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Child symptoms, parent behaviors, and family strain in long-term survivors of childhood acute lymphoblastic leukemia.

How family environment and parental factors affect health status and symptoms in childhood cancer survivors is understudied. We examined the influence of family cohesion, parent distress, and overprotection on child symptom burden and health-related quality of life (HRQOL) and family strain in survivors of childhood acute lymphoblastic leukemia. Parents of 213 children treated with chemotherapy only completed a survey when survivors were at least 5-year postdiagnosis. Family Environment Scale, Brief Symptom Inventory-18, Parent Protection Scale, Pediatric Quality of Life Inventory, and Impact on Family were used to assess family cohesion, parental distress, overprotection, child symptom burden and HRQOL, and family strain, respectively. Path analysis was conducted to quantify effects of family cohesion on family strain through parental distress, overprotection, child symptoms, and HRQOL. Lower family cohesion (β 0.06, 95% CI, 0.01-0.13), higher parental distress (β 0.35, 95% CI, 0.20-0.45), and overprotection (β 0.17, 95% CI, 0.01-0.32) were associated with more child symptom burden. More symptom burden were associated with poorer child HRQOL (β 0.66, 95% CI, 0.57-0.75), which in turn was associated with more family strain (β 0.11, 95% CI, 0.01-0.22). Lower maternal education was associated with overprotection (β -0.23, 95% CI, -0.33 to -0.12), more child symptoms (β -0.30, 95% CI, -0.41 to -0.16), poorer child HRQOL (β -0.36, 95% CI, -0.46 to -0.21), and more family strain (β -0.15, 95% CI, -0.23 to -0.08). Family and parental factors contributed to health outcomes of childhood acute lymphoblastic leukemia survivors. Interventions to enhance family cohesion, decrease parental distress and overprotection, and ameliorate child symptoms may improve family functioning.

Vincristine-associated Neuropathy With Antifungal Usage A Kaiser Northern California Experience.

The dose-limiting toxicity for vincristine is peripheral neuropathy which can be potentiated with concurrent usage of azole antifungals. The current retrospective study assessed the incidence of concurrent vincristine and azole antifungal usage to determine if it led to increased neurotoxicity for the Kaiser Northern California pediatric acute lymphoblastic leukemia (ALL) and Hodgkin lymphoma patient population. Data were obtained from the electronic medical record (2007 to 2014). In total, 130 subjects received at least one dose of vincristine for ALL or Hodgkin lymphoma (median age 9, 88% ALL, 58% male, 47% Caucasian). Thirty one percent of patients received concurrent antifungal usage (fluconazole, 78% voriconazole, 10% fluconazolevoriconazole, 12%) however, concurrent antifungal usage accounted for <15% of vincristine doses. Grade 2 or greater neuropathy occurred in 51% of patients grade 3 neuropathy was present in 8% of patients. No difference in the incidence of grade 2 or greater neuropathy was observed with the concurrent use of antifungal therapy (P0.35), sex (P0.59), type of cancer (P0.41), ethnicity (P0.29), or age (P0.39), but was higher with increasing amount of vincristine doses (P0.004). These results suggest that concurrent azole antifungal usage with vincristine for patients with ALL and Hodgkin lymphoma was low in the Kaiser Northern California population and limited usage as needed may be reasonable and safe.

Nasogastric Tube Syndrome A Diagnostic Dilemma.

Nasogastric tubes have been used in the pediatric age group to supplement nutrition in cases of malignancy and failure to thrive due to a variety of causes. Breathing difficulty may occur after the insertion of a nasogastric tube and it can have multiple causes. Here we discuss 2 patients of acute lymphoblastic leukemia (ALL) who developed a rare condition called the Sofferman syndrome (nasogastric tube syndrome). We will also briefly outline a diagnostic algorithm to facilitate its fast and correct diagnosis. We present 2 cases of pediatric ALL who were undergoing chemotherapy in the pediatrics department. They presented with respiratory distress and stridor within a few days of nasogastric tube insertion. Two cases of ALL developed stridor within 48 hours of nasogastric tube insertion. The stridor gradually progressed over days. Both the patients required tracheostomy to secure the airway. Removal of the nasogastric tube did not reverse the airway obstruction. Nasogastric tube syndrome is a potentially life-threatening condition and has to be considered as a possibility in immune-compromised patients who present with voice change and stridor after nasogastric tube insertion.

Cost-Effectiveness Analysis of an Adherence-Promotion Intervention for Children With Leukemia A Markov Model-Based Simulation.

Improving medication adherence among children with B-cell precursor acute lymphoblastic leukemia (B-ALL) has the potential to reduce relapse rates but requires an investment in resources. An economic evaluation is needed to understand the potential costs and benefits of delivering adherence-promotion interventions (APIs) as part of standard clinical care. A Markov decision analytic model was used to simulate the potential incremental cost-effectiveness per quality-adjusted life year (QALY) to be gained from an API for children with B-ALL in first continuous remission compared with treatment as usual (TAU, no intervention). Model parameter estimates were informed by previously published studies. The primary outcome was incremental cost (2015 US$) per QALY gained for API compared with TAU. The model predicts the API to result in superior health outcomes (4.87 vs. 4.86 QALYs) and cost savings ($43,540.73 vs. $46,675.71) as compared with TAU, and simulations indicate that, across a range of plausible parameter estimates, there is a 95% chance that the API is more effective and less costly than TAU. The API was estimated to remain more effective and less costly than TAU in situations where the prevalence of nonadherence exceeds 32% and when API improves baseline adherence in at least 3% of patients. Providing APIs to children with B-ALL may improve health outcomes and save costs over a 6-year period.

Advances on chimeric antigen receptor-modified T-cell therapy for oncotherapy.

Tumor treatment is still complicated in the field of medicine. Tumor immunotherapy has been the most interesting research field in cancer therapy. Application of chimeric antigen receptor T (CAR-T) cell therapy has recently achieved excellent clinical outcome in patients, especially those with CD19-positive hematologic malignancies. This phenomenon has induced intense interest to develop CAR-T cell therapy for cancer, especially for solid tumors. However, the performance of CAR-T cell treatment in solid tumor is not as satisfactory as that in hematologic disease. Clinical studies on some neoplasms, such as glioblastoma, ovarian cancer, and cholangiocarcinoma, have achieved desirable outcome. This review describes the history and evolution of CAR-T, generalizes the structure and preparation of CAR-T, and summarizes the latest advances on CAR-T cell therapy in different tumor types. The last section presents the current challenges and prospects of CAR-T application to provide guidance for subsequent research.

Improving the safety of high-dose methotrexate for children with hematologic cancers in settings without access to MTX levels using extended hydration and additional leucovorin.

A lack of access to methotrexate levels is common in low- and middle-income countries (LMIC), relevant for 80% of children with cancer worldwide. We evaluated whether high-dose methotrexate (HD-MTX) can be administered safely with extended hydration and leucovorin rescue, with monitoring of serum creatinine and urine pH. The prospective study was conducted at a single centre in Chandigarh, India in 2015. Patients with B-cell acute lymphoblastic leukemia (ALL) or with T-cell ALL or non-Hodgkin lymphoma (T-NHL) were administered 3 and 5 gmm The study included 100 cycles of HD-MTX in 53 patients B-ALL 25 patients (51 cycles), T-ALL 16 patients (28 cycles), T-NHL 10 patients (18 cycles), and relapsed ALL 2 patients (3 cycles). The mean age was 6.8 ± 3.2 years. Patients were underweight in 15 (15%) cycles. Patients in 23% of cycles had a rise in creatinine to >1.25 times the baseline. Toxicities (NCI CTCAE v4.0) included mucositis (32%), diarrhoea (10%), and febrile neutropenia (9%). One patient died from dengue shock syndrome. It is safe to administer 3 or 5 gmm

Abnormally high expression of POLD1, MCM2, and PLK4 promotes relapse of acute lymphoblastic leukemia.

This study aimed to explore the underlying mechanism of relapsed acute lymphoblastic leukemia (ALL).Datasets of GSE28460 and GSE18497 were downloaded from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) between diagnostic and relapsed ALL samples were identified using Limma package in R, and a Venn diagram was drawn. Next, functional enrichment analyses of co-regulated DEGs were performed. Based on the String database, protein-protein interaction network and module analyses were also conducted. Moreover, transcription factors and miRNAs targeting co-regulated DEGs were predicted using the WebGestalt online tool.A total of 71 co-regulated DEGs were identified, including 56 co-upregulated genes and 15 co-downregulated genes. Functional enrichment analyses showed that upregulated DEGs were significantly enriched in the cell cycle, and DNA replication, and repair related pathways. POLD1, MCM2, and PLK4 were hub proteins in both protein-protein interaction network and module, and might be potential targets of E2F. Additionally, POLD1 and MCM2 were found to be regulated by miR-520H via E2F1.High expression of POLD1, MCM2, and PLK4 might play positive roles in the recurrence of ALL, and could serve as potential therapeutic targets for the treatment of relapsed ALL.

A case report of B lymphoblastic lymphoma with brain metastases Clinical and pathological significance of head trauma misdiagnosis.

B lymphoblastic lymphoma (B-LBL) is a rare type of lymphoma that originates from precursor lymphocytes. B-BLB in adults with brain metastases is extremely rare as the disease mainly affects children and adults. Therefore, such a seldom-seen case can easily trigger a dispute regarding clinical diagnosis and treatment.This paper reports the case of a 22-year-old man hospitalized for a head injury that resulted from a physical altercation. Upon admission to the hospital, the patient was diagnosed with a diffuse axonal injury (DAI). Accordingly, the patient receiving follow-up treatments, but died 30 days later. After a systematic necropsy, immunohistochemical staining, radiological consultation, and a complete review of the clinical dates, we defined the case as a brain metastasis of B lymphoblastic lymphoma. Imaging results of the intracranial lymphoma were nearly indistinguishable from DAI during the acute phase, which led to misdiagnosis and incorrect treatment for B-LBL. We present this case to broaden the scope of pathologic and clinical diagnosis for intracranial tumors and to inform physicians, general neurologists, and even medical examiners with an added degree of differential awareness in dealing with the clinical materials before further diacrisis and disposal.

Enhanced stability of L-asparaginase by its bioconjugation to poly(styrene-co-maleic acid) and Ecoflex nanoparticles.

Acute lymphoblastic leukemia (ALL) is the white blood cell cancer in children. L-asparaginase (L-ASNase) is one of the first drugs used in ALL treatment. Anti-tumor activity of L-ASNase is not specific and indicates limited stability in different biological environments, in addition to its quick clearance from blood. The purpose of the present study was to achieve a new L-ASNase polymer bioconjugate to improve pharmacokinetic, increase half-life and stability of the enzyme. The conjugations were achieved by the cross-linking agent of 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide (EDC) which activates the carboxylic acid groups of polymeric nanoparticles to create amide bond. EDC conjugated the L-ASNase to two biodegradable polymers including Ecoflex

Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System.

Chimeric antigen receptor (CAR) T cell therapy has proven clinically beneficial against B cell acute lymphoblastic leukemia and non-Hodgkins lymphoma. However, suboptimal clinical outcomes have been associated with decreased expansion and persistence of adoptively transferred CAR T cells, antigen-negative relapses, and impairment by an immunosuppressive tumor microenvironment. Improvements in CAR T cell design are required to enhance clinical efficacy, as well as broaden the applicability of this technology. Here, we demonstrate that interleukin-18 (IL-18)-secreting CAR T cells exhibit enhanced in vivo expansion and persistence and significantly increase long-term survival in syngeneic mouse models of both hematological and solid malignancies. In addition, we demonstrate that IL-18-secreting CAR T cells are capable of modulating the tumor microenvironment, as well as enhancing an effective endogenous anti-tumor immune response. IL-18-secreting CAR T cells represent a promising strategy to enhance the clinical outcomes of adoptive T cell therapy.

The severe cytokine release syndrome in phase I trials of CD19-CAR-T cell therapy a systematic review.

CD19 chimeric antigen receptor (CAR) T cell therapy has shown impressive results in treating acute lymphoblastic leukemia (B-ALL), chronic lymphoblastic leukemia (B-CLL), and B-cell non-Hodgkin lymphoma (B-NHL) over the past few years. Meanwhile, the cytokine release syndrome (CRS), which could be moderate or even life-threatening, has emerged as the most significant adverse effect in the clinical course of this novel targeting immunotherapy. In this systematic review, we analyzed the incidence of severe CRS in 19 clinical trials selected from studies published between 2010 and 2017. The pooled severe CRS proportion was 29.3% (95% confidence interval CI 12.3-49.1%) in B-ALL, 38.8% (95%CI 12.9-67.6%) in B-CLL, and 19.8% (95%CI 4.2-40.8%) in B-NHL. In the univariate meta regression analysis, the proliferation of CD19-CAR-T cell in vivo was correlated with the severe CRS. Specifically, total infusion cell dose contributed to the severe CRS occurring in B-ALL patients but not in B-CLL or B-NHL patients. Tumor burden was strongly associated with the severity of CRS in B-ALL. Besides, post-HSCT CD19 CAR-T cell infusion represented lower severe CRS incidence. Further investigations into the risk factors of CRS in B-CLL and B-NHL are needed.

Effects of CB2 and TRPV1 receptors stimulation in pediatric acute T-lymphoblastic leukemia.

T-Acute Lymphoblastic Leukemia (T-ALL) is less frequent than B-ALL, but it has poorer outcome. For this reason new therapeutic approaches are needed to treat this malignancy. The EndocannabinoidEndovanilloid (ECEV) system has been proposed as possible target to treat several malignancies, including lymphoblastic diseases. The ECEV system is composed of two G-Protein Coupled Receptors (CB1 and CB2), the Transient Potential Vanilloid 1 (TRPV1) channel, their endogenous and exogenous ligands and enzymes. CB1 is expressed mainly in central nervous system while CB2 predominantly on immune and peripheral cells, therefore we chose to selectively stimulate CB2 and TRPV1. We treated T-ALL lymphoblasts derived from 4 patients and Jurkat cells with a selective agonist at CB2 receptor JWH-133 100 nM and an agonist at TRPV1 calcium channel RTX 5 uM at 6, 12 and 24 hours. We analyzed the effect on apoptosis and Cell Cycle Progression by a cytofluorimetric assays and evaluated the expression level of several target genes (Caspase 3, Bax, Bcl-2, AKT, ERK, PTEN, Notch-1, CDK2, p53) involved in cell survival and apoptosis, by Real-Time PCR and Western Blotting. We observed a pro-apoptotic, anti-proliferative effect of these compounds in both primary lymphoblasts obtained from patients with T-ALL and in Jurkat cell line. Our results show that both CB2 stimulation and TRPV1 activation, can increase the apoptosis

Clinical application of minimal residual disease detection in childhood acute leukemia.

