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The depletion of PHF6 decreases the drug sensitivity of T-cell acute lymphoblastic leukemia to prednisolone.

Mutation of PHF6 has been identified in Börjeson-Forssman-Lehmann syndrome and some types of subsets of childhood leukemia. However, the molecular function and the relationship of PHF6 mutation with glucocorticoid drug resistance during T-ALL treatment remains elusive. Here we report the influence of PHF6 expression on the drug response of T-ALL to prednisolone, and the underlying mechanism of this. Through sanger sequencing and western blotting assays, we identified two T-ALL cell lines with wild-type PHF6 expression, including SIL-ALL and CCRF-CEM, and two T-ALL cell lines without PHF6 expression, including TALL-1 and HPB-ALL, due to the nonsense and frameshift mutations in the coding region of PHF6. MTT assays showed that SIL-ALL and CCRF-CEM were much more sensitive to prednisolone. However, TALL-1 and HPB-ALL were much more resistance to prednisolone. Further knockout of PHF6 led to the resistant of both SIL-ALL and CCRF-CEM cells to prednisolone. On the contrary, the correction of the PHF6 point mutation in HPB-ALL cells with CRISPR-CAS9 method increased the sensibility of both cell lines to prednisolone. Then we found that PHF6 repress p21 expression through direct binding and recruiting RBPP4 to its promoter region. Finally, the co-treatment of p21 inhibitor increased the sensitivity of TALL-1 and HPB-ALL cells to prednisolone. Collectively, our findings not only enrich our understanding of the relationship between PHF6 mutation and drug resistance but also indicate a new therapeutic potential for those T-ALL patients containing the PHF6 mutation.

TCF7L2 activated HOXA-AS2 decreased the glucocorticoid sensitivity in acute lymphoblastic leukemia through regulating HOXA3EGFRRasRafMEKERK pathway.

Acute lymphoblastic leukemia (ALL) is characterized by abnormal lymphoblasts accumulation in the bone marrow and blood. Despite great efforts have been made in exploring novel therapeutic method, the prognosis of children with ALL is still unsatisfied. Glucocorticoid (GC) resistance is a great obstacle for the clinical treatment of ALL. Therefore, it is essential to investigate the molecular mechanism underlying the GC resistance. According to previous reports, long noncoding RNAs (lncRNAs) are involved in drug resistance of various human cancers. LncRNA HOXA cluster antisense RNA2 (HOXA-AS2) has been reported in several human malignancies due to its oncogenic property. However, the molecular mechanism of HOXA-AS2 involved in the GC resistance of ALL still needs to be further clarified. At first, we found that lncRNA HOXA-AS2 was highly expressed both in prednisone insensitive ALL cell lines and patient samples. Gain or loss-of-function assays revealed that HOXA-AS2 enhanced GC resistance via promoting cell proliferation and inhibiting cell apoptosis. Furthermore, we validated that HOXA-AS2 upregulated HOXA3, thereby activating EGFRRasRafMEKERK signaling pathway. Our findings showed that HOXA-AS2 may be a potential therapeutic target for ALL patients with poor GC resistance.

Cost-Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Pediatric RelapsedRefractory B-Cell Acute Lymphoblastic Leukemia.

Chimeric antigen receptor T-cell (CAR-T) therapy is a promising new class of cancer therapy but has a high up-front cost. We evaluated the cost-effectiveness of CAR-T therapy among pediatric patients with relapsedrefractory B-cell acute lymphoblastic leukemia (B-ALL). We built a microsimulation model for pediatric patients with relapsedrefractory B-ALL receiving either CAR-T therapy or standard of care. Outcomes included costs, quality of life (health utility), complications, and survival. We measured cost-effectiveness with the incremental cost-effectiveness ratio (ICER), with ICERs under $100 000 per quality-adjusted life-year (QALY) considered cost effective. One-way and probabilistic sensitivity analyses were used to test model uncertainty. Compared to standard of care, CAR-T therapy increased overall cost by $528 200 and improved effectiveness by 8.18 QALYs, resulting in an ICER of $64 600QALY. The model was sensitive to assumptions about long-term CAR-T survival, the complete remission rate of CAR-T patients, and the health utility of long-term survivors. The base model assumed a 76.0% one-year survival with CAR-T, although if this decreased to 57.8%, then CAR-T was no longer cost effective. If the complete remission rate of CAR-T recipients decreased from 81% to 56.2%, or if the health utility of disease-free survivors decreased from 0.94 to 0.66, then CAR-T was no longer cost effective. Probabilistic sensitivity analysis found that CAR-T was cost effective in 94.8% of iterations at a willingness to pay of $100 000QALY. CAR-T therapy may represent a cost-effective option for pediatric relapsedrefractory B-ALL, although longer follow-up of CAR-T survivors is required to confirm validity of these findings.

Prevention of mercaptopurine-induced hypoglycemia using allopurinol to reduce methylated thiopurine metabolites.

Skewing of mercaptopurine (6-MP) metabolism preferentially toward the 6-methylmercaptopurine (6-MMP) metabolite over the antileukemic metabolite 6-thioguanine (6-TGN) is associated with 6-MP-related hepatotoxocity. Allopurinol when coadministered with 6-MP can reduce this skewing and ameliorate the associated adverse effects. The cases we report here demonstrate that aberrant overproduction of 6-MMP is also associated with profound 6-MP-associated hypoglycemia, which can be reversed by administration of allopurinol. This case series contributes to the scant literature on 6-MP-induced hypoglycemia and provides evidence that addition of allopurinol to reduced dose 6-MP can successfully manage this severe toxicity.

CARs, CRS and neurotoxicity severe complications after administration of immunotherapy Essentials for intensivists.

The development of chimeric antigen receptor (CAR) T‑cells has shown promising results in relapsedrefractory B‑cell acute lymphoblastic leukemialymphoma (B-ALL) and diffuse large cell B‑cell lymphoma. Complications, especially cytokine release syndrome (CRS) and CAR T‑cell related encephalopathy syndrome (CRES), can be life threatening. The management of both plays a key role in CAR T‑cell therapy. Diagnosis, clinical presentation and development of complications in the treatment with CAR T‑cells. Summary of incidence, mortality and treatment of severe complications after administration of CAR T‑cells referring to current studies and therapy recommendations. Complications after administration of CAR T‑cells, especially CRS and CRES, can be life threatening. The timely identification of side effects and their appropriate treatment usually leads to complete recovery. Using a therapy algorithm in the treatment with CAR T‑cells allows safe management of toxicities and can be helpful in recognizing them in time.

Optimized induction of mitochondrial apoptosis for chemotherapy-free treatment of BCR-ABLacute lymphoblastic leukemia.

BCR-ABLacute lymphoblastic leukemia (ALL) in adults has a poor prognosis with allogeneic stem cell transplantation (SCT) considered the best curative option for suitable patients. We here characterize the curative potential of BH3-mimetics differentially targeting mitochondrial BCL2-family members using a combination therapy approach with dexamethasone and tyrosine kinase inhibitors targeting BCR-ABL. In BCR-ABL ALL BH3-mimetics act by redistribution of mitochondrial activator BIM, which is strongly required for cytotoxicity of the BCL2-specific BH3-mimetic ABT-199, tyrosine kinase inhibitors (TKIs) and dexamethasone. BIM expression is enhanced by dexamethasone and TKIs and both synergize with ABT-199 in BCR-ABL ALL. Triple combinations with ABT-199, dexamethasone and TKIs efficiently attenuate leukemia progression both in tissue culture and in primary cell xenotransplantation models. Notably, the dasatinib-containing combination led to treatment- and leukemia-free long-term survival in a BCR-ABL mouse model. Finally, response to BH3-mimetics can be predicted for individual patients in a clinically relevant setting. These data demonstrate curative targeted and chemotherapy-free pharmacotherapy for BCR-ABL ALL in a preclinical model. Clinical evaluation, in particular for patients not suitable for allogeneic SCT, is warranted.

Somatic and germline genomics in paediatric acute lymphoblastic leukaemia.

Advances in genomic research and risk-directed therapy have led to improvements in the long-term survival and quality of life outcomes of patients with childhood acute lymphoblastic leukaemia (ALL). The application of next-generation sequencing technologies, especially transcriptome sequencing, has resulted in the identification of novel molecular subtypes of ALL with prognostic and therapeutic implications, as well as cooperative mutations that account for much of the heterogeneity in clinical responses observed among patients with specific ALL subtypes. In addition, germline genetic variants have been shown to influence the risk of developing ALL andor the responses of non-malignant and leukaemia cells to therapy shared pathways for drug activation and metabolism are implicated in treatment-related toxicity and drug sensitivity or resistance, depending on whether the genetic changes are germline, somatic or both. Indeed, although once considered a non-hereditary disease, genomic investigations of familial and sporadic ALL have revealed a growing number of genetic alterations or conditions that predispose individuals to the development of ALL and treatment-related second cancers. The identification of these genetic alterations holds the potential to direct genetic counselling, testing and possibly monitoring for the early detection of ALL and other cancers. Herein, we review these advances in our understanding of the genomic landscape of childhood ALL and their clinical implications.

Replacing cyclophosphamidecytarabinemercaptopurine with cyclophosphamideetoposide during consolidationdelayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia a report from the COG.

With modern chemotherapy, approximately 90% of patients with pediatric acute lymphoblastic leukemia are now cured. However, subsets of patients can be identified who remain at very high risk of relapse with expected 4-year disease-free survival rates <80% such patients are appropriate candidates for intensive therapeutic strategies designed to improve survival. The AALL1131 trial was designed to determine, in a randomized fashion, whether substitution with cyclophosphamideetoposide (experimental arm 1) would improve the 4-year disease-free survival of children, adolescents, and young adults with very high-risk B-cell acute lymphoblastic leukemia compared to a modified Berlin-Frankfurt-Münster regimen (control arm). Patients 1-30 years of age with newly diagnosed very high-risk B-cell acute lymphoblastic leukemia were randomized after induction in a 12 fashion to the control arm or experimental arm 1 in which they were given cyclophosphamide (440 mgm

Comprehensive analysis of Methylenetetrahydrofolate reductase C677T in younger acute lymphoblastic leukemia patients A single-center experience.

Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms, mainly the C677T, have been implicated as risk factors for several cancers as the acute lymphoblastic leukemia (ALL). In addition, a potential effect of such variant on the efficacy of methotrexate (MTX) has been reported. In this study, we evaluated the impact of the C677T variant of MTHFR on MTX-related toxicity in ALL patients from Tunisia to provide new insights for a personalized therapy based on the human genotype. Genotyping was carried out with restriction fragment length polymorphism (RFLP) on blood samples from a total of 35 younger patients suffering from ALL. In the ALL patients, the MTHFR 677CT genotype confers a greater risk of toxicity with 1.3 times as relative risk mainly the hepatic toxicity when compared with MTHFR 677CC. Our findings suggest that C677T polymorphism of MTHFR seems to be a good marker for MTX-related toxicity in ALL.

Methotrexate-induced Acute Myelopathy in a Teenager With High-risk Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is one of the most frequent malignancies in childhood whose long-term survival has increased up to 80% thanks to modern therapy enhancements. Nevertheless, methotrexate (MTX) remains a mainstay of ALL therapy, but also represents one of the major causes of neurotoxicity in patients with ALL. MTX-induced toxicity occurs in about 9% of patients treated for ALL. It usually affects deep white matter region leading to leukoencephalopathy, which has varying clinical manifestations ranging from acute neurologic disturbances to seizures or chronic permanent encephalopathy. Here we describe a 13-year-old girl affected with ALL who developed lower limbs hypesthesia and static ataxia due to transverse myelopathy after intrathec administration of MTX therapy. A high-dose corticotherapy combined to vitamin supplementation and rehabilitation was tested. Neurological evolution was characterized by slow and partial recovery.

Identification of biomarkers for the prediction of relapse‑free survival in pediatric B‑precursor acute lymphoblastic leukemia.

B‑precursor acute lymphoblastic leukemia (B‑ALL) is the most common cancer diagnosed in children and adolescents. Despite the fact that the 5‑year survival rate has increased from 60 to 90%, approximately a quarter of children suffer from relapse with poor outcome. To improve the clinical management of B‑ALL, there is an urgent need for prognostic biomarkers for the prediction of B‑ALL outcomes. In the present study, we performed a comprehensive analysis of the gene expression data of 456 samples from five independent cohorts. We first sought to identify B‑ALL‑associated genes by differential gene expression analysis by applying linear models. Then, the statistical modelling was applied to identify candidates related to relapse‑free survival. We identified a total of 1,273 B‑ALL‑associated genes that have functions relevant to chemokine signaling. From these genes, 59 genes were identified as prognostic biomarkers. Based on expression patterns of these genes, we successfully distinguished high‑ and low‑risk groups of B‑ALL patients (log-rank test, P‑value0.025). We further investigated the 59‑gene expression levels in ALL chemotherapy‑treated cohorts and identified 4 genes as potential drug targets associated with drug sensitivity. Our results provided a novel biomarker panel. By leveraging the large scale of data and statistical modelling, we believe this 59‑gene biomarker could help to unveil the mechanisms underlying B‑ALL progression and become potential drug targets.

Immunosuppression-associated posterior reversible encephalopathy syndrome in an acute leukemia case.

Posterior reversible encephalopathy syndrome (PRES) was described in 1996. Herein, we aimed to report an immunosuppression- related PRES case. A 34-year-old woman was diagnosed as t-cell acute lymphoblastic leukemia and allogeneic hematopoietic stem cell transplantation (HSCT) was performed. Cyclosporine was given for GVHD prophylaxis in addition to the other routine medications of HSCT. She was hospitalized for acute renal failure and due to the possible contribution of acute renal failure cyclosporine was stopped. Tacrolimus was started for GVHD prophylaxis at a dose of 1 mgday. However, fifteen days after the initiation of tacrolimus, blurred vision occurred in our patient. Petechial bleeding sites were detected in bilateral cerebral and cerebellar hemisphere by MR imaging. Tacrolimus dosage was reduced to 0.5 mgday. She had hypertension which was difficult to control and followed-up in the intensive care unit. She had seizures. Control cranial MR resulted as diffusion limitation in bilateral cerebellar hemisphere, bilateral occipital and frontal-parietal regions with vasogenic edema findings contrast involvement in left frontal-parietal and right cerebellar regions. She had vision loss and lethargy. Control cranial MR favored PRES syndrome secondary to immunosuppression. Hypertensive state was taken under control with antihypertensive treatment and all immunosuppressive agents were stopped. Two weeks later her clinical condition was slightly improved. MR test which was conducted 2 weeks after the diagnosis revealed the regression of PRES lesions. The characteristic signs on neuroimaging are the symmetrical white matter edema in the posterior cerebral hemispheres, particularly the parietal- occipital regions. In conclusion, PRES rarely develops secondary to the immunosuppressive agents and the clinicians should suspect and promptly diagnose PRES which might cause otherwise serious irreversible clinical complications.

Fluorescence

Acute lymphoblastic leukemia (ALL) affects both children and adults. However, the prognosis of the two cohorts is quite different. The present aim was to review and evaluate one potential cause of why survival is poorer in adult ALL than pediatric ALL via fluorescence

Patient characteristics, treatment patterns, and mortality in elderly patients newly diagnosed with ALL.

