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Ex vivo resistance in childhood acute lymphoblastic leukemia Correlations between BCRP, MRP1, MRP4 and MRP5 ABC transporter expression and intracellular methotrexate polyglutamate accumulation.

Chemoresistance is an important factor in the treatment failure of childhood acute lymphoblastic leukemia (ALL). One underlying mechanism of chemoresistance involves (over)expression of ATP-dependent drug efflux transporters such as multidrug resistance protein 1-5 (MRP1-5) and breast cancer resistance protein (BCRP), which can extrude the important antileukemia drug methotrexate (MTX). Survival of childhood ALL critically depends on the leukemic blasts capacity for intracellular retention of MTX and MTX-polyglutamates. This pilot study assessed whether expression of MRP1, MRP4, MRP5 and BCRP (real-time PCR) in primary childhood ALL blasts (n 23) correlated with ex vivo resistance to MTX (assayed by in situ thymidylate synthase inhibition assay (TSIA)), ex vivo accumulation of (radioactive) MTX polyglutamates, and patient survival. Results show that high MRP4 expression is correlated with ex vivo MTX resistance assayed by TSIA (P 0.01). Moreover, elevated MRP4 and BCRP expression correlated with lower accumulation of MTX-PGs (P 0.004 and P 0.03, respectively). Combined high expression of BCRP and MRP4 even further impacted reduced MTX-PG accumulation (P 0.02). Overall survival was lower (P logrank 0.04) in children with ALL cells which featured a relatively high expression of both BCRP and MRP4 transporters. These results underscore the impact of high drug efflux transporter expression, notably MRP4 and BCRP, in diminished MTX response in childhood ALL.

Decreased Early Mortality in Young Adult Patients With Acute Lymphoblastic Leukemia Treated at Specialized Cancer Centers in California.

Studies suggest that patients with acute lymphoblastic leukemia (ALL) have superior survival when treated at specialized cancer centers (SCCs). However, the association of early mortality (< 60 days) with location of initial care, sociodemographic factors, and complications has not been evaluated in pediatric and young adult (YA) patients with ALL. Using the California Cancer Registry linked to hospitalization data, we identified pediatric and YA patients with ALL who received inpatient leukemia treatment between 1991 and 2014. Patients were classified as receiving all or partnone of their care at an SCC (Childrens Oncology Group- or National Cancer Institute-designated cancer center). Propensity scores were created for treatment at an SCC in each age group. Multivariable, inverse probability-weighted Cox proportional hazards regression models identified factors associated with early mortality. Results are presented as hazard ratios (HRs) and 95% CIs. Among 6,531 newly diagnosed pediatric (≤ 18 years) and YA (19 to 39 years of age) patients with ALL, 1.6% of children and 5.4% of YAs died within 60 days of diagnosis. Most children received all of their care at an SCC (n 4,752 85.7%) compared with 35.5% of YAs (n 1,779). Early mortality rates were lower in pediatric patients and those receiving all care at an SCC (pediatric all, 1.5%, v partnone, 2.4% P .049 YAs all, 3.2%, v partnone, 6.6% P .001). However, in adjusted models, receiving all care at an SCC was associated with significantly lower early mortality in YAs (HR, 0.51 95% CI, 0.32 to 0.81), but not in pediatric patients (HR, 0.77 95% CI, 0.47 to 1.25). YAs with ALL experience significant reductions in early mortality after treatment at SCCs.

Apoptosis induced by synthetic compounds containing a 3,4,5-trimethoxyphenyl fragment against lymphoid immature neoplasms.

T-cell acute lymphoblastic leukemia is an aggressive hematological malignancy originating from the malignant transformation of progenitor T cells at different stages of development. The treatment causes severe adverse effects and is associated with relapses and high morbidity and mortality rates. The present study aimed to evaluate the cytotoxic activity of 28 new compounds containing 3,4,5-trimethoxyphenyl analogues on hematological neoplastic cells lines. Cytotoxicity screening by the MTT method revealed that compound 1d was the most promising. Cell viability of neoplastic cells decreased in a concentration- and time-dependent manner, with compound 1d not causing hemolysis or reducing peripheral blood mononuclear cells viability, suggesting a selective cytotoxicity. We also suggested that compound 1d induced apoptotic-like cell death with mitochondrial involvement in Jurkat cells.

A genetic variant in miR-100 is a protective factor of childhood acute lymphoblastic leukemia.

In the past decade, miR-100, miR-146a, and miR-210 were reported to be dysregulated in childhood acute lymphoblastic leukemia (ALL). However, effects of genetic variants in these three microRNAs have not been investigated in Chinese population. In this study, we conducted a case-control study to evaluate the relationship between genetic variants in miR-100, miR-146a, and miR-210 and the risk of childhood ALL in Chinese population. Subsequently, plasma expression level of miR-100 was also detected. We found that subjects carrying mutant homozygous TT genotype of miR-100 rs543412 had a statistically significantly decreased risk of childhood ALL (adjusted odds ratio OR 0.73, 95% confidence interval CI 0.55-0.97, P 0.029). This protective effect was also observed among subjects whose parents were ever drinkers (adjusted OR 0.53, 95% CI 0.29-0.94), or whose living house were ever painted (adjusted OR 0.57, 95% CI 0.34-0.94). Besides, rs543412 variant homozygous TT had a significantly protective role in patients with childhood B-ALL. Finally, we found that expression level of miR-100 in plasma of childhood ALL cases was significantly higher than that of noncancer controls. Our study suggested that there was significant association between the polymorphisms in miR-100 (rs543412) and decreased susceptibility to childhood ALL.

Tisagenlecleucel Model-Based Cellular Kinetic Analysis of Chimeric Antigen Receptor-T Cells.

Tisagenlecleucel is a chimeric antigen receptor-T cell therapy that facilitates the killing of CD19

No evidence that G6PD deficiency affects the efficacy or safety of daunorubicin in acute lymphoblastic leukemia induction therapy.

Anthracyclines are used in induction therapy of pediatric acute lymphoblastic leukemia (ALL) and are known to generate oxidative stress whether this translates into enhanced antileukemic activity or hemolytic effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency is unknown. Among 726 pediatric patients with newly diagnosed ALL treated at St. Jude Childrens Research Hospital, 22 had deficient G6PD activity. We compared the prevalence of positive minimal residual disease (MRD) ≥1% at Day 15Day 19 of induction or ≥0.01% at Day 42Day 46 (end of induction) and the number of red blood cell (RBC) transfusions after daunorubicin in induction between patients with or without G6PD deficiency, adjusting for ALL risk group, treatment protocol, age, and gender. There was no difference in Day 1519 (P 1) or end of induction MRD (P 0.76) nor in the number of RBC transfusions (P 0.73) the lack of association with MRD was confirmed in a dataset of 1192 newly diagnosed male patients enrolled in a Childrens Oncology Group trial (P 0.78). We found no evidence that G6PD deficiency affects daunorubicin activity during induction treatment for ALL.

Clinician Concepts of Cure in Adult Relapsed and Refractory Philadelphia-Negative B Cell Precursor Acute Lymphoblastic Leukemia A Delphi Study.

Despite the poor prognosis for adults with relapsed or refractory (RR) Philadelphia chromosome (Ph)-negative B cell precursor acute lymphoblastic leukemia (ALL), long-term survival is possible and may even be considered as cure. This study used a Delphi panel approach to explore concepts of cure in RR Ph-negative B cell precursor ALL. Ten European experts in this disease area participated in a survey and face-to-face panel meeting. Findings showed that clinicians conceptualize cure as a combination of three broad treatment outcomes that vary depending on the treatment stage complete remission early in treatment (1-3 months) indicates initial success eradicating cancer cells (minimal residual disease negative status) consolidates the early clinical response leukemia-free survival is required in the long term. Although such terminology remains contested, clinicians would begin considering cure as early as 2 years provided the patient is off therapy, with most considering the term applicable by the third year. Amgen Inc.

PAX5 biallelic genomic alterations define a novel subgroup of B-cell precursor acute lymphoblastic leukemia.

Chromosomal rearrangements and specific aneuploidy patterns are initiating events and define subgroups in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Here we analyzed 250 BCP-ALL cases and identified a novel subgroup (PAX5-plus, n 19) by distinct DNA methylation and gene expression profiles. All patients in this subgroup harbored mutations in the B-lineage transcription factor PAX5, with p.P80R as hotspot. Mutations either affected two independent codons, consistent with compound heterozygosity, or suffered LOH predominantly through chromosome 9p aberrations. These biallelic events resulted in disruption of PAX5 transcriptional programs regulating B-cell differentiation and tumor suppressor functions. Homozygous CDKN2AB deletions and RAS-activating hotspot mutations were highly enriched as cooperating events in the genomic profile of PAX5-plus ALL. Together, this defined a specific pattern of triple alterations, exclusive to the novel subgroup. PAX5-plus ALL was observed in pediatric and adult patients. Although restricted by the limited sample size, a tendency for more favorable clinical outcome was observed, with 10 of 12 adult PAX5-plus patients achieving long-term survival. PAX5-plus represents the first BCP-ALL subgroup defined by sequence alterations in contrast to gross chromosomal events and exemplifies how deregulated differentiation (PAX5), impaired cell cycle control (CDKN2AB) and sustained proliferative signaling (RAS) cooperatively drive leukemogenesis.

Correction Inotuzumab ozogamicin in pediatric patients with relapsedrefractory acute lymphoblastic leukemia.

We thank the research coordinators and following physicians at pediatric cancer centers for contributing data to this project Prashant Hiwarkar and Jayashree Motwani, Birmingham Womens and Childrens Hospital, UK Kelly Malone, Childrens Hospital of Colorado, USA Mylene Bassal, Childrens Hospital of Eastern Ontario, Canada Yoav Messinger and Joanna Perkins, Childrens Hospital of Minnesota, USA Van Huynh, Childrens Hospital of Orange County, USA Richard Ho, Childrens Hospital at Vanderbilt, USA Joanne Chuah and Jessa Morales, Childrens Hospital at Westmead, Australia Donald Wells, Dell Childrens Hospital, USA Nicolas Boissel, Hospital Saint-Louis, France Tannie Huang, Kaiser Permanente, USA Stacey Marjerrison, McMaster Childrens Hospital, Canada William Carroll and Joanna Pierro, New York University Langone Medical Center, USA Ajay Vora, Sheffield Childrens Hospital, UK Donna Lancaster, The Royal Marsden Hospital, UK Lucie Šrámková, University Hospital Motol, Czech Republic Chatchawin Assanasen, University of Texas Health Science Center, San Antonio, USA Rupert Handgretinger, University of Tübingen, Germany.

Philadelphia chromosome-positive acute lymphoblastic leukemia relapsing with an anterior chamber lesion of the eye.

A 48-year-old Filipino woman underwent umbilical cord blood stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia under non-remission status. Left aqueous humor puncture was performed owing to the development of left eye pain and exacerbation of anterior eye chamber inflammation 72 days after the transplantation this revealed the relapse of leukemia in the anterior chamber. Subsequently, the patient tested positive for peripheral blood minimal residual disease. Therefore, doctors should take note that anterior chamber disease may appear as a non-typical relapse of leukemia.

Osteonecrosis in Children and Adolescents With Acute Lymphoblastic Leukemia Early Diagnosis and New Treatment Strategies.

In the last few decades, treatment strategies for acute lymphoblastic leukemia (ALL) have been associated not only with improvement of prognosis, but also with an increasing rate of late complication as osteonecrosis (ON). Herein, the cumulative incidence, risk factors, new conservative therapeutic strategies as hyperbaric oxygen therapy (HBO), and outcome of symptomatic ON were studied in pediatric patients with ALL. Between 2000 and 2017, 495 children and young adolescents with a diagnosis of ALL were evaluated. All the symptomatic patients underwent magnetic resonance imaging (MRI) to detect bone vascularization and structure. Twenty-three out of 495 patients presented ON (4.6%). ON was associated with an older age (p<0.0001) and a higher steroid dose (p0.0013). All the patients underwent standard therapies and HBO was performed in 8 of 23 patients. During the follow-up, 15 patients were stable 6 were totally asymptomatic, 5 complained of pain during activity, and 4 presented mild function limitation. Our data highlight the importance of early diagnosis of ON by screening MRI in asymptomatic patients, in order to start conservative treatment strategies. Moreover, HBO could have beneficial effects on ON patients.

Association of

The association of matrix metalloproteinase-2 (MMP-2) genotypes with adult leukemia has been reported only once, but never for childhood leukemia. This study aimed to determine the role of MMP-2 promoter -1306 (rs243865) and -735 (rs2285053) genotypes in childhood leukemia risk. This case-control study included 266 patients and 266 age- and gender-matched healthy controls. The polymorphic sites of MMP-2 were genotyped by typical polymerase chain reaction-restriction fragment length polymorphism. The CC, CT and TT of rs243865 genotype were 75.2, 23.7 and 1.1% in the case group and 69.2, 28.9 and 1.9% in the control group, respectively. The CT and TT genotypes caused a 0.75- and 0.55-fold increase in the risk of childhood leukemia, respectively. There was no differential distribution of rs2285053 genotypes. Allelic frequency analysis showed that the T allele of MMP-2 promoter -1306 and -735 conferred lower susceptibility than the C allele. The MMP-2 promoter genotypes play a minor role in determining personal susceptibility to childhood leukemia among the Taiwanese.

Comparative features and outcomes between paediatric T-cell and B-cell acute lymphoblastic leukaemia.

Contemporary paediatric clinical trials have improved 5-year event-free survival above 85% and 5-year overall survival above 90% in B-cell acute lymphoblastic leukaemia (ALL) in many study groups, whilst outcomes for T-cell ALL are still lagging behind by 5-10% in most studies. Several factors have contributed to this discrepant outcome. First, patients with T-cell ALL are generally older than those with B-cell ALL and, therefore, have poorer tolerance to chemotherapy, especially dexamethasone and asparaginase, and have increased risk of extramedullary relapse. Second, a higher proportion of patients with B-cell ALL have favourable genetic subtypes (eg, ETV6-RUNX1 and high hyperdiploidy), which confer a superior outcome compared with favourable subtypes of T-cell ALL. Third, T-cell ALL blasts are generally more resistant to conventional chemotherapeutic drugs than are B-cell ALL blasts. Finally, patients with B-cell ALL are more amendable to available targeted therapies, such as Philadelphia chromosome-positive and some Philadelphia chromosome-like ALL cases to ABL-class tyrosine kinase inhibitors, and CD19-positive and CD22-postive B-cell ALL cases to a variety of immunotherapies. Several novel treatments under investigation might narrow the gap in survival between T-cell ALL and B-cell ALL, although novel treatment options for T-cell ALL are limited.

