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Discontinuation of L-asparaginase and poor response to prednisolone are associated with poor outcome of ETV6-RUNX1-positive pediatric B-cell precursor acute lymphoblastic leukemia.

ETV6-RUNX1-positive B precursor acute lymphoblastic leukemia (B-ALL) is a common subtype of pediatric B-ALL that has shown excellent outcomes in contemporary clinical trials for pediatric B-ALL. Examinations of the possibility of reducing therapeutic intensity may thus be explored. This prospective study examined outcomes in 205 pediatric patients with ETV6-RUNX1-positive B-ALL uniformly treated following the Japan Association of Childhood Leukemia Study Group (JACLS) ALL-02 protocol. The JACLS ALL-02 protocol does not employ minimal residual disease detected by polymerase chain reaction (PCR-MRD)-based risk stratification however, 4-year event-free survival (EFS) and overall survival (OS) were 94.4 ± 1.6 and 97.5 ± 1.1%, respectively. In particular, 92 of 205 (44.9%) patients were successfully treated with a less intensive regimen involving only two cycles of high dose methotrexate and one course of re-induction therapy comprising vincristine, L-asparaginase (L-asp), pirarubicin, and prednisolone. Multivariate analysis revealed that discontinuation of L-asp and poor response to prednisolone was, respectively, associated with poor EFS (HR 6.3 95% CI 1.3-27.0) and OS (HR 17.5 95% CI 2.3-130), suggesting that the majority of ETV6-RUNX1-positive B-ALL cases may be cured by a less-intensive chemotherapy regimen if the risk stratification system including PCR-MRD monitoring and insufficient use of L-asp is avoided.

Evaluation of Insulin-mediated Regulation of AKT Signaling in Childhood Acute Lymphoblastic Leukemia.

Hyperglycemia increases the risk of early recurrence and high mortality in some adult blood cancers. In response to increased glucose levels, insulin is secreted, and several studies have shown that insulin-induced AKT signaling can regulate tumor cell proliferation and apoptosis. The AKT pathway is aberrantly activated in adult acute lymphoblastic leukemia (ALL), but the mechanisms underlying this activation and its impact in pediatric patients with ALL are unclear. We evaluated the insulin-induced chemoresistance and AKT pathway activation by measuring cell proliferation, apoptosis, and other parameters in ALL cell lines (Jurkat and Reh cells), as well as in primary pediatric leukemic cell samples, after culture with insulin, the chemotherapeutic drugs daunorubicin (DNR), vincristine (VCR), and L-asparaginase (L-Asp), or anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody. DNR, VCR, and L-Asp-induced toxicity in Jurkat and Reh cells was reduced in the presence of insulin. DNR promoted cell proliferation, whereas DNR, VCR, and L-Asp all reduced apoptosis in both cell lines cotreated with insulin compared with that in cell lines treated with chemotherapeutics alone (P<0.05). Furthermore, addition of an anti-IGF-1R monoclonal antibody promoted apoptosis, downregulated IGF-1R expression, and decreased the phosphorylation of AKT, P70S6K, and mTOR intracellular signaling pathway proteins in both cell lines, as well as in primary cultures (P<0.05). Our results suggest that insulin-induced chemoresistance and activation of the AKT signaling pathway in pediatric ALL cells.

Prevention of Long-term Adverse Health Outcomes With Cardiorespiratory Fitness and Physical Activity in Childhood Acute Lymphoblastic Leukemia Survivors.

Most childhood acute lymphoblastic leukemia (ALL) survivors develop chronic treatment-related adverse effects several years after the end of therapy. A regular practice of physical activity and a good cardiorespiratory fitness have the potential to reduce the risk of chronic disease and improve quality of life. The aim of this study was to evaluate in a cohort of ALL survivors, the association between a good cardiorespiratory fitness or the respect of physical activity guidelines and major long-term health outcomes. In total, 247 ALL survivors underwent a cardiopulmonary exercise test, completed a physical activity questionnaire and a battery of clinical examinations. We calculated the odds ratio to obtain the preventive fraction (PF) to evaluate the effects of the cardiorespiratory fitness and physical activity levels on health outcomes (ie, obesity, metabolic health, cardiac health, cognitive health and mood, bone health). Despite their young age, 88% of the participants presented at least one adverse health outcome, and 46% presented ≥3. Their cardiorespiratory fitness was also lower than expected with a median VO2 peak reaching 84% of the predicted value. In the analyses using cardiorespiratory fitness, statistically significant PFs were observed for obesity (0.30), low-high-density lipoprotein-cholesterol (0.21) and depression (0.26). In the physical activity level analyses, statistically significant PFs were observed for obesity, depression, and low bone mineral density, with a PF of 0.55, 0.81, and 0.60, respectively. Our results indicate that a good cardiorespiratory fitness and physical activity level induced a preventive action for most health outcomes studied and was associated with a lower late adverse effects prevalence in ALL survivors.

A 3-Year Retrospective Study of the Epidemiology of Acute Respiratory Viral Infections in Pediatric Patients With Cancer Undergoing Chemotherapy.

Acute viral respiratory infections are common causes of febrile episodes in children. There are still limited data about distribution of acute viral respiratory infections in children with cancer. The first aim of this study was to evaluate the viral etiology and seasonality of acute viral respiratory infection in pediatric patients with cancer in a 3-year study. Our second aim was to evaluate the impact of viral infections on delaying the patients chemotherapy or radiotherapy. This cross-sectional study was conducted from January 2014 to July 2017. Nasopharyngeal aspirates were analyzed in patients younger than 21 years with acute respiratory infections. Patients were treated in the Pediatric Hematology and Oncology Department of Dr. Behçet Uz Childrens Hospital with real-time multiplex polymerase chain reaction. Data were analyzed to determine the frequency and seasonality of infections. The χ or the Fisher exact tests were used. A total of 219 samples of nasopharyngeal aspirates and blood were analyzed. The mean patient age was 76.8±59.3 months, with 46.3% female and 53.7% male children in a total of 108 patients. Of this total, 55% (60108 cases) had multiple acute respiratory infections. Acute lymphoblastic leukemia (48.1%) was the most prevalent disease. The 3 most prevalent viruses were human rhinovirus (HRV) (33.1%), parainfluenza (PI) (18.7%), and coronavirus (CoV) (14.8%). In terms of the seasonal distribution of viruses, PI was most common in winter 2014, HRV in spring 2014, HRV in fall 2014, PI in winter 2015 and summer 2015, CoV in spring 2015, HRV in fall 2015, both influenza and HRV in winter 2016, both human metapneumovirus and bocavirus in spring 2016, HRV in summer 2016, both HRV and PI in fall 2016, both respiratory syncytial virus and influenza in winter 2017, HRV in spring 2017, and both HRV and adenovirus in summer 2017. The mean duration of neutropenia for patients with viral respiratory infection was 17.1±13.8 (range 2 to 90) days. The mean duration of symptoms of viral respiratory infection was 6.8±4.2 (range 2 to 31) days. A delay in chemotherapy treatment owing to viral respiratory infection was detected in 73 (33.3%) patients. The mean duration of delay in chemotherapy treatment was 9.6±5.4 (range 3 to 31) days. In conclusion, we report our 3-year experience about the frequency and seasonality of respiratory viruses in children with cancer.

Acral Involvement of Lymphoblastic Lymphoma Revealed on FDG PETCT.

Lymphoma rarely involves hand or foot. We presented the FDG PETCT findings of lymphoblastic lymphoma in a 28-year-old man who had recurrent disease in many bones, including those of the hand and foot without any lymph node involvement 17 years after initial diagnosis.

Development of L-Asparaginase Biobetters Current Research Status and Review of the Desirable Quality Profiles.

L-Asparaginase (ASNase) is a vital component of the first line treatment of acute lymphoblastic leukemia (ALL), an aggressive type of blood cancer expected to afflict over 53,000 people worldwide by 2020. More recently, ASNase has also been shown to have potential for preventing metastasis from solid tumors. The ASNase treatment is, however, characterized by a plethora of potential side effects, ranging from immune reactions to severe toxicity. Consequently, in accordance with Quality-by-Design (QbD) principles, ingenious new products tailored to minimize adverse reactions while increasing patient survival have been devised. In the following pages, the reader is invited for a brief discussion on the most recent developments in this field. Firstly, the review presents an outline of the recent improvements on the manufacturing and formulation processes, which can severely influence important aspects of the product quality profile, such as contamination, aggregation and enzymatic activity. Following, the most recent advances in protein engineering applied to the development of biobetter ASNases (i.e., with reduced glutaminase activity, proteolysis resistant and less immunogenic) using techniques such as site-directed mutagenesis, molecular dynamics, PEGylation, PASylation and bioconjugation are discussed. Afterwards, the attention is shifted toward nanomedicine including technologies such as encapsulation and immobilization, which aim at improving ASNase pharmacokinetics. Besides discussing the results of the most innovative and representative academic research, the review provides an overview of the products already available on the market or in the latest stages of development. With this, the review is intended to provide a solid background for the current product development and underpin the discussions on the target quality profile of future ASNase-based pharmaceuticals.

CAR-T cells Lymphocytes that express a chimeric antigen receptor.

CAR-T cells are genetically modified human lymphocytes and gene therapy medicinal products. They are developed to treat cancers that express a membrane antigen targeted by the CAR. The FDA approved the two first-in-class medicinal products in 2017 and EMA in August 2018 both are autologous CAR-T cells targeting CD19 that is expressed at the surface of normal B-cells throughout their differentiation, and on B-cell lymphoid malignancies. Clinical efficacy was demonstrated for B-cell acute lymphoblastic leukemias, non-Hodgkins lymphoma and chronic lymphocytic leukemia, although the marketing authorizations are less liberal in terms of indications. Manufacturing of these personalized treatments necessitates that a novel organization and supply chain be set in place, to ensure product preservation, patient safety and compliance with complex regulatory requirements. Side effects are commensurate with clinical efficacy and can be life-threatening proper management imposes tight coordination between various specialists, particularly between hematologists and intensive care practitioners. High pricing for these treatments is part of a long-term trend for increasing costs of innovations in hematology and oncology it questions the ability of healthcare systems to sustain their reimbursement.

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The prognosis for acute lymphoblastic leukemia (ALL) in adults remains poor in refractory or relapsed (RR) situations. Among the immunotherapy strategies that have recently been developed, CAR-T cells (chimeric antigen receptor modified T-cells) represent a major technological and therapeutic advance in the management of adult and pediatric patients with such resistant diseases. The first CAR-T trials targeting the ubiquitous B-cell antigen CD19 showed very encouraging results with complete remission rates of approximately 80%. Cytokine release syndrome (CRS) and neurotoxicity are two major and potentially life-threatening adverse events, that require coordinated management with intensive care units and graduated use of IL-6 pathway blocking antibodies and steroids. In addition to immediate toxicity, many clinical issues arise such as ALL treatment from apheresis to CAR-T infusion, the role of allogeneic hematopoietic stem cell transplant (HSCT) before or after CAR-T therapy, or the reduction of escape mechanisms mostly driven by the loss of target expression. The development of these strategies in other subtypes of acute leukemias, including myeloid acute leukemia, is confronted with the expression of antigenic targets by healthy tissues and the potential risk of prolonged cytopenias. This review adopts a clinical perspective to detail the main results of CD19 CAR-T in ALL and the challenges raised by this new therapeutic approach. Cet article fait partie du numéro supplément Les cellules CAR-T une révolution thérapeutique réalisé avec le soutien institutionnel des partenaires Gilead Kite et Celgene.

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CURRENT INDICATIONS IN CHILDREN AND PERSPECTIVES Acute lymphoblastic leukemia (ALL) is the first cause of cancer in children. Five-year overall survival is greater than 90% but leukemia remains a major cause of death from cancer in children. A new class of immunotherapy based on a chimeric antigen receptor CAR targeting the CD19 on the B leukemic cells and that is transduced in an autologous or allogenic T lymphocyte will allow to transform the prognosis of refractory or relapsed B-ALL. Overall response rates range from 60 to 90% in phase I-II studies in patients with second relapse or more or with refractory disease. Persistent remissions and even cures have been observed. These very good results could lead to use this treatment in first line for patients with very high-risk disease. However, CAR-T cells production, costs and adverse events management represent major issues for the future of this therapeutic. The occurrence of CD19 negative relapses has led to develop bispecific CAR-T cells. Allogeneic CAR would permit to obtain a CAR garage off the shelf available from the diagnosis. Perspectives for CAR-T cells are immense but will involve technological progresses around the CAR conception and production, leading to further improve results in leukemias (ALL but also AML) and lymphomas and hopefully to the emergence of efficacy in childhood solid tumors. Cet article fait partie du numéro supplément Les cellules CAR-T une révolution thérapeutique réalisé avec le soutien institutionnel des partenaires Gilead Kite et Celgene.

Folate pathway genetic polymorphisms modulate methotrexate-induced toxicity in childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is one of the major malignancies affecting children in Jordan. Methotrexate (MTX) is the cornerstone of chemotherapy for ALL, and works by targeting enzymes involved in the folate pathway. We hypothesize that genetic polymorphisms of the folate pathway are associated with MTX toxicity in children with ALL. A total of 64 children with ALL were included in this study 31 (48.4%) boys and 33 (51.6%) girls aged 2-16 years. The folate pathway genes were genotyped using polymerase chain reaction followed by sequencing and studying the association between genetic polymorphisms and MTX toxicity. The immunophenotype was B-lineage in 55 patients (85.9%) and T-lineage in nine patients (14.1%). All genetic polymorphisms, except for dihydropyrimidine dehydrogenase polymorphisms, were associated with hematological toxicities and did not appear to precipitate any non-hematological adverse events. Patients with ALL carrying dominant alleles of methylene tetrahydrofolate (MTHFR) C677T and dihydrofolate reductase 19 bp deletion were at a higher risk of developing severe leucopenia OR (95% CI) 4.5 (1.2-17), p 0.03 5.4 (1.6-17.8) p 0.006 while minor allele carriers of MTHFR A1298C were more likely to develop neutropenia OR (95% CI) 6.1 (1.3-29.5) 0.04. Furthermore, dominant allele carriers of thymidylate synthase 1494 del6 were at a higher risk of developing neutropenia OR (95% CI) 6 (1.2-31.1) p 0.04. Genetic polymorphisms of the folate pathway may modulate MTX-induced toxicity in childhood ALL.

Alternative splicing of Ikaros regulates the FUT4Le

Unveiling the mechanism of the relapse of acute lymphoblastic leukemia (ALL) is the key to improve the prognosis of ALL and remains a huge challenge. Glycan-based interactions play a vital role in immune surveillance, cell-cell adhesion and cell-matrix interaction, contributing to treatment failure in tumor. However, the glycan essential for leukemia development and its upstream regulatory mechanism by oncogenic drivers were rarely reported. Here, we demonstrated that Le

Monitoring of cytomegalovirus infection in non-transplant pediatric acute lymphoblastic leukemia patients during chemotherapy.

