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Participation in Physical Activity and Physical Education in School Among Children With Acute Lymphoblastic Leukemia After Intensive Chemotherapy.

Pterostilbene increases Fas expression in T-lymphoblastic leukemia cell lines.

Treatment of acute lymphoblastic leukemia (ALL) has been promising in last decades, but side effects still persist and searching for the least toxic agents continue. Pterostilbene (PTE) is a natural compound with several anti-cancer and anti-oxidant properties. Fas, as a member of death inducing family of tumor necrosis factor (TNF) receptors with an intracellular death domain, can initiate the extrinsic apoptosis signaling pathway. Here after the half maximal inhibitory concentration (IC

Kdm6b regulates context-dependent hematopoietic stem cell self-renewal and leukemogenesis.

The histone demethylase KDM6B (JMJD3) is upregulated in blood disorders, suggesting that it may have important pathogenic functions. Here we examined the function of Kdm6b in hematopoietic stem cells (HSC) to evaluate its potential as a therapeutic target. Loss of Kdm6b lead to depletion of phenotypic and functional HSCs in adult mice, and Kdm6b is necessary for HSC self-renewal in response to inflammatory and proliferative stress. Loss of Kdm6b leads to a pro-differentiation poised state in HSCs due to the increased expression of the AP-1 transcription factor complex (Fos and Jun) and immediate early response (IER) genes. These gene expression changes occurred independently of chromatin modifications. Targeting AP-1 restored function of Kdm6b-deficient HSCs, suggesting that Kdm6b regulates this complex during HSC stress response. We also show Kdm6b supports developmental context-dependent leukemogenesis for T-cell acute lymphoblastic leukemia (T-ALL) and M5 acute myeloid leukemia (AML). Kdm6b is required for effective fetal-derived T-ALL and adult-derived AML, but not vice versa. These studies identify a crucial role for Kdm6b in regulating HSC self-renewal in different contexts, and highlight the potential of KDM6B as a therapeutic target in different hematopoietic malignancies.

Detection of a cryptic

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm involving the bone marrow and blood that accounts for ∼15% of childhood and 25% of adult ALL. Whereas multiple, recurrent genetic abnormalities have been described in T-ALL, their clinical significance is unclear or controversial. Importantly,

Evaluation of anticancer activity of α-defensins purified from neutrophils trapped in leukoreduction filters.

The α-defensins or human neutrophil peptides (HNP 1-3) that exist in azurophilic granules are found to have anticancer activity. The pattern of disulfide bonds in α-defensins is crucial for the functional properties. Therefore, synthesis using the chemical and recombinant approaches is a challenging. A safe source for the production of α-defensins can be the use of leukoreduction filters in blood banks that contain large quantities of neutrophils and are discarded after use. The aim of this study was to purify α-defensins from neutrophils trapped in leukofilters and to investigate its anticancer activity. Immunoprecipitation was performed to purify α-defensins and the presence of protein was confirmed by Western Blot. The Jurkat T-cell line was incubated with different concentrations (5, 10 and 15 μgml) of purified HNP1-3 for 16 h. Cell viability was measured using a WST-1 assay and apoptosis was analyzed for Annexin VPI markers. Caspase-37 activity was determined using fluorescence assay. The effects of purified α-defensins were compared to commercial HNP 1-3. Purified HNP 1-3 decreased the viability at 10 and 15 μgml and commercial HNP 1-3 at 15 μgml concentrations. Following to the purified HNP1-3 treatment, the percentage of Annexin V positive population and caspase-3 activity were significantly increased compared to control (p 0.000 and p 0.001, respectively) and commercial HNP1-3 (p 0.034 and p 0.018, respectively). Results indicated the anticancer activity of HNP1-3 which can be used as future chemotherapeutic drugs. Furthermore, leukofilters can be considered as economic source for purifying these peptides.

Lineage switch from acute myeloid leukemia to acute lymphoblastic leukemia report of a case.

1例急性髓细胞白血病（AML）患儿治疗后系别转换为急性淋巴细胞白血病（ALL），初诊时及系别转换后白血病细胞的分子生物学及细胞遗传学结果提示它们来源于同一克隆，系疾病的复发。AML复发后转换为ALL临床罕见。.

Bacterial translocation in acute lymphocytic leukemia.

Bloodstream infection (BSI) is the major cause of mortality in acute lymphocytic leukemia (ALL). Causative pathogens in BSI originate from the gut microbiota due to an increase in intestinal permeability, a process known as bacterial translocation (BT). The gut microbiota in physiological conditions is controlled by a large number of immune cells as part of the gut-associated lymphoid tissue (GALT).The aim of the current study was to investigate the mechanism of bacterial translocation in leukemia by identifying and characterizing alterations in the GALT in leukemic mouse model. Our studies revealed a severe impairment of the GALT characterized by a loss of lymphatic cells in ALL, which eventually led to BSI. We identified differentially expressed genes in the intraepithelium and the lamina propria, which may contribute to BT and to the impairment of lymphocyte migration.

Bladder Artery Embolization for Massive Hematuria Treatment in a Patient With Ataxia-Telangiectasia Acute Lymphoblastic Leukemia.

Ataxia-telangiectasia (AT) is a hereditary recessive autosomal disorder following a course of progressive cerebellar ataxia, and oculocutaneous telangiectasia. Disease-specific telangiectasias are generally localized in the oculocutaneous region, while telangiectasias located within the bladder are rarely seen in patients with AT. The patient who had been followed-up with a diagnosis of AT since the age of 3 years was later diagnosed with acute lymphoblastic leukemia at the age of 8 years. The patient developed hematuria approximately in the 29th month of treatment. The cystoscopy revealed regions of extensive hemorrhagic telangiectasis, which was interpreted as the bladder involvement of AT. The case presented here underwent several cycles of intravesical steroid and tranexamic acid treatments and intravesical cauterization procedures, but the patient was unresponsive to all medical treatment approaches. The patient was consequently evaluated by an interventional radiology unit for a selective arterial embolization. The patients hematuria resolved after embolization. Bladder wall telangiectasia may, on rare occasions, develop in patients with AT, and can result in life-threatening hemorrhages. We also suggest that a selective arterial embolectomy can be safely carried out in pediatric patients with treatment-resistant intravesical bleeding.

A novel thiosemicarbazone as a promising effective and selective compound for acute leukemia.

Acute leukemias are a heterogeneous group of aggressive malignant neoplasms associated with severe morbidities due to the nonselectivity of current chemotherapeutic drugs to nonmalignant cells. The investigation of novel natural and synthetic structures that might be used for the development of new drugs with greater efficiency and selectivity to leukemic cells is mandatory. In this context, thiosemicarbazones have been well described in the literature by their several biological properties and their reaction is known as versatile, low-cost, and highly chemoselective. With this perspective, this study aimed to investigate the cytotoxic effect and the main death mechanisms of a novel thiosemicarbazone (LAP17) on acute leukemia cell lines K562 and Jurkat. The results show that the strong cytotoxic effect of LAP17 to leukemic cells is due to apoptosis induction, which resulted in caspase-3 activation and DNA fragmentation. Intrinsic apoptosis seems to be related to the inversion of BaxBcl-2 expression, ΔΨm loss, and AIF release, whereas extrinsic apoptosis was initiated by FasR. Gene-expression profiling of HL-60 cells treated with LAP17 by the microarray technique revealed a significant enrichment of gene sets related to cell cycle arrest at G2M. Accordingly, K562 and Jurkat cells treated with LAP17 revealed a clear arrest at G2M phase. Taking into consideration that LAP17 was not cytotoxic to nonhematological cells (peripheral blood mononuclear cell and erythrocytes), these results suggest that LAP17 is a promising new compound that might be used as a prototype for the development of new antileukemic agents.

Assessment of trace elements in serum of acute lymphoblastic and myeloid leukemia patients.

Trace elements play a key role in human metabolism. The aim of the present study was to measure essential trace elements in the serum of patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). 32 patients with ALL and 16 patients with AML were studied. The control group consisted of 36 subjects. Serum levels of the trace elements selenium, copper and zinc were measured by spectrophotometry. The mean of copper concentrations in the groups of patients with AML and ALL was significantly higher than in the control group (p < 0.0001), whereas serum levels of selenium and zinc were significantly lower in AML patients (p < 0.0001). Also in ALL patients the levels of selenium and zinc were significantly decreased compared with the control group (p < 0.0001 p 0.0003). Our results indicate that the levels of zinc and selenium are significantly decreased and copper levels are significantly increased in the serum of patients with acute leukemia (AML, ALL).

Methotrexate Disposition in Pediatric Patients with Acute Lymphoblastic Leukemia What Have We Learnt From the Genetic Variants of Drug Transporters.

Methotrexate (MTX) is one of the leading chemotherapeutic agents with the bestdemonstrated efficacies against childhood acute lymphoblastic leukemia (ALL). Due to the narrow therapeutic range, significant inter- and intra-patient variabilities of MTX, non-effectiveness andor toxicity occur abruptly to cause chemotherapeutic interruption or discontinuation. The relationship between clinical outcome and the systemic concentration of MTX has been well established, making the monitoring of plasma MTX levels critical in the treatment of ALL. Besides metabolizing enzymes, multiple transporters are also involved in determining the intracellular drug levels. In this mini-review, we focused on the genetic polymorphisms of MTX-disposition related transporters and the potential association between the discussed genetic variants and MTX pharmacokinetics, efficacy, and toxicity in the context of MTX treatment. We searched PubMed for citations published in English using the terms methotrexate, transporter, acute lymphoblastic leukemia, polymorphisms, and therapeutic drug monitoring. The retrieval papers were critically reviewed and summarized according to the aims of this mini-review. Solute carrier (SLC) transporters (SLC19A1, SLCO1A2, SLCO1B1, and SLC22A8) and ATP-binding cassette (ABC) transporters (ABCB1, ABCC2, ABCC3, ABCC4, ABCC5, and ABCG2) mediate MTX disposition. Of note, the influences of polymorphisms of SLC19A1, SLCO1B1 and ABCB1 genes on the clinical outcome of MTX have been extensively studied. Overall, the data critically reviewed in this mini-review article confirmed that polymorphisms in the genes encoding SLC and ABC transporters confer higher sensitivity to altered plasma levels, MTX-induced toxicity, and therapeutic response in pediatric patients with ALL. Pre-emptive determination may be helpful in individualizing treatment.

Long noncoding RNA PVT1 potential oncogene in the development of acute lymphoblastic leukemia.

Emerging evidence shows that long noncoding RNAs (lncRNAs) participate in various cellular processes, and that plasmacytoma variant translocation 1 (PVT1), a newly described oncogene that interacts with various molecules such as p15, p16, NOP2, and c-Myc, is a major contributing factor in tumor development. However, the role of this oncogene remains unknown in the pathogenesis of acute lymphoblastic leukemia (ALL), the most prevalent form of childhood leukemia. In this study, we first measure the expression level of PVT1 in a Jurkat cell line, then small interfering (siRNA) PVT1 is applied to demonstrate the impact of PVT1 knockdown in apoptosis, proliferation, the cell cycle, and its downstream targets. Our findings show that lncRNA was significantly higher in the ALL cell line than normal lymphocytes and that PVT1 knock-down increased the rate of apoptosis, caused G0G1 arrest in the cell cycle, reduced the proliferation rate, and, above all, reduced the stability of c-Myc protein. All findings were confirmed at the molecular level. Our results may indicate the role of PVT1 knock-down in the suppression of ALL development and might provide an option for targeted therapy for leukemic conditions.

Clinical features and risk factors of hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.

Pathway genes and metabolites in thiopurine therapy in Korean children with acute lymphoblastic leukaemia.

We aimed to investigate the impact of various genetic polymorphisms affecting thiopurine metabolism pathways and toxicity in paediatric acute lymphoblastic leukaemia patients for the first time in Korea. From May 2006 to September 2016, 139 paediatric acute lymphoblastic leukaemia patients treated with combination chemotherapy including 6-mercaptopurine were included in the study. One hundred and twenty-three variants in 43 genes, including TMPT and NUDT15, were screened using targeted genotyping, such as a MassARRAY system, direct sequencing and polymerase chain reaction-restriction fragment length polymorphism methods. Among the polymorphisms screened, 103 polymorphisms of 43 genes were included for further analyses. The genetic polymorphisms in the ABCC4, AHCY, ATIC, FAM8A6P, GART, GNG2, GSTA1, MTHFD1, MTHFR, NUDT15, PACSIN2, TYMS and XDH genes, and an intronic polymorphism between HIVEP2 and AIG1, and TPMT genotype were associated with thiopurine metabolism (P < 0.05). Genetic polymorphisms in the ABCC4, ADK, ATIC, GART, GMPS, GSTP1, IMPDH1, ITPA, KCNMA1, MOCOS, MTRR, NUDT15, SLC19A1, SLC28A3, SLC29A1, SLCO1B1, TYMP and XDH genes were associated with thiopurine-related toxicities neutropenia, hepatotoxicity and treatment interruption (P < 0.05). Findings of this study may provide basic knowledge for personalized medicine for thiopurinxe treatment in paediatric acute lymphoblastic leukaemia patients.

Will CAR T cell therapy have a role in AML Promises and pitfalls.

Relapsed andor refractory acute myeloid leukemia (RR AML) has a dismal prognosis. While chimeric antigen receptor T cells (CART) have been successful in improving treatment outcomes for B-lineage acute lymphoblastic leukemia by targeting CD19, the success of this strategy necessitates a cell surface antigen whose depletion can be clinically tolerated. The primary barrier currently preventing the use of CART therapy for AML is the lack of a myeloid equivalent to CD19-that is, an expendable antigen. All currently known cell surface targets on leukemic blasts are shared with healthy hematopoietic stem and progenitor cells or their progeny. Hence, while targeting CD19-expressing cells leads to prolonged B-cell aplasia which is clinically benign, targeting myeloid antigens would lead to prolonged myeloablation which is not clinically tolerable. Creative solutions are being developed to try to circumvent these challenges, using not only CART but a range of adoptive cellular immunotherapy modalities and novel transplant-related approaches to try to extend the successes of CART therapy to patients with AML.

High RASD1 transcript levels at diagnosis predicted poor survival in adult B-cell acute lymphoblastic leukemia patients.