In recent years, great progress has been made in the treatment outcome of childhood acute leukemia with the improvement of chemotherapy regimens and the introduction of risk-stratified therapy however, minimal residual disease (MRD) is still a difficult problem which affects the prognosis of acute leukemia. MRD influences the selection of chemotherapy regimens and recurrence risk stratification, and meanwhile, it can be used for prognostic prediction. At present, flow cytometry and polymerase chain reaction are mainly used for MRD detection. The next-generation sequencing also plays an important role in MRD detection, especially in MRD detection after stem cell transplantation. This article reviews the methodology and significance of MRD detection in childhood acute leukemia. 近年来，儿童急性白血病（AL）治疗效果随化疗方案的改进和危险分层治疗的引入取得很大进展。但微小残留病变（MRD）仍然是影响AL预后的一大难题。MRD水平影响化疗方案的选择、复发风险的分级，同时还可用于判断预后。目前检测MRD的方法主要有流式细胞术（FCM）和PCR。随着二代测序技术（NGS）的不断成熟与发展，其在MRD检测尤其在干细胞移植（SCT）后MRD检测方面扮演着重要角色。本文对微小残留病变检测在儿童急性白血病中的应用进行综述。

Its ALL in the Family IKZF1 and Hereditary Leukemia.

IKZF1 plays an essential role in lymphopoiesis, and somatic IKZF1 variants in acute lymphoblastic leukemia (ALL) are associated with poor prognosis. In this issue of Cancer Cell, Churchman et al. add to the list of leukemia predisposition genes with the identification and characterization of germline IKZF1 variants in childhood ALL.

Maternal folate genes and aberrant DNA hypermethylation in pediatric acute lymphoblastic leukemia.

There is evidence that maternal genotypes in folate-related genes are associated with pediatric acute lymphoblastic leukemia (ALL) independent of offspring genotype. We evaluated the relationship between maternal genotypes in methionine synthase (MTR) and DNA methylation status in ALL to better characterize the molecular mechanism underlying this association. We obtained bone marrow samples from 51 patients with ALL at diagnosis and from 6 healthy donors. Mothers of patients provided a saliva sample and were genotyped at 11 tagSNPs in MTR. DNA methylation was measured in bone marrow mononuclear cells of patients and six healthy marrow donors. We used hierarchical clustering to identify patients with a hypermethylator phenotype based on 281 differentially methylated promoter CpGs. We used logistic regression to estimate the effects of maternal genotype on the likelihood of DNA hypermethylation in ALL and Ingenuity Pathway Analysis to identify networks enriched for differentially methylated genes. Twenty-two cases (43%) demonstrated promoter hypermethylation, which was more frequent among those with ETV6-RUNX1 fusion and initial white blood cell count < 50 x 109L. Maternal rs12759827 was associated with aberrant DNA methylation (odds ratio OR 4.67, 95% confidence interval 1.46-16.31) non-significantly elevated ORs were observed for all other SNPs. Aberrantly methylated promoter CpGs aligned to genes with known cancer-related functions. Maternal folate metabolic genotype may be associated with DNA methylation patterns in ALL in their offspring. Therefore, the effect of maternal genotypes on ALL susceptibility may act through aberrant promoter methylation, which may contribute to the in utero origins of ALL.

Kymriah A Sign of More Difficult Decisions To Come.

The CAR-T therapy may pass ICER cost-effectiveness muster, but can the health care system afford more drugs like it

Growth Plate Suppression in an Adolescent Patient With Acute Lymphoblastic Leukemia After Treatment.

Osteotoxic effect is a common adverse effect of chemotherapy for childhood acute lymphoblastic leukemia. The pathophysiology of impaired bone growth is multifactorial and can affect both osteoblast and osteoclast function. Significant contribution in affecting skeletal metabolism belongs to high-dose corticosteroid treatment. We present the case of a 12-year-old adolescent girl who was treated for high-risk pro-B acute lymphoblastic leukemia. The Tc-MDP bone scan, as a sensitive indicator of osteoblastic activity, shows that growth plate inhibition after intensive treatment may be temporary and reversible.

Advanced parental age as risk factor for childhood acute lymphoblastic leukemia results from studies of the Childhood Leukemia International Consortium.

Advanced parental age has been associated with adverse health effects in the offspring including childhood (0-14 years) acute lymphoblastic leukemia (ALL), as reported in our meta-analysis of published studies. We aimed to further explore the association using primary data from 16 studies participating in the Childhood Leukemia International Consortium. Data were contributed by 11 case-control (CC) studies (7919 cases and 12,942 controls recruited via interviews) and five nested case-control (NCC) studies (8801 cases and 29,690 controls identified through record linkage of population-based health registries) with variable enrollment periods (1968-2015). Five-year paternal and maternal age increments were introduced in two meta-analyses by study design using adjusted odds ratios (OR) derived from each study. Increased paternal age was associated with greater ALL risk in the offspring (OR

Genomics and pharmacogenomics of pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukaemia (ALL) is a prevalent form of pediatric cancer that accounts for 70-80% of all leukemias. Genome-based analysis, exome sequencing, transcriptomics and proteomics have provided insight into genetic classification of ALL and helped identify novel subtypes of the disease. B and T cell-based ALL are two well-characterized genomic subtypes, significantly marked by bone marrow disorders, along with mutations in trisomy 21 and T53. The other ALLs include Early T-cell precursor ALL, Philadelphia chromosome-like ALL, Down syndrome-associated ALL and Relapsed ALL. Chromosomal number forms a basis of classification, such as, hypodiploid ALL, near-haploid, low-hypodiploid, high-hypodiploid and hypodiploid-ALL. Advances in therapies targeting ALL have been noteworthy, with significant pre-clinical and clinical studies on drug pharmacokinetics and pharmacodynamics. Methotrexate and 6-mercaptopurine are leading drugs with best demonstrated efficacies against childhood ALL. The drugs in combination, following dose titration, have also been used for maintenance therapy. Methotrexate-polyglutamate is a key metabolite that specifically targets the disease pathogenesis, and 6-thioguanine nucleotides, derived from 6-mercaptopurine, impede replication and transcription processes, inducing cytotoxicity. Additionally, glucocorticoids, asparaginase, anthracycline, vincristine and cytarabine that trans-repress gene expression, deprives cells of asparagine, triggers cell cycle arrest, influences cytochrome-P450 polymorphism and inhibits DNA polymerase, respectively, have been used in chemotherapy in ALL patients. Overall, this review covers the progress in genome technology related to different sub-types of ALL and pharmacokinetics and pharmacodynamics of its medications. It also enlightens adverse effects of current drugs, and emphasizes the necessity of genome-wide association studies for restricting childhood ALL.

Stevens-Johnson Syndrome associated with methotrexate treatment for acute lymphoblastic leukemia a case report.

Toxic epidermal necrolysis and Stevens-Johnson syndrome are rare mucocutaneous diseases which are associated with a prolonged course and potentially lethal outcome. They are mostly drug induced and mortality rates are very high. Although mostly skin is involved, multiple organ systems such as cardiovascular, pulmonary, gastrointestinal, and urinary systems may be affected. Here, we report a case of Stevens- Johnson Syndrome associated with methotrexate treatment who developed acute cardiac failure and gastrointestinal hemorrhage beside skin findings. He had been treated with intravenous immunglobulin and methylprednisolone succesfully and continued chemotherapy with methotrexate treatment again. La necrólisis epidérmica tóxica y el síndrome de Stevens- Johnson son enfermedades mucocutáneas raras que están asociadas a una evolución prolongada y a un desenlace potencialmente mortal. Principalmente están inducidas por fármacos y las tasas de mortalidad son muy elevadas. Aunque la piel es la más comprometida, también pueden estar afectados múltiples aparatos o sistemas como el cardiovascular, pulmonar, gastrointestinal y urinario. En este artículo, describimos el caso de un paciente con síndrome de Stevens-Johnson asociado al tratamiento con metotrexato, quien desarrolló insuficiencia cardíaca aguda y hemorragia gastrointestinal además de las manifestaciones en la piel. El paciente recibió un tratamiento satisfactorio con metilprednisolona e inmunoglobulina por vía intravenosa y continuó la quimioterapia con metotrexato.

Infectious Risks and Complications in Adult Leukemic Patients Receiving Blinatumomab.

Blinatumomab is an anti-CD19 immunotherapy approved for relapsedrefractory B-cell acute lymphoblastic leukemia (ALL) with significantly increased survival rate. While blinatumomab showed lower rates of infection, neutropenia and mucosal barrier injury versus chemotherapy, its infection risks are not well described. All patients who received blinatumomab for ≥ seven days at an academic cancer center from May 2015 to April 2017 were included. Patient characteristics pertinent to infectious risks and complications were examined. Twenty patients with refractory (25%), relapsed (70%), or remitted (5%) B-ALL who received a total of 35 cycles were included. Ten of the 35 cycles were interrupted, none of which were due to infections. Twenty-six infections (n) were observed with lower respiratory (9), gastrointestinal (6) and bacteremia (5) being most common. Compared to patients without nodular, possible mold pneumonia (n16), patients with nodular pneumonia (n4) had significantly lower baseline absolute neutrophil count (ANC) (2319 v. 208μL, p0.011). There were no differences in baseline characteristics including ANC between bacteremic and non-bacteremic patients. One patient was discharged with no antibacterial prophylaxis since ANC recovered to >500cellsμL, but developed Pseudomonal bacteremia within a week with ANC 100cellsμL. Despite blinatumomabs relatively modest myelosuppression and the lack of mucotoxicity, host factors (e.g., duration and degree of neutropenialymphopenia) play a key role and should be considered when choosing anti-microbial prophylaxis. In relapsedrefractory disease, the ANC should be monitored closely post blinatumomab since neutropenia can unexpectedly develop after treatment which may be compounded by the underlying disease and recent chemotherapy effects.

New and traditional directions in the biology and management of childhood acute lymphoblastic leukemia.

Owing to clinical trials and improvement over the past few decades, the majority of children with acute lymphoblastic leukemia (ALL) survive by first-line chemotherapy and combat with the problems of returning to community. However, many patients may have severe acute or late therapeutic side effects, and the survival rate in some groups (e.g., patients with MLL rearrangements, hypodiploidy, IKZF1 mutation or early precursor T cell phenotype) is far behind the average. Innovative strategies in medical attendance provide better clinical outcomes for them complete gene diagnostics, molecularly targeted anticancer treatment, immuno-oncology and immune cell therapy. The number of genes with identified alterations in leukemic lymphoblasts is over thirty and their pathobiologic role is only partly clear. There are known patient groups where the use of specific drugs is based on gene expression profiling (e.g., tyrosine kinase inhibitors in Philadelphia-like B-cell ALL). The continuous assessment of minimal residual disease became a routine due to the determination of a leukemia-associated immunophenotype by flow cytometry or a sensitive molecular marker by molecular genetics at diagnosis. Epitopes of cluster differentiation antigens on blast surface (primarily CD19, CD20 and CD22 on malignant B cells) can be attacked by monoclonal antibodies. Moreover, antitumor immunity can be strengthened utilizing either cell surface markers (bispecific T cell engagers, chimeric antigen receptor T cell therapy) or tumor-specific immune cells (immune checkpoint inhibitors). This review gives an insight into current knowledge in these innovative therapeutic directions. Orv Hetil. 2018 159(20) 786-797.

Grouped gene selection and multi-classification of acute leukemia via new regularized multinomial regression.

Diagnosing acute leukemia is the necessary prerequisite to treating it. Multi-classification on the gene expression data of acute leukemia is help for diagnosing it which contains B-cell acute lymphoblastic leukemia (BALL), T-cell acute lymphoblastic leukemia (TALL) and acute myeloid leukemia (AML). However, selecting cancer-causing genes is a challenging problem in performing multi-classification. In this paper, weighted gene co-expression networks are employed to divide the genes into groups. Based on the dividing groups, a new regularized multinomial regression with overlapping group lasso penalty (MROGL) has been presented to simultaneously perform multi-classification and select gene groups. By implementing this method on three-class acute leukemia data, the grouped genes which work synergistically are identified, and the overlapped genes shared by different groups are also highlighted. Moreover, MROGL outperforms other five methods on multi-classification accuracy.

Ingrown Toenails During Chemotherapy and Stem Cell Transplantation in Children With Hematologic Malignancies and Solid Tumors.

At our institution, we noted that children with hematologic malignancies and solid tumors often suffered from ingrown toenails (IGTNs) during hospitalization for chemotherapy and stem cell transplantation. However, only few reports have dealt with IGTNs in the above setting. Between August 2007 and July 2017, 180 children who received treatment for hematologic malignancies and solid tumors at our institute were enrolled in this study. Twelve patients with insufficient data and 7 patients with past histories of IGTNs were excluded. A total of 161 patients were analyzed. Median age at admission was 7.9 years (range, 1.0 to 25.4 y), with 92 males and 69 females. Diagnoses were hematologic diseases in 128 patients, including acute lymphoblastic leukemia (ALL) in 75 patients, and solid tumors in 33 patients. A total of 22 patients (13.7%) suffered from IGTNs (or toe paronychia) during hospitalization. Multivariable analysis disclosed a strong correlation between the occurrence of IGTNs and older age (over 9.0 y) and ALL. Patient-related factors, such as age over 9 years and ALL were associated with IGTNs. This is the first report of a survey on IGTNs in patients with hematologic malignancies and solid tumors hospitalized for chemotherapy and stem cell transplantation.

