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Leukemia cutis as the presenting symptom of acute myeloid leukemia report of three cases.

Leukemia cutis (LC), a rare cutaneous manifestation of leukemia, can precede, follow, occur concurrently with, or present in the absence of (aleukemic) systemic leukemia. Leukemia cutis is especially rare as the presenting symptom of leukemia and is associated with a poor prognosis. Although more commonly seen in acute leukemias of myeloid and monocytic lineage, lymphocyticlymphoblastic leukemias can also involve the skin. Three cases of LC presented with diverse skin lesions ranging from an erythematous rash to violaceous macules and papules to subcutaneous nodules. One case clinically mimicked fixed drug eruption. All the patients had acute myeloid leukemia (AML). Lesions showed two overarching histologic patterns atypical perivascular infiltrate or nodular dermal histiocytoid infiltrate. Our cases expressed myeloperoxidase (MPO), a helpful marker to distinguish myeloid from non-myeloid cells, and CD68, a monocytic marker frequently expressed in cutaneous AML. CD14, a marker of monocyte maturity, was negative. In the absence of systemic leukemia, common diagnostic tools for hematologic malignancies such as bone marrow biopsy and flow cytometry are non-contributory, making morphologic and immunohistochemical analysis of the skin lesions key to diagnosis.

Bone Marrow versus Peripheral Blood from Unrelated Donors for Children and Adolescents with Acute Leukemia.

Graft-versus-host disease (GVHD) rates are higher after unrelated donor transplantation thus, we examined whether there would be differences in transplant outcomes by graft type in children and adolescents with acute leukemia. The primary endpoint was overall survival. We studied 872 patients <18 years old who were transplanted with bone marrow (n 650) or peripheral blood (n 222) from unrelated donors. The characteristics of the 2 groups were comparable, except recipients of bone marrow were younger than recipients of peripheral blood (median age, 10 versus 12 years). Grades 2 to 4 (hazard ratio HR, 1.48 P < .001) and grades 3 and 4 acute (HR, 1.69 P < .001) and chronic GVHD (HR, 1.92 P < .001) were higher with transplantation of peripheral blood than with bone marrow. Although relapse risks were lower after peripheral blood transplants (HR, 0.76 P .05), transplant-related mortality (HR, 1.91 P .003) and overall mortality (HR, 1.34 P .032) were higher than with bone marrow transplants. The 8-year probability of overall survival after transplantation of bone marrow was 47% compared with 42% after peripheral blood. The 8-year probability of leukemia-free survival was 40% after transplantation of bone marrow and peripheral blood. Lower relapse after transplantation of peripheral blood negated the survival advantage after transplantation of bone marrow. The observed higher acute and chronic GVHD seen with peripheral blood suggest cautious use of this graft in children and adolescents with acute leukemia.

Evaluation of BAX and BCL-2 Gene Expression and Apoptosis Induction in Acute Lymphoblastic Leukemia Cell Line CCRFCEM after High- Dose Prednisolone Treatment.

Objective Glucocorticoids are one of the most important drugs in the treatment of acute lymphoblastic leukemia for children. It is very important to response to glucocorticoid in the prognosis of these patients. Therefore, resistance to treatment is a major problem in lymphoid leukemia cases. In, this study, CCRF-CEM cell line was selected as a chemotherapy-resistant model. The aim of this study was to evaluate the effect of high dose prednisolone on induction of apoptosis and changes in BAX and BCL-2 gene expression at different times. Methods CCRF-CEM cell lines were grown in standard conditions. Based on previous studies, a dose of 700 μM as subtoxic dose was selected. Changes in gene expression of BAX and BCL-2 were evaluated by using real time PCR techniques. Also stained with annexin V and the induction of apoptosis was assessed by FACS machine. Results In this study it was found that prednisolone in high doses at different times significantly increased the gene expression of BAX and on the other hand the amount of BCL-2 expression was reduced. Cells that treated for 48 hours had more significant changes in gene expression. Based on flowcytometry data, prednisolone can induce apoptosis in a time dependent manner on this cancerous resistant cell line. Conclusions Apoptosis induced by high-dose prednisolone in the CCRF-CEM cells, which is almost resistant, and possibly mediated by reducing the expression of BCL-2 and BAX up-regulation.

Biphenotypic Acute Leukemia versus Myeloid Antigen-Positive ALL Clinical Relevance of WHO Criteria for Mixed Phenotype Acute Leukemia.

Updated WHO criteria define mixed phenotype acute leukemia (MPAL) with more stringent diagnostic criteria than the formerly described entity biphenotypic acute leukemia (BAL). The changes in diagnostic criteria influence management by assigning weight to aberrantly expressed markers and minimizing expression of myeloid markers other than myeloperoxidase (MPO), potentially foregoing consolidative allogeneic transplant for an otherwise favorable lymphoid phenotypic leukemia. We present a case of MPO-negative, myeloid antigen-positive acute lymphoblastic leukemia who progressed with refractory phenotypic acute myeloid leukemia while receiving lymphoid-directed therapy and discuss concerns raised by the adoption of the new, more stringent diagnostic criteria for BAL.

Phase II Clinical Trial for Newly Diagnosed Children and Adolescents with Localized Lymphoblastic Lymphoma (Japanese LeukemiaLymphoma Study Group Trial LLB-NHL03) Study Protocol for Nationwide Multicenter Trial.

Pediatric patients with lymphoblastic lymphoma are generally treated using the Berlin-Frankfurt-Munster (BFM) 90 protocol, which is the standard treatment strategy for pediatric acute lymphoblastic leukemia, and have a favorable outcome. However, this intense regimen includes high total doses of anthracycline and alkylating agents, and is known to cause late complications. We therefore planned a clinical trial to examine the efficacy and safety of a modified BFM regimen. We expect that this phase II, nationwide multicenter trial will help to establish an effective and safer standard therapy for stage III pediatric lymphoblastic lymphoma.

Purification, characterization and immunogenicity assessment of glutaminase free L-asparaginase from Streptomyces brollosae NEAE-115.

L-asparaginase is a potential therapeutic enzyme widely used in the chemotherapy protocols of pediatric and adult patients with acute lymphoblastic leukemia. However, its use has been limited by a high rate of hypersensitivity in the long-term used. Hence, there is a continuing need to search for other L-asparaginase sources capable of producing an enzyme with less adverse effects. Production of extracellular L-asparaginase by Streptomyces brollosae NEAE-115 was carried out using submerged fermentation. L-asparaginase was purified by ammonium sulphate precipitation and pure enzyme was reached using ion-exchange chromatography, followed by enzyme characterization. Anticancer activity towards Ehrlich Ascites Carcinoma (EAC) cells was investigated in female Swiss albino mice by determination of tumor size and the degree of tumor growth inhibition. The levels of anti-L-asparaginase IgG antibodies in mice sera were measured using ELISA method. The purified L-asparaginase showed a total activity of 795.152 with specific activity of 76.671 Umg protein and 7.835 - purification fold. The enzyme purity was confirmed by using SDS-PAGE separation which revealed only one distinctive band with a molecular weight of 67 KDa. The enzyme showed maximum activity at pH 8.5, optimum temperature of 37 °C, incubation time of 50 min and optimum substrate concentration of 7 mM. A Michaelis-Menten constant analysis showed a K The study reveals the excellent property of this enzyme which makes it highly valuable for development of chemotherapeutic drug.

Expression of Micro-RNA 128 and Let-7b in Pediatric Acute Lymphoblastic Leukemia Cases.

Background MicroRNAs (miRNAs) play important roles in the pathogenesis of leukemia and their altered expression is associated with many types of solid and hematological malignancies. Methods The study was performed on 70 consecutive newly diagnosed pediatric acute lymphoblastic leukemia (ALL) patients, of which 56 were evaluated for both bone marrow miR-128 and let-7b (all 70 for let-7b) by real-time quantitative reverse transcriptase polymerase chain reaction (RT-qPCR). In addition, seven age and sex matched healthy controls were assessed. Results miR-128 expression was significantly higher in ALL patients compared with healthy controls (p<0.001). However, the expression levels of let-7b showed no statistical significant difference between the groups. No significant links were noted with clinical details, laboratory data and response to treatment. Conclusion The results suggest that determination of miR-128 expression level may provide a tool for confirmation of a diagnosis of childhood ALL, follow up for response of treatment and a possible predictor of early relapse. Any role of let-7b in pediatric ALL needs to be further assessed.

Selective Cytotoxicity of α-Santonin from the Persian Gulf Sponge Dysidea Avara on Pediatric ALL B-lymphocytes via Mitochondrial Targeting.

Background Acute lymphoblastic leukemia (ALL) is one of the most dominant malignancies among children, characterized by production of immature and dysfunctional blasts which are resistant to cytotoxic chemotherapeutic agents. Therefore, research protocols are currently focusing on discovery of novel anti-cancer agents to enhance survival rates and decrease unwanted side effects. Approximately two-thirds of the planet is covered by oceans with a massive range of marine organisms of interest to scientists in pharmaceutical fields. Methods Among marine resources, sponges are known to have beneficial effects in the treatment of numerous malignancies. One fraction of crude extracts containing α-Santonin was made from the Persian Gulf marine sponge, Dysidea avara, and investigated for anticancer effects. Results Treatment of ALL B-lymphocytes with the Dysidea avara extract caused augmentation in ROS generation, decline in mitochondrial membrane potential, mitochondrial swelling, release of cytochrome c from mitochondria and activation of caspase-3 only in mitochondria isolated from B-ALL lymphocytes. Conclusion In brief, our results suggest that Dysidea avara extracts may selectively induce apoptosis in malignant pediatric lymphocytes.

Improved Survival for Children and Young Adults With T-Lineage Acute Lymphoblastic Leukemia Results From the Childrens Oncology Group AALL0434 Methotrexate Randomization.

Early intensification with methotrexate (MTX) is a key component of acute lymphoblastic leukemia (ALL) therapy. Two different approaches to MTX intensification exist but had not been compared in T-cell ALL (T-ALL) the Childrens Oncology Group (COG) escalating dose intravenous MTX without leucovorin rescue plus pegaspargase escalating dose, Capizzi-style, intravenous MTX (C-MTX) regimen and the Berlin-Frankfurt-Muenster (BFM) high-dose intravenous MTX (HDMTX) plus leucovorin rescue regimen. COG AALL0434 included a 2 × 2 randomization that compared the COG-augmented BFM (ABFM) regimen with either C-MTX or HDMTX during the 8-week interim maintenance phase. All patients with T-ALL, except for those with low-risk features, received prophylactic (12 Gy) or therapeutic (18 Gy for CNS3) cranial irradiation during either the consolidation (C-MTX second month of therapy) or delayed intensification (HDMTX seventh month of therapy) phase. AALL0434 accrued 1,895 patients from 2007 to 2014. The 5-year event-free survival and overall survival rates for all eligible, evaluable patients with T-ALL were 83.8% (95% CI, 81.2% to 86.4%) and 89.5% (95% CI, 87.4% to 91.7%), respectively. The 1,031 patients with T-ALL but without CNS3 disease or testicular leukemia were randomly assigned to receive ABFM with C-MTX (n 519) or HDMTX (n 512). The estimated 5-year disease-free survival ( P .005) and overall survival ( P .04) rates were 91.5% (95% CI, 88.1% to 94.8%) and 93.7% (95% CI, 90.8% to 96.6%) for C-MTX and 85.3% (95% CI, 81.0%-89.5%) and 89.4% (95% CI, 85.7%-93.2%) for HDMTX. Patients assigned to C-MTX had 32 relapses, six with CNS involvement, whereas those assigned to HDMTX had 59 relapses, 23 with CNS involvement. AALL0434 established that ABFM with C-MTX was superior to ABFM plus HDMTX for T-ALL in approximately 90% of patients who received CRT, with later timing for those receiving HDMTX.

Protective effect of breastfeeding against childhood leukemia in Zhejiang Province, P. R. China a retrospective case-control study.

Our research investigated the relationship between childhood leukemia and breastfeeding in the P. R. of China. We conducted a retrospective case-control study from March 2008 to April 2017 at the Childrens Hospital of Zhejiang University, Zhejiang province, P. R. of China, which reviewed 958 children who had been diagnosed with leukemia in case group and 785 healthy children in control group. Data were obtained from medical records, and if the medical records were incomplete, we called mothers of children by phone to complete the data. Breastfeeding reduces the risk of childhood leukemia the effect is greater, if feeding continued for 7-9 months (p 0.002). In addition, we suggest that some factors such as maternal age, smoking during pregnancy, abortion history, genetic factors, parents use of hair dye, and the history of using birth control pills before pregnancy can increase the risk of childhood leukemia. This study indicates that promoting breastfeeding for 7-9 months may help lower the childhood leukemia incidence. Our study firstly demonstrates that breastfeeding has protective effects against childhood leukemia in the P. R. of China. ALL Acute lymphocytic leukemia AML Acute myeloid leukemia.

Common variable immunodeficiency (CVID) is one of the predominant antibody deficiency disorders, some evidence of which indicates that chromosome instability is present in these patients. An increased risk of cancer in patients with CVID has been documented. This study was undertaken to highlight radiation sensitivity in CVID patients and to clarify the genetic basis of this defect in these cases. Stimulated lymphocytes of the studied subjects were exposed to low-dose gamma-rays in the G2 phase or the G0 phase of the cell cycle and chromosomal aberrations were scored. Lymphocytes of healthy individuals, ataxia telangiectasia (AT) cases and a group of acute lymphoblastic leukemia (ALL) patients were investigated in the same way as controls. By two methods of analysis (one-way ANOVA and unpaired t-test), the CVID cases were significantly more radiosensitive than healthy controls based on the results of the G2 and the G0 assays. First-degree relatives of CVID patients were radiosensitive by the micronucleus assay which showed a significant difference as compared with normal controls (p 0.001). In conclusion, this study may support that chromosomal radiosensitivity in CVID patients is a marker of genetic predisposition to the disease. The results might be a clue to describe the increased risk of cancer in CVID patients.

Simple deep sequencing-based post-remission MRD surveillance predicts clinical relapse in B-ALL.

