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Ribosomal Lesions Promote Oncogenic Mutagenesis.

Ribosomopathies are congenital disorders caused by mutations in ribosomal proteins (RP) or assembly factors and are characterized by cellular hypoproliferation at an early stage. Paradoxically, many of these disorders have an elevated risk to progress to hyperproliferative cancer at a later stage. In addition, somatic RP mutations have recently been identified in various cancer types, for example, the recurrent RPL10-R98S mutation in T-cell acute lymphoblastic leukemia (T-ALL) and RPS15 mutations in chronic lymphocytic leukemia (CLL). We previously showed that RPL10-R98S promotes expression of oncogenes, but also induces a proliferative defect due to elevated oxidative stress. In this study, we demonstrate that this proliferation defect is eventually rescued by RPL10-R98S mouse lymphoid cells that acquire 5-fold more secondary mutations than RPL10-WT cells. The presence of RPL10-R98S and other RP mutations also correlated with a higher mutational load in patients with T-ALL, with an enrichment in NOTCH1-activating lesions. RPL10-R98S-associated cellular oxidative stress promoted DNA damage and impaired cell growth. Expression of NOTCH1 eliminated these phenotypes in RPL10-R98S cells, in part via downregulation of PKC-θ, with no effect on RPL10-WT cells. Patients with RP-mutant CLL also demonstrated a higher mutational burden, enriched for mutations that may diminish oxidative stress. We propose that oxidative stress due to ribosome dysfunction causes hypoproliferation and cellular insufficiency in ribosomopathies and RP-mutant cancer. This drives surviving cells, potentiated by genomic instability, to acquire rescuing mutations, which ultimately promote transition to hyperproliferation. SIGNIFICANCE Ribosomal lesions cause oxidative stress and increase mutagenesis, promoting acquisition of rescuing mutations that stimulate proliferation.

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.

The Medical Care of People With Intellectual Disability.

An estimated 1.5 million persons in Germany are intellectually disabled. Persons with intellectual disability (ID) are especially vulnerable to somatic and mental illnesses. This review is based on pertinent literature retrieved by selective searches in PubMed and the Cochrane Library. Genetic abnormalities are a frequent cause of diseases that affect multiple organs and need interdisciplinary treatment. A number of somatic diseases are more common in persons with ID than in the general population, including epilepsy (30-50% in persons with severe or very severe ID, vs. 0.5% in the general popu- lation) and dementia (five times more common than in the general population). Patients with Down syndrome are 20 times more likely than the general population to develop acute lymphoblastic leukemia. Some mental illnesses, too, are more common in persons with ID, e.g., autism spectrum disorders (7.5-15% vs. 1% in the general population). The history and the findings of the physical and psychiatric examination are assessed in accordance with the biopsychosocial model of disease, and in the light of the patients mental developmental age. Structured instruments for behavioral evaluation and diagnosis are an important additional component of the diagnostic assessment. A holistic approach is required that takes multiple life areas into account and involves the patients familial and social environment, while obeying the rules of simple language. Psychotherapeutic and psychosocial measures must be adapted to the patients cognitive abilities and mental developmental age. Intellectually disabled persons can be treated in a multimodal, multiprofessional approach. As of early 2019, there were 38 medical centers for adults with intellectual disability or severe multiple disabilities in Germany (Medizinische Behandlungszentren für Erwachsene mit geistiger Behinderung oder schweren Mehrfachbehinderungen, MZEB), where they can be cared for with due attention to their special needs.

Skeletal Morbidity in Children and Adolescents during and following Cancer Therapy.

Skeletal abnormalities are common in children and adolescents diagnosed and treated for a malignancy. The spectrum ranges from mild pain to debilitating osteonecrosis and fractures. In this review, we summarize the impact of cancer therapy on the developing skeleton, provide an update on therapeutic strategies for prevention and treatment, and discuss the most recent advances in musculoskeletal research. Early recognition of skeletal abnormalities and strategies to optimize bone health are essential to prevent long-term skeletal sequelae and diminished quality of life in childhood cancer survivors.

Early vs. late MRD response- and risk-based treatment intensification of childhood acute lymphoblastic leukemia a prospective pilot study from Saudi Arabia.

Refinement of risk-based treatment stratification by minimal residual disease (MRD) at different time points has improved outcomes of childhood acute lymphoblastic leukemia (ALL). In this prospective study we evaluated effects of such stratification, including intensification of therapy based on response assessment at day-15 and MRD at day-29 of induction to test if treatment intensification would improve outcomes. 241 patients, 1-14 years old, newly diagnosed with ALL, were recruited and stratified by risk and MRD response into three treatment Arms (A, B, or C). Arm A was modified from COG AALL0331, B from AALL0232, and C from AALL0232 and AALL0434. Assignments were according to NCI risk, phenotype, rapid vs. slow early response (SER), steroid pretreatment, MLL rearrangement ( 5-year OS, EFS, and CIR were 89.5% ± 4.0%, 87.6% ± 4.3%, and 7.1% ± 3.5%. No significant difference was found by B- vs. T cell phenotype. 5-year OS, EFS, and CIR for B-cell ALL were 90.5% ± 2.4%, 88.7% ± 2.6%, and 6.4% ± 2.0%. Outcomes for patients with Arm switching to a more intensive protocol had mixed results. Assigning patients by end-of-induction MRD-risk alone did not reflect response kinetics of the different NCI-risk groups. Although late treatment intensification improved outcomes of NCI-SR patients with positive MRD at end-of-induction, further refinement is needed to improve outcomes of NCI-HR with SER. Integration of NCI-risk group with specific MRD value and time point allows more refined treatment stratification.

Bilateral Proptosis in a Child A Rare Presentation of Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL), a common hematological malignancy observed in children, typically presents with fever, pallor, easy bruising, hepatosplenomegaly and lymphadenopathy. However, when ALL manifests with unusual signs and the blood counts and peripheral smears are normal, it causes a diagnostic dilemma. We report a 5-year-old boy who presented with bilateral proptosis as the initial manifestation of ALL. He presented with fever and bilateral knee pain attributed to a fall while playing. There was a history of progressive bilateral proptosis for a 3-month period not associated with any other complaints such as fever, eye pain, redness, or tearing. Thyroid function tests were normal. Blood counts acquired upon proptosis presentation were normal. When he presented to us three months later, blood counts revealed a pancytopenia but the peripheral smear showed no abnormal cells. Magnetic resonance imaging of the brain and orbits was normal. Bone marrow aspirate flow cytometry confirmed the diagnosis of B cell acute lymphoblastic lymphoma. Ophthalmologists should be aware of the unusual ophthalmologic manifestations of acute leukemia, as they may precede overt leukemia and cause diagnostic dilemmas. Knowledge about the rare and isolated extramedullary manifestations of ALL facilitates early diagnosis and thereby improves prognosis.

Involvement of miRNA polymorphism in mucositis development in childhood acute lymphoblastic leukemia treatment.

Mucositis, linked to methotrexate, daunorubicin or cyclophosphamide, is a frequent childhood acute lymphoblastic leukemia (ALL) therapy side effect. miRNAs regulate the expression of pharmacokineticpharmacodynamic pathway genes. SNPs in miRNAs could affect their levels or function, and affect their pharmacokineticpharmacodynamic pathway target genes. Our aim was to determine the association between miRNA genetic variants targeting mucositis-related genes and mucositis-developing risk. We analyzed 160 SNPs in 179 Spanish children with B-cell precursor ALL homogeneously treated with LALSHOP protocols. We identified three SNPs in miR-4268, miR-4751 and miR-3117 associated with mucositis, diarrhea and vomiting, respectively. The effect of these SNPs on genes related to drug pharmacokineticspharmacodynamics could explain mucositis, diarrhea and vomiting development during ALL therapy.

Efficacy and safety of bispecific T-cell engager (BiTE) antibody blinatumomab for the treatment of relapsedrefractory acute lymphoblastic leukemia and non-Hodgkins lymphoma a systemic review and meta-analysis.

Multiple clinical trials have been conducted to investigate the therapeutic effects of blinatumomab on acute lymphoblastic leukemia (ALL) and non-Hodgkins lymphoma (NHL). We did a meta-analysis including 8 clinical trials to verify the efficacy and safety of blinatumomab in patients with relapsedrefractory ALL and NHL. We searched and investigated all relevant publications from PubMed, Web of Science, Embase, and ClinicalTrials.gov. The primary endpoint was complete remission (CR). The secondary end points were the minimal residual disease (MRD) response, and the adverse effects including cytokine release syndrome (CRS) and grade ≥ 3 neurological events. Our study showed that the pooled CR rate was 0.45 (95% CI 0.37-0.53) in ALL and 0.20 (0.12-0.27) in NHL respectively. The pooled CR rate is higher in ALL patients with BM blasts <50% than that of patients with BM blasts ≥50% (0.75 versus 0.33). A history of allo-HSCT has no effect on the CR rate. The pooled MRD response rate was 0.42 (95% CI 0.29-0.54) in ALL. For adverse effects, the pooled occurrence rate of grade ≥3 CRS was 0.04 (95% CI 0.01-0.06), and the pooled occurrence rate of grade ≥ 3 neurological events was 0.12 (95% CI 0.08-0.16). Blinatumomab is effective in treating relapsedrefractory ALL and NHL. ALL patients manifested better therapeutic response than NHL patients and a reduced tumor load favored the clinical response. For adverse effects, severe CRS and neurological events did not happen very often. Blinatumomab shows valid therapeutic effects and limited adverse response in treating relapsedrefractory ALL and NHL in our meta-analysis.

Severely bothersome fatigue in children and adolescents with cancer and hematopoietic stem cell transplant recipients.

Objectives were to describe bothersome fatigue in children with cancer and hematopoietic stem cell (HSCT) recipients and to identify factors associated with severely bothersome fatigue. We included children ages 8-18 years treated for cancer or HSCT recipients from three groups 1 receiving active cancer treatment and admitted to hospital for at least 3 days, 2 attending outpatient clinic for acute lymphoblastic leukemia maintenance therapy, and 3 attending outpatient clinic following treatment completion. Fatigue was measured using the Symptom Screening in Pediatrics Tool (SSPedi) severely bothersome fatigue was defined as a lot or extremely bothersome fatigue (score of 3-4 on 0-4 scale). Factors associated with severely bothersome fatigue were examined using univariate and multiple logistic regression. Of 502 children included, 414 (82.5%) reported some degree of bothersome fatigue (scores 1-4), and 123 (24.5%) reported severely bothersome fatigue (score 3 or 4). In multiple regression analysis, factors significantly associated with severely bothersome fatigue were child age 11-14 and 15-18 years vs 8-10 years (odds ratio (OR) 2.11, 95% confidence interval (CI) 1.21-3.77 and OR 2.96, 95% CI 1.66-5.44), and inpatients receiving cancer treatment vs outpatients who had completed therapy (OR 3.85, 95% CI 2.17-7.27). We found that 82.5% of children with cancer or HSCT recipients reported bothersome fatigue and 24.5% of children reported severely bothersome fatigue. Risk factors for severely bothersome fatigue were older age and inpatients receiving active cancer treatment. Future work should evaluate systematic symptom screening in clinical practice and apply interventions to reduce fatigue.

