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30,389,682 | PDX models recapitulate the genetic and epigenetic landscape of pediatric T-cell leukemia. | We compared 24 primary pediatric T-cell acute lymphoblastic leukemias (T-ALL) collected at the time of initial diagnosis and relapse from 12 patients and 24 matched patient-derived xenografts (PDXs). DNA methylation profile was preserved in PDX mice in 97.5% of the promoters (ρ 0.99). Similarly, the genome-wide chromatin accessibility (ATAC-Seq) was preserved remarkably well (ρ 0.96). Interestingly, both the ATAC regions, which showed a significant decrease in accessibility in PDXs and the regions hypermethylated in PDXs, were associated with immune response, which might reflect the immune deficiency of the mice and potentially the incomplete interaction between murine cytokines and human receptors. The longitudinal approach of this study allowed an observation that samples collected from patients who developed a type 1 relapse (clonal mutations maintained at relapse) preserved their genomic composition whereas in patients who developed a type 2 relapse (subset of clonal mutations lost at relapse), the preservation of the leukemias composition was more variable. In sum, this study underlines the remarkable genomic stability, and for the first time documents the preservation of the epigenomic landscape in T-ALL-derived PDX models. |
30,389,459 | Considerations for monitoring minimal residual disease using immunoglobulin clonality in patients with precursor B-cell lymphoblastic leukemia. | Minimal residual disease (MRD) monitoring is a powerful tool to predict the risk of relapse. Herein, we present an MRD monitoring strategy for B-cell lymphoblastic leukemia (B-ALL) using high-throughput sequencing (HTS) of immunoglobulin (Ig) clonality before implementation into routine practice. We selected 74 bone marrow (BM) specimens from 47 patients who were diagnosed with B-ALL. Ig clonality was analyzed using both fragment analysis and HTS. The performance of Ig clonality was evaluated through comparison of the results from real-time quantitative polymerase chain reaction (qPCR) of leukemia-specific fusion transcripts and flow cytometry. IGH clonality was observed in all patients, and the sum of clonal burden varied (9.47%-96.77%). IGK clonality was identified in 70% of patients and availed in cases with low IGH clonal burden. The total IGH clonal burden was significantly correlated with the proportion of leukemic blasts, leukemia-specific fusion transcripts, and flow cytometry. We recognized the different responses of each clone and emerging clones originating from the trace of Ig rearrangement presented in the initial specimen. IGH clonal burden after chemotherapy represented patient outcomes well. IGH assay also provided information of repertoire diversity of IGH rearrangement. The Ig clonality assay via HTS will be a promising tool for MRD monitoring of B-ALL through an adequate strategy to identify and monitor individual clones and determine repertoire diversity. |
30,389,174 | Next-generation antigen receptor sequencing of paired diagnosis and relapse samples of B-cell acute lymphoblastic leukemia Clonal evolution and implications for minimal residual disease target selection. | Antigen receptor gene rearrangements are frequently applied as molecular targets for detection of minimal residual disease (MRD) in B-cell precursor acute lymphoblastic leukemia patients. Since such targets may be lost at relapse, appropriate selection of antigen receptor genes as MRD-PCR target is critical. Recently, next-generation sequencing (NGS) - much more sensitive and quantitative than classical PCR-heteroduplex approaches - has been introduced for identification of MRD-PCR targets. We evaluated 42 paired diagnosis-relapse samples by NGS (IGH, IGK, TRG, TRD, and TRB) to evaluate clonal evolution patterns and to design an algorithm for selection of antigen receptor gene rearrangements most likely to remain stable at relapse. Overall, only 393 out of 1446 (27%) clonal rearrangements were stable between diagnosis and relapse. If only index clones with a frequency >5% at diagnosis were taken into account, this number increased to 65% including only index clones with an absolute read count >10,000, indicating truly major clones, further increased the stability to 84%. Over 90% of index clones at relapse were also present as index clone at diagnosis. Our data provide detailed information about the stability of antigen receptor gene rearrangements, based on which we propose an algorithm for selecting stable MRD-PCR targets, successful in >97% of patients. |
30,388,846 | Imidazo1,2- | Leukemia, the malignancy of the hematopoietic system accounts for 10% of cancer cases with poor overall survival rate in adults therefore, there is a high unmet medical need for the development of novel therapeutics. Eight imidazo1,2- |
30,388,418 | IGF1 Brings Growing Pains for T-ALL LSCs. | Hematopoietic progenitors undergo marked shifts during transition from fetal to postnatal life, and the implication of these changes for the cell-of-origin of childhood leukemia are unclear. In this issue of Cell Stem Cell, Giambra et al. (2018) show that epigenetically regulated IGF1 signaling regulates the ability of fetal-liver- or bone-marrow-derived cells to initiate T-ALL. |
30,387,229 | NOTCH1 pathway activating mutations and clonal evolution in pediatric T-cell acute lymphoblastic leukemia. | Molecular mechanisms involved in the relapse of T-cell acute lymphoblastic leukemia (T-ALL) are not fully understood, although activating NOTCH1 signaling due to NOTCH1FBXW7 alterations is a major oncogenic driver. To unravel the relevance of NOTCH1FBXW7 mutations associated with relapse, we performed whole-exome sequencing in 30 pediatric T-ALL cases, among which 11 diagnosis-relapse paired cases were further investigated to track the clonal evolution of relapse using amplicon-based deep sequencing. NOTCH1FBXW7 alterations were detected in 73.3% (diagnosis) and 72.7% (relapse) of cases. Single nucleotide variations in the heterodimerization domain were the most frequent (40.0%) at diagnosis, whereas proline, glutamic acid, serine, threonine-rich (PEST) domain alterations were the most frequent at relapse (54.5%). Comparison between non-relapsed and relapsed cases at diagnosis showed a predominance of PEST alterations in relapsed cases (P .045), although we failed to validate this in the TARGET cohort. Based on the clonal analysis of diagnosis-relapse samples, we identified NOTCH1 switching characterized by different NOTCH1 mutations in a major clone between diagnosis and relapse samples in 2 out of 11 diagnosis-relapse paired cases analyzed. We found another NOTCH1 switching case in a previously reported Berlin-Frankfurt-Münster cohort (n 13), indicating NOTCH1 importance in both the development and progression of T-ALL. Despite the limitations of having a small sample size and a non-minimal residual disease-based protocol, our results suggest that the presence of NOTCH1 mutations might contribute to the disease relapse of T-ALL. |
30,386,740 | CART Immunotherapy Development, Success, and Translation to Malignant Gliomas and Other Solid Tumors. | T cell chimeric antigen receptor (CAR) technology has allowed for the introduction of a high degree of tumor selectivity into adoptive cell transfer therapies. Evolution of this technology has produced a robust antitumor immunotherapeutic strategy that has resulted in dramatic outcomes in liquid cancers. CAR-expressing T-cells (CARTs) targeting CD19 and CD20 have been successfully used in the treatment of hematologic malignancies, producing sustained tumor regressions in a majority of treated patients. These encouraging results have led to a historic and unprecedented FDA approval of CTL019, Novartis CAR T-cell therapy for the treatment of children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). However, the translation of this technology to solid tumors, like malignant gliomas (MG), has thus far been unsuccessful. This review provides a timely analysis of the factors leading to the success of CART immunotherapy in the setting of hematologic malignancies, barriers limiting its success in the treatment of solid tumors, and approaches to overcome these challenges and allow the application of CART immunotherapy as a treatment modality for refractory tumors, like malignant gliomas, that are in desperate need of effective therapies. |
30,385,870 | Hematopoietic stem cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission a position statement of the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). | Allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission is a standard of care for adult patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) and high risk of relapse. However, the stratification systems vary among study groups. Inadequate response at the level of minimal residual disease is the most commonly accepted factor indicating the need for alloHSCT. In this consensus paper on behalf of the European Working Group for Adult Acute Lymphoblastic Leukemia and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize available evidence and reflect current clinical practice in major European study groups regarding both indications for HSCT and particular aspects of the procedure including the choice of donor, source of stem cells and conditioning. Finally, we propose recommendations for daily clinical practice as well as for planning of prospective trials. |
30,385,715 | MERTK inhibition alters the PD-1 axis and promotes anti-leukemia immunity. | MERTK is ectopically expressed and promotes survival in acute lymphoblastic leukemia (ALL) cells and is thus a potential therapeutic target. Here we demonstrate both direct therapeutic effects of MERTK inhibition on leukemia cells and induction of anti-leukemia immunity via suppression of the coinhibitory PD-1 axis. A MERTK-selective tyrosine kinase inhibitor, MRX-2843, mediated therapeutic anti-leukemia effects in immunocompromised mice bearing a MERTK-expressing human leukemia xenograft. In addition, inhibition of host MERTK by genetic deletion (Mertk-- mice) or treatment with MRX-2843 significantly decreased tumor burden and prolonged survival in immune-competent mice inoculated with a MERTK-negative ALL, suggesting immune-mediated therapeutic activity. In this context, MERTK inhibition led to significant decreases in expression of the coinhibitory ligands PD-L1 and PD-L2 on CD11b monocytesmacrophages in the leukemia microenvironment. Furthermore, although T cells do not express MERTK, inhibition of MERTK indirectly decreased PD-1 expression on CD4 and CD8 T cells and decreased the incidence of splenic FOXP3 Tregs at sites of leukemic infiltration, leading to increased T cell activation. These data demonstrate direct and immune-mediated therapeutic activities in response to MERTK inhibition in ALL models and provide validation of a translational agent targeting MERTK for modulation of tumor immunity. |
30,385,479 | Diagnosis of intrathyroidal ectopic thymus in thyroid fine needle aspiration samples. | Intrathyroidal ectopic thymus (ITET) is a rare cause of paediatric thyroid nodules. Although ultrasonography of ITET demonstrates a characteristic appearance similar to that of normal thymus, accurate differentiation from other thyroid nodule etiologies by ultrasonography is difficult, and so that fine needle aspiration (FNA) is usually performed for further analysis. The aim of this study was to evaluate the utility of flow cytometry (FCM) in confirming the diagnosis of ITET in thyroid FNA samples. Five cases of ITET were retrieved from our thyroid FNA database within a 3-year period. Their clinical information, ultrasonographic features, cytology and FCM findings were retrospectively reviewed. The FCM results were compared with those of 22 T-cell acute lymphoblastic leukaemialymphoblastic lymphoma (T-ALLLBL) cases. The FNA smears of all five ITET cases demonstrated abundant lymphocytes of variable sizes, which included some immature lymphoid cells. No Hassalls bodies or atypical epithelioid cells were recognised. By multicolour FCM analysis including antibodies against CD1a, CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD34, TDT and TCR, all ITET cases showed antigen expression patterns consistent with normal thymocyte maturation. All T-ALLLBL cases exhibited significant immunophenotypic aberrancy. The diagnosis of ITET based on FNA cytology is often inconclusive. The presence of immature lymphocytes often raises the concern for LBL. FCM with adequate antigen coverage can reliably distinguish ITET from T-ALLLBL and make the diagnosis of ITET in FNA samples. Avoiding unnecessary further invasive procedures, providing reassurance to clinician and patient, the accurate diagnosis of ITET by FCM in FNA samples is clinically important. |
30,382,603 | DNA methylation and obesity in survivors of pediatric acute lymphoblastic leukemia A report from the Childhood Cancer Survivor Study. | Because survivors of pediatric acute lymphoblastic leukemia (ALL) are more likely to be obese than unaffected contemporaries, we compared DNA methylation profiles between normal-weight and obese survivors at adiposity-associated CpG sites previously-reported by epigenome-wide association studies (EWAS) of body mass index (BMI) in the general population. We selected 96 ALL survivors from the Childhood Cancer Survivor Study 48 obese and 48 normal weight. The Illumina HumanMethylation450 BeadChip was used to compare DNA methylation at 211 loci identified in EWAS of BMI in the general population. Thirty-nine loci were associated (false discovery rate <0.05) with obesity among survivors who only received chemotherapy (n 49). No loci were significantly associated with obesity among CRT-exposed survivors (n 47). Our results suggest that previously identified BMI-DNA methylation loci are associated with obesity in ALL survivors who were spared CRT, while no loci were significantly associated with obesity in survivors who received CRT. |
30,382,305 | Long-term results of a pilot study evaluating hyperbaric oxygen therapy to improve umbilical cord blood engraftment. | Umbilical cord blood (UCB) transplantation is a promising option for hematopoietic stem cell transplantation in patients with hematologic malignancies who lack an HLA-matched sibling or well-matched unrelated donor however, it has a higher incidence of delayed or failed engraftment because cell doses are low and bone marrow homing is inefficient. We have demonstrated that pre-treating irradiated immune-deficient mice with hyperbaric oxygen (HBO) prior to UCB CD34 cell transplantation lowered host systemic erythropoietin (EPO) and improved UCB CD34 cell homing and engraftment. These findings suggested that EPO-EPO-R signaling plays a role in UCB CD34 homing and engraftment. In a pilot clinical trial, we showed that recipients of HBO therapy prior to UCB cell infusion had reduced systemic EPO, which was associated with improved kinetics of blood count recovery. Although early clinical outcomes at day 100 were encouraging, with improved overall survival, the long-term effects of HBO therapy on UCB-transplanted patients were not evaluated. In this study, we examined the long-term outcome of patients in our pilot study, compared with a historic control group, and correlated their clinical outcomes to serum EPO response to HBO. While 50% of HBO-treated patients received single UCB units, 90% of the control patients received double UCB units. Although HBO patients had much better rates of survival at 6 months, their 1-year survival did not significantly differ from the control group. HBO-treated patients had on average lower relapse and non-relapse mortality rates, and less chronic graft versus host disease (GVHD), but had increased acute GVHD. However, these differences were not statistically significant, probably because of the small sample size. In the HBO-treated cohort, immune reconstitution analysis showed significant improvement in early B cell recovery, with a trend toward improvement in early NK cell recovery. When we evaluated the ratio of 8 h to baseline EPO levels, we found a non-significant trend toward lower EPO values in those who neither relapsed nor died by 1 year, compared to those who died or relapsed. This result suggests that EPO response to HBO may be associated with better outcomes. Disease progression-free survival was also improved in those who had more than 80% reduction in EPO levels in response to HBO. Our study highlights the long-term safety of HBO therapy when used prior to UCB transplantation. Future UCB transplant patients who receive HBO should have their serum EPO response measured, as it may be a marker of relapsemortality. |