Next-generation sequencing (NGS) of the rearranged immunoglobulin heavy-chain gene has emerged as a highly sensitive method to detect minimal residual disease (MRD) in B acute lymphoblastic leukemialymphoma (B-ALL). However, a sensitive and easily implemented NGS methodology for routine clinical laboratories is lacking and clinical utility of NGS-MRD surveillance in a post-remission setting to predict clinical relapse has not been determined. Here we described a simple and quantitative NGS platform and assessed its performance characteristics, quantified NGS-MRD levels in 122 B-ALL samples from 30 B-ALL patients, and explored the clinical merit of NGS-based MRD surveillance. The current NGS platform has an analytic sensitivity of 0.0001% with excellent specificity and reproducibility. Overall, it performs better than routine multi-color flow cytometry (MCF) in detecting MRD. Utilizing this assay in MRD surveillance in a post-remission setting showed that it detected conversion to positive MRD (CPMRD) in patients with NGS-based molecular remission much earlier than MCF, and that positive MRD conversion could be detected as early as 25.6 weeks prior to clinical relapse in closely surveilled patients. Post-remission CPMRD, but not NGS-based MRD positivity at end of induction, can accurately predict clinical relapse in our limited cohort of B-ALL patients. This pilot proof-of-concept study illustrates the clinical utility of a simple, sensitive, and clinically feasible MRD detection platform in post-remission NGS-based MRD surveillance and early relapse detection in B-ALL patients.

Long Non-Coding RNAs Guide the Fine-Tuning of Gene Regulation in B-Cell Development and Malignancy.

With the introduction of next generation sequencing methods, such as RNA sequencing, it has become apparent that alterations in the non-coding regions of our genome are important in the development of cancer. Particularly interesting is the class of long non-coding RNAs (lncRNAs), including the recently described subclass of circular RNAs (circRNAs), which display tissue- and cell-type specific expression patterns and exert diverse regulatory functions in the cells. B-cells undergo complex and tightly regulated processes in order to develop from antigen naïve cells residing in the bone marrow to the highly diverse and competent effector cells circulating in peripheral blood. These processes include V(D)J recombination, rapid proliferation, somatic hypermutation and clonal selection, posing a risk of malignant transformation at each step. The aim of this review is to provide insight into how lncRNAs including circRNAs, participate in normal B-cell differentiation, and how deregulation of these molecules is involved in the development of B-cell malignancies. We describe the prognostic value and functional significance of specific deregulated lncRNAs in diseases such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, Burkitt lymphoma and multiple myeloma, and we provide an overview of the current knowledge on the role of circRNAs in these diseases.

Long-term results of the risk-stratified treatment of childhood acute lymphoblastic leukemia in China.

Long-term follow-up data for childhood acute lymphoblastic leukemia (ALL) are scarce in China because of lacking population-based and hospitalized registry system. This retrospective study, conducted at Shanghais Childrens Medical Center in China (SCMC), aimed to investigate the long-term results of childhood ALL and to identify prognostic factors. The Pediatric Oncology Network Database, designed by St. Jude Childrens Research Hospital, USA, were used to collect data for the enrolled patients starting in 2005. From 2005 to 2014, 1085 evaluable patients with ALL aged 1 to 18 years old were enrolled and treated using SCMC-ALL-2005 risk-stratified protocol. Complete remission was achieved in 95.6% of patients. At 5 and 10 years, the event-free survival rate was 68.3 ± 1.4% and 64.6 ± 1.6%, and the overall survival rate was 80.0 ± 1.2% and 76.3 ± 1.6%, respectively. The 5-year event-free survival rates were 81.8 ± 2.0%, 67.0 ± 1.9%, and 14.3 ± 4.0% for patients in low-risk, intermediate-risk, and high-risk groups, respectively. The cumulative risk of relapse was 24.5% at 10 years. Induction failure conferred worse prognosis. Patients younger than 1 year of age at diagnosis, intermediate-riskhigh-risk group, male gender, and positive minimal residual disease (MRD) results at day 55, both in the univariate and multivariate analysis, were associated with significantly worse prognosis (P < .05). Patients with positive MRD at both day 35 and day 55 were related to a significantly poor outcome (P < .0001), but not for patients with negitive MRD at day 35. The overall outcomes for ALL patients treated with protocol SCMC-ALL-2005 in SCMC are lower than in developed countries. Factors including age, gender, risk group and MRD results at day 55 were associated with treatment outcomes in childhood ALL.

Apoptotic effect of resveratrol on human T-ALL cell line CCRF-CEM is unlikely exerted through alteration of BAX and BCL2 promoter methylation.

One of the fundamental barriers leading to failure of leukemia therapy is the resistance against conventional chemotherapies, common modality used to cure leukemia. Having the potential to trigger apoptosis in various human leukemia cell lines, resveratrol is regarded as a robust agent in chemotherapy regimens. The current study was aimed to assess whether the apoptotic effect of resveratrol on T-cell acute lymphoblastic leukemia cell line, CCRF-CEM, is exerted through DNA methylation of BAX and BCL2 gene promoters. For this purpose, the CCRF-CEM cells were treated by resveratrol under standard cell culture. To analyze the promoter DNA methylation changes, we used methylation-specific polymerase chain reaction technique following the resveratrol treatment at different dosages and time intervals. Based on our previous study, the resveratrol treatment can trigger apoptosis in CCRF-CEM cell line via upregulation of apoptotic BAX gene and downregulation of antiapoptotic BCL2 gene. Despite these alterations in gene expression, the current study reveals no changes in DNA methylation patterns of subjected genes following the resveratrol treatment. Unchanged status of DNA methylation of BAX and BCL2 genes may suggest that resveratrol causes the gene expression changes through a distinct mechanism which requires further studies to be understood.

Trisomy 5 as the sole chromosomal anomaly in acute lymphoblastic leukaemia.

Trisomy 5 as the sole cytogenetic aberration in acute lymphoblastic leukaemia (ALL) is exceedingly rare. As such, its prognostic and therapeutic relevance remains unknown. We report a case of an 18-year-old young man who was diagnosed with B cell ALL with trisomy 5 as the sole chromosomal abnormality. He was treated with chemotherapy and went into complete remission. On the 14th month of treatment, he relapsed with central nervous system involvement characterised by leukaemic infiltration of the optic nerve and facial palsy. He subsequently underwent reinduction chemotherapy with aggressive intrathecal chemotherapy followed by posterior globe and whole brain radiation therapy. He is currently on his 26th month of treatment, in second remission, with complete resolution of leukaemic infiltrative optic neuropathy and facial paralysis. As more cases of this nature are reported, we will be able to determine the relevance of this distinct cytogenetic entity.

Cross-sectional physician survey on the use of minimal residual disease testing in the management of pediatric and adult patients with acute lymphoblastic leukemia.

Minimal residual disease (MRD) is a strong prognostic factor in acute lymphoblastic leukemia (ALL), which progresses quickly and is fatal within months if untreated. This study explored use of MRD testing in adult and pediatric B-cell ALL patients, and academic versus community settings. A survey was administered to US-based hematologistsoncologists currently managing ≥5 B-cell ALL patients and using MRD tests. Descriptive analyses (frequencies and percentages) and Pearsons chi square testing assessed any differences in various characteristics. 150 adult treaters (treating physicians 100 community, 50 academic) and 30 pediatric treaters participated. Use of MRD testing was higher among pediatric treaters (93% of patients) than adult treaters (73% of patients) (p < 0.05), and higher among adult treaters at academic centers than in community settings (84% and 67% of patients, respectively p < 0.01). MRD testing is part of a standard protocol for 93% of pediatric treaters versus 53% of adult treaters. Pediatric treaters most commonly administer an MRD test duringafter induction or upon relapse. No consensus on timing among adult treaters was noted. MRD testing is an important tool in the prediction of relapse in ALL. Resolving barriers could improve detection of molecular relapse in patients with ALL, particularly among adults and in community settings. MRD testing is fairly common in treatment of ALL, but some barriers still exist in access.

Clinical characteristics and prognosis of pediatric patients with B cell acute lymphoblastic leukemia relapse.

The aim of the present study was to investigate the clinical characteristics and prognosis of pediatric patients with B cell acute lymphoblastic leukemia (B-ALL) relapse. A total of 390 pediatric patients diagnosed as B-ALL and receiving regular chemotherapy in Jining First Peoples Hospital from August 2010 to May 2016 were selected. The clinical characteristics, therapeutic response and prognosis were compared between the two groups. There were significant differences in the comparisons of age, leukocyte count in the initial diagnosis and glucocorticoid sensitive test between B-cell ALL (B-ALL) relapse group and non-relapse group the minimal residual disease (MRD) levels of pediatric patients in the two groups at 33 days and 12 weeks were significantly different. The 3-year event-free survival (EFS) rates of pediatric patients with early, medium and late B-ALL relapse were 12.5±7.8%, 33.1±9.8% and 63.6±6.1%, respectively, and the prognosis of late relapse was significantly better than that of early relapse (P<0.001). The 3-year EFS rates of pediatric patients with bone marrow relapse in standard risk group, intermediate risk group and high risk group were 29.1±6.9, 31.3±6.5 and 28.3±6.3%, respectively there were no statistically significant differences (P0.387, P>0.05). Pediatric patients with B-ALL relapse are characterized by higher onset age (≥10 years old), high leukocyte count and hormone insensitivity. Dynamic monitoring of MRD level in B-ALL pediatric patients can predict the relapse.

Analysis of Clinical Profile and Outcome of Tuberculosis in Patients with Acute Leukemia.

Patients with acute leukemia (AL) are predisposed to develop infections including tuberculosis (TB). The risk is specifically higher in patients from TB endemic areas. Patients (≥12 years) with AL treated between January-2014 to January-2017 who developed TB were reviewed. Patients were classified into three groups acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and acute promyelocytic leukemia (APML) and a systematic analysis of clinical features and outcomes was conducted. Over the study period, 26 patients of AL developed TB. The median time to diagnosis of TB was 8 weeks (0-432 weeks) following the diagnosis of AL and it was comparable between the three leukemia groups. The diagnosis of TB required alteration of anti-leukemia therapy in 26.9% patients and rescheduling in another 42.3% patients. Therapy alterationrescheduling were more frequent in patients with AML as compared to ALL and APML (

Acute Lymphoblastic Leukemia in Young Adults Treated with Intensive Pediatric Type Protocol.

Young adults with acute lymphoblastic leukemia do better when treated on pediatric protocols. Young adults (18-30 years) with Ph-negative ALL treated between 2000 and 2014 were retrospectively analyzed. Two-hundred and thirty-two patients were included median age 21 years (18-30) 176 (76%) males median WBC 16,000cmm. Protocols used were BFM 95 (N 147, 63%), MCP-841 (N 51, 22%), GMALL (N 21, 9%), INCTR (N 9, 4%) and UKALL (N 4, 2%). Complete remission was achieved in 194232 (84%). Twenty patients (9%) died due to toxicity which was higher with BFM versus others (18147 vs. 285

Transcriptome-wide analysis uncovers the targets of the RNA-binding protein MSI2 and effects of MSI2s RNA-binding activity on IL-6 signaling.

The RNA-binding protein Musashi 2 (MSI2) has emerged as an important regulator in cancer initiation, progression, and drug resistance. Translocations and deregulation of the

The emerging story of acute lymphoblastic leukemia among the Latin American population - biological and clinical implications.

Higher incidence rates and poor outcomes have been reported among Latin American patients (Latinos) with acute lymphoblastic leukemia (ALL). Distinct patterns in recent genomic studies allude to a predisposing genetic component. In this review, we critically examine the increasing amount of empirical information on the epidemiology, outcomes and genomics of Latinos with ALL. We discuss the immense diversity within the Latino community and varying definitions of what is considered Latino, which pose an epidemiological challenge. Environmental factors have been evaluated as possible predisposing factors in the development of ALL but studies have produced conflicting results. In this review we describe chromosomal abnormalities and the specific genomic landscape in Latinos with ALL and their association with unfavorable prognosis, focusing on the higher frequency of Philadelphia chromosome-Like ALL. Recent data suggest an association between polymorphisms that are commonly found in indigenous Americans and high rates of ALL. The review compares the distribution of ALL throughout the various countries in Latin America in an attempt to shed some epidemiological light on the genetic ancestry of ALL. We additionally identify areas where research is warranted in efforts toward the advent of novel targeted agents that are relevant in improving outcomes within the Latino community.

NPM1 alternative transcripts are upregulated in acute myeloid and lymphoblastic leukemia and their expression level affects patient outcome.

Expression of the NPM1 gene, encoding nucleophosmin, is upregulated in cancers. Although more than ten NPM1 transcripts are known, the reports were usually limited to one predominant transcript. In leukemia, the NPM1 expression has not been widely studied so far. In acute myeloid leukemia (AML), the mutational status of the gene seems to play a pivotal role in carcinogenesis. Therefore, the aim of the study was to quantify alternative NPM1 transcripts in two types of acute leukemia, AML and ALL (acute lymphoblastic leukemia). Using droplet digital PCR, we analyzed the levels of three protein-coding NPM1 transcripts in 66 samples collected from AML and ALL patients and 16 control samples. Using RNA-seq, we detected 8 additional NPM1 transcripts, including non-coding splice variants with retained introns. For data analysis, Welch two sample t-test, Pearsons correlation and Kaplan-Meier analysis were applied. The levels of the particular NPM1 transcripts were significantly different but highly correlated with each other in both leukemia and control samples. Transcript NPM1.1, encoding the longest protein (294 aa), had the highest level of accumulation and was one of the most abundant transcripts in the cell. Comparing to NPM1.1, the levels of the NPM1.2 and NPM1.3 transcripts, encoding a 265-aa and 259-aa proteins, were 30 and 3 times lower, respectively. All three NPM1 transcripts were proportionally upregulated in both types of leukemia compared to control samples. In AML, the levels of NPM1 transcripts decreased in complete remission and increased again with relapse of the disease. Low levels of NPM1.1 and NPM1.3 were associated with better prognosis. The contribution of non-coding transcripts to the total level of NPM1 gene seemed to be marginal, except for one short 5-end transcript accumulated at high levels in AML and control cells. Aberrant proportions of particular NPM1 splice variants could be linked to abnormal expression of genes encoding alternative splicing factors. The levels of the studied NPM1 transcripts were different but highly correlated with each other. Their upregulation in AML and ALL, decrease after therapy and association with patient outcome suggests the involvement of elevated NPM1 expression in the acute leukemia pathogenesis.