Targeting EIF4E signaling with ribavirin in infant acute lymphoblastic leukemia.

The poor outcomes in infant acute lymphoblastic leukemia (ALL) necessitate new treatments. Here we discover that EIF4E protein is elevated in most cases of infant ALL and test EIF4E targeting by the repurposed antiviral agent ribavirin, which has anticancer properties through EIF4E inhibition, as a potential treatment. We find that ribavirin treatment of actively dividing infant ALL cells on bone marrow stromal cells (BMSCs) at clinically achievable concentrations causes robust proliferation inhibition in proportion with EIF4E expression. Further, we find that ribavirin treatment of KMT2A-rearranged (KMT2A-R) infant ALL cells and the KMT2A-AFF1 cell line RS411 inhibits EIF4E, leading to decreases in oncogenic EIF4E-regulated cell growth and survival proteins. In ribavirin-sensitive KMT2A-R infant ALL cells and RS411 cells, EIF4E-regulated proteins with reduced levels of expression following ribavirin treatment include MYC, MCL1, NBN, BCL2 and BIRC5. Ribavirin-treated RS411 cells exhibit impaired EIF4E-dependent nuclear to cytoplasmic export andor translation of the corresponding mRNAs, as well as reduced phosphorylation of the p-AKT1, p-EIF4EBP1, p-RPS6 and p-EIF4E signaling proteins. This leads to an S-phase cell cycle arrest in RS411 cells corresponding to the decreased proliferation. Ribavirin causes nuclear EIF4E to re-localize to the cytoplasm in KMT2A-AFF1 infant ALL and RS411 cells, providing further evidence for EIF4E inhibition. Ribavirin slows increases in peripheral blasts in KMT2A-R infant ALL xenograft-bearing mice. Ribavirin cooperates with chemotherapy, particularly L-asparaginase, in reducing live KMT2A-AFF1 infant ALL cells in BMSC co-cultures. This work establishes that EIF4E is broadly elevated across infant ALL and that clinically relevant ribavirin exposures have preclinical activity and effectively inhibit EIF4E in KMT2A-R cases, suggesting promise in EIF4E targeting using ribavirin as a means of treatment.

Chromosomal translocation-mediated evasion from miRNA induces strong MEF2D fusion protein expression, causing inhibition of PAX5 transcriptional activity.

MEF2D fusion genes are newly discovered recurrent gene abnormalities that are detected in approximately 5% of acute lymphoblastic leukemia cases. We previously demonstrated that the vector-driven expression of MEF2D fusion proteins was markedly stronger than that of wild-type MEF2D however, the underlying mechanisms and significance of this expression have yet to be clarified. We herein showed that the strong expression of MEF2D fusion proteins was caused by the loss of the target site of miRNA due to gene translocation. We identified the target region of miRNA located in the coding region and selected miR-122 as a candidate of the responsible miRNA. Mutations at a putative binding site of miR-122 increased MEF2D expression, while the transfection of its miRNA mimic reduced the expression of wild-type MEF2D, but not MEF2D fusion proteins. We also found that MEF2D fusion proteins inhibited the transcriptional activity of PAX5, a B-cell differentiation regulator in a manner that depended on fusion-specific strong expression and an association with histone deacetylase 4, which may lead to the differentiation disorders of B cells. Our results provide novel insights into the mechanisms underlying leukemia development by MEF2D fusion genes and the involvement of the deregulation of miRNA-mediated repression in cancer development.

Hand Mirror Cells and Hypercalcemia A Rare Presentation of Pediatric Acute Lymphoblastic Leukemia.

Hand mirror cell (HMC) leukemia is a variant of acute lymphoblastic leukemia previously described in the adult population where lymphoblasts manifest distinctive hand mirror morphologic features. HMC has been previously identified in 23% of childhood acute lymphoblastic leukemia patients, but its prognostic significance in children is not well understood. Hypercalcemia is also uncommon in childhood leukemias. Hypercalcemia associated with HMC leukemia has not been previously reported. We report a 5-year-old boy with HMC B-lymphoblastic leukemia who presented with hypercalcemia.

Successful Management of Unusual Multiple Gut Colonization With Extremely Drug-resistant Bacteria in an Infant Undergoing Hematopoietic Cell Transplantation.

Enterobacterales represent a serious threat to transplant patients due to their increase frequency of carbapenem resistance and wide spreading. We present a case of an infant with acute lymphoblastic leukemia undergoing hematopoietic stem cell transplantation. Before transplantation an unusual double colonization of the gastrointestinal tract with extremely resistant Escherichia coli and Klebsiella pneumoniae strains producing metallo-beta-lactamase was diagnosed. Respective epidemiologic management was implemented, based on the strict reverse isolation in patient-protective environment, and intensified antimicrobial surveillance. After granulocyte recovery, no extremely drug-resistant strains were found, and no case of isolation andor transmission of carbapenem-resistant bacteria has been identified in the transplant center during the following 6 months.

Assessment of Nutritional Status and Malnutrition Risk at Diagnosis and Over a 6-Month Treatment Period in Pediatric Oncology Patients With Hematologic Malignancies and Solid Tumors.

In total, 74 pediatric oncology patients with hematologic malignancies (n56) or solid tumors (n18) and a median age of 78.5 months were included in this prospective study. The aims were to assess malnutrition risks and nutritional status over a 6-month treatment period measured at regular intervals. The rate of patients with high risk for malnutrition at diagnosis was 28.4% by Screening Tool for Risk of Impaired Nutritional Status and Growth tool and 36.5% by Pediatric Yorkhill Malnutrition Score. Body mass index (BMI) z-scores at diagnosis showed 12.3% undernutrition (<-2 SD) and 6.8% overnutrition (>2 SD), which changed to 6.7% and 11.1% at the sixth month, respectively. Malnutrition (BMI<5th age percentile) was detected in 13.7% at diagnosis. Despite an initial deterioration noted in BMI, BMI for age percentile, and z-scores at month 1 in all malignancy subgroups (at month 3 for acute lymphoblastic leukemia), the scores improved later on. There was an increase in weight from baseline in 88.2% of patients over 6 months. This study revealed a decrease in the prevalence of undernutrition and malnutrition over a 6-month treatment period with improved anthropometrics despite an initial deterioration in all malignancy subgroups and even in patients with high risk for malnutrition at baseline screening. Solid tumors and acute lymphoblastic leukemia seem to be associated with higher likelihood of undernutrition and overnutrition, respectively, during treatment.

Prevalence and Risk Factors for Arterial Hypertension Development in Childhood Acute Lymphoblastic Leukemia Survivors.

Childhood acute lymphoblastic leukemia (ALL) survivors are at an increased risk of cardiovascular disease including arterial hypertension (AH). The objectives of this study were to assess the prevalence of AH using 24-hour ambulatory blood pressure monitoring, explore characteristics of AH, and define risk factors for the development of AH in childhood ALL survivors. The study comprised 81 childhood ALL survivors (5 to 25 y of age) after a median follow-up time of 5 years. The control group consisted of 52 healthy children (5 to 17 y of age) without any known severe or chronic medical condition. Ambulatory blood pressure monitoring was performed in all patients and controls. Serum lipids were measured in all patients and controls. ALL survivors were more likely to have AH than controls (odds ratio, 2.47 95% confidence interval, 1.08-5.63 P0.0315). The mean time from ALL diagnosis until diagnosis of AH was 5.1±2.97 years. Day-time diastolic SDS and day-time mean arterial pressure SDS were significantly higher in ALL cohort compared with the controls (-0.3±1.43 vs. -0.76±0.95 P0.04 and 1.44±1.64 vs. 0.92±1.03 P0.047). Childhood ALL survivors with AH were more likely to be systolic extreme dippers and reverse systolicdiastolic dippers compared with those with normal blood pressure (P<0.05). There was no association of AH with leukemia subtype, leukemia risk group, sex, central nervous system irradiation, and obesity. The prevalence of AH in childhood ALL survivors may be as high as 37%. We recommend regular monitoring of blood pressure in childhood ALL survivors early in the follow-up.

Prevalence of TPMT, ITPA and NUDT 15 genetic polymorphisms and their relation to 6MP toxicity in north Indian children with acute lymphoblastic leukemia.

Toxicity of 6-Mercaptopurine (6MP) is related to single nucleotide polymorphism (SNP) in genes coding for metabolizing enzymes, with TPMT analysis being recommended prior to maintenance therapy. However, ITPA and NUDT15 polymorphisms appear more important in the Asian population. In this study 63 consecutive patients with ALL, entering maintenance phase of therapy, were evaluated for TPMT, ITPA and NUDT15 polymorphisms by PCR RFLP and confirmed by sequencing. Hematological and hepatic toxicities were monitored for 36 weeks. The groups with and without any of the three studied polymorphisms (Risk SNP and Risk SNP-) were compared. Eighteen (28.6%) patients had major polymorphisms, 17 being heterozygous. ITPA(198CA) 11(17.5%) NUDT (415CT) 6(9.5%) and TPMT3C in 2(3.1%). Mean cumulative dose of 6MP was lower 10927 mgm Polymorphisms in ITPA and NUDT15 have a greater prevalence in the north Indian population. Patients with these SNPs tolerate lower doses of 6MP.

IKZF2 Drives Leukemia Stem Cell Self-Renewal and Inhibits Myeloid Differentiation.

Leukemias exhibit a dysregulated developmental program mediated through both genetic and epigenetic mechanisms. Although IKZF2 is expressed in hematopoietic stem cells (HSCs), we found that it is dispensable for mouse and human HSC function. In contrast to its role as a tumor suppressor in hypodiploid B-acute lymphoblastic leukemia, we found that IKZF2 is required for myeloid leukemia. IKZF2 is highly expressed in leukemic stem cells (LSCs), and its deficiency results in defective LSC function. IKZF2 depletion in acute myeloid leukemia (AML) cells reduced colony formation, increased differentiation and apoptosis, and delayed leukemogenesis. Gene expression, chromatin accessibility, and direct IKZF2 binding in MLL-AF9 LSCs demonstrate that IKZF2 regulates a HOXA9 self-renewal gene expression program and inhibits a CEBP-driven differentiation program. Ectopic HOXA9 expression and CEBPE depletion rescued the effects of IKZF2 depletion. Thus, our study shows that IKZF2 regulates the AML LSC program and provides a rationale to therapeutically target IKZF2 in myeloid leukemia.

Disseminated trichosporonosis with atypical histologic findings in a patient with acute lymphocytic leukemia.