To describe patient characteristics and treatment patterns among elderly patients (≥66 years) newly diagnosed with acute lymphoblastic leukemia (ALL), we analyzed 100% Medicare ALL data from 2007 to 2015. Only 764 out of 1428 (53.5%) elderly patients received treatment within 90 d of diagnosis with ≥30-d follow-up 32.4% received chemotherapy without tyrosine kinase inhibitors (TKIs), 8.8% received both chemotherapy and TKIs, 9.8% received steroids only and 2.6% received TKIs only. Among 717 patients receiving chemotherapy any time during follow-up, 65.8% received only one course of treatment. Patients treated with chemotherapy or TKIs compared to untreated patients were younger (<75 years 51.5 vs. 21.7%) and had a lower comorbidity burden (Charlson Comorbidity index ≤ 2 90.9 vs. 71.4%). Overall, 67.5% of patients died within 3 years of diagnosis. Our findings demonstrate that many elderly ALL patients are not treated in the real-world setting and highlight the need for tolerable therapies for these patients.

Occurrence and Antibiotic Resistance of Enterobacteriaceae in Acute Leukemia Patients.

Acute leukemia (AL) is a heterogeneous group of malignant hematopoietic diseases and is divided into two basic types acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Patients with these diseases are highly immunosuppressed and therefore at a high risk of serious infections. This study aimed to perform active surveillance of enterobacteria, which cause these infections, and to determine their antibiotic resistance in patients with AL who were hospitalized at the Hemato-Oncology Center of University Hospital Olomouc. This study involved 49 patients with AL, of whom 37 had AML (16 women and 21 men) and 12 had ALL (6 women and 6 men). The mean age of the patients was 50.5 years. Samples of clinical material were obtained over 12 months (September 2015 to August 2016) and subjected to standard microbiological examinations. Bacterial strains were identified by MALDI-TOF MS, and their antibiotic susceptibility was established by microdilution method. A total of 292 samples were obtained from patients with AL. Some of these samples were excluded from analysis to prevent the inclusion of identical strains from the same patient. Consequently, 146 clinical samples obtained from the following nine types of clinical materials were analyzed - throat swabs (n 47), stools (n 40), urine (n 33), hemocultures (n 11), buccal swabs (n 5), perianal swabs (n 4), wound swabs (n 3), sputum (n 2), and puncture fluid (n 1). The most prevalent enterobacteria was Escherichia coli (n 42), followed by Klebsiella spp. (n 46), specifically Klebsiella pneumoniae (n 34) and Klebsiella oxytoca (n 12), and Enterobacter cloacae (n 19). The most of enterobacteria were highly resistant to many tested antibiotics. Antibiotic-resistant enterobacteria colonize patients with hemato-oncological diseases and can cause serious infections. These antibiotic-resistant microorganisms are a serious and frequent problem. These findings together with the high level of immunosuppression mean that patients with hemato-oncological diseases are at a high risk of developing serious infections and consequently active surveillance is crucial.

High hyperdiploid acute lymphoblastic leukemia is a highly curable subtype of childhood leukemia.

Acute lymphoblastic leukemia (ALL) is the most frequent malignancy in children. In Hungary 60-70 new cases are diagnosed annually. The survival rate is 85-90% in developed countries with current treatment protocols. The most common genetic category of childhood ALL is the high hyperdiploid subtype (HHD) with chromosome numbers of 51 to 67. It accounts for approximately 25% of all cases. The prognosis is very good, though relapse occurs in 15% of cases and there are data on the heterogeneity of this subgroup as well. In this paper we give an overview of the cytogenetic, clinical, epidemiological and prognostic features of this subgroup. We also demonstrate our interphase fluorescent in situ hybridization (iFISH) analysis performed retrospectively on 168 untreated bone marrow samples of precursor B pediatric ALL patients to reveal the numerical aberrations of chromosomes 4, 6, 10, 14, 17, 18, 21 and X, which are most frequently affected by gain in HHD ALL. Data from 48 high hyperdiploid patients indicated that high modal number (>55 chromosomes) and specific chromosomal gains (4, 46, 417, 418) exhibited significance in terms of beneficial overall survival. Az akut limfoblasztos leukémia (ALL) a leggyakoribb gyermekkori rosszindulatú megbetegedés. Magyarországon évente 60-70 új betegség kerül felismerésre. A fejlett országokban jelenleg alkalmazott terápiás protokollokkal gyógyulása 85−90%. A legnagyobb, a betegek egynegyedét magába foglaló citogenetikai alcsoport a magasan hiperdiploid ALL a limfoblasztok a normális diploid kromoszómakészlet helyett 51−67 kromoszómát tartalmaznak. Prognózisa nagyon jó, bár a betegek 15%-ánál késõbb relapszus lép fel, és vannak a csoport heterogenitása melletti adatok is. Közleményünkben összefoglaljuk ezen alcsoport citogenetikai, klinikai, epidemiológiai és prognosztikai jellemzõit. Bemutatjuk saját kutatási eredményeinket, melyben 168 prekurzor B-sejtes leukémiával diagnosztizált gyermek csontvelõmintájának sejtszintû analízise során vizsgáltuk a nyolc leggyakrabban érintett teljes kromoszóma (4, 6, 10, 14, 17, 18, 21 és X) kópiaszám-növekedési mintázatát. A 48 magas hiperdiploiditású beteg adatait elemezve a magas modális kromoszómaszám (>55) és bizonyos triszómiák és kombinációik (4, 46, 417, 418) jelenléte kimagaslóan kedvezõ kimenetelû alcsoportot határoztak meg.

Severe hypercalcemia A rare and unusual presentation of acute lymphoblastic leukemia.

Hypercalcemia is a rare and unusual complication of childhood malignancies. Acute lymphoblastic leukemia (ALL) presenting with hypercalcemia and lytic bone lesions is very rare in children. Here, we report a case of a 4-year-old girl with ALL who presented with severe hypercalcemia and radiological evidence of osteolytic lesions. Malignancies are the most common parathyroid hormone-independent cause of hypercalcemia. Severe hypercalcemia is a life-threatening emergency that should be addressed immediately. Effective treatment includes intense hydration, frusemide, calcitonin, and bisphosphonate in addition to the treatment of underlying cause.

Basic Procedures for Detection and Cytotoxicity of Chimeric Antigen Receptors.

Chimeric antigen receptors against CD19 (anti-CD19-CAR) are widely recognized and used by not only researchers associated with immunology, molecular biology, and cell biology but also physicians to treat B-cell malignancies. Anti-CD19-CAR is currently clinically available as one of the therapeutic modalities for refractory acute B-cell-typed lymphoblastic leukemia (B-ALL) patients. However, to detect CAR on the cell surface and investigate the efficacy of CAR-T cells, there are numerous experimental modalities including flow cytometry, the Cr-releasing assay, immunoblot, and immunostaining. We have chosen several techniques, which are necessary and sufficient as well as reliable and reproducible to detect and assess the killing effect of CAR-T cells. Here, we describe protocols for basic experiments and procedures for the detection of CAR on transduced cells and in in vitro coculture experiments to assess cytotoxicity using CAR-T cells.

Interactions Between

Acute Lymphoblastic Leukemia (ALL) remains the most frequent cause of cancer-related mortality in children and novel therapies are needed for the treatment of relapsedrefractory childhood ALL. One approach is the targeting of ALL blasts with the

Associations between the

Despite several studies being conducted to examine the associations between the All eligible studies published in English up to May 2018 were identified by searching PubMed, Web of Science, Embase, and the Cochrane Library. Pooled OR and 95% CI were calculated using fixed- or random-effect model. In all, total of 14 studies containing 918 patients and 2,341 controls were included of these, 8 studies concerned inflammatory bowel disease (IBD) and 4 concerned acute lymphoblastic leukemia (ALL). Overall, the results indicated that the This meta-analysis verified the strong association between the

By reducing global mRNA translation in several ways, 2-deoxyglucose lowers MCL-1 protein and sensitizes hemopoietic tumor cells to BH3 mimetic ABT737.

Drugs targeting various pro-survival BCL-2 family members (BH3 mimetics) have efficacy in hemopoietic malignancies, but the non-targeted pro-survival family members can promote resistance. Pertinently, the sensitivity of some tumor cell lines to BH3 mimetic ABT737, which targets BCL-2, BCL-XL, and BCL-W but not MCL-1, is enhanced by 2-deoxyglucose (2DG). We found that 2DG augmented apoptosis induced by ABT737 in 3 of 8 human hemopoietic tumor cell lines, most strongly in pre-B acute lymphocytic leukemia cell line NALM-6, the focus of our mechanistic studies. Although 2DG can lower MCL-1 translation, how it does so is incompletely understood, in part because 2DG inhibits both glycolysis and protein glycosylation in the endoplasmic reticulum (ER). Its glycolysis inhibition lowered ATP and, through the AMPKmTORC1 pathway, markedly reduced global protein synthesis, as did an ER integrated stress response. A dual reporter assay revealed that 2DG impeded not only cap-dependent translation but also elongation or cap-independent translation. MCL-1 protein fell markedly, whereas 12 other BCL-2 family members were unaffected. We ascribe the MCL-1 drop to the global fall in translation, exacerbated for mRNAs with a structured 5 untranslated region (5UTR) containing potential regulatory motifs like those in MCL-1 mRNA and the short half-life of MCL-1 protein. Pertinently, 2DG downregulated two other short-lived oncoproteins, MYC and MDM2. Thus, our results support MCL-1 as a critical 2DG target, but also reveal multiple effects on global translation that may well also affect its promotion of apoptosis.

Case report of neurotoxicity with blinatumomab and concurrent intrathecal chemotherapy in second relapse of acute lymphoblastic leukemia with central nervous system disease.

A 26-year-old male with a history of pre-B cell acute lymphoblastic leukemia and seizures presented with second relapse of acute lymphoblastic leukemia and central nervous system involvement, 19 years after the initial diagnosis. Over the next two months, the patient received six doses of triple intrathecal chemotherapy (cytarabine, methotrexate, and hydrocortisone), three concurrently with continuous blinatumomab in the second month. Approximately 12 days after blinatumomab initiation, he developed central nervous system toxicity manifesting as speech impairment, altered mental status, incontinence, and diffuse weakness. Blinatumomab was discontinued, and he was started on dexamethasone. Within the next couple of months, his neurologic status recovered, and he was able to perform all of his baseline activities without limitation. Unfortunately, the patient eventually expired after further relapse approximately one year later. To our knowledge, this is the first published case report of severe neurotoxicity in a patient who was given blinatumomab concurrently with intrathecal chemotherapy.

Allogeneic Hematopoietic Stem Cell Transplantation, Especially Haploidentical, May Improve Long-Term Survival for High-Risk Pediatric Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in the Tyrosine Kinase Inhibitor Era.

The role of allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly haploidentical (haplo)-HSCT, in pediatric patients with Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL) in the tyrosine kinase inhibitor (TKI) era is unclear. This study aimed to identify prognostic factors and explore the role of haplo-HSCT in the treatment of Ph ALL in the TKI era. We analyzed clinical data of Ph ALL patients aged 1 to 18 years who received imatinib added to intensive chemotherapy at the start of induction therapy. Among the 68 patients who completed at least 2 consolidation cycles, 44 underwent transplantation (transplant arm) and 24 received continuous TKI with chemotherapy (nontransplant arm). At the 3-year follow-up the cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS) were 23.5%, 73.4%, and 80.3%, respectively. Multivariate analysis showed that hematologic response (whether complete remission CR was achieved) at the induction end, BCR-ABL levels (whether major molecular response MMR was achieved) at 3 months, and transplantation were independent affecting factors for CIR, EFS, and OS. In the risk stratification analysis based on the first 2 prognostic factors mentioned above, no significant difference existed between the transplant and nontransplant arms for the probabilities of 3-year OS, EFS, and CIR in the standard-risk group (no poor prognostic factors). Meanwhile, OS, EFS, and CIR rates were significantly better in the transplant arm in the high-risk group (≥1 poor prognostic factor). Among the 44 patients in the transplant arm, 37 underwent haplo-HSCT. Achieving CR at the induction end, MMR at 3 months, and haplo-transplant were also independent favorable factors of CIR, EFS, and OS in the nontransplant and haplo-HSCT arms. Haplo-HSCT showed a significant survival advantage in the high-risk group only. Hematologic response at the induction end and BCR-ABL levels at 3 months are likely to be useful for identifying pediatric Ph ALL patients at a high risk of relapse in the TKI era. Children with Ph ALL in first CR may benefit from allo-HSCT, particularly those at high risk. Haplo-HSCT could achieve good long-term survival for pediatric Ph ALL. Thus, haplo-HSCT can be an alternative approach for high-risk Ph ALL patients.

Significant effect of infection and food intake on sirolimus pharmacokinetics and exposure in pediatric patients with acute lymphoblastic leukemia.

Sirolimus is increasingly investigated as a new targeted therapy in pediatric populations. To date, population pharmacokinetic (PK) studies have identified several factors that explain in part the large between-patient variability in sirolimus PK. However, within-patient variability in sirolimus PK is not well documented. This study presents examples of model-based PK-guided dosing of sirolimus in children with acute lymphoblastic leukemia (ALL), where patients experienced significant changes in sirolimus blood concentrations due to infection and food intake during the treatment period. Clinical PK data were obtained as part of a prospective pilot study of sirolimus combined with multiagent chemotherapy in pediatric patients with ALL (ClinicalTrial.gov identifier NCT01658007). A PK model-informed loading dose of 1.8 mgm Three patients were enrolled in this study. Two patients achieved target concentration attainment with the PK model-informed loading dose on day 1 of sirolimus treatment. Subsequent unexpected high sirolimus concentrations were observed in two patients, where patients had flulike symptoms such as fever and cough. A sudden decrease in sirolimus concentrations was observed in one patient after switching sirolimus administration from the fed to the fasting state. This study highlights within-patient fluctuations in sirolimus concentrations associated with intercurrent infection and with changes in diet. These findings highlight the challenge of maintaining a target sirolimus concentration as a patients clinical status changes, and the benefit of intensive monitoring of therapeutic drug levels in children treated with sirolimus. Intra-patient alternations in sirolimus PK due to similar diseasefood interactions may be relevant in pediatric patients treated with sirolimus for other disease indications.

Lymphocyte-Specific Chromatin Accessibility Pre-determines Glucocorticoid Resistance in Acute Lymphoblastic Leukemia.

Glucocorticoids play a critical role in the treatment of lymphoid malignancies. While glucocorticoid efficacy can be largely attributed to lymphocyte-specific apoptosis, its molecular basis remains elusive. Here, we studied genome-wide lymphocyte-specific open chromatin domains (LSOs), and integrated LSOs with glucocorticoid-induced RNA transcription and chromatin modulation using an in vivo patient-derived xenograft model of acute lymphoblastic leukemia (ALL). This led to the identification of LSOs critical for glucocorticoid-induced apoptosis. Glucocorticoid receptor cooperated with CTCF at these LSOs to mediate DNA looping, which was inhibited by increased DNA methylation in glucocorticoid-resistant ALL and non-lymphoid cell types. Our study demonstrates that lymphocyte-specific epigenetic modifications pre-determine glucocorticoid resistance in ALL and may account for the lack of glucocorticoid sensitivity in other cell types.

Glucocorticoid Resistance in Acute Lymphoblastic Leukemia BIM Finally.