B-cell acute lymphoblastic leukemia (B-ALL) in adults remains a highly challenging disease. Identifying new prognostic biomarkers is necessary to help select the best therapeutic schedules and to improve prognosis. We performed bioinformatics analyses of transcriptomic data to identify aberrantly-expressed mRNA transcripts in B-ALL and focused on RASD1 (Ras-related dexamethasone-induced 1). To date, no information is available on the prognostic value of RASD1 in B-ALL. Fifty-three consecutive adults with de novo B-ALL were enrolled in this study. Our data suggested that RASD1 was abnormally overexpressed in B-ALL. High RASD1 transcript levels at diagnosis were associated with lower survival probabilities (44% 20%-61% vs. 79% 60%-97% P 0.037) and were also an independent prognostic factor in adult B-ALL (HR 4.9 1.5-15.9 P 0.008). Functional in vitro analyses and bioinformatic analyses indicated that RASD1 promoted cell proliferation, cell cycle progression and chemotherapy resistance and inhibited cell apoptosis. These data demonstrated that RASD1 might serve as a novel prognostic biomarker for adult B-ALL and as a potential therapeutic target in adult B-ALL patients.

Treatment of venous thromboembolism in acute leukemia A systematic review.

The safety and efficacy of venous thromboembolism (VTE) treatment in patients with acute leukemia (AL) are not well understood and the optimal treatment strategy is unclear. We conducted a systematic review of the literature aiming to identify observational studies and randomized trials describing treatment of VTE in the setting of AL including, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), and acute lymphoblastic leukemia (ALL). Due to the heterogeneity of findings, no meta-analysis was attempted. A total of 13 observational studies (11 cohorts and 2 case-control) totaling 5359 participants were included. The number of patients with VTE among the total population was 304 (5.7% 95% CI 5.1-6.3). In patients with VTE, 221 patients received treatment with anticoagulation using either of low-molecular-weight heparin, unfractionated heparin, andor vitamin K antagonists. Most studies adjusted the anticoagulant dose based on platelet count. The reported recurrence rate ranged from 0 to 29% among different studies and varied according to the duration of anticoagulant treatment and follow up. Bleeding events were not uniformly reported but the total number was low among anti-coagulated patients. There is a significant lack of data in this area with a high degree of heterogeneity in the choice of anticoagulant, dose adjustments for thrombocytopenia, and duration of anticoagulation. Further studies are required to develop guidelines and suggestions for treatment of VTE in AL.

Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study.

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate used for adults with relapsedrefractory B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The INotuzumab Ozogamicin trial to inVestigAte Tolerability and Efficacy (INO-VATE) previously reported improved outcomes with InO versus standard-of-care (SoC) chemotherapy. This article reports the final INO-VATE results (≥2 years of follow-up) and additional analyses of patient characteristics associated with improved outcomes. Between August 27, 2012, and January 4, 2015, this multicenter, parallel, open-label, phase 3 trial randomized 326 adults with relapsedrefractory ALL to InO (n 164) or SoC (n 162) 307 received 1 or more doses of the study drug (164 in the InO arm and 143 in the SoC arm). The complete remission (CR)complete remission with incomplete hematologic recovery (CRi) rate was higher with InO versus SoC (73.8% vs 30.9% 1-sided P < .0001), with consistent CRCRi rates across patient subgroups. The median overall survival (OS) was 7.7 months with InO and 6.2 months with SoC, with 2-year OS rates of 22.8% and 10.0%, respectively (overall hazard ratio, 0.75 97.5% confidence interval CI, 0.57-0.99 1-sided P .0105). The predictors of OS with InO were the best minimal residual disease status, baseline platelet count, duration of first remission, achievement of CRCRi, and follow-up hematopoietic stem cell transplantation (HSCT all 2-sided P values < .05). More InO arm patients proceeded directly to HSCT after achieving CRCRi before any follow-up induction therapy (39.6% 95% CI, 32.1%-47.6% vs 10.5% 6.2%-16.3% 1-sided P < .0001). The most frequent all-grade and grade 3 or higher adverse events in both arms were hematologic. Veno-occlusive disease (VOD)sinusoidal obstruction syndrome (SOS) was more frequent with InO (23 of 164 14.0% vs 3 of 143 2.1%). In patients with relapsedrefractory BCP ALL in INO-VATE, InO was associated with a greater likelihood of CRCRi across key patient subgroups, and it served as a bridge to HSCT. Potential VODSOS risk factors must be considered when InO treatment decisions are being made.

Acute Lymphoblastic Leukemia with Malignant Hypercalcemia A Case Report.

BACKGROUND Malignant hypercalcemia is a rare finding in the pediatric population, even more rare in hematological malignancies, such as leukemia. CASE REPORT We present a case of a 6-year-old female patient who was diagnosed with acute lymphoblastic leukemia, with secondary hypercalcemia. She started chemotherapy following the IC-BFM ALL2002 protocol with simultaneous calcitonin, diuretics and aggressive hydration for hypercalcemia, and went into complete remission after the induction therapy. After 4 months of chemotherapy, she was diagnosed with relapse associated again with malignant hypercalcemia, and underwent chemotherapy with the relapse protocol. There was no response after the first 2 cycles, so we decided to start her on clofarabine. Due to the severe hypercalcemia and consecutive osteolysis, she developed several bone fractures and needed gypsum immobilization. We started her again on calcitonin, but she developed severe adverse reactions, so we found it necessary to start bisphosphonates, first zoledronic acid intravenously, and afterwards clodronate orally. Consolidation of bone fractures was achieved, but due to prolonged immobilization she developed bedsores, superinfected with Lichtheimia corymbifera. We started posaconazole orally, but she rapidly went into severe sepsis with multiple organ failure. The leukemia showed no response to chemotherapy, progressed rapidly, and the patient died. CONCLUSIONS Malignant hypercalcemia is associated with a poor prognosis in leukemia, and might need a more aggressive therapy.

Optimizing pegylated asparaginase use An institutional guideline for dosing, monitoring, and management.

The incorporation of L-asparaginase and pegylated asparaginase into pediatric-inspired regimens has conferred a survival advantage in treatment of adults with acute lymphoblastic leukemia. Use of asparaginase products requires careful prevention, monitoring, and management of adverse effects including hypersensitivity, hepatotoxicity, pancreatitis, coagulopathy, and thrombosis. Currently, there is limited published literature to offer guidance on management of these toxicities. At the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, a standard of practice guideline was created to prevent and manage asparaginase-related adverse events. By sharing our long-term experience with asparaginase products and clinical management of asparaginase-induced toxicities, this article aims to improve patient safety and optimize treatment outcomes.

Ikaros family zinc finger 1 mutation is a poor prognostic factor for adult Philadelphia chromosome positive acute lymphoblastic leukemia.

Dasatinib as an investigational drug for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia in adults.

Acute lymphoblastic leukemia (ALL) with BCR-ABL1 translocation is an aggressive malignancy that is usually treated with intensive chemotherapy with the possibility of allogeneic stem cell transplantation. The encoded fusion protein may be important for leukemogenesis clinical studies show that dasatinib has an antileukemic effect in combination with steroids alone or intensive chemotherapy. Areas covered Relevant publications were identified through literature searches (the used terms being acute lymphoblastic leukemia plus dasatinib) in the PubMed database. We searched for original articles and reviews describing the pharmacology and clinical use of dasatinib in ALL with BCR-ABL1. The mechanism of action, pharmacology and clinical study findings are examined. Expert opinion Dasatinib is associated with a high complete remission rate in ALL when used alone and in combination with steroids or intensive chemotherapy. However, mutations at T315 and F317 are associated with dasatinib resistance. Overall toxicity has been acceptable in these studies and no unexpected toxicity was observed. It is not known whether the antileukemic effect of dasatinib differs between subsets of BCR-ABL1

The poor prognosis of low hypodiploidy in adults with B-cell precursor acute lymphoblastic leukaemia is restricted to older adults and elderly patients.

The prognostic significance of low-hypodiploidy has not been extensively evaluated in minimal residual disease (MRD)-oriented protocols for adult acute lymphoblastic leukaemia (ALL). We analysed the outcome of hypodiploid adult ALL patients treated within Programa Español de Tratamientos en Hematología (PETHEMA) protocols. The 5-year cumulative incidence of relapse (CIR) of low-hypodiploid B-cell precursor (BCP)-ALL was significantly higher than that of high-hypodiploids (52% vs. 12%, P 0.013). Low-hypodiploid BCP-ALL patients aged ≤35 years showed superior survival (71% vs. 21%, P 0.026) and lower 5-year CIR (17% vs. 66%, P 0.090) than low-hypodiploids aged >35 years. Older adults and elderly low-hypodiploid BCP-ALL patients show dismal prognosis although achieving an end-induction good MRD response.

S100A16 suppresses the growth and survival of leukaemia cells and correlates with relapse and relapse free survival in adults with Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia.

Refinement of risk stratification in Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukaemia (ALL) might aid the identification of patients who are likely to relapse. Abnormal S100 calcium binding protein A16 (S100A16) has been implicated in various cancers, but its function remains unclear. We found S100A16 transcript levels were higher in 130 adults with newly-diagnosed Ph-negative B-cell ALL compared with 33 healthy controls. In 115 of 130 patients who achieved first complete remission, those with high S100A16 transcript levels displayed a lower 3-year cumulative incidence of relapse (CIR 34% 21, 47% vs. 40% 48, 72% P 0·012) and higher 3-year relapse-free survival (RFS 65% 53, 78% vs. 35% 23, 46% P 0·012), especially when receiving chemotherapy only. In multivariate analysis a low S100A16 transcript level was independently-associated with a higher CIR (Hazard ratio HR 3·74 1·01-13·82 P 0·048) and inferior RFS (HR 5·78 1·91, 17·84 P < 0·001). Function analysis indicated that knockdown of S100A16 promoted proliferation and anti-apoptosis and reduced chemosensitivity. S100A16 over-expression revealed an opposite trend, especially in a xeno-transplant mouse model. Western blotting analysis showed upregulation of PI3KAKT and ERK12 in S100A16-knockdown and S100A16-overexpression B-cell ALL cell lines respectively. Inhibition assays suggested these two signalling pathways participated in the S100A16-mediated proliferation and survival effects in B-cell ALL cell lines. Trial Registration Registered in the Chinese Clinical Trial Registry ChiCTR-OCH-10000940 httpwww.chictr.org.cn.

Primary Cutaneous T-Cell Lymphoblastic Lymphoma Case Report and Literature Review.

Cutaneous involvement by precursor T-cell lymphoblastic leukemialymphoma (T-ALLLBL) is rare, and almost all cases are seen in association with bone marrow, blood, andor lymph node involvement. Presentation with isolated skin involvement is very rare. Literature review revealed only one case report of primary cutaneous T-cell LBL. We discuss here another patient diagnosed with primary cutaneous T-cell LBL at our institute. This patient was initially misdiagnosed as having peripheral T-cell lymphoma NOS. Cytogenetic analysis showed the CDKN2A deletion (-9p21×2) in addition to three intact copies of ABL1 (9q34). Although she failed multiple lines of intensive chemotherapy, her disease remained confined to the skin. We believe that this presentation of T-LBL is underreported, and many patients are likely misdiagnosed as having high-grade cutaneous T-cell lymphomas. With this case and literature review, we would like to highlight the importance of keeping lymphoblastic lymphoma on the differential diagnosis of cutaneous T-cell lymphoma-like lesions to avoid delay in diagnosis and inappropriate treatment of this aggressive disease.

Detection of novel fusion-transcripts by RNA-Seq in T-cell lymphoblastic lymphoma.

Fusions transcripts have been proven to be strong drivers for neoplasia-associated mutations, although their incidence in T-cell lymphoblastic lymphoma needs to be determined yet. Using RNA-Seq we have selected 55 fusion transcripts identified by at least two of three detection methods in the same tumour. We confirmed the existence of 24 predicted novel fusions that had not been described in cancer or normal tissues yet, indicating the accuracy of the prediction. Of note, one of them involves the proto oncogene TAL1. Other confirmed fusions could explain the overexpression of driver genes such as COMMD3-BMI1, LMO1 or JAK3. Five fusions found exclusively in tumour samples could be considered pathogenic (NFYG-TAL1, RIC3-TCRBC2, SLC35A3-HIAT1, PICALM MLLT10 and MLLT10-PICALM). However, other fusions detected simultaneously in normal and tumour samples (JAK3-INSL3, KANSL1-ARL17AB and TFG-ADGRG7) could be germ-line fusions genes involved in tumour-maintaining tasks. Notably, some fusions were confirmed in more tumour samples than predicted, indicating that the detection methods underestimated the real number of existing fusions. Our results highlight the potential of RNA-Seq to identify new cryptic fusions, which could be drivers or tumour-maintaining passenger genes. Such novel findings shed light on the searching for new T-LBL biomarkers in these haematological disorders.

Inhibition of PI3KmTOR Pathways with GDC-0980 in Pediatric Leukemia Impact on Abnormal FLT-3 Activity and Cooperation with Intracellular Signaling Targets.

GDC-0980 is a selective small molecule inhibitor of class I PI3K and mTOR pathway with a potent anti-proliferative activity. We set out to evaluate the efficacy of GDC-0980, in pre-clinical studies, against pediatric leukemia cells. The anti-neoplastic activity of GDC-0980 was evaluated in vitro using five different pediatric leukemia cells. Our data show that GDC-0980 significantly inhibited the proliferation of leukemia cell lines, KOPN8 (IC50, 532 nM), SEM (IC50,720 nM), MOLM-13 (IC50,346 nM), MV411 (IC50,199 nM), and TIB-202 (IC50, 848 nM), compared to normal control cells (1.23 µM). This antiproliferative activity was associated with activation of cellular apoptotic mechanism characterized by a decrease in Bcl-2 protein phosphorylation and enhanced PARP cleavage. Western blot analyses of GDC-0980 treated cells also showed decreased phosphorylation levels of mTOR, Akt and S6, but not ERK12. Notably, FLT3 phosphorylation was decreased in Molm-13 and MV411 cells following the application of GDC-0980. We further examined cellular viability of GDC-0980-treated primary leukemia cells isolated from pediatric leukemia patients. This study revealed a potential therapeutic effect of GDC-0980 on two ALL patients (IC50s, 1.23 and 0.625 µM, respectively). Drug combination analyses of GDC-0980 demonstrated a synergistic activity with the MEK inhibitor Cobimetinib (MV4-11 11, CI, 0.25, SEM, CI, 0.32, and TIB-202, CI, 0.55) and the targeted FLT3 inhibitor, Crenolanib (MV4-11 11, CI, 0.25, SEM, CI, 0.7, and TIB-202, CI, 0.42). These findings provide initial proof-of-concept data and rationale for further investigation of GDC-0980 in selected subgroups of pediatric leukemia patients.