We report a case of disseminated Trichosporon asahii in a patient on systemic antifungal therapy who presented with multiple cutaneous nodules suggestive of fungal infection. Histologic features resembled neutrophilic eccrine hidradenitis but staining with periodic acid-Schiff and Gomori methenamine silver confirmed the clinical diagnosis. This case highlights the importance of maintaining suspicion for trichosporonosis and contextualizing histologic findings within the underlying clinical picture.

Distinguishing thymoma from T-lymphoblastic leukaemialymphoma a case-based evaluation.

T-lymphoblastic lymphoma and thymoma are distinct primary mediastinal neoplasms that can have similar clinical presentations and overlapping histological features. Microscopic distinction is occasionally difficult because the immature lymphocytes associated with thymoma may resemble T-lymphoblastic leukaemialymphoma cells, morphologically and immunohistochemically. An accurate diagnosis assumes particular importance since the treatment approaches for these two entities differ considerably. Multimodality diagnostic approaches incorporating histological, flow cytometry immunophenotypic and molecular approaches are required. In this article, we describe four patients, each presenting with a mediastinal tumour in different clinicopathological settings. A detailed report of each case will follow, illustrating the challenges involved in the diagnosis in patients with these mediastinal neoplasms.

Trypsin-encoding

Asparaginase-associated pancreatitis is a life-threatening toxicity to childhood acute lymphoblastic leukemia treatment. To elucidate genetic predisposition and asparaginase-associated pancreatitis pathogenesis, ten trial groups contributed remission samples from patients aged 1.0-17.9 years treated for acute lymphoblastic leukemia between 2000 and 2016. Cases (n244) were defined by the presence of at least two of the following criteria (i) abdominal pain (ii) levels of pancreatic enzymes ≥3 × upper normal limit and (iii) imaging compatible with pancreatitis. Controls (n1320) completed intended asparaginase therapy, with 78% receiving ≥8 injections of pegylated-asparaginase, without developing asparaginase-associated pancreatitis. rs62228256 on 20q13.2 showed the strongest association with the development of asparaginase-associated pancreatitis (odds ratio3.75

Expression and significance of CD47, PD1 and PDL1 in T-cell acute lymphoblastic lymphomaleukemia.

Although dose intensification strategies achieve a favorable prognosis for pediatric patients of T-lmphoblastic lymphomaleukemia (T-LBLALL), numerous side effects have been followed. Molecular targeted therapies will be needed to optimize the current treatment strategy for T-LBLALL. The aim of this study was to analyse expression and significance of CD47, PD1 and PDL1 in. T-LBLALL. We performed immunohistochemistry staining and real time fluorescence quantitative PCR (qRT-PCR) on FFPE tissues. Immunohistochemistry results showed that the high expression rate of CD47 protein was 46.4% (2656) and the positive expression rate of PDL1 protein was 37.5% (2156). PD1 expression was observed in tumor infiltrating lymphocytes in approximately 20% of T-LBLALL patients, but not expressed on tumor cells of T-LBLALL. And the results of qRT-PCR showed that the relative expression levels of CD47, PDL1 and PD1 mRNA in 56 cases of T LBLALL were significantly higher than those in control group (6.915 vs 4.050, 12.255 vs 2.575, 37.990 vs 3.615), and the differences were all statistically significant (p all <0.05). Univariate analysis showed that age, CD47 protein, CD47 mRNA,PDL1 protein and PDL1 mRNA expression were closely correlated with prognosis (P all <0.05). We found that the overall one-year survival rates of patients with a high expression (≥M) of CD47 and PDL1 mRNA were higher than in patients with low expression (<M). However, the overall one-year survival rate of patients with a high expression (≥M) of CD47 and PDL1 protein were lower than in patients with low expression (<M). And patients with ≤25 years old had a worse prognosis than with >25 years old. Multivariate Cox regression analysis showed that the high expression of CD47 and PDL1 protein were independent prognostic factors (both p < 0.05). In a word, PD1PDL1 and CD47 may be involved in the disease progression and prognosis of T-LBLALL, and detection and targeting of CD47 and PD1PDL1 may provide a rational basis to for treatment of T-LBLALL.

Should immunologic strategies be incorporated into frontline ALL therapy

Survival rates in adult patients with acute lymphoblastic leukemia (ALL) have markedly improved during the past decade. The one-size-fits-all-ages approach has been replaced with adaptation of pediatric-inspired treatment protocols for younger adults. Yet different treatment strategies for older patients are needed due to chemotherapy-related toxicities. A new era of immunotherapy has arrived, offering opportunities for targeted treatments for ALL subtypes. While CD20 targeting with rituximab has been demonstrated to improve survival when combined with chemotherapy, it has little activity as a single agent in ALL. In contrast, antibody targeting of CD19 and CD22 with blinatumomab and inotuzumab ozogamicin, respectively, has had remarkable single-agent activity in the relapsed setting. Studies are now underway to test these agents in combination with chemotherapy in the frontline setting. The goal of these studies is to improve event-free survival and overall survival by using these approaches in the frontline to eradicate minimal residual disease and, particularly in older adults with ALL, to reduce treatment-related toxicity by limiting the exposure to traditional multi-agent chemotherapy with its attendant toxicities. This review focuses on new immunotherapeutic treatment options and strategies for frontline treatment, including a brief discussion of the use of true immunotherapy, chimeric antigen receptor T-cells, for relapsed B-cell ALL, the potential for targeting CD38 in T-cell ALL, and how these approaches are facilitating the next steps to improve survival for adult patients with ALL.

Can one target T-cell ALL

Progress in our understanding of the central genes, pathways, and mechanisms in the pathobiology of T-cell acute lymphoblastic leukemia (T-ALL) has identified key drivers of the disease, opening new opportunities for therapy. Drugs targeting highly prevalent genetic alterations in NOTCH1 and CDKN2A are being explored, and multiple other targets with readily available therapeutic agents, and immunotherapies are being investigated. The molecular basis of T-ALL is reviewed here and potential targets and therapeutic targets discussed.

Allogeneic transplantation for patients with Philadelphia chromosome positive acute lymphoblastic leukemia Is it imperative in the tyrosine kinase inhibitor era

Before the advent of tyrosine kinase inhibitors (TKIs), Philadelphia chromosome positive acute lymphoblastic leukemia (Ph ALL) was associated with dismal survival without allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recent evidence has demonstrated that the combination of TKI and chemotherapy can result in a high rate of complete remission, thereby enabling more patients to proceed to allo-HSCT. However, with more studies reporting non-inferior outcomes with TKI and chemotherapy combination without allo-HSCT, the need for allo-HSCT in Ph ALL has become less certain. This review summarizes evidence that will address the relevance of allo-HSCT in Ph ALL.

Why and how to treat Ph-like ALL

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL), or BCR-ABL1-like ALL, is a high-risk subtype of B-cell precursor ALL characterized by a gene expression profile similar to Ph-positive ALL, a high frequency of IKZF1 alterations, and poor outcome. The prevalence of Ph-like ALL is common among all ages, ranging from 10% to 15% in children to over 25% in young adults. Patients with Ph-like ALL harbor a diverse range of genetic alterations that activate cytokine receptor and kinase signaling and can be targeted with tyrosine kinase inhibitors. The majority of Ph-like ALL alterations are divided into two main groups based on activation of ABL-class or JAK-STAT alterations. Accordingly, preclinical studies and anecdotal reports suggest patients harboring ABL-class fusions are candidates for ABL1-inhibitors, whilst alterations activating the JAK-STAT pathway may be amenable to treatment with JAK inhibitors. Diagnostic screening approaches and precision medicine trials are now being developed and implemented to test the efficacy of targeted therapy with a backbone of chemotherapy, similar to the treatment of Ph-positive ALL.

CTLA-4 polymorphism rs231775 Influence on relapse and survival after allogeneic hematopoietic stem cell transplantation in childhood.

Relapse following allogeneic hematopoietic stem cell transplantation (HSCT) is still linked to a poor prognosis. Mainly, donors T-cells mediate the graft-versus-leukemia effect. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is an inhibitory molecule which down-regulates T-cell activation. Single nucleotide polymorphism (SNP) in CTLA-4 may have an effect on immune response. Eighty-eight children with acute leukemia and their donors were genotyped of CTLA-4 gene for rs231775. We searched for an association of CTLA-4 SNP with relapse and survival after allogeneic HSCT. We identified a significantly reduced relapse rate in children who received a transplant from a donor with the CTLA-4 genotypes AG or GG in comparison with genotype AA of rs231775 (19% vs 40%, P 0.026). In addition, we observed a significant difference in event-free survival (EFS) depending on the donor´s genotype. The EFS was 70% or 46% if the patient was transplanted from a donor with CTLA-4 genotype AGGG or AA, respectively (P 0.025). In multivariate analysis, CTLA-4 genotype was an independent risk factor for relapse rate (P 0.028). This study suggests that CTLA-4 polymorphism rs231775 is relevant for relapse and survival after allogeneic HSCT in childhood and should be further investigated in clinical trials.

Novel BenzoBFurans with Anti-Microtubule Activity Upregulate Expression of Apoptotic Genes and Arrest Leukemia Cells in G2M Phase.

Novel derivatives of benzobfuran were found to be highly toxic towards human chronic myelogenous (K562), acute myelogenous (HL-60) and acute lymphoblastic (MOLT-4) leukemia cells. The objective was the characterization of the biological activity of novel benzofurans (influence on apoptosis, mitogen-activated protein kinases and on the cell cycle). Cellular protein(s) targeted by test benzofurans and mechanism of action were identified. The methods utilized in the study were chemical synthesis, fluorescence assays, flow cytometry, gene expression by DNA microarray and real-time RT-PCR, western blotting, cytotoxicity assays, pull-down assay, mass spectroscopy, in vitro polymerization of tubulin, molecular docking. 1,1-3-(bromomethyl)-5,6- dimethoxy-1-benzofuran-2,7-diyldiethanone (1) and methyl 4-bromo-6- (dibromoacetyl)-5-hydroxy-2-methyl-1-benzofuran-3-carboxylate (2) induced apoptosis in K562 and MOLT-4 cells. The profiling of gene expression revealed that 1 and 2 increased the expression of proapoptotic genes involved in both receptor (TNFRSF 10A, TNFRSF 10B, CASP8) and mitochondrial (BAX, BID, NOXA, APAF1) pathways of apoptosis. Test benzobfurans activated c-Jun N-terminal kinase (JNK) and p38 kinase in K562 cells. Tubulin was identified as a protein target for benzobfurans in pull-down experiments with biotinylated 2. Test benzobfurans inhibited polymerization of tubulin monomers in vitro, decreased the level of cellular microtubules and arrested cells in a G2M phase. Molecular docking suggests that benzobfurans 1 and 2 bind to tubulin via colchicine binding pocket and the complex is stabilized mainly by hydrophobic interactions. Novel benzobfurans with anti-microtubule activity were identified. They induce apoptosis in cancer cells and cause G2M cell cycle arrest. Biological activity of 1 and 2 makes them potential lead compounds for development as anticancer drugs.

