg/L and fibrinogen: 12 g/L. Serum electrolytes, and renal and liver function tests were normal, as well as serological tests for Legionella pneumonia, Mycoplasma, Chlamydia, Coxiella psittaci, hepatitis C and B viruses, and HIV. Antinuclear antibody, perinuclear antineutrophil cytoplasmic antibody (P-ANCA), cytoplasmic-ANCA, and cyclic citrullinated protein antibody tests were negative. Urine cocaine test was negative. Bronchoalveolar lavage (BAL) showed 400 x 103 cells/mL, comprising 73% macrophages, 18% lymphocytes, 5% neutrophils, and 4% eosinophils. Golde score was normal (40). Testing for Pneumocystis jiroveci, Mycobacterium tuberculosis, and yeasts remained negative. Transbronchial biopsies were not contributive. Pulmonary function test results were as follows: FEV1: 1.34 L (34%), FVC: 1.94 L (40%), FEV1/VC: 69%, TLC: 4.24 L (61%), DLCO: 11.59 mL min-1 mm Hg-1 (42%) and KCO: 3.83 mL min-1 mm Hg-1 (97%). To rule out an infectious disease, lung biopsies were performed under video-assisted thoracoscopy (VATS). Gross examination of slides disclosed a patchy nodular pattern. On microscopic examination, lung architecture was preserved. Nodules consisted in buds of granulation tissue fulfilling distal airspaces and extending from one alveolus to the next one, mimicking in some areas a butterfly pattern. Fibrotic buds disclosed bronchiolocentric predominance and in some areas extended into bronchiolar lumen. No granuloma was seen in lung parenchyma or in peribronchiolar areas. Mild inflammatory infiltrates was seen around fibrotic areas but interstitial inflammation was not present at distance of fibrotic plugs (Fig. 2). No pathogen was identified on Grocott and PAS staining and on biopsy cultures. This histological pattern was consistent with OP. The lack of marked interstitial inflammation and absence of granuloma ruled out other diagnoses such as sarcoidosis or hypersensitivity pneumonia. Oral corticosteroid therapy was started at 1 mg/kg/day. Improvement of dyspnea was observed after 1 month of treatment, and CT micronodules had dramatically decreased (Fig. 1D). Steroids were tapered over 6 months and lung CT scan returned to normal with no signs of relapse at 5-year follow-up. Informed consent was signed by the patient.

(B) HRCT scan showing diffuse small centrilobular nodules.

PMC5903134_01

Female

The patient was a 29-year-old Japanese woman. She had been experiencing a high fever for 2 weeks. In another hospital, she was diagnosed with SLE due to pancytopenia, abnormal urinalysis (proteinuria and hematuria), low complement, positive antinuclear antibody, and anti-dsDNA antibody. In addition, she had multiple small granular lesions in the lungs appearing like miliary tuberculosis (TB) on computed tomography (Fig. 1a). Therefore, she was transferred to the TB ward of our hospital. On physical examination, her height was 160.5 cm and her body weight was 58.8 kg. She had a temperature of 38.8 C. Her blood pressure was normal at 111/77 mm Hg. Oral ulcers and a discoid rash were observed. There was slight edema in the lower extremities. The laboratory tests showed a slightly elevated serum creatinine of 0.91 mg/dL, a normal total cholesterol of 122 mg/dL, a C-reactive protein of 0.57 mg/dL, proteinuria of 5.1 g per day, and microhematuria. On serological testing, antinuclear antibody was positive, the anti-dsDNA antibody titer was very high at 400 IU/mL, and serum C3 and C4 were very low at 26.4 and 4.3 mg/dL, respectively. Anti-neutrophil cytoplasmic antibody was not detected. While awaiting the TB test results, she was isolated in a private room in consultation with the pulmonologist. On day 4, her fever persisted, and laboratory tests revealed progression of pancytopenia. It was thought to be highly likely that she had hemophagocytic syndrome. Thus, we determined that this situation was emergent and initiated intravenous prednisolone (PSL) 60 mg daily. After treatment, she immediately became afebrile. Five days after treatment, we changed from intravenous PSL 60 mg to oral PSL 50 mg daily. After improvement in her general condition, we performed a kidney biopsy 7 days after the start of the initial treatment. The kidney biopsy results are shown in Figure 2. Two cores of kidney tissue containing 55 glomeruli were present, none of which were globally sclerosed. Most of the glomeruli showed multiple wire loop lesions and endocapillary proliferation. The wire loop lesions were more conspicuous than endocapillary proliferation (Fig. 2a). Crescent formation, necrosis, or glomerular sclerosis were not present. In addition, vasculopathy was not present. Immunofluorescence staining demonstrated positive staining of the glomerular tuft, mesangial area, and part of the endothelial area for IgG, IgA, IgM, C3, C1q, and fibrinogen (Fig. 2b). On electron microscopy, the glomeruli revealed massive electron-dense deposits in the endothelial and mesangial areas, but no noticeable subepithelial deposition (Fig. 2c). In addition, electron-dense deposit was present in the peritubular capillaries, but not in the tubulointerstitial area or arteries (Fig. 2d). The histological diagnosis was LN with massive wire loop lesions, ISN/RPS class IV-G (A). We did not add immunosuppressants such as cyclophosphamide or mycophenolate mofetil because we considered that LN would respond well to PSL alone. Her proteinuria and hematuria almost disappeared within 1 month. Furthermore, her lung disease disappeared after immunosuppressive therapy (Fig. 1b). In addition, we did not detect Mycobacterium tuberculosis from the sputum, gastric fluid, or bone marrow. After that, she remained in complete remission for several years using low-dose PSL only.

class iv-g, lupus nephritis, wire loop lesions

Multiple small granular lesions (arrow) in the lungs on computed tomography before.

PMC5604059_01

Male

Before this study, the written informed consent was obtained from the patient, and the study was approved by the regional ethics committee of The First Affiliated Hospital of Yangtez University Medical School, and performed in accordance with the Declaration of Helsinki. The patient is a 58-year-old Chinese male who was mentally able to work as a policeman 1 year ago. He was normal nutritional and has no drug addiction habits as well as psychiatric disorders before. Six months ago, he began to suffer mild insomnia and episodes of recent memory loss, then sought medical treatment in our hospital. His pulse was 78 beats/min and regular, and blood pressure was 130/65 mm Hg. The consciousness was sensitive and Glasgow Coma Scale sore was 15. Cranial nerves examination was negative. For motor function, the patient had normal muscle strength (grade 5) and normal muscle tone (grade 0). According to Kendall report, the grading scale of muscle strength ranges from 0 to 5. Briefly, grade 0, no visible or palpable contraction; grade 1, visible or palpable contraction with no motion; grade 2, full range of motion (ROM) gravity eliminated; grade 3, full ROM against gravity; grade 4, full ROM against gravity, moderate resistance; grade 5, normal, full ROM against gravity, maximum resistance. In terms of muscle tone, based on the Ashworth classification, muscular tone was divided into 5 grades from normal (grade 0) to limited flexion and extension (grade 4). Stance and gait was freely without involuntary movements. Finger-to-nose test, heel-knee-shin test and Romberg sign test were all negative. Sensory examination was normal. Finally, reflexes check shows symmetrical and pathologic reflexes were negative. Laboratory examinations of routine blood, homocysteine, VitB12 and folic acid were normal. For the first time, MRI scans were not performed due to the patient's implanted metal dentures. In order to get his MRI image, with the consent of the patient, his implanted dentures were removed before MRI scans so as to avoid inhalation of the respiratory tract and other potential hazards. His mini-mental state examination (MMSE) score was 27 (see Table 1). These results were almost normal and acceptable in this aged people. Montreal Cognitive Assessment (MoCA) screening for MCI is more sensitive than MMSE (Nasreddine et al.,). Then we conducted MCI exam with a serial scale for this patient. The results showed that his MoCA examination score was 25 out of 30 with mainly deficits in visuospatial/executive (4/5), delayed recall (3/5) and orientation (4/6; see Table 2). In addition, we tested Activity of Daily Living Scale (ADL) for daily life functioning, and Hamilton Anxiety and Depression Scale (HAMA, HAMD) for mental state. These results showed that memory impairments were not relevant in daily life and state of mind during his work in a police office. Therefore, we gave a diagnosis of MCI at that time according to National Institute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders (NINCDS-ADRDA) Criteria 2011 (Guo et al.,). Then, the patient was treated with alprazolam and donepezil but did not return regularly for follow-up visits. Six months after his first visit, he began to have severe sleepless and misidentification with movie characters and his family members. In addition, he could not perform simple calculations or shopping alone, even routine daily-work. His cerebrospinal fluid was collected, the pressures was 155 mm H2O. Bacterial and virus battery, 14-3-3, total tau, phosphorylated tau181 and Abeta42 were analyzed. All the above measurements showed negative results. The patient's MMSE score was 18 (see Table 1), therefore we gave a diagnosis of probable Alzheimer's disease according to NINCDS-ADRDA Criteria 2011. Moreover, compared with the matched control whose brain shows mild atrophy without SPC, and his cognitive functions are normal (Figures 1A,B). The MRI results showed that the double lateral ventricles were significantly expanded (Figure 1C) and the space-occupying lesions in the midline area were clearly observed (Figure 1D). In consideration of the above tests, the final diagnosis for this patient was suspected dementia induced by SPC. Then, he was transferred to the department of neurosurgery for minimally invasive surgical treatment. Neuroendoscopic fenestration of the SPC was successfully performed via a right frontal approach using a high-resolution flexible neuroendoscopic system without complication. Communication between the cyst cavity and bilateral ventricles was constructed via a single trajectory. Two months after treatment, the patient returned us a visit. We rechecked him by MRI and MMSE. The MRI results confirmed a shrinkage of the expanded lateral ventricles (Figure 1E) and elimination of SPC (Figure 1F). Meanwhile, his MMSE score was 28 (see Table 1), and he was able to be competent at both his job and daily life. In the later 2 months of brief follow-up period, the patient showed better adherence and tolerability and no adverse events could be observed.

cognitive impairment, dementia, mini-mental state exam, montreal cognitive assessment, neuroendoscopy, septum pellucidum cyst

PMC7318866_01

Female

In 2010, a 57-year-old female patient presented with mild polydipsia, polyuria, blurred vision, and weight loss. Diabetes mellitus was diagnosed by oral glucose tolerance test results (OGTT, determination of glucose and insulin at 0 and 120 min). The HbA1c level at that time was 3.6% and glycated albumin (GA) was 16.3% (normal range: 10.8-17.1%). Type 1 diabetes-associated antibodies such as Islet Cell Antibodies (ICA), Glutamic Acid Decarboxylase antibodies (GAD), Insulin Autoantibodies (IAA), and insulinoma-antigen 2 (IA2A) were all negative. Total bilirubin (TBil) was 38.7 umol/L (normal range: 5.1-22.2) and direct bilirubin (DBil) was 11.6 umol/L (normal range: 0-6.8). Other laboratory tests including serum alanine transaminase (ALT), albumin, and renal function test were all within the normal range. Upon diagnosing her with diabetes mellitus, the primary doctor prescribed nateglinide to control the hyperglycemia. In recent years, her HbA1c level were found repeatedly reduced, while the level of GA remained high. Hemoglobin (Hgb) and albumin were still in the normal range, and the bilirubin level was found slightly elevated. In terms of screening for diabetic complications, the patient had completed the fundus examination, renal ultrasound, cardiac ultrasound, lower limb artery ultrasound, 24 h urine protein, and urine albumin-to-creatinine ratio, and no abnormalities were found. However, the carotid ultrasound showed the presence of atherosclerotic plaques. Past medical history showed the patient suffered from keratoconjunctivitis sicca for 10 years and carotid atherosclerosis for 3 years. The family history showed her mother also suffered from diabetes mellitus with similarly low HbA1c level (3.4%) and slightly decreased Hgb (102 G/L). Her mother also had Sjogren syndrome and passed away at age of 70 years old without further investigation of the causes of low HbA1c. In addition, both her mother and daughter had hyperbilirubinemia. The complete blood count of the daughter showed that normal Hgb (156 G/L) and increased reticulocyte (169.9 x 109/L, normal range: 24.0-84.0 x 109/L), normal white blood cell (6.55 x 109/L) and Platelet (321 x 109/L). After recent hospitalization in our medical center, the abnormally low HbA1c levels attracted our attention. To confirm the problem, we performed repeated HbA1c test by both ion-exchange chromatography and immunization method. However, the low HbA1c level persisted. Hemoglobin electrophoresis revealed no abnormality. After excluding laboratory error and variation of hemoglobin, we performed further laboratory examinations (Table 1): Hgb was 129 G/L, reticulocyte was 265.4 x 109/L (normal range: 24.0-84.0 x 109/L), TBil was 29 umol/L, DBil was 7.6 umol/L, and the life span of red blood cells measured by CO breath test was significantly shortened to 43 days (normal range: > 75 days). All these results above indicated the presence of hemolytic anemia. However, screening for common causes (erythrocyte osmotic fragility, 6-phosphate glucose dehydrogenase test and plasma free hemoglobin test, Ham test, Rous test, and Coombs test were all in normal range) of acquired hemolytic disease led to exclusion of autoimmune hemolysis, glucose-6-phosphate dehydrogenase deficiency, paroxysmal hemoglobinuria, and so on. Pancreatic MRI showed slightly atrophied pancreatic body, but iron deposition in the pancreas was normal (23.7 ms at T2 *). Both the patient and her daughter showed heterozygous variant in PIEZO1 gene (c.6017T > A, p.V2006D) by whole exome sequencing of the blood with confirmation of sanger sequencing (Figure 1), which is associated with dehydration hereditary stomatocytosis (DHS). After this diagnosis, nateglinide was changed to sitagliptin to reduce the burden of the pancrea islet function.

piezo1 gene, diabetes, glycated albumin, glycated hemoglobin, hemolytic anemia

PMC3099209_01

Male

A 57-year-old HIV-negative aboriginal male was initially admitted with community-acquired pneumonia, which progressively worsened. A subsequent bronchoscopy with bronchoalveolar lavage revealed acid-fast bacilli on ziehl-neelsen staining. A subsequent CT chest demonstrated bilateral pulmonary infiltrates and cavitating lesions consistent with active pulmonary tuberculosis infection. His treatment was initiated with the standard 4-drug regimen: pyrazinamide, rifampin, ethambutol, and isoniazid (INH). Sputum mycobacterial TB culture demonstrated susceptibility to the 4-drug regimen. During his admission to hospital, he developed diffuse abdominal pain with peritonitis on examination. He also developed tachycardia and hypotension, and an abdominal X-ray revealed free air under the diaphragm. Arrangements were made for emergent exploratory laparotomy in the operating room. Intraoperatively a single contiguous inflammatory mass was found in the left upper quadrant, which revealed a gangrenous necrotic splenic colon. A left hemicolectomy was preformed. This revealed a region of necrotic-appearing pancreatic tissue which was likely associated with the necrosis of the adjacent splenic colon. Further exploration of this inflammatory mass demonstrated particulate matter and peritoneal fluid and a large perforation in the posterior wall of the stomach, which was the initial insult. Peritoneal fluid mixed with enteric contents from the gastric perforation was sent for culture and was positive for mycobacterium tuberculosis. An intraoperative gastroscopy was preformed which identified an ulcer approximately 5-10 cm from the gastroesophageal junction. The patient hemodynamic status worsened in the operating room despite ongoing resuscitation and significant quantities of norepinephrine intravenously were needed. It was decided to stabilize the patient with a damage control laparotomy and take the patient to the intensive care unit rather than perform a definitive repair of the gastric perforation because of the severe hemodynamic instability. Drains surrounding the ulcer were placed and the skin closed. Plans were made to return to the operating room in 24 hours for definitive treatment if the patient's hemodynamic status improved. The patient's condition stabilized in the intensive care unit, and he was brought to the operation room the following day. Multiple biopsies of the large 3 cm gastric ulcer were taken. The patient was deemed to be unable to tolerate a total gastrectomy at this time, and unfortunately wedge resection of the stomach was not possible due to the position and size of the ulcer. Thus, the ulcer was repaired with primary closure, and creation of a feeding jejunostomy was completed. The patient was returned to the intensive care unit. Biopsies from the gastric ulcer revealed no malignancy but did demonstrate fungal elements (Candida albicans) indicative of secondary infection. Also, focal reactive changes in the surface epithelium suggested a reactive process. No granulomata or giant cells were identified. Biopsies were also negative for Helicobacter pylori. The patient did not receive nonsteroidal anti-inflammatory medications and was on Pantoprazole to prevent stress-related ulceration. The peritoneal fluid cultures collected during operation for the gastric perforation demonstrated mycobacterium tuberculosis and fungal elements. Gastric tissue sent intraoperatively for culture was positive for mycobacterium TB, which led to the presumptive diagnosis of gastric perforation, associated with TB. Pathologic examination of the resected left colon revealed an area of necrosis, but no perforation. Microscopic examination demonstrated numerous caseating granulomas with multinucleated giant cells, demonstrating mycobacterial colitis. The patient remained in the intensive care unit, and a small-bowel follow-through with contrast revealed no extravasation of contrast. The TB-associated gastric perforation was adequately repaired. Postoperatively the patient was continued on INH 300 mg intramuscularly and rifampin 600 mg intravenously daily according to sensitivities from peritoneal fluid cultures. Imipenum, levofloxacin, and fluconazole were also continued according to culture results. The patient's pulmonary tuberculosis persisted over the subsequent weeks despite appropriate antituberculosis treatment. Deteriorating lung function was likely a combination of previous smoking damage, edema secondary to recent aggressive fluid resuscitation, and persistent pneumothorax. Eventually multiorgan failure ensued, and life support was discontinued following discussion with the family.

PMC8261067_08

Male

Takayama et al. reported a case of pneumonia treated by Kampo medicine gokoto (case 17). A 52-year-old male patient presented with cough, sputum, and joint pain. Chest radiography revealed interstitial shadow in the right lung that was diagnosed as moderate stage I COVID-19. After administration of gokoto, a Kampo medicine for cough and sputum, for symptom relief, cough and sputum improved within 4 days. Takayama et al. also reported 5 cases (cases 18-22) of COVID-19-related olfactory disorder treated by kakkontokasenkyushin'i. The symptoms improved within 3-5 days after administration of kakkontokasenkyushin'i. Kakkontokasenkyushin'i can be used for treating nasal congestion, rhinitis, and inflammation in the nasal mucosa. Olfactory disorder in COVID-19 has been reported to be associated with inflammation and congestion, especially in the olfactory bulb and olfactory cleft. They concluded that kakkontokasenkyushin'i may be considered as a treatment alternative for the olfactory disorder related to COVID-19. On the other hand, some reports have suggested the clinical efficacy of Chinese medicine in COVID-19. Ke et al. have reported the efficacy of Lianhua Qingwen (LH) capsules in patients with COVID-19, using a multi-center, prospective, randomized controlled trial. Certain LH components overlap in the Kampo medicine maoto or maotokasekko that were administered to cases 1-4, 6-11, and 14-22, as shown in Tables 1, 2. The efficacy of LH was compared between conventional treatment alone or in combination with LH for 14 days. The rate of recovery of symptoms including fever, fatigue, and cough was significantly shortened by LH administration. Zheng et al. reported that LH treatment modulates the inflammatory process, exerts antiviral effects and repairs lung injury in the network pharmacology analysis of the therapeutic mechanisms of LH in COVID-19. Furthermore, a national retrospective registry study reported by Lihua et al. suggested that QFPDT was associated with a substantially lower risk of in-hospital mortality. Modified QFPDT in Japan was administered to cases 10, 11, 15, and 16, as shown in Tables 1, 2. Although these reports have revealed the efficacy of traditional medicine, further clinical trials are required to evaluate the efficacy of Kampo medicine on COVID-19-related symptoms and conditions. The JSOM has prepared a research project for clinical trials of Kampo medicine in patients with COVID-19, some of which are currently in progress. Table 3 shows the list of the clinical studies being planned or conducted in the JSOM projects. In particular, studies one through three are referred to as an Integrative Management in Japan for Epidemic Disease (IMJEDI). Study 1 is a multi-centered, randomized trial to test our hypothesis that the Kampo medicine, hochuekkito, has a preventive effect on the symptoms of COVID-19 among healthy hospital workers. While we hope for an effective and widely available vaccine, the efficacy of the current vaccines has not been shown in a large number of patients. Furthermore, the efficacy of the vaccines may be reduced if SARS-CoV-2 persistently and consistently undergoes mutations. The possible mechanisms of the preventive effect of hochuekkito (bu Zhong yi qi tang) against COVID-19 have reported by Takayama et al.. Thus, clinical trials are being conducted to assess the efficacy of Kampo medicine for preventing COVID-19. Medical staff, overextended from the increase in critical patient care and the other circumstances involved with the COVID-19 pandemic, are thought to have decreased immunity along with physical and mental health issues. Furthermore, they are at an increased risk of infection when providing medical care. Therefore, we considered it necessary to verify the effectiveness of Kampo medicine in preventing illness among staff members who continue to provide medical care despite these challenges. Study 2 is a multi-centered, retrospective, observational study to investigate the efficacy of the actual treatment (conventional and Kampo medicine) in patients with mild-to-moderate or even suspected COVID-19. Several clinical trials on antiviral drugs are currently in progress; however, evidence on its efficacy remains limited. Kampo medicine has a long history of repeated use in viral epidemics and was also used during the Spanish influenza pandemic, approximately 100 years ago. Several cases of COVID-19 treated with Kampo medicine have already been reported. The next step in establishing Kampo medicine as a treatment strategy for COVID-19 is organizing a clinical study with a large number of cases. In Japan, many COVID-19 patients are treated with a combination of Kampo medicine and Western medicine, and an observational study that would collect data from a multi-center setting would be ideal. Study 3 is a multi-centered, randomized trial to test our hypothesis that additional administration of Kampo medicines kakkonto and shosaikotokakikyosekko is more effective in relieving symptoms and preventing the onset of severe infection in mild-to-moderate COVID-19 patients compared to those treated with conventional treatment alone. The symptoms and signs associated with acute infectious diseases were categorized into six-stage patterns in the original concept of Kampo medicine described in the Shanhanlun, which is a traditional Asian medical textbook of infectious diseases written by Zhan Zhongjing. The Shanhanlun explains that infectious diseases progress through six-stage patterns: early, middle, and late yang patterns and early, middle, and late yin patterns. Characteristic symptoms are chill and fever in the early yang pattern, alternating chill and fever with respiratory and intestinal symptoms in the middle yang pattern, and marked fever with thirst in the late yang pattern. The symptoms also include coldness with intestinal symptoms in the early yin pattern, coldness with marked fatigue in the middle yang pattern, and coldness with circulation failure with disturbance of consciousness in the late yang pattern. To study the efficacy and safety of Kampo medicines for COVID-19 patients, it is necessary to focus on a certain type of Kampo medicine. COVID-19 symptoms include chills, fever, muscle pain, joint pain, nasal congestion and discharge, sore throat, a cough producing sputum, loss of appetite, diarrhea, impaired smell and taste, and malaise, which progress from the early yang pattern to the middle and late yang patterns described in Shanhanlun. The type of Kampo formula depends on the stage of clinical manifestation: mao formula in the early yang pattern, saiko formula in the middle yang pattern, and sekko in the late yang pattern. A combination of mao formula, saiko formula, and sekko is an ideal choice for treating diseases such as COVID-19, which transition from the early to the middle and late yang patterns in the Kampo concept. Thus, these combinations were included in saikatsugekito, which was used for the Spanish flu, and case series have already reported the use of saikatsugekito for COVID-19. Saikatsugekitois applied in combination with kakkonto and shosaikotokakikyosekko under the permissions of the national health insurance. The possible mechanisms of saikatsugekito against SARS-CoV-2 and COVID-19 have been reported by Arita et al.. While study 4 is a multi-centered, prospective, observational study to investigate the efficacy of Kampo medicines in patients with COVID-19-related sequelae. After the stabilization of COVID-19 patients, continued support for recovery and management of sequelae is needed. Future research interests include epidemiological investigations of sequelae and case series that summarize the experience of patients who used Kampo medicine for treatment.

covid-19, japan society for oriental medicine, kampo, sars-cov-2, prevention, recovery, treatment

PMC5350332_01

Male

We present the case of a 10-year-old male presented to our institution for a second opinion regarding his recent diagnosis of Legg-Calve-Perthes disease. He initially presented to a pediatric orthopedist at an outside institution with a complaint of right knee pain without known injury. His knee pain was described as diffuse, sharp, and worse with ambulation. Initial imaging of his knee was negative. He was diagnosed with tendinitis and prescribed NSAIDs and physical therapy. He continued to have knee pain despite these modalities and was evaluated by his pediatrician who recommended crutches and nonweight bearing. An MRI was ordered but was denied by insurance. His pain continued to worsen to the point that he stopped playing football and in one occurrence prompted a visit to the emergency department. In the emergency department, imaging of his pelvis was obtained for the first time and an abnormality of the right femoral head was noted. He was referred back to the initial pediatric orthopaedic surgeon who diagnosed him with Legg-Calve-Perthes disease and advised him to continue nonweight bearing and crutches.

PMC7276590_01

Male

A 30-year-old man with no underlying disease sustained a crush injury to his foot and ankle and lower legs in a car crash. He was brought to our hospital in an ambulance. He sustained open fractures to the left foot and ankle (Gustilo Anderson classification Type IIIB) and bilateral open tibial shaft fractures(the right was aTypeI and the other was a TypeII). The tarsal bones were crushed, and a part of the bone protruded from the wound (Fig. 1). There was no damage to important internal organs, such as the brain or heart, and his physical status was stable. The radiograph and computed tomography scan showed dislocation of the ankle joint; severe foot and ankle instability were seen (Fig. 2a and b). The mangled extremity severity score (MESS) was six and the limb salvage index (LSI) was five on arrival. Amputation is recommended when the MESS is >=7 and LSI is >=6. We opted to perform limb salvage, because the blood flow was maintained by the posterior tibial artery and the sensory nerve in the foot sole was intact. Table 1 summarizes the lesion characteristics. The ankle and foot were stabilized using Kirschner wires (K-wire) on the day of injury. We maximally removed the necrotic tissue and bone. We also provided temporary fixation for both open tibial shaft fractures with external fixators and covered the soft tissue defect with artificial dermis. On the next day, we performed second-look surgery and started negative pressure wound therapy(NPWT). After several debridement procedures, a wide bone defect had developed in the midfoot (Fig. 3a and b). Open reduction and internal fixation (ORIF) for both tibial shaft fractures was performed with intramedullary nails on the 6thday after the trauma. Two days postoperatively, we performed ORIF for the left foot and ankle fracture. We corrected the alignment of the hallux and fixed it with a titanium plate. We also fixed the lateral arch with some K-wires (Fig. 4a). Simultaneously, plastic surgeons performed soft tissue coverage with a latissimus dorsi flap (Fig. 4b). Thoracodorsal blood vessels were anastomosed to the posterior tibial artery and vein. However, the flap necrosed quickly. Therefore, a second grafting was performed using an anterolateral thigh (ALT) flap on the 21st day from injury. Perforating branches of the descending lateral femoral circumflex artery were connected to the anterior tibial artery and vein. To reduce the risk of infection, we removed the plate. We also removed necrotic navicular bone and stabilized the foot with K-wires. Then, we placed cement blocks into the bone defect. The final surgery was performed 12 weeks after the second flap was grafted. We grafted an autologous bone block (corticocancellous bone, 1 cm x 1 cm x 1.5 cm) from the iliac crest on the bone defect, according to the Masquelet technique, and inserted a cannulated cancellous screw (CCS) from the fifth metatarsal bone to the talus, which passed through the autologous bone. We also grafted cancellous bone chips around the other bone defect (Fig. 5a-c). Eight weeks after the final fixation, we allowed the patient to walk, with partial weight-bearing, while wearing a rocker bottom shoe. Fullweightbearing gait was initiated 4 months post-surgery. Presently, he can walk independently withoutpain, and there are no callosities in either sole (Fig. 6a and b). He was able to return to work 1 year after the injury and 2 years after the final operation, all screws were removed. He reported a high level of satisfaction. Regarding his ankle range of motion, plantarflexion was 15 , dorsiflexion was 0 , and the lower extremity functional scale score was 51 points at the time of return to work. On the radiograph, the M1-M5 angle was 22 , and the calcaneal pitch angle was 0 .Three years after the final fixation, when we performed the final follow-up examination, the sole sense was maintained, ankle plantarflexion was 20 , and dorsiflexion was 0 . At the same time point, on the radiograph, bone fusion was complete and no notable complications were observed (Fig. 7).

mangled foot, limb salvage, soft tissue injury

PMC4808524_01

Male

A 37-year-old African-American male with past medical history of HIV (detected in 2001; transmitted by heterosexual intercourse; latest CD4 count 320 cells/mm3 with undetectable viral load; compliant with highly active antiretroviral therapy (HAART); no opportunistic infections in past) and nephrolithiasis presented to emergency department of our hospital with progressively worsening epigastric pain and nausea for one week. Pain was constant and was rated severe and radiated to his back. The patient denied hematemesis, hematochezia, or diarrhea. However, he reported weight loss of 12 lbs in last 2 months but denied night sweats. There was no history of recent travel, sick contacts, or illicit drug use. Vital signs were notable for tachycardia of 120 beats/minute and low-grade fever of 38.8 C. The physical examination revealed epigastric tenderness with no rebound. Initial laboratory evaluation showed elevated levels of lipase 629 IU/L (33-200), amylase 250 IU/L (30-110), lactate dehydrogenase (LDH) 936 IU/L (313-618), and C-reactive protein 3.6 mg/dL (0-1), with normal liver and renal function tests. White cell count was 3.8 x 109cells/L (3.8-9.8 x 109), hemoglobin was 13.2 g/dL (13.5 to 17.5), and platelets were 139 x 109 cells/L (150-450 x 109). Cardiac troponins came out negative with unchanged EKG. Preliminary diagnosis of acute pancreatitis was made. Subsequently, abdominal computed tomography (CT) demonstrated multiple, well-defined, peripancreatic, soft tissue masses to left of the uncinate process (Figure 1), posterior to the pancreatic tail, and near the hepatic hilum (Figure 2). The peripancreatic masses were found to be compressing the body of pancreas, causing acute pancreatitis in our patient. Furthermore, there was partial compression of the portal vein with multiple surrounding portal venous system collaterals. Differential diagnoses included lymphoma, mycobacterium avium complex (MAC), disseminated fungal infection, and tuberculosis (TB). The case was discussed in the multidisciplinary tumor board. It was concluded that, due to the advanced disease, tissue diagnosis will be difficult employing surgery or interventional radiology. Thereafter, an uneventful endoscopic ultrasound (EUS)-guided fine-needle aspiration biopsy of one of the masses was performed, and preliminary pathology suggested lymphoma. Cancer antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), and serotonin levels were within normal limits. Sputum AFB culture and QuantiFERON-TB Gold (QFT) were negative ruling out TB. Fungal cultures and isolated bacterial cultures for MAC also came out negative. Total body scan showed subcentimeter bilateral mediastinal and axillary lymphadenopathy. Histopathology analysis revealed diffused infiltration of large B-cells with plasmablastic (cells with rounded nuclei, coarser chromatin, and smaller two to three nucleoli) and immunoblastic morphological features (cells with vesicular enlarged nuclei and single prominent nucleolus). A high proliferative index with frequent apoptosis and focal necrosis was demonstrated. Immunohistochemistry of the peripancreatic specimen revealed neoplastic cells positive for BOB1, MUM1, and EBER-ISH, partially positive for CD79a, and negative for CD20, CD56, CD138, CD3, CD5, AE1/AE3, and HHV8, most consistent with plasmablastic lymphoma. A bone marrow biopsy was performed for staging purposes. It revealed normocellular marrow with maturing trilineage hematopoiesis with no evidence of excess blasts or lymphoma. Furthermore, lumber puncture cytology was negative for malignant cells and CSF flow cytometry did not show any abnormal cells; based on these findings, the patient was deemed as stage III. Subsequently, epigastric pain improved with oral opioids and other pancreatitis-related symptoms resolved with the symptomatic treatment. The patient was discharged from the hospital with oncology out-patient follow-up. Therein, he was initiated on cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy. Central nervous system prophylaxis was achieved by employing intrathecal chemotherapy. Filgrastim (G-CSF) was administered twenty-four hours after CHOP cycles and was continued daily for seven days. Our patient tolerated the treatment well, with no significant interactions with HAART for his HIV-infection, and achieved remission after six cycles of chemotherapy. Contrast-enhanced CT at the level of pancreas 3 months after initiation of CHOP treatment demonstrated near complete resolution of previously seen soft tissue masses (Figure 3). The patient has been disease-free for over a year now without any additional specific therapy.