Proof-of-principle that a decoy virus protects oncolytic measles virus against neutralizing antibodies.

Attenuated oncolytic measles virus (OMV) is a promising antitumor agent in early-phase clinical trials. However, pre-existing immunity against measles might be a hurdle for OMV therapy. OMV was inactivated with short-wavelength ultraviolet light (UV-C). Loss of replication and oncolytic activity of UV-inactivated OMV were confirmed by tissue culture infective dose 50 (TCID UV-inactivation abrogates OMV replication while maintaining its antigenicity. UV-inactivated OMV sequesters pre-existing anti-MV antibodies in Jurkat cell culture, thereby protecting active OMV from neutralization and preserving oncolytic activity. We prove the principle that a non-replicating OMV can serve as a decoy for neutralizing anti-MV antibodies, thereby allowing antitumor activity of OMV.

Downregulated miR-17, miR-29c, miR-92a and miR-214 may be related to BCL11B overexpression in T cell acute lymphoblastic leukemia.

BCL11B overexpression is a characteristic of most T cell acute lymphoblastic leukemia (T-ALL) cases, and downregulated BCL11B in leukemic T cells inhibits cell proliferation and induces apoptosis. The purpose of this study was to analyze the miRNA expression pattern that may be related to BCL11B regulation in T-ALL. Quantitative real-time PCR was used to detect the miRNAs miR-17-3p, miR-17-5p, miR-29c-3p, miR-92a-3p, miR-214-3p and miR-214-5p, the BCL11B expression level in peripheral blood mononuclear cells which was obtained from 17 de novo and untreated T-ALL patients, and 15 healthy individuals (HIs) served as control. Correlations between the relative miRNA expression levels and BCL11B were analyzed. Based on the computational prediction that certain miRNAs bind the BCL11B 3-UTR, miR-17-3p, miR-17-5p, miR-29c-3p, miR-92a-3p, miR-214-3p and miR-214-5p were found to be candidates for regulating BCL11B. The expression levels of the six miRNAs were decreased compared with HIs, and with the exception of miR-17-5p, statistically significant differences in expression levels were found in the T-ALL group. Moreover, while significantly higher BCL11B expression was found in the T-ALL group, a negative trend in the correlation level for all six miRNAs could be found in all groups however, statistical significance was only found for miR-214-3p in the T-ALL group. miRNA downregulation together with BCL11B upregulation suggests that miR-17, miR-29c, miR-92a and miR-214 might be involved in BCL11B regulation. The therapeutic promise of regulating the expression of these miRNAs for T-ALL therapy may be considered in the future.

C‑Myc inhibitor 10058‑F4 increases the efficacy of dexamethasone on acute lymphoblastic leukaemia cells.

The long‑term survival rate in paediatric acute lymphoblastic leukaemia (ALL) exceeds 80% however, the outcome of adult ALL remains to be poor. Glucocorticoids (GCs) are the preferred drugs in the traditional treatment of ALL patients. In the anti‑leukaemia molecular mechanisms of GCs, c‑Myc inhibition serves a critical role. In the present study, a c‑Myc inhibitor that increased the sensitivity to GCs in NALM6 cells of the B‑cell‑ALL cell line and CEM cells of the T‑cell‑ALL cell line was investigated. The data demonstrated that 10058‑F4, a c‑Myc inhibitor, increased the growth inhibition, G0G1 phase arrest and apoptosis of the NALM6 and CEM cells as induced by dexamethasone (DXM), a type of GC. Additionally, 10058‑F4 reinforced the decreased expressions of c‑Myc, cyclin‑dependent kinase (CDK)‑4 and CDK6 in the NALM6 and CEM cells treated with DXM. These findings indicated that DXM in combination with the c‑Myc inhibitor 10058‑F4 may be a novel, potent therapeutic strategy for the treatment of ALL.

Effect of ursodeoxycholic acid and vitamin E in the prevention of liver injury from methotrexate in pediatric leukemia.

Ursodeoxycholic acid (UDCA) and antioxidants such as vitamin E are considered to have a protective role in preventing chemotherapy-induced liver damage. The aim of this study was to assess the efficacy of these agents for hepatoprotection in pediatric patients with B-cell acute lymphoblastic leukemia (ALL), who were treated with methotrexate in their maintenance phase of treatment. Eighty children with B-cell ALL were randomly divided into four groups. Group 1 was administered oral vitamin E (400 mgday) group 2 was administered oral UDCA (15 mgkgday) group 3 was administered a combination of the two drugs and group 4 served as a control group and was administered no drug except their chemotherapy drugs. Complete blood count, liver function test, liver ultrasonography, and liver fibroscan were requested, and the results were compared. Group 1 showed a slight increase in total bilirubin levels compared to baseline levels during the study (P0.036). Group 2 showed a decline in aspartate aminotransferase and alanine aminotransferase levels during the study and at 6 months after discontinuing the drug however, these differences were not statistically significant (P0.051 and 0.083, respectively). None of the patients showed the evidence of significant fibrosis on liver fibroscan. Eight patients showed some evidence of mild-to-moderate fibrosis (F1, F2), but the results were not different between the groups as well as between pre- and post-study periods in each group. Low-dose methotrexate does not cause significant liver fibrosis in pediatric leukemia. UDCA and vitamin E have minimal roles in hepatoprotection among pediatric patients with ALL.

CD47-ligation induced cell death in T-acute lymphoblastic leukemia.

CD47 is a cell-surface marker well recognized for its anti-phagocytic functions. As such, an emerging avenue for targeted cancer therapies involves neutralizing the anti-phagocytic function using monoclonal antibodies (mAbs) to enhance tumour cell immunogenicity. A lesser known consequence of CD47 receptor ligation is the direct induction of tumour cell death. While several mAbs and their derivatives with this property have been studied, the best characterized is the commercially available mAb B6H12, which requires immobilization for induction of cell death. Here, we describe a commercially available mAb, CC2C6, which induces T-cell acute lymphoblastic leukemia (ALL) cell death in soluble form. Soluble CC2C6 induces CD47-dependent cell death in a manner consistent with immobilized B6H12, which is characterized by mitochondrial deficiencies but is independent of caspase activation. Titration studies indicated that CC2C6 shares a common CD47-epitope with B6H12. Importantly, CC2C6 retains the anti-phagocytic neutralizing function, thus possessing dual anti-tumour properties. Although CD47-ligation induced cell death occurs in a caspase-independent manner, CC2C6 was found to stimulate increases in Mcl-1 and NOXA levels, two Bcl-2 family proteins that govern the intrinsic apoptosis pathway. Further analysis revealed that the ratio of Mcl-1NOXA were minimally altered for cells treated with CC2C6, in comparison to cells treated with agents that induced caspase-dependent apoptosis which alter this ratio in favour of NOXA. Finally, we found that CC2C6 can synergize with low dose chemotherapeutic agents that induce classical apoptosis, giving rise to the possibility of an effective combination treatment with reduced long-term sequelae associated with high-dose chemotherapies in childhood ALL.

Antileukemic Efficacy of BET Inhibitor in a Preclinical Mouse Model of MLL-AF4

Cytogenetic Profile of Moroccan Pediatric Acute Lymphoblastic Leukemia Analysis of 155 Cases With a Review of the Literature.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, with a peak incidence at 2 to 3 years of age and accounting for almost 30% of all cancers in this age group. It is well established that the identification of cytogenetic abnormalities is highly relevant for the prognosis of and therapeutic decisions in ALL. The purpose of the present study was to define the frequency of recurrent chromosomal abnormalities of ALL in Moroccan patients referred exclusively to the BIOLAB Laboratory of the Childrens Hospital of Rabat during a 4-year period and compare our findings to the reported data. We performed conventional karyotyping of 155 ALL cases, with a successful cell culture rate of 94%. We identified chromosomal abnormalities in 66% of the total studied cases, of which 70% revealed important recurrent abnormalities with high prognostic value, such as hyperdiploidy, hypodiploidy, t(922), t(814), t(119), and MLL rearrangements. In total agreement with the reported data, most of the patients (56%) in the present study were aged 1 to 5 years, with a male predominance, and B-ALL was the most common blast phenotype (85%). The frequency of most chromosomal rearrangements successfully identified in our study and their lineage correlated with those reported in the published data.

High-Throughput Flow Cytometry Identifies Small-Molecule Inhibitors for Drug Repurposing in T-ALL.

Kinase inhibitors have dramatically increased patient survival in a multitude of cancers, including hematological malignancies. However, kinase inhibitors have not yet been integrated into current clinical trials for patients with T-cell-lineage acute lymphoblastic leukemia (T-ALL). In this study, we used a high-throughput flow cytometry (HTFC) approach to test a collection of small-molecule inhibitors, including 26 FDA-approved tyrosine kinase inhibitors in a panel of T-ALL cell lines and patient-derived xenografts. Because hypoxia is known to cause resistance to chemotherapy, we developed a synthetic niche that mimics the low oxygen levels found in leukemic bone marrow to evaluate the effects of hypoxia on the tested inhibitors. Drug sensitivity screening was performed using the Agilent BioCel automated liquid handling system integrated with the HyperCyt HT flow cytometry platform, and the uptake of propidium iodide was used as an indication of cell viability. The HTFC dose-response testing identified several compounds that were efficacious in both normal and hypoxic conditions. This study shows that some clinically approved kinase inhibitors target T-ALL in the hypoxic niche of the bone marrow.

Aberrant activity of NKL homeobox gene NKX3-2 in a T-ALL subset.

T-cell acute lymphoblastic leukemia (T-ALL) is a hematopoietic malignancy originating from T-cell progenitors in which differentiation is blocked at early stages. Physiological expression of specific NKL homeobox genes obeys a hematopoietic NKL-code implicated in the process of lymphopoiesis while in differentiated T-cells these genes are silenced. We propose that this developmental expression pattern underlies the observation that NKL homeobox genes are the most ubiquitous group of transcription factors deregulated in T-ALL, including TLX1, TLX3, NKX2-5 and NKX3-1. Here, we describe a novel member of the NKL homeobox gene subclass, NKX3-2 (BAPX1), which is aberrantly activated in 18% of pediatric T-ALL patients analyzed while being normally expressed in developing spleen. Identification of NKX3-2 expression in T-ALL cell line CCRF-CEM qualified these cells to model its deregulation and function in a leukemic context. Genomic and chromosomal analyses demonstrated normal configuration of the NKX3-2 locus at chromosome 4p15, thus excluding cytogenetic dysregulation. Comparative expression profiling analysis of NKX3-2 patient data revealed deregulated activity of BMP- and MAPK-signalling. These candidate pathways were experimentally confirmed to mediate aberrant NKX3-2 expression. We also show that homeobox gene SIX6, plus MIR17HG and GATA3 are downstream targets of NKX3-2 and plausibly contribute to the pathogenesis of this malignancy by suppressing T-cell differentiation. Finally, NKL homeobox gene NKX2-5 was activated by NKX3-2 in CCRF-CEM and by FOXG1 in PEER, representing mutually inhibitory activators of this translocated oncogene. Together, our findings reveal a novel oncogenic NKL homeobox gene subclass member which is aberrantly expressed in a large subset of T-ALL patients and participates in a deregulated gene network likely to arise in developing spleen.

UFD1 contributes to MYC-mediated leukemia aggressiveness through suppression of the proapoptotic unfolded protein response.

Despite the pivotal role of MYC in tumorigenesis, the mechanisms by which it promotes cancer aggressiveness remain incompletely understood. Here, we show that MYC transcriptionally upregulates the ubiquitin fusion degradation 1 (UFD1) gene in T-cell acute lymphoblastic leukemia (T-ALL). Allelic loss of ufd1 in zebrafish induces tumor cell apoptosis and impairs MYC-driven T-ALL progression but does not affect general health. As the E2 component of an endoplasmic reticulum (ER)-associated degradation (ERAD) complex, UFD1 facilitates the elimination of misfoldedunfolded proteins from the ER. We found that UFD1 inactivation in human T-ALL cells impairs ERAD, exacerbates ER stress, and induces apoptosis. Moreover, we show that UFD1 inactivation promotes the proapoptotic unfolded protein response (UPR) mediated by protein kinase RNA-like ER kinase (PERK). This effect is demonstrated by an upregulation of PERK and its downstream effector CEBP homologous protein (CHOP), as well as a downregulation of BCL2 and BCLxL. Indeed, CHOP inactivation or BCL2 overexpression is sufficient to rescue tumor cell apoptosis induced by UFD1 knockdown. Together, our studies identify UFD1 as a critical regulator of the ER stress response and a novel contributor to MYC-mediated leukemia aggressiveness, with implications for targeted therapy in T-ALL and likely other MYC-driven cancers.

Recurrent SPI1 fusions in pediatric T-cell acute lymphoblastic leukemia novel mutations with poor prognosis.

The outcome of treatment-refractory andor relapsed pediatric T-cell acute lymphoblastic leukemia (T-ALL) is extremely poor, and the genetic basis of these cases remains poorly understood. Here, we report comprehensive profiling of 121 cases of pediatric T-ALL using RNA sequencing andor targeted capture sequencing through which we identified new recurrent gene fusions involving SPI1 (STMN1-SPI1 and TCF7-SPI1). Cases positive for fusions involving SPI1 (encoding PU.1), which accounted for 3.9% (7181) of the total examined pediatric T-ALL cases, had uniformly poor overall survival. These cases represent a subset of pediatric T-ALL distinguishable from the known T-ALL subsets in terms of expression of genes involved in T cell pre-commitment, establishment of T cell identity, and post-β-selection maturation with respect to mutational profile. PU.1 fusion proteins retained transcriptional activity and induced cell proliferation on constitutive expression in mouse stemprogenitor cells, resulting in a maturation block. Our findings highlight the unique role of SPI1 fusions in high-risk pediatric T-ALL.

Allogeneic hematopoietic stem cell transplantation using myeloablative conditioning including total body irradiation for pediatric acute lymphoblastic leukemia a single-center retrospective analysis.