Glucocorticoid resistance represents a major challenge in treating acute lymphoblastic leukemia. In this issue of Cancer Cell, Jing and colleagues show epigenetic deregulation of glucocorticoid-induced BIM activation in glucocorticoid-resistant leukemia cells, and restore glucocorticoid-receptor-induced BIM upregulation with DNA demethylating agents to effectively enhance glucocorticoid response.

Inhibition of HOXB7 suppresses p27-mediated acute lymphoblastic leukemia by regulating basic fibroblast growth factor and ERK12.

Acute lymphoblastic leukemia (ALL) is characterized by abnormal proliferation of immature lymphocytes in the bone marrow, peripheral blood, and other tissues. HOXB7 is upregulated in tumors and is related to cell proliferation and cell cycle. However, the role of HOXB7 in ALL progression remains unclear. In this study, we explored the molecular mechanism of HOXB7 in cell viability and cell cycle in ALL cell lines. Peripheral blood lymphocytes was isolated by Isopycnic Ficoll-Hypaque solution Relative mRNA expression of HOXB7 was measured by RT-qPCR Relative protein expressions of HOXB7, p27, bFGF, pERK12 were tested by Western blot assay Cell viability was tested by MTT Cell proliferation was detected by BrdU assay 2.8. Cell cycle was analyzed by flow cytometry. HOXB7 was significantly elevated in peripheral blood lymphocytes of patients with ALL. HOXB7 was inhibited by HOXB7 siRNA transfection cell viability decreased and cell cycle was arrested in ALL cell lines. Meanwhile, HOXB7 suppression significantly induced the protein expression of p27 (cyclin-dependent kinase inhibitor). We also demonstrated the molecular mechanism of HOXB7 regulation on p27. HOXB7 suppression obviously inhibited the protein expressions of b basic fibroblast growth factor (bFGF) and p-ERK12. Also, the inhibitory effects of HOXB7 suppression on p-ERK12, cell viability, and cell cycle in ALL cell lines were markedly reversed after culturing with bFGF (9 ngmL) for 24 h. After incubating with bFGF, cells with HOXB7 inhibition were treated with a specific ERK12 inhibitor, PD98095, after which the effects of bFGF on protein expression of p27, cell viability, and cell cycle were obviously reversed. Our study suggests that inhibiting HOXB7 suppresses p27-mediated ALL progression by regulating bFGFERK12.

A single institutional review of pediatric Bacillus spp. bloodstream infections demonstrates increased incidence among children with cancer.

Bacillus species are known to cause severe infection in immunocompromised hosts. The incidence of Bacillus bloodstream infections and characteristics of infection among children with cancer or indication for hematopoietic cell transplant (HCT) is unknown. We performed a retrospective medical record review of all cases of Bacillus bacteremia between January 1, 2005, and December 31, 2014, at Boston Childrens Hospital. We report average incidences from 2012 to 2014. We performed a detailed review of infections among children with cancer or undergoing HCT and a case-control study to evaluate whether neutropenia at diagnosis caries higher risk of Bacillus infection for children with acute lymphoblastic leukemia (ALL). One hundred fourteen children developed Bacillus bacteremia during the study period, with an estimated incidence of 0.271,000 patients. Among children treated for cancer or undergoing HCT, there were 37 bloodstream infections (2.01,000 patients). Of the 37 oncologyHCT patients, oncologic diagnoses included ALL (18), acute myeloid leukemia (3), myelodysplastic syndrome (1), solid tumors (8), and 7 children were undergoing HCT. The incidence of infection among children with ALL was 341,000 patients and all central nervous system (CNS) infections (6) and deaths (3) occurred in this population. Neutropenia at time of diagnosis in children with ALL was not associated with risk of infection (P 0.17). We report the first hospital-wide analysis of Bacillus infection and found that immunocompromised children experience a significant proportion of Bacillus infections. Children with ALL have a high incidence of infection and are at higher risk of CNS involvement and death.

Effect of inotuzumab ozogamicin on the QT interval in patients with haematologic malignancies using QTc-concentration modelling.

The aim of this study was to characterize the effect of inotuzumab ozogamicin on QT interval in patients with B-cell malignancies. Data were pooled from three clinical studies including 250 patients (n 2743) who received inotuzumab ozogamicin monotherapy. Patients with relapsedrefractory acute lymphoblastic leukaemia (NCT01564784 and NCT01363297) received 1.8 mg m QTc intervals had a small but positive correlation with inotuzumab ozogamicin concentration. Based on 1000 simulations, median (upper 95% CI) QTcS and QTcF changes from baseline were <10 ms at both therapeutic (2.70 ms 5.40 ms and 2.53 ms 4.92 ms, respectively) and supratherapeutic (4.14 ms 8.28 ms and 3.87 ms 7.54 ms, respectively) concentrations. Inotuzumab ozogamicin (1.8 mg m

Prognostic value of the response to prednisone for children with acute lymphoblastic leukemia a meta-analysis.

To systematically review prednisone induced test results in the prognosis assessment of acute lymphoblastic leukemia in children. Based on the established inclusion and exclusion criteria, studies of prednisone induced test in evaluating the prognosis of childhood acute lymphoblastic leukemia were electronically searched from January 1990 to November 2016 using Pubmed, Embase, The Cochrane Library, Web of Science, WanFang, VIP, and CNKI database. Two independent researchers browsed literature, extracted data and assessed the risk of bias of studies. Meta-analysis was performed using RevMen 5.3 software. A total of 17 articles were included. Meta-analysis showed that after complete prednisone induced test in children, 5y-EFS, 8y-EFS adverse reactions, persistent remission and relapse were statistically significant differences between the prednisone good response (PGR) and prednisone poor response (PPR). There were statistical significance in T cell immune typing and the initial WBC of the two groups. Prognosis of prednisone good response group is better than prednisone poor response group. The prednisone induction test is an important factor in predicting the prognosis of children with ALL.

Comparison of gabexate mesilate and nafamostat mesilate for disseminated intravascular coagulation associated with hematological malignancies.

We evaluated clinical outcomes of disseminated intravascular coagulation (DIC) in patients with hematological malignancies treated with synthetic protease inhibitors (SPIs) and compared the effects of gabexate mesilate (FOY) and nafamostat mesilate (FUT). We retrospectively examined 127 patients acute myeloid leukemia (n 48), acute lymphoblastic leukemia (n 25), and non-Hodgkin lymphoma (n 54) with DIC, who were diagnosed according to Japanese Ministry of Health, Labour and Welfare criteria and treated with SPIs FOY (n 55) and FUT (n 72) at our hospital from 2006 to 2015. The DIC resolution rates on days 7 and 14 were 42.6% and 62.4%, respectively. No significant differences were observed in DIC resolution rates between the FUT and FOY groups 40.3% vs. 45.5% (day 7), P 0.586 56.3% vs. 69.8% (day 14), P 0.179, respectively. Multivariate analysis revealed that response to chemotherapy was the only independent predictor of DIC resolution on days 7 and 14 (ORR 2.81, 95% CI 1.32-5.98, P 0.007 ORR 2.51, 95% CI 1.12-5.65, P 0.026). Resolution of DIC was correlated with improvement of background hematological malignancies, and no significant differences were observed between the two SPIs.

Pain in patients with newly diagnosed or relapsed acute leukemia.

Acute leukemia (AL) is associated with substantial morbidity and mortality. We assessed the prevalence and correlates of pain in patients with newly diagnosed or relapsed AL. Patients with newly diagnosed or relapsed AL admitted to a comprehensive cancer center completed the Memorial Symptom Assessment Scale (MSAS), which assesses prevalence, severity, and distress associated with pain and other symptoms. Factors associated with severe pain were assessed using logistic regression. Two raters completed chart reviews in duplicate for patients with severe pain (MSAS severity ≥ 34) to determine the site of pain. Three hundred eighteen patients were recruited from January 2008 to October 2013 245 (77.0%) had acute myeloid or acute promyelocytic leukemia (AMLAPL) and 73 (23.0%) had acute lymphoblastic leukemia (ALL) 289 (90.9%) were newly diagnosed and 29 (9.1%) had relapsed disease. Pain was reported in 156318 (49.2%), of whom 55156 (35.3%) reported severe pain (≥ 34). Pain was associated with all psychological symptoms (all p < 0.005) and some physical symptoms. Severe pain was associated with younger age (p 0.02), worse performance status (p 0.04), ALL diagnosis (p 0.04), and time from onset of chemotherapy (p 0.03), with pain peaking at 4 weeks after chemotherapy initiation. The most common sites of severe pain were oropharynx (22 40%), head (12 21.8%), and abdomen (11 20%). Only 3 patients (0.9%) were referred to the symptom controlpalliative care team during the month prior to or following assessment. Pain is frequent, distressing, and predictable in patients undergoing induction chemotherapy for AL. Further research is needed to assess the efficacy of early supportive care in this population.

Impact of short stature on health-related quality of life in long-term survivors of acute lymphoblastic leukemia in childhood and adolescence.

Some survivors of acute lymphoblastic leukemia (ALL) in childhood and adolescence exhibit short stature, especially if their treatment included cranial irradiation. The impact of this outcome on health-related quality of life (HRQL) is uncertain and so formed the basis for the investigation reported here. This study examined the association between self-reported HRQL and measured height in a cohort (n 75) of survivors of ALL more than 10 years from diagnosis. HRQL was expressed as utility scores generated from a multi-attribute preference-based measure, the Health Utilities Index (HUI) which includes the complementary systems HUI2 and HUI3. For single attributes the range is from 1.00 (no limitations) to 0.00 (lowest level of function). For overall HRQL the range is 1.00 (perfect health) to 0.00 (equivalent to being dead). A negative score is associated with states of health worse than being dead. There were no statistically significant differences in overall HRQL between subjects <25th (n 16, 21%), 15th (n 11, 15%) and 10th (n 10, 13%) centiles. A greater amount of emotional morbidity, focused on anger and depression, was manifest in those <25th and 15th centiles, with clinically important differences of 0.07 (p 0.03) and 0.077 (p 0.016) respectively, but not in the shortest group who were < 10th centile. Studies in large cohorts of young adults in the general population has reported an inconsistent relationship between height and HRQL. Results from the current study suggest that no such relationship exists in long-term survivors of ALL in childhood and adolescence.

Wntβ‑catenin inhibition reverses multidrug resistance in pediatric acute lymphoblastic leukemia.

Although 80% of newly diagnosed pediatric patients with acute lymphoblastic leukemia (ALL) become disease‑free following appropriate treatment, relapses frequently occur, with dismal prognosis. Therefore, it is urgent to develop novel therapeutic modalities. Resistance to chemotherapy is a major obstacle for the treatment of relapsed ALL. It has been indicated that Wnt pathway is potentially associated with leukemia recurrence. In the current study, a vincristine (VCR)‑resistant variant of the human ALL cell line BALL‑1 (BALL‑1VCR) that also had relatively specific resistance to both doxorubicin and etoposide was generated. Over‑activation of the Wntβ‑catenin signaling pathway was observed in BALL‑1VCR cells, whereas Dickkopf‑related protein 1 selectively suppressed the Wnt signaling pathway and sensitized the response of BALL‑1VCR to anticancer agents. In addition, prednisolone exposure in combination with Wnt inhibition restored chemo‑sensitivity in relapsed ALL blasts. Since the resistance of BALL‑1VCR cells is potentially attributed to the overexpression of MDR‑associated protein 1 (MRP1), the development of drug resistance in relapsed ALL may associated with the overexpression of MRP1 and P‑glycoprotein. The results of this study demonstrated that, as a potential candidate to mimic relapsed ALL, BALL‑1VCR could be used in further research, while Wnt‑inhibition may become a promising therapeutic approach for treating ALL.

Potential efficacy and prognosis of silencing the CRLF2‑mediated AKTmTOR pathway in pediatric acute B‑cell lymphoblastic leukemia.

Acute B‑cell lymphoblastic leukemia (B‑ALL) is a common type of blood cancer, which is associated with aberrant gene expression. Cytokine receptor‑like factor 2 (CRLF2) serves a crucial role in the growth and allergic and inflammatory responses of dendritic cells and T cells. The purpose of the present study was to investigate the potential therapeutic and prognostic effect of silencing the CRLF2‑mediated RAC‑α serinethreonine‑protein kinase (AKT)serinethreonine‑protein kinase mTOR (mTOR) pathway in B‑ALL. In our study, bone marrow specimens were collected from 128 children with B‑ALL and 26 healthy children. The expression of CRLF2 in bone marrow tissue was detected using immunohistochemistry. The survival rates were compared among the children with high and low CRLF2 expression levels. BaF3 leukemia cells were treated with CRLF2 short hairpin RNA knockdown andor the AKTmTOR pathway specific inhibitor LY294002. mRNA and protein expression associated with CRLF2 and the AKTmTOR pathway in each group was detected by reverse transcription‑quantitative polymerase chain reaction analysis and western blotting. The viability of BaF3 cells in all the groups was assessed by Cell Counting Kit‑8 assay the migration and invasion of BaF3 cells were determined by wound healing and Transwell invasion assays and the sensitivity of BaF3 cells to the chemotherapeutic drug imatinib was detected using flow cytometry. The results demonstrated that CRLF2 overexpression is associated with a poor prognosis in B‑ALL, and the CRLF2AKTmTOR pathway is involved in the migration, invasion and chemotherapeutic agent‑induced apoptosis of BaF3 cells.

Cyr61 decreases Cytarabine chemosensitivity in acute lymphoblastic leukemia cells via NF-κB pathway activation.

Elevated Cyr61 levels have been reported in various malignancies. Elevation of Cyr61 protein levels contributes to the proliferation, metastasis, and chemotherapy resistance of malignant cells. Previously, it was discovered that Cyr61 is elevated in both the plasma and the bone marrow supernatants of patients with acute lymphoblastic leukemia (ALL), promoting ALL cell survival. However, the role of Cyr61 in the chemotherapeutic resistance of ALL cells remains unknown. The aim of the current study was to investigate the role of Cyr61 in regulating ALL cell chemosensitivity to Ara‑C. It was found that Cyr61 is overexpressed in bone marrow mononuclear cells from patients with ALL. Increased Cyr61 effectively decreased Ara‑C‑induced apoptosis of ALL cells, and its function was blocked by the use of the anti‑Cyr61 monoclonal antibody 093G9. Furthermore, Cyr61 increased the level of Bcl‑2 in Ara‑C‑treated ALL cells. Mechanistically, it was shown that Cyr61 affected ALL cell resistance to Ara‑C partially via the NF‑κB pathway. Taken together, the present study is the first, to the best of our knowledge, to reveal that Cyr61 is involved in ALL cell resistance through the NF‑κB pathway. The findings support a functional role for Cyr61 in promoting chemotherapy resistance, suggesting that targeting Cyr61 directly or its relevant effector pathways may improve the clinical responses of patients with ALL.

Successful treatment of disseminated fusariosis in a febrile neutropenic patient with combined antifungal therapy of voriconazol plus amphotericin B deoxycholate.

We report a case of a patient with acute lymphoblastic leukemia (ALL), who developed a disseminated infection by Fusarium verticillioides during chemotherapy-induced neutropenia. He was successfully treated only after combination therapy with voriconazole plus amphotericin B deoxycolate was used, but not when these compounds were used in an isolated form.

Epidemiology and risk factors for prolonged hospital length of stay in children with leukemia and bacteremia. Cohort study.