Retrospective analysis of 36 fusion genes in 2479 Chinese patients of de novo acute lymphoblastic leukemia.

Fusion genes are major molecular biological abnormalities in hematological malignancies. To depict the common recurrent gene-fusion landscape in acute lymphoblastic leukemia (ALL), 36 recurrent fusion genes in hematologic malignancies were assessed using multiplex-nested RT-PCR in 2479 patients with de novo ALL. 17 kinds of distinct fusion genes were detected in 712 (28.72%) cases. Co-occurrence of different fusion genes was observed in 6 (0.24%) patients. Incidence of fusion genes in B-ALL was significantly higher than in T-ALL (31.40% vs. 14.50%, P < 0.001). Pediatric ALL had higher prevalence of ETV6-RUNX1, TCF3-PBX1, and STIL-TAL1, while BCR-ABL1 and SET-NUP214 were more common in adult ALL. BCR-ABL1, TCF3-PBX1, KMT2A-AFF1 and ETV6-RUNX1 were more frequent in B-ALL. On the contrary, KMT2A-MLLT4, SET-NUP214 and STIL-TAL1 were of higher incidence in T-ALL. In comparison with Western cohorts, the incidence of BCR-ABL1 (5.94%) was much higher in our series, while the occurrence of ETV6-RUNX1 (13.19%) was significantly lower in pediatric B-ALL patients in our study than in Western reports. This study provides a genetic landscape of common fusion genes in ALL patients and may serve as a foundation for further improvement of a fusion gene screening panel for clinical applications.

Does socioeconomic status account for racial and ethnic disparities in childhood cancer survival

For many childhood cancers, survival is lower among non-Hispanic blacks and Hispanics in comparison with non-Hispanic whites, and this may be attributed to underlying socioeconomic factors. However, prior childhood cancer survival studies have not formally tested for mediation by socioeconomic status (SES). This study applied mediation methods to quantify the role of SES in racialethnic differences in childhood cancer survival. This study used population-based cancer survival data from the Surveillance, Epidemiology, and End Results 18 database for black, white, and Hispanic children who had been diagnosed at the ages of 0 to 19 years in 2000-2011 (n 31,866). Black-white and Hispanic-white mortality hazard ratios and 95% confidence intervals, adjusted for age, sex, and stage at diagnosis, were estimated. The inverse odds weighting method was used to test for mediation by SES, which was measured with a validated census-tract composite index. Whites had a significant survival advantage over blacks and Hispanics for several childhood cancers. SES significantly mediated the raceethnicity-survival association for acute lymphoblastic leukemia, acute myeloid leukemia, neuroblastoma, and non-Hodgkin lymphoma SES reduced the original association between raceethnicity and survival by 44%, 28%, 49%, and 34%, respectively, for blacks versus whites and by 31%, 73%, 48%, and 28%, respectively, for Hispanics versus whites ((log hazard ratio total effect - log hazard ratio direct effect)log hazard ratio total effect). SES significantly mediates racialethnic childhood cancer survival disparities for several cancers. However, the proportion of the total raceethnicity-survival association explained by SES varies between black-white and Hispanic-white comparisons for some cancers, and this suggests that mediation by other factors differs across groups.

Malignant Peritoneal Mesothelioma in an Infant With Familial ATM Mutations.

Ataxia-telangiectasia (A-T), an autosomal recessive disorder characterized by progressive neurologic dysfunction, oculocutaneous telangiectasia, immunodeficiency, and cancer susceptibility, is caused by mutations in the ATM gene. A previous study of 4 A-T patients identified 2 rare homozygous missense mutations residing on the same allele of the ATM gene c.1514T>C and c.1547T>C, which were shown to decrease ATM levels and increase T-cell acute lymphoblastic leukemia predisposition. We studied 5 patients from 2 consanguineous Bedouin families of the same tribe, presenting with A-T. Whole-exome sequencing data identified the 2 aforementioned mutations in ATM, which segregated within all family members as expected of autosomal recessive heredity. Interestingly, one individual was diagnosed with malignant peritoneal mesothelioma (MPM), an extremely rare neoplasm in pediatric patients. Here, we describe a case of a 4-month-old infant homozygous for the 2 ATM mutations, who developed MPM and died by the age of 2 years. To the best of our knowledge, this is the first case of peritoneal mesothelioma in an infant bearing ATM mutations, and one of the youngest pediatric mesotheliomas described. Thus, the risk of MPM might be considered in the follow-up of A-T patients, and ATM mutations sought in cases of early-onset MPM.

P-glycoprotein Activity Correlates With Treatment Response in 2 Leukemia Child Patients.

Acute lymphoblastic leukemia is the most important childhood cancer. Multidrug resistance is an important factor of poor prognosis. We present the P-glycoprotein (P-gp) activity in 2 patients with different outcomes. Both patients had B-cell acute lymphoblastic leukemia they were responding properly to the treatment, but one of them had an increment in the P-gp activity that correlates with an increment in the disease manifestation, the patient had to be hospitalized and developed sepsis and subsequently died. P-gp levels were correlated with disease progression. P-gp activity needs to be evaluated during treatment to assess and prevent disease relapse or the patient´s death.

Trichodysplasia Spinulosa Polyomavirus in Respiratory Tract of Immunocompromised Child.

Trichodysplasia spinulosa polyomavirus causes trichodysplasia spinulosa, a skin infection, in immunocompromised persons, but the virus is rarely detected in respiratory samples. Using PCR, we detected persistent virus in respiratory and skin samples from an immunocompromised boy with respiratory signs but no characteristic skin spicules. This virus may play a role in respiratory illness.

Is the cancer survival improvement in European and American adolescent and young adults still lagging behind that in children

Improvements during 1978 to 2006 in the 5-year survival rate of adolescents and young adults (AYAs, age 15-39) and children with cancers common to both age groups were evaluated for 1978 to 2006 in Europe and the USA. AYAs had absolute survival increases of 25% and 15% in Europe and the USA, respectively, but in both cases, AYA 5-year survival was, as of 2006, 4% lower than those in children. Acute lymphoblastic leukemia (ALL) explained most of the survival difference between AYAs and children on both the continents. In the USA, 20- to 39-year-olds with ALL have had less survival improvement than those in Europe.

Successful Use of Nilotinib in the Therapy of a Patient with a Chemoresistant Relapse of BCR-ABL1-Like Phenotype Acute Lymphoblastic Leukemia.

Relapse of acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic cell transplantation (HCT) is a therapeutic challenge. We present the case of a 20-year-old patient with a relapse of Philadelphia chromosome-negative ALL B-common over 2 years after HCT with no response to salvage chemotherapy or blinatumomab, who finally responded to a molecularly tailored therapy adjusted to the BCR-ABL1-like phenotype. The BCR-ABL1-like phenotype was diagnosed on the basis of an increased expression of ABL1 and CRLF2 genes. We combined a nilotinib-based therapy targeting the overexpressed ABL1 gene with a proteasome inhibitor and Peg-asparaginase, achieving a spectacular response the percentage of lymphoblasts in the bone marrow was reduced from 70% to 5%, which enabled a second HCT to be performed. Moreover, the relatively low toxicity of the treatment led to a good quality of life and no need for prolonged hospitalization. To our knowledge, this is the first successful use of nilotinib in BCR-ABL1-like phenotype ALL. This case should encourage routine clinical use of molecular data to individualize therapies targeting the overexpressed pathways responsible for leukemic cell proliferation, as a means to overcome chemoresistance.

Liver Complications Following Treatment of Hematologic Malignancy With Anti-CD22-Calicheamicin (Inotuzumab Ozogamicin).

Treatment of hematological malignancy with antibody-drug conjugates (ADCs) may cause liver injury. ADCs deliver a toxic moiety into antigen-expressing tumor cells, but may also injure hepatic sinusoids (sinusoidal obstruction syndrome SOS). We studied patients who received an anti-CD22calicheamicin conjugate (inotuzumab ozogamicin InO) to gain insight into mechanisms of sinusoidal injury, given that there are no CD22

CAR-T Cell Therapy for Acute Lymphoblastic Leukemia Transforming the Treatment of Relapsed and Refractory Disease.

Genetically engineered T cells expressing a chimeric antigen receptor (CAR-T) targeting specific antigens present on acute lymphoblastic leukemia (ALL) blasts have generated promising results in children and adults with relapsed and refractory disease. We review the current evidence for CAR-T cell therapy in ALL, associated toxicities, and efforts to improve durable response to therapy. CD19-directed CAR-T cells have recently been approved by the FDA for use in children and young adults with ALL and in adults with diffuse large B cell lymphoma (DLBCL) in the relapsedrefractory setting. CD22-directed CAR-T cells have shown efficacy against leukemia as well in a recent clinical trial, representing the first alternative CAR target to approach comparable efficacy to CD19 CAR-T cells. Standardization of toxicity grading and management, strategies to combat significant relapse rates after CAR-T therapy, and applicability of CAR-T cells to treat central nervous system (CNS) disease remain challenges in the field and represent priorities for continued research. CAR-T cells are a feasible, effective, and rapidly evolving therapy for patients with relapsed and refractory B cell malignancies.

The CAR-T cells are here.

Due to immunotherapy, a new era of treatment is opening up for the treatment of solid cancers and hematological tumors. T cells genetically modified with a chimeric antigen receptor (CAR-T cells) have recently been proved efficient in hematological malignancies expressing CD19. On June 20th 2018, the European Medicines Agency gave a favorable opinion on two types of anti-CD19 CAR-T cells - tisagenlecleucel and axicabtagène ciloleucel - in the management of malignant hemopathies B after two lines of treatment. Their remarkable efficacy has been demonstrated in the first clinical trials conducted in the United States, but they present new and potentially serious side effects (cytokine release syndrome, neurotoxicity, among others). However, this new class of gene therapy raises practical problems regarding its production circuit, its delivery conditions and its high cost.

Genetic polymorphisms in candidate genes are not associated with increased vincristine-related peripheral neuropathy in Arab children treated for acute childhood leukemia a single institution study.

The aim of this study was to evaluate the potential association between candidate genetic polymorphisms and vincristine-related peripheral neuropathy in Arab children with acute lymphoblastic leukemia (ALL). This is a retrospective evaluation of 133 Arab children treated for ALL at the Childrens Cancer Center of Lebanon. Incidence and severity of, as well as the timing (in weeks) at which grade 2 or higher peripheral neuropathy occurred were recorded. Genotyping for ABCB1 (rs1045642), ABCB1 (rs1128503), ABCC2 (rs717620), CEP72 (rs924607), ETAA1 (rs17032980), and MTNR1B (rs12786200) was performed. A total of 26 (19.5%) individuals developed peripheral neuropathy, three of which occurred during the induction phase. No statistically significant associations were revealed for any of the polymorphisms with either incidence of vincristine-related toxicity, toxicity severity, or time to the first episode of grade 2 or higher vincristine-related peripheral neuropathy. This study presents the first pharmacogenetic analysis of vincristine-related peripheral neuropathy in children with ALL in an Arab country. We have shown that genetic polymorphisms in candidate genes are not associated with peripheral neuropathy secondary to chronic therapy with high-dose vincristine (2 mgm) during the continuation phase. Concerning CEP72, our results are in line with the findings from the St Jude cohort of children treated for ALL with higher vincristine doses during chronic treatment. Larger high-throughput genetic analyses may be warranted to evaluate variants in other candidate genes such as CYP3A5 and reveal new nonpreviously reported alleles that may be peculiar to this region of the world.

The advances in therapy of blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy that contributes to <1% of all hematologic neoplasms. Before the introduction of various targeted agents, the therapeutic approach was based on regimens used for acute lymphoblastic or myeloid leukemia and non-Hodgkins lymphoma (e.g. hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high dose methotrexate and cytarabine) and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) -based regimens) followed by allogeneic stem cell transplantation for eligible patients. Given that this disease primarily affects older patients, there is a significant barrier to using these highly toxic regimens, even though these regimens are usually associated with the most durable response. In this review, we briefly discuss outcomes with the use of leukemia-based induction regimens as well as the use of stem cell transplant. We also review low-intensity chemotherapeutic regimens. Finally, we will describe both preclinical and early clinical data regarding novel targeted strategies for treating BPDCN without the use of cytotoxic chemotherapy, with a focus on the use of CD123 directed therapy. While the current standard treatment for BPDCN is acute leukemia-based regimen followed by hematopoietic stem cell transplantation for transplant-eligible patients, there are very promising results for CD123 directed therapies. The future of BPDCN treatment may include targeted therapies without the need for cytotoxic chemotherapy.

Juvenile xanthogranuloma A herald to the diagnosis of Erdheim-Chester disease in an adult with acute leukemia.

A 21-year-old man with B-cell acute lymphoblastic leukemia developed an eruption of multiple flesh-colored nodules and persistent fevers. A lesional biopsy showed diffuse dermal infiltrates of histiocytes, foam cells, and Touton giant cells consistent with juvenile xanthogranulomatosis. Upon further investigation, the patients constellation of findings fit criteria for Erdheim-Chester disease.

Genomic and clinical characterization of BT mixed phenotype acute leukemia reveals recurrent features and T-ALL like mutations.

The BT subtype of mixed phenotype acute leukemia (BT MPAL) is defined by co-expression of antigens of both B- and T-cell lineages on leukemic blasts. Although it has been suggested that multilineage antigen expression portends poor response to chemotherapy, the clinical characteristics and driver mutations that underlie the pathogenesis of this rare subtype of acute leukemia are scarcely known. We identified nine cases of BT MPAL from multiple institutions and correlated clinical and immunophenotypic findings with next-generation sequencing data. We report that BT MPAL commonly presents with lymphadenopathy in adolescence and young adulthood. While the tumors have diverse cytogenetic and genomic perturbations, recurrent acquired aberrations include mutations in the putative transcriptional regulator PHF6 and the JAK-STAT and Ras signaling pathways. Alterations were also identified in genes encoding hematopoietic transcription factors, cell cycle regulatorstumor suppressors, and chromatin modifying enzymes. The genomic landscape of BT MPAL strongly resembles that of T-ALL subgroups associated with early developmental arrest, while genetic alterations that are common in B-ALL were rarely seen. Two-thirds of the patients responded to ALL-based chemotherapy with or without stem cell transplantation. Our observations lay the groundwork for further study of the unique biology and clinical trajectory of BT MPAL.