A cross-sectional follow-up study of physical morbidities, neurocognitive function, and attention problems in post-treatment childhood acute lymphoblastic leukemia survivors.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. While ALL therapies are highly effective, western studies have shown excesses late life effects of therapies in survivors. In this survey, we recruited subjects being diagnosed as ALL before the age of 18-year-old and had been in complete continuous remission for at least 3 years. Subjects were arranged to receive three cognitive tests (Wechsler intelligence test, Conners continuous performance test, and Wisconsin card sorting test). Standardized questionnaires were used to inquiry about attention problem in real life context. Treatment outcome were compared between the standard risk and highvery high risk groups. Final survivors were 42 subjects (26 males, 16 females) with median current age of 17.8 years. Subjects were diagnosed to be with ALL at a median age of 4.8 years. The median survival time (from discontinuation of ALL treatment to the study date) was 8.4 years. Results indicated that 17 subjects (40.5%) had chronic physical conditions in need of clinical management and six subjects (14.3%) had mental condition. For the performance-based cognitive outcome, the average full scale intelligence quotient was 91.7 ± 13.8. Ten percent of the subjects had problem in test of attention, 20% had problem in test of impulsivity and 42.8% of the subject had problems in executive function. When judged from real life contexts, 19 subjects (42%) were with obvious attention problems. Group comparison between standard risk vs highvery high risk patients revealed no difference in neurocognitive outcomes. We hope that this information may benefit the implementation of follow-up program for Taiwanese pediatric leukemia survivors.

Tungsten Blocks Murine B Lymphocyte Differentiation and Proliferation Through Downregulation of IL-7 ReceptorPax5 Signaling.

Tungsten is an emerging environmental toxicant associated with several pediatric leukemia clusters, although a causal association has not been established. Our previous work demonstrated that tungsten exposure resulted in an accumulation of pre-B cells in the bone marrow, the same cell type that accumulates in pediatric acute lymphoblastic leukemia (ALL). To better understand the relevant molecular mechanisms, we performed RNA-sequencing on flow sorted pre-B cells from control and tungsten-exposed mice. Tungsten decreased the expression of multiple genes critical for B cell development, including members of the interleukin-7 receptor (IL-7R) and pre-B cell receptor signaling pathways, such as Jak1, Stat5a, Pax5, Syk, and Ikzf3. These results were confirmed in an in vitro model of B cell differentiation, where tungsten arrested differentiation at the pro-B cell stage and inhibited proliferation. These changes were associated with decreased expression of multiple genes in the IL-7R signaling pathway and decreased percentage of IL-7R, phosphorylated STAT5 double-positive cells. Supplementation with IL-7 or overexpression of Pax5, the transcription factor downstream of IL-7R, rescued the tungsten-induced differentiation block. Together, these data support the hypothesis that IL-7RPax5 signaling axis is critical to tungsten-mediated effects on pre-B cell development. Importantly, many of these molecules are modulated in ALL.

The effect of adopting pediatric protocols in adolescents and young adults with acute lymphoblastic leukemia in pediatric vs adult centers An IMPACT Cohort study.

Retrospective studies have shown adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) have superior survival when treated in pediatric versus adult centers (locus of care LOC). Several adult centers recently adopted pediatric protocols. Whether this has narrowed LOC disparities in real-world settings is unknown. The IMPACT Cohort is an Ontario population-based cohort that captured demographic, disease and treatment (treatment protocol, chemotherapy doses) data for all 15-21 year olds diagnosed with ALL 1992-2011. Cancer outcomes were determined by chart abstraction and linkage to provincial healthcare databases. Treatment protocols were classified as pediatric- or adult-based. We examined predictors of outcome, including LOC, protocol, disease biology, and time period. Of 271 patients, 152 (56%) received therapy at adult centers. 5-year event-free survival (EFS ± SE) among AYA at pediatric vs adult centers was 72% ± 4% vs 56% ± 4% (P 0.03) 5-year overall survival (OS) was 82% ± 4% vs 64% ± 4% (P < 0.001). After adjustment, OS remained inferior at adult centers (hazard ratio 2.5 95% confidence interval 1.1-6.1 P 0.04). In the most recent period (2006-2011), 3959 (66%) AYA treated at adult centers received pediatric protocols. These AYA had outcomes superior to the 20 AYA treated on adult protocols, but inferior to the 44 AYA treated at pediatric centers (EFS 72% ± 5% vs 60% ± 9% vs 81% ± 6% P 0.02 OS 77% ± 7% vs 65% ± 11% vs 91% ± 4% P 0.004). Induction deaths and treatment-related mortality did not vary by LOC. Survival disparities between AYA with ALL treated in pediatric vs adult centers have persisted over time, partially attributable to incomplete adoption of pediatric protocols by adult centers. Although pediatric protocol use has improved survival, residual disparities remain, perhaps due to other differences in care between adult and pediatric centers.

The effect of decitabine on the expression and methylation of the PPP1CA, BTG2, and PTEN in association with changes in miR-125b, miR-17, and miR-181b in NALM6 cell line.

Precursor B-cell acute lymphoblastic leukemia (B-ALL) is the most prevalent pediatric cancer. DNA methylation and changes in the microRNAs (miRNAs) expression are known to be important causes of B-ALL. Decitabine as a DNA methyltransferase inhibitor agent is able to induce hypomethylation in several tumor suppressor genes. Much evidence has proven BTG2, PPP1CA, and PTEN act as tumor suppressor genes in many malignancies. In this case control study, the messenger RNA (mRNA) expression of PPP1CA, BTG2, and PTEN genes using quantitative real-time polymerase chain reaction (rRT-PCR) in Nalm6 cell line and five patients suffer from ALL with mean age 5.6 years were determined in compare with seven normal healthy donors age and sex matched. qRT-PCR analysis revealed that the expression levels of PPP1CA, BTG2, and PTEN genes were significantly decreased in Nalm6 (FC 0.46, FC 0.046, FC 0.54) and according to the Methylation-specific PCR (MSP) analysis, these genes were hypermethylated in Nalm6. In next step, the effects of decitabine treatment on the methylation and expression of these genes in association with changes in miR-125b, miR-17, and miR-181b expression levels were evaluated in optimal concentration 2.5 µM of decitabine. Our data showed that decitabine is able to restore the expression levels of aforementioned genes and downregulate expression levels of oncomiRs including miR-125b, miR-17, and miR-181b in Nalm6 cell line. Therefore, it seems that decitabine can be used as a potential drug for the first line treatment of patients with B-ALL, but further in vivo investigation is necessary.

WP1130 reveals USP24 as a novel target in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is a lymphoid malignancy caused by the oncogenic transformation of immature T-cell progenitors with poor outcomes. WP1130 has shown potent activity against a variety of cancer but whether WP1130 has anti-T-ALL activity is not clear. USP24, one target of WP1130, is one of the largest deubiquitinases and its detailed mechanism is poorly understood. The aim of this study was to explore whether WP1130 could suppress T-ALL and the role of USP24 in T-ALL. Molecular docking and cellular thermal shift assay were performed to determine whether and how WP1130 directly interact with USP24. Mitochondrial transmembrane potential assay was measured via Rhodamine 123 staining. USP24 was reactivated using the deactivated CRISPR-associated protein 9 (dCas9)-synergistic activation mediator (SAM) system. The in vivo results were examined by tumor xenografts in NOD-SCID mice. All statistical analyses were performed with the SPSS software package. WP1130 treatment decreased the viability and induces apoptosis of T-ALL cells both in vitro and in vivo. Furthermore, we demonstrated that knockdown of USP24 but not USP9X could significantly induce growth inhibition and apoptosis of T-ALL cells. Oncomine database showed that USP24 expression was upregulated in T-ALL samples and Kaplan-Meier results indicated that the USP24 was negatively but USP9X was positively associated with survival in T-ALL patients. Additionally, we proposed that WP1130 directly interacts with the activity site pocket of USP24 in T-ALL cells, which leads to the decrease of its substrates Mcl-1. Mechanistically, WP1130 induces apoptosis by accelerating the collapse of mitochondrial transmembrane potential via USP24-Mcl-1 axis. Altogether, using WP1130 as a chemical probe, we demonstrate that USP24 but not USP9X is a novel target in T-ALL cells. Moreover, we uncovered that WP1130 induces apoptosis by accelerating the collapse of mitochondrial transmembrane potential via USP24-Mcl-1 axis. These results provide that USP24-Mcl-1 axis may represent a novel strategy in the treatment of T-ALL and WP1130 is a promising lead compound for developing anti-T-ALL drugs.

Bone Loss in Pediatric Survivors of Acute Lymphoblastic Leukemia.

Bone mineral density (BMD) in children may be negatively affected by acute lymphoblastic leukemia (ALL) or its treatment protocol. The aim of our study was to evaluate bone health by measuring BMD after ALL treatment. The age, anthropometric measurements, and lumbar spine BMDs were recorded in 39 pediatric survivors of ALL, with no history of relapse, secondary malignancy, or transplantation. The lumbar spine BMD was measured by dual energy x-ray absorptiometry. The BMD risk factors, pubertal status, age at diagnosis, risk category, the time interval from the completion of the chemotherapy, and cranial radiotherapy were investigated. Serum calcium, phosphate, alkaline phosphates, magnesium, parathormone, and 25-hydroxy vitamin D levels were determined. The mean BMD value was calculated as 0.668±0.176 gcm Early detection and intervention strategies to optimize bone health are essential in pediatric patients with ALL.

Characterization of 6-Mercaptopurine Transport by the SLC43A3-Encoded Nucleobase Transporter.

6-Mercaptopurine (6-MP) is a nucleobase analog used in the treatment of acute lymphoblastic leukemia and inflammatory bowel disorders. However, the mechanisms underlying its transport into target cells have remained elusive. The protein encoded by SLC43A31 equilibrative nucleobase transporter 1 (ENBT1) has recently been shown to transport endogenous nucleobases. A splice variant (SLC43A32), encoding a protein with 13 additional amino acids in the first extracellular loop, is also expressed but its function is unknown. We hypothesized that 6-MP is a substrate for both variants of ENBT1. Human embryonic kidney 293 (HEK293) cells (lacking endogenous ENBT1 activity) were transfected with each of the coding region variants of SLC43A3. ENBT1 function was assessed via the rate of flux of

Genetics and mechanisms of NT5C2-driven chemotherapy resistance in relapsed ALL.

Mutations in the cytosolic 5 nucleotidase II (

Restraining the Proliferation of Acute Lymphoblastic Leukemia Cells by Genistein through Up-regulation of B-cell Translocation Gene-3 at Transcription Level.

Acute lymphoblastic leukemia (ALL) is a highly prevalent pediatric cancer accounting for approximately 78% of leukemia cases in patients younger than 15 years old. Different studies have demonstrated that B-cell translocation gene 3 ( ALL cell lines (MOLT4, MOLT17, and JURKAT) were cultured in standard conditions. Cytotoxicity of genistein was detected using MTT assay. The cells were treated with different concentrations of genistein (10, 25, 40, and 55μM) for 24, 48, and 72 hours, and then cell viability and growth rate were measured. The quantitative real-time polymerase chain reaction was applied to investigate the effect of genistein on The percentage of vital cells treated with genistein significantly decreased compared to the non-treated cells, showed an inverse relationship with an increasing genistein concentration. The present study suggests a dose of 40μM for genistein as a potent anticancer effect. Genistein could elevate Up-regulation of

Development of acute lymphoblastic leukemia following treatment for acute myeloid leukemia in children with Down syndrome A case report and retrospective review of Childrens Oncology Group acute myeloid leukemia trials.

Children with Down syndrome have a 150-fold increased risk of developing acute myeloid leukemia (AML) and 20-fold increased risk of developing acute lymphoblastic leukemia (ALL). Although the risk of developing AML and ALL is significantly increased in children with Down syndrome, the development of both malignancies in the same patient is very rare. We describe a patient with Down syndrome who developed ALL 6 years after being diagnosed with AML. We performed a literature review and Childrens Oncology Group query and discovered eight published cases and five cases of ALL following AML in pediatric patients with Down syndrome, as well as six cases of ALL following AML in non-Down syndrome patients. There was a similar cumulative incidence of ALL after treatment for AML in the Down syndrome and non-Down syndrome populations. Overall survival in patients with Down syndrome who developed ALL after treatment for AML was comparable to overall survival for patients with Down syndrome with de novo ALL with an average follow-up of 7 years after ALL diagnosis. Clinical data collected were used to discuss whether this phenomenon represents a secondary leukemia, second primary cancer, or mixed-lineage leukemia.

Clinical Predictors and Prognostic Model for Pediatric Lymphoblastic Lymphoma Treated With Uniform BFM90 Protocol A Single-Center Experience of 65 Patients From Asia.

There is a lack of clinical predictors for prognosticating lymphoblastic lymphoma (LBL). In view of this lacuna, we evaluated outcomes and prognostic factors for LBL treated with a uniform protocol at our center. This study included consecutive patients of pediatric LBL aged ≤18 years from January 2003 to January 2017. Patients were staged using the St Jude staging system. All patients were treated with acute lymphoblastic leukemia like BFM90 protocol. The Kaplan-Meier method was used for survival analysis. A statistical model was made using stepwise regression and forward selection of the factors predicting event-free survival (EFS) and overall survival (OS). Sixty-five patients were evaluated with a median age of 12 years (range, 1-18 years) and malefemale ratio of 2.251. Fifty-four patients presented with mediastinal disease. Median follow-up was 54.57 months (range, 0.6-140.5 months). EFS at 10 years was 62 ± 6% (95% confidence interval CI, 0.49-0.73) and OS 71 ± 5% (95% CI, 0.57-0.81). In multivariate analysis, symptom duration ≤30 days, white blood cell (WBC) count >12000µL and serum albumin ≤3.5 gdL predicted inferior EFS and OS. A prognostic model with these 3 factors suggested that those without any of these risk factors had an OS of 92 ± 5% whereas those with 2 or 3 factors had an OS of 37 ± 14%. Our outcomes are 15% to 20% lower than in the published literature. Low albumin level, high WBC count at baseline, and symptom duration <30 days emerged as adverse predictors for EFS and OS. These clinical predictors and prognostic model for pediatric LBL should be validated in prospective cohorts.