30,381,299 | Autophagy inhibition as a potential future targeted therapy for ETV6-RUNX1-driven B-cell precursor acute lymphoblastic leukemia. | Translocation t(1221), resulting in the ETV6-RUNX1 (or TEL-AML1) fusion protein, is present in 25% of pediatric patients with B-cell precursor acute lymphoblastic leukemia and is considered a first hit in leukemogenesis. A targeted therapy approach is not available for children with this subtype of leukemia. To identify the molecular mechanisms underlying ETV6-RUNX1-driven leukemia, we performed gene expression profiling of healthy hematopoietic progenitors in which we ectopically expressed ETV6-RUNX1. We reveal an ETV6-RUNX1-driven transcriptional network that induces proliferation, survival and cellular homeostasis. In addition, Vps34, an important regulator of autophagy, was found to be induced by ETV6-RUNX1 and up-regulated in ETV6-RUNX1-positive leukemic patient cells. We show that induction of Vps34 was transcriptionally regulated by ETV6-RUNX1 and correlated with high levels of autophagy. Knockdown of Vps34 in ETV6-RUNX1-positive cell lines severely reduced proliferation and survival. Inhibition of autophagy by hydroxychloroquine, a well-tolerated autophagy inhibitor, reduced cell viability in both ETV6-RUNX1-positive cell lines and primary acute lymphoblastic leukemia samples, and selectively sensitized primary ETV6-RUNX1-positive leukemia samples to L asparaginase. These findings reveal a causal relationship between ETV6-RUNX1 and autophagy, and provide pre-clinical evidence for the efficacy of autophagy inhibitors in ETV6-RUNX1-driven leukemia. |
30,381,081 | A Cross-sectional Study of Two Chemotherapy Protocols on Long Term Neurocognitive Functions in Egyptian Children Surviving Acute Lymphoblastic Leukemia. | Subtle neurocognitive deficits have been recently observed in Acute Lymphoblastic Leukemia (ALL) survivors. We aim to assess the neurocognitive functions of ALL survivors who had been treated with chemotherapy only using two different protocols, and to identify treatment-related risk factors. We carried a multicenter study involving 3 pediatric oncology centers on 100 children who were treated for ALL. Fifty patients were treated by the modified Childrens Cancer Group (CCG) 1991 protocol with low dose methotrexate and 50 children were treated by Total XV protocol with high dose methotrexate. Fifty healthy children were included as a control group. Psychometric assessment using Arabic version of Wechsler intelligence scale for children (WISC III) was performed for all patients and controls. Patients had significantly lower mean full scale IQ, performance IQ and verbal IQ than controls. Patients ≤ 5 years at diagnosis had significantly lower mean full scale IQ and performance IQ than patients>5 years at diagnosis, while the verbal IQ showed no significant difference between both age groups. Female patients had significantly lower mean full scale IQ, performance IQ and verbal IQthan males. Patients who received Total XV protocol with high dose methotrexate had significantly lower mean full scale IQ, performance IQ and verbal IQ than patients who received modified CCG 1991 protocol with low dose methotrexate. CNS directed chemotherapy might appear to affect neurocognitive functions in children with ALL, which is more significant in young children at diagnosis, in girls and in those receiving high dose methotrexate. |
30,380,973 | Blinatumomab, a bispecific B-cell and T-cell engaging antibody, in the treatment of B-cell malignancies. | Blinatumomab (Blincyto, Amgen), a bi-specific antibody, is a first-in-class, targeted immunotherapy agent for treatment of B-cell malignancies with a novel mechanism of action which involves in-vivo engagement of the patients T cells with CD19-expressing tumour cells. Clinical trials have demonstrated its efficacy in relapsed B-cell Acute Lymphoblastic Leukaemia (B-ALL) and B-cell Non-Hodgkins Lymphoma including in patients who are refractory to chemotherapy. This review summarises the development and design of Blinatumomab, the outcome of clinical studies demonstrating its efficacy and how to manage the administration, practically, including relevant toxicities. We compare and contrast it to other emerging agents for treatment of B-cell malignancies. |
30,380,185 | Long non-coding RNA SNHG16 has Tumor suppressing effect in acute lymphoblastic leukemia by inverse interaction on hsa-miR-124-3p. | Acute lymphoblastic leukemia (ALL) is one of the deadly forms of childhood cancers in the world. In the present study, we used both in vitro and in vivo models to evaluate the functional mechanisms of a long noncoding RNA (lncRNA), small nucleolar RNA host gene 16 (SNHG16) in ALL. SNHG16 gene expression was evaluated by quantitative real-time PCR (qPCR) in both in vitro ALL cell lines and in vivo human samples of T lymphocytes. Lentivirus-mediated SNHG16 downregulation was performed in MOLT3 and SUP-B15 cells, to evaluate its functional effects on ALL cell proliferation, migration in vitro, and ALL transplant in vivo. Epigenetic regulation of SNHG16 on human miR-124-3p (hsa-miR-124-3p) was evaluated by dual-luciferase activity assay and qPCR. Hsa-miR-124-3p was inhibited in SNHG16-downregulated MOLT3 and SUP-B15 cells to further evaluate the functional correlation between SNHG16 and hsa-miR-124-3p in ALL. SNHG16 is upregulated in both in vitro ALL cell lines and in vivo human leukemic T-cells. SNHG16 downregulation suppressed ALL proliferation and migration in vitro, and ALL explant in vivo. Hsa-miR-124-3p was demonstrated to interact with SNHG16, and upregulated in SNHG16-downregulated ALL cells. In addition, inhibiting hsa-miR-124-3p reversed SNHG16-downregulation-mediated tumor suppressive functions in ALL. SNHG16 is upregulated in ALL, and its inhibition has tumor suppressive effect in ALL, likely through epigenetic interaction on hsa-miR-124-3p. © 2018 IUBMB Life, 71(1)134-142, 2019. |
30,376,844 | Nucleotide excision repair is a predictor of early relapse in pediatric acute lymphoblastic leukemia. | Nucleotide Excision Repair (NER) is a major pathway of mammalian DNA repair that is associated with drug resistance and has not been well characterized in acute lymphoblastic leukemia (ALL). The objective of this study was to explore the role of NER in relapsed ALL patients. We hypothesized that increased expression of NER genes was associated with drug resistance and relapse in ALL. We performed secondary data analysis on two sets of pediatric ALL patients that all ultimately relapsed, and who had matched diagnosis-relapse gene expression microarray data (GSE28460 and GSE18497). GSE28460 included 49 precursor-B-ALL patients, and GSE18497 included 27 precursor-B-ALL and 14 T-ALL patients. Microarray data were processed using the Plier 16 algorithm and the 20 canonical NER genes were extracted. Comparisons were made between time of diagnosis and relapse, and between early and late relapsing subgroups. The Chi-square test was used to evaluate whether NER gene expression was altered at the level of the entire pathway and individual gene expression was compared using t-tests. We found that gene expression of the NER pathway was significantly increased upon relapse in patients that took 3 years or greater to relapse (late relapsers, P .007), whereas no such change was evident in patients that relapsed in less than 3 years (early relapsers, P .180). Moreover, at diagnosis, the NER gene expression of the early relapsing subpopulation was already significantly elevated over that of the late relapsing group (P < .001). This pattern was validated by an NER score established by averaging the relative expression of the 20 canonical NER genes. The NER score at diagnosis was found to be significantly associated with disease-free survival in precursor-B-ALL (P < .001). Patients are over two times more likely to undergo early relapse if they have a high NER score at diagnosis, hazard ratio 2.008, 95% CI (1.256-3.211). The NER score may provide a underlying mechanism for time to remission, a known prognostic factor in ALL, and a rationale for differential treatment. |
30,376,198 | Mass spectrometric discrimination of phospholipid patterns in cisplatin-resistant and -sensitive cancer cells. | Development of therapy-resistant cancer is a major problem in clinical oncology, and there is an urgent need for novel markers identifying development of the resistant phenotype. Lipidomics represents a promising approach to discriminate lipid profiles of malignant phenotype cells. Alterations in phospholipid distribution or chemical composition have been reported in various pathologies including cancer. Here we were curious whether quantitative differences in phospholipid composition between cisplatin-resistant and -sensitive model cancer cell lines could be revealed by mass spectrometric means. The phospholipid contents of cell membranes of the cancer cell lines CCRF-CEM and A2780, both responsive and resistant to cisplatin, were analyzed by solid-phase extraction (SPE) and electrospray ionization mass spectrometry (ESI-MS and tandem mass spectrometry (MSMS)). Extracts were obtained by disruption of cells with a dounce tissue grinder set followed by centrifugation. To minimize the enzymatic activity, phospholipids were extracted from cell extracts by SPE immediately after the cell lysis and analyzed by MS. Both supernatant and pellet fractions of cell extracts were analyzed. A phospholipid profile specific for cell lines and their phenotypes was revealed. We have documented by quantitative analysis that phosphocholines PC P-340, PC 341, PC 202160, LPC 181 and LPC 160 PLs were present in the 200-400 μM concentration range in CCRF-CEM cisplatin-responsive cells, but absent in their cisplatin-resistant cells. Similarly, PC 341, LPC 181 and LPC 160 were increased in cisplatin-responsive A2780 cells, and PC 202160 was downregulated in cisplatin-resistant A2780 cells. In this work we showed that the ESI-MS analysis of the lipid content of the therapy-resistant and -sensitive cells can clearly distinguish the phenotypic pattern and determine the potential tumor response to cytotoxic therapy. Lipid entities revealed by mass spectrometry and associated with development of therapy resistance can thus support molecular diagnosis and provide a potential complementary cancer biomarker. |
30,376,048 | Cryptococcal infective endocarditis in a child with acute lymphocytic leukaemia. | A 4-year-old boy with acute lymphocytic leukaemia presented with left hemiplegia during chemotherapy. Computed tomography revealed cerebral infarction, and an echocardiogram showed vegetation in the right and left ventricles. Despite antifungal therapy, he experienced another stroke and 9 days after the first stroke, he underwent total extirpation of the vegetative nodules and fragile vegetation. The postoperative course was unremarkable with no recurrence of infective endocarditis. Although a bacterial culture of the vegetation could not identify the presence of any organism, a pathological specimen examination revealed Cryptococcus with a round and mucinous capsule. |
30,372,691 | Long-Term Molecular Remission Achieved by Antibody Anti-CD22 and Ponatinib in a Patient Affected by Ph Acute Lymphoblastic Leukemia Relapsed after Second Allogeneic Hematopoietic Stem Cell Transplantation A Case Report. | Ph acute lymphoblastic leukemia (Ph-ALL) is an oncohematologic disorder for which allogeneic bone marrow transplantation still offers the only chance of cure. However, relapse is the main reason for treatment failure, also after hematopoietic stem cell transplantation (HSCT). New drugs, such as third generation tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, have expanded the therapeutic landscape, especially in patients who relapsed before HSCT. Very few reports, up to now, have described the use of both classes of these new agents in combination with donor lymphocyte infusions (DLI) in the setting of patients who relapsed after HSCT. We report on a young patient affected by Ph-ALL, who relapsed after the second HSCT and who reached molecular remission and long-term disease control by treatment with the anti-CD22 monoclonal antibody inotuzumab ozogamicin, DLI, and the 3rd generation TKI ponatinib. |
30,372,552 | Pediatric Bone Mineral Accrual Z-Score Calculation Equations and Their Application in Childhood Disease. | Annual gains in BMC and areal bone mineral density (aBMD) in children vary with age, pubertal status, height-velocity, and lean body mass accrual (LBM velocity). Evaluating bone accrual in children with bone health-threatening conditions requires consideration of these determinants. The objective of this study was to develop prediction equations for calculating BMCaBMD velocity SD scores (velocity-Z) and to evaluate bone accrual in youth with health conditions. Bone and body compositions via DXA were obtained for up to six annual intervals in healthy youth (n 2014) enrolled in the Bone Mineral Density in Childhood Study (BMDCS) . Longitudinal statistical methods were used to develop sex- and pubertal-status-specific reference equations for calculating velocity-Z for total body less head-BMC and lumbar spine (LS), total hip (TotHip), femoral neck, and 13-radius aBMD. Equations accounted for (1) height velocity, (2) height velocity and weight velocity, or (3) height velocity and LBM velocity. These equations were then applied to observational, single-center, 12-month longitudinal data from youth with cystic fibrosis (CF n 65), acute lymphoblastic leukemia (ALL) survivors (n 45), or Crohn disease (CD) initiating infliximab (n 72). Associations between BMCaBMD-Z change (conventional pediatric bone health monitoring method) and BMCaBMD velocity-Z were assessed. The BMCaBMD velocity-Z for CF, ALL, and CD was compared with BMDCS. Annual changes in the BMCaBMD-Z and the BMCaBMD velocity-Z were strongly correlated, but not equivalent LS aBMD-Z 1 equated with LS aBMD velocity-Z -3. In CF, BMCaBMD velocity-Z was normal. In posttherapy ALL, BMCaBMD velocity-Z was increased, particularly at TotHip (1.01 -.047 1.7, p < 0.0001). In CD, BMCaBMD velocity-Z was increased at all skeletal sites. LBM-velocity adjustment attenuated these increases (eg, TotHip aBMD velocity-Z 1.13 0.004 2.34 versus 1.52 0.3 2.85, p < 0.0001). Methods for quantifying the BMCaBMD velocity that account for maturation and body composition changes provide a framework for evaluating childhood bone accretion and may provide insight into mechanisms contributing to altered accrual in chronic childhood conditions. © 2018 American Society for Bone and Mineral Research. |
30,371,970 | Esophageal Mycobacterium avium-intracellulare infection in a bone marrow transplant patient Case report and literature review. | Mycobacterium avium-intracellulare complex (MAC) is the most common cause of nontuberculous mycobacterial (NTM) disease in humans. We report a case of esophageal MAC disease in a patient who had allogeneic bone marrow transplant for acute lymphoblastic leukemia. Although pulmonary MAC in immunocompromised host is not uncommon, there are only a few cases of NTM-associated esophageal mass reported. Our report and literature review highlight the importance of considering MAC in the differential diagnosis of dysphagia or odynophagia. |
30,370,942 | Loss of the GPI-anchor in B-lymphoblastic leukemia by epigenetic downregulation of PIGH expression. | Adult B-lymphoblastic leukemia (B-ALL) is a hematological malignancy characterized by genetic heterogeneity. Despite successful remission induction with classical chemotherapeutics and novel targeted agents, enduring remission is often hampered by disease relapse due to outgrowth of a pre-existing subclone resistant against the treatment. In this study, we show that small glycophosphatidylinositol (GPI)-anchor deficient CD52-negative B-cell populations are frequently present already at diagnosis in B-ALL patients, but not in patients suffering from other B-cell malignancies. We demonstrate that the GPI-anchor negative phenotype results from loss of mRNA expression of the PIGH gene, which is involved in the first step of GPI-anchor synthesis. Loss of PIGH mRNA expression within these B-ALL cells follows epigenetic silencing rather than gene mutation or deletion. The coinciding loss of CD52 membrane expression may contribute to the development of resistance to alemtuzumab (ALM) treatment in B-ALL patients resulting in the outgrowth of CD52-negative escape variants. Additional treatment with 5-aza-2-deoxycytidine may restore expression of CD52 and revert ALM resistance. |