Combined Casein Kinase II inhibition and epigenetic modulation in acute B-lymphoblastic leukemia.

The tumor suppressor protein phosphatase and tensin homolog (PTEN) is a key regulator of the PI3KAKT pathway which is frequently altered in a variety of tumors including a subset of acute B-lymphoblastic leukemias (B-ALL). While PTEN mutations and deletions are rare in B-ALL, promoter hypermethylation and posttranslational modifications are the main pathways of PTEN inactivation. Casein Kinase II (CK2) is often upregulated in B-ALL and phosphorylates both PTEN and DNA methyltransferase 3A, resulting in increased PI3KAKT signaling and offering a potential mechanism for further regulation of tumor-related pathways. Here, we evaluated the effects of CK2 inhibitor CX-4945 alone and in combination with hypomethylating agent decitabine on B-ALL proliferation and PI3KAKT pathway activation. We further investigated if CX-4945 intensified decitabine-induced hypomethylation and identified aberrantly methylated biological processes after CK2 inhibition. In vivo tumor cell proliferation in cell line and patient derived xenografts was assessed by longitudinal full body bioluminescence imaging and peripheral blood flow cytometry of NSG mice. CX-4945 incubation resulted in CK2 inhibition and PI3K pathway downregulation thereby inducing apoptosis and anti-proliferative effects. CX-4945 further affected methylation patterns of tumor-related transcription factors and regulators of cellular metabolism. No overlap with decitabine-affected genes or processes was detected. Decitabine alone revealed only modest anti-proliferative effects on B-ALL cell lines, however, if combined with CX-4945 a synergistic inhibition was observed. In vivo assessment of CX-4945 in B-ALL cell line xenografts resulted in delayed proliferation of B-ALL cells. Combination with DEC further decelerated B-ALL expansion significantly and decreased infiltration in bone marrow and spleen. Effects in patient-derived xenografts all harboring a t(411) translocation were heterogeneous. We herein demonstrate the anti-leukemic potential of CX-4945 in synergy with decitabine in vitro as well as in vivo identifying CK2 as a potentially targetable kinase in B-ALL.

Epigenetics of B-ALL.

Precursor B-cell acute lymphoblastic leukemia (B-ALL) is one of the most common neoplasms. It is characterized by genetic and epigenetic aberrations. The most remarkable mechanisms involved in epigenetic abnormalities are DNA methylation and acetylation. Methylation of CpG islands in promoter regions and acetylation of lysine residues regulate gene expression. Several studies have shown that patients with B-ALL show aberrant DNA methylation in a genome-wide scale. Histone deacetylases (HDAC) regulate gene expression by removing acetyl groups from lysine residues and histone acetyltransferase (HAT) adds acetyl groups. A hematologic malignancy like B-ALL may be very sensitive to small-molecule inhibitors that target these epigenetic mechanisms and therefore may induce expression of pro-apoptotic factors. Thus, HDAC inhibitors (HDACi), DNA methyltransferase inhibitors (DNMTi) and histone acetyltransferase inhibitors (HATi) have been developed as therapies. The objective of this review is to summarize the different epigenetic mechanisms involved in B-ALL.

Reduced vs. standard dose native E. coli-asparaginase therapy in childhood acute lymphoblastic leukemia long-term results of the randomized trial Moscow-Berlin 2002.

Favorable outcomes were achieved for children with acute lymphoblastic leukemia (ALL) with the first Russian multicenter trial Moscow-Berlin (ALL-MB) 91. One major component of this regimen included a total of 18 doses of weekly intramuscular (IM) native Escherichia coli-derived asparaginase (E. coli-ASP) at 10000 Um Between April 2002 and November 2006, 774 SR patients were registered in 34 centers across Russia and Belarus, 688 of whom were randomized. In arm ASP-5000 (n 334), patients received 5000 Um Probabilities of disease-free survival, overall survival and cumulative incidence of relapse at 10 years were comparable 79 ± 2%, 86 ± 2% and 17.4 ± 2.1% (ASP-5000) vs. 75 ± 2% and 82 ± 2%, and 17.9 ± 2.0% (ASP-10000), while death in complete remission was significantly lower in arm ASP-5000 (2.7% vs. 6.5% p 0.029). Our findings suggest that weekly 5000 Um

Absolute count of leukemic blasts in cerebrospinal fluid as detected by flow cytometry is a relevant prognostic factor in children with acute lymphoblastic leukemia.

Usually, central nervous system (CNS) involvement in acute lymphoblastic leukemia (ALL) is diagnosed by cytomorphology (CM) of cerebrospinal fluid (CSF) on cytospin slides. Multicolor flow cytometry (MFC) provides the opportunity to detect low numbers of leukemia cells undetectable by CM. The present study aimed at evaluating the clinical significance of MFC for the diagnosis of CNS involvement at initial manifestation of childhood ALL. In 155 children with ALL, CSF samples were studied in parallel by CM and MFC. Patients were treated according to protocol ALL-MB-2008 for childhood ALL. The prognostic impact of the leukemia burden in CSF was determined categorizing the findings as positivenegative. In addition, the absolute blast cell count per 1 ml of CSF was studied as a continuous variable. CSF positivity was significantly more frequent using MFC compared with CM (35.3% vs. 15.3% of patients). The outcome of MFC-positive and MFC-negative patients was not different in clinically relevant patient risk groups-CNS1, standard and intermediate-risk groups. Using the quantitative approach, at the threshold level of 20 blasts per ml of CSF, patients could be divided into two groups with a significantly different outcome, irrespective of the clinical risk group, the type of CNS-directed therapy, and the CNS status determined by CM. Our data do not support the concept of re-stratification and modification of therapy based on qualitative CSF investigation by MFC. However, MFC is a highly sensitive technique of CSF investigation improving the definition of CNS involvement in childhood ALL, and quantitative measurement of blast cells in CSF, if well-organized, can be a useful additional tool for stratification of patients in clinical trials.

Risk of selected childhood cancers and parental employment in painting and printing industries A register-based case‒control study in Denmark 1968-2015.

Objectives Parental exposures and offsprings risk of cancer have been studied with inconsistent results. We investigated parental employment in painting and printing industries and risk of childhood leukemia, central nervous system (CNS) cancers, and prenatal cancers (acute lymphoblastic leukemia, Wilms tumor, medulloblastoma, neuroblastoma, retinoblastoma, and hepatoblastoma). Methods Using Danish registries, children aged ≤19 years diagnosed from 1968-2015 with leukemia (N1999), CNS cancers (N1111) or prenatal cancers (N2704) were linked to parents and their employment history one year before birth to birth for fathers, and one year before birth to one year after for mothers. Twenty randomly selected controls per case were matched by age and sex. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using conditional logistic regression. Results For fathers, we found increased risks for acute myeloid leukemia (AML) consistent in painting (OR 2.26, 95% CI 1.07-4.80) and printing industries (OR 2.43, 95% CI 0.94-6.23) and these industries combined (OR 2.10, 95% CI 1.14-3.87). For mothers, increased risks of CNS cancers were found for painting industries (OR 2.34, 95% CI 1.10-4.95) and painting and printing combined (OR 1.97, 95% CI 1.08-3.64). For fathers working in combined industries, the OR for CNS was increased (OR 1.54, 95% CI 1.02-2.31), most prominently in printing industries (OR 2.09, 95% CI 1.17-3.75). Conclusion We observed increased risks of CNS tumors in offspring after parental employment in painting and printing industries. Children of fathers employed in painting and printing industries had a two-fold increase in AML.

Alternative Splicing of MXD3 and Its Regulation of MXD3 Levels in Glioblastoma.

The transcription factor MXD3 is an atypical member of the MYCMAXMXD transcriptional network and has been previously shown to be an important regulator of cell proliferation. MXD3 has been shown to be overexpressed and to be required for medulloblastoma and acute lymphoblastic leukemia cell proliferation. In this study we leveraged datasets from The Cancer Genome Atlas to examine MXD3 across several cancers. We find that MXD3 transcripts are significantly overexpressed in 72% of the available datasets. The gene itself is not frequently altered, while the promoter appears to be hypomethylated. We examine the possibility that aberrant regulation of the MXD3 message is the cause of abnormal MXD3 expression across cancers. Specifically, we looked at MXD3 alternative splicing in glioblastoma multiforme (GBM) and find notable functional differences between the splice variants. The 3UTR confers differential message stability. Furthermore, the different coding sequences lead to different protein stabilities and localizations. Altogether, these data extend our knowledge of MXD3 in the context of human cancers while characterizing a previously unstudied splice variant of MXD3.

Infectious Complications Are Associated With Alterations in the Gut Microbiome in Pediatric Patients With Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia is the most common pediatric cancer. Fortunately, survival rates exceed 90%, however, infectious complications remain a significant issue that can cause reductions in the quality of life and prognosis of patients. Recently, numerous studies have linked shifts in the gut microbiome composition to infection events in various hematological malignances including acute lymphoblastic leukemia (ALL). These studies have been limited to observing broad taxonomic changes using 16S rRNA gene profiling, while missing possible differences within microbial functions encoded by individual species. In this study we present the first combined 16S rRNA gene and metagenomic shotgun sequencing study on the gut microbiome of an independent pediatric ALL cohort during treatment. In this study we found distinctive differences in alpha diversity and beta diversity in samples from patients with infectious complications in the first 6 months of therapy. We were also able to find specific species and functional pathways that were significantly different in relative abundance between samples that came from patients with infectious complications. Finally, machine learning models based on patient metadata and bacterial species were able to classify samples with high accuracy (84.09%), with bacterial species being the most important classifying features. This study strengthens our understanding of the association between infection and pediatric acute lymphoblastic leukemia treatment and warrants further investigation in the future.

Mechanisms of resistance to CAR T cell therapy.

The successes with chimeric antigen receptor (CAR) T cell therapy in early clinical trials involving patients with pre-B cell acute lymphoblastic leukaemia (ALL) or B cell lymphomas have revolutionized anticancer therapy, providing a potentially curative option for patients who are refractory to standard treatments. These trials resulted in rapid FDA approvals of anti-CD19 CAR T cell products for both ALL and certain types of B cell lymphoma - the first approved gene therapies in the USA. However, growing experience with these agents has revealed that remissions will be brief in a substantial number of patients owing to poor CAR T cell persistence andor cancer cell resistance resulting from antigen loss or modulation. Furthermore, the initial experience with CAR T cells has highlighted challenges associated with manufacturing a patient-specific therapy. Understanding the limitations of CAR T cell therapy will be critical to realizing the full potential of this novel treatment approach. Herein, we discuss the factors that can preclude durable remissions following CAR T cell therapy, with a primary focus on the resistance mechanisms that underlie disease relapse. We also provide an overview of potential strategies to overcome these obstacles in an effort to more effectively incorporate this unique therapeutic strategy into standard treatment paradigms.

miR-101 Represses T-Cell Acute Lymphoblastic Leukemia by Targeting CXCR7STAT3 Axis.

Although miR-101 is involved in the development and progression of T-cell acute lymphoblastic leukemia (T-ALL), the underlying molecular mechanisms remain unclear. In this article, we report that miR-101 expression was inversely correlated with CX chemokine receptor 7 (CXCR7) level in T-ALL. Introducing miR-101 inhibited T-ALL cell proliferation and invasion in vitro and suppressed tumor growth and lung metastasis in vivo. CXCR7 was identified as a direct target of miR-101. The inhibitory effects of miR-101 were mimicked and counteracted by CXCR7 depletion and overexpression, respectively. Mechanistically, miR-101 targets CXCR7STAT3 axis to reduce T-ALL growth and metastasis. Overall, these findings implied the potential application of miR-101 and CXCR7 in T-ALL treatment.

Expression, purification, and characterization of asparaginase II from Saccharomyces cerevisiae in Escherichia coli.

l-asparaginase catalyzes the conversion of l-asparagine to l-aspartate and ammonium. This protein is an important therapeutic enzyme used for the treatment of acute lymphoblastic leukemia. In this study, the asparaginase II-encoding gene ASP3 from Saccharomyces cerevisiae was cloned into the expression vector pET28a in-fusion with a 6x histidine tag and was expressed in Escherichia coli BL21 (DE3) cells. The protein was expressed at a high level (225.6 IUg cells) as an intracellular and soluble molecule and was purified from the supernatant by nickel affinity chromatography. The enzyme showed very low activity against l-glutamine. The denaturing electrophoresis analysis indicated that the recombinant protein had a molecular mass of ∼38 kDa. The native enzyme was a tetramer with a molecular mass of approximately 178 kDa. The enzyme preparation showed antitumor activity against the K562 and Jurkat cell lines comparable or even superior to the E. coli commercial asparaginase.

Potent and Highly Selective Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors Act as Chemotherapeutic Potentiators in Acute Myeloid Leukemia and T-Cell Acute Lymphoblastic Leukemia.

Aldo-keto reductase 1C3 (AKR1C3) catalyzes the synthesis of 9α,11β-prostaglandin (PG) F

Plasma creatinine as predictor of delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia A Danish population-based study.

Severely delayed elimination of methotrexate (MTX) is difficult to predict in patients treated with high-dose MTX (HD-MTX), but it may cause life-threatening toxicity. It has not been defined how an increase in plasma creatinine can be best used as a predictor for severely delayed MTX elimination, thus providing a guide for therapeutic interventions to minimize renal toxicity. Pharmacokinetic data were retrospectively collected on 218 Danish children with acute lymphoblastic leukemia treated with HD-MTX 5 or 8 gm Median 42-hour plasma MTX was 0.61 μM (interquartile range, 0.4-1.06 μM). Of 1295 MTX infusions with 5 gm A 25 μM increase or a 1.5-fold in plasma creatinine within 36 hours after start of an HD-MTX infusion can predict delayed MTX elimination, thus allowing intensification of hydration and alkalization to avoid further renal toxicity and promote the elimination of MTX.

Chk1 Inhibition Restores Inotuzumab Ozogamicin Citotoxicity in CD22-Positive Cells Expressing Mutant p53.

Inotuzumab ozogamicin (IO) is an anti-CD22 calicheamicin immunoconjugate that has been recently approved for the treatment of relapsed or refractory B-Acute Lymphoblastic Leukemia (rr B-ALL). We employed both immortalized and primary cells derived from CD22-positive lymphoproliferative disorders to investigate the signaling pathways contributing to IO sensitivity or resistance. We found that the drug reduced the proliferation rate of CD22-positive cell lines expressing wild-type p53, but was remarkably less effective on cells exhibiting mutant p53. In addition, CD22-positive cells surviving IO were mostly blocked in the G2M phase of the cell cycle because of Chk1 activation that, in the presence of a wild-type p53 background, led to p21 induction. When we combined IO with the Chk1 inhibitor UCN-01, we successfully abrogated IO-induced G2M arrest regardless of the underlying p53 status, indicating that the DNA damage response triggered by IO is also modulated by p53-independent mechanisms. To establish a predictive value for p53 in determining IO responsiveness, we expressed mutant p53 in cell lines displaying the wild-type gene and observed an increase in IO IC

Socioeconomic inequalities in survival of children with acute lymphoblastic leukemia insured by social security in Mexico a study of the 2007-2009 cohorts.