Successful alternative treatment for relapsed adult acute lymphoblastic leukemia with dendritic cells-cytokine-induced killer cells combined with a rituximab-based regimen.

Acute lymphoblastic leukemia (ALL) is a malignant disease characterized by the accumulation of lymphoblasts, and a poor prognosis for adults with ALL is closely associated with disease recurrence. Thus far, treatment approaches have been limited, particularly in patients who are unable to tolerate chemotherapy. In this study, we report an effective treatment for such patients. A 52-year-old man diagnosed with Ph-negative B-precursor ALL went into remission after inductive treatment. Unfortunately, when he subsequently relapsed, severe complications drove him to refuse intensive chemotherapy. Instead, he received a cycle of dendritic cells-cytokine-induced killer cells (DC-CIK) before chemotherapy. The patient tolerated rituximab in combination with a vincristine, daunorubicin, l-asparaginase, and prednisone regimen without complications, and was in remission after DC-CIK infusion. After consolidation chemotherapy, including rituximab followed by eight cycles of DC-CIK, the patient has been free of leukemia for 2 years since the relapse. This case of relapsed ALL was successfully treated with DC-CIK combined with a rituximab regimen.

Pre-B acute lymphoblastic leukemia expresses cell surface nucleolin as a 9-O-acetylated sialoglycoprotein.

Precursor B acute lymphoblastic leukemias (pre-B ALLs) abnormally express a specific glycan structure, 9-O-acetylated sialic acid (9-O-Ac-Sia), on their cell surface, but glycoproteins that carry this modification have not been identified. Using three different lectins that specifically recognize this structure, we establish that nucleolin (NCL), a protein implicated in cancer, contains 9-O-Ac-Sia. Surprisingly, antibodies against the glycolipid 9-O-Ac-Sia GD3 also detected 9-O-Ac-Sia NCL. NCL is present on the surface of pre-B ALL cells as a sialoglycoprotein that is partly 9-O-acetylated and conversely, 9-O-Ac-Sia-containing structures other than NCL are present on these cells as well. Interestingly, NCL and the 9-O-Ac-Sia signal had less co-localization on normal pre-B cells. We also investigated regulation of NCL on the cell surface and found that sialidase treatment increased the percentage of cells positive for cell surface NCL, suggesting that sialylation of NCL promotes internalization. Treatment of pre-B ALL cells with the chemotherapy drug vincristine also increased the percentage of cells with surface NCL and correlated with increased 9-O-Ac-Sia expression. All tested leukemia cells including primary samples expressed NCL, suggesting it as a possible therapeutic target. We confirmed this by showing inhibition of cell proliferation in some pre-B ALLs by exposure to a NCL-specific aptamer AS1411.

Human asparagine synthetase associates with the mitotic spindle.

Cancer cells are characterized by extensive reprogramming of metabolic pathways in order to promote cell division and survival. However, the growth promotion effects of metabolic reprogramming can be due to moonlighting functions of metabolic enzymes as well as the redirection of flux through particular pathways. To identify metabolic enzymes that might have potential moonlighting functions in oncogenesis, we have examined recent screens of the yeast GFP strain collection for metabolic enzymes that have been implicated in cancer metabolism with an unusual subcellular localization. Asparagine synthetase forms filaments in yeast in response to nutrient limitation and is part of a pathway that is a chemotherapy target in acute lymphoblastic leukemia. Interestingly, while yeast asparagine synthetase forms cytoplasmic filaments in response to nutrient stress, human asparagine synthetase is associated with the centrosomes and mitotic spindles. This localization is disrupted by both nocodazole and asparaginase treatments. This failure to localize occurs even though asparagine synthetase is highly upregulated in response to asparaginase treatment. Together, these results argue that human asparagine synthetase undergoes regulated recruitment to the mitotic spindles and that it may have acquired a second role in mitosis similar to other metabolic enzymes that contribute to metabolic reprogramming in cancer cells.

GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts.

Chimeric antigen receptor T (CAR-T) cell therapy is a new pillar in cancer therapeutics however, its application is limited by the associated toxicities. These include cytokine release syndrome (CRS) and neurotoxicity. Although the IL-6R antagonist tocilizumab is approved for treatment of CRS, there is no approved treatment of neurotoxicity associated with CD19-targeted CAR-T (CART19) cell therapy. Recent data suggest that monocytes and macrophages contribute to the development of CRS and neurotoxicity after CAR-T cell therapy. Therefore, we investigated neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) as a potential strategy to manage CART19 cell-associated toxicities. In this study, we show that GM-CSF neutralization with lenzilumab does not inhibit CART19 cell function in vitro or in vivo. Moreover, CART19 cell proliferation was enhanced and durable control of leukemic disease was maintained better in patient-derived xenografts after GM-CSF neutralization with lenzilumab. In a patient acute lymphoblastic leukemia xenograft model of CRS and neuroinflammation (NI), GM-CSF neutralization resulted in a reduction of myeloid and T cell infiltration in the central nervous system and a significant reduction in NI and prevention of CRS. Finally, we generated GM-CSF-deficient CART19 cells through CRISPRCas9 disruption of GM-CSF during CAR-T cell manufacturing. These GM-CSF

First CAR to Pass the Road Test Tisagenlecleucels Drive to FDA Approval.

In August 2017, the FDA took historic action in granting the first approval of gene therapy to tisagenlecleucel. This landmark step brought CAR T-cell therapy to the commercial space and heralded a new era in managing refractory B-cell malignancies and FDA oversight of gene-modified therapies.See related article by OLeary et al., p. 1142.

The role of stem cell transplantation in the management of Philadelphia chromosome-positive acute lymphoblastic leukemia.

The concurrent administration of tyrosine kinase inhibitors (TKIs) with standard chemotherapy together with allogeneic hematopoietic stem cell transplantation (alloHSCT) has improved the outcome of patients with Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL). Although to date, no study has shown alloHSCT to be inferior to chemotherapy plus TKIs in any subgroup of adult Ph ALL, there is some evidence suggesting no additional benefit of alloHSCT in patients with deep molecular responses to intensive chemotherapy with a second-generation, and especially, third-generation TKI. As none of these positive and negative studies are controlled, randomized trials are needed to fully define the role of alloHSCT in Ph ALL, especially in those with deep molecular response. However, if studies combining TKIs with new approaches such as immunotherapy lead to durable responses, alloHSCT in the first complete remission could be avoided in the near future in the majority of patients with Ph ALL.

Inotuzumab ozogamicin for the treatment of acute lymphoblastic leukemia.

Therapy for adult acute lymphoblastic leukemia (ALL) with multiagent cytotoxic chemotherapy has not been as successful as that for pediatric patients. The advent of targeted monoclonal antibodies against common cell surface antigens (i.e. CD19, CD20, and CD22) has resulted in improved outcomes without additional toxicities. Inotuzumab ozogamicin is an anti-CD22 antibody-drug conjugate approved for the treatment of relapsed or refractory B-cell precursor ALL. It improved outcomes compared with standard salvage chemotherapy. Its combination with low-intensity chemotherapy in the relapse setting and in frontline elderly patients is promising.

Uncommon Presentation of Childhood Leukemia in Emergency Department The Usefulness of an Early Multidisciplinary Approach.

Leukemia is the most common childhood malignancy, and it is often characterized by pallor, fatigue, cytopenia, and organomegaly sometimes musculoskeletal symptoms, mainly characterized by diffuse bone pain in the lower extremities, are the onset clinical characteristics of the disease. In these cases, the disease may initially be misdiagnosed as reactive arthritis, osteomyelitis, or juvenile idiopathic arthritis delaying appropriate diagnosis and management. Even if leukopenia, thrombocytopenia, and a history of nighttime pain are reported to be the most important predictive factors for a pediatric leukemia, blood examinations can sometimes be subtle or within normal limits, and this represents a further diagnostic difficulty. Radiological findings of leukemic bone involvement are described in patients with musculoskeletal symptoms of acute lymphoblastic leukemia and often appear before hematologic anomalies, but they are not specific for the disease. However, they could be helpful to get the right diagnosis if integrated with other features thus, it is important knowing them, and it is mandatory for the multidisciplinary comparison to talk about dubious cases even in an emergency setting. We describe 4 patients visited in the emergency department for musculoskeletal complaints and having radiological lesions and a final diagnosis of acute lymphoblastic leukemia, in whom the onset of the manifestations could mimic orthopedicrheumatologic diseases.

CD47 agonist peptide PKHB1 induces immunogenic cell death in T-cell acute lymphoblastic leukemia cells.

T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis derived from its genetic heterogeneity, which translates to a high chemoresistance. Recently, our workgroup designed thrombospondin-1-derived CD47 agonist peptides and demonstrated their ability to induce cell death in chronic lymphocytic leukemia. Encouraged by these promising results, we evaluated cell death induced by PKHB1 (the first-described serum-stable CD47-agonist peptide) on CEM and MOLT-4 human cell lines (T-ALL) and on one T-murine tumor lymphoblast cell-line (L5178Y-R), also assessing caspase and calcium dependency and mitochondrial membrane potential. Additionally, we evaluated selectivity for cancer cell lines by analyzing cell death and viability of human and murine non-tumor cells after CD47 activation. In vivo, we determined that PKHB1-treatment in mice bearing the L5178Y-R cell line increased leukocyte cell count in peripheral blood and lymphoid organs while recruiting leukocytes to the tumor site. To analyze whether CD47 activation induced immunogenic cell death (ICD), we evaluated damage-associated molecular patterns (DAMP) exposure (calreticulin, CRT) and release (ATP, heat shock proteins 70 and 90, high-mobility group box 1, CRT). Furthermore, we gave prophylactic antitumor vaccination, determining immunological memory. Our data indicate that PKHB1 induces caspase-independent and calcium-dependent cell death in leukemic cells while sparing non-tumor murine and human cells. Moreover, our results show that PKHB1 can induce ICD in leukemic cells as it induces CRT exposure and DAMP release in vitro, and prophylactic vaccinations inhibit tumor establishment in vivo. Together, our results improve the knowledge of CD47 agonist peptides potential as therapeutic tools to treat leukemia.

Chimeric antigen receptors unleashing a new age of anti-cancer therapy.