This study aimed to investigate the clinical outcomes of hematopoietic stem cell transplantation (HSCT) with total body irradiation-based myeloablative conditioning (TBI-MAC) in pediatric patients with acute lymphoblastic leukemia (ALL). We retrospectively examined patients with ALL who underwent HSCT with TBI-MAC from January 2000 to August 2016 at our institute. We enrolled 67 patients with a median follow-up period of 8 years. The 5-year event-free survival (EFS) and overall survival (OS) were 51.2% and 59.6%, respectively. At the first complete remission, HSCT exhibited significantly superior EFS and OS in our patients than that in patients with other diseases. We encountered 57.9% of patients with at least one late complication. Major late complications were short stature (26.3%) and hypogonadism (18.4%). While late complications were observed in several recipients of HSCT, late complication-related deaths occurred in three patients. The TBI-MAC regimen led to favorable clinical outcomes in pediatric patients with ALL who underwent HSCT. Thus, proper evaluation and management of late complications are mandatory.

A CD19CD3 bispecific antibody for effective immunotherapy of chronic lymphocytic leukemia in the ibrutinib era.

The Bruton tyrosine kinase inhibitor ibrutinib induces high rates of clinical response in chronic lymphocytic leukemia (CLL). However, there remains a need for adjunct treatments to deepen response and to overcome drug resistance. Blinatumomab, a CD19CD3 bispecific antibody (bsAb) designed in the BiTE (bispecific T-cell engager) format, is approved by the US Food and Drug Administration for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Because of its short half-life of 2.1 hours, blinatumomab requires continuous intravenous dosing for efficacy. We developed a novel CD19CD3 bsAb in the single-chain Fv-Fc format (CD19CD3-scFv-Fc) with a half-life of ∼5 days. In in vitro experiments, both CD19CD3-scFv-Fc and blinatumomab induced >90% killing of CLL cells from treatment-naïve patients. Antileukemic activity was associated with increased autologous CD8 and CD4 T-cell proliferation, activation, and granzyme B expression. In the NODSCIDIL2Rγnull patient-derived xenograft mouse model, once-weekly treatment with CD19CD3-scFv-Fc eliminated >98% of treatment-naïve CLL cells in blood and spleen. By contrast, blinatumomab failed to induce a response, even when administered daily. We next explored the activity of CD19CD3-scFv-Fc in the context of ibrutinib treatment and ibrutinib resistance. CD19CD3-scFv-Fc induced more rapid killing of CLL cells from ibrutinib-treated patients than those from treatment-naïve patients. CD19CD3-scFv-Fc also demonstrated potent activity against CLL cells from patients with acquired ibrutinib-resistance harboring

Philadelphia chromosome-positive acute lymphoblastic leukemia in adults current treatments and future perspectives.

Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL) accounts for approximately one-fourth of cases of adult ALL. It typically presents with an aggressive clinical course, responds poorly to standard chemotherapy, and carries a high risk for relapse. The landscape of Ph ALL therapy has changed favorably since the development of tyrosine kinase inhibitors (TKIs). With the successful incorporation of TKIs into chemotherapy regimens, remissions occur more frequently and patients live longer. Imatinib was the first TKI that targeted the BCR-ABL1 oncoprotein in Ph ALL. Since then, nilotinib, dasatinib, bosutinib, and ponatinib have been developed. Despite the significant progress that has been made in inducing remission, frequent relapses remain a challenge, especially among those with resistant BCR-ABL1 mutations. Still, the therapeutic armamentarium of ALL therapy is expanding at a breathtaking pace today compared with a decade ago. Novel drugs, such as potent later-generation TKIs, antibody-drug conjugates, bispecific monoclonal antibodies, and chimeric antigen receptor T-cell therapies, are being developed and investigated in patients with Ph ALL. In this review, we summarize the current treatment options for Ph ALL and highlight the therapies that may become the standard of care in the near future.

Management of acute lymphoblastic leukemia in young adults.

Substantial interest in acute lymphoblastic leukemia (ALL) in young adults (YAs) and investigations focused on this patient population have resulted in therapeutic advancements that are changing the management paradigm and improving outcomes. The pediatric ALL approach is feasible and effective when administered by medical oncologists. Advanced diagnostics and minimal residual disease measurements aid in prognostication and have resulted in shifting recommendations regarding allogeneic hematopoietic cell transplant in first remission. Blinatumomab, inotuzumab, and chimeric antigen receptor T-cell therapies are transforming the treatment of relapsedrefractory ALL. This comprehensive review of the current management of ALL in YAs summarizes recent scientific developments and clinical trial findings related to ALL biology, frontline management approaches, novel therapies, and supportive care specific to this patient population. Finally, a practical guide to modern YA management for practicing clinicians is provided.

Evaluation of minimal residual disease in childhood ALL.

Childhood acute lymphoblastic leukemia is one of the most frequent cancers of that age range. Tremendous progress has been achieved in the treatment of these diseases, and increasing numbers of patients are actually cured and live normal lives thereafter. The treatment however remains a complex and serious ordeal. Although statistics are more than encouraging, the specific care of any given patient must be considered with a personalized approach. Among modern tools of disease monitoring, minimal residual disease assessment has earned increasing appeal and now tends to be rather dubbed measurable residual disease as the major goal of therapy was the complete eradication of the pathological clone. In this review, the basic characteristics of ALL diagnosis will be briefly recalled, before summarizing available techniques and providing some considerations on the clinical relevance and strategies of childhood ALL MRD evaluation.

Phenolic acid content, antioxidant and cytotoxic activities of four

Phenolic acid composition, antioxidant, and cytotoxic activities in leaves of four

New therapeutic opportunities from dissecting the pre-B leukemia bone marrow microenvironment.

The microenvironments of leukemia and cancer are critical for multiple stages of malignancies, and they are an attractive therapeutic target. While skeletal abnormalities are commonly seen in children with acute lymphoblastic leukemia (ALL) prior to initiating osteotoxic therapy, little is known about the alterations to the bone marrow microenvironment during leukemogenesis. Therefore, in this study, we focused on the development of precursor-B cell ALL (pre-B ALL) in an immunocompetent BCR-ABL1

Single-cell sequencing reveals the origin and the order of mutation acquisition in T-cell acute lymphoblastic leukemia.

Next-generation sequencing has provided a detailed overview of the various genomic lesions implicated in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL). Typically, 10-20 protein-altering lesions are found in T-ALL cells at diagnosis. However, it is currently unclear in which order these mutations are acquired and in which progenitor cells this is initiated. To address these questions, we used targeted single-cell sequencing of total bone marrow cells and CD34

Graft-versus-host disease in recipients of male unrelated donor compared with parous female sibling donor transplants.

Optimal donor selection is critical for successful allogeneic hematopoietic cell transplantation (HCT). Donor sex and parity are well-established risk factors for graft-versus-host disease (GVHD), with male donors typically associated with lower rates of GVHD. Well-matched unrelated donors (URDs) have also been associated with increased risks of GVHD as compared with matched sibling donors. These observations raise the question of whether male URDs would lead to more (or less) favorable transplant outcomes as compared with parous female sibling donors. We used the Center for International Blood and Marrow Transplant Research registry to complete a retrospective cohort study in adults with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, who underwent T-cell replete HCT from these 2 donor types (parous female sibling or male URD) between 2000 and 2012. Primary outcomes included grade 2 to 4 acute GVHD (aGVHD), chronic GVHD (cGVHD), and overall survival. Secondary outcomes included disease-free survival, transplant-related mortality, and relapse. In 2813 recipients, patients receiving male URD transplants (n 1921) had 1.6 times higher risk of grade 2 to 4 aGVHD (

Health-related quality of life in adults with relapsedrefractory acute lymphoblastic leukemia treated with blinatumomab.

In the phase 3 TOWER study, blinatumomab significantly improved overall survival in adults with relapsed or refractory (RR) Philadelphia chromosome-negative (Ph

A genome-wide survey of mutations in the Jurkat cell line.

The Jurkat cell line has an extensive history as a model of T cell signaling. But at the turn of the 21st century, some expression irregularities were observed, raising doubts about how closely the cell line paralleled normal human T cells. While numerous expression deficiencies have been described in Jurkat, genetic explanations have only been provided for a handful of defects. Here, we report a comprehensive catolog of genomic variation in the Jurkat cell line based on whole-genome sequencing. With this list of all detectable, non-reference sequences, we prioritize potentially damaging mutations by mining public databases for functional effects. We confirm documented mutations in Jurkat and propose links from detrimental gene variants to observed expression abnormalities in the cell line. The Jurkat cell line harbors many mutations that are associated with cancer and contribute to Jurkats unique characteristics. Genes with damaging mutations in the Jurkat cell line are involved in T-cell receptor signaling (PTEN, INPP5D, CTLA4, and SYK), maintenance of genome stability (TP53, BAX, and MSH2), and O-linked glycosylation (C1GALT1C1). This work ties together decades of molecular experiments and serves as a resource that will streamline both the interpretation of past research and the design of future Jurkat studies.

Effect of combining glucocorticoids with Compound A on glucocorticoid receptor responsiveness in lymphoid malignancies.

Glucocorticoids (GCs) are a cornerstone in the treatment of lymphoid malignancies such as multiple myeloma (MM) and acute lymphoblastic leukemia (ALL). Yet, prolonged GC use is hampered by deleterious GC-related side effects and the emergence of GC resistance. To tackle and overcome these GC-related problems, the applicability of selective glucocorticoid receptor agonists and modulators was studied, in search of fewer side-effects and at least equal therapeutic efficacy as classic GCs. Compound A (CpdA) is a prototypical example of such a selective glucocorticoid receptor modulator and does not support GR-mediated transactivation. Here, we examined whether the combination of CpdA with the classic GC dexamethasone (Dex) may improve GC responsiveness of MM and ALL cell lines. We find that the combination of Dex and CpdA does not substantially enhance GC-mediated cell killing. In line, several apoptosis hallmarks, such as caspase 37 activity, PARP cleavage and the levels of cleaved-caspase 3 remain unchanged upon combining Dex with CpdA. Moreover, we monitor no additional inhibition of cell proliferation and the homologous downregulation of GR is not counteracted by the combination of Dex and CpdA. In addition, CpdA is unable to modulate Dex-liganded GR transactivation and transrepression, yet, Dex-mediated transrepression is also aberrant in these lymphoid cell lines. Together, transrepression-favoring compounds, alone or combined with GCs, do not seem a valid strategy in the treatment of lymphoid malignancies.

Burden Experience of Caregivers of Acute Lymphoblastic Leukemia Impact of Coping and Spirituality.

When a child is diagnosed with cancer the parents as caregivers experience severe anxiety, trauma, ambiguity, and grief. Caregivers of cancer patients thus deal with the management of their own psychological distress along with the childs illness. Coping plays a crucial role in improving the caregivers physical and emotional well-being. Spirituality is an important means of consolation, strength, and emotional support during this phase. The present study aims to investigate the impact of coping and spirituality on caregiver burden. A total of 100 caregivers of children between the age group of 3-11 years, diagnosed with acute lymphoblastic leukemia were the participants of the study. The participants were recruited from cancer hospitals in Hyderabad. The study adopted a between-group design to find out if mothers and fathers differed in their coping strategies, spirituality, and caregiver burden. The study also adopted a correlation design to find the relationship between coping, spirituality, and caregiver burden. Descriptive statistics and multiple linear regression analysis were conducted to identify if coping and spirituality predict caregiver burden. The results showed no significant difference in the burden experienced by both mothers and fathers however, mothers and fathers used different coping strategies and differed on the dimensions of spirituality. The results of multiple linear regression indicated that dimensions of coping and spirituality were significant predictors of caregiver burden. Cancer in the child impacts the parents burden but providing sufficient support and implementing effective coping strategies, will help in mitigating the intensity of caregiver burden. It is essential that the hospital authorities and policymakers understand that a professional health psychologist could be a liaison between the doctor, patient, and the caregiver in bringing down the levels of burden and psychological distress in caregivers as well as patients.

miR-339 Promotes Development of Stem Cell LeukemiaLymphoma Syndrome via Downregulation of the

The development of myeloid and lymphoid neoplasms related to overexpression of FGFR1 kinases as a result of chromosome translocations depends on the promotion of a stem cell phenotype, suppression of terminal differentiation, and resistance to apoptosis. These phenotypes are related to the stem cell leukemialymphoma syndrome (SCLL), which arises through the effects of the activated FGFR1 kinase on gene transcription, which includes miRNA dysregulation. In a screen for miRNAs that are directly regulated by FGFR1, and which stimulate cell proliferation and survival, we identified miR-339-5p, which is highly upregulated in cells carrying various different chimeric kinases. Overexpression of miR-339-5p in SCLL cell types enhances cell survival and inhibition of its function leads to reduced cell viability. miR-339-5p overexpression protects cells from the consequences of FGFR1 inactivation, promoting cell-cycle progression and reduced apoptosis. Transient luciferase reporter assays and qRT-PCR detection of endogenous miR-339-5p expression in stably transduced cell lines demonstrated that BCR-FGFR1 can directly regulate miR-339-5p expression. This correlation between miR-339-5p and FGFR1 expression is also seen in primary human B-cell precursor acute lymphoblastic leukemia. In a screen to identify targets of miR-339-5p, we identified and verified the

Growth patterns of survivors of retinoblastoma treated with ophthalmic artery chemosurgery.