Preliminary investigation on the abnormal mechanism of CD4

The current study aimed to investigate the changes and regulatory mechanism of cluster of differentiation (CD)4

The notch pathway promotes NF-κB activation through Asb2 in T cell acute lymphoblastic leukemia cells.

Oncogenic Notch1 is known to activate the NF-κB pathway in T cell acute lymphoblastic leukemia (T-ALL) and to up-regulate the transcription of Asb2α, a specificity factor for an E3 ubiquitin ligase complex that plays an important role in hematopoietic differentiation. Therefore, we hypothesize that Notch1 might regulate the NF-κB pathway through Asb2α. The study involved down-regulation of Notch1 in T-ALL cell lines (CCRF-CEM cells and MOLT-4 cells) through treatment with gamma-secretase inhibitor (GSI) as well as the modulation of Asb2 in CCRF-CEM cells and MOLT-4 cells through transduction with lentivirus carrying Here, we demonstrated for the first time that Notch1 can activate the transcription of Asb2α, which then stimulates activation of NF-κB in T-ALL cells. Asb2α exerts its effects by inducing degradation and dissociation of IκBα from NF-κB in T-ALL cells. Moreover, specific suppression of Asb2α expression can promote apoptosis and inhibit proliferation of T-ALL cells. Notch1 modulates the NF-κB pathway through Asb2α, indicating that Asb2α inhibition is a promising option for targeted therapy against T-ALL.

Extramedullary relapses of acute leukemias after allogeneic hematopoietic stem cell transplantation clinical features, cumulative incidence, and risk factors.

The aim of this study was to evaluate extramedullary (EM) relapses and its features in an allogeneic hematopoietic stem cell transplantation (alloHSCT) cohort, which consisted of patients with acute leukemia and advanced-phase chronic myeloid leukemia. One hundred and twenty-eight alloHSCT patients transplanted between the years 2001 and 2014 were analyzed. EM relapses observed in acute lymphoblastic leukemia (ALL) were more frequent than that of in acute myeloid leukemia (AML) and CML, although calculation of cumulative risk incidence, BM relapse, EM relapse, and non-relapse mortality were considered as competing risks of each other. At the 60

ETV6RUNX1-positive childhood acute lymphoblastic leukemia in China excellent prognosis with improved BFM protocol.

In childhood B-precursor acute lymphoblastic leukemia (B-ALL), the ETV6RUNX1 fusion transcript is considered to have an excellent outcome. However, few studies of children with ETV6RUNX1-positive ALL from China have been conducted. It is largely unknown whether clinical outcomes for patients with this genotype and important factors that influence such outcomes are similar to those reported in other countries. Therefore, it is important to analyze the outcomes of children with ETV6RUNX1-positive ALL treated at our institution with the aim of identifying significant prognostic variables in a Chinese population. We studied the clinical characteristics and treatment outcomes for 77 pediatric patients diagnosed with ETV6RUNX1-positive ALL between 2005 and 2015 at our institution. The 5-year event-free survival (EFS) and the disease-free survival (DFS) were reported to be 90% ± 3% and 96% ± 3% respectively. Two patients had a relapse at a median of 42 months from diagnosis and the 5-year cumulative incidence of relapse was 2.1%. Despite intensive chemotherapy or allogeneic hematopoietic cell transplantation, the 2 relapsed patients succumbed to the disease progression and the 5-year overall survival (OS) was 97% ± 2%. Multivariate analysis for EFS revealed that the minimal residual disease (MRD) ≥10 In conclusion, patients with ETV6RUNX1 fusion transcript can achieve a high rate of complete remission and the long-term curative effect was excellent under risk-stratified treatment. In case of relapse, the MRD level at the end of induction therapy should be taken into consideration while deciding the appropriate chemotherapy dosage.

Secondary acute lymphoblastic leukemia, a retrospective analysis from Washington University and meta-analysis of published data.

Secondary acute lymphoblastic leukemia (s-ALL) is rare and poorly defined and data regarding outcomes post-transplant are lacking. Here, we report a detailed analysis of s-ALL at our Institution. Among 211 eligible patients with ALL from 2006 to 2017, 30 (14%) were defined as s-ALL and the remaining as primary ALL (p-ALL). s-ALL patients were older and had higher incidence of adverse risk factors. Overall response (OR) after induction was not different between s-ALL and p-ALL (79% versus 90% respectively, p 0.106). S-ALL group had a higher risk of relapse (RFS) and death (RFS HR 1.93, 95% CI 1.2-3.12, p 0.007. OS HR 1.95, 95% CI 1.18-3.23, p 0.01). In multivariate analysis, the adverse effect of s-ALL on RFS and OS was no longer significant, however a pooled meta-analysis of our and published data indicated that s-ALL is an independent risk factor for lower OS (HR 1.30, 95% CI 1.11-1.52, p < 0.01). Myeloablative allogeneic transplantation in s-ALL was associated with lower rates of relapse and higher transplant related mortality without improvement in OS. These data indicate that s-ALL status should be considered for risk- stratification of newly diagnosed ALL. The optimal conditioning regimen for s-ALL patients undergoing allogeneic stem cell transplantation needs to be evaluated in a larger study.

Easy discrimination of hematogones from lymphoblasts in B-cell progenitor acute lymphoblastic leukemia patients using CD81CD58 expression ratio.

The discrimination of leukemia lymphoblasts (LB) in diagnosis and follow-up of B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) by multiparameter flow cytometry (MFC) may be difficult due to the presence of hematogones (HG). The aim of this study was to compare lymphoblasts of BCP-ALL and HG for the expression of the most discriminating antigens. A total of 82 bone marrow samples (39 BCP-ALL and 43 patients with HG) were analyzed using MFC. Mean fluorescence intensity (MFI) was measured for ten markers commonly used in hematology laboratories CD45, CD19, CD10, CD34, CD38, CD20, CD22, CD58, CD81, and CD123. Statistical comparison of the MFI between LB and HG was performed. The presence on LB of aberrant expression of myeloid andor T-cell markers was also investigated. Qualitative pattern expression of antigens showed overexpression on LB of CD58, CD22, CD34, CD10 and underexpression of CD81, CD45, CD38 when compared to HG. Expression of CD123 was positive in 34% of BCP-ALL LB and always absent on HG. Aberrant antigen expression (myeloid andor T-cell marker) including CD123 was observed in 58% of BCP-ALL patients. The use of a MFI antigen ratio of the most discriminating markers (CD81CD58) (analysis of variance, P < 0.005) increased the distinction of LB versus HG with a high specificity and sensitivity as demonstrated by the use of ROC curve analysis (AUC of CD81CD58 0.995). We demonstrate in this study that routine use of the MFI antigen ratio (CD81CD58) in addition to the MFC evaluation using WHO classical criteria appears to be an efficient approach to discriminate LB from HG.

Successful treatment of a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia complicated by bone marrow necrosis and acute renal insufficiency A case report.

Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) complicated by bone marrow necrosis (BMN) and acute renal insufficiency (ARI) is rare in clinical practice. The aim of the present study was to summarize the clinical characteristics and treatment methods of a case of Ph

Simultaneous B and T cell acute lymphoblastic leukemias in zebrafish driven by transgenic MYC implications for oncogenesis and lymphopoiesis.

Precursor-B cell acute lymphoblastic leukemia (pre-B ALL) is the most common pediatric cancer, but there are no useful zebrafish pre-B ALL models. We describe the first highly- penetrant zebrafish pre-B ALL, driven by human MYC. Leukemias express B lymphoblast-specific genes and are distinct from T cell ALL (T-ALL)-which these fish also develop. Zebrafish pre-B ALL shares in vivo features and expression profiles with human pre-B ALL, and these profiles differ from zebrafish T-ALL or normal B and T cells. These animals also exhibit aberrant lymphocyte development. As the only robust zebrafish pre-B ALL model and only example where T-ALL also develops, this model can reveal differences between MYC-driven pre-B vs. T-ALL and be exploited to discover novel pre-B ALL therapies.

Safety and Efficacy of VDMP Re-induction Regimen in Chinese Children with Relapsed Acute Lymphoblastic Leukemia-A Report from Jiangsu Childhood Hematology Group.

To evaluate the therapeutic safety and efficacy of VDMP re-induction regimen in Chinese children with relapsed acute lymphoblastic leukemia (ALL). Forty-one patients with relapsed ALL were prospectively enrolled in this study. All the patients were distributed in 3 childrens hospitals and treated with VDMP regimen as the first re-induction chemotherapy. Therapeutic efficacy and side-effects were analyzed. The ratio of male to female was 2714. The median age was 7.9 (2.2-15.4) years old. Patients relapsed at very early, early, and late stage were 7 cases, 11 cases, and 23 cases, respectively.The immunophenotype analysis showed that 38 cases were B-ALL, and 3 cases were T-ALL. All patients suffered from grade 4 of neutropenia and forty(97.6%) cases got infection, of them one case died. Thirty-nine(95.1%) cases had nonhematologic adverse event at least one organ involved grade 3 in 38 out of 41 cases, the VDMP therapy was completed, 34(89.5%) cases achieved a complete remission (CR), 1 case achieved partial remission(PR), and 3 cases didnt get remission. Follow-up data of 38 cases with completing VDMP chemotherapy were obtained, only one case was lost. Among 37 cases available for evaluation, 16 cases received allo-hematopoietic stem cell transplantation(allo-HSCT) after chemotherapy, and 13 patients survived, while 21 cases did not receive allo-HSCT(treated with chemotherapy only), and 8 patients survived.The overall survival rate of allo-HSCT group was significantly higher than that of those treated with chemotherapy only(P<0.05). VDMP re-induction regimen is effective and well tolerable for pafients in the treated children with relapsed ALL. After remission, allo-HSCT is recommended with the aim of long survival.

Analysis of Factors Influencing Prognosis of 87 Adults with Ph Chromosome Negative ALL.

To explore the factors influencing total complete remission (CR), recurrence, disease-free survival (DFS) rate and overall survival (OS) rate in adults with Philadelphia (Ph) chromosome negative acute lymphoblastic leukemia (ALL) and the effect of subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT) on prognosis. The clinical data of 87 adult patients with Ph negative ALL were retrospectively analyzed, the CHOP regimen plus L-asparaginase (L-Asp) was used for the induction therapy, and the CHOP modified Hyper-CVAD or methotrexate was set up as the consolidation chemotherapy regimen. After consolidation chemotherapy for 3-6 courses, 45 patients (51.72%) received allo-HSCT , and 42 patients (48.28%) continually received the maintained consolidation chemotherapy. The average follow up time of the surviving patients was 40.13 (3-60 months). Out of 87 patients with Ph Patients with central nervous system leukemia, high white blood cell count (≥100×10

Analysis of Prognostic Factors for 96 Patients with Acute Lymphoblastic Leukemia.

To investigate the clinical characteristics and clinical prognostic factors of patients with acute lymphoblastic leukemia (ALL). Ninety-six ALL patients in our hospital from June 2012 to August 2014 were selected and their clinical data were collected. The related clinical data of patients were recorded, and the relation between clinical characteristics and therapeutic efficacy was analyzed. The COX analysis was used to reveal the risk factors affecting the patients OS and DFS time. Among 96 ALL patients, 65 patients achieved complete remission (CR) after treatment. The age, immunophenotype, central nervous system leukemia (CNSL) and peripheral blood WBC count correlated with complete remission (P<0.05). The age, WBC count, platelet level, immune typing and consolidation therapy were the prognostic factors (P<0.05), the 2 year OS rate was influenced by age, WBC count, CD34 and consolidation therapy (P<0.05), the 2 year DFS rate was influenced by age, CD34 and consolidation therapy (P<0.05). Age, WBC counts, CD34 and consolidated treatment after remission are prognostic factors for ALL patients, which has guiding significance for clinical treatment of ALL.

Effect of Leukodepleted Blood Transfusions on the Balance of Th1Th2 Cells in Peripheral Blood of Patients with Acute Lymphoblastic Leukemia.

To investigate the effect of leukodepleted blood transfusions on peripheral blood Th1Th2 cell balance in patients with acute lymphoblastic leukemia (ALL). Fifty-seven ALL patients in our hospital from March 2016 to August 2017 were selected, 31 of them received routine blood transfusion were enrolled in group A, and 26 patients received depleted-blood leukotransfusion were enrolled in group B, 36 cases in normal physical examination at the same period were enrolled in control group. And the basic clinical characteristics of patients were recorded the ratio of Th1Th2 cells in peripheral blood of patients was analyzed by flow cytometrythe serum levels of IL-2, IFN-γ, IL-4, IL-10 were detected by ELISA method the mRNA levels of T-bet and GATA-3 in lymphocytes were detected by RT-PCRthe protein levels of T-bet and GATA-3 in lymphocyte were detected by Western blot. The Th1Th2 ratio in peripheral blood of ALL patients significantly related with patient age and risk grade (P<0.05).After treatment,the change of Th1Th2 ratio in group A showed no statistical difference from Th1Th2 ratio before treatment (P>0.05), while the Th1Th2 ratio in group B increased (P<0.05)the levels of IL-2, IFN-γ, IL-4 and IL-10 secreted from Th1 and Th2 cells of ALL patients in A group were not changed significantly(P>0.05), while the levels of IL-2 and IFN-γ secreted from Th1 cells of ALL patients in group B increased, the levels of IL-4 and IL-10 secreted from Th2 cells in group B decreased with statistical difference (P<0.05) the RT-PCR and Western blot showed that the expression levels of T-bet mRNA and T-bet protein in group A were lower than those in control group, while the expression levels of T-bet mRNA and T-bet protein in group B were higher than those in group A (P<0.05) the expression levels of mRNA and GATA-3 protein in group A were higher than those in control group, the expression levels of mRNA and GATA-3 protein in group B were lower than those in group A (P<0.05). The leukoreduced blood transfusion helps to improve the balance of Th1Th2 cells in peripheral blood and improve the immune function of patients, which may closely relate with the expression levels of T-bet and GATA-3.

Expression and Significance of PTEN and Survivin in Acute Lymphoblastic Leukemia.