Chimeric antigen receptors (CARs) represent a novel facet of modern day synthetic biology that exemplifies personalized medicine at work through their ability to harness and redirect a patients immune system to fight cancer. By combining the target-specificity of antibodies to the effector capabilities of T cells, CARs have yielded high remission rates for many late staged and relapsedrefractory (rr) hematological malignancies, including acute lymphoblastic leukemias (ALL) and Non-Hodgkins lymphomas. Despite toxicities of cytokine release syndrome and neurotoxicity, recent studies have uncovered their underlying mechanisms and devised effective therapies to manage and possibly prevent them. In 2017, CAR T cell therapy became a reality for the general public despite the high costs, when Novartiss Kymriah, became the first product to receive FDA approval for pediatric rr B cell ALL with Gileads Yescarta following several months later. Although effective in hematological malignancies, CAR response has been limited in solid tumors largely attributed to the heterogeneous and immunosuppressive tumor microenvironment along tumor defense mechanisms, such as antigenic escape. Despite the current challenges of CAR T therapy, this technology is still in its infancy and its promise will continue to grow as scientists continue to develop novel approaches to enhance its efficacy. As its prevalence continues to increase, institutions and pharmaceuticals worldwide are investing in this technology in hopes of driving therapeutic innovation, while providing greater access to their respective populations through clinical trials.

CAR-T bridging to allo-HSCT as a treatment strategy for relapsed adult acute B-lymphoblastic leukemia a case report.

Adults with relapsed acute lymphoblastic leukemia (ALL) have a poor prognosis, especially in patients who relapsed within 6 months of complete remission 1 (CR1). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the treatment of choice. However, this can only be considered after complete remission 2 (CR2) is achieved. Therefore, bridging treatment is urgently needed. In the present study, we report a relapsed adult B-cell ALL case that achieved CR2 after treatment with CD19-directed chimeric antigen receptor (CAR)-modified T cell (CAR-T) therapy. After subsequent allo-HSCT, the patient acquired 21 months of disease-free survival. The present results confirm that both CAR-T and allo-HSCT are effective for treating refractory or relapsed B-ALL. However, a novel sequential treatment strategy with these two therapeutic methods may achieve longer disease-free survival time.

Isavuconazole Case Report and Pharmacokinetic Considerations.

Invasive fungal disease (IFD) is one of the major causes of morbidity and mortality in immunocompromised patients. Voriconazole (VCZ) and posaconazole (PCZ) remain the most widely used antifungals for the prophylaxis and treatment of IFD. However, VCZ and PCZ are liable for drug-drug interactions and show a pharmacokinetic variability that requires therapeutic drug monitoring (TDM). Isavuconazole (IVZ) is a newest generation triazole antifungal approved for the treatment of invasive aspergillosis (IA) in adult patients and for the treatment of invasive mucormycosis in adult patients for whom treatment with amphotericin B is inappropriate. In clinical trials, IVZ showed linear pharmacokinetics and little or no evidence for interactions with other drugs. There is only modest evidence on IVZ pharmacokinetics and TDM in real-life settings. Here, we report on IVZ pharmacokinetics in a young adult with Ph chromosome-negative acute lymphoblastic leukemia (ALL) who developed a probable IA during induction chemotherapy. The patient was initially treated with VCZ, but she developed a severe hepatic toxicity that was associated to the high plasma levels of VCZ. Therefore, VCZ was discontinued and the patient was switched to IVZ. After a loading dose of IVZ, the patient remained on IVZ for 5 months while also receiving standard maintenance chemotherapy for ALL. At day 65 after the start of IVZ, the patient experienced a significant hepatic toxicity however, no change in IVZ plasma concentrations was observed in the face of a concomitant administration of many other drugs (cancer drugs, antiemetics, other anti-infectives). Hepatic toxicity resolved after discontinuing maintenance chemotherapy but not IVZ. These results show that (i) IVZ plasma concentrations remained stable throughout and were not affected by concomitant ALL therapy, and (ii) there was no relation between IVZ plasma concentration and hepatic toxicity. Thus, in clinical practice IVZ may not require TDM.

mHealth Supportive Care Intervention for Parents of Children With Acute Lymphoblastic Leukemia Quasi-Experimental Pre- and Postdesign Study.

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Caring for children with ALL is challenging for parents. A mobile health (mHealth) supportive care intervention was developed to meet parents needs. This study aims to evaluate the potential effectiveness of this mHealth supportive care intervention on emotional distress, social support, care burden, uncertainty in illness, quality of life, and knowledge. We conducted a quasi-experimental pre- and postdesign study from June 2015 to January 2016. In total, 101 parents were enrolled in the study, with 50 in the observation group and 51 in the intervention group. Parents in the observation group received the standard health education and were observed for 3 months. Parents in the intervention group received the mHealth supportive care intervention, in addition to the standard health education. The intervention consisted of 2 parts-an Android smartphone app Care Assistant (CA) and a WeChat Official Account. The CA with 8 modules (Personal Information, Treatment Tracking, Family Care, Financial and Social Assistance, Knowledge Center, Self- Assessment Questionnaires, Interactive Platform, and Reminders) was the main intervention tool, whereas the WeChat Official Account was supplementary to update information and realize interaction between parents and health care providers. Data of parents social support, anxiety, depression, care burden, uncertainty in illness, quality of life, their existing knowledge of ALL and care, and knowledge need were collected before and after the 3-month study period in both groups. For the intervention group, parents experience of receiving the intervention was also collected through individual interviews. Overall, 43 parents in the observation group and 49 in the intervention group completed the study. Results found that the intervention reduced parents anxiety (D The mHealth intervention in supporting parents of children with ALL is effective. This study is informative for other future studies on providing mHealth supportive care for parents of children with cancer.

Chemosensitivity is differentially regulated by the SDF-1CXCR4 and SDF-1CXCR7 axes in acute lymphoblastic leukemia with MLL gene rearrangements.

Although recent advances in chemotherapy have markedly improved outcome of acute lymphoblastic leukemia (ALL), infantile ALL with MLL gene rearrangements (MLLALL) is refractory to chemotherapy. We have shown that specific cytokines FLT3 ligand and TGFβ1 both of which are produced from bone marrow stromal cells synergistically induced MLLALL cells into chemo-resistant quiescence, and that treatment of MLLALL cells with inhibitors against FLT3 andor TGFβ1 receptor partially but significantly converts them toward chemo-sensitive. In the present study, we showed that MLLALL cells expressed CXCR4 and CXCR7, both receptors for the same chemokine stromal cell derived factor-1 (SDF-1), but their biological events were differentially regulated by the SDF-1CXCR4 and SDF-1CXCR7 axes and particularly exerted an opposite effect for determining chemo-sensitivity of MLLALL cells enhancement via the SDF-1CXCR4 axis vs. suppression via the SDF-1CXCR7 axis. Because cytosine-arabinoside-induced apoptosis of MLLALL cells was inhibited by pretreatment with the CXCR4 inhibitor but rather accelerated by pretreatment with the CXCR7 inhibitor, an application of the CXCR7 inhibitor may become a good treatment option in future for MLLALL patients. MLLALL has a unique gene profile distinguishable from other types of ALL and AML, and should be investigated separately in responses to biological active agents including chemokine inhibitors.

Galectins as potential emerging key targets in different types of leukemia.

Galectins are carbohydrate-binding proteins and these have very high affinity for β-galactoside containing glycoproteins and glycolipids. Amongst sixteen types of galectin, the role of galectin 1, 3, 9 and 12 is defined in the development and progression of different types of leukemia including acute myeloid leukemia, acute promyelocytic leukemia, B-cell precursor acute lymphoblastic leukemia, adult T cell leukemia and chronic lymphocytic leukemia. There are multiple mechanisms through which these galectins may affect tumor proliferation. These may include increased production of tumor resistance conferring proteins such as multidrug resistance (MDR-1) and myeloid cell leukemia (MCL-1). Moreover, galectin-9 may act on Tim-3 receptors present on the circulating CD8

Hemorrhagic Cystitis Treatment With Hyperbaric Oxygen Therapy in Patients With Acute Lymphoblastic Leukemia.

Hyperbaric oxygen therapy is a rare treatment modality for hemorrhagic cystitis (HC) following BK virus reactivation in the immunosuppressed population. Clinicians need to be aware of the etiology, preventive measures, complications, and various management techniques in HC while treating patients undergoing bone marrow transplantation. This study details the pathologic progression of HC in a patient with acute lymphoblastic leukemia harboring BK virus after cytotoxic induction chemotherapy and haploidentical marrow transplantation. A search of PubMed for literature published from 1973-2018 was conducted using keywords. Hyperbaric oxygen therapy in chemotherapy-induced and BK virus-associated HC is a viable management option in parallel with tapering of immunosuppressives, bladder irrigation, and IV resuscitation within the post-transplantation acute lymphoblastic leukemia population.

CD123 expression levels in 846 acute leukemia patients based on standardized immunophenotyping.

While it is known that CD123 is normally strongly expressed on plasmacytoid dendritic cells and completely absent on nucleated red blood cells, detailed information regarding CD123 expression in acute leukemia is scarce and, if available, hard to compare due to different methodologies. CD123 expression was evaluated using standardized EuroFlow immunophenotyping in 139 pediatric AML, 316 adult AML, 193 pediatric BCP-ALL, 69 adult BCP-ALL, 101 pediatric T-ALL, and 28 adult T-ALL patients. Paired diagnosis-relapse samples were available for 57 AML and 19 BCP-ALL patients. Leukemic stem cell (LSC) data was available for 32 pediatric AML patients. CD123 expression was evaluated based on mean fluorescence intensity, median fluorescence intensity, and percentage CD123 positive cells. EuroFlow panels were stable over time and between laboratories. CD123 was expressed in the majority of AML and BCP-ALL patients, but absent in most T-ALL patients. Within AML, CD123 expression was lower in erythroidmegakaryocytic leukemia, higher in NPM1 mutated and FLT3-ITD mutated leukemia, and comparable between LSC and leukemic blasts. Within BCP-ALL, CD123 expression was higher in patients with (high) hyperdiploid karyotypes and the BCR-ABL fusion gene. Interestingly, CD123 expression was increased in BCP-ALL relapses while highly variable in AML relapses (compared to CD123 expression at diagnosis). Authors evaluated CD123 expression in a large cohort of acute leukemia patients, based on standardized and reproducible methodology. Our results may facilitate stratification of patients most likely to respond to CD123 targeted therapies and serve as reference for CD123 expression (in health and disease). © 2018 The Authors. Cytometry Part B Clinical Cytometry published by Wiley Periodicals, Inc. on behalf of International Clinical Cytometry Society.

Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008.

Asparaginase is essential in childhood acute lymphoblastic leukaemia (ALL) treatment, however hypersensitivity reactions to pegylated asparaginase (PEG-asparaginase) hampers anti-neoplastic efficacy. Patients with PEG-asparaginase hypersensitivity have been shown to possess zero asparaginase enzyme activity. Using this measurement to define the phenotype, we investigated genetic predisposition to PEG-asparaginase hypersensitivity in a genome-wide association study (GWAS). From July 2008 to March 2016, 1494 children were treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol. Cases were defined by clinical hypersensitivity and no enzyme activity, controls had enzyme activity ≥ 100 iul and no hypersensitivity symptoms. PEG-asparaginase hypersensitivity was reported in 13·8% (2061494) of patients. Fifty-nine cases and 772 controls fulfilled GWAS inclusion criteria. The CNOT3 variant rs73062673 on 19q13.42, was associated with PEG-asparaginase allergy (P 4·68 × 10

Intrathecal Methotrexate-Induced Necrotizing Myelopathy A Case Report and Review of Histologic Features.