30,370,525 | Knockdown of MAML1 inhibits proliferation and induces apoptosis of T-cell acute lymphoblastic leukemia cells through SP1-dependent inactivation of TRIM59. | Notch exerts important functions in cell proliferation, survival, and differentiation, which plays a critical role in tumor development when aberrantly activated. Mastermind-like protein 1 (MAML1) has been functioning as crucial coactivators of Notch receptors and is required for stable formation of Notch transcriptional complexes. However, the mechanism whereby MAML1 induces T-cell acute lymphoblastic leukemia (T-ALL) tumorigenesis is largely unknown. The CCK-8 and flow cytometry assay were performed to examine the effect of MAML1 knockdown on T-ALL cell proliferation, apoptosis, and cell cycle. The expression of MAML1, cell cycle, and apoptosis-related gene, as well as TRIM family members and specific protein 1 (SP1) was measured by western blot analysis and qPCR. Our results showed that MAML1 knockdown significantly inhibited cell proliferation and induced G0G1 cell cycle arrest and apoptosis in Jurkat and MOLT-4 cells. Cell cycle and apoptosis-related gene expression, including CDK2, Bcl-2, Bax, and Bad, was modified by the MAML1 knockdown. MAML1 knockdown obviously inhibited the CDK2 and Bcl-2 expression and increased the Bax, p53, and Bad expression. Moreover, the TRIM family members, including TRIM13, TRIM32, TRIM44, and TRIM59, were significantly decreased by the MAML1 knockdown, with the highest decrease detected in TRIM59 expression. Interesting, overexpression of SP1 not only increased the expression of MAML1 and TRIM59, but also promoted the promoter activation of TRIM59. Taken together, knockdown of MAML1 inhibits proliferation and induces apoptosis of T-ALL cells through SP1-dependent inactivation of TRIM59, and therefore suggest that MAML1-SP1-TRIM59 axis may serve as potentially interesting therapeutic targets for treatment of T-ALL. |
30,370,408 | Prognostic significance of receptor for hyaluronan acid-mediated motility (CD168) in acute pediatric leukemias - assessment of clinical outcome, post induction, end of treatment and minimal residual disease. | The extracellular matrix protein hyaluronan acid plays an active in role in tumor cell proliferation and invasion. Hyaluronan acid receptors, namely CD168 or the receptor for hyaluronan acid-mediated motility (RHAMM) and CD44 have been implicated in promoting malignancy. There is a lacuna in data on the expression of the receptor in pediatric leukemias. Pediatric patients with acute leukemia who were diagnosed, treated and followed up in our center were enrolled. The bone marrow biopsies performed prior to treatment were subjected to immunohistochemical staining (54 biopsies acute lymphoblastic leukemia - 45, acute myeloid leukemia - 9). Blast counts were carried out at diagnosis, end of the induction phase and end of chemotherapy, the minimal residual disease was assessed and follow up details were collected. Positivity was correlated with initial blast count, post-induction blast count, minimal residual disease and patient survival. There was no correlation between the initial blast count and the percentage of blasts with RHAMM expression. The positive correlation between percentage of blasts expressing RHAMM and the post-induction blast count was moderate in acute myeloid leukemia (0.74) and mild in acute lymphoblastic leukemia (0.48). There was a statistically significant difference in RHAMM expression between the two minimal residual disease risk groups ( This study shows that blasts in acute myeloid leukemia show more RHAMM positivity than those of acute lymphoblastic leukemia indicating the aggressive nature of this type of leukemia. In acute leukemias, patients with high percentages of RHAMM-positive blasts had more post-induction blasts, blasts in minimal residual disease and poorer prognosis. |
30,370,059 | USP7 deubiquitinates and stabilizes NOTCH1 in T-cell acute lymphoblastic leukemia. | T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive leukemia that is primarily caused by aberrant activation of the NOTCH1 signaling pathway. Recent studies have revealed that posttranslational modifications, such as ubiquitination, regulate NOTCH1 stability, activity, and localization. However, the specific deubiquitinase that affects NOTCH1 protein stability remains unestablished. Here, we report that ubiquitin-specific protease 7 (USP7) can stabilize NOTCH1. USP7 deubiquitinated NOTCH1 in vivo and in vitro, whereas knockdown of USP7 increased the ubiquitination of NOTCH1. USP7 interacted with NOTCH1 protein in T-ALL cells, and the MATH and UBL domains of USP7 were responsible for this interaction. Depletion of USP7 significantly suppressed the proliferation of T-ALL cells in vitro and in vivo, accompanied by downregulation of the NOTCH1 protein level. Similarly, pharmacologic inhibition of USP7 led to apoptosis of T-ALL cells. More importantly, we found that USP7 was significantly upregulated in human T-ALL cell lines and patient samples, and a USP7 inhibitor exhibited cell cytotoxicity toward primary T-ALL cells, indicating the clinical relevance of these findings. Overall, our results demonstrate that USP7 is a novel deubiquitinase that stabilizes NOTCH1. Therefore, USP7 may be a promising therapeutic target in the currently incurable T-ALL. |
30,369,734 | Role of Immunohistochemistry in Acute Leukemias with Myelonecrosis. | Myelonecrosisis a rare antemortem finding most commonly seen in haematopoeitic neoplasms, especially in acute leukemia. When myelonecrosis occurs at the time of presentation, it imposes certain diagnostic issues in sub categorization of leukemias which is necessary for therapeutic as well as prognostic purposes. Flow cytometry, though is a powerful modality, has its own limitations especially when the cells are not fresh and viable and when the specimen is not of adequate cellularity which is usual in cases of myelonecrosis. In such situations, immunocytochemistry (ICC) or immunohistochemistry (IHC) may play a major role in lineage specification in leukemias as the necrosed marrow with the ghost cells can still retain the antigenicity for certain immunomarkers. Four such interesting cases of common B acute lymphoblastic leukemia (ALL) where IHC was used for diagnosis were included. ICC and IHC done on the necrosed marrow contributed to the diagnosis of ALL in all the four cases and contributed to subsequent management. ICC and IHC if contributory can play a major role in identifying the primary cause of myelonecrosis as the ghost cells can retain the antigenicity despite being morphologically non-viable. |
30,369,727 | Keeping PACE with Ph Positive to Ph-Like Detection in B-Lineage Acute Lymphoblastic Leukemia A Practical and Cost Effective (PACE) Approach in a Resource Constrained Setting. | Philadelphia (Ph)-like or BCR-ABL like acute lymphoblastic leukemia (ALL) is defined on the basis of a gene expression profile that is similar to Ph-positive ALL. It comprises a wide spectrum of genetic lesions affecting primarily the cytokine receptor andor kinase signalling genes. It accounts for approximately 10-15% of pediatric ALL, and is more common in patients who are high-risk according to the National Cancer Institute criteria. Presence of Ph-like mutations is an independent predictor of poor outcome. However, there is vast potential to utilize targeted therapy to improve survival in this group. The sizeable range of genetic lesions varying from translocations, fusions, point mutations and deletions make the diagnosis challenging. Hence, a practical and cost effective approach is required to enable identification in resource constrained settings. Patients with recurrent cytogenetic abnormalities such as ETV6-RUNX1, high hyperdiploidy, TCF3-PBX1, BCR-ABL1 and KMT2A (MLL) rearrangement need not be tested, as these are mutually exclusive with BCR-ABL like mutations. Detection of CRLF2 overexpression, which is the commonest abnormality, is employed as the first step. In patients lacking overexpression, testing for tyrosine kinase fusions can be performed. However, the goal should be to employ a combination of molecular diagnostic techniques such as reverse transcriptase polymerase chain reaction (PCR), real time quantitative PCR, fluorescence in situ hybridization and Sanger sequencing to detect genetic lesions that are amenable to targeted therapy. |
30,369,593 | Renal Function and Plasma Methotrexate Concentrations Predict Toxicities in Adults Receiving High-Dose Methotrexate. | BACKGROUND Methotrexate (MTX) is an effective drug for the treatment of adult malignancies, but toxicity remains a significant problem. Toxic reactions may occur when patients use high-dose MTX (HD-MTX), but the correlation between its toxicity and concentration in adults is controversial. The purpose of this study was to examine the relationship between MTX concentration and renal function, as well as to assess toxic reactions to MTX in Chinese adults with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). MATERIAL AND METHODS This retrospective study enrolled 97 patients who had been diagnosed with ALL or NHL, and who were treated at the Hemopathology Department of Shanghai Changhai Hospital from January 2015 to June 2016. RESULTS Forty-one (27.5%) episodes of elimination delay were observed. We found negative correlations between creatinine clearance rate before MTX infusion and the plasma concentrations of MTX at 36 h after MTX infusion (P0.005). The serum creatinine at 48 h and plasma concentrations of MTX at 48 h and72 h were significantly and positively correlated (both p0.000). High blood concentration of MTX was positively associated with nephrotoxicity > grade 1 (P<0.01). Infection > grade 1 was more likely to occur if a patient had high MTX levels at 36 h,48 h, and 72 h (P<0.01). CONCLUSIONS Our results show that renal function is associated with MTX concentration, and high MTX concentration can predict the occurrence of renal toxicity and infection related to MTX. |
30,369,203 | The expression of CRLF2 in adult Ph negative acute B lymphocytic leukemia and its prognostic significance. | null |
30,369,181 | Clinical significance of minimal residual disease in patients with Ph-negative precursor B-acute lymphoblastic leukemia. | null |
30,369,180 | Multicenter clinical trial of acute lymphoblastic leukemia in elder children and adolescents. | null |
30,365,467 | Haploidentical Hematopoietic Stem Cell Transplant Complicated by Atypical Hemolytic Uremic Syndrome and Kidney Transplant From the Same Donor With No Immunosuppression but C5 Inhibition. | Atypical hemolytic uremic syndrome (aHUS) is life-threatening condition particularly when complicating allograft hematopoietic stem cell transplant (HSCT). In the past, the outcome was very poor with the majority of patients reaching end-stage renal disease or dying with little or no chances of kidney transplant (KTx) due to the high risk of relapse. The availability of C5 inhibition has opened up significant therapeutic opportunities and has improved the outcome particularly if complement dysregulation (CD) is the underlying pathogenetic mechanism. We describe a peculiar case of a girl with aHUS complicating HSCT and her subsequent successful KTx received from the same donor thus performed without immunosuppression but anti-C5 inhibition. Soon after HSCT performed for acute lymphoblastic leukemia, the patient developed a TMA due to CD and reached end-stage renal disease. After 2 years on dialysis, the patient received a KTx from her father who was already the HSCT donor. Given the full chimerism, no immunosuppressive agent was prescribed except a short (2 days) course of steroids and eculizumab to prevent aHUS relapse. Nine months after the KTx, the patient is well with normal renal function, no immunosuppression and continues eculizumab prevention of aHUS (1 infusion every 21 days). All patients with transplant-associated thrombotic microangiopathy should be screened for the causes of CD. C5 inhibition with eculizumab is an important therapeutic resource to manage this complication. When KTx is necessary, immunosuppression can be safely withhold in case of same donor for both grafts and documented full chimerism. |
30,364,637 | Triazolo4,5 | Cellular stress signals activate adaptive signaling pathways of the mammalian integrated stress response (ISR), of which the unfolded protein response (UPR) is a subset. These pathways converge at the phosporylation of eIF2α. Drug-like, potent and selective chemical inhibitors (valid chemical probes) targeting major ISR kinases have been previously identified, with the exception of GCN2. We synthesized and evaluated a series of GCN2 inhibitors based on a triazolo4,5 |
30,362,248 | Feasibility and safety of delivering full-dose anticoagulation therapy in children treated according to Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium therapy protocols. | The literature is void of an evidence-based anticoagulation therapy (ACT) management strategy in the context of thrombocytopenia. We examined the impact of thrombocytopenia on low-molecular-weight heparin (LMWH) dosing and incidence of bleeding in children with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) who developed thromboembolism (TE) during therapy according to DFCI ALL protocols. Patient records from our tertiary care center were reviewed for demographics, details of diagnoses and therapy of ALLLL and TE diagnoses, platelet counts during ACT, LMWH dosing, and bleeding episodes. Thirty-nine TEs were diagnosed in 33 patients mean age 9 years (range, 2.5-18) 16 males and 31 with ALL during the study period. A majority (85%) of patients were diagnosed with TE in the consolidation phase with mean time to TE 5.75 months from ALLLL diagnosis. All patients received LMWH, and the median duration of ACT was 5.9 months (range, 1-11 months). Platelets were measured weekly. On 29 occasions, platelet nadir was <50 × 10 Ability to administer full-dose LMWH, expected bleeding rate, and completion of asparaginase doses while on ACT suggest full-dose ACT is feasible and safe in children with ALLLL who develop TE during DFCI ALL consortium therapy protocols. |
30,362,242 | Obesity in pediatric patients with acute lymphoblastic leukemia increases the risk of adverse events during pre-maintenance chemotherapy. | Obesity correlates with adverse events (AEs) in children with acute myelogenous leukemia and during maintenance therapy for acute lymphoblastic leukemia (ALL). Less is known about AEs in obese ALL patients during pre-maintenance chemotherapy. We evaluated the relationship between obesity (body mass index (BMI) ≥ 95th percentile) and AEs during pre-maintenance chemotherapy in pediatric patients with ALL. One hundred fifty-five pediatric ALL patients diagnosed at a single institution between 2006 and 2012 were retrospectively evaluated for infections, treatment-requiring hypertension, insulin-requiring hyperglycemia, pancreatitis, pediatric intensive care unit admissions, sepsis, febrile neutropenia (FN) admissions, thrombosis, hepatotoxicity, and nephrotoxicity. Univariate and multivariable analyses compared proportions of obese versus nonobese patients experiencing AEs. AEs occurring significantly more frequently in obese patients by univariate analysis included treatment-requiring hypertension (17.5% vs 6.1% OR, 3.27 95% CI, 1.1-10.0, P 0.0497) and insulin-requiring hyperglycemia (25.0% vs 11.3% OR, 2.62 95% CI, 1.04-6.56, P 0.04). Obese patients had greater incidence rates for recurrent admission-requiring infections (incidence rate ratio (IRR) 1.64 95% CI, 1.08-2.48, P 0.02) and recurrent FN admissions (IRR, 1.53 95% CI, 1.10-2.12, P 0.01). Accounting for combined age and NCI risk status, obesity was a risk factor for treatment-requiring hypertension (OR, 3.90 95% CI, 1.19-12.76, P 0.02), insulin-requiring hyperglycemia (OR, 3.92 95% CI, 1.39-11.05, P 0.01), and FN admission (OR, 2.92 95% CI, 1.27-6.73, P 0.01). During pre-maintenance chemotherapy for ALL, obesity is a risk factor for the development of hypertension, hyperglycemia, and FN admissions. This research provides implications for augmented preventive and supportive care guidelines in obese ALL patients. |