PMC8053476_01

Female

A 50-year-old woman complained of the right-sided neck swelling of 6 months duration. It was a gradually increasing 4x3 cm, soft-firm, non-tender, slightly mobile mass. On ultrasonogram (USG) neck, there was massive, necrotic lymphadenopathy which suggested the possibility of tuberculosis and a small (0.9 x 0.7 cm size) cystic lesion in the thyroid gland. The patient revealed a history of similar neck swelling 3 years back, which regressed completely after aspiration, reports of which were not available. The fine-needle aspiration cytology of neck mass yielded approximately 5 ml, thin, hemorrhagic fluid; the swelling regressed partially after aspiration. The procedure was repeated from the residual mass. The FNA smears from neck nodes are provided. Q1: What is the possible diagnosis? Metastasis of papillary thyroid carcinoma Nasopharyngeal carcinoma Follicular dendritic cell sarcoma Lymphoma Ectopic meningioma Answer: (c) Follicular dendritic cell sarcoma The literature search reveals that follicular dendritic cell (FDC) sarcoma usually display cellular smears presenting as thick syncytial groups, whorls, fascicles, or single cells intimately admixed with mature lymphocytes and plasma cells. The cytological features are better highlighted on May-Grunwald Giemsa (MGG) stain [Figure 1a]. The cells are round to oval, with mild-to-moderate pale wispy cytoplasm; indistinct cell borders [Figure 1b], round to oval to plump nuclei with fine chromatin, prominent nucleoli, and many stripped nuclei. Nuclear atypia is variable. Bilobed and multinucleated tumor cells can be seen. Nuclear grooves and intranuclear inclusions have also been reported [Figure 1c]. Our case presented majority of the above described cytoarchitectural features. In addition, microfollicular arrangement and vague papilloid structures were also seen. The nuclei were hyperchromatic, however, prominent nucleoli were not observed [Figure 1d]. Considering the primary presentation of enlarged neck nodes, USG favoring solitary hypoechoic lesion in thyroid and cytomorphology of vague papillary structures, microfollicular pattern, [Figure 1d] nuclear grooves, and intranuclear inclusions highlighted under MGG stain [Figure 1c]; metastasis of papillary thyroid carcinoma is the most probable diagnosis. However, the classical features such as papillary structures with core, metaplastic cytoplasm, and stringy colloid were absent The other differential diagnosis can be nasopharyngeal carcinoma (NPC) undifferentiated type, which it mimics clinically and presents as enlarged neck nodes. The smears reveal mostly dissociated and loose groups of cells with few enlarged pleomorphic and lobulated nuclei against a background of mature lymphocytes. The presence of nuclear grooves, inconspicuous nucleoli, and low mitotic count was against the diagnosis of NPC Possibility of lymphoma Hodgkin's type was less likely, the pointers for lymphoma can be presence few atypical cells with pleomorphic, lobulated nuclei, and admixture with lymphocytes, plasma cells, and eosinophils. However, classical Reed-Sternberg cells were absent Ectopic meningioma can also be a likely differential, especially when clinical presentation is neck mass. The overlapping features were oval to plump to elongated cells with bland chromatin, inconspicuous nucleoli, and intranuclear inclusions. However, the absence of whorl formation and admixture of lymphocytes with tumor cell makes the possibility of conventional meningioma less likely. Question 2: FDC sarcoma is categorized as Low-grade malignancy High-grade malignancy Intermediate-grade malignancy Benign tumor Answer: (c) Intermediate-grade malignancy Question 3: All are common extranodal sites of this condition except GIT Brain Skin Liver Answer: (b) Brain Question 4: Which of the following is false about poor prognostic factors of FDC sarcoma? Tumor size >10 cm Mitosis >5/10 hpf Coagulation necrosis Significant cellular atypia Answer: (a) Tumor size more than 10 cm The patient was investigated, further his CT scan revealed a right cervical lymphadenopathy, seen as multiple, enlarged lymph nodes with cystic component and single 9 x 7 mm, cyst in the right lobe of thyroid. It also revealed ipsilateral enlargement of tonsil measuring 3 x 3 cm and left para pharyngeal heterogeneous, enhancing, lobulated mass favoring lymph node metastasis. FNA from parapharyngeal lymph nodes yielded similar cytomorphological features as that from cervical nodes [Figure 2]. The tonsillar biopsy showed subepithelial tumor which composed of solid nests whorls and rare foci with storiform pattern of spindle to oval to plump cells, admixed with lymphoplasmacytic infiltrate [Figure 3]. The cells have scant to moderate pale cytoplasm and central round to oval vesicular nuclei with nucleoli in some. Occasional mitotic activity was noted. The histology was suggestive of FDC sarcoma. The tumor cells expressed CD21 membranous positivity and therefore substantiated the diagnosis of FDC sarcoma [Figure 4]. The patient underwent bilateral tonsillectomy with ipsilateral radical neck dissection. The contralateral tonsil was uninvolved by tumor while the cervical lymph nodes showed evidence of metastasis. Post-surgery, the patient received radiation therapy. FDCs also called dendritic reticulum cells form the network in germinal centers of lymph nodes. They present antigens to T lymphocytes so that memory B cells and plasma cells can be generated. FDC sarcoma is a rare and under-recognized intermediate grade malignancy. Chan et al. reported recurrence in 40% while 25% metastasized and mortality rate of 16.7%. It is a neoplastic proliferation of spindled to ovoid cells showing morphologic and immunophenotypic features of FDCs. Most cases occur in lymph nodes of neck, mediastinum, and axilla and often present as slow growing painless mass. Around 30% are found in extranodal sites such as palate, tonsil, pharynx, thyroid, mediastinum, soft tissue, skin, liver, spleen, and gastrointestinal tract. The presentation of FDC sarcoma as a cystic swelling is a rare event. Its accurate diagnosis often requires a combination of histology, immunohistochemistry (IHC), or even ultrastructural study. Although cytomorphology has been described in the literature, a pre-operative diagnosis of FDC sarcoma poses a diagnostic challenge for the cytopathologist, as most of the previously reported FNA cases were misdiagnosed as NPC, meningioma, lymphoma, or even spindle cell carcinoma depending on anatomical location of the lesion. These tumors have a heterogeneous histology with spindle-shaped tumor cells that possess variable degrees of pleomorphism and are arranged in whorls, fascicular, or storiform patterns. The neoplasm displays a characteristic immunohistochemical profile, expressing CD21, CD23, and CD35 markers. Adverse clinical outcome is correlated with large tumor size (>6 cm), nuclear pleomorphism, necrosis, and high mitotic count. The line of management of FDC sarcoma is variable. If the tumor is localized to anatomical site; the choice includes excision with wide surgical margin. In cases with aggressive disease, additional radiotherapy should be considered. The high index of suspicion and knowledge about cytomorphology can allow a pre-operative recognition of FDC sarcoma. The diagnostic confirmation can further be achieved by histopathology and judicious use of IHC. Our aim is to complement the current knowledge about cytology and alert cytopathologist about this rare entity to avoid misdiagnosis.

PMC9679338_01

Male

The patient was a 62-year-old, right-handed man who had worked as a chef. He had received 12 years of education. He was urgently admitted to the hospital because of paralysis of the right upper and lower limbs. The patient was diagnosed with left putamen hemorrhage (size: 3 x 2 cm) (Fig. 1) and underwent nonsurgical treatment. In the next hospital, he underwent a physical and language rehabilitation program for about 3.5 months and was discharged home 93 days after onset. At 192 days after onset, the patient visited our hospital to begin language rehabilitation on an outpatient basis. The patient's Functional Independence Measure (FIM) score was 114/126 (motor FIM: 84, cognitive FIM: 30). Neurological findings included lucidity and right hemiplegia, and neuropsychological findings consisted of no nonverbal intellectual disability [Raven's colored progressive matrices (RCPM): 31/36] and subcortical aphasia. Written informed consent was obtained from the patient to publish information in a case report. In the baseline evaluation, the patient's language and speech abilities were evaluated 1 month before and immediately before the start of CIAT. To evaluate the training effect, language function was assessed immediately after the end of CIAT and at intervals of 1 month, 3 months, and 6 months after CIAT ended. Language function, in which word frequency and imageability were controlled, was assessed by the Japanese version of the Western Aphasia Battery (WAB)) and the single-word-naming task in the Test of Lexical Processing in Aphasia (TLPA).) The Verbal Activity Log (VAL) was used to assess the patient's level of spontaneous real-world spoken language.,) We confirmed that the patient showed VAL scores of 3.0 points or less at 6 months or more after stroke onset and had moderate aphasia. We also confirmed the absence of the following factors: untreated serious illness, severe hearing loss, traumatic brain injury, and neurodegenerative disease. The WAB Aphasia Quotient (AQ) was 75.6 at 1 month before CIAT and 77.3 immediately before CIAT. The patient's WAB score was 65/80 at 1 month before CIAT and 70/80 immediately before CIAT. The patient's spontaneous speech score declined, and we observed that he mainly uttered only words or two phrases when describing a picture. During word naming, once word finding became difficult for the patient, he was unable to resume speaking or answer the next question. Inconsistent articulation errors in the TLPA confirmed apraxia of speech. Given that some oral gestures, such as mouth opening, tongue protrusion, whistling gesture, blowing up cheeks, throat clearing, and tongue tapping, could be achieved upon verbal instruction, we judged that there was no oral apraxia. The patient showed good performance in yes/no questions and auditory word recognition for auditory verbal comprehension of the WAB, but the number of errors increased as the number of clauses increased in sequential commands. A previous study reported that the average change in AQ was 5.3 in patients with chronic aphasia.) Because the difference in AQ between 1 month before and immediately before CIAT was 1.7, we judged that the spontaneous recovery of language function had reached a plateau. The number of correct answers for the TLPA single-word naming was 138/200 (high frequency, 77; low frequency, 61) 1 month before and 129/200 (high frequency, 72; low frequency, 56) just before CIAT; therefore, we judged there was no recovery. The learned nonuse of verbal language was confirmed by a reduction in spontaneous speech in daily life and scores below 2.5 on the two VAL scales.) A Japanese version of CIAT,,) based on CIAT II,) was used in this case. The therapy sessions involved the following activities: 1. Confirmation of homework and review of spontaneous real-world spoken language from the previous day (30 minutes) 2. Word repetition drills (20 minutes) 3. Phrase repetition drills (20 minutes) 4. Language card game (40 minutes) 5. Picture description (20 minutes) 6. Role-play activity (30 minutes) 7. Home skill assignment (10 minutes) During the word and phrase repetition drills, the patient repeated as much as possible the words and phrases that were familiar to him, such as food and drinks provided at his restaurant and the tools he used at his work. These words and phrases were also used in the later role-play task. When the patient was unable to repeat or name words correctly, we encouraged him to speak the word by: (1) talking about his episodes related to the word, and (2) repeating the word and short sentences using the word many times. The difficulties of the tasks were adjusted by changing the number, type, and position of the syllables. In the language card game, the patient and the therapist were each given about ten picture cards. In an effort to accumulate pairs, the patient and therapist asked each other for a matching card by using the question: "Do you have XX (name)?" This activity required the patient (and therapist) to name the object on the card. If the opponent had the specified card, they provided the card to the questioner and then aimed to make the same pair as soon as possible. In the picture description, the patient explained a landscape painting of daily life drawn in black and white. The therapist urged the patient to explain the details of the picture following his initial overview. If the patient was unable to recall the target word, then the therapist presented the first syllable of the word and the episode associated with the word as a hint for verbal output. In the role-play activity, verbal conversation was practiced while assuming the daily situations of patients who require communication. A "transfer package" (TP)) was also introduced to transfer the therapeutic gain of CIAT to daily communication. As the first step of TP, we clarified what the patient wanted to achieve by improving speech before the start of CIAT. The patient and his wife agreed to communicate verbally as a daily task during the CIAT program instead of using nonverbal communication. When confirming homework, the therapist checked the patient's schedule from the previous day and his use of speech in his daily activities. The therapist provided feedback each time and encouraged the patient to communicate by verbal language, as much as possible, using demonstrative pronouns and circumlocutions. The therapist also instructed the patient's wife not to speak on the patient's behalf. The CIAT tasks were carried out for 3 hours per day, 5 days per week, for 3 weeks (45 hours). During the training, the patient was instructed not to use compensatory strategies, such as writing and nonverbal gestures, and he was encouraged to use only verbal language. Immediately after CIAT, the WAB AQ had increased by 4.5 points from 1 month before therapy and by 2.8 points from immediately before therapy (Table 1). Immediately after CIAT and 3 months after therapy, the improvement from 1 month prior to treatment did not reach 5.3 points, which is the average change in WAB AQ in the chronic stage of aphasia.) However, at 6 months after therapy, the WAB AQ score had increased by 6.1 points from 1 month before CIAT. Improvements were noted in auditory word recognition, sequential commands, and word-naming scores. The number of correct answers for the TLPA immediately after CIAT increased by 10 points from 1 month before treatment and by 19 points from immediately before therapy. In particular, the number of correct answers for high-frequency words tended to increase after treatment. However, these improvements for high-frequency words had decreased at 3 and 6 months after treatment. In addition, the error type of paraphasia and the number of occurrences of apraxia of speech in the TLPA were evaluated. The criteria used to classify the paraphasia error types and apraxia of speech were based on previous reports) as follows: 1) No response: no verbal response; 2) Phonological fragments: phonologically related to the target word; 3) Other phonological fragments: phonologically unrelated to the target word; 4) Formal paraphasia: not semantically similar but phonologically similar to the target word; 5) Mixed paraphasia: phonologically and semantically related to the target word; 6) Semantic paraphasia: semantically related to the target word; 7) Phonemic paraphasia: nonwords that are phonologically incorrect with the target word; 8) Monemic paraphasia: paraphasia consisting of two or more morphemes; 9) Irrelevant paraphasia: paraphasia that is semantically unrelated to the target word; 10) Perseverative paraphasia: paraphasia with verbal perseveration. Apraxia of speech was evaluated by nine characteristics, namely, sound substitutions, imprecise consonants, revisions, repetitions, prolongations, abnormal stress, slow rate, restricted pitch variation, and inconsistent errors.) After CIAT, there were fewer errors in phonological fragments, semantic paraphasia, monemic paraphasia, irrelevant paraphasia, and apraxia of speech when compared with assessments 1 month before and immediately before therapy (Table 2). However, the number of errors in phonological fragments and semantic paraphasia after CIAT, monemic paraphasia after 3 and 6 months, and irrelevant paraphasia immediately after therapy only showed a one-point difference from that before CIAT; thus, there was no clear difference. Monemic paraphasia was not observed immediately after therapy but was observed again at 3 months after therapy. There was no significant change in errors of no response between before and after CIAT. However, instances of no response tended to become more frequent at 3 months after therapy when compared to immediately after CIAT. Errors of apraxia of speech were not observed immediately after CIAT. The VAL score at 3 months after CIAT was 2.5 points or higher, which is the criterion for learned nonuse of verbal language. However, the VAL at 6 months after CIAT was obviously below this level. In an interview, the patient's wife revealed that the spread of COVID-19 had reduced the number of opportunities to go out or eat out. She also indicated that they used to spend time at home with friends before the outbreak but that their reduced number of visits had reduced opportunities for conversation.

ciat, rehabilitation, stroke

PMC5395678_01

Male

A1 had a normal male karyotype and normal microarray results. Testing for mutations in candidate genes for GLUT1 deficiency syndrome and mitochondrial disorders, including SLC2A1, POLG, and DGOUK, yielded negative results. Repeated EEGs including prolonged EEGs encompassing sleep for both siblings showed a mild excess of slow activity, but no evidence of epileptiform activity. Polygraphic electromyogram (EMG) recordings of right and left deltoids, biceps, forearm, and quadriceps muscles demonstrated myoclonias of approximately 80-110 ms duration in all the EMG channels without any evidence of spread from one to another. A few myoclonias were more hypersynchronous, approximately 40-60 ms in duration (Supplementary Figure 2). Back-averaging did not reveal any preceding EEG change in either child. Nerve conduction studies and somatosensory evoked potential tests were normal. A1 had serial cranial magnetic resonance imaging (MRI) scans from the age of 2 months to 19 months. These demonstrated hypoplasia of the frontal and temporal lobes. The deep grey matter appeared normal with no evidence of cortical dysplasia (Figure 1A). A computed tomography (CT) head scan showed tiny non-specific foci of calcification in the basal ganglia (Figure 1B). Cranial MRI and MR spectroscopy performed at 6 weeks of age for A2 were normal. However, a repeat MRI scan at 3 years 10 months showed atrophy of the lateral aspects of the cerebellar hemispheres and symmetrical signaling abnormalities (Figure 1C). A1 received trials of treatment with an extensive range of medication including anti-epileptics (valproate, carbamazepine, nitrazepam, levetiracetam, clobazam), metabolic supplements (coenzyme Q10, biotin, riboflavin, thiamine), levodopa, and piracetam. None of these achieved sustained benefit, although levetiracetam and clobazam each controlled myoclonus briefly. Immunotherapy had no significant effect. Levetiracetam exacerbated A2's symptoms and pyridoxine was ineffective. She did not tolerate the ketogenic diet. Bromocriptine resulted in dyskinetic movements, which terminated with discontinuation of the medication. Carbamazepine afforded her some symptomatic relief. For both siblings as symptoms were abolished by sleep, the best therapeutic strategy seemed to be chloral hydrate used, as required, to induce sleep during periods of distress. Variants identified through whole-exome sequencing were filtered by the following criteria: 1) very low frequency in control populations (exclusion of variants with a minor allele frequency > 0.1% in the established databases and 2,000 in-house analyzed exomes); 2) presentation of homozygous or compound heterozygous changes considering an autosomal recessive inheritance pattern; and 3) prediction of putative pathogenicity based on mutation type or in silico prediction of effects on protein function and/or structure. Using these criteria, two heterozygous variants confirmed by Sanger sequencing were identified in TBC1D24 (Supplementary Figure 1): 1) a previously reported missense change c.457G>A (p.Glu153Lys; rs376712059) and 2) a previously unreported frameshift mutation, c.545del (p.Thr182Serfs*6) predicted to cause nonsense-mediated RNA decay or result in a truncated protein. Both mutations showed appropriate familial segregation. Other possible disease-causing mutations identified in the two subjects that passed selection criteria were excluded (Supplementary Table 2). Mutations found in two genes (NOTCH4 and PRR21) could not be verified as it was not possible to design primers for confirmatory Sanger sequencing and segregation studies because of highly repetitive sequences. We note that whole-exome sequencing false-positive rates for indels can be as high as nearly 50%. Considering their phenotype, TBC1D24 was thus deemed to be the most likely candidate gene accounting for our patients' symptoms.

tbc1d24, myoclonus

PMC3200122_01

Female

A 21-year-old female from hilly area of Kashmir, presented with pus discharge of from two openings on the right breast for last 6 years. These aberrant openings on breast had often spontaneous pus discharge followed by cessation of discharge on its own. There were neither any constitutional symptoms nor any discharge or any abnormality of the nipple. She had already taken antitubercular therapy (ATT) thrice but was defaulter all times and reluctant for further antitubercular therapy (ATT) intake. Systemic examination was normal. Local examination showed no abnormality in left breast. A 1.5 centimeter opening was seen in inferior and outer quadrant breast, through which whitish pus was discharging along with a scar superior to discharging sinus which used to discharge pus 2 weeks before. (Figure 1). No swelling was palpable. Two firm tracts, inferior one with length of 4 cm, superior with 2.5 cm, were run posterior-superiorly ending on fifth rib. No axillary lymphadenopathy was evident. Erythrocyte sedimentation rate (ESR) was raised. Montoux test was positive (16x14 mm). X-ray chest showed an osteolytic lesion in anterior part of fifth rib. Computed tomography scan of chest could not reveal any foci of tuberculosis in lungs; only two sinus tracts in breast tissue and the necrosed rib were seen. Purulent aspirate was sterile for tubercle bacilli. Breast ultrasound showed ill-defined sinus tract and opening. Given the reluctance to antitubercular therapy (ATT) intake and recurrent disease coupled with apprehension of further followup, surgical intervention was done through fifth intercostal space. Excision of fibrous tract and resection of involved rib were carried out. (Figures 2 and 3) About 12 cm of rib containing pus and necrosed tissue were resected. Histopathology of specimen was chronic inflammatory cell infiltrate, with areas of caseous necrosis, giant cells (Figure 4). After proper counseling and understanding the nature of disease by patient and her parents the affected woman was motivated for antitubercular therapy (ATT) intake and with daily dose of 300 mg isoniazid, 600 mg rifampicin, 1500 mg pyrazinamide, ethambutol, and 10 mg pyridoxine for 9 months. She had regularly attended our followup clinics during last two years, with no recurrence of disease being recorded.

PMC8331315_01

Male

A 13-year-old previously healthy male presented 8 weeks after his initial diagnosis of COVID-19 infection to his pediatrician with complaints of dizziness, fatigue, difficulty sleeping, and a presyncopal episode. The patient was unable to participate in daily activities without getting easily fatigued. Parents reported increased appetite but still a documented weight loss of 8 lbs (5.3% bodyweight) since his COVID-19 illness over a period of 2 months. Further review of system revealed significant heat intolerance requiring multiple fans pointed at him while sleeping without any covers. He also had an itchy groin rash for which he was using topical cotrimoxazole cream with some improvement. He denied any sexual activity or illicit drug use. He was diagnosed with COVID-19 on a nasal PCR test 8 weeks prior to current presentation. He had a mild course with low-grade fever, congestion, cough, and body aches that resolved in few days. All family members were positive at the same time with his father requiring a three-week hospital stay for COVID-19 pneumonia. Other than his recent COVID-19 illness, he had no significant past medical history. He was born in Mexico and had immigrated to the United States three years ago. His immunizations were up to date. Family history was negative for any rheumatological or autoimmune disorders. He was at 98th percentile for height and 93rd percentile for weight with a BMI of 81st percentile for age. Examination was significant for tachycardia at 102 beats per minute with mild exophthalmos and palpable thyroid. He had an erythematous lesion in intertriginous left groin. His electrocardiogram showed sinus tachycardia. Results of initial blood work revealed elevated free T4 at 2.5 ng/dL (normal range: 0.7-1.5 NG/DL), undetectable TSH at <0.01 uIU/mL (normal range 0.50-4.80 uIU/mL), normal complete blood count, normal sedimentation rate, and a negative QuantiFERON TB gold test. Further workup showed elevated antithyroid peroxidase (TPO) antibodies at 946.2 IU/ml (normal <9.0 IU/ML) and elevated thyroid-stimulating immunoglobulins (TSIs) at 28.2 IU/L (normal <0.10 IU/L). Given the presence of antibodies for both Graves and Hashimoto's (with TSI predominance), he was diagnosed with hyperthyroidism from autoimmune thyroid disease. He was started on methimazole 10 mg once daily at that time. At 2-month follow-up, he had some symptomatic improvement in his energy levels with some weight gain, but still had palpitations and difficulty sleeping with some heat intolerance. Propranolol 10 mg twice daily was added for symptomatic relief. He also reported worsening of his groin rash despite changing to different antifungal creams. Upon dermatology consultation, he was determined to have psoriasis vulgaris and was treated with topical steroids resulting in complete resolution. At 4-month follow-up, he showed biochemical improvement while on thionamide therapy, as his free T4 had normalized to 1.2 ng/dl, but his TSH remained at < 0.01 uIU/ml. However, he clinically continued to have mixed thyroid symptomology with fatigue, weight gain, poor concentration, insomnia, depression/anxiety, heat intolerance, and palpitations. This reiterates that long COVID-19 may persist in some long haulers even after other medical conditions are controlled.

PMC5646309_01

Female

A 67-year-old woman presented with a long-standing history of dysphagia and recurrent strictures. She did not have typical heartburn or regurgitation symptoms consistent with reflux disease. Her medical history included psoriasis and hypothyroidism. Exam findings of oral lesions or skin findings consistent with LP were not identified. Laboratory investigations were remarkable for a positive antinuclear antibody with titres of 1 : 320 in a homogenous pattern with other autoimmune markers being nonreactive. Hepatitis C antibody was also nonreactive. Histopathology specimens predominantly showed nonspecific findings of acute and chronic inflammation suggestive of reflux disease. She underwent multiple esophagogastroduodenoscopies (EGD) with findings of mucosal friability, webs, and strictures (Figures 1-3). Initial examinations revealed strictures in the lower third of the esophagus. Later, strictures were discovered in both the proximal and mid-esophagus. Strictures ranged in diameter within 9-14 mm. Initial treatment consisted of twice daily proton pump inhibitor (PPI) for initially suspected reflux esophagitis, which offered no improvement in symptoms. A trial of inhaled swallowed fluticasone propionate 440 mcg twice daily for at one point suspected eosinophilic esophagitis provided no relief. Endoscopic bougie and balloon dilations provided transient improvement but this became less sustained over time. The primary modality of treatment that offered prolonged benefit was recurrent dilations with triamcinolone acetonide injections (10 mg/mL concentration) to strictures though the time interval of relief ultimately decreased as well. A trial of systemic glucocorticoids (40 mg/daily with a tapered course over 10 weeks) was also given for a suspected autoimmune etiology and did not provide any relief. Seven years after her initial presentation, deep esophageal biopsy specimens were obtained showing severe acute and chronic esophagitis with a lichenoid-like pattern of chronic inflammation with notable features of lymphocytic infiltrate involving the basal layer of the epithelium and scattered apoptotic keratinocytes (Civatte bodies) (Figures 4 and 5) raising strong consideration of ELP. After a multidisciplinary review of these findings along with her consistent history, a diagnosis of ELP was made. By this time, her symptoms had already become severely debilitating with worsening strictures and narrowing throughout the esophagus, carrying a substantial risk for perforation with continued dilations (Figure 6). The patient ultimately made a decision to undergo a minimally invasive esophagectomy for definitive management with acute and chronic inflammation seen on surgical pathology. Her symptoms significantly improved in the months following her surgery. However, she gradually developed symptoms of dysphagia, abdominal cramping, nausea, emesis, and weight loss. This was felt to be secondary to delayed gastric emptying and a mild anastomotic stricture. She underwent Botox injection into the pylorus along with therapeutic dilation and triamcinolone acetonide injection to stricture. Her symptoms improved after these interventions.

PMC7289076_01

Male

A 56-year-old man with a history of hypertension, coronary artery disease required coronary artery bypass grafting, and ascending aortic aneurysm presented to our emergency department in Houston, Texas with a 2-day history of fever, shortness of breath, nausea, vomiting, severe abdominal pain, and bloody bowel movements. Patient had not traveled outside Houston area, neither had he contacted with anyone known to have COVID-19. Physical examination revealed temperature of 101.1 F, blood pressure of 184/109 mmHg, pulse of 143 beats per minute, respiratory rate of 16 breaths per minutes, and oxygen saturation of 98% on ambient air. Lung auscultation was clear. Abdominal examination revealed distended abdomen and generalized tenderness to palpation. Bright red blood was present on bed sheet. Blood tests on presentation (Table 1) revealed leukocytosis, lymphopenia, thrombocytopenia, elevated C-reactive protein, and lactic acid. Chest X-ray (CXR) showed bibasilar sub-segmental atelectasis (Fig. 1). Computerized tomography (CT) scan of the chest, abdomen, and pelvic with contrast revealed no pulmonary airspace disease but demonstrated wall thickening of the ascending, transverse, and descending colon which was compatible with colitis (Fig. 2). Blood cultures, HIV serology, and acute viral hepatitis serology were negative. Stool gastrointestinal pathogen panel polymerase chain reaction (PCR) was negative. Given an ongoing COVID-19 outbreak in the community, nasopharyngeal swab was obtained for COVID-19 qualitative PCR test, which was reported as detected on the day of admission. On hospital day 2, patient had persistent abdominal pain and bloody diarrhea with no respiratory symptom. His laboratory findings during hospitalization were showed in Table 1. His hemoglobin level dropped and he developed worsening thrombocytopenia and elevated CRP. Repeat CXR showed no pulmonary infiltrate. Enteral hydroxychloroquine 800 mg once followed by 400 mg daily in combination with ribavirin 400 mg three times a day were initiated. His abdominal pain improved and bloody diarrhea stopped within the next 48 h. His hemoglobin and hematocrit had been stable. Therefore, endoscopic examination was not performed during this admission. On hospital day 5, CT angiogram of abdomen and pelvic with intravenous contrast was performed which did not reveal evidence of vascular abnormality but demonstrated improvement of colitis. His two sets of nasopharyngeal swabs collected for COVID-19 PCR were not detected on hospital day 6 and 7 consecutively. The patient was discharged on hospital day 7 after he completed a 5-day course of hydroxychloroquine and ribavirin with a satisfactory response in both clinical and laboratory findings.

covid-19, colitis, sars-cov-2 infection

PMC4717558_01

Female

A 41-year-old North African woman with a history of chronic anemia with iron supplementation intake presented to our emergency department. She had massive rectal bleeding. She had an iron deficiency anemia. She did not complete the investigations so the cause was not yet diagnosed. She had no chronic bleeding, neither gynecologic nor digestive. She was treated by oral iron with no regular follow up. She had no past surgical interventions, and no other medical condition. She had no contact with animals. There were no medical conditions in her family, no cancers and no current infections. No one in her family or neighborhood was diagnosed with tuberculosis. In our admission unit, her hemodynamic parameters showed that she was in shock: her blood pressure was 80/40 mmHg and her pulse was up to 120 beats per minute. She was pale, her conjunctivas were discolored and her limbs were cold. While examining her, we found profuse rectal bleeding with clots. A quick abdominal and pelvis examination including proctologic examination appeared normal. She was transferred to our intensive care unit and monitored. Noradrenaline was administered because the crystalloid fluids and the transfusion were not sufficient to compensate for her blood loss. Several blood tests were conducted, including blood count and clotting tests. Her hemoglobin was 8 g/dl and hematocrit was 29 %. The rest of the formula and the clotting tests returned normal results as shown in Table 1. She first underwent an esogastroduodenoscopy, to identify the source of the bleeding. No abnormality was detected in the said procedure: the esophageal and gastric mucosa were normal, no ulcerations or traces of blood were found, and the duodenal mucosa was also explored and appeared normal. A colonoscopy could not be carried out because of the profuse rectal bleeding. She underwent a computed tomography (CT) of her abdomen which revealed a wall thickening in the terminal ileum with hypervascularization and regional adenomegalies (Figs. 1, 2, 3 and 4). This aspect suggested either a tumor or an inflammatory bowel disease. Because her bleeding and her hemodynamic collapse persisted, it was decided to proceed with surgery with the aim of diagnosis and treatment. She underwent exploratory laparotomy immediately. It confirmed the wall thickening in her ileocecal junction. Her appendix was inflamed. An ileocecal resection was performed with an ileocolic anastomosis, removing 10 cm from her ileum. The specimen was sent for histological examination. Gross examination showed a round ulcer 5 cm from the ileal end, next to another ulcerative lesion; eight lymphatic nodes were found. The blood vessel under the deep ulcer was the origin of the profuse bleeding. The histopathological examination showed an inflammatory ulcerative reaction with microabscesses (Figs. 5, 6 and 7). A granulomatous necrotic reaction was revealed in the examination of all eight nodes (Fig. 8). The pathologist's report concluded with diagnosis of an infection due to Yersinia enterocolitica. Her immediate postoperative outcome was favorable, the bleeding stopped, and her hemodynamic parameters remained stable. She had a normal transit on the fifth day after the intervention. After receiving the pathologist's report, it was decided to treat her with fluoroquinolones 500 mg twice daily without discontinuing the iron supplementation, and a clinical control was scheduled. At the control 3 weeks later, she had no clinical symptoms, her diarrhea and bleeding had ended, and signs of anemia were diminishing. Antibiotherapy was discontinued.