Cytomegalovirus (CMV) infection is a significant cause of morbidity and mortality in the posttransplant setting however, it is increasingly recognized in pediatric leukemia during chemotherapy. This study assessed the prevalence and associated factors of CMV infection in pediatric non-transplant leukemia patients.This was a cross-sectional study of 50 pediatric acute lymphoblastic leukemia (ALL) patients receiving chemotherapy at Ramathibodi Hospital from December 2015 to December 2016. CMV viral load quantified by DNA polymerase chain reaction (PCR) was monitored in different phases of chemotherapy enrolment, post-induction, post-consolidation, post-intensification, and maintenance.One hundred forty one blood tests were evaluated from 50 patients. Overall prevalence of CMV DNAemia (≥20 copiesmL) and high-level CMV DNAemia (≥1000 copiesmL) was 52% (26 of 50) and 16.0% (8 of 50), respectively. All patients with high-level CMV DNAemia were in the maintenance phase of chemotherapy. One patient had CMV retinitis, while the rest had no end-organ CMV diseases. Increased lymphocyte count was significantly associated with protection from high-level CMV DNAemia (odds ratio 0.997, P .02). Receiver operating characteristic curve identified a cut-off value of 798 cellsmm of absolute lymphocyte count (ALC) as a discriminator for the presence of high-level CMV DNAemia (area under the curve 0.756, 95% CI 0.645-0.867, P .001) with 88.9% sensitivity and 50.4% specificity.CMV infection predominantly occurred during maintenance chemotherapy. Low ALC was significantly associated with high-level CMV DNAemia. CMV infection surveillance by quantitative CMV DNA PCR during maintenance chemotherapy in patients with ALC <800 cellsmm may be considered.

Cytomegalovirus pneumonia in a patient with T-lymphoblastic leukemialymphoma after allogeneic hematopoietic stem cell transplantation A case report.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important treatment for hematological malignancies. Common complications are opportunistic infections and graft-versus-host disease (GVHD). Cytomegalovirus (CMV) is one of the most common causes of opportunistic infections. A 30-year-old male was diagnosed with T-cell lymphoma after persistent cough and lymphadenopathy. Fever, abdominal pain, diarrhea, rash, and dyspnea occurred after HSCT. The young man developed severe CMV infection with CMV detected in the bronchoalveolar lavage fluid and gastrointestinal tract. Intravenous ganciclovir and high-dose glucocorticoids were administered after the patient was diagnosed with CMV pneumonia and enteritis. After 3 weeks, the young man died from respiratory failure and infectious toxic shock caused by severe CMV infection. Patients after HSCT should be closely monitored CMV-DNA in blood and other specimen, and treated first if necessary, so as to avoid the occurrence of severe infections such as CMV gastroenteritis and pneumonia.

Factors affecting same-day cancelation of outpatient pediatric oncologic procedural sedation.

Children with cancer undergo serial invasive, painful procedures as a part of their diagnosis, treatment, and surveillance regimens that require procedural sedation (PS). Some may have a delay in their treatment plan due to same-day cancelation (SDC) of the procedure due to issues related to sedation or other factors. The objective of this report was to evaluate the factors resulting in the SDC of hematology and oncology patients in an outpatient pediatric sedation service. Retrospective review of children with cancer or other hematologic disorders undergoing outpatient procedures using a dedicated pediatric sedation team from January 2012 to December 2017. The children with SDC were compared to controls (ie, patients not canceled) during the above study period. A total of 100 patients had SDC during the study. The median age was 10 years (25th percentile to 75th percentile 7-10 years). The overall SDC rate was 3% and 78100 (78%) had acute lymphoblastic leukemia. Most common procedure was lumbar puncture with intrathecal chemotherapy in 82100 (82%) patients. Inadequate blood counts, acute illness, and not nil per os (NPO) accounted for 83% of the reasons for SDC. Type of health insurance, estimated household income, or distance traveled to the clinic did not impact SDC. The most common factors for SDC included inadequate blood counts, acute illness, and not meeting NPO guidelines. Understanding factors affecting SDC may help improve the efficiency of time-sensitive care delivered to children with cancer and other hematologic concerns by a pediatric sedation service.

An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer.

Chimeric antigen receptor (CAR) T-cell therapy represents a major advancement in personalized cancer treatment. In this strategy, a patients own T cells are genetically engineered to express a synthetic receptor that binds a tumor antigen. CAR T cells are then expanded for clinical use and infused back into the patients body to attack and destroy chemotherapy-resistant cancer. Dramatic clinical responses and high rates of complete remission have been observed in the setting of CAR T-cell therapy of B-cell malignancies. This resulted in two recent FDA approvals of CAR T cells directed against the CD19 protein for treatment of acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Thus, CAR T cells are arguably one of the first successful examples of synthetic biology and personalized cellular cancer therapy to become commercially available. In this review, we introduce the concept of using CAR T cells to break immunological tolerance to tumors, highlight several challenges in the field, discuss the utility of biomarkers in the context of predicting clinical responses, and offer prospects for developing next-generation CAR T cell-based approaches that will improve outcome.

Cutaneous involvement as the first manifestation of T-lymphoblastic lymphoma and review of the literature.

Lymphoblastic lymphomas (LBLs) are uncommon malignant neoplasms derived from immature T- or B-lymphoid progenitor cells. Although cutaneous involvement may reach 33% in B-LBL, only 12 cutaneous cases of T-LBL have been published. We report the case of a 49-year-old woman with 2-month history of erythematous-violaceous plaques in the sternal region and breasts. Histopathologic examination showed a dense monomorphus infiltrate in dermis and positive immunostainings for CD3, CD99 and terminal deoxynucleotidyl transferase, thus indicating T-LBL. Staging work-up only revealed a mediastinal mass at diagnosis. After a 51-month follow-up and different treatment regimens, the patient remains alive although she has presented four relapses, all of them extramedullary.

Minimal residual disease status determined by multiparametric flow cytometry pretransplantation predicts the outcome of patients with ALL receiving unmanipulated haploidentical allografts.

This study evaluated the effects of pretransplantation minimal residual disease (pre-MRD) on outcomes of patients with acute lymphoblastic leukemia (ALL) who underwent unmanipulated haploidentical stem cell transplantation (haplo-SCT). A retrospective study including 543 patients with ALL was performed. MRD was determined using multiparametric flow cytometry. Both in the entire cohort of patients and in subgroup cases with T-ALL or B-ALL, patients with positive pre-MRD had a higher incidence of relapse (CIR) than those with negative pre-MRD in MSDT settings (P < 0.01 for all). Landmark analysis at 6 months showed that MRD positivity was significantly and independently associated with inferior rates of relapse (HR, 1.908 P 0.007), leukemia-free survival (LFS) (HR, 1.559 P 0.038), and OS (HR, 1.545 P 0.049). The levels of pre-MRD according to a logarithmic scale were also associated with leukemia relapse, LFS, and OS, except that cases with MRD <0.01% experienced comparable CIR and LFS to those with negative pre-MRD. A risk score for CIR was developed using the variables pre-MRD, disease status, and immunophenotype of ALL. The CIR was 14%, 26%, and 59% for subjects with scores of 0, 1, and 2-3, respectively (P < 0.001). Three-year LFS was 75%, 64%, and 42%, respectively (P < 0.001). Multivariate analysis confirmed the association of the risk score with CIR and LFS. The results indicate that positive pre-MRD, except for low level one (MRD < 0.01%), is associated with poor outcomes in patients with ALL who underwent unmanipulated haplo-SCT.

Low burden of minimal residual disease prior to transplantation in children with very high risk acute lymphoblastic leukaemia The NOPHO ALL2008 experience.

The population-based NordicBaltic acute lymphoblastic leukaemia (ALL) Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol combined minimal residual disease (MRD)-driven treatment stratification with very intense first line chemotherapy for patients with high risk ALL. Patients with MRD ≥5% at end of induction or ≥10

Enhanced hemato-endothelial specification during human embryonic differentiation through developmental cooperation between

The t(411)(q21q23) translocation is associated with high-risk infant pro-B-cell acute lymphoblastic leukemia and arises prenatally during embryonicfetal hematopoiesis. The developmentalpathogenic contribution of the t(411)-resulting

Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis.

B-cell acute lymphoblastic leukemia is the commonest childhood cancer. In infants, B-cell acute lymphoblastic leukemia remains fatal, especially in patients with t(411), present in 80% of cases. The pathogenesis of t(411)KMT2A-AFF1

ZEB2 and LMO2 drive immature T-cell lymphoblastic leukemia via distinct oncogenic mechanisms.

ZEB1 and ZEB2 are structurally related E-box binding homeobox transcription factors that induce epithelial to mesenchymal transitions during development and disease. As such, they regulate cancer cell invasion, dissemination and metastasis of solid tumors. In addition, their expression is associated with the gain of cancer stem cell properties and resistance to therapy. Using conditional loss-of-function mice, we previously demonstrated that

Delayed methotrexate clearance in patients with acute lymphoblastic leukemia concurrently receiving dasatinib.

We aimed to determine whether patients receiving dasatinib or imatinib concurrently with high-dose methotrexate (HDMTX) had slower methotrexate clearance than patients not receiving a tyrosine kinase inhibitor (TKI) during the HDMTX infusion. Patients concurrently receiving dasatinib and HDMTX (N 7) had significantly slower MTX clearance (P 0.008) than patients not receiving a TKI (N 111). Two patients receiving a TKI during a HDMTX infusion required glucarpidase. In vitro studies showed that dasatinib significantly inhibited methotrexate uptake by SLCO1B1-expressing cells (P 0.009). There may be an interaction between dasatinib and HDMTX, mediated by the transporter SLCO1B1, that causes a delay in MTX clearance.

Critical Care Management of Chimeric Antigen Receptor T Cell-related Toxicity. Be Aware and Prepared.

CAR (chimeric antigen receptor) T cells (CARTs) are genetically engineered T cells that express CARs, with impressive clinical activity in relapsed and refractory hematologic malignancies, primarily acute lymphoblastic leukemia and diffuse large B-cell lymphoma. The most frequent life-threatening adverse events after CART infusion are cytokine release syndrome and CAR-related encephalopathy syndrome, which can occur within hours or days after administration. IL-6 released by macrophages and monocytes plays a major role in the pathogenesis of cytokine release syndrome and CAR-related encephalopathy syndrome, and IL-6 blockade and steroids contribute to fast resolution of symptoms. Critical care management plays an important role in patients receiving CARTs, as up to half of patients might need an admission to the ICU and lifesaving interventions. As new treatment indications and CART constructs enter the clinic, the number of patients requiring ICU admission will rapidly increase, with profound consequences for the use of ICU resources, training requirements, clinical expertise, multidisciplinary collaboration, and hospital organization. Research is also needed to validate at large scale biomarkers that allow doctors to risk-stratify patients for both their risk to develop severe toxicity and their likelihood to respond to therapy.

Significance of NUDT15 gene in individualized treatment with 6-mercaptopurine in children with acute lymphoblastic leukemia.

As an important drug during maintenance treatment of acute lymphoblastic leukemia (ALL), 6-mercaptopurine (6-MP) has several side effects, including hepatotoxicity and bone marrow suppression. Since its tolerability varies from person to person, 6-MP treatment should be individualized. The deficiency of thiopurine methyltransferase (TPMT) enzyme activity is associated with 6-MP intolerance. There is a lower frequency of mutation in TPMT alleles among Asian patients. Recent studies have shown that in ALL patients with NUDT15 gene mutation, the maximum tolerated dose of 6-MP is lower than the conventional dose. The article reviews the significance of NUDT15 gene in individualized treatment with 6-MP in children with ALL. 6-巯基嘌呤（6-MP）是急性淋巴细胞白血病（ALL）维持治疗阶段的重要药物，其副作用包括肝毒性和骨髓抑制，不同个体对6-MP的耐受差异较大，6-MP治疗需个体化。巯嘌呤甲基转移酶（TPMT）活性缺乏与6-MP不耐受具有相关性。但亚洲患者TPMT等位基因的突变频率较低。近来发现存在NUDT15基因突变的ALL患者6-MP耐受剂量低于常规剂量。该文就NUDT15基因型对ALL患儿6-MP个体化治疗的影响进行综述。

Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

With the introduction of tyrosine kinase inhibitors (TKIs) in the management of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL), the prognosis of patients has improved dramatically. Currently, the standard of care in the frontline setting for fit patients is TKI in combination with chemotherapy. Age-adjusted chemotherapy or corticosteroids alone have been used with TKIs in elderly patients with comorbidities with modest long-term benefit. The primary goal of treatment is the achievement of early deep molecular remission as the achievement of complete molecular remission (CMR) at 3 months has been demonstrated to be predictive of higher long-term survival. The probability of attaining this goal by a more potent TKIs like dasatinib or ponatinib is higher, thus we recommend the use of second- or third-generation TKIs over imatinib. Clinicians should be aware of possible fatal cardiovascular events mainly related to ponatinib. Allogeneic hematopoietic stem cell transplantation (alloHSCT) should still be considered in first remission, especially for younger patients treated with imatinib combination therapy. A subset of patients achieving CMR at 3 months may be able to continue consolidation and maintenance with chemotherapy and TKI without the need for alloHSCT. Because of higher risk of relapses in the central nervous system, intrathecal chemoprophylaxis is mandatory for all patients. New strategies incorporating novel agents, such as antibody-drug conjugates, bispecific monoclonal antibodies, potent TKIs, and CAR T cells are under investigation.

Identification of novel lncRNAs involved in the pathogenesis of childhood acute lymphoblastic leukemia.

This study aimed to explore novel long non-coding RNAs (lncRNAs) and the underlying mechanisms involved in childhood acute lymphoblastic leukemia (cALL). The GSE67684 dataset was downloaded from the Gene Expression Omnibus. Differentially expressed genes (DEGs) and lncRNAs (DELs) between Days 0, 8, 15 and 33 were isolated using random variance model corrective analysis of variance. Overlapping DEGs and DELs were clustered using Cluster 3.0. Bio-functional enrichment analysis was performed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Interactions between lncRNAs and mRNAs were calculated using dynamic simulations, and interactions among mRNAs were predicted using the STRING database. lncRNA-mRNA and protein-protein interaction (PPI) networks were visualized using Cytoscape. Subsequently, the expression levels of lncRNAs in biological samples from children with or without cALL were validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A total of 593 overlapping DEGs and 21 DELs were identified. After clustering, Profile 26 exhibited a continuously increasing temporal trend, whereas Profile 1 exhibited a continuous decreasing trend. Upregulated DEGs were significantly enriched in 1,825 GO terms and 166 KEGG pathways, whereas downregulated DEGs were significantly enriched in 196 GO terms and 90 KEGG pathways. The lncRNAs NONHSAT027612.2 and NONHSAT134556.2 were the top two regulators in the lncRNA-mRNA network. Toll-like receptor 4, cathepsin G, nucleotide-binding oligomerization domain containing 2 and cathepsin S may be considered the hub genes of the PPI network. RT-qPCR results indicated that the expression levels of the lncRNAs NONHSAT027612.2 and NONHSAT134556.2 were significantly elevated in the blood and bone marrow of patients with cALL compared with the controls. In conclusion, the lncRNAs NONHSAT027612.2 and NONHSAT134556.2 may serve important roles in the pathogenesis of cALL via regulating immune response-associated pathways.