30,362,157 | miRNA-155 and miRNA-181a as prognostic biomarkers for pediatric acute lymphoblastic leukemia. | Mortality rates of acute lymphoblastic leukemia (ALL) have improved over the past 20 years however, a significant portion of deaths stems from the lack of prognostic biomarkers, which can direct therapy and overcome drug resistance. microRNA-155a (miRNA-155a) and miRNA-181a are two single-stranded miRNAs involved in the pathogenesis of many types of leukemia and lymphoma and is linked to drug resistance. We investigated their expression levels in 55 patients, 45 diagnosed with ALL and 10 as a control group. We found that miRNA-155a and miRNA-181a were significantly upregulated in the ALL group with both being linked to high levels of minimal residual disease and poor prognosis. miRNA-155a cutoff value was significant in discriminating between high- and low-risk ALL patients as well as between ALL patients and healthy controls, miRNA-181a cutoff value, however, was not significant. Both markers levels were significantly downregulated after therapy. We conclude that miR-155 is correlated with poor prognosis in ALL, whereas we couldnt link miRNA-181a to the prognosis in ALL. Moreover, the marked decrease in their expression after therapy could reflect their impact on disease outcome. |
30,362,152 | Loss of miR-146b-5p promotes T cell acute lymphoblastic leukemia migration and invasion via the IL-17A pathway. | Metastatic disease remains the primary cause of death for individuals with T cell acute lymphoblastic leukemia (T-ALL). microRNAs (miRNAs) play important roles in the pathogenesis of T-ALL by inhibiting gene expression at posttranscriptional levels. The goal of the current project is to identify any significant miRNAs in T-ALL metastasis. We observed miR-146b-5p to be downregulated in T-ALL patients and cell lines, and bioinformatics analysis implicated miR-146b-5p in the hematopoietic system. miR-146b-5p inhibited the migration and invasion in T-ALL cells. Interleukin-17A (IL-17A) was predicted to be a target of miR-146b-5p this was confirmed by luciferase assays. Interestingly, T-ALL patients and cell lines secreted IL-17A and expressed the IL-17A receptor (IL-17RA). IL-17AIL-17RA interactions promoted strong T-ALL cell migration and invasion responses. Gene set enrichment analysis (GSEA) and quantitative polymerase chain reaction (qPCR) analysis indicated that matrix metallopeptidase-9 (MMP9), was a potential downstream effector of IL-17A activation, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling was also implicated in this process. Moreover, IL-17A activation promoted T-ALL cell metastasis to the liver in IL17A |
30,361,418 | CD123 expression patterns and selective targeting with a CD123-targeted antibody-drug conjugate (IMGN632) in acute lymphoblastic leukemia. | The potential of CD123-targeted therapies in acute lymphoblastic leukemialymphoma remains largely unexplored. We examined CD123 expression levels in a large cohort of patients with acute lymphoblastic leukemialymphoma and assessed the |
30,358,906 | Changes in body mass index, height, and weight in children during and after therapy for acute lymphoblastic leukemia. | Children with acute lymphoblastic leukemia (ALL) have an increased risk of obesity and short stature. To the authors knowledge, data regarding patients treated on contemporary protocols without cranial irradiation are limited. Changes in z scores for body mass index (BMI), height, and weight from the time of diagnosis to 5 years off therapy were evaluated using multivariable analysis in 372 children with ALL who were aged 2 to 18 years at the time of diagnosis and were enrolled on the St. Jude Childrens Research Hospital Total XV protocol from 2000 through 2007. The percentage of overweightobese patients increased from 25.5% at the time of diagnosis to approximately 50% during the off-therapy period. Median BMI z scores increased significantly during glucocorticoid therapy (induction ∆0.56 95% confidence interval 95% CI, 0.29-0.64 P<.001 and reinduction II ∆0.22 95% CI, 0.13-0.49 P.001) and during the first year after therapy (∆0.18 95% CI, 0.08-0.46 P.006). Among patients who were of healthy weightunderweight at the time of diagnosis, those aged 2 to <10 years at diagnosis had a significantly higher risk of becoming overweightobese during or after therapy compared with those aged ≥10 years (P.001). Height z scores declined during treatment and improved after therapy. Being aged 2 to <10 years at the time of diagnosis, being of low-risk status, having a white blood cell count < 50×10 The results of the current study demonstrate that obesity is prevalent, and height growth, especially in patients with identified risk factors, appears compromised. Multidisciplinary intervention should begin during induction therapy and continue during the off-therapy period. |
30,358,451 | Current and future role of bispecific T-cell engagers in pediatric acute lymphoblastic leukemia. | The clinical application of immunotherapy has resulted into a significant improvement in the outcome of children with relapsedrefractory B-cell precursor acute lymphoblastic leukemia (rr BCP-ALL). In this setting, the use of bispecific T-cell-engager antibodies (BiTEs), such as blinatumomab, which harness the cytotoxic activity of T cells against CD19-positive lymphoblasts, has emerged as a most promising and impactful strategy. Areas covered This review discusses the main structural and functional features of BiTEs, as well as the current status of their clinical application in childhood ALL. Moreover, future prospects to increase the efficacy of BiTEs are addressed. Expert commentary The promising results obtained in patients with advanced BCP-ALL pave the way for further improvement in the context of less resistantadvanced disease. Future research is rapidly progressing on several aspects, including the use of blinatumomab in first-line protocols, identification of factors predicting response, use of combinatorial approaches and bioengineering of new molecules with dual specificity or increased potency, stability and half-life. The results of these studies, expected to be available in the next future, will provide further advancement in the development of effective, impactful, targeted immunotherapy for treatment of childhood BCP-ALL, with the concrete potential to revolutionize the clinical practice. |
30,357,359 | Aberrant splicing in B-cell acute lymphoblastic leukemia. | Aberrant splicing is a hallmark of leukemias with mutations in splicing factor (SF)-encoding genes. Here we investigated its prevalence in pediatric B-cell acute lymphoblastic leukemias (B-ALL), where SFs are not mutated. By comparing these samples to normal pro-B cells, we found thousands of aberrant local splice variations (LSVs) per sample, with 279 LSVs in 241 genes present in every comparison. These genes were enriched in RNA processing pathways and encoded ∼100 SFs, e.g. hnRNPA1. HNRNPA1 3UTR was most pervasively mis-spliced, yielding the transcript subject to nonsense-mediated decay. To mimic this event, we knocked it down in B-lymphoblastoid cells and identified 213 hnRNPA1-regulated exon usage events comprising the hnRNPA1 splicing signature in pediatric leukemia. Some of its elements were LSVs in DICER1 and NT5C2, known cancer drivers. We searched for LSVs in other leukemia and lymphoma drivers and discovered 81 LSVs in 41 additional genes. Seventy-seven LSVs out of 81 were confirmed using two large independent B-ALL RNA-seq datasets, and the twenty most common B-ALL drivers, including NT5C2, showed higher prevalence of aberrant splicing than of somatic mutations. Thus, post-transcriptional deregulation of SF can drive widespread changes in B-ALL splicing and likely contributes to disease pathogenesis. |
30,357,334 | A mathematical model of white blood cell dynamics during maintenance therapy of childhood acute lymphoblastic leukemia. | Acute lymphoblastic leukemia is the most common malignancy in childhood and requires prolonged oral maintenance chemotherapy to prevent disease relapse after remission induction with intensive intravenous chemotherapy. In maintenance therapy, drug doses of 6-mercaptopurine (6-MP) and methotrexate (MTX) are adjusted to achieve sustained antileukemic activity without excessive myelosuppression. However, uncertainty exists regarding timing and extent of drug dose responses and optimal dose adaptation strategies. We propose a novel comprehensive mathematical model for 6-MP and MTX pharmacokinetics, pharmacodynamics and myelosuppression in acute lymphoblastic maintenance therapy. We personalize and cross-validate the mathematical model using clinical data and propose a real-time algorithm to predict chemotherapy responses with a clinical decision support system as a potential future application. |
30,357,314 | Clearance of Treatment Refractory Adenoviremia via Adenovirus-specific Donor T-Cell Transfer During Aplasia After αβTCR-CD19-Depleted Stem Cell Transplantation. | Here, we report the case of severe adenoviremia in a 7-year-old boy with highly-resistant, acute leukemia. A combined approach of αβTCR-CD19-depleted stem cell transplantation, enabling immunosuppression-free post-transplant care, and early transfer of adenovirus-specific donor T cells during aplasia resulted in rapid and complete clearance of the treatment-refractory adenoviremia. |
30,356,155 | Characterizing Deformability of Drug Resistant Patient-Derived Acute Lymphoblastic Leukemia (ALL) Cells Using Acoustic Tweezers. | The role of cell mechanics in cancer cells is a novel research area that has resulted in the identification of new mechanisms of therapy resistance. Single beam acoustic (SBA) tweezers are a promising technology for the quantification of the mechanical phenotype of cells. Our previous study showed that SBA tweezers can be used to quantify the deformability of adherent breast cancer cell lines. The physical properties of patient-derived (primary) pre-B acute lymphoblastic leukemia (ALL) cells involved in chemotherapeutic resistance have not been widely investigated. Here, we demonstrate the feasibility of analyzing primary pre-B ALL cells from four cases using SBA tweezers. ALL cells showed increased deformability with increasing acoustic pressure of the SBA tweezers. Moreover, ALL cells that are resistant to chemotherapeutic drugs were more deformable than were untreated ALL cells. We demonstrated that SBA tweezers can quantify the deformability of nonadherent leukemia cells and discriminate this mechanical phenotype in chemotherapy-resistant leukemia cells in a contact- and label-free manner. |
30,355,579 | Driver mutations in Janus kinases in a mouse model of B-cell leukemia induced by deletion of PU.1 and Spi-B. | Precursor B-cell acute lymphoblastic leukemia (B-ALL) is associated with recurrent mutations that occur in cancer-initiating cells. There is a need to understand how driver mutations influence clonal evolution of leukemia. The E26-transformation-specific (ETS) transcription factors PU.1 and Spi-B (encoded by |
30,353,996 | Capturing B type acute lymphoblastic leukemia cells using two types of antibodies. | One way to monitor minimal residual disease (MRD) is to screen cells for multiple surface markers using flow cytometry. In order to develop an alternative microfluidic based method, isolation of B type acute lymphoblastic cells using two types of antibodies should be investigated. The immunomagnetic beads coated with various antibodies are used to capture the B type acute lymphoblastic cells. Single beads, two types of beads and surface immobilized antibody were used to measure the capture efficiency. Both micro and nanosize immunomagnetic beads can be used to capture B type acute lymphoblastic cells with a minimum efficiency of 94% and maximum efficiency of 98%. Development of a microfluidic based biochip incorporating immunomagnetic beads and surface immobilized antibodies for monitoring MRD can be an alternative to current cost and time inefficient laboratory methods. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 35 e2737, 2019. |
30,351,463 | Classification of acute lymphoblastic leukemia using deep learning. | Acute Leukemia is a life-threatening disease common both in children and adults that can lead to death if left untreated. Acute Lymphoblastic Leukemia (ALL) spreads out in childrens bodies rapidly and takes the life within a few weeks. To diagnose ALL, the hematologists perform blood and bone marrow examination. Manual blood testing techniques that have been used since long time are often slow and come out with the less accurate diagnosis. This work improves the diagnosis of ALL with a computer-aided system, which yields accurate result by using image processing and deep learning techniques. This research proposed a method for the classification of ALL into its subtypes and reactive bone marrow (normal) in stained bone marrow images. A robust segmentation and deep learning techniques with the convolutional neural network are used to train the model on the bone marrow images to achieve accurate classification results. Experimental results thus obtained and compared with the results of other classifiers Naïve Bayesian, KNN, and SVM. Experimental results reveal that the proposed method achieved 97.78% accuracy. The obtained results exhibit that the proposed approach could be used as a tool to diagnose Acute Lymphoblastic Leukemia and its sub-types that will definitely assist pathologists. |
30,349,379 | The effect of intravenous hydration strategy on plasma methotrexate clearance during intravenous high-dose methotrexate administration in pediatric oncology patients. | High-dose methotrexate (HD-MTX) is widely used as a standard chemotherapeutic agent in pediatric cancers. Most research studies have confirmed the therapeutic efficacy of HD-MTX however, strategies to prevent side effects vary among institutions, especially in developing countries, with limited monitoring of plasma methotrexate level. To evaluate the effect of intravenous hydration during HD-MTX administration on plasma methotrexate clearance in pediatric oncology patients. This study retrospectively reviewed 165 courses of HD-MTX administered to children with acute lymphoblastic leukemia (ALL), non-Hodgkins lymphoma (NHL), or osteosarcoma. Demographic data of patients were collected. Adverse complications related to HD-MTX and 72-hour plasma methotrexate level were analyzed between patients receiving intravenous hydration ≥3,000 mLm Among 56 HD-MTX (1.5 gm Intravenous hydration of ≥3,000 mLm |
30,346,660 | Influence of thiopurine S-methyltransferase polymorphisms in mercaptopurine pharmacokinetics in healthy volunteers. | Mercaptopurine is a drug commonly used in the treatment of different types of cancer, especially acute lymphoblastic leukaemia, and autoimmune diseases such as ulcerative colitis or Crohns disease and in patients receiving organ transplants. It is metabolized by three cytosolic enzymes. One of them, thiopurine S-methyltransferase (TPMT), is responsible for catalysing the methylation reaction of mercaptopurine to 6-methylmercaptopurine, thus inactivating the drug. Individuals with TPMT loss-of-function alleles (2, 3A, 3B or 3C) can be extremely sensitive to the effect of mercaptopurine, since it can be accumulated, therefore producing haematological toxicity. The objective of this study was to evaluate the role of TPMT polymorphisms on the pharmacokinetics of mercaptopurine. For that purpose, we used collected pharmacokinetic data from 48 healthy volunteers (all males) who received a single oral dose of mercaptopurine 50 mg in two bioequivalence studies. The volunteers were subsequently genotyped for TPMT 2, 3A, 3B and 3C alleles by real-time PCR. There were four carriers (8.3%) of TPMT2 and TPMT3A alleles. Mercaptopurine elimination was affected by TPMT loss-of-function polymorphisms, since heterozygous subjects show 18% higher half-life compared to wild-type individuals. This fact is consistent with the expected since the presence of loss-of-function alleles decreases TPMT enzymatic activity and, thus, affects mercaptopurine elimination. Moreover, mercaptopurine pharmacokinetic parameters were different among races, since Latins showed higher plasma concentrations and lower clearance compared to Caucasians. This fact might be due to a different distribution of polymorphisms in genes, other than TPMT, that also influence the pharmacokinetics of mercaptopurine. |