Although acute lymphoblastic leukemia (ALL) 5 years survival in minors has reached 90%, socioeconomic differences have been reported among and within countries. Within countries, the difference has been related to the socioeconomic status of the parents, even in the context of public health services with universal coverage. In Mexico, differences in the mortality of children with cancer have been reported among sociodemographic zones. The Instituto Mexicano del Seguro Social (IMSS), the countrys main social security institution, has reported socioeconomic differences in life expectancy within its affiliated population. Here, the socioeconomic inequalities in the survival of children (< 15 years old) enrolled in the IMSS were analyzed. Five-year survival data were analyzed in cohorts of patients diagnosed with ALL during the period 2007-2009 in the two IMSS networks of medical services that serve 7 states of the central region of Mexico. A Cox proportional risk model was developed and adjusted for the socioeconomic characteristics of family, community of residence and for the clinical characteristics of the children. The slope of socioeconomic inequality of the probability of dying within five years after the diagnosis of ALL was estimated. For the 294 patients studied, the 5 years survival rate was 53.7% the median survival was 4.06 years (4.9 years for standard-risk diagnosis 2.5 years for high-risk diagnosis). The attrition rate was 12%. The Cox model showed that children who had been IMSS-insured for less than half their lives had more than double the risk of dying than those who had been insured for their entire lives. We did not find evidence of socioeconomic inequalities in the survival of children with ALL associated with family income, educational and occupational level of parents. However, we found a relevant gradient related social security protection the longer childrens life insured by social security, the higher their probability of surviving ALL was. These results add evidence of the effectiveness of social security, as a mechanism of wealth redistribution and a promoter of social mobility. Extending these social security benefits to the entire Mexican population could promote better health outcomes.

Pharmacogenomic and Pharmacotranscriptomic Profiling of Childhood Acute Lymphoblastic Leukemia Paving the Way to Personalized Treatment.

Personalized medicine is focused on research disciplines which contribute to the individualization of therapy, like pharmacogenomics and pharmacotranscriptomics. Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. It is one of the pediatric malignancies with the highest cure rate, but still a lethal outcome due to therapy accounts for 1%⁻3% of deaths. Further improvement of treatment protocols is needed through the implementation of pharmacogenomics and pharmacotranscriptomics. Emerging high-throughput technologies, including microarrays and next-generation sequencing, have provided an enormous amount of molecular data with the potential to be implemented in childhood ALL treatment protocols. In the current review, we summarized the contribution of these novel technologies to the pharmacogenomics and pharmacotranscriptomics of childhood ALL. We have presented data on molecular markers responsible for the efficacy, side effects, and toxicity of the drugs commonly used for childhood ALL treatment, i.e., glucocorticoids, vincristine, asparaginase, anthracyclines, thiopurines, and methotrexate. Big data was generated using high-throughput technologies, but their implementation in clinical practice is poor. Research efforts should be focused on data analysis and designing prediction models using machine learning algorithms. Bioinformatics tools and the implementation of artificial i Lack of association of the CEP72 rs924607 TT genotype with intelligence are expected to open the door wide for personalized medicine in the clinical practice of childhood ALL.

The prognostic significance of minimal residual disease detection after first induction treatment in adult acute lymphoblastic leukemia patients treated with autologous stem cell transplantation.

Blinatumomab administered concurrently with oral tyrosine kinase inhibitor therapy is a well-tolerated consolidation strategy and eradicates measurable residual disease in adults with Philadelphia chromosome positive acute lymphoblastic leukemia.

Incorporation of ABL-targeted oral tyrosine kinase inhibitors (TKIs) into frontline therapeutic regimens has improved outcomes for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL). However, patients with persistent minimal residual disease (MRD) exhibit increased risk of relapse. Combining consolidative chemotherapy with TKIs may increase rates of infectious complications, organ toxicity, hospitalization, and non-relapse mortality. Blinatumomab has demonstrated single-agent activity in patients with relapsed B-ALL or persistent MRD, including Ph B-ALL. We have used blinatumomab concomitantly with commercially available TKIs as consolidative therapy to spare toxicities of conventional chemotherapy. We evaluated 11 adults with previously treated Ph B-ALL who received blinatumomab concurrent with TKI (ponatinib, n 5 dasatinib, n 4 nilotinib, n 1 imatinib, n 1) to eradicate MRD or sustain MRD-negativity. Eight of 9 patients with MRD achieved BCR-ABL1 negativity (complete molecular response, CMR) after a median of one cycle 22 patients without measurable disease durably maintained CMR. Cytokine release syndrome (all grade 1-2) was observed in 311 patients one patient experienced transient grade 1 neurologic toxicity. Transient grade 2 transaminitis was observed in 611 patients, including 45 recipients of blinatumomab ponatinib. This small series suggests blinatumomab TKI is a safe and effective consolidation strategy for patients with Ph ALL to achieve or maintain CMR.

Psychosocial Experiences of Young Adults Diagnosed With Acute Leukemia During Hospitalization for Induction Chemotherapy Treatment.

The diagnosis of cancer for anyone is a time of fear and uncertainty. For young adults (YAs) diagnosed with acute leukemia (AL), there are the additional challenges related to lengthy aggressive in-hospital treatment, multiple concurrent symptoms, and decreased well-being. The purpose of this study was to explore the experiences of YAs with AL undergoing induction chemotherapy. This study used a nested qualitative longitudinal design with a convenience sample. Qualitative data were collected using semistructured interviews, and participants were invited to maintain journals. The semistructured interviews were audiotaped, transcribed, and loaded into Atlas.ti for analysis. Common themes and categories were verified and used to disseminate the findings. Seven YAs, mean age 32 (SD, 4) years, participated in this study. Three thematic classifications emerged getting through, supported yet isolated, and information exchange preferences, which detail how these YAs processed and coped during treatment. The findings from this study provide important insights for nurses regarding coping mechanisms that YAs apply, which included relying on technology and social media platforms. Additionally, the YAs in this study discussed their need for information. The findings from this study may provide insights for clinicians currently caring for YAs with AL, while also directing future palliative care research endeavors.

Chimeric Antigen Receptor-modified Donor Lymphocyte Infusion Improves the Survival of Acute Lymphoblastic Leukemia Patients With Relapsed Diseases After Allogeneic Hematopoietic Stem Cell Transplantation.

The value of chimeric antigen receptor-modified donor lymphocyte infusion (CAR-DLI) is unclear in B-cell acute lymphoblastic leukemia (B-ALL), particularly in patients with relapsed diseases after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, 5 B-ALL patients who relapsed after allo-HSCT received CAR-DLI (CAR-DLI group), and the outcome was compared with 27 relapsed B-ALL patients who received DLI therapy (DLI group). The median complete remission duration of CAR-DLI group was significantly (P0.020) longer when compared with DLI group 9 months (range, 2-29) versus 3.2 months (range, 0-17.4). Furthermore, patients receiving CAR-DLI showed significant (P0.049) survival advantage over DLI group, with median overall survival of 12 months (range, 3-29) and 3.7 months (range, 0-65), respectively. Of note, no patient developed acute graft versus host disease in the CAR-DLI group, while incidence of acute graft versus host disease grades I-II and grades III-IV were 2 (7%) and 4 (14.8%) in the DLI group, respectively. In addition, cytokine release syndrome in CAR-DLI group was manageable. Overall, our study demonstrated that CAR-DLI significantly improved the survival of B-ALL patients relapsed after allo-HSCT, thus indicating that CAR-DLI may represent an alternative and more effective therapy for B-ALL patients with relapsed diseases.

Septum Pellucidum Cavernoma A Case Report and Anatomical Consideration of an Extremely Rare Lesion.

Cavernous angiomas (cavernomas) are vascular malformations of the brain characterized by abnormal capillaries. Ventricular cavernomas are considered rare however, an extremely unusual topography is the septum pellucidum, with only five reported cases in the English literature. These malformations may rupture and cause very large hematomas, leading to neurological impairment. Cavernomas can be familial or sporadic additionally, these may appear following brain radiotherapy in extremely rare cases. Herein, we present an extremely rare and unique case of a septum pellucidum cavernoma that occurred in a young male who had previously undergone brain radiotherapy in childhood due to acute lymphoid leukemia. Following presentation, he was diagnosed with generalized seizures. The cavernoma was resected via an anterior interhemispheric transcallosal approach, following which the patient remained stable without neurological sequelae. To conclude, ventricular cavernomas are rare lesions, especially when located at the septum pellucidum, thus constitute a challenging neurosurgical approach.

Design and synthesis of various quinizarin derivatives as potential anticancer agents in acute T lymphoblastic leukemia.

A series of quinizarin derivatives containing quaternary ammonium salts andor thiourea groups were synthesized and their anticancer activities against leukemia cell lines have been tested. Results showed that most of quinizarin derivatives could inhibit the proliferation of leukemia cells. Among these derivatives, compound 3 showed good inhibition activity against various leukemia cells with IC

Targeting T Cell Malignancies Using CD4CAR T-Cells and Implementing a Natural Safety Switch.

T cell malignancies are aggressive diseases with no standard treatment available, often resulting in poor patient outcomes. Lately, the recent FDA approval of a CD19 CAR T cell therapy for B cell acute lymphoblastic leukemia has earned nationwide attention, leading to the possibility that success of CD19 CAR therapy can be extended to T cell malignancies. However, the impact of T cell depletion due to a shared antigen pool remains an issue to be resolved. Here, we describe a CD4CAR capable of eliminating CD4-positive T cell acute lymphoblastic leukemia in a systemic mouse model, with CAMPATH (alemtuzumab) as a natural safety switch to deplete the infused CD4CAR T cells to prevent toxicities associated with CD4 cell aplasia. Our data support the potential use of CD4CAR T cells for the treatment of CD4-postive T-cell acute lymphoblastic leukemia malignancies or refractory disease in clinical settings.

Dynamic changes in specific anti-L-asparaginase antibodies generation during acute lymphoblastic leukemia treatment.

L-asparaginase (L-asp) remains one of the key components of acute lymphoblastic leukemia therapy. Immune reactions to the drug are associated with its diminished activity. The aim of the study was to determine the level of IgM, IgG and IgE-class anti-L-asp antibodies during the induction and reinduction phases of acute lymphoblastic leukemia therapy and their influence on L-asp activity. The study group comprised 65 patients treated for acute lymphoblastic leukemia in one pediatric oncology center. L-asp antibodies were assessed using ELISA at the end of the induction and reinduction phases. L-asp activity was assessed prior to each drug administration by colorimetry. At the end of the first exposure to L-asp antibodies were detected in 35 patients (54%). In the reinduction phase of the treatment anti-L-asp antibodies were found in 3855 patients (69%). In the induction phase patients with inadequate L-asp activity had higher IgM concentrations (median 5.88 versus 2.81 μgmL, p 0.03). In the reinduction phase IgG and IgM levels correlated inversely with L-asp activity. Patients with L-asp allergy had higher levels of IgG (median 61.6 versus 18.36 μgmL, p 0.01), whereas higher IgE levels were noted in the group of patients with inadequate drug activity (median 0.91 versus 0.64 μgmL, p 0.03). Subsequent exposure to L-asp in the treatment of acute lymphoblastic leukemia was associated with the increase of anti-L-asp antibodies in all studied classes. However, the changes observed in specific classes of antibodies were not distinctive for L-asp hypersensitivity or inactivation, suggesting that the mechanism is more complex.

Outcomes of patients with childhood B-cell precursor acute lymphoblastic leukaemia with late bone marrow relapses long-term follow-up of the ALLR3 open-label randomised trial.

The ALLR3 trial investigated outcomes of children with B-cell precursor acute lymphoblastic leukaemia who had late bone marrow relapses. We analysed long-term follow-up outcomes of these patients. ALLR3 was an open-label randomised clinical trial that recruited children aged 1-18 years with B-cell precursor acute lymphoblastic leukaemia who had late bone marrow relapses. Eligible patients were recruited from centres in Australia, Ireland, the Netherlands, New Zealand, and the UK. Patients were randomly assigned from Jan 31, 2003, to Dec 31, 2007, and the trial closed to recruitment on Oct 31, 2013. Randomly assigned patients were allocated to receive either idarubicin or mitoxantrone in induction by stratified concealed randomisation after randomisation stopped in Dec 31, 2007, all patients were allocated to receive mitoxantrone. After three blocks of therapy, patients with high minimal residual disease (≥10 Between Feb 2, 2003, and Oct 28, 2013, 228 patients with B-cell precursor acute lymphoblastic leukaemia and late bone marrow relapses were treated. After a median follow-up of 84 months (IQR 48-109), progression-free survival of all randomly assigned patients was 60% (95% CI 54-70). 220 patients achieved second complete remission, and minimal residual disease was evaluable in 192 (87%). 110 patients with late bone marrow relapses and high minimal residual disease at the end of induction were allocated to undergo stem-cell transplantation, and 82 patients with low minimal residual disease at the end of induction were allocated to receive chemotherapy. In the patients allocated to undergo stem-cell transplantation, four relapses and three deaths were reported before the procedure, and 11 patients were not transplanted. Of the 92 patients transplanted, 58 (63%) remained in second complete remission, 13 (14%) died of complications, and 21 (23%) relapsed after stem-cell transplantation. In patients allocated to receive chemotherapy, one early treatment-related death was reported and 11 patients were transplanted. Of the 70 patients who continued on chemotherapy, 49 (70%) remained in second complete remission, two (3%) died of complications, and 19 (27%) relapsed. Progression-free survival at 5 years was 56% (95% CI 46-65) in those with high minimal residual disease and 72% (60-81) in patients with low minimal residual disease (p0·0078). Treatment-related serious adverse events were not analysed in the long-term follow-up. Patients with B-cell precursor acute lymphoblastic leukaemia with late bone marrow relapses and low minimal residual disease at end of induction had favourable outcomes with chemotherapy without undergoing stem-cell transplantation. Patients with high minimal residual disease benefited from stem-cell transplantation, and targeted therapies might offer further improvements in outcomes for these patients. Bloodwise (Formerly Leukaemia and Lymphoma Research) UK, Cancer Research UK, Sporting Chance Cancer Foundation, National Health and Medical Research Council Australia, KindreneKankervrij Netherlands, European Union Seventh Framework Programme, India Alliance Wellcome DBT Margdarshi Fellowship.