The proportion of different BCR-ABL1 transcript types in chronic myeloid leukemia. An international overview.

There are different BCR-ABL1 fusion genes that are translated into proteins that are different from each other, yet all leukemogenic, causing chronic myeloid leukemia (CML) or acute lymphoblastic leukemia. Their frequency has never been systematically investigated. In a series of 45503 newly diagnosed CML patients reported from 45 countries, it was found that the proportion of e13a2 (also known as b2a2) and of e14a2 (also known as b3a2), including the cases co-expressing e14a2 and e13a2, was 37.9% and 62.1%, respectively. The proportion of these two transcripts was correlated with gender, e13a2 being more frequent in males (39.2%) than in females (36.2%), was correlated with age, decreasing from 39.6% in children and adolescents down to 31.6% in patients ≥ 80 years old, and was not constant worldwide. Other, rare transcripts were reported in 66634561 patients (1.93%). The proportion of rare transcripts was associated with gender (2.27% in females and 1.69% in males) and with age (from 1.79% in children and adolescents up to 3.84% in patients ≥ 80 years old). These data show that the differences in proportion are not by chance. This is important, as the transcript type is a variable that is suspected to be of prognostic importance for response to treatment, outcome of treatment, and rate of treatment-free remission.

Treatment of two cases on the same day of intrathecal methotrexate overdose using cerebrospinal fluid exchange and intrathecal instillation of carboxypeptidase-G2.

Two 14-year old boys with acute lymphocytic leukemia were treated according to the NOPHO-ALL-08 protocol with intrathecal methotrexate (MTX) on the same day. Due to a preparation error in the hospital pharmacy, they were both given 240 mg of MTX instead of the prescribed 12 mg. Treatment (or methods) Both patients developed acute neurotoxicity with confusion, pain and seizures. Intravenous dexamethasone and folinic acid (leucovorin) was given. Exchange of cerebrospinal fluid was performed. Intrathecal glucarpidase (carboxypeptidase-G2) was administered after 11 h. One patient developed a toxic arachnoiditis. Three years after the incident, one patient has no neurological or neuropsychological sequelae after the overdose, while the other reports some loss of short-term memory. Fast recognition and treatment of intrathecal MTX overdose is critical to survival and outcome. Efforts to prevent such overdoses are of vital importance.

Population pharmacokinetics of lenalidomide in patients with B-cell malignancies.

Lenalidomide is an immunomodulatory imide drug used broadly in the treatment of multiple myeloma and lymphoma. It continues to be evaluated in chronic lymphocytic leukaemia (CLL) at lower doses due to dose-related toxicities including tumour flare and tumour lysis syndrome. This study aimed to develop a population pharmacokinetic model for lenalidomide in multiple cancers, including CLL, to identify any disease-related differences in disposition. Lenalidomide concentrations from 4 clinical trials were collated (1999 samples, 125 subjects), covering 4 cancers (multiple myeloma, CLL, acute myeloid leukaemia and acute lymphoblastic leukaemia) and a large dose range (2.5-75 mg). A population pharmacokinetic model was developed with NONMEM and patient demographics were tested as covariates. The data were best fitted by a 1-compartment kinetic model with absorption described by 7 transit compartments. Clearance and volume of distribution were allometrically scaled for fat-free mass. The population parameter estimates for apparent clearance, apparent volume of distribution and transit rate constant were 12 Lh (10.8-13.6), 68.8 L (61.8-76.3), and 13.5 h This is the first report of a lenalidomide population pharmacokinetic model to evaluate lenalidomide pharmacokinetics in patients with CLL and compare its pharmacokinetics with other B-cell malignancies. As no differences in pharmacokinetics were found between the observed cancer-types, the unique toxicities observed in CLL may be due to disease-specific pharmacodynamics.

Approaches for generation of anti-leukemia specific T cells.

As three decades ago, it was reported that adoptive T cell immunotherapy by infusion of autologous tumor infiltrating lymphocytes (TILs) mediated objective cancer regression in patients with metastatic melanoma. A new era of T cell immunotherapy arose since the improvement and clinical use of anti-CD19 chimeric antigen receptor T cells (CAR-T) for the treatment of refractory and relapsed B lymphocyte leukemia. However, several challenges and difficulties remain on the way to reach generic and effective T cell immunotherapy, including lacking a generic method for generating anti-leukemia-specific T cells from every patient. Here, we summarize the current methods of generating anti-leukemia-specific T cells, and the promising approaches in the future.

The journey to CAR T cell therapy the pediatric and young adult experience with relapsed or refractory B-ALL.

Outcomes of pediatric and young adult patients diagnosed with acute lymphoblastic leukemia (ALL) have improved significantly in the past few decades. Treatment advances have provided 5-year survival rates ranging from 78 to 91% depending on the age at diagnosis. However, approximately 2-3% of patients will present with refractory disease that is unresponsive to chemotherapy, and 10-15% of patients will relapse. Outcomes post-relapse show significantly reduced 5-year survival rates that continue to decrease with each subsequent relapse. Despite our increased understanding of risk factors and disease predictors, treatment strategies for patients with relapsed or refractory (rr) disease, including variations of chemotherapy and stem cell transplant, remain ineffective for many patients. To improve outcomes of patients with rr disease, immunotherapies targeting specific B cell antigens are being developed. Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy recently approved by the US Food and Drug Administration for patients with refractory leukemia or those with second or later relapse. In this treatment strategy, a patients own T cells are transduced to express an anti-CD19 CAR that, when reintroduced into the patient, directs specific binding and killing of CD19 B cells. In a phase 2, single-arm, multicenter, global study, tisagenlecleucel resulted in a remission rate of 81% in pediatric and adolescent patients with rr B cell ALL. This review article summarizes four typical cases of pediatric and adolescent rr B-cell ALL, focusing on the patients journey from initial diagnosis to treatment with CAR T cell therapy.

NUP214 in Leukemia Its More than Transport.

NUP214 is a component of the nuclear pore complex (NPC) with a key role in protein and mRNA nuclear export. Chromosomal translocations involving the

Targeting PI3K Signaling in Acute Lymphoblastic Leukemia.

Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stroma cells triggers intracellular signals regulating cell-adhesion-mediated drug resistance (CAM-DR). Stromal cell protection of ALL cells has been shown to require active AKT. In chronic lymphocytic leukemia (CLL), adhesion-mediated activation of the PI3KAKT pathway is reported. A novel FDA-approved PI3Kδ inhibitor, CAL-101idelalisib, leads to downregulation of p-AKT and increased apoptosis of CLL cells. Recently, two additional PI3K inhibitors have received FDA approval. As the PI3KAKT pathway is also implicated in adhesion-mediated survival of ALL cells, PI3K inhibitors have been evaluated preclinically in ALL. However, PI3K inhibition has yet to be approved for clinical use in ALL. Here, we review the role of PI3K in normal hematopoietic cells, and in ALL. We focus on summarizing targeting strategies of PI3K in ALL.

Black Phosphorus-Based Drug Nanocarrier for Targeted and Synergetic Chemophotothermal Therapy of Acute Lymphoblastic Leukemia.

As one of the novel two-dimensional nanomaterials, black phosphorus nanosheets (BP NS) have been proven to be excellent carrier materials for drugs, owing to their fine optical properties and biocompatibility. In this work, a composite drug nanocarrier based on BP NS is proposed, which can perform a synergetic and targeted chemophotothermal therapy of acute lymphoblastic leukemia (ALL). First, BP NS were prepared by an improved liquid exfoliation technique. Then, polyethylene glycol (PEG) was modified on the surfaces of BP NS through electrostatic adsorption. Drug molecules can also be loaded onto the BP NS via electrostatic adsorption. The PEG layer can effectively protect the interior BP NS from water and air to enhance their physiological stability. The obtained PEGylated BP NS (BP NSPEG) not only demonstrated an excellent photothermal conversion efficiency and photothermal stability but also exhibited a good pH and photothermal dual-responsive drug release behavior. In addition, the BP NSPEG were further modified with Sgc8 aptamers through covalent bonding. The aptamers provided an efficient specificity toward ALL cells (CCRF-CEM) and greatly increased the endocytosis of the nanocarriers through a receptor-mediated manner, which can further improve the therapeutic effect. Hence, the presented BP NS-based multifunctional nanocarrier can achieve a targeted and synergetic chemophotothermal therapy of ALL, which shows a promising potential in improving the curative efficiency.

Thromboembolism in children with cancer a retrospective multicenter study in Korea.

Thromboembolism (TE) is a major cause of morbidity and mortality in adult cancer patients however, there is a lack of sufficient knowledge on TE in pediatric cancer patients. We aimed to determine the epidemiology of TE in Korean children with cancer. Between January 2000 and July 2015, we retrospectively analyzed pediatric patients newly diagnosed with cancer at six tertiary hospitals in Korea. Of 3611 children with cancer, 33 (0.91%) had TE. A higher number of patients with acute lymphoblastic leukemia (n 13), brain tumors (n 6), lymphoma (n 4), and bonesoft tissue sarcomas (n 5) tended to develop TE. The malefemale ratio was 1716, and the median age at TE diagnosis was 10 years and 2 months. TE was detected a median of 2 months after cancer diagnosis. Symptoms including pain and swelling were present in 18 of the 33 patients. In terms of location, three intracerebral, 23 upper venous, six lower venous and one combined upper and lower venous system TEs were observed. Additional risk factors for TE included central venous catheter (CVC) use in 12 patients, steroid andor L-asparaginase use in nine, and CVC and steroid andor L-asparaginase use in seven. The TE incidence rate was quite low among Korean children with cancer, but higher than in the general pediatric population and among children hospitalized for diseases other than cancer. Further investigation of a larger pool of patients is warranted to determine the most effective strategies to prevent and treat TE in Korean children with cancer.

Industrys Giant Leap Into Cellular Therapy Catalyzing Chimeric Antigen Receptor T Cell (CAR-T) Immunotherapy.

We describe the significant technological leap from bench to bedside that was achieved through a strong academic-industry collaboration between dedicated clinicians and researchers at the University of Pennsylvania, the Childrens Hospital of Philadelphia, and Novartis to commercialize the chimeric antigen receptor T cell (CAR-T) therapy tisagenlecleucel (CTL019 Kymriah® Novartis Pharma AG, Basel, Switzerland). Tisagenlecleucel was the first CAR-T therapy and the first gene therapy to receive US Food and Drug Administration approval in 2017, with an initial indication for pediatric and young adult patients with relapsed or refractory (rr) acute lymphoblastic leukemia, followed by approval in May 2018 for a second indication in adult patients with rr diffuse large B cell lymphoma. Subsequent approvals in the European Union, Switzerland, and Canada soon followed. The tisagenlecleucel success story represents the development and commercialization of a first-of-its-kind personalized cellular therapy with a manufacturing process that supports commercial production and ongoing global clinical trials in a growing number of countries.

Cytokine Release Syndrome With the Novel Treatments of Acute Lymphoblastic Leukemia Pathophysiology, Prevention, and Treatment.

T cell-based therapies (blinatumomab and CAR T cell therapy) have produced unprecedented responses in relapsed and refractory (rr) acute lymphoblastic leukemia (ALL) but is accompanied with significant toxicities, of which one of the most common and serious is cytokine release syndrome (CRS). Here we will review the pathophysiology, prevention, and treatment of CRS. Efforts have been initiated to define and grade cytokine release syndrome (CRS), to identify patients at risk, to describe biomarkers that predict onset and severity, to understand the pathophysiology, and to prevent and treat severe cases to reduce T cell immunotherapy-related morbidity and mortality. Optimizing the timing of T cell-based therapies in ALL, identifying new biomarkers, and investigating novel anti-cytokine agents that have anti-CRS activity are likely to be fruitful avenues of study.

Author Correction Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia.

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article the PDF version was correct at the time of publication.

Impact of IgG Monitoring and IVIG Supplementation on the Frequency of Febrile Illnesses in Pediatric Acute Lymphoblastic Leukemia Patients Undergoing Maintenance Chemotherapy.

Monitoring serum immunoglobulin G (IgG) levels in pediatric oncology patients and treating subtherapeutic levels with intravenous immunoglobulin (IVIG) may prevent infections however, evidence is limited. This retrospective study assessed pediatric acute lymphoblastic leukemia patients diagnosed 2006 to 2011 to evaluate if monitoringsupplementing IgG would reduce febrile illnesses during maintenance chemotherapy. A subject was categorized as ever IgG monitored if they had ≥1 IgG levels checked and their risk days were stratified into not IgG monitored days and IgG monitored days. IgG monitored days were further stratified into IgG monitored with IVIG supplementation, monitored with no IVIG supplementation (IgG level >500 mgdL) and monitored with no IVIG supplementation days (IgG level <500 mgdL). Generalized linear mixed effects poisson models were used to compare events (febrile episode, positive blood culture, and febrile upper respiratory infection rates among these groups. In 136 patients, the febrile episode rate was higher in the ever IgG monitored cohort than the never monitored cohort (5.26 vs. 3.78 episodes1000 d). Among monitored patients, IVIG monitoring and supplementation did not significantly impact the febrile episode, febrile upper respiratory infection, or the positive blood culture rates. These data suggest that monitoringsupplementing low IgG is not indicated for infection prophylaxis in acute lymphoblastic leukemia patients during maintenance chemotherapy.

Improved Outcome of Newly Diagnosed Childhood Mature B-Cell LymphomaLeukemia With High Tumor Burden Treated With BFM95-based Protocol Combining Rituximab A Report From Shanghai, China.

In this study we evaluated children with newly diagnosed advanced (stage III and stage IV) mature B-cell non-Hodgkin lymphoma (B-NHL) or mature B-cell acute leukemia (B-AL), who were treated with Berlin-Frankfurt-Münster (BFM)95-based protocol combined with rituximab (RBFM95). Our study recruited 46 patients who were treated with BFM95 protocol combined with rituximab. There are 23 patients as the historical control treated with BFM90 protocol. Compared with patients treated with BFM90 protocol, the 5-year event-free survival (EFS) rate of patients under RBFM95 was higher (83.7%±5.7% vs. 69.6%±9.6% P0.1062). Among subgroups of our patients, the 5-year EFS of patients with stage III was 87.3%±6.1% vs. 77.8%±9.8% (P0.2998), stage IVB-AL was 72.7%±13.4% versus 40.0%±21.9% (P0.0878) between patients treated with RBFM95 and BFM90, respectively. Among patients whose lactate dehydrogenase (LDH) level were <500 UL at diagnosis, RBFM95 protocol reached 100% survival, nevertheless the 5-year EFS of patients in this group was not statistically different from that of patients treated with BFM90 (92.3%±7.4% P0.2994). Among patients had LDH≥500 UL at diagnosis, the 5-year EFS in RBFM95 group was 77.2%±7.7% (32 patients) and significantly higher than that of BFM90 group (40.0%±15.5%, 10 patients P0.0048). We found that rituximab has improved the EFS of childhood B-NHLB-AL with LDH≥500UL. Our results require validation from future studies with large cohort.

