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Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents.

T-cell redirecting bispecific antibodies (bsAbs) or antibody-derived agents that combine tumor antigen recognition with CD3-mediated T cell recruitment are highly potent tumor-killing molecules. Despite the tremendous progress achieved in the last decade, development of such bsAbs still faces many challenges. This work aimed to develop a mechanism-based pharmacokineticpharmacodynamic (PKPD) modeling framework that can be used to assist the development of T-cell redirecting bsAbs. A Target cell-Biologics-Effector cell (TBE) complex-based cell killing model was developed using in vitro and in vivo data, which incorporates information on binding affinities of bsAbs to CD3 and target receptors, expression levels of CD3 and target receptors, concentrations of effector and target cells, as well as respective physiological parameters. This TBE model can simultaneously evaluate the effect of multiple system-specific and drug-specific factors on the T-cell redirecting bsAb exposure-response relationship on a physiological basis it reasonably captured multiple reported in vitro cytotoxicity data, and successfully predicted the effect of some key factors on in vitro cytotoxicity assays and the efficacious dose of blinatumomab in humans. The mechanistic nature of this model uniquely positions it as a knowledge-based platform that can be readily expanded to guide target selection, drug design, candidate selection and clinical dosing regimen projection, and thus support the overall discovery and development of T-cell redirecting bsAbs.

Systematic Review and Meta-Analysis of Selected Cancers in Petroleum Refinery Workers.

We studied the risk of 11 cancers of a priori interest in petroleum refinery workers. Iterative searches identified 36 studies for the 11 cancer sites. Statistical heterogeneity and publication bias were assessed to enhance interpretation of meta-relative risks. Statistical heterogeneity was marked for mesothelioma, but was largely due to study quality. Higher quality studies showed a meta-relative risk (RR) of 3.22, (95% prediction interval 1.45 to 7.23). Melanoma (meta-RR 1.23) and acute lymphoid leukemia (meta-RR 1.51), showed results consistent with higher risk, but both were driven by one or two studies. Eight other cancer outcomes showed summary meta-RRs consistent with unity. Most cancer outcomes are consistent with background risk in refinery workers. This work has clarified an excess mesothelioma risk, conditional on study quality stratification. Continued surveillance is warranted for melanoma and ALL.

Induction chemotherapy reduces extracellular heat shock protein 72 levels, inflammation, lipoperoxidation and changes insulin sensitivity in children and adolescents newly diagnosed with acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is associated with higher levels of pro-inflammatory cytokines and oxidative stress. Recently, the levels of extracellular heat shock protein 72 (eHSP72) were found to be elevated in ALL, and its elevation associated with poor prognosis. Therefore, considering the possible role of eHSP72 as a modulator of the immunological system and metabolism, the aim of this study was to describe the response of eHSP72 to the induction phase of chemotherapy, along with metabolic, inflammatory and oxidative stress markers, in children and adolescents newly diagnosed with ALL. Nineteen patients were recruited and analysed before and after the induction phase of chemotherapy (with 28 days of duration). Blood samples were taken for the analysis of C-reactive protein (CRP), levels of lipoperoxidation, insulin (and HOMA-IR), cortisol, glucose, lipid profile and eHSP72. We found that induction phase of chemotherapy leads to a drop in glucose levels (from 101.79±19 to 75.8±9.7 mgdL), improvements on inflammation (CRP levels, p<0.01) and oxidative stress (TBARS levels, p<0.01), reduction on eHSP72 (p0.03) and improved insulin sensitivity (HOMA-IR, p0.02). Our results indicate that eHSP72 may have an immune and metabolic role and could be used as a marker of the treatment success and metabolic changes in children with ALL.

Neurocognitive Sequelae in Adult Childhood Leukemia Survivors Related to Levels of Phosphorylated Tau.

Central nervous system-directed prophylactic chemotherapy increases survival in childhood leukemia, but possible late neurocognitive sequelae remain a concern. We compared intellectual performance (WAIS IV), memory (AVLT), and executive functioning (ANT) between adult leukemia survivors (n 31) and control individuals (n 35). In survivors, cerebrospinal fluid (CSF) levels of phosphorylated Tau (p-Tau) during treatment and total intrathecal methotrexate dose correlated with adult intellectual performance (Pearsons and Spearmans coefficients, respectively). Long-term memory and attentional control, both maturing before survivors mean age at diagnosis, were unaffected (P > .05 on all four subtests), in contrast to cognitive flexibility and information processing (P < .05 for eight of the subtests), which mature during adolescence. CSF p-Tau and methotrexate dose negatively correlated with intellectual performance (r -0.414, P .04 and r -0.484, P .007, respectively), but not with each other (r 0.219, P .29). These data identify CSF p-Tau as a predictor of late neurocognitive sequelae (in addition to methotrexate dose). Early identification of children at risk could inspire interventions to prevent or remediate chemotherapy-induced cognitive sequelae.

Clinker visualizing fusion genes detected in RNA-seq data.

Genomic profiling efforts have revealed a rich diversity of oncogenic fusion genes. While there are many methods for identifying fusion genes from RNA-sequencing (RNA-seq) data, visualizing these transcripts and their supporting reads remains challenging. Clinker is a bioinformatics tool written in Python, R, and Bpipe that leverages the superTranscript method to visualize fusion genes. We demonstrate the use of Clinker to obtain interpretable visualizations of the RNA-seq data that lead to fusion calls. In addition, we use Clinker to explore multiple fusion transcripts with novel breakpoints within the P2RY8-CRLF2 fusion gene in B-cell acute lymphoblastic leukemia. Clinker is freely available software that allows visualization of fusion genes and the RNA-seq data used in their discovery.

Survival from childhood cancers in Eastern Africa A population-based registry study.

Cancers occurring in children in Africa are often underdiagnosed, or at best diagnosed late. As a result, survival is poor, even for cancers considered curable. With limited population-level data, understanding the actual burden and survival from childhood cancers in Africa is difficult. In this study, we aimed at providing survival estimates for the most common types of cancers affecting children aged 0-14 years, in three population-based Eastern African registries Harare, Zimbabwe (Kaposi sarcoma, Wilms tumour (WT), non-Hodgkin lymphoma (NHL), retinoblastoma, and acute lymphocytic leukaemia (ALL)), Kampala, Uganda (Burkitt lymphoma, Kaposi sarcoma, WT, and retinoblastoma), and Nairobi, Kenya (ALL, retinoblastoma, WT, Burkitt lymphoma, and Hodgkin lymphoma). We included cases diagnosed within the years 1998-2009 and followed up till the end of 2011. We estimated the observed and relative survival at 1, 3, and 5 years after diagnosis. We studied 627 individual patient records. Median follow-up ranged from 2.2 months for children with Kaposi sarcoma in Harare to 30.2 months for children with ALL in Nairobi. The proportion of children lost to follow-up was highest in the first year after diagnosis. In Harare and Kampala, the 5-year relative survival was <46% for all cancer types. The 5-year relative survival was best for children in Nairobi, though with wider confidence intervals. Survival from childhood cancers in Africa is still poor, even for cancers with good prognosis and potential for cure. Supporting cancer detection, treatment, and registration activities could help improve survival chances for children with cancers in Africa.

Incidence, course, and outcome of Clostridium difficile infection in children with hematological malignancies or undergoing hematopoietic stem cell transplantation.

Clostridium difficile infection (CDI) is one of the most common causes of nosocomial infectious diarrhea in children during anticancer therapy or undergoing hematopoietic stem cell transplantation (HSCT) in Europe. Immunosuppression in these patients is a risk factor for CDI. Malignant diseases, age, acute graft-versus-host disease (aGVHD), HLA mismatch, or use of total body irradiation may play an important role in CDI course. The aim of this study was to evaluate the incidence, course, and outcome of CDI in children treated for malignancy or undergoing HSCT. Between 2012 and 2015, a total number of 1846 patients were treated for malignancy in Polish pediatric oncological centers (PHO group) and 342 underwent transplantation (HSCT group). In PHO group, episodes of CDI occurred in 210 patients (14%). The incidence of CDI was higher in patients with hematological malignancies in comparison to that with solid tumors. Patients with acute myeloblastic leukemia had shorter time to episode of CDI than those with acute lymphoblastic leukemia. Patients over 5 years and treated for acute leukemia had more severe clinical course of disease in PHO group. In HSCT group, CDI occurred in 29 (8%) patients. The incidence of CDI was higher in patients transplanted for acute leukemia. The recurrence rate was 14.7% in PHO and 20.7% in HSCT patients. CDI incidence was highest in patients with hematological malignancies. Most of patients experienced mild CDI. Age < 5 years and diagnosis other than acute leukemia were the positive prognostic factors influencing clinical CDI course.

Genetic predisposition to B-cell acute lymphoblastic leukemia at 14q11.2 is mediated by a CEBPE promoter polymorphism.

Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. Genome-wide association studies have shown variation at 14q11.2 influences ALL risk. We sought to decipher causal variant(s) at 14q11.2 and the mechanism of tumorigenesis. We show rs2239630 G>A resides in the promoter of the CCAT enhancer-binding protein epsilon (CEBPE) gene. The rs2239630-A risk allele is associated with increased promotor activity and CEBPE expression. Depletion of CEBPE in ALL cells reduces cell growth, correspondingly CEBPE binds to the promoters of electron transport and energy generation genes. RNA-seq in CEBPE depleted cells demonstrates CEBPE regulates the expression of genes involved in B-cell development (IL7R), apoptosis (BCL2), and methotrexate resistance (RASS4L). CEBPE regulated genes significantly overlapped in CEBPE depleted cells, ALL blasts and IGH-CEBPE translocated ALL. This suggests CEBPE regulates a similar set of genes in each, consistent with a common biological mechanism of leukemogenesis for rs2239630 associated and CEBPE translocated ALL. Finally, we map IGH-CEBPE translocation breakpoints in two cases, implicating RAG recombinase activity in their formation.

PARP1 Stabilizes CTCF Binding and Chromatin Structure To Maintain Epstein-Barr Virus Latency Type.

Epstein Barr virus (EBV) is a potentially oncogenic gammaherpesvirus that establishes a chronic, latent infection in memory B cells. The EBV genome persists in infected host cells as a chromatinized episome and is subject to chromatin-mediated regulation. Binding of the host insulator protein CTCF to the EBV genome has an established role in maintaining viral latency type. CTCF is posttranslationally modified by the host enzyme PARP1. PARP1, or poly(ADP-ribose) polymerase 1, catalyzes the transfer of a poly(ADP-ribose) (PAR) moiety from NAD

Identification and Quantification of Heterogeneously-methylated DNA Fragments Using Epiallele-sensitive Droplet Digital Polymerase Chain Reaction (EAST-ddPCR).

DNA methylation plays an important role in the initiation and propagation of carcinogenesis however, the role of heterogeneously methylated epialleles is currently not well studied, also due to the lack of sensitive, unbiased and high throughput methods. Here, a newly developed droplet digital PCR (ddPCR)-based method was evaluated regarding its ability to quantify such heterogeneously methylated epialleles with sufficient analytical sensitivity and specificity. Genomic DNA from blood leukocytes and bone marrow aspirate of an 8-year old male with B-cell acute lymphoblastic leukemia (B-ALL) and from normal and malignant prostate cell lines were analysed using ddPCR. By using these DNA samples, the specificity of an applied set of fluorescence-labeled probes was demonstrated as a proof of concept. All individual heterogeneously-methylated epialleles were quantifiable by a set of fluorescence-labeled probes with complementary sequences to epialleles in a closed-tube and high-throughput manner. The new method named epiallele-sensitive droplet digital PCR (EAST-ddPCR) may give new insights in the generation and regulation of epialleles and may help in finding new biomarkers for the diagnosis of benign und malignant diseases.

Complex Karyotype in Hematological Diseases A 6-Year Single Centre Study from Pakistan.

Most of the hematological disorders are heterogenous with regard to morphology, immunophenotype, and genetic rearrangements. Multiple recurrent chromosomal aberrations have been identified by conventional cytogenetic analysis, which is now widely recognized as one of the most important diagnostic and prognostic determinants in these patients. Though rarer, complex karyotype has been associated with worst prognosis. A total of 1185 bone marrow or peripheral blood cytogenetics samples were taken with different hematological diseases. They included both benign and malignant disease entities. In each case, cells were cultured and conventional cytogenetic analysis was performed. Among 1185 subjects, 41 (3.4%) patients possessed complex cytogenetic abnormalities. Out of these 41, 33 (80%) were males. The mean age was 37 years (median age 39 years). Myelodysplastic syndromes had the most numbers of complex karyotypes (8%), followed by acute myeloid leukemia (7%) and acute lymphoblastic leukemia (4%). Also we found few patients with acute promyelocytic leukemia, aplastic anemia , chronic myeloid leukemia, and diffuse large B cell Lymphoma possessing complex karyotype. Frequencies of different cytogenetic abnormalities were assessed with respect to disease as well as independently. Trisomy 21 was the most common chromosomal abnormality found in 28% of patients. Complex karyotype was most frequently associated with myelodysplastic syndromes and acute myeloid leukemia. Trisomy 21 and deletion 5q were the commonest cytogenetic abnormalities found. We also assessed complex karyotype in benign diseases and detected one patient of aplastic anemia with complex karyotype. This is the first study highlighting the presence of complex karyotypes in hematological disorders in our region.

Possible roles of genetic variations in chemotherapy related cardiotoxicity in pediatric acute lymphoblastic leukemia and osteosarcoma.