PMC7717484_01

Female

A 55-year-old female presented with altered mental status and hydrocephalus. She had blunt head trauma associated with subarachnoid and intraventricular haemorrhage. A head computed tomography scan showed blood in occipital horns bilaterally and increased ventriculomegaly of the lateral, third and fourth ventricles. An EVD was placed at the bedside. She subsequently developed worsening altered mental status, fever and tremors with rising serum white blood cell count. Cerebrospinal fluid (CSF) was obtained from the EVD on day 5 as part of initial work up that showed pleocytosis and hypoglycorrhachia. CSF studies were repeated 5 days later and revealed worsening parameters despite empiric antibiotics. Gram stain showed gram-positive bacilli and acid-fast stain was positive. CSF was analysed at the Indiana University microbiology laboratory via Mycobacteria Growth Indicator Tube (MGIT) liquid media while Nucleic Acid Amplification Testing (NAAT) was negative for Mycobacterium tuberculosis . Growth on solid media using Middlebrook 7H10 agar was observed and matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) MS identified the rapidly growing non-tuberculous M. mucogenicum . Parenteral therapy with amikacin 1 g every 24 h, cefoxitin 2 g every 6 h, and sulfamethoxazole-trimethoprim 15 mg kg-1 day-1 in three divided doses was initiated. The EVD was replaced and 4 weeks later a ventriculoperitoneal shunt was placed when repeated CSF studies were markedly improved (Table 1). The patient's neurological exam improved and was nearly back to baseline 6 weeks later.

external ventricular drain, meningitis, non-tuberculous mycobacterium

PMC4983108_01

Male

We present the case of a 59-year-old male patient with past medical history of Diabetes Mellitus type 2 who developed progressive fatigue, shortness of breath and dry cough by the end of 2012. Within the next 7 months patient had worsening of symptoms with rapid weight loss of 55kg (121bs) associated fever, chills, night sweat, loss of appetite and relentless weakness. Patient had traveled only to Ecuador for vacation with his family in 2010. During this travel he denied exposure to sick contacts or crowded household conditions. A chest x-ray and PPD skin test was performed by his primary care physician for the initial evaluation of symptoms. The PPD revealed no skin induration. Chest x-ray showed multiple pulmonary nodules with no obvious cavitary lesion. Patient was referred to a pulmonary specialist for further evaluation. He underwent bronchoscopy that resulted inconclusive and the patient has lost to follow-up. In mid-2013, because of worsening of his symptoms as described above he returned to the pulmonary disease specialist who repeated the bronchoscopy due to suspected malignancy vs. infectious process. Samples from the bronchoalveolar lavage had positive AFB smear, with positive culture growth for M. tuberculosis. Initial culture resulted pansensitive for TB. Other studies were remarkable for an indeterminate Quantiferon-TB Gold test (see Table 1), chest x-ray with right upper lung opacity and chest CT scan showing right upper lobe consolidate with central cavitation (see Fig. 1, Fig. 2). He was placed on airborne isolation and started in 4 anti-tuberculous drugs regimen including isoniazid, pyrazinamide, ethambutol, and rifampin. After 36 days of treatment and 3 negative sputum samples for AFB smear the patient was removed from negative pressure room, airborne precaution and discharged home. The patient was followed by the Department of Health (TB office) as outpatient with Direct Observed Therapy (DOT). Two months after been discharged form hospital and while still on TB treatment symptoms reappeared. For this reason patient was readmitted and repeated sputum cultures for M. tuberculosis were done on January 2014. Samples sent to the Centers of Disease Control (CDC) found to have multidrug resistant tuberculosis with resistance to isoniazid, rifampin, ethambutol and streptomycin. Genotype G24767 revealed the first of its kind genomic sequence not classified in the known cluster of Puerto Rico nor in the United States Population. The patient was hospitalized and started on second line anti-tuberculous drugs which included linezolid, levofloxacin, amikacin and cycloserine. The patient remained in hospital isolated for 46 days until 3 negative sputum for AFB smear were reported, but had to continue on at least three effective drugs and one injectable after culture conversion. The patient has at this point completed the 18 months after culture conversion, is symptom free and has gained all his lost weight.

mdr-tb, pulmonary tuberculosis

PMC9257338_01

Male

An 83 year old man was admitted with a five month history of recurrent back pain, with no history of trauma. Episodic low grade fever, night sweats, loss of appetite, along with significant weight loss (about 10 kg over the past four months) were also reported. On examination, he appeared cachectic and unwell, presenting left flank tenderness without rebound. Apart from slight elevation of C reactive protein (9.4 mg/dL), no remarkable findings resulted from the blood chemistry. Ultrasound revealed a left retroperitoneal collection, better defined on computed tomography angiography (CTA) as a multiloculated psoas muscle collection with perivascular fistulisation to the terminal aorta and proximal left common iliac artery (LCIA) posterolateral wall. At this arterial level six mm diameter, 6 mm depth wall ulceration was visible (Fig. 1). Chest Xray and computed tomography (CT) scan were performed, revealing bilateral reticulonodular infiltrates in both lung fields. Sputum and blood cultures were negative as were immunological tests (anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, rheumatoid factor, C3, C4 and immunoglobulins). Magnetic resonance imaging ruled out spondylodiscitis but documented the arterial wall involvement (Fig. 2). Percutaneous needle biopsy of the psoas collection was performed, under CT guidance. About 30 mL of a cheese like liquid was aspirated and sent to analysis. Both the acid fast bacillus test and the molecular test for Mycobacterium tuberculosis DNA were positive. The patient immediately started anti-tuberculous treatment (isoniazid, rifampicin, pyrazinamide, and ethambutol), and was discharged home after clinical improvement. He was compliant with medication and there were no side effects. During treatment he showed an impressive improvement of his clinical condition: fever remitted completely, he regained his body weight, and became functional and fully oriented. CTA follow up at three months showed complete resolution of the psoas collection with no changes in the known arterial ulceration. However, the six month CTA (Fig. 1) revealed ulceration evolution to a 40 mm pseudoaneurysm. The patient did not report any change in symptoms during this period. Despite his age, the patient was considered fit for surgery, and open repair was selected considering the infectious cause. Intra-operatively the pseudoaneurysm was excised revealing complete disruption of the terminal aorta and proximal left common iliac posterolateral wall (Fig. 3A). Surrounding tissues (caseous necrotic tissues and pus) were thoroughly debrided. An aorto-bi-iliac interposition graft was performed (16 x 8 mm silver acetate/triclosan collagen coated polyester graft Intergard Synergy Getinge ) (Fig. 3B). The histopathological report of the aneurysm wall was caseating granulomatous inflammation consistent with tuberculosis infection. The M. tuberculosis DNA test was also positive in the tissues (aortic wall and adjacent soft tissues) that were collected intra-operatively. The post-operative course was uneventful. After consulting with the Infectious Diseases Department, it was decided to maintain oral anti-TB treatment for one year after intervention. After nine months the patient remained asymptomatic and positron emission tomography CT showed no pseudoaneurysm recurrence or signs suggestive of graft re-infection.

mycobacterium tuberculosis, mycotic aneurysm, open repair

PMC6143694_01

Female

A 26-year-old woman was diagnosed with systemic lupus erythematosus in 2002 and was treated with prednisolone, mycophenolate, and hydroxychloroquine. In September 2013, she was admitted with nephrotic-range proteinuria. Renal biopsy confirmed class IV lupus nephritis. After failure of treatment with mycophenolate mofetil, enalapril, and high doses of steroids, she received two 1000-mg doses of rituximab one month apart. Prior to receiving rituximab, a chest x-ray showed normal findings, but a tuberculin skin test (TST) was not performed. A pre-employment TST performed in 2010 showed negative findings. Following rituximab she was maintained on 10-15 mg prednisolone daily. Four months after the second dose of rituximab, she presented with fever as well as pain and swelling in her right knee and left elbow. Her temperature was 39 C and erythrocyte sedimentation rate was 117 mm/hr. Gram stains and culture of aspirates from the knee and elbow joints yielded negative results for bacteria, as did a blood culture. A combination of methylprednisolone and intravenous ceftriaxone was given for a possible flare of lupus. Her condition improved, and she was discharged home. Two weeks later, she presented with similar symptoms accompanied by cough and shortness of breath. The patient's temperature was 38.3 C. Both her right knee and left elbow joints were erythematous and tender; her other joints were normal. The anti-nuclear antibody titre was 1:2560 (normal <1:40); anti-double-stranded DNA level, 110 IU/mL (normal: 0-200); creatinine, 57 mumol/L; serum calcium, 2.63 mmol/L (normal: 2.06-2.44); and vitamin D, 43.6 nmol/L (optimal >=75). A plain x-ray of the left elbow showed cranial displacement of a proximal fractured fragment of the olecranon process with intra-articular extension associated with swelling of the olecranon bursa (Fig. 1A). Magnetic resonance imaging scan (MRI)of left elbow joint showing avulsion fracture involving the olecranon process (White arrow) with possible underlying osteomyelitis of the avulsed fragment in addition to synovitis and reactive bursitis of the left elbow joint (Fig. 1B). MRI of the right knee joint revealed arthritis with synovial thickening, rice pad in the suprapatellar pouch, and large lateral femoral condyle erosion in addition to severe bone marrow edema involving almost the entire lateral femoral condyle. MRI findings were highly suggestive of tuberculous arthritis (Fig. 2). A computed tomography (CT)-guided biopsy confirmed acute-on-chronic osteomyelitis of the right knee. A synovial fluid smear yielded positive results for acid-fast bacilli, and culture confirmed MTB. An initial chest radiograph was reported as normal; conversely, a CT scan of the chest showed marked miliary nodular shadowing consistent with miliary tuberculosis (Fig. 3). Sputum smear yielded negative findings for acid-fast bacilli; however, sputum polymerase chain reaction (PCR) test using a GeneXpert system (Cepheid, Sunnyvale, CA, USA) yielded positive results for MTB. The gene mutation for rifampicin resistance was not detected. A fully sensitive MTB was isolated from both the sputum and synovial fluid culture.

PMC5717942_02

Female

Table 1 outlines available data on maternal, neonatal, infant and child mortality. Given the difficulty of obtaining accurate data on maternal and child deaths due to the conflict, these figures are not disaggregated to include conflict-related mortality. Estimates indicate a reduction in neonatal mortality rate in Syria, possibly due to geographical exclusion of hard-to-reach areas. Part of the excess mortality burden due to conflict is occurring in under 5 year olds, which is partially due to reduced healthcare access in conflict-affected areas. In Syria in 2009, 83.6% of demand for family planning was met (table 2), and this is estimated to have increased within Syria to 88.7% and among non-camp refugees living in Amman, Jordan. These numbers are lower in Lebanon (63.9%) (table 2), where access to RH services is reportedly hindered by cost, travel and limited female healthcare providers. There were no reliable figures on fertility among refugees or within Syria. This issue of fertility and forced displacement internationally is a subject of debate, with some attributing a possible increase in fertility to the need to replace lost children, whereas others suggest that fertility is decreasing because of the stress and uncertainties of displacement. Within Syria, coverage of at least one ANC visit with a skilled professional has declined from 87.7% to 62%, likely related to the widespread displacement, the exodus of healthcare professionals and the destruction of health facilities. Coverage in Lebanon and Jordan remains at similar levels to prewar Syria, whereas coverage of at least four ANC visits is much lower (in non-camp refugee populations) (table 2). No data on ANC were available for Turkey. Rates of skilled birth attendance at delivery have dropped in Syria from 96.2% to 72%, whereas they remain almost universal among refugees in neighbouring countries, likely as a result of special provisions by UNHCR in Lebanon and Jordan (table 2). Available data indicate increases in C-section rates both within Syria (where nationally the rate was 26.4% preconflict) and among refugees since the conflict began (table 2). Data from the largest public maternity hospital in Damascus show C-section rates increasing from 29% in 2010 to 46% in 2014 (Personal communication with Bashar Kurdi, 2015). This could be explained by the need for women and their physicians to schedule delivery around the security situation. It could however also be an unintended consequence of interventions introduced to help women reach RH services, such as the voucher system introduced to enable women to obtain free maternal health and emergency obstetric services including C-section. In Lebanon, in 2013, 35.3% of Syrian refugee deliveries in UNHCR-contracted hospitals were C-sections, and the corresponding figures were 36% in 2014 and 33.7% in 2015 out of all referrals for delivery (Personal communication with Marie Akiki and Dr Diana Aoun, UNHCR, 2016). Potential explanations for this high rate are limited access to and utilisation of ANC increasing the risk for high-risk pregnancies, privatised healthcare system, predominance of male obstetric providers or UNHCR's financial coverage of most C-sections. Postnatal visits to health facilities were low at 27% in Syria in 2009 (table 2). Limited data are available for an analysis of changes since the crisis; however, within a camp setting in Jordan, where several specialised RH facilities have been established, postnatal care is higher at approximately 50%. No data on postnatal care coverage for the newborn were identified. Table 3 shows that available data on coverage of measles, diphtheria-tetanus-pertussis (DTP3) and Haemophilus influenzae type B (Hib) vaccinations in Syria was high prior to the conflict (at 81.9%, 99% and 82.1%, respectively) and has suffered setbacks during the war except for DTP3 vaccine coverage, which increased. Refugee children are also reported to have lower than optimal coverage rates with scarce data showing large variations in coverage. Other indicators of child health were also high prior to the conflict, but no data on care seeking and antibiotic treatment for pneumonia nor for oral rehydration therapy for diarrhoea in Syria or neighbouring countries exist for the period since the conflict began (table 3). This highlights the partial development and implementation of health policies concerning these interventions in this context and the lack of surveillance data.

child health, maternal health, public health

PMC7452413_01

Female

A 15-year-old female presented to our hospital after a delay of 7 months with chief complaints of pain in right leg along with swelling for the past 7 months. Parents initially consulted non orthopaedic doctors at their local vicinity and were advised painkillers and rest but she did not get relief and then was referred to our hospital for further management. The pain was insidious in onset (parents noticed swelling 10 days after the onset of pain) progressively worsened with time but no diurnal variation was present. Pain was more on standing and walking and did not relieve on taking analgesics. There was no history of any preceding trauma, chronic cough, expectoration, respiratory complaints, evening rise of temperature, and weight loss or arthralgia. There was no significant family history of tuberculosis or contact with any tuberculosis patient present. She was afebrile and haemodynamically stable. There was a firm, diffuse, tender swelling over the lateral aspect of distal one-third shaft region of right fibula without any fixity to the overlying skin and no local rise of temperature on palpation. There was mild oedema of the overlying skin, but no discharge or pus from the lesion. The left ankle joint and knee joint were normal with no swelling, tenderness or any restriction in the range of movement. No lymphadenopathy was present. Rest of the systemic examination was normal. A clinical diagnosis of diaphyseal bone tumour with other possibilities including ewings sarcoma, chronic infective osteomyelitis, brodie's abscess, cystic bone lesions were considered. Raised erythrocyte sedimentation rate of 44 mm in first hour with haemoglobin 9 g/dl was present. Tuberculin skin test was positive. Plain radiograph of the right leg showed an intracortical lytic bony lesion with adjacent sclerosis but no cortical breach in fibula shaft region (Figs. 1 & 2). MRI right leg (Figs. 3 & 4) confirmed an intramedullary diaphyseal lesion in fibula shaft, 6.2 cm away from ankle joint, with associated marked thinning of overlying cortex with focal cortical breech along anterior cortex. (suggestive of ewings sarcoma with osteosarcoma kept as another possibility). CT scan of thorax, abdomen and pelvis was performed that showed lungs were clear. The visualized skeleton was normal. Liver, pancreas and both kidneys were unremarkable. There was no free peritoneal fluid or free peritoneal air or abdominal or pelvic lymph node enlargement. Examination of the other systems was also normal. Needle biopsy was done which on histopathology showed (Fig. 5) epitheloid cell granulomas, occasional langhans giant cells and moderate mixed inflammatory infiltrate. Acid fast bacilli were negative on microscopy culture. She was put on category 1 antitubercular regimen, under Revised National Tuberculosis Control Programme (RNTCP) as per revised WHO guidelines. Anti-tubercular therapy included 2 months of daily intensive therapy with four drugs: isoniazid (H) 10 mg/kg, rifampicin (R) 15 mg/kg, pyrazinamide (Z) 35 mg/kg and ethambutol (E) 20 mg/kg followed by maintenance therapy with drugs (HR) in the same daily doses. Currently patient is on anti- tuberculosis treatment (ATT) for past 12 months and reports alleviation of clinical symptoms with healed lesion on plain x-ray radiograph of right fibula taken at 12 months (Fig. 6).

case report, diaphysis, ewings sarcoma, fibula, tuberculosis

PMC8523682_02

Female

29-year-old Caucasian woman with an associates' degree reported a history of physical and emotional abuse. Violent altercations involved door, wall, and fist. Her symptoms included (i) memory problems such as losing childhood memories and memories of friends, difficulty finding words, (ii) communication problems, including issues with speech, expressing herself and understanding directions, (iii) affect regulation problems, such as being easily aggravated and overwhelmed, and difficulty understanding her own feelings, (iv) sensory problems such as issues with vision, taste, and smell, (v) feelings of disconnection including losing interest in hobbies and relationships, and preferring to be alone. Imaging review from the radiologist found considerable TBI encephalomalacia, gliosis, hemosiderin in bilateral orbitofrontal (R>L), and more superiorly left frontal lobe.

abusive relationship, brain imaging, intimate partner violence, mental health, traumatic brain injury

PMC5396945_01

Female

An 18-year-old girl hailing from Kozhikode, South India, with no past history of any illness, visited our hospital with complaints of fever of 1 week duration. She also had headache that was increasing in intensity and aggravated in the early morning. She also had two episodes of vomiting. She complained of double vision on the third day of admission, which was followed by asymmetric weakness of both proximal distal muscles of all four limbs. There was no history of sensory disturbances and bladder or bowel dysfunction. On examination, her vitals were stable. There was no pallor, icterus, clubbing, lymphadenopathy, rashes or eschar on general examination. Neurological examination on admission revealed normal speech, intelligence and memory. There was no papilledema. She developed bilateral lateral rectus palsy (Figure 1A and B), with normal upgaze and papillary reflexes. Other cranial nerves were within normal limits. Motor system examination showed normal muscle bulk. Muscle groups in all limbs showed hypotonia with grade 3/5 power in the right lower limb, grade 2/5 power in the left lower limb and grade 4/5 power in both upper limbs. All deep tendon reflexes were sluggish. Sensory system examination was normal. There was neck stiffness with other signs of meningeal irritation. Rest of the systems were within normal limits. Her clinical course is summarized in Figure 2. Initial investigations revealed normal hemogram, with an elevated erythrocyte sedimentation rate (ESR) of 95 mm in the first hour. Blood sugar, serum electrolytes and renal and liver function tests were within normal limits. Computerized tomography of brain was within normal limits. With a history of fever and headache and findings of meningitis, lumbar puncture was done, which showed an opening pressure of 190 mm of cerebrospinal fluid (CSF). CSF analysis revealed a CSF total count of 30 cells with 80% lymphocytes. CSF sugar was normal, and protein was mildly elevated (60 mg/dL [normal 20-40 mg/dL]). Bacterial cultures were sterile. CSF adenosine deaminase and culture for Mycobacterium tuberculosis were negative. India ink stain for cryptococci was negative. Cytology did not show any malignant cells. CSF viral serology turned out to be positive for JE virus with positive IgM antibodies specific for the same insignificant titer. Autoimmune markers in CSF (NMDAR, LGI1, Caspr2, AMPAR [GluR1 and GluR2 subunits] and GABA-B-R) were negative. Magnetic resonance imaging (MRI) of the brain showed hyperintensities in bilateral thalami and in the limbic region, suggestive of limbic encephalitis (Figure 3). MRI of the spine showed T2-weighted hyperintense signal intensities in the spinal cord caudally till the L1 level, predominantly involving the anterior horn cells, and rostrally, they extended upto pons, suggestive of longitudinal myelitis (Figure 4). Electroencephalogram displayed slowing of delta waves in the frontotemporal region. The patient was treated with supportive measures. However, she deteriorated with the development of altered sensorium and intermittent hypothermia. Oral, axillary, rectal temperature revealed a temperature <94 F on multiple occasions. Electrocardiogram at the time of hypothermia showed bradycardia, prolonged QT interval and Osborn wave (Figure 5). Other causes of hypothermia such as hypothyroidism and hypoadrenalism were ruled out with normal thyroid function tests and fasting serum cortisol levels. Warm saline infusions and intermittent rewarming were given at the time of hypothermia. She developed intractable seizures and autonomic instability and succumbed to her illness after 2 weeks of hospital care. Written informed consent was obtained from the parents of the patient for the publication of this report and accompanying images.

japanese encephalitis, hypothermia, limbic system

PMC6348249_03

Female

A second sister died at age 9 months of lung lymphoma. She started at 4 months old, with three episodes of pneumonia and one of sepsis; she suffered from milk protein allergy, vulvovaginal candidiasis, and diaper area dermatitis; her laboratory workup found: transient peripheral lymphopenia, low T-cells subsets (CD4+ 8 to 403 cells/mm3, CD8+ 6 to 232/mm3) with normal B and NK cells; normal serum immunoglobulin levels (IgG 853mg/dL, IgM 41, IgA 64 mg/dL, IgE < 18 IU/ml); positive CMV viral load, Acinetobacter baumanii cultured from blood, Enterococcus faecium from urine, and Enterobacter aerogenes from bronchial aspirate. Cystic fibrosis, HIV infection, tuberculosis, and gastroesophageal reflux disease were ruled out; a nitroblue tetrazolium (NBT) reduction assay was normal at 81%. The chest X-ray showed a paravertebral mediastinal mass; a chest computed tomography (CT) confirmed a well-delimited, right retrocardiac rounded mass shortly before her death. She deteriorated abruptly with metabolic acidosis, progressive respiratory distress and heart failure; she was admitted to the intensive care unit and received mechanical ventilation support, broad-spectrum antibiotic, milrinone, and cyclophosphamide, without improvement. The autopsy confirmed a diffuse large B-cell lymphoma; EBV staining was not performed. Our patient, the third sibling, received the BCG vaccine at birth, without complications. Before 1 year of age he was treated for uncomplicated pharyngitis and avascular necrosis of the femoral head (Legg-Calve-Perthes disease). Given his family history, he was started on oral trimethoprim/sulfamethoxazole (TMP/SMZ) and sent to our hospital for evaluation.

dna repair defects, case series, clinical spectrum, inborn error of immunity, ligase iv deficiency, primary immunodeficiency

PMC4937763_01

Male

A 44-year-old man with AML-M3 for two months was admitted to our hospital with fever and neutropenia (absolute neutrophil count = 400 cells/mm3) starting seven days after chemotherapy. At the time of admission, the patient presented with an oral temperature of 38 C; physical examination was otherwise normal. Specimens were obtained for blood culture (B/C), urine analysis (U/A), and urine culture (U/C). Meropenem was started subsequently. Chest X-ray showed patchy consolidation in both upper lung lobes, and the patient had a provisional diagnosis of health care associated pneumonia. Parenteral vancomycin and ciprofloxacin were added to meropenem; however, P. jiroveci was also probable according to CXR. High resolution computed tomography scan (HRCT) of the lungs was performed and revealed bilateral symmetrical peribronchovascular infiltration in both upper lobes and superior segment of lower lobes in favor of P. jiroveci (Figure 1). Co-trimoxazole and hydrocortisone (due to hypoxemia, with arterial oxygen pressure of 50 mm Hg while breathing room air) were administered. First B/C and U/C were negative. Due to continuous fever, B/C, U/C and CXR were repeated; serum galactomannan was measured; and amphotericin B deoxycholate was started empirically. However, after the administration of amphotericin B, the patient developed severe chills and rigors. Thus, amphotericin B was changed to caspofungin. On day nine, he complained of shortness of breath and dyspnea; he remained febrile but leukocyte count increased to 4300/mm3 with a normal differential. Due to poor response to initial treatment for P. jiroveci, we changed co-trimoxazole to primaquine and clindamycin. One day later, a serum galactomannan index (GMI) of 1.7 was reported (GMI>=0.5 is regarded as positive). Therefore, a probable diagnosis of invasive pulmonary aspergillosis (IPA) was made, and consequently caspofungin was replaced with voriconazole. Bronchoscopy, bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBLB) were performed; specimens were sent for tuberculosis polymerase chain reaction (PCR), P. jiroveci PCR, cytomegalovirus (CMV) PCR, herpes simplex virus PCR, galactomannan, cytology and bacterial and fungal culture. All of the above tests were negative except for the BAL sample for CMV PCR (quantitative PCR=1404 copies/mL). Because of this result and the clinical deterioration of the patient, we decided to add ganciclovir to his treatment protocol. On day 13, the fungal culture of BAL revealed Penicillium SP. This specimen was sent to the Reference Mycology Research Center and cultured on Sabouraud glucose agar (SGA), which revealed green-blue color and velvety appearance. Slide culture and lacto phenol staining were done. Penicillium notatum was identified based on slide culture morphology and colony shape (Figure 2 A,B). On the other hand, TBLB (methylene blue staining of lung section) revealed severe interstitial inflammatory cells, fibrin deposition and reactive pneumocytes (Figure 3A) and intra alveolar eosinophilic material (Figure 3B) suggestive of P. jiroveci; accordingly, primaquine and clindamycin were continued for 14 days. In addition, the pathology report showed angioinvasion of fungal organism. After eight days of receiving voriconazole, the patient's fever subsided and his dyspnea improved. This course of treatment was continued during the next 12 weeks. He is currently asymptomatic and repeated CXR revealed a regression of infiltration.

acute myeloid leukemia, penicillium notatum, pneumocystis jiroveci, pulmonary

PMC9874630_01

Female

The clinical timeline, treatments and main diagnostic assessments in this patient are summarized in Figure 1A . In July 2017, a 55-year-old woman underwent quadrantectomy and axillary lymphadenectomy for a multifocal (G3) ductal infiltrating breast carcinoma of the luminal B subtype: estrogen receptor (ER) 90%, progesterone receptor (PgR) 5%, Ki67 50%, HER2-low (immunohistochemistry 2+; non-amplified by in situ hybridization). In December 2017, one month only after the end of adjuvant therapy, early metastatic dissemination to the lung, bones and parasternal soft tissue called for first-line therapy with CDK4/6i plus Letrozole. Unfortunately, further rapid progression occurred (July 2018) involving the lung and spine (L2/L3), which prompted to surgical removal of a thoracic subcutaneous metastasis for diagnostic re-assessment and targeted NGS (see below). Routine immunohistochemistry of the metastatic tissue confirmed the ER+/PgR+/HER2 2+ status detected in the primary, and in addition revealed a very slight HER2 copy number gain (HER2/CEP17 SISH ratio: 2.4). Since Trastuzumab deruxtecan was not available in year 2018, a combined regimen was attempted of Trastuzumab plus Pertuzumab and weekly Taxol for double HER2/hormone blockade (2nd line). However, novel pleural and left costal lesions developed after 5 cycles. This prompted us to initiate 3rd line therapy with Trastuzumab emtansine (T-DM1) plus Letrozole. This combination was administered in the context of a LB study, now published. LB detected progressive accumulation of 3 actionable ESR1 circulating alterations (see below) during treatment, despite apparently stable disease. Clinical progression (massive dissemination to the lung, pleura and liver) occurred in June 2019 (total body CT scan, Figure 1B ). The patient was referred to the Regina Elena intramural Molecular Tumor Board (MTB) in very poor general conditions and dyspnoic. Off-label Fulvestrant was recommended (see below) exclusively based on LB data, in association with Capecitabine (4th line), but the latter had to be discontinued after a single cycle due to severe gastrointestinal intolerance. In contrast, Fulvestrant was well tolerated and, despite administration as single-agent, it resulted in a quick and dramatic improvement with disappearance of most lung lesions and associated pleural exudate, as well as drastic regression of the extensive liver invasion ( Figure 1C ). Response lasted 8 months until early February 2020, when the patient, who was otherwise in good general conditions and essentially asymptomatic, suddenly experienced dyspnea and chest pain due to a pleural exudate requiring thoracentesis. Salvage treatment with Trastuzumab plus Vinorelbine (5th line) resulted in partial response of the pleural effusion and apparently stable thoracic disease for about 7 additional months, until massive pleural/lung recurrence and death in November 2020. Tumor DNAs (tDNAs) were obtained from the three sampled tumor lesions: the primary tumor, the subcutaneous metastasis, and neoplastic cells isolated from the pleural effusion following overnight adherence to plastic dishes. Circulating tumor DNAs (ctDNAs) were obtained from 14 blood drawings. All 3 tDNAs and 8/14 ctDNAs ( Figure 1A , asterisks) were tested by NGS (Life Technologies, see Supplementary for technical details) with two targeted panels of different complexity. The tDNA-grade Oncomine Comprehensive Assay Plus detected 9 single nucleotide variants (SNVs) and 19 copy number alterations (CNA) in a total of 505 tested genes. These 27 alterations are listed along with variant allele frequencies (VAFs) and estimated copy numbers in Figures 1D, E, J . Due to its smaller size (it detects SNVs, CNAs and fusions in 52, 12 and 92 genes, respectively), the ctDNA-grade Oncomine PanCancer Cell-Free Assay could only assess 3 of 9 SNVs and 2 of 19 CNAs. Results are shown for 7 representative blood drawings ( Figures 1F-M ; n.a.: not assessed). The distribution of the 9 SNVs among the three tDNAs readily revealed marked phylogenetic divergence during tumor evolution: 5 SNVs (BRCA2 p.C1820, MGA p.R1106*, PRDM1 p.A546T, REG3G p.Q69H and TP53 p.G245S) were exclusive of the primary, 3 (HRAS p.A146T, RUNDC3B p.R4W and ESR1 p.D538G) were exclusive of the subcutaneous metastasis, and only one (KMT2C p.T816) was shared between any two lesions, namely between the subcutaneous metastasis and the neoplastic pleural effusion ( Figures 1D, E, J , top section; SNVs color-coded by site of detection in panel d). Particularly in light of rapid clinical progression, BRCA p.C1820 and TP53 p.G245S losses appeared counterintuitive. The former is a potentially inheritable, likely pathogenic variant (), and the latter is a loss-of-function cancer driver strongly associated with poor outcome (OncoKB level Px1; ). These considerations prompted to orthogonal testing by custom-designed digital PCR (dPCR) assays. However, NGS calling was confirmed, and dPCR-assessed VAFs differed marginally (within +/- 3%) from NGS-assessed VAFs (see representative TP53 testing in Table S1 ). Likewise, dPCR confirmed that BRCA2 p.C1820 was undetectable at both tested metastatic sites and in leukocyte DNA (not shown), conclusively ruling out a germ line origin. Next, we focused on the similarly puzzling observation of a simultaneous presence of three gain-of-function ESR1 SNVs (p.D538G, p.Y537S and p.Y537N), all known to be actionable and associated with resistance to hormone blockade. Interestingly, these three SNVs displayed very different origins and accumulation kinetics, as may be seen by comparing tDNA from the skin metastasis, and ctDNAs obtained before the T-DM1/Letrozole and Fulvestrant treatments, at progression, and at later time points ( Figures 1E-M ). Specifically, ESR1 p.D538G was the only ESR1 alteration to be detected in tissues. It displayed a very low VAF at onset both in tDNA and ctDNA, and then marked blood increases mostly coincident with clinical progression. In contrast, ESR1 p.Y537S and p.Y537N, initially undetectable, appeared de novo in blood, and their association with clinical outcome appeared to be less stringent. None of the three SNVs could be detected in the pleural effusion ( Figure 1J ). Also these changes were confirmed by orthogonal dPCR validation (representative results shown in Table S1 ). In summary, BRCA2 p.C1820 and TP53 p.G245S were negatively selected, whereas ESR1 alterations were positively selected by successive events taking place for the most part at undetermined tumor sites. Strikingly in contrast to the heterogeneous SNV distribution, the primary site and the skin lesion did share a large set of 19 collinear CNAs ( Figure 1D, E , bottom section). Most CNAs appeared to be inherited en bloc, since copy number gains and gene-to-gene ratios were roughly conserved between the two lesions. Only FAM135B displayed a discordant trend (increase instead of decrease/stability in copy numbers). Unfortunately, not all CNAs were testable by the ctDNA-grade NGS panel. Despite this limitation, we were able to confirm that both FGFR1 and MYC (the only two CNAs testable in blood) were amplified and, similar to tissues, copy number gains persisted in serial blood drawings, undergoing limited absolute and relative variations ( Figures 1F-L , bottom). Of special interest, FGFR1 and MYC amplifications were detected in peripheral blood collected at the time of thoracentesis despite tDNA from the pleural neoplastic cells had lost FGFR1, MYC, and all the other CNAs ( Figure 1J vs K ). The easiest interpretation of these results is that a clonal expansion containing at least FGFR1 and MYC CNAs was present throughout disease course, e.g. in the primary tumor, skin metastatic site and other unidentified tumor sites, as indirectly revealed by LB, but it was lost in the last lesion that had been sampled, e.g. tumor cells from the pleural cavity. To display multiple SNV and CNA trajectories, longitudinal series of %VAF values and DNA copy numbers were elaborated by the fishplot package for RStudio. The 6 ctDNAs not tested by NGS were included by incorporating dPCR data in the model. To portray tumor evolution in its entirety we chose to represent SNVs and CNAs in the same graph, and generated separate fishplots for blood and tumor lesions ( Figures 2A, B ). For simplified CNA rendering, we focussed on FGFR1 and MYC copy numbers, that are available for both blood and tissues. These were averaged and merged into a single fishplot. However, since %VAF and gene copy numbers are incommensurable, the latter were displayed in background and not to scale. It is acknowledged that no inference can be made about relative SNV/CNA subclonal representation, whereas quantitative relationships among multiple SNVs are faithfully graphed. Specifically, the fishplot in Figure 2A clearly shows relative abundance and kinetics of ESR1 p.D538G p.Y537S and p.Y537N. Quite strikingly, the two most abundant variants displayed a roughly reciprocal relationship whereby expansion of either is mirrored by contraction of the other. Unsurprisingly, circulating ESR1 alterations were prodromic to life-threatening clinical progression (see case description), which led to seek MTB multidisciplinary advice. In elaborating therapeutic recommendations, the MTB considered the following points: (a) the 3 actionable (OncoKB level 3A) ESR1 SNVs had disabled two consecutive codons in the catalytic ESR1 site; (b) they had occurred in rapid succession within 7 months from the first T-DM1/Letrozole administration; (c) their distinct kinetics and tissue/blood distribution were suggestive of convergent adaptive events in distinct founders; (d) their timing of appearance and subsequent clinical progression at lung and liver foci was compatible with an elective topographical distribution of at least some ESR1 variants at these sites. Preliminary evidence was also considered from the plasmaMATCH trial, now published, that subclonal ESR1 alterations when detected in blood do not confer sensitivity to targeted treatment. Nevertheless, in light of arguments (a-d), and in the absence of alternative therapeutic options, off-label Fulvestrant was recommended exclusively based on LB data, and in association with Capecitabine. As outlined in case description, only Fulvestrant was tolerated, and dramatic clinical improvement (CT scans in Figure 1C , performed in November) was mirrored, in December 2019, by nearly complete blood clearance of the newly arisen ESR1 p.Y537S and p.Y537N variants, although the ESR1 p.D538G clone (chronologically the first to appear) re-expanded, and FGFR1/MYC CNAs kept expanding steadily in blood ( Figure 2A ). These results formally prove direct variant (particularly ESR1 p.Y537S) targeting by Fulvestrant, and provide evidence for a dissociated response, both molecular and clinical. At the time of further pleural relapse in early February 2020, the ESR1 p.D538G variant and the FGFR1 and MYC copy number gains were all abundant in blood ( Figure 2A ). However, none was detectable in tumor cells obtained on the same day from the neoplastic pleural effusion, that only retained a single 'undruggable' KMT2C SNV ( Figure 2B ) first seen in the 2018 cutaneous metastasis. While further supporting clearance of ESR1 variants from the pleural space, these results prevented target FGFR1 treatment, and prompted instead to Trastuzumab plus Vinorelbine as a possible salvage therapy. Partial response of the pleural effusion was accompanied by decreases in FGFR1, MYC and ESR1 p.D538G variants, and (re)-expansion of ESR1 p.Y537S ( Figure 2A ). Subsequent increases of all variants in October 2020 ( Figure 2A , last blood drawing) heralded massive pleural/lung recurrence and death in November 2020. For synoptic view, the CNA trunk and the 11 SNVs detected in tDNAs and ctDNAs were assigned to specific tumor lesions and blood drawings by applying the pigeonhole principle and logical deduction. The inferred tumor phylogenetic tree is shown in Figure 2C .