30,345,902 | Novel motif of variable number of tandem repeats in TPMT promoter region and evolutionary association of variable number of tandem repeats with TPMT3 alleles. | SNPs in the gene for TPMT exemplify one of the most successful translations of pharmacogenomics into clinical practice. This study explains the correlation between common SNPs and variable number of tandem repeats (VNTR) in promoter of the gene. We determined VNTR polymorphisms, as well as TPMT2 and TPMT3 SNPs and TPMT activity in Slovenian and Italian individuals and lymphoblastoid cell lines. We observed a previously unreported VNTR allele, AB7C, in a TPMT3A heterozygous individual. VNTRs with two (AB2C) and three or more (ABnC, n ≥ 3) B motifs were statistically significant in complete linkage disequilibrium (D 1, r The study provides insights into the stepwise evolution of TPMT3 alleles from 3C to 3A, with increasing number of B motifs in the VNTR region. |
30,345,005 | New biological and genetic classification and therapeutically relevant categories in childhood B-cell precursor acute lymphoblastic leukemia. | Traditionally, genetic abnormalities detected by conventional karyotyping, fluorescence |
30,343,495 | Adult leukemia survival trends in the United States by subtype A population-based registry study of 370,994 patients diagnosed during 1995-2009. | The lifetime risk of developing leukemia in the United States is 1.5%. There are challenges in the estimation of population-based survival using registry data because treatments and prognosis vary greatly by subtype. The objective of the current study was to determine leukemia survival estimates in the United States from 1995 to 2009 according to subtype, sex, geographical area, and race. Five-year net survival was estimated using data for 370,994 patients from 43 registries in 37 states and in 6 metropolitan areas, covering approximately 81% of the adult (15-99 years) US population. Leukemia was categorized according to principal subtype (chronic lymphocytic leukemia, acute myeloid leukemia, and acute lymphocytic leukemia), and subcategorized in accordance with the HAEMACARE protocol. We analyzed age-standardized 5-year net survival by calendar period (1995-1999, 2000-2004, and 2005-2009), leukemia subtype, sex, race, and US state. The age-standardized 5-year net survival estimates increased from 45.0% for patients diagnosed during 1995-1999 to 49.0% for those diagnosed during 2000-2004 and 52.0% for those diagnosed during 2005-2009. For patients diagnosed during 2005-2009, 5-year survival was 18.2% (95% confidence interval 95% CI, 17.8%-18.6%) for acute myeloid leukemia, 44.0% (95% CI, 43.2%-44.8%) for acute lymphocytic leukemia, and 77.3% (95% CI, 76.9%-77.7%) for chronic lymphocytic leukemia. For nearly all leukemia subtypes, survival declined in successive age groups above 45 to 54 years. Men were found to have slightly lower survival than women however, this discrepancy was noted to have fallen in successive calendar periods. Net survival was substantially higher in white than black patients in all calendar periods. There were large differences in survival noted between states and metropolitan areas. Survival from leukemia in US adults improved during 1995-2009. Some geographical differences in survival may be related to access to care. We found disparities in survival by sex and between black and white patients. |
30,343,295 | Survival Outcome of Alternative Medicine Treatment for Newly Diagnosed Acute Leukemia in Children. | There is scarce information on the efficacy of alternative medicine (AM) alone as a treatment for newly diagnosed acute leukemia in children. We aimed to compare overall survival (OS) between children with newly diagnosed acute leukemia who received AM alone as the first-line treatment and those treated with conventional chemotherapy (CCT). Two-to-one nearest-neighbor propensity score-matching using sex, initial white blood cell count, phenotype of leukemia, and period of diagnosis was performed on 184 patients who received CCT and 92 who received AM alone after being diagnosed with leukemia. A multivariable Cox proportional-hazards regression model was then applied to assess the effect of treatment on OS after adjusting for potential confounders. Hazard ratios (HR) and 95% confidence intervals (CI) are provided. After adjusting for initial white cell count and subtype of leukemia, children treated with AM alone had worse OS (HR 5.14, 95% CI 3.75-7.04) than those given CCT. The 5-year OS rate for newly diagnosed acute leukemia treated with AM medicine alone was 0%. AM without CCT is associated with poorer survival when compared with CCT. |
30,343,286 | A Bortezomib-Based Protocol Induces a High Rate of Complete Remission with Minor Toxicity in Adult Patients with RelapsedRefractory Acute Lymphoblastic Leukemia. | The treatment of relapsedrefractory acute lymphoblastic leukemia (RR-ALL) presents a true clinical challenge. In 2012, a protocol combining bortezomib, dexamethasone, asparaginase, doxorubicin, and vincristine administered to children with RR-ALL was published with encouraging results. Over the past 5 years, we have implemented this protocol in the adult RR-ALL population (> 18 years) and addressed its feasibility in terms of remission rate and toxicity. Here, we present the results of our experience in 9 patients, all of whom received multiple previous chemotherapy protocols, two of them relapsing after an allogeneic bone marrow transplantation. All of the five B-ALL patients, and two of the four T-ALL achieved complete remission. Of the seven patients achieving complete remission, two patients were referred for allogeneic bone marrow transplantation, two patients were subsequently given blinatumomab, and one patient subsequently received donor lymphocyte infusion followed by blinatumomab. Thus, five out of nine patients treated (55%) were able to proceed to best available therapy in a complete remission. We observed minimal adverse effects, mainly hematological toxicity. We conclude that the bortezomib-based protocol should be evaluated as an effective and well-tolerated treatment option for adult patients either unfit for or failing standard salvage chemotherapy, as a bridge to immunotherapy or allogeneic bone marrow transplantation. |
30,341,373 | Genome wide mapping of ETV6 binding sites in pre-B leukemic cells. | Genetic alterations in the transcriptional repressor ETV6 are associated with hematological malignancies. Notably, the t(1221) translocation leading to an ETV6-AML1 fusion gene is the most common genetic alteration found in childhood acute lymphoblastic leukemia. Moreover, most of these patients also lack ETV6 expression, suggesting a tumor suppressor function. To gain insights on ETV6 DNA-binding specificity and genome wide transcriptional regulation capacities, we performed chromatin immunoprecipitation experiments coupled to deep sequencing in a t(1221)-positive pre-B leukemic cell line. This strategy led to the identification of ETV6-bound regions that were further associated to gene expression. ETV6 binding is mostly cell type-specific as only few regions are shared with other blood cell subtypes. Peaks localization and motif enrichment analyses revealed that this unique binding profile could be associated with the ETV6-AML1 fusion protein specific to the t(1221) background. This study underscores the complexity of ETV6 binding and uncovers ETV6 transcriptional network in pre-B leukemia cells bearing the recurrent t(1221) translocation. |
30,340,942 | Eculizumab and thrombotic microangiopathy after hematopoietic stem cell transplantation A report on its efficacy and safety in two pediatric patients. | Thrombotic microangiopathy (TMA) is a severe complication after hematopoietic stem cell transplantation (HSCT), with the reported mortality rate in such cases usually reaching 90%. We report on two pediatric cases of patients successfully treated by eculizumab for severe HSCT-TMA, occurring in two girls (8.4 and 3.6 years). The first patient developed TMA with hematologic abnormalities and renalpulmonary lesions after allogeneic HSCT for Philadelphia-positive acute lymphoblastic leukemia she received eculizumab 7 months after HSCT, with a dramatic improvement of renal function. The second patient developed severe TMA (cardiac tamponade, renal failure requiring dialysis, gastritis) after autologous HSCT for metastatic neuroblastoma. She received eculizumab for 7 months, with a dramatic improvement of renal function. No side effects were observed. The use of eculizumab as first-line therapy in pediatric patients with severe HSCT-TMA with multisystemic lesions appears promising. Larger international studies are required to confirm its benefit and safety for this specific indication. |
30,339,656 | Elements Associated With Early Mortality in Children With B Cell Acute Lymphoblastic Leukemia in Chiapas, Mexico A Case-control Study. | Childhood Lymphoblastic leukemias (ALL) early mortality (EM) is an undesirable treatment outcome for a disease for which >90% long term success is achievable. In the Western world EM constitutes no >3% yet, in Chiapas, Mexico, remains around 15%. With the objective of improving on EM, we determined associated elements in 28 ALL who died within 60 days of arriving at Hospital de Especialidades Pediátricas in Chiapas (HEP), by comparing them to those in 84 controls who lived beyond the first 90 days. χ, t test, and binary logistic regression (BLR) were used to determine significant individual and multiple variables associated to outcome. On arrival, fever, liver and spleen enlargement, active bleeding, lower albumin, less platelets, higher creatinine, and uric acid, more diploid and less hyperdiploid cases were associated with EM cases. Time to diagnosis, nutritional status, risk group and leukocyte count were not related. Antileukemic treatment approach was similar in both groups. The BLR model including fever, active bleeding, liver enlargement, <10,000 plateletsµL, and >2X upper normal lactic dehydrogenase, determined outcome in 66.7% EM and 90.2% controls. To improve on EM in ALL, patients with characteristics defined here ought to be treated differently at HEP. |
30,336,522 | Rapidly Progressive, Fata Infection Caused by Bacillus Cereus in a Patient with Acute Lymphoblastic Leukemia. | We herein report a fatal case of fulminant septicemia caused by Bacillus cereus in a 49-year-old female with T-cell acute lymphoblastic leukemia receiving chemotherapy. Her two blood culture sets were positive for Gram-positive, rod-shaped bacterium. Bacillus cereus was identified by high-throughput MALDI-TOF mass spectrometry and 16S ribosomal RNA gene sequencing. The patient died within 12 hours from the onset of B cereus infection. Patients with acute leukemia presented with fever and unexplained multiple organ lesions, especially accompanied by CNS symptoms, should alert to the possibility of Bacillus cereus infection. |
30,335,538 | Esophageal Varices in Adolescent and Young Adult Males with Acute Lymphocytic Leukemia. | Hepatic late effects are not commonly reported in survivors of childhood leukemia. Four young male patients with acute lymphoblastic leukemia (ALL) were diagnosed with bleeding esophageal varices (EVs) during or shortly after completion of maintenance chemotherapy. EVs were identified from 0 to 60 months after completion of leukemia therapy. All four patients were men between 20 to 24 years old. Hematemesis was the most common presenting symptom. Associated features included splenomegaly, cytopenias, azole therapy, alcohol use, and hepatic iron overload. EVs may be an under-recognized complication of ALL therapy, with adolescent and young adult males at highest risk. |
30,334,962 | The distinguishable DNA whole genome methylation profile of 2 cases of pediatric precursor B acute lymphoblastic leukaemia (BCP ALL) with prodromal, preleukemic phase A case report. | A prolonged, prodromal phase before definitive paediatric precursor B acute lymphoblastic leukaemia (BCP ALL) diagnosis is rarely observed. In the first, the patient presented with an aplastic preleukemic phase, whilst the second presented with a rheumatic-like preliminary phase. The case reports of two patients with BCP ALL with a prodromal phase lasting a few weeks are presented. DNA whole genome profile methylation analysis of bone marrow cells obtained at diagnosis revealed a pattern of methylation that was readily distinguishable from both healthy and standard course BCP ALL bone marrow samples. The biological implication of this observation remains unclear, with many differentially methylated loci involved in many processes like neurogenesis, cell projection organization and adhesion along with leucocyte activation and apoptosis. The prevalence and clinical significance of these methylation changes is unknown but this data indicates that the epigenetic basis of BCP ALL with a prolonged, prodromal phase requires a more detailed assessment. |
30,334,451 | miR-451a induced apoptosis of Philadelphia chromosome-positive acute lymphoblastic leukemia cells by targeting IL-6R. | Philadelphia chromosome positive (Ph) acute lymphoblastic leukemia (ALL) is the most fatal leukemia due to the BCRABL fusion protein. This fusion protein can induce interleukin 6 (IL-6) expression in leukemia stem cells (LSCs) which sustain stemness by binding IL-6R and activating the Janus kinase (JAK)signal transducer and activator of the transcription (STAT) pathway. IL-6R was one of the targets of miR-451a down-regulated in LSCs by BCRABL. We investigated the relationship between miR-451a, IL-6R, and BCRABL in Ph ALL and created a strategy to treat this disease. The expression levels of miR-451a and BCRABL of Ph ALL patients were examined by real-time quantitative polymerase chain reaction (RT-qPCR) and serum IL-6 was tested by enzyme-linked immunosorbent assay. Ph ALL cell line SUP-B15 and Ph- ALL cell line Nalm-6 were treated with miR-451a mimic and inhibitor, respectively proliferation rate was assessed by CCK-8, apoptosis rate was tested by AnnexinPI and the expression levels of Bcl-XL, Bax, cyclin D2 and c-myc were examined by qPCR and western blot (WB). The levels of STAT3, p-STAT3, JAK2, and p-JAK2 were tested by WB. We found that BCRABL was inversely related to miR-451a and positively related to IL-6 in Ph ALL. MiR-451a inhibited the proliferation of SUP-B15 through the apoptosis pathway. The oncogene c-myc was down-regulated by miR-451a. We confirmed that miR-451a could target IL-6R and inhibit activation of JAK and STAT3. In conclusion, miR-451a is down regulated in Ph ALL and increasing the expression levels of miR-451a in leukemia cells can increase the potential of curing this disease. |
30,327,352 | ClonoSEQ Cleared for Residual Cancer Testing. | The FDA granted marketing authorization to the first-ever next-generation sequencing assay for detecting minimal residual disease in patients with acute lymphoblastic leukemia or multiple myeloma. |
30,326,394 | Characteristics and survival of children with acute leukemia with Down syndrome or other birth defects in New York State. | Acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML) among DS children have been studied extensively using data from clinical trials or institutional reports. The purpose of this study was to link population-based cancer and birth defects data to evaluate characteristics and survival of children with acute leukemia according to the presence of DS or other birth defects. ALL and AML cases diagnosed between 1983 and 2012 among children aged 0-14 years were obtained from the New York State Cancer Registry. Birth defect status (DS, other birth defects, or no birth defects) was determined by linking with birth defects data. Associations between birth defect status and demographic characteristics were evaluated using contingency table analysis. Ten-year survival was calculated by birth defect status and other potential prognostic factors. Cox proportional hazards regression analysis was also performed. Among 2941 ALL children, 1.6% had DS, 3.8% had other birth defects, and 94.5% had no birth defects. Birth defect status was significantly associated with age at ALL diagnosis. Survivals were similar among three groups. Among 563 AML children, 11.0% had DS, 6.0% had other birth defects, and 83.0% had no birth defects. Children with DS were more likely to be diagnosed with AML at a younger age and showed the best survival. Age at leukemia diagnosis was significantly associated with the birth defect status. Comparable survival was observed for ALL children. However, AML children with DS demonstrated superior survival compared to children with other birth defects or no birth defects. |