To explore expression and significance of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and survivin in acute lymphoblastic leukemia (ALL). Peripheral blood samples were collected from 68 patients with ALL in our hospital including 48 newby diagnosed patients, 13 patients in remission, 7 patients in relapse, and 20 healthy volunteers (control). The expressions of PTEN and survivin mRNA and protein were detected by real time PCR, Western blot and respectively, and clinical pathological parameter was analyzed. The expressions of PTEN mRNA and protein in newby diagnosed, remission and relapsed group were lower than that in control group (P<0.01). The expressions of PTEN mRNA and protein in newly diagnosed and relapsed groups were lower than that in remission group (P<0.01). The expressions of survivin mRNA and protein in newly diagnosed, remission and relapsed group were higher than that in control group (P < 0.01). The expressions of survivin mRNA and protein in newly diagno sed and relapsed groups were higher than that in remission group (P < 0.01). The expressions of PTEN and survivin mRNA did not relahed with the age, sex and white blood count in ALL patients, and also did not related with the morphological classification in newly diagnosed ALL (P>0.05), but related with immunological calssification in newly diagnosed ALL (P < 0.01). The expressions of PTEN and survivin were negatively correlated in ALL (P < 0.01). PTEN and survivin play an important role in the occurrence, development and prognosis in ALL, and may be one of the potential targets for ALL treatment.

Study on Immunophenotypes and Gene of Acute Lymphoblastic Leukemia.

To retrospectively analyze the immunophenotyping, fusion gene and gene mutation of 30 acute lymphoblastic leukemia (ALL) cases and to investigate the relationship between the analysis results and the clinical therapeutic effect and prognosis. Thirty All phtients were collected from the First Hospital of Harbin, Institute of Hematology and Oncology Department of Pediatrics from August 2015 to June 2016. According to the classification of FAB standard, 27 cases were B system ALL, 3 cases were T system ALL. All patients were diagnosed by bone marrow cell morphology, immunophenotype, cytogenetics and molecular biology detetions, the differentiation antigens on membrane surface and in cytoplasm of ALL cells, and 43 kinds of fusion gene qualitative screening（BCR-ABL， AML1-ETO, PML-RARα and so on） were qualitative screened and ALL gene mutations（IKZF1, TP53, PAX5, JAK1, JAK2, CRLF2, PHF6, NOTCH1, FBXW7, PTEN）were detected by next generation sequencing(NGS). (1) Among 30 ALL patients, the incidence of B-ALL(90.00%) was higher than that of T-ALL(10.00%). (2) 27 cases of B-ALL expressed CD19, CD22, CD10, CD34 and so on. CD19 and CD22 were the most diagnostic antigens of B-ALL. (3) 3 cases of T-ALL mainly expressed cCD3, CD7, CD10, cTDT and so on cCD3 and CD7 were the most diagnostic antigens of T-ALL. (4) The quantitative screening of 30 cases of ALL 43 fusion genes found BCR-ABL,TEL-AML1 and E2A-PBX1, MLL-AF6, MLL-AF4, and SIL-TAL1 fusion gene was positive in 1 case each NGS detection of gane mutations associated with ALL showed that 3 cases of B-ALL found that TP53 mutation occured 3 casas of B-ALL, TET2 I1762V mutations in 1 cases, 3 patients (2 cases of T-ALL, 1 cases of B-ALL) showed NOTCH1 gene mutation. After a cycle of treatment, the efficacy of adult B-ALL treatment (28.57%) was significantly lower than that of child B-ALL (95.00%), and the survival rate of child B-ALL was significantly better than that of adult B-ALL until July 10, 2017, and the differences were significant. The immunophenotype technology of leukemia and molecular biology has an important guiding role in the diagnosis of leukemia, selection of treatment plan and evaluation of curative effect, and it is the complement of bone marrow cell morphology diagnosis.

Late effects in survivors of childhood acute lymphoblastic leukemia in the context of selected gene polymorphisms.

It has been shown that approximately half of survivors of childhood acute lymphoblastic leukemia (ALL) have symptomatic late effects (LE) that may be severe or life-threatening. The aim of our study was to assess the health status of childhood ALL survivors after over 10 years of follow-up and to assess its relationships with gene polymorphisms, numbers and types of LEs, as well as with intensity of chemotherapy and cranial radiotherapy (CRT). We conducted a telephone survey in 125 ALL survivors (median time from completion of treatment was 12 years) and compared the results with those obtained in our previous study. Most of the patients were followed-up by local providers. The prevalence of LEs of approximately 50% was similar in both study groups. More than one LE was found in almost 25% of patients. Endocrine LEs were less frequent than in our previous study (44% vs 22%), probably due to underdiagnosis. The prevalence of hepatitis BC decreased from 30%50 to 18% (counted together), and prevalence of neurologic LEs decreased from 18 to 6%. The increase in the rate of second malignancies was not significant (2% vs. 3%). Sixty four percent of patients continued their education at the time of the study. Approximately 51% of ALL survivors who have completed their education by the time of the study had no permanent employment, including 4 mothers of infants and 3 persons qualified for a disability living allowance. These employment problems may have been due to cognitive impairment. The offspring of the ALL survivors included 11 children, all of them healthy. Further analysis showed higher prevalence of hepatitis in patients treated with CRT (p 0.0001). Genetic studies revealed higher prevalence of hepatitis in patients homozygous for the rs9939609A variant of the FTO gene compared with other patients (p 0.03). Moreover, wild-type rs1137101 polymorphism (Q223R) of the and leptin receptor gene was more frequent in patients with psychological LEs (p 0.03). The prevalence of LEs in ALL survivors is of key importance. The transition of childhood ALL survivors from pediatric to adult care should be urgently improved to maintain continued follow-up provide high-quality care. Bioethics Committee of the Jagiellonian University approved the study protocol. Registration number KBET113B2006.

Tisagenlecleucel for the treatment of B-cell acute lymphoblastic leukemia.

Cure rates for pediatric and young adult patients with refractory or recurrently relapsed acute lymphoblastic leukemia (ALL) are dismal. Survival from time of relapse is typically measured in weeks to months, and standard chemotherapy and currently approved targeted therapy achieve remission in less than a third of affected patients. To date, the only definitive curative therapy has been allogeneic hematopoietic stem cell transplant (HSCT). Advances in immunotherapy, with the introduction of chimeric antigen receptor T-cell therapies and the development of tisagenlecleucel, have changed the landscape. Areas covered This review will describe the pharmacology of tisagenlecleucel and summarize the clinical evidence for its use in the treatment of multiple-relapsed or refractory B-cell ALL (B-ALL). Also discussed are other immunotherapies for B-ALL as well as the most commonly-encountered toxicities and corresponding management strategies. Expert commentary Early phase trials indicate that tisagenlecleucel significantly improves survival for patients with B-ALL that is refractory or in second or later relapse. In responding patients, remissions have been reported on the order of years, and thus, tisagenlecleucel may herald a dramatic shift in the treatment paradigm of this largely fatal disease.

The application of CAR-T cell therapy in hematological malignancies advantages and challenges.

Chimeric antigen receptor T cell (CAR-T cell) therapy is a novel adoptive immunotherapy where T lymphocytes are engineered with synthetic receptors known as chimeric antigen receptors (CAR). The CAR-T cell is an effector T cell that recognizes and eliminates specific cancer cells, independent of major histocompatibility complex molecules. The whole procedure of CAR-T cell production is not well understood. The CAR-T cell has been used predominantly in the treatment of hematological malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, and multiple myeloma. Solid tumors including melanoma, breast cancer and sarcoma offer great promise in CAR-T cell research and development. CD19 CAR-T cell is most commonly used, and other targets, including CD20, CD30, CD38 and CD138 are being studied. Although this novel therapy is promising, there are several disadvantages. In this review we discuss the applications of CAR-T cells in different hematological malignancies, and pave a way for future improvement on the effectiveness and persistence of these adoptive cell therapies.

Cooperative Enhancer Activation by TLX1 and STAT5 Drives Development of NUP214-ABL1TLX1-Positive T Cell Acute Lymphoblastic Leukemia.

The NUP214-ABL1 fusion is a constitutively activated tyrosine kinase that is significantly associated with overexpression of the TLX1 and TLX3 transcription factors in T cell acute lymphoblastic leukemia (T-ALL). Here we show that NUP214-ABL1 cooperates with TLX1 in driving T-ALL development using a transgenic mouse model and human T-ALL cells. Using integrated ChIP-sequencing, ATAC-sequencing, and RNA-sequencing data, we demonstrate that TLX1 and STAT5, the downstream effector of NUP214-ABL1, co-bind poised enhancer regions, and cooperatively activate the expression of key proto-oncogenes such as MYC and BCL2. Inhibition of STAT5, downregulation of TLX1 or MYC, or interference with enhancer function through BET-inhibitor treatment leads to reduction of target gene expression and induction of leukemia cell death.

CD19 Alterations Emerging after CD19-Directed Immunotherapy Cause Retention of the Misfolded Protein in the Endoplasmic Reticulum.

We previously described a mechanism of acquired resistance of B-cell acute lymphoblastic leukemia to CD19-directed chimeric antigen receptor T-cell (CART) immunotherapy. It was based on in-frame insertions in or skipping of CD19 exon 2. To distinguish between epitope loss and defects in surface localization, we used retroviral transduction and genome editing to generate cell lines expressing CD19 exon 2 variants (CD19ex2vs) bearing vesicular stomatitis virus G protein (VSVg) tags. These lines were negative by live-cell flow cytometry with an anti-VSVg antibody and resistant to killing by VSVg-directed antibody-drug conjugates (ADCs), suggestive of a defect in surface localization. Indeed, pulse-chase and α-mannosidase inhibitor assays showed that all CD19ex2vs acquired endoplasmic reticulum (ER)-specific high-mannose-type sugars but not complex-type glycans synthesized in the Golgi apparatus. When fused with green fluorescent protein (GFP), CD19ex2vs (including a mutant lacking the relevant disulfide bond) showed colocalization with ER markers, implying protein misfolding. Mass spectrometric profiling of CD19-interacting proteins demonstrated that CD19ex2vs fail to bind to the key tetraspanin CD81 and instead interact with ER-resident chaperones, such as calnexin, and ER transporters involved in antigen presentation. Thus, even the intact domains of CD19ex2vs cannot be easily targeted with ADCs or current CD19 CARTs but could serve as sources of peptides for major histocompatibility complex (MHC)-restricted presentation and T-cell receptor (TCR)-mediated killing.

A case of subacute combined degeneration of the spinal cord due to folic acid and copper deficiency.

Subacute combined degeneration of the spinal cord (SACD) is a rare neurologic disorder manifesting progressive symptoms of paresthesia and spastic paralysis. Herein we present an autopsy case of SACD caused by folic acid and copper deficiency. A 16-year-old male presented with gradually worsening unsteady gait, and bladder and rectal dysfunction. He had a medical history of T-cell acute lymphoblastic leukemia (T-ALL), diagnosed 1.5 years previously. The patient had undergone chemotherapy, including methotrexate, as well as allogeneic bone mallow transplantation. Laboratory tests revealed normal vitamin B

FOXP3 knockdown inhibits the proliferation and reduces NOTCH1 expression of T cell acute lymphoblastic leukemia cells.

Forkhead box P3 (FOXP3) is a master transcriptional factor of regulatory T-cells (Tregs). Recent studies have shown that FOXP3 is associated with growth inhibition of cancer cells. However, the role of FOXP3 in acute T-lymphoblastic leukemia (T-ALL) cells is not known. It was also reported that NOTCH signaling promoted the expression of FOXP3 in Tregs. However, the effect of FOXP3 on NOTCH expression in T-ALL cells is little known. Therefore, we examined the effect of FOXP3 knockdown on the proliferation of T-ALL cells and NOTCH1 signaling. Two T-ALL cell lines Jurkat and KOPT-K1, harboring activating NOTCH1 mutations, were transfected with small interfering RNA against FOXP3. Cell growth was assessed with a colorimetric assay and morphology was observed under a microscope. FOXP3 knockdown significantly reduced cell growth and induced morphological changes suggesting apoptosis. Quantitative polymerase chain reaction revealed that FOXP3 knockdown caused the downregulation of mRNA expression of NOTCH1 and HES1. These findings suggest that FOXP3 supports the growth of T-ALL cells although this can not be generalized because we examined only two cell lines. The observed growth suppression can be partly due to the downregulation of NOTCH1 signaling. FOXP3 may be a potential therapeutic target in T-ALL.

Combination of cabazitaxel and plicamycin induces cell death in drug resistant B-cell acute lymphoblastic leukemia.

Bone marrow microenvironment mediated downregulation of BCL6 is critical for maintaining cell quiescence and modulating therapeutic response in B-cell acute lymphoblastic leukemia (ALL). In the present study, we have performed a high throughput cell death assay using BCL6 knockdown REH ALL cell line to screen a library of FDA-approved oncology drugs. In the process, we have identified a microtubule inhibitor, cabazitaxel (CAB), and a RNA synthesis inhibitor, plicamycin (PLI) as potential anti-leukemic agents. CAB and PLI inhibited cell proliferation in not only the BCL6 knockdown REH cell line, but also six other ALL cell lines. Furthermore, combination of CAB and PLI had a synergistic effect in inhibiting proliferation in a cytarabine-resistant (REHAra-C) ALL cell line. Use of nanoparticles for delivery of CAB and PLI demonstrated that the combination was very effective when tested in a co-culture model that mimics the in vivo bone marrow microenvironment that typically supports ALL cell survival and migration into protective niches. Furthermore, exposure to PLI inhibited SOX2 transcription and exposure to CAB inhibited not only Mcl-1 expression but also chemotaxis in ALL cells. Taken together, our study demonstrates the utility of concomitantly targeting different critical regulatory pathways to induce cell death in drug resistant ALL cells.

Semaphorin-3A inhibits multiple myeloma progression in a mouse model.