Cellular immunotherapy for acute myeloid leukemia How specific should it be

Significant improvements in the survival of patients with hematological cancers following hematopoietic stem cell transplantation provide evidence supporting the potency of immune cell-mediated anti-leukemic effects. Studies focusing on immune cell-based cancer therapies have made significant breakthroughs in the last few years. Adoptive cellular therapy (ACT), and chimeric antigen receptor (CAR) T cell therapy, in particular, has significantly increased the survival of patients with B cell acute lymphoblastic leukemia and aggressive B cell lymphoma. Despite antigen-negative relapses and severe toxicities such as cytokine release syndrome after treatment, CAR-T cell therapies have been approved by the FDA in some conditions. Although a number of studies have tried to achieve similar results for acute myeloid leukemia (AML), clinical outcomes have not been as promising. In this review, we summarize recent and ongoing studies on cellular therapies for AML patients, with a focus on antigen-specific versus -nonspecific approaches.

Pediatric Malignant Mediastinal Masses.

To describe the clinical spectrum and outcome-associated variables of pediatric malignant mediastinal masses in a resource-limited setting. Descriptive study. Department of Pediatric Hematology-Oncology, The Childrens Hospital, Lahore, from October 2016 to November 2017. Children with malignant mediastinal masses were enrolled. The variables studied were median age at presentation, gender distribution, immunisation status, socio-economic background, causes of delayed presentation, presenting complaints, complications of disease, methods for mass biopsy, final diagnosis, staging, and outcome of the disease. Results were described in terms of descriptive statistics. The median age at diagnosis was 7.5 years with male-to-female ratio of 21. The commonest presenting complaint was fever (82%), respiratory distress (58%), and lymphadenopathy (51%). Seventy-eight percent patients belonged to lower socio-economic class. Eighty-six percent of patients had delayed presentation to the tertiary care hospital and the most common reason was delayed diagnosis by the medical professionals (49%). Fifty-one percent patients had weight-for-age less than 5th percentile. Common complications were airway obstruction (35%), pericardial effusion (19.6%), superior vena cava syndrome and gross pleural effusion (13.7% each). Commonest diagnosis was T-cell acute lymphoblastic leukemia (35%) followed by lymphoblastic lymphoma and Hodgkins lymphoma (15.7% each). Fourtyfive percent patients expired, 2% defaulted treatment and 5.9% completed treatment 25% patients were under treatment, 3.9% patients had progressive disease while outcome of 17.6% of patients could not be known. The most significant factor associated with the outcome primary diagnosis (p<0.001), delayed presentation (p0.007) and educational status of the family. The pattern of clinical presentation, complications and diagnoses of pediatric malignant mediastinal masses showed some variation from the already reported. Low literacy rate and delay in presentation are common and contribute significantly to the poor outcome.

Pegaspargase-induced hypertriglyceridemia in a patient with acute lymphoblastic leukemia.

Pegaspargase, a long acting formulation of L-asparaginase, is an asparagine specific enzyme that selectively kills leukemic cells by depleting plasma asparagine. Pegaspargase is FDA approved for the first-line treatment of adult acute lymphoblastic leukemia and is a critical component of numerous multi-chemotherapeutic regimens. Pegaspargase is associated with well-described toxicities including hypersensitivity reactions, hepatotoxicity, and thrombosis. However, hypertriglyceridemia is a much rarer complication of pegaspargase and has only been described in a limited number of reports. We present a case of severe hypertriglyceridemia after a single dose of pegaspargase. The patient was re-challenged with pegaspargase and again developed hypertriglyceridemia which was complicated by pancreatitis. Here, we summarize published reports and a literature review describing the incidence of pegaspargase-induced hypertriglyceridemia in common acute lymphoblastic leukemia protocols.

Ionising radiation and childhood leukaemia revisited.

Increased incidences of childhood acute leukaemia were noted among survivors of the atomic bombings of Hiroshima and Nagasaki. In Western societies, Childhood Acute Lymphoblastic Leukaemia has a distinct epidemiology peaking at 3 years old. Exposure to ionising radiation is an established hazard but it is difficult to gauge the precise risk of less than 100 mSv. Since 1983 significant leukaemia incidences have been reported among families residing near nuclear installations. The target cells (naïve neonatal lymphocytes) get exposed to multiple xenobiotic challenges and undergo extraordinary proliferation and physiological somatic genetic change. Population movements and ionising radiation are considered taking account of updated understanding of radiation biology, cancer cytogenetics and immunological diversity. Double Strand Breaks in DNA arise through metabolic generation of Reactive Oxygen Species, and nearly always are repaired but mis-repairs can be oncogenic. Recombinant Activating Gene enzymes in rapidly dividing perinatal pre-B lymphocytes being primed for antibody diversity are targeted to Signal Sequences in the Immunoglobulin genes. off target pseudo-sequences may allow RAG enzymes to create autosomal DSBs which, when mis-repaired, become translocated oncogenes. Immunogens acting by chance at crucial stages may facilitate this. In such circumstances, oncogenic DSBs from ionising radiation are less likely to be significant.

HAP1 loss confers l-asparaginase resistance in ALL by downregulating the calpain-1-Bid-caspase-312 pathway.

l-Asparaginase (l-ASNase) is a strategic component of treatment protocols for acute lymphoblastic leukemia (ALL). It causes asparagine deficit, resulting in protein synthesis inhibition and subsequent leukemic cell death and ALL remission. However, patients often relapse because of the development of resistance, but the underlying mechanism of ALL cell resistance to l-asparaginase remains unknown. Through unbiased genome-wide RNA interference screening, we identified huntingtin associated protein 1 (

Prognostic miRNA classifiers in t cell acute lymphoblastic leukemia Study protocol for a systematic review and meta-analysis of observational clinical studies.

The prognostic value of microRNA (miRNA) expression in T-cell acute lymphoblastic leukemia (T-ALL) has generated significant research interest in recent years. However, most diagnostic and prognostic studies with regards to miRNA expression have been focused on combined B cell and T cell lymphoblastic leukemia. There are very few studies reporting the prognostic effects of miRNA expression on T-ALL. Therefore, a pioneer systematic review and meta-analysis was proposed to explore the possibilities of miRNAs as viable prognostic markers in T-ALL. This study is intended to be useful as a guideline for future research into drug evaluation and targeting miRNA as a biomarker for the treatment and prognosis of T-ALL. The systematic review will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. The study search will be conducted by using Cochrane, EMBASE, Medline, Science Direct, and SCOPUS bibliographic databases. The reference lists of included studies will be manually searched to further bolster the search results. A combination of keywords will be used to search the databases. To explore the effect of miRNA on prognosis, forest plots will be generated to assess pooled HR and 95% CI. Upregulation, downregulation, and deregulation of specific miRNAs will be individually noted and used to extrapolate patient prognosis when associated with risk factors involved in T-ALL. Subgroup analysis will be carried out to analyze the effect of deregulation of miRNA expression on patient prognosis. A fixed or random-effects model of meta-analysis will be used depending upon between-study heterogeneity. This systematic review and meta-analysis will identify and synthesize evidence to determine the prognosis of miRNA in T-ALL and suggest the possible miRNA from meta-analysis results to predict as a biomarker for further detection and treatment of T-ALL.

Time-Delayed Integration-Spectral Flow Cytometer (TDI-SFC) for Low-Abundance-Cell Immunophenotyping.

We describe a unique flow cytometer (TDI-SFC) for the immunophenotyping of low-abundance cells, particularly when cell counts are sample-limited and operationally difficult for analysis by fluorescence microscopy (>100 cells) or multiparameter flow cytometry (MFC, <10 000 cells). TDI-SFC combines the high spectral resolution of spectral flow cytometry (SFC) with a CCD operated in time-delayed integration (TDI) for improved duty cycle and sensitivity. Cells were focused with a 1D-sheathing microfluidic device, and fluorescence emission generated from a 488 nm laser was collected by epi-illumination and dispersed along one axis of a CCD by a spectrograph. Along the other axis, the CCDs shift rate was clocked at a rate that closely matched the cells velocity through the field of view. This TDI-SFC format allowed the CCD shutter to remain open during signal acquisition, providing a duty cycle ∼100% and assurance that ∼95% cells were interrogated. We used fluorescent beads to optimize synchronization of TDI clocking with the sheathed-cell velocity and to improve sensitivity via the excitation intensity, epi-illumination numerical aperture, and integration time. TDI achieved integrated signals of 10

Treatment of higher risk acute lymphoblastic leukemia in young people (CCG-1961), long-term follow-up a report from the Childrens Oncology Group.

Childrens Cancer Group CCG-1882 improved outcome for 1-21-year old with high risk acute lymphoblastic leukemia and Induction Day 8 marrow blasts ≥25% (slow early responders, SER) with longer and stronger post induction intensification (PII). This CCG-1961 explored alternative PII strategies. We report 10-year follow-up for patients with rapid early response (RER) and for the first time details our experience for SER patients. A total of 2057 patients were enrolled, and 1299 RER patients were randomized to 1 of 4 PII regimens standard vs. augmented intensity and standard vs. increased length. At the end of interim maintenance, 447 SER patients were randomized to idarubicincyclophosphamide or weekly doxorubicin in the delayed intensification phases. The 10-year EFS for RER were 79.4 ± 2.4% and 70.9 ± 2.6% (hazard ratio 0.65, 95% CI 0.52-0.82, p < 0.001) for augmented and standard strength PII the 10-year OS rates were 87.2 ± 2.0% and 81.0 ± 2.2% (hazard ratio 0.64, 95% CI 0.48-0.86, p 0.003). Outcomes remain similar for standard and longer PII, and for SER patients assigned to idarubicincyclophosphamide and weekly doxorubicin. The EFS and OS advantage of augmented PII is sustained at 10 years for RER patients. Longer PII for RER patients and sequential idarubicincyclophosphamide for SER patients offered no advantage. CCG-1961 is the platform for subsequent COG studies.

SH2B3 inactivation through CN-LOH 12q is uniquely associated with B-cell precursor ALL with iAMP21 or other chromosome 21 gain.

In more than 30% of B-cell precursor acute lymphoblastic leukaemia (B-ALL), chromosome 21 sequence is overrepresented through aneuploidy or structural rearrangements, exemplified by intrachromosomal amplification of chromosome 21 (iAMP21). Although frequent, the mechanisms by which these abnormalities promote B-ALL remain obscure. Intriguingly, we found copy number neutral loss of heterozygosity (CN-LOH) of 12q was recurrent in iAMP21-ALL, but never observed in B-ALL without some form of chromosome 21 gain. As a consequence of CN-LOH 12q, mutations or deletions of the adaptor protein, SH2B3, were converted to homozygosity. In patients without CN-LOH 12q, bi-allelic abnormalities of SH2B3 occurred, but only in iAMP21-ALL, giving an overall incidence of 18% in this sub-type. Review of published data confirmed a tight association between overrepresentation of chromosome 21 and both CN-LOH 12q and SH2B3 abnormalities in B-ALL. Despite relatively small patient numbers, preliminary analysis linked 12q abnormalities to poor outcome in iAMP21-ALL (p 0.03). Homology modelling of a leukaemia-associated SH2 domain mutation and in vitro analysis of patient-derived xenograft cells implicated the JAKSTAT pathway as one likely target for SH2B3 tumour suppressor activity in iAMP21-ALL.

Sex ratio among childhood cancers by single year of age.

The male excess in childhood cancer incidence is well-established however, the underlying biologic mechanisms remain unknown. Examining the association between male sex and childhood cancer by single year of age and tumor type may highlight important periods of risk such as variation in growth and hormonal changes, which will inform etiologic hypotheses. Using data from the Surveillance, Epidemiology, and End Results (SEER) 18 registries (2000-2015), incidence rate ratios (IRR) and 95% confidence intervals (95% CI) were estimated as the measure of association between male sex and childhood cancer by single year of age (0-19). The IRR for male cancer overall was 1.19 (95% CI, 1.18-1.20) and was similar in magnitude at nearly every year of age. Burkitt lymphoma was strongly associated with male sex (IRRs ≥2 at each year of age). Increased incidence was observed among males for acute lymphoblastic leukemia, Hodgkin and non-Hodgkin lymphomas for nearly all years of age. Medulloblastoma was the only central nervous system tumor with a significant male predominance at nearly every age. Male sex displayed a consistent inverse association with nephroblastoma and thyroid carcinoma over the ages studied. Male sex was positively associated with most cancers. The higher incidence rates observed in males remained consistent over the childhood and adolescent periods, suggesting that childhood and adolescent hormonal fluctuations may not be the primary driving factor for the sex disparities in childhood cancer. The observed incidence disparities may be due to sex differences in exposures, genetics, or immune responses.

Time dependent response of daunorubicin on cytotoxicity, cell cycle and DNA repair in acute lymphoblastic leukaemia.

Daunorubicin is commonly used in the treatment of acute lymphoblastic leukaemia (ALL). The aim of this study was to explore the kinetics of double strand break (DSB) formation of three ALL cell lines following exposure to daunorubicin and to investigate the effects of daunorubicin on the cell cycle and the protein kinases involved in specific checkpoints following DNA damage and recovery periods. Three ALL cell lines CCRF-CEM and MOLT-4 derived from T lymphocytes and SUP-B15 derived from B lymphocytes were examined following 4 h treatment with daunorubicin chemotherapy and 4, 12 and 24 h recovery periods. Cell viability was measured via MTT (3-(4,5-dimethylthiazol-2-yl)-2-5 diphenyltetrazolium bromide) assay, reactive oxygen species (ROS) production by flow cytometry, double stranded DNA breaks by detecting γH2AX levels while stages of the cell cycle were detected following propidium iodide staining and flow cytometry. Western blotting was used to detect specific proteins while RNA was extracted from all cell lines and converted to cDNA to sequence Ataxia-telangiectasia mutated (ATM). Daunorubicin induced different degrees of toxicity in all cell lines and consistently generated reactive oxygen species. Daunorubicin was more potent at inducing DSB in MOLT-4 and CCRF-CEM cell lines while SUP-B15 cells showed delays in DSB repair and significantly more resistance to daunorubicin compared to the other cell lines as measured by γH2AX assay. Daunorubicin also causes cell cycle arrest in all three cell lines at different checkpoints at different times. These effects were not due to mutations in ATM as sequencing revealed none in any of the three cell lines. However, p53 was phosphorylated at serine 15 only in CCRF-CEM and MOLT-4 but not in SUP-B15 cells. The lack of active p53 may be correlated to the increase of SOD2 in SUP-B15 cells. The delay in DSB repair and lower sensitivity to daunorubicin seen in the B lymphocyte derived SUP-B15 cells could be due to loss of function of p53 that may be correlated to increased expression of SOD2 and lower ROS production.