Purtscher-like retinopathy A rare presentation of hematopoietic stem cell transplant-associated thrombotic microangiopathy.

Hematopoietic stem cell transplant (HSCT)-associated (TA) thrombotic microangiopathy (TMA) is an acquired disorder and a potentially life-threatening complication after allogeneic HSCT. TA-TMA causes endothelial damage and results in micro-thrombi in capillaries and arterioles. Early detection and treatment of complications associated with TA-TMA might improve outcomes. Purtscher-like retinopathy (PLR) is associated with micro-thrombi that occlude the retinal arteries and cause retinal injury. PLR has been associated with multiple entities, including HUS and TTP, but has not previously been described in the setting of TA-TMA. Here, we describe an 18-year-old male who underwent a mismatched unrelated donor HSCT for relapsed acute lymphoblastic leukemia. The patient was diagnosed with TA-TMA based on standard defined criteria. He presented with acute onset of blurred vision with findings of multiple white retinal patches, retinal hemorrhages, and macular edema, thought initially to be hypertensive retinopathy. However, on further evaluation using fluorescein angiography and optical coherence tomography, the diagnosis was determined to be PLR. The patient was treated with intravitreal steroid injections (triamcinolone acetonide) with dramatic improvement of vision. The aim of this report is to make clinicians aware of PLR as a potential ocular complication associated with TA-TMA and that prompt intervention might reverse visual impairment.

Effects of GST null genotypes on individual susceptibility to leukemia A meta-analysis.

Whether glutathione S-transferases (GST) null genotypes influence individual susceptibility to leukemia remains controversial. Thus, we performed this meta-analysis to better analyze potential influences of GST null genotypes on individual susceptibility to leukemia. Literature retrieve was conducted in PubMed, Web of Science and Embase. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Totally fifty-one studies were enrolled for analyses. Significant associations with elevated individual susceptibility to leukemia were detected for GSTM1 (p < .0001, OR 1.28, 95%CI 1.16-1.41), GSTP1 (p .003, OR 1.22, 95%CI 1.07-1.40) and GSTT1 (p < .0001, OR 1.53, 95%CI 1.35-1.74) null genotypes in overall analyses. Further subgroup analyses by type of disease revealed that GSTM1, GSTP1 and GSTT1 null genotypes were all significantly associated with elevated individual susceptibility to acute lymphoblastic leukemia, GSTM1 and GSTT1 null genotypes were significantly associated with elevated individual susceptibility to acute myeloid leukemia, and GSTT1 null genotype was also significantly associated with elevated individual susceptibility to chronic leukemia. When we stratified data according to ethnicity of participants, positive results were found for all investigated variants in Caucasians and West Asians. Additionally, GSTM1 null genotype was also significantly correlated with elevated individual susceptibility to leukemia in East Asians. Our findings indicated that GSTM1, GSTT1 and GSTP1 null genotypes might serve as potential genetic biomarkers of leukemia in certain ethnicities.

Epigenetic Silencing Affects l-Asparaginase Sensitivity and Predicts Outcome in T-ALL.

Biological explanation for discrepancies in patient-related response to chemotherapy depending on the underlying oncogenic events is a promising research area. TLX1- or TLX3-deregulated T-cell acute lymphoblastic leukemias (T-ALL TLX13 We compared TLX1 We show that TLX1 We conclude that

A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia results of CALGB 10403.

Retrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Childrens Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled 295 were eligible and evaluable for response. Median age was 24 years (range, 17-39 years). Use of the pediatric regimen was safe overall treatment-related mortality was 3%, and there were only 2 postremission deaths. Median event-free survival (EFS) was 78.1 months (95% confidence interval CI, 41.8 to not reached), more than double the historical control of 30 months (95% CI, 22-38 months) 3-year EFS was 59% (95% CI, 54%-65%). Median overall survival (OS) was not reached. Estimated 3-year OS was 73% (95% CI, 68%-78%). Pretreatment risk factors associated with worse treatment outcomes included obesity and presence of the Philadelphia-like gene expression signature. Use of a pediatric regimen for AYAs with ALL up to age 40 years was feasible and effective, resulting in improved survival rates compared with historical controls. CALGB 10403 can be considered a new treatment standard upon which to build for improving survival for AYAs with ALL. This trial was registered at www.clinicaltrials.gov as NCT00558519.

PIM inhibitor SMI-4a induces cell apoptosis in B-cell acute lymphocytic leukemia cells via the HO-1-mediated JAK2STAT3 pathway.

The serinethreonine PIM protein kinases are critical regulators of tumorigenesis in multiple cancers. However, whether PIMs are potential therapeutic targets for treating B-cell acute lymphocytic leukemia (B-ALL) remains unclear. Therefore, here, PIM expression was detected in B-ALL patients and the effects of SMI-4a, a pan-PIM small molecule inhibitor, were investigated in B-ALL cells. PIM1 and PIM2 expression in 26 newly diagnosed B-ALL cases was detected by real-time PCR and Western blot. B-ALL cells were treated with varied SMI-4a doses and the viability of treated cells was investigated using a cell-counting kit-8 (CCK-8) assay. Apoptosis and cell cycles were analyzed by flow cytometry. Western blot analysis was then used to explore the expression of apoptosis-related proteins and the JAK2STAT3 pathway. PIM1 and 2 were overexpressed in B-ALL patients with high HO-1 level. SMI-4a induced decreases in PIMs and HO-1 expressions and inhibited B-ALL cell viability. Treatment with SMI-4a induced apoptosis by downregulating Bcl-2, upregulating Bax and other antiapoptotic proteins, and decreasing protein levels of p-JAK2 and p-STAT3. In addition, upregulation of HO-1 alleviated decrease in p-JAK2 and p-STAT3 expression, reduced SMI-4a-induced apoptosis of B-ALL cells, and influenced B-ALL cell survival. PIMs were highly expressed in B-ALL patients. SMI-4a inhibited B-ALL proliferation and induced apoptosis via the HO-1-mediated JAK2STAT3 pathway. SMI-4a might be applicable for treatment of B-ALL cells.

Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia A Retrospective Multinational Study.

We determined the prognostic factors and utility of allogeneic hematopoietic cell transplantation among children with newly diagnosed hypodiploid acute lymphoblastic leukemia (ALL) treated in contemporary clinical trials. This retrospective study collected data on 306 patients with hypodiploid ALL who were enrolled in the protocols of 16 cooperative study groups or institutions between 1997 and 2013. The clinical and biologic characteristics, early therapeutic responses as determined by minimal residual disease (MRD) assessment, treatment with or without MRD-stratified protocols, and allogeneic transplantation were analyzed for their impact on outcome. With a median follow-up of 6.6 years, the 5-year event-free survival rate was 55.1% (95% CI, 49.3% to 61.5%), and the 5-year overall survival rate was 61.2% (95% CI, 55.5% to 67.4%) for the 272 evaluable patients. Negative MRD at the end of remission induction, high hypodiploidy with 44 chromosomes, and treatment in MRD-stratified protocols were associated with a favorable prognosis, with a 5-year event-free survival rate of 75% (95% CI, 66.0% to 85.0%), 74% (95% CI, 61.0% to 89.0%), and 62% (95% CI, 55.0% to 69.0%), respectively. After exclusion of patients with high hypodiploidy with 44 chromosomes and adjustment for waiting time to transplantation and for covariables in a Poisson model, disease-free survival did not differ significantly ( P .16) between the 42 patients who underwent transplantation and the 186 patients who received chemotherapy only, with an estimated 5-year survival rate of 59% (95% CI, 46.5% to 75.0%) versus 51.5% (95% CI, 44.7% to 59.4%), respectively. Transplantation produced no significant impact on outcome compared with chemotherapy alone, especially among the subgroup of patients who achieved a negative MRD status upon completion of remission induction. MRD-stratified treatments improved the outcome for children with hypodiploid ALL. Allogeneic transplantation did not significantly improve outcome overall and, in particular, for patients who achieved MRD-negative status after induction.

Evaluation of the Incidence of Hematologic Malignant Neoplasms Among Breast Cancer Survivors in France.

Breast cancer survivors are at an increased risk of developing certain types of hematologic malignant neoplasm after diagnosis. To estimate the incidence of various types of hematologic malignant neoplasm in breast cancer survivors, both in absolute terms and in association with the general population. This nationwide cohort study conducted in France used data from the French National Health Data System, a database that contains all of French residents health-related expenses. All French women aged 20 to 85 years with an incident breast cancer diagnosis between July 1, 2006, and December 31, 2015, were included (n 439 704) and followed up until hematologic malignant neoplasm occurrence, death, loss of follow-up, or December 31, 2016, whichever came first. Comparisons were made with all French women in the general population who were registered in the French general health insurance program each year from January 1, 2007, and December 31, 2016. Data analysis was performed from January 23, 2018, to May 25, 2018. Main outcomes were incident hematologic malignant neoplasm cases occurring at least 6 months after breast cancer diagnosis. The various types of hematologic malignant neoplasm considered were acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), multiple myeloma (MM), Hodgkin lymphoma or non-Hodgkin lymphoma (HLNHL), and acute lymphoblastic leukemia or lymphocytic lymphoma (ALLLL). Incidence of these various types was estimated among breast cancer survivors and compared with the incidence in women in the general population. The 439 704 women in the study had a median (interquartile range IQR) age of 59 (50-69) years and were followed up for a median (IQR) duration of 5 (2.8-7.5) years. Overall, 3046 cases of hematologic malignant neoplasm occurred 509 cases (16.7%) of AML (crude incidence rate CIR per 100 000 person-years, 24.5 95% CI, 22.4-26.8), 832 cases (27.3%) of MDS (CIR, 40.1 95% CI, 37.4-42.9), and 267 cases (8.8%) of MPN (CIR, 12.8 95% CI, 11.4-14.5). Lymphoid neoplasm cases included 420 cases (13.8%) of MM (CIR, 20.3 95% CI, 18.4-22.3), 912 cases (29.9%) of HLNHL (CIR, 44.4 95% CI, 41.1-50.0), and 106 cases (3.5%) of ALLLL (CIR, 5.1 95% CI, 4.2-6.2). Compared with the general population, breast cancer survivors had statistically significantly higher incidence of AML (standardized incidence rate ratio SIRR, 2.8 95% CI, 2.5-3.2) and MDS (SIRR, 5.0 95% CI, 4.4-5.7) and, to a lesser extent, MM (SIRR, 1.5 95% CI, 1.3-1.7) and ALLLL (SIRR, 2.0 95% CI, 1.3-3.0). The finding that AML and MDS still occur among breast cancer survivors today, and that ALLLL and MM may also be of concern, merits the continuous monitoring of hematologic malignant neoplasms and the thorough investigations into their underlying mechanisms.

Validation of an instrument to measure the quality of life in children with oropharyngeal mucositis undergoing cancer treatment.

Oropharyngeal mucositis (OM) is one of the primary complications arising during oncological treatment, which significantly reduces the patients quality of life (QoL). The aim of this study was to translate, culturally adapt, and validate the use of a new Spanish version of the Oropharyngeal Mucositis-Specific Quality-of-Life instrument (OMQoL) for pediatric patients. A multicentric, cross-sectional validation study was conducted to translate and adapt OMQoL from English to Spanish for its use by children with OM aged 8-16 years. Reliability was measured using Cronbachs alpha content and construct validity, in conjunction with exploratory factor analysis. The convergent validity, with the correlations of the scales for OM defined by the WHO, OMAS (Oropharingeal Mucositis Assessment Scale) and the PedsQL-3 cancer module in Spanish. One hundred and ninety-three children with mean age of 10.91 ± 2.38 years participated in the study, out of which 101 (52.3%) were females. In this sample, 80 children (41.5%) suffered from acute lymphoblastic leukemia and 111 (57.5%) had grade 2 and 3 OM. The factorial analysis resulted in four dimensions with loads >0.40. Among the 31 items of the OMQoL, six were eliminated. Cronbach alpha of OMQoL-Spanish was 0.954. Spearman´s correlations (r) with the OMS and OMAS scales were significant (with r -0.720 and r -0.689 p < 0.01, respectively). Moderate correlation was observed with the PedsQL-3 cancer module (r 0.426 p < 0.01). OMQoL-Spanish demonstrated adequate psychometric properties, resulting in a reliable and valid instrument for measuring QoL in children with MO. La mucositis orofaríngea (MO) es una de las principales complicaciones del tratamiento oncológico que reduce significativamente la calidad de vida (CV) del paciente. El objetivo fue traducir, adaptar de manera cultural y validar una nueva versión en español del instrumento Oropharyngeal Mucositis–Specific Quality-of-Life (OMQoL) en pacientes pediátricos. Estudio transversal de validación, multicéntrico, realizado para la traducción y adaptación del OMQoL del inglés al español en pacientes de entre 8 y 16 años con MO. Se midió la confiabilidad mediante el Alfa de Cronbach la validez del contenido y el constructo, con un análisis factorial exploratorio y la validez convergente, con las correlaciones de las escalas para MO de la Organización Mundial de la Salud (OMS), la Oropharingeal Mucositis Assessment Scale (OMAS) y con el Pediatric Quality of Life-3 (PedsQL-3) módulo cáncer en español. Participaron en el estudio 193 niños con una media de edad de 10.91 ± 2.38 años, de los cuales 101 (52.3%) fueron de sexo femenino. En esta muestra, 80 niños (41.5%) presentaron leucemia aguda linfoblástica y 111 (57.5%) presentaron MO grado 2 y 3. El análisis factorial resultó con cuatro dimensiones con cargas > 0.40. De los 31 ítems del OMQoL, seis fueron eliminados. El Alfa de Cronbach del OMQoL español fue de 0.954. Las correlaciones de Spearman (r) con las escalas de la OMS y OMAS fueron significativas (r −0.720 y r −0.689 p<0.01, respectivamente) con el PedsQL-3 módulo cáncer existió una moderada correlación (r 0.426 p < 0.01). La nueva versión del OMQoL en español demostró propiedades psicométricas adecuadas, y resulta un instrumento confiable y válido para medir la CV en niños con MO.

Hematopoietic Cell Transplantation in Young Adult Acute Lymphoblastic Leukemia A United States Population-Level Analysis.

In this population-based evaluation of adolescents and young adults (AYA) acute lymphoblastic leukemia (ALL), we describe patterns of care (POC) and outcomes regarding hematopoietic cell transplantation (HCT) in first complete remission (CR1). Data were abstracted from the 2013 United States Surveillance, Epidemiology, and End Results POC study newly diagnosed AYA ALL were included. Multivariable logistic regression evaluated associations with HCT in CR1 Cox proportional hazards regression evaluated survival associations. Of 399 AYAs with ALL included, 102 (28.5%) underwent HCT in CR1. High-risk cytogenetics (odds ratio OR 4.86, 95% confidence interval CI 3.02-7.83) and hyper-cyclophosphamide, vincristine, adriamycin, and dexamethasone (CVAD) induction (OR 1.84, 95% CI 1.07-3.16) were associated with HCT in CR1. Two-year cumulative incidence of relapse, relapse-free survival (RFS), and overall survival (OS) of the entire cohort were 28.3% (95% CI 23.4-33.4), 69.3% (95% CI 63.6-74.3%), and 84.1% (95% CI 79.7-87.5), respectively. Two-year RFS was significantly higher in patients receiving CR1 HCT relative to chemotherapy (83.6%, 95% CI 72.6-90.5% vs. 64.3%, 95% CI 57.5-70.3), but no difference was seen in 2-year OS (88.9%, 95% CI 80.8-93.7 vs. 82.5%, 95% CI 77.2-86.7). Treatment at a nonteaching hospital was independently associated with inferior OS (hazard ratio 2.15, 95% CI 1.23-3.76). Although the ALL landscape is changing, these data provide a snapshot of the use and outcomes of HCT for AYA ALL across the United States.