Previous studies revealed that progression of multiple myeloma (MM) is associated with downregulation of semaphorin-3A (sema3A) expression in bone marrow endothelial cells. We therefore determined if serum sema3A concentrations are correlated with MM progression and if sema3A can affect MM progression. We find that the concentration of sema3A in sera of MM patients is strongly reduced and that the decrease is correlated with disease progression. A similar depletion is found in patients having acute myeloid leukemia and acute lymphoblastic leukemia but not in cancer forms that do not involve the bone marrow such as in colon cancer. Expression of a modified sema3A furin-resistant sema3A (FR-sema3A) stabilized against cleavage by furin-like proprotein convertases in CAG MM cells did not affect their behavior in-vitro. CAG cells injected into the tail vein of severe combined immunodeficient (SCID) mice home to the bone marrow and proliferate, mimicking MM disease progression. Disease progression in mice injected with CAG cells expressing FR-sema3A was inhibited, resulting in prolonged survival and a lower incidence of bone lesions. Histological examination and fluorescence-activated cell sorting analysis revealed that FR-sema3A expression reduced the infiltration of the CAG cells into the bone marrow, reduced bone marrow necrosis and reduced angiogenesis induced by the MM cells in the bone marrow. Our results suggest that measurement of sema3A serum concentrations may be of use for the diagnosis and for the monitoring of malignancies of the bone marrow such as MM. Furthermore, our results suggest that FR-sema3A may perhaps find use as an inhibitor of MM disease progression.

cAMP-mediated autophagy inhibits DNA damage-induced death of leukemia cells independent of p53.

Autophagy is important in regulating the balance between cell death and survival, with the tumor suppressor p53 as one of the key components in this interplay. We have previously utilized an

Acute lymphoblastic leukaemia with osteolytic bone lesions diagnostic dilemma.

A previously healthy 37-year-old man presented with a 10-month history of intractable back pain. On examination, there was tenderness to palpation along lower thoracic and lumbar spine. Complete blood count showed mild anaemia but was otherwise unremarkable. Imaging studies revealed compression deformities with multiple osteolytic lesions involving multiple levels of the thoracic and lumbar spine. Bone marrow aspiration and biopsy were performed and demonstrated blast cells involving 80% of the bone marrow cellularity. Findings on flow cytometry were consistent with B-lymphoblastic leukaemia. He was subsequently started on hyper-CVAD (fractionated cyclophosphamide, vincristine, Adriamycin and dexamethasone) induction chemotherapy.

Psychosocial interventions for reduction of distress in children with leukemia during bone marrow aspiration and lumbar puncture.

Children with cancer undergo many invasive medical procedures that are often painful and highly distressing, including bone marrow aspiration (BMA) and lumbar puncture (LP). Psychosocial interventions have been demonstrated to reduce childrens distress resulting from invasive medical procedures. The aim of the study is to assess the efficacy of psychosocial interventions to reduce distress in children with cancer undergoing BMA and LP in a pediatric cancer center in Taiwan. Children with cancer who received treatment between March 2015 and December 2016 at Chang Gung Memorial Hospital, Linkou, Taiwan were eligible for the study. The psychosocial intervention comprised preparation and cognitive behavioral intervention and was provided by a certified child life specialist. The assessment instrument was the revised version of the Observational Scale of Behavioral Distress (OSBD-R). The behavioral distress of patients who underwent psychosocial interventions for BMA and LP was compared with patients without interventions. We also analyzed the difference of behavioral distress in patients pre- and post-psychosocial intervention for BMA and LP. Eighteen patients were enrolled into this study. The mean age of diagnosis of leukemia was 6.6 years old (range 3-11 years). Fifteen patients were diagnosed with acute lymphoblastic leukemia, and 3 were diagnosed with acute myeloid leukemia. The mean of OSBD-R total scores in 7 patients with psychosocial intervention was significantly lower than the mean score in 6 patients without intervention (0.65 vs. 4.81, p 0.002). Pre- and post-psychosocial intervention for BMA and LP behavioral distress were evaluated for the remaining 5 patients. Consistently, there was a significant reduction of the OSBD-R score following interventions (3.04 vs. 7.81, p 0.025). Psychosocial interventions provided by a certified child life specialist have a significant potential to reduce childrens distress during BMA and LP in pediatric healthcare settings in Taiwan.

Early achievement of full donor chimerism after allogeneic hematopoietic stem cell transplantation predicts lower relapse risk in patients with acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) remains one of the most difficult-to-cure hematological malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) provides curative potential but a substantial proportion of patients eventually will relapse. It is unknown if there are any modifiable factors exists that could improve survival or predict relapse immediately after HSCT is unknown. The aim of this study was to explore whether achieving early (<30 days) full donor chimerism (FDC) could predict disease relapse after allogeneic HSCT in ALL patients. A second objective is to examine the impact of achieving early donor chimerism on survival. This study retrospectively enrolled 55 ALL patients undergoing allogeneic HSCT during the 10-year period from 1999 to 2008. Analysis of short tandem repeats (STR) was used to determine donor chimerism, and was prospectively followed at the time of engraftment and on days 30. Patients with early treatment-related mortality (<30 days), without STR analysis, or who were lost to follow-up before FDC were excluded. Survival analyses were performed using Kaplan-Meier Methods. Cox proportional hazard analyses were performed for poor prognostic factors associated with overall survival (OS) and relapse-free survival (RFS). The general characteristics were comparable between patients with early donor chimerism (n 31) and those with late donor chimerism (n 24). Survival analyses showed patients with early FDC had both lower probability of relapse (χ Our results indicate that the achievement of early FDC within 30 days after allogenic HSCT can be used as a significant predictor of RFS. The results underscored the need to improve outcome in ALL patients with late FDC.

The association between birth order and childhood leukemia may be modified by paternal age and birth weight. Pooled results from the International Childhood Cancer Cohort Consortium (I4C).

The delayed infection hypothesis states that a paucity of infections in early childhood may lead to higher risks of childhood leukemia (CL), especially acute lymphoblastic leukemia (ALL). Using prospectively collected data from six population-based birth cohorts we studied the association between birth order (a proxy for pathogen exposure) and CL. We explored whether other birth or parental characteristics modify this association. With 2.2 × 10

A Phase IIIa Trial Using CD19-Targeted Third-Generation CAR T Cells for Lymphoma and Leukemia.

The chimeric antigen receptor (CAR) T-cell therapy has been effective for patients with CD19 Fifteen patients with B-cell lymphoma or leukemia were treated with CAR T cells. The patients with lymphoma received chemotherapy during CAR manufacture and 11 of 15 were given low-dose cyclophosphamide and fludarabine conditioning prior to CAR infusion. Peripheral blood was sampled before and at multiple time points after CAR infusion to evaluate the persistence of CAR T cells and for immune profiling, using quantitative PCR, flow cytometry, and a proteomic array. Treatment with third-generation CAR T cells was generally safe with 4 patients requiring hospitalization due to adverse reactions. Six of the 15 patients had initial complete responses 411 lymphoma and 24 acute lymphoblastic leukemia (ALL), and 3 of the patients with lymphoma were in remission at 3 months. Two patients are still alive. Best predictor of response was a good immune status prior to CAR infusion with high IL12, DC-Lamp, Fas ligand, and TRAIL. Responding patients had low monocytic myeloid-derived suppressor cells (MDSCs CD14 Third-generation CARs may be efficient in patients with advanced B-cell lymphoproliferative malignancy with only modest toxicity. Immune profiling pre- and posttreatment can be used to find response biomarkers.

The clinical significance of CDX2 in leukemia A new perspective for leukemia research.

CDX2 gene encodes a transcription factor involved in primary embryogenesis and hematopoietic development however, the expression of CDX2 in adults is restricted to intestine and is not observed in blood tissues. The ectopic expression of CDX2 has been frequently observed in acute myeloid and lymphoid leukemia which in most cases is concomitant with poor prognosis. Induction of CDX2 in mice leads to hematologic complications, showing the leukemogenic origin of this gene. CDX2 plays significant role in the most critical pathways as the regulator of important transcription factors targeting cell proliferation, multi-drug resistance and survival. On the whole, the results indicate that CDX2 has the potential to be suggested as the diagnostic marker in hematologic malignancies. This review discusses the role of aberrant expression of CDX2 in the prognosis and the response to treatment in patients with different leukemia in clinical reports in the recent decades. The improvement in this regard could be of high importance in diagnosis and treatment methods.

Baseline characteristics and outcomes of children with cancer in the English-speaking Caribbean A multinational retrospective cohort.

English-speaking Caribbean (ESC) childhood cancer outcomes are unknown. Through the SickKids-Caribbean Initiative (SCI), we established a multicenter childhood cancer database across seven centers in six ESC countries. Data managers entered patient demographics, disease, treatment, and outcome data. Data collection commenced in 2013, with retrospective collection to 2011 and subsequent prospective collection. A total of 367 children were diagnosed between 2011 and 2015 with a median age of 5.7 years (interquartile range 2.9-10.6 years). One hundred thirty (35.4%) patients were diagnosed with leukemia, 30 (8.2%) with lymphoma, and 149 (40.6%) with solid tumors. A relative paucity of children with brain tumors was seen (N 58, 15.8%). Two-year event-free survival (EFS) for the cohort was 48.5% ± 3.2% 2-year overall survival (OS) was 55.1% ± 3.1%. Children with acute lymphoblastic leukemia (ALL) and Wilms tumor (WT) experienced better 2-year EFS (62.1% ± 6.4% and 66.7% ± 10.1%), while dismal outcomes were seen in children with acute myeloid leukemia (AML 22.7 ± 9.6%), rhabdomyosarcoma (21.0% ± 17.0%), and medulloblastoma (21.4% ± 17.8%). Of 108 deaths with known cause, 58 (53.7%) were attributed to disease and 50 (46.3%) to treatment complications. Death within 60 days of diagnosis was relatively common in acute leukemia 1398 (13.3%) ALL, 826 (30.8%) AML. Despite this, traditional prognosticators adversely impacted outcome in ALL, including higher age, higher white blood cell count, and T-cell lineage. ESC childhood cancer outcomes are significantly inferior to high-income country outcomes. Based on these data, interventions for improving supportive care and modifying treatment protocols are under way. Continued data collection will allow evaluation of interventions and ensure maximal outcome improvements.

Returning research results caregivers reactions following computerized cognitive training among childhood cancer survivors.

Few researchers routinely disseminate results to participants however, there is increasing acknowledgment that benefits of returning results outweigh potential risks. Our objective was to determine whether use of specific guidelines developed by the Childrens Oncology Group (COG) when preparing a lay summary would aid in understanding results. Specifically, to determine if caregivers of childhood cancer survivors found a lay summary comprehensive, easy to understand, and helpful following participation in a computerized cognitive training program. In a previous study, 68 childhood survivors of acute lymphoblastic leukemia or brain tumor with identified cognitive deficits were randomly assigned to participate in a computerized cognitive intervention or assigned to a wait list. Following conclusion of this study, participants caregivers were contacted and provided with a summary of results based on COG guidelines and survey. Forty-three participants returned the surveys, examining caregivers interpretation of the summary, reaction to the results, and information regarding preference for receiving results. Caregivers reported results as important (93%), helpful (93%), easy to understand (98%), and relevant to their child (91%). They interpreted the results as generally positive, with many caregivers endorsing satisfaction (84%) however, concern of long-term implications was expressed (25%). Most preferred receiving results through postal letter (88%) or email (47%). Benefits of returning research results to families appear to outweigh potential negative consequences. Returning results may help inform families when making future health care-related decisions. There is a great need to develop and assess the utility of guidelines for returning research results.

Incidence, outcomes, and risk factors of pleural effusion in patients receiving dasatinib therapy for Philadelphia chromosome-positive leukemia.

Dasatinib, a second-generation BCR-ABL1 tyrosine kinase inhibitor, is approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, both as first-line therapy and after imatinib intolerance or resistance. While generally well tolerated, dasatinib has been associated with a higher risk for pleural effusions. Frequency, risk factors, and outcomes associated with pleural effusion were assessed in two phase 3 trials (DASISION and 034Dose-optimization) and a pooled population of 11 trials that evaluated patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia treated with dasatinib (including DASISION and 034Dose-optimization). In this largest assessment of patients across the dasatinib clinical trial program (N2712), pleural effusion developed in 6-9% of patients at risk annually in DASISION, and in 5-15% of patients at risk annually in 034Dose-optimization. With a minimum follow up of 5 and 7 years, drug-related pleural effusion occurred in 28% of patients in DASISION and in 33% of patients in 034Dose-optimization, respectively. A significant risk factor identified for developing pleural effusion by a multivariate analysis was age. We found that overall responses to dasatinib, progression-free survival, and overall survival were similar in patients who developed pleural effusion and in patients who did not.

Cord blood-derived cytokine-induced killer cells combined with blinatumomab as a therapeutic strategy for CD19

Cytokine-induced killer cells (CIKs) are an advanced therapeutic medicinal product (ATMP) that has shown therapeutic activity in clinical trials but needs optimization. We developed a novel strategy using CIKs from banked cryopreserved cord blood units (CBUs) combined with bispecific antibody (BsAb) blinatumomab to treat CD19 CB-CIKs were expanded in vitro and fully characterized in comparison with peripheral blood (PB)-derived CIKs. CB-CIKs, like PB-CIKs, were mostly CD3 We conclude that CB-CIKs, combined with bispecific T-cell-engaging antibodies, offer a novel, effective treatment strategy for leukemia.

Association between Toxoplasma gondii exposure and paediatrics haematological malignancies a case-control study.

The possible association between Toxoplasma gondii infection and paediatric haematological malignancies in a group of patients and control subjects was evaluated in the present study. We performed an age-, gender- and residence frequency-matched case-control study of 101 blood cancer patients under 18 years of age, all of which were treated in Amirkola Pediatric Hospital. One hundred and thirty-eight control samples were gathered from the outpatient clinic in the hospital. All cases and controls were tested for the presence of anti-Toxoplasma IgG antibodies and then IgG-positive subjects were evaluated for IgM antibodies by enzyme-linked immunoassays. Anti-T. gondii IgG antibodies were found in 37 (36.6%) of the cases and 12 (8.7%) subjects in the control group (odds ratio 6.07, 95% confidence interval 2.963-12.437, P < 0.0001). The median and interquartile range (IQR) of IgG titre from case group (7.7 (IQR 0.25-13.5)) was higher than the control (0.2 (IQR 0.1-0.5)) (P < 0.0001). The frequency of anti-T. gondii antibodies (IgG) in lymphoblastic leukaemia (acute lymphoblastic leukaemia), Hodgkins lymphoma and T-cell lymphoma were 33 (31.9%), 3 (50%) and 1(100%), respectively. Anti-T. gondii IgM was not detected in the IgG-positive patients in case group. In the case subjects, no significant difference was seen in the positive rates of T. gondii infection between genders (37.3% in male 35.7% in female P 0.52) and ages groups (P 0.31). This study demonstrated that T. gondii infection is prevalent in children with blood cancer. It also showed that toxoplasmosis may possibly be linked with an increased risk of childhood haematologic malignancies. Furthermore, these results may be helpful in research on blood neoplasia aetiology.