Poly (lactic-co-glycolic acid) nanospheres allow for high l-asparaginase encapsulation yield and activity.

l-Asparaginase (ASNase) is an amidohydrolase used as a chemotherapeutic agent for the treatment of acute lymphoblastic leukemia (ALL). The nanoencapsulation of this enzyme is strategic to avoid its immediate immunogenic effects that lead to a decrease in the enzyme half-life. In this work, ASNase-containing nanoparticles (NPs) were prepared by double emulsification, through an ultrasonic sonicator or an Ultra-Turrax, using two copolymers of 5050 (ww) poly (lactic-co-glycolic acid) (PLGA) with different ranges of molecular weight (24-38 kDa and 30-60 kDa) and varying the concentration of polyvinyl alcohol (PVA) as a stabilizer (0.5, 1.0, 1.5 and 2.0%) as well as the emulsification time (30 and 60 s). Using 24-38 kDa PLGA and 1.0% PVA, we obtained by cavitation NPs with hydrodynamic diameter of 384 nm, polydispersity index of 0.143 and Zeta potential of -16.4 mV, whose ASNase encapsulation efficiency was as high as 87 ± 2%. The encapsulated enzyme showed an activity 22% higher than that of the free enzyme, and no conformational changes were detected by circular dichroism. The enzyme release from NPs entrapped in dialysis bags (500 kDa molecular weight cut-off) allowed selecting a controlled system able to release about 60% of the enzyme within 14 days, for which the Korsmeyer-Peppas model provided the best correlation (R

The Population Pharmacokinetics of High-Dose Methotrexate in Infants with Acute Lymphoblastic Leukemia Highlight the Need for Bedside Individualized Dose Adjustment A Report from the Childrens Oncology Group.

Infants with acute lymphoblastic leukemia (ALL) treated with high-dose methotrexate may have reduced methotrexate clearance (CL) due to renal immaturity, which may predispose them to toxicity. The aim of this study was to develop a population pharmacokinetic (PK) model of methotrexate in infants with ALL. A total of 672 methotrexate plasma concentrations were obtained from 71 infants enrolled in the Childrens Oncology Group (COG) Clinical Trial P9407. Infants received methotrexate 4 gm Methotrexate was best characterized by a two-compartment model with allometric scaling. Weight was the only covariate included in the final model. The coefficient of variation for interoccasion variability (IOV) on CL was relatively high at 25.4%, compared with the interindividual variability for CL and central volume of distribution (10.7% and 13.2%, respectively). Simulations identified that 21.1% of simulated infants benefitted from bedside dose adjustment, and adjustment of methotrexate doses during infusions can avoid supratherapeutic concentrations. Infants treated with high-dose methotrexate demonstrated a relatively high degree of IOV in methotrexate CL. The magnitude of IOV in the CL of methotrexate suggests that use of a bedside algorithm may avoid supratherapeutic methotrexate concentrations resulting from high IOV in methotrexate CL.

Association of ARID5B and IKZF1 Variants with Leukemia from Northern India.

Leukemia is a heterogeneous disorder, characterized by elevated proliferation of white blood cells. Various genetic studies have assessed the contributory roles of several single nucleotide polymorphisms with the development of leukemia. The role of genetic variation in the ARID5B and IKZF1 genes has previously been identified in various population groups however, the role of these variants in the north Indian populations of Jammu and Kashmir is unknown. In this study, we explored the association of the newly identified genetic variants, rs10740055 of ARID5B and rs6964823 of IKZF1, with leukemic patients from Jammu and Kashmir of northern India. The variants were genotyped using TaqMan allele discrimination assays for 616 individuals (210 leukemic cases and 406 healthy controls). The association of each SNP with the disease was evaluated using logistic regression. It was observed that the variants rs6964823 (IKZF1) and rs10740055 (ARID5B) showed significant associations with odds ratio (OR) and p-values of 1.5 (1.0-2.3 at 95% confidence interval CI) and 0.04 and 2.5 (1.5-4.1 at 95% CI) and 0.0002, respectively. We also evaluated the cumulative effect for both the variants by combining the risk genotypes and obtained and OR of 4.9. It was found that the variants rs10740055 of ARID5B and rs6964823 of IKZF1 act individually and additively as risk factors in the development of leukemia in the populations of Jammu and Kashmir in Northern India.

The Incidence and Immunophenotypic and Genetic Features of JL1 Expressing Cells and the Therapeutic Potential of an Anti-JL1 Antibody in

JL1 is a newly identified CD43 epitope that specifically recognizes leukemic cells. We analyzed the incidence of JL1 expression and compared the clinical, immunophenotypic, and genetic characteristics of Seventy-eight patients with pediatric acute leukemia (52 with ALL, 26 with AML) diagnosed between December 2014 and January 2016 were enrolled prospectively. Flow cytometry for JL1 expression was performed at diagnosis. Clinical, immunophenotypic, and genetic characteristics were compared with respect to JL1 expression status by the Student t-testMann-Whitney U test and chi-square testFishers exact test. The incidence of JL1 expression was 76.9% and 84.6% in ALL and AML patients, respectively. ALL patients with JL1 expression showed higher CD10 and cytoplasmic IgM expressions than those without JL1 expression ( Our findings support the potential therapeutic role of anti-JL1 monoclonal antibodies JL1 expression was associated with specific immunophenotypes and genetic abnormalities. Future studies should examine the prognostic impact of JL1 expression in pediatric acute leukemias.

Lymphoblastic lymphoma in children and adolescents review of current challenges and future opportunities.

Lymphoblastic lymphoma (LBL) is the second most common type of Non-Hodgkin Lymphoma (NHL) in childhood and adolescence, accounting for 25-35% of all cases. The majority, 70-80%, is of T-lymphoblastic origin while 20-25% arise from B lymphoblasts. With current therapy, the event-free and overall survivals for paediatric LBL patients now exceeds 80%. Therapy, especially in T-LBL with large mediastinal tumours, is challenging, with both significant morbidity and late sequela. An additional challenge is the dismal prognosis of patients with refractory or relapsed disease. This review article will focus on the growing knowledge of the pathogenesis and biology of LBL, recent advances and challenges in the therapy of LBL, and ongoing and future efforts and opportunities in optimizing therapy and developing novel targeted treatment approaches.

The impact of the graft-versus-leukemia effect on survival in acute lymphoblastic leukemia.

Allogeneic hematopoietic cell transplant is a potential curative therapy for acute lymphoblastic leukemia (ALL). Delineating the graft-versus-leukemia (GVL) effect as a function of graft-versus-host disease (GVHD) offers the potential to improve survival. We examined 5215 transplant recipients with ALL reported to the Center for International Blood and Marrow Transplant Research registry. Overall survival (OS) was compared according to the presence and severity of GVHD and evaluated in 3 cohorts 2593 adults in first or second complete remission (CR1CR2), 1619 pediatric patients in CR1CR2, and 1003 patients with advanced (CR ≥3 or active disease) ALL. For patients in CR1CR2, development of acute GVHD (aGVHD) or chronic GVHD (cGVHD) was associated with lower risk of relapse than no GVHD (hazard ratio HR, 0.49-0.69). Patients with advanced ALL developing grades III and IV aGVHD or cGVHD were also at lower risk of relapse (HRs varied from 0.52 to 0.67). Importantly, adult and children in CR1CR2 with grades I and II aGVHD without cGVHD experienced the best OS compared with no GVHD (reduction of mortality with HR, 0.83-0.76). Increased nonrelapse mortality accompanied grades III and IV aGVHD (HRs varied from 2.69 to 3.91) in all 3 cohorts and abrogated any protection from relapse, resulting in inferior OS. Patients with advanced ALL had better OS (reduction in mortality HR, 0.69-0.73) when they developed cGVHD with or without grades I and II aGVHD. In conclusion, GVHD was associated with an increased GVL effect in ALL. GVL exerted a net beneficial effect on OS only if associated with low-grade aGVHD in CR1CR2 or with cGVHD in advanced ALL.

Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells.

Chimeric antigen receptor (CAR) T cells have emerged as a promising class of cell-based immunotherapy in refractory malignancies. Neurotoxicity represents a common and potentially life-threatening adverse effect of CAR T cells, and clinical experience is limited. Here, we describe the clinical presentation and management of 25 adult patients who presented with neurotoxic syndromes after CAR T-cell therapy at the Massachusetts General Hospital. This cohort includes 24 patients treated with CD19-directed CAR T cells for non-Hodgkin lymphoma (n 23) and acute lymphoblastic leukemia (n 1), and 1 patient treated with α-fetoprotein-directed CAR T cells for hepatocellular carcinoma (n 1). Twelve of the 25 patients (48%) developed grade 1-2 neurotoxicity and 13 patients (52%) presented with grade 3-4 neurotoxicity. We found that lower platelet counts at time of CAR T-cell infusion were associated with more severe neurotoxicity (

Higher Reported Lung Dose Received During Total Body Irradiation for Allogeneic Hematopoietic Stem Cell Transplantation in Children With Acute Lymphoblastic Leukemia Is Associated With Inferior Survival A Report from the Childrens Oncology Group.

To examine the relationship between lung radiation dose and survival outcomes in children undergoing total body irradiation (TBI)-based hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia on the Childrens Oncology Group trial. TBI (1200 or 1320 cGy given twice daily in 6 or 8 fractions) was used as part of 3 HSCT preparative regimens, allowing institutional flexibility regarding TBI techniques, including lung shielding. Lung doses as reported by each participating institution were calculated for different patient setups, with and without shielding, with a variety of dose calculation techniques. The association between lung dose and transplant-related mortality, relapse-free survival, and overall survival (OS) was examined using the Cox proportional hazards regression model controlling for the following variables TBI dose rate, TBI fields, patient position during TBI, donor type, and pre-HSCT minimal residual disease level. Of a total of 143 eligible patients, 127 had lung doses available for this analysis. The TBI techniques were heterogeneous. The mean lung dose was reported as 904.5 cGy (standard deviation, ±232.3). Patients treated with lateral fields were more likely to receive lung doses ≥800 cGy (P < .001). The influence of lung dose ≥800 cGy on transplant-related mortality was not significant (hazard ratio HR, 1.78 P .21). On univariate analysis, lung dose ≥800 cGy was associated with inferior relapse-free survival (HR, 1.76 P .04) and OS (HR, 1.85 P .03). In the multivariate analysis, OS maintained statistical significance (HR, 1.85 P .04). The variability in TBI techniques resulted in uncertainty with reported lung doses. Lateral fields were associated with higher lung dose, and thus they should be avoided. Patients treated with lung dose <800 cGy in this study had better outcomes. This approach is currently being investigated in the Childrens Oncology Group AALL1331 study. Additionally, the Imaging and Radiation Oncology Core Group is evaluating effects of TBI techniques on lung doses using a phantom.

Two Occurrences of Leukemia Relapse Due to Mismatched HLA Loss After Haploidentical Stem Cell Transplantation From Different Family Donors With KIR Ligand Mismatch.

Mismatched HLA loss is a cause of leukemia relapse after HLA-haploidentical stem cell transplantation (haplo-SCT). We report a patient with a history of 2 occurrences of leukemia relapse due to mismatched HLA loss after haplo-SCT. He received haplo-SCT from his father but showed leukemia relapse with loss of the maternal HLA haplotype. He then underwent haplo-SCT from his mother, and developed relapse with loss of the paternal HLA haplotype. Both donors had killer cell immunoglobulin-like receptor-ligand mismatch but alloreactive natural killer cells could not prevent relapse. Second haplo-SCT should be conducted carefully for patients with relapse due to mismatched HLA loss.

Treatment of Recurrent Refractory Pediatric Pre-B Acute Lymphoblastic Leukemia Using Inotuzumab Ozogamicin Monotherapy Resulting in CD22 Antigen Expression Loss as a Mechanism of Therapy Resistance.

Inotuzumab ozogamicin is a novel antibody-drug conjugate that targets CD22, a common antigen on pre-B acute lymphoblastic leukemia cells. A 7-year-old boy with pre-B acute lymphoblastic leukemia in his second relapse was given 2 cycles of inotuzumab ozogamicin. He responded morphologically with a negative bone marrow evaluation. However, he relapsed in cycle 3 of therapy with a loss of CD22 expression on his lymphoblast population. To our knowledge, this is the first published case of CD22 expression loss as a mechanism of therapy resistance for inotuzumab ozogamicin.

Development of Secondary Osteosarcoma After TBI and Allogeneic Bone Marrow Transplant A Case Series of 3 Patients.

Osteosarcoma can rarely occur as a subsequent malignant neoplasm after cancer therapy. Children who underwent treatment for cancer and received an allogeneic hematopoietic cell transplant are at a higher risk to develop secondary malignancies. Radiation is also a known risk factor, but estimating the quantitative risk is difficult due to the rarity of the condition and long latency period between primary and secondary cancer. In this report, we present 3 patients diagnosed with leukemia as young children who received hematopoietic cell transplants with total body irradiation as part of the conditioning regimen, and later went on to develop secondary osteosarcoma.

Hematopoietic Stem Cell Transplantation in Pediatric Acute Lymphoblastic Leukemia.

The remarkable improvement in the prognosis of children with acute lymphoblastic leukemia (ALL) has been mainly achieved through the administration of risk-adapted therapy, including allogeneic hematopoietic stem cell transplantation (HSCT). This paper reviews the current indications to HSCT in ALL children, as well as the type of donor and conditioning regimens commonly used. Finally, it will focus on future challenges in immunotherapy. As our comprehension of disease-specific risk factors improves, indications to HSCT continue to evolve. Future studies will answer the year-old question on the best conditioning regimen to be used in this setting, while a recent randomized controlled study fixed the optimal anti-thymocyte globulin dose in unrelated donor HSCT. HSCT, the oldest immunotherapy used in clinical practice, still represents the gold standard consolidation treatment for a number of pediatric patients with high-riskrelapsed ALL. New immunotherapies hold the promise of further improving outcomes in this setting.

Classification and regression tree-based prediction of 6-mercaptopurine-induced leucopenia grades in children with acute lymphoblastic leukemia.