Bacteremia is a frequent complication in children with cancer, which is associated with greater severity, prolonged hospitalization and mortality. Prolonged hospitalization conditions greater morbidity and risk of acquisition of intranosocomial infections. To describe risk factors for prolonged hospital length of stay in children with leukemia and bacteremia. Cohort study. Episodes of bacteremia in patients with leukemia at Garrahan Hospital from 112015 to 31122016 were reviewed. We compared data from patients with a LOS of 14 days or more with those admitted for less than 14 days. Bivariate and logistic regression analysis was performed. We used Stata 13 statistical package. n 121. Median age 59 months.81 patients (67%) had a diagnosis of acute lymphoblastic leukemia, followed by acute myeloid leukemia in 40 (33%). 96 patients (79%) had a central venous catheter (CVC), 94 patients (78%) were neutropenic. Blood cultures were positive for Enterobacteriaceae in 55 cases (45%), coagulase-negative staphylococci in 28 cases (23%), Group viridans Streptococcus in 19 (16%), Pseudomonas aeruginosa in 8 (7%). (9%). By the multivariate analysis, three factors remained significantly associated with length of stay of more than 14 days CVC associated bacteremia (OR 21,73 CI95% 1.2-43.2 p 0.04), severe neutropenia (OR 1.75 CI95% 1.82-1.28 p 0.03) and coinfection (OR 27.4 CI95% 2.8-260.8 p 0.004). CVC associated bacteremia, severe neutropenia and viral coinfection were associated with hospital LOS of more than 14 days.

Effect of metformin added to chemotherapy on the survival of patients with acute lymphoblastic leukemia.

Metformin has antineoplastic and cancer protective effects in vitro, sensitizing leukemia cells to chemotherapeutic agents, inducing apoptosis and cell cycle arrest. To assess the effect of metformin on the induction stage in patients with ALL and its impact on overall survival and relapse. We included 123 patients treated with metformin and without metformin. The dose used was 850 mg PO at 8 h intervals. The survival analysis was used by Kaplan-Meier method, the difference between the distinct groups was performed using the log Rank test. The overall survival at a median follow up of 700 days of follow-up was 43%, with a disease-free survival of 47%. Regarding the treatment groups, patients with metformin had a lower rate of relapse compared to the group receiving only chemotherapy (6.5% vs 17.1%, p 0.006). The addition of metformin to the conventional treatment of ALL was associated with an improvement in survival, this association being independent of the type of biological risk at diagnosis.

Endothelial Function in Children with Acute Lymphoblastic Leukemia (ALL) May Reflect the Clinical Outcome.

Endothelial dysfunction is a common feature of early complications of hemato-oncologic therapy. The aim of our study was to assess the profile of endothelial function at diagnosis time, then during initial treatment phase of acute lymphoblastic leukemia (ALL), and to verify the presence of its correlation with early clinical outcome (ECO). 28 ALL children and 18 healthy age-matched control ones were recruited. Study group was examined at baseline and at 33rd and 78th day of treatment. At each protocol step the endothelial function was assessed by measurement of sP-selectin (CD62-P), PAI-1(serpinE1), sE-selectin (CD62E), sICAM-1(sCD54), sVCAM-1(sCD106), and VEGF concentrations. Higher baseline sICAM-1 and sVCAM-1 levels and lower sP-selectin and VEGF were observed in children with ALL. sICAM-1, sVCAM-1, and sE-selectin levels were decreasing following the treatment with protocol I. Higher sE-selectin and lower baseline sICAM-1 levels were observed in children treated unsuccessfully. Lower PAI-1 levels were observed in children who survived. Higher baseline sE-selectin levels and lower sICAM-1 and VEGF were observed in children treated unsuccessfully. A decrease in sE-selectin and lower PAI-1 at the 78th day of therapy were associated with better ECO. High baseline VEGF and sE-selectin levels, significant increase in PAI-1, and low initial sICAM-1 levels are prognostics for poorer prognosis in the ALL children.

Successful Use of Negative-pressure Wound Therapy and Dermal Substitute in the Treatment of Gluteal Ecthyma Gangrenosum in a 2-year-old Girl.

Ecthyma Gangrenosum is a manifestation of

A Pharmacogenetic Study of VDR fok1 and TYMS Polymorphisms and Their Association With Glucocorticoid-Induced Osteonecrosis in Egyptian Children With Acute Lymphoblastic Leukemia.

The rare translocation t(1421)(q11q22) detected in a Moroccan patient with T-cell acute lymphoblastic leukemia.

Cytogenetic studies of acute lymphoblastic leukemia have been at the forefront of research in the pathogenesis of cancer. The presence of recurring chromosomal abnormalities (either numeral or structural rearrangements) provides immediate clues to the genetic events leading to leukemia and many abnormalities have important prognostic significance. The rare translocation t(14,21)(q11.2q22) has been described in pediatric T lineage ALL in only one case so far in 2000. The present study is a case report of an ALL case in which we found a t(14,21)(q11.2q22) as a non random chromosomal abnormality among 70 analyzed pediatric ALL cases referred exclusively to BIOLAB Laboratory from the children hospital of Morocco.

The contribution of

A growing body of evidence shows an association between DNA repair protein genotypes and susceptibility to various cancers. However, few studies have assessed the contribution of the genotype of We recruited 266 patients with childhood ALL and 266 healthy controls. Genomic DNA was isolated from peripheral blood samples. The Genotypes with the rs861539 polymorphism were significantly associated with the risk of childhood ALL. The allelic distribution analyses suggested a significant association between the T allele at rs861539 with an increased risk of childhood ALL in the Taiwanese population. Polymorphic variants of Our findings suggest that

Bone marrow T helper cells with a Th1 phenotype induce activation and proliferation of leukemic cells in precursor B acute lymphoblastic leukemia patients.

Precursor B cell acute lymphoblastic leukemia (BCP-ALL) constitutes the leading cause of cancer-related death in children. While chromosomal alterations contribute to BCP-ALL pathogenesis, they are insufficient for leukemia development. Epidemiological data and evidence from a mouse model suggest that immune responses to infections may trigger the emergence of leukemia, but the mechanisms remain unclear. Here, we show that T helper (Th) cells from bone marrow of pediatric BCP-ALL patients can be attracted and activated by autologous BCP-ALL cells. Bone-marrow Th cells supportively interacted with BCP-ALL cells, inducing upregulation of important surface molecules and BCP-ALL cell proliferation. These Th cells displayed a Th1-like phenotype and produced high levels of IFN-γ. IFN-γ was responsible for the upregulation of CD38 in BCP-ALL cells, a molecule which we found to be associated with early relapse, and accountable for the production of IP-10, a chemokine involved in BCP-ALL migration and drug resistance. Thus, our data provide mechanistic support for an involvement of Th cell immune responses in the propagation of BCP-ALL and suggest that BCP-ALL cell-supportive Th cells may serve as therapeutic target.

CNOT3 targets negative cell cycle regulators in non-small cell lung cancer development.

Lung cancer is one of the major causes of cancer death and clarification of its molecular pathology is highly prioritized. The physiological importance of mRNA degradation through the CCR4-NOT deadenylase has recently been highlighted. For example, mutation in CNOT3, a gene coding for CNOT3 subunit of the CCR4-NOT complex, is found to be associated with T-cell acute lymphoblastic leukemia, T-ALL, though its contribution to other cancers has not been reported. Here, we provide evidence suggesting that CNOT3 is required for the growth of non-small cell lung cancer. Depletion of CNOT3 suppresses proliferation of A549 human non-small cell lung cancer cells with enhanced mRNA stability and subsequent elevated expression of p21. In addition, we identified the mRNA for Krüppel-like factor 2 transcription factor, an inducer of p21, as a novel mRNA degradation target of CNOT3 in non-small cell lung cancer cells. Aberrant up-regulation of Krüppel-like factor 2 by CNOT3 depletion leads to impairment in the proliferation of A549 cells. Consistent with these findings, elevated mRNA expression of CNOT3 in non-small cell lung cancer in comparison with the paired normal lung epithelium was confirmed through scrutinization of the RNA-sequencing datasets from The Cancer Genome Atlas. Moreover, we found an inverse correlation between CNOT3 and CDKN1A (encoding p21) mRNA expression using the combined datasets of normal lung epithelium and non-small cell lung cancer. Thus, we propose that the up-regulation of CNOT3 facilitates the development of non-small cell lung cancer through down-regulation of Krüppel-like factor 2 and p21, contrary to tumor suppressive functions of CNOT3 in T-ALL.

Recurrent thrombosed external hemorrhoids due to L-asparaginase administration in a Philadelphia chromosome-positive acute lymphoblastic leukemia patient.

A 13-year-old female developed L-asparaginase (L-ASP) -associated thrombosed external hemorrhoids (TEH) during chemotherapy for Philadelphia chromosome-positive acute lymphoblastic leukemia. While undergoing induction therapy combined with imatinib, she experienced intense anal pain a day after the four-time administration of L-ASP. The anal verge contained painful bluish hemorrhoids, which reportedly were absent before the therapy commencement. Hemorrhoids occurred 5-9 days after every L-ASP treatment, which was eventually diagnosed as L-ASP-associated TEH. After the failure of conservative treatment, opioid therapy was initiated. During myeloid reconstitution, she underwent divided ligation of hemorrhoids however, the hemorrhoids became necrotic and formed an ulcerated tissue bed. This case suggests that while undertaking L-ASP therapy in adolescents and young adults with acute lymphoblastic leukemia, physicians should monitor signs of hemorrhoids and consider divided ligation when appropriate.

Recent advances in CAR T-cell toxicity Mechanisms, manifestations and management.

Chimeric antigen receptor (CAR) T-cell therapy is an effective new treatment for hematologic malignancies. Two CAR T-cell products are now approved for clinical use by the U.S. FDA tisagenlecleucel for pediatric acute lymphoblastic leukemia (ALL) and adult diffuse large B-cell lymphoma subtypes (DLBCL), and axicabtagene ciloleucel for DLBCL. CAR T-cell therapies are being developed for multiple myeloma, and clear evidence of clinical activity has been generated. A barrier to widespread use of CAR T-cell therapy is toxicity, primarily cytokine release syndrome (CRS) and neurologic toxicity. Manifestations of CRS include fevers, hypotension, hypoxia, end organ dysfunction, cytopenias, coagulopathy, and hemophagocytic lymphohistiocytosis. Neurologic toxicities are diverse and include encephalopathy, cognitive defects, dysphasias, seizures, and cerebral edema. Our understanding of the pathophysiology of CRS and neurotoxicity is continually improving. Early and peak levels of certain cytokines, peak blood CAR T-cell levels, patient disease burden, conditioning chemotherapy, CAR T-cell dose, endothelial activation, and CAR design are all factors that may influence toxicity. Multiple grading systems for CAR T-cell toxicity are in use a universal grading system is needed so that CAR T-cell products can be compared across studies. Guidelines for toxicity management vary among centers, but typically include supportive care, plus immunosuppression with tocilizumab or corticosteroids administered for severe toxicity. Gaining a better understanding of CAR T-cell toxicities and developing new therapies for these toxicities are active areas of laboratory research. Further clinical investigation of CAR T-cell toxicity is also needed. In this review, we present guidelines for management of CRS and CAR neurotoxicity.

Impact of anti-thymocyte globulin on results of allogeneic peripheral blood stem cell transplantation for patients with Philadelphia-positive acute lymphoblastic leukaemia An analysis by the Acute Leukemia Working Party of the EBMT.

Anti-thymocyte globulin (ATG) is widely used to prevent graft-versus-host disease (GVHD) after allogeneic peripheral blood stem cell transplantation (alloPBSCT). The goal of this study was to retrospectively assess the effect of ATG on outcomes in the setting of Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph ALL). In the analysis, 1170 adult patients undergoing alloPBSCT from human leucocyte antigen-matched sibling or unrelated donors in the first complete remission between 2007 and 2016 were included. ATG was used in 429575 (75%) and 121595 (20%) patients transplanted from unrelated or sibling donors, respectively. The incidence of chronic GVHD was 35% for patients treated with ATG compared with 52% in those not receiving ATG (p < 0.001), while the rate of extensive chronic GVHD was 16% and 36%, respectively (p < 0.001). The probability of survival free from GVHD and relapse (GRFS) was 42% and 32%, respectively (p 0.002). In a multivariate model, the use of ATG was associated with reduced risk of overall chronic GVHD (hazard ratio HR 0.52, p < 0.001) and extensive chronic GVHD (HR 0.46, p < 0.001). It was also associated with better GRFS (HR 0.77, p 0.007), despite increased risk of relapse (HR 1.41, p 0.02). No significant effect was found with regard to the risk of non-relapse mortality and overall mortality. The use of ATG for patients with Ph ALL undergoing alloPBSCT is associated with reduced risk of chronic GVHD without impact on survival and therefore, could be considered. However, increased risk of relapse suggests the need for strict monitoring of minimal residual diseases and appropriate interventions after transplantation.

Chemotherapy-free and reduced intensity approaches in elderly patients with B-lineage acute lymphoblastic leukemia.

Management of older patients - defined by convention above the age of 60 years, but varying widely within study groups - with acute lymphoblastic leukemia (ALL) is still a challenge. The complete remission (CR) rate in these patients is lower than in other age groups and the percentage of deaths in induction or in CR remains high, ranging from 7 to 40%. Overall survival rates do not exceed 30%, depending on the age group included in the different trials group and on the follow-up duration. These unsatisfactory results are sustained by the fact that pre-existing comorbidities often hamper treatment delivery and if treatment intensification improves the CR rates it also increases toxicity and the percentage of deaths. Overall, the median life expectancy is rising world-wide, being in the western world aroundover 80 years (and increasing) in addition, the proportion of elderly individuals is growing progressively. This means that the management of these frail patients represents a true clinical unmet need. While in Ph ALL the introduction of tyrosine kinase inhibitors (TKI) has markedly impacted on the outcome of patients of all ages, in Ph- ALL prognosis in the elderly still remains largely unsatisfactory. Novel strategies - mostly based on the use of monoclonal antibodies or of targeted strategies if druggable mutations can be identified - are largely needed. In the present review, we will discuss the past and current scenario, and provide an overview on the developing approaches for both Ph- and Ph elderly ALL, represented in particular by immunotherapy.

WITHDRAWN Fok1 and Col1A1 Gene Polymorphisms and Development of Treatment-Related Bone Complications in Children with Acute Lymphoblastic Leukemia focus on molecular change.

Ahead of Print article withdrawn by Editor.

Minimal residual disease-based long-term efficacy of reduced-intensity conditioning versus myeloablative conditioning for adult Philadelphia-positive acute lymphoblastic leukemia.