esr1, her2, breast cancer, cancer evolution, liquid biopsy, molecular tumor board

PMC5705882_01

Male

A 61-year-old Vietnamese male with a past medical history of coronary artery disease, peripheral vascular disease, and abdominal aortic aneurysm underwent an axillary-bifemoral bypass and bilateral lower extremity thromboembolectomy. He was referred to our tertiary care center when his preoperative course was complicated by malaise, productive cough, and weight loss of 5 pounds over 5 weeks. The patient was a smoker and was currently employed as an electronics engineer. He denied night sweats, tuberculosis exposure, foreign travel, or animal contact in the past six months. He did report a cattle field along his route to work. Abnormal laboratory values were as follows: erythrocyte sediment rate more than 120 mm/hr, white blood cell count of 18.8 x 109 per liter (L), 82% neutrophils, 12% lymphocytes, 6% monocytes, and hemoglobin of 8.5 g/dL. Computed tomography (CT) scan of the chest showed bilateral ground glass opacities, most prominent in the right lower lobe, consistent with pulmonary edema. There was no evidence of a mass lesion in the chest. Abdominal computed tomography angiography (CTA) showed a retroperitoneal 13.1 x 10 x 5 cm hypodense mass lesion at the L3-L5 level, extending to the bilateral psoas muscles (Figure 1). The mass was associated with bone destruction and sclerosis of the adjacent L4 vertebral body. Magnetic resonance imaging of the abdomen confirmed a 13.9 x 5.1 x 10.3 cm lobulated retroperitoneal mass extending from the left to right psoas muscle. Possible invasion to the posterior wall of the infrarenal abdominal aorta and ventral L4 vertebral body was seen, raising concern for an infectious or neoplastic process. QuantiFERON-TB testing was negative, as was serologic testing for Treponema pallidum, Cryptococcus, Histoplasma, Coccidioides, and Brucella. Semiquantitative indirect immunofluorescent assay showed high anti-C. burnetii antibody titers: phase I IgG titer of 1 : 16384 with reference range of <1 : 16 (performed by ARUP laboratories) and phase II IgG titer of 1 : 4096 with reference range of <1 : 16 (performed by ARUP laboratories). CT-guided core biopsy was performed to evaluate the retroperitoneal mass, which revealed ischemic necrosis involving skeletal muscle and fibro connective tissue (Figure 2). Acid-fast bacilli (AFB) and Gomori methenamine silver (GMS) stains were negative for acid-fast bacilli and fungal organisms. Immunohistochemistry for CD34, CD117, S100, and pankeratin was negative. Desmin and myogenin immunostains were positive in benign skeletal muscle. Because there was a high index of suspicion for a malignant process, a second CT-guided core biopsy was performed one week later; histopathological findings were reminiscent of the first biopsy and showed no evidence of malignancy. At this point, the overall clinical and histopathological findings raised a high index of suspicion for C. burnetii infection. Tissue from the core biopsy was sent to the Health Department of Orange County, California, where a direct PCR test for C. burnetii confirmed the diagnosis. The patient began treatment for Q fever with doxycycline 100 mg twice a day and hydroxychloroquine 600 mg daily. He showed marked clinical improvement with this treatment regime. Three months later, a repeat CT scan showed significant decrease in the size of the retroperitoneal mass, with maximum dimension decrease to 6.5 cm, down from 13.9 cm at presentation. The patient recently completed an 18 month treatment course without complication. Final posttreatment imaging and serology are not available at our institution for review.

PMC9486261_01

Male

A 32-year-old male was admitted to the Psychiatry ward, Jigme Dorji Wangchuck National Referral Hospital with symptoms of severe depression. The history was obtained from the individual, his friends of the monastic school, and his family members who seemed reliable. His past psychiatry history revealed he had two episodes during which he exhibited elevated and irritable mood, disinhibition, increased talkativeness, becoming violent at home, and with increased energy and reduced need for sleep, suggestive of mania but was never evaluated by a psychiatrist. These episodes resolved spontaneously after about a month. He had normal inter-episodic functioning. There was no significant history of drug or alcohol use. He has a younger brother who has a psychiatric disorder suggestive of schizophrenia. The mental state examination revealed prominent self-neglect, no eye contact, poverty of speech, tearfulness, and significant psychomotor retardation. His speech needed repeated prompting with low tone and volume, and the contents were reduced. His mood was low and the affect was depressed. There were no delusions or any perceptual disturbances. His cognitive function was intact and insight was partially intact. He reported passive suicidal ideations, but there were no past attempts. His physical examination, especially neurological examination, was unremarkable. A diagnosis of bipolar affective disorder and current episode of severe depression was made using the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5). A CT scan of the brain of the index person revealed bilateral calcifications of the basal ganglia, thalamus, and cerebellum as indicated by arrows in Figure 1(a) and (b) respectively. His blood calcium was normal. Despite the minimal decrease in vitamin D-25-hydroxyl level, the parathyroid hormone level was normal. Therefore, hypoparathyroidism was excluded. Other laboratory investigations such as thyroid, liver, and renal tests were normal. Infectious causes such as tuberculosis and human immunodeficiency virus infection were also excluded. Therefore, the primary cause of basal ganglia calcification could not be established. His blood workups are depicted in Table 1. We traced the reports of his younger brother and found that he also had bilateral symmetrical calcifications of globus pallidus, bilateral dentate nuclei, and cerebellar folia with no known cause, and that he was being managed as schizophrenia. He has been on maintenance antipsychotics with risperidone 2 mg in the night and olanzapine 5 mg in the night. He lives with his parents and engages in household works under his parent's supervision. Figure 2(a) and (b) shows the bilateral symmetrical calcifications of basal ganglia and cerebellum folia, respectively, of the index person's younger brother. A diagnosis of Bipolar Affective Disorder Type I with current episode of severe depression secondary to FD was made. He improved with mood stabilizers (sodium valproate 200 mg in the morning and 400 mg in the night) and second-generation antipsychotics (risperidone 2 mg three times a day). He is in the monastic school at his village and continuing his monastic schooling and is being followed up at the local hospital of his village. However, genetic testing of both the index and his brother was not carried out due to unavailability of the facility.

fahr’s disease, basal ganglia calcification

PMC9421359_01

Male

An 8-month-old Chinese boy was referred to this tertiary hospital on 29 December, 2021 for fever and cough, 6-days in duration. On admission vital signs were body temperature 37.3 C, blood pressure 82/54 mmHg, pulse 132 beats per minute, respiratory rate 32 breaths per minute, and poor spirit. The superficial lymph nodes were palpable in the neck and behind the ear, a few moist rales were heard over both lungs. The child's abdomen was soft, liver and spleen were not palpable, and the neurological examination was normal. With only a fever, the child was sent to a local hospital for blood tests. Results of those test were white blood cell (WBC) 24.62*10 9/L, neutrophil percentage (N%) 44.1%, and C-reactive protein (CRP) 32.4 mg/L. Antibacterial treatment for 5-days produced no improvement and the child was referred again to our hospital. The parents indicated that the patient had normal psychomotor development and physical growth, but had recurrent episodes of respiratory infections from delivery until now. Upon admission, routine blood test results were WBC 21.5*10 9/L, N% 40.6%,CRP 47.98 mg/L, procalcitonin (PCT) 0.28 ng/ml, (1, 3)-beta-D-glucan test (G test), purified protein derivative (PPD) test, and T-spot test for tuberculosis were negative. Serological tests for HIV, cytomegalovirus (CMV), herpes virus, and rubella virus were negative. A chest computed tomography (CT) scan showed lung inflammation and a small amount of liquid in the right pleural cavity, foliar consolidation in the upper left lung, and multiple calcified nodules in bilateral axillary fossa, with multiple enlarged lymph nodes in the bilateral supraclavicular fossa. Echocardiographic showed no dilation of the coronary arteries. Brain magnetic resonance imaging (MRI) and abdominal ultrasound results were normal. Lymphocyte counts, as measured by flow cytometry, were CD3+ cells (total T lymphocytes) 58.57% (peripheral blood reference range 49.1-83.6%); CD19+ cells (total B lymphocytes) 35.4% (higher than normal 6.5-27.0%); CD3+CD4+ T helper cells (Th) 50.06% (28.2-62.8%); CD3+CD8+ T cells (Ts) 6.8% (10.2-40.1%); Th/Ts 7.36% (0.7-2.8%); and NK (natural killer) cells 4.23% (7-40%). The IgG, IgA, and IgM concentrations were; 0.49 g/L (reference 2.32-14.11 g/L), 0.07 g/L (reference 0.0-0.83 g/L), and 0.94 g/L (reference 0.0-1.45 g/L), respectively. The patient received antibacterial (cefoperazone sulbactam, imipenem cilastatin) treatment and supportive care, including human gamma globulin. The child's condition did not improve. Temperature exceeded 39 C, with WBC 16.5*10 9/L, N% 52.0%, and CRP 62.38 mg/L. After 8-days of administration and a poor response to antibiotic therapy, blood was collected for mNGS (Figure 1). Fourteen hours later TM was identified by mNGS. Microbiological blood culture confirmed TM infection on the 9th day of hospitalization, and with the quick mNGS results (Figure 2), intravenous amphotericin B (0.1-0.5 mg/kg/day, with gradual increase every 2 days) and oral itraconazole (4 mg/kg/dose bid) were administered. The patient's condition improved dramatically. On the 13th day of hospitalization, the patient's fever was <38 C. He was discharged from the hospital on December 30, 2022 when his body temperature had remained normal for 1 week. This was the 30th day of hospitalization. The patient was young and HIV- negative. However, his lymphocyte counts and immunoglobulin levels were abnormal and therefore congenital immunodeficiency was not excluded. Blood exon sequencing was performed to identify possible CD40LG gene variations. Analysis demonstrated the proband to be a hemizygous intron variant (c.346+1G>T) of the CD40LG gene (NM_000074), which was inherited from his mother, who was heterozygous. The father had the wild-type sequence (Figure 3). The patient was diagnosed with TM-BSI and a CD40LG mutation. For follow up, the patient has returned to the hospital for outpatient examination. His general condition remains normal without any apparent abnormalities. Oral itraconazole treatment has continued.

hiv negative, talaromyces marneffei, bloodstream infection, case report, metagenomic next-generation sequencing

PMC3038954_01

Female

A 91-year-old African-American woman was referred to our out-patient gastroenterology (GI) clinic for evaluation of mild epigastric pain and intermittent melena. Melena had been occurring for a week. Our patient denied any history of nausea, vomiting, early satiety, weight loss, hematemesis, heartburn, or alcohol use, and had never had any previous episodes of abdominal pain. Her vital signs showed no signs of orthostasis. An abdominal examination revealed a soft, non-tender abdomen. Rectal examination revealed hemoccult-positive dark colored stool. Laboratory test results revealed anemia (hematocrit 30%, white blood cell count 4.7 cells/mL, platelet count of 243 cells/mL) and abnormal liver function tests (LFTs; total bilirubin of 0.8 mg/dL, alkaline phosphatase of 664IU/L, aspartate aminotransferase (AST) 54 U/L, alanine aminotransferase (ALT) 188 U/L), consistent with cholestasis. Her alpha-fetoprotein, carbohydrate antigen (CA) 19-9, and hepatitis serologies were normal. Abdominal computed tomography (CT) studies were remarkable for multiple hepatic cysts, but malignancy could not be excluded (Figures 1,2,3). On esophagogastroduodenoscopy (EGD), the esophagus, gastric and duodenal mucosas were normal, whereas multiple blood clots were revealed at the ampulla of Vater. Hemobilia was suspected as the cause of melena and occult biliary obstruction. Our patient underwent an ERCP procedure that showed a single 18 mm large filling defect in the common hepatic duct wall at the junction of the right and left hepatic duct, adjacent to one of the hepatic cysts. The obstructing blood clots (Figures 4 and 5) were removed with a 9 mm balloon and a 7-French 10 cm stent was placed in the proximal common hepatic duct. Cytology brushing results were negative for malignancy. The presence of blood clots in the common hepatic duct (CHD) as well the adjacent localization of a hepatic cyst were strong indications that the cause of hemobilia was the hepatic cyst. Our patient's hospitalization period was uneventful and she was well one month after the intervention with no signs of hemobilia recurrence.

PMC9936882_04

Male

No shortage of PPE in this HC. But midwives are reluctant the utilization of these PPE for every labor and delivery care service. They usually use them when more than one delivery clients come at a time. This is because of the negligence that midwives have towards using these PP". [late twenty years old male HC head] Moreover, personal protective equipment (surgical glove, goggle, apron) and national delivery care guidelines were available in all HCs (Table 3). According to the results indicated by key informant interviews, the personal protective equipment was not being utilised well despite their presence in the HCs. The overall availability score of the delivery service was 78.5%. Medical equipment items, parenteral IV infusions, and delivery care guidelines were 100.0% available in all HCs, whereas the availability of rooms for laboring, delivery, and postpartum per national standard was only in one-fourths of HCs (Table 4). The use of partograph for all mothers admitted in labor is recommended. But midwives do not plot findings on the partograph throughout the labor process. This is because of both the negligence and lack of refreshment training of health workers on partograph utilisation. [male HC head] In the client's medical record review, a history of present pregnancy like gravida, parity, and ANC visits was recorded for 87.5% of mothers. About abdominal examinations such as fundal height, fetal position, fetal descent, and fetal heartbeat were recorded for 62.5%, 46.9%, 56.3%, and 65.6% of mothers, respectively. Furthermore, vaginal examination at the initial assessment; status of the membrane (68.8%), cervical dilation (81.3%), and fetal presentations (78.1%) were documented. Additionally, some recording files were not safely kept to be easily accessed whenever necessary; they were not also stapled together and had no folders. During the direct observation, monitoring of labor using partograph such as plotting cervical dilation and maternal blood pressure every four hours were observed to be practised for 72.0% and 65.6% of mothers, respectively. Washing before and after every L&D care procedure is essential for the mothers and ourselves to prevent infections. But we sometimes attain delivery care without washing hands, simply by wearing gloves. Because we do not have access to water near to the delivery room since there is no hand washing basin in the delivery room [female midwife-nurse delivery service coordinator]. Furthermore, the health-care providers had washed hands during delivery preparation and used sterile gloves for 50% and 96.9% of births, respectively. Likewise, health-care providers were observed to be adhered to checking the completeness of the placenta and contraction of the uterus after the delivery of the placenta for 81.3% and 65.6% of delivering mothers, respectively. On the other hand, 71.9% of births were recorded in the medical record and 75.0% of newborn babies have started breastfeeding within an hour. Moreover, 53.0% of delivering mothers were checked for blood pressure every 15 minutes after the complete delivery of the placenta (Table 5). The overall score of the compliance dimension was found to be 70.6%. Moreover, the proportion of clients who were checked for completeness of placenta was 81.3% which was the highest score and the proportion of delivering clients checked for vaginal bleeding every 15 minutes in the first hour after delivery of the placenta were 59.0% rated as the lowest score under the compliance dimension (Table 6). A total of 363 mothers participated in this study. One hundred thirty-two (36.4%) of mothers were aged 25-29 years; the mean age was 26.6 (SD: +-4.8) years. Religious preference for 80.4% was Orthodox; 80.4% were urban dwellers. About 88.2% of them were married; 32.2% went to secondary school (Table 7). Nearly 12% of mothers' recent pregnancy was unplanned. Fifty-eight percent of mothers had ANC visit four times and above, 59.0% of mothers were multigravida and 56.7% had two or more deliveries. Seven percent of the mothers ever had a history of abortion. On the other hand, 3% of mothers ever had a history of stillbirth. Moreover, 96.4% of mother had spontaneous vaginal delivery (SVD) which was the predominant mode of delivery and 2 (0.6%) of delivery ended with newborn death (Table 8). There is only one toilet in the HC. The toilet has no hand washing basin and it doesn't get clean regularly because of shortage of water accessibility in the HC. We have informed the head of the HC to discuss different stake holders on the possibilities of building additional toilets and water accessing full days. [female midwife-nurse] Out of the respondents, 65.6% were perceived that the waiting area was convenient. Nearly two-thirds of mothers were satisfied with the cleanliness of the delivery room. The majority (93.3%) of delivering mothers were satisfied with the delivery room's light and air condition. About 72.5% of delivering mothers were satisfied with the waiting time; 85.0% were satisfied with the delivery room's silence and 48.6% were satisfied with the appropriateness of proximity of the toilet. Further, the level of mothers' satisfaction regarding the accommodation of delivery service structure was 68.8% (Table 9). The finding of the evaluation showed that the overall acceptability level of delivery service was 80.2%. Of this, 80.4% of mothers responded that health-care providers answered their questions and concerns during delivery care service, and 67.0% accepted the information given by health-care providers about the benefit and side effects of medical treatments and procedures. About 77.7% of mothers accepted the courtesy of health-care providers. The evaluation also showed that 83.8% of mothers were informed about the procedures of the L&D care. Moreover, 94.2% of mothers were responded to recommend the HC's delivery service for friends and families (Table 10). In our analysis, residence and having ANC during the recent pregnancy were the factors that affect the delivery services. Accordingly, the odds of acceptance of delivery services by rural dweller mothers is significantly lower compared to mothers from urban areas (AOR: 0.13; 95% CI: 0.06-0.30). Mothers who had ANC visits of 1 to 3 compared to mothers who never had any ANC visit (AOR: 2.65; 95% CI: 1.05-6.74) and mothers who had ANC4 or more visits compared to who never had any ANC visit (AOR: 5.57; 95% CI: 2.09-14.84) had significantly higher odds to acceptance delivery services (Table 11).

acceptability, accommodation, availability, compliance, evaluation, institutional delivery

PMC9678965_01

Male

A 39-year-old man, apartment building labor, was referred to Masih Daneshvari Hospital, a university-affiliated respiratory hospital In Tehran, Iran in June 2022, complaining of high-grade fever, chills and shortness of breath. Dyspnea has been a complaint of the patient for 6 months, which has intensified since last month. There has been no evidence of hemoptysis, anorexia, or significant weight loss and no relevant personal history including atopy and allergic reactions in the past or family history such as tuberculosis or asthma has been reported. Additionally, he had no known recent COVID-19 exposures or history of a recent viral illness. A 20-year history of smoking cigarettes (20 packs per year) was also reported by the patient. A temperature of 38.5 C, heart rate of 88 bpm, blood pressure of 115/80 mm Hg, oxygen saturation of 93%, and respiratory rate of 20 breaths/min were measured and arterial blood gas revealed hypoxemia and mild respiratory alkalosis. Examination of his chest showed reduced breath sound intensity on the left side. The rest of the physical examination was unremarkable. The laboratory data showed an elevated C-reactive protein level (48 mg/dL) and eosinophil count (450/muL, reference range: less than 400/muL). The serum immunoglobulin (Ig) E level was 480 IU/mL (reference range: less than 150 IU/mL). Specific IgE and IgG to Aspergillus and anti-neutrophil cytoplasmic antibodies were negative. Hydatid cyst and galactomannan serology tests resulted negative. In addition, the COVID-19 PCR test was negative. Examination of a chest radiograph indicated left-sided pleural effusion (Fig. 1). Consequently, a computed tomography (CT) scan was requested, which demonstrated left-sided pleural effusion (Fig. 2). The echocardiography confirmed proper cardiac function without any structural abnormalities. Additionally, there was no evidence of pericardial effusion. After that, a thoracocentesis was performed. A cytological examination of the pleural fluid revealed neutrophilia and nuclear debris (exudative pleural effusion with 6 x 10^3/microL leukocyte containing 80% neutrophil), but no malignant cells. Fig. 3 shows post-thoracocentesis radiography. Further evaluation of the patient included bronchoscopy, which revealed the following: there were no tumoral lesions found, the opening of the LLL was obstructed with a thick mucoid plug that did not clear with suction, and several biopsies were obtained to assess the pathology. Despite receiving a wide range of antibiotics (ceftriaxone, clindamycin, ceftazidime, meropenem, vancomycin, and levofloxacin) and glucocorticoid therapy, symptoms of the patient persisted, and no clinical improvement was observed. Finally, the patient was referred to the surgery ward, where he underwent surgery for lobectomy of the left lower lobe. Gross pathology (Fig. 4) of the lesion was suggestive of endoluminal impaction but patient didn't meet the diagnostic criteria of ABPA (IgE = 480, galactomannan = negative). Fig. 5 demonstrates the surgical pathology of specimens from left lower lobectomy of the lung, showing noticeably dilated and inflamed bronchus (A). Additionally, numerous degenerating eosinophils with relatively acellular mucin is observed (B and C). Furthermore, the gimsa staining was performed and no parasite or fungal infection have been detected. Post-surgical follow up showed clinical improvement with no sign of previously persistent symptoms and eventually patient was discharged with good general condition.

abpa, allergic bronchopulmonary aspergillosis, ct, computed tomography, chronic consolidation, ig, immunoglobulin, mib, mib, mucoid impaction of the bronchi

PMC3610351_01

Male

A 62-year-old man presented with history of a left-sided neck swelling for 20 days which was progressive in nature associated with odynophagia and hoarseness. He gave history of chronic nonproductive cough for three months with loss of appetite. There was no history of fever or hemoptysis. His past history was insignificant except for a residual left hemiparesis due to a cerebrovascular accident 7 years ago. Examination revealed an ill-defined swelling on the left anterior aspect of the neck, approximately 4 x 3 cms which was cystic, fluctuant, and nontender. There were no palpable neck nodes, and oral cavity was normal. Flexible nasal endoscopy (Olympus flexible endoscope) revealed a normal laryngopharynx except for a mucosal swelling on the left side of vallecula. A provisional diagnosis of neck abscess was made. We aspirated the abscess with an 18G needle and drained 20 mL of pus. The pus was sent for routine culture, fungal smears, and AFB (acid fast bacilli) smears which did not yield any positive result. Three samples of sputum for AFB were sent in view of a cavity seen in the left upper zone on the chest X-ray (Figure 1), which were negative. Blood investigations done showed no immunocompromised status or other sources of infection. A contrast enhanced computed tomography of the neck and thorax revealed an enhancing ill-defined osteolytic lesion of the body of hyoid with peripherally enhancing collection. The collection extended anteroinferiorly beneath the strap muscles along the anterior aspect of the thyroid cartilage (Figure 2). Posteriorly the collection was found to protrude into the preepiglottic space (Figure 3). An incision and drainage of the abscess were planned. However as the patient suddenly developed a muffled voice, an elective tracheostomy was performed in anticipation of an impending airway compromise. Intraoperatively there was a necrotic tissue with sero-sanguineous collection in the preepiglottic space. About 20 mL of fluid was drained. The body and the greater and lesser cornu of hyoid bone on the left side were found to be necrotic. Histopathology of the hyoid revealed fibrocollagenous tissue with many discrete and confluent granulomas composed of epitheloid histiocytes and Langhans-type multinucleate giant cells rimmed by lymphocytes. Special stains done for fungal organisms were negative. A polymerase chain reaction study confirmed the diagnosis of tuberculosis.

PMC5911659_01

Female

A 76-year-old woman applied at the Department of Internal Medicine because of the persistent fever (38.8 C for approximately 4 weeks), constant feeling of tiredness, periodically occurring non-specific headache and severe pain in the right lumbosacral region radiating to the right lower extremity which occurred at rest and intensified when moving. In the medical history the patient reported that she suffers from diabetes type 2 (metformin 850 mg once daily), hypertension (ramipril 10 mg once daily, hydrochlorothiazide 12.5 mg once daily), hyperlipidemia (rosuvastatin 10 mg once daily) and hypothyroidism (levothyroxine 75 microg once daily). In the laboratory tests were found following disorders: leukocytosis 17.7 x 109/l, anemia (hemoglobin 8.4 g/dl) and CRP 265 mg/l (n < 5 mg/l). Blood and urine cultures were sterile. In lumbar spine magnetic resonance (MRI) degenerative changes with multilevel discopathy were noted. The patient was consulted by a neurologist and a specialist of infectious diseases. In the treatment empirical antibiotic (ciprofloxin 200 mg i.v. twice daily and amoxicillin 1000 mg p.o. twice daily) and non-steroidal anti-inflammatory drugs ware administered. As a result of this therapy the patient's general condition had improved (a decrease of fever and lumbosacral pain relief). There was no basis for the diagnosis of inflammatory spondyloarthropathy or rheumatoid arthritis. The recurrence of the described symptoms occurred about two months later. The patient applied at the Department of Rheumatology and Internal Diseases. Physical examination showed the following disorders: fever (39 C), limitation of motion of the hip joints, knee joints and lumbosacral spine, painfulness compression of the L4-S1 segment of the spine, which was more perceptible on the right side of the spine and on the right buttock. No pathological changes of the skin or muscles were noticed. Lymph nodes were not palpable. The laboratory tests performed have shown a leukocytosis 13.98 x 109/l (nv 4-10) with neutrophils 10.72 x 109/l (nv 2.5-6.0), erythrocytes 3.13 x 1012/l (nv 4-5), hemoglobin 8.4 g/dl (nv 12-16), hematocrit 26.7% (nv 37-47), platelets 560 x 109/l (nv 140-440), hypoalbuminemia [albumin 3.2 g/dl (nv 4.3-5.1), 42.7% (nv 60-71)], hypergammaglobulinemia [gamma globulin 1.5 g/dl (nv 0.6-1.2), 20.3% (nv 8-16)], ESR 121 mm (nv 3-15), ultra-sensitive CRP 181.98 mg/l (nv 0-5), fibrinogenactivity > 9.10 g/l (nv 1.8-3.5), procalcitonin 0.06 ng/ml (nv 0-0.05). All other parameters like fasting glycaemia, transaminases, creatinine, eGFR, electrolytes, APTT, INR, TSH or tumor markers were normal. Occult blood fecal analysis (chromatography) for 3 consecutive days did not showed any abnormalities. In several times made urine analysis characterizing bacteriuria was found, but the urine culture was negative. X-ray of the chest was normal. USG of the abdominal cavity revealed widening of the renal pelvis in the left kidney.Based on the echocardiography mitral regurgitation without hemodynamic significance was found (EF: 67%). The myelogram showed hyperplasiaof the bone marrow granulocytic component (76.4%), mainly of the older form - of segmented kernel. The morphological characteristics of cells were without significant disorders. The X-ray and the USG of the hip joints illustrated significant degenerative changes. In the X-ray of the sacroiliac joints a mixed but unspecific picture of the right sacroiliac joint was found (Fig. 1). Because of this further MRI was arranged. The MRI image of the sacroiliac joints has shown extensive, stalactite inflammation of the right sacroiliac joint with the infiltration of the muscles (Figs. 2, 3). There were also visible small abscesses in the right piriformis muscle and invasion of sacral canal spinal stenosis on the level of L4/L5. In addition, the twice made blood culture was positive and Staphylococcus aureus methicillin sensitive (MSSA) had been isolated. The patient was diagnosed with sacroiliac joint inflammation of infectious etiology (Staphylococcus aureus). It was the reason for starting antibiotic therapy according to the antibiogram: cefuroxime 3 x 750 mg i.v. (used for ten weeks in total) and ciprofloxacin i.v. 2 x 200 mg (for four weeks in total). Then, clindamycin 3 x 300 mg i.v. (for eight weeks in total) and after the patient has being discharged from the hospital clindamycin 3 x 300 mg p.o. (for other eight weeks). Due to the spinal stenosis the patient was also consulted by a neurosurgeon and due to a slight widening of the renal pelvis of the left kidney the patient was consulted by a nephrologist and urologist in order to find a primary outbreak of the infection. But there had not been stated any association with urinary system. Two months after the start of antibiotic therapy the control CT of sacroiliac joints was performed. In this image the regression of all the pathological changes was observed (Fig. 4). After five months of antibiotic therapy a relief of pain and fever had been achieved, the laboratory parameters had normalized (leukocytes 8 x 109/l, CRP 5 mg/l) and the patient had been discharged from the hospital. After six and after nine months after diagnosis the control MRI of the sacroiliac joints was performed. Their images showed further regression of the pathological changes. The patient is now being under the control of a rheumatologist and a neurosurgeon. Due to lasting back pain there are also plans for orthopedic surgery of the right sacroiliac joint.