Utility of 18-fluorodeoxyglucose positron emission tomography in children with relapsedrefractory leukemia.

Few data are available on the clinical significance of 18-fluorodeoxyglucose positron emission tomography (FDG-PETCT) results in patients with leukemia. We investigated the utility of FDG-PETCT at the time of relapsedrefractory disease in pediatric patients with leukemia. Medical records of 28 children with suspected leukemia progression or recurrence duringafter chemotherapy or allogeneic stem cell transplantation (allo-SCT) were retrospectively reviewed to determine the utility of FDG-PETCT. Twenty-two of the 28 patients have documented abnormal imaging findings during clinical follow-up, while six had were interpreted as not demonstrating signal consistent with active leukemia. Of the 22 patients with abnormal FDG-PETCT studies 14 were found to have FDG-PETCT reported as consistent with active leukemia and increased leukemia blasts on bone marrow biopsy. Regarding the eight patients without positive FDG-PETCT and proven leukemia relapse, four had discordant findings on FDG-PETCT and biopsy, and four had FDG-PETCT reported as infection. Mean maximum standardized uptake values (SUVmax) were significantly higher among patients whose FDG-PETCT findings were positive for leukemia as opposed to infectious disease (p < .05). Mean SUVmax was also significantly higher among patients with multifocal lesions on FDG-PETCT than among those with diffuse lesions (p < .05). The findings suggest that FDG-PETCT may be a complementary imaging modality that could be combined with bone marrow examination to improve detection of subtle leukemic infiltration in children with suspected leukemia progression or recurrence after chemotherapy or allo-SCT.

Case report of granular acute lymphoblastic leukemia and review of the literature.

Granular acute lymphoblastic leukemia (ALL) is a rare variant of the disease that is associated with a lower remission rate to standard induction chemotherapy. Flow immunophenotyping, cytogenetics, and molecular diagnostics should be utilized to confirm the diagnosis of ALL versus acute myeloid leukemia (AML) in order to provide appropriate management.

Variation of nicotinic subtype α7 and muscarinic subtype M3 acetylcholine receptor expression in three main types of leukemia.

Cholinergic receptors, such as α7-nicotinic acetylcholine receptor (α7-nAChR) and M3-muscarinic acetylcholine receptor (M3-mAChR), have been demonstrated to serve a significant role in the proliferation, differentiation and apoptosis of leukemic cells. However, the expression of these receptors in samples from patients with leukemia remains unclear. The present study aimed to determine the expression of M3-mAChR and α7-nAChR in the bone marrow or peripheral blood of 51 patients with leukemia, including acute myeloid leukemia (AML n33), acute lymphoblastic leukemia (ALL n13), and chronic myeloid leukemia (CML n5). Peripheral blood mononuclear cells (PBMCs) were also isolated from healthy subjects (n5) for comparison. Western blot analysis was performed to determine the protein expression profiles, and a pattern of decreased α7-nAChR levels in patients with leukemia was observed. Among the leukemia types, the lowest expression of α7-nAChR and M3-mAChR were identified in patients with T-cell ALLlymphoma (T-ALL). CML exhibited the highest level of M3-mAChR, which was significantly different from APL and AML-M4, yet not from healthy subjects (P<0.05). Therefore, different expression profiles of α7-nACR and M3-mAChR were detected amongst the leukemia types. Collectively, the present study supports the potential role of cholinergic signaling in mediating leukemogenesis. However, further studies in larger cohorts are required to validate these findings.

Class I and II human leukocyte antibodies in pediatric haploidentical allograft candidates prevalence and risk factors.

Donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) were associated with graft failure (GF) following haploidentical stem cell transplantation (Haplo-HSCT). The prevalence and risk factors of DSAs in pediatric candidates remain to be determined. In a prospective trial (ChiCTR-OPC-15006672), 486 children with hematological diseases were enrolled to screen for the presence of anti-HLA class I and II antibodies of immunoglobulin G type. Fifty two patients (10.7%) demonstrated positive panel-reactive antibody (PRA) for class I 24 (4.9%), for class II and 13 (2.7%), for both. Multivariate analysis showed diagnosis was the independent risk factor for antibodies, as acute lymphoblastic leukemia (ALL) patients (HR0.141, 95% CI 0.037-0.538, p 0.004) had a lower incidence of class II PRAs and DSAs against HLA-B, DQ, and DR, whereas myelodysplastic syndrome (MDS) patients had a higher incidence of PRAs for both class I and class II (HR4.790, 95% CI 1.010-22.716, p 0.049), and DSAs against HLA-A, B, C, DP, and DQ. Older age (>12 vs. ≤12) was associated with DSAs against HLA-DP (HR0.194, 95% CI 0.041-0.918, p 0.039). Our findings provided novel evidence for prevalence and risk factors for PRAs and DSAs in pediatric candidates receiving haplo-HSCT, possibly benefiting anti-HLA antibody monitoring and donor selection.

Glucocorticoids and selumetinib are highly synergistic in RAS pathway-mutated childhood acute lymphoblastic leukemia through upregulation of BIM.

New drugs are needed for the treatment of relapsed acute lymphoblastic leukemia and preclinical evaluation of the MEK inhibitor, selumetinib, has shown that this drug has excellent activity in those leukemias with RAS pathway mutations. The proapoptotic protein, BIM is pivotal in the induction of cell death by both selumetinib and glucocorticoids, suggesting the potential for synergy. Thus, combination indices for dexamethasone and selumetinib were determined in RAS pathway-mutated acute lymphoblastic leukemia primagraft cells

The prognostic implications of

CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors.

Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T-cell therapy of pediatric solid tumors, including those arising in the central nervous system. We developed a novel B7-H3 CAR whose binder is derived from a mAb that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. We tested B7-H3 CAR T cells in a variety of pediatric cancer models. B7-H3 CAR T cells mediate significant antitumor activity B7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies, and should be tested in carefully designed clinical trials.

Mesothelin-targeted second generation CAR-T cells inhibit growth of mesothelin-expressing tumors

Non-small cell lung cancer (NSCLC) and mesothelioma are renowned for being diagnosed at a late stage and poor prognosis. Although surgery, chemotherapy, and radiotherapy have yielded successful outcomes, the improvement on the survival rate of NSCLC and mesothelioma have been less marked. Recently, adoptive immunotherapy, particularly chimeric antigen receptor T (CAR-T) cell therapy demonstrated promise for improving the survival of acute lymphoblastic leukemia with minimum toxicity. However, its application in solid tumors still warrants in-depth investigations and multiple consistent trial results, particularly in eliminating off-tumor toxicity. To explore CAR-T therapy in NSCLC and mesothelioma, second-generation CAR-T cells were constructed targeting mesothelin (MSLN), which is abundant in NSCLC and mesothelioma but is under expressed in normal tissues. The second-generation design incorporated co-stimulatory CD28 and 4-1BB signaling domains to enhance the proliferation. Following the successful analysis of CAR-T cells by flow cytometry, cytotoxicity experiments were performed using the LDH kit to verify the killing effect of CAR-T cells on target cells. Otherwise, the

T Cell Acute Lymphoblastic Leukemia as a Consequence of Thymus Autonomy.

Thymus autonomy is the capacity of the thymus to maintain T lymphocyte development and export independently of bone marrow contribution. Prolonging thymus autonomy was shown to be permissive to the development of T cell acute lymphoblastic leukemia (T-ALL), similar to the human disease. In this study, performing thymus transplantation experiments in mice, we report that thymus autonomy can occur in several experimental conditions, and all are permissive to T-ALL. We show that wild type thymi maintain their function of T lymphocyte production upon transplantation into recipients with several genotypes (and corresponding phenotypic differences), i.e.,

Antagonism of IAPs Enhances CAR T-cell Efficacy.

Chimeric antigen receptor (CAR) T-cell therapy has proven successful in the treatment of hematological malignancies, notably acute lymphoblastic leukemia and B-cell lymphoma. However, the efficacy of CAR T cells against solid tumors is poor, likely due to tumor-associated immunosuppression. Here, we demonstrated that antagonizing the inhibitor of apoptosis proteins with the clinical smac-mimetic, birinapant, significantly enhanced the antitumor activity of CAR T cells in a tumor necrosis factor (TNF)-dependent manner. Enhanced tumor cell death occurred independently of the perforin-mediated granule exocytosis pathway, underscoring the cytotoxic potential of CAR T-cell-derived TNF. Combining CAR T-cell therapy with birinapant significantly reduced established tumor growth

Validation of the United Kingdom copy-number alteration classifier in 3239 children with B-cell precursor ALL.

Genetic abnormalities provide vital diagnostic and prognostic information in pediatric acute lymphoblastic leukemia (ALL) and are increasingly used to assign patients to risk groups. We recently proposed a novel classifier based on the copy-number alteration (CNA) profile of the 8 most commonly deleted genes in B-cell precursor ALL. This classifier defined 3 CNA subgroups in consecutive UK trials and was able to discriminate patients with intermediate-risk cytogenetics. In this study, we sought to validate the United Kingdom ALL (UKALL)-CNA classifier and reevaluate the interaction with cytogenetic risk groups using individual patient data from 3239 cases collected from 12 groups within the International BFM Study Group. The classifier was validated and defined 3 risk groups with distinct event-free survival (EFS) rates good (88%), intermediate (76%), and poor (68%) (

Ophthalmic manifestations of acute leukaemias.

To determine the incidence of ocular pathological findings in a group of patients with acute leukemia. To define the predictive value of the presence of the ocular pathological findings. Retrospective evaluation of a group of 67 patients with acute leukemia (age 1-75 years) examined at the Ophthalmology Clinic, Faculty Hospital Ostrava, from 2005 to 2014. Ocular pathological findings were found in 13 patients of the group (19.4 %) - 7 patients with acute myeloid leukemia (10.9 %) and 6 patients with acute lymphoblastic leukemia (8.5 %). 10 patients died due to of the underlying disease. Ocular pathological findings were found in 6 of them (60 %). A higher prognostic value was found in a group of patients with AML. Ophthalmology examination is a necessary part of the examination of patients with acute leukemia. This prognostic benefit is particularly significant in patients with AML. Key words acute myeloid leukemia, fundus leucaemicus, Roths spot, ophthalmology examination.

Isobaric Multiplex Labeling Reagents for Carbonyl-Containing Compound (SUGAR) Tags A Probe for Quantitative Glycomic Analysis.

Glycans are highly complex entities with multiple building units and different degrees of branched polymerization. Intensive research efforts have been directed to mass spectrometry (MS)-based qualitative and quantitative glycomic analysis due to the important functions of glycans. Among various strategies, isobaric labeling has become popular because of its higher multiplexing capacity. Over the past few years, several isobaric chemical tags have been developed for quantitative glycomics. However, caveats also exist for these tags, such as relatively low reporter ion yield for aminoxyTMT-labeled complex glycans. To overcome the limitations of existing isobaric chemical tags, we designed a class of novel isobaric multiplex reagents for carbonyl-containing compound (SUGAR) tags that can be used to label glycans for quantitative glycomic analysis. The quantitative performance including labeling efficiency, quantification accuracy, and dynamic range of these SUGAR tags has been evaluated, showing promising results. Finally, the 4-plex SUGAR tags have been utilized to investigate N-glycan changes of B-cell acute lymphoblastic leukemia (ALL) pediatric patients before and after chemotherapy.

Regenerative NanoOctopus Based on Multivalent-Aptamer-Functionalized Magnetic Microparticles for Effective Cell Capture in Whole Blood.

Isolation of specific rare cell subtypes from whole blood is critical in cellular analysis and important in basic and clinical research. Traditional immunomagnetic cell capture suffers from suboptimal sensitivity, specificity, and time- and cost-effectiveness. Mimicking the features of octopuses, a device termed a NanoOctopus was developed for cancer cell isolation in whole blood. The device consists of long multimerized aptamer DNA strands, or tentacle DNA, immobilized on magnetic microparticle surfaces. Their ultrahigh sensitivity and specificity are attributed to multivalent binding of the tentacle DNA to cell receptors without steric hindrance. The simple, quick, and noninvasive capture and release of the target cells allows for extensive downstream cellular and molecular analysis, and the time- and cost-effectiveness of fabrication and regeneration of the devices makes them attractive for industrial manufacture.

A comprehensive catalog of LncRNAs expressed in T-cell acute lymphoblastic leukemia.

Several studies have demonstrated that LncRNAs can play major roles in cancer development. The creation of a catalog of LncRNAs expressed in T cell acute lymphoblastic leukemia (T-ALL) is thus of particular importance. However, this task is challenging as LncRNA expression is highly restricted in time and space manner and thus may greatly differ between samples. We performed a systematic transcript discovery in RNA-Seq data obtained from T-ALL primary cells and cell lines. This led to the identification of 2560 novel LncRNAs. After the integration of these transcripts into a large compendium of LncRNAs (

Extensive Forehead Swelling Including the Periorbital Area in a Child A Rare Manifestation of Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) manifestations in a child are varied. We report a unique and rare presentation of acute lymphoblastic leukemia in a child who presented with frontal swelling involving bilateral upper lids. A previously healthy one-year-old girl presented with progressively increasing frontal swelling of seven months duration. An examination revealed erythematous, firm, nontender forehead swelling that extended up to the medial part of bilateral upper eye lids. The extraocular muscle movement was normal. The anterior segment and fundus examination were also normal in both eyes. Other systemic examination revealed multiple leukemic cutis on the scalp. The cervical lymph nodes were also palpable with hepatosplenomegaly. A full blood picture (FBP) showed the presence of leucoerythroblastic blood film with 62% blast cells. Flow cytometry and bone marrow aspiration confirmed the diagnosis. Computed tomographic (CT) scan images revealed multiple well-defined hyperdense lesions at the subcutaneous skull with the largest lesion at the anterior glabella. Upon diagnosis, the patient was started on chemotherapy and the swelling resolved after one month post treatment. Extensive forehead swelling is a rare manifestation of acute lymphoblastic leukemia. A high index of suspicion aided with diagnostic investigations could help the doctors arrive at a correct diagnosis and treatment.

Matrix association regionscaffold attachment region the crucial player in defining the positions of chromosome breaks mediated by bile acid-induced apoptosis in nasopharyngeal epithelial cells.