Central nervous system (CNS) relapse of acute lymphoblastic leukemia (ALL) is associated with a poor prognosis. However, prophylactic measures, including intrathecal (IT) methotrexate, reduce the incidence of CNS relapse in these patients considerably. Unfortunately, IT methotrexate can cause several neurologic complications, including transverse myelopathy ie, the development of isolated spinal cord dysfunction over hours or days following the IT infusion of methotrexate, but in the absence of a compressive lesion. Transverse myelopathy following IT methotrexate is a well-established clinical phenomenon, but the histologic features have been described only very rarely. We report the autopsy findings from a 31-year-old man with a history of T-cell ALL who received prophylactic IT methotrexate in anticipation of a bone marrow transplant. Microscopic examination showed transverse necrosis of the thoracic cord, with massive infiltration by macrophages and lymphocytes, and perivascular lymphocytic infiltrates. There was cavitary necrosis of cervical and lumbar spinal cord involving the entire gray matter and focal white matter, as well as extensive subpial vacuolar degeneration of the dorsal and lateral columns.

MinimalMeasurable Residual Disease Detection in Acute Leukemias by Multiparameter Flow Cytometry.

Minimal or measurable residual disease (MRD) detected by multiparameter flow cytometry (MFC) is an independent prognostic indicator in acute leukemia. However, the predictive value of MFC MRD is affected by technical challenges, interpretive complexities, and inadequate standardization, particularly in acute myeloid leukemia (AML). Here, we critically review the methodological principles of the MFC MRD assay and discuss clinical implications of MRD. Key components of MFC MRD assays to be discussed include the principles of MFC, panel selection, analysis approaches, level of quantifiable MRD and calculation, reporting, and areas of improvements. Key components of clinical implications include context-dependent detection threshold and the integral role of MRD assessment by MFC in the era of ever-expanding molecular testing. With advancements in technology and standardization, MFC along with molecular assays will continue to play an important role in MRD assessment to evaluate treatment response and risk stratification.

Panel-based next-generation sequencing identifies prognostic and actionable genes in childhood acute lymphoblastic leukemia and is suitable for clinical sequencing.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although the cure rate of ALL has greatly improved, a considerable number of patients suffer from relapse of leukemia. Therefore, ALL remains the leading cause of death from cancer during childhood. To improve the cure rate of these patients, precisely detecting patients with high risk of relapse and incorporating new targeted therapies are urgently needed. This study investigated inexpensive, rapid, next-generation sequencing of more than 150 cancer-related genes for matched diagnostic, remission, and relapse samples of 17 patients (3 months to 15 years old) with relapsed ALL. In this analysis, we identified 16 single-nucleotide variants (SNVs) and insertiondeletion variants and 19 copy number variants (CNVs) at diagnosis and 28 SNVs and insertiondeletion variants and 22 CNVs at relapse. With these genetic alterations, we could detect several B cell precursor ALL patients with high-risk gene alterations who were not stratified into the highest-risk group (58, 62.5%). We also detected potentially actionable genetic variants in about half of the patients (817, 47.1%). Among them, we found that one patient harbored germline TP53 mutation as a secondary finding. This inexpensive, rapid method can be immediately applied as clinical sequencing and could lead to better management of these patients and potential improvement in the survival rate in childhood ALL.

The EBMT Handbook Hematopoietic Stem Cell Transplantation and Cellular Therapies

ALL is a malignant transformation and proliferation of lymphoid progenitor cells in the bone marrow, blood, and extramedullary sites. While 80% of ALL occurs in children, it represents a devastating disease in adults.

The EBMT Handbook Hematopoietic Stem Cell Transplantation and Cellular Therapies

Although the majority of children and adolescents with acute lymphoblastic leukemia (ALL) are curable with current chemotherapy regimens, poor outcome persists in some individuals (Eckert et al. 2011 von Stackelberg et al. 2011 Schrappe et al. 2012).

Fecal microbiota transplantation with frozen capsules for a patient with refractory acute gut graft-versus-host disease.

Bacterial diversity was restored after FMT with oral frozen capsules, with improvement of diarrhea. Oral FMT for steroid-refractory acute gGVHD is feasible and could be effective.

A clinical perspective on immunoglobulin heavy chain clonal heterogeneity in B cell acute lymphoblastic leukemia.

B cell acute lymphoblastic leukemia (B ALL) is a genetically heterogeneous neoplasm often demonstrating extensive subclone diversity within each patients disease. The immunoglobulin heavy chain (IGH) locus is a marker of clonal variation in B ALL due to its intrinsic role in B lymphocyte development and its diverse Vh(D)Jh rearrangement patterns. B ALL IGH evolution may contribute to limitations in minimal residual disease (MRD) monitoring methods. Evolving technologies for IGH high-throughput sequencing (HTS) have demonstrated MRD detection as sensitive as 1 cell in 1,000,000. These methods may enhance the surveillance of B ALL in the setting of extensive subclone evolution and provide opportunities for detection and intervention before the onset of relapse. However, HTS MRD methods will need to be evaluated in the context of clinical trials in order to gain further insights about the clinical relevance of such sensitive B ALL MRD detection.

Block alignment New representation and comparison method to study evolution of genomes.

Genomes are not random sequences because natural selection has injected information in biological sequences for billions of years. Inspired by this idea, we developed a simple method to compare genomes considering nucleotide counts in subsequences (blocks) instead of their exact sequences. We introduce the Block Alignment method for comparing two genomes and based on this comparison method, define a similarity score and a distance. The presented model ignores nucleotide order in the sequence. On the other hand, in this block comparison method, due to exclusion of point mutations and small size variations, there is no need for high coverage sequencing which is responsible for the high costs of data production and storage moreover, the sequence comparisons could be performed with higher speed. Phylogenetic trees of two sets of bacterial genomes were constructed and the results were in full agreement with their already constructed phylogenetic trees. Furthermore, a weighted and directed similarity network of each set of bacterial genomes was inferred ab initio by this model. Remarkably, the communities of these networks are in agreement with the clades of the corresponding phylogenetic trees which means these similarity networks also contain phylogenetic information about the genomes. Moreover, the block comparison method was used to distinguish rob(1521)c-associated iAMP21 and sporadic iAMP21 rearrangements in subgroups of chromosome 21 in acute lymphoblastic leukemia. Our results show a meaningful difference between the number of contigs that mapped to chromosomes 15 and 21 in these cases. Furthermore, the presented block alignment model can select the candidate blocks to perform more accurate analysis and it is capable to find conserved blocks on a set of genomes.

Functional Improvement of Chimeric Antigen Receptor Through Intrinsic Interleukin-15Rα Signaling.

Recent studies on CD19-specific chimeric antigen receptor (CAR)-modified T cells (CARTs) have demonstrated unprecedented successes in treating refractory and relapsed B cell malignancies. The key to the latest CART therapy advances can be attributed to the improved costimulatory signals in the CAR design. Here, we established several novel CARs by incorporating T cell signaling domains of CD28 in conjunction with intracellular signaling motif of 4-1BB, CD27, OX40, ICOS, and IL-15Rα. These novel CARs were functionally assessed based on a simple target cell killing assay. The results showed that the CD28IL-15Rα co-signaling (153z) CAR demonstrated the fastest T cell expansion potential and cytotoxic activities. IL-15 is a key cytokine that mediates immune effector activities. The 153z CARTs maintained prolonged killing activities after repetitive rounds of target cell engagement. Consistent with the enhanced target killing function, the 153z CARTs produced increased amount of effector cytokines including IFN-γ, TNFα and IL-2 upon interaction with the target cells. In a follow-up clinical study, an acute lymphoblastic leukemia (ALL) patient, who experienced multiple relapses of central nervous system leukemia (CNSL) and failed all conventional therapies, was enrolled to receive the CD19-specific 153z CART treatment. The patient achieved complete remission after the 153z CART cell infusion. The translational outcome supports further investigation into the safety and enhanced therapeutic efficacy of the IL-15Rα-modified CART cells in cancer patients.

The Expression of Interferon Gamma (IFN-γ) and Interleukin 6 (IL6) in Patients with Acute Lymphoblastic Leukemia (ALL).

Interferon gamma (IFN-γ) and interleukin 6 (IL-6) are including the most important cytokines which have been associated with the biological behavioral and immune responses in malignancies. Based on the critical roles which these two cytokines play against tumor cells, the present study was aimed to investigate the genes expression level of IL6 and IFN-γ in patients with Acute Lymphoblastic Leukemia and compare with normal controls. Fifty-two patients with ALL and 13 healthy volunteer were under studied. The peripheral blood mononuclear cells of all patients and normal controls were separated by ficoll. The expression of interferon gamma and interleukin 6 genes were determined by RQ-PCR. Finally all data were analyzes using T student, one way ANOVA and Mann-Whitney tests were use to analyze all samples data. Our finding showed that the level of IFN-γ gene expression was significant decreased in patients with All as compared with healthy controls (83 change fold, p < 0.0001). The level of IL-6 Gene expression was not changeable in B-ALL patients as compared with healthy control (p 0.4), but in T-ALL patients, was significantly reduced (p < 0.01). The results of present study indicated that IFN-γ gene expression reduced in ALL patients. It provides a valuable insight that immune system may disrupted in patients with ALL, which cause tumor cells escape from immune surveillance.

How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia.

The introduction of agents targeted at specific molecular events is changing the treatment paradigms in a number of malignancies. Historically, we have relied entirely on DNA-interactive, cytotoxic drugs for treating patients with leukemia. Increased understanding of the leukemic cell biology and pathogenesis, and the ways they evade the immune surveillance mechanisms, will likely lead to the development of more effective agents, and regimens less reliant on chemotherapy, able to achieve deep levels of disease eradication. In Philadelphia chromosome-positive acute lymphoblastic leukemia, the introduction of increasingly potent tyrosine kinas inhibitors (TKIs) has revolutionized therapy. These drugs have been established as the cornerstone of any therapeutic strategy in this disease, and a number of trials have better defined the best ways to incorporate them into the established paradigms. Despite using TKIs, we have continued to remain reliant on cytotoxic chemotherapy regimens and allogeneic hematopoietic cell transplant to achieve the best long-term outcomes. However, with the introduction of more potent TKIs and other novel agents, as well as better methods for monitoring minimalmeasurable residual disease, we are entering an era where we hope to diminish our reliance on transplantation and cytotoxic chemotherapy in this disease.

Inotuzumab ozogamicin is effective in relapsedrefractory extramedullary B acute lymphoblastic leukemia.