Cut-and-Run A Distinct Mechanism by which V(D)J Recombination Causes Genome Instability.

V(D)J recombination is essential to generate antigen receptor diversity but is also a potent cause of genome instability. Many chromosome alterations that result from aberrant V(D)J recombination involve breaks at single recombination signal sequences (RSSs). A long-standing question, however, is how such breaks occur. Here, we show that the genomic DNA that is excised during recombination, the excised signal circle (ESC), forms a complex with the recombinase proteins to efficiently catalyze breaks at single RSSs both in vitro and in vivo. Following cutting, the RSS is released while the ESC-recombinase complex remains intact to potentially trigger breaks at further RSSs. Consistent with this, chromosome breaks at RSSs increase markedly in the presence of the ESC. Notably, these breaks co-localize with those found in acute lymphoblastic leukemia patients and occur at key cancer driver genes. We have named this reaction cut-and-run and suggest that it could be a significant cause of lymphocyte genome instability.

First case of neutropenia and thrombocytopenia in the setting of cerebral cavernous malformation 3.

Cerebral cavernous malformation 3 (CCM3) is a vascular malformation disorder causing brain slow-flow vascular parenchymal lesions. These lesions are the result of variants in the Programmed Cell Death Protein 10 (PDCD10) gene, located on 3q26.1. We report an 8-month-old patient who was presented with seizures and intracranial abscesses and was found to have a variant of PDCD10 on whole exome sequencing, representing, to our knowledge, the youngest case of CCM3 described in the literature. Her clinical course was complicated by the development of neutropenia, requiring granulocyte colony-stimulating factor, and thrombocytopenia, requiring intermittent platelet transfusions, with later development of B acute lymphoblastic leukemia 2 years after initial presentation. This case represents the first description in the literature of hematologic complications in the setting of CCM3. We hypothesize that these hematological manifestations are the result of alterations in the actin and microtubule cytoskeleton, affecting the process of hematopoiesis in a similar fashion to the documented effect of the PDCD10 variant on neuronal migration.

Metabolomics of neonatal blood spots reveal distinct phenotypes of pediatric acute lymphoblastic leukemia and potential effects of early-life nutrition.

Early-life exposures are believed to influence the incidence of pediatric acute lymphoblastic leukemia (ALL). Archived neonatal blood spots (NBS), collected within the first days of life, offer a means to investigate small molecules that reflect early-life exposures. Using untargeted metabolomics, we compared abundances of small-molecule features in extracts of NBS punches from 332 children that later developed ALL and 324 healthy controls. Subjects were stratified by early (1-5 y) and late (6-14 y) diagnosis. Mutually-exclusive sets of metabolic features - representing putative lipids and fatty acids - were associated with ALL, including 9 and 19 metabolites in the early- and late-diagnosis groups, respectively. In the late-diagnosis group, a prominent cluster of features with apparent 182 fatty-acid chains suggested that newborn exposure to the essential nutrient, linoleic acid, increased ALL risk. Interestingly, abundances of these putative 182 lipids were greater in infants who were fed formula rather than breast milk (colostrum) and increased with the mothers pre-pregnancy body mass index. These results suggest possible etiologic roles of newborn nutrition in late-diagnosis ALL.

Nasal embryonal rhabdomyosarcoma with bone marrow metastasis simulating acute leukemia A case report and review of the literature.

We present a case of a nasal rhabdomyosarcoma (RMS) in a 27-year-old male with epistaxis and nasal obstruction due to a mass, which was subjected to prophylactic tumor embolization. However, histopathological study on the nasal biopsy was impossible due to necrotic changes. As blast cells were present in peripheral blood samples, a bone marrow biopsy was recommended in order to reach a definitive diagnosis. The possibility of an RMS in cases of bone marrow infiltration by a diffuse tumor constituted by small, round, blast-like cells mimicking acute leukemia should be assessed. Immunohistochemical staining in bone marrow biopsy and flow cytometry in aspirate samples may help to establish the diagnosis (CD45 negativity and CD56 positivity) and cytogenetic studies can be useful in identifying a RMS subtype. When clinically possible, it is desirable to await the results of the tumor immunophenotype and those of the primary mass or bone marrow biopsy to avoid possible errors of diagnosis and treatment.

Development and validation of a UPLC-UV method for the quantification of thiopurine methyltransferase enzyme activity in human erythrocytes.

Thiopurines are drugs widely used for the treatment of autoimmune conditions, inflammatory bowel disease or acute lymphoblastic leukemia. Determination of thiopurine methyltransferase activity (TPMT), a major determinant of thiopurines toxicity, has been suggested before implementing thiopurine treatment. An ultraperformance liquid chromatography (UPLC) method was developed and validated for the quantification of TPMT enzyme activity based on the conversion of 6-mercaptopurine (6-MP) to 6-methylmercaptopurine (6-MMP) using S-adenosyl-L-methionine (SAM) as methyl donor in red blood cell lysates (RBC). This method was improved from a previous laborious high performance liquid chromatography (HPLC) method, using a lower volume of injection and with a shorter runtime. After incubation and protein precipitation 6-MMP was separated on a HSS-T3 (2.1 × 50 mm, 1.8 μm) column and monitored by UV detection (290 nm). A change on the organic solvent used to dissolve 6-MP resulted in a reduction of interference by endogenous or non-enzymatic methylated 6-MMP. A full validation of the 6-MMP assay was performed according to the FDA and EMA guidelines. The method was linear from 0.125 to 2 nmolmL, with acceptable values of accuracy and precision. The method was applied in 106 patients treated with thiopurines whose TPMT activity was previously quantified by HPLC. Evaluation through Bland-Altman plot showed that TPMT activities were in agreement between both methods.

Nonmetropolitan residence and other factors affecting clinical trial enrollment for adolescents and young adults with cancer in a US population-based study.

Cancer survival rates in adolescents and young adults (AYAs) have shown slow improvements in comparison with other age groups, and this may be due to lower participation in clinical trials. Little evidence has been provided regarding how nonmetropolitan residence may influence clinical trial enrollment for AYAs with cancer. This study sought to determine whether AYAs from nonmetropolitan areas have lower rates of clinical trial enrollment than their urban counterparts and to examine factors associated with enrollment variation. Data from the National Cancer Institutes 2006 and 2013 Surveillance, Epidemiology, and End Results Patterns of Care AYA cohorts were analyzed. Patients with acute lymphoblastic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and sarcoma were included (n 3155). Urban influence codes were used to measure the rurality of the county of residence at diagnosis, which was categorized as large metropolitan, small metropolitan, or nonmetropolitan. Logistic regression compared trial participants and nonparticipants while adjusting for patient and provider factors. Compared with AYAs from large metropolitan counties, AYAs from small metropolitan (odds ratio OR, 2.04 95% confidence interval CI, 1.57-2.64) or nonmetropolitan counties (OR, 1.86 95% CI, 1.23-2.81) experienced greater trial enrollment. AYAs treated at a hospital with a residency program (OR, 2.27 95% CI, 1.63-3.16) or by a pediatric oncologist (OR, 4.02 95% CI, 3.03-5.32) were associated with greater enrollment. There was a significant interaction between rurality and hospital size, which had the greatest impact on nonmetropolitan enrollment. Clinical trial enrollment was higher among AYAs from nonmetropolitan counties than those from metropolitan counties, predominantly when they were treated at large hospitals.

Invasive fusariosis masquerading as extramedullary disease in rapidly progressive acute lymphoblastic leukemia.

Invasive fusariosis (IF) most commonly occurs in patients with hematologic malignancies and severe neutropenia, particularly during concomitant corticosteroid use. Breakthrough infections can occur in high-risk patients despite Aspergillus-active antifungal prophylaxis. We describe a patient with rapid acute lymphoblastic leukemia (ALL) progression who presented with multifocal skin nodules thought to be choloromatous disease. These lesions were ultimately diagnosed as IF and the patient had two simultaneously active disease processes. This case highlights the importance of pathologic diagnosis of new skin lesions in ALL patients, even during leukemia progression, and demonstrates that IF can occur despite normal neutrophil counts and Aspergillus-active prophylaxis.

Health-related quality of life in paediatric patients up to five years post-treatment completion for acute lymphoblastic leukaemia a systematic review.

Despite survival rates greater than 90%, treatment for paediatric acute lymphoblastic leukaemia (ALL) remains challenging for families. The early post-treatment phase is an especially unique time of adjustment. The primary aim of this review was to identify and synthesise research on health-related quality of life (HRQoL) for patients up to five years post-treatment. The secondary aim was to identify if theorised riskresistance model factors could explain any variance in reported HRQoL. We conducted a systematic review using the PRISMA guidelines across five databases Embase, Medline, Psychinfo, Pubmed, and Cochrane. Only studies examining HRQoL up to five years post-treatment were included. Studies were excluded if they covered periods greater than five years post-treatment or did not differentiate between patients with ALL and other cancers. After assessing the quality of each study sample size, patient characteristics, HRQoL outcomes and HRQoL correlates were extracted and summarised. A total of 14 studies representing 1254 paediatric patients, aged 2-18 years, were found. HRQoL findings were mixed, dependent on time since completion and comparison group. Patient HRQoL was mostly lower compared to normative data, whilst higher compared to healthy control groups, patients on treatment, and patients with other types of cancers. Lower HRQoL was also found to be associated with demographic (age and sex), family dysfunction, and treatment-related factors. Completing treatment signalled a significant improvement in HRQoL for patients compared to being on treatment. Overall, however, HRQoL was still significantly lower than the population during the early post-treatment period.

Absolute Lymphocyte Count at the End of Induction as a Surrogate Marker for Minimal Residual Disease in T-cell Acute Lymphoblastic Leukemia.

The relation of absolute lymphocyte count (ALC) with minimal residual disease (MRD) in T cell - acute lymphoblastic leukemia (T-ALL) is not known. The objective of the study was to correlate ALC with MRD, steroid-response and complete remission (CR). De-novo T- ALL patients (age 1-18 y) recruited prospectively 52 enrolled, 9 excluded, and 43 analyzed. 39 achieved CR and MRD was available for 28 patients 23 were MRD negative. ALC did not correlate with steroid response and CR. Median (range) ALC at the end of induction was significantly higher in patients who were MRD negative compared to MRD positive 1.24 (0.12, 6.69) vs 0.62 (0.15, 0.87) P0.03, respectively. Patients having ALC ≥700 ×109 L were significantly more likely to be MRD negative than those with lower values (P 0.028). Our study suggests that ALC is a favorable factor, and may act as surrogate marker for MRD.

A population-based analysis of invasive fungal disease in haematology-oncology patients using data linkage of state-wide registries and administrative databases 2005 - 2016.

Little is known about the morbidity and mortality of invasive fungal disease (IFD) at a population level. The aim of this study was to determine the incidence, trends and outcomes of IFD in all haematology-oncology patients by linking Victorian hospital data to state-based registries. Episodes of IFD complicating adult haematological malignancy (HM) and haematopoietic stem cell transplantation (HSCT) patients admitted to Victorian hospitals from 1 There were 619,702 inpatient-episodes among 32,815 HM and 1,765 HSCT-patients. IFD occurring twelve-months from HM-diagnosis was detected in 669 (2.04%) HM-patients and 111 (6.29%) HSCT-recipients, respectively. Median time to IFD-diagnosis was 3, 5, 15 and 22 months in acute myeloid leukaemia, acute lymphoblastic leukaemia, Hodgkin lymphoma and multiple myeloma, respectively. Median survival from IFD-diagnosis was 7, 7 and 3 months for invasive aspergillosis, invasive candidiasis and mucormycosis, respectively. From 2005-2016, IFD incidence decreased 0.28% per 1,000 bed-days. Fungal incidence coincided with spring peaks on time-series analysis. Data linkage is an efficient means of evaluating the epidemiology of a rare disease, however the burden of IFD is likely underestimated, arguing for better quality hospital level surveillance data to improve management strategies.

Umbilical cord blood‑derived Helios‑positive regulatory T cells promote angiogenesis in acute lymphoblastic leukemia in mice via CCL22 and the VEGFA‑VEGFR2 pathway.

Regulatory T cells (Tregs) maintain immune homeostasis and modulate tumor‑induced neovascularization. However, the mechanisms underlying the role of Tregs in acute lymphoblastic leukemia (ALL) remain to be elucidated. Helios, combined with forkhead box P3, is considered a suitable marker for discriminating functional Tregs. In the present study, a microenvironment was created with a high proportion of Helios Tregs in T cell‑deficient nude mice to determine the mechanism underlying Tregs expressing Helios in ALL. It was revealed that umbilical cord blood‑derived Helios Tregs had proliferation and immunosuppression abilities similar to those of normal pediatric Tregs. The accumulation of Helios Tregs accelerated leukemogenesis and the infiltration of leukemic cells into the bone marrow. Importantly, a high expression of Helios in Tregs promoted angiogenesis in the bone marrow via the vascular endothelial growth factor (VEGF)AVEGF receptor 2 (VEGFR2) pathway. Furthermore, the expression of chemokine CC‑chemokine ligand 22 (CCL22) in the bone marrow and serum of ALL mice infused with Helioshigh Treg cells was increased. The results demonstrated that Helios promotes the secretion of chemokine CCL22, which may recruit more Tregs into the bone marrow. Increased Helios Treg cells promoted angiogenesis in the bone marrow of ALL mice via the VEGFAVEGFR2 pathway. Therefore, Helios may be a target to manipulate Treg activity in clinical settings.

Timosaponin A‑III induces autophagy of T‑cell acute lymphoblastic leukemia Jurkat cells via inhibition of the PI3KAktmTOR pathway.

Timosaponin A‑III (TAIII) is a saponin isolated from anemarrhena asphodeloides and possesses the inhibitory effect on proliferation of multiple tumor cells. In the present study, the antitumor effect of TAIII and its underlying molecular mechanisms were investigated in vitro in T‑cell acute lymphoblastic leukemia (T‑ALL) Jurkat cells. The results demonstrated that TAIII inhibits the viability of Jurkat cells in a time‑ and dose‑dependent manner, and induces apoptosis of Jurkat cells in a dose‑dependent manner. Transmission electron microscopy demonstrated the formation of numerous autophagosomes in TAIII‑treated Jurkat cells. Furthermore, monodansylcadaverine (MDC)‑labeled autophagic vacuoles were observed following TAIII treatment by an inverted fluorescence microscope and MDC accumulation increased notably in TAIII treatment groups in a concentration‑dependent manner. B‑cell lymphoma‑2 (Bcl‑2)‑associated X (Bax) was upregulated while Bcl‑2 was reduced following TAIII treatment, indicating that the pro‑apoptotic mechanism of TAIII may be associated with upregulation of Bax. Further investigation revealed that TAIII promotes the expression of autophagy‑associated proteins Beclin 1 and LC3‑II, and inhibits the phosphoinositide 3‑kinaseAktmechanistic target of rapamycin kinase pathway. The present study revealed that the antitumor activity of TAIII was primarily achieved by the induction of cell apoptosis and autophagy, indicating a promising potential as a novel effective reagent against T‑ALL.