It has been found that chronic rhinosinusitis (CRS) increases the risk of developing nasopharyngeal carcinoma (NPC). CRS can be caused by gastro-oesophageal reflux (GOR) that may reach nasopharynx. The major component of refluxate, bile acid (BA) has been found to be carcinogenic and genotoxic. BA-induced apoptosis has been associated with various cancers. We have previously demonstrated that BA induced apoptosis and gene cleavages in nasopharyngeal epithelial cells. Chromosomal cleavage occurs at the early stage of both apoptosis and chromosome rearrangement. It was suggested that chromosome breaks tend to cluster in the region containing matrix association regionscaffold attachment region (MARSAR). This study hypothesised that BA may cause chromosome breaks at MARSAR leading to chromosome aberrations in NPC. This study targeted the AF9 gene located at 9p22 because 9p22 is a deletion hotspot in NPC. Potential MARSAR sites were predicted in the AF9 gene by using MARSAR prediction tools. Normal nasopharyngeal epithelial cells (NP69) and NPC cells (TWO4) were treated with BA at neutral and acidic pH. Inverse-PCR (IPCR) was used to identify chromosome breaks in SAR region (contains MARSAR) and non-SAR region (does not contain MARSAR). To map the chromosomal breakpoints within the AF9 SAR and non-SAR regions, DNA sequencing was performed. In the AF9 SAR region, the gene cleavage frequencies of BA-treated NP69 and TWO4 cells were significantly higher than those of untreated control. As for the AF9 non-SAR region, no significant difference in cleavage frequency was detected between untreated and BA-treated cells. A few breakpoints detected in the SAR region were mapped within the AF9 region that was previously reported to translocate with the mixed lineage leukaemia (MLL) gene in an acute lymphoblastic leukaemia (ALL) patient. Our findings suggest that MARSAR may be involved in defining the positions of chromosomal breakages induced by BA. Our report here, for the first time, unravelled the relation of these BA-induced chromosomal breakages to the AF9 chromatin structure.

Regulatory network analysis reveals the oncogenesis roles of feed-forward loops and therapeutic target in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Aberrant expressed genes contribute to the development and progression of T-ALL. However, the regulation underlying their aberrant expression remains elusive. Dysregulated expression of transcription factors and miRNAs played important regulatory roles in the pathogenesis of T-ALL. In this study, we analyzed the alteration of transcriptome profiling and regulatory networks between T-ALL sample and normal T cell samples at transcriptional and post-transcriptional levels. Our results demonstrated that genes related to cell cycle and cell proliferation processes were significantly upregulated in T-ALL comparing to normal samples. Meanwhile, regulatory network analyses revealed that FOXM1, MYB, SOX4 and miR-2119b as core regulators played vital roles in the development of T-ALL. FOXM1-miR-21-5p-CDC25A and MYBSOX4-miR-19b-3p-RBBP8 were identified as important feed-forward loops involved in the oncogenesis of T-ALL. Drug-specific analyses showed that GSK-J4 may be an effective drug, and CDC25ACAPN2MCM2 could serve as potential therapeutic targets for T-ALL. This study may provide novel insights for the regulatory mechanisms underlying the development of T-ALL and potential therapeutic targets.

Exposure-response analysis of blinatumomab in patients with relapsedrefractory acute lymphoblastic leukaemia and comparison with standard of care chemotherapy.

The relationship between blinatumomab exposure and efficacy endpoints (occurrence of complete remission CR and duration of overall survival OS) or adverse events (occurrence of cytokine release syndrome CRS and neurological events) were investigated in adult patients with relapsedrefractory acute lymphoblastic leukaemia (rr ALL) receiving blinatumomab or standard of care (SOC) chemotherapy to evaluate appropriateness of the blinatumomab dosing regimen. Exposure, efficacy and safety data from adult patients (n 646) with rr ALL receiving stepwise (9 then 28 μgday, 4-week cycle) continuous intravenous infusion (n 537) of blinatumomab or SOC (n 109) chemotherapy were pooled from phase 2 and 3 studies. The occurrence of CR, neurological and CRS events, and duration of OS were analysed using Cox proportional hazards models or logistic regression, as appropriate. Confounding factors were tested multivariately as needed. Blinatumomab steady-state concentration following 28 μgday dosing was associated with the probability of achieving CR (odds ratio and 95% confidence interval 1.073 1.033-1.114), and a longer duration of OS compared to SOC (hazard ratio and 95% confidence interval 0.954 0.936-0.973, P < .05) in multivariate analyses. The exposure-safety analyses indicated that blinatumomab steady-state concentration following the 9 or 28 μgday dose was not associated with increased probability of CRS or neurological events, after accounting for blinatumomab treatment effect (P > .05). Blinatumomab step-dosing regimen of 928 μgday provided treatment benefit in achieving CR and increasing the duration of OS over SOC and was appropriate in management of CRS and neurological events in patients with rr ALL.

Tamoxifen induces toxicity, causes autophagy, and partially reverses dexamethasone resistance in Jurkat T cells.

Estrogens demonstrate biological activity in numerous organ systems, including the immune system, and exert their effects through estrogen receptors (ER) of two types intracellular ERα and ERβ that activate transcriptional factors and membrane G protein-coupled ER GPER. The latter is capable to mediate fast activation of cytosolic signaling pathways, influencing transcriptional events in response to estrogens. Tamoxifen (TAM), widely used in chemotherapy of ERα-positive breast cancer, is considered as an ERα antagonist and GPER agonist. TAM was shown to possess off-target cytotoxicity, not related to ER in various tumor types. The present work was designed to study biological effects of TAM on the glucocorticoid (GC)-resistant cell line Jurkat, derived from acute lymphoblastic leukemia of T lineage (T-ALL). We have shown that T-ALL cell lines, in contrast to healthy T cells, express only GPER, but not ERα or ERβ. TAM compromised mitochondrial function and reduced the viability and proliferation of Jurkat cells. Additionally, TAM induced autophagy in a GPER-dependent manner. Gene expression profiling revealed the up-regulation of autophagy-related gene ATG5. Interestingly, TAM sensitized Jurkat cells to dexamethasone (DEX) treatment, which may be related to its capacity to cause autophagy. We suggest that TAM-based adjuvant therapy may represent a novel strategy in T-ALL patients handling.

Rapidly Progressive, Isolated Subretinal Leukemic Relapse A Case Report.

The aim of this paper is to describe a case of relapsed pediatric acute lymphoblastic leukemia (ALL) presenting as a rapidly progressive subretinal infiltrate, as diagnosed by ultrasound-guided fine needle aspiration (FNA). We conducted a clinical pathological retrospective chart review. Eleven months after documented remission of T-cell ALL while on maintenance therapy, this 17-year-old patient presented with acute open angle glaucoma in the right eye. B-scan ultrasonography suggested total retinal detachment. Eight weeks later, based on routine cerebrospinal fluid analysis, the patient was diagnosed with central nervous system relapse of T-cell ALL. Repeat B-scan 1 week later showed a new hyperechoic subretinal mass. FNA of the mass confirmed leukemic infiltrate. The involved eye was enucleated, demonstrating leukemic cells throughout the subretinal space, choroid, and the optic nerve. Following hematopoietic stem cell transplant, the patient continues to maintain bone marrow remission 5 months after enucleation without involvement in the opposite eye. Retinal detachment in any patient with a history of leukemia should raise the possibility of relapse and may warrant aspirationbiopsy if other means of diagnosing relapse are inconclusive. Subretinal infiltrate may progress rapidly and prompt diagnosis is paramount to tailoring therapy and preserving vision.

Discovery of a ZIP7 inhibitor from a Notch pathway screen.

The identification of activating mutations in NOTCH1 in 50% of T cell acute lymphoblastic leukemia has generated interest in elucidating how these mutations contribute to oncogenic transformation and in targeting the pathway. A phenotypic screen identified compounds that interfere with trafficking of Notch and induce apoptosis via an endoplasmic reticulum (ER) stress mechanism. Target identification approaches revealed a role for SLC39A7 (ZIP7), a zinc transport family member, in governing Notch trafficking and signaling. Generation and sequencing of a compound-resistant cell line identified a V430E mutation in ZIP7 that confers transferable resistance to the compound NVS-ZP7-4. NVS-ZP7-4 altered zinc in the ER, and an analog of the compound photoaffinity labeled ZIP7 in cells, suggesting a direct interaction between the compound and ZIP7. NVS-ZP7-4 is the first reported chemical tool to probe the impact of modulating ER zinc levels and investigate ZIP7 as a novel druggable node in the Notch pathway.

PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia.

Recent genomic studies have identified chromosomal rearrangements defining new subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL), however many cases lack a known initiating genetic alteration. Using integrated genomic analysis of 1,988 childhood and adult cases, we describe a revised taxonomy of B-ALL incorporating 23 subtypes defined by chromosomal rearrangements, sequence mutations or heterogeneous genomic alterations, many of which show marked variation in prevalence according to age. Two subtypes have frequent alterations of the B lymphoid transcription-factor gene PAX5. One, PAX5alt (7.4%), has diverse PAX5 alterations (rearrangements, intragenic amplifications or mutations) a second subtype is defined by PAX5 p.Pro80Arg and biallelic PAX5 alterations. We show that p.Pro80Arg impairs B lymphoid development and promotes the development of B-ALL with biallelic Pax5 alteration in vivo. These results demonstrate the utility of transcriptome sequencing to classify B-ALL and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis.

Long non-coding RNAs defining major subtypes of B cell precursor acute lymphoblastic leukemia.

Long non-coding RNAs (lncRNAs) have emerged as a novel class of RNA due to its diverse mechanism in cancer development and progression. However, the role and expression pattern of lncRNAs in molecular subtypes of B cell acute lymphoblastic leukemia (BCP-ALL) have not yet been investigated. Here, we assess to what extent lncRNA expression and DNA methylation is driving the progression of relapsed BCP-ALL subtypes and we determine if the expression and DNA methylation profile of lncRNAs correlates with established BCP-ALL subtypes. We performed RNA sequencing and DNA methylation (Illumina Infinium microarray) of 40 diagnosis and 42 relapse samples from 45 BCP-ALL patients in a German cohort and quantified lncRNA expression. Unsupervised clustering was applied to ascertain and confirm that the lncRNA-based classification of the BCP-ALL molecular subtypes is present in both our cohort and an independent validation cohort of 47 patients. A differential expression and differential methylation analysis was applied to determine the subtype-specific, relapse-specific, and differentially methylated lncRNAs. Potential functions of subtype-specific lncRNAs were determined by using co-expression-based analysis on nearby (cis) and distally (trans) located protein-coding genes. Using an integrative Bioinformatics analysis, we developed a comprehensive catalog of 1235 aberrantly dysregulated BCP-ALL subtype-specific and 942 relapse-specific lncRNAs and the methylation profile of three subtypes of BCP-ALL. The 1235 subtype-specific lncRNA signature represented a similar classification of the molecular subtypes of BCP-ALL in the independent validation cohort. We identified a strong correlation between the DUX4-specific lncRNAs and genes involved in the activation of TGF-β and Hippo signaling pathways. Similarly, Ph-like-specific lncRNAs were correlated with genes involved in the activation of PI3K-AKT, mTOR, and JAK-STAT signaling pathways. Interestingly, the relapse-specific lncRNAs correlated with the activation of metabolic and signaling pathways. Finally, we found 23 promoter methylated lncRNAs epigenetically facilitating their expression levels. Here, we describe a set of subtype-specific and relapse-specific lncRNAs from three major BCP-ALL subtypes and define their potential functions and epigenetic regulation. The subtype-specific lncRNAs are reproducible and can effectively stratify BCP-ALL subtypes. Our data uncover the diverse mechanism of action of lncRNAs in BCP-ALL subtypes defining which lncRNAs are involved in the pathogenesis of disease and are relevant for the stratification of BCP-ALL subtypes.

Computational modeling of early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) to identify personalized therapy using genomics.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is an aggressive hematological malignancy for which optimal therapeutic approaches are poorly characterized. Using computational biology modeling (CBM) in conjunction with genomic data from cell lines and individual patients, we generated disease-specific protein network maps that were used to identify unique characteristics associated with the mutational profiles of ETP-ALL compared to non-ETP-ALL (T-ALL) cases and simulated cellular responses to a digital library of FDA-approved and investigational agents. Genomics-based classification of ETP-ALL patients using CBM had a prediction sensitivity and specificity of 93% and 87%, respectively. This analysis identified key genomic and pathway characteristics that are distinct in ETP-ALL including deletion of nucleophosmin-1 (NPM1), mutations of which are used to direct therapeutic decisions in acute myeloid leukemia. Computational simulations based on mutational profiles of 62 ETP-ALL patient models identified 87 unique targeted combination therapies in 56 of the 62 patients despite actionable mutations being present in only 37% of ETP-ALL patients. Shortlisted two-drug combinations were predicted to be synergistic in 11 profiles and were validated by in vitro chemosensitivity assays. In conclusion, computational modeling was able to identify unique biomarkers and pathways for ETP-ALL, and identify new drug combinations for potential clinical testing.

Minimal Residual Disease-guided Risk Restratification and Therapy Improves the Survival of Childhood Acute Lymphoblastic Leukemia Experience From a Tertiary Childrens Hospital in China.

The minimal residual disease (MRD) has been shown to be very important to evaluate the prognostic significance in childhood acute lymphoblastic leukemia (ALL), but the impact under the current treatment protocol in China has not been fully elucidated. The aim of this study was to investigate the efficacy of MRD-guided risk restratification of ALL. A total of 676 children with ALL were enrolled. In the predictive study group, 476 patients were enrolled with 5-year cumulative incidence of relapse rates of the low-risk (LR), intermediate-risk (IR), and high-risk groups being 11.0%±2.3%, 12.6%±3.3%, and 32.7%±4.9%, respectively. In the intervention study group, 19200 patients enrolled were reclassified into risk groups according to the MRD levels. The 3-year event-free survival and overall survival were 85.2%±2.9% and 90.6%±2.1%, respectively, which were higher than those of the predictive study group (79.1%±1.9% and 84.7%±1.7%, respectively P<0.05). The 3-year cumulative incidence of relapse in the LR and IR groups of the intervention study group were 4.2%±3.1% and 6.4%±3.1%, respectively, which were significantly lower than those in the predictive study group (7.2%±1.8% and 11.8%±3.2%, respectively P<0.05). We conclude that the risk of relapse in the LR and IR groups can be significantly reduced after MRD-guided risk restratification.

Human Fibrinogen Concentrate and Fresh Frozen Plasma in the Management of Severe Acquired Hypofibrinogenemia in Children With Acute Lymphoblastic Leukemia Results of a Retrospective Survey.