Advances in the genetics of acute lymphoblastic leukemia in adults and the potential clinical implications.

Acute lymphoblastic leukemia (ALL) is a clonal disease of the hematopoietic system characterized by unique genetic characteristics. The significance of these genetic features has evolved over the past three decades. In the 1980s and 1990s, the primary interest was in excluding the Philadelphia chromosome a finding more common in older adults which uniformly predicted for a rapidly fatal outcome. Areas covered Over the past 15 years, much has evolved. Tyrosine kinase inhibitors completely changed the prognosis of Ph-positive ALL. In addition, the genetic characterization of Ph-negative ALL has significantly advanced through systematic progressive analyses of genetic data from large trial groups. These led to specific and more accurate prognostication, particularly at initial diagnosis. Expert commentary These cytogenetic and molecular features will be reviewed in this paper and their ongoing significance will be critically analyzed in the era of minimal residual disease (MRD) determination, which has now superseded all the major known historic prognostic factors.

Physcion 8-O-β-glucopyranoside exhibits anti-leukemic activity through targeting sphingolipid rheostat.

Acute lymphoblastic leukemia (ALL) is the most common fatal cancer in people younger than 20 years of age. This study was designed to explore the anti-leukemia activity of physcion 8-O-β-glucopyranoside (PG) in B-cell ALL. NALM6 and SupB15 cells were used as model cell lines. Cell viability, cell apoptosis, cell cycle distribution were determined by CCK-8 assay, DNA fragmentation assay and flow cytometry, and flow cytometry, respectively. Expression of proteins involved in cell apoptosis and cell cycle regulation was determined by western blot and the levels of ceramide and sphingosine 1-phosphate (S1P) were determined by ELISA. Activity of sphingosine kinase 1 (SphK1) was also determined with a Sphingosine Kinase Assay Kit. In the present study, both model cell lines were transfected with siRNA targeting SphK1 or an overexpression plasmid to examine the role of SphK1 in the anti-leukemia activity of PG. Moreover, the efficacy of PG was examined in vivo in a mouse model by measuring survival and spleen weight. Our results provided experimental evidence that PG could significantly induce apoptosis and cell cycle arrest in vitro. Mechanistically, the anti-leukemia activity of PG was mediated by its ability to repress SphK1 and thus modulate ceramide-S1P rheostat. Moreover, the anti-leukemia activity of PG was also verified in a murine model. Collectively, our results indicate that PG may be a promising agent for the treatment of B-cell leukemia.

Zinc-chitosan nanoparticles induced apoptosis in human acute T-lymphocyte leukemia through activation of tumor necrosis factor receptor CD95 and apoptosis-related genes.

Chitosan (CS), a novel biomaterial is widely used as a drug nano-carrier for cancer treatments. Towards this aim, anticancer and antibacterial activities of CS-nanoparticles-linked zinc (Zn-CSNPs) were evaluated. The particle size of CSNPs was lowered (113.09 nm) compared to Zn-CSNPs (160.7 nm). Both nanoparticles (CSNPs and Zn-CSNPs) were spherical in shape, polydispersive and homogenous. Fourier transforms infrared spectrophotometer (FTIR) and energy dispersive X-ray spectroscopy (EDX) analysis confirmed the different molecular arrangement of NPs and the presence of Zn in Zn-CSNPs and CS in both NPs, respectively. Zn-CSNPs had higher inhibitory activity against tested pathogens with a minimal inhibitory concentration (MIC) of 9.25-13.5 μg·mL

Inotuzumab Ozogamicin A Review in RelapsedRefractory B-Cell Acute Lymphoblastic Leukaemia.

The intravenous CD22-directed antibody drug conjugate inotuzumab ozogamicin (Besponsa

Anti-CD37 chimeric antigen receptor T cells are active against B- and T-cell lymphomas.

Chimeric antigen receptor (CAR) T cells have emerged as a novel form of treatment of patients with B-cell malignancies. In particular, anti-CD19 CAR T-cell therapy has effected impressive clinical responses in B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma. However, not all patients respond, and relapse with antigen loss has been observed in all patient subsets. Here, we report on the design and optimization of a novel CAR directed to the surface antigen CD37, which is expressed in B-cell non-Hodgkin lymphomas, in chronic lymphocytic leukemia, and in some cases of cutaneous and peripheral T-cell lymphomas. We found that CAR-37 T cells demonstrated antigen-specific activation, cytokine production, and cytotoxic activity in models of B- and T-cell lymphomas in vitro and in vivo, including patient-derived xenografts. Taken together, these results are the first showing that T cells expressing anti-CD37 CAR have substantial activity against 2 different lymphoid lineages, without evidence of significant T-cell fratricide. Furthermore, anti-CD37 CARs were readily combined with anti-CD19 CARs to generate dual-specific CAR T cells capable of recognizing CD19 and CD37 alone or in combination. Our findings indicate that CD37-CAR T cells represent a novel therapeutic agent for the treatment of patients with CD37-expressing lymphoid malignancies.

Inotuzumab ozogamicin a CD22 mAb-drug conjugate for adult relapsed or refractory B-cell precursor acute lymphoblastic leukemia.

Despite improved rates of remission and cure in newly diagnosed adult acute lymphoblastic leukemia (ALL), the prognosis for patients with relapsed or refractory disease remains poor and the 5-year overall survival rate after relapse is under 10%. A recent paradigm shift has focused on the promise of targeted immunotherapy rather than standard chemotherapy, as ALL blast cells express a variety of antigens, and monoclonal antibodies may be developed to identify and destroy the leukemic cells. Inotuzumab ozogamicin is a CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin. CD22 expression is detected on leukemic blasts in over 90% of patients with ALL. Based on promising results from preclinical studies, inotuzumab ozogamicin was tested in Phase 12 and Phase 3 clinical trials and it demonstrated improved complete remission rates, progression-free survival and overall survival in relapsed or refractory adult ALL compared to standard therapy. Ongoing studies are evaluating the value of inotuzumab ozogamicin when given in combination with chemotherapy as part of upfront treatment. This review discusses the drugs biochemical properties and mechanism of action, preclinical research outcomes, clinical trial results, adverse events and toxicities, drug approval and ongoing investigations.

High-mobility group box 1 protein-mediated necroptosis contributes to dasatinib-induced cardiotoxicity.

Dasatinib shows remarkable activity against imatinib-refractory chronic myelogenous leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph

Psychological risk in long-term survivors of childhood acute lymphoblastic leukemia and its association with functional health status A PETALE cohort study.

Recent research has suggested that long-term pediatric cancer survivors were at risk of important physical and psychological morbidities. To date, we do not know to what extent functional health status contributes to psychological risk and which domains are most important. The aim of this study was to systematically explore which functional domain could explain anxiety, depression, and distress symptoms. We used data available for 105 adolescents and 182 adults successfully treated for childhood acute lymphoblastic leukemia at two Canadian sites part of the PETALE cohort. Participants were ≥5 years postdiagnosis, aged 22 ± 6 years, 52% female, and 49% acute lymphoblastic leukemia high-risk status. The contribution of health functional status (15D16D questionnaires) to self-reported anxiety, depression, and distress (Beck scales and distress thermometer) was evaluated using adjusted logistic regression models. Prevalence rates found for mild-severe anxiety, depression, and distress were 14%, 21%, and 30% among adolescents and 27%, 20%, and 19% among adults. Frequent health domains associated with psychological risk were sleeping and breathing in adolescents, and vitalityfatigue, discomfortsymptoms, mental function, and sleeping in adults. Mental function was systematically associated with psychological risk across age groups (median OR 10.00, 95% CI 3.01-33.71). Exploratory mediation bootstrapping analyses suggested that the effect on psychological risk of overall health status and mental function problems was partly explained by socialworkschool functioning. The results identified important functional health domains that could be targeted for interventions preventing psychological risk vitalityfatigue, discomfortsymptoms, sleeping, and mental function issues. Health domains probably affect mood partly by limiting socialworkschool functioning.

Tisagenlecleucel for B-Cell Acute Lymphoblastic Leukemia and Diffuse Large B-Cell Lymphoma — Project Protocol, Implementation and Ethics Section

Tisagenlecleucel is a new chimeric antigen receptor (CAR) T-cell therapy that may offer clinical benefit for adults with relapsed or refractory diffuse large B-cell lymphoma and children and young adults (25 years or younger) with relapsed or refractory acute lymphoblastic leukemia. It is a multi-stage procedure involving T-cell harvesting, transportation and storage, and manufacturing (which involves modifying the DNA of harvested T cells to include CARs), and then reinfusion. The purpose of this analysis is to support decision-making relating to the provision of tisagenlecleucel in Canadian health care systems. The purpose of the ethics review is to identify, describe, and provide guidance on key ethical considerations in the implementation and provision of tisagenlecleucel for adults with relapsed or refractory diffuse large B-cell lymphoma and children and young adults with relapsed or refractory acute lymphoblastic leukemia. The issues raised in this review necessarily go beyond narrowly defined ethical concerns to encompass broader legal, social, and cultural considerations, as well. It is common in the ethics literature, across a broad range of health-related issues, to refer to ELSI —ethical, legal, and social issues — when addressing broader values and related considerations. While the primary emphasis here will be on ethical considerations, legal and social issues may also figure in the analysis.

LiverTox Clinical and Research Information on Drug-Induced Liver Injury

Inotuzumab ozogamicin is a humanized monoclonal antibody-cytotoxin conjugate which is used in the therapy of refractory or relapsed acute lymphoblastic leukemia. Inotuzumab ozogamicin has been linked to frequent serum enzyme elevations during therapy and with instances of clinically apparent acute liver injury, including acute sinusoidal obstruction syndrome which can be severe and even fatal.

Kala-Azar and leukemia A rare association.

Visceral leishmaniasis is an infectious disease that infects and multiplies in macrophages of the liver, spleen, and bone marrow. The most common clinical features are fever, splenomegaly, and anemia. Anemia, leucopenia, and thrombocytopenia are the main hematologic abnormalities commonly seen in visceral leishmaniasis. These findings can be seen in several types of hematologic disorders. The findings are similar to most hematologic disorders and so may make diagnosis problematic. It is difficult to confirm when it is seen except in epidemiologic areas. It can be fatal if it is not treated and appropriate treatment can be lifesaving. In this article a 12 year-old male patient who was followed-up with diagnosis of acute lymphoblastic leukemia and received maintenance therapy while being under remission after BFM-ALL-2000 treatment protocol and diagnosed with hemophagocytic lymphohistiocytosis due to Kala-azar during this period was presented.

Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy.

In 2017, an autologous chimeric antigen receptor (CAR) T cell therapy indicated for children and young adults with relapsed andor refractory CD19

Chylothorax in children with cancer A milky predicament.

Chylothorax is an uncommon complication in children. Although surgery and trauma are the most common causes encountered, hematological as well as solid malignancies can present with chylothorax. This study aimed to describe the presentation and management of malignant chylothorax in children. This is a case series from a pediatric hematology-oncology unit. Chylothorax was diagnosed by demonstrating high triglyceride content in the pleural fluid and a low cholesterol concentration in relation to the serum cholesterol. Cytology for malignant cells and investigations for tuberculosis were performed in all patients. Initial management included placement of an intercostal tube and administration of a fat-free diet with the addition of medium-chain triglycerides. Appropriate treatment of the underlying malignancy was initiated simultaneously. Three children with diagnoses of Stage IV neuroblastoma, lymphoblastic lymphoma, and Hodgkin lymphoma developed chylothorax. Malignant cytology was positive in the patient with T-NHL. All patients were found to have associated hypoproteinemia and hypoalbuminemia. The chylothorax resolved with conservative measures in two patients. It remained intractable in the child with T-NHL, in whom the lymphoma was refractory to chemotherapy. Chylothorax is a rare but challenging complication that can accompany childhood malignancies. Surgical interventions, radiotherapy, and pleurodesis are alternatives if the chylothorax is refractory to medical management.

Clinicoepidemiological profiles, clinical practices, and the impact of holistic care interventions on outcomes of pediatric hematolymphoid malignancies - A 7-year audit of the pediatric hematolymphoid disease management group at Tata Memorial Hospital.

The Pediatric Hematolymphoid Disease Management Group (PHL-DMG) at a tertiary cancer care hospital developed extensive patient support programs to improve retention and outcomes while focusing on protocols adapted to meet patient needs. An audit of measures and outcomes was done for a 7-year period from January 2010 to December 2016. DMG protocols and patient support activities over the study period were documented and audited. Data was retrieved from internal databases and records. Measures taken and their impact were assessed by descriptive analytical tools. Survival outcomes were calculated using Kaplan-Meier method on SPSS v. 24™ software. Holistic patient support measures were undertaken through a charitable foundation entirely under pediatric oncology. Activities included infrastructure growth, socioeconomic support, provision of accommodation, nutrition, education, and multiple blood component donation drives. Patient registrations increased from 502 in 2009 to 874 in 2016, with the steepest rise in acute lymphoblastic leukemia (ALL) - 330 (2009) to 547 (2016). Treatment refusal and abandonment rates decreased from 32% to 3.4% over the same period, and male to female ratio decreased from 2.56 to 2.281. Early mortality in acute myeloid leukemia (AML) fell within 2 years from 26.7% in 2009 to 7%. Five-year overall survival (OS) was 69.5% for all patients registered in 2010, whereas disease-specific 5-year OS was ALL 67.1%, AML 49.3%, chronic myeloid leukemia 100%, Hodgkin lymphoma 90.4%, and non-Hodgkin lymphoma 74.2%. Holistic patient support-specific activities and adapted protocols made a measurable impact on patient outcomes. High survival outcomes of patients have been achieved despite relatively few receiving salvage therapies or stem cell transplant.