Although studies from pediatric cancers (largely acute lymphoblastic leukemia) have shown that patients undergoing systemic chemotherapy may experience decreased growth velocity during the treatment phase, no such data exist for retinoblastoma patients treated with systemic chemotherapy or ophthalmic artery chemosurgery (OAC). The purpose of this study is to report growth patterns of our retinoblastoma (Rb) population who were treated with OAC in a retrospective, single center (Memorial Sloan Kettering Cancer Center) review of 341 patients treated between 2006 and 2016. Children who only received OAC were classified as naive those who were treated initially with systemic chemotherapy and subsequently presented to our center for OAC were termed secondary and a small group of patients who received single-agent systemic chemotherapy prior to OAC were labeled bridge. For all patients, height and weight were recorded at monthly intervals during OAC (short-term) and then annually during a follow-up period (long-term) up to 3 years after treatment. Excluded from this study were children who received external radiation therapy and those with genetic syndromes, which are independently associated with growth derangements. During OAC, there was no significant difference in growth velocity between the naïve and secondary groups. In either group, number of treatments also did not affect growth rate. Three years after the end of OAC, naïve patients were in the 68th percentile by height (95% CI 61.30, 74.63) compared to secondary patients in the 61st percentile (95% CI 51.1, 71.47). Both groups were in the same weight percentiles during the first two years of follow-up but at the three-year follow-up period, naïve patients were in the 63rd percentile (95% CI 57.4, 69.4) and secondary patients were in the 60th percentile (95% CI 50.4, 69.7). OAC for retinoblastoma does not appear to impact short-term growth velocity, weight gain during the treatment period or after three years.

Endoglin is Highly Expressed in Human Mast Cells.

Endoglin, known to be expressed in proliferating vessels, is of worth when evaluating microvessel density as a prognostic factor in many types of malignancies, including some subtypes of leukemia cells. In childhood acute lymphoblastic leukemia, endoglin is associated with adverse outcome. In bone marrow, endoglin identifies the repopulating hematopoietic stem cells. Mast cells are a component of normal tissue and play an important role in the regulation of several processes, including inflammation and neoplasia. The aim of this study was to evaluate the use of endoglin as a biological marker of mast cells compared with the gold standard stains. We studied 15 specimens of neurofibroma, 9 of mastocytosis, and 6 of fibrous scar tissue through immunohistochemistry (for endoglin and mast cell tryptase) and histochemical staining using toluidine blue. Quantitative analysis of the cells was performed by counting 5 hotspots. The validity of endoglin as a mast cell marker was assessed by intraclass correlation coefficient. The Kruskal-Wallis test was used to compare mast cell count for each marker. A strong endoglin expression was found in the cytoplasmic granules of mast cells within the 3 groups. Similar results were observed with mast cell tryptase as well as toluidine blue. The intraclass correlation coefficient revealed that endoglin is a highly reliable biomarker of mast cells when compared with mast cell tryptase and toluidine blue. In conclusion, endoglin may assist in the diagnosis and pathogenesis study of various processes associated with mast cells. An endoglin-neutralizing treatment for solid cancers and leukemia could also affect mastocytes and the immunologic system.

Impact of a Vitamin D Replacement Algorithm in Children and Young Adults With Acute Lymphoblastic Leukemia.

Pediatric cancer patients have a high prevalence of vitamin D deficiency. Children and young adults with acute lymphoblastic leukemia are at high risk for associated poor bone outcomes due to contributing effects of chemotherapy and supportive care. Evidence-based vitamin D guidelines are lacking in this population. This is a retrospective study following the implementation of an institutional guideline for standardized monitoring and supplementing vitamin D based on 25-hydroxyvitamin D levels and patient age. Goal 25-hydroxyvitamin D level was defined as ≥30 ngmL and levels were checked every 3 months. Over a period of 22 months, 69 patients (median age, 6.7 y) were included. At diagnosis, 42 patients (60.8%) were insufficient. Among insufficient patients at diagnosis, 83.3% became sufficient at first repeat level following supplementation. At completion of the study 95.6% of patients were sufficient. Insufficiency was more common in winter than summer at baseline (74.3% vs. 47.1%, P0.03), though the impact of seasonality was overcome following the algorithm. Throughout the study 4 patients had supratherapeutic but nontoxic levels. Vitamin D replacement guidelines implemented in the pediatric and young adult acute lymphoblastic leukemia population markedly increased the percentage of vitamin D sufficient patients in a short period of time.

RUNX1 promotes cell growth in human T-cell acute lymphoblastic leukemia by transcriptional regulation of key target genes.

RUNX1 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL). The spectrum of RUNX1 mutations has led to the notion that it acts as a tumor suppressor in this context however, other studies have placed RUNX1, along with transcription factors TAL1 and NOTCH1, as core drivers of an oncogenic transcriptional program. To reconcile these divergent roles, we knocked down RUNX1 in human T-ALL cell lines and deleted Runx1 or Cbfb in primary mouse T-cell leukemias. RUNX1 depletion consistently resulted in reduced cell proliferation and increased apoptosis. RUNX1 upregulated variable sets of target genes in each cell line, but consistently included a core set of oncogenic effectors including insulin-like growth factor 1 receptor (IGF1R) and NRAS. Our results support the conclusion that RUNX1 has a net positive effect on cell growth in the context of established T-ALL.

Survival analysis of adult patients with ALL in Mexico City first report from the Acute Leukemia Workgroup (ALWG) (GTLA).

Acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by the clonal expansion of hematopoietic lymphoid progenitors. With new target therapies, the survival of adults with ALL has improved in the past few decades. Unfortunately, there are no large ALL patient series in many Latin American countries. Data from the Acute Leukemia Workgroup that includes five Mexico City referral centers were used. Survival was estimated for adult patients with ALL during 2009-2015. In total, 559 adults with ALL were included. The median age was 28 years 67% were classified into the adolescent and young adult group. Cytogenetic information was available in 54.5% of cases. Of the 305 analyzed cases, most had a normal caryotype (70.5%) and Philadelphia-positive was present in 16.7%. The most commonly used treatment regimen was hyper-CVAD. In approximately 20% of cases, there was considerable delay in the administration of chemotherapy. Primarily refractory cases accounted for 13.1% of patients. At the time of analysis, 26.7% of cases had survived. The 3-year overall survival was 22.1%. The main cause of death was disease progression in 228 (55.6%). Clinical and public health strategies are needed to improve diagnosis, treatment and survivorship care for adult with ALL. This multicentric report represents the largest series in Mexico of adult ALL patients in which a survival analysis and risk identification were obtained.

Solanine induced apoptosis and increased chemosensitivity to Adriamycin in T-cell acute lymphoblastic leukemia cells.

Solanine is an alkaloid and is the main extract of the traditional Chinese herb,

Functional vision and quality of life in children with microphthalmiaanophthalmiacoloboma-a cross-sectional study.

To determine the childs and parental perception of functional visual ability (FVA), vision-related and health-related quality of life (VR-QoL, HR-QoL) in children with microphthalmiaanophthalmiacoloboma (MAC). Between June 25, 2014, and June 3, 2015, we carried out a cross-sectional observational study at Moorfields Eye Hospital, London, UK, enrolling 45 children 2-16 years of age with MAC attending our clinics, and their parents. To assess FVA, VR-QoL, and HR-QoL we asked participants to complete three validated tools, the Cardiff Visual Ability Questionnaire for Children (CVAQC), the Impact of Vision Impairment for Children (IVI-C) instrument, and the PedsQL V 4.0. The main outcome measures were the FVA, VR-QoL, and HR-QoL scores, reported by children and parents. In children with MAC, FVA is moderately reduced, with a median CVAQC score of -1.4 (IQR, -2.4 to 0.4 range, -3.0 higher FVA to 2.8 lower FVA). VR-QoL and HR-QoL are greatly reduced, with an IVI-C median score of 63 (IQR, 52-66 normal VR-QoL, 96), a median self-reported PedsQL score of 77 (IQR, 71-90 normal HR-QoL, 100) and parental score of 79 (IQR, 61-93), and a family impact score of 81 (67-93). Psychosocial well-being scores are lower than physical well-being scores. Parents and children have a different perception of the impact of the condition on the childs HR-QoL. MAC has a significant impact on a childs FVA and QoL, similar to that described by children with acute lymphoblastic leukaemia and chronic systemic conditions. Children and families may benefit from psychosocial support.

Outcome of children with multiply relapsed B-cell acute lymphoblastic leukemia a therapeutic advances in childhood leukemia lymphoma study.

The survival of pediatric patients with multiply relapsed andor refractory (RR) B-cell acute lymphoblastic leukemia has historically been very poor however, data are limited in the current era. We conducted a retrospective study to determine the outcome of multiply RR childhood B-ALL treated at 24 TACL institutions between 2005 and 2013. Patient information, treatment, and response were collected. Prognostic factors influencing the complete remission (CR) rate and event-free survival (EFS) were analyzed. The analytic set included 578 salvage treatment attempts among 325 patients. CR rates (mean ± SE) were 51 ± 4% for patients with bone marrow RR B-ALL who underwent a second salvage attempt, 37 ± 6% for a third attempt, and 31 ± 6% for the fourth through eighth attempts combined. For patients achieving a CR after their second, third, and fourth through eighth attempts, the 2 year EFS was 41 ± 6%, 13 ± 7%, and 27 ± 13% respectively. Our results showed slight improvement when compared to previous studies. This is the largest and most recent study to date that evaluates the outcome of this patient population. Our data will provide detailed reference for the evaluation of new agents being developed for childhood B-ALL.

Decitabine demonstrates antileukemic activity in B cell precursor acute lymphoblastic leukemia with MLL rearrangements.

Promotor hypermethylation of CpG islands is common in B cell precursor acute lymphoblastic leukemia (BCP-ALL) with mixed lineage leukemia (MLL) gene rearrangements. Hypomethylating agents (HMA) such as azacitidine (AZA) and decitabine (DEC) reduce DNA hypermethylation by incorporation into DNA and were successfully introduced into the clinic for the treatment of myeloid neoplasias. Here, we investigated whether HMA induce comparable biological effects in MLL-positive BCP-ALL. Further, efficacy of HMA and concomitant application of cytostatic drugs (cytarabine and doxorubicin) were evaluated on established SEM and RS411 cell lines. In addition, promising approaches were studied on BCP-ALL cell line- and patient-derived xenograft models. In general, DEC effects were stronger compared to AZA on MLL-positive BCP-ALL cells. DEC significantly reduced proliferation by induction of cell cycle arrest in G0G1 phase and apoptosis. Most sensitive to HMA were SEM cells which are characterized by a fast cell doubling time. The combination of low-dose HMA and conventional cytostatic agents revealed a heterogeneous response pattern. The strongest antiproliferative effects were observed when ALL cells were simultaneously exposed to HMA and cytostatic drugs. Most potent synergistic effects of HMA were induced with cytarabine. Finally, the therapeutic potential of DEC was evaluated on BCP-ALL xenograft models. DEC significantly delayed leukemic proliferation in xenograft models as demonstrated longitudinally by non-invasive bioluminescence as well as Our data reveal that DEC is active in MLL-positive BCP-ALL and warrant clinical evaluation.

Efficacy and safety of recombinant E. coli asparaginase in children with previously untreated acute lymphoblastic leukemia A randomized multicenter study of the Dutch Childhood Oncology Group.

The efficacy and safety of recombinant Escherichia coli-asparaginase (rASNase) was compared to native E.coli asparaginase (Asparaginase medac). One hundred and ninety-nine children with newly diagnosed acute lymphoblastic leukemia were randomized to receive one of both agents at a dose of 5,000 Um² during induction (eight doses) and 10,000 Um² during the postinduction phase (only high-risk patients standard- and medium-risk patients received pegaspargase). Median trough serum asparaginase activity levels were comparable between both groups they ranged from 143 to 182 Ul during induction and were above the target value of 100 Ul. Complete asparagine depletion in serum was achieved in 97.9% of patients, with no significant differences between both groups. On day 33 (end of induction), only two (2%) evaluable patients in each group had measurable asparagine serum levels, and complete asparagine depletion in the cerebrospinal fluid was achieved in 98.8% and 93.6% of the patients with rASNase and Asparaginase medac, respectively. During induction, 2.1% and 5% of patients developed an allergic reaction to rASNase or Asparaginase medac, respectively. Approximately 41% of the patients in both groups had a clinical allergy or enzyme inactivation to the first dose of any asparaginase preparation in postinduction. A comparable proportion of patients in both groups developed anti-asparaginase antibodies (57%) during repeated administration of asparaginase. Minimal residual disease levels at the end of induction, 5-year event-free survival, and 5-year cumulative incidence of relapse did not differ between both groups. The efficacy, safety, and immunogenicity of both asparaginase preparations are comparable. This trial was registered at www.clinicaltrials.gov as NCT00784017 EudraCT number 2006-003180-31.

Outcomes in obese patients undergoing induction therapy for acute leukemia.

Obesity continues to be a growing epidemic in the United States. Guidelines published by American Society of Clinical Oncology in 2012 recommend dosing chemotherapy using actual body weight. However, the guidelines do not provide guidance for patients with hematologic malignancies. The objective of this study was to evaluate outcomes in obese patients undergoing induction chemotherapy for acute leukemia versus nonobese patients using actual body weight dosing. This single center retrospective chart review from November 2012 to August 2016 evaluated newly diagnosed leukemia patients who received induction chemotherapy dosed on actual body weight. The primary outcome was rate of complete remission following induction chemotherapy between obese patients versus nonobese patients. Secondary outcomes included time to absolute neutrophil count and platelet recovery, incidence of febrile neutropenia, clinical or microbiological infections, early (0-15 days) and in-hospital mortality, and overall survival at six months. Obese patients had similar rates of complete remission versus nonobese patients with acute myeloid leukemia (60% vs. 61.9% p 0.86) and acute lymphoblastic leukemia (87.5% vs. 92.8% p 0.31). Obese patients with acute myeloid leukemia were more likely to receive re-induction chemotherapy following 14-day bone marrow biopsy vs. nonobese patients (53.3% vs. 23.2% p 0.019). There were no significant differences in secondary outcomes in either group when comparing obese versus nonobese patients. Obese patients have similar rates of complete remission compared to nonobese patients following induction chemotherapy in acute leukemia. Continued research is needed to determine optimal dosing and long-term outcomes in this patient population.

Two novel fusion genes, AIF1L-ETV6 and ABL1-AIF1L, result together with ETV6-ABL1 from a single chromosomal rearrangement in acute lymphoblastic leukemia with prenatal origin.