staphylococcus aureus, infectious arthritis, sacroiliitis, septic arthritis

PMC2671152_01

Female

In summary, S has displayed delayed physical development and delayed puberty. Despite medications, S's physical development has never fully recovered, being at the 5th-10th percentile in weight (43.5Kg) and less than the 5th percentile in height (136.5cm) at time of scanning. For comparison, her weight of 43.5Kg is typical of a 12-12.5 year-old, while her height of 136.5cm is typical of a 9.5-10 year old girl. [Norms from ]. S's head size was 3% larger than the average of our control group at the time of testing. Despite requiring these significant medical interventions, S did not miss a considerable amount of school. Her initial diagnosis occurred when she was 4 years of age. Therefore, her expected enrollment into a small private pre-school was delayed by one year, to the age of 5. She began kindergarten at 6 years of age, missing only four months at the end of kindergarten due to medical interventions. She started the 1st Grade the following year and completed the year without any interruption. The only other school interruption occurred in December of 2nd Grade but was limited to approximately three weeks around the winter break. From 2nd Grade until the present (S is currently in 11th Grade) there have been no interruptions in her educational experience. In summary, we would not expect her profound dyslexia and other cognitive deficits to be due to missing several months of kindergarten, although subtle effects cannot be ruled out. White matter damage following radiation therapy was initially progressive, as was the development of large cystic regions in the left frontal and parietal lobes (compare Figures 1 and 2). S has also suffered several cognitive problems. Her most profound deficits are in reading acquisition and visuospatial processing, despite extensive reading remediation as well as math interventions. Since Kindergarten she has been in the public school system, and an Individual Education Program (IEP) allows for reading and math services during the day. She is in regular classes with an individual aide for all other subjects. S has undergone several speech and language screenings by the school district but never qualified for services. S participated in the Lindamood-Bell (LB ) Learning Processes (Lindamood-Bell, San Luis Obispo, CA) programs on multiple occasions. LB 's programs are based on the premise that reading requires the integration of sensory-cognitive functions and skills. S received a combination of two of their programs: 1) LiPS (Lindamood Phonemic Sequencing for Reading Spelling and Speech), which promotes phonemic awareness, and 2) Seeing Stars (Symbol Imagery for Sight Words, Reading, Phonemic Awareness, and Spelling), which targets word identification and reading fluency. In the fall of 1999, when S was in the 3rd grade, she had one semester of LB instruction 2 hours per day. By January of 2000 she had received 60 hours of LiPS and 105 hours of SI . In the summer of 2000, after 3rd grade, S attended an LB clinic 4 hours per day for 6 weeks and received a total of 58 hours of LiPS and 58 hours of SI . In the 8th grade (2004), she was administered LB for 2 hours per day for one semester and received 160 hours of SI . In the 9th grade (2005), she was administered one year of LB for 2 hours each day, and received 310 hours of SI . In the 10th grade, she received assistance with writing strategies by an LB consultant. Pre- and post-testing of S's reading skills were assessed using the Gray Oral Reading Test-3 (GORT-3) (Widerholt and Bryant, 1994) and Gray Oral Reading Test-4 (GORT-4), the Wide Range Achievement-Test-3 (WRAT-3) Reading subtest, the Woodcock Reading Mastery Test-Revised (WRMT-R) Word Attack subtest. Examining all reading scores it is evident that S demonstrated a flat learning curve based on her raw scores and a widening gap between her and same age peers over time based on her age corrected percentile scores (Table 1). When S was in the 9th grade, her mother administered Read Naturally, a computerized reading fluency program. The participant practices reading the same stories multiple times with the goal of increasing reading speed. S practiced at the 1st grade level and improved her speed on average by 55 words per minute to 69 words per minute. The program is not designed to improve reading accuracy. There was no formal pre- and post-testing administered. In 10th grade she began a computerized math intervention program (Math Concepts and Skills 2) from SuccessMaker Enterprise (Pearson Digital Learning, Pearson Education Inc., Phoenix, AZ) for one class per day; she also worked on it at night and on the weekends. The computer program started at the 3.0 grade level and was adjusted to the 3.5 grade level after administering a series of calculations to S. S spent approximately 83 hours on this program which covered computations (addition, division, multiplication, and subtraction) and applications (geometry, measurement, number concepts, probability and statistics, problem solving, science applications, word problems). By the end of the program S's cumulative performance was at the 4.87 grade level. There was no formal pre- and post-testing administered. S is a right-handed female who was 15 years, 11 months at the time of our neuropsychological evaluation and DTI and fMRI scans. She had previously undergone neuropsychological evaluation at age 11 and a psycho-educational evaluation at age 13. These past assessments were notable for verbal abilities within the average range with significantly lower visuospatial and visuoperceptual skills, including well below average constructional skills. In these assessments there was no indication of difficulty with complex language comprehension, though speech was reported as "mildly dysnomic." More precise understanding of S's dysnomia is not known because no scores were listed in the report, but her dysnomia is not severe enough to be noticeable in normal conversation. Her memory was described as generally adequate with no marked distinction between verbal and visual memory. Problem-solving skills were reported to be within the average range. Her academic skills in reading and math were well below average. The neuropsychological assessment at age 11 was comprised of the following: Beery Test of Visuomotor Integration, Boston Naming Test, California Verbal Learning Test, three subtests (not specified in the report) of the Children's Memory Scale, Facial Recognition Test, Token Test, Rey Osterrieth Figure, the Wechsler Individual Achievement Test, and the Wechsler Intelligence Scale for Children-III (WISC-III). The only raw scores provided in the report of the neuropsychological evaluation were the WISC-III. All available test scores are presented in Table 2. Consent from the mother and assent from the child were obtained at the beginning of the study, consistent with the approved human subjects protocol by the Stanford Panel on Human Subjects in Medical Research. Our neuropsychological evaluation of S consisted of the following measures: Laterality-Edinburgh Handedness Inventory (EHI); Intellectual Functioning- Wechsler Intelligence Scale for Children-IV (WISC-IV); Achievement- Woodcock-Johnson Tests of Achievement-III (WJ-III), the GORT-4, Test of Word Reading Efficiency (TOWRE); Phonological Processing-Comprehensive Test of Phonological Processing (CTOPP); Language-Clinical Evaluation of Language Fundamentals-4 (CELF-4), Controlled Oral Word Association Test, Animal Naming Test, Boston Naming Test-2; Executive Function- Wisconsin Card Sorting Test; Memory- Wechsler Memory Scale-III. Diffusion-weighted imaging (DWI) data were acquired on a 1.5T Signa LX (Signa CVi, GE Medical Systems, Milwaukee, WI) using a self-shielded, high performance gradient system capable of providing a maximum gradient strength of 50mT/m at a gradient rise time of 268mus for each of the gradient axes. A standard quadrature head coil, provided by the vendor, was used for excitation and signal reception. Head motion was minimized by placing cushions around the head and securing a Velcro strap across the forehead. The DWI protocol used eight 90-second whole-brain scans; these were averaged to improve signal quality. The pulse sequence was a diffusion-weighted single-shot spin-echo, echo planar imaging sequence (TE =63ms; TR = 6s; FOV = 260 x 260 mm; acquisition and reconstruction matrix size = 128 x 128; bandwidth = +-110kHz; partial k-space acquisition). We acquired 56 axial, 2 mm thick slices (no skip) for b = 0 and b = 800 s/mm2. The higher b-value was obtained by applying gradients along 12 different diffusion directions (six non-colinear directions). Two gradient axes were energized simultaneously to minimize TE. The polarity of the effective diffusion-weighting gradients was reversed for odd repetitions. DTI data were pre-processed using a custom program that removed eddy current distortion effects and determined a constrained non-rigid image registration using normalized mutual information. The six elements of the diffusion tensor were determined by multivariate regression. The eigenvalue decomposition of the diffusion tensor was also computed. For each subject, the T2-weighted (b=0) images were coregistered to the corresponding T1-weighted 3D SPGR anatomical images. The coregistration was initiated using the scanner coordinates stored in the image headers to achieve an approximate alignment. This alignment was refined using a mutual-information 3D rigid-body coregistration algorithm from SPM2. Several anatomical landmarks, including the anterior commissure (AC), the posterior commissure (PC) and the mid-sagittal plane, were identified by hand in the T1 images. With these landmarks, we computed a rigid-body transform from the native image space to the conventional AC-PC aligned space. The DTI data were then resampled to this AC-PC aligned space with 2 mm isotropic voxels using a spline-based tensor interpolation algorithm, taking care to rotate the tensors to preserve their orientation with respect to the anatomy. The T1 images were resampled to AC-PC aligned space with 1 mm isotropic voxels. We confirmed by visual inspection of each dataset that this coregistration technique aligns the DTI and T1 images to within 1-2 millimeters in the brain regions of interest. However, geometric distortions inherent in EPI acquisition limit the accuracy in regions prone to susceptibility artifacts, such as orbito-frontal and anterior temporal regions. We used standard non-linear spatial normalization methods from SPM2 to align the 54 control brains and build a template from them (see). The diffusion data for subject S had significant geometric distortions in the cerebellum and inferior occipital lobe due to the spinal fusion hardware in her neck. For this reason, we independently aligned her T1-weighted images and her DTI data to the control template brain. S's T1-weighted images were aligned to the control brain T1-weighted template. Her DTI data were normalized to this same coordinate space by aligning her non-diffusion-weighted EPI data to the template EPI. The resulting non-linear deformation was applied to the tensor field, taking care to rotate the tensors to preserve their orientation with respect to the anatomy by converting the local deformation field at each voxel to an affine transform and then applying the preservation of principal direction algorithm to the tensor at each voxel. The final result of these image manipulations produced a good alignment both between S's T1 and tensor data and between her brain and that of the 28 controls, as assessed by careful inspection. However, some severe artifacts due to the metal implants remained in the lower part of S's tensor data, especially in the cerebellum. Therefore, we restricted our analyses to the axial plane at or above the anterior commissure (Z>=0), which was about one centimeter above the artifact region. Because we had suspected that certain pathways might be missing in subject S's brain, we did not want to compute the spatial normalization based on the diffusion-weighted data [e.g., using a method such as FSL's TBSS ]. Such methods are useful for finding diffusion differences between corresponding pathways but are not designed to find differences that might include the presence or absence of pathways. We used an auditory covert verb generation paradigm to measure language related brain responses in S and identify her lateralization for language stimuli. Auditory presentation was used to overcome S's reading difficulties. During the scans, S was asked to covertly generate verbs for each presented noun, and listen attentively to noise stimuli. We confirmed, using a short behavioral test, that S could perform the task overtly at a presentation rate of one word every three seconds. Experimental stimuli consisted of high frequency English nouns, presented aurally through MRI compatible headphones (Avotec, Inc., Stuart, FL). Control stimuli were auditory noise patterns created by randomizing the phase of the word stimuli, while maintaining their amplitude envelope. Each condition was repeated in six 15s blocks (consisting of 5 stimuli, ISI=3s) presented in pseudorandom order and interleaved with 15s rest periods. The whole experiment was divided into 2 short runs, 207s per run. Continuous MR data acquisition was used during these runs. FMRI measurements were performed on a 3T General Electric scanner with a custom-built volume head coil. Head movements were minimized by padding and tape. Functional MR data were acquired with a spiral pulse sequence. Twenty-six oblique slices were prescribed approximately along the AC-PC plane, covering the whole temporal lobe and most of the frontal lobe (3 mm thick, no gap). The sampling rate of the BOLD signal (TR) was 3s and the voxel size was 2.5 x 2.5 x 3 mm. In-plane anatomical images were acquired before the functional scans using a fast SPGR sequence. These T1-weighted slices were taken at the same location of the functional slices, and were used to align the functional data with the high-resolution T1 anatomical data acquired on the 1.5T scanner during the DTI scan session. The spiral sequence used for the fMRI was much less affected by the spinal fusion hardware in S's neck than the EPI-based DTI sequence, so no additional steps were necessary to obtain adequate alignment between the fMRI data and the subject's T1-weighted anatomical images. FMRI data were analyzed using the freely-available mrVista tools (http://white.stanford.edu/software/). Images acquired from the functional scans were inspected for motion by an experienced analyst, who concluded that excessive motion in the second run (>5mm) was not corrected by our motion compensation procedure. Therefore the analysis was restricted to the first run. Our results thus rely on one functional run in which each condition was presented in 3 blocks. This is not uncommon in neurological patients and constitutes the main reason for using a powerful task that is known to activate language regions robustly even with very short scans. Baseline drifts were removed from the time series by high pass temporal filtering. A small amount of spatial smoothing (with a 3 mm FWHM Gaussian kernel) was applied to the data to enhance sensitivity to small signal changes. A general linear model (GLM) was fit to each voxel's time course, estimating the relative contribution of each condition (verb generation, auditory noise) to the time course. GLM predictors were constructed as a boxcar for each condition convolved with a standard hemodynamic response model. Statistical maps were computed as voxel-wise t-tests for each predictor and between the weights of the two predictors. For visualization purposes, the statistical maps were interpolated to the high resolution volume anatomy.

PMC8334716_01

Female

The patient was a 74-year-old woman with chronic obstructive pulmonary disease. In June 20XX, she observed a lump in her right supraclavicular fossa, which increased in size over 2 months, and she consulted a local doctor in mid-September. Computed tomography (CT) images showed a nodule in the upper lobe of the right lung and enlargement of the mediastinal and right supraclavicular fossa lymph nodes, and she was referred to our department. At the first visit, she had right cervical lymphadenopathy with hard consistency. The T-SPOT . TB test result was positive, whereas the tumor marker levels were not elevated. On chest radiography, the right mediastinal lymph node appeared to protrude into the right lung (Fig. 1). Dynamic CT revealed a significantly enlarged lymph node in the right supraclavicular fossa (Fig. 2), a small nodule (maximum diameter, 13 mm) in the upper lobe of the right lung, and an enlarged lymph node in the right supraclavicular fossa and mediastinum. Fluorodeoxyglucose (FDG)-positron emission tomography/CT performed at the first visit showed high FDG accumulation in the longitudinal and right supraclavicular fossa lymph nodes, whereas little FDG uptake was observed in the right upper lobe lesion (Fig. 3). In late September, the patient underwent supraclavicular lymph node puncture aspiration, and cytological examination confirmed class IV suspected malignancy on cytology, but the cytological diagnosis of malignancy could not be concluded because of few viable cells. Concomitantly, the culture of Mycobacterium tuberculosis (M. tuberculosis) from the punctured lymph nodes became positive within 1 week of culture in the Mycobacterium growth indicator tube (MGIT), and the patient was diagnosed with lymph node tuberculosis. In the middle of October, anti-tuberculosis treatment was started with isoniazid, rifampicin, ethambutol, and pyrazinamide. Although experimental resistance to the drugs was not observed using the MGIT 960 SIRE kit (Nippon Becton Dickinson Company, Ltd.), the right supraclavicular fossa and mediastinal lymph nodes continued to increase in size. Moreover, the patient's pain increased, and airway compression was noted. Incision and drainage of the enlarged lymph nodes were scheduled, but in mid-December, the patient's dyspnea worsened, and she was transported to our hospital via ambulance for respiratory failure. Wheezing was observed, and blood examination showed elevated levels of SCC (5.4 ng/mL), CYFRA (10.19 ng/mL), and NSE (28.13 mg/dL). CT showed further enlargement of the right supraclavicular fossa lymph nodes and airway displacement (Fig. 4). Airway displacement by the tumor was considered to cause an aggravation of dyspnea. After admission, we performed a partial resection of the right supraclavicular lymph node, in which we initially conducted puncture aspiration to alleviate the airway displacement, as well as a tissue biopsy. No pus was observed, and the specimen was pathologically diagnosed as squamous cell carcinoma. Radiation therapy was initiated to relieve the symptoms, and tumor reduction was observed. Endoscopic examinations were performed in the otolaryngology and gastroenterology departments, but no primary lesions could be identified. A small nodule in the right lung was suspected to be the primary site. Chemotherapy with carboplatin and nab-paclitaxel was administered for stage IIIC squamous cell carcinoma of the lung. CT images acquired after radio- and chemotherapy showed resolution of the airway displacement due to the enlarged right supraclavicular lymph node (Fig. 4).

cervical lymph node, coexistence, computed tomography, ct, lung cancer, mycobacterium growth indicator tube, mgit, mycobacterium tuberculosis, m tuberculosis, squamous cell carcinoma, squamous cell carcinoma, scc, tuberculosis, fluorodeoxyglucose, fdg, lymph node, ln, positron emission tomography, pet

Image changes from hospitalization to post-treatment. CT images taken after radiotherapy and chemotherapy show a reduction in the enlarged right supraclavicular lymph nodes. This is well recognized by comparing the anterior and posterior diameters of the tumors. The tumor volume has decreased and the patient is in the supine position, which results in a lateral tumor pushing the orbit laterally, and a sheath-shaped airway is captured on CT. The nodule in the right lung field has not changed after treatment.

PMC9391599_01

Male

A 64-year-old patient, chronic smoker for 40 years, had a dry cough since 6 months along with mMRC stage 2 dyspnea which became complicated 1 month ago by the worsening of dyspnea resulting in mMRC stage 3, all evolving in a context of preservation of general condition. On clinical examination, his desaturation level was at 78% in ambient air with polypnea at 25 cycles per minute, cyanosis of the extremities and signs of respiratory struggle. The pleuropulmonary examination revealed crackles on the left. The chest X-ray showed bilateral alveolar opacities. At the biological level: hypereosinophilia was noted on several occasions (going up to 1170), a hemoglobin level at 15.9g/l, white blood cells at 13,700/mm3 and platelets at 320,000/mm3, a correct renal function, a negative covid 19 PCR test, a negative genexpert for tuberculosis in the sputum and a negative cytobacteriological examination of the sputum. The total IgE level was not done. Faced with hypereosinophilia, a stool parasitology was requested which returned negative. The thoracic CT scan (Fig. 1) showed diffuse foci of pulmonary parenchymal condensation, involving the various pulmonary lobes with areas of ground glass. A bronchial fibroscopy was performed showing a normal endoscopic appearance. Staged bronchial biopsies returned to normal, fibroaspiration in search of neoplastic cells was done but did not detect tumor cells and the patient did not tolerate BAL. A spirometry objectified a ventilatory disorder of restrictive pace with a forced vital capacity at 3.02l or 43% and an arterial blood gas: hypoxia at 40 mmHg. The diagnosis of the eosinophilic lung was retained on the radiological aspect and hypereosinophilia and the patient was put on a bolus of corticosteroids followed by an oral corticosteroid therapy at a dose of 1mg/kg/day. The initial evolution after 15 days was marked by an improvement in the patient's dyspnea with an increase in saturation to 83% in ambient air, a slight decrease in the eosiniphil level to 1000/mm3 and radiological stability. The patient was discharged on oral corticosteroid therapy and oxygen therapy 3l per minute. The follow-up at 2 months showed reaggravation of symptoms with stage 3 dyspnea, 78% desaturation on AA and the appearance of recurrent episodes of low abundance hemoptysis. Eosinophil count increased to 3630/mm3. A thoraco-abdomino-pelvic CT scan was redone showing the same radiological appearance with no lesions outside the lung. The diagnosis of eosinophilic lung was questioned, therefore a CT-guided biopsy was performed, and the result showed tumoral proliferation consisting of atypical cells cohesively colonizing the alveolar structures without signs of stromal invasion which is histological appearance of a non mucinous lepidic adenocarcinoma (Fig. 2). The case of our patient was presented in a multidisciplinary consultation meeting (RCP) and the diagnosis of invasive lepidic adenocarcinoma was retained because of the radiological presentation. It was decided to put the patient on chemotherapy and to search for the EGFR mutation. The patient received his first course of carboplatin - pemetrexed.

eosinophilic lung, hypereosinophilia, lepidic adenocarcinoma, lung cancer

PMC8728862_01

Female

A 5-year-old girl with accidental needle penetration into the right side of the chest while playing was referred to our medical center from a rural hospital. The interval between referral and arrival at our center was 12 hours. Upon arrival, the patient was transferred to the pediatric intensive care unit due to the possibility of cardiovascular events. She was asymptomatic at admission with a visible scar mark on the right side of the chest at the entrance site of the needle. She had normal vital signs and heart and lung sounds. The rest of her physical examination revealed nothing remarkable except for intermittent restlessness in the absence of associated dyspnea. Eleven hours after hospitalization, via chest radiography and transthoracic echocardiography (TTE), our pediatric cardiologist detected a hyper-refractile linear structure behind the sternum. The object was tangent to the RV wall and superior to the tricuspid valve. One end of the needle was tangent to the lateral wall of the RV, and the other end was embedded into the lung tissue and moving with each heartbeat (Figures 1 & 2). The patient's restlessness was aggravated with time. Two hours after TTE, a chest computed tomography (CT) scan showed the needle in the RV inside the pericardium. The difference in the location of the needle in the scan relative to that in echocardiography suggested the migration of the needle into the heart wall (Figure 3). The patient was treated with prophylaxis antibiotics for any infection possibilities. After consultation with a cardiac surgeon, she was sent to the operating room just 72 hours after needle penetration. A right thoracotomy revealed 0.5 cm of the needle, but the remainder of the needle (3 cm) was lodged in the RV. The surgeon grasped the needle with anatomical forceps and extracted it from the heart gently, without incising the muscle (Figure 4). Afterward, the laceration was repaired, and 100 mL of blood was evacuated from the pericardium cavity. The control TTE and chest X-ray showed no remaining pericardial effusion.

echocardiography, foreign-body migration, heart ventricles, needles

PMC9459224_01

Male

A 59-year-old man was admitted to our hospital for the treatment of centrally located squamous cell-lung carcinoma and pulmonary tuberculosis. The computed tomography (CT) scans showed that the malignant lesion, located between the left upper and lower lobes, had invaded the left pulmonary artery ( Figure 1 ). Pathological and etiological findings revealed a combined diagnosis of squamous cell-lung cancer (T3N0M0) and pulmonary tuberculosis. Anti-tuberculosis therapy, which including Isoniazid (300 mg per day), Rifampicin (450 mg per day), Ethambutol (750 mg per day), and Pyrazinamide (1250 mg per day), without any adverse events, was administered to cure the pulmonary tuberculosis. Neoadjuvant therapy, including sintilimab and conventional chemotherapy, was administered to achieve a complete response (CR) or partial response (PR). After three cycles of neoadjuvant therapy, the patient underwent video-assisted thoracoscopic surgery (VATS) left lower lobectomy, because the malignant lesion had shrunk and the left pulmonary artery had been isolated from the tumor. No cutaneous toxicity was observed during the first three cycles of neoadjuvant therapy. According to the post-operative pathologic results, the neoadjuvant therapy resulted in a PR. Therefore, the sintilimab and conventional therapy were continued as post-operative adjuvant therapy. Ten days after the post-operative adjuvant therapy, the patient suffered severe TEN, which rapidly progressed to cover >50% of the skin. TEN was associated with rashes of the trunk, pruritus, and a fever of >40 C. Massive maculopapular were observed in the chest and abdomen. Oral mucositis was also observed. The cutaneous lesions accounted for approximately 95% of the whole body surface ( Figure 2 ). No pulmonary, gastrointestinal, or cardiac AEs were presented in this patient. Physical examinations showed the positive Nikolsky sign. Laboratory results showed that the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), C-reactive protein was 3.48, 217.39 and 53.28, respectively. The white blood cell was lower than normal because of chemotherapy. Due to financial constraints, no further skin biopsies were taken for pathological analysis. Because of the shortage of pathologic results, a dermatologist diagnosed TEN due to the history of sintilimab use, epidermal necrolysis, positive Nikolsky sign, high NLR and PLR, and so on. Exfoliative dermatitis, which was similar to TEN was suspected, but the Nikolsky sign was negative. Intravenous methylprednisolone (40 mg per day) was administered to this patient immediately. Additionally, prednisone (60 mg per day) was prescribed for out-patient use. Supportive management included wound care, nutritional supplementation, and analgesic use. Furthermore, Levofloxacin (500 mg per day) was administered to treat infections resulting from damage to the skin barrier. Four weeks after discharge from the hospital, we observed gradual healing of the epidermis with slight scars. Anti-tuberculosis therapy was continued for 4 months after diagnosis of TEN without any adverse events. The timeline of the treatment of the patient was presented in Figure 3 .

immune-related adverse events (ir-aes), neoadjuvant therapy, non-small cell lung cancer, pulmonary tuberculosis, toxic epidermal necrolysis

PMC4147643_01

Male

A 44-year-old man was presented to emergency department after a motor vehicle accident. On physical examination local tenderness and swelling was present over both thighs and right knee. His vital signs were 90/60 mmHg blood pressure and 130/min pulse rate. The hemoglobin level was 10.2 g/dl initially. Bilateral intertrochanteric femur fractures (OTA classification - 31A.1.2) and bilateral femoral diaphyseal fractures (OTA classification - 32A.2) and nondisplaced right proximal tibial fracture (OTA classification - 41B.1) were determined in radiographs (Fig. 1). He was operated on the fifth day of admission after hemodynamic stabilization. Transtibial skeletal tractions were applied for both sides up to surgery. In a single session, locked intramedullary nails were used for the fixation of intertrochanteric and diaphyseal femoral fractures after closed reduction for both extremities. Open reduction and internal fixation with cannulated screws were performed for right proximal tibial fracture. Four units of packed red blood cells and two units of fresh frozen plasma were given to the patient totally. A rehabilitation program was started immediately after surgery. One week after surgery seropurulent discharge was observed from the incision of right tibia. Staphylococcus aureus was cultivated. Infection was treated with oral antibiotics. Patient was discharged 12 days after operation. Weightbearing was allowed 6 weeks after surgery for both sides. Dynamization of both nails were performed at 4th month due to delayed union. (Fig. 2) Complete union of fractures were showed with radiographs at 8th month follow up. Implants were removed three years later. Patient had mild pain, especially in his right hip, and limp at 12th year control. Degenerative changes were observed at right hip on radiographs. (Fig. 3) Although movements of right hip were restricted, he was able to do his daily activities with minimal limitation and without medication (Fig. 4).

bilateral, femoral diaphyseal fracture, intertrochanteric fracture

PMC7708870_01

Male

Our case was a 33 years old male, a resident of Kathmandu, who was admitted two and a half years ago with fever on and off for one month, productive cough and shortness of breath. He was of average weight, was non-vegetarian, with history of consumption of crabs and snails over the last three years. He was found to have pleural effusion on ultrasound. Laboratory reports at the time showed leukocytosis, 15,400/cu mm with normal differential counts and a raised ESR of 25 mm in 1 hour. CRP was positive. The peripheral blood smear did not show any abnormal cells and liver function test and renal function test were also normal. Sputum test was negative for acid fast bacilli (AFB) or parasitic structures. Pleural fluid was tapped under image guidance and sent for biochemical, microbiological and cytological evaluation. It showed raised protein (6.4g/dL) and Lactate dehydrogenase (LDH) (1243IU/L). No organisms were found. The cell count was low but consisted predominantly of lymphocytes. Based on these finding, even though no definite proof of tuberculosis was found, patient was started on antitubercular treatment. Initially the patient showed improvement. However, about one year later patient presented again to the hospital with cough, heaviness in chest and hemoptysis. HRCT chest showed a small irregular cavitary lesion measuring 18 x 14 x 15mm with small fluid level in the superior segment of lower lobe of left lung. The cavity was surrounded by ground glass density, multiple small nodules and linear streaks extending to the pleura in the medial aspect. No abnormal enhancement was seen on the contrast enhanced images (Fig. 1). Overall impression was of pulmonary TB. His laboratory tests showed a normal complete blood count but raised ESR, 49mm in 1 hr. His lipid profile was deranged but otherwise, renal and liver function tests were normal. Patient also underwent bronchoscopy which did not reveal any additional abnormality. Sputum, bronchial brushing and bronchoalveolar lavage were also examined, all of which were negative for any organisms and for malignant cells. This time sputum examination by geneXpert, i.e. (Polymerase chain react) was also done which also did not reveal any tubercle bacilli. Mantoux test was positive with an induration of 21mm. Patient was sent home with antibiotics and reassurance and kept on follow up. However, his symptoms got worse with increasing hemoptysis and fever and the patient was suspected to have aspergillosis in the cavitary lesion identified by HRCT and so he underwent a lobectomy. Gross examination of the lung showed a shiny pleura and spongy brown cut surface. A tiny cavitary lesion measuring 5 mm was identified. Representative sections were taken. Hematoxylin and eosin stained sections revealed a parasitic structure within the cavity with a thick cuticle and some serous glands within the body cavity. The cavity had denuded epithelium and was lined by palisading histiocytes. There was dense lymphohistocytic infiltration along with few eosinophils and many foreign body granulomas. Within these foreign body giant cells, multiple refractile oval to angulated ova were identified. These structures were positive on Periodic acid Schiff (PAS) stain (Fig. 2, Fig. 3). The surrounding lung parenchyma showed mild edema. With these findings a diagnosis of paragonimiasis was made. Species identification was not possible. Serological tests were not available for confirmation.

nepal, paragonimiasis, tuberculosis

CT Lung window showing a cavitating lesion, small nodules and linear streaks extending to the pleura.

PMC5292123_01

Female

A 27-year-old female with a history of cholecystectomy for symptomatic cholelithiasis three years prior to admission presented with epigastric pain radiating to the right upper quadrant and back. Initial laboratory tests on presentation were a total bilirubin (TBili) 5.5 mg/dL, alkaline phosphatase (ALP) 288 U/L, aspartate aminotransferase (AST) 316 U/L, and alanine aminotransferase (ALT) 394 U/L, and magnetic resonance cholangiopancreatography (MRCP) revealed a fluid collection in continuity with the cystic duct and a nine-millimeter stone at the confluence of the cystic and common hepatic duct, resulting in both biliary and cystic duct dilatation with adjacent inflammation (Figures 1 and 2). Using ERCP, the cystic duct was cannulated and a filling defect consistent with a nine-millimeter stone was confirmed, along with proximal cystic duct dilatation and extravasation of contrast suggestive of a contained bile leak (Figures 3 and 4). Following failed attempts at balloon-assisted stone extraction, cholangioscopy was performed. A single therapeutic endoscopist who has performed >30 interventions using the SpyGlass system was the primary operator and the case was performed under general anesthesia. A Pentax ED-3490TK therapeutic duodenoscope (Pentax Medical; Tokyo, Japan) was used to facilitate passage of the SpyGlass system. The 10 Fr SpyGlass cholangioscope measuring 250 cm in length was then used to directly visualize the stone in the cystic duct (Figure 5). The visualized stone was irrigated using saline prior to EHL, which was achieved using a Nortech Autolith system (Northgate Technologies Inc.; Elgin, IL) and a 1.9 Fr EHL probe. Power was set to 90 W with a rate of 3 pulsations/second, the latter of which was escalated as needed to achieve stone fragmentation. Subsequent balloon sweeps of the cystic duct successfully cleared stone fragments (Figure 6) and repeat MRCP (Figure 7) one year after hospital discharge revealed no evidence of fluid collection or stone in the cystic duct.