Ezh2 loss propagates hypermethylation at T cell differentiation-regulating genes to promote leukemic transformation.

Early T cell precursor acute lymphoblastic leukemia (ETP-ALL) is a new pathological entity with poor outcomes in T cell ALL (T-ALL) that is characterized by a high incidence of loss-of-function mutations in polycomb repressive complex 2 (PRC2) genes. We generated a mouse model of ETP-ALL by deleting Ezh2, one of the PRC2 genes, in p53-null hematopoietic cells. The loss of Ezh2 in p53-null hematopoietic cells impeded the differentiation of ETPs and eventually induced ETP-ALL-like disease in mice, indicating that PRC2 functions as a bona fide tumor suppressor in ETPs. A large portion of PRC2 target genes acquired DNA hypermethylation of their promoters following reductions in H3K27me3 levels upon the loss of Ezh2, which included pivotal T cell differentiation-regulating genes. The reactivation of a set of regulators by a DNA-demethylating agent, but not the transduction of single regulator genes, effectively induced the differentiation of ETP-ALL cells. Thus, PRC2 protects key T cell developmental regulators from DNA hypermethylation in order to keep them primed for activation upon subsequent differentiation phases, while its insufficiency predisposes ETPs to leukemic transformation. These results revealed a previously unrecognized epigenetic switch in response to PRC2 dysfunction and provide the basis for specific rational epigenetic therapy for ETP-ALL with PRC2 insufficiency.

Nutritional Intervention for a Patient with Acute Lymphoblastic Leukemia on Allogeneic Peripheral Blood Stem Cell Transplantation.

Hematopoietic stem cell transplantation (HSCT) causes many complications such as anorexia, nausea, vomiting, diarrhea, and mucositis. Most patients undergoing HSCT have risk for malnutrition in the process of transplantation so artificial nutrition support is required. The purpose of this case report is to share our experience of applying nutrition intervention during the transplantation period. According to HSCT process, the change of the patients gastrointestinal symptoms, oral intake and nutritional status was recorded. By encouraging oral intake and providing parenteral nutrition, the patient had only 0.3%, losing weight during the transplantation period. In conclusion, it emphasized that the nutritional status changes during the HSCT period should be closely monitored and nutritional management through appropriate nutritional support and interventions in hospital and after discharge.

Genetic basis of pediatric T-cell acute lymphoblastic leukemia and its clinical impact.

Despite an improvement in the prognosis of pediatric T-cell acute lymphoblastic leukemia (T-ALL), the outcome of patients with relapse or refractory T-ALL remains dismal. Activating mutations of the NOTCH pathway and the loss-of-function mutations of CDKN2A are frequent genetic alterations in T-ALL however, these changes exert no prognostic impact. Furthermore, several gene fusions, including STIL-TAL1, were recently detected in T-ALL however, other genetic events are necessary for the development of T-ALL. Recently, we detected novel recurrent SPI1 fusions in T-ALL by RNA sequencing using next-generation sequencing technology. Patients with SPI1 fusions revealed highly poor prognosis, suggesting that these fusions would be useful prognostic markers in T-ALL. Furthermore, the intensification of treatment of patients with SPI1 fusions may contribute to the improvement of the outcome of patients with T-ALL.

Understanding of molecular pathogenesis of T-cell leukemia by super-enhancer profiling.

Super-enhancers comprise of clusters of enhancers that are typically defined by the ChIP-seq analysis for active histone marks. Although the biological significance of super-enhancers is still controversial, this concept is gaining prominence as useful characteristics of genes that play crucial roles in normal development and pathogenesis of cancer. In various cancer cells, super-enhancers are often associated with genes involved in carcinogenesis. For example, in T-cell acute lymphoblastic leukemia, the oncogenic transcription factor TAL1 and its regulatory partners (GATA3, RUNX1 and MYB) are regulated by super-enhancers these genes are sensitive to transcriptional inhibition, for example, via the pharmacological approach using a small-molecule CDK7 inhibitor. This preferential inhibition of cancer genes can also be observed for other types of cancer. Based on these findings, we recently performed super-enhancer profiling combined with gene expression analysis in adult T-cell leukemialymphoma, which is a genetically complicated hematological malignancy, to identify critical genes responsible for the pathogenesis. This review article aims to discuss the concept of super-enhancers, their significance in biomedical research, and their potential utility in elucidating the molecular pathogenesis of cancer.

FGFR1-mutated B-cell acute lymphoblastic leukemia transforming to myelodysplastic myeloproliferative neoplasm and acute myeloid leukemia.

A 77-year-old male with hyperleukocytosis and thrombocytopenia was diagnosed with Philadelphia chromosome (Ph) -negative B-cell acute lymphoblastic leukemia (ALL) he was treated with induction chemotherapy. Despite an initial complete remission, hyperleukocytosis was returned 18 months later. A bone marrow smear revealed a substantial increase in the number of myeloid cells with each stage of differentiation, which was markedly different from the initial presentation, resulting in the diagnosis of Ph-negative myelodysplastic syndromemyeloproliferative neoplasm (MDSMPN). After a month, an autopsy revealed that the disease had progressed to acute myelogenous leukemia (AML). Since the first diagnosis, a chromosomal translocation, t (813) (p12q12), was identified this was subsequently confirmed by fluorescence in situ hybridization (FISH) analysis to comprise a genomic rearrangement of the fibroblast growth factor receptor 1 (FGFR1) gene. Collectively, this is a rare case of a myeloidlymphoid neoplasm with an FGFR1 genomic rearrangement that initially presented as B-cell ALL, before developing into MDSMPN and finally into AML. In the literature, although a transformation of MPN into ALL is often reported, the transformation of B-cell ALL into MPN is an infrequent event.

Novel Therapies in Acute Lymphoblastic Leukemia.

Treatment options for patients with acute lymphoblastic leukemia (ALL) beyond standard chemotherapy have grown significantly in recent years. In this review, we highlight new targeted therapies in ALL, with an emphasis on immunotherapy. Major advances include antibody-based therapies, such as naked monoclonal antibodies, antibody-drug conjugates and bispecific T cell engaging (BiTE) antibodies, as well as adoptive cellular therapies such as chimeric antigen receptor (CAR) T cells. Apart from the above immunotherapeutic approaches, other targeted therapies are being employed in Philadelphia chromosome-positive (Ph) ALL, Philadelphia-like (Ph-like) ALL, and T cell ALL. These new treatment strategies are changing the treatment landscape of ALL and challenging the current standard of care. Clinical trials will hopefully help determine how to best incorporate these novel therapies into existing treatment algorithms.

Transcriptional activation of the miR-17-92 cluster is involved in the growth-promoting effects of MYB in human Ph-positive leukemia cells.

MicroRNAs, non-coding regulators of gene expression, are likely to function as important downstream effectors of many transcription factors including MYB. Optimal levels of MYB are required for transformationmaintenance of

Ultrasound-based cell sorting with microbubbles A feasibility study.

The isolation and sorting of cells is an important process in research and hospital labs. Most large research and commercial labs incorporate fluorescently or magnetically labeled antibodies adherent to cell surface antigens for cell identification and separation. In this paper, a process is described that merges biochemical labeling with ultrasound-based separation. Instead of lasers and fluorophore tags, or magnets and magnetic particle tags, the technique uses ultrasound and microbubble tags. Streptavidin-labeled microbubbles were mixed with a human acute lymphoblastic leukemia cell line, CCL 119, conjugated with biotinylated anti-CD7 antibodies. Tagged cells were forced under ultrasound, and their displacement and velocity quantified. Differential displacement in a flow stream was quantified against erythrocytes, which showed almost no displacement under ultrasound. A model for the acoustic radiation force on the conjugated pairs compares favorably with observations. This technology may improve on current time-consuming and costly purification procedures.

Philadelphia-like acute lymphoblastic leukemia diagnostic dilemma and management perspectives.

Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy characterized by suboptimal outcomes in the adult age group. Recently, a new subtype called Philadelphia (Ph)-like ALL has been described. This subgroup is characterized by high cytokine receptor and tyrosine kinase signaling expression, resulting in kinase activation through stimulation of two main pathways, the ABL and JAKSTAT pathways. The diagnostic method or approach for Ph-like ALL is still not standardized and efforts are ongoing to identify an easy and applicable diagnostic method. Accurate and standard testing approaches are much needed and this will facilitate better understanding of this subgroup, including better estimation of the prevalence and incidence in different age groups and the clinical outcomes of such new entity. Here, we review the currently available diagnostic tools, activated pathways, and different therapeutic approaches used to target this subgroup.

Long-term Effects of Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients with Acute Lymphoblastic Leukemia.

Allogeneic hematopoetic stem cell transplantation (HSCT) is a curative option for children and adolescents with high-risk leukemia. Although acute complications were reduced during the last decade, considerable late effects are still limiting the overall success rate. This article emphasizes the specific pediatric aspects of long-term aftercare following myeloablative HSCT and provides an organ-based overview that covers main clinical patterns, incidence, and risk factors enhanced by current references and screening guidelines. In the last years, several attempts were made to separate pediatric outcome data from findings in adults. It turned out that not only the indication for but also the time and the procedures of HSCT substantially differ. Nearly any organ might be affected after the complex transplantation process and includes endocrinopathies, musculoskeletal disorders, cardiopulmonary complications, and secondary malignancies. Patients after HSCT in childhood have a high risk for developing a wide range of late sequelae and may benefit from regular screening and early intervention. The occurrence and patterns of late effects depend on the intensity and severity of conditioning and are strongly associated with patients age at transplant and beginning of complications.

Protective Role of Silymarin in Early Doxorubicin-induced Cardiac Dysfunction in Children with Acute Lymphoblastic Leukemia.

Doxorubicin is a well-established chemotherapeutic agent for the treatment of childhood acute lymphoblastic leukemia (ALL), but its efficacy is often limited by its related cardiotoxicity. Protection against doxorubicin-induced cardiotoxicity can be of great value, especially for children. Silymarin has a potent antioxidant property that can be helpful in preventing cardio-toxicity. To assess the possible protective role of silymarin against early doxorubicin-induced cardiotoxicity in children with ALL. This study was conducted on 80 children with ALL, including 40 patients under doxorubicin therapy and silymarin 420 mgday for one week after each doxorubicin dose starting from the day of doxorubicin infusion (Group I) and 40 patients under doxorubicin therapy and placebo (Group II). Conventional echo-Doppler measures of left ventricular systolic and diastolic functions and pulsed wave tissue Doppler of lateral mitral annulus were done for all patients. After doxorubicin therapy, there was a significant higher reduction of systolic function ejection fraction (EF), fraction shortening (FS) and s wave in Group II compared with Group I and non-significant reduction of diastolic function EA ratio or ea ratio in both Groups. Although serum troponin increases in both groups after doxorubicin therapy, the increase of troponin is significantly lower in group I compared with group II. Silymarin decreased early Doxorubicin-induced left ventricular systolic function disturbances and can be recommended as an adjuvant drug in patients with ALL under doxorubicin therapy. Multicenter studies on a large number of patients with longer follow up periods to prove the protective role of silymarin in early and late Doxorubicin-induced cardiotoxicity.

BCL2 inhibitor ABT-199 and JNK inhibitor SP600125 exhibit synergistic cytotoxicity against imatinib-resistant Ph ALL cells.

Imatinib (IMT), a specific tyrosine kinase inhibitor (TKI), has drastically changed the treatment strategy for Ph ALL (Philadelphia chromosome-positive acute lymphoblastic leukemia). However, TKI resistance remains a serious problem for patient prognosis. Here, a Ph ALL cell line NphA2 and the IMT-resistant subline NphA2STIR were analyzed to identify a potential novel treatment strategy. We also examined other Ph ALL cells, MR87 and its IMT-resistant subline, MR87STIR. IMT induced apoptosis of NphA2 and MR87 but had no effect on resistant sublines. Increased phosphorylated ERK and BCL2, but not BCL-XL, were observed in NphA2STIR compared with NphA2. NphA2STIR but not NphA2 was moderately sensitive to U0126, an ERK inhibitor. Interestingly, SP600125, a JNK inhibitor, was potent in cell growth inhibition and apoptosis induction of both parental and IMT-resistant NphA2 and MR87 cells. Moreover, NphA2 and MR87 and their IMT-resistant sublines were sensitive to ABT-199, a specific BCL2 inhibitor. The combination of SP600125 and ABT-199 synergistically suppressed both parental and IMT-resistant cells, including one with T315I mutation, suggesting that Ph ALL exhibits high sensitivity to ABT-199 and SP600125 regardless of TKI resistance. This combination might be a possible therapeutic strategy for Ph ALL in the future.

Drug resistant epilepsy with mesial temporal sclerosis as possible late neurological complication in two AML survivors after stem cell transplantation.

•Mesial temporal sclerosis (MTS) is a potential late complication of hematological malignancies.•Seizures are usually drug resistant with MTS yet seizure freedom may be achieved by surgery.•Early evaluation for epilepsy surgery is warranted for drug resistant seizures due to AML.

Venetoclax Targeting BCL2 in Hematological Cancers.

Over the last years, targeted anti-cancer therapy with small-molecule inhibitors and antibodies moved to the forefront as a strategy to treat hematological cancers. These novel agents showed outstanding effects in treatment of patients, often irrespective of their underlying genetic features. However, evolution and selection of subclones with continuous treatment leads to disease relapse and resistance toward these novel drugs. Venetoclax (ABT-199) is a novel, orally bioavailable small-molecule inhibitor for selective targeting of B-cell lymphoma 2 (BCL2). Venetoclax is in clinical development and shows high efficacy and safety in particular in the treatment of chronic lymphocytic leukemia (CLL), but preliminarily also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). The most important and impressive outcomes of venetoclax treatment include a rapid induction of apoptosis and drastic reduction of the tumor bulk within a few hours after administration. Venetoclax was approved by the FDA and EMA in 2016 for patients with previously treated CLL with del(17p13) and patients failing B cell receptor signaling inhibitors (EMA only), on the basis of a single-arm phase II trial demonstrating a tremendous response rate of 79% with complete remission in 20% of cases and an estimated 1-year progression-free survival of 72%. This review focuses on the mode of action, the preclinical models, and outcomes from various clinical trials with venetoclax in different hematologic cancers as well as future development.