The sensitivity of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) to reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) versus myeloablative conditioning (MAC) allogeneic HCT by minimal residual disease (MRD) kinetics is not well established. This study compared long-term outcomes based on MRD kinetics for 79 patients with RIC transplants and 116 patients with MAC transplants in first complete remission (CR1) after tyrosine kinase inhibitor-based chemotherapy (median follow-up, 67.1 months). MRD monitoring was centrally evaluated by real-time quantitative polymerase chain reaction for all patients. RIC showed a cumulative incidence of relapse (CIR 30.6% vs 31.7%), nonrelapse mortality (17.5% vs 14.9%), disease-free survival (DFS 51.9% vs 53.4%), and overall survival (61.1% vs 61.4%) comparable to those associated with MAC. In all MRD kinetics-based subgroups, no differences in CIR (early complete molecular response CMR, 19.3% vs 4.8% early major molecular response MMR, 17.0% vs 26.8% late CMR, 20.0% vs 14.3% late MMR, 28.3% vs 31.0% poor molecular response PMR, 57.9% vs 62.4%) or DFS (early CMR, 71.6% vs 76.2% early MMR, 66.9% vs 52.1% late CMR, 50.0% vs 64.3% late MMR, 50.7% vs 53.7% PMR, 31.6% vs 34.1%) were observed between RIC and MAC. In a multivariate analysis, the conditioning intensity had no significant impact on transplantation outcomes. RIC is a valid alternative choice for long-term disease control and is worthy of further investigation in prospective trials for adult Ph-positive ALL in CR1.

CTL019 (tisagenlecleucel) CAR-T therapy for relapsed and refractory B-cell acute lymphoblastic leukemia.

Over the past decades, survival of patients with acute lymphoblastic leukemia (ALL) has dramatically improved, but the subgroup of patients with relapsedrefractory ALL still continues to have dismal prognosis. As an emerging therapeutic approach, chimeric antigen receptor-modified T-cells (CAR-T) represent one of the few practice-changing therapies for this subgroup of patients. Originally conceived and built in Philadelphia (University of Pennsylvania), CTL019 or tisagenlecleucel, the first CAR-T approved by the US Food and Drug Administration, showed impressive results in refractoryrelapsed ALL since the publication on two pediatric patients in 2013. It is in this context that we provide a review of this product in terms of manufacturing, pharmacology, toxicity, and efficacy studies. Evaluation and management of toxicities, particularly cytokine release syndrome and neurotoxicity, is recognized as an essential part of the patient treatment with broader use of IL-6 receptor inhibitor. An under-assessed aspect, the quality of life of patients entering CAR-T cells treatment, will also be reviewed. By their unique nature, CAR-T cells such as tisagenlecleucel operate in a different way than typical drugs, but also provide unique hope for B-cell malignancies.

A retrospective comparison of allogenic and autologous chimeric antigen receptor T cell therapy targeting CD19 in patients with relapsedrefractory acute lymphoblastic leukemia.

The source of CAR T cells can be autologous (autoCAR) or allogeneic (alloCAR). The latter is seen in patients with a history of allogeneic hematopoietic stem cell transplantation, and can be either donor-derived (DD-alloCAR) or recipient-derived (RD-alloCAR). While autoCAR is activated by CAR only, alloCAR receives activation signals from both T-cell receptor (TCR) and CAR. As a result, the biological differences could impact clinical outcomes. We retrospectively reviewed 31 patients 17 received autoCAR, 11 received RD-alloCAR, and 3 received DD-alloCAR. After a median follow-up of 9 months, CR rate was 88.2% (95% CI 63.6-98.5%) in autoCAR and 100% (95% CI 71.5-100%) in RD-alloCAR. The median peak expansion in the autoCAR was significantly higher than the RD-alloCAR group (p 0.007). RD-alloCAR group had significantly less patients with severe CRS (Grade ≥ 3) than the autoCAR group (p 0.049). Acute graft-versus-host disease (GVHD) occurred in 2 (18.2%) of RD-alloCAR patients and 1 (33.3%) of DD-alloCAR patients. Univariate subgroup analysis of alloCAR group showed the presence of cGVHD at the time of T-cell collection was significantly associated with less than 6-month relapses (p 0.022). RD-alloCAR patients with or without cGVHD at PBMC collection did not differ regarding the peak CAR T-cell expansion, CRS grades and OS.

Eradication of Central Nervous System Leukemia of T-Cell Origin with a Brain-Permeable LSD1 Inhibitor.

Lysine-specific demethylase 1 (LSD1) regulates several biological processes via the bifunctional modulation of enhancer functions. Recently, we reported that LSD1 overexpression is a founder abnormality of T-cell leukemogenesis and is maintained in fully transformed T-cell acute lymphoblastic leukemia (T-ALL) cells. On the basis of this finding, we attempted to develop novel LSD1 inhibitors effective for T-ALL with central nervous system (CNS) involvement. We chemically modified the prototype LSD inhibitor tranylcypromine (TCP) and screened for cytotoxicity against TCP-resistant T-ALL cell lines. We found robust cytotoxicity against T-ALL cells, but not normal bone marrow progenitors, for two These findings provide a molecular basis and rationale for the inclusion of a brain-permeable LSD1 inhibitor, S2157, in treatment strategies for T-ALL with CNS involvement.

FLAGFLAG-IDA regimen for children with relapsedrefractory acute leukemia in the era of targeted novel therapies.

Outcomes of relapsedrefractory childhood acute leukemia remain poor. We analyzed the safetyefficacy of fludarabine, cytarabine, and granulocyte colony stimulating factor, withwithout idarubicin (FLAG ± IDA) as salvage therapy compared with recent published results of novel therapies. This retrospective study included children aged 1 to 15 years with relapsedrefractory acute leukemia who received FLAG ± IDA salvage therapy from January 2000 to December 2014. Patients with infant leukemia, mixed lineage leukemia, Philadelphia-positive acute leukemia, or secondary leukemia were excluded. Fifty patients were identified 25 with acute lymphoblastic leukemia and 25 with acute myeloid leukemia. The median age at initiation of FLAG ± IDA was seven years. Site of relapse was the bone marrow in 29, isolated central nervous system in 11, and combined in 10 patients. FLAG ± IDA was used after first relapse in 68% and after multiple relapses in 32%. Complete remission was achieved in 34 (68%) patients. No variables predictive of complete remission were identified. Grade 3 or greater toxicity was observed in 96% and 6% died from toxicity. Toxicities included hematologic toxicity (96%), infection (52%), and enterocolitis (28%). Twenty-four of 50 (48%) patients achieved a sustained complete remission and survived to bone marrow transplantation. The five-year overall survival was 23.9% ± 6.9%. Patients achieving second complete remission and patients proceeding to bone marrow transplantation following second complete remission demonstrated significantly improved overall survival (p 0.001). Despite a 68% complete remission rate using FLAG ± IDA, only 48% of patients survived to bone marrow transplantation. The regimen was associated with 96% toxicity and only one in four patients was alive at five years. This underscores the need to find more effective lower toxicity salvage regimens.

Quantification of Thiopurine Nucleotides in Erythrocytes and Clinical Application to Pediatric Acute Lymphoblastic Leukemia.

Concentrations of 6-thioguanine (6TG) nucleotides and 6-methylmercaptopurine (6MMP) nucleotides in RBCs were measured using liquid chromatography-tandem mass spectrometry (LC-MSMS). This assay was validated for clinical use and was applied to blood samples from patients taking mercaptopurine (6MP). RBCs were hemolyzed and deproteinized using perchloric acid, followed by heating for the hydrolysis of nucleotides, and the resultant base was measured using LC-MSMS. Precision, recovery, linearity, matrix effect, and limit of quantification was validated for clinical application. Our results were compared with another institutions established LC-MSMS assay. We measured the concentrations of 6TG and 6MMP in RBCs of pediatric patients with acute lymphoblastic leukemia (ALL), and the clinical impact of those metabolites was investigated. The imprecision coefficient of variations of 6TG and 6MMP were 5.7%-8.1%, and the bias was within 5%. Lower limits of quantification were set at 54 ngmL for 6TG and 1036 ngmL for 6MMP. Correlation coefficients for 6TG and 6MMP were 0.997 and 1.0 in a comparison study. For clinical proof-of-concept, 74 blood samples were collected from 37 pediatric ALL patients receiving maintenance therapy. Concentration of 6TG ranged from 16.1 to 880 pmol8 × 10 RBCs and that of 6MMP from 55 to 20,937 pmol8 × 10 RBCs. The 6MP metabolites were not correlated with WBC or absolute neutrophil count. On the other hand, the higher 6MMP level was associated with elevated alanine aminotransferase and aspartate aminotransferase. In this study, an assay for the quantification of 6TG and 6MMP in RBCs was established and applied to pediatric ALL patients. Interindividual variability in 6MP metabolite concentrations was considerable and associated with elevation of liver enzymes, which may be useful in the clinical monitoring of 6MP maintenance therapy in pediatric ALL patients.

In Vitro Cytotoxicity of Folate-Silica-Gold Nanorods on Mouse Acute Lymphoblastic Leukemia and Spermatogonial Cells.

The purpose of this study was to evaluate in vitro cytotoxicity of gold nanorods (GNRs) on the viability of spermatogonial cells (SSCs) and mouse acute lymphoblastic leukemia cells (EL4s). In this experimental study, SSCs were isolated from the neonate mice, following enzymatic digestion and differential plating. GNRs were synthesized, then modified by silica and finally conjugated with folic acid to form F-Si-GNRs. Different doses of F-Si-GNRs (25, 50, 75, 100, 125 and 140 μM) were used on SSCs and EL4s. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) proliferation assay was performed to examine the GNRs toxicity. Flow cytometry was used to confirm the identity of the EL4s and SSCs. Also, the identity and functionality of SSCs were determined by the expression of specific spermatogonial genes and transplantation into recipient testes. Apoptosis was determined by flow cytometry using an annexin Vpropidium iodide (PI) kit. Flow cytometry showed that SSCs and EL4s were positive for Plzf and H-2kb, respectively. The viability percentage of SSCs and EL4s that were treated with 25, 50, 75, 100, 125 and 140 μM of F-Si-GNRs was 65.33 ± 3.51%, 60 ± 3.6%, 51.33 ± 3.51%, 49 ± 3%, 30.66 ± 2.08% and 16.33 ± 2.51% for SSCs and 57.66 ± 0.57%, 54.66 ± 1.5%, 39.66 ± 1.52%, 12.33 ± 2.51%, 10 ± 1% and 5.66 ± 1.15% for EL4s respectively. The results of the MTT assay indicated that 100 μM is the optimal dose to reach the highest and lowest level of cell death in EL4s and in SSCs, respectively. Cell death increased with increasing concentrations of F-Si-GNRs. Following utilization of F-Si-GNRs, there was a significant difference in the extent of apoptosis between cancer cells and SSCs.

Genetic Variants Associated With Vincristine-Induced Peripheral Neuropathy in Two Populations of Children With Acute Lymphoblastic Leukemia.

Vincristine is one of the core chemotherapy agents used in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, one of the major toxicities resulting from vincristine exposure is vincristine-induced peripheral neuropathy (VIPN). When VIPN results in significant morbidity, the vincristine dose may need to be reduced, thus potentially decreasing the effectiveness of treatment. To date, there are no robust biomarkers used clinically to determine which patients will be at risk for worse neuropathy. The current study included genomewide association study (GWAS) in two independent cohorts Pediatric Oncology Group (POG) ALL trials and a multicenter study based at Indiana University in children with ALL. A meta-analysis of the cohorts identified two single-nucleotide polymorphisms (SNPs), rs1045644 and rs7963521, as being significantly (P value threshold 0.054749 1.05E-05) associated with neuropathy. Subsequently these SNPs may be effective biomarkers of VIPN in children with ALL.

Genetics and prognosis of ALL in children vs adults.

Acute lymphoblastic leukemia (ALL) is characterized by genetic alterations that block differentiation, promote proliferation of lymphoid precursor cells, and are important for risk stratification. Although ALL is less common in adolescents and young adults (AYAs) and adults than children, survival rates are inferior, and long-term prognosis for adults is poor. Thus, ALL remains a challenging disease to treat in the AYA and adult populations. A major contributing factor that influences prognosis in this population is the reduced prevalence of genetic subtypes associated with favorable outcome and a concomitant increase in subtypes associated with poor outcome. Recent advances in genomic profiling across the age spectrum continue to enhance our knowledge of the differences in disease biology between children and adults and are providing important insights into novel therapeutic targets. Philadelphia chromosome-like (Ph-like) ALL is one such subtype characterized by alterations that deregulate cytokine receptor or tyrosine kinase signaling and are amenable to inhibition with approved tyrosine kinase inhibitors. One of the greatest challenges now remaining is determining how to implement this breadth of genomic information into rapid and accurate diagnostic testing to facilitate the development of novel clinical trials that improve the outcome of AYAs and adults with ALL.

No free rides management of toxicities of novel immunotherapies in ALL, including financial.

Therapeutic options for acute lymphoblastic leukemia, especially in the relapsedrefractory setting, have expanded significantly in recent times. However, this comes at the cost of toxicities medical as well as financial. We highlight some of the unique toxicities associated with the novel agents to apprise our readers about what to expect, how to recognize them, and how to manage these toxicities. One of the toxicities seen with inotuzumab, a CD22 antibody drug conjugate, is sinusoidal obstruction syndrome, which can be fatal in >80% of patients if associated with multiorgan failure. Blinatumomab, a monoclonal antibody targeting CD19, is associated with cytokine release syndrome (CRS) and neurotoxicity, both of which require prompt recognition and management primarily with corticosteroids. CRS and neurotoxicity are more common and more severe with chimeric antigen receptor T-cell therapy (CAR-T). The fact that CAR-T cannot be discontinued on demand adds a layer of complexity to the management of related toxicities of this therapy. Tocilizumab, an interleukin-6 receptor blocker, is used to treat severe CRS from CAR-T, whereas corticosteroids remain the mainstay for neurotoxicity management. Although effective, these drugs carry a high price tag, and we review the available data on cost-effectiveness of these agents, keeping in mind that median follow-up on most of these studies is limited and that long-term data on durability of response remain to be seen.

Are CAR T cells better than antibody or HCT therapy in B-ALL

Multicenter trials in children and young adults using second-generation CD19-targeted chimeric antigen receptor (CAR) T cells have shown dramatic levels of remission in patients with multiply relapsedrefractory disease (80% to ≥90%). Early results in adult trials have also shown significant responses, and strategies aimed at mitigating toxicities associated with the therapy have improved tolerability. Therefore, if available, CAR T-cell therapy deserves consideration for salvage of children and adults with B-lineage acute lymphoblastic leukemia (B-ALL) who are multiply relapsed, refractory, or relapsed after a previous allogeneic transplantation. For patients with a first relapse or who have persistent minimal residual disease (MRD) after initial or relapse therapy, treatment with blinatumomab or inotuzumab is reasonable to help patients achieve MRD

Antibody-based therapies in patients with acute lymphoblastic leukemia.

The use of multiagent combination chemotherapy regimens results in cure rates of >90% for children and ∼40% for adults with acute lymphoblastic leukemia (ALL) but is associated with extensive toxicity and disappointingly low efficacy in relapsed patients. ALL blast cells express several surface antigens, including CD20, CD22, and CD19, which represent valuable targets for immunotherapy. Monoclonal antibodies, antibody-drug conjugates, and bispecific T-cell-engaging antibodies targeting these antigens offer novel mechanisms of action. Within the last several years, the anti-CD20 antibody rituximab has been added to chemotherapy for newly diagnosed patients <60 years with CD20

Exploring the Potential of a Pretend Play Intervention in Young Patients With Leukemia.