The treatment of acute lymphoblastic leukemia (ALL) and osteosarcoma (OSC) is very effective the vast majority of patients recover and survive for decades. However, they still need to face serious adverse effects of chemotherapy. One of these is cardiotoxicity which may lead to progressive heart failure in the long term. Cardiotoxicity is contributed mainly to the use of anthracyclines and might have genetic risk factors. Our goal was to test the association between left ventricular function and genetic variations of candidate genes. Echocardiography data from medical records of 622 pediatric ALL and 39 OSC patients were collected from the period 1989-2015. Fractional shortening (FS) and ejection fraction (EF) were determined, 70 single nucleotide polymorphisms (SNPs) in 26 genes were genotyped. Multivariate logistic regression and multi-adjusted general linear model were performed to investigate the influence of genetic polymorphisms on the left ventricular parameters. Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method was applied to test for the potential interaction of the studied cofactors and SNPs. Our results indicate that variations in ABCC2, CYP3A5, NQO1, SLC22A6 and SLC28A3 genes might influence the left ventricular parameters. CYP3A5 rs4646450 TT was 17% among ALL cases with FS lower than 28, and 3% in ALL patients without pathological FS (p 5.60E-03 OR 6.94 (1.76-27.39)). SLC28A3 rs7853758 AA was 12% in ALL cases population, while only 1% among controls (p 6.50E-03 OR 11.56 (1.98-67.45)). Patients with ABCC2 rs3740066 GG genotype had lower FS during the acute phase of therapy and 5-10 years after treatment (p 7.38E-03, p 7.11E-04, respectively). NQO1 rs1043470 rare T allele was associated with lower left ventricular function in the acute phase and 5-10 years after the diagnosis (p 4.28E-03 and 5.82E-03, respectively), and SLC22A6 gene rs6591722 AA genotype was associated with lower mean FS (p 1.71E-03), 5-10 years after the diagnosis. Genetic variants in transporters and metabolic enzymes might modulate the individual risk to cardiac toxicity after chemotherapy.

Benign TdT-positive cells in pediatric and adult lymph nodes a potential diagnostic pitfall.

Benign terminal deoxynucleotidyl transferase (TdT)-positive cells have been documented in a variety of nonhematopoietic tissues. Scant data are, however, available on their presence in nonneoplastic lymph nodes. This study is aimed to (1) characterize the presencedistribution of benign TdT-positive cells in pediatric and adult reactive lymph nodes and (2) define the phenotype and nature of such elements. This retrospective study considered 141 reactive lymph nodes from pediatric and adult patients without history of neoplastic disease. TdT-positive cells were characterized by immunohistochemical and morphometric analyses, and their presence was correlated with the clinical-pathological features. The nature of TdT-positive cells was investigated by (1) double immunostaining for early lymphoid cell markers and (2) assessment of TdT expression in fetal lymph nodes. Sparse TdT-positive cells were documented in all pediatric cases and in most (76%) adult lymph nodes. TdT-positive cell density was higher in children than adults (15.9mm

Brain morphology and information processing at the completion of chemotherapy-only treatment for pediatric acute lymphoblastic leukemia.

Cytomegalovirus Colitis during Dasatinib Treatment for Patients with Hematologic Malignancy Case Series and Literature Review.

Dasatinib, a tyrosine kinase inhibitor, is widely used for patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Although the drug has a potent immunosuppressive effect, infectious complications during dasatinib treatment have been reported rarely. We describe five patients who developed cytomegalovirus (CMV) colitis during dasatinib treatment, in whom the colitis was initially confused with other causes. The patients, three with chronic myeloid leukemia, and two with acute lymphoblastic leukemia, were diagnosed with CMV colitis based on endoscopic and histologic findings. The patients who examined blood CMV polymerase chain reaction were all positive. The patients received antiviral therapy in the form of either ganciclovir or valganciclovir, and the overall treatment outcome was fair. These cases suggest that physicians should consider the possibility of CMV reactivation when treating diarrhea andor hematochezia in patients on dasatinib.

Origins of STIL-TAL1 fusion genes in children who later developed paediatric T-cell acute lymphoblastic leukaemia An investigation of neonatal blood spots.

SCLTAL1 interrupting locus (STIL)-T-cell acute leukaemia (TAL1) fusion genes are present in approximately 11-27% of children with paediatric T-cell acute lymphoblastic leukaemia (T-ALL), but the developmental timing of the rearrangement is still unknown. To investigate whether the fusion gene can be detected in neonatal blood spots (NBSs) from paediatric patients diagnosed with T-cell ALL, we analysed DNA from 38 paediatric patients with T-ALL by nested polymerase chain reaction and electrophoresis. The STIL-TAL1 fusion gene was not detected in NBSs from any of the 38 patients with T-ALL, suggesting that STIL-TAL1 fusion genes are most probably postnatal events in paediatric T-ALL.

Expression of miR-652-3p and Effect on Apoptosis and Drug Sensitivity in Pediatric Acute Lymphoblastic Leukemia.

MicroRNAs (miRNAs) expression profiles were screened in plasma samples from pediatric patients with acute lymphoblastic leukemia (ALL) and healthy controls, using qRT-PCR-based TaqMan low-density miRNA arrays. MiR-652-3p (a circulating miRNA) was downregulated in new diagnosis (ND) patients compared with healthy controls. The levels of miR652-3p were restored in complete remission (CR) but were downregulated again in disease relapse (RE). The expression pattern of miR-652-3p was validated in bone marrow (BM) samples from other pediatric ALL patients. MiR-652-3p was significantly upregulated in BM when the patients (

In vitro combinatorial anti-proliferative and immunosuppressive effects of Brucea javanica extract with CX-4945 and imatinib in human T-cell acute lymphoblastic leukemia cells.

Since 1970, the isolated and identified components of Brucea javanica (L.) Merr. have been known to contain anticancer effects, particularly antileukemic effect. In this study, the inhibitory effect of Brucea javanica (BJ) on cell growth and inflammation was confirmed in human T-cell acute lymphocytic leukemia (T-ALL) cells, and its efficacy as an antileukemic agent was verified. Our results showed that BJ extract induced caspase-dependent apoptosis of T-ALL Jurkat cells through inhibition of the CK2-mediated signaling pathway, while exerting no significant cytotoxicity in normal peripheral blood mononuclear cells. Moreover, BJ extract suppressed the NF-κB signaling pathway, thus, inhibiting the interleukin (IL)-2 expression induced by phorbol 12-myristate 13-acetate (PMA) and phytohemagglutinin (PHA). Notably, combined treatment with BJ extract plus CX-4945 or imatinib exerted enhanced inhibitory effects on T-ALL cell growth and IL-2 production. Overall, these results suggest that BJ extract can be a potent therapeutic herbal agent for T-ALL treatment and prevention of IL-2 mediated inflammatory immune responses.

Congestive heart failure among children with acute leukemia a population-based matched cohort study.

The purpose was to describe the incidence and risk factors of congestive heart failure (CHF) among children with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). We included 2053 children (≤18 years) with first primary ALL and AML diagnosed 1992-2010 and registered in the Pediatric Oncology Group of Ontario Networked Information System. We identified CHF events through linked administrative databases. At 10 years, the cumulative incidence of CHF was 1.7% in ALL and 7.5% in AML. Factors associated with CHF in ALL were female gender, age <1 year at cancer diagnosis, irradiation and cumulative anthracycline dose ≥250 mgm

Deletion of CDKN2AB is associated with inferior relapse free survival in pediatric B cell acute lymphoblastic leukemia.

Considering conflicting data on CDKN2AB deletion in ALL, this study to assess its prognostic significance as an independent marker in a total of 96 pediatric B and T-ALL cases was planned. The overall frequency of CDKN2AB deletion was 44% (n 43) with 36% (3083) in B-ALL and 100% (1313) in T-ALL. CDKN2AB deletion was significantly associated with high WBC count (p .002) and National Cancer Institute risk (p .01) in B-ALL. Importantly, CDKN2AB deletion cases had poor EFS of 42% at 28 months compared to EFS of 90% in rest (p .0004). Further, relapse free survival was only 56% for cases with CDKN2AB deletions (n 25), compared to 100% in control group (p .001). Moreover, CDKN2AB deletion was the only risk factor associated with early relapse (p .01) compared to IKZF1 deletion (p .73) or occurrence of BCR-ABL1 fusion transcript (p .26). Thus our study data highlights potential prognostic role of CDKN2AB deletions in early disease stratification in pediatric B-ALL.

Daunorubicin during delayed intensification decreases the incidence of infectious complications - a randomized comparison in trial CoALL 08-09.

Anthracyclines are integral components of antileukemic treatment. Apart from cardiotoxicity, myelosuppression and infectious complications have been described for doxorubicin (DOX) and daunorubicin (DNR) as predominant side effects, but little is known about their differential toxicities. To address the question whether DNR is associated with a lower rate of infectious complications compared with DOX, 307 children with newly diagnosed acute lymphoblastic leukemia, enrolled in trial CoALL 08-09, were randomized to receive either DOX 30 mgm

Tailoring antimicrobials in febrile neutropenia using faster diagnostic and communication tools to improve treatment in the era of extensively resistant pathogens.

Febrile Neutropenia represents a medical emergency and the use of appropriate antimicrobial therapy is essential for a better outcome. Although being time-consuming, conventional cultures and antimicrobial susceptibility tests remain the golden standard practices for microbiology identification. Final reports are typically available within several days. Faster diagnostic tools, such as species identification trough Matrix Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) and molecular techniques might help to shorten time to diagnostic and also guide definitive therapy in this scenario. Here we present a case in which the use of a diagnostic molecular workflow combining MALDI-TOF and real-time PCR for relevant genes codifying antibiotic resistant integrated with instant communication report, led to a tailored and more appropriate treatment in a patient presenting with febrile neutropenia.

Leukemia propagating cells in Philadelphia chromosome-positive ALL a resistant phenotype with an adverse prognosis.

Targeted therapy has revolutionized the management of Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL) however, relapse still occurs because of the presence of quiescent stem cells, termed leukemia propagating cells (LPCs). This study aimed to assess the phenotypic diversity of LPCs in adult patients with Ph B-Acute ALL (B-ALL) and to assess its prognostic impact. Seventy adults with newly diagnosed Ph B-ALL were recruited at the Mansoura Oncology Center. Multiparameter flow cytometry studies of mononuclear blast cells for cluster of differentiation (CD)34, CD38, and CD58 were performed. Seventeen patients had blasts with the pattern of LPCs (CD34CD38-CD58-), while 53 cases had other diverse phenotypic patterns. The rate of complete response was significantly lower in patients with the LPC phenotype (47% vs. 81%, The presence of CD34CD38-CD58- LPCs at diagnosis allows rapid identification of higher risk patients. Risk stratification of these patients is needed to further guide therapy and develop effective LPCs-targeted therapy to improve treatment outcome.

The Incidence and Predictive Factors in the Development of Acute Hepatitis in Patients with Leukemia.

Liver involvement is common in hematological malignancies, but the incidence and pattern of liver injury vary among the different types. The aims of our study were to determine the incidence and clinical course of acute hepatitis and the important factors for its development in patients with leukemia after chemotherapy. All patients with the diagnosis of leukemia who were treated at the Department of Hematology between January 2008 and January 2013 were included in the study. A detailed medical history, clinical and laboratory findings, treatment modalities, complications, and clinical course were recorded retrospectively. A total of 124 patients (64 females) with the diagnosis of leukemia were included in the study. The mean age was 45.2 years (16-89 years) and mean follow-up time was 29.7 months (0.25-192 months). A total of 43 (34.6%) patients had acute hepatitis after chemotherapy. Pattern of liver injury was hepatocellular in 31 patients, cholestasis in 2, and mix in 10 patients. Age (p 0.001), hepatitis B surface antigen (HBsAg, p 0.007), acute leukemia (p < 0.001), positive blood culture (p 0.004), the amount of transfused red blood cell (p 0.001), and amount of transfused platelets (p 0.002) were significantly different under univariate analysis between the acute hepatitis group and the nonacute hepatitis group. Under multivariate analysis, only acute lymphoblastic leukemia (ALL) was identified as independent predictive factor for development of acute hepatitis after starting chemotherapy. Acute and self-limited hepatitis develops in the substantial proportion of patients with leukemia. The most important factor for development of acute hepatitis is the type of leukemia.

Effect of allogeneic blood transfusion on levels of IL-6 and sIL-R2 in peripheral blood of children with acute lymphocytic leukemia.

Effect of allogeneic blood transfusion on the expression of interleukin-6 (IL-6) and soluble interleukin-2 receptor (sIL-2R) in peripheral blood of children with acute lymphoblastic leukemia (ALL) was investigated. A total of 91 ALL children admitted to Nanfang Hospital from June 2014 to January 2017 were selected as the study group. Patients were randomly divided into allogeneic blood transfusion group (n38) and non-transfusion group (n53). In addition, a total of 64 healthy children were also selected from June 2014 to January 2017 as the control group. Patients in allogeneic blood transfusion group were transfused with red blood cell suspension and machine-collected platelets, while patients in non-transfusion group were not treated with blood transfusion. Peripheral venous blood was collected before and at 4, 8 and 12 weeks after blood transfusion to prepare serum. Serum IL-6 and sIL-2R levels were measured by enzyme-linked immunosorbent assay (ELISA). Before transfusion, serum levels of IL-6 and sIL-2R were significantly lower in the study group than those in control group (p<0.05), and no significant differences in serum levels of IL-6 and sIL-2R were found between the allogeneic blood transfusion and non-transfusion group. After transfusion, serum levels of IL-6 and sIL-2R were stable for 12 weeks in the non-transfusion group, while IL-6 and sIL-2R levels were significantly increased in the allogeneic blood transfusion group. The results showed that serum level of IL-6 and sIL-2R was increased in ALL patients with allogeneic blood transfusion, which resulted in reduced antibody production and decreased cellular immunity. The patients had low immunity, and attention should be paid on the pathogen infection prevention.

Incidence of upper digestive tract inflammation in children with acute lymphoblastic leukemia at diagnosis.

Inflammatory lesions in upper digestive tract are common adversary events in children with acute lymphoblastic leukemia (ALL). However, when these lesions initiate is still not clear. In this study, we retrospectively analyzed the endoscopic detection results of 129 children who suffered from ALL at diagnosis. 107 (82%) patients were found with gastrointestinal inflammation, of which 101 patients had lesions in the stomach, 11 had lesions in the esophagus and 51 had lesions in the duodenal bulb. Only 2 patients were found with helicobacter pylori infection, and 1 patient was found with a mycotic infection in the esophagus. We demonstrate that most patients with ALL have gastrointestinal inflammation at the diagnosis of the basic disease, and in contrast to adult patients in China, these inflammatory lesions were mostly not caused by HP infection.

Addressing Administration Challenges Associated With Blinatumomab Infusions A Multidisciplinary Approach.