The rationale of the current study was to develop 6-mercaptopurine (6-MP)-mediated hematological toxicity prediction model for acute lymphoblastic leukemia (ALL) therapeutic management. A total of 96 children with ALL undergoing therapy with MCP-841 protocol were screened for all the ten exons of TPMT, exon 2, exon 3 and intron 2 of ITPA using bidirectional sequencing. This dataset was used to construct prediction models of leucopenia grade by constructing classification and regression trees (CART) followed by smart pruning. The developed CART model indicated TPMT12 and TPMT3C as the key determinants of toxicity. TPMT int3, int4 and int7 polymorphisms exert toxicity when co-segregated with one mutated allele of TPMT12 or TPMT3C or ITPA exon 3. The developed CART model exhibited 93.6% accuracy in predicting the toxicity. The area under the receiver operating characteristic curve was 0.9649. TPMT 3C and TPMT12 are the key determinants of 6-MP-mediated hematological toxicity while other variants of TPMT (int3, int4 and int7) and ITPA ex2 interact synergistically with TPMT3C or TPMT12 variant alleles to enhance the toxicity. TPMT and ITPA variants cumulatively are excellent predictors of 6-MP-mediated toxicity.

Congenital B-cell Acute Lymphoblastic Leukemia with Congenital Rubella Infection.

Congenital B-cell Acute lymphoblastic leukemia (ALL) is a rare malignancy. A newborn infant presented with purpuric spots and ecchymotic patches, blueberry muffin rash, depressed neonatal reflexes, respiratory distress and hepatosplenomegaly. Peripheral smear revealed atypical blast cells. Serum ELISA was positive for Rubella IgM and IgG antibodies. Flow cytometry suggested congenital B-cell ALL. The baby died after 3 days due to suspected intracranial hemorrhage. Congenital leukemia may be rarely associated with congenital rubella infection.

The Genetic Variants of IKZF1 Gene Linked with the Growing Risk of Childhood Acute Lymphoblastic Leukaemia.

The zinc finger protein IKAROS (IKZF1) is an essential transcription factor in haematopoiesis that is involved primarily in lymphoid tissue differentiation. Many studies have indicated that IKZF1 alterations may be associated with acute lymphoblastic leukaemia, but the results remain controversial. We aimed to investigate the association of the rs4132601 TG and rs10272724 TC IKZF1 gene polymorphisms with the risk of childhood acute lymphoblastic leukaemia and to determine whether these genetic variants affect the clinical parameters and the iron profiles of these children cohort. This case control study was conducted on 170 Egyptian children comprising of two groups group (I) included 90 children diagnosed with acute lymphoblastic leukaemia and group (II) comprised of 80 ages and sex-matched healthy control children. The studied polymorphisms were genotyped using PCR restriction fragment length polymorphism (PCR-RFLP). A higher frequency of the mutant GG genotype and G allele of rs4132601 was found in the patient group than in the control group. The results also showed a significant difference among the rs10272724 genotypes, with a higher frequency of the mutant CC genotype and C allele in the patients than in controls. The mutant GG genotype of rs4132601 and the mutant CC genotype of rs10272724 were associated with a higher serum ferritin level and transferrin saturation and an older age at diagnosis of acute lymphoblastic leukaemia than the other genotypes. IKZF1 rs4132601 and rs10272724 could be considered significant risk contributors to childhood acute lymphoblastic leukaemia and may impact the iron profiles in these children.

S194-P-FADD as a marker of aggressiveness and poor prognosis in human T-cell lymphoblastic lymphoma.

T-cell lymphoblastic lymphoma is a haematological disease with an urgent need for reliable prognostic biomarkers that allow therapeutic stratification and dose adjustment. The scarcity of human samples is responsible for the delayed progress in the study and the clinical management of this disease, especially compared with T-cell acute lymphoblastic leukaemia, its leukemic counterpart. In the present work, we have determined by immunohistochemistry that S194-P-FADD protein is significantly reduced in a cohort of 22 samples from human T-cell lymphoblastic lymphoma. Notably, the extent of such reduction varies significantly among samples and has revealed determinant for the outcome of the tumour. We demonstrate that Fas-associated protein with death domain (FADD) phosphorylation status affects protein stability, subcellular localization and non-apoptotic functions, specifically cell proliferation. Phosphorylated FADD would be more stable and preferentially localized to the cell nucleus there, it would favour cell proliferation. We show that patients with higher levels of S194-P-FADD exhibit more proliferative tumours and that they present worse clinical characteristics and a significant enrichment to an oncogenic signature. This supports that FADD phosphorylation may serve as a predictor for T-cell lymphoblastic lymphoma aggressiveness and clinical status. In summary, we propose FADD phosphorylation as a new biomarker with prognostic value in T-cell lymphoblastic lymphoma.

Relapse after Prolonged Remission in Philadelphia-Like Acute Lymphoblastic Leukemia.

We describe a case of late relapse of Philadelphia-like acute lymphoblastic leukemia. The patient relapsed several years from diagnosis and responded to second salvage treatment. The case highlights the open questions regarding management of Philadelphia-like acute lymphoblastic leukemia.

Multidisciplinary analysis of pediatric T-ALL 9q34 gene fusions.

T-cell acute lymphoblastic leukemia (T-ALL) is not as frequently reported as the B-cell counterpart (B-ALL), only occurring in about 15% of pediatric cases with a typically heterogeneous etiology. Approximately 8% of childhood T-ALL cases have rearrangements involving the ABL1 tyrosine kinase gene at 9q34.12 although a t(922), resulting in a fusion of ABL1 with the BCR gene at 22q11.23 is a common occurrence in B-ALL, it is not a typical finding in T-ALL. A subset of 10 of 40 documented cases of T-ALL analyzed over a 5-year period is presented, each having gene rearrangements within band 9q34 that resulted in fusions other than BCRABL1. These cases included fusions involving ABL1, SET (9q34.11), NUP214 (9q34.13), SPTAN1 (9p34.11), and TNRC6B (22q13.1). Among the 10 cases are six SETNUP214 fusions, two ABL1NUP214 fusions (one of which was associated with episomal amplification) and novel SPTAN1ABL1 and TNRC6BABL1 fusions. The evaluations of these clones were each significantly aided by FISH analysis, which directed subsequent microarray and anchored multiplex PCR testing for fusion confirmations.

Stage at diagnosis for children with blood cancers in Australia Application of the Toronto Paediatric Cancer Stage Guidelines in a population-based national childhood cancer registry.

Information on stage at diagnosis for childhood blood cancers is essential for surveillance but is not available on a population basis in most countries. Our aim was to apply the internationally endorsed Toronto Paediatric Cancer Stage Guidelines to children (<15 years) with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), or non-Hodgkin lymphoma (NHL) and to assess differences in survival by stage at diagnosis. Stage was defined by extent of involvement of the central nervous system (CNS) for ALL and AML and using the Ann Arbor and St Jude-Murphy systems for HL and NHL, respectively. The study cohort was drawn from the population-based Australian Childhood Cancer Registry, consisting of children diagnosed with one of these four blood cancers between 2006 and 2014 with follow-up to 2015. Five-year observed survival was estimated from the Kaplan-Meier method. Stage was assigned to 2201 of 2351 eligible patients (94%), ranging from 85% for AML to 95% for ALL, HL, and NHL. Survival following ALL varied from 94% (95% CI 93%-95%) for CNS1 disease to 89% (95% CI 79%-94%) for CNS2 (P 0.07), whereas for AML there was essentially no difference in survival between CNS These results provide the first population-wide picture of the distribution and outcomes for childhood blood cancers in Australia by extent of disease at diagnosis and provide a baseline for future comparisons.

A unique phenotype of T-cell acute lymphoblastic leukemia in a patient with GATA2 haploinsufficiency.

Germline or acquired mutations involving the GATA-binding protein gene (GATA2) have been linked to a variety of clinical conditions. In addition, patients harboring GATA2 mutations have a striking predisposition to develop myeloid malignancies, such as myelodysplastic syndrome or acute myeloid leukemia, but not acute lymphoblastic leukemia (ALL). We report here a unique occurrence of early T-cell precursor ALL in a young child with GATA2 haploinsufficiency.

Home care of acute leukaemia patients From active therapy to end-of-life and palliative care. The 3-year experience of a single centre.

The aim of the study was to evaluate the feasibility and the potential effects of the Haematological Home Care (HHC) programme for acute leukaemia (AL) patients, either in active chemotherapy or in the terminal phase of disease. We retrospectively assessed a group of AL patients assisted at home in terms of number of hospitalisations, accesses to emergency department and place of death. We also used historical data to evaluate potential effects of HHC. The study group consisted of 44 patients, 36 of whom (82%) required palliative treatment, and eight (18%) had ongoing active chemotherapy. The mean number of hospitalisations was 0.64 (range 0-7) per patient, and the number of emergency department (ED) visits was 0.82 (range 0-4) per patient. Place of death was at home for 51.4% of patients and in hospital for 40.5%. Considering a historical group of 17 patients assisted at home the rate of hospitalisations and ED visits were 2.53 (range 0-9) and one (range 0-3), respectively. Place of death was home and hospital in 6% and 65%, respectively. Haematological Home Care for AL patients is feasible and has potential positive effects in terms rate of hospitalisations and place of death.

Fed-Batch Production of

L-Asparaginase (ASNase) is used in the treatment of acute lymphoblastic leukemia, being produced and commercialized only from bacterial sources. Alternative

Recovery of MicroRNA from Stored Bone Marrow Aspirate Slides.

Archived bone marrow aspirate slides are almost infinite, readily available resource of biospecimens that enable retrospective molecular investigations of diseases. RNAs obtained from slides has limitations in utility because of their low quality and highly fragmented nature. MicroRNAs are small (<22 nt) noncoding RNAs with various cellular regulatory roles. Due to their small size, microRNAs are less prone to degradation and modification, therefore, can be preserved well in archived tissues. The current study investigated the efficacy of archived bone marrow aspirate slides for miRNA expression analysis in pediatric leukemia. Total RNA was isolated from air-dried unstained archived slides using High pure miRNA isolation Kit with some modifications and from fresh samples using TRizol. After cDNA synthesis, RT-qPCR was then carried out using specific hsa-miR-326 LNA primers. Finally, statistical analyses were conducted using GraphPad Prism 6 software. The difference observed in miRNA expression due to disease state was far greater than the differences between archived slides and their matching fresh bone marrow specimens. In fact, the expression of archival slide smears for the miR-326 closely mimicked that of fresh-frozen tissues (0.035±0.04 The demonstration that archived bone marrow aspirate slides can be utilized for miRNA expression studies offers tremendous potential for future investigations into the role that miRNAs play in the development and long term outcome of hematologic, as well as non-hematologic diseases.

Dasatinib Reinitiation After Poststroke Thrombolysis Associated with Symptomatic Intracerebral Hemorrhage.

Dasatinib, a tyrosine kinase inhibitor commonly used in treatment of acute lymphoblastic leukemia and chronic myelogenous leukemia, is often associated with hemorrhagic complications. Safety of dasatinib after thrombolytic therapy in acute ischemic stroke is unknown. A 63-year-old man with multiple vascular risk factors and chronic myelogenous leukemia (in molecular remission) on dasatinib presented with signs and symptoms of right hemispheric stroke owing to acute intracranial internal carotid artery occlusion that was treated with intravenous thrombolysis and mechanical thrombectomy resulting in near-complete resolution of stroke symptoms. The patient developed clinical worsening (>24 hours of thrombolytic therapy) after receiving a second dose of dasatinib that was due to symptomatic intracerebral hemorrhage and necessitated decompressive hemicraniectomy. Routine coagulation profile was normal. The etiology of this hemorrhagic complication was likely secondary to primary platelet dysfunction due to dasatinib as reported in some recent in vitro and ex vivo studies. It is advisable to withhold dasatinib during the poststroke period owing to its associated risk of symptomatic intracerebral hemorrhage.

Trombosis of mesenterial vessels in acute lymphoblastic leukemia (case report).

The article presents data on classification, diagnostic problems, treatment of acute lymphoblastic leukemia in children. Remaining unresolved problems of protocol chemotherapy complications of acute lymphoblastic leukemia. The presented clinical case of successful treatment of thrombosis of mesenteric vessels in a child with acute lymphoblastic leukemia, which included the stages of thrombolytic therapy and surgical treatment for resection of necrotized part of the ileum.

Taking a BiTE out of ALL blinatumomab approval for MRD-positive ALL.

Blinatumomab, a bispecific T-cell engager (BiTE) associated with improved survival in relapsed or refractory acute lymphoblastic leukemia (ALL), was recently approved for treatment of minimal residual disease (MRD). MRD is an important predictor of survival in ALL, and recent studies suggest that achievement of MRD-negativity with blinatumomab improves outcomes in patients with ALL. However, further research is needed to determine how to optimally incorporate blinatumomab, and other novel therapies, into current therapies for ALL.

Fratricide-resistant CD1a-specific CAR T cells for the treatment of cortical T-cell acute lymphoblastic leukemia.

Relapsedrefractory T-cell acute lymphoblastic leukemia (T-ALL) has a dismal outcome, and no effective targeted immunotherapies for T-ALL exist. The extension of chimeric antigen receptor (CAR) T cells (CARTs) to T-ALL remains challenging because the shared expression of target antigens between CARTs and T-ALL blasts leads to CART fratricide. CD1a is exclusively expressed in cortical T-ALL (coT-ALL), a major subset of T-ALL, and retained at relapse. This article reports that the expression of CD1a is mainly restricted to developing cortical thymocytes, and neither CD34

Feasibility and Potential Benefits of an Exercise Intervention in a Male With Down Syndrome Undergoing High-Dose Chemotherapy for Acute Lymphoblastic Leukemia A Case Report.

In patients with hematological malignancies, exercise is studied as a supportive measure with potential benefits on therapy and disease-related side effects. However, clinical trials have not yet integrated people with Down syndrome (DS), although this disability is associated with an increased risk for hematological malignancies. Therefore, we examined safety and feasibility of a mixed-modality exercise intervention in a male with DS undergoing high-dose chemotherapy for acute lymphoblastic leukemia. Furthermore, physical capacity and fatigue were assessed. Exercise sessions took place 3 timeswk over a 5-week period. Adherence to the exercise program was 100%, and no serious adverse events occurred. In contrast to the training sessions, applied endurance testing was not feasible. Furthermore, maintenance of fatigue level was observed. In conclusion, cancer patients with DS suffering from leukemia should not be excluded from physical activity or exercise programs.

Targeting mTOR in Acute Lymphoblastic Leukemia.