The aims of the study are 1) to gain knowledge of parents and professionals perceptions about cancer stricken childrens resources, burdens, and ability to pretend play, and 2) to prepare the initiation of a pretend play intervention based on childrens needs and included parents and professionals feedback. Qualitative design using semi-structured interviews with 13 parents of children diagnosed with leukemia and 15 professionals in the field of pediatric oncology. Themes were derived with content analysis via deductive and inductive coding. Analysis resulted in five topics. (1) Ability to play in the context of leukemia (2) ways of coping with leukemia (3) difficulty in transition to normality (4) parental quality of life and parents needs (5) perceptions of the potential of pretend play. Study results indicate the potential of pretend play interventions for young cancer patients and the need for additional professional support of parents. Pretend play is a tool children carry with them regardless of their circumstances. If we can enhance their ability to play, doing so should give them an advantage in creative problem solving and creative expression as they deal with a life threatening disease.

Philadelphia chromosome-like acute lymphoblastic leukemia A review of the genetic basis, clinical features, and therapeutic options.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a recently identified high-risk subtype of B-lineage ALL (B-ALL), characterized by a gene expression profile similar to that of Philadelphia-positive (Ph) ALL, but without the hallmark BCR-ABL1 oncoprotein. Ph-like ALL represents approximately 15% of childhood ALL and its frequency rises with age, peaking among adolescents, and young adults with B-ALL. This subtype is associated with adverse clinical features, persistence of minimal residual disease, and a poor prognosis despite modern chemotherapy regimens. While Ph-like ALL lacks the BCR-ABL1 fusion, it is characterized by a diverse spectrum of kinase fusions and cytokine receptor gene rearrangements that may be similarly amenable to molecularly targeted therapies. While survival rates for childhood ALL have drastically improved with intensive conventional chemotherapy, Ph-like ALL represents a novel paradigm of precision medicine in ALL. This review aims to provide a comprehensive review of the clinical picture and genetic basis of Ph-like ALL and to illustrate how these findings can translate into tailored targeted therapies with the hopes of improving the outcomes of Ph-like ALL patients.

Imatinib treatment of paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (EsPhALL2010) a prospective, intergroup, open-label, single-arm clinical trial.

The EsPhALL2004 randomised trial showed a 10% advantage in disease-free survival for short, discontinuous use of imatinib after induction compared with no use of imatinib in patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia receiving Berlin-Frankfurt-Münster chemotherapy and haemopoietic stem-cell transplantation (HSCT). Other contemporary studies showed an advantage from continuous protracted exposure to imatinib, challenging the indications to transplant. The EsPhALL2010 study was designed to assess whether imatinib given from day 15 of induction and continuously throughout chemotherapy led to a different outcome to that obtained in EsPhALL2004, despite decreasing the number of patients having HSCT. This prospective, intergroup, open-label, single-arm clinical trial (EsPhALL2010) was done at 11 study groups across Europe, Chile, and Hong Kong. Patients aged 1-17 years with the translocation t(922)(q34q11) who were recruited into national front-line trials for acute lymphoblastic leukaemia were eligible for this trial. Patients with abnormal renal or hepatic function or an active systemic infection were ineligible. Patients received imatinib 300 mgm 158 patients were screened for eligibility, of whom 155 were enrolled between Jan 1, 2010, and Dec 31, 2014. 151 (97%) patients achieved first complete remission after induction and four after the consolidation phase, with 102 (66%) patients categorised as good risk and 53 (34%) as poor risk according to EsPhALL risk stratification criteria. 59 (38%) patients had HSCT during their first complete remission. 40 (26%) patients relapsed and 41 (26%) patients died during the study (25 61% during complete continuous remission, and 16 39% after relapse). The 5-year event-free survival was 57·0% (95% CI 48·5-64·6) and 5-year overall survival was 71·8% (63·5-78·5). 154 serious adverse events were reported in 80 (52%) of 155 patients. The most common toxicity was infection (61 39% patients, mostly bacterial) gastrointestinal disorders occurred in ten (6%) patients and osteonecrosis in eight (5%). Serious adverse events occurred mainly during high-risk blocks and delayed intensifications, including 14 fatal events (one in the consolidation phase, six in high-risk blocks, six in first delayed intensification, and one in second delayed intensification). Although HSCT was done in a smaller proportion of patients in EsPhALL2010 than in EsPhALL2004, event-free and overall survival were similar between the two studies. Our data suggest that imatinib given early and continuously with intensive chemotherapy might increase toxicity. Projet Hospitalier de Recherche Clinique-Cancer and Novartis France Bloodwise and Cancer Research UK Ministry of Health, Czech Republic.

Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia long-term follow-up of a single-centre, phase 2 study.

The combination of chemotherapy and ponatinib in Philadelphia chromosome-positive acute lymphoblastic leukaemia has the potential to be a new standard of care for the disease however, long-term efficacy and safety data are needed. Our aim was to evaluate the long-term efficacy and safety of this regimen in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia in this ongoing phase 2 trial. In our single-centre, phase 2, single-arm trial in the USA, adult patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia were sequentially enrolled. Eligible patients had newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia, were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 2 or less, a left ventricular ejection fraction above 50%, and adequate hepatic and renal function (serum bilirubin ≤3·0 mgdL and serum creatinine ≤3·0 mgdL, unless higher levels were believed to be due to leukaemia at the discretion of the investigator). Patients received eight cycles of 21 days, alternating between two drug combinations hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and high-dose methotrexate and cytarabine. Ponatinib was given orally at 45 mg per day for the first 14 days of cycle 1 then continuously at 45 mg per day for the subsequent cycles. After 37 patients were treated, the protocol was amended to reduce the dose of ponatinib to 30 mg per day at cycle 2, with further reduction to 15 mg once a complete molecular response (defined as absence of quantifiable BCR-ABL1 transcripts) was achieved. Patients in complete remission received maintenance with ponatinib daily (30 mg or 15 mg) indefinitely, and with vincristine (2 mg intravenously on day 1) and prednisone (200 mg orally on days 1-5) monthly for 2 years. The primary endpoint was 3-year event-free survival in the intention-to-treat population. The trial is registered at ClinicalTrials.gov, number NCT01424982, and is ongoing and still enrolling patients. 76 patients with a median age of 47 years (IQR 39-61) were enrolled and treated between Nov 19, 2011, and April 4, 2018. The 3-year event-free survival was 70% (95% CI 56-80). The most common grade 3 or 4 adverse events were infection (n65, 86%), increased transaminases (n24, 32%), increased bilirubin (n13, 17%), pancreatitis (n13, 17%), hypertension (n12, 16%), bleeding (n10, 13%), and skin rash (n9, 12%). Six patients died while still on study treatment. Three patients (4%) died from infection and one (1%) from haemorrhage. Two patients died from myocardial infarction related to early ponatinib use neither death occurred after protocol revision. The combination of chemotherapy with ponatinib is effective in achieving long-term remission in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia. This regimen could represent a new standard of care for this population. A randomised, phase 3 study to evaluate the efficacy of this combination compared with chemotherapy plus earlier-generation tyrosine-kinase inhibitors is warranted. Takeda Oncology.

Study on Immunophenotypes and Gene of Acute Lymphoblastic Leukemia--Review.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is one of the fatal complications of hematopoietic stem cell transplantation(HSCT). The pathogenesis of TA-TMA has not been fully elucidated. The latest researches show that the abnormal activation of the complement system may lead to widespread endothelial injury which may play an important role in the pathogenesis of this disease. Incontrotable hypertension, proteinuria, increase of soluble C5b-9 concentration and early pericardial effusion are the risk factors of TA-TMA . In this review, the latest advances of pathogenesis, early diagnosis, treatment and other aspects of the progress of TA-TMA are summarized, so as to provide new ideas to early diagnosis and treatment in TA-TMA.

Effect of IL-8 on the Immune Function of Patients with Acute -Lymphoblastic Leukemia and Its Mechanism.

To investigate the effect of interleukin -8 (IL-8) on immune function in acute lymphoblastic leukemia patients and its related mechanisms. Forty-five ALL patients were selected from January 2014 to September 2017 in our hospital. Out of them, 32 relieved patients were included in group A, 13 patients did not relieved patients after treatment and were included in the group B. The serum IL-8 level was detected by ELISA.Th1 and Th2 cells were measured by flow cytometry. After Th cells were treated with different concentration of IL-8, the Western blot was used to detect the translation levels of p-STAT3 and JAK in cells. The difference of white blood cell count and clinical risk level between the 2 groups was statistically significant (P<0.05). The serum IL-8 levels in group A and B were significantly higher than that in control group (P<0.05). The serum IL-8 level in group B was significantly higher than that in group A (P<0.05). After treatment, the level of Th1 cells in group B was 6.15%±1.22%, significantly lower than that in group A (P<0.05), and Th2 cell level in group B was 2.76%±0.24%, significantly higher than that in group A (P<0.05) Th1Th2 in group B was 2.23%±0.09, significantly lower than that in group A (P<0.05). The protein level of p-STAT3 and JAK in the Th cells was lower than that in control group at different levels of IL-8 after treatment (P<0.05). After stimulating Th cells with 20 ngml IL-8, the levels of p-STAT3 and JAK protein in cells were lower than those after 10 ngml IL-8 treatment (P<0.05). IL-8 level had no significant effect on the protein expression of STAT3 in Th cells (P>0.05). IL-8 can interfere the balance of Th1Th2 through STAT3 signaling pathway, and has effect on the immune function of ALL patients.

Global and disease-free survival in a peruvian cohort of patients with acute lymphoblastic leukemia.

To know the five-year survival and its associated factors in patients with Acute Lymphoblastic Leukemia (ALL) in Peru. A retrospective cohort of patients with ALL treated with chemotherapy in a Peruvian hospital for 13 years was studied. The dependent variables were overall survival (OS) and disease-free survival (DFS). Possible factors that might be associated with diagnosis and response to treatment were evaluated using the Cox proportional risk method. The mortality rate was 32.5% and the relapse rate was 66.1%. The factors associated with lower overall survival were leukocyte count at diagnosis (HR 1.01 95% CI 1.01-1.03), lineage other than B (HR 2.15 95% CI 1,06-4,41), age at diagnosis (HR 1,09 95% CI 1,03-1,16), bone marrow relapse (HR 6,81 95% CI 4,14- 11,21) and induction failure (HR 3,04 95% CI 1,47-6,32). Factors associated with lower disease-free survival male gender (HR 1.43 95% CI 1.10-1.86), age at diagnosis (HR 1.06 95% CI 1.02-1.10) and leukocytes at diagnosis (HR 1.01 95% CI 1.002-1.011). The five-year OS and DFS figures for our population are lower than those for the world. More studies are needed to know the factors involved in this reality and thus generate interventions aimed at improving the survival and quality of life of our patients. The variables associated with the decrease in both survival indicators were age and leukocyte count at the time of diagnosis, so the process of disease diagnosis must be improved. Objetivos. Conocer la supervivencia a los cinco años y sus factores asociados, en pacientes con Leucemia Linfoblástica Aguda (LLA) en Perú. Materiales y Métodos. Se estudió una cohorte retrospectiva sobre pacientes con LLA tratados con quimioterapia en un hospital peruano por 13 años. Las variables dependientes fueron sobrevida global (SG) y sobrevida libre de enfermedad (SLE). Los posibles factores que pudieran estar asociados con el diagnóstico y la respuesta al tratamiento se evaluaron a través del método de riesgos proporcionales de Cox. Resultados. La tasa de mortalidad fue 32,5 % y de recaídas fue 66,1 %. Los factores asociados a menor sobrevida global fueron recuento leucocitario al diagnóstico (HR 1,01 IC95 % 1,01-1,03), estirpe distinta a B (HR 2,15 IC95 % 1,06-4,41), edad al diagnóstico (HR 1,09 IC95 % 1,03-1,16), recaída en médula ósea (HR 6,81 IC95 % 4,14-11,21) y falla a la inducción (HR 3,04 IC95 % 1,47-6,32). Los factores asociados a menor sobrevida libre de enfermedad género masculino (HR 1,43 IC95 % 1,10-1,86), edad al diagnóstico (HR 1,06 IC95 % 1,02-1,10) y leucocitos al diagnóstico (HR 1,01 IC95 % 1,002-1,011). Conclusiones. Las cifras de SG y SLE a cinco años de nuestra población son inferiores a las mundiales. Se requieren más estudios para conocer los factores involucrados a esta realidad y así, generar intervenciones destinadas a mejorar la sobrevida y calidad de vida de nuestros pacientes. Las variables asociadas a la disminución de ambas sobrevidas fueron la edad y el recuento de leucocitos al momento del diagnóstico, por lo que se deben mejorar el proceso de diagnóstico de esta enfermedad.

Cost associated with hematopoietic stem cell transplantation a retrospective claims data analysis in Germany.

Quantify hematopoietic stem cell transplantation (HSCT) costs in German patients with acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). The primary outcome was direct and indirect costs in patients with ALLDLBCLFL who received HSCT between 2010 and 2014. Costs were evaluated two to four quarters before to eight quarters after HSCT. Among 258 patients with HSCT, direct costs were €290,125patient (pediatric ALL), €246,266patient (adult ALL), €230,399patient (DLBCLFL allogeneic) and €107,457patient (DLBCLFL autologous). Indirect costs with HSCT were €52,939patient (adult ALL), €20,285patient (DLBCLFL allogeneic) and €29,881patient (DLBCLFL autologous). Direct and indirect costs associated with HSCT are substantial for patients with ALL, DLBCL and FL. Novel therapies that reduce HSCT use could reduce medical costs.

Identification of Deregulated Signaling Pathways in Jurkat Cells in Response to a Novel Acylspermidine Analogue-N

Natural polyamines such as putrescine, spermidine, and spermine are crucial in the cell proliferation and maintenance in all the eukaryotes. However, the requirement of polyamines in tumor cells is stepped up to maintain tumorigenicity. Many synthetic polyamine analogues have been designed recently to target the polyamine metabolism in tumors to induce apoptosis. N

Centromere-associated protein E expresses a novel mRNA isoform in acute lymphoblastic leukemia.

The alternative splicing plays an important role to generate protein diversity. Recent studies have shown alterations in alternative splicing, resulting in loss, gain or changes of functions in the resulting protein. Specific products of alternative splicing are known to contribute in cancer-related mechanisms, such as angiogenesis, migration, adhesion and cell proliferation, among others. We using high-density microarrays reported a CENP-E as a one of significant transcript expressed and potentially is alternatively spliced in cancer. We focus in validate alternative splicing of CENP-E transcript using RT-PCR and sequencing in different cancer cell lines. We performed RT-PCR using specific primers designed to delimit the non-reported alternative splicing in CENP-E transcript. Our results showed the co-expression of the variant one and two of CENP-E in all cell lines evaluated. We detected more expression of variant one than two. Moreover, we identify an alternative 5splice site of CENP-E in the exon 38 and was observed in RoVa cell line. Additionally, we characterized alternative skipping from exon 20 (NAT-CENP-E), these alternative splicing was observed in all cell lines evaluated except RoVa. Finally, we corroborate alternative mRNA splicing in leukemia patients using quantitative RT-PCR, in 71.8% of the patients NAT-CENP-E is downregulated and 28.2% is overexpressed.

Single-cell mutation identification via phylogenetic inference.