Blinatumomab has shown great potential for patients with chemotherapy-resistant B-cell acute lymphocytic leukemia. Blinatumomabs toxicity profile includes central nervous system toxicities, as well as cytokine release syndrome. Although neurological toxicities associated with blinatumomab are almost always reversible, early detection and intervention of these toxicities is vital to ensure that patients continue their full course of treatment. Guidelines for the preparation and administration of blinatumomab in both inpatient and outpatient settings, as well as a standardized neurological nursing assessment, were developed to ensure safe and effective administration of blinatumomab.

Development of a Fluorescence in Situ Hybridization Probe for Detecting IKZF1 Deletion Mutations in Patients with Acute Lymphoblastic Leukemia.

Intragenic deletion of IKZF1 is a recurrent genomic alteration in acute lymphoblastic leukemia. The deletions are mediated by illegitimate variable(diversity)joining recombination via cryptic recombination signal sequences (RSSs). We developed a fluorescence in situ hybridization (FISH) probe set that can detect any type of IKZF1 deletion, including the commonly deleted exon 4 to 7 region. The probe set consists of a designed probe for the commonly deleted region (Cy3 red) and a bacterial artificial chromosomes clone probe for detecting the 3 flanking region (Spectrum Green). Intact IKZF1 showed a fusion signal, and the deleted allele showed loss of the red signal (0R1G1F). The FISH probes worked correctly for human leukemic cell lines and clinical samples. One case showed an atypical break-apart signal (1R1G1F). Inverse PCR of the case revealed rearrangement of the excised IKZF1 fragment into a legitimate RSS site at Ig κ on chromosome 2, suggesting a pathogenic role of this recombination-activating gene 12-mediated event. In this study, we established FISH probe detecting IKZF1 deletion in a quick, quantitative, and cost-effective manner, and the results provided a novel insight into B-cell receptor editing by rearrangement of a cryptic RSS-mediated genomic fragment in acute lymphoblastic leukemia pathology.

Comparison of target volume and clinical effects of four radiotherapy plans for acute lymphoblastic leukemia prior to hematopoietic stem cell transplantation.

The present study aimed to investigate the variations in target volume, clinical reaction and transplantation effects of helical tomotherapy (HT)‑total body irradiation (TBI), HT‑total marrow and lymphatic irradiation (TMLI), intensity modulated radiotherapy (IMRT)‑TBI and IMRT‑TMLI within patients with acute lymphoblastic leukemia (ALL). A total of 18 patients with ALL were treated with the four aforementioned radiotherapy plans prior to hematopoietic stem cell transplantation. A planned prescribed dose of 12 Gy6 Frequency was administered to determine planning target volume (PTV). Dosimetry evaluation indexes in PTV and organs at risk were analyzed. Comparison of clinical untoward effects and the results of transplantation among the four plans were performed. The conformity index of HT plans was significantly increased compared with those in IMRT plans. The mean dose (D) to the lung and volume ratio of target volume occupied by 5 Gy (V5) in TMLI plans were lower compared with TBI plans. Doses to organs were controlled within the normal range. Dmax, Dmean and V5 of bilateral lungs and Dmax and Dmean of bilateral crystalline lens in IMRT plans were significantly higher compared with HT plans. There were no significant differences in untoward effects among the four plans. Subsequent to symptomatic treatments with antiemetic, antidiarrheal and fluid infusion, untoward effects improved, and all patients demonstrated tolerance to these therapies. A total of six patients treated with HT‑TBI revealed complete and successful transplantation however, one patient following transplantation suffered from severe rejection and had succumbed to mortality due to severe infection. Patients treated with HT‑TMLI, IMRT‑TBI and IMRT‑TMLI completed successful transplantation and no rejection responses were observed. Conformity of HT plans are higher than that of IMRT plans. The four radiotherapy plans exhibit similar clinical untoward effects and the same transplantation success rate. HT‑TMLI is more feasible in dosimetry compared with HT‑TBI, IMRT‑TBI and IMRT‑TMLI, which require further long‑term observation.

Prevalence and Predictors of Invasive Fungal Infections in Children with Persistent Febrile Neutropenia Treated for Acute Leukemia - A Prospective Study.

To ascertain the prevalence of invasive fungal infections (IFI), predictors of IFI, identify etiological species and outcome (mortalitydischarge) in persistent febrile neutropenia in children with acute leukemia. It was a prospective, observational study conducted from January 2013 through June 2014 in a tertiary care centre in New Delhi. Children between 1 and 12 y of age, on chemotherapy for acute leukemia with persistent febrile neutropenia (> 96 h) were enrolled. These children were not on any antifungal prophylaxis. Diagnosis of IFI was based on European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTCMSG) criteria. Prevalence and outcome was reported in mean ± 95% CI form and etiological species were presented in the form of the frequency distribution. Three hundred nineteen episodes involving 187 children of febrile neutropenia were screened and 74 were enrolled. Prevalence of IFI was 22.97% (13.99-34.21). Positive cases were further classified into proven 3(17.6%), probable 11(64.8%) and possible 3(17.6%) according to EORTCMSG criteria. On multivariate analysis, abnormal CXR and clinical sinusitis were important predictors of IFI. Most common fungi isolated was Aspergillus sp. followed by Candida sp. Mortality rate was 9.45% (3.89-18.52). Thus, prevalence of IFI is very high in children with persistent febrile neutropenia who are not on antifungal prophylaxis. Abnormal chest x- ray and clinical sinusitis are important predictors of IFI.

Exposure-adjusted adverse events comparing blinatumomab with chemotherapy in advanced acute lymphoblastic leukemia.

In the phase 3 TOWER study, blinatumomab demonstrated an overall survival benefit over standard-of-care chemotherapy (SOC) in adults with relapsed or refractory (rr) Philadelphia chromosome-negative (Ph

Combination of Blinatumomab and Vincristine Sulfate Liposome Injection for Treatment of Relapsed Philadelphia Chromosome Positive B-cell Acute Lymphoblastic Leukemia.

Relapsed Philadelphia chromosome (Ph) positive Acute Lymphoblastic Leukemia (ALL) is an aggressive lymphoid malignancy with a poor prognosis and no randomized studies demonstrating superiority of any single salvage regimen. We present the case of a 33-year-old woman with relapsed Ph positive precursor (pre) B-cell ALL with rapidly rising peripheral blasts while on blinatumomab monotherapy initially, but ultimately responded with the addition of Vincristine Sulfate Liposome Injection (VSLI). Ponatinib was added later when it became available for the patient, and she ultimately achieved a complete remission. Further study is warranted to explore mechanisms of potential synergy, and the safety and efficacy of the combination of blinatumomab and VSLI.

Updates in the Pathology of Precursor Lymphoid Neoplasms in the Revised Fourth Edition of the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues.

Acute lymphoblastic leukemias (ALL) are malignant disorders of immature B or T cells that occur characteristically in children, usually under the age of 6 (75%). Approximately 6000 new cases of ALL are diagnosed each year in the USA, 80-85% of which represent B-ALL forms. Most presentations of B-ALL are leukemic, whereas T-ALL presents with a mediastinal mass, with or without leukemic involvement. The revised fourth edition of the World Health Organization (WHO) classification (2017) has introduced some changes in both B and T-ALL. Here, we summarize the categories of lymphoblastic leukemialymphomas as defined by the WHO and recent developments in the understanding of this group of hematologic malignancy. Two provisional categories of B-ALL have now been identified including B-ALL, BCR-ABL1-like, and B-ALL with iAMP21. The Philadelphia chromosome-like B-ALL includes forms of the disease that shares the expression profiling of B-ALL with t(922) but lack such rearrangement. The second one shows amplification of part of the chromosome 21. Both entities are associated with worse prognosis. Within the T-ALL group, an early precursor T cell form has now been introduced as a provisional category. Such group demonstrates expression of stem cell and myeloid markers in conjunction with the T cell antigens. The current review summarizes the recent updates to the WHO classification.

Acute leukemia cells resistant to PI3KmTOR inhibition display upregulation of P2RY14 expression.

The PI3KmTOR pathway is the second most frequently deregulated pathway in a majority of cancers such as breast cancer, lung cancer, and melanomas as well as leukemia. Mutations in the genes coding for receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs) are quite common in all forms of acute leukemia. This can be a major cause of deregulation of the PI3K-mTOR pathway. To understand how cells display resistance to the dual PI3KmTOR inhibitor, we used a panel of 25 acute leukemia cell lines. We observed that while a number of cell lines displayed sensitivity to the dual PI3KmTOR pathway inhibitor PKI-587, many cells displayed substantial resistance. Cells sensitive to PKI-587 also showed aberrant activation of PI3KmTOR pathway components such as AKT and S6K and also displayed sensitivity to a panel of various other PI3KmTOR inhibitors. Using RNA sequencing data, we observed that expression of a G protein-coupled receptor, P2RY14, was upregulated nine-fold in cells showing resistance to the PI3KmTOR inhibitor. P2RY14 has not been much studied in hematologic malignancies. However, this receptor seems to have a role in the localization of hematopoietic stem cells (HSCs) and in promoting regenerative capabilities following injury. We observed that acute lymphoblastic leukemia (ALL) and FLT3-ITD-positive acute myeloid leukemia (AML) patients with higher expression of P2RY14 mRNA displayed relatively poor survival compared to patients carrying lower expression of P2RY14 suggesting a role of P2RY14 in patient survival. To understand the role of this receptor in cell signaling, we used phospho-protein arrays and observed activation of distinct signaling cascades. Furthermore, array data were verified using murine pro-B cell line BaF3 stably transfected with P2RY14. We observed that activation of P2RY14 by its ligand, UDP-glucose, resulted in selective induction of ERK12 phosphorylation. Taken together, our data suggest that acute leukemia cells resistant to PI3KmTOR inhibition display upregulation of a GPCR, P2RY14, which has a role in patient survival and also couples to the activation of ERK signaling.

Relationship between Early Treatment Response and Prognosis in Children with Acute Lymphoblastic Leukemia.

To analyze the relationship between the early treatment response and the pregnosis in children with acute lymphoblastic leukemia(ALL). Two hundred and Seventy-eight ALL children diagnosed and treated in Hainan general hospital from March 2013 to March 2017 were collected. All ALL children received therapy with CCLg-ALL-2008 regimen. The 3 year event-free survival (EFS) rate of ALL children in different groups was analyzed in terms of 4 indexes including sensitivity response to prednison at day 8 (D8-SRP), bone marrow remission at day 15 (D15-BMR) and at day 33 (D33-BMR), and minimal residual disease at day 33 (D33-BMR), and minimal residual disease at day 33(D33-MRD). These 4 indexes and other indexes possibly affecting the prognosis of ALL children were enrolled in Cox regression model for analysis of independent factors affecting the prognosis of ALL children. The D8-SRP test showed that among 269 ALL children, 240(89.22%) cases displayed prednisone poor response (PPR) the 3-year EFS rate in predrisone good response(PGR) group was significantly higher than that in PPR group(P<0.05). The D15-BMR detection showed that among 262 ALL children, the bone marrow remission(BMR) as M1 was observed in 230 cases (87.79%), M2 in 20 cases (7.63%) and M3 in 9 cases (4.58%) the 3-year EFS rate showed as followsM1 group >M2 group >M3 group(P<0.05). The D33-BMR detection showed that among 257 ALL children, the BMR as M1 was observed in 227 cases (88.33%), M2 in 21 cses(8.17%) and M3 in 9 caes (3.51%) the 3-year EFS rate in 3 groups showed as follows M1 group >M2 group >M3 group(P<0.05). The D33-MRD detection showed that among 185 ALL children, MRD<10 The early treatment response can predict the prognosis of ALL children, which is an independent prognostic factor for ALL children.

Establishment of Drug-resistant Acute Lymphoblastic Leukemic Cell Lines and Their Resistance Mechanism.

To establish the adriamycin(ADR)-resistant ALL cell lines and to investigate their drug-resistan mechanisms. The drug-resistant cell lines SUP-B15ADR and RS411ADR were derived by exposing the parental cells SUP-B15(Ph The drug-resistant cell lines SUP-B15ADR and RS411ADR were successfully established, their resistance indexes were 14.088±0.763 and 10.473±1.024, respectively. After the cryopreserved SUP-B15ADR and RS411ADR cells were resuscitated, their survival rates were 88.4±1.2% and 89.3±1.6% respectively, while their resistance indexes were 13.976±0.967 and 10.342±0.846 respectively (P>0.05). When the drug-resistant cells were cultured in the medium without ADR for 1 month, their drug-resistance indexes dropped down to 12.893±1.255 and 9.327±0.321 respectively(P<0.05). Drug-resistant cell lines had the cross-resistance to cytarabine and etoposide. The expression of P-gp and MDR1 in drug-resistant cells was significantly higher than that in wild-type cells. Two drug-resistant ALL cell lines have been successfully established by exposing to the ascending concentration of ADR. The over-expression of MDR1 and P-gp in drug-resistant cells may be one of the mechanisms underlying the drug resistance.

HER2 Expression in Childhood ETV6RUNX1

To explore the HER22 expression in children with ETV6RUNX1 (ER)-positive acute lymphoblastic leukemia(ALL) and to investigate the relationship between the HER2 expression and clinical features. Thirty-seven newly diagnosed ER-positive ALL children and 6 controls (4 cases of ITP and 2 healthy children) were selected in Institute of hematology and blood disease hospital. The 37 patients were divided into standard risk (SR), intermediate risk(IR), high risk(HR) groups according to risk stratification and they were divided into relapse and non-relapse groups according to follow-up result. The CD10 Among the 37 cases, 51.35% (n19) were boys and 48.65% (n18) were girls and their median age was 4.72 (1.72-11.99) years old. Among the 6 controls, 50% (n3) were boys and 50% (n3) were girls and the median age was 5.24 (1.53-13.17) years old. The expression level of HER2 in ER-positive ALL patients were lower than that in controls (P<0.05). Although the difference of HER2 expression level between the 2 groups failed to achieve statistical significance, the expression level of HER2 in relapse patients were significantly lower than that in non-relapse patients, and the HER2 expression in HR group patients were lower than that in SR and IR groups. In addition, there was no significant correlation between the expression level of HER2 and the sex, age, initial white blood cell count, blast cell percentage and the level of LDH (P>0.05). The expression level of HER2 in ER

Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia An Update.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood malignancy that arises from the clonal expansion of transformed T-cell precursors. Although T-ALL prognosis has significantly improved due to the development of intensive chemotherapeutic protocols, primary drug-resistant and relapsed patients still display a dismal outcome. In addition, lifelong irreversible late effects from conventional therapy are a growing problem for leukemia survivors. Therefore, novel targeted therapies are required to improve the prognosis of high-risk patients. The mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct multiprotein complexes, which are referred to as mTOR complex 1 (mTORC1) and mTORC2. These two complexes regulate a variety of physiological cellular processes including protein, lipid, and nucleotide synthesis, as well as autophagy in response to external cues. However, mTOR activity is frequently deregulated in cancer, where it plays a key oncogenetic role driving tumor cell proliferation, survival, metabolic transformation, and metastatic potential. Promising preclinical studies using mTOR inhibitors have demonstrated efficacy in many human cancer types, including T-ALL. Here, we highlight our current knowledge of mTOR signaling and inhibitors in T-ALL, with an emphasis on emerging evidence of the superior efficacy of combinations consisting of mTOR inhibitors and either traditional or targeted therapeutics.