30,325,134 | Stuck tunneled central venous catheters in children Four cases removed by angiography assistance. | Ateş U, Taştekin NY, Mammadov F, Ergün E, Göllü G, Can ÖS, Uçar T, Bingöl-Koloğlu M, Yağmurlu A, Aktuğ T. Stuck tunneled central venous catheters in children Four cases removed by angiography assistance. Turk J Pediatr 2018 60 221-224. Adherent tunneled catheters can usually be removed by a surgical cut down, but in some cases the line can become stuck to the wall of the central veins. In such cases, forceful traction can cause vascular injury, or fracture of the catheter. We present four cases of fixated cuffed tunneled catheters. Three children had acute lymphoblastic leukemia and one had an immunodeficiency syndrome. All catheters were made from polyurethane. Indwelling times were 12-24 months. All patients catheters were removed with great difficulty by trans-femoral access. The angiography-assisted technique is safe and easily-applied for the removal of stuck catheters in pediatric patients. These cases raise important questions concerning the maximum indwelling time and the choice of catheter material when implanting permanent central venous catheters (CVCs) in children. |
30,324,566 | Time and Cost of Hospitalisation for Salvage Therapy in Adults with Philadelphia Chromosome-Negative B Cell Precursor Relapsed or Refractory Acute Lymphoblastic Leukaemia in Spain. | Philadelphia chromosome-negative (Ph-) relapsed or refractory (RR) B-cell precursor acute lymphoblastic leukaemia (ALL) is rare, and information on its impact on healthcare systems is scarce. To quantify the time and reimbursement associated with hospitalisations of patients with RR ALL in a Spanish hospital. Retrospective review of medical charts identified patients aged ≥ 18 years with Ph- RR ALL hospitalised between 1998 and 2014. Data were collected from the date of first diagnosis of RR ALL (index) until death or loss to follow-up. The primary endpoint was the proportion of time hospitalised during chemotherapy. Reimbursement associated with hospitalisations (including associated chemotherapy) was also assessed. Thirty-two patients were eligible for inclusion. Their median age was 41 years, and 50% had a first remission duration of ≤ 1 year 34% had undergone allogeneic haematological stem-cell transplantation (alloHSCT). Overall, 31 patients had received intensive salvage chemotherapy, during which there were 42 hospitalisations (mean 1.4patient mean duration 26 days). Patients spent a mean of 71% of the chemotherapy period in hospital. Total mean reimbursement was €26,417 per patient, almost all (€25,723) attributable to inpatient stays (€18,986hospitalisation). From the index date to death or loss to follow-up (excluding alloHSCT-related hospitalisations), there were 80 hospitalisations (mean duration 24 days) mean reimbursement was €16,692 per hospitalisation and €41,730 per patient. AlloHSCT (n 8) involved 18 hospitalisations (mean reimbursement €39,782hospitalisation €89,510patient). Data from this sample of patients suggest that hospitalisations in RR ALL are lengthy and associated with high costs in Spain. |
30,324,284 | Taste changes in children with cancer and hematopoietic stem cell transplant recipients. | Objectives were to describe bothersome self-reported changes in taste in pediatric oncology and hematopoietic stem cell (HSCT) patients and to identify patient and treatment-related factors associated with bothersome taste changes. We prospectively enrolled children and adolescents with cancer or pediatric HSCT recipients 8-18 years of age from three groups inpatients receiving cancer treatments outpatients in maintenance therapy for acute lymphoblastic leukemia (ALL) and outpatients in survivorship. Bothersome changes in taste was self-reported using the Symptom Screening in Pediatrics Tool (SSPedi) nausea was self-reported using the Pediatric Nausea Assessment Tool (PeNAT). Among the 502 children included, 226 (45.0%) reported bothersome taste changes and 48 (9.6%) reported severely bothersome taste changes. In multiple regression, factors independently associated with severely bothersome taste changes were inpatients receiving cancer treatments vs outpatients in survivorship (odds ratio (OR) 12.28, 95% confidence interval (CI) 2.50-222.27), ALL in maintenance vs outpatients in survivorship (OR 7.43, 95% CI 1.06-147.77), current nausea (OR 1.59, 95% CI 1.04-2.42), vomiting (OR 2.18, 95% CI 1.06-4.38), and first language not English (OR 2.09, 95% CI 0.97-4.28). We found that 45% of children with cancer and pediatric HSCT recipients reported bothersome changes in taste and these were severely bothersome in 9.6% of children. Inpatients receiving cancer treatment, those experiencing more nausea and vomiting and children whose first language was not English were at greater risk of severely bothersome changes in taste. Future work should evaluate systematic symptom screening in clinical practice and identify interventions focused on addressing bothersome taste changes. |
30,324,220 | Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy. | Methotrexate polyglutamates (MTXpg) facilitate incorporation of thioguanine nucleotides into DNA (DNA-TG, the primary cytotoxic thiopurine metabolite and outcome determinant in MTX6-mercaptopurine treatment of childhood ALL). We hypothesized that mapping erythrocyte levels of MTXpg with 1-6 glutamates and their associations with DNA-TG formation would facilitate future guidelines for maintenance therapy dosing. Summed MTX with 1-6 glutamates resolved by LCMS median (interquartile) 5.47 (3.58-7.69) nmolmmol hemoglobin was in agreement with total MTX by radio ligand assay. In 16,389 blood samples from 1426 ALL maintenance therapy patients, MTXpg3 21.0 (15.2-27.4)% was the predominant metabolite, and MTXpg1 (the maternal drug) constituted 38.6 (27.2-50.2)% of MTXpg1-6. All subsets correlated the strongest associations were between metabolites with similar polyglutamate lengths. Correlations of MTXpg1 with MTXpg2 and MTXpg3,4,5,6 were r Measuring erythrocyte MTXpg4 simplifies and can replace longer chain MTXpg monitoring. Resolving individual MTXpg identifies samples that are unsuitable for dose guidance due to high levels of MTXpg1 remaining in the plasma fraction because of recent MTX intake. All tested MTXpg subsets correlated with DNA-TG and may be used for ALL maintenance therapy dose adjustments, but the most informative subset remains to be identified. |
30,323,696 | Impact of blinatumomab on patient outcomes in relapsedrefractory acute lymphoblastic leukemia evidence to date. | Relapsedrefractory (RR) acute lymphoblastic leukemia (ALL) is associated with a poor prognosis in both children and adults. Traditionally, there were limited options for salvage therapy, which consisted mostly of conventional chemotherapy. However, in the past 5 years, novel agents have changed our treatment strategies in this population. Blinatumomab, a bispecific CD19 directed CD3 T-cell engager, has shown to be effective in both minimal residual disease and RR B-cell ALL. In RR B-cell ALL, blinatumomab was associated with an improved median overall survival of 7.7 months vs 4.0 months with traditional chemotherapy (HR for death, 0.71 95% CI, 0.55-0.93 |
30,323,566 | Characterization of clinical grade CD19 chimeric antigen receptor T cells produced using automated CliniMACS Prodigy system. | Chimeric antigen receptor (CAR) T-cell therapy is highly effective for treating acute lymphoblastic leukemia and non-Hodgkins lymphoma with high rate complete responses. However, the broad clinical application of CAR T-cell therapy has been challenging, largely due to the lack of widespread ability to produce and high cost of CAR T-cell products using traditional methods of production. Automated cell processing in a closed system has emerged as a potential method to increase the feasibility of producing CAR T cells locally at academic centers due to its minimal reliance on experienced labor, thereby making the process less expensive and more consistent than traditional methods of production. In this study, we describe the successful production of clinical grade CD19 CAR T cells using the Miltenyi CliniMACS Prodigy Automated Cell Processor at University of Colorado Anschutz Medical Campus in a rapid manner with a high frequent CD19 CAR expression. The final CAR T-cell product is highly active, low in immune suppression, and absent in exhaustion. Full panel cytokine assays also showed elevated production of Th1 cytokines upon IL-2 stimulation when specifically killing CD19 target cells. These results demonstrate the feasibility of producing CAR T cells locally in a university hospital setting using automated cell processor for future clinical applications. |
30,323,192 | SHQ1 regulation of RNA splicing is required for T-lymphoblastic leukemia cell survival. | T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with complicated heterogeneity. Although expression profiling reveals common elevated genes in distinct T-ALL subtypes, little is known about their functional role(s) and regulatory mechanism(s). We here show that SHQ1, an HACA snoRNP assembly factor involved in snRNA pseudouridylation, is highly expressed in T-ALL. Mechanistically, oncogenic NOTCH1 directly binds to the SHQ1 promoter and activates its transcription. SHQ1 depletion induces T-ALL cell death in vitro and prolongs animal survival in murine T-ALL models. RNA-Seq reveals that SHQ1 depletion impairs widespread RNA splicing, and MYC is one of the most prominently downregulated genes due to inefficient splicing. MYC overexpression significantly rescues T-ALL cell death resulted from SHQ1 inactivation. We herein report a mechanism of NOTCH1-SHQ1-MYC axis in T-cell leukemogenesis. These findings not only shed light on the role of SHQ1 in RNA splicing and tumorigenesis, but also provide additional insight into MYC regulation. |
30,322,878 | Plasma Exchange Can Be an Alternative Therapeutic Modality for Severe Cytokine Release Syndrome after Chimeric Antigen Receptor-T Cell Infusion A Case Report. | Tumor immunotherapy with chimeric antigen receptor-T cells (CAR-T) is a promising new treatment for B-cell malignancies and has produced exciting results. However, cytokine release syndrome (CRS) is the most significant toxicity associated with this treatment and can be life-threatening. A 23-year-old male patient had been diagnosed with relapsed and refractory B-cell acute lymphocytic leukemia. The patient was recruited into our CAR-T clinical trial, and 1 × 10 CRS is caused by an exaggerated systemic immune response, potentially resulting in organ damage that can be fatal. Although therapeutic plasma exchange is not included in CRS management guidelines, this case shows that plasma exchange is feasible in at least some patients with severe CRS. |
30,322,619 | Structural basis for multiple gene regulation by human DUX4. | DUX4 plays critical role in the molecular pathogenesis of the neuromuscular disorder facioscapulohumeral muscular dystrophy and acute lymphoblastic leukemia in humans. As a master transcription regulator, DUX4 can also bind the promoters and activate the transcription of hundreds ZGA-associated genes. Here we report on the structural and biochemical studies of DUX4 double homeodomains (DUX4-DH), representing the only structures contain both homeodomain 1 (HD1) and homeodomain 2 (HD2). HD1 and HD2 adopt classical homeobox fold via the helix inserted into the major groove and the N-terminal extended loop inserted into the minor groove, HD1 and HD2 recognize the box1 (5-TAA-3) and box2 (5-TGA-3) nucleotides of the consensus sequence, respectively. Among the box1 and box2 linking nucleotides (CCTAA), the two adenine residues are reported to be highly conserved however, they are not directly recognized by DUX4-DH in the structures. Besides different nucleotides, our ITC analysis indicated that DUX4-DH can also tolerate various changes in the linker length. Our studies not only revealed the basis for target DNA recognition by DUX4, but also advanced our understanding on multiple gene activation by DUX4. |
30,322,332 | Antithrombin supplementation did not impact the incidence of pegylated asparaginase-induced venous thromboembolism in adults with acute lymphoblastic leukemia. | Pegylated asparaginase (PEG-Asp), a key component in the treatment of acute lymphoblastic leukemia (ALL), is associated with coagulopathy and an increased risk of venous thromboembolism (VTE). PEG-Asp also lowers antithrombin (AT) levels. Between April 2014 and October 2017, 75 adult ALL patients were identified to have received at least one dose of PEG-Asp. Patients were assigned to the AT group if a physician monitored AT levels with an intention to correct low AT levels (<60%). Incidence of VTE was not significantly different, with 17% (847) of the AT patients and 11% (328) of the control patients experiencing a VTE event (p .52). The occurrence of coagulopathies was not significantly different. Within the AT group, 37 patients (78%) received AT, and median AT% prior to supplementation was 49%. The median number of AT doses received was 2 (range 0-12) and the mean cost of AT per patient was $11,847. |
30,320,932 | Phosphorylation of serinearginine-rich splicing factor 1 at tyrosine 19 promotes cell proliferation in pediatric acute lymphoblastic leukemia. | Serinearginine-rich splicing factor 1 (SRSF1) has been linked to various human cancers including pediatric acute lymphoblastic leukemia (ALL). Our previous study has shown that SRSF1 potentially contributes to leukemogenesis however, its underlying mechanism remains unclear. In this study, leukemic cells were isolated from pediatric ALL bone marrow samples, followed by immunoprecipitation assays and mass spectrometry analysis specific to SRSF1. Subcellular localization of the SRSF1 protein and its mutants were analyzed by immunofluorescence staining. Cell growth, colony formation, cell apoptosis, and the cell cycle were investigated using stable leukemic cell lines generated with lentivirus-mediated overexpressed WT or mutant plasmids. Cytotoxicity of the Tie2 kinase inhibitor was also evaluated. Our results showed the phosphorylation of SRSF1 at tyrosine 19 (Tyr-19) was identified in newly diagnosed ALL samples, but not in complete remission or normal control samples. Compared to the SRSF1 WT cells, the missense mutants of the Tyr-19 phosphorylation affected the subcellular localization of SRSF1. In addition, the Tyr-19 phosphorylation of SRSF1 also led to increased cell proliferation and enhanced colony-forming properties by promoting the cell cycle. Remarkably, we further identified the kinase Tie2 as a potential therapeutic target in leukemia cells. In conclusion, we identify for the first time that the phosphorylation state of SRSF1 is linked to different phases in pediatric ALL. The Tyr-19 phosphorylation of SRSF1 disrupts its subcellular localization and promotes proliferation in leukemia cells by driving cell-cycle progression. Inhibitors targeting Tie2 kinase that could catalyze Tyr-19 phosphorylation of SRSF1 offer a promising therapeutic target for treatment of pediatric ALL. |
30,320,607 | Co-operation of ABT-199 and gemcitabine in impeding DNA damage repair and inducing cell apoptosis for synergistic therapy of T-cell acute lymphoblastic leukemia. | T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk subtype of acute lymphoblastic leukemia with limited therapeutic options available. Here, we evaluated the therapeutic potential of the combination of the Bcl-2 antagonist ABT-199 and cytotoxic agent gemcitabine in T-ALL cell lines. Our results showed that the combination of ABT-199 and gemcitabine exhibited synergistic cytotoxicity and induced significant apoptosis in human T-ALL cell lines (Jurkat and Molt4). The augmented apoptosis induced by combination treatment was accompanied by the greater extent of mitochondrial depolarization and enhanced DNA damage. Importantly, single agent induced DNA damage alone but did not inhibit RAD51BRCA1-mediated repair for DNA double-strand breaks. In contrast, the combination of ABT-199 and gemcitabine disrupted RAD51BRCA1-dependent DNA repair and remarkably activated caspase-3 and PARP to trigger apoptosis. Moreover, ABT-199 exerted an antagonistic action towards Bcl-2 and Bcl-xL, but to a certain extent moderately increased Mcl-1 level that could be compromised by gemcitabine. In conclusion, our study showed that the combination of ABT-199 and gemcitabine exhibited synergistic cytotoxicity in T-ALL cells by cooperatively targeting DNA damage repair pathway and Bcl-2 family proteins. |