Reconstructing the evolution of tumors is a key aspect towards the identification of appropriate cancer therapies. The task is challenging because tumors evolve as heterogeneous cell populations. Single-cell sequencing holds the promise of resolving the heterogeneity of tumors however, it has its own challenges including elevated error rates, allelic drop-out, and uneven coverage. Here, we develop a new approach to mutation detection in individual tumor cells by leveraging the evolutionary relationship among cells. Our method, called SCIΦ, jointly calls mutations in individual cells and estimates the tumor phylogeny among these cells. Employing a Markov Chain Monte Carlo scheme enables us to reliably call mutations in each single cell even in experiments with high drop-out rates and missing data. We show that SCIΦ outperforms existing methods on simulated data and applied it to different real-world datasets, namely a whole exome breast cancer as well as a panel acute lymphoblastic leukemia dataset.

Matrix association regionscaffold attachment region (MARSAR) sequence its vital role in mediating chromosome breakages in nasopharyngeal epithelial cells via oxidative stress-induced apoptosis.

Oxidative stress is known to be involved in most of the aetiological factors of nasopharyngeal carcinoma (NPC). Cells that are under oxidative stress may undergo apoptosis. We have previously demonstrated that oxidative stress-induced apoptosis could be a potential mechanism mediating chromosome breakages in nasopharyngeal epithelial cells. Additionally, caspase-activated DNase (CAD) may be the vital player in mediating the chromosomal breakages during oxidative stress-induced apoptosis. Chromosomal breakage occurs during apoptosis and chromosome rearrangement. Chromosomal breakages tend to cluster in certain regions, such as matrix association regionscaffold attachment region (MARSAR). We hypothesised that oxidative stress-induced apoptosis may result in chromosome breaks preferentially at the MARSAR sites. The AF9 gene at 9p22 was targeted in this study because 9p22 is a deletion site commonly found in NPC. By using MARSAR recognition signature (MRS), potential MARSAR sites were predicted in the AF9 gene. The predicted MARSAR sites precisely match to the experimentally determined MARSARs. Hydrogen peroxide (H These results reaffirm our previous findings that oxidative stress-induced apoptosis could be one of the potential mechanisms underlying chromosome breakages in nasopharyngeal epithelial cells. MARSAR may play a vital role in defining the location of chromosomal breakages mediated by oxidative stress-induced apoptosis, where CAD is the major nuclease.

The influence of polymorphisms in the drug transporter, ABCB1 on the toxicity of glucocorticoids in Saudi children with acute lymphoblastic leukaemia.

Glucocorticoids play essential roles in the treatment of childhood acute lymphoblastic leukaemia (ALL) however, treatment with these agents can result in severe side-effects. This study, the first of its kind in a Saudi population, investigates associations of ABCB1 gene polymorphisms (pharmacodynamics and pharmacokinetic) with the development of toxicity and side effects (glucose abnormality, liver toxicity and infection) in a small population of Saudi children with ALL. Three single nucleotide polymorphisms (SNPs) of the ABCB1 gene (rs 3213619 T129C, rs 2032582 G2677T and rs1045642 C3435T) were analysed in 70 Saudi children with ALL and 60 control subjects. Participants were treated according to the ALL 2000 study protocol. Toxicities were assessed and associations with genotypes were evaluated according to Common Toxicity Criteria (NCI-CTC). Significant associations were observed among carriers and the mutated genotype C3435T (ABCB1), which had an incidence of infection (p 0.05). Although no correlations were found between liver toxicity and glucose abnormalities for patients carrying ABCB1 SNPs, risk factors for liver toxicity were elevated by a factor of three for patients carrying the SNP G2677T, OR 3.00 (1.034-8.702). The risk factor of glucose abnormality toxicity for the patients carring T129C were increased three times OR 3.06 (0.486-19.198). In terms of infection incidence, polymorphism C3435T may contribute to potential life-threatening infections during paediatric ALL therapy, through glucocorticoid usage.

Ocular manifestations in acute lymphoblastic leukemia A five-year cohort study of pediatric patients.

To characterize ocular manifestations (OM) of pediatric patients treating for acute lymphoblastic leukemia (ALL) and to evaluate whether they are associated with well-described predictive risk factors for relapse, protocol (1999 or 2009), gender and cerebrospinal fluid infiltration. A prospective cohort study was conducted in children and adolescents with ALL from January 2013 to December 2017. The patients underwent ophthalmologic evaluations before starting treatment (D0), on the eighth day (D8), at the 28th day (D28), and at six months (D6 months). Ocular hypertension (OH) was considered in results above 21 mmHg. Measures of visual acuity <2040 were considered visual loss (VL). Fifty-five patients were examined and 18 (32.7%) presented OM, been OH (61.1%), retinal hemorrhage (22.2%) and VL (22.2%) the most frequent finds. A strong association was found between patients with OM and those with a high risk of relapse (p 0.035, Cramer V 0.31) and who used the 1999 protocol (p 0.022, Cramer V 0.32). The risk of OM in patients from the 1999 protocol was 2.917 (CI 1.099-7.742), while the risk of relapse it was 0.327 (CI 95% 0.107-0.999). Patients with ALL have a high incidence of OM due to the treatment and the disease itself, and it may even be asymptomatic and evolve with VL. Of these, we can highlight OH as the most prevalent. Patients submitted to the 1999 protocol and at high risk of relapse are more likely to present OM and these variables are strongly associated.

Characterization and optimization of extracellular L-Asparaginase production by selected Actinomycete strain isolated from an algerian wheat bran.

L-Asparaginase is an enzyme that hydrolyses the amino acid L-Asparagine into aspartic acid and ammonia. As a medication, L-Asparaginase is used in chemotherapy to treat acute lymphoblastic leukaemia by depleting circulating Asparagine and depriving tumor cells. Interest in Actinomycetes as potential producers of antibiotics and enzymes encouraged us to investigate an isolated strain (CA01) from soft wheat bran.The Actinomycete strain was characterized based on its morphological and biochemical characteristics and selected due to a proved promising ability to produce L-Asparaginase optimized in both solid and liquid media cultures.The conditions of enzyme production were standardized according to a one-factor-at-a-time (OFAT) experimental design.To obtain optimal medium combination, a Box-Behnken Response Surface Methodology (RSM) has been adopted by choosing the most influential factors. The optimal conditions for the enzyme production were (gl) L-Asparagine 10.7 Glucose 2.7 starch 7, in based medium containing (gl) K2HPO4 0.5 MgSO4, 7H2O 0.1, corresponding to an optimal enzymatic activity of 8.03 IUml at 27.83°C. The maximum production of enzyme was reached on the sixth day of experiment. The ANOVA test (P value ˂ 0.05) and adjusted R2 values close to the experimental R2 show that the obtained model of the active L-Asparaginase of CA01 strain production is significant with the following linear terms temperature, substrate concentration, Glucose concentration and there squared.

IKZF1 deletion and co-occurrence with other aberrations in a child with chronic myeloid leukemia progressing to acute lymphoblastic leukemia.

Chronic myeloid leukemia (CML) is a rare disease in children. Different from that in adults, childhood CML involves transformative events occurring over a short time period. CML transformation to lymphoid blast phase (BP) is associated with copy number abnormalities, characteristic of BCR-ABL1 positive acute lymphoblastic leukemia, but not of CML in the chronic phase. Here, we present an unusual case of CML progressing to BP in a 1.6-year-old child, harboring IKZF1, PAX5, CDKN2A, and ETV6 deletions at diagnosis. It remains to be addressed whether distinct mechanisms might account for CML pathogenesis in early childhood.

Epidemiology of invasive fungal infections in immunocompromised children an Australian national 10-year review.

A thorough understanding of local and contemporary invasive fungal infection (IFI) epidemiology in immunocompromised children is required to provide a rationale for targeted prevention and treatment strategies. Retrospective data over 10 years from four tertiary pediatric oncology and hematopoietic stem cell transplant (HSCT) units across Australia were analyzed to report demographic, clinical, and mycological characteristics of IFI episodes, and crude IFI prevalence in select oncologyHSCT groups. Kaplan-Meier survival analyses were used to calculate 180-day overall survival. A total of 337 IFI episodes occurred in 320 children, of which 149 (44.2%), 51 (15.1%), and 110 (32.6%) met a modified European Organization for Research and Treatment of Cancer (mEORTC) criteria for proven, probable, and possible IFI, respectively. There were a further 27 (8.0%) that met a modified possible IFI criteria. Median age at IFI diagnosis was 8.4 years. Crude mEORTC IFI prevalence in acute lymphoblastic leukemia, acute myeloid leukemia, solid tumor, and allogeneic HSCT cohorts was 10.6%, 28.2%, 4.4%, and 11.7%, respectively. Non-Aspergillus species represented 48102 (47.1%) molds identified, and non-albicans Candida represented 6693 (71.0%) yeasts identified. There were 56 deaths among 297 children who met mEORTC criteria, with 180-day overall survival for proven, probable, and possible IFIs of 79.7%, 76.2%, and 84.4%, respectively. Non-Aspergillus molds and non-albicans Candida contributed substantially to pediatric IFI in our study, with high IFI prevalence in leukemia and allogeneic HSCT cohorts. Inclusion of IFIs outside of European Organization for Research and Treatment of Cancer criteria revealed an IFI burden that would go otherwise unrecognized in published reports.

Salvage and bridging to allogeneic hematopoietic cell transplantation with ponatinib in patients with relapsed or refractory Philadelphia chromosome-positive leukemia.

A single-center retrospective study was performed with consecutive patients who received salvage therapy using ponatinib for the aim of allogeneic hematopoietic cell transplantation (HCT) for relapsed or refractory Ph-leukemia between January 2017 and July 2018. A total of ten patients-seven with Ph-acute lymphoblastic leukemia (ALL) and three with chronic phase (CP)accelerated phase chronic myeloid leukemia (CML)-were eligible. Eight patients had a history of a single tyrosine kinase inhibitor (TKI) use prior to ponatinib. Any mutation of the tyrosine kinase domain was detected in eight patients, including seven of T315I. The median dose of ponatinib was 15 mg with a median duration of 7 weeks (range 4-23 weeks). The median duration from the start of ponatinib to HCT was 54 days (range 35-175 days). Hematological remission was obtained in five Ph-ALL patients. Maintenance therapy of ponatinib was applied to five patients. No vascular occlusion event has occurred over this series of treatments. Salvage therapy with low-dose ponatinib appears to be safe and effective in patients with relapsed or refractory Ph-leukemia, which may immediately bridge to HCT.

Novel susceptibility variants at the

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Characterized by high levels of Native American ancestry, Hispanics are disproportionally affected by this cancer with high incidence and inferior survival. However, the genetic basis for this disparity remains poorly understood because of a paucity of genome-wide investigation of ALL in Hispanics. Performing a genome-wide association study (GWAS) in 940 Hispanic children with ALL and 681 ancestry-matched non-ALL controls, we identified a novel susceptibility locus in the

Inhibitory effect of berberine on interleukin-2 secretion from PHA-treated lymphocytic Jurkat cells.

Berberine is an isoquinoline alkaloid isolated from herb plants, such as Cortex phellodendri (Huangbai) and Rhizoma coptidis (Huanglian). Huanglian and Huangbai have been used as heat-removing agents. In addition, berberine has been reported to exert anti-inflammatory effect both in vivo and in vitro, where mitogen-activated protein kinase (MAPK) and cyclooxygenase-2 (COX-2) expressions are critically implicated. We herein tested the hypothesis that berberine exerts an anti-inflammatory effect through MAPK and COX-2 signaling pathway in T-cell acute lymphoblastic leukemia (T-ALL). In Jurkat cells, we found that PHA exposure caused elevation on interleukin-2 (IL-2) production in a time-dependent manner. PHA-stimulated reactions were steeply suppressed by berberine, such as IL-2 mRNA expression and protein secretion. However, berberine did not exert any cytotoxic effect at doses of 40 μgml. In addition, the possible molecular mechanism of anti-inflammation effect of berberine could be the inhibition of PHA-evoked phosphorylation of p38, since c-Jun N-terminal kinases (JNK) and extracellular signal-regulated kinase (ERK) expressions did not alter. Consistent with above results, berberine inhibition on PHA-induced IL-2 secretion could be reversed by treatment of SB203580, a specific inhibitor of p38-MAPK. Interestingly, upregulation of PHA-induced COX-2 expression was also observed following berberine treatment of Jurkat cells. Furthermore, flow cytometry analysis showed berberine-induced cell cycle arrest at G1 phase after PHA stimulation and decreased percentage of G2M phase. In conclusion, our study demonstrated that the anti-inflammatory effect of berberine largely potentially results from its ability to attenuate p38 MAPK expression, and does not exclude a positive action of berberine on cell cycle arrest. These results provide an innovative medicine strategy to against or treat T-ALL patients.

Methotrexate induces astrocyte apoptosis by disrupting folate metabolism in the mouse juvenile central nervous system.

Methotrexate (MTX) is a folic acid antagonist and widely used for acute lymphoblastic leukemia (ALL) in children. MTX is associated with acute and chronic neurotoxicity during treatment, however the underlying mechanism is still poorly understood. In this study we investigate whether MTX is neurovirulent to astrocytes in the Central Nervous System (CNS) of adolescent mice. We demonstrated that MTX induced severe cytotoxicity in C6 astrocyte-like cell line and rat primary cultures of astrocytes in a dose-dependent manner. Moreover, GFAP-labeled astrocyte cells significantly decreased in the mouse spinal cord and brain. Furthermore, protein levels of PARP and pro-Caspase-3 were reduced by MTX, indicating MTX-induced apoptosis leads to the astrocytes loss. Notably, overexpression of dihydrofolate reductase (DHFR) or exogenous addition of folate markedly reversed the astrocytes toxicity induced by MTX through activating folate metabolism pathway. Taken together, our study provides evidence for neurotoxic effect of MTX-induced astrocytes apoptosis both in vitro and in vivo with disruption of folate metabolism, and additional supplement of folate may provide novel approaches for alleviating the astrocytes toxicity induced by MTX in the clinic.

Hypercalcemia With Disseminated Osteolytic Lesions A Rare Presentation of Adulthood Acute Lymphoblastic Leukemia.

Osteolytic bone lesions and hypercalcemia without peripheral blasts B-cell acute lymphoblastic leukemia (B-ALL) are reported in children but rarely seen in adults. Herein, we described two patients with B-ALL presenting with hypercalcemia and symptomatic osteolytic bone lesions. They were treated by standard induction chemotherapy after correction of hypercalcemia with supportive measures. With this two case reports we would like to emphasize the importance of clinical awareness of hypercalcemia and osteolytic bone lesions as rare presentations of ALL. The prognostic implication of bone lesions and hypercalcemia in ALL is unclear and needs to be verified in large prospective studies. However, immediate recognition and treatment of hypercalcemia and the underlying B-ALL are vital since a delay of diagnosis poses a possible life-threatening risk.

Interplay between transcription regulators RUNX1 and FUBP1 activates an enhancer of the oncogene c-KIT and amplifies cell proliferation.