Pediatric Cancer Immunotherapy Opportunities and Challenges.

Cancer immunotherapies, widely heralded as transformational for many adult cancer patients, are becoming viable options for selected subsets of pediatric cancer patients. Many therapies are currently being investigated, from immunomodulatory agents to adoptive cell therapy, bispecific T-cell engagers, oncolytic virotherapy, and checkpoint inhibition. One of the most exciting immunotherapies recently FDA approved is the use of CD19 chimeric antigen receptor T cells for pre-B-cell acute lymphoblastic leukemia. With this approval and others, immunotherapy for pediatric cancers is gaining traction. One of the caveats to many of these immunotherapies is the challenge of predictive biomarkers determining which patients will respond to a given therapy is not yet possible. Much research is being focused on which biomarkers will be predictive and prognostic for these patients. Despite many benefits of immunotherapy, including less long-term side effects, some treatments are fraught with immediate side effects that range from mild to severe, although most are manageable. With few downsides and the potential for disease cures, immunotherapy in the pediatric population has the potential to move to the front-line of therapeutic options.

Recent Advances in the Biology and Treatment of T Cell Acute Lymphoblastic Leukemia.

This article provides an overview of the current knowledge regarding the biology and treatment of T cell acute lymphoblastic leukemia (T-ALL) and highlights the most recent findings in this field over the past 5 years. Remarkable progress has been made in the genomic landscape of T-ALL over the past few years. The discovery of activating mutations of NOTCH1 and FBXW7 in a majority of patients has been a seminal observation, with several early phase clinical trials currently exploring these as potential therapeutic targets. Characterization of early T cell precursor ALL, incorporation of minimal residual disease assessment into therapeutic protocols, and use of pediatric-intensive regimens along with judicious use of allogeneic HCT have significantly improved risk stratification and treatment outcomes. Improved risk stratification and the use of novel targeted therapies based on recent genomic discoveries are expected to change the therapeutic landscape of T-ALL and hopefully improve the outcomes of this historically poor prognosis disease.

Systemic Antifungal Prophylaxis in Patients Hospitalized in Hematology Units in France The AFHEM Cross-Sectional Observational Study.

The frequency of invasive fungal diseases (IFDs) has increased in recent years. Within a context where both treatments and guidelines are fast evolving, we aim to shed new light on IFD management in hematologic departments in France. A multicenter cross-sectional observational study was prospectively conducted in 24 French centers in September and October 2013. Four hundred ninety-four hospitalized children and adult patients suffering from hematologic malignancy were enrolled 147 (30%) were allogeneic hematopoietic stem cell transplant (HSCT) recipients, 131 (27%) were patients with acute myeloblastic leukemia or myelodysplastic syndrome (MDS), 71 (14%) were patients with acute lymphoblastic leukemia who did not undergo allogeneic HSCT, and the 145 (29%) remaining patients did not belong to the three above groups. Two hundred forty-six patients (50%) received antifungal treatment, which was prophylactic in 187 (76%) treated patients. These rates were similar across all groups (63-80%). Patients received prophylaxis with an azole (79%), intravenous amphotericin B formulation (10%), echinocandin (9%), or two combination drugs (2%). Results indicate that prophylaxis is the leading antifungal strategy in French hematology units, regardless of the disease condition, representing 76% of prescriptions for antifungal therapy. Astellas Pharma France.

Significant drug interaction between voriconazole and dexamethasone A case report.

Voriconazole is extensively metabolized by the CYP450 isoenzymes 2C19 and 3A4 and to a lesser extent by CYP2C9 therefore, any medication that affects this pathway can alter its plasma concentration. Treatment failure can probably occur if subtherapeutic levels are achieved. A 32-year-old woman who suffered from acute lymphoblastic leukemia was admitted and received treatment with vincristine and dexamethasone. After several days, to control her fever, based on two consecutive positive serum galactomannan test results, voriconazole as an antifungal agent was added to Aspergillus infection treatment. Through the first week after voriconazole initiation, its plasma concentrations were subtherapeutic. The most suspicious medication for interaction was dexamethasone, which can induce CYP450 isoenzymes and reduce plasma concentration. As a result of the narrow therapeutic window of voriconazole and the relationship between efficacy and plasma concentration of azoles, therapeutic drug monitoring of voriconazole in patients receiving a high dose of glucocorticoids is recommended, in order to achieve optimal response to treatment and toxicity reduction. Further studies regarding the interaction between voriconazole and dexamethasone to prevent clinically relevant interactions should be considered.

Anti-E Detected in a 7-Month-Old Infant with Acute Lymphoblastic Leukemia after Transfusion.

Only a few cases of infantile anti-red blood cell alloantibody production have been reported. A 7-month-old girl with acute lymphoid leukemia developed anti-E alloantibody 13 days after transfusion of E-positive red blood cells. Antibody screening was performed before and at 2, 6, 13, 18, 27, 34, and 49 days after red blood cell transfusion. Identification test, direct immunoglobulin test, acid elution, and dithiothreitol test were also performed. Anti-E alloantibody was detected in the blood 13 days after the first transfusion. The detected antibody was IgM and it decreased below detectable levels within 49 days after the first transfusion. Follow-up testing for the presence of post-transfusion alloantibody at appropriate times is important, even in infants.

Comparing osteonecrosis clinical phenotype, timing, and risk factors in children and young adults treated for acute lymphoblastic leukemia.

Treatment-related osteonecrosis (ON) is a serious complication of treatment of acute lymphoblastic leukemia (ALL). This study included 1,489 patients with ALL, aged 1-45 years, treated according to the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol, using alternate-week dexamethasone during delayed intensification, with prospective registration of symptomatic ON. We aimed at comparing risk factors, timing, and clinical characteristics of ON in children and young adults. ON was diagnosed in 67 patients, yielding a 5-year cumulative incidence of 6.3%, but 28% in female adolescents. Median age at ALL diagnosis was 12.1 years and 14.9 years for females and males, respectively. At ON diagnosis, 59 patients had bone pain (91%) and 30 (46%) had multiple-joint involvement. The median interval between ALL and ON diagnosis was significantly shorter in children aged 1.0-9.9 years (0.7 years range 0.2-2.1) compared with adolescents (1.8 years range 0.3-3.7, P < 0.001) and adults (2.1 years range 0.4-5.3, P 0.001). Female sex was a risk factor in adolescent patients (hazard ratio HR 2.1, 95% confidence interval CI 1.1-4.2) but not in children aged 1.1-9.9 years (HR 2.4, 95% CI 0.9-6.2, P 0.08) or adults aged 19-45 years (HR 1.1, 95% CI 0.3-4.0). Age above 10 years at ALL diagnosis (odds ratio OR 3.7, P 0.026) and multiple joints affected at ON diagnosis (OR 3.4, P 0.027) were risk factors for developing severe ON. We provide a detailed phenotype of patients with ALL with symptomatic ON, including description of risk factors and timing of ON across age groups. This awareness is essential in exploring measures to prevent development of ON.

Relatively favorable prognosis for MLL-rearranged childhood acute leukemia with reciprocal translocations.

Mixed-lineage leukemia (MLL) with multifarious partner genes leads to aggressive leukemia with dismal outcomes. Using panel-based targeted sequencing, we examined 90 cases with MLL-rearranged (MLL-r) childhood acute leukemia, including 55 with acute lymphoblastic leukemia (ALL) and 35 with acute myeloid leukemia (AML). MLL breakpoints and complete rearrangements were identified. A total of 37.8% (3490) of patients displayed a single direct MLL fusion gene, 15.6% (1490) carried a single reciprocal fusion, and 27.8% (2590) had both reciprocal MLL fusion alleles. The remaining 17 MLL-r cases exhibited complex translocations with homozygous disruptions on chromosome 11 or two breakpoints on the same MLL allele with a deletion of functional regions. A total of 77 patients (45 ALL and 32 AML) received chemotherapy with a median follow-up of 2.5 years. Unexpectedly, we identified children with reciprocal MLL fusions who exhibited relatively favorable outcomes compared with those in children with complex translocations or a single direct MLL fusion allele (66.1% vs. 24.6% and 27.6%, P 0.001). Reciprocal MLL fusion may be functionally rescued by a partially truncated MLL protein. Comprehensive MLL-r analysis by targeted next-generation sequencing can provide detailed molecular information and is helpful for precise stratified treatment and clinical prognosis determination.

Usefulness of high-frequency ultrasonography in the assessment of cutaneous lesions in children with hematologic malignancies.

High-frequency ultrasonography is a bedside tool increasingly used for the assessment of skin lesions, but there have been few reports about its importance in children with skin signs of hematologic disease. We present three cases to highlight the usefulness of high-frequency ultrasonography in assisting with the diagnosis of these skin lesions.

Multiple Spitz nevi after allogeneic hematopoietic stem cell transplantation.

Spitz nevus commonly appears as a solitary lesion. A 12-year-old male patient presented with a 6-month history of several pigmented lesions on his trunk and lower extremities. He had undergone chemoradiotherapy and unrelated umbilical cord blood transplantation against recurring acute lymphoblastic leukemia for 6 years. After that, several pigmented lesions abruptly developed on his trunk and lower extremities, and the number of those increased significantly. Pathologically, the diagnosis of multiple Spitz nevi was made. In a clinical correlation, we diagnosed multiple Spitz nevi resulting from such an immunocompromised condition. This is the first description of clinical, dermoscopic, and histopathologic features of multiple Spitz nevi in the hematopoietic cell transplantation (HSCT) recipient child.

A new baby in the c-Myc-directed transcriptional machinery Che-1AATF.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common malignancy in childhood. Despite the high cure-rate, identifying new druggable molecular targets is still of great interest. In a cohort of BCP-ALL pediatric patients, irrespectively of the moleculekaryotype lesions found, we recently observed high expression of c-Myc and Che-1AATF, which disappears at time of remission. Study of the molecular mechanisms involved in this co-expression revealed that Che-1 expression was crucial for induction of blast-cell proliferation driven by c-Myc. Furthermore, Che-1AATF silencing in primary BCP-ALL cell lines improves responsiveness to chemotherapy. These data individuate Che-1 as a possible novel target in the treatment of BCP-ALL able to affect c-Myc-driven tumorigenicity.

Imatinib-induced Hepatitis in a Patient Treated for Gastrointestinal Stromal Tumor A Rare Adverse Effect.

Gastrointestinal stromal tumors (GISTs) are rare neoplasms of the digestive tract. The clinical behavior of GISTs varies greatly, has extended follow-up, and almost all of the tumors have malignant potential. The introduction of imatinib has led to extraordinary improvements in the treatment of individuals with GISTs (as well as those with Philadelphia chromosome-positive chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL)). However, there have been notable postmarketing reports of adverse drug reactions of hepatotoxicity with the use of imatinib. By our search, among individuals taking imatinib for the treatment of GIST, only six cases of drug-induced liver injury (DILI) have been reported. Here, we present an interesting case of an elderly woman who developed DILI after taking imatinib for the treatment of GIST. As the liver function tests (LFTs) initially did not improve, it was decided to proceed with an interventional radiology (IR)-guided liver biopsy, which showed a histologic pattern of acute hepatitis, consistent with DILI. Ultimately, discontinuation of the antineoplastic agent led to recovery in the patients clinical condition along with normalization of her LFTs over the next several weeks. Thus, it is essential that physicians remain alert for and suspect DILI for any patient being treated with imatinib who presents with a sudden elevation of LFTs. The key to making the diagnosis is stopping the offending agent and closely monitoring the liver enzymes for improvement. When discontinuation of imatinib alone does not lead to improvement in LFTs and the patients clinical status, a detailed history should be taken and initial diagnostic testing performed to exclude other etiologies. And, if they are negative, a liver biopsy should be considered.

Ikaros family zinc-finger 1 mutation is an independent factor for the poor prognosis of adult B-cell acute lymphoblastic leukemia, and allogeneic hematopoietic stem cell transplantation can improve clinical outcomes.

To investigate the prognosis of patients with adult B-cell acute lymphoblastic leukemia (B-ALL) with Ikaros family zinc-finger 1 (IKZF1) mutation and determine the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in improving the clinical outcome, we detected the IKZF1 mutation and BCR-ABL fusion gene at diagnosis in the bone marrow of 164 adult patients with B-ALL, and analyzed the clinical data of these patients retrospectively. Our analysis showed that grade III-IV acute graft-versus-host disease and IKZF1 mutation in the transplantation group and age and IKZF1 mutation in the non-transplantation group were independent factors for poor prognosis by univariate and multivariate analyses.The 3-year overall survival (OS) and leukemia-free survival (LFS) rates were much lower in the IKZF1BCR-ABL subgroup than in the IKZF1BCR-ABL- and IKZF1-BCR-ABL- subgroups in both the transplantation and non-transplantation groups. The 3-year OS and LFS rates were significantly higher in the transplantation group than in the non-transplantation group with IKZF1 mutation.The study demonstrated that IKZF1 mutation was an independent factor indicating the poor prognosis of adult B-ALL and much worse prognosis in the BCR-ABL subgroup in both non-transplantation and transplantation groups. However, allo-HSCT significantly improved the OS and LFS of patients and also their clinical outcomes.