Fusion genes resulting from chromosomal rearrangements represent a hallmark of childhood acute lymphoblastic leukemia (ALL). Unlike more common fusion genes generated via simple reciprocal chromosomal translocations, formation of the ETV6-ABL1 fusion gene requires 3 DNA breaks and usually results from an interchromosomal insertion. We report a child with ALL in which a single interchromosomal insertion led to the formation of ETV6-ABL1 and 2 novel fusion genes AIF1L-ETV6 and ABL1-AIF1L. We demonstrate the prenatal origin of this complex chromosomal rearrangement, which apparently initiated the leukemogenic process, by successful backtracking of the ETV6-ABL1 fusion into the patients archived neonatal blood. We cloned coding sequences of AIF1L-ETV6 and ABL1-AIF1L in-frame fusion transcripts from the patients leukemic blasts and we show that the chimeric protein containing the DNA binding domain of ETV6 is expressed from the AIF1L-ETV6 transcript and localized in both the cytoplasm and nucleus of transfected HEK293T cells. Transcriptomic and genomic profiling of the diagnostic bone marrow sample revealed Ph-like gene expression signature and loss of the IKZF1 and CDKN2AB genes, the typical genetic lesions accompanying ETV6-ABL1-positive ALL. The prenatal origin of the rearrangement confirms that ETV6-ABL1 is not sufficient to cause overt leukemia, even when combined with the 2 novel fusions. We did not find the AIF1L-ETV6 and ABL1-AIF1L fusions in other ETV6-ABL1-positive ALL. Nevertheless, functional studies would be needed to establish the biological role of AIF1L-ETV6 and ABL1-AIF1L and to determine whether they contribute to leukemogenesis andor to the final leukemia phenotype.

Dogs with acute myeloid leukemia or lymphoid neoplasms (large cell lymphoma or acute lymphoblastic leukemia) may have indistinguishable mediastinal masses on radiographs.

Acute myeloid leukemia is an uncommon hematopoietic neoplasm of dogs that should be differentiated from lymphoid neoplasms, such as lymphoma, because of different treatment protocols and a worse prognosis. Thoracic radiography is performed frequently in dogs with suspected hematopoietic neoplasia, and detecting a mediastinal mass often prioritizes lymphoma as the most likely diagnosis. However, we have observed a mediastinal mass in several dogs with acute myeloid leukemia and hypothesized that (1) the frequency of a mediastinal mass was higher and (2) the size of the mass was larger in dogs with acute myeloid leukemia compared to dogs with lymphoid neoplasms. In this analytical study (observational, retrospective, and cross-sectional), the sample population included 238 dogs with hematopoietic neoplasia. These dogs were divided into lymphoid (large cell lymphoma, acute lymphoblastic leukemia) and myeloid groups based on standard phenotyping tests. A mediastinal mass was detected during thoracic radiography in 73218 (33%) and nine of 20 (45%) dogs in the lymphoid and myeloid groups (P 0.21), respectively. The median size ratio of mediastinal mass to cardiac silhouette was 0.20 and 0.23 in the lymphoid and myeloid groups (P 0.96), respectively. Additionally, we observed normal thoracic radiographs in 111218 (51%) dogs in the lymphoid group and nine of 20 (45%) dogs in the myeloid group. In conclusion, acute myeloid leukemia should be considered when a mediastinal mass is detected during radiography in dogs with suspected hematopoietic neoplasia-but the presence or size of a mediastinal mass does not differentiate between myeloid and lymphoid neoplasms.

Role of a non-canonical splice variant of the

T-cell acute lymphoblastic leukemia is a hematopoietic malignant disease, which arises from a genetic defect in the T-cell maturation signaling pathway. As a result, it is necessary to identify the molecules that impact T-cell development and control lymphoid-lineage malignancy. The present study utilized Jurkat T lymphoblastic cells as a well-established approach for the investigation into the function of the non-canonical alternative splice variant of Helios for the

Natural history of GATA2 deficiency in a survey of 79 French and Belgian patients.

Heterozygous germline

Ibrutinib improves the development of acute lymphoblastic leukemia by activating endoplasmic reticulum stress-induced cell death.

The current study mainly aims to evaluate the effects of ibrutinib on endoplasmic reticulum stress (ERS)-induced apoptosis in Reh cells, which may shed light on the treatment of acute lymphoblastic leukemia (ALL) among children. In line with previous studies, our data show that ibrutinib significantly suppressed Reh cell viability in a time- and dose-dependent manner. We further evaluated the role of ibrutinib on Reh cell colony formation and apoptosis. Ibrutinib inhibited clonogenic capacity and induced Reh cell apoptosis, suggesting an anti-tumor effects of ibrutinib in the progression of ALL. Further study showed that ibrutinib treatment increased ERS-related protein expression, including Bip, ATF4 and CHOP, suggesting the induction of ER-stress in Reh cells. More importantly, once ER-stress was suppressed by tauroursodeoxycholic acid (TUDCA), an ER-stress inhibitor, the upregulation of Bip, ATF4, CHOP, cleaved-caspase3 and cleaved-PARP after ibrutinib treatment was partially reversed, suggesting that induction of ALL cell apoptosis by ibrutinib was partially attributed to activation of ER stress. In summary, we showed novel data that ER-stress induced cell apoptosis plays a key role in the therapeutic effects of ibrutinib on ALL cell malignancies.

Backtracked analysis of preleukemic fusion genes and DNA repair foci in umbilical cord blood of children with acute leukemia.

The first event in origination of many childhood leukemias is a specific preleukemic fusion gene (PFG) that arises, often in utero, in hematopoietic stemprogenitor cells (HSPC) from misrepaired DNA double strand break (DSB). An immanently elevated level of DSB and impaired apoptosis may contribute to origination and persistence of PFG and donor cell-derived leukemia in recipients of allogeneic transplantation of umbilical cord blood (UCB). We investigated DSB, apoptosis and PFG in the backtracked UCB cells of leukemic patients. RNA from UCB of three patients with acute lymphoblastic leukemia, patient with acute megakaryoblastic leukemia and Down syndrome, and four healthy children was screened for common PFG by RT-qPCR. Presence of PFG was validated by sequencing. Endogenous γH2AX and 53BP1 DNA repair foci, cell populations, and apoptosis were analyzed in UCB CD34- cells with imaging and standard flow cytometry. We found

International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia.

Despite attempts to improve the definitions of ambiguous lineage leukemia (ALAL) during the last 2 decades, general therapy recommendations are missing. Herein, we report a large cohort of children with ALAL and propose a treatment strategy. A retrospective multinational study (International Berlin-Frankfurt-Münster Study of Leukemias of Ambiguous Lineage iBFM-AMBI2012) of 233 cases of pediatric ALAL patients is presented. Survival statistics were used to compare the prognosis of subsets and types of treatment. Five-year event-free survival (EFS) of patients with acute lymphoblastic leukemia (ALL)-type primary therapy (80% ± 4%) was superior to that of children who received acute myeloid leukemia (AML)-type or combined-type treatment (36% ± 7.2% and 50% ± 12%, respectively). When ALL- or AML-specific gene fusions were excluded, 5-year EFS of CD19

First pediatric experience of SL-401, a CD123-targeted therapy, in patients with blastic plasmacytoid dendritic cell neoplasm report of three cases.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive hematological malignancy with extremely poor outcome. The median overall survival for adult patients is 9-13 months. Pediatric patients are exceedingly rare with an unclear clinical course. Currently, no standardized therapy has been established, although an acute lymphoblastic leukemia type of treatment appears to be more effective in those patients who are able to tolerate aggressive chemotherapy. SL-401 is a targeted therapy directed to CD123, a protein ubiquitously expressed at high level on the surface of BPDCN blasts. In adult phase 2 trials, it has demonstrated efficacy with 90% overall response rate. No pediatric patients with BPDCN using SL-401 have been reported. Here, we report the first pediatric experience of three children with BPDCN treated with SL-401 at our institution. All patients tolerated SL-401 without significant toxicities. One patient with multiply relapsed and refractory disease had no response. The other two cases had significant and rapid clinical improvement after the two courses of treatment. However, the response was transient, and growth of soft tissue mass was observed in-between cycles in both patients with large tumor burden. This is the first report of SL-401 in pediatric patients with BPDCN. Sl-401 was well tolerated and can produce a promising response. Further testing this agent in children is warranted.

Optimal predictor for 6-mercaptopurine intolerance in Chinese children with acute lymphoblastic leukemia NUDT15, TPMT, or ITPA genetic variants

6-mercaptopurine (6-MP) contributes substantially to remarkable improvement in the survival of childhood acute lymphoblastic leukemia (ALL) patients. However, 6-MP also has dose-limiting toxicities, particularly life-threatening myelosuppression, due to genetic polymorphisms in enzymes that metabolize 6-MP. Promising biomarkers for predicting 6-MP-induced leukopenia is still unclear in Chinese population. Here, we evaluated the associations of NUDT15, TPMT and ITPA genotypes with 6-MP intolerance in our cohort of childhood ALL patients. A total of 105 Chinese pediatric patients with a confirmed diagnosis of ALL were enrolled. We identified the NUDT15 coding variant rs116855232 (c.415C > T), a newly discovered 6-MP toxicity-related locus in Asians, and polymorphisms in TPMT rs1142345 and ITPA rs11273540. Associations between genotypes and 6-MP dose sensitivity, leukopenia, hepatotoxicity, and therapy interruption were evaluated. The minor allele frequencies (MAFs) of NUDT15 rs116855232, TPMT rs1142345 and ITPA rs11273540 were 15.7, 2.9, and 18.1%, respectively. NUDT15 and TPMT genetic variants were strongly associated with 6-MP dose intensity. Patients with NUDT15 homogenous genotype (TT) were highly sensitive to 6-MP (dose intensity of 60.27%) compared to these with heterozygous genotype (TC) or wild type (CC), who tolerated an average dose intensity of 83.83 and 94.24%, respectively. The NUDT15 variant was a predictor for leukopenia (OR 3.62, 95% CI 1.377-9.501, P 0.009) and early-onset leukopenia (OR 9.63, 95% CI 2.764-33.514, P 3.75 × 10 NUDT15 variant is an optimal predictor for 6-MP intolerance in Chinese pediatric ALL patients and may have greatly clinical implications for individualized therapy.

Characterization of a new B-ALL cell line with constitutional defect of the Notch signaling pathway.

Notch signaling contribution to B-cell acute lymphoblastic leukemia (B-ALL) development is still under investigation. The serendipitous onset of B-ALL in a patient affected by the germinal Notch mutation-dependent Alagille syndrome allowed us to establish a B-ALL cell line (VR-ALL) bearing a genetic loss of function in components of Notch signaling. VR-ALL is a common-type B-ALL cell line, grows in conventional culture medium supplemented with 10% serum, and gives rise, once injected into immunodeficient NOG mice, to a mouse xenograft model of B-ALL. Exome sequencing revealed deleterious mutations in some components of Notch signaling, including Jagged1, Notch1, and Notch2. In addition, VR-ALL is sensitive both

Osteonecrosis in children with acute lymphoblastic leukemia at initial diagnosis and prior to any chemotherapy.

Osteonecrosis (ON) is a common and debilitating side effect of anti-leukemic treatment in children with acute lymphoblastic leukemia (ALL). However, the impact of leukemia itself on ON development remains elusive. We analyzed 76 children enrolled in the ongoing OPAL trial, who had magnetic resonance imaging (MRI) studies at diagnosis. MRI screening revealed 14 osteonecrotic lesions (5 × hips, 9 × knees) of any grade (I-III) in 7 (9.2%) patients. Six months on, the number of ON per patient increased (1 patient), remained constant (2), and decreased (2). The severity increased from grade I to II in two patients, remained constant (1), completely resolved (2), and decreased from grade III to osteoedema (1). No differences between adolescents initially presenting withwithout ON were observed concerning age, pubertal stage, body mass index, leukemia characteristics, and clinical presentation. In MRI screening, a remarkable number of adolescents with ALL present with ON at diagnosis. The course of these ON remains highly unpredictable.

Targeting FLT3 in acute myeloid leukemia using ligand-based chimeric antigen receptor-engineered T cells.

Chimeric antigen receptor-engineered T (CAR-T) cells have extraordinary effect in treating lymphoblastic leukemia. However, treatment of acute myeloid leukemia (AML) using CAR-T cells remains limited to date. Leukemogenesis always relates with the abnormalities of cytogenetics, and nearly one third of AML patients have activating mutations in Fms-like tyrosine kinase 3 (FLT3) which reminded poor prognosis. Considering the FLT3 expressed in AML patients blast cells, it may be a new candidate target for CAR-T therapy to treat FLT3 The FLT3L CAR-T using FLT3 ligand as recognizing domain was constructed. The specific cytotoxicity against FLT3 FLT3L CAR-T cells could specifically kill FLT3 The ligand-based FLT3L CAR-T cells could be a promising strategy for FLT3

Influence of Nitrosative Stress on Fatigue During Childhood Leukemia Treatment.

The focus on a cure for childhood leukemia over the last three decades has resulted in survival rates of more than 80%. However, efforts to manage leukemia-treatment symptoms have not kept pace with new therapies. Symptom toxicity during treatment can result in complications, treatment delays, and therapy dose reductions. Compromise in therapy can negatively influence the quality of life and, even more notably, jeopardize chances for long-term survival. This study examined biologic mechanisms that influence fatigue caused by increased reactive oxidative species (ROS) or actual failure of the antioxidant defense system due to genetic variation by investigating reactive nitrosative species, a downstream consequence of ROS. The specific aims of this study were to characterize the trajectory of nitrosative stress during acute lymphoblastic leukemia treatment and evaluate the influence of nitrosative stress on fatigue. A repeated measures design was used to evaluate the fatigue experienced by 186 children and adolescents, 3-18 years of age, with a diagnosis of leukemia during the most intense phase of treatment. An established biomarker of nitrosative stress, protein 3-nitrotyrosine (3NT) residues in the cerebral spinal fluid, was evaluated at diagnosis, postinduction, and consolidation phases of treatment. Higher fatigue was associated with higher 3NT levels at the beginning of treatment. Two distinct groups of children experienced either consistently high or consistently low 3NT levels across the treatment trajectory, from diagnosis to 12 months postinduction. Findings from this study support continued exploration into the phenotypic biochemical mechanisms that influence a reactive response to childhood cancer treatment.