Runt-related transcription factor 1 (RUNX1) is a well-known master regulator of hematopoietic lineages but its mechanisms of action are still not fully understood. Here, we found that RUNX1 localizes on active chromatin together with Far Upstream Binding Protein 1 (FUBP1) in human B-cell precursor lymphoblasts, and that both factors interact in the same transcriptional regulatory complex. RUNX1 and FUBP1 chromatin localization identified c-KIT as a common target gene. We characterized two regulatory regions, at 700 bp and 30 kb within the first intron of c-KIT, bound by both RUNX1 and FUBP1, and that present active histone marks. Based on these regions, we proposed a novel FUBP1 FUSE-like DNA-binding sequence on the 30 kb enhancer. We demonstrated that FUBP1 and RUNX1 cooperate for the regulation of the expression of the oncogene c-KIT. Notably, upregulation of c-KIT expression by FUBP1 and RUNX1 promotes cell proliferation and renders cells more resistant to the c-KIT inhibitor imatinib mesylate, a common therapeutic drug. These results reveal a new mechanism of action of RUNX1 that implicates FUBP1, as a facilitator, to trigger transcriptional regulation of c-KIT and to regulate cell proliferation. Deregulation of this regulatory mechanism may explain some oncogenic function of RUNX1 and FUBP1.

Comparing serum levels of zinc, copper, certain antioxidant vitamins and dietary intakes in acute lymphoblastic leukemia (ALL) patients before and after chemotherapy.

Acute lymphoblastic leukemia (ALL) is a malignant hematologic disease. Cancer and its treatments can affect biological functions and change the nutritional status of patients. Zinc and copper are important cofactors for several enzymes and play an important role in maintaining the integrity of DNA. In ALL, we have oxidative conditions in the body that can cause oxidative damage to lipids and the production of malondialdehyde (MDA). So that the aim of this study is comparing serum levels of copper, zinc and inflammation before and after chemotherapy. Thirty ALL patients between 15 to 65 years old participated in this study. A blood sample of 10 cc was taken before and after eight course of chemotherapy. We observed a significant increase in serum zinc as well as a significant decrease in serum copper, vitamin D and Malondialdehyde. We have not seen any significant differences in hs-CRP after chemotherapy. These changes might be due to chemotherapy and changing lifestyle of patients toward healthy eating nutrition and serum vitamin D get worse and because of sedentary life style in these patients there is an essential need to anthropometric measurements during treatment.

Correlation of expression of aberrant immunophenotypic markers in T-ALL with its morphology A pilot study.

Aberrant expression of immunophenotypic markers is commonly found in patients of acute leukemia. T-ALL also shows aberrant markers such as CD13, CD33, CD117, CD10, and CD79a. Morphologically, T-ALL has been categorized into L1, L2, and L3 subtypes. Till now, no study has been done to correlate these markers with morphological features of T-ALL. This study aimed to correlate the expression of aberrant immunophenotypic markers with morphology in T-ALL. All the cases of T-ALL diagnosed by flow cytometry over a period of 2½ year were taken out from the records of Hematology Section of Department of Pathology of University College of Medical Science and Guru Teg Bahadur Hospital and Max Hospital, Saket. Their peripheral blood smear was screened to correlate the morphology of blasts with the expression of aberrant markers. A total of 40 cases of T-ALL were identified during 2½ year period of our study. Morphological correlation was available for 23 cases. Aberrant expression of CD10 was present in 6 (35.3%) cases, CD79a in 9 (47.36%) cases, CD117 in 5 (42.28%) cases and myeloid antigen CD33 in 5 (38.46%) cases. CD117 and CD33-positive cases showed L2 morphology with the presence of convolutions, while cases with expression of CD79a had L1 morphology with absent-slight convolutions. CD10-positive cases had L1L2 morphology with absent occasionally present convolutions. There seems to be an association of aberrant markers with L1 and L2 morphology. However, this needs to be tested for statistical significance on a larger sample size.

Neoplastic Meningitis A Study from a Tertiary Care Hospital from Coastal India.

Neoplastic involvement of cerebrospinal fluid (CSF) secondary to known or unknown primaries elsewhere is a poor prognostic factor and is equivalent to stage IV disease. The aim of the study is to analyse the cytological features of neoplastic meningitis in a tertiary care center. A retrospective study of 400 consecutive CSF samples was done in the cytology laboratory of our hospital. The fluid obtained by spinal tap was sent for microbiological, biochemical and cytological evaluation. Smears that showed the presence of malignant cells were included in this study. Out of 400 cases, 36 (9%) showed neoplastic meningitis. Of which, 13 cases (36%) revealed leukemic infiltration, 2 (6%) lymphomatous infiltration and 21 (58%) carcinomatous meningitis. The leukemia cases included seven cases of acute lymphoblastic leukemia and six cases of acute myeloid leukemia. Among the carcinomatous meningitis cases, eight were metastasis from carcinoma breast, six from lung carcinoma and one each from malignancies of gallbladder, stomach and retinoblastoma. Four cases were metastatic adenocarcinoma from unknown primary. Pleocytosis was a significant finding seen in 58% cases ( A combined diagnostic approach including biochemical, microbiological and pathological evaluation was useful in eliminating infectious meningitis and confirming neoplastic meningitis in these cases. Cytology should be performed on cerebrospinal specimens from all patients with known or suspected malignancy with meningismus. Detection of malignant cells on cytological examination of CSF is the diagnostic gold standard for neoplastic meningitis.

Clinical value of the quantitation of average daily platelet increase during the recovery period in childhood acute lymphoblastic leukaemia.

The time to platelet recovery (TPR) is becoming a predicting factor during the treatment of childhood acute leukaemia. However, the initial pre-treatment platelet count (PPC) could interfere with TPR. Here, we integrated both TPR and PPC as the average daily platelet amount increase (Ap) to predict the prognosis in childhood B-ALL during the recovery period.148 patients were enrolled. The relationship between the Ap and MRD was evaluated, and Multivariate analysis was performed to evaluate whether Ap was independently associated with a better EFS. The PPC was inversely correlated with TPR (

Combined heparinacid citrate dextrose solution A anticoagulation in the Optia continuous mononuclear cell protocol for pediatric lymphocyte apheresis.

Collecting a sufficient number of T-cells is a critical first step in the production of chimeric antigen receptor (CAR)-T cells. Herein, we report a successful implementation of anticoagulation with combined heparin and acid citrate dextrose solution A (ACD-A) for the continuous mononuclear cell (CMNC) protocol on the Spectra Optia in a 20-month-old, 7.5 kg patient with refractory acute lymphoblastic leukemia for manufacture of tisagenlecleucel, a CAR-T cell therapy. Combined heparinACD-A was used following clotting issues when ACD-A was used alone during initial CMNC collections. To our knowledge, this is the first reported case in pediatrics of combined heparinACD-A anticoagulation with the Spectra Optia CMNC protocol.

Expression of Survivin and Its Splice Variants in Pediatric Acute Lymphoblastic Leukemia.

Impact of financial support and focussed group counselling on treatment abandonment in children with acute lymphoblastic leukaemia. Experience over 22 years from North India.

Efforts are being made worldwide to prevent abandonment in children with leukaemia. The study aimed to determine changes in treatment refusal, treatment abandonment rates, and its reasons in response to financial support and focussed group counselling. A retrospective cohort study conducted at paediatric haematology-oncology unit, King Georges Medical University, Lucknow among children <18 years admitted with acute lymphoblastic leukaemia from 1995 to 2017. Study divided into three periods Phase 1 (1995-March 2003) Basic support, Phase 2 (April 2003-June 2009) Financial support and Phase 3 (July 2009-2017) Financial, social support with group counselling. Phase 3- subdivided into 3a group counselling and 3b intensified group counselling. Number of children registered for treatment during phase 1, 2, 3a, 3b 176, 200, 360, and 305. Treatment refusal decreased significantly over time 21% vs 14.5% vs 12.5% vs 5.9% (P < 0.001), especially during phase 3b. Although no change was found in treatment abandonment during phase 2, abandonment significantly reduced in phase 3a (20.3%) as compared with phase 1 (30.2%), with the proportion of children abandoning, due to financial constraints, declining. Abandonment further reduced in phase 3b vs phase 3a (11.1% vs 20.3%) (P 0.001). After adjusting for other variables, abandonment was found to decrease independently in phase3 (a, b) as compared with phase 1 (P1 0.017, P2 0.007). Although helpful, financial assistance unaccompanied by counselling may be insufficient to bring a radical change. Hence, parental counselling, emphasising on treatment adherence and the aftermaths of treatment abandonment, is indispensable for preventing abandonment in semi-literate populations.

Optimization of culture conditions and bench-scale production of anticancer enzyme L-asparaginase by submerged fermentation from Aspergillus terreus CCT 7693.

L-Asparaginase amidohydrolase (EC 3.5.1.1) has received significant attention owing to its clinical use in acute lymphoblastic leukemia treatment and non-clinical applications in the food industry to reduce acrylamide (toxic compound) formation during the frying of starchy foods. In this study, a sequential optimization strategy was used to determine the best culture conditions for L-asparaginase production from filamentous fungus Aspergillus terreus CCT 7693 by submerged fermentation. The cultural conditions were studied using a 3-level, central composite design of response surface methodology, and biomass and enzyme production were optimized separately. The highest amount of biomass (22.0 g·L

Experience with generic pegylated L-asparaginase in children with acute lymphoblastic leukemia and monitoring of serum asparaginase activity.

Pegylated asparaginase (P-Asp) though integral to acute lymphoblastic leukemia (ALL) therapy is often not accessible to patients in developing countries. We share our clinical experience with generic P-Asp along with monitoring of asparaginase activity. In this prospective observational study, patients ≤18 years of age with ALL were assigned to receive either generic P-Asp or native asparaginase (N-Asp) in a non-randomized manner. Treatment protocol was based on ALL BFM-95 backbone. The dose of P-Asp was 1500 IUm N-Asp or P-Asp was administered to 52 and 54 of the 106 eligible patients respectively. Demographic and disease characteristics were comparable in both arms. The mean trough levels for N-Asp and P-Asp were 156.87 ± 22.35 IUL and 216.03 ± 73.40 IUL, respectively (p value <0.001) and all patients achieved therapeutic levels during Ia. Incidence of asparaginase-attributable toxicity was similar in the two arms in both phases of treatment, although hospitalization due to noninfectious causes was more common in P-Asp arm during Ia (13% versus 0%, p value, 0.01). Clinical hypersensitivity and silent inactivation were not observed during Ia while these occurred in 13% and 5% of patients in the N-Asp arm and P-Asp arms of IIa, respectively. The 2-year event free survival for P-Asp and N-Asp groups was 84% and 80.7%, respectively (p value 0.85). Generic P-Asp was observed to be efficacious and well tolerated in our patients and adequate therapeutic levels were sustained for 2 weeks.

A prospective study of a simple algorithm to individually dose high-dose methotrexate for children with leukemia at risk for methotrexate toxicities.

High-dose methotrexate (HDMTX) is critical to the successful treatment of pediatric acute lymphoblastic leukemia (ALL) but can cause significant toxicities. This study prospectively evaluated the effectiveness of a fixed algorithm which requires no real-time pharmacokinetic modeling and no previous patient exposure to HDMTX, to individualize HDMTX dosing for at-risk patients with the aim of avoiding methotrexate-related toxicities. We developed a simple algorithm to individualize HDMTX infusions with 0-2 rate adjustments based on methotrexate levels during the infusion. This was a prospective, open-label, study eligible patients were identified and referred by their oncologist. Fifty-four evaluable cycles of HDMTX (5 gm This algorithm is a simple, safe and effective method for individualizing HDMTX in pediatric patients with ALL. CLINICALTRIALS. NCT02076997.

Single-cell analysis identifies CRLF2 rearrangements as both early and late events in Down syndrome and non-Down syndrome acute lymphoblastic leukaemia.

Deregulated expression of the type I cytokine receptor, CRLF2, is observed in 5-15% of precursor B-cell acute lymphoblastic leukaemia (B-ALL). We have previously reported the genomic landscape of patients with CRLF2 rearrangements (CRLF2-r) using both whole genome and exome sequencing, which identified a number of potential clonal and sub-clonal genomic alterations. In this study, we aimed to assess when the CRLF2-r IGH-CRLF2 or P2RY8-CRLF2, arose during the evolution of both Down syndrome-ALL (DS-ALL) and non-DS-ALL. Using fluorescence in situ hybridisation, we were able to track up to four structural variants in single cells from 47 CRLF2-r B-ALL patients, which in association with our multiplex single-cell analysis of a further four patients, permitted simultaneous tracking of copy number alterations, structural and single nucleotide variants within individual cells. We observed CRLF2-r arising as both early and late events in DS and non-DS-ALL patients. Parallel evolution of discrete clones was observed in the development of CRLF2-r B-ALL, either involving the CRLF2-r or one of the other tracked abnormalities. In-depth single-cell analysis identified both linear and branching evolution with early clones harbouring a multitude of abnormalities, including the CRLF2-r in DS-ALL patients.

Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases.

Most B cell precursor acute lymphoblastic leukemia (BCP ALL) can be classified into known major genetic subtypes, while a substantial proportion of BCP ALL remains poorly characterized in relation to its underlying genomic abnormalities. We therefore initiated a large-scale international study to reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA sequencing. Fourteen BCP ALL gene expression subgroups (G1 to G14) were identified. Apart from extending eight previously described subgroups (G1 to G8 associated with

Low Expression of Leucocyte Associated Immunoglobulin Like Receptor-1 (LAIR-1CD305) in a Cohort of Pediatric Acute Lymphoblastic Leukemia Cases.

Background Immunophenotypic markers can play significant role in prognostic assessment for different cancers and leukocyte-associated Ig-like receptor (LAIR-1) is a recently identified inhibitory immuno-receptor. Methods We measured LAIR-1 expression in paediatric ALL patients (n-42) and appropriate controls by flow cytometry. Median fluorescence intensities (MFIs) were calculated and correlated with demographic and clinical variables and early treatment outcome parameters. Results The ALL cohort had an age range of 1 - 11 y and a MF ratio of 2.51. 64% had WBC counts <50 x 109L and 15 (36%) >50 x 109L, 52% being standard risk and 48% high risk. There were 6 cases of T-ALL and 36 of B-ALL. AML1-TEL, E2A-PBX, BCR-ABL and MLL-AF4 transcripts were noted in 3, 6, 2 and 1 patient, respectively. Day 8 ABC was <1,000 in 31 and >1,000 in 8 cases, while 30 had low and 7 high MRD (both >0.01) at day 35 of treatment. The median MFI for LAIR-1 expression in control cases was 8.2 (range 7.76-11.69) and in ALL cases 4.02 (range 0.56 to 11.87), with 74% (n-31) of ALL cases showing reduced LAIR-1 expression. However, no significant correlations were found between standard ALL risk factors and LAIR-1 expression. Out of 42 patients, 4 died during induction treatment and one exited therapy, 60% (n-35) of these featuring low expression of LAIR-1. Also ALL patients with low LAIR-1 expression had t (1221), t (119) and t (411) translocations in 2, 4 and 1 samples, respectively, but none had t (922). Of those with high LAIR-1 expression, 2 had t (922) (MFIs-14.43 and 11.87). Conclusions This pilot study of LAIR-1expression in ALL suggests low expression of the inhibitory molecule in leukemic cells. However, the findings need to be confirmed with larger cohort, along with studies focusing on pathophysiological roles in leukemic clone survival and escape from the immune system.

CD99 expression is strongly associated with clinical outcome in children with B-cell precursor acute lymphoblastic leukaemia.

Our study aimed to determine the expression pattern and clinical relevance of CD99 in paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). Our findings demonstrate that high expression levels of CD99 are mainly found in high-risk BCP-ALL, e.g. BCR-ABL1 and CRLF2