Incidence and Risk Factors for Hypertension During Childhood Acute Lymphoblastic Leukemia Therapy.

To determine the incidence of hypertension among children during the induction and re-induction phases of acute lymphoblastic leukemia (ALL) therapy and association with possible risk factors. A retrospective analysis of 208 consecutive pediatric (age <18 y) ALL patients, treated per BFM-95 protocol between January 2009 and December 2013. Data were analyzed to determine the incidence of hypertension and risk factors for its development. Incidence of hypertension requiring antihypertensive medication, was 29% (61208) during induction and 17% (33198) during re-induction (P0.003). Median (range) age of patients developing hypertension was 4 y (4 mo to 8 y). Age <10 y and presence of constipation were independently predictive of hypertension by multivariate analysis. The present study reports a high incidence of hypertension among children undergoing ALL induction therapy.

JDP2 An oncogenic bZIP transcription factor in T cell acute lymphoblastic leukemia.

A substantial subset of patients with T cell acute lymphoblastic leukemia (T-ALL) develops resistance to steroids and succumbs to their disease.

Refining risk classification in childhood B acute lymphoblastic leukemia results of DFCI ALL Consortium Protocol 05-001.

Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05-001 tested a new risk stratification system in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL). At study entry, B-ALL patients were classified as standard risk (SR) or high risk (HR) based on age, white blood cell (WBC) count, and central nervous system status. After achieving complete remission (CR), patients with high end-induction minimal residual disease (MRD) (≥10

Safety profile of a single pegylated asparaginase (PEG-ASP) dose in remission induction for acute lymphoblastic leukemia (ALL).

The incorporation of pegylated asparaginase (PEG-ASP) in pediatric and adult acute lymphoblastic leukemia (ALL) protocols remains a worldwide therapeutic approach. However the safety profile remains a challenge, and herein we report the toxicity of an intravenous single dose of 1000 IUm2 PEG-ASP administered in remission induction for adult ALL patients. Thirty-two patients at median diagnostic age of 32 years (median of 19-65) were included in this analysis. Most patients had B-cell lymphoblastic leukemia (n26 78%) and 81% of cases were <55 years at study entry. 75% of patients had <30x109l leukocyte count at diagnosis and median follow-up was 14 months (range 0.8-69). All grade 34 adverse events (AEs) after PEG-ASP administration were observed in 24 patients (75%). The most common grade 34 AEs were decreased fibrinogen (58%), increased bilirubin (31%) and increased GGTP (27%). Clinical manifestations related to PEG-ASP were seen in 9 patients and included abdominal pain (n6), thrombosis (n2), diarrhea (n1) and pancreatitis (n1). The median time from PEG-ASP administration to first toxic symptoms was 7 days (range 1-19), and there were also 4 (13%) early induction deaths. All deaths were observed in ≥50-year-old patients after a median of 5 days following PEG-ASP (range 1-9). Three of these four patients had massive obesity. While all expired patients had grade 4 neutropenia and thrombocytopenia at the time of death, sepsis was not present. Administration of PEG-ASP in induction remission for ALL patients resulted in a significant, but mostly reversible hepatotoxicity. This PEG-ASP treatment should be administered with caution for older, obese patients.

The presence of mutated and deleted PTEN is associated with an increased risk of relapse in childhood T cell acute lymphoblastic leukaemia treated with AIEOP-BFM ALL protocols.

Notwithstanding the improvement in treatment results for paediatric T cell acute lymphoblastic leukaemia (T-ALL) it remains important to understand if genetic aberrations influence therapy response. PTEN tumour suppressor gene inactivation is a frequent event in T-ALL but its effect on patient therapy response is debatable. We analysed the effect of the presence of mutated PTEN on outcome in 257 children with T-ALL treated with Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP)-Berlin-Frankfürt-Münster (BFM) protocols. PTEN mutations were present in 31 (12·1%) patients and were significantly associated with increased risk of relapse. PTEN mutations also indicate a poor prognosis in T-ALL patients in the absence of NOTCH1 mutations or in the group of patients with co-presence of PTEN mutation and deletions. These results indicate that PTEN genomic aberrations and the biologically consequential PTEN inactivation contribute to adverse therapy response in T-ALL patients PTEN status as a biomarker may contribute to the development of new molecularly-defined stratification algorithms.

Brain Network Connectivity and Executive Function in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia.

Chemotherapeutic agents used to treat acute lymphoblastic leukemia (ALL), the most common cancer affecting young children, have been associated with long-term cognitive impairments that reduce quality of life. Executive dysfunction is one of the most consistently observed deficits and can have substantial and pervasive effects on academic success, occupational achievement, psychosocial function, and psychiatric status. We examined the neural mechanisms of executive dysfunction by measuring structural and functional connectomes in 161 long-term survivors of pediatric ALL, age 8-21 years, who were treated on a single contemporary chemotherapy-only protocol for standardhigh- or low-risk disease. Lower global efficiency, a measure of information exchange and network integration, of both structural and functional connectomes was found in survivors with executive dysfunction compared with those without dysfunction (p < 0.046). Patients with standardhigh- versus low-risk disease and those who received greater number of intrathecal treatments containing methotrexate had the lowest network efficiencies. Patients with executive dysfunction also showed hyperconnectivity in sensorimotor, visual, and auditory-processing regions (p 0.037) and poor separation between sensorimotor, executiveattention, salience, and default mode networks (p < 0.0001). Connectome disruption was consistent with a pattern of delayed neurodevelopment that may be associated with reduced resilience, adaptability, and flexibility of the brain network. These findings highlight the need for interventions that will prevent or manage cognitive impairment in survivors of pediatric acute lymphoblastic leukemia.

Leukocyte Telomere Length Shortening, hTERT Genetic Polymorphisms and Risk of Childhood Acute Lymphoblastic Leukemia.

Background Telomeres are involved in chromosomal stability, cellular immortality and tumorigenesis. Human telomerase reverse transcriptase (TERT) is essential for the maintenance of telomere DNA length. Recently, a variable tandem-repeats polymorphism, MNS16A, located in the downstream region of the TERT gene, was reported to have an effect on TERT expression and telomerase activity. Previous studies have linked both relative telomere length (RTL) and TERT variants with cancer. Therefore, we evaluated associations between RTL, TERT gene polymorphisms (hTERT, rs2735940 CT and MNS16A InsDel) and risk of childhood acute lymphoblastic leukemia (ALL) in an Iranian population. Methods RTL was determined by a multiplex quantitative PCR-based method, and variants of the hTERT, rs2735940 CT and MNS16A InsDel, were genotyped by amplification refractory mutation system PCR (ARMS-PCR), and PCR, respectively. Results Our results indicated that RTL was shorter in ALL patients (1.53±0.12) compared to the control group (2.04±0.19) (P0.029). However, no associations between hTERT gene variants or haplotypes and the risk of childhood ALL were observed (P>0.05). Also hTERT polymorphisms were not associated with RTL or patient clinicopathological characteristics, including age (P0.304), sex (P0.061) organomegally (P0.212) CSF involvement (P0.966) or response to treatment (P0.58). Conclusions We found that telomere attrition may be related to the pathogenesis of childhood ALL, irrespective to TERT variants.

Ancistrolikokine I and further 5,8-coupled naphthylisoquinoline alkaloids from the Congolese liana Ancistrocladus likoko and their cytotoxic activities against drug-sensitive and multidrug resistant human leukemia cells.

The Congolese liana Ancistrocladus likoko (Ancistrocladaceae) produces naphthylisoquinoline alkaloids that are, chemotaxonomically remarkable, all based on the same coupling type, with the biaryl axis located between C-5 and C-8. About 20 alkaloids, belonging to the subclass of 5,8-linked naphthylisoquinolines, have so far been discovered in this plant species. Here, we report on the isolation and structure elucidation of six further such 5,8-coupled monomeric alkaloids, named ancistrolikokines I (9), C

Overweight and obesity management strategies in survivors of paediatric acute lymphoblastic leukaemia a systematic review protocol.

Acute lymphoblastic leukaemia is the most common paediatric cancer. Survivors of childhood acute lymphoblastic leukaemia (SALL) are at risk of obesity and related cardiometabolic diseases including type 2 diabetes, hypertension, stroke and cardiovascular events. Therefore, it is important to address obesity in this population as this may help mitigate future cardiometabolic comorbidities. In this systematic review, we aim to assess current treatment strategies including lifestyle interventions, pharmacotherapy and bariatric surgery to manage overweight and obesity in SALL. We will search the following databases for primary studies CINAHL, SPORTDiscus, EMBASE, MEDLINE, PsycINFO, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. In addition, unpublished primary studies will be searched in ClinicalTrials.gov as well as conference proceedings, presentations, abstracts, editorials and ProQuest Dissertations and Theses AI. Reviewers will perform title, abstract, and full-text screening as well as data abstraction and risk of bias assessment independently with a third reviewer to be consulted to resolve disagreements. Searches will be run and updated through May 1st, 2018. The overall quality of the evidence will be determined using the Grading of Recommendations, Assessment, Development, and Evaluation criteria for each outcome. A meta-analysis will be performed if two studies deploying similar interventions, populations, and design and outcomes are identified. As individual patient data will not be included, we do not require ethics approval. This review will be published in a peer-reviewed journal. CRD42016051031.

Successful treatment of invasive mucormycosis with isavuconazole in pediatric patients.

Invasive mold infections (IMIs) are a leading cause of mortality among immunocompromised patients. Isavuconazole is a new drug that shows promise in the adult population for the treatment of IMIs. No data regarding the use of isavuconazole in pediatric patients have been published. Patients with a diagnosis of IMI from our pediatric hemato-oncology division, treated with isavuconazole between 2010 and 2016, were identified using the hospitals computerized database. Data including demographics, clinical course, and outcome were collected. Pharmacokinetic samples were obtained from two younger patients to guide dosing. In total, three patients (4.5, 5, and 19 years of age) with invasive mucormycosis who were treated with isavuconazole were identified. All patients were treated with isavuconazole as a second line therapy and experienced improvement following the initiation of this treatment. Based on our limited clinical experience, isavuconazole may be a safe and effective treatment option for children and adolescents afflicted by IMI. Prospective clinical trials should be performed in order to evaluate the pharmakokinetics and safety of isavuconazole in the pediatric population.

Progress and Innovations in the Management of Adult Acute Lymphoblastic Leukemia.

Remarkable progress has occurred in understanding the pathophysiology and in developing improved personalized therapies in adult acute lymphoblastic leukemia (ALL). We searched MEDLINE (1990-2018), the American Society of Clinical Oncology, and American Society of Hematology websites (2010-2018). We used the search terms acute lymphoblastic or lymphocytic leukemia or ALL. We largely selected publications in the past 5 years but did not exclude commonly referenced and highly regarded older publications. Target therapies toward specific transcripts (eg, BCR-ABL1 tyrosine kinase oncoprotein by tyrosine kinase inhibitors) and specific leukemic cell surface antigens (eg, CD20, CD22, and CD19 monoclonal antibodies) are major breakthroughs. Current treatments produce long-term survival in 50% of patients with precursor B-cell ALL including 50% to 70% with Philadelphia chromosome (Ph)-positive ALL, 50% to 60% with T-cell ALL, and 80% with mature B-cell ALL. Next-generation sequencing and genomic profiling in ALL have identified new prognostic markers, targets, and ALL subtypes (eg, Ph-like ALL). Monoclonal antibodies, bispecific antibody constructs, and chimeric antigen receptor T cellular therapies developed in the past 5 to 7 years have revolutionized the treatment of ALL and resulted in US Food and Drug Administration approvals of blinatumomab in 2014, as well as inotuzumab and tisagenlecleucel in 2017 as ALL salvage strategies. Their use in combined modalities as salvage and frontline therapies is currently under investigation. Therapies targeting specific transcripts or leukemic cell surface antigens are major breakthroughs in the treatment of adults with ALL. The incorporation of new monoclonal antibodies and other targeted approaches into frontline regimens is showing promising results. If confirmed, such strategies may increase the cure rates in adults to levels achieved in pediatric ALL and reduce the need for intensive and prolonged chemotherapy.

Evaluate the Response Rate of Acute Lymphocytic Leukemia Patients to Hyper Cyclophosphamide, Vincristine, Adriamycin, and Dexamethasone Regimen and Remission Rate to Stay Until the End of the Arbitrary Treatment.

This study aimed to determine the effect of Hyper-Cyclophosphamide, Vincristine, Adriamycin, and Dexamethasone (CVAD) in the treatment of acute lymphoblastic leukemia (ALL) patients and remission duration. During a cross-sectional study in the Seyed Al-Shohada Hospital in Isfahan, patients with ALL who were admitted and treated from 2011 to 2015 because of the risk of ALL were selected and through the records investigation, demographic information, disease information, treatment, remission duration, current status, and duration of survival were collected in the form of data and are sick after going into remission, including the duration and recurrence remission survival time in treatment were analyzed and consequence, whether the patient is going into remission, remission and relapse and survival time based on the duration of treatment were analyzed. Of the 62 patients, 13 patients after starting of treatment did not go to remission and died, but 49 patients (79%) went into complete remission. 21 of them of Hyper-CVAD group and 28 patients of classical treatment group (757% vs. 84%), but the difference was not significant ( Hyper-CVAD regimen resulted in increased survival time of patients with ALL and less disease recurrence and therefore contraindications for use if the existing rules, and under the supervision of treatment, can be used.

The ribosomal RPL10 R98S mutation drives IRES-dependent BCL-2 translation in T-ALL.

The R98S mutation in ribosomal protein L10 (RPL10 R98S) affects 8% of pediatric T-cell acute lymphoblastic leukemia (T-ALL) cases, and was previously described to impair cellular proliferation. The current study reveals that RPL10 R98S cells accumulate reactive oxygen species which promotes mitochondrial dysfunction and reduced ATP levels, causing the proliferation defect. RPL10 R98S mutant leukemia cells can survive high oxidative stress levels via a specific increase of IRES-mediated translation of the anti-apoptotic factor B-cell lymphoma 2 (BCL-2), mediating BCL-2 protein overexpression. RPL10 R98S selective sensitivity to the clinically available Bcl-2 inhibitor Venetoclax (ABT-199) was supported by suppression of splenomegaly and the absence of human leukemia cells in the blood of T-ALL xenografted mice. These results shed new light on the oncogenic function of ribosomal mutations in cancer, provide a novel mechanism for BCL-2 upregulation in leukemia, and highlight BCL-2 inhibition as a novel therapeutic opportunity in RPL10 R98S defective T-ALL.