Extramedullary involvement of B-cell Acute Lymphoblastic Leukemia (EM-ALL) is a rare occurrence, characterized by dismal outcome and the absence of a defined and shared therapeutic approach. In the landscape of innovative compounds, inotuzumab ozogamicin (IO) is a promising drug, whose mechanism of action relies on the killing of CD22 positive leukemic cells, through the delivery, after cell binding, of a molecule of calicheamicin. We report two cases of CD22 positive relapsed EM-ALL treated with IO, obtained as compassionate use. Case 1, a 66 years old woman, affected by Philadelphia (Ph) negative B-ALL, relapsed with extramedullary involvement after 6 standard chemotherapy courses, who reached a complete metabolic response with IO treatment. Case 2, a 67 years old man with Ph positive B-ALL, initially treated with ponatinib, a third generation tyrosine-kinase inhibitor (TKI), obtaining a prolonged deep molecular remission. Nevertheless, for skin relapse during TKI treatment, the patient received local radiotherapy and, shortly after, standard chemotherapy, as multiple abdominal sites of relapse were detected too, with no response. The patient then received IO, obtained as compassionate use, with a good metabolic response. These two cases suggest a possible key role of IO in the setting of advanced CD22 positive ALL, and underline its potential activity also in patients with EM involvement, relapsed after or refractory to conventional chemotherapy. Despite the well known hepatotoxic effect of the compound (Sinusoid Occlusive Syndrome), neither of them had such adverse event, moreover the second patient safely underwent allogeneic bone marrow transplantation.

Very long intergenic non-coding RNA transcripts and expression profiles are associated to specific childhood acute lymphoblastic leukemia subtypes.

Very long intergenic non-coding RNAs (vlincRNAs) are a novel class of long transcripts (50 kb to 1 Mb) with cell type- or cancer-specific expression. We report the discovery and characterization of 256 vlincRNAs from a cohort of 64 primary childhood pre-B and pre-T acute lymphoblastic leukemia (cALL) samples, of which 61% are novel and specifically expressed in cALL. Validation was performed in 35 pre-B and pre-T cALL primary samples. We show that their expression is cALL immunophenotype and molecular subtype-specific and correlated with epigenetic modifications on their promoters, much like protein-coding genes. While the biological functions of these vlincRNAs are still unknown, our results suggest they could play a role in cALL etiology or progression.

Impairment of Vα24-Jα18

Type I natural killer T (NKT) cells are attractive candidates for cancer immunotherapy. In this study, we examined the characteristics of type I NKT cells in patients with adult B-cell acute lymphoblastic leukemia (ALL). We first identified type I NKT cells as Vα24-Jα18 and Vβ11 double-positive CD3

Bone disorders and complications of pediatric acute lymphoblastic leukemia monocentric study and review of the literature.

Bone pain associated with bone marrow infiltration is often present at diagnosis of pediatric acute lymphoblastic leukemia (ALL). It sometimes signs the presence of pathological fracture, lytic lesions, arthritis, or osteitis associated to ALL that can delay the diagnosis. During treatment, bone complications (pain, osteopenia, fracture, avascular necrosis, ...) are also reported. In order to describe bone involvement (BI) of pediatric LLA, we reviewed the records of 104 patients followed in our unit. The overall incidence of BI was 67 %. At diagnosis, 50 % of patients had BI and in 19 %, the diagnosis of ALL was delayed. During and after treatment, respectively 28 % and 37 % of patients presented bone complications (pain, fractures, avascular necrosis, osteopenia). Patients with BI had a lower leukocytosis inferior to 10x109l (p 0.005) and an ALL of average risk (p 0.019). 38 % of patients with BI during treatment were over 10 years old and 55 % were girls (vs. 21 % and 38 % in the entire cohort, respectively). Osteoporosis was more severe at diagnosis than during treatment, suggesting the presence of constitutional promoting factors. In our cohort, the majority of BI was resolved at the end of treatment with no long-term sequelae. Des douleurs osseuses sont souvent présentes au diagnostic des leucémies lymphoblastiques aiguës (LLA) pédiatriques. Elles signent aussi parfois la présence de fracture pathologique, de lésions lytiques, d’arthrite, ou d’ostéite associées qui peuvent retarder le diagnostic. Lors des traitements, des complications osseuses (douleurs, ostéopénie, fracture, nécrose avasculaire, …) sont également rapportées. Afin de décrire les atteintes osseuses (AO) des LLA pédiatriques, nous avons revu les dossiers de 104 patients suivis dans notre unité. L’incidence globale des AO était de 67 %. Au diagnostic, 50 % des patients avaient une AO et, chez 19 % d’entre eux, le diagnostic de LLA a été retardé. Pendant et après les traitements, respectivement 28 et 37 % des patients ont présenté des complications osseuses (douleurs, fractures, nécrose avasculaire, ostéopénie). Les patients avec AO avaient une leucocytose plus basse inf�rieur a 10x109l (p 0,005) et une LLA de risque moyen (p 0,019). Chez les patients avec AO pendant les traitements, 38 % avaient plus de 10 ans et 55 % étaient des filles (vs 21 % et 38 % dans la cohorte entière). L’ostéoporose était plus sévère au diagnostic que pendant les traitements, suggérant la présence de facteurs favorisants constitutionnels. Dans notre cohorte, la majorité des AO étaient résolues après les traitements de LLA sans séquelles à long terme.

T-Cell Receptor Rearrangements Determined Using Fragment Analysis in Patients With T-Acute Lymphoblastic Leukemia.

Chromosomal abnormalities and common genetic rearrangements related to T-acute lymphoblastic leukemia (T-ALL) are not clear. We investigated T-cell receptor ( In 51 Korean patients diagnosed as having T-ALL, Thirty-eight patients (74.5%) had 62 clonal products of The overall detection rate of

Impact of cytogenetics on outcomes in pediatric acute lymphoblastic leukemia.

In acute lymphoblastic leukemia (ALL), the most important prognostic factors are age, leukocyte count at presentation, immunophenotype, and cytogenetic abnormalities. The cytogenetic abnormalities are associated with distinct immunologic phenotypes of ALL and characteristic outcomes. The present study was primarily aimed at analyzing the impact of cytogenetics on postinduction responses and event-free survival (EFS) in pediatric patients with ALL. The secondary objective was to study the overall survival (OS). A total of 240 patients with age <18 years and diagnosed with ALL between January 2011 and June 2016 were retrospectively analyzed. Cytogenetics was evaluated with conventional karyotyping or reverse transcriptase polymerase chain reaction. Based on cytogenetic abnormalities, the patients were grouped into five categories, and the outcomes were analyzed. Of the 240 patients, 125 (52%) patients had evaluable cytogenetics. Of these, 77 (61.6%) patients had normal cytogenetics, 19 (15.2%) had t(922) translocation, 10 (8%) had unfavorable cytogenetics which included t(911), hypodiploidy, and complex karyotype, 10 (8%) had favorable cytogenetics which included t(1221), t(119), and high hyperdiploidy, 9 (7.2%) had miscellaneous cytogenetics. Seventy-one percent of patients were treated with MCP 841 protocol, while 29% of patients received BFM-ALL 95 protocol. The 3-year EFS and OS of the entire group were 52% and 58%, respectively. On univariate analysis, EFS and OS were significantly lower in t(922) compared to normal cytogenetics ( Cytogenetics plays an important role in the molecular characterization of ALL defining the prognostic subgroups. Patients with unfavorable cytogenetics and with t(922) have poorer outcomes.

CD44 Expression Profile Varies According to Maturational Subtypes and Molecular Profiles of Pediatric T-Cell Lymphoblastic Leukemia.

CD44 is a glycoprotein expressed in leucocytes and a marker of leukemia-initiating cells, being shown to be important in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). In this study, we have (i) identified the aberrant antigenic pattern of CD44 and its isoform CD44v6 in T-ALL (ii) tested the association with different T-cell subtypes and genomic alterations (iii) identified the impact of CD44 status in T-ALL outcome. Samples from 184 patients (123 T-ALL and 61 AML <19 years) were analyzed throughout multiparametric flow cytometry. Mutations in

Severe Neuropathic Pain With Concomitant Administration of Vincristine and Posaconazole.

Vincristine is a chemotherapeutic agent with a potential toxicity of sensorimotor peripheral neuropathy. Patients receiving chemotherapy are in an immunocompromised state and may require antifungal agents. Triazole antifungals are known inhibitors of cytochrome P450 (CYP) enzymes. Vincristine is a known CYP3A4 and CYP3A5 substrate, and concomitant administration with fluconazole or voriconazole has been reported to increase vincristine toxicity and peripheral neuropathy, but there is limited literature on posaconazole in this regard. This 5-year-old girl with pre-B-cell acute lymphoblastic leukemia received vincristine while receiving posaconazole for a mucormycosis infection and developed unexpectedly severe peripheral neuropathy. After recovery, the child continued on mucormycosis prophylaxis with posaconazole with instructions to hold for 2 days before and on the day of vincristine administration. This case illustrates the potentiating effect that posaconazole had on vincristine-associated neurotoxicity, and our approach to mitigating that negative interaction.

Trisomy of a Down Syndrome Critical Region Globally Amplifies Transcription via HMGN1 Overexpression.

Down syndrome (DS, trisomy 21) is associated with developmental abnormalities and increased leukemia risk. To reconcile chromatin alterations with transcriptome changes, we performed paired exogenous spike-in normalized RNA and chromatin immunoprecipitation sequencing in DS models. Absolute normalization unmasks global amplification of gene expression associated with trisomy 21. Overexpression of the nucleosome binding protein HMGN1 (encoded on chr21q22) recapitulates transcriptional changes seen with triplication of a Down syndrome critical region on distal chromosome 21, and HMGN1 is necessary for B cell phenotypes in DS models. Absolute exogenous-normalized chromatin immunoprecipitation sequencing (ChIP-Rx) also reveals a global increase in histone H3K27 acetylation caused by HMGN1. Transcriptional amplification downstream of HMGN1 is enriched for stage-specific programs of B cells and B cell acute lymphoblastic leukemia, dependent on the developmental cellular context. These data offer a mechanistic explanation for DS transcriptional patterns and suggest that further study of HMGN1 and RNA amplification in diverse DS phenotypes is warranted.

Diabetic ketoacidosis following PEG-asparaginase therapy.

We report a case of a 21-year-old African American female with history of pre-diabetes, and a diagnosis of a rare leukemia, blastic-plasmacytoid dendritic neoplasm (BPDCN), who developed diabetic ketoacidosis (DKA) after the third dose of PEG-asparaginase infusion. She was successfully treated with insulin. Asparaginase is a vital part of treatment protocols for acute lymphoblastic leukemia (ALL) in combination with other chemotherapeutic drugs. Asparaginase therapy has been reported to cause hyperglycemia especially when used in conjunction with glucocorticoids for the treatment of ALL in the pediatric population. Multiple mechanisms for hyperglycemia have been hypothesized which include decreased insulin secretion, impaired insulin receptor function and excess glucagon formation. Hyperglycemia is usually self-limiting but can deteriorate to diabetic ketoacidosis. DKA is a rare adverse effect with asparaginase therapy with an incidence rate of about 0.8%. Learning points •• DKA is a rare finding following asparaginase therapy. •• Hyperglycemia is most commonly seen with asparaginase treatment when used along with glucocorticoid. •• Frequent blood glucose monitoring and prompt initiation of insulin treatment with hyperglycemia can prevent severe complications. •• Patients and physician education on this complication can reduce morbidity due to DKA.