Insights from parents of a child with leukaemia and healthcare professionals about sharing illness and treatment information A qualitative research study.

Many parents report a strong desire to take on information-giving roles, and believe they are best positioned to discuss their childs illness with their child. Healthcare professionals have a supporting role to reduce the burden on parents who feel responsible for conveying information to their child and other family members. To examine parents and healthcare professionals perceptions of roles in receiving and communicating information when a child is diagnosed with and treated for acute lymphoblastic leukaemia. We used the principles of a grounded theory approach. This was a single site study, recruiting from a principal childrens cancer treatment centre in the United Kingdom. The sample included parents of children receiving and completed treatment for acute lymphoblastic leukaemia (n 28), and healthcare professionals (n 34). Methods included individual interviews, face-to-face and telephone, focus groups, and an online forum. Communication touch points are many over the course of a childs cancer journey. We describe often mismatched communication encounters where those seeking information and those providing information have different goals. Healthcare professionals in the encounter have expertise at the outset while parents have less expertise, but this expertise grows over time and this can increase the perceptions of this mismatch and create different challenges. Considered in the context of middle range transition theory, we might suggest that parental foreground (seeking information directly) and background (passive actors) roles are the result of differing levels of uncertainty, and depend on the situation and preferences and child and family needs that may present differently over time in different contexts. Our work contributes to the emerging consensus that communication is more than a core set of skills that healthcare professionals just need to learn clear specifications of mutual roles, responsibilities and a shared understanding of goals is also essential.

The Role of TAL1 in Hematopoiesis and Leukemogenesis.

TAL1 (SCLTAL1, T-cell acute leukemia protein 1) is a transcription factor that is involved in the process of hematopoiesis and leukemogenesis. It participates in blood cell formation, forms mesoderm in early embryogenesis, and regulates hematopoiesis in adult organisms. TAL1 is essential in maintaining the multipotency of hematopoietic stem cells (HSC) and keeping them in quiescence (stage G0). TAL1 forms complexes with various transcription factors, regulating hematopoiesis (E2AHEB, GATA1-3, LMO1-2, Ldb1, ETO

Inotuzumab ozogamicin in the treatment of relapsedrefractory acute B cell lymphoblastic leukemia.

The improvement in outcomes of adult patients with acute lymphoblastic leukemia (ALL) has been modest, with the exception of Philadelphia chromosome-positive disease, despite advances in supportive care and stem cell transplantation. The recent approvals of novel agents, including the bispecific T-cell engager blinatumomab, the antibody-drug conjugate inotuzumab ozogamicin, and chimeric antigen receptor T-cell products are changing the management of B-ALL, which traditionally relied on chemotherapy-based approaches. Inotuzumab ozogamicin is a humanized CD22 monoclonal antibody linked to the cytotoxic agent calicheamicin. CD22 is expressed on leukemic blasts in >90% of ALL patients, and inotuzumab ozogamicin has shown excellent clinical activity even among heavily pretreated relapsedrefractory (RR) B-ALL patients and elderly B-ALL patients. Clinical trials have shown superior survival with the drug over chemotherapy-based approaches in the first- or second-line salvage therapy for relapsed B-ALL as monotherapy. Currently, new trials are evaluating inotuzumab ozogamicin in the frontline setting in combination-based approaches. In this review, we summarize the preclinical and clinical data of inotuzumab ozogamicin in RR B-ALL and foresee the future use of this drug in the clinic.

Factors associated with receipt of hematopoietic cell transplantation for acute lymphoblastic leukemia.

To evaluate practice patterns of hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia. We utilized the National Cancer Database to extract patient-level data of adults (aged 18-80 years) diagnosed with acute lymbhoblastic leukemia between 2003 and 2012. We performed multivariable logistic regression to determine variables associated with the use of HCT. Out of a total of 11,871 patients, 12.7% received HCT. In a multivariate analysis, older age, male sex, higher Charlson co-morbidity score, nonacademic treatment center, poor education and MedicareMedicaid or no insurance were associated with lower likelihood of receiving HCT. Our study demonstrates variations in the utilization of HCT based on socioeconomic and health system factors.

The prognostic role of E2A-PBX1 expression detected by real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) in B cell acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation.

The E2A-PBX1 rearrangement is common in B cell acute lymphoblastic leukemia (B-ALL). However, whether this fusion gene can be used as a reliable marker for minimal residual disease (MRD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unknown. In this study, clinical data were collected from 28 consecutive B-ALL patients who received allo-HSCT. Their MRD was evaluated by E2A-PBX1 and leukemia-associated immunophenotype (LAIP). The median follow-up was 374 days (55-2342 days). Of the enrolled patients, seven (25%) patients died of leukemia relapse. A total of nine (32.1%) patients experienced relapse at a median of 164 days (75-559 days) after transplantation. The median expression level in the first positive sample was 0.14% (0.0071-902.4%). The duration from E2A-PBX1-positive results to hematological relapse was 74 days (30-469 days). E2A-PBX1 expression generally became positive prior to flow cytometry. Patients with positive E2A-PBX1 gene expression pre-transplantation were more likely to have positive E2A-PBX1 expression after transplantation. Taken all together, E2A-PBX1 expression determined by real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) could be used to evaluate MRD status after allo-HSCT. Patients with positive E2A-PBX1 expression after transplant will have a poor prognosis.

Blinatumomab Approval Expanded Based on MRD.

The FDA recently expanded the approval of blinatumomab using minimal residual disease (MRD) as a regulatory endpoint, which could signal more such approvals to come. The drug can now be used to treat adults and children with B-cell precursor acute lymphoblastic leukemia who are in remission and have MRD.

T-cell acute lymphoblastic leukemia from miRNA perspective Basic concepts, experimental approaches, and potential biomarkers.

T-cell acute lymphoblastic leukemia (T-ALL) is a rare, aggressive and heterogeneous malignancy originating from T-cell precursors. The mechanisms of T-ALL pathogenesis related to non-protein coding part of the genome are currently intensively studied. miRNAs are short, non-coding molecules acting as negative regulators of gene expression which shape phenotype of cells in a complex and context-specific manner. miRNAs may act as oncogenes or tumor suppressors several miRNAs have been related to drug resistance and treatment response in various malignancies. Here we present the review of the state-of-the-art knowledge on the role of miRNAs in T-ALL pathogenesis, with detailed overview of the studies reporting on miRNAs with oncogenic and tumor suppressor potential. We discuss whether miRNAs might be considered candidate biomarkers of prognosis in T-ALL and leukemia subtype-specific markers. We also describe experimental approaches and a typical workflow applied in research on the involvement of miRNAs in oncogenesis.

Thrombosis in pediatric patients with leukemia.

Acute lymphoblastic leukemia (ALL) is the most common type of cancer diagnosed in children. It is reportedly the most common malignancy associated with thromboembolism in the pediatric age group. Over the last 2 decades, venous thromboembolism (VTE) has been increasingly diagnosed among pediatric ALL patients with an estimated incidence ranging from about 5% (for symptomatic cases) to about 30-70% (following sequential imaging studies in asymptomatic children). The etiology is multifactorial and may stem from alterations of the hemostatic system following various chemotherapy protocols (including use of l-Asparaginase), the presence of central venous lines (CVL), as well as comorbidities, e.g. inherited thrombophilia risk factors. Most symptomatic thrombotic events occur in the upper venous system or in the central nervous system (CNS). Prospective studies on the establishment of guidelines for treatment or prevention are lacking. The following review will address the epidemiology, etiology and risk factors for thrombosis, describe the currently available evidence, and address issues associated with diagnosis and treatment.

Prevalence and Safety of Intravenous Immunoglobulin Administration During Maintenance Chemotherapy in Children with Acute Lymphoblastic Leukemia in First Complete Remission A Health Maintenance Organization Perspective.

Children with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) experience hypogammaglobulinemia and are at risk of sepsis during maintenance chemotherapy. Intravenous immunoglobulin (IVIG) has been used to try to circumvent this risk, but no data exist regarding its safety and prevalence in a health maintenance organization. To evaluate the prevalence and safety of IVIG in children with ALL in CR1 during maintenance chemotherapy. A multicenter, retrospective cohort study of consecutive children with ALL in CR1 during maintenance chemotherapy from 2008 to 2014. Groups treated with or without IVIG were compared using nonparametric statistics. Multivariate logistic regression involved all variables available before maintenance therapy began. One hundred eighteen patients were included (53% males), aged 9 months to 19 years. Thirty of 31 patients (97%) who had immunoglobulins analyzed before IVIG were hypogammaglobulinemic. Thirty-six patients (30%) received IVIG during maintenance chemotherapy. Patients received an average of 10.5 IVIG doses (range 1-31). Ninety-seven percent of doses were administered without a transfusion reaction. Other factors associated with IVIG use were prior double-delayed intensification (odds ratio 5.36, 95% confidence interval 1.3-27.49, p 0.026) and episodes of bacteremia or fungemia before maintenance chemotherapy (odds ratio 3.04, 95% confidence interval 1.25-7.51, p 0.015). Use of IVIG in children with ALL in CR1 with hypogammaglobulinemia occurred in approximately 30% of patients and was well tolerated. Administration of IVIG significantly correlated with a history of double-delayed intensification and prior bacteremia or fungemia.

Acid-suppressing Drugs and a Low 1 Level of Antithrombin as Risk Factors for L-Asparaginase-associated Pancreatitis A Case-control Study in the Japan Association of Childhood Leukemia Study (JACLS).

L-Asparaginase has significantly improved outcome for children with acute lymphoblastic leukemia and has become an essential component of multiagent chemotherapy. However, there are many adverse events due to L-asparaginase, including acute pancreatitis. The pathology of L-asparaginase-associated pancreatitis (AAP) remains unclear. We compared patients who developed AAP (n29) and random matched controls (n36) who had been enrolled in the Japan Association of Childhood Leukemia Study of the ALL-02 protocol. AAP and control patients were matched for age, sex, treatment, and protocol risk. We examined correlations between AAP development and clinical symptoms, laboratory data, and concomitant medication. Abdominal pain and nausea were common presenting symptoms for AAP. There was an increased risk of AAP in patients using gastric acid-suppressing agents and antithrombin (AT) supplementation. Mean fibrinogen and AT levels before the onset of AAP were lower in AAP patients than in controls. Decreased AT and fibrinogen levels resulting from the strong suppression of protein synthesis by L-asparaginase were predictive signs for AAP. Our epidemiological approach should prove clinically useful for the diagnosis the AAP as early as possible.

APRIL is Involved in the Proliferation and Metastasis of Acute Lymphoblastic Leukemia Cells.

Our previous work showed that a proliferation-inducing ligand (APRIL) was involved in the development of acute lymphoblastic leukemia (ALL) in children. However, the precise role of APRIL in ALL remains unknown. To investigate this issue, we silenced and overexpressed APRIL in Nalm-6 ALL cells using short hairpin RNA targeting the APRIL gene and recombinant human APRIL, respectively, and evaluated the effects on cell proliferation, apoptosis, and migration. APRIL mRNA and APRIL and matrix metalloproteinase-2 protein levels were evaluated by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and western blott, respectively. We found that APRIL expression was reduced by shRNA-mediated knockdown in Nalm-6 cells this was associated with a decrease in cell proliferation (P<0.05). APRIL knockdown increased apoptosis (P<0.01) but suppressed cell migration along with matrix metalloproteinase-2 protein level. Overexpressing recombinant human APRIL had the opposite effects in each case (P<0.05). These results demonstrate a link between APRIL expression and ALL development and suggest that APRIL is a potential therapeutic target for ALL treatment.

Genetic Variation of Costimulatory Molecules, Including Cytotoxic T-Lymphocyte Antigen 4, Inducible T-Cell Costimulator, Cluster Differentiation 28, and Programmed Cell Death 1 Genes, in Iranian Patients With Leukemia.

There are limited studies about the possible relationship between genetic variations of costimulatory genes and susceptibility to hematologic malignancies like leukemia and lymphoma. This cross-sectional study included 59 leukemia patients. The polymorphisms of costimulatory molecules, including the CTLA-4 gene (-318 CT, -1722 TC, -1661 AG, 49 AG), PD-1 gene (1.3 AG, 1.9 CT), ICOS gene (1720 CT), and CD28 gene (17 CT), were analyzed by polymerase chain reaction-restriction fragment length polymorphism methods. Our results showed that the TT genotype and T allele of the CTLA-4 -318 TC polymorphism, the AA genotype of CTLA-4 49 AG polymorphism, and the CT genotype of PD-1 1.9 CT polymorphism were significantly higher in healthy controls (P < .05). However, the AG genotype of the CTLA-4 49 AG, the CC genotype of the PD-1 1.9 CT, and the CT genotype of the CD28 17CT polymorphism were significantly increased in patients with leukemia (P < .05). When the genotype frequency of costimulatory genes was compared between different leukemia groups, we observed that the A allele of the CTLA-4 49 AG and the CC genotype and C allele of the CD28 17 CT polymorphism were significantly higher in patients with acute leukemia than in those with chronic leukemia (P < .05). Among leukemia patients, the AA genotype of CTLA-4 49AG polymorphism was significantly increased in patients with acute myeloid leukemia, whereas the AG genotype was more prevalent in patients with acute lymphoblastic leukemia (P < .05). We show for the first time that genetic variations of costimulatory molecules CTLA-4, CD28, and PD-1 may be associated with susceptibility of Iranian patients to leukemia.

Laboratory testing in BCR-ABL1-like (Philadelphia-like) B-lymphoblastic leukemialymphoma.

BCR-ABL1-like B-lymphoblastic leukemialymphoma (BCR-ABL1-like B-ALL), also known as Philadelphia-like (Ph-like) ALL, is a neoplasm of B-lineage lymphoblasts characterized by a pattern of gene expression similar to that of B-ALL with the BCR-ABL1 translocation but lacking the BCR-ABL1 fusion protein. The diagnosis of BCR-ABL1-like B-ALL is associated with a high rate of relapse and poor clinical outcomes. In recognition of the difficulty in screening these leukemias for diagnostic workup, the 2016 updaterevision to the World Health Organization (WHO) 2008 edition included BCR-ABL1-like B-ALL as a provisional entity. This review addresses the various clinical considerations and methodologies currently used in the pathologic diagnosis, subclassification, and molecular characterization of cases of BCR-ABL1-like B-ALL, with particular attention paid to emerging methods useful in identification of molecular lesions potentially amenable to targeted therapy.