T Cell-Replete Haploidentical Peripheral Blood Hematopoietic Cell Transplantation for Treatment of T-Lymphoblastic Lymphoma.

BACKGROUND There is currently little information on haploidentical hematopoietic cell transplantation (haplo-HCT) for T-lymphoblastic lymphoma (T-LBL). Data about peripheral blood stem cells (PBSC) as a reliable graft source for T-LBL treatment are lacking. MATERIAL AND METHODS T-LBL patients who underwent T cell-replete haploidentical peripheral blood hematopoietic cell transplantation (haplo-PBHCT) from July 2007 to January 2017 were retrospectively evaluated. RESULTS A total of 25 patients (age ≥15 years) with median age of 24 (range 15-51) years were enrolled. The median number of CD34 cells infused was 5.0 (1.6-14.4) 106kg. Sustained myeloid engraftment with full donor chimerism was achieved in all patients. The cumulative incidence of grades 2 to 4 acute graft-versus-host disease (GVHD) at day 100 was 24%. Two-year extensive chronic GVHD cumulative incidence was 20%. The 3-year overall survival rate for all patients was 70%. The median survival time of the complete remission (CR) group was better than that of the non-CR group (not reached vs. 9 m) (P<0.01). The relapse rate was 17% for patients who obtained CR and were given haplo-HCT as consolidation treatment. CONCLUSIONS This study indicates that haplo-PBHCT is a safe and effective method for the treatment of T-LBL.

Single-Dose Daily Fractionation Is Not Inferior to Twice-a-Day Fractionated Total-Body Irradiation Before Allogeneic Stem Cell Transplantation for Acute Leukemia A Useful Practice Simplification Resulting From the SARASIN Study.

Total-body irradiation (TBI) is a major constituent of myeloablative conditioning regimens. The standard technique consists of 12 Gy in 6 fractions over a period of 3 days. The Standard-fractionation compAred to one-daily fRaction total body irrAdiation prior to tranSplant In LEUkemia patieNts (SARASIN) study aimed to compare standard fractionation with once-daily fractionation before transplant in leukemia. We retrospectively compared TBI regimens delivered in 2993 patients from the European Society for Blood and Marrow Transplantation database, who underwent transplantation between 2000 and 2014 for acute lymphoblastic leukemia (ALL, n 1729) or acute myeloid leukemia (AML, n 1264). TBI was delivered as either 12 Gy in 6 fractions (group 1, considered the reference group 1362 ALL and 857 AML patients), 9 to 12 Gy in 2 fractions (group 2, 173 ALL and 256 AML patients), or 12 Gy in 3 to 4 fractions (group 3, 194 ALL and 151 AML patients). The median follow-up was 60 and 84 months in ALL and AML patients, respectively. At 5 years, the leukemia-free survival rate, overall survival rate, relapse incidence, and nonrelapse mortality rate were 46.6%, 50.4%, 28.8%, and 24.6%, respectively, in ALL patients and 46.6%, 48.9%, 29.7%, and 23.6%, respectively, in AML patients. In multivariate analyses, the outcomes of groups 2 and 3 were not statistically different from those in group 1. The cumulative incidence of secondary malignancies (SMs) was significantly higher in group 2 (7.2% P < 10 We showed that the 12-Gy fractionated TBI dose delivered either in 2 fractions or in 1 fraction per day over a period of 3 to 4 days resulted in nonsignificant differences in disease control and survival. However, 1-day fractionation may be associated with a higher risk of mucositis and hemorrhagic cystitis. The absence of a significant difference in the SM incidence in the non-T-cell-depleted group should be interpreted with caution in the context of a retrospective study design. Our findings are important to consider for radiation therapy department organization. In-depth analyses of other nonlethal toxicities and late effects are required.

Breakthrough infection of Geotrichum capitatum during empirical caspofungin therapy after umbilical cord blood transplantation.

We experienced a breakthrough fungal infection caused by Geotrichum capitatum during empirical therapy with caspofungin. A 68-year-old male patient with refractory acute lymphoblastic leukemia had received umbilical cord blood transplantation after two courses of induction therapy. Empirical therapy with caspofungin was initiated 5 days before transplantation. Tacrolimus was continuously infused to prevent graft-versus-host disease. A minidose of methotrexate was intravenously administered on days 1 and 3 post-transplantation, which was changed to prednisolone from day 7 due to severe mucositis. During a recurrence of fever on day 11, blood cultures were found to be positive for a yeast-like organism, which was later confirmed by mass spectrometry to be G. capitatum. The serum levels of beta-D-glucan were elevated to 747 pgmL. Caspofungin was switched to liposomal amphotericin B however, radiological findings revealed pulmonary, splenic, and central nervous system involvement. Progressive renal and hepatic dysfunction subsequently developed. The patient died on day 25 post-transplantation secondary to the development of hemophagocytic syndrome and respiratory failure. We emphasize that recurrent febrile episodes, prolonged neutropenia, and underlying gastrointestinal mucosal damage require extreme caution due to the possibility of breakthrough infection caused by new fungal pathogens during empirical therapy with caspofungin.

Low spontaneous apoptosis index at diagnosis predicts a high-risk phenotype in paediatric acute lymphoblastic leukaemia.

Significance of apoptosis as a prognostic marker is less well studied in paediatric acute lymphoblastic leukaemia (ALL) cases. Hence, a prospective study, involving 30 paediatric ALL cases, was done to assess the clinical relevance of in vivo apoptosis. Peripheral blood mononuclear cells from all patients were subjected to annexin Vpropidium iodide staining to detect the degree of apoptosis apoptotic index (AI) at day 0 and day 35 post-induction chemotherapy. In addition, Bax and Bcl2 apoptotic protein expressions were studied at day 0 and their relative fluorescence mean intensity (RFMI) ratios were calculated. Mean age of patients was 5.1 years. Of the 30 cases, 21 (70%) were at standard-risk, five (17%) at intermediate and four (13%) at high risk. Majority (83%) were B-ALL. Day 8 absolute blast count was >1000μl in seven (23%) and <1000μl in 23 of 30 (77%) cases. Day 35 marrow was M1 in 23 (92%) and M2 in two of 25 (8%) cases. AI at day 0 and day 35 ranged from 0.9 to16.6 per cent and 1.4 to 62.8 per cent with a mean of 5.90 and 19.64 per cent, respectively. The BaxBcl2 ratio ranged from 0.2 to 3.5 with a mean of 0.83. The ratio was predominantly anti-apoptotic, i.e. <1 (77%). A significant association was noted between low AI at day 0 and high total leucocyte count (P0.02), T-cell phenotype (P0.043) and high-risk as per NCI category (P0.025). Significant increase (>30%) in day 35 AI was seen in only six cases. Our study showed that low AI at day 0 was associated with a high-risk clinical phenotype in paediatric ALL. However, studies on larger group, especially with longer follow up or study of relapse cases, will help draw conclusions regarding apoptosis assessment in paediatric ALL.

Economic burden associated with adverse events of special interest in patients with relapsed Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia in the United States.

Infections, cytopenia, and gastrointestinal (GI) toxicity are adverse events of special interest (AESI) affecting most relapsed Philadelphia chromosome-negative (Ph-) B-cell acute lymphocytic leukemia (ALL) patients. This study quantified real-world rates and economic burden of these events among relapsed Ph- B-cell ALL patients in the United States. Adults with relapsed Ph- B-cell ALL during 1 April 2009-31 October 2016 were selected from MarketScan® healthcare claims databases. Outcomes included proportions of patients with AESIs and AESI-related costs during 100 days after relapsed hospitalization. Of 400 relapsed Ph- B-cell ALL patients, 92.5% experienced ≥1 AESI during the median 100-day follow-up, of which 64.6% had infections, 94.6% cytopenia, and 46.2% GI toxicities. Mean (SD median) AESI-related total cost per patient during follow-up was $197,213 ($308,551 $105,731), with a mean of 2 AESI-related hospitalizations comprising 32.2 inpatient days. Mean (SD median) healthcare costs were highest for infections ($164,461 $347,083 $64,528), followed by cytopenia ($125,210 $165,141 $67,475) and GI events ($11,652 $40,231 $1349). The economic burden of AESIs is substantial, with infections the most expensive, followed by cytopenia and GI toxicity. New therapies that can improve outcomes in relapsed Ph- B-cell ALL while offering a favorable safety profile are needed.

BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia.

Genome-wide association studies of childhood acute lymphoblastic leukemia (ALL) have identified regions of association at PIP4K2A and upstream of BMI1 at chromosome 10p12.31-12.2. The contribution of both loci to ALL risk and underlying functional variants remain to be elucidated. We carried out single nucleotide polymorphism (SNP) imputation across chromosome 10p12.31-12.2 in Latino and non-Latino white ALL cases and controls from two independent California childhood leukemia studies, and additional Genetic Epidemiology Research on Aging study controls. Ethnicity-stratified association analyses were performed using logistic regression, with meta-analysis including 3,133 cases (1,949 Latino, 1,184 non-Latino white) and 12,135 controls (8,584 Latino, 3,551 non-Latino white). SNP associations were identified at both BMI1 and PIP4K2A. After adjusting for the lead PIP4K2A SNP, genome-wide significant associations remained at BMI1, and vice-versa (p

A decrease in vitamin D levels is associated with methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia.

Children with acute lymphoblastic leukemia (ALL) are at increased risk of vitamin D deficiency, which might make them more susceptible to developing adverse events. Previous studies showed that low vitamin D levels were associated with an increased inflammatory mucosal state and impaired mucosal tissue barriers. We examined the prevalence of vitamin D deficiency and studied the association between vitamin D levels and methotrexate (MTX)-induced oral mucositis in pediatric ALL. We assessed 25-hydroxyvitamin D (25(OH)D Vitamin D deficiency occurred in respectively 8% (< 30 nmolL) and 33% (< 50 nmolL) of the patients at T0, and more frequently in children > 4 years of age as compared to children between 1 and 4 years of age. A decrease in 25(OH)D This study showed that vitamin D deficiency occurs frequently in pediatric ALL patients above the age of 4 years. A decrease in 25(OH)D

Advances in B-cell Precursor Acute Lymphoblastic Leukemia Genomics.

In childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), cytogenetic abnormalities remain important diagnostic and prognostic tools. A number of well-established abnormalities are routinely used in risk stratification for treatment. These include high hyperdiploidy and

Oncogenic TRK fusions are amenable to inhibition in hematologic malignancies.

Rearrangements involving the neurotrophic receptor kinase genes (NTRK1, NTRK2, and NTRK3 hereafter referred to as TRK) produce oncogenic fusions in a wide variety of cancers in adults and children. Although TRK fusions occur in fewer than 1% of all solid tumors, inhibition of TRK results in profound therapeutic responses, resulting in Breakthrough Therapy FDA approval of the TRK inhibitor larotrectinib for adult and pediatric patients with solid tumors, regardless of histology. In contrast to solid tumors, the frequency of TRK fusions and the clinical effects of targeting TRK in hematologic malignancies are unknown. Here, through an evaluation for TRK fusions across more than 7,000 patients with hematologic malignancies, we identified TRK fusions in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), histiocytosis, multiple myeloma, and dendritic cell neoplasms. Although TRK fusions occurred in only 0.1% of patients (8 of 7,311 patients), they conferred responsiveness to TRK inhibition in vitro and in vivo in a patient-derived xenograft and a corresponding AML patient with ETV6-NTRK2 fusion. These data identify that despite their individual rarity, collectively, TRK fusions are present in a wide variety of hematologic malignancies and predict clinically significant therapeutic responses to TRK inhibition.

MAP3K7 is recurrently deleted in pediatric T-lymphoblastic leukemia and affects cell proliferation independently of NF-κB.

Deletions of 6q15-16.1 are recurrently found in pediatric T-cell acute lymphoblastic leukemia (T-ALL). This chromosomal region includes the mitogen-activated protein kinase kinase kinase 7 (MAP3K7) gene which has a crucial role in innate immune signaling and was observed to be functionally and prognostically relevant in different cancer entities. Therefore, we correlated the presence of MAP3K7 deletions with clinical parameters in a cohort of 327 pediatric T-ALL patients and investigated the function of MAP3K7 in the T-ALL cell lines CCRF-CEM, Jurkat and MOLT-4. MAP3K7 deletions were detected by multiplex ligation-dependent probe amplification (MLPA). T-ALL cell lines were transduced with adeno-associated virus (AAV) vectors expressing anti-MAP3K7 shRNA or a non-silencing shRNA together with a GFP reporter. Transduction efficiency was measured by flow cytometry and depletion efficiency by RT-PCR and Western blots. Induction of apoptosis was measured by flow cytometry after staining with PE-conjugated Annexin V. In order to assess the contribution of NF-κB signaling to the effects of MAP3K7 depletion, cells were treated with TNF-α and cell lysates analyzed for components of the NF-κB pathway by Western blotting and for expression of the NF-κB target genes BCL2, CMYC, FAS, PTEN and TNF-α by RT-PCR. MAP3K7 is deleted in approximately 10% and point-mutated in approximately 1% of children with T-ALL. In 32 of 33 leukemias the deletion of MAP3K7 also included the adjacent CASP8AP2 gene. MAP3K7 deletions were associated with the occurrence of SIL-TAL1 fusions and a mature immunophenotype, but not with response to treatment and outcome. Depletion of MAP3K7 expression in T-ALL cell lines by shRNAs slowed down proliferation and induced apoptosis, but neither changed protein levels of components of NF-κB signaling nor NF-κB target gene expression after stimulation with TNF-α. This study revealed that the recurrent deletion of MAP3K7CASP8AP2 is associated with SIL-TAL1 fusions and a mature immunophenotype, but not with response to treatment and risk of relapse. Homozygous deletions of MAP3K7 were not observed, and efficient depletion of MAP3K7 interfered with viability of T-ALL cells, indicating that a residual expression of MAP3K7 is indispensable for T-lymphoblasts.