30,319,272 | Extramedullary relapse of acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation treated by CAR T-cell therapy a case report. | Philadelphia chromosome-positive (Ph-positive) acute leukemia (ALL) accounts for around one quarter of adult cases of ALL and is usually associated with poor prognosis. The patients still encounter a high rate of relapse even after they receive hematopoietic stem cell transplantation (HSCT). HSCT is considered the established therapy and best option for many malignant ALL cases, however, disease relapse remains the main reason of failure. In recent years, chimeric antigen receptor (CAR) T-cell therapy has become a promising treatment for patients with advanced blood cancers. Here, we report a rare case of a Ph-positive ALL patient with extramedullary relapse in her cervix after receiving allogeneic HSCT. Given the unsatisfactory response to chemotherapy, tyrosine kinase inhibitor (TKI) treatment, and HSCT transplantation, she had received CD19 CAR T-cell therapy 8 months earlier. The following ultrasound check indicated that her cervix relapse went through significant remission with almost undetectable tumor mass. This case strongly supports the efficacy of CAR T-cell therapy on adult ALL with extramedullary relapse. |
30,318,517 | Maternal exposure to gasoline and exhaust increases the risk of childhood leukaemia in offspring - a prospective study in the Norwegian Mother and Child Cohort Study. | In the prospective population-based Norwegian Mother and Child Cohort Study (MoBa), comprising 113 754 offspring, we investigated the association between parental exposure to gasoline or exhaust, as a proxy for benzene exposure, and childhood leukaemia. Around gestational week 17, mothers and fathers responded to a questionnaire on exposure to various agents during the last 6 months and 6 months pre-conception, respectively. Benzene exposure was assessed through self-reported exposure to gasoline or exhaust. Cases of childhood leukaemia (n 70) were identified through linkage with the Cancer Registry of Norway. Risk was estimated by hazard ratios (HRs) with 95% confidence intervals (95%CI), comparing offspring from exposed and unexposed parents using a Cox regression model. Maternal exposure to gasoline or exhaust was associated with an increased risk of childhood leukaemia (HR 2.59 95%CI 1.03, 6.48) and acute lymphatic leukaemia (HR 2.71 95%CI 0.97, 7.58). There was an increasing risk for higher exposure (p value for trend 0.032 and 0.027). The association did not change after adjustment for maternal smoking. In spite of rather few cases, the findings in this prospective study, with the exposure metric defined a priori, support previous observations relating maternal exposure to benzene from gasoline and other petroleum-derived sources and the subsequent development of childhood leukaemia in the offspring. |
30,318,009 | Isolation, Purification, Characterisation and Application of L-ASNase A Review. | L-ASNase (L-asparagine aminohydrolase EC 3.5.1.1) is used for the conversion of L-asparagine to L-aspartic acid and ammonia and also it was found as an agent of chemotherapeutic property according to recent patents. It is known as an anti-cancer agent and recently it has received an immense attention. Various microorganisms have the ability to secrete the L-ASNase. It is famous world-wide as anti-tumor medicine for acute lymphoblastic leukemia and lymphosarcoma. L-ASNase helps in deamination of Asparagine and Glutamine. L-ASNase mainly found in two bacterial sources Escherichia coli and Erwinia carotovora. Isolation from plants Endophytes were also a great source of L-ASNase. It was isolated from four types of plants named as C. citratus, O. diffusa, M. koengii, and also P. bleo. L-ASNase is used as a potential anti-tumor medicine. It plays a very much essential role for the growth of tumor cells. Tumor cells require a lot of asparagine for their growth. But ASNase converts to aspartate and ammonia from asparagine. So the tumor cell does not proliferate and fails to survive. The L-ASNase is used as the medicine for the major type of cancer like acute lymphocytic leukemia (ALL), brain. It also used as a medicine for central nervous system (CNS) tumors, and also for neuroblastoma. Two types of L-ASNase have been found. L-ASNase becomes a powerful anti-tumor medicine and researchers should develop a potent strain of asparaginase which can produce asparaginase in the industrial level. It is also used in the pharmaceutical industry and food industry on a broader scale. |
30,317,726 | Clinicopathologic features of breast lymphoma in core needle biopsy. | null |
30,316,108 | Prevalence, predictors, causes of treatment refusal and abandonment in children with acute lymphoblastic leukaemia over 18 years in North India. Treatment phase affecting factors A step towards better focussed counselling. | Treatment refusal or abandonment are among the major causes of the survival gap between developed and developing countries. This retrospective observational study analyzed records of children aged <18 years with acute lymphoblastic leukemia (ALL) registered for treatment at a tertiary-care teaching hospital, North India, between 1995 and 2012. Children who refused or abandoned therapy were tracked, and reasons for refusalabandonment were recorded by telephone interviews or by surface mail. Sociodemographic parameters were compared using chi-squareStudent t-test to identify predictors of refusalabandonment. Treatment refusal was noted in 16.8% (96572) of children with ALL it was statistically higher for infants (p 0.004), girls (p 0.04), children of parents with poor literacy (p < 0.001), and those of lower socioeconomic status (p < 0.001). Main causes of treatment refusal were financial constraints (59.4%) and a misplaced belief about the incurability of cancer (22.9%). Therapy once started, was abandoned by 139476 children (29.2%), the majority (41%) during induction, followed by maintenance (17.9%). Major reasons for abandonment were financial constraints (34.5%), false perception of cure (20%), poor general condition of the child (15%), no improvement in the child (13%), and blood donation refusal (3%). The reasons cited were different in different treatment phases. Abandonment was statistically higher in children from rural background (p < 0.001) or lower socioeconomic status (p < 0.001), and in those with fathers having a lower literacy status (p < 0.001). Low hemoglobin (p 0.01) and severe wasting (p 0.01) was greater in children who abandoned treatment. Treatment refusal or abandonment, noted in 40% of children, was due mainly to monetary difficulties, disbeliefs regarding curability, or false perceptions of cure these factors need to be addressed to improve survival, particularly in children from rural areas and those of parents with a lower literacy status. |
30,313,079 | Diagnostic challenges in T-lymphoblastic lymphoma, early T-cell precursor acute lymphoblastic leukemia or mixed phenotype acute leukemia A case report. | The diagnosis of hematological malignancies depends on laboratory analysis and often requires multiple experimental methods to judge, otherwise misdiagnosis is apt to happen. Lymph node biopsy immunohistochemistry (IHC) for T-lymphoblastic lymphoma (T-LBL) requires the establishment of antibody set screening. For identifying T-LBL and early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) by lymph node biopsy and IHC, WHO has not yet proposed a better IHC antibody combination. Here we reported 1 case with tortuous diagnosis experience. Initially, a 51-year-old man was diagnosed as T-LBL by lymph node biopsy, but in another hospital acute myeloid leukemia (AML) was confirmed by bone marrow puncture. Finally, it was diagnosed as mixed phenotype acute leukemia (MPAL) through our comprehensive evaluation including bone marrow cell morphology, cytochemical staining and flow cytometry analysis. Importantly, the experience about differential diagnosis and our appreciation among the T-LBL, ETP-ALL and MPAL was discussed to enlighten readers. The patient was diagnosed with mixed phenotype acute leukemia (TMy)-NOS. The patient received 1 cycle of VDCLP scheme treatment firstly. The effect of chemotherapy is satisfactory, and then he received continuous treatment and was currently in good condition. This patient is alive at present. The follow-up period has been 1 year. For the diagnosis of T-LBL, the molecular markers of the myeloid and lymphoid tissues need to be included, such as CD117, CD33, Lys and MPO. The bone marrow puncture also needs to be conducted to distinguish T-LBL and T-ALL. Secondly, to identify ETP-ALL and MPAL, bone marrow cell morphology, cytochemical staining as well as flow cytometric analysis were needed to make a clear diagnosis. It is recommended that at least CD8, CD1a, Lys and MPO should be included in the panel to identify ETP-ALL. |
30,311,693 | Aptamer-targeted DNA nanostructures with doxorubicin to treat protein tyrosine kinase 7-positive tumours. | Aptamer sgc8c is a short DNA sequence that can target protein tyrosine kinase 7 (PTK7), which was overexpressed on many tumour cells. This study aimed to fabricate a novelty DNA nanostructure drug delivery system target on PTK7-positive cells-CCRF-CEM (human T-cell ALL). Aptamer-modified tetrahedron DNA was synthesized through one-step thermal annealing process. The sgc8c-TDNs (s-TDNs) loading DOX complexes were applied to investigate the effect to PTK7-negative and -positive cells. When s-TDNDOX acted on PTK7-positive and -negative cells respectively, the complexes exhibited specific toxic effect on PTK7-positive cells but not on PTK7-negative Ramos cells in vitro research. In this work, we successfully constructed a PTK7-targeting aptamer-guided DNA tetrahedral nanostructure (s-TDN) as a drug delivery system via a facile one-pot synthesis method. The results showed that s-TDNDOX exhibited enhanced cytotoxicity against PTK7-positive CCRF-CEM cells, with a minor effect against PTK7-negative Ramos cells. Hence, this functionalized TDNs drug delivery system displayed its potential application in targeting PTK7-positive tumour T-cell acute lymphoblastic leukaemia. |
30,311,452 | Two novel alleles, HLA-A32010109 and 32010110, identified by Pacific Biosciences SMRT sequencing. | Pacific Biosciences SMRT DNA sequencing was used to identify two novel intronic variants of HLA-A32010101. |
30,310,051 | Bone marrow infiltrated Lnc-INSR induced suppressive immune microenvironment in pediatric acute lymphoblastic leukemia. | Immune escape due to immunosuppressive microenvironments, such as those associated with regulatory T (Treg) cells is highly associated with initial occurrence and development of solid tumors or hematologic malignancies. Here, we employed high-throughput transcriptome screening to demonstrate immunosuppression-associated increases in the long noncoding (lnc) RNA lnc-insulin receptor precursor (INSR), which was corrected with INSR expression in CD4 T cells extracted from the bone marrow of patients with childhood acute T lymphoblastic leukemia. Loss-of-function and gain-of-function assays in vitro and in vivo revealed that membrane-localized and cytoplasm-localized lnc-INSR promoted Treg distribution and decreased the percentage of cytotoxic T lymphocytes, which induced tumor growth. Through direct binding with INSR, lnc-INSR blocked the INSR ubiquitination site, causing abnormal activation of INSR and the phosphatidylinositide 3-kinaseAKT-signaling pathway. These results indicated that lnc-INSR might promote immune suppression by enhancing Treg-cell differentiation and serve as valuable therapeutic targets in the immunosuppressive tumor microenvironment. |
30,309,857 | FDA Approval Summary Tisagenlecleucel for Treatment of Patients with Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia. | Tisagenlecleucel (Kymriah Novartis Pharmaceuticals) is a CD19-directed genetically modified autologous T-cell immunotherapy. On August 30, 2017, the FDA approved tisagenlecleucel for treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory in second or later relapse. Approval was based on the complete remission (CR) rate, durability of CR, and minimal residual disease (MRD) <0.01% in a cohort of 63 children and young adults with relapsed or refractory ALL treated on a single-arm trial (CCTL019B2202). Treatment consisted of fludarabine and cyclophosphamide followed 2 to 14 days later by a single dose of tisagenlecleucel. The CR rate was 63% (95% confidence interval, 50%-75%), and all CRs had MRD <0.01%. With a median follow-up of 4.8 months, the median duration of response was not reached. Cytokine release syndrome (79%) and neurologic events (65%) were serious toxicities reported in the trial. With implementation of a Risk Evaluation and Mitigation Strategy, the benefit-risk profile was considered acceptable for this patient population with such resistant ALL. A study of safety with 15 years of follow-up is required as a condition of the approval.See related commentary by Geyer, p. 1133. |
30,307,611 | Chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD, with or without blinatumomab, is highly effective in patients with Philadelphia chromosome-negative acute lymphoblastic leukemia in first salvage. | The outcomes of patients with relapsed or refractory (R-R) acute lymphoblastic leukemia (ALL) are poor. Inotuzumab ozogamicin and blinatumomab have single-agent activity in R-R ALL. Their addition to low-intensity chemotherapy may further improve the outcomes of patients with ALL in their first relapse. The chemotherapy was lower in intensity than conventional hyperfractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone and was called mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone (or mini-HCVD). Inotuzumab was given on day 3 of each of the first 4 cycles at 1.8 to 1.3 mgm Forty-eight patients with Philadelphia chromosome-negative ALL with a median age of 39 years were treated during their first relapse. Overall, 44 patients (92%) responded, with 35 of them (73%) achieving a complete response. The overall minimal residual disease negativity rate among the responders was 93%. Twenty-four patients (50%) underwent allogeneic stem cell transplantation (ASCT). Veno-occlusive disease of any grade occurred in 5 patients (10%). With a median follow-up of 31 months, the median progression-free survival (PFS) and the median overall survival (OS) were 11 and 25 months, respectively. The 2-year PFS and OS rates were 42% and 54%, respectively. Of the 24 patients (50%) who underwent ASCT, 14 patients were alive at the last follow-up (13 54% in remission). Of the remaining 20 responding patients who did not undergo subsequent ASCT, 6 (30%) remained in remission at the last follow-up. According to propensity score matching, the combination of mini-HCVD and inotuzumab with or without blinatumomab conferred better outcomes than intensive salvage chemotherapy or inotuzumab alone. The combination of inotuzumab and low-intensity mini-HCVD chemotherapy with or without blinatumomab shows encouraging results in patients with ALL in first salvage. |