Association between NAT2 polymorphisms and acute leukemia risk A meta-analysis.

N-acetyl-transferase 2 (NAT2) polymorphisms have been demonstrated to be associated with acute leukemia (AL) however, the results remain controversial. The present meta-analysis was performed to provide more precise results. Pubmed, Embase, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases were used to identify eligible studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between NAT2 polymorphisms and AL risk. Increased risk was found under both heterozygous (OR 1.24, 95% CI 1.02-1.51) and recessive model (OR 1.28, 95% CI 1.06-1.55) for rs1801280. The slow acetylator phenotype (OR 1.22, 95% CI 1.07-1.40) also increased AL risk. Subgroup analysis demonstrated that rs1801280 increased AL risk under the recessive model (OR 1.14, 95% CI 0.93-1.41) in Caucasian population and the co-dominant (OR 1.77, 95% CI 1.40-2.23), homozygous (OR 3.06, 95% CI 1.88-4.99), dominant (OR 2.22, 95% CI 1.56-3.17), recessive model (OR 2.06, 95% CI 1.35-3.16) in the Mixed populations. Association between rs1799929 and decreased AL risk was found in the co-dominant (OR 0.82, 95% CI 0.70-0.97), homozygous (OR 0.65, 95% CI 0.46-0.93), heterozygous (OR 0.71, 95% CI 0.51-1.00), and the recessive model (OR 0.68, 95% CI 0.49-0.94) in the Caucasian group. As for rs1799931, the same effects were found in the co-dominant (OR 0.68, 95% CI 0.49-0.94) and the dominant model (OR 0.68, 95% CI 0.48-0.97) in the mixed group. rs1801280 and the slow acetylator phenotype are risk factors for AL.

Extracellular vesicles derived from natural killer cells use multiple cytotoxic proteins and killing mechanisms to target cancer cells.

Extracellular vesicles (EVs) are secreted membrane vesicles, which play complex physiological and pathological functions in intercellular communication. Recently, we isolated natural killer (NK) cell-derived EVs (NK-EVs) from

A systematic literature review and meta-analysis of minimal residual disease as a prognostic indicator in adult B-cell acute lymphoblastic leukemia.

Minimal (or measurable) residual disease in acute lymphoblastic leukemia appears to be a prognostic indicator, with potential value in informing individualized treatment decisions. Complete understanding of the strength of the association between minimal residual disease and long-term outcomes is, however, lacking. A systematic literature review and meta-analysis were performed to elucidate the clinical significance of minimal residual disease with respect to relapse-free survival and overall survival in precursor B-cell acute lymphoblastic leukemia. A total of 23 articles and abstracts, most published between 2012 and 2016, were identified for inclusion in the primary meta-analysis. Typically, patients were in their first complete remission at the time of minimal residual disease assessment in two studies, all patients were in their second, or later, complete remission. The primary analysis revealed improved relapse-free survival across all studies for patients who achieved minimal residual disease negativity (random effects hazard ratio, 2.34 95% confidence interval, 1.91-2.86). Improved overall survival for patients who achieved minimal residual disease negativity was also observed (hazard ratio, 2.19 95% confidence interval, 1.63-2.94). There was no observed difference in the impact of minimal residual disease status in subgroups based on disease stage, minimal residual disease sensitivity threshold level, Philadelphia chromosome status, histological phenotype, risk group, minimal residual disease testing location, minimal residual disease timing after induction, or minimal residual disease detection method. Despite heterogeneity in study design and patient populations between the contributing studies, these data provide a compelling argument for minimal residual disease as a clinical tool for assessing prognosis and guiding treatment decisions in precursor B-cell acute lymphoblastic leukemia.

Chimeric antigen receptor T-cell therapy Foundational science and clinical knowledge for pharmacy practice.

The Food and Drug Administration has recently approved two autologous chimeric antigen receptor T-cell immunotherapies tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta™) for patients with advanced lymphocytic malignancies. Both immunotherapies target the CD19-positive B-cell neoplasms. Kymriah™ is indicated for the treatment of relapsed or refractory acute lymphoblastic leukemia and large B-cell lymphoma. Yescarta™ is indicated for lymphoma only. Although the new therapy offers a promise for patients with advanced disease, it is associated with adverse events including neurotoxicity and cytokine release syndrome, which can be fatal and may require a high level of multidisciplinary supportive care. Due to the risks, both Kymriah™ and Yescarta™ are subject to Risk Evaluation and Mitigation Strategy (REMS) protocols. As active members of multidisciplinary clinical teams, pharmacists are likely to be responsible for the execution of Kymriah™ and Yescarta™ REMS programs. This manuscript describes foundational science and clinical knowledge of chimeric antigen receptor T-cell immunotherapies, common therapy-specific toxicities and REMS requirements for Kymriah™ and Yescarta™ in relation to practice of pharmacy.

Downregulation of PHF6 Inhibits Cell Proliferation and Migration in Hepatocellular Carcinoma.

The Clinical and Cost Effectiveness of Inotuzumab Ozogamicin for the Treatment of Adult Relapsed or Refractory B-Cell Acute Lymphoblastic Leukaemia An Evidence Review Group Evaluation of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited Pfizer, the manufacturer of inotuzumab ozogamicin (henceforth inotuzumab), to submit clinical- and cost-effectiveness evidence for inotuzumab as part of NICEs single technology appraisal process. The Centre for Reviews and Dissemination and the Centre for Health Economics, both at the University of York, were commissioned as the independent evidence review group (ERG). The clinical-effectiveness data were from a multicentre randomised controlled trial that compared inotuzumab with standard of care (SoC), where SoC was the investigators choice of chemotherapy. Inotuzumab demonstrated statistically significant improvements in response rates or in the proportion of patients progressing to haematopoietic stem cell transplant (HSCT) but failed to meet the second primary objective of longer overall survival. Treatment-emergent adverse events were more frequent in the SoC arm, except veno-occlusive disease, which was more frequent in the inotuzumab arm. The companys economic model split patients into three post-hoc subgroups and used a partitioned survival approach within each group, with a cure assumption 3 years after receiving HSCT. In contrast with the trial results, the economic model estimated substantial improvement in survival with inotuzumab compared with SoC, providing an additional 5.2 life-years and 2.2 quality-adjusted life-years (QALYs) using a discount rate of 1.5% per annum. The ERGs critique highlighted a number of concerns, including the use of a post-hoc post-randomisation patient subset for extrapolation, the choice of a 1.5% discount rate, the complexity of the parametric modelling, the assumption of further treatment benefit post-HSCT, the nature of the cure assumption, and the length of inpatient stay while receiving treatment. The combination of the ERGs adjustments resulted in an incremental cost-effectiveness ratio (ICER) of £122,174 per QALY gained using Kaplan-Meier survival estimates and £114,078 per QALY gained with parametric survival models fit to the trial data. The final determination of the appraisal followed four NICE Appraisal Committee meetings, an appeal by the company and other stakeholders, two patient access schemes, and a company response to each appraisal consultation. The final ICER post-consultation was between £33,749 and £37,497 per QALY gained compared with SoC (excluding the confidential discount for blinatumomab received as subsequent therapy). The Appraisal Committee concluded that the ICER for inotuzumab was within the range usually considered cost effective for end-of-life care and recommended inotuzumab within its licensed indication.

Merger of dynamic two-photon and phosphorescence lifetime microscopy reveals dependence of lymphocyte motility on oxygen in solid and hematological tumors.

Low availability of oxygen in tumors contributes to the hostility of the tumor microenvironment toward the immune system. However, the dynamic relationship between local oxygen levels and the immune surveillance of tumors by tumor infiltrating T-lymphocytes (TIL) remains unclear. This situation reflects a methodological difficulty in visualizing oxygen gradients in living tissue in a manner that is suitable for spatiotemporal quantification and contextual correlation with individual cell dynamics tracked by typical fluorescence reporter systems. Here, we devise a regimen for intravital oxygen and cell dynamics co-imaging, termed Fast Scanning Two-photon Phosphorescence Lifetime Imaging Microscopy (FaST-PLIM). Using FaST-PLIM, we image the cellular motility of T-lymphocytes in relation to the microscopic distribution of oxygen in mouse models of hematological and solid tumors, namely in bone marrow with or without B-cell acute lymphocytic leukemia (ALL), and in lungs with sarcoma tumors. Both in bone marrow leukemia and solid tumor models, TILs encountered regions of varying oxygen concentrations, including regions of hypoxia (defined as pO This study demonstrates a versatile and highly contextual FaST-PLIM method for phosphorescence lifetime-based oxygen imaging in living animal tumor immunology models. The initial results of this method application to ALL and solid lung tumor models highlight the importance of oxygen supply for the maintenance of intratumoral T cell migration, define a 5 mmHg local oxygen concentration threshold for TIL motility, and demonstrate efficacy of supplementary oxygen breathing in TIL motility enhancement coincident with reduction of tumor hypoxia.

Intrathecal dose intensification by CNS status at diagnosis in the treatment of children with acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) with CNS2 status predicts inferior outcome and a high rate of CNS relapse, similar to overt CNS leukemia (CNS3). The purpose of this study was to determine if intrathecal (IT) dose intensification during induction would improve outcomes and reduce CNS relapse for CNS2 disease. From January 2001 to December 2014, children (1-14 years) with newly diagnosed ALL were treated at the Princess Noorah Oncology Centre (PNOC) following modifications of the Childrens Oncology Group (COG) protocols. We intensified IT methotrexate (ITM) during induction for patients with CNS2 disease. Patients were evaluated for overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (CIR). 449 children with T-cell (14.3%) or B-cell (85.7%) ALL were treated using PNOC-SR or PNOC-HR regimens (Jan 2001- Dec 2007) or CALL08 regimens (Arm A SR, Arm B IR, and Arm C HR) (Jan 2008 - Dec 2014). The 5-year OS, DFS, and CIR were 87.2 ± 1.6%, 81.7 ± 1.9%, and 13.0 ± 1.7%, respectively. The OS and DFS of patients with CNS2 were significantly superior to that of patients with CNS3 (P 0.025 and P 0.019, respectively). Patients with CNS2 had similar OS and DFS to those with CNS1. None of the patients with CNS2 at initial diagnosis experienced CNS relapse. ITM intensification during induction was associated with elimination of CNS recurrence in patients with CNS2 disease and childhood ALL. Controlled studies are needed to confirm this observation.

Bilateral Primary Renal Lymphoma Presented As Homogenous Renal Enlargement And Acute Interstitial Nephritis.

Primary renal lymphoma(PRL) is an extremely rare form of extranodal lymphoma andexhibitsas single (10-20%), multifocal nodules (60%), renal invasion from contiguous retroperitoneal disease (25-30%), diffuse infiltration (20%) or perirenal involvement (10%)1 .Here we report a case of bilateral primary renal lymphoma in a 13 year-old boy who presented with homogenous nephromegaly and acute interstitial nephritis(AIN).The renal biopsy revealed primary renal T lymphoblastic lymphoma. Hyper-CVAD regimen was initiated and the renal function had been recovered after the first round of chemotherapy. To our knowledge, there have only been three reports of primary renal T lymphoblastic lymphoma including ours so far. All the three patients were young and showed as AIN and bilateral renal enlargement. We also reviewed 16 cases of PRL presenting with AIN and enlarged kidneys that have been reported since 1997. Although PRL is quite rare, it must be taken into account when making a differential diagnosis of AIN. Renal biopsy is the gold standard and intensive chemotherapy can preserve the renal function.

Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy.

With immunotherapy innovations for cancer treatment, in particular chimeric antigen receptor (CAR) T cells, becoming more successful and prevalent, strategies to mitigate and manage their toxicities are required. Anti-CD19 CAR T-cell therapy has revolutionized the treatment of relapsedrefractory pediatric and adult acute lymphoblastic leukemia and refractory adult non-Hodgkin lymphoma, resulting in the expanded use of CAR T cells in multicenter trials and as US FDA-approved products. Cytokine release syndrome (CRS) and CAR-associated neurotoxicity, which can occur independently or concurrently with CRS, are two potentially life-threatening toxicities of CAR T-cell therapy. In this review, we will focus on describing the pathophysiology behind CRS, the proposed definitions of and grading systems for CRS, and innovative options for treating this potentially lethal systemic inflammatory condition.

CAR T-Cell Therapy Update on the State of the Science.

Chimeric antigen receptor (CAR) T-cell therapy leverages the power of the patients own immune system by serving as a bridge to connect genetically modified T cells to the surface antigens of tumor cells based on targeted ligands. Clinical trials have demonstrated compelling overall response and survival rates in individuals with B-cell malignancies. The current approved agents target CD19, an antigen commonly overexpressed in B-cell hematologic and other malignancies. This article provides information on the current state of the science related to commercially available CAR T-cell products and examines how CAR T-cell science is evolving. An overview of pathophysiology, indications, and nursing implications of the currently approved CAR T-cell agents is presented. Future directions for CAR T-cell development and treatment indications are discussed. Tisagenlecleucel (Kymriah®) and axicabtagene ciloleucel (Yescarta®) received approval in 2017 for the treatment of B-cell precursor acute lymphoblastic leukemia in pediatric and young adult patients, and relapsed or refractory diffuse large B-cell lymphoma after two or more lines of systemic therapy in adult patients, respectively. Additional indications have since been approved, and new agents are in development.

Pediatric Survivorship Considerations Following CAR T-Cell Therapy.