PMC6563654_01

Female

The female infant was born to healthy non-consanguineous parents (25-year-old father, and 22-year-old mother) after an uncomplicated first pregnancy and 40 weeks of gestation. A Cesarean section was performed due to a failed vaginal delivery, but the Apgar score until 15 min after birth and birth weight was normal (3,300 g). The patient was intubated after developing progressive tachypnea, moaning, and severe hypoglycemia (0.9 mmol/L). The patient developed hyperbilirubinemia that was unresponsive to phototherapy, but the parents took the baby home, for home care at the age of 9 days. At the age of 1.4 months, the patient was admitted to a provincial hospital for jaundice, vomiting, afebrile seizures, and pneumonia. The lowest blood glucose level during the hospital stay was 1.4 mmol/L. The serum cortisol levels were extremely low (13.8-29.3 nmol/L, normal range 138-690 nmol/L) while adrenocorticotropic hormone levels were slightly lower or normal (6.0-18.5 pg/ml, normal range 6.4-40 pg/ml). A cortisol deficiency was diagnosed, but parents refused hormone replacement therapy. The patient was discharged after the pneumonia was resolved and blood glucose levels were stabilized. At the age of 3.2 months, the patient was presented to our hospital for cholestasis without obvious symptoms of hypoglycemia, infection, alacrima, or achalasia. Repeated morning serum cortisol levels were extremely low (8.8-10.6 nmol/L, normal range 138-690 nmol/L), while ACTH was extremely elevated (1656.9-1911.8 pg/ml, normal range 6.4-40 pg/ml). Upon physical examination, significant jaundice, skin hyperpigmentation and slight hepatosplenomegaly (liver 2-2.5 cm below the right costal margin, and 2.5 cm below the xiphoid process; spleen 1.5-2.0 cm below the left costal margin) were observed. Slight dysmorphic features such as a transverse palmar crease in the right hand, a prominent forehead, hypertelorism (inner canthal distance greater than the palpebral fissure length) were noted. The palmar crease, and the changes in skin pigmentation are presented in Figure 1. Written informed consent was obtained from the parents for the publication of this case report and related images. Changes in body weight/length, complete blood count, procalcitonin, serum biochemistry, blood coagulation, and endocrine profiles throughout the disease course are provided in Table 1. Genetic screening for abnormalities related to congenital adrenal hyperplasia (list of 44 genes are provided in Table 3), and multiplex ligation-dependent probe amplification (MLPA) analysis of the CYP21A2 gene were performed by a commercial genetic testing company (Customized target capture sequencing, http://www.mygenostics.com/ServiceTechnology.aspx?nid=263&pid=268). The result showed compound heterozygous variants in the melanocortin 2 receptor (MC2R) gene, but the result of the CYP21A2 gene MLPA analysis was negative for hot-spot mutations and copy number variants (Supplementary Figure 1). We conducted protein modeling with SWISS-model (https://www.swissmodel.expasy.org) using the most similar structure (5jtb.1.A, Adenosine receptor A2a), and polar contacts of wild-type and mutated amino acid residues were compared with Pymol software (https://pymol.org/2/). The c.433C>T/p.R145C was reported in the dbSNP152 (http://www.ncbi.nlm.nih.gov/snp/rs139218324), and gnomAD (http://gnomad-old.broadinstitute.org/variant/18-13885085-G-A), but not in the 1000 Genome Database (http://www.1000genomes.org/) and Exome Variant Server (http://evs.gs.washington.edu/EVS/). The c.712C>T/p.H238Y variant was not reported in the dbSNP152, gnomAD, 1000 Genome Database, and Exome Variant Server. The c.433C>T/p.R145C variant of maternal origin caused the change of arginine (polar, basic) at the amino acid position of 145 to cysteine (non-polar, neutral). R145 is a relatively conserved amino acid residue, and five out of eight in-silico prediction tools (Table 2) predicted this variant as pathogenic. This is a known disease-causing variant (HGMD CM116421, rs139218324), and reported to be associated with FGD1 in an adopted Chinese girl. Protein modeling showed no effect of R145C residue change on polar contact with V149. The c.712C>T/p.H238Y variant of paternal origin caused the change of amino acid residue histidine (polar, basic) at the position of 238 to tyrosine (polar, neutral). H238 is a strictly conserved residue, and all eight in-silico prediction tools predicted this variant as pathogenic (Table 2). Protein modeling showed that the H238Y mutation changed polar contact of the amino acid residue in the position of 238 with adjacent residues, and polar contact with N261 in the transmembrane domain (TMD) 7 was lost. Confirmation with Sanger sequencing, conservation status of amino acid residue that have been affected, protein modeling results, and in-silico pathogenicity prediction results for both MC2R variants are provided in Figure 2 and Table 2. Extensive etiologic evaluations from birth until the last follow-up (4.9 months) are provided in Table 3. After ruling out other causes of hypoglycemia, cholestasis, and adrenal deficiency, a diagnosis of FGD1 was made. Oral hydrocortisone was started at a dose of 30 mg/m2 body surface area (divided into three doses) at the age of 3.4 months. Cholestasis was resolved at 4.9 months, skin hyperpigmentation was improved, and no further episodes of hypoglycemia occurred. Morning serum cortisol levels 1 h after hydrocortisone intake was normal, while ACTH levels returned to near normal levels. However, parents decided to stop the medication at the age of 7.4-months, and serum cortisol/ACTH levels returned to extreme levels at the age of 8.1-months (Table 1).

adrenocorticotropic hormone (acth), cholestasis, cortisol, familial glucocorticoid deficiency (fgd) type 1, hypoglycemia, linear overgrowth, melanocortin 2 receptor (mc2r), skin hyperpigmentation

PMC8600159_01

Female

An 88-year-old woman visited our emergency department due to hemoptysis. She had hypertension, diabetes mellitus, and dementia due to cerebral infarction. She also had interstitial pneumonia and had been followed up at our hospital but had voluntarily interrupted treatment. At the time of this admission, her vital signs were normal, and fine crackles were heard from bilateral lower lungs. White blood cells count was increased (19,140 /microL) and serum level of C-reactive protein was slightly increased (3.71 mg/dL). Her hemoglobin level was 8.0 g/dl, hematocrit was 23.1 %, Mean Corpuscular Volume was 80.5 fL, platelet count was 290,000 /microL. Antinuclear antibody, perinuclear-antineutrophil cytoplasmic antibody (ANCA) and C-ANCA were all negative. The result of Interferon-Gamma Release Assay was indeterminate. Chest radiography (Figure 1(Fig. 1)) showed bilateral reticular shadows but no finding of cavity lesions. Contrast-enhanced chest CT showed a honeycomb lung in the right lower lung field and infiltrative shadow and ground glass shadow in the left lower lung field (Figure 2A(Fig. 2)). A contrast-enhancing aneurysm was seen within the infiltrative shadow in the left lower lung, but no obvious cavitary lesion was seen (Figure 2B-D(Fig. 2)). We thought the patient's hemoptysis was caused by an aneurysm in the lower left lung field. We performed angiography (Figure 3(Fig. 3)) and successfully performed endovascular coil embolization of an aneurysm in the pulmonary artery. After these treatments, sputum screening tested positive for acid-fast bacillus. She was diagnosed with pulmonary TB based on the result of polymerase chain reaction positive for mycobacterium TB. She was treated with isoniazid (INH), rifampicin (RFP), and ethambutol (EB) without pyrazinamide (PZA) due to problems with liver function. No recurrence of hemoptysis was observed after successfully treating pulmonary TB.

hemoptysis, pulmonary aneurysm, pulmonary tuberculosis

Contrast-enhanced chest CT on admission revealed grand-grass shadow and findings of honeycomb lung in bilateral lower lungs, and infiltrating shadow in the lower left lung field (A).

PMC3108760_01

Female

An 18-year-old female presented with complaints of generalized edema of three months duration in January 2008. She also had loss of appetite, low grade fever, and right-sided upper abdominal pain for the same duration. She did not have any discoloration of urine, joint pain, skin rash, or hair loss. She had no history of allergies, tuberculosis, or hypertension. On admission to the hospital she had pallor and anasarca with ascites. She was afebrile with normal blood pressure. Her liver was enlarged and extended 4 cm below the costal margin in midcalvicular line. Liver was firm and tender. No other organomegaly was noted. Urine was positive for protein on dipstick and contained red cells, pus cells, and proteinaceous casts. She was excreting 3.2 g of urinary protein in 24 hours. Renal function was normal. Her hemoglobin was 9.8 g/dL with normochromic, normocytic picture with no evidence of hemolysis. Her complete blood count was normal and autoantibody screen (antinuclear and antineutrophil cytoplasmic) was negative. The complement levels C3 and C4 were normal. The liver function was normal except for that serum albumin level was significantly low with a value of 1.8 g/dL and total protein was 4.3 g/dL. The serum cholesterol level was elevated and was 465 mg/dL. Chest X-ray revealed a raised right hemidiaphragm. Renal ultrasound showed normal kidneys except for slightly increased echogenecity. Liver ultrasound showed fluid filled cavity of 9.3 x 8.1 cm with multiple cysts within it in the left lobe of liver. Ultrasound also revealed mild ascites. Serology for Echinococcus granulosus (IgG/IgM) was positive. Computed tomography (CT) scan of the abdomen showed an 11 x 10 x 6 cm cystic lesion with areas of rim calcification and few small cysts within it in the left lobe of liver which was extending into the lesser sac (Figure 1). Mild ascites were also noted. The above findings confirmed the diagnosis of hydatid disease of liver. The patient was subjected to renal biopsy as it was a nephrotic presentation. Renal biopsy revealed mesangial proliferation with acute on chronic tubulo-interstitial nephritis (Figures 2, 3). Electron microscopy was not done as there was no in-house facility. Treatment was started with diuretics, albumin infusion, and high protein diet. The patient was also initiated with albendazole 400 mg twice a day. After three weeks of preparation, hepatic cyst resection was done. The laparotomy was uneventful and histopathological evaluation of the resected specimen confirmed the diagnosis of hydatid cyst. Two weeks after surgery, the serum albumin had only marginal improvement to 2.2 g/dL and 24-hour urine protein excretion was 2.5 g. One month after surgery, the 24-hour urine protein excretion decreased to less than 1 g. Two months after surgery, the serum albumin level became 3.6 g/dL and 24-hour urine protein excretion became less than 300 mg. Follow-up urine examination and ultrasound was normal for one year after surgery, which confirmed good renal recovery and absence of residual hepatic Echinococcus disease. Albendazole was given for a total of twelve weeks. The patient was never treated with steroids or any other immunosuppressant.

echinococcosis, hydatid cyst, kidney, nephrotic syndrome, tubulointerstitial nephritis

PMC8053452_01

Male

A 38-year-old male patient presented to the outpatient department with a history of mid-back pain for 1 year and progressive weakness in both lower limbs for 3 months. The pain in the mid-back was insidious in onset, progressive in nature, dull-aching in character, initially aggravated by walking and movements of the trunk but had pain even at rest at the time of presentation. Back pain was also associated with a history of difficulty in walking and pain in both lower limbs for the past 3 months. The patient walked with help of walking aid. There was no history of trauma or constitutional symptoms such as fever, weight and loss or loss of appetite. He consulted elsewhere, where he was clinicoradiologically diagnosed with spinal tuberculosis and was started on the anti-tubercular therapy, but there was no relief in his symptoms even after 2 months of taking anti-tubercular therapy. The family and personal history were not significant. On examination, there was deep tenderness over the thoracolumbar junction. There was no local warmth/swelling over the back. The neurological examination suggested paraparesis [Table 1]. Thoracolumbar radiographs (AP/Lateral) and CT scan suggested huge lytic lesions with complete destruction of T12 and L1 vertebral body as well as pedicles and posterior elements and complete collapse of body of T12 with partial collapse of the body of L1 [Figure 1]. MRI suggested abnormal marrow signal intensity lesion involving vertebral body and posterior elements with pathological collapse of T12 with similar signal intensity changes in T11 and L1 bodies [Figure 1]. Prominent flow voids were seen in predominantly anterior but also posterior epidural space from T9-L2, likely to be prominent epidural blood vessels [Figure 1]. The primary differential diagnoses were spinal tuberculosis and neoplastic etiologies. After discussion with the patient and his family, the patient was advised surgical decompression. After informed consent, the patient was operated under general anesthesia wherein T9 to L3 stabilization with pedicle screw instrumentation and anterior decompression by pediculectomy of the left T12 and L1 by a posterior approach was performed. The surgeon encountered massive bleeding at the time of anterior decompression and was controlled by the use of local and systemic hemostatic agents. A vascular etiology of spinal compression was suspected and tissue from the destroyed vertebrae was sent for histopathological examination and culture-sensitivity tests. The histopathological examination suggested no evidence of malignant cells/granuloma. Culture sensitivity testing and TB-PCR were negative for infection. DSA was performed after 2 months of surgery through the right femoral artery which revealed EDAVFs fed by the vessels arising from T10-L2 vertebrae and transcatheter embolization of the predominant right T12 feeders was performed with 25% glue (2 ml) [Figure 2]. Angiographically, it was an extradural Type 1 single vessel dural fistula. However, the atypical nature of massive vertebral destruction precluded it from grouping into any single entity. DSA performed after the embolization revealed 30 % reduction of fistula fed by vessels from the right T12 pedicle [Figure 2]. At follow-up after 21 months of surgery, the patient is free from pain, walking independently with normal neurological examination findings [Figure 3].

av fistula, extradural arteriovenous fistula, paraparesis, rare, vertebral body

PMC7718636_01

Female

A 30-year-old female came to our practice complaining of primary infertility over the last 4 years. Her history indicated that in 2014, tuberculotic peritonitis had been diagnosed and treated laparoscopically, following which she received TB chemotherapy for 6 months. In 2016, the right Fallopian tube was laparoscopically resected and a pathology examination confirmed the tuberculotic nature of the lesions. Afterward, TB chemotherapy was reinstated for another year. Wishing to become pregnant, she requested IVF. Before carrying out the procedure, both a tuberculin skin test (TST) and chest computed tomography (CT) were carried out. The TST showed a water bubble after 72 h, and the CT scan showed streaking on the medial segment of the middle lobe of the right lung and a protuberance under an enlarged lymph node. In view of her having twice received anti-TB treatment, it was decided not to repeat that treatment; ovarian stimulation was initiated following administration of a short-acting depot gonadotropin-releasing hormone analogue for pituitary suppression. Because of the husband's asthenospermia, the intracytoplasmic sperm injection technique was used. On the third day after fertilization, two grade II embryos were transferred, and three others were frozen. Eleven days after the embryo transfer, the patient complained of diarrhea. At that time, her serum hormone levels were as follows: beta-human chorionic gonadotropin (beta-HCG), 49.5 mlU/mL; oestradiol (E 2) 80.8 pg/mL; and progesterone (P) 12.8 ng/mL The symptoms improved following intravenous fluids and antibiotics. On day 14 after the transfer, the patient presented with intermittent fever, from 37.8 to 38.5 C, and a cough; she again received symptomatic treatment. On day 18 the patient's body temperature rose once more to 38.9 C. At this point serum, blood levels were beta-HCG 371.6 mIU/mL, E 2 235.2, and P 14.2 pg/mL A routine blood test showed the following: white blood cells (WBC) 20.34 x 106/mL; neutrophil ratio 83.7%; hemoglobin 103 g/L; and erythrocyte sedimentation rate 110 mm/h. Transvaginal sonography (TVS) revealed no clear echo indicating the presence of the pregnant sac in the uterine cavity or the annex area. After a review of the patient's history, a TB recurrence was suspected and confirmed by the Gansu Province TB specialized hospital. The patient received a four-drug chemotherapy, but still had a low fever. On day 28, a new TVS showed that there was no pregnancy sac in the uterine cavity, but a cyst image about 11 x 10 mm appeared at the level of the cervix; no definite embryo image or heartbeats could be detected. Also, a low-density mass measuring 79 x 70 mm became visible on the right ovary. At this point a diagnosis of cervical pregnancy was suspected, combined with a right ovarian tuberculotic cyst. A decision was then made to terminate the pregnancy, and the gestational sac was injected with 50 mg of methotrexate through the cervical canal; in addition, 50 mg of mifepristone tablets were administered three times daily. 4 days later, the gestational sac was expelled. A pathological examination confirmed that it was indeed a cervical pregnancy. 1 week later, she underwent laparoscopy for the right salpingectomy and oophorectomy. The specimen contained about 150 mL of purulent discharge, which was sent for culture; the cystic wall was sent for histologic examination. Pathology demonstrated chronic nonspecific inflammation in the oviduct and ovarian suppurative inflammation. Cultures for acid-fast bacilli were negative.

ivf, infertility, pregnant, treatment, tuberculosis

PMC3508748_01

Female

A 78-year-old female presented with a 5-day history of blurred vision in the right eye, periocular pain, swelling, and photophobia. Past medical history was unremarkable except for recent bronchoscopy and transbronchial biopsy for a suspicious pulmonary nodule. The histopathology and immunohistochemistry confirmed the diagnosis of malignant melanoma. On ophthalmological examination, visual acuity in her right eye was reduced to hand movements only and in her left eye it was 6/6. Slit lamp examination of her right eye showed intense inflammatory activity in the anterior chamber with a hazy view of the fundus. The pupil was poorly dilated due to almost 360 of posterior synechiae. B-scan of the posterior segment revealed vitreous opacities and dense condensations on the posterior vitreous face. Clinical diagnosis of possible endophthalmitis or pseudo tumor was made. As pulmonary nodule biopsy performed a week earlier showed malignant melanoma, choroidal melanoma was included in the differential diagnosis. Urgent computerized tomography (CT) and magnetic resonance imaging (MRI) examinations were organized. Contrast-enhanced CT showed marked enhancement of the uveal tract on the right with preseptal edema and lateral thickening of the orbital septum (Figure 1), however, there was no retrobulbar fat stranding or posterior chamber abscess detected. Fluid attenuation inversion recovery (FLAIR) axial images demonstrated a definite signal change in the right vitreous chamber and a high signal subchoroidal effusion was seen (Figure 2A). Diffusion-weighted imaging (DWI) and apparent diffusion coefficients (ADC) were the key sequences showing restricted diffusion within the posterior chamber suggestive of subchoroidal abscess or effusion. Effusion was seen as a linear high signal within the right globe laterally extending up to the level of the optic nerve head (Figures 2B and C). The ADC value from the abscess measured 602 x 10-6 mm2/s in comparison to the central portion of 2650 x 10-6 mm2/s, implying true restriction. On postcontrast T1 fat saturated images, diffuse enhancement of the thickened sclera and the entire uveal was identified (Figure 3). Also seen was extension of this inflammatory process into the orbital septum as well as the extra-ocular muscles with marked thickening of the right lateral rectus muscle which also enhanced with contrast. The extraconal inflammatory change was localized more in the superolateral part of the right orbit. Recent diagnosis of melanoma from a pulmonary nodule caused a diagnostic dilemma and ocular melanoma or melanoma metastases were included in the initial differential diagnoses. MRI immensely helped in narrowing the differential diagnosis as there was no T1 bright lesion seen in the choroid to suggest melanoma. Cytology from the initial vitreous aspirate did not yield malignant cells and subsequent cultures were negative. Blood tests showed moderate neutrophilia of 8.2 x 109/L, ESR of 20 mm/hour, and a normal serum ACE level of 35 U/L. Quantiferon TB Gold, VDRL, and blood cultures were also negative. Toxoplasmosis testing showed IgG reactivity with IgM nonreactivity. Culture from a repeated vitreous aspirate sample grew S. apiospermum. Antifungal susceptibility testing showed sensitivity to itraconazole and voriconazole with a minimum inhibitory concentration (MIC) of 0.5 mug/mL and 0.25 mug/mL, respectively. The patient was then started on a 6-month regimen of oral voriconazole. Despite therapy, patient's vision showed no improvement and vision remained restricted to hand movements only at the 12-month follow-up.

secosporidium apiospermum, contrast-enhanced magnetic resonance imaging, diffusion-weighted imaging, endophthalmitis, magnetic resonance imaging, subchoroidal abscess

PMC4617008_01

Male

A 32-year-old male patient came for the management of diabetes mellitus to the Diabetes Centre KLES Dr. Prabhakar Kore Hospital and Medical Research Centre, Belgaum, Karnataka, South India. He was diagnosed to have diabetes mellitus since 2 years. He had a history of missing insulin doses frequently for extended periods and was never hospitalized after the initial diagnosis. There was no documented episode of diabetic ketoacidosis. He presented with complaints of frequent hypoglycemia, tiredness, loss of bodyweight and appetite and neuropathic symptoms. There was no history hypertension, dyslipidemia, tuberculosis and any other medical illnesses such as alcoholic pancreatitis and hyperparathyroidism. His diet was irregular and erratic. He was nonsmoker and nonalcoholic. General physical examination showed body mass index (BMI) - 14.72, pulse rate (PR) - 80b/min, blood pressure (BP) - 140/100 mmHg, relative risk - 20 cyc/min. No pallor, icterus, clubbing, lymphadenopathy, edema, and thyromegaly. Systemic examination (respiratory, cardiovascular, and central nervous system) was within normal limits. Per abdomen, examination showed hepatomegaly. The patient was hospitalized for further investigations and was started with premix insulin oral hypoglycemic agents (OHA) and pancreatic enzyme supplements. Patient tolerated the combination well. On the day admission fasting plasma glucose was 159 mg/dl and 2 h postprandial plasma glucose was 200 mg/dl and HbA1c - 6.7%. During hospitalization his blood sugars were monitored 5 times in a day (fasting blood sugar [FBS], postprandial blood sugar [PPBS], prelunch, predinner, and bedtime random blood sugar [RBS]) and there were no episodes of hypoglycemia. Laboratory investigations revealed that hemogram, liver function tests (LFT), kidney function tests, thyroid and lipid profile were within normal limits. Chest X-ray and electrocardiogram (ECG) findings were normal. Serum amylase (69 U/L) and serum lipase (142 U/L) were within normal limits. Fundus examination showed normal study. By ultrasonography of the abdomen [Figure 1] it was possible to evaluate the size of the pancreas and also confirm the intraductal location of calculi and the degree of fibrous. Further, the patient was evaluated with computed tomography (CT) scan of abdomen [Figure 2] it showed chronic calcific pancreatitis with dilated pancreatic duct with intramural calculi with hepatomegaly. During hospital stay the patient improved clinically and glycemically. On discharge patient was advised to take (i) Two doses of premix insulin, (ii) OHA once a daily and (iii) pancreatic enzyme supplements twice daily. Nutrition counseling and diabetes education (insulin injection technique and self-monitoring of blood glucose) was given to the patient. Later, the patient was followed up at 1st month, 3rd month, and 6th month. He was regular in taking treatment and follow diet and exercise.

fibrocalculous pancreatic diabetes, insulin, pancreatic diabetes

PMC4617008_02

Male

A 43-year-old male patient came for the management of diabetes mellitus to the Diabetes Centre KLES Dr. Prabhakar Kore Hospital and Medical Research Centre, Belgaum, Karnataka, South India. He was diagnosed to have diabetes mellitus since 2 years. He presented with body pain, tiredness, and loss of bodyweight. There was no history hypertension, dyslipidemia, asthma, tuberculosis and any other medical illnesses such as alcoholic pancreatitis and hyperparathyroidism. His diet was irregular and erratic. He is a smoker and smokes 2-3 cigarettes a day. He has a history of having alcoholic drinks and beverages regularly, since 8 months he has stopped drinking. General physical examination showed BMI - 20.56, PR - 80b/min, BP - 110/70 mmHg HbA1c - 15.4. Per abdomen, examination showed hepatomegaly. Patient on further investigations and was started with premix insulin OHA and pancreatic enzyme supplements. The patient tolerated the combination well. On the day admission fasting plasma glucose was 339 mg/dl and 2 h postprandial plasma glucose was 503 mg/dl and HbA1c - 15.4%. After the following above administrations, his blood sugars were monitored 5 times in a day (FBS, PPBS, prelunch, predinner, and bedtime RBS) and there were no episodes of hypoglycemia. Laboratory investigations revealed that hemogram, LFT, kidney function tests, thyroid and lipid profile were within normal limits. Chest X-ray and ECG findings were normal. Further, the patient was evaluated with CT scan of abdomen [Figures 3 and 4] it showed chronic calcific pancreatitis with dilated pancreatic duct with intramural calculi with hepatomegaly. He is practicing storage of grains in the house with the enclosure of cow dung.

fibrocalculous pancreatic diabetes, insulin, pancreatic diabetes

PMC10032218_01

Female

A 17-year-old female with the second relapse of B-ALL received chimeric antigen T-cell (CART) salvage therapy, followed by co-transplantation of haploidentical stem cells and unrelated cord blood in September 2021. The patient had a previous disseminated pulmonary tuberculosis infection during the first relapse in July 2020. However, she recovered well after treatment with anti-tuberculosis drugs, including isoniazid (10 mg/kg/day), rifampicin (10 mg/kg/day), and levofloxacin (10 mg/kg/day) from July 2020 to April 2021, and continued to receive oral isoniazid prophylaxis until 3 days prior to HSCT. Chest computed tomography (CT) revealed no residual tuberculosis lesions and interferon-gamma (IFN-gamma) release assays was negative prior to transplantation. Furthermore, there was no evidence of fungal infection during chemotherapy or prior to HSCT. The patient received a myeloablative conditioning regimen consisting of cyclophosphamide, busulfan, fludarabine, and thiotepa without total body irradiation. The post-transplant immunosuppressants included of post-transplant cyclophosphamide, cyclosporine, and mycophenolate mofetil. In addition, oral posaconazole (200 mg every 8h) was commenced 3 days after HSCT as an antifungal prophylaxis. Additionally, neutrophils and platelets were engrafted on 15 and 24 days after transplantation, respectively. Engraftment syndrome with fever, skin rashes, and elevated bilirubin levels was observed during cell engraftment from day 14 after transplantation. However, these symptoms resolved after intravenous administration of methylprednisolone (1 mg/kg/day for 4 days from day 15 to day 18, after which the dose was tapered and discontinued on 27 days after HSCT). No other severe complications were noted. The patient began to cough slightly from 23 days after HSCT. Since this patient had a history of tuberculosis infection, rifapentine (600 mg per week) was administered in combination with isoniazid (10 mg/kg/day) for tuberculosis prophylaxis. However, the patient showed no signs of respiratory distress, including dyspnea, tachypnea, and hypoxemia. The cough lasted five days, and the patient developed a throbbing, dull pain in the back. A chest CT was performed, and a large nodular lesion (32.02 mm x 24.77 mm x 42.73 mm) with a faint surrounding vitreous subpleural of the right upper lobe was observed (Figure 1A and B). Therefore the patient was suspected of having tuberculosis or an IFI, and a bronchoscopy was performed. Caspofungin (loading dose at 70 mg/m2 for 1 day and then 50 mg/m2/day) was commenced on day 27 after HSCT, and posaconazole was switched to intravenous voriconazole (loading dose at 9mg/kg, every 12h, for 1 day and then 8mg/kg, every 12h) because the patient developed a fever 4 days later. The bronchoalveolar (BAL) fluid was positive for cytomegalovirus (CMV), human herpes virus 6 (HHV-6), and Actinomyces odontolyticus using next-generation sequencing. However, in contrast, using the PCR-based analysis, the BAL fluid was negative for fungi and tuberculosis. In addition, bacterial and fungal cultures of the BAL fluid were negative. The antibiotics, imipenem (15mg/kg, every 6h) and high-dose penicillin (100,000 U/kg, every 6 h) were administered to treat Actinomyces infections for 2 months. Ganciclovir (5 mg/kg, every 12h) was also commenced for antiviral treatment. Despite the above treatment, the patient began to have hemoptysis, and a reassessment of the chest CT showed that the lung lesion was unresolved. Therefore, a wedge resection of the lung lesion was performed because the lesion was still localized. The next-generation sequencing analysis of the lung tissue revealed C. cinerea infection (NCBI accession PRJNA938261). This was later confirmed when septate hyphae were observed by both Wright-Giemsa and hexamine-silver staining of lung sections, indicative of C. cinerea infection (Figure 2). Therefore, antifungal treatment was switched to amphotericin B (starting from 0.1 mg/kg/day then gradually increased to 0.7 mg/kg/day) for 2 weeks, followed by oral voriconazole as follow-up therapy. Chest CT scans showed no new lung lesions 5 months after the wedge resection surgery (Figure 1C).

coprinopsis cinerea, hormographiella aspergillata, case report, hematopoietic stem cell transplantation, invasive fungal infection, leukemia

Chest computed tomography images of the patient before and after wedge resection of the lung lesions. Representative axial.

PMC10032218_01

Female

A 17-year-old female with the second relapse of B-ALL received chimeric antigen T-cell (CART) salvage therapy, followed by co-transplantation of haploidentical stem cells and unrelated cord blood in September 2021. The patient had a previous disseminated pulmonary tuberculosis infection during the first relapse in July 2020. However, she recovered well after treatment with anti-tuberculosis drugs, including isoniazid (10 mg/kg/day), rifampicin (10 mg/kg/day), and levofloxacin (10 mg/kg/day) from July 2020 to April 2021, and continued to receive oral isoniazid prophylaxis until 3 days prior to HSCT. Chest computed tomography (CT) revealed no residual tuberculosis lesions and interferon-gamma (IFN-gamma) release assays was negative prior to transplantation. Furthermore, there was no evidence of fungal infection during chemotherapy or prior to HSCT. The patient received a myeloablative conditioning regimen consisting of cyclophosphamide, busulfan, fludarabine, and thiotepa without total body irradiation. The post-transplant immunosuppressants included of post-transplant cyclophosphamide, cyclosporine, and mycophenolate mofetil. In addition, oral posaconazole (200 mg every 8h) was commenced 3 days after HSCT as an antifungal prophylaxis. Additionally, neutrophils and platelets were engrafted on 15 and 24 days after transplantation, respectively. Engraftment syndrome with fever, skin rashes, and elevated bilirubin levels was observed during cell engraftment from day 14 after transplantation. However, these symptoms resolved after intravenous administration of methylprednisolone (1 mg/kg/day for 4 days from day 15 to day 18, after which the dose was tapered and discontinued on 27 days after HSCT). No other severe complications were noted. The patient began to cough slightly from 23 days after HSCT. Since this patient had a history of tuberculosis infection, rifapentine (600 mg per week) was administered in combination with isoniazid (10 mg/kg/day) for tuberculosis prophylaxis. However, the patient showed no signs of respiratory distress, including dyspnea, tachypnea, and hypoxemia. The cough lasted five days, and the patient developed a throbbing, dull pain in the back. A chest CT was performed, and a large nodular lesion (32.02 mm x 24.77 mm x 42.73 mm) with a faint surrounding vitreous subpleural of the right upper lobe was observed (Figure 1A and B). Therefore the patient was suspected of having tuberculosis or an IFI, and a bronchoscopy was performed. Caspofungin (loading dose at 70 mg/m2 for 1 day and then 50 mg/m2/day) was commenced on day 27 after HSCT, and posaconazole was switched to intravenous voriconazole (loading dose at 9mg/kg, every 12h, for 1 day and then 8mg/kg, every 12h) because the patient developed a fever 4 days later. The bronchoalveolar (BAL) fluid was positive for cytomegalovirus (CMV), human herpes virus 6 (HHV-6), and Actinomyces odontolyticus using next-generation sequencing. However, in contrast, using the PCR-based analysis, the BAL fluid was negative for fungi and tuberculosis. In addition, bacterial and fungal cultures of the BAL fluid were negative. The antibiotics, imipenem (15mg/kg, every 6h) and high-dose penicillin (100,000 U/kg, every 6 h) were administered to treat Actinomyces infections for 2 months. Ganciclovir (5 mg/kg, every 12h) was also commenced for antiviral treatment. Despite the above treatment, the patient began to have hemoptysis, and a reassessment of the chest CT showed that the lung lesion was unresolved. Therefore, a wedge resection of the lung lesion was performed because the lesion was still localized. The next-generation sequencing analysis of the lung tissue revealed C. cinerea infection (NCBI accession PRJNA938261). This was later confirmed when septate hyphae were observed by both Wright-Giemsa and hexamine-silver staining of lung sections, indicative of C. cinerea infection (Figure 2). Therefore, antifungal treatment was switched to amphotericin B (starting from 0.1 mg/kg/day then gradually increased to 0.7 mg/kg/day) for 2 weeks, followed by oral voriconazole as follow-up therapy. Chest CT scans showed no new lung lesions 5 months after the wedge resection surgery (Figure 1C).

coprinopsis cinerea, hormographiella aspergillata, case report, hematopoietic stem cell transplantation, invasive fungal infection, leukemia

Chest computed tomography images of the patient before and after wedge resection of the lung lesions. coronal. CT scan images revealed a large nodular lesion (32.02 mm x 24.77 mm x 42.73 mm) with a faint surrounding vitreous subpleural located in the right upper lobe.

PMC10032218_01

Female

A 17-year-old female with the second relapse of B-ALL received chimeric antigen T-cell (CART) salvage therapy, followed by co-transplantation of haploidentical stem cells and unrelated cord blood in September 2021. The patient had a previous disseminated pulmonary tuberculosis infection during the first relapse in July 2020. However, she recovered well after treatment with anti-tuberculosis drugs, including isoniazid (10 mg/kg/day), rifampicin (10 mg/kg/day), and levofloxacin (10 mg/kg/day) from July 2020 to April 2021, and continued to receive oral isoniazid prophylaxis until 3 days prior to HSCT. Chest computed tomography (CT) revealed no residual tuberculosis lesions and interferon-gamma (IFN-gamma) release assays was negative prior to transplantation. Furthermore, there was no evidence of fungal infection during chemotherapy or prior to HSCT. The patient received a myeloablative conditioning regimen consisting of cyclophosphamide, busulfan, fludarabine, and thiotepa without total body irradiation. The post-transplant immunosuppressants included of post-transplant cyclophosphamide, cyclosporine, and mycophenolate mofetil. In addition, oral posaconazole (200 mg every 8h) was commenced 3 days after HSCT as an antifungal prophylaxis. Additionally, neutrophils and platelets were engrafted on 15 and 24 days after transplantation, respectively. Engraftment syndrome with fever, skin rashes, and elevated bilirubin levels was observed during cell engraftment from day 14 after transplantation. However, these symptoms resolved after intravenous administration of methylprednisolone (1 mg/kg/day for 4 days from day 15 to day 18, after which the dose was tapered and discontinued on 27 days after HSCT). No other severe complications were noted. The patient began to cough slightly from 23 days after HSCT. Since this patient had a history of tuberculosis infection, rifapentine (600 mg per week) was administered in combination with isoniazid (10 mg/kg/day) for tuberculosis prophylaxis. However, the patient showed no signs of respiratory distress, including dyspnea, tachypnea, and hypoxemia. The cough lasted five days, and the patient developed a throbbing, dull pain in the back. A chest CT was performed, and a large nodular lesion (32.02 mm x 24.77 mm x 42.73 mm) with a faint surrounding vitreous subpleural of the right upper lobe was observed (Figure 1A and B). Therefore the patient was suspected of having tuberculosis or an IFI, and a bronchoscopy was performed. Caspofungin (loading dose at 70 mg/m2 for 1 day and then 50 mg/m2/day) was commenced on day 27 after HSCT, and posaconazole was switched to intravenous voriconazole (loading dose at 9mg/kg, every 12h, for 1 day and then 8mg/kg, every 12h) because the patient developed a fever 4 days later. The bronchoalveolar (BAL) fluid was positive for cytomegalovirus (CMV), human herpes virus 6 (HHV-6), and Actinomyces odontolyticus using next-generation sequencing. However, in contrast, using the PCR-based analysis, the BAL fluid was negative for fungi and tuberculosis. In addition, bacterial and fungal cultures of the BAL fluid were negative. The antibiotics, imipenem (15mg/kg, every 6h) and high-dose penicillin (100,000 U/kg, every 6 h) were administered to treat Actinomyces infections for 2 months. Ganciclovir (5 mg/kg, every 12h) was also commenced for antiviral treatment. Despite the above treatment, the patient began to have hemoptysis, and a reassessment of the chest CT showed that the lung lesion was unresolved. Therefore, a wedge resection of the lung lesion was performed because the lesion was still localized. The next-generation sequencing analysis of the lung tissue revealed C. cinerea infection (NCBI accession PRJNA938261). This was later confirmed when septate hyphae were observed by both Wright-Giemsa and hexamine-silver staining of lung sections, indicative of C. cinerea infection (Figure 2). Therefore, antifungal treatment was switched to amphotericin B (starting from 0.1 mg/kg/day then gradually increased to 0.7 mg/kg/day) for 2 weeks, followed by oral voriconazole as follow-up therapy. Chest CT scans showed no new lung lesions 5 months after the wedge resection surgery (Figure 1C).

coprinopsis cinerea, hormographiella aspergillata, case report, hematopoietic stem cell transplantation, invasive fungal infection, leukemia

Chest computed tomography images of the patient before and after wedge resection of the lung lesions. The chest CT scans show no new lung lesions 5 months after the wedge resection (C).