Philadelphia chromosome-positive lymphoblastic lymphoma-Is it rare or underdiagnosed

Lymphoblastic lymphomas (LBLs) are neoplasms of precursor B and T cells they are considered in the same spectrum as precursor B and T cell acute lymphoblastic leukemia (ALL). The World Health Organization classification classifies both LBL and ALL as one disease entity. While chromosome abnormalities are well defined with all of their therapeutic and prognostic implications in ALL, these are not well studied in LBL. Here, we describe a case of Philadelphia chromosome-positive LBL and review the available literature regarding this entity.

Use of MTHFR C677T polymorphism and plasma pharmacokinetics to predict methotrexate toxicity in patients with acute lymphoblastic leukemia.

Methotrexate (MTX) is a key component of acute lymphoblastic leukemia (ALL) therapy, but it is associated with serious toxicities in a considerable number of patients. The aim of the current study was to determine which variables were associated with MTX toxicity in children, adolescents and young adults with ALL. In this prospective study, 35 patients with newly diagnosed ALL, treated according to the 58951 European Organization for Research and Treatment of Cancer - Childrens Leukemia Group (EORTC-CLG) protocol, were prospectively enrolled. Toxicity data was collected objectively after each high-dose methotrexate (HD-MTX) course. The risk factors of MTX toxicity were determined using multiple linear regression analysis, with age, gender, immunophenotype, risk group, plasma MTX levels, plasma homocysteine (HCY) levels, and MTHFR C677T included as independent variables. Twenty-five (71.4%) patients experienced toxicity on at least 1 course of HD-MTX. In the univariate linear regression, the global toxicity score was associated with a significant rise in plasma HCY concentrations within 48 h after MTX administration (β 0.4 R2 0.12 p 0.02). In the multiple regression model, the global toxicity score was significantly associated with a higher MTX plasma levels at 48 h (β 0.5 R2 0.38 p 0.001) and CT 677 MTHFR genotype (β 0.3 R2 0.38 p 0.01). Routine monitoring of plasma MTX concentrations is essential to detect patients at a high risk of MTX toxicity. MTHFR C677T genotyping may be useful for predicting MTX toxicity.

Autologous CD19-Targeted CAR T Cells in Patients with Residual CLL following Initial Purine Analog-Based Therapy.

Patients with residual chronic lymphocytic leukemia (CLL) following initial purine analog-based chemoimmunotherapy exhibit a shorter duration of response and may benefit from novel therapeutic strategies. We and others have previously described the safety and efficacy of autologous T cells modified to express anti-CD19 chimeric antigen receptors (CARs) in patients with relapsed or refractory B cell acute lymphoblastic leukemia and CLL. Here we report the use of CD19-targeted CAR T cells incorporating the intracellular signaling domain of CD28 (19-28z) as a consolidative therapy in 8 patients with residual CLL following first-line chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab. Outpatients received low-dose conditioning therapy with cyclophosphamide (600 mgm

CARs and other T cell therapies for MM The clinical experience.

Harnessing the endogenous immune system to eliminate malignant cells has long been an intriguing approach. After considerable success in the treatment of B-cell acute lymphoblastic leukemia, chimeric antigen receptor (CAR)-modified T cells have entered early clinical evaluation in the field of multiple myeloma (MM). The choice of suitable non-CD19 target antigens is challenging and a variety of myeloma-associated surface molecules have been under preclinical investigation. Most recent clinical protocols have focused on targeting B-cell maturation antigen (BCMA), and early results are promising. The trials differ in receptor constructs, patient selection, dosing strategies and conditioning chemotherapy and will thus pave the way to eventually define the optimal parameters. Other sources for autologous T-cell therapy of MM include affinity-enhanced T-cell receptor-modified cells and marrow infiltrating lymphocytes. In summary, adoptive T-cell transfer for the treatment of MM is still in its infancy, but if early response rates indicate durability, will be a paradigm changing therapeutic modality for the treatment of MM.

Additional Cytogenetic Abnormalities with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia on Allogeneic Stem Cell Transplantation in the Tyrosine Kinase Inhibitor Era.

Cytogenetic abnormalities are well known and powerful independent prognostic factors for various hematologic disorders. Although the combination of chemotherapy with tyrosine kinase inhibitor (TKI) is now considered the standard of care in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia, little is known about the impact of additional cytogenetic abnormalities (ACAs). Therefore, we retrospectively evaluated 1375 adult patients who underwent their first allogeneic hematopoietic stem cell transplantation in the TKI era. In this study, 224 patients had ACAs (16.3%). The ACAs that were seen in more than 20 cases (1.5%) were as follows -7, der(22), der(9), 8, and X. Overall survival at 4 years was 56.9% (95% confidence interval CI, 49.4% to 63.7%) in the group with ACAs and 60.5% (95% CI, 57.3% to 63.5%) in the group without ACAs (P .266). The cumulative incidence of relapse at 4 years was 28.9% (95% CI, 22.6% to 35.6%) in the group with ACAs and 21.9% (95% CI, 19.4% to 24.6%) in the group with Ph alone (P .051). In multivariate analyses there were no statistically significant differences in the risk of overall mortality or risk of relapse between the groups with and without ACAs. In the subgroup analyses of specific ACAs, although the presence of 8 was associated with a higher relapse rate in univariate and multivariate analyses, no specific ACA was associated with poor overall survival. Further studies will be needed to verify the impact of specific ACAs on transplantation outcomes.

Killer cell immunoglobulin-like receptor ligand mismatching and outcome after haploidentical transplantation with post-transplant cyclophosphamide.

Haploidentical stem cell transplantation with T cell-replete grafts and post-transplant cyclophosphamide (PTCy) is increasingly used with encouraging outcome. Natural killer (NK) cell alloreactivity, predicted by missing killer cell immunoglobulin-like receptor (KIR) ligands in the recipient that are present in their donor improves outcome of T cell-depleted haploidentical transplants. We explored the role of KIR ligand mismatching in 444 acute leukemia patients after T cell-replete transplants with PTCy. Thirty-seven percent of all patients had KIR ligand mismatching. Patients were in first remission (CR1) (39%), second remission (CR2) (26%), or active disease (35%). Stem cell source was peripheral blood (PBSC, 46%) or bone marrow (54%). The 2-year relapse, non-relapse mortality (NRM), and survival rates were 36.0% (95% confidence interval (CI), 31.4-40.7), 23.9% (20.0-28.0), and 45.9% (40.8-51.0), respectively. Multivariate analysis identified acute myeloid leukemia compared with acute lymphoblastic leukemia (hazard ratio (HR) 0.55, P 0.002), female gender (HR 0.72, P 0.04), and good performance status (HR 0.71, P 0.04) as factors associated with better survival, while advanced age (HR 1.13, P 0.04), active disease (HR 3.38, P < 0.0001), and KIR ligand mismatching (HR 1.41, P 0.03) as associated with worse survival. KIR ligand mismatching was associated with a trend for higher relapse but not with graft-versus-host disease or NRM. The KIR ligand-mismatching effect was more prominent in patients given PBSC. In conclusion, there is no evidence that KIR ligand mismatching results in better outcome in the PTCy setting.

JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias.

Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration FDA-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2

Therapy-related acute lymphoblastic leukemia has distinct clinical and cytogenetic features compared to

Therapy-related acute lymphoblastic leukemia remains poorly defined due to a lack of large data sets recognizing the defining characteristics of this entity. We reviewed all consecutive cases of adult acute lymphoblastic leukemia treated at our institution between 2000 and 2017 and identified therapy-related cases - defined as acute lymphoblastic leukemia preceded by prior exposure to cytotoxic chemotherapy andor radiation. Of 1022 patients with acute lymphoblastic leukemia, 93 (9.1%) were classified as therapy-related. The median latency for therapy-related acute lymphoblastic leukemia onset was 6.8 years from original diagnosis, and this was shorter for patients carrying the

A new case of pityriasis rubra pilaris-like eruption associated with ponatinib, a tyrosine kinase inhibitor.

Pityriasis rubra pilaris (PRP) is a cutaneous syndrome of unknown origin. Most cases are sporadic and acquired. Herein we report a fifth case of PRP-like eruption associated with ponatinib, a tyrosine kinase inhibitor (TKI). A 60-year-old woman presented at the dermatology department with an erythemato-squamous eruption present for 2weeks. The patient was also being treated in haematology for recurrence of acute lymphoblastic leukaemia. Treatment with ponatinib had been initiated 6weeks earlier. Despite the low specific cutaneous histology, a diagnosis of induced PRP-like eruption was made based on the characteristic clinical aspect. Treatment with local corticosteroids resolved the eruption. The literature contains 6 reported cases of PRP-like eruptions associated with TKI, including 4 with ponatinib. The eruption began from 2weeks to 2-3 months after treatment induction. Prescribed topical corticosteroids have yielded mixed results. A better understanding of the physiopathology of these eruptions associated with TKI could shed light on the pathogenic mechanisms in relation to idiopathic PRP.

Role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies.

The chemokine receptor CXCR4 and its ligand stromal cell-derived factor-1 (SDF-1CXCL12) are important players in the cross-talk among lymphoma, myeloma and leukemia cells and their microenvironments. In hematological malignancies and solid tumors, the overexpression of CXCR4 on the cell surface has been shown to be responsible for disease progression, increasing tumor cell survival and chemoresistance and metastasis to organs with high CXCL12 levels (e.g., lymph nodes and bone marrow (BM)). Furthermore, the overexpression of CXCR4 has been found to have prognostic significance for disease progression in many type of tumors including lymphoma, leukemia, glioma, and prostate, breast, colorectal, renal, and hepatocellular carcinomas. In leukemia, CXCR4 expression granted leukemic blasts a higher capacity to seed into BM niches, thereby protecting leukemic cells from chemotherapy-induced apoptosis, and was correlated with shorter disease-free survival. In contrast, neutralizing the interaction of CXCL12CXCR4 with a variety of antagonists induced apoptosis and differentiation and increased the chemosensitivity of lymphoma, myeloma, and leukemia cells. The role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies and the clinical therapeutic potential of CXCR4 antagonists in these diseases is discussed.

Oral diseases in children with acute lymphoblastic leukemia with chemotherapy treatment.

Pediatric patients with acute lymphoblastic leukemia (ALL) usually develop oral manifestations due to the disease itself, as well as side effects of chemotherapy that severely affect their health and quality of life. The aim of this paperis to determine the prevalence of oral diseases in pediatric all patients with and without chemotherapy and its relation to the different phases of chemotherapy. A cross-sectional observational study was conducted in 103 pediatric patients with all between 3-15 years. They were classified into groups without chemotherapy and with chemotherapy at phase of consolidation, enhancement, maintenance and monitoring. Clinical diagnosis was performed and gingival inflammation index (IMPA) and caries criteria (dmf and DMF) were applied. The prevalence oral manifestations in the chemotherapy group were mucositis (98%), ulcers (90%), gingivitis (86%) and candidiasis (78%). The induction phase related with mucositis RM 7.6, 95%CI 4.4-13, p 0.0001 candidiasis OR 103, 95%CI 13.0-818, p 0.0001 gingivitis OR 16.2, 95%CI 5.5-47, p 0.0001 ulcers OR 61.5, 95%CI 8.7-432, p 0.0001. The frequency and severity of oral diseases was hight and associated with the induction phase of chemotherapy, altering the overall nutrition and health of children. los pacientes pediátricos con leucemia linfoblástica aguda habitualmente desarrollan manifestaciones bucales debidas a la propia enfermedad, así como por efectos secundarios de la quimioterapia (QT) que afectan severamente su salud y calidad de vida. El objetivo de este trabajo fue determinar la prevalencia de patologías bucales en pacientes pediátricos con leucemia linfoblástica aguda (LLA) con y sin tratamiento QT, así como su relación con las fases del tratamiento QT. se realizó un estudio transversal, observacional y analítico en pacientes pediátricos con LLA de 3 a 15 años. Se clasificaron en varios grupos sin tratamiento, con tratamiento QT en fase de inducción, consolidación, intensificación, mantenimiento y vigilancia. Se realizó un examen clínico de los tejidos bucales y se aplicaron los índices de inflamación gingival (IPMA) y caries (ceod y CPOD). el grupo bajo QT presentó mucositis (98%), úlceras (90%), gingivitis (86%) y candidiasis (78%). La fase de inducción se asoció con la presencia de mucositis RM 7.6, IC95% 4.4-13, p 0.0001 candidiasis RM 103, IC95% 13.0-818, p 0.0001 gingivitis RM 16.2, IC95% 5.5-47, p 0.0001 úlceras RM 61.5, IC95% 8.7-432, p 0.0001. la mayor frecuencia y severidad de las patologías bucodentales se asociaron a la fase de inducción, alterando la alimentación y la salud integral de los niños.

Nephrogenic diabetes insipidus in initial stage of acute lymphoblastic leukemia and relapse after haploidentical hematopoietic stem-cell transplantation A case report.

Nephrogenic diabetes insipidus (NDI) rarely presents in the initial stage of acute lymphoblastic leukemia (ALL) and relapse due to renal infiltration is also rare. A 19-year-old man presented with weakness, polydipsia, and polyuria for 1 month. NDI was diagnosed with insignificant response to a water deprivation test after stimulation with vasopressin injection. Bone marrow examination combined with immunophenotypic analysis, cerebrospinal cytology, and abdominal ultrasonography confirmed the diagnoses of precursor B cell ALL with renal infiltration. The patient accepted standardized combination chemotherapy and ultimately had sustained remission, and his polydipsia and polyuria disappeared after 3 days of treatment. The ALL relapsed 1 year later and he received haploidentical stem cell transplantation (haplo-SCT) from his father. One year later, he again developed NDI, with bilateral renal enlargement because of extramedullary relapse, leading to subsequent death. This case demonstrates unusual early renal involvement in ALL presenting with initial NDI. Interestingly, the NDI returned with the relapse of renal infiltration 1 year after haplo-SCT. This case suggests that NDI was probably secondary to renal leukemic infiltration.

Health Status and Health-related Quality of Life Measurement in Pediatric Cancer Clinical Trials An Examination of the DFCI 00-01 Acute Lymphoblastic Leukemia Protocol.