Acute Lymphoblastic Leukemia (ALL) is an aggressive hematologic disorder and constitutes approximately 25% of cancer diagnoses among children and teenagers. Pediatric patients have a favourable prognosis, with 5-years overall survival rates near 90%, while adult ALL still correlates with poorer survival. However, during the past few decades, the therapeutic outcome of adult ALL was significantly ameliorated, mainly due to intensive pediatric-based protocols of chemotherapy. Mammalian (or mechanistic) target of rapamycin (mTOR) is a conserved serinethreonine kinase belonging to the phosphatidylinositol 3-kinase (PI3K)-related kinase family (PIKK) and resides in two distinct signalling complexes named mTORC1, involved in mRNA translation and protein synthesis and mTORC2 that controls cell survival and migration. Moreover, both complexes are remarkably involved in metabolism regulation. Growing evidence reports that mTOR dysregulation is related to metastatic potential, cell proliferation and angiogenesis and given that PI3KAktmTOR network activation is often associated with poor prognosis and chemoresistance in ALL, there is a constant need to discover novel inhibitors for ALL treatment. Here, the current knowledge of mTOR signalling and the development of anti-mTOR compounds are documented, reporting the most relevant results from both preclinical and clinical studies in ALL that have contributed significantly into their efficacy or failure.

Management of cytokine release syndrome and neurotoxicity in chimeric antigen receptor (CAR) T cell therapy.

Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated remarkable anti-tumor activity in B-cell malignancies and is under investigation in other hematologic malignancies and solid tumors. While highly efficacious, post-infusion T cell activity often results in massive cytokine release precipitating cytokine release syndrome (CRS), the signature toxicity of CAR T cells. This toxicity is characterized by systemic immune activation resulting in fever, hypotension, respiratory insufficiency and capillary leak. Either in conjunction with or in the absence of CRS, a subset of patients may also develop mild to severe neurotoxicity. Although the precise pathogenesis of CRS and neurotoxicity arent fully elucidated, risk factors and mitigation strategies have been reported. Areas covered This manuscript provides an in-depth overview of the pathogenesis, clinical characteristics, current toxicity management strategies, and future perspectives pertaining to CRS and neurotoxicity. Expert Opinion As CAR T cell based therapies gain popularity in the management of various malignancies, the complimentary toxicities of CRS and neurotoxicity pose a clinical challenge in practice. Risk adaptive modeling incorporating disease profile, patient demographics, lymphodepletion, cell dosing, CAR T construct, and potentially cytokine gene polymorphisms may be instructive to assess individualized risk and optimal CRSneurotoxicity management.

Revisiting the complete blood count and clinical findings at diagnosis of childhood acute lymphoblastic leukemia 10-year experience at a single center.

Heterogeneity regarding clinical and laboratory findings at diagnosis of acute lymphoblastic leukemia exists. The frequency of complete blood count abnormalities and its combinations, symptoms and physical findings were investigated in Hispanic children from an open population at the diagnosis of acute lymphoblastic leukemia. The patient charts and electronic records of under 16-year-old children diagnosed with acute lymphoblastic leukemia over 10 years at a regional hematology center of a university hospital were analyzed to retrieve data concerning the complete blood count at first evaluation. Type and distribution of abnormal data, frequency of symptoms and physical findings at presentation were documented. The records of 203 children aged 0-15 years diagnosed with acute lymphoblastic leukemia from 2006 to 2016 were revisited. The results of the blood workup showed a median white blood cell count of 7120 × 10 Data differing from those classically expected at diagnosis of acute lymphoblastic leukemia in children were documented in a cohort of Hispanic children over one decade with a wide spectrum of complete blood count abnormalities, forms of presentation and frequency of physical findings.

The case of undiagnosed immunodeficiency in child from mother with leukemia anamnesis.

Acute lymphoblastic leukemia (ALL) in pregnant women is rare experience, but it can complicate the gestation by increasing the risk of miscarriage and premature birth. However, the adequate carrying of the pregnancy is possible for women who suffered from leukemia in childhood and achieved the remission during the treatment. Furthermore, there are some facts about the possibility of immunosuppression in children whose parents suffer from various immunodeficiency disorders, including ALL. This clinical case demonstrates the importance of correct diagnostics in order to reveal the congenital pathologies of the immune system in children, whose parents suffered from lymphocytic leukemia, even in case of full clinical and laboratory remission for a significant period of time. In the hospital, the thread metric approach was used for sepsis diagnostics. Conducted treatment was ineffective due to the inadequate immune response in the child and lack of the targeted adjusted measures to immunodeficiency disorder. The present case demonstrates the congenital T-cells immunodeficiency in a child who was complicated by the development of acute ulceronecrotic enterocolitis after vaccination. The treatment that was targeted mainly at the agent eradication did not give the desired results due to non-responsiveness of the immune system of the child.

Establishment and utility assessment of posterior reversible encephalopathy syndrome early warning scoring (PEWS) scale establishment and utility assessment of PEWS scale.

Posterior reversible encephalopathy syndrome (PRES) is a complication that occurs during various diseases treatment. Imaging examination is the gold standard for diagnosis. PRES frequently occurrence in patients with hematological malignancies results in poorer prognosis and higher mortality. We aim to establish a practical and operable scale for early prediction, assessment of the severity of the Posterior Reversible Encephalopathy Syndrome, and timely intervention for better prognosis. The scale designed by reviewing the literature and by referring to clinical practice. We assessed the reliability and validity of the scale. Scale-based assessment of children undergoing chemotherapy for acute lymphoblastic leukemia conducted as early warning and intervention for those who may have PRES. Establishment of Posterior Reversible Encephalopathy Syndrome early warning scoring (PEWS) scale included three parts, as follows (1) risk factors, including underlying disease, hypertension, Infection, and drug toxicity (2) clinical features, including high cranial pressure, visual symptoms, seizure, and disturbance of consciousness and (3) EEG features, including slow wave and epileptiform discharges. Utility assessment of PEWS scale showed that in 57 patients with acute lymphoblastic leukemia, 54 scored less than 10 and none of them detected as PRES. The other two had scores of 12 and 13 both diagnosed with PRES by brain MRI scan. PEWS scale can predict PRES early. PRES was highly suspected when the score was 10 points and more. Thus, prophylactic intervention can give to improve the prognosis of PRES.

CRTAM

Due to their increasing rates of morbidity and mortality, childhood malignancies are considered a global health priority, with acute lymphoblastic leukemias (ALLs) showing the highest incidence worldwide. Control of malignant clone emergence and the subsequent normal-leukemic hematopoietic cell out-competition require antitumor monitoring mechanisms. Investigation of cancer surveillance innate cells may be critical to understand the mechanisms contributing in either disease progression or relapse, and to promote displacement of leukemic hematopoiesis by the normal counterpart. We report here that NK cell production is less and low hematopoietic progenitor numbers contribute to this defect. By investigating the expression of the activation molecule class I restricted T-cell associated molecule (CRTAM) along the hematopoietic lineage differentiation pathway, we have identified lymphoid precursor populations coexpressing CD34, CD56CD3CD19, and CRTAM as the earliest developmental stage where activation may take place in specialized niches that display the ligand nectin-like-2. Of note, bone marrow (BM) from patients with ALL revealed high contents of preactivated CD56

Concise Review Regulation of Self-Renewal in Normal and Malignant Hematopoietic Stem Cells by Krüppel-Like Factor 4.

Pluripotent and tissue-specific stem cells, such as blood-forming stem cells, are maintained through a balance of quiescence, self-renewal, and differentiation. Self-renewal is a specialized cell division that generates daughter cells with the same features as the parental stem cell. Although many factors are involved in the regulation of self-renewal, perhaps the most well-known factors are members of the Krüppel-like factor (KLF) family, especially KLF4, because of the landmark discovery that this protein is required to reprogram somatic cells into induced pluripotent stem cells. Because KLF4 regulates gene expression through transcriptional activation or repression via either DNA binding or protein-to-protein interactions, the outcome of KLF4-mediated regulation largely depends on the cellular context, cell cycle regulation, chromatin structure, and the presence of oncogenic drivers. This study first summarizes the current understanding of the regulation of self-renewal by KLF proteins in embryonic stem cells through a KLF circuitry and then delves into the potential function of KLF4 in normal hematopoietic stem cells and its emerging role in leukemia-initiating cells from pediatric patients with T-cell acute lymphoblastic leukemia via repression of the mitogen-activated protein kinase 7 pathway. Stem Cells Translational Medicine 20198568-574.

A near-haploid clone harboring a BCRABL1 gene fusion in an adult patient with newly diagnosed B-lymphoblastic leukemia.

The detection of recurrent genetic abnormalities in B-lymphoblastic leukemia (B-ALL) is critical for risk stratification and therapy-related decisions. Near-haploidy (24-30 chromosomes), a subgroup of hypodiploidy (<46 chromosomes), and BCRABL1 gene fusions are both recurrent genetic abnormalities in B-ALL and are considered adverse prognostic findings, although outcomes in BCRABL1-positive patients have improved with tyrosine kinase inhibitor therapy. While near-haploid clones are primarily observed in children and rarely harbor structural abnormalities, BCRABL1-positive B-ALL is primarily observed in adults. Importantly, recurrent genetic abnormalities are considered mutually exclusive and rarely exist within the same neoplastic clone. We report only the second case to our knowledge of a near-haploid clone that harbors a BCRABL1 fusion in an adult with newly diagnosed B-ALL. Conventional chromosome studies revealed a near-haploid clone (27 chromosomes) along with a der(22)t(922)(q34.1q11.2) in 17 of 20 metaphases analyzed. Our B-ALL fluorescence in situ hybridization (FISH) panel confirmed the BCRABL1 fusion and monosomies consistent with chromosome studies in approximately 95% of interphase nuclei. Moreover, no evidence of a doubled near-haploid clone was observed by chromosome or FISH studies. This highly unusual case illustrates that while rare, recurrent genetic abnormalities in B-ALL can exist within the same neoplastic clone.

Highly efficient novel recombinant L-asparaginase with no glutaminase activity from a new halo-thermotolerant

Molecular Players in Hematologic Tumor Cell Trafficking.

The trafficking of neoplastic cells represents a key process that contributes to progression of hematologic malignancies. Diapedesis of neoplastic cells across endothelium and perivascular cells is facilitated by adhesion molecules and chemokines, which act in concert to tightly regulate directional motility. Intravital microscopy provides spatio-temporal views of neoplastic cell trafficking, and is crucial for testing and developing therapies against hematologic cancers. Multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and acute lymphoblastic leukemia (ALL) are hematologic malignancies characterized by continuous neoplastic cell trafficking during disease progression. A common feature of these neoplasias is the homing and infiltration of blood cancer cells into the bone marrow (BM), which favors growth and survival of the malignant cells. MM cells traffic between different BM niches and egress from BM at late disease stages. Besides the BM, CLL cells commonly home to lymph nodes (LNs) and spleen. Likewise, ALL cells also infiltrate extramedullary organs, such as the central nervous system, spleen, liver, and testicles. The α4β1 integrin and the chemokine receptor CXCR4 are key molecules for MM, ALL, and CLL cell trafficking into and out of the BM. In addition, the chemokine receptor CCR7 controls CLL cell homing to LNs, and CXCR4, CCR7, and CXCR3 contribute to ALL cell migration across endothelia and the blood brain barrier. Some of these receptors are used as diagnostic markers for relapse and survival in ALL patients, and their level of expression allows clinicians to choose the appropriate treatments. In CLL, elevated α4β1 expression is an established adverse prognostic marker, reinforcing its role in the disease expansion. Combining current chemotherapies with inhibitors of malignant cell trafficking could represent a useful therapy against these neoplasias. Moreover, immunotherapy using humanized antibodies, CAR-T cells, or immune check-point inhibitors together with agents targeting the migration of tumor cells could also restrict their survival. In this review, we provide a view of the molecular players that regulate the trafficking of neoplastic cells during development and progression of MM, CLL, and ALL, together with current therapies that target the malignant cells.

Utility of the number needed to treat in paediatric haematological cancer randomised controlled treatment trials a systematic review.

The primary objective was to assess the utility of the number needed to treat (NNT) to inform decision-making in the context of paediatric oncology and to calculate the NNT in all superiority, parallel, paediatric haematological cancer, randomised controlled trials (RCTs), with a comparison to the threshold NNT as a measure of clinical significance. Systematic review DATA SOURCES MEDLINE, EMBASE and the Cochrane Childhood Cancer Group Specialized Register through CENTRAL from inception to August 2018. Superiority, parallel RCTs of haematological malignancy treatments in paediatric patients that assessed an outcome related to survival, relapse or remission reported a sample size calculation with a delta value to allow for calculation of the threshold NNT, and that included parameters required to calculate the NNT and associated CI. A total of 43 RCTs were included, representing 45 randomised questions, of which none reported the NNT. Among acute lymphoblastic leukaemia (ALL) RCTs, 29.2% (724) of randomised questions were found to have a NNT corresponding to benefit, in comparison to acute myeloid leukaemia (ALM) RCTs with 50% (36), and none in lymphoma RCTs (013). Only 28.6% (27) and 33.3% (13) had a NNT that was less than the threshold NNT for ALL and AML, respectively. Of these, 100% (22 ALL and 11 AML) were determined to be possibly clinically significant. We recommend that decision-makers in paediatric oncology use the NNT and associated confidence limits as a supportive tool to evaluate evidence from RCTs while placing careful attention to the inherent limitations of this measure.

Fear and Coping in Children 5-9 years old Treated for Acute Lymphoblastic Leukemia - A Longitudinal Interview Study.

The aim of this study was to describe the fears of 5- to 9-year-old children related to having acute lymphoblastic leukemia (ALL) and their strategies for coping with those fears. The study had a qualitative descriptive longitudinal design and included a total of 35 interviews with 13 children at three different times during their treatment period. Data were analyzed using a matrix-based method inspired by the work of Miles et al. RESULTS Initially, most children reported a fear of needles, but during the treatment period, fewer children reported this fear. Childrens coping strategies also changed over time, as they wanted more involvement and control during needle-related procedures. Other fears were having adhesive tapes removed, having a nasogastric tube, and taking tablets. During the treatment period, existential fears related to the seriousness of ALL and its consequences, such as having impaired physical fitness and being different from before and different from others, became more prominent and caused feelings of loneliness and alienation. The children described various fears through their treatment period, which they coped with using cognitive, emotional, and functional strategies. Over the 2.5-year period, their strategies changed. Because fears changed over time and varied among these different children, each child must be approached individually and attentively in every encounter.

Steroid-induced diabetes in the paediatric population.