30,305,606 | Increasing G9a automethylation sensitizes B acute lymphoblastic leukemia cells to glucocorticoid-induced death. | Synthetic glucocorticoids (GCs) are used to treat lymphoid cancers, but many patients develop resistance to treatment, especially to GC. By identifying genes that influence sensitivity to GC-induced cell death, we found that histone methyltransferases G9a and G9a-like protein (GLP), two glucocorticoid receptor (GR) coactivators, are required for GC-induced cell death in acute lymphoblastic leukemia (B-ALL) cell line Nalm6. We previously established in a few selected genes that automethylated G9a and GLP recruit heterochromatin protein 1γ (HP1γ) as another required coactivator. Here, we used a genome-wide analysis to show that HP1γ is selectively required for GC-regulated expression of the great majority of GR target genes that require G9a and GLP. To further address the importance of G9a and GLP methylation in this process and in cell physiology, we found that JIB-04, a selective JmjC family lysine demethylase inhibitor, increased G9a methylation and thereby increased G9a binding to HP1γ. This led to increased expression of GR target genes regulated by G9a, GLP and HP1γ and enhanced Nalm6 cell death. Finally, the KDM4 lysine demethylase subfamily demethylates G9a in vitro, in contrast to other KDM enzymes tested. Thus, inhibiting G9aGLP demethylation potentially represents a novel method to restore sensitivity of treatment-resistant B-ALL tumors to GC-induced cell death. |
30,305,536 | Therapeutic approaches to hematological malignancies in adolescents and young adults. | Hematological malignancies (HM) comprise the major proportion of the cancer incidence and mortality in the adolescent and young adult (AYA) age group. Even though age-related differences in tumor biology have been reported in HM, further biological studies are warranted for elucidating age-related differences in AYAs. Hemato-oncologists and pediatric oncologists frequently follow various treatment strategies for HM, as the treatment strategy that is more suitable for this age group remains unclear. Recently, the involvement of pediatric oncologists has increased because the advantage of pediatric-type treatment has been demonstrated in acute lymphoblastic leukemia (ALL) and the significance of long-term follow-up has been clarified. However, for HM, except for ALL, the pediatric- and adult-type therapy that is more suitable for AYAs remains unclear. This review aimed to describe the challenges in the context of major HM affecting the AYA age group (acute leukemia and lymphoma). For assessing the outcome of AYAs with HM, we need to consider not only the treatment strategy but also other factors such as differences in aging and tumor biology. Furthermore, it is imperative to develop a therapy that resolves psychosocial problems peculiar to AYAs. |
30,305,535 | Genetic background and treatment of pediatric ALL. | Molecular genomic studies for acute lymphoblastic leukemia (ALL) have been focused on genetic alterations in leukemic cells, while germline cells are mainly used as a control to identify the somatic mutation. However, recent studies demonstrate that germline mutations may contribute to the pathogenesis of ALL, and currently, the genetic background has been found to play an essential role in the development of pediatric ALL. An association between polymorphism and adverse events has already been reported, and recent genomic analyses of familial ALL cases identified inherited causative genes for ALL. Moreover, non-syndromicfamilial ALL cases may present pathogenic germline variants in cancer predisposition genes. These variants could not only contribute to poor response to treatment but also lead to an increased risk of secondary neoplasms. Comprehensive understanding of the biology in both ALL cells and germline cells is required. |
30,305,505 | Current management of adult Philadelphia chromosome-positive acute lymphoblastic leukemia. | Tyrosine kinase inhibitors (TKIs) have improved the response and survival in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) (PhALL). Although the second and third generation TKIs are expected to greatly enhance treatment outcomes, no study has demonstrated the inferiority of allogeneic hematopoietic stem cell transplantation (allo-HSCT) to chemotherapy combined with TKIs in any subgroup of adults with PhALL. Because the PCR-based detection of minimal residual disease (MRD) is easy and reliable, physicians can judge the level of treatment response. Recently, the molecular genetics risk factors of PhALL in the TKI era have been revealed. These diagnostic advancements have enabled physiciansto precisely evaluate the disease risk before commencing initial treatment and to select the most suitable therapy via MRD monitoring during the treatment. Currently, new antibody therapies have been included as candidate therapies for PhALL. This review discusses available treatments for adult patients with PhALL. |
30,305,504 | Strategy for treatment of acute lymphoblastic leukemia. | The treatment outcomes of adult acute lymphoblastic leukemia (ALL) have improved. Furthermore, the introduction of pediatric specific therapies has enhanced ALL treatment results in adolescents and young adult (AYAs). Age-related molecular signatures have also been identified, such as Philadelphia chromosome (Ph)-like ALL and DUX4ERG gene-associated ALL. The measurement of minimal residual disease (MRD) has enabled the early detection of patients susceptible to relapse, and they become candidates for hematopoietic stem cell transplantation (HSCT). However, new generation tyrosine kinase inhibitor (TKI) therapy has enabled the avoidance of HSCT in Ph-positive ALL cases. Novel agents targeting CD19 and CD22 molecules will be available in the near future that should improve treatment outcomes in patients newly diagnosed with ALL. |
30,305,495 | Cancer therapy using bispecific antibodies. | Bispecific antibodies comprise two antigen-binding sites that recognize different antigens or epitopes. Blinatumomab, a bispecific T-cell engager (BiTE) that lacks the Fc portion, recognizes CD19 on B tumor cells and CD3 on T cells and induces the T cell-mediated killing of the B tumor cells. The Food and Drug Administration has approved the use of blinatumomab for the treatment of precursor B-cell acute lymphoblastic leukemia (ALL) with minimal residual disease and relapsedrefractory ALL. Various bispecific antibodies have been developed, including BiTEs that target surface molecules on myeloma cells or intracellular antigens presented on the major histocompatibility complex and Fc portion-containing bispecific antibodies that have a potent T cell-activating capacity and a long half-life. These efforts could lead to the development of potent, off-the-shelf bispecific antibodies for the treatment of a broad array of hematological malignancies. |
30,304,948 | Targeting the mitochondrial apoptosis pathway by a newly synthesized COX-2 inhibitor in pediatric ALL lymphocytes. | Acute lymphoblastic leukemia (ALL) is known as a barely curable malignancy. Particular mutations involved in apoptosis may have a main role in the onset of ALL in the pediatric patients. It has been proven that cycloxygenase-2 is capable of impairing the apoptosis pathway through mitochondria in tumor cells. In this study, we investigated selective toxicity of a newly synthesized chalconeferrocenyl derivative as a selective cycloxygenase-2 inhibitor in ALL and healthy B-lymphocytes, and also isolated mitochondria obtained from them. For this purpose, we evaluated the cellar parameters like viability, apoptosisnecrosis, caspase-3 activation and ATP content, and also mitochondrial parameters like mitochondrial membrane potential decline, reactive oxygen species formation, cytochrome C release and mitochondrial swelling. Our results implied that this compound can selectively induce cellular and mitochondrial toxicity in cancerous ALL B-lymphocytes and obtained mitochondria from them without any detrimental effects on healthy subjects. |
30,304,769 | A Novel t(814)(q24q11) Rearranged Human Cell Line as a Model for Mechanistic and Drug Discovery Studies of NOTCH1-Independent Human T-Cell Leukemia. | null |
30,304,722 | Comparison between Hyper-CVAD and PETHEMA ALL-93 in Adult Acute Lymphoblastic Leukemia A Single-Center Study. | Although cure rates in pediatric acute lymphoblastic leukemia (ALL) are quite high with combined chemotherapy regimens, complete response (CR) and long-term survival rates in adults are 80-90 and 30-40%, respectively. Currently, combined chemotherapy regimens, such as Hyper-CVAD and PETHEMA, are used in patients with adult ALL. However, there has been no study comparing the results of Hyper-CVAD and PETHEMA ALL-93. In this retrospective single-center study, we evaluated the results of Hyper-CVAD and PETHEMA ALL-93 in 51 ALL patients treated between September 2008 and March 2017 at the Department of Hematology, Faculty of Medicine, Karadeniz Technical University. Thirty-eight patients were treated with Hyper-CVAD and 13 with PETHEMA ALL-93. CR was obtained in 90 and 100% of patients, respectively. Survival estimates were comparable between Hyper-CVAD and PE-THEMA ALL-93, with a median overall survival (OS) and a median disease-free survival (DFS) of 17.5 and 12.1 months, respectively, for Hyper-CVAD and of 18.6 and 12.9 months, respectively, for PETHEMA ALL-93. The 2-year OS rates for Hyper-CVAD and PETHEMA ALL-93 were 30 and 40%, respectively, and the 2-year DFS rates were 28 and 44%, respectively. PETHEMA ALL-93 resulted in more hepatotoxicity, hypofibrinogenemia, aspergillus infection, and skin rash than Hyper-CVAD. Although Hyper-CVAD and PE-THEMA ALL-93 showed similar effects, Hyper-CVAD was tolerated better. Age and comorbidities should be taken into account before a chemotherapy regimen is determined for patients with ALL. |
30,304,407 | Long-term Survival and Value of Chimeric Antigen Receptor T-Cell Therapy for Pediatric Patients With Relapsed or Refractory Leukemia. | Among children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia, the rate of 5-year disease-free survival is 10% to 20%. Approval of tisagenlecleucel, a chimeric antigen receptor T-cell therapy, represents a new and potentially curative treatment option. However, tisagenlecleucel is expensive, with a current list price of $475 000 per one-time administration. To estimate the long-term survival and value of tisagenlecleucel for children and young adults with B-cell acute lymphoblastic leukemia. In this cost-effectiveness analysis, a decision analytic model was designed to extrapolate trial evidence to a patient lifetime horizon. The survival evidence for the model was extracted from 3 studies B2202 (enrolled patients from April 8, 2015, to November 23, 2016), B2205J (enrolled patients from August 14, 2014, to February 1, 2016), and B2101J (enrolled patients from March 15, 2012, to November 30, 2015). Long-term survival and outcomes of patients younger than 25 years with B-cell acute lymphoblastic leukemia that is refractory or in second or later relapse were derived using flexible parametric modeling from the direct extrapolation of event-free survival and overall survival curves. The published Kaplan-Meier curves were digitized from November 1, 2017, to November 30, 2017, using an algorithm to impute patient-level time-to-event data. Sensitivity and scenario analyses assessed uncertainty in the evidence and model assumptions to further bound the range of cost-effectiveness. Data were analyzed from December 1, 2017, to March 31, 2018. The primary intervention of interest was tisagenlecleucel. The comparator of interest was the chemoimmunotherapeutic agent clofarabine. Model outcomes included life-years gained, quality-adjusted life-years (QALYs) gained, and incremental costs per life-year and QALY gained. Forty percent of patients initiating treatment with tisagenlecleucel are expected to be long-term survivors, or alive and responding to treatment after 5 years. Tisagenlecleucel had a total discounted cost of $667 000, with discounted life-years gained of 10.34 years and 9.28 QALYs gained. The clofarabine comparator had a total discounted cost of approximately $337 000, with discounted life-years gained of 2.43 years and 2.10 QALYs gained. This difference resulted in an incremental cost-effectiveness ratio of approximately $42 000 per life-year gained and approximately $46 000 per QALY gained for tisagenlecleucel vs clofarabine. These results were robust to probabilistic sensitivity analyses. Across scenario analyses that included more conservative assumptions regarding long-term relapse and survival, the incremental cost-effectiveness ratio ranged from $37 000 to $78 000 per QALY gained. Tisagenlecleucel likely provides gains in survival and seems to be priced in alignment with these benefits. This study suggests that payers and innovators should develop novel payment models that reduce the risk and uncertainty around long-term value and provide safeguards to ensure high-value care. |
30,303,521 | To delay or not to delay, that is the question for patients with acute lymphoblastic leukemia who do not receive prophylactic cranial irradiation. | To determine the impact of delaying diagnostic lumbar puncture and initial intrathecal therapy on treatment outcome of children with newly diagnosed acute lymphoblastic leukemia (ALL) treated without prophylactic cranial irradiation, Yeh and colleagues updated their TPOG-ALL-2002 clinical trial. They found that this treatment strategy reduced the rate of traumatic lumbar puncture with blasts to zero, and tended to improve outcome of patients with a CNS-2 or CNS-3 status based on the event-free survival, the overall survival, and the cumulative risk of CNS relapse, as compared to historical controls. |
30,303,520 | Treatment of childhood acute lymphoblastic leukemia with delayed first intrathecal therapy and omission of prophylactic cranial irradiation Results of the TPOG-ALL-2002 study. | To eliminate cranial irradiation (CrRT)-related sequelae and to minimize the adverse impact of traumatic lumbar puncture (TLP) with blasts, the Taiwan Pediatric Oncology Group (TPOG) introduced a modified central nervous system (CNS)-directed regimen characterized by delayed triple intrathecal therapy (TIT) and the omission of CrRT for all children with newly diagnosed acute lymphoblastic leukemia (ALL). This study compared the treatment outcomes of patients overall and patients with a non-CNS-1 status (CNS-2, CNS-3, or TLP with blasts) in 2 treatment eras, one before and another after the revision of the TPOG-ALL-2002 protocol by the introduction of the modification (era 1 2002-2008 with CrRT and era 2 2009-2012 with delayed first TIT and no CrRT). There were no statistically significant differences in major outcomes between the 903 patients treated in era 1 and the 444 patients treated in era 2 the 5-year event-free survival (EFS) rates were 75.7% ± 1.4% and 72.1% ± 2.4%, respectively (P .260), and the cumulative risks of isolated CNS relapse were 4.0% ± 0.7% and 4.1% ± 1.0%, respectively (P .960). There were also no differences between non-CNS-1 patients treated in era 1 (n 76) and era 2 (n 28) the 5-year EFS rates were 52.3% ± 5.8% and 62.9% ± 9.4%, respectively (P .199), and the cumulative risks of isolated CNS relapse were 6.3% ± 3.1% and 3.6% ± 3.5%, respectively (P .639). Notably, TLP with blasts was completely eliminated after the first TIT was delayed in era 2. The delay of the first TIT until the clearance of circulating blasts and the total omission of CrRT did not compromise survival or CNS control in patients with childhood ALL, including those with a non-CNS-1 status. |
30,302,234 | Management of older adults with acute lymphoblastic leukemia challenges current approaches. | The management of acute lymphoblastic leukemia (ALL) in older patients is challenging. Older patients often have multiple comorbidities and poor performance status, and disease factors associated with poor prognosis are more common in this age group. Patient and disease-related factors should be taken into account to determine whether intensive therapy is appropriate. The use of comorbidity indices and comprehensive geriatric assessment tools can be valuable in this setting. Fit patients should be considered for aggressive therapies including allogeneic hematopoietic stem cell transplantation, whereas low intensity options may be more suitable for the frail. The Philadelphia (Ph) chromosome is present in up to half of the cases of ALL in older patients. The incorporation of TK inhibitors into the treatment plans of older patients with Ph-positive ALL has improved the outcomes significantly. For less fit patients with Ph-positive ALL, the use of TK inhibitors with reduced-intensity chemotherapy or steroids alone results in high rates of remission, but, without further consolidation, relapses are inevitable. Many novel targeted and immunotherapeutic agents are being developed, offering more effective and tolerable treatment options. |