Health-related quality of life (HRQL) improved progressively during therapy and beyond in children treated for acute lymphoblastic leukemia on the Dana-Farber Cancer Institute (DFCI) 95-01 protocol. This study aimed to validate that trajectory in a successor study (DFCI 00-01) and to compare the HRQL of patients in the 2 studies. Children aged above 5 years were assessed during each phase of treatment (N4) and 2 years after completion of therapy. Health status and HRQL were measured using Health Utilities Index (HUI) instruments, HUI2 and HUI3. Quality-adjusted life years (QALYs) were calculated and compared with the general population, and patients treated on DFCI 95-01. Over 5 intervals and 758 HUI assessments, mean HRQL increased progressively from remission induction to the time after treatment (P<0.001). During intensification, high-risk patients had lower HRQL than standard-risk patients (P<0.001). During remission induction, patients on DFCI 95-01 had lower HRQL than patients on DFCI 00-01. Patients on DFCI 00-01 had 0.2 and 0.3 fewer QALYs than controls, measured by HUI2 and HUI3, respectively. QALYs for DFCI 00-01 patients during treatment were similar to those for DFCI 95-01 patients. The trajectory of improvement in HRQL during the treatment of acute lymphoblastic leukemia in children was confirmed.

Data for the measurement of serum vitamin D metabolites in childhood acute lymphoblastic leukemia survivors.

This article describes data related to a companion research paper entitled Vitamin D nutritional status and bone turnover biomarkers in childhood acute lymphoblastic leukemia (cALL) survivors. (Delvin et al., submitted for publication) 1. Various methods for the measurement of serum 25OHD

Acute myeloid leukemia chimeric antigen receptor T-cell immunotherapy how far up the road have we traveled

Chemotherapy resistance and relapse remain significant sources of mortality for children and adults with acute myeloid leukemia (AML). Further intensification of conventional cytotoxic chemotherapy is likely not feasible due to the severity of acute and long-term side effects upon normal tissues commonly induced by these drugs. Successful development and implementation of new precision medicine treatment approaches for patients with AML, which may improve leukemia remission and diminish toxicity, is thus a major priority. Tumor antigen-redirected chimeric antigen receptor (CAR) T-cell immunotherapies have induced remarkable responses in patients with relapsed or chemorefractory B-lymphoblastic leukemia, and similar strategies are now under early clinical study in adults with relapsedrefractory AML. However, potential on targetoff tumor toxicity of AML CAR T-cell immunotherapies, notably aplasia of normal myeloid cells, may limit broader implementation of such approaches. Careful selection of optimal target antigens, consideration of toxicity mitigation strategies, and development of methodologies to circumvent potential CAR T-cell resistance are essential for successful implementation of cellular immunotherapies for patients with high-risk AML.

Surface expression of Cytokine Receptor-Like Factor 2 increases risk of relapse in pediatric acute lymphoblastic leukemia patients harboring

We prospectively examined whether surface expression of Cytokine Receptor-Like Factor 2 (CRLF2) on leukemic blasts is associated with survival and induction treatment response in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients. Flow cytometric analysis of bone marrow-derived leukemia cells revealed that 7.51% (29286) of 386 pediatric BCP-ALL patients were CRLF2-positive (CRLF2pos) at diagnosis. The median minimal residual disease (MRD) was lower in CRLF2pos than CRLF2-negative (CRLF2neg) patients on day 15 (MRD15) after induction therapy 0.01% (0.001-0.42%) vs. 0.45% (0.05-3.50%) p0.001. By contrast, the MRD15 was higher in Ikaros family Zinc Finger Protein 1 (

Hematopoietic stem cell transplantation for isolated extramedullary relapse of acute lymphoblastic leukemia in children.

Relapse of acute lymphoblastic leukemia (ALL) may occur in extramedullary sites, mainly central nervous system (CNS) and testis. Optimal post-remissional treatment for isolated extramedullary relapse (IEMR) is still controversial. We collected data of children treated with hematopoietic stem cell transplantation (HSCT) for ALL IEMR from 1990 to 2015 in Italy. Among 281 patients, 167 had a relapse confined to CNS, 73 to testis, 14 to mediastinum, and 27 to other organs. Ninety-seven patients underwent autologous HSCT, 79 received allogeneic HSCT from a matched family donor, 75 from a matched unrelated donor, and 30 from an HLA-haploidentical donor. The 10-year overall survival was 56% and was not influenced by gender, ALL blast immune-phenotype, age, site of relapse, duration of first remission, and type of HSCT. In multivariable analysis, the only prognostic factors were disease status at HSCT and year of transplantation. Patients transplanted in third or subsequent complete remission (CR) had a risk of death 2.3 times greater than those in CR2. Children treated after 2000 had half the risk of death than those treated before that year. Our results suggest that both autologous and allogeneic HSCT may be considered for the treatment of pediatric ALL IEMR after the achievement of CR2.

The safety and efficacy of clofarabine in combination with high-dose cytarabine and total body irradiation myeloablative conditioning and allogeneic stem cell transplantation in children, adolescents, and young adults (CAYA) with poor-risk acute leukemia.

Acute leukemias in children with CR3, refractory relapse, or induction failure (IF) have a poor prognosis. Clofarabine has single agent activity in relapsed leukemia and synergy with cytarabine. We sought to determine the safety and overall survival in a Phase III trial of conditioning with clofarabine (doses 40 - 52 mgm

Spontaneous reversion of a lineage switch following an initial blinatumomab-induced ALL-to-AML switch in

A case of

Prodigiosin produced by Serratia marcescens inhibits expression of MMP-9 and survivin and promotes caspase-3 activation with induction of apoptosis in acute lymphoblastic leukaemia cells.

Matrix metalloproteinase-9 (MMP-9) and survivin are involved in several steps of carcinogenesis in acute lymphoblastic leukaemia (ALL). Yet, no MMP-9 and survivin-modulating drugs with low toxicity on normal cells but high efficacy against high MMP-9- and survivin-expressing leukaemia cells have been approved for clinical application in ALL. Prodigiosin, a secondary metabolite of Serratia marcescens, induces apoptosis in different kinds of cancer cells with low toxicity on normal cells. However, little is known about the effects of this compound on the high MMP-9- and survivin-expressing leukaemia cells. CCRF-CEM cells as a model for high MMP-9- and survivin-expressing ALL cells were treated with 100, 200 and 400 nmol l The inhibitory effects of prodigiosin on MMP-9 and survivin expression, as well as its pro-apoptotic capacity, represent a novel therapeutic avenue against ALL cells. These findings provide an important and interesting basis to develop a new therapeutic compound with high potential against ALL cells.

Acute lymphoblastic leukemia in adolescent and young adults treat as adults or as children

Adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) are recognized as a unique population with specific characteristics and needs. In adolescents age 15 to 20 years, the use of fully pediatric protocols is supported by many comparative studies of pediatric and adult cooperative groups. In young adults, growing evidence suggests that pediatric-inspired or even fully pediatric approaches may also dramatically improve outcomes, leading to long-term survival rates of almost 70%, despite diminishing indications of hematopoietic stem-cell transplantation. In the last decade, better knowledge of the ALL oncogenic landscape according to age distribution and minimal residual disease assessments has improved risk stratification. New targets have emerged, mostly in the heterogeneous B-other group, particularly in the Philadelphia-like ALL subgroup, which requires both in-depth molecular investigations and specific evaluations of targeted treatments. The remaining gap in the excellent results reported in children has many other contributing factors that should not be underestimated, including late or difficult access to care andor trials, increased acute toxicities, and poor adherence to treatment. Specific programs should be designed to take into account those factors and finally ameliorate survival and quality of life for AYAs with ALL.

Extramedullary relapse and discordant CD19 expression between bone marrow and extramedullary sites in relapsed acute lymphoblastic leukemia after blinatumomab treatment.

Blinatumomab, a bispecific T-cell engager antibody construct targeting CD19, has been shown to improve the outcome in patients with relapsed andor refractory B-cell acute lymphoblastic leukemia. Treatment with blinatumomab demonstrated significant survival benefit over chemotherapy, supporting its use as a bridge therapy to allogeneic hematopoietic stem cell transplantation. Unfortunately, following initial response, approximately 50% of responding patients eventually relapse. At the time of failure, the majority of patients have CD19-positive blasts, yet a concerning number of CD19-negative relapses has been reported. In the data reported herein, we present an interesting case of a 42-year-old patient with primary refractory B-cell acute lymphoblastic leukemia who achieved complete morphologic remission after one cycle of blinatumomab as a single agent. Notably, and in the absence of extramedullary disease history, the response in marrow coincided with the emergence of CD19-positive extramedullary relapse including sites of previous punctures for blood and bone marrow samples, as confirmed by biopsy, as well as parenchymal organs (eg breast and lung). During the second cycle of blinatumomab, a CD19-negative morphological relapse emerged. The loss of CD19 was a transient event, as leukemic cells partially regained it after chemotherapy. This study illustrates a challenging situation of relapsed and refractory acute lymphoblastic leukemia complicated with extramedullary disease after exposure to a bispecific T-cell engager antibody, such as blinatumomab. Physicians should maintain a high level of suspicion for the evolution of extramedullary leukemia. This pattern of resistance andor relapse to blinatumomab resembles the graft-versus-leukemia effect after allogeneic transplantation (stronger in blood and marrow than in other tissues). Mechanisms of resistance to blinatumomab are not yet clear. Combination treatments for refractory patients and those at high risk for exramedullary disease may warrant future assessment.

The influence of fibronectin on proliferation and apoptosis of acute lymphoblastic leukaemia cells in vitro.

The extracellular matrix (ECM) is a dynamic environment involved in the regulation of haematopoiesis. A crucial role of this structure is the promotion of proliferation, maturation, and differentiation of haematopoietic stem cells (HSC), and adhesion and migration of HSC in bone marrow. In the present study the effect of ECM proteins (fibronectin, collagens, laminin, thrombospondin, and vitronectin) on proliferation and apoptosis of acute lymphoblastic leukaemia cells isolated from acute lymphoblastic leukaemia (ALL) patients (

Galactose protects against cell damage in mouse models of acute pancreatitis.

Acute pancreatitis (AP), a human disease in which the pancreas digests itself, has substantial mortality with no specific therapy. The major causes of AP are alcohol abuse and gallstone complications, but it also occurs as an important side effect of the standard asparaginase-based therapy for childhood acute lymphoblastic leukemia. Previous investigations into the mechanisms underlying pancreatic acinar cell death induced by alcohol metabolites, bile acids, or asparaginase indicated that loss of intracellular ATP generation is an important factor. We now report that, in isolated mouse pancreatic acinar cells or cell clusters, removal of extracellular glucose had little effect on this ATP loss, suggesting that glucose metabolism was severely inhibited under these conditions. Surprisingly, we show that replacing glucose with galactose prevented or markedly reduced the loss of ATP and any subsequent necrosis. Addition of pyruvate had a similar protective effect. We also studied the effect of galactose in vivo in mouse models of AP induced either by a combination of fatty acids and ethanol or asparaginase. In both cases, galactose markedly reduced acinar necrosis and inflammation. Based on these data, we suggest that galactose feeding may be used to protect against AP.

Malignancy associated hemophagocytic lymphohistiocytosis in children.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder of immune dysregulation resulting in abnormal T-cell activation and inflammatory cytokine production which produces a constellation of clinical features unique to HLH. Pediatric secondary HLH is usually triggered by infection, malignancy, or rheumatological disorders. The diagnosis of malignancy-associated HLH (MA-HLH) poses a difficult challenge as clinical features may be attributed to the underlying disease or chemotherapy. Our study aimed to see the occurrence of this rare entity at our centre. Data were collected from all pediatric oncology patient treated at our center with the diagnosis of MA-HLH from January 2012 to December 2014. Data were collected for age, sex, underlying disease, treatment protocol, stage of chemotherapy, any underlying infection, treatment given for HLH, and outcome. There were five patients with a diagnosis of MA-HLH in the study period. Age ranged from 18 months to 9 years. Of the five MA-HLH, two patients had acute lymphoblastic leukemia, two acute myeloid leukemia, and one had Hodgkin lymphoma. The three patients who had documented microbiological infection also did not improve after appropriate treatment. Two patients died during treatment. One patient improved completely on steroid alone. One patient received HLH 2004 induction. The delay in the diagnosis of MA-HLH in pediatric patients may be due to decrease awareness about the condition the timely diagnosis of MA-HLH is crucial for a better outcome. Herein, we discuss our experience with this rare entity in pediatric oncology patients with review of literature.

1,25-OH

In acute lymphoblastic leukemia (ALL), steroid resistance and hypovitaminosis D are both associated with a poor prognosis. We show that methylprednisolone, calcitriol and the AKT-inhibitor MK-2206 have a synergistic effect on the apoptosis of steroid resistant T-ALL cells. Compared to methylprednisolone monotherapy, calcitriol increases methylprednisolone induced apoptosis dose-dependently (1.37-1.92-fold p < 0.05). Pre-incubation with calcitriol increases the apoptotic effect of MK-2206 even further (3.6-fold p < 0.05). It also potentiates synergism between MK-2206 and methylprednisolone (vehicle control 38% vs. calcitriol 58%, p < 0.01). The combination of calcitriol and AKT inhibition should be investigated further as treatment options for steroid resistance in T-ALL.

Clonal dynamics of donor-derived myelodysplastic syndrome after unrelated hematopoietic cell transplantation for high-risk pediatric B-lymphoblastic leukemia.

Donor-derived hematologic malignancies are rare complications of hematopoietic cell transplantation (HCT). Although these are commonly either a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), in general, they are a heterogeneous group of diseases, and a unified mechanism for their development has remained elusive. Here we report next-generation sequencing, including whole-exome sequencing (WES), whole-genome sequencing (WGS), and targeted sequencing, of a case of donor-derived MDS (dMDS) following HCT for high-risk B-lymphoblastic leukemia (B-ALL) in an adolescent. Through interrogation of single-nucleotide polymorphisms (SNPs) in the WGS data, we unequivocally prove that the MDS is donor-derived. Additionally, we sequenced 15 samples from 12 time points, including the initial B-ALL diagnostic sample through several post-HCT remission samples, the dMDS, and representative germline samples from both patient and donor, to show that the MDS-related pathologic mutations, including a canonical