SETDB2 Links E2A-PBX1 to Cell-Cycle Dysregulation in Acute Leukemia through CDKN2C Repression.

Acute lymphoblastic leukemia (ALL) is associated with significant morbidity and mortality, necessitating further improvements in diagnosis and therapy. Targeted therapies directed against chromatin regulators are emerging as promising approaches in preclinical studies and early clinical trials. Here, we demonstrate an oncogenic role for the protein lysine methyltransferase SETDB2 in leukemia pathogenesis. It is overexpressed in pre-BCR

Final analysis of the JALSG PhALL202 study tyrosine kinase inhibitor-combined chemotherapy for PhALL.

The Japan Adult Leukemia Study Group (JALSG) PhALL202 study reported a high complete remission (CR) rate for Philadelphia chromosome-positive acute lymphoblastic leukemia (PhALL) patients treated with imatinib-combined chemotherapy. However, the long-term treatment efficacy remains uncertain. Here, we report a final analysis of the JALSG PhALL202 study. The outcomes were compared with those of the JALSG ALL93 and ALL97 studies, which were conducted in the pre-imatinib era. Ninety-nine newly diagnosed PhALL patients were enrolled in PhALL202 (median age, 45 years median follow-up, 4.5 years). CR was achieved in 9699 (97%) patients. Fifty-nine of these 96 patients (61%) underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in their first CR (CR1). The 5-year overall and disease-free survival (DFS) rates were 50 and 43%, respectively, which were significantly higher compared to those in the pre-imatinib era (15 and 19%, respectively). Multivariate analysis revealed that imatinib administration, allo-HSCT in CR1, and a white blood cell count < 30 × 10

MicroRNA-9 suppresses cancer proliferation and cell cycle progression in acute lymphoblastic leukemia with inverse association of neuropilin-1.

Acute lymphoblastic leukemia (ALL) is one of the most common and most malign childhood cancers. In this work, we investigated the expression and function of human mature microRNA-9 (miR-9) in ALL. In ALL in vitro cell lines and in situ clinical specimens, gene expression of miR-9 was tested by qRT-PCR. MiR-9 was overexpressed in CEMC1 and Molt-3 cells to investigate its possible anti-cancer effects on ALL in vitro proliferation, cell-cycle progression, and in vivo explant growth. The possible downstream target of miR-9, neuropilin-1 (NRP1), was examined by dual-luciferase activity assay, qRT-PCR, and Western blot. NRP1was upregulated in miR-9-overexpressed CEMC1 and Molt-3 cells to investigate the functional involvement of NRP1 in miR-9-mediated regulation on ALL in vitro proliferation and cell-cycle progression. MiR-9 was downregulated in ALL cell lines and leukemic T-cells of ALL patients. Lentivirus-mediated miR-9 overexpression inhibited ALL in vitro proliferation, cell-cycle progression, and in vivo explant growth. NRP1 was confirmed be the downstream target of miR-9, and inversely modulated by miR-9 in ALL. NRP1 upregulation reversed the anti-cancer regulations of miR-9 on ALL in vitro proliferation and cell-cycle progression. MiR-9 is downregulated in ALL. Overexpressing miR-9 may inhibit ALL development, possible through its downstream target of NRP1.

How to prophylax against invasive fungal infections in adult ALL An unmet need.

Although the benefit for any type of antifungal prophylaxis in patients with acute myelogenous leukaemia is well accepted, less is known about the risk for invasive fungal infections (IFIs) and the optimal prophylaxis strategies in patients with acute lymphocytic leukaemia (ALL). Based on recent studies, ALL is a disease that appears to be associated with significant risk for IFIs. The pharmacokinetic interactions between azoles and vincristine, an antineoplastic agent that is part of modern combination chemotherapies in ALL, results in clinically significant neurotoxicity that makes the use of azoles problematic. However, a number of questions regarding azole-vincristine interactions remain unanswered. In this viewpoint, we call for a renewed interest in antifungal prophylaxis studies in ALL in view of the availability of several non-azole novel antifungal agents that are under preclinical andor clinical development. This is clearly a major unmet need in modern clinical mycology.

Quantification of 6-Mercaptopurine and Its Metabolites in Patients with Acute Lympoblastic Leukemia Using Dried Blood Spots and UPLC-MSMS.

This research aimed to quantitatively bioanalyze 6-mercaptopurine (6-MP), 6-methylmercaptopurine (6-MMP), and 6-thioguanosine-5prime-monophosphate (6-TGMP) in dried blood spots (DBS) prepared from a small volume of acute lymphoblastic leukemia (ALL) patients. Analytes on the DBS card were extracted using 90% methanol with 5-fluorouracil (5-FU) as an internal standard. Analytical separation was performed on a Waters Acquity

Circular RNA PVT1 expression and its roles in acute lymphoblastic leukemia.

The roles of circular RNA PVT1 (circPVT1) are explored in the patients with acute lymphoblastic leukemia (ALL). The circPVT1 level was detected by qRT-PCR and western blot. The apoptotic cells were examined by the annexin V assay in lentiviral shRNA knockdown cells. circPVT1 was highly expressed in ALL compared with normal bone marrow samples. circPVT1 expression was also significantly higher in ALL cell lines. circPVT1 knockdown inhibited cell proliferation and induced cell apoptosis through suppression of its neighbor gene c-Myc, and antiapoptotic Bcl-2 protein expression. circPVT1 is upregulated in ALL. Silencing circPVT1 results in cell growth arrest and apoptosis of the cells. Our results also suggested a therapeutic potential of targeting circPVT1 in ALL.

Institutional-based tumor registry of hematopoietic malignancies A 4 years preliminary report from Karachi.

Pakistan has a population of over 198 million making it the worlds sixth populous country. However, operational population-based cancer registries in Pakistan are lacking. Limited data are available based on institutional or Karachi Cancer Registry from Karachi however, no exclusive registry for hematological malignancies is established till date. Hence, we decided to conduct a database analysis to determine the frequencies of various hematological cancers in our tertiary care center in Karachi. Retrospective assessment of 366 patients presented to Hematology Department, Liaquat National Hospital and Medical College from May 2012 to May 2016 with confirmed diagnosis of hematological cancers was performed. Data were retrieved from hospital-based tumor registry. All pro forma was filled by qualified medical research officer, which included demographic data as age, gender, history, disease type, and its stage at presentation. Male gender was predominant and accounted for 69.9% ( Our institution-based tumor registry indicates CML and AML were the most common cancers in males and females, respectively, followed by ALL. Chronic lymphoid leukemia, unlike in the West, is seen infrequently in our population. National and provisional hematological tumor registry will be beneficial for future health planning and research.

Liposomes Co- encapsulating Anticancer Drugs in Synergistic Ratios as an Approach to Promote Increased Efficacy and Greater Safety.

The era of chemotherapy began in the 1940s, but it was in the 1960s that it was seen as really promising when the first patients with childhood acute lymphoblastic leukemia were cured with combination chemotherapy. Today, it is known that due to resistance to single agents, combination therapy is essential for tumor eradication and cure. In the last decade, studies have shown that anticancer drug combinations can act synergistically or antagonistically against tumor cells

ENO2 Promotes Cell Proliferation, Glycolysis, and Glucocorticoid-Resistance in Acute Lymphoblastic Leukemia.

The metabolic features of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. The expression of glycolytic enzyme enolase 2 (ENO2) was found to be closely associated with the clinical features of acute lymphoblastic leukemia (ALL) patients, but its functions remain unclear in ALL. We evaluated the association between ENO2 mRNA expression in bone marrow mononuclear cells (BM-MNCs) and the efficacy of chemotherapy, and further explored the function of ENO2 in ALL. The molecular mechanisms of ENO2 expression and its effects on cell growth, glycolysis and glucocorticoid resistance were explored by Cell Counting Kit-8, glucose-consumption assay, Quantitative RT-PCR, Western blotting and in vivo tumorigenesis in NODSCID mice. The results showed that ENO2 mRNA expression in BM-MNCs was significantly decreased when patients completed induction chemotherapy and reached complete remission (CR). ENO2 mRNA expression was increased when patients suffered relapse. Functional studies demonstrated that ENO2 promoted cell growth, glycolysis, and glucocorticoid resistance, all of which were effectively inhibited when ENO2 was silenced with shRNAs. Further studies revealed that ENO2 up-regulated various glycolysis-related genes and enhanced Akt activity with subsequent glycogen synthase kinase3β (GSK-3β) phosphorylation, inducing cell proliferation and glycolysis. The combination of silencing ENO2 and 2-deoxyglucose (2-DG) synergistically inhibited leukemia cell survival. These results indicate that ENO2 may be a biological marker for monitoring chemotherapeutic efficacy and relapse in ALL. ENO2 may provide a potential therapeutic strategy for ALL.

Molecular Minimal Residual Disease Monitoring in Acute Myeloid Leukemia Challenges and Future Directions.

The ability to sensitively monitor minimal residual disease (MRD) has played a key role in improving the management and outcomes for a number of leukemias, particularly acute promyelocytic leukemia and childhood acute lymphoblastic leukemia. By contrast, MRD monitoring in acute myeloid leukemia (AML) has been limited by variable assay methodologies and a relative paucity of patient-specific MRD markers. Inter- and intratumor genetic heterogeneity poses significant challenges for the identification of molecular markers suitable for MRD monitoring in AML, particularly for those cases without structural chromosomal rearrangements associated with fusion genes. Furthermore, the need to discriminate which mutations may be suitable for MRD monitoring creates additional complexity. The mainstay of current molecular MRD monitoring is real-time quantitative PCR, targeting fusion genes, mutations, and gene overexpression. New technologies, particularly next-generation sequencing approaches, offer new ways to overcome these limitations. Here, the authors review the techniques available for molecular MRD monitoring in AML and discuss their utility in clinical practice.

Relapse in teenage and young adult patients treated on a paediatric minimal residual disease stratified ALL treatment protocol is associated with a poor outcome results from UKALL2003.

Outcomes for teenage and young adult (TYA) patients with acute lymphoblastic leukaemia (ALL) who relapse on contemporary risk-adapted paediatric protocols are largely unknown and there is no consensus on optimal salvage strategies. We assessed the treatment and outcome of TYA patients (aged 16-24 years) recruited to the UKALL2003 trial, who relapsed following attainment of complete morphological remission. Forty-two of 223 patients (18·8%) relapsed, the majority (n 26, 62%) on treatment. Thirty-eight (90%) patients received salvage treatment, with 22 (58%) achieving second remission (CR2) and 21 patients receiving an allogeneic haematopoietic cell transplant (alloHSCT). Post-relapse outcomes were poor with a 5-year overall survival (OS) of 23% (95% confidence interval 11-37%). Outcomes for patients relapsing on active treatment were inferior to those relapsing after completing treatment (5-year OS 9% vs. 52%, log-rank P 0·001). No patient with B cell ALL relapsing on treatment was alive at the end of the study period. TYA patients with ALL who relapse on the UK paediatric protocol, UKALL2003, are largely unsalvageable with conventional approaches aimed at achieving CR2 followed by alloHSCT. Future efforts should be aimed at identifying those patients who are destined to relapse and exploring novel treatment approaches for this high-risk group and for those who do relapse.

Enhanced Expression of Anti-CD19 Chimeric Antigen Receptor in

Adoptive T cell therapy using chimeric antigen receptor (CAR)-modified T cells is a promising cancer immunotherapy. We previously developed a non-viral method of gene transfer into T cells using a

Successful Management of a Child With Drug-induced Necrotizing Pancreatitis During Acute Lymphoblastic Leukemia Therapy A Case Report.

Acute pancreatitis in children acute lymphoblastic leukemia is commonly caused by drugs, for example, L-Asparaginase, pegapargase, steroids. The incidence of this complication is estimated at 6.7% to 18%. Although the majority of drug-induced acute pancreatitis cases are mild, severe cases can rarely occur. This work presents a case of successful management of a child with drug-induced necrotizing pancreatitis during acute lymphoblastic leukemia therapy. This case illustrates that comprehensive care and immediate intensive treatment can rescue patient despite poor prognosis. Administration of octreotide may serve a role in limiting the severity of the disease.

SLCO1B1 Polymorphisms are Associated With Drug Intolerance in Childhood Leukemia Maintenance Therapy.

Therapy discontinuations and toxicities occur because of significant interindividual variations in 6-mercaptopurine (6-MP) and methotrexate (MTX) response during maintenance therapy of childhood acute lymphoblastic leukemia (ALL). 6-MPMTX intolerance in some of the patients cannot be explained by thiopurine S-methyl transferase (TPMT) gene variants. In this study, we aimed to investigate candidate pharmacogenetic determinants of 6-MP and MTX intolerance in Turkish ALL children. In total, 48 children with ALL who had completed or were receiving maintenance therapy according to Childrens Oncology Group (COG) protocols were enrolled. Fifteen single-nucleotide polymorphisms in 8 candidate genes that were related to drug toxicity or had a role in the 6-MPMTX metabolism (TPMT, ITPA, MTHFR, IMPDH2, PACSIN2, SLCO1B1, ABCC4, and PYGL) were genotyped by competitive allele-specific PCR (KASP). Drug doses during maintenance therapy were modified according to the protocol. The median drug dose intensity was 50% (28% to 92%) for 6-MP and 58% (27% to 99%) for MTX in the first year of maintenance therapy, which were lower than that scheduled in all patients. Among the analyzed polymorphisms, variant alleles in SLCO1B1 rs4149056 and rs11045879 were found to be associated with lower 6-MPMTX tolerance. SLCO1B1 rs4149056 and rs11045879 polymorphisms may be important genetic markers to individualize 6-MPMTX doses.