This article presents an overview of pediatric relapsed and refractory acute lymphoblastic leukemia (ALL) and chimeric antigen receptor (CAR) T-cell therapy in pediatric patients. Acute and chronic post-CAR T-cell effects and considerations are discussed, along with survivorship considerations. A case study illustrates the identification and management of physiologic and psychosocial sequelae. B-cell aplasia, hypogammaglobulinemia, infections, and cumulative effects of CAR T-cell therapy and other treatments are a concern in the pediatric population. Unique to pediatric and young adult survivors of childbearing potential are implications for post-treatment fertility. Financial toxicities and psychosocial needs require a family-centered approach to interventions that address the impact of CAR T-cell therapy not only on the patient, but also on caregivers and siblings.

Efficacy of levofloxacin as an antibacterial prophylaxis for acute leukemia patients receiving intensive chemotherapy a systematic review and meta-analysis.

The incidence of febrile neutropenia (FN) in acute leukemia patients following induction or consolidation chemotherapy is high. Several clinical practice guidelines recommend the use of a fluoroquinolone prophylaxis to prevent bacterial infection in patients being prone to prolonged profound neutropenia. This systematic review and meta-analysis aimed to investigate the efficacy and complications of levofloxacin as a prophylaxis for FN patients following chemotherapy for acute leukemia. Two databases from MEDLINE and EMBASE were searched for published studies indexed before 10 July 2018. A total of 862 acute leukemia patients were included, with 356 in the levofloxacin prophylaxis arm and 506 in the no-prophylaxis arm. Patients receiving levofloxacin had a significantly lower FN rate than patients who did not receive the antibiotic prophylaxis (odds ratio OR 0.43, 95% confidence interval CI 0.32-0.58, p < .00001, I Although the levofloxacin prophylaxis for the acute leukemia patients receiving intensive chemotherapy showed advantages for infectious complications, it did not affect mortality.

Relapsed T Cell ALL Current Approaches and New Directions.

Patients with relapsed T cell acute lymphoblastic leukemia (T-ALL) have limited therapeutic options and a poor prognosis. Although a variety of salvage chemotherapy regimens may be used, response rates are unsatisfactory. This article summarizes current approaches and promising emerging strategies for the treatment of relapsed T-ALL. Although nelarabine is the only agent approved specifically for T-ALL, recent studies have identified a variety of genetic alterations and signaling pathways that are critical in its pathogenesis. Based on these findings, a number of small-molecule inhibitors and other targeted therapies are being studied for relapsed T-ALL, including gamma-secretase inhibitors, BCL-2 inhibitors, cyclin-dependent kinase inhibitors, and mTOR inhibitors. In addition, pre-clinical studies of chimeric antigen receptor T cells targeting CD5 and CD7 as well as the monoclonal antibody daratumumab have shown promising results for T-ALL. Relapsed T-ALL currently remains challenging to treat, but recent pre-clinical studies of targeted and immunotherapeutic agents have shown encouraging results. A number of clinical trials investigating these approaches for T-ALL are currently underway.

Meningioma Screening With MRI in Childhood Leukemia Survivors Treated With Cranial Radiation.

Radiation-induced meningioma is a known late effect of cranial radiation therapy. Cranial magnetic resonance imaging (MRI) can detect small meningiomas, but its potential value as a screening tool is unknown. MRI was used to screen asymptomatic survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation therapy ≥10 years previously. The incidence of radiation-induced meningioma and outcomes of this group were compared with a historical cohort of survivors with the same exposure who underwent imaging only to investigate clinical signs or symptoms. One hundred seventy-six childhood leukemia survivors were included in this study 70 in the screening group and 106 unscreened. Screening MRI was performed a median of 25 years after radiation therapy and detected meningioma in 15 (21.4%). In the unscreened group, 17 patients (16.0%) had neurologic symptoms leading to an MRI a median interval of 24 years after radiation therapy, 9 of whom (8.5%) were diagnosed with meningioma. There was no significant difference between screened versus unscreened patients in the size of meningioma (mean diameter, 1.6 cm vs 2.6 cm P .13), meningioma incidence (7.4% vs 4.0% at 25 years P .19), or extent of resection. Three patients had persistent neurologic symptoms in the unscreened group versus none among screened patients (P .28). Screening MRI was able to detect small meningiomas that were not clinically apparent however, we could not demonstrate a significant improvement in the chance of total resection or a significant decrease in morbidity. A larger sample could clarify potential reduction in neurologic sequelae associated with screening.

Current Status and Perspectives of Irradiation-Based Conditioning Regimens for Patients with Acute Leukemia Undergoing Hematopoietic Stem Cell Transplantation.

Acute myeloid leukemia and acute lymphoblastic leukemia are the most common indications for allogeneic hematopoietic stem cell transplantation. Total body irradiation (TBI) is an important part of conditioning regimens. TBI-based regimens offer advantages in sanctuary sites but are associated with significant risks of early and late side effects, including pulmonary toxicity, growth retardation, and second malignancy. TBI is also associated with technical problems, such as dose heterogeneity. With evolving techniques in radiation oncology, it is possible to focus the dose to the entire skeleton while sparing the rest of the body. This technique is called total marrow irradiation (TMI). TMI is able to deliver the same or higher doses to bone marrow while reducing toxicity. With the success of TMI, we are moving toward ultra-personalized conditioning. We review the clinical role of the irradiation-based regimens currently in clinical use, emphasizing on their strengths and limitations. Novel technologies with targeted irradiation accompanied by the modern imaging techniques and increased knowledge of the disease process can help us achieve our goal of maximum response with minimum toxicity.

Recent Advances in Adult Acute Lymphoblastic Leukemia.

This article reviews the recent advances in the pathophysiology and management of acute lymphoblastic leukemia (ALL) in adults. Addition of rituximab to standard chemotherapy improves survival in the frontline treatment of B cell ALL, and measurable residual disease (MRD) is the most important prognostic factor. Tyrosine kinase inhibitors (TKI), particularly ponatinib, in combination with Hyper-CVAD significantly improve outcomes in Ph ALL challenging the benefit of allogeneic stem cell transplant in first line for these patients. Blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor (CAR) T cells are better options than chemotherapy alone for the treatment of relapsed or refractory ALL. Combination of these agents with chemotherapy and their incorporation in the frontline setting show promises to improve cure rates of ALL. Development of monoclonal antibodies, CAR T, and potent TKI has improved the outcome of ALL. Advances in our understanding of ALL biology are expected to bring new therapeutic strategies in the upcoming years.

MicroRNA as a diagnostic biomarker in childhood acute lymphoblastic leukemia systematic review, meta-analysis and recommendations.

Several studies detected abnormal mi-RNAs expression levels in childhood Acute Lymphoblastic Leukemia (ALL) with potential diagnostic value. We conducted a systematic search on certain microRNAs in childhood ALL. We included 17 studies with a total of 928 ALL children and 307 controls. Ten studies provided miRNAs expression levels and seven provided frequency data. Sensitivity and specificity of a single miRNA ranged from 46.55% to 100% and from 71.8% to 100%, respectively. The highest diagnostic odds ratio (DOR) was for the diagnostic panel (miR-128a and miR-223) reaching 546 95% CI 73.768-4041.282. Also, miR-128a, miR-128b, miR-223, let-7b, miR-155 and miR-24 can be used as diagnostic discriminatory biomarkers between ALL and AML. Further large cohort studies are needed to confirm our results.

IKZF1 Deletions with COBL Breakpoints Are Not Driven by RAG-Mediated Recombination Events in Acute Lymphoblastic Leukemia.

IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBL is a hotspot for breakpoints in leukemia and could promote IKZF1 deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of B-ALL with COBL rearrangements (COBL-r). Patients with B-ALL and IKZF1 deletion (n 133) were included. IKZF1 ∆1-8 were associated with large alterations within chromosome 7 monosomy 7 (18%), isochromosome 7q (10%), 7p loss (19%), and interstitial deletions (53%). The latter included COBL-r, which were found in 12% of the IKZF1 ∆1-8 cohort. Patients with COBL-r are mostly classified as intermediate cytogenetic risk and frequently harbor ETV6, PAX5, CDKN2AB deletions. Overall, 56% of breakpoints were located within COBL intron 5. Cryptic recombination signal sequence motifs were broadly distributed within the sequence of COBL, and no enrichment for the breakpoint cluster region was found. In summary, a diverse spectrum of alterations characterizes ΔIKZF1 and they also include deletion breakpoints within COBL. We confirmed that COBL is a hotspot associated with ΔIKZF1, but these rearrangements are not driven by RAG-mediated recombination.

Elevated BNP caused by recombinant human interleukin-11 treatment in patients with chemotherapy-induced thrombocytopenia.

Thrombocytopenia is a condition characterized by abnormally low levels of thrombocytes and often induced by chemotherapy. Recombinant human interleukin-11 (rhIL-11) is a cytokine that can stimulate thrombopoiesis and is commonly used to treat thrombocytopenia. We observed the side effects of rhIL-11 in 24 leukemia patients with chemotherapy-induced thrombocytopenia. To determine the cardiovascular effects of rhIL-11, we detected changes in the patients serum brain natriuretic peptide (BNP), blood pressure fluctuations, weight change, and whether edema or heart failure occurred in leukemia patients after chemotherapy. The results showed that BNP was significantly elevated after using rhIL-11 (P < 0. 05) but regressed after 2-4 days. Furthermore, nine patients had edema and experienced weight gain, and four experienced acute left heart failure. In addition, the average blood pressure was 11975 mmHg (range 13986 mmHg to 9964 mmHg) before rhIL-11 administration and 12779 mmHg (range 14689 mmHg to 10869 mmHg) after rhIL-11 use. In conclusion, although rhIL-11 is useful for treating chemotherapy-induced thrombocytopenia, it is important to monitor the patients clinical status and re-examine BNP levels frequently during the use of rhIL-11. Furthermore, senile patients should be given special attention. However, the appropriate timing to begin and discontinue rhIL-11 treatment needs further investigation.

Significance tests for analyzing gene expression data with small sample sizes.

Under two biologically different conditions, we are often interested in identifying differentially expressed genes. It is usually the case that the assumption of equal variances on the two groups is violated for many genes where a large number of them are required to be filtered or ranked. In these cases, exact tests are unavailable and the Welchs approximate test is most reliable one. The Welchs test involves two layers of approximations approximating the distribution of the statistic by a t-distribution, which in turn depends on approximate degrees of freedom. This study attempts to improve upon Welchs approximate test by avoiding one layer of approximation. We introduce a new distribution that generalizes the t-distribution and propose a Monte Carlo based test that uses only one layer of approximation for statistical inferences. Experimental results based on extensive simulation studies show that the Monte Carol based tests enhance the statistical power and performs better than Welchs t-approximation, especially when the equal variance assumption is not met and the sample size of the sample with a larger variance is smaller. We analyzed two gene-expression datasets, namely the childhood acute lymphoblastic leukemia gene-expression dataset with 22 283 genes and Golden Spike dataset produced by a controlled experiment with 13 966 genes. The new test identified additional genes of interest in both datasets. Some of these genes have been proven to play important roles in medical literature. R scripts and the R package mcBFtest is available in CRAN and to reproduce all reported results are available at the GitHub repository, httpsgithub.comiullah1980MCTcodes. Supplementary data is available at Bioinformatics online.

Copy number alterations in B-cell development genes, drug resistance, and clinical outcome in pediatric B-cell precursor acute lymphoblastic leukemia.

Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is associated with a high frequency of copy number alterations (CNAs) in IKZF1, EBF1, PAX5, CDKN2AB, RB1, BTG1, ETV6, andor the PAR1 region (henceforth B-cell development genes). We aimed to gain insight in the association between CNAs in these genes, clinical outcome parameters, and cellular drug resistance. 71% of newly diagnosed pediatric BCP-ALL cases harbored one or more CNAs in these B-cell development genes. The distribution and clinical relevance of these CNAs was highly subtype-dependent. In the DCOG-ALL10 cohort, only loss of IKZF1 associated as single marker with unfavorable outcome parameters and cellular drug resistance. Prednisolone resistance was observed in IKZF1-deleted primary high hyperdiploid cells (1500-fold), while thiopurine resistance was detected in IKZF1-deleted primary BCR-ABL1-like and non-BCR-ABL1-like B-other cells (2.7-fold). The previously described risk stratification classifiers, i.e. IKZF1

A structural in silico analysis of the immunogenicity of l-asparaginase from Escherichia coli and Erwinia carotovora.

Acute lymphoblastic leukemia (ALL) is a type of cancer with a high incidence in children. The enzyme l-asparaginase (ASNase) constitutes a key element in the treatment of this disease. Four formulations of ASNase from a bacterial source are currently available. However, these formulations are characterized by their high immunogenicity, resulting in the inactivation of the drug, as well as in the occurrence of hypersensitivity reactions in a large number of patients. In this work, we performed an immunoinformatic analysis in order to clarify structural aspects of the immunogenicity of the asparaginase from Escherichia coli and Erwinia carotovora. For this purpose, we performed the prediction of immunogenic and allergenic epitopes in the structure of asparaginases by using the relative frequency of immunogenic peptides for the eight alleles most frequently distributed worldwide. This study showed that there are no significant differences in the level of immunogenicity between the two enzymes, while asparaginase from E. coli presented a higher relative frequency of allergenic epitopes. These results are consistent with previously published reports. However, from a structural point of view, to the best of our knowledge, this is the first report describing the structural determinants that contribute to the hypersensitivity response to this treatment.

Whole transcriptome sequencing reveals a KMT2A-USP2 fusion in infant acute myeloid leukemia.

Infant acute lymphoblastic leukemia with lysine (K)-specific methyltransferase 2A (KMT2A) rearrangements usually has a poor prognosis regardless of the fusion partners of KMT2A. However, the prognosis of pediatric acute myeloid leukemia (AML) with KMT2A rearrangements depends on its translocation partners. We herein report the case of a 9-month-old boy with a KMT2A-USP2 fusion, which required diagnosis by whole transcriptome sequencing after the failure of detection of known translocation partners by conventional screening approaches. As this first report of a patient with AML with a KMT2A-USP2 fusion illustrates, identification of the partners in all patients with KMT2A-rearranged AML is critical to elucidate the outcomes associated with specific rearrangements and to develop appropriate treatment strategies. Moreover, development of additional methods to detect specific translocation partners of KMT2A and leukemia-specific targeting drugs is important to improve further the outcomes of KMT2A-rearranged AML.

Schwannoma Formation in Childhood Cancer Survivors Exposed to Total Body Irradiation Case Series.