PMC6038330_01

Female

A 67-year-old woman with fever and cough was referred to a general hospital. A chest computed tomography (CT) scan revealed mediastinal lymphadenopathy and ground glass opacities in both lung fields. Initial blood examinations revealed a white blood cell (WBC) count of 11700/muL and an eosinophil count of 2925/muL. Cellular analysis of the bronchoalveolar lavage fluid (BALF) revealed 12.5% eosinophils. Histological findings from transbronchial lung biopsy (TBLB) specimens showed eosinophilic infiltration (5 cells/high-powered field [HPF]) (Fig. 1a). The patient was initially diagnosed with eosinophilic pneumonia, and oral prednisolone (PSL) was started at 30 mg/day. Thereafter, the ground glass opacities partially disappeared, and PSL was reduced to 10 mg/day. However, infiltrative opacities started appearing in the right middle lobe and the left lingula segment in chest CT. The patient was referred to our department for further examination. Her medical history included steroid diabetes mellitus, surgery for extra-uterine pregnancy at the age of 30 years, and retinal detachment surgery at the age of 53. She had smoked four cigarettes a day for 20 years. She was receiving PSL 10 mg/day (prescribed for EP by the previous doctor), famotidine 20 mg/day, carbocysteine 1500 mg/day, and insulin lispro (8 U/day) for steroid diabetes mellitus. Her body temperature was 35.9 C and her oxygen saturation was 98% on room air. Fine crackles were heard in the bilateral lower lungs, without wheezing. Superficial lymph nodes and submandibular glands were not palpable. She had no obvious symptoms of dry eyes, dry mouth, eruption, or numbness in the extremities. Laboratory data on admission were as follows: C-reactive protein (CRP), 17.8 mg/dL (normal range, < 0.30 mg/dL); WBC count of 10100/muL (eosinophil count of 0/muL); IL-6, 35.9 pg/mL (normal range, < 4.0); IgE, 237 IU/mL (normal range, < 170); IgG, 3916 mg/dL (normal range, 870-1700); IgG4, 435 mg/dL (normal range, 4.5-117); KL-6, 573 U/mL (normal range, < 500); RF, 110 IU/mL (normal range, < 15); ANA, titer 1/80; MPO-ANCA < 1.0 IU/mL; ACE 7.1 IU/L (normal range, 8.3-21.4). She had negative findings for human immunodeficiency virus antibodies and human herpesvirus 8 on polymerase chain reaction tests. Arterial blood gas analysis on room air yielded the following findings: partial pressure of oxygen, 79 mmHg; partial pressure of carbon dioxide, 36 mmHg; pH 7.47. A chest CT scan showed swelling of the mediastinal lymph nodes, centrilobular granular nodules, ground glass opacity, thickening of the interlobular septa predominantly in the lower lung, and invasive opacity in the right middle lobe and the left lingula segment (Fig. 2). Gallium scintigraphy showed accumulation in the lower lungs, but not in the submandibular or lacrimal glands (Fig. 3). An abdominal CT scan did not show any abnormal findings in the structure of the pancreas or other abdominal organs. MCD was suspected on the basis of clinical features such as the steroid-refractory nature of the condition, chest CT findings, polyclonal hypergammaglobulinemia, thrombocytosis (platelet count of 61.9 x 104/muL), anemia (hemoglobin, 9.1 g/dL), high IL-6 and CRP levels, and normal ANA, ACE, and MPO-ANCA levels. Bronchoscopy was therefore performed again and cellular analysis of BALF from the right B3 yielded the following findings: neutrophils, 2.0%; lymphocytes, 7.1%; eosinophils, 0.4%; macrophages, 90.6%; and CD4+/CD8+ ratio, 0.51. No pathogen was cultured and TBLB specimens showed mild alveolitis with fibrosis, and alveolar macrophage proliferation. A lower paratracheal right lymph node (#4R LN) specimen obtained by endobronchial ultrasound-guided transbronchial needle aspirate showed IgG4-positive plasma cell infiltration, with an IgG4+ to IgG+ plasma cell ratio of 12.9% (17/132 cells). Since histological diagnosis could not be confirmed by lung and lymph node specimens, thoracoscopic surgical biopsy samples were obtained from the right S10 lung and #4R LN. In the right S10 specimen, patchy plasma cell-dominant inflammatory cell infiltration was apparent, but interstitial fibrosis or eosinophilic infiltration was not observed (Fig. 1d). In the #4R LN specimen, an atrophic germinal center and plasma cell proliferation in the follicle center were observed, but obliterative phlebitis, dense fibrosis, or eosinophilic infiltration were not apparent. IgG4+ plasma cells were observed in both the #4R LN and right S10 specimens (Fig. 1b and c), and the IgG4+/IgG+ plasma cell ratio was 36.4% (242/665 cells) in the #4R LN and 24.1% (123/510 cells) in the right S10, neither of which met the Comprehensive Diagnostic Criteria for IgG4-RD (IgG4+/IgG+ plasma cell ratio > 40%). Taken together, we concluded that the clinical and histological findings of the patient were consistent with those of MCD. Since PSL monotherapy (at 10 mg/day) was not effective, we implemented administration of tocilizumab (8 mg/kg q2w) in addition to PSL, and the fever and cough disappeared. In the chest CT scan, the ground glass opacities in the left lower lobe and the consolidation in the left lingula segment and the right middle lobe improved partially (Fig. 4). Thereafter, tocilizumab administration was continued and the dose of PSL was successfully reduced until no further administration was required.

balf, bronchoalveolar lavage fluid, crp, c-reactive protein, ct, computed tomography, egpa, eosinophilic granulomatosis with polyangiitis, ep, eosinophilic pneumonia, hpf, high-powered field, igg4-rd, igg4-related disease, mcd, multicentric castleman's disease, psl, prednisolone, tblb, transbronchial lung biopsy, ucd, unicentric castleman's disease, wbc, white blood cell

Chest computed tomography scan obtained at the first admission showed centrilobular granular nodules, ground glass opacity, thickening of the interlobular septa predominantly in the lower lung, consolidation in the right middle lobe and left lingula segment and swelling of the #4R lymph node.

PMC6038330_01

Female

A 67-year-old woman with fever and cough was referred to a general hospital. A chest computed tomography (CT) scan revealed mediastinal lymphadenopathy and ground glass opacities in both lung fields. Initial blood examinations revealed a white blood cell (WBC) count of 11700/muL and an eosinophil count of 2925/muL. Cellular analysis of the bronchoalveolar lavage fluid (BALF) revealed 12.5% eosinophils. Histological findings from transbronchial lung biopsy (TBLB) specimens showed eosinophilic infiltration (5 cells/high-powered field [HPF]) (Fig. 1a). The patient was initially diagnosed with eosinophilic pneumonia, and oral prednisolone (PSL) was started at 30 mg/day. Thereafter, the ground glass opacities partially disappeared, and PSL was reduced to 10 mg/day. However, infiltrative opacities started appearing in the right middle lobe and the left lingula segment in chest CT. The patient was referred to our department for further examination. Her medical history included steroid diabetes mellitus, surgery for extra-uterine pregnancy at the age of 30 years, and retinal detachment surgery at the age of 53. She had smoked four cigarettes a day for 20 years. She was receiving PSL 10 mg/day (prescribed for EP by the previous doctor), famotidine 20 mg/day, carbocysteine 1500 mg/day, and insulin lispro (8 U/day) for steroid diabetes mellitus. Her body temperature was 35.9 C and her oxygen saturation was 98% on room air. Fine crackles were heard in the bilateral lower lungs, without wheezing. Superficial lymph nodes and submandibular glands were not palpable. She had no obvious symptoms of dry eyes, dry mouth, eruption, or numbness in the extremities. Laboratory data on admission were as follows: C-reactive protein (CRP), 17.8 mg/dL (normal range, < 0.30 mg/dL); WBC count of 10100/muL (eosinophil count of 0/muL); IL-6, 35.9 pg/mL (normal range, < 4.0); IgE, 237 IU/mL (normal range, < 170); IgG, 3916 mg/dL (normal range, 870-1700); IgG4, 435 mg/dL (normal range, 4.5-117); KL-6, 573 U/mL (normal range, < 500); RF, 110 IU/mL (normal range, < 15); ANA, titer 1/80; MPO-ANCA < 1.0 IU/mL; ACE 7.1 IU/L (normal range, 8.3-21.4). She had negative findings for human immunodeficiency virus antibodies and human herpesvirus 8 on polymerase chain reaction tests. Arterial blood gas analysis on room air yielded the following findings: partial pressure of oxygen, 79 mmHg; partial pressure of carbon dioxide, 36 mmHg; pH 7.47. A chest CT scan showed swelling of the mediastinal lymph nodes, centrilobular granular nodules, ground glass opacity, thickening of the interlobular septa predominantly in the lower lung, and invasive opacity in the right middle lobe and the left lingula segment (Fig. 2). Gallium scintigraphy showed accumulation in the lower lungs, but not in the submandibular or lacrimal glands (Fig. 3). An abdominal CT scan did not show any abnormal findings in the structure of the pancreas or other abdominal organs. MCD was suspected on the basis of clinical features such as the steroid-refractory nature of the condition, chest CT findings, polyclonal hypergammaglobulinemia, thrombocytosis (platelet count of 61.9 x 104/muL), anemia (hemoglobin, 9.1 g/dL), high IL-6 and CRP levels, and normal ANA, ACE, and MPO-ANCA levels. Bronchoscopy was therefore performed again and cellular analysis of BALF from the right B3 yielded the following findings: neutrophils, 2.0%; lymphocytes, 7.1%; eosinophils, 0.4%; macrophages, 90.6%; and CD4+/CD8+ ratio, 0.51. No pathogen was cultured and TBLB specimens showed mild alveolitis with fibrosis, and alveolar macrophage proliferation. A lower paratracheal right lymph node (#4R LN) specimen obtained by endobronchial ultrasound-guided transbronchial needle aspirate showed IgG4-positive plasma cell infiltration, with an IgG4+ to IgG+ plasma cell ratio of 12.9% (17/132 cells). Since histological diagnosis could not be confirmed by lung and lymph node specimens, thoracoscopic surgical biopsy samples were obtained from the right S10 lung and #4R LN. In the right S10 specimen, patchy plasma cell-dominant inflammatory cell infiltration was apparent, but interstitial fibrosis or eosinophilic infiltration was not observed (Fig. 1d). In the #4R LN specimen, an atrophic germinal center and plasma cell proliferation in the follicle center were observed, but obliterative phlebitis, dense fibrosis, or eosinophilic infiltration were not apparent. IgG4+ plasma cells were observed in both the #4R LN and right S10 specimens (Fig. 1b and c), and the IgG4+/IgG+ plasma cell ratio was 36.4% (242/665 cells) in the #4R LN and 24.1% (123/510 cells) in the right S10, neither of which met the Comprehensive Diagnostic Criteria for IgG4-RD (IgG4+/IgG+ plasma cell ratio > 40%). Taken together, we concluded that the clinical and histological findings of the patient were consistent with those of MCD. Since PSL monotherapy (at 10 mg/day) was not effective, we implemented administration of tocilizumab (8 mg/kg q2w) in addition to PSL, and the fever and cough disappeared. In the chest CT scan, the ground glass opacities in the left lower lobe and the consolidation in the left lingula segment and the right middle lobe improved partially (Fig. 4). Thereafter, tocilizumab administration was continued and the dose of PSL was successfully reduced until no further administration was required.

balf, bronchoalveolar lavage fluid, crp, c-reactive protein, ct, computed tomography, egpa, eosinophilic granulomatosis with polyangiitis, ep, eosinophilic pneumonia, hpf, high-powered field, igg4-rd, igg4-related disease, mcd, multicentric castleman's disease, psl, prednisolone, tblb, transbronchial lung biopsy, ucd, unicentric castleman's disease, wbc, white blood cell

In chest computed tomography scans performed after 3 months of tocilizumab and prednisolone therapy, ground glass opacities in the lower lobe, on both sides, and consolidation in the left lingula segment and the right middle lobe were improved.

PMC2878410_01

Male

A 30-year-old renal transplant recipient presented with fever of 2-month duration in August 2008. Five years back, he had undergone renal transplantation with his sister as donor. His basic kidney disease was unknown and he was on triple immunosuppression with cyclosporine (CsA), azathioprine (AZA) and prednisolone. His baseline serum creatinine was 1.2 mg/dl. In addition to the fever, he also complained of malaise and weight loss of 5 kg during the last 2 months. He had no history of cough, expectoration, loose stools, dysuria or increased urinary frequency. He had no history of tuberculosis in the past. On examination, he was febrile and had pallor but there were no palpable lymph nodes. His blood pressure was 130/90 mmHg. Examination of the various organ systems was essentially unremarkable. His hemoglobin was 9.2 g/dl, total leukocyte count 2400/mm3, platelet count of 160 x 103/ mm3, erythrocyte sedimentation rate 30 mm/1st hour, serum creatinine was 1 mg/dl, sodium 142 mEq/L, potassium 4.7 mEq/L, serum bilirubin 0.73 mg/dl, aspartate aminotransferase 40 IU/L, alanine aminotransferase 26 IU/L, alkaline phosphatase 446 IU/L, serum total protein 7.5 g/dl, serum albumin 3.4 g/dl and the fasting serum glucose was 104 mg/dl. Ultrasonography of the abdomen revealed 5 x 6 cm hypo-echoic lesion in segment V of the liver. A contrast- enhanced computed tomographic scan of the thorax and abdomen revealed multiple, confluent hypodense lesions in the liver, spleen, the renal allograft [Figure 1] and prostate [Figure 2], along with multiple enlarged lymph nodes in the mesentery with central necrosis. The prostate showed multiple air specks also. The high-resolution computed tomography of lungs showed typical miliary pattern. Fine-needle aspiration cytology from the lesion in the liver showed numerous acid-fast bacilli; acid- fast bacilli were also demonstrated in the overnight urine sample. A bone marrow examination, which was performed in view of persistent leucopenia, showed hypocellularity with megaloblastosis, but there were no acid-fast bacilli or granuloma seen. HBsAg (hepatitis B surface antigen) and anti-HCV (hepatitis C virus) antibody were negative, HIV serology was non-reactive and his serum was negative for Cytomegalovirus DNA. Urine cultures performed repeatedly were sterile despite persistent pyuria. He was started on 4-drug anti-tuberculous therapy (ATT) with isoniazid, ciprofloxacin, ethmbutol and pyrazinamide. AZA was stopped in view of the severe leucopenia. The cyclosporine dose was also reduced. He became afebrile by the end of first week of ATT. He also required treatment with granulocyte colony-stimulating factor as the leucopenia worsened further despite discontinuation of AZA.

genitourinary tuberculosis, renal transplantation

PMC8421329_01

Male

A 55-year-old male known HIV-positive patient on antiretroviral therapy (TDF 300 mg + FTC 200 mg + EFV 600 mg) for the last 3 years was referred from Gidda Ayana District Hospital on May 26, 2021 to Wollega University referral hospital. Upon arrival to the emergency department, he complained of shortness of breath of five days' duration, which began suddenly, and became more and more persistent, associated with productive cough, high-grade fever, malaise, and severe headache. In addition, he had a loss of appetite, weight loss, chest pain, night sweats, and fatigue. Moreover, he had a history of bloody sputum one month prior to the current complaint. He has tolerated well but had poor adherence to his ART medication and had no previous history of alcohol consumption and other illicit drugs. He has reported receiving cotrimoxazole prophylaxis for three years, but often missed some doses. His current CD4 count was 266 cells/mm3, and HIV-1 RNA level was 9000 copies/mL. Upon physical examination at presentation, the patient looked acutely sick, and blood pressure was measured at 110/60 mmHg, a body temperature of 39.3 C, and pulse rate of 112 beats per minute, classed as tachycardia. His respiratory rate was 38/minute, and his oxygen saturation was 87% on room air. His breathing was shallow, rapid, and used respiratory accessory muscles. There was dullness over the left lower lobe. Breathing sounds were vesicular on the right side but markedly reduced at the base. There was coarse crepitation over the left upper and lower lobes. He was conscious and oriented. Immediately the patient was admitted as a medical emergency and put on intranasal oxygen. Necessary laboratory investigations were performed. Accordingly, random blood sugar was 110 mg/dL, complete blood count with differential revealed only leukocytosis (15.2 x 103/L) with lymphocyte predominance, erythrocyte sedimentation rate (ESR) of 86 mm/hour; blood film (BF) showed no hemoparasite, serum creatinine was 0.9 mg/dL, and liver function test showed no abnormal value. Chest X-ray showed perihilar patchy opacities (Figure 1). Gene Expert test was done from sputum and was positive for TB (no rifampin resistance), and nasopharyngeal sample for SARS CoV-2 PCR was positive. On his 2nd day of admission, he was transferred to a COVID-19 dedicated treatment center located in the same hospital with the diagnosis of severe COVID-19, pulmonary TB, and WHO stage-3 RVI. During his stay, oxygen supplementation for an SpO2 target >=92-96% was provided with 6-10 L O2 via a nasal cannula. Conservative IV fluid management with empiric antimicrobials for possible bacterial infection was started with cefepime 2 g IV TID for 3 days then changed to an oral antibiotic. In addition, dexamethasone 6 mg once per day IV was given with close monitoring of vital signs, work of breathing, and mental status. Anti-TB drugs were initiated with RHZE (rifampicin, isoniazid, pyrazinamide, and ethambutol) at the intensive phase on the 3rd day of admission. Highly active antiretroviral therapy was continued with the same regimen he was taking before presentation to the hospital. On his 6th day of admission, the patient became afebrile and started to maintain his oxygen saturation >94% with room air. The patient's general condition also improved. Follow-up RT-PCR test for COVID-19 was done, and the results were negative. On June 6, 2021 the patient was discharged from hospital after 10 days of hospital stay, and a follow-up appointment at the ART and TB clinic within two weeks was given.

covid-19, ethiopia, hiv, ptb, co-infection

PMC7196970_01

Female

A 37-year-old, single, Caucasian woman presented to the emergency department with a 3-month history of experiencing progressive shortness of breath that was associated with bilateral lung infiltrates. She was examined in several clinics and was treated with several courses of different oral antibiotics; however, her condition did not improve, and her shortness of breath progressively worsened over time. She reported a history of low-grade fever, a dry cough, fatigue, and the loss of appetite. Furthermore, she did not have a history of skin lesions, joint pains, or any symptoms that suggested connective tissue diseases. Additionally, her past history revealed that she had been suffering from severe depression for which she was taking oral antidepressants. Upon presentation, she was found to be on daily doses of two SSRI medications. She was prescribed paroxetine 50 mg to be taken once daily, which she was taking for the last 1 year, and owing to a misunderstanding, she was also prescribed escitalopram 10 mg to be taken once daily. As a result, she was taking both medications together for at least the last 6 months. A physical examination disclosed that the young lady was suffering from moderate respiratory distress and peripheral cyanosis and that her oxygen saturation, measured by pulse oximetry, was 84% in the room air. During chest auscultation, she exhibited fine bilateral basal crepitations, but she did not exhibit wheezing. Furthermore, she did not present finger clubbing, skin abnormalities, or palpable lymphadenopathy. The examination of her cardiovascular system was unremarkable, and an abdominal examination did not reveal palpable organomegaly. The musculoskeletal and central nervous system examinations also did not reveal any abnormalities. Furthermore, her initial investigations revealed a normal complete blood count (CBC), and her renal and liver function tests were normal as well. Her arterial blood gases showed type I respiratory failure with a partial pressure of oxygen (PO2) of 54 mmHg and a normal pH. The electrocardiogram (ECG) displayed sinus tachycardia with a heart rate of 125 per minute. A chest X-ray captured on presentation revealed a bilateral interstitial pattern with prominent hila that is suggestive of enlarged hilar adenopathy without pleural reactions. She was initially admitted for a chest infection; however, her condition did not improve with IV antibiotics. The results of a further work-up were consistent with those associated with a diagnosis of interstitial lung disease (ILD). A high-resolution computed tomography (HRCT) scan of her chest confirmed a bilateral micronodular interstitial pattern with hilar adenopathy (Figure 1). Consequently, she required fibro-optic bronchoscopy and a transbronchial lung biopsy. The biopsy revealed a noncaseating granuloma (Figure 2). However, the results of all the microbiological examinations, including those of the polymerase chain reaction (PCR) tests, were negative for Mycobacterium tuberculosis. Further, the results of all the autoimmune screening tests were also negative. Following a complete discussion, during a chest department team meeting, she was diagnosed with sarcoidosis. Subsequently, she was started on IV methylprednisolone 60 mg BD, and due to her history of severe depression, she was orally administered escitalopram 10 mg once daily as well. Nevertheless, her respiratory status continued to deteriorate, and her oxygen requirement increased. Her condition worsened over the next few days, and she was eventually intubated and shifted to ICU for mechanical ventilation. At this stage, due to the lack of an adequate response to systemic steroids, she underwent a full re-evaluation, including another bronchoscopy (without a biopsy), by ICU team, which did not generate any new findings. Following this, broad-spectrum antibiotic coverage was added to her treatment plan for a possible nosocomial infection. However, a full septic screen failed to show any positive outcomes. A quick literature review disclosed that there is a possible correlation between granulomatous lung diseases and antidepressants. For this reason, escitalopram was discontinued in the ICU, and the methylprednisolone dose was increased to 100 mg BD. After a few days, she started to exhibit progressive signs of improvement in her respiratory status, and she was weaned off mechanical ventilation within 12 days. She was then shifted to the general ward where she continued to demonstrate remarkable improvement in her condition. She was subsequently examined by the psychiatry department, and it was decided that she should avoid taking SSRIs while being treated for her depression. As a result, she was started on amitriptyline orally, the IV steroids were replaced with oral prednisolone 50 mg OD, and all the antibiotics were discounted. Consequently, she continued to show progressive improvement in the general ward, and she was able to walk without an oxygen supply; furthermore, her oxygen saturation approached 90% in the room air. Within 10 days, she was discharged from the hospital. Her doses of oral steroids were kept the same, and she was given an appointment for a follow-up at the chest clinic after a month. During her follow-up, it was observed that she continued to show progressive improvement with normal oxygen saturation and good exercise tolerance. Her oral steroid doses were gradually reduced to prednisolone 15 mg once daily to be taken over 6 months. Unfortunately, 8 months following her discharge, she presented with a deterioration in her respiratory status during her regular follow-up appointment. She reported experiencing an increase in breathlessness and was found to have a reduction in her oxygen saturation that decreased to 88% in the room air. On further clarification, it was uncovered that she had started taking oral escitalopram 10 mg once daily again. She received a prescription for this medication from a private psychiatry clinic that was not aware of her previous history. A chest X-ray captured at this stage revealed a worsening of the interstitial pattern that was consistent with a flare-up of sarcoidosis. Consequently, she was advised to discontinue the use of escitalopram, and the dosage of oral prednisolone was again increased to 50 mg once daily; as a result, she did not require readmission. An examination during a follow-up visit after 2 weeks revealed good improvement clinically and radiologically. She was again advised to avoid all SSRI medications; however, she was not satisfied with the effect of amitriptyline in controlling her depression. Following this visit, she requested a full written report as she was moving to another city, and she did not attend anymore of her follow-ups.

PMC4109228_01

Female

A 57-year-old Caucasian woman was referred to our rheumatology outpatient center from the orthopedics service for assessment of a possible inflammatory etiology for her rapidly destructive arthritis. Table 1 summarizes the major clinical, lab, and imaging findings. She initially presented with 6 months of progressive right hip and groin pain with no preceding trauma or chronic steroid use. There was a leg length discrepancy with the right leg 3 cm shorter and severe limitation of the right hip and some decreased range of motion on internal and external rotation of her left hip. She did not have any neurovascular compromise. Over 5 months, she became severely disabled and was unable to ambulate. With respect to her other joints, she had chronic pain in her metatarsal phalangeal joints (MTPs) and toes for approximately 3 years with progressive deformities, with recent episodes of swelling. Subsequent to her right hip pain, she also developed right knee pain with multiple episodes of warmth and swelling. Morning stiffness in affected joints was approximately 2 hours. Her initial swollen joint count (SJC) was 8 out of 66 joints examined, involving her right knee and multiple metatarsal phalangeal joints (MTPs). Over the next few visits, her swollen joint count of her small joints reached 11. There was also an unintentional 50-pound (lb) weight loss since the onset of her illness, partially due to decreased appetite secondary to pain. Initial diagnostic work-up was significant for elevated inflammatory markers, weakly positive antinuclear antibody (ANA) and otherwise negative autoimmune markers including both rheumatoid factor (RF) and anticitrullinated peptide (anti-CCP) (Table 1). All cultures, including three sets of anaerobic and aerobic cultures and one set of systemic fungal and mycobacterial culture, were negative. Metabolic panel showed normal renal, thyroid, and liver function. Angiotensin-converting enzyme (ACE) serum level was within normal limits. Malignancy work-up was negative: serum and urine electrophoresis, CEA, CA-125, total body position-emission tomography (PET) scan, and bone scan were all within normal range. Two incidental pulmonary nodules were found on computed tomography (CT) thorax with focal ground glass appearance, but negative for malignancy on bronchoscopy and on repeat imaging. CT abdomen and pelvis was negative for any abdominal masses and showed a soft tissue calcified mass in the right sacroiliac (SI) fossa and right gluteal muscles. Initial plain films of her right hip and pelvis showed femoral head lucencies compatible with subchondral cysts (but no definite fracture) and moderate diffuse articular joint space loss with flattening of the femoral head (Figure 1(a)). Over a 5-month span, there was complete destruction of the right femoral head, erosion of the right acetabulum, and lateral subluxation of the proximal femur (Figure 1(b)). CT pelvis with contrast (Figure 1(c)) showed fragmented bone within the acetabular fossa, which was remnants of the femoral head resorption process. Magnetic resonance imaging (MRI) of the right hip showed extensive synovial hypertrophy consistent with inflammatory arthritis (Figure 2). There were also minimal bone marrow edema and a fluid collection in the iliopsoas bursa extending posteriorly to the sciatic notch and enlargement of the hip joint capsule (Figure 2). X-rays of her feet revealed erosive changes in the MTPs and X-rays of her hands showed periarticular osteopenia in her metacarpal phalangeal (MCP) joints and ulnar deviation. There were degenerative changes on imaging of her knees, shoulders, and spine. Three right hip aspirations were attempted with sufficient sample in only one attempt, which showed bloody fluid, 0.6 nucleated cells (17% neutrophils), and presence of only extracellular but not intracellular calcium pyrophosphate dehydrate (CPPD) crystals. Synovial biopsy did not reveal any crystals. Historically, CPPD crystal deposition disease can cause such acutely destructive disease on imaging and pathology, but the most common sites of CPPD joint involvement are the knees, wrists, and symphysis pubis with hip involvement being rarer with a prevalence of 5%. This patient's plain-film images of her hands, knees, and pelvis were helpful in that there were no typical features of crystal arthropathy such as cartilage or joint capsule calcification and her blood work was also negative for an underlying metabolic precipitant of CPPD. Furthermore, single joint aspiration of her right knee showed no crystals, with bloody fluid and 35 nucleated cells (96% neutrophils). The major differential diagnosis of this atypical case of destructive arthritis is outlined in Table 2. The patient's initial plain films showed evidence of degenerative changes but very unlikely to be primary osteoarthritis given the atypical symmetric joint space narrowing on plain imaging, complex joint effusion, and synovial thickening with chronic inflammatory changes on biopsy. She also did not have any evidence of a subchondral insufficiency fracture, which has been linked to the pathogenesis of the rapid destruction of osteoarthritic joints. Other potential etiologies that could rarely cause such severe arthritis were considered on the differential including systemic diseases such as multicentric histiocytosis and sarcoidosis, but the patient lacked any other features of these diseases. Her neurovascular status was intact throughout and no evidence of a neurological problem or predisposing factors such as diabetes to cause Charcot's or neuropathic arthropathy. An avascular type necrosis (AVN) with subsequent inflammation was possible, but unusual without a history of steroidal use prior to her initial presentation or other risk factors for AVN. The imaging was also not classic for AVN and the patient did not have monoarthritis. Although seronegative, she did not have any inflammatory back pain, dactylitis, enthesitis, DIP involvement, inflammatory bowel disease, psoriasis, or other features of seronegative spondyloarthropathy. X-rays of her spine and CT pelvis did not show evidence of sacroiliitis. In order to definitively differentiate between chronic sepsis, malignancy, and a chronic inflammatory process, an open biopsy of the hip was performed by the orthopaedic service, which showed overall morphology with features of chronic inflammation, fibrosis, multinucleated giant cell reaction with dystrophic calcification, and reactive synovial proliferation (Figure 3). Cultures of synovial tissue were negative for fungus and mycobacteria, ruling out tuberculosis. Although the biopsy results were not specific for an exact etiology of rapid joint destruction, we were able to exclude neoplastic, infectious, osteoarthritis, and osteonecrotic etiologies. An inflammatory etiology was most likely given multiple swollen joints, elevated inflammatory markers, constitutional symptoms, evidence of inflammatory features on imaging, and other causes excluded. Hence, a diagnosis of seronegative rheumatoid arthritis (RA) was ultimately made, fulfilling 4/7 of the 1987 RA American College of Rheumatology (ACR) classification criteria and scoring 6 points for the 2010 ACR//European League Against Rheumatism (EULAR) classification criteria (Table 3). Given the extent of right hip destruction, the patient received a total hip arthroplasty with good results. To prevent destruction of her other joints, triple disease modifying antirheumatic drugs (DMARD) therapy with hydroxychloroquine 400 mg daily, leflunomide 20 mg daily, and methotrexate 25 subcutaneously weekly was initiated. For symptom relief, she was given an 80 mg intramuscular Depo-Medrol injection and joint injection to her right knee. At her 2-month follow-up visit, she had significantly reduced swelling of her knees and MTP's with much symptomatic relief. Adalimumab was added because of incomplete response and patient had further improvement. Over a 6-month period, SJC decreased from 8 to 1/66.

PMC3817060_01

Female

The patient was a 77-year-old female, diagnosed with dry eye at another clinic and treated with sodium hyaluronate ophthalmic solution and diquafosol sodium eye drops for several weeks. She has never worn contact lenses on a regular basis. Because of lack of improvement in her subjective symptoms, she visited Maebashi Red Cross Hospital. Her ocular symptoms were dryness and blurred vision in the right eye. Slit-lamp microscopy with fluorescein staining showed diffuse corneal erosion in the superior cornea and lid wiper staining with hyperemia of the palpebral conjunctiva in the right eye (Figure 1, upper panels). With a diagnosis of LWE, rebamipide eye drops four times daily were prescribed and her other eye drops were discontinued. Fluorescein staining of the cornea and lid margin was remarkably improved (Figure 1, lower panels) and subjective symptoms were reduced in 2 weeks from the start of rebamipide eye drops. Tear film break-up time (TBUT), Schirmer's 1 test, and decimal visual acuity were examined before and 2 weeks after administration of rebamipide (Table 1). For TBUT, corneal staining with fluorescein solution was examined under standard illumination using a slit-lamp microscope with a cobalt blue filter. TBUT was measured three times using a stopwatch as the time from normal blinking to the first appearance of a dry spot in the tear film. Schirmer's 1 test was performed to measure tear volume.

mucosta®, corneal erosion, dry eye, lid wiper, mucin, rebamipide

PMC3817060_02

Female

The patient was a 71-year-old female on no medication during follow-up after cataract surgery 3 years earlier. She complained of foreign body sensation and blurred vision in the left eye and visited our hospital. Slit-lamp microscopy with fluorescein staining showed band-shaped corneal erosion in the central cornea and lid wiper staining with hyperemia of the palpebral conjunctiva in the right eye (Figure 2, upper panels). We diagnosed this as LWE and administered rebamipide eye drops four times daily to her right eye. Fluorescein staining of the cornea and lid margin was remarkably improved (Figure 2, lower panels) and subjective symptoms resolved in 3 weeks. TBUT, Schirmer's 1 test, and decimal visual acuity were examined before and 3 weeks after administration of rebamipide in the same way as in case 1 (Table 1).

mucosta®, corneal erosion, dry eye, lid wiper, mucin, rebamipide

PMC6735170_01

Female

This is a case of 25-year-old G4P1021 diagnosed with an in utero fetal stroke at 26 weeks gestation. She had ultrasounds at 19 weeks and 23 weeks, which showed no anatomic abnormalities (see Figures 1(a) and 1(b)). She presented to labor and delivery at 26 weeks complaining of vaginal spotting. Labor and rupture of membranes were ruled out; however she had a Category II tracing with minimal to absent variability. Ultrasound exam revealed severe ventriculomegaly, a left-sided frontal porencephalic cyst, enlarged 4th ventricle, mild abdominal ascites, open hands, and echogenic bowel (see Figures 1(c) and 1(d)). A thrombophilia panel, antiphospholipid panel, cytomegalovirus and toxoplasmosis antibodies, and neonatal alloimmune thrombocytopenia panel were ordered and were negative. She went into spontaneous preterm labor at 26 weeks 4 days' gestation and delivered a female infant, weighing 895g with APGARS of 1, 1, and 1, at 1, 5, and 10 minutes of life. Heart rate was in the 60s and abnormal rigid tone was noted. Intubation did not improve saturations (never over 60% despite correct placement confirmed), and chest x-ray showed bilateral whited out lungs. Compressions and chest tube placement did not yield improvement. Umbilical vein catheterization was unsuccessful and surfactant and epinephrine were given via the endotracheal tube. Despite extensive resuscitative efforts, there was no improvement in the clinical status, and the mother opted to switch to comfort care. Vesicular lesions were noted on the infant, which were positive for HSV2 by PCR (see Figure 2). A postmortum ventricular tap was performed and cerebral spinal fluid was also positive for HSV 2. Her first clinically documented HSV outbreak was immediately prior to pregnancy and she was treated with acyclovir. She became pregnant approximately 5 weeks later. A 6-week ultrasound confirmed those dates. She was seen for her initial prenatal exam at 11 weeks, which confirmed a positive HSV-2 IgG. She had no further outbreaks during pregnancy, and her pregnancy was otherwise uncomplicated. She was not on suppression during her pregnancy, though it was planned for 36 weeks.