The role of tumor suppressor of resveratrol and prednisolone by downregulation of YKL-40 expression in CCRF-CEM cell line.

Acute lymphoblastic leukemia (ALL) is characterized by excessive accumulation of lymphoblast and progenitors. Leukemia is the most common cancer in children and ALL is the most common subtype. Many studies have shown that the YKL-40 gene is one of the most widely expressed genes in tumors, including leukemia, but not in healthy blood cells. Clinical studies have shown that serum YKL-40 levels have a positive correlation with tumor expansion, in addition to being a prognostic agent independent of a short relapse-free interval, as well as a brief overall survival in patients with various cancers. The previous study shows that YKL-40 is closely related to the degree of pathology or degree of human leukemia pathology and plays an important role in cell proliferation. Hence, the YKL-40 can be an attractive target in designing anticancer therapies. CCRF-CEM cells were treated with resveratrol and prednisolone. For analysis of YKL-40 expression changes under medication, real-time polymerase chain reaction (PCR) and Western blot techniques were used at resonating intervals of 24 and 48 hours. The effect of 15, 50, and 100 μM resveratrol and 700 μM of prednisolone on CCRF-CEM cells reduced YKL-40. The YKL-40 gene was quantitatively measured using RT-PCR. The Western blot method was used to evaluate changes in the expression of YKL-40 protein. In this study, we first evaluated YKL-40 expression and resveratrol and prednisolone effect on YKL-40 in ALL. This finding supports the idea of targeting YKL-40 as a new drug treatment of ALL and extends the use of resveratrol in antileukemia research.

Hepatitis E virus infection after haploidentical haematopoietic stem cell transplantation incidence and clinical course.

Hepatitis E virus (HEV) is increasingly found to cause hepatitis in allogeneic haematopoietic stem cell transplantation (HSCT) patients. However, little is known about HEV infection in patients receiving haploidentical HSCT (haplo-HSCT). Here, we retrospectively evaluate the incidence and clinical course of HEV infection in haplo-HSCT patients. From January 2014 to July 2017, 177 patients with unexplained elevated transaminases after receiving haplo-HSCT at Peking University Institute of Haematology were screened for HEV using HEV serology. HEV RNA was assessed in blood samples when HEV-IgG andor IgM antibodies were positive. Acute HEV infection was identified in 7 patients (3·9%), 1 of whom had developed a chronic HEV infection. The median time from haplo-HSCT to HEV infection was 17·5 (range, 6-55) months. HEV infection was confirmed by the presentation of anti-HEV IgM anti-HEV IgG (rising) (n 5) or HEV-RNA anti-HEV IgM anti-HEV IgG (n 2). None of the patients died of HEV infection directly 2 patients with HEV infection died showing signs of ongoing hepatitis, and 5 patients cleared HEV with a median duration of HEV infection of 1·5 (range, 1·0-5·7) months. In conclusion, HEV infection is a rare but serious complication after haplo-HSCT. We recommend screening of HEV in haplo-HSCT.

Acute Pre-B Lymphoblastic Leukemia and Congenital Anomalies in a Child with a

Microdeletions and microduplications are recurrent in the q11.2 region of chromosome 22. The 22q11.2 duplication syndrome is an extremely variable disorder with a phenotype ranging from severe intellectual disability, facial dysmorphism, heart defects, and urogenital abnormalities to very mild symptoms. Both benign and malignant hematological entities are rare. A male patient was diagnosed with mild facial dysmorphia, congenital heart anomalies shortly after birth and acute bowel obstruction due to malrotation of the intestine at the age of 3 years. A whole-genome single nucleotide polymorphism (SNP) array revealed a

Defining the in vivo characteristics of acute myeloid leukemia cells behavior by intravital imaging.

The majority of acute myeloid leukemia (AML) patients have a poor response to conventional chemotherapy. The survival of chemoresistant cells is thought to depend on leukemia-bone marrow (BM) microenvironment interactions, which are not well understood. The CXCL12CXCR4 axis has been proposed to support AML growth but was not studied at the single AML cell level. We recently showed that T-cell acute lymphoblastic leukemia (T-ALL) cells are highly motile in the BM however, the characteristics of AML cell migration within the BM remain undefined. Here, we characterize the in vivo migratory behavior of AML cells and their response to chemotherapy and CXCR4 antagonism, using high-resolution 2-photon and confocal intravital microscopy of mouse calvarium BM and the well-established MLL-AF9-driven AML mouse model. We used the Notch1-driven T-ALL model as a benchmark comparison and AMD3100 for CXCR4 antagonism experiments. We show that AML cells are migratory, and in contrast with T-ALL, chemoresistant AML cells become less motile. Moreover, and in contrast with T-ALL, the in vivo exploratory behavior of expanding and chemoresistant AML cells is unaffected by AMD3100. These results expand our understanding of AML cells-BM microenvironment interactions, highlighting unique traits of leukemia of different lineages.

Aberrant ARID5B expression and its association with Ikaros dysfunction in acute lymphoblastic leukemia.

Mutations and single nucleotide polymorphisms of AT-rich interactive domain-containing protein 5B (ARID5B) are involved in the oncogenesis of acute lymphoblastic leukemia (ALL) and treatment outcomes. However, ARID5B expression and clinical significance in ALL remain unclear. We found ARID5B is significantly down-regulated in ALL compared to healthy bone marrow controls. ARID5B also interacts with PHD finger protein 2 (PHF2). Low expression of ARID5B (ARID5B

Testing for minimal residual disease in adults with acute lymphoblastic leukemia in Europe a clinician survey.

In acute lymphoblastic leukemia (ALL), the presence of minimal residual disease (MRD) after inductionconsolidation chemotherapy is a strong prognostic factor for subsequent relapse and mortality. Accordingly, European clinical guidelines and protocols recommend testing patients who achieve a complete hematological remission (CR) for MRD for the purpose of risk stratification. The aim of this study was to provide quantitative information regarding real-world clinical practice for MRD testing in five European countries. A web-based survey was conducted in MarchApril 2017 in France, Germany, Italy, Spain, and the UK. The survey was developed after consultation with specialist clinicians and a review of published literature. Eligible clinicians (20 per country 23 in Spain) were board-certified in hemato-oncology or hematology, had at least five years experience in their current role after training, had treated at least two patients with B-cell precursor ALL in the 12 months before the survey or at least five patients in the last five years, and had experience of testing for MRD in clinical practice. MRD testing is now standard practice in the treatment of adult ALL across the five European countries, with common use of recent treatment protocols which specify testing. Respondents estimated that, among clinicians in their country who conduct MRD testing, 73% of patients in first CR (CR1) and 63% of patients in second or later CR (CR2) are tested for MRD. The median time point reported as most commonly used for the first MRD test, to establish risk status and to determine a treatment plan was four weeks after the start of induction therapy. The timing and frequency of tests is similar across countries. An average of four or five post-CR1 tests per patient in the 12 months after the first MRD test were reported across countries. This comprehensive study of MRD testing patterns shows consistent practice across France, Germany, Italy, Spain, and the UK with respect to the timing and frequency of MRD testing, aligning with use of national protocols. MRD testing is used in clinical practice also in patients who reach CR2 .

A novel mixed hemimicelles dispersive micro-solid phase extraction using ionic liquid functionalized magnetic graphene oxidepolypyrrole for extraction and pre-concentration of methotrexate from urine samples followed by the spectrophotometric method.

Methotrexate (MTX) is an anticancer drug that is widely used in a variety of cancers including primary central nervous system lymphoma. It is also administrated in the treatment of some autoimmune diseases. A simple, accurate, sensitive, and precise mixed hemimicelles dispersive micro-solid phase extraction was proposed for MTX quantification in human urine samples. MTX was quantified by spectrophotometer after dispersive micro-solid phase extraction using ionic liquid functionalized magnetic graphene oxidepolypyrrole. Interactions of adsorbent and MTX were modeled by molecular docking and the interaction energy was predicted to be -8.35 kcalmol. A larger absolute value of binding energy represents larger adsorption strength, indicating that graphene oxide nanosheets could perform higher adsorption strength toward MTX. The concentrations of MTX were proportional to analytical response in amounts ranging from 10 to 1000 ngmL with a good correlation (R

High-dose methotrexate vs. Capizzi methotrexate for the treatment of childhood T-cell acute lymphoblastic leukemia.

Sixty-three children (1-14 years of age) newly diagnosed with T-cell acute lymphoblastic leukemia were treated from January 2001 to December 2014. Patient outcomes were evaluated based on the regimen received Capizzi methotrexate (C-MTX) vs. high-dose methotrexate (HDMTX). Complete remission (CR) was achieved in 54 of 60 (90.0%) patients and 3 patients died during induction. The 5-year overall survival (OS) and disease-free survival (DFS) were 88.3 ± 6.5% and 85 ± 7.5%, respectively. Post-induction, 35 patients were treated with HDMTX and 25 with C-MTX. There was no difference in OS or DFS for patients treated with HDMTX vs. C-MTX (

T-ALL leukemia stem cell stemness is epigenetically controlled by the master regulator SPI1.

Leukemia stem cells (LSCs) are regarded as the origins and key therapeutic targets of leukemia, but limited knowledge is available on the key determinants of LSC stemness. Using single-cell RNA-seq analysis, we identify a master regulator, SPI1, the LSC-specific expression of which determines the molecular signature and activity of LSCs in the murine

Characteristics and Therapeutic Targeting of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Early response to therapy, especially the measurement of minimal residual disease (MRD), remains the most reliable and strongest independent prognostic parameter. Intriguingly, little is known on the mechanisms sustaining MRD in that disease. Here, we summarize existing evidence on the influences of molecular genetics and clonal architecture of childhood ALL on disease persistence. Also, the impact of the leukemic niche on residual leukemia cells in the bone marrow and extramedullary compartments is reviewed. We further discuss existing in vivo models of minimal residual disease based on different cellular labelling strategies and engraftment of ALL cells in immunodeficient mouse strains. We finally draw some conclusions on potential strategies targeting residual ALL cells, with a focus on cellular and antibody-based immunotherapy.

Switch to low-fat diet improves outcome of acute lymphoblastic leukemia in obese mice.

It is becoming increasingly recognized that weight and nutritional status can impact cancer survival. We have previously shown that obese mice with syngeneic acute lymphoblastic leukemia (ALL) have