Childhood cancer survivors are at risk for ongoing health risks related to their initial treatment. One potential long-term complication following radiation is the development of secondary tumors, including peripheral nerve tumors, such as schwannomas. We present three adolescent and young adult (AYA)-aged survivors of pediatric cancer (22-40 years), followed in our AYA survivorship clinic. Each was found to have a schwannoma many years following total body irradiation for a childhood primary malignancy. We highlight a late effect of low-dose total body irradiation as well as the importance of long-term monitoring in this population.

Cancer immune therapy for the treatment of haematological malignancies.

Cancer immune therapy is now used routinely for the treatment of several solid malignancies, albeit just recently having entered the clinic for treatment of haematological malignancies. Several studies demonstrate that cancer immune therapy is a promising treatment modality for the latter. Especially treatment with chimeric antigen receptor T cells for acute lymphoblastic leukaemia and lymphoma is promising. Other promising treatment modalities are immune check point inhibitors for both lymphoid and myeloid malignancies, as well as therapeutic cancer vaccination targeting tumour antigens.

Fungal Infections In Paediatric Patients With Acute Lymphoblastic Leukaemia While On Induction Chemotherapy.

Acute Lymphoblastic Leukaemia (ALL) is one of the most common haematological malignancies seen in children. Despite steadily improving long-term outcomes, infections remain a major cause of morbidity and mortality in children receiving therapy for leukaemia. The incidence and risk of invasive fungal infections (IFIs) continue to rise. In some settings, IFIs caused by moulds are more frequent than those caused by yeasts, and Aspergillus spp. is the most common pathogens. The aim of the study was to determine the frequency, type of fungal infection seen during induction chemotherapy and outcomes.. This observational retrospective study was conducted in paediatric oncology department at Shaukat Khanum Cancer Hospital Lahore from January 2015 to December 2016 after taking International research board (IRB) approval. The study includes all the patients aged 1-15 who were diagnosed with acute lymphoblastic leukaemia while on induction chemotherapy. The data was retrieved of 165 patients from the hospital database after informed written consent.. The mean age of the patients was 4.6±2.80 with range 1-15years. Total 154 (93%) of the children were of age between 1-5 years whereas only 11 (6.7%) were between 5-10 years. Male sex was predominant in 117 (70.9%) and 48 (29.1%) were girls. Pre-B Acute lymphoblastic leukaemia was diagnosed in 93.3% of the patients and rest 11 (6.7%) were diagnosed with Pre-T Acute lymphoblastic leukaemia. NCI Standard risk patients were 132 (80%) and 33 (20%) were stratified as high risk. Fungal infections were documented in 18 (11%) patients out of which 7(39%) were probable infections, and only 11 (61%) were proven fungal infections. Aspergillus was the commonest organism in 5 (28%) patients. Death was observed in 21 (13%) patients and causes were sepsis due to infections in 18 (86%) out of which fungal infections were 11(61%), bacterial 4(22%), combine bacterial and fungal 3(17%). Remaining 3 (14%) patients death causes include, neutropenic colitis was observed in first patient, second patient died of infection without any identifiable focus, and third patient died due to chemotherapy related toxicity.. Our study concludes that the fungal infection was the most common cause of mortality in induction in our patients. A prospective study in the form of clinical trial is needed to see if use of prophylactic antifungal can improve outcomes in our setting.

Hexamethylene bisacetamide impairs NK cell-mediated clearance of acute T lymphoblastic leukemia cells and HIV-1-infected T cells that exit viral latency.

The hexamethylene bisacetamide (HMBA) anticancer drug was dismissed due to limited efficacy in leukemic patients but it may re-enter into the clinics in HIV-1 eradication strategies because of its recently disclosed capacity to reactivate latent virus. Here, we investigated the impact of HMBA on the cytotoxicity of natural killer (NK) cells against acute T lymphoblastic leukemia (T-ALL) cells or HIV-1-infected T cells that exit from latency. We show that in T-ALL cells HMBA upmodulated MICB and ULBP2 ligands for the NKG2D activating receptor. In a primary CD4

DNA damage signalling from the placenta to foetal blood as a potential mechanism for childhood leukaemia initiation.

For many diseases with a foetal origin, the cause for the disease initiation remains unknown. Common childhood acute leukaemia is thought to be caused by two hits, the first in utero and the second in childhood in response to infection. The mechanism for the initial DNA damaging event are unknown. Here we have used in vitro, ex vivo and in vivo models to show that a placental barrier will respond to agents that are suspected of initiating childhood leukaemia by releasing factors that cause DNA damage in cord blood and bone marrow cells, including stem cells. We show that DNA damage caused by in utero exposure can reappear postnatally after an immune challenge. Furthermore, both foetal and postnatal DNA damage are prevented by prenatal exposure of the placenta to a mitochondrially-targeted antioxidant. We conclude that the placenta might contribute to the first hit towards leukaemia initiation by bystander-like signalling to foetal haematopoietic cells.

PAI-1 and protein C as early markers of veno-occlusive disease in patients treated for Wilms tumor.

Hepatic veno-occlusive (VOD) disease has been described in hematopoietic stem cell transplantation (HSCT), solid tumors, and acute lymphoblastic leukemia. The incidence of VOD in Wilms tumor (WT) ranges from 1.2% to 8%. The diagnosis of VOD is clinical, and there are no validated laboratory biomarkers. We prospectively evaluated the specificity and sensitivity of plasminogen-activator inhibitor-1 (PAI-1) and protein C as diagnostic markers of VOD in WT patients. Fifty patients treated from 2008 to 2016 for WT were eligible. VOD was diagnosed according to modified Seattle criteria and retrospectively reclassified according to the recently published criteria for VOD in pediatric HSCT patients. VOD occurred in 6 of 50 patients (12%) after 20 to 97 days from starting chemotherapy. The average duration of VOD was 10 days (range, 4-13 days). PAI-1 levels were elevated in all VOD patients, while a decrease in protein C levels was observed in 33% of patients with VOD. PAI-1 antigen (Ag) values ≥ 26.4 ngmL demonstrated high sensitivity and specificity for the clinical diagnosis of VOD with sensitivity 100%, specificity 93% whereas protein C levels below 34.5% had sensitivity 67%, specificity 100%. Both PAI-1 and protein C had an high negative predictive value PAI-1 Ag 100% protein C 95%. PAI-1 Ag and protein C have good sensitivity and specificity for the diagnosis of VOD in WT patients. Their high negative predictive value can be used in the differential diagnosis of liver toxicity, especially in VOD episodes with absent or delayed hyperbilirubinemia.

High rates of ovarian function preservation after hematopoietic cell transplantation with melphalan-based reduced intensity conditioning for pediatric acute leukemia an analysis from the Japan Association of Childhood Leukemia Study (JACLS).

Women are at high risk of hypergonadotropic hypogonadism after hematopoietic cell transplantation (HCT). Hypogonadism is universal after irradiation or busulfan. We hypothesized that reduced intensity conditioning (RIC) might protect ovarian function after HCT. We retrospectively reviewed data from patients with acute leukemia treated according to the Japan Association of Childhood Leukemia Study and nationwide multicenter study protocol. We selected 11 female patients with acute leukemia who received first HCT with RIC, had survived for three or more years after HCT, and were aged ≥ 12 years at the last follow-up visit. Median age at diagnosis, HCT, and last visit were 8, 10, and 17 years. Six patients received HLA-matched bone marrow (BM), two HLA-mismatched BM, and three cord blood. Melphalan was used as conditioning regimen in all patients. At the last visit, six of seven post-pubertal patients at transplantation recovered menstruation, and four of four patients who underwent transplantation at the pre-pubertal began menstruation. Height z scores showed no significant reduction between pre-transplant and post-transplant. No patients received growth hormone treatment. Only one recipient displayed subclinical hypothyroidism. Melphalan-based RIC may be an encouraging option for patients with acute leukemia to avoid ovarian and endocrine dysfunction after HCT.

Altered proteome of high-density lipoproteins from paediatric acute lymphoblastic leukemia survivors.

Acute lymphoblastic leukemia (ALL) is the most frequent malignancy in children. With the use of more modern, efficient treatments, 5-year survival has reached more than 90% in this population. However, this achievement comes with many secondary and long-term effects since more than 65% of the survivors experience at least one severe complication, including the metabolic syndrome and cardiovascular diseases. The main objective of the present work was to characterize the composition of HDL particles isolated from pediatric ALL survivors. HDLs from 8 metabolically healthy ALL survivors, 8 metabolically unhealthy ALL survivors and 8 age- and gender-matched controls were analyzed. The HDL fraction from the survivors contained less cholesterol than the controls. In addition, proteomic analyses revealed an enrichment of pro-thrombotic (e.g., fibrinogen) and pro-inflammatory (e.g., amyloid A) proteins in the HDLs deriving from metabolically unhealthy survivors. These results indicate an alteration in the composition of lipid and protein content of HDL from childhood ALL survivors with metabolic disorders. Although more work is needed to validate the functionality of these HDLs, the data seem relevant for survivor health given the detection of potential biomarkers related to HDL metabolism and functionality in cancer.

Integrated analysis of relapsed B-cell precursor Acute Lymphoblastic Leukemia identifies subtype-specific cytokine and metabolic signatures.

Recent efforts reclassified B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) into more refined subtypes. Nevertheless, outcomes of relapsed BCP-ALL remain unsatisfactory, particularly in adult patients where the molecular basis of relapse is still poorly understood. To elucidate the evolution of relapse in BCP-ALL, we established a comprehensive multi-omics dataset including DNA-sequencing, RNA-sequencing, DNA methylation array and proteome MASS-spec data from matched diagnosis and relapse samples of BCP-ALL patients (n 50) including the subtypes DUX4, Ph-like and two aneuploid subtypes. Relapse-specific alterations were enriched for chromatin modifiers, nucleotide and steroid metabolism including the novel candidates FPGS, AGBL and ZNF483. The proteome expression analysis unraveled deregulation of metabolic pathways at relapse including the key proteins G6PD, TKT, GPI and PGD. Moreover, we identified a novel relapse-specific gene signature specific for DUX4 BCP-ALL patients highlighting chemotaxis and cytokine environment as a possible driver event at relapse. This study presents novel insights at distinct molecular levels of relapsed BCP-ALL based on a comprehensive multi-omics integrated data set including a valuable proteomics data set. The relapse specific aberrations reveal metabolic signatures on genomic and proteomic levels in BCP-ALL relapse. Furthermore, the chemokine expression signature in DUX4 relapse underscores the distinct status of DUX4-fusion BCP-ALL.

Bcl-2 Is a Therapeutic Target for Hypodiploid B-Lineage Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The highest rates of treatment failure occur in specific genetic subsets of ALL, including hypodiploid B-cell ALL (B-ALL), for which effective alternative therapies to current intensive chemotherapy treatments have yet to be developed. Here, we integrated biochemical and genomic profiling with functional drug assays to select effective agents with therapeutic potential against hypodiploid B-ALL. ABT-199, a selective Bcl-2 inhibitor, was effective in reducing leukemic burden

PREVAPIX-ALL Apixaban Compared to Standard of Care for Prevention of Venous Thrombosis in Paediatric Acute Lymphoblastic Leukaemia (ALL)-Rationale and Design.

Venous thromboembolic (VTE) complications in children and adolescents with acute lymphoblastic leukaemia (ALL) and T or B cell lymphoblastic lymphoma (TB cell LL) can result not only in life-threatening acute complications but also contribute to significant long-term sequelae. The PREVAPIX-ALL study is an open-label randomized controlled study comparing outcomes of treatment with prophylactic dose apixaban versus no anticoagulation (standard of care) in children and adolescents with ALL and TB cell LL receiving standard induction chemotherapy with asparaginase and the presence of a central venous access device. On day 29 of induction, all patients undergo screening imaging with duplex ultrasonography and echocardiography. The primary efficacy endpoint of the study is a composite of symptomatic and asymptomatic VTE that includes deep vein thrombosis, pulmonary embolism, cerebral sinovenous thrombosis or VTE-related death. The primary safety outcome is major bleeding. Secondary outcomes are central line-associated infections, patency and line replacement, superficial thrombosis, arterial events and death. A planned sample size of 500 randomized paediatric patients enrolled over a period of 5 years is based on the estimation of VTE rates of 20 and 10% in the standard of care and apixaban groups, respectively. An optional biomarker study in 150 patients will examine predictors of increased VTE risk and study in vivo anticoagulant effects of apixaban in children by measuring specific biomarkers in the haemostatic system and inflammatory pathway. This study will provide valuable information for the safety and efficacy of apixaban in VTE prevention during induction in paediatric ALL.

Targeting the thioredoxin system as a novel strategy against B-cell acute lymphoblastic leukemia.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a genetically heterogeneous blood cancer characterized by abnormal expansion of immature B cells. Although intensive chemotherapy provides high cure rates in a majority of patients, subtypes harboring certain genetic lesions, such as MLL rearrangements or BCR-ABL1 fusion, remain clinically challenging, necessitating a search for other therapeutic approaches. Herein, we aimed to validate antioxidant enzymes of the thioredoxin system as potential therapeutic targets in BCP-ALL. We observed oxidative stress along with aberrant expression of the enzymes associated with the activity of thioredoxin antioxidant system in BCP-ALL cells. Moreover, we found that auranofin and adenanthin, inhibitors of the thioredoxin system antioxidant enzymes, effectively kill BCP-ALL cell lines and pediatric and adult BCP-ALL primary cells, including primary cells cocultured with bone marrow-derived stem cells. Furthermore, auranofin delayed the progression of leukemia in MLL-rearranged patient-derived xenograft model and prolonged the survival of leukemic NSG mice. Our results unveil the thioredoxin system as a novel target for BCP-ALL therapy, and indicate that further studies assessing the anticancer efficacy of combinations of thioredoxin system inhibitors with conventional anti-BCP-ALL drugs should be continued.

Bovine Colostrum Against Chemotherapy-Induced Gastrointestinal Toxicity in Children With Acute Lymphoblastic Leukemia A Randomized, Double-Blind, Placebo-Controlled Trial.