In this study we aimed to retrospectively evaluate how centers, belonging to the Associazione Italiana Ematologia e Oncologia Pediatrica (AIEOP), manage severe acquired hypofibrinogenemia in children with acute lymphoblastic leukemia, particularly evaluating the therapeutic role of human fibrinogen concentrate (HFC) and fresh frozen plasma (FFP). We conducted a survey among AIEOP centers thereafter, we collected and analyzed data with regard to the treatment of episodes of severe acquired hypofibrinogenemia occurring during the induction and reinduction phases of the AIEOP-BFM ALL 2009 protocol. In total, 15 of the 37 AIEOP centers invited to join the survey agreed to collect the data, with 10 and 5 centers declaring to react to severe acquired hypofibrinogenemia (<70 mgdL) by administering HFC or FFP, respectively. Of the 150 episodes of severe hypofibrinogenemia occurring in 101 patients, 47.3% were treated with HFC and 52.7% with FFP, with a normalization of fibrinogen levels achieved in greater proportion and in a shorter amount of time in the HFC group as compared with the FFP group. None of the patients presented with bleeding or thrombosis during the observation period. Even with the limitations of the retrospective nature of this study, HFC seems to be a safe and effective alternative to FFP for replacement therapy in case of severe hypofibrinogenemia in children with acute lymphoblastic leukemia.

Dysregulation of miR-335-3p, targeted by NEAT1 and MALAT1 long non-coding RNAs, is associated with poor prognosis in childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most prevalent cancer among children, and multidrug efflux mediated by overexpression of ABC transporters is the major impediment to successful chemotherapy in this malignancy. The goal of this study is to identify the non-coding RNAs (ncRNAs) which may affect the expression levels of ABCA3 the previously identified prognostic biomarker for multidrug resistance (MDR) in childhood ALL (cALL). Bone marrow samples from 64 cALLs, including 46 de novo and 18 relapsed patients, in addition to 30 non-cancer controls were collected, and ncRNAs were nominated using in silico studies. Quantitative RT-PCR showed low expression profiles of miR-335-3p in cALLs compared with the control group (P 0.018). Inverse correlation was determined between the miR-335-3p and ABCA3 mRNA expression profiles in cALL patients (r 0.5019, P 0.002). Moreover, it was shown that the expression levels of miR-335-3p was downregulated in the drug-resistant samples (MDR group) compared with the drug-sensitive patients (mrd- group), (P 0.0005, AUC 0.801). On the other hand, negative correlations were identified between the expression levels of miR-335-3p and the selected LncRNAs, NEAT1 and MALAT1, in the MDR group compared with the mrd- patients (P 0.009), suggesting a sponge effect for these LncRNAs. The current study showed a potential regulatory role for miR-335-3p in ABCA3 expression targeted by NEAT1 and MALAT1 long non-coding RNAs. This negative impact may possibly contribute to the development of chemoresistance in childhood ALL, and provide an exceptional insight to new therapeutic approaches.

Small molecule inhibitor of c-Myc 10058-F4 inhibits proliferation and induces apoptosis in acute leukemia cells, irrespective of PTEN status.

Based on the frequent over-expression of c-Myc in hematologic malignancies and its crucial role in the regulation of diverse oncogenic pathways involved in leukomogenesis, intense interest has recently focused on this factor as an appealing therapeutically target in leukemia. In the present study, we aimed to investigate the anti-leukemic property of small molecule inhibitor of c-Myc 10058-F4 in two distinct acute leukemia cell lines consist of acute promyelocytic leukemia (APL)-derived NB4 cells (with wild-type PTEN) and acute lymphoblastic leukemia (ALL)-derived Nalm-6 cells (with down-regulated PTEN). 10058-F4 effectively reduced survival of leukemic cells however, we found a different cell sensitivity pattern in the tested cell lines. To the best of our knowledge, no study has addressed the underlying mechanisms responsible for leukemic cell resistance to 10058-F4, and we propose for the first time that the effectiveness of c-Myc inhibition might be attenuated through over-activated phosphoinositide 3-kinase (PI3K) in less sensitive Nalm-6 cells. Notably, we failed to find an obvious correlation between PTEN status and cell sensitivity to the inhibitor in a panel of hematologic malignant cells. Beyond 10058-F4 cytotoxicity as a single agent, synergistic experiments also delineated that pharmaceutical targeting of c-Myc could potentiate the anti-cancer effect of both vincristine and Arsenic trioxide in ALL and APL cells, respectively. In conclusion, this study sheds light on the potent anti-leukemic characteristics of 10058-F4 and provide an interesting evidence to the application of this agent in combination with PI3K inhibitors especially in acute leukemia with over-activated PI3K, irrespective of PTEN status.

Fluctuations in dietary intake during treatment for childhood leukemia A report from the DALLT cohort.

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Nutritional morbidities are a persistent problem facing pediatric patients during and after treatment and age-gender groups that are at risk for nutritional conditions have not been clearly identified. Therapy is a contributing factor however, the role of dietary intake remains largely unknown. Prior to conduct of interventional trials, an understanding of the effects of treatment on fluctuations in dietary intake is necessary. We enrolled 794 children with ALL in a prospective clinical trial. Dietary intake was collected with a food frequency questionnaire at diagnosis and throughout the course of treatment for pediatric ALL. Reported values were compared to the Dietary Recommended Intake (DRI), and normative values (NHANES). Hierarchical linear models and multilevel mixed-effects ordered logistic regression models were used to evaluate longitudinal changes in dietary intake independent samples t-test with Bonferroni correction was performed to compare to NHANES. Of the evaluable participants at each timepoint, dietary intake was obtained on 81% (n 640), 74% (n 580) and 74% (n 558) at diagnosis, end of induction phase of treatment, and continuation, respectively. Despite exposure to corticosteroids, caloric intake decreased over therapy for most age-gender groups. Predictive models of excess intake found reduced odds of over-consuming calories (OR 0.738, P < 0.05) however, increased odds of over-consuming fat (OR 6.971, P < 0.001). When compared to NHANES, we consistently found that ≥13 of children were consuming calories in excess of normative values. For select micronutrients, a small proportion of participants were above or below the DRI at each time evaluated. Our study suggests that dietary intake fluctuates during treatment for ALL as compared to age-gender recommended and normative values. Improving our understanding of nutrient fluctuations and dietary quality will facilitate subsequent analyses addressing relationships of dietary intake, toxicity, and survival.

Use of blinatumomab in children acute lymphoblastic leukemia in the Grand Ouest interregion A chance for all.

Relapsedrefractory acute lymphoblastic leukemia (ALL) in children has a pejorative prognosis and justifies to be treated by hematopoietic stem cell transplantation (HSCT). A minimal residual disease (MRD) before transplantation is a major part of prognosis. Blinatumomab, a bispecific antibody CD19 Patients between 0 and 23 years old, from the 7 centers of the french Grand Ouest interregional network, treated by blinatumomab for a relapsed or refractory ALL, from January 2015 to January 2018, were included. The efficiency of blinatumomab was assessed in terms of complete remission, minimal residual disease, overall survival, and tolerability of treatment. Thirteen of 18 patients achieved a complete remission, with negative minimal residual disease for ten of them. Fourteen patients proceeded to stem cell transplantation,. Eight out of 14 patients obtained long term remission after HSCT. As far as tolerance is concerned, no serious adverse event, neurological or psychiatric disorder, was observed. Thanks to an interregional network collaboration, all children with high risk ALL coming from the western french interregion could be treated by blinatumomab. Blinatumomab offered good hematological conditions to undergo HSCT with a good tolerability.

A Glycomic Approach Towards Identification of Signature Molecules in CD34

Umbilical cord blood (UCB) is a powerful storehouse for normal CD34

Overexpression of CD59 inhibits apoptosis of T-acute lymphoblastic leukemia via AKTNotch1 signaling pathway.

T-acute lymphoblastic leukemia (T-ALL) was a hematological malignancy characterized by the accumulation of immature T cells in bone marrow and peripheral blood. In this study, we tried to explore the physiological role of CD59 in T-ALL. In this study, we collected the bone marrow samples from 17 T-ALL patients and 38 healthy participants to find differences in CD59 expression patterns. Then, CD59 was over-expressed in T-ALL cell line Jurkat, and its biological functions were detected. In addition, in order to understand the active site of CD59, the Trp40 was mutated. Further, we constructed a mouse model by transplanting Jurkat cells into the nude mice to verify the function of CD59 in vitro. At last, mechanism studies were performed by western blot. We found that the proportion of T lymphocytes expressing CD59 in bone marrow of T-ALL patients was significantly higher than that of healthy individuals. Then, we found that the overexpression of CD59 in Jurkat cells was beneficial to the cell survival by inhibiting apoptosis and promoting IL-2 secretion. In this process, Trp40 of CD59 was a key functional site. Further, the high expression of CD59 inhibited apoptosis of bone marrow and peripheral blood cells, and promoted IL-2 secretion in mouse model. At last, mechanism studies showed that the activation of AKT, STAT5 and Notch1 signaling pathways in Jurkat cells, may be involved in the regulation of apoptosis by CD59 and mutation in the Trp40 affect the interaction of CD59 with these signaling pathways. In conclusion, CD59 inhibited apoptosis of T-ALL by regulating AKTNotch1 signaling pathway, providing a new perspective for the treatment of T-ALL.

Nilotinib combined with multi-agent chemotherapy in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia a single-center prospective study with long-term follow-up.

The aim of this study is to investigate the efficacy and safety of nilotinib combined with multi-agent chemotherapy in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL). Thirty patients with Ph ALL were recruited. Standard induction chemotherapy was given for 4 weeks. Nilotinib was administered beginning on day 15 of induction. After achieving hematologic complete remission (HCR), patients received either seven courses of consolidation or hematopoietic cell transplantation (HCT). Nilotinib was continued 2 years after achieving HCR or before stem cell transplantation conditioning. HCR and molecular complete response (MCR), overall survival (OS), hematologic relapse-free survival (HRFS), molecular relapse-free survival (MRFS), toxicity, and nilotinib levels in the serum and cerebrospinal fluid were evaluated. All patients achieved HCR, and cumulative MCR rate was 83.3%. The median HRFS and OS were 18 and 47.5 months, respectively. Four-year HRFS and OS rates were 54% and 45%, respectively. The median MRFS and 4-year MRFS for the patients with MCR were 19 months and 45%, respectively. The molecular response of patients after induction cycle had no impact on HRFS, MRFS, or OS. The patients who achieved MCR after 3 and 6 months had superior HRFS. The HCT cohort in the first HCR had significantly lower rates of relapse and longer MRFS, HRFS, and OS. Most adverse events were reversible with dose reduction or transient interruption of nilotinib therapy. Only traces of nilotinib were detected in cerebrospinal fluid. Nilotinib combined with cytotoxic chemotherapy was effective and translated to a high HCR and MCR for patients with Ph ALL. It should be noted that nilotinib cannot cross the blood-brain barrier.

Immune cell constitution in bone marrow microenvironment predicts outcome in adult ALL.

As novel immunological treatments are gaining a foothold in the treatment of acute lymphoblastic leukemia (ALL), it is elemental to examine ALL immunobiology in more detail. We used multiplexed immunohistochemistry (mIHC) to study the immune contexture in adult precursor B cell ALL bone marrow (BM). In addition, we developed a multivariate risk prediction model that stratified a poor survival group based on clinical parameters and mIHC data. We analyzed BM biopsy samples of ALL patients (n 52) and healthy controls (n 14) using mIHC with 30 different immunophenotype markers and computerized image analysis. In ALL BM, the proportions of M1-like macrophages, granzyme BCD57CD8 T cells, and CD27 T cells were decreased, whereas the proportions of myeloid-derived suppressor cells and M2-like macrophages were increased. Also, the expression of checkpoint molecules PD1 and CTLA4 was elevated. In the multivariate model, age, platelet count, and the proportion of PD1TIM3 double-positive CD4 T cells differentiated a poor survival group. These results were validated by flow cytometry in a separate cohort (n 31). In conclusion, the immune cell contexture in ALL BM differs from healthy controls. CD4PD1TIM3 T cells were independent predictors of poor outcome in our multivariate risk model, suggesting that PD1 might serve as an attractive immuno-oncological target in B-ALL.

NG2 antigen is a therapeutic target for MLL-rearranged B-cell acute lymphoblastic leukemia.

B cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer, with cure rates of ∼80%. MLL-rearranged (MLLr) B-ALL (MLLr-B-ALL) has, however, an unfavorable prognosis with common therapy refractoriness and early relapse, and therefore new therapeutic targets are needed for relapsedrefractory MLLr-B-ALL. MLLr leukemias are characterized by the specific expression of chondroitin sulfate proteoglycan-4, also known as neuron-glial antigen-2 (NG2). NG2 was recently shown involved in leukemia invasiveness and central nervous system infiltration in MLLr-B-ALL, and correlated with lower event-free survival (EFS). We here hypothesized that blocking NG2 may synergize with established induction therapy for B-ALL based on vincristine, glucocorticoids, and L-asparaginase (VxL). Using robust patient-derived xenograft (PDX) models, we found that NG2 is crucial for MLLr-B-ALL engraftment upon intravenous (i.v.) transplantation. In vivo blockade of NG2 using either chondroitinase-ABC or an anti-NG2-specific monoclonal antibody (MoAb) resulted in a significant mobilization of MLLr-B-ALL blasts from bone marrow (BM) to peripheral blood (PB) as demonstrated by cytometric and 3D confocal imaging analysis. When combined with either NG2 antagonist, VxL treatment achieved higher rates of complete remission, and consequently higher EFS and delayed time to relapse. Mechanistically, anti-NG2 MoAb induces neither antibody-dependent cell-mediated not complement-dependent cytotoxicity. NG2 blockade rather overrides BM stroma-mediated chemoprotection through PB mobilization of MLLr-B-ALL blasts, thus becoming more accessible to chemotherapy. We provide a proof of concept for NG2 as a therapeutic target for MLLr-B-ALL.

CDKN2B downregulation and other genetic characteristics in T-acute lymphoblastic leukemia.

We identified principal genetic alterations in 97.1% (99102) of patients with T-acute lymphoblastic leukemia (T-ALL) using integrative genetic analyses, including massive parallel sequencing and multiplex ligation-dependent probe amplification (MLPA). A total of 133 mutations were identified in the following genes in descending order NOTCH1 (66.7%), FBXW7 (19.6%), PHF6 (15.7%), RUNX1 (12.7%), NRAS (10.8%), and DNMT3A (9.8%). Copy number alterations were most frequently detected in CDKN2B, CDKN2A, and genes on 9p21.3 in T-ALL (45.1%). Gene expression data demonstrated the downregulation of CDKN2B in most cases of T-ALL, whereas CDKN2A downregulation was mainly restricted to deletions. Additional quantitative methylation analysis demonstrated that CDKN2B downregulation stemmed from deletion and hypermethylation. Analysis of 64 patients with CDKN2B hypermethylation indicated an association with an older age of onset and early T cell precursor ALL, which involved very early arrest of T cell differentiation. Genes associated with methylation and myeloid neoplasms, including DNMT3A and NRAS, were more commonly mutated in T-ALL with CDKN2B hypermethylation. In particular, a CDKN2B biallelic deletion or high methylation level (≥45%), the age of onset, and the GATA3 and SH2B3 mutations were factors associated with a poor prognosis. This study clarifies that one of the most important genetic events in T-ALL, namely, CDKN2B downregulation, occurs mechanistically via deletion and hypermethylation. Different susceptible genetic backgrounds exist based on the CDKN2B downregulation mechanism.