Steroid-induced diabetes is a rare disease in the paediatric population. High doses of corticosteroids are used in diseases such as acute lymphoblastic leukaemia (ALL), lymphomas, or connective tissue diseases. Post-steroid hyperglycaemia arises as a result of increased gluconeogenesis and increased glycogen synthesis. Steroid-induced diabetes most often is asymptomatic therefore it is important to monitor the glycaemic level in patients receiving systemic glucocorticoids. So far, no separate guidelines for steroid-induced diabetes have been developed, so the criteria for diagnosing drug-related diabetes mellitus do not differ from the criteria for diagnosing type 2 diabetes. Hyperglycaemia adversely affects the immune system it impairs the function of granulocytes, immunoglobulins, and also causes T-lymphocyte apoptosis. A hyperglycaemic environment favours the development of bacterial and fungal infections. Numerous studies confirm that hyperglycaemia increases the risk of infection and severity of infection. There have also been reports of adverse effects of steroid-induced hyperglycaemia in the course of treatment for the underlying disease in the adult population. Reports related to the paediatric population are not as numerous. There are studies that have proven an increased risk of infection in paediatric patients with ALL and steroid-induced diabetes, as well as studies that proved an unfavourable effect of diabetes on survival in children with ALL and as well the studies that proved that risk of life-threatening infection and survival does not differ statistically in the group of patients with hyperglycaemia and in the group of patients who did not develop diabetes. Cukrzyca posteroidowa to rzadkie schorzenie w populacji pediatrycznej. Należy do grupy cukrzyc polekowych. Wysokie dawki kortykosteroidów stosuje się w takich schorzeniach, jak ostra białaczka limfoblastyczna (acute lymphoblastic leukemia – ALL), chłoniaki czy choroby tkanki łącznej. Hiperglikemia posteroidowa powstaje wskutek wzmożenia glukoneogenezy oraz wzmożenia syntezy glikogenu. Cukrzyca posteroidowa najczęściej przebiega bezobjawowo, dlatego ważne jest monitorowanie stężenia glikemii u pacjentów otrzymujących glikokortykosteroidy ogólnoustrojowo. Dotychczas nie opracowano oddzielnych wytycznych dla cukrzycy polekowej, zatem kryteria rozpoznania cukrzycy posteroidowej nie różnią się od kryteriów rozpoznania cukrzycy typu 2. Leczeniem z wyboru cukrzycy posteroidowej w populacji pediatrycznej jest insulinoterapia. Ponadto należy wdrożyć odpowiednią dietę oraz wyedukować pacjenta i jego opiekunów. Hiperglikemia wpływa niekorzystnie na działanie układu immunologicznego upośledza funkcje granulocytów, immunoglobulin, a także powoduje apoptozę limfocytów T. Środowisko hiperglikemiczne sprzyja rozwojowi infekcji bakteryjnych i grzybiczych. Liczne badania potwierdzają, że hiperglikemia zwiększa ryzyko infekcji oraz powoduje ich cięższy przebieg. Opublikowano również doniesienia o niekorzystnym wpływie hiperglikemii posteroidowej na przebieg leczenia choroby podstawowej w populacji dorosłych. Doniesienia odnoszące się do populacji pediatrycznej nie są tak liczne i istnieją zarówno badania, w których udowodniono zwiększone ryzyko infekcji u onkologicznych pacjentów pediatrycznych z ALL z rozpoznaną cukrzycą posteroidową, oraz niekorzystny wpływ cukrzycy posteroidowej na przeżywalność u dzieci z ALL, jak i badania, w których udowodniono, że ryzyko wystąpienia infekcji zagrażającej życiu oraz przeżywalność nie różnią się statystycznie w grupie pacjentów z rozpoznaną hiperglikemią posteroidową oraz w grupie pacjentów, u których powikłanie to się nie rozwinęło.

Multimedia Appendix Correction mHealth Supportive Care Intervention for Parents of Children With Acute Lymphoblastic Leukemia Quasi-Experimental Pre- and Postdesign Study.

This corrects the article DOI 10.2196mhealth.9981..

Pak1 gene functioned differentially in different BCR-ABL subtypes in leukemiagenesis and treatment response through STAT5 pathway.

The BCR-ABL fusion gene (BCR-ABL) has different subtypes such as p210 and p190 with p190 appear to lead to a worse prognosis. To explore the mechanism of difference in pathogenesis and prognosis in different BCR-ABL subtype-related leukemia, expression profile microarray analysis was conducted between p190 and p210 patients and verified by RT-PCR. The p21-activated kinase (PAK1) gene was chosen and regulation of the PAK1-STAT5 biological axis and its influence on proliferation and apoptosis in leukemia cells were also analyzed. The results showed that PAK1 might be an important molecular mechanism of the pathogenic difference between different BCR-ABL subtypes. In P210 () chronic myelogenous leukemia (CML), down-regulated PAK1 gene expressions may lead to the suppression of cell proliferation and promotion of apoptosis through phosphorylation of STAT5, with a reverse effect in P190 () acute lymphoblastic leukemia(ALL), especially acute B lymphoblastic leukemia (B-ALL). Additionally, in P210 () CML, down-regulated PAK1 expression may enhance the effect of TKI, whereas the reverse is true in P190 () B-ALL, demonstrating that PAK1 might also be an important therapeutic target between different BCR-ABL subtypes.

Chimeric antigen receptor T cells for acute lymphoblastic leukemia.

Chimeric antigen receptor (CAR) modified T cells targeted to CD19 have resulted in unprecedented remission rates for adult and pediatric patients with relapsed and refractory B cell acute lymphoblastic leukemia (ALL). With regulatory approval for tisagenlecleucel and many other agents under active investigation, the use of CAR T cells for ALL continues to expand. While some remissions from anti-CD19 CAR T cells are durable without a consolidative allogeneic stem cell transplantation, CD19 positive and negative relapses remain a significant concern fueling investigations into the biology of CAR T cell persistence and the development of CARTs that target more than 1 antigen. The treatment related toxicities of cytokine release syndrome and neurologic events are potentially life threatening but recent advances have improved understanding and management strategies. This review summarizes outcomes for patients with ALL treated with CD19-CAR T cells while exploring the fields challenges and future directions.

3D culture enhances chemoresistance of ALL Jurkat cell line by increasing DDR1 expression.

Three dimensional (3D) culture has gradually become a research hotspot in the field of drug screening, stem cell research, and tissue engineering due to its more physiological-like morphology and function. In this study, we compared the differences of cell proliferation, population, protein expression and chemoresistance profiles between two dimensional (2D) and 3D culture of acute lymphoblastic leukemia (ALL) Jurkat cell line. Polycaprolactone (PCL) is used for 3D culture owing to its biochemical properties and compatibility. Culturing of ALL Jurkat cell line in collagen type I coated polycaprolactone scaffold for 168 h increased cell proliferation, attachment, as well as the drug resistance to cytarabine (Ara-C) and daunorubicin (DNR) without changing the original CD2

Sinusoidal obstruction syndrome in a paediatric patient with acute lymphoblastic leukaemia after completion of reinduction therapy according to ALL Intercontinental Berlin-Frankfurt-Münster 2009.

Sinusoidal obstruction syndrome (SOS), also termed veno-occlusive disease (VOD) of the liver, is a well-known complication of haematopoietic stem cell transplantation (HSCT) both in children and adults. In the medical literature there are occasional reports of SOS in patients receiving conventional chemotherapy. In children with solid tumours this entity occurs during treatment of nephroblastoma, rhabdomyosarcoma, and medulloblastoma. In the late 1990s SOS was quite often observed as the complication of oral 6-thioguanine (6-TG) in patients suffering from acute lymphoblastic leukaemia (ALL), who received 6-TG throughout maintenance. In current protocols, the syndrome has become uncommon because treatment with 6-TG is limited to two weeks of oral therapy. Here, we report a case of a nine-year-old boy with ALL, who developed sinusoidal obstruction syndrome shortly after completing the reinduction block of chemotherapy (cyclophosphamide, cytarabine, thioguanine) according to the ALL Intercontinental Berlin-Frankfurt-Münster 2009 (ALL IC BFM 2009) treatment protocol.

The TLR3 Agonist Poly InosinicCytidylic Acid Significantly Augments the Therapeutic Activity of an Anti-CD7 Immunotoxin for Human T-cell Leukaemia.

We have previously shown that antibody-dependent cellular cytotoxicity (ADCC) cooperates with immunotoxin (IT)-mediated killing of human leukaemia cells in an severe combined immunodeficient (SCID) mouse model of human T-cell acute lymphoblastic leukaemia (SCID-HSB-2 mice), but not in an equivalent non-obese diabetic (NOD)SCID mouse model. In these earlier studies, we reasoned that diminished ADCC due to the functional deficit in natural killer (NK) cell activity in NODSCID mice resulted in a failure of effective perforingranzyme-mediated cytotoxicity necessary for the delivery of the augmentative effect. Poly-inosinic-cytidylic acid poly (IC) is a synthetic dsRNA toll-like receptor 3 (TLR3) agonist that possesses a number of biological properties that includes the in vivo activation of NK cells. We show here that intravenous (i.v.) injection of SCID mice with poly (IC) results in characteristic time-related changes in serum interleukin 2 (IL-2), IL-12, and interferon γ (INFγ) cytokine levels that are consistent with TLR3 driven activation of SCID mouse NK cells. Concomitantly, there are changes in the expression levels of CD2, CD1632 (FcγRIIRIII), CD161 (NK1.1), and F480 in the bulk splenocyte population. These observed changes correlate with an increase in the in vitro lytic capabilities of putative NK cells from within the splenocyte population of poly (IC) treated SCID mice. We demonstrate that the in vivo activation of NK cells with poly (IC) in SCID mice bearing disseminated human T-cell leukaemia xenografts resulted in a significant improvement in the therapeutic activity exerted by an intact murine monoclonal antibody against human CD7. This was also seen for a saporin-based immunotoxin constructed with the same intact antibody (HB2-SAPORIN), but not with an F(ab)₂ derivative of the same antibody or of an IT constructed with the same F(ab)₂ HB2 antibody derivative. This study further demonstrates the previously reported reinforcing role of ADCC for the therapeutic activity of IT in an SCID mouse model of human T-ALL and the potential to significantly boost this further with poly (IC). Our study provides the rationale to justify the exploration of the clinical utility of IT based therapeutics in combination with TLR3 agonists, such as poly (IC), for the treatment of haematological, and possibly other, malignancies.

Attenuating the abnormally high expression of AEBP1 suppresses the pathogenesis of childhood acute lymphoblastic leukemia via p53-dependent signaling pathway.

This study aimed to explore the candidate genes and their potential mechanism in childhood acute lymphoblastic leukemia (cALL). Differentially expressed genes (DEGs) were screened from GSE67684 (treatment), GSE28460 (relapse), and GSE60926 (relapse). The expression of AEBP1 at different stages of cALL was analyzed followed by functional enrichment analysis of its co-expressed genes. Expression of AEBP1 was determined in different leukemia cell lines and knocked down in Jurkat cells. Cell behaviors as well as the expression of p53, Bax, and Bcl-2 were also evaluated after silencing AEBP1 in Jurkat cells. Two clusters Profile 1 (downward) and Profile 26 (upward) were identified in GSE67684, and 53 Profile 1-specific DEGs were identified compared with DEGs in GSE28460 and GSE60926. AEBP1 was one of these genes and was significantly downregulated after treatment but upregulated in relapse samples. Functional enrichment analysis revealed that AEBP1 co-expressed genes were significantly enriched in GO terms including immune response, blood coagulation etc. and in the hematopoietic cell lineage and PI3KAkt signaling pathways. AEBP1 was significantly increased in leukemia cell lines, especially in Jurkat cells, compared with the Pbmc cells. Silencing AEBP1 markedly reduced proliferation and induced cell cycle arrest in Jurkat cells, but also promoted apoptosis of Jurkat cells. Silencing AEBP1 also inhibited the expression of p53 and Bcl-2 but promoted Bax in Jurkat cells. AEBP1 was highly-expressed in the diagnosis and relapse cALL, and silencing AEBP1 significantly reduced proliferation but promoted apoptosis in Jurkat cells via a p53-dependent pathway.

Doxorubicin treatments induce significant changes on the cardiac autonomic nervous system in childhood acute lymphoblastic leukemia long-term survivors.

Acute lymphoblastic leukemia (ALL) is one of the leading malignancies in children worldwide. The cardiotoxicity of anti-cancer treatments leads to a dysfunction of the cardiac autonomic nervous system. Protection strategies, with dexrazoxane treatments, were used to counter these adverse effects. The aim of this study was to investigate the effects of the treatments on the cardiac autonomic nervous system. A total of 203 cALL survivors were included in our analyses and were classified into 3 categories based on the prognostic risk group standard risk, high risk with and without dexrazoxane. A 24-h Holter monitoring was performed to study the cardiac autonomic nervous system. The frequency domain heart rate variability (HRV) was used to validate the cardiac autonomic nervous system modifications. Other analyses were performed using linear HRV indexes in the time domain and non-linear indexes. A frequency domain HRV parameters analysis revealed significant differences on an overall time-period of 24 h. A repeated measures ANOVA indicated a group-effect for the low frequency (p 0.029), high frequency (p 0.03) and LFHF ratio (p 0.029). Significant differences in the time domain and in the non-linear power spectral density HRV parameters were also observed. Anti-cancer treatments induced significant changes in the cardiac autonomic nervous system. The HRV was sensitive enough to detect cardiac autonomic nervous system alterations depending on the cALL risk category. Protection strategies (i.e., dexrazoxane treatments), which were used to counter the adverse effects of doxorubicin, could prevent changes observed in the cardiac autonomic nervous system.

A Phase II Study of Alisertib in Children with RecurrentRefractory Solid Tumors or Leukemia Childrens Oncology Group Phase I and Pilot Consortium (ADVL0921).

Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centrosome and spindle maturation. Alisertib (MLN8237) is a potent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816). Alisertib (80 mgm A total of 139 children and adolescents (median age, 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 μmolL, exceeding the 1 μmolL target trough concentration in 67% of patients. No correlations between PG or PK and toxicity were observed. Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single-agent alisertib was less than 5%.

A Case of Renal Involvement in B Lymphoblastic Lymphoma Leukemia.

Renal involvement is rare in B lymphoblastic lymphoma (B-LBL). The authors describe a rare case of renal involvement in a 21-year-old male patient with B lymphoblastic lymphoma leukemia, presenting with severe lactic acidosis. Hematologic investigation, bone marrow aspirate and biopsy, cytogenetic analysis and renal biopsy were performed. The patient achieved complete hematological remission (CHR) after induction therapy with the regimen of VDCP and received consolidation chemotherapy regularly. He remained CHR until now. Renal biopsy, bone marrow aspirate, and biopsy are important to confirm a correct diagnosis. Renal involvement in B-LBL as a prognostic factor needs further studies.

Acute Lymphoblastic Leukemia Presenting Solely as Low Back Pain.

A 23-year-old man with acute lymphoblastic leukemia presented to the emergency department without any history of constitutional symptoms (fatigue, anorexia, or weight loss), dyspnea, bruising, or bleeding. Presentation of acute leukemia solely as musculoskeletal pathology is common in pediatric populations but rare among adult patients. Recognizing this presentation of acute leukemia in adult patients could help prevent delayed diagnoses.