The toxic effect of chemotherapy on the gastrointestinal tract may lead to mucositis and is associated with the pathogenesis of other treatment-related complications. We hypothesized that nutrition supplementation with bovine colostrum, rich in bioactive factors, would ameliorate gastrointestinal toxicity and reduce the incidence of fever and infectious complications during induction treatment for childhood acute lymphoblastic leukemia (ALL). Children with newly diagnosed ALL were included in a 2-center, randomized, double-blind, placebo-controlled clinical trial. Patients were randomized to receive a daily colostrum or placebo supplement during 4 weeks of induction treatment. Data on fever, bacteremia, need for antibiotics, and mucosal toxicity were prospectively collected. (Trial registration www.clinicaltrials.gov NCT01766804). Sixty-two patients were included. No differences were found for the primary outcome (number of days with fever). No difference was observed for neutropenic fever, intravenous antibiotics, or incidence of bacteremia. Peak severity of oral mucositis was significantly reduced by colostrum (729 patients, 24% mild 629, 21% moderate 129, 3% severe) compared with placebo (1231, 39% mild 131, 3% moderate 731, 23% severe) (P 0.02). Among patients receiving at least 1 dose of supplement (colostrum n 22 placebo n 30), the peak weekly self-reported oral mucositis score was overall significantly less severe in the colostrum group (P 0.009). The use of prophylactic bovine colostrum showed no effect on fever, infectious morbidity, or inflammatory responses. Nevertheless, these data may suggest protective effects on the oral mucosa during induction therapy in childhood ALL, encouraging additional studies confirming these findings.

Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth.

Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells represent a promising effector cell type for adoptive cancer immunotherapy. Both, genetically modified donor-derived NK cells as well as continuously expanding NK-92 cells are currently under clinical development. To enhance their therapeutic utility for the treatment of pre-B-cell acute lymphoblastic leukemia (B-ALL), we engineered NK-92 cells by lentiviral gene transfer to express a FMS-like tyrosine kinase 3 (FLT3)-specific CAR that contains a composite CD28-CD3ζ signaling domain. FLT3 has primarily been described as a therapeutic target for acute myeloid leukemia, but overexpression of FLT3 has also been reported in B-ALL. Exposure of FLT3-positive targets to CAR NK-92 cells resulted in conjugate formation between NK and leukemia cells, NK-cell degranulation and selective cytotoxicity toward established B-ALL cell lines and primary blasts that were resistant to parental NK-92. In a SEM B-ALL xenograft model in NOD-SCID IL2R γ

ATP-Binding Cassette transporters gene expression in pediatric patients with acute leukemia a comprehensive analysis of published reports through PubMed search engine.

Multidrug resistance based on ABC transporters gene expression is one of the most important health challenges through chemotherapy of patients. This resistance can cause relapse or treatment failure. The goal of this conducted study was to evaluate the results of published reports which considered ABC transporters gene expression in pediatric patients with acute leukemia. PubMed as a free search engine was chosen. The following Mesh terms were used as ATP-binding cassette transporters OR ABC-transporters AND gene expression AND leukemia OR ALL OR AML OR acute leukemia. Age was set as an additional filter with the age range of birth to 18 years old. Initial screening was performed according to inclusion and exclusion criteria and the quality of the selected papers was assessed. Papers categorized into three sections as pediatric patients with ALL (6 papers from 1998-2015) pediatric patients with AML (3 papers from 1992-2011) and pediatric patients with ALL and AML (7 papers from 1992-2014). Totally 1118 patients enrolled in the searched studies (ALL and AML 488 ALL 405 AML 225). The common method for evaluating gene expression of ABC transporters was RT-PCR. More than 50% of the papers showed the influence of ABC transporters gene expression on prognosis and treatment failures of patients. Despite controversial results, the gathered information in the current report serves as a comprehensive referential resource, which can be beneficial for future planning around this title, especially in developing countries.

GATA3 germline variant is associated with CRLF2 expression and predicts outcome in pediatric B-cell precursor acute lymphoblastic leukemia.

The germline variant at rs3824662 in GATA3 is a risk locus for Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL), the biological subtype of B-cell precursor (BCP)-ALL defined by a distinct gene expression profile and the presence of specific somatic aberrations including rearrangements of CRLF2. In this study, we investigated whether rs3824662 in GATA3 associates with CRLF2 expression in leukemic cells and predicts prognosis in pediatric BCP-ALL patients treated according to the ALL Intercontinental Berlin-Frankfurt-Münster (IC BFM) 2009 (n 645) and the ALL IC BFM 2002 (n 216) protocols. High expression of CRLF2 was observed at both protein and mRNA levels (fourfold higher in AA than in CA CC) among GATA3 AA variant carriers, independent of the presence of P2RY8-CRLF2 fusion. Additionally, the AA variant at rs3824662 was a significant factor affecting minimal residual disease level at the end of induction phase and overall survival regardless of the risk group and the protocol. The germline variant at rs3824662 in GATA3 is a prognostic factor which associates with CRLF2 expression in leukemic cells supporting the hypothesis that GATA3 may have a regulatory effect on the CRLF2 pathway in pediatric BCP-ALL.

Population pharmacokinetics of inotuzumab ozogamicin in relapsedrefractory acute lymphoblastic leukemia and non-Hodgkin lymphoma.

This population pharmacokinetics analysis evaluated the target-mediated drug disposition of inotuzumab ozogamicin (InO) through an empirical time-dependent clearance (CL

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Spectrum and Immunophenotypic Profile of Acute Leukemia A Tertiary Center Flow Cytometry Experience.

For diagnosis, sub-categorization and follow up of Acute Leukemia (AL), phenotypic analysis using flow cytometry is mandatory. We retrospectively analyzed immunophenotypic data along with cytogeneticsmolecular genetics data (wherever available) from 631 consecutive cases of AL diagnosed at our flow cytometry laboratory from January 2014 to August 2017. Of the total 631 cases, 52.9% (n334) were acute lymphoblastic leukemia (ALL), 43.9% (n277) acute myeloid leukemia (AML), 2.2% (n14) mixed phenotypic acute leukemia (MPAL), 0.5% (n3) acute undifferentiated leukemia (AUL) and 0.5% (n3) chronic myeloid leukemia in blast crisis (CML-BC). ALL cases comprised of 81.7% (n273334) B-cell ALLs (95.2%, n260273 common B-ALLs and 4.8%, n13273 Pro B-ALLs). CD13 was the commonest cross lineage antigen, expressed in B-ALL (25.6%, n70273), followed by CD33 (17.9%, n49) and combined CD13CD33 (11.3%, n31273) expression. T-ALLs constituted 18.3% (n61334) of total ALLs and included 27.9% (n1761) cortical T- ALLs. CD13 was commonest (32.7%, n2061) aberrantly expressed antigen in T-ALLs, followed by CD117 (19.1%, n947). AML cases included 32.1% (n89277) AML with recurrent genetic abnormalities, 9.0% (n25277) with FLT3NPM1c mutation and 58.9% (n163277) AML NOS including 14.7% (n24163) AML M4M5, 1.8% (n3163) AML M6 and 3.7% (n6163) AML M7. In AMLs, CD19 aberrancy was the most common (20.2%, n56277) followed by CD56 (15.8%, n42265). In this study, we document the spectrum, correlate the immunophenotype with genetic data of all leukemias, especially concerning T-ALL where the data from India is scarce.

Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1.

Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primerprobe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1ABL1 ratios within half a log difference were 4067 (60%) and 5267 (78%) at 10

Allogeneic stem cell transplantation in the era of novel therapies for acute lymphoblastic leukaemia.

Immunotherapy is changing the treatment of acute lymphoblastic leukaemia (ALL) in adults and children. However, regardless of these new therapies, allogeneic hematopoietic cell transplantation (allo-HCT) still play a key role in the treatment of ALL, although it is uncertain how these new therapies will impact on the transplant procedure and indications. This article reviews the indications of allo-HCT for children and adults diagnosed with ALL, the different sources and conditioning regimens for transplantation as well as the role of measurable residual diseases pre- and post-HCT in the era of the new therapies for ALL.

Isolating Malignant and Non-Malignant B Cells from lckeGFP Zebrafish.

Zebrafish (Danio rerio) are a powerful model to study lymphocyte development. Like mammals, D. rerio possess an adaptive immune system that includes B and T lymphocytes. Studies of zebrafish lymphopoiesis are difficult because antibodies recognizing D. rerio cell surface markers are generally not available, complicating isolation and characterization of different lymphocyte populations, including B-lineage cells. Transgenic lines with lineage-specific fluorophore expression are often used to circumvent this challenge. The transgenic lckeGFP line has been used to study D. rerio T cell development, and has also been utilized to model T cell development and acute lymphoblastic leukemia (T-ALL). Although lckeGFP fish have been widely used to analyze the T-lineage, they have not been used to study B cells. Recently, we discovered that many zebrafish B cells also express lck, albeit at lower levels. Consequently, lckeGFP B cells likewise express low levels of GFP. Based on this finding, we developed a protocol to purify B-lineage cells from lckeGFP zebrafish, which we report here. Our method describes how to utilize a fluorescent-activated cell sorter (FACS) to purify B cells from lckeGFP fish or related lines, such as double-transgenic rag2hMYC lckeGFP fish. In these lines, B cells, particularly immature B cells, express GFP at low but detectable levels, allowing them to be distinguished from T cells, which express GFP highly. B cells can be isolated from marrow, thymus, spleen, blood, or other tissues. This protocol provides a new method to purify D. rerio B cells, enabling studies focused on topics like B cell development and B lymphocyte malignancies.

Cardiovascular disease after childhood acute lymphoblastic leukaemia a cohort study.

Cardiovascular diseases (CVD) increase late morbidity and mortality in survivors of acute lymphoblastic leukaemia (ALL). We compared the risk of CVD in ALL survivors to siblings, examined time trends, quantified treatment-related risks, and investigated whether risk extends beyond patients treated with anthracyclines and chest radiotherapy. The Swiss Childhood Cancer Survivor Study assessed CVD by patient questionnaire in 5-year ALL survivors diagnosed between 1976 and 2005 and their siblings. Participants were asked whether a physician had ever told them that they had hypertension, arrhythmia, heart failure, myocardial infarction, angina pectoris, stroke, thrombosis or valvular problems. We investigated treatment-related risk factors for CVD using multivariable logistic regression, adjusting for demographic and socioeconomic factors, BMI, smoking, diabetes mellitus, alcohol consumption and physical activity. We contacted 707 survivors and 1299 siblings, 511 (72%) and 709 (55%) of whom responded, respectively. Survivors had a higher risk of developing CVD than siblings (odds ratio OR 1.9, 95% confidence interval 1.3ndash2.8), in particular heart failure (OR 13.9, 1.8ndash107.4). Compared to patients treated 1976ndash85, the risk of CVD was 1.4 (0.7ndash2.8) for those treated 1985ndash1994 and 1.5 (0.6ndash3.7) for those treated 1995ndash2005. The overall CVD risks after anthracycline treatment (OR 3.1, 2.0ndash4.7), haematopoietic stem cell transplantation (OR 8.0, 2.4ndash26.9) or relapse (OR 4.1, 1.9ndash8.8) were increased compared to those of siblings, while the CVD risks of survivors treated without anthracycline or chest radiotherapy were similar (OR 1.0 0.5ndash2.0). Despite attempts to reduce cardiotoxicity in childhood cancer treatment, CVD risks in ALL survivors treated more recently do not seem to have declined.

Anterior segment infiltration of acute lymphoblastic leukemia case report and systematic review.

Acute lymphoblastic leukemia (ALL) relapse implies a poor prognosis and demands emergency treatment. Leukemic infiltration of the anterior segment can masquerade as intraocular inflammation a high index of suspicion for this complication is essential. We describe a case of ocular relapse in a 2-year-old male on maintenance therapy for ALL. A systematic review of all known cases of similar leukemic infiltration of the anterior segment of the eye in ALL was performed. A total of 106 patients in 43 reports described leukemic infiltration of the eye as an initial presentation of ALL or relapse. Ocular relapse may be the first visible manifestation of systemic disease, with concurrent disease in the CNS, bone marrow, or testes. Prognosis for ALL patients with ocular relapse is poor, with death after initial presentation reported as early as 16 days. Patients with a history of ALL presenting with any sign of ocular inflammation should be assessed for relapse and leukemic infiltration. As soon as a diagnosis of relapse has been confirmed, appropriate leukemia therapy should be initiated.

A fully human anti-IL-7Rα antibody promotes antitumor activity against T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer for which treatment options often result in incomplete therapeutic efficacy and long-term side-effects. Interleukin 7 (IL-7) and its receptor IL-7Rα promote T-ALL development and mutational activation of IL-7Rα associates with very high risk in relapsed disease. Using combinatorial phage-display libraries and antibody reformatting, we generated a fully human IgG1 monoclonal antibody (named B12) against both wild-type and mutant human IL-7Rα, predicted to form a stable complex with IL-7Rα at a different site from IL-7. B12 impairs IL-7IL-7R-mediated signaling, sensitizes T-ALL cells to treatment with dexamethasone and can induce cell death per se. The antibody also promotes antibody-dependent natural killer-mediated leukemia cytotoxicity in vitro and delays T-cell leukemia development in vivo, reducing tumor burden and promoting mouse survival. B12 is rapidly internalized and traffics to the lysosome, rendering it an attractive vehicle for targeted intracellular delivery of cytotoxic cargo. Consequently, we engineered a B12-MMAE antibody-drug conjugate and provide proof-of-concept evidence that it has increased leukemia cell killing abilities as compared with the naked antibody. Our studies serve as a stepping stone for the development of novel targeted therapies in T-ALL and other diseases where IL-7Rα has a pathological role.

What are you crying for I dont even know you - The experiences of teenagers communicating with their peers when returning to school.

Young people (YP) returning to school after a cancer diagnosis and treatment have to decide who has the right to know about their cancer experiences and how to distribute this information to peers. Young people face unique challenges in this area because of their life stage, their need to reintegrate with peers, and their own approach to their disease and treatment. This paper explores the perspectives of young people as they return to school during and after curative cancer treatment. 12 young people (6 females, 6 males) from the north of England (aged 13-16 years at time of recruitment) took part in photo elicitation interviews conducted at three time points during the year following a diagnosis of lymphoma, Hodgkins lymphoma, osteosarcoma, A-plastic anaemia or acute lymphoblastic leukaemia. Interviews were transcribed and analysed using Interpretative Phenomenological Analysis (IPA). Three main themes emerged approaches to telling, lives becoming public property and owning the story. Within these themes participants experienced stressors related to altered peer group dynamics, being propelled into the foreground of the school environment, being responsible for the feelings and needs of others, and conflicts between their perception of coping and the reactions of others. Re-entering school following a diagnosis of cancer can result in challenging dynamics for a young person, which they are not always equipped to manage. Participants displayed individual differences in their approaches and preferences, but inevitably all had to cope with their lives becoming public property and managing the narrative of their cancer experience.