PRMT5-mediated H4R3sme2 Confers Cell Differentiation in Pediatric B-cell Precursor Acute Lymphoblastic Leukemia.

Little is known about the function of histone arginine methylation in acute lymphoblastic leukemia (ALL). The objective was to evaluate whether protein arginine methyltransferase 5 (PRMT5) plays a role in pediatric ALL and to determine the possible mechanism of epigenetic regulation. We used bone marrow samples from patients with pediatric ALL, the Nalm6 cell line, mature B-cell lines, and mouse xenograft models to evaluate the function of PRMT5 in ALL tumorigenesis. This study showed that PRMT5 and the symmetric dimethylation of H4R3 (H4R3sme2) were upregulated in most initially diagnosed ( We demonstrate that enhanced PRMT5 promotes BCP-ALL leukemogenesis partially by the dysregulation of B-cell lineage differentiation. H4R3sme2 and PRMT5 may serve as potential sensitive biomarkers of pediatric BCP-ALL. Suppression of the activation of PRMT5 may offer a promising therapeutic strategy against pediatric BCP-ALL.

Assessment of l-Asparaginase Pharmacodynamics in Mouse Models of Cancer.

l-asparaginase (ASNase) is a metabolism-targeted anti-neoplastic agent used to treat acute lymphoblastic leukemia (ALL). ASNases anticancer activity results from the enzymatic depletion of asparagine (Asn) and glutamine (Gln), which are converted to aspartic acid (Asp) and glutamic acid (Glu), respectively, in the blood. Unfortunately, accurate assessment of the in vivo pharmacodynamics (PD) of ASNase is challenging because of the following reasons (i) ASNase is resilient to deactivation (ii) ASNase catalytic efficiency is very high and (iii) the PD markers Asn and Gln are depleted ex vivo in blood samples containing ASNase. To address those issues and facilitate longitudinal studies in individual mice for ASNase PD studies, we present here a new LC-MSMS bioanalytical method that incorporates rapid quenching of ASNase for measurement of Asn, Asp, Gln, and Glu in just 10 µL of whole blood, with limits of detection (sn ≥ 101) estimated to be 2.3, 3.5, 0.8, and 0.5 µM, respectively. We tested the suitability of the method in a 5-day, longitudinal PD study in mice and found the method to be simple to perform with sufficient accuracy and precision for whole blood measurements. Overall, the method increases the density of data that can be acquired from a single animal and will facilitate optimization of novel ASNase treatment regimens andor the development of new ASNase variants with desired kinetic properties.

Treatment outcome of pediatric acute lymphoblastic leukemia in Yeungnam region Multicenter retrospective study of Study Alliance of Yeungnam Pediatric Hematology-Oncology (SAYPH).

We aimed to evaluate treatment outcomes of pediatric acute lymphoblastic leukemia (ALL) subgroups by risk-stratification, in the Yeungnam region of Korea. We reviewed the courses of 409 newly diagnosed ALL patients from January 2004 to December 2013 in the Yeungnam region. All patients were classified into three risk groups standard risk (SR, n212), high risk (HR, n153) and very high risk (VHR, n44). The mean follow-up time was 73.6 ± 39.4 months. The 7-year event-free survival (EFS) and overall survival (OS) rates were 78.7 ± 2.1% and 86.8 ± 1.8%, respectively. Significant 7-year EFS and OS rates for SR (84.0 ± 2.7%, 93.7 ± 1.8%), HR (76.5 ± 3.5%, 82.1 ± 3.3%), and VHR (60.6 ± 7.5%, 69.9 ± 7.5%) were observed (P<0.001), respectively. Relapse occurred in 52 patients, and the cumulative 7-year incidence of relapse differed according to risk groups (SR vs. HR vs. VHR12.6% vs. 14.0% vs. 29.6%, P0.003).For the 46 relapsed patients who were treated, the 3-year EFS and OS were 42.3 ± 8.3%and 46.4± 8.4%. Among the 44 VHR patients, EFS was not significantly different between the chemotherapy-treated patients and those received hematopoietic stem cell transplantation (P0.533). The 7-year EFS of the hyperleukocytosis subgroup (24 cases, 14 under 10 years of age)showed a tendency for better prognosis than that of the other VHR subgroups (P0.178). Our results revealed improved outcomes in pediatric ALL patients with risk-stratified therapy. The hyperleukocytosis subgroup without any combined chromosomal abnormalities may respond favorably to chemotherapy alone after first complete remission.

Asparaginase treatment in infants with acute lymphoblastic leukemia pharmacokinetics and asparaginase hypersensitivity in Interfant-06.

Acute lymphoblastic leukemia (ALL) is a rare disease in infants. Asparaginase is an essential part of the treatment, and there Acute is a need to evaluate the efficiency and safety of this drug in this age group. We evaluated the pharmacokinetics of intramuscularly administered native

Treatment patterns, survival, and hospitalization in adult patients with acute lymphoblastic leukemia an observational cohort study using SEER Medicare data.

There is little evidence about whether additional risk stratification for adult patients with acute lymphoblastic leukemia age 65 and older is warranted. Using the Surveillance, Epidemiology, and End Results data linked to Medicare claims, we examined the effects of age, comorbid conditions, and mobility limitations on treatment and survival in a cohort of 795 patients diagnosed with ALL between 1 January 2000 and 31 December 2009. In the cohort, 54% received chemotherapy within the first 90 days, of whom 74% were hospitalized during the first chemotherapy administration. Unadjusted median survival was 172 days (95% CI 244-379) for the overall cohort, 325 days (95% CI 244-379) for those age 65-69, but only 59 days (95% CI 45-76) for those age ≥80. In multivariate analyses, older age groups (70-74, 75-79, and ≥80) and comorbidity score ≥2 were independently associated with poorer survival. Treatment and outcomes vary considerably among subgroups of older patients suggesting that further risk stratification may be useful.

Allogeneic CAR T cell therapies for leukemia.

Allogeneic chimeric antigen receptor T (CAR T) cells can offer advantages over autologous T cell therapies, including the availability of fit cells for production, and elimination of risks associated with inadvertent transduction of leukemic blasts. However, allogeneic T cell therapies must address HLA barriers and conventionally rely on the availability of a suitable HLA-matched donor if graft-vs-host-disease and rejection effects are to be avoided. More recently, the incorporation of additional genome editing manipulations, to disrupt T cell receptor expression and address other critical pathways have been explored. Clinical trials are underway investigating non-HLA matched T cells expressing anti-CD19 CARs for the treatment of B cell acute lymphoblastic leukemia (B-ALL) and anti-CD123 CAR for acute myeloid leukemia (AML). Such approaches continue to be refined and improved to widen accessibility and reduce the cost of T cell therapies for a wider range of conditions.

Thrombophilia screening and thromboprophylaxis may benefit specific ethnic subgroups with paediatric acute lymphoblastic leukaemia.

This study investigated the prevalence of inherited thrombophilia, risk of venous thromboembolism (VTE) and benefit of low molecular weight heparin prophylaxis in 476 Israeli children with acute lymphoblastic leukaemia (ALL) treated between 2004 and 2016. Thrombophilia was found in 15·5%. Arab children had a higher prevalence of F5 R506Q (factor V Leiden) than Jewish children (19·4% vs. 2·9%, P < 0·01). Patients with thrombophilia had higher VTE rates VTE (26·5% vs. 5·6%, P < 0·001). None of the thrombophilic children given prophylaxis had severe VTE. Routine evaluation for inherited thrombophilia followed by thromboprophylaxis when findings are positive may benefit at-risk patients with ALL.

Wnt5a and ROR1 activate non-canonical Wnt signaling via RhoA in TCF3-PBX1 acute lymphoblastic leukemia and highlight new treatment strategies via Bcl-2 co-targeting.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with TCF3-PBX1 fusion gene expression has constitutively elevated levels of Wnt16b and ROR1 (receptor tyrosine kinase-like orphan receptor), a ligand and a receptor from the Wnt signaling pathway, respectively. Although survival rate is usually high after the initial chemotherapy, many TCF3-PBX1 BCP-ALL patients relapse and subsequently develop treatment resistance, resulting in poor prognosis. Here, we aimed to investigate the molecular signaling associated with Wnt16b and ROR1 overexpression in TCF3-PBX1 cell lines and primary samples, and to identify effective treatment options via ROR1 targeting. We detected higher ROR1 expression on TCF3-PBX1 leukemic cells even at a later stage of patient relapse, providing a strong rationale for the use of ROR1-targeted therapy. We found that Wnt5a-ROR1 signaling enhances proliferation of TCF3-PBX1 cells via RhoARac1 GTPases activation and STAT3 upregulation. Wnt16b also activated the RhoARac1 signaling cascade suggesting the activation of a non-canonical Wnt pathway in TCF3-PBX1 cells. Wnt16 could interact with ROR1 but not in TCF3-PBX1 cells, suggesting that Wnt5a is the ligand signaling via ROR1 in TCF3-PBX1 cells. By high throughput drug-sensitivity testing of TCF3-PBX1 cells before and after ROR1 knockdown we found that targeting ROR1 significantly improves the therapeutic efficacy of Bcl-2 family inhibitors venetoclax and navitoclax, and this synergism was confirmed ex vivo using a drug-resistant primary sample from a relapsed TCF3-PBX1 patient. Our work underlines a new type of targeted combination therapy that could be clinically advantageous for patients with TCF3-PBX1 BCP-ALL.

The side population enriches for leukemia-propagating cell activity and Wnt pathway expression in zebrafish acute lymphoblastic leukemia.

Cancer stem cells have been strongly linked to resistance and relapse in many malignancies. However, purifying them from within the bulk tumor has been challenging, so their precise genetic and functional characteristics are not well defined. The side population assay exploits the ability of some cells to efflux Hoechst dye via ATP-binding cassette transporters. Stem cells have increased expression of these transporters and this assay has been shown to enrich for stem cells in various tissues and cancers. This study identifies the side population within a zebrafish model of acute lymphoblastic leukemia and correlates the frequency of side population cells with the frequency of leukemia stem cells (more precisely referred to as leukemia-propagating cells within our transplantation model). In addition, the side population within the leukemia evolves with serial transplantation, increasing in tandem with leukemia-propagating cell frequency over subsequent generations. Sorted side population cells from these tumors are enriched for leukemia-propagating cells and have enhanced engraftment compared to sorted non-side population cells when transplanted into syngeneic recipients. RNA-sequencing analysis of sorted side population cells compared to non-side population cells identified a shared expression profile within the side population and pathway analysis yielded Wnt-signaling as the most overrepresented. Gene set enrichment analysis showed that stem cell differentiation and canonical Wnt-signaling were significantly upregulated in the side population. Overall, these results demonstrate that the side population in zebrafish acute lymphoblastic leukemia significantly enriches for leukemia-propagating cells and identifies the Wnt pathway as a likely genetic driver of leukemia stem cell fate.

Genomic landscape of pediatric B-other acute lymphoblastic leukemia in a consecutive European cohort.

Novel biological subtypes and clinically important genetic aberrations (druggable lesions, prognostic factors) have been described in B-other acute lymphoblastic leukemia (ALL) during the last decade however, due to a lack of studies on unselected cohorts, their population frequency and mutual associations still have to be established. We studied 110 consecutively diagnosed and uniformly treated childhood B-other patients using single nucleotide polymorphism arrays and whole exometranscriptome sequencing. The frequency of

Recent advances and future directions in CAR-T cell therapy in pediatric oncology.

Fighting leukemia using the immune system (antibodies, lymphocytes) is an old idea, which has already been fulfilled in allogeneic bone marrow transplantation. Indeed, the effectiveness of the transplant depends on the action of the donor lymphocytes. To limit the adverse effects on bystander organs (graft-versus-host disease), autologous T cells can be engineered to express synthetic chimeric antigen receptors (CARs) with artificially redirected antigen specificity. Autologous T cells engineered to express a CAR targeting CD19 have shown unprecedented efficacy in clinical trials for relapsedrefractory B-cell leukemias and lymphomas. In this review article, we describe the therapeutic strategies, clinical trial results, side effects and future direction of CAR T cell therapy in B cell acute lymphoblastic leukemia and other pediatric cancers and its future role in the Swiss setting. Combattre la leucémie en utilisant les armes immunologiques, via les anticorps et les lymphocytes, est une idée ancienne, qui a déjà connu un accomplissement dans la greffe de moelle osseuse. Pour limiter les effets néfastes sur d’autres organes (maladie du greffon contre l’hôte), des cellules T autologues peuvent être modifiées pour exprimer des récepteurs d’antigènes chimères synthétiques (CAR) avec spécificité antigénique. Dans le cadre d’essais cliniques, les cellules CAR-T anti-CD19 ont montré une efficacité importante dans les leucémies et les lymphomes B en rechute ou réfractaires. Dans cet article, nous décrivons les approches proposées, les résultats des essais cliniques, les effets secondaires et l’orientation future de ces thérapies dans les leucémies et d’autres cancers pédiatriques ainsi que leurs perspectives dans le contexte suisse.

Successful Management of Hepatosplenic Infection Due to Saccharomyces cerevisiae in a Child With Acute Lymphoblastic Leukemia.

Saccharomyces cerevisiae is an emerging pathogen within the immunocompromised. We present a 4-year-old boy with acute lymphoblastic leukemia presenting with polymerase chain reaction-confirmed hepatosplenic S. cerevisiae infection and significant immune reconstitution symptoms. We explore the challenges of monitoring treatment efficacy using C-Reactive protein, β-D-glucan, and imaging and the administration of chemotherapy alongside antifungals and steroids for control of immune reconstitution syndrome.

Effect of Neutropenic Diet on Infection Rates in Cancer Patients With Neutropenia A Meta-analysis of Randomized Controlled Trials.

Neutropenic diets are commonly prescribed to cancer patients with neutropenia with the intention of reducing rates of infection. These diets are restrictive and are associated with lower patient satisfaction and possibly malnutrition. Further, it is unclear if these restrictive diets are effective in reducing infection. We performed a meta-analysis on the rates of infection reported in trials comparing the neutropenic diet to unrestricted diets in cancer patients with neutropenia. A comprehensive database search for all published randomized controlled trials comparing infection rates in cancer patients receiving a neutropenic diet versus an unrestricted diet was performed for all publications in English language from databases inception until September 12, 2017. The search strategy, study selection, and subsequent analysis adhered to PRISMA guidelines. Random effects modeling was used to obtain pooled relative risks. The primary outcome measure was the rate of infection. Five randomized controlled trials with a total of 388 patients were included in the final analysis. Patients mostly had acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or sarcoma. Infection was noted in 53.7% patients in the neutropenic diet group, as compared with 50% in the unrestricted diet group. No significant difference in infection rate was observed between the neutropenic diet versus unrestricted diet groups, pooled risk ratio (RR) 1.13 (95% CI, 0.98-1.30 P0.10). This meta-analysis of randomized controlled trials suggests that the use of neutropenic diet was not associated with decreased risk of infection in neutropenic cancer patients. The continued use of neutropenic diets should be questioned.