PMC4729029_01

Female

The most common form of GF occurs as a benign, slowly progressive and non-hemorrhagic enlargement of the gingiva. It affects the masticatory mucosa (the marginal and attached gingiva and the interdental papilla), but it does not spread beyond the muco-gingival junction. GF can be generalized, idiopathic or hereditary (non-syndromic) (Figs. 1a and 2a) or associated with different genetic diseases. Clinically, the onset coincides with the eruption of primary or permanent dentition, and rarely presents at birth. GF may also occur as a local, nodular-like lesion. The excess gingival tissue can cover part of or the entire crown, and can result in diastemas, teeth displacement, or retention of primary or impacted teeth, and may also cause masticatory, phonetic, psychological, and esthetic problems. An example of a local, nodular-like lesion in the posterior maxillary region of the gingiva in a 35-year-old patient diagnosed as an IGF is depicted in Fig. 3a. Clinical features of isolated HGF, and genetic syndromes and diseases co-existing with HGF are presented in Table 1. DIGO usually occurs as a generalized (diffuse) enlargement usually visible within several months after the onset of systemic therapy. This is in contrast to HGF, which is characterized by a slow, progressive growth of the gingival tissue. GO may vary from mild to severe, depending on the dose of the drug. Combination therapy, such as with amlodipine, a calcium channel blocker used in the management of hypertension and angina, and cholesterol-lowering drugs, can result in more severe GO than single-agent therapy. Although the clinical appearance of lesions resulting from different medications is similar, the histopathology of DIGO lesions varies depending on the inducing drug. Hyperplastic gingiva usually presents a normal coloration or can be erythematous. Periodontal problems, such as bleeding and bone loss, might occur due to the excess of gingival tissue, presence of pseudopockets and plaque accumulation. The typical histopathology of the lesion involves hyperplasia of the epithelium with elongated rete ridges extending into the underlying connective tissue (Figs. 1b and 2b). The connective tissue consists of excess collagen, but has relatively few fibroblasts and blood vessels (Fig. 1b). Enlarged fibroblasts appear to alternate with thin and thick collagen fibrils. Elastic and oxytalan fibers are also present in GF lesions. Unlike in normal gingiva, coarse and fine dense collagen fiber bundles are oriented in all directions (Fig. 3b). Small osseous calcifications and abundant neurovascular bundles may also be present. The excess of gingival tissue may provide new niches for the growth of microorganisms, plaque accumulation and pseudopockets formation resulting in inflammatory infiltration of the gingival connective tissue (Fig. 2b). Enlargement associated with non-genetic diseases GF can be directly or indirectly linked to poor nutrition (vitamin C deficiency), systemic hormonal stimulation (pregnancy or puberty), blood dyscrasias (leukemia), Wegener's granulomatosis, orofacial granulomatosis, pyogenic granuloma and sarcoidosis. It may also be associated with pseudotumors, benign neoplasms, e.g. giant cell fibroma, gingival and oral myofibroma, papilloma, giant cell granuloma, and malignant neoplasms, e.g. oral squamous cell carcinoma, salivary gland tumors, melanoma, adenoma and mucoepidermoid carcinoma. Enlargement associated with inflammatory diseases of the oral cavity Gingival enlargement may develop during the course of inflammatory diseases of the oral cavity, for example localized and generalized aggressive periodontitis (AP) and primary gingival tuberculosis. Plaque accumulation and bacterial infection resulting from poor oral hygiene are significant predisposing factors. Other examples are inflammatory pseudotumors and inflammatory fibrous hyperplasia due to local irritants. Enlargement associated with hereditary factors and co-existing with genetic diseases and syndromes Drug-induced gingival enlargement Gingival enlargement of unknown etiology Gingival enlargement covers broad etiological entities classified into five general groups: HGF (ORPHA 2024, MIM 135300) is a rare and slowly progressive condition characterized by etiological heterogeneity. Additionally, it may co-exist with several genetic diseases or syndromes (Table 1). Moreover, it may occur sporadically in several other syndromes and diseases. An example is Cowden syndrome (multiple hamartoma syndrome, CWS1-6, ORPHA201, MIM 158350), a rare autosomal dominant disorder characterized by multiple hamartomas and a high risk of development of malignancy. It is now believed that 25 % of CWS cases (CWS1) are caused by germline mutations in the phosphatase and tensin homolog (PTEN) gene (10q23), which encodes PTEN, a dual-specificity phosphatase. Patients with CWS and CWS-like phenotypes without PTEN involvement have been found to have germline promoter methylation of KLLN (10q23; CWS4) (30 % of cases); germline variations in SDHB (1p36; CWS2), SDHC or SDHD (11q23; CWS3) (10 % of cases); or germline mutations in AKT1 (14q32; CWS6) or PIK3CA (3q26; CWS5) (10 % of cases). The most predominant features of the syndrome are small papular cutaneous lesions, papillomatous outgrowth, and fibromas of the oral mucosa and tongue. The co-existence of gingival hyperplasia with Cowden syndrome was reported by two groups. Another example is Bardet-Biedl syndrome (BBS1-19, ORPHA 110, MIM 209900), a rare, heterogeneous, oligogenic or autosomal recessive condition with a prevalence in Europe estimated at between 1/125,000 and 1/175,000. Clinical features include obesity, pigmentary retinopathy, post-axial polydactyly, polycystic kidneys, hypogenitalism, and learning disabilities, many of which appear several years after disease onset. The clinical expression is variable, but most patients exhibit the majority of these clinical features during the disease course. Dental anomalies, regarded as secondary manifestations, include hypodontia, microdontia, short roots, and a deep palate. The first case of BBS with generalized GO was reported by Drugowick et al.. An example of a disease where genetic and infective factors are involved is AP. It is a rare, severe, and rapidly progressive form of periodontitis that develops as a result of complex interactions between specific host genes and the local microenvironment of the oral cavity. Factors which increase the risk of AP development include: familial aggregation, single nucleotide polymorphisms, functional defects in neutrophils, antibodies to specific bacteria, herpes virus infection, stress and smoking. Though GF and AP usually occur as separate entities, several reports describe the co-existence of these diseases. The first report was published by Mahajan et al., followed by reports by Jadwat et al., Chaturvedi, Sandhu et al., and Vishnoi and Phadnaik. Recently, Ramachandra et al. reported a case of gingival enlargement associated with generalized AP and the presence of mesiodens. The common features of GF and localized AP are their onset around puberty, female predilection, hereditary background, and progression in the presence of minimal local factors, although secondary involvement can aggravate the pre-existing condition. HGF may be transmitted as a Mendelian trait in an autosomal dominant or, less commonly, an autosomal recessive fashion. Linkage analysis has provided clues about the etiology of the disease, and showed several chromosomal regions that may contain mutations responsible for HGF. Loci for isolated, non-syndromic autosomal dominant forms of HGF have been localized to chromosome 2p21-p22 in a Brazilian family, and to chromosome 5q13-q22 and 11p15 in a number of Chinese families. The candidate loci are GINGF, GINGF2 and GINGF4, respectively. After sequencing 16 genes in the candidate interval (2p21-p22), a single base insertion in the Son-of-Sevenless-1 (SOS-1) gene (MIM 182530) underlying GINGF locus, was detected in a Brazilian family, but not in three Chinese families. Similar to the observations of Ma et al., our recent study did not confirm the presence of a single nucleotide insertion in the SOS-1 gene in two Polish families diagnosed with non-syndromic HGF (unpublished data). Interestingly, in four other Chinese families, non-syndromic HGF was linked to a mutation in the 2p21 locus (GINGF), as previously reported by Hart et al.. A mutation in the SOS-1 gene has been suggested as one possible etiological factor/causing gene for isolated, non-syndromic HGF, but considering the genetic heterogeneity of HGF, mutations in other genes are also likely to be involved. By haplotype construction and analysis in a five-generation Chinese family segregating autosomal dominant HGF, Ye et al. identified a novel locus, which they designated GINGF3, in an 11.4 cM interval between markers D2S2221 and D2S1788 on chromosome 2p23.3-p22.3. Authors noted that this locus is distal to and does not overlap with the previously described GINGF locus on 2p22-p21. Drug-induced GF occurs in susceptible individuals as a side effect of systemic medications, including the anti-epileptic drug phenytoin, the immunosuppressant CsA, and calcium channel blockers, namely, dihydropyridines, particularly nifedipine, diltiazem, and verapamil, which are widely used to control hypertension. Currently, more than 20 drugs are associated with gingival enlargement. Although the drugs that can cause GO have distinct mechanisms of action and act on different primary target tissues, they all seem to have a similar adverse effect on the gingival connective tissue. In addition to being disfiguring, GO may also lead to poor oral hygiene and decreased oral function in individuals already suffering from conditions such as epilepsy, cardiovascular diseases, or immunosuppression. The pathogenesis of DIGO is dependent on several factors, such as: age, genetic predisposition, pharmacokinetic variables, alterations in gingival connective tissue homeostasis, pre-existing dental plaque and gingival inflammation, and interaction of drugs and growth factors. The pathologic manifestation of GF is excessive accumulation of ECM proteins, including collagen type I. Thus far, however, the molecular and biochemical mechanisms that trigger this pathological process are not completely understood. During collagen biosynthesis, nascent single procollagen polypeptides undergo post-translational modification in the endoplasmic reticulum (ER), form triple-helical chains, and are secreted into the extracellular space. This process involves heat shock protein 47 (HSP47), a 47 kDa glycoprotein localized in the ER. It binds to the nascent type I procollagen peptides to prevent premature folding and aggregation of procollagen chains, and participates in the translocation and secretion of procollagen I into the extracellular space. Type I collagen and HSP47 mRNA and protein levels are increased significantly in fibroblast cultures derived from patients with HGF. Moreover, transforming growth factor (TGF)-beta1 and interleukin (IL)-6 induce the expression of type I collagen and HSP47 and to downregulate matrix metalloproteinase (MMP)-1 and MMP-2 in fibroblast cultures from HGF patients. The effect of TGF-beta1 and IL-6 on the synthesis of other ECM proteins was also reported in DIGO. By contrast, interferon-gamma (IFN-gamma) reduced collagen I and HSP47 expression, and it slightly affected MMP-1 and MMP-2 expression. This observation suggests that HSP47 may be a crucial molecule in the post-translational processing of the overproduced type I procollagen chains, while enhanced TGF-beta1 and IL-6 production in patients with GF may favor the accumulation of collagen fibrils in the gingiva. Prolyl 4 hydroxylases (P4Hs) are equally essential enzymes in the biosynthesis and folding of newly-synthesized collagen polypeptide chains into triple-helical molecules. P4Hs are alpha2beta2 tetramers consisting of one of three isoforms of subunit alpha [alpha(I), alpha(II), or alpha(III)] that have similar catalytic activity. The expression of the alpha subunit of P4Hs limits the rate of active P4H formation, P4H activity, and collagen synthesis. Increased levels of P4H activity are reported in a number of fibrotic conditions such as keloids and hepatic fibrosis. Some studies report increased expression and activity of prolyl hydroxylases in IGF, DIGO, and HGF. Notably, Meng et al. identified isoform I of the alpha subunit of P4Halpha as the isoform associated with GO, while the type II and III forms of P4H were not affected. These findings suggest that P4Halpha (I) might be involved in the pathogenesis of HGF and confirm that HGF fibroblasts are deregulated at the level of post-translational protein modification. Alterations in the expression of MMPs, key enzymes regulating the composition of the ECM, have been implicated in the pathogenesis of GF. Several studies show a significant decrease in the expression and activity of MMP-1 and MMP-2 in fibroblasts from HGF patients in comparison with controls. MMP-1 is a collagenase that degrades interstitial collagen, while MMP-2 acts predominantly on type IV collagen, but it has also been shown to degrade type I collagen in its native form. Similarly, the inhibition of MMP-1, MMP-2, and MMP-3 has been reported in CsA-induced GO, a condition also associated with enhanced TGF-beta1 production. The catalytic activity of the MMPs is regulated at the transcriptional level as well as by tissue matrix metalloproteinase inhibitors (TIMPs). Interestingly, addition of anti-TGF-beta1 antibodies in the study by Coletta et al. resulted in a slight increase in MMP-1 and a decrease in MMP-2 expression, whereas TIMP-1 and TIMP-2 expression were unaffected. These results confirm previous observations that enhanced TGF-beta1 production may lead to the accumulation of ECM by altering the proteolytic activities of fibroblasts. Systemic therapy with CsA, phenytoin, and nifedipine modulates cytokine levels and indirectly affects gingival connective tissue metabolism. For example, Hong and Trackman observed that the mRNA expression of lysyl oxidase and collagen type I by human gingival fibroblasts decreased to 53 % and to less than 10 % of control levels, respectively, after 48 h of treatment with 1 nM basic fibroblast growth factor (bFGF), while lysyl oxidase enzymatic activity was downregulated by 10-20 %. By contrast, interleukin - 1 (IL-1), IL-6, and platelet-derived growth factor-BB (PDGF-BB) did not significantly regulate the enzymatic activity of lysyl oxidase or the mRNA levels of lysyl oxidase, collagen type I or elastin. The opposite effect was found by stimulation of gingival fibroblasts with TGF-beta1. In brief, TGF-beta1 upregulated lysyl oxidase and collagen type I, but not elastin, in a dose- and time-dependent manner. The maximal effect on lysyl oxidase activity and mRNA expression, as well as the mRNA expression of collagen I occurred after 48 h of treatment of gingival fibroblastic cells with 400 pM TGF-beta1. It has also been shown that mRNA and protein synthesis of connective tissue growth factor (CTGF or CCN2) are significantly induced by TGF-beta1 in human gingival fibroblasts. CTGF/CCN2 is a member of the CCN family, members of which contain conserved cysteine-rich domains and have a variety of biological activities. CTGF promotes the proliferation of various cell types and is highly expressed in a wide variety of fibrotic lesions, including skin and kidney fibrosis, and atherosclerosis. Uzel et al. assessed the expression and localization of CTGF in GO induced by three different systemic medications. CTGF expression was significantly higher in phenytoin-induced GO than in CsA- or nifedipine-induced GO. Similar observations are reported by Hong et al.. Considering that phenytoin-induced lesions are more fibrotic than nifedipine- and CsA-induced lesions, it seems that CTGF levels correlate positively with fibrosis and have a role in promoting and maintaining fibrosis. Development of fibrotic events can involve the process known as epithelial/mesenchymal transition (EMT). It occurs physiologically during organ and tissue development. In this process, partial destruction of the basement membrane can lead to inappropriate diffusion of factors between the connective tissue and the epithelial layers of gingival tissues. These factors can stimulate epithelial cells to lose cell-cell contacts, decrease E-cadherin expression, and increase cell motility, promoting their invasion into the underlying connective tissue stroma, where they differentiate further into cells that are indistinguishable from fibroblasts and myofibroblasts. These fibroblastic cells, in turn, produce connective tissue proteins that contribute to fibrosis. A diagnosis of GF is made mainly on the basis of clinical and periodontal examination, a medical and family history and laboratory tests. Clinical examination, medical history and laboratory tests determine initially whether the condition is inherited or acquired, the presence of other diseases, the prior therapies used, and the involvement of primary dentition. Histopathological analysis characterizes the typical features of fibromatotic gingiva, such as the rate of epithelial acanthosis, connective tissue density and cellular content, the extent of fibrosis or inflammatory infiltrates. Periodontal examination, including X-ray and histopathology serve mainly to assess the type (local, diffuse, fibrous or inflammatory) and the severity of gingival involvement, including bone erosion, and allow the physician to choose the optimal treatment option. If a genetic background is found, it is important to verify whether the lesion is an isolated entity or occurs as part of a multisystem pathology. The list of the syndromes associated with periodontal involvement is presented in Table 1. Particularly important are neoplasms, though benign tumors and pseudotumors can given similar patterns of clinical involvement. Amongst benign tumors of the gingiva, giant cell fibroma, irritation fibroma, neurofibroma, angiofibroma (tuberous sclerosis or Bourneville-Pringle disease), inflammatory myofibroblastoma and epulis fissuratum should be considered. Epulis fissuratum is a specific condition usually found in patients with removable full dentures. Inflammatory myofibroblastoma ranges from completely benign to malignant tumors with a fatal outcome. Malignant neoplasms which have to be considered are oral squamous cell carcinoma, salivary gland adenocarcinoma, melanoma ], adenoma and mucoepidermoid carcinoma. Regarding DIGO, it may occur not only for calcium channel blockers, CsA and phenytoin but also with other immunosuppressants or anticonvulsants, antibiotics, and oral contraceptives. Differential diagnosis of GF with granulomatous lesions includes systemic diseases such as sarcoidosis, Crohn's disease, and tuberculosis, as well as lesions localized to the orofacial region like orofacial granulomatosis. Although leukemia is a malignant disease of the blood, where the uncontrolled proliferation of immature blood cells takes place, leukemic infiltration of oral tissues may occur, resulting in a pale mucosa, poor wound healing, and bleeding, which in some cases can resemble GF. Lymphomas rarely manifest initially in the oral cavity, but misdiagnosis is highly probable because maxillary and mandibular swelling can mimic fibrotic lesion. All these conditions require thorough analysis of medical history, laboratory tests, and histopathology as a delay in the diagnosis, particularly in the case of malignancy may worsen the prognosis. HGF may present as an autosomal-dominant or less commonly autosomal-recessive mode of inheritance, as an isolated disorder or as part of a syndrome. Autosomal dominant forms are usually isolated (non-syndromic) and have been genetically linked to several loci, i.e. GINGF, GINGF2, GINGF3, GINGF4 (Table 1). If clinical/periodontal examination, family history and laboratory tests initially indicate a genetic background, other family members are called to the clinic to confirm the presence of HGF, draw up a pedigree diagram, and determine whether it constitutes an isolated entity or co-exists with another disease or syndrome. If a systemic disease or syndrome is suspected, the patient is directed to a geneticist for additional clinical examination and specialized diagnostic tests. In such cases psychological support is needed to assess a risk of occurrence in future pregnancies, the option of early prenatal diagnosis and optimal treatment. The patient's medical history (e.g. patient's age and the presence of other diseases) and the findings of the clinical examination (e.g. the type and severity of overgrowth) influence the patient's management. While some surgical approaches, such as the use of laser excision, reportedly reduce the recurrence, re-growth of the excised gingival tissue due to the continuous use of the drug presents a significant challenge. The usual treatment of GF includes external bevel gingivectomy using a scalpel, unless this is complicated by bony defects, in which case, a flap surgery is carried out. The surgery is followed by 0.12 % chlorhexidine oral rinses twice a day for 2 weeks. Removal of the hypertrophic tissue can be also done by electrosurgery or by laser, reducing the risk of bleeding and pain. This type of procedure decreases significantly the quantity of local anesthetic used, leads to better visibility, which reduces the chairside time, and results in better patient acceptance. Non-surgical treatment includes scaling and root planing, oral hygiene instructions and administration of antibiotics, usually amoxicillin and metronidazole, along with anti-inflammatory (ibuprofen) and analgesic (paracetamol) drugs and the use of chlorhexidine mouth rinses. At the end of the fourth week, internal bevel gingivectomy along with open flap debridement is carried out. This procedure eliminates the pocket, reduces the bulk of the tissue and makes plaque control much easier. Management of patients diagnosed with GF and AP includes non-surgical treatments, surgery with regenerative or resective therapy and anti-microbial treatment. Regenerative techniques include the use of bone grafts, barrier membranes, wound healing agents and enamel matrix protein. Local drug delivery, full mouth disinfection and host immune response modulation are other modes of treatment. Because of difficulties in the treatment of DIGO, the status of oral health prior to and during drug administration, in combination with drug serum levels and the duration of therapy, are key factors in the management of the condition. Discontinuing or dramatically lowering the dose of the drug often results in resolution of clinical signs and lesions. However, this is not always medically feasible, particularly in whole-organ transplant recipients. Evidence suggests that 34 % of cases demonstrate recurrence during the 18 months following periodontal surgery regardless of the drug. Although GO lesions are not directly life-threatening and may be tolerated by some patients without treatment, the quality of life is clearly compromised among affected individuals. Therefore, to stabilize the long-term outcomes and alleviate suffering for those who are adversely affected, non-surgical therapies to treat GO are of importance. Although progress in the clinical management of human GO has been made in relatively affluent societies, approaches of drug substitutions and careful dose adjustments are not universally practiced by physicians worldwide, and this contributes to the global public health impact of GO. Complications related to GF include difficulties with mastication, speech problems, displacement of teeth, esthetic effects, and psychological difficulties for the patient; therefore, appropriate treatment and postoperative management are crucial. Gingival enlargement as a form of periodontal tissue reaction may impose a challenge to periodontists as well. Routine treatment of minimal and local enlargements relies on keeping appropriate oral hygiene and/or root scaling, while cases of advanced, diffuse gingival enlargement require surgical intervention. Recurrence can occur several months to several years after surgery.

PMC5309421_01

Male

A 20-year-old, otherwise healthy, male presented to the Emergency Department (ED) after falling on his back while playing basketball. The patient landed on his right buttock on the hardwood floor. On presentation to the ED, he denied back pain, numbness, and weakness but did notice progressive swelling in the area of the fall. He denied any other injuries and had no previous bleeding or bruising history. His medical history was unremarkable for bleeding disorders or anticoagulation. He denied previous issues with hematomas, subcutaneous fluid collections, or abscesses. On physical exam, the patient was not in acute distress and showed equivalent and intact strength and sensation in all four extremities. There was no weakness, numbness, or tingling in the lower extremities. All distal pulses were equal and palpable. The patient had mild pain in the right gluteal region with impressive swelling in the area. There was no lumbar, sacral, or pelvic tenderness to palpation. Point of care ultrasound demonstrated an 8 x 2.8 cm2 fluid collection in the right gluteal region which was incorrectly thought to be located within the muscle belly. He was given an ice pack, instructed to use Tylenol, and given a referral to Orthopaedics. He was instructed to return to the ED if the pain worsened or if he developed fevers, chills, nausea, vomiting, or other symptoms and was discharged the same evening. The patient returned to the ED four days later for worsening pain and swelling of his buttock. He was unable to tolerate running and had worsening pain upon walking. The patient was concerned for a possible abscess at the injured area as it had become increasingly tender to touch since his previous visit to the ED. The skin at the area was intact and the patient denied drainage. He did not present with any constitutional symptoms including fevers, chills, nausea, vomiting, abdominal pain, lightheadedness, dizziness, or syncope. Physical exam was positive for myalgia in the right upper gluteal region. A complete blood count (CBC) revealed mildly microcytic RBCs of 78.3 fL (normal = 79.9-99.0), decreased mean corpuscular hemoglobin of 26.5 fmol/cell (normal = 27.0-32.0), and a decreased monocyte percentage of 5.8 (normal = 6.0-13.0). White blood cell count was 6.3 x 103 cells/mL (normal = 4.0-10.0), hemoglobin was 13.7 gm/dL (normal = 13.5-17.0), RBC count was 5.17 x 103 cells/mL (normal = 4.40-5.70), platelet count was 228 x 103 cells/mL (normal = 150-400), platelet thromboplastin time (PTT) was 25.1 seconds (normal = 22.0-32.0), prothrombin time (PT) was 10.9 seconds (normal = 9.5-12.0), and International Normalized Ratio (INR) was 1.0. A radiology-based musculoskeletal ultrasound was performed on the right upper gluteal region. The exam was notable for a large hypoechoic fluid collection deep to the subcutaneous tissue and superior to the gluteal musculature (Figures 1 and 2). The fluid collection had increased to 13 x 2 x 9 cm3. Internal echoes and fat globules were found within the hypoechoic fluid collection. These findings were suggestive of a Morell-Lavallee closed degloving lesion. Plastic Surgery was consulted and opted not to perform drainage of the lesion as there was no superficial skin breakdown. The patient was given a pressure dressing for the lesion and recommended to follow up with Plastic Surgery clinic for further management of the lesion.

PMC8278854_01

Female

Ms PM is a 28-year-old female, originally from Eastern Cape Province in South Africa (SA). She was first admitted in July 2017 for severe respiratory distress at a district hospital in Gauteng Province, with a working diagnosis of multi-lobar pneumonia. Further examination revealed significant wasting, pallor and oral candidiasis. Her oxygen saturation was 82% on room air, which improved to 100% on supplemental oxygen. She was hypotensive (blood pressure 89/65 mmHg), and tachycardic (120 beats per minute) due to sepsis. Her chest X-ray showed diffuse, multiple thin-walled cysts (one with air-fluid level) of varying sizes in both lung fields; as well as the peri-cardiac region (Fig. 1). Due to the patient's rural background, hydatid lung disease was now the working diagnosis. A computed tomography (CT) scan of the chest could not be performed at this district hospital as the scan machine was not operational. Blood results showed acute kidney injury (resolved with crystalloid fluids), a raised c-reactive protein (CRP) of 143 mmol/L, and a normocytic anaemia attributed to her HIV infection. The hydatid serology and the serum cryptococcal latex antigen test (sCLAT) performed was negative. Sputum investigations were negative for tuberculosis, yeast and/or fungal species. Bronchoscopy equipment was not available at this hospital, and no further biological samples could be collected.

hiv, atypical, disseminated cryptococcus, pulmonary crptococcosis

PMC5848349_01

Male

A 25-year-old Asian Indian male patient was seen by us 8 months following penetrating trauma to his left eye. He had developed defective vision of 4-month duration in the left eye and 3 months in the right eye. He had been treated with topical steroid drops but continued to have diminishing vision. He developed pain and defective vision in the right eye. He had undergone a vitrectomy with endolaser and intraocular foreign body removal in his left eye elsewhere before he was referred to us. He had a history of eruptive Lichen planus several years ago for which he was treated with a course of oral prednisolone. His best-corrected visual acuity was 6/9 and N6 in the right eye and no perception of light and less than N36 in his left eye. Applanation tonometry was 10 mm in the right eye and not recordable in the left eye as it was very soft. Slit-lamp examination of the right eye revealed mutton-fat keratic precipitates and aqueous cells1 + and aqueous flare 1+. The cornea and pupil were normal. Left eye had pigments on the corneal endothelium, early cataract, and posterior synechiae but no anterior chamber reaction. Fundus examination of the right eye showed 1+ vitreous haze and disc hyperemia with multiple Dalen-Fuchs nodules, perivascular retinitis, and extensive vascular sheathing, and the left eye had no view of the fundus [Figure 1]. Fundus fluorescein angiography showed a perivasculitis with an FBA-like picture. Optical coherence tomography in the right eye revealed an altered foveal contour, an epiretinal membrane, retinal thickening nasal to the fovea with posterior vitreous detachment, and a bumpy retinal pigment epithelial cell layer. Ultrasonography in the right eye showed peripapillary choroidal thickening of 1.6 mm. Investigations for sarcoidosis and tuberculosis was negative. As the patient required immunomodulators and immunosuppressives such as cyclosporine and azathioprine, respectively, his blood urea, creatinine, blood pressure, and full blood count were done and found to be normal. There was no evidence of systemic infections. We started the patient initially on tablet azathioprine 50 mg 3 times daily and tablet prednisolone 60 mg along with antacid and calcium supplements. The inflammation continued and tablet cyclosporine, 150 mg twice daily was added to his treatment. He improved significantly, and examination showed no anterior chamber and vitreous cells. The perivasculitis and hyperemia of disc resolved after 4 months of treatment. The vision at the end of 3 months of treatment is now 6/6, N6 in the right eye, and inaccurate projection of light in the left eye. The immunosuppressives are being tapered now, and the patient is being followed up at regular intervals. Follow-up of 1 year showed no reactivation.

dalen-fuchs nodules, frosted branch angiitis, immunosuppressives, perivascular retinitis, sympathetic ophthalmia

PMC7784231_01

Female

Patient 1 was a 59-year-old female with a background history of diabetes mellitus and hypertension. Her medications included perindopril, amlodipine, metformin and gliclazide. She was diagnosed with pulmonary tuberculosis one month prior to admission (PTA), having presented with 3-month history of fever, cough and constitutional symptoms. She was started on antituberculosis treatment. Unfortunately, she developed epigastric pain and vomiting and was started on pantoprazole a month later. She requested at-own-risk discharge from hospital on two days after starting the PPI. Three days later, she was admitted again due to persistent vomiting and epigastric pain. On her 1st hospital day (HD) she developed an episode of narrow-complex tachycardia with prolonged QTc and went into respiratory distress. She required intubation and was transferred to the intensive care unit. Her blood investigations showed multiple electrolyte abnormalities, including hypomagnesaemia, hypocalcaemia, hypophosphatemia and hypokalemia. She was given multiple doses of parenteral magnesium sulfate, calcium gluconate and potassium chloride to correct those deficiencies. However, the serum magnesium, potassium and calcium levels failed to return to normal despite multiple corrections given. On the 3rd HD, pantoprazole was discontinued. Thereafter, the serum levels of magnesium, potassium and calcium started to respond to the IV corrections and slowly returned to normal. (Table 1 and Figure 1). Unfortunately, the patient developed hospital-acquired pneumonia and succumbed to septicemia two weeks later.

proton pump inhibitors, hypocalcaemia, hypokalemia, hypomagnesaemia

PMC3177425_01

Male

A 42-year-old man with complaints of dry cough and breathlessness for 15 days was referred to the Radiology Department for Computed Tomography of the thorax. His chest X-ray showed cavitation and fibrosis with patchy consolidation in the right upper zone. Patient was a diagnosed case of sputum-positive pulmonary tuberculosis and had received the complete course of antitubercular treatment 2 years earlier. On present Computed Tomography of the thorax (axial images), there were multiple thick-walled cavitary lesions in the posterior segment of right upper lobe with multiple parenchymal nodular opacities indicative of endobronchial spread of infection [Figure 1]. In addition to these findings, there was an air-filled tubular structure alongside the esophagus on the left side, beginning at the level of the T2 vertebra and communicating with the normal esophagus at the level of carina [Figure 2]. We considered a provisional diagnosis of pulsion diverticula or possibly proximal esophageal duplication as an incidental finding along with the findings of sequelae of post-primary pulmonary tuberculosis. Barium swallow study [Figure 3] was done to rule out diverticulum. On barium study, a contrast-filled tubular structure was seen alongside the normal esophagus on the left side extending from the T2 to the T4 vertebral level and communicating with the esophagus both superiorly and inferiorly. Fluoroscopically, swallowing mechanism was normal with normal mucosa and presence of peristalsis in the duplicated segment. There was no evidence of any aspiration or gastroesophageal reflux. Gastroesophageal junction was normal. With these definitive findings, diagnosis of incomplete communicating tubular duplication of upper esophagus was considered.

individualized treatment, rare anomaly, tubular esophageal duplication

Plain CT upper thorax lung window shows multiple cavitary lesions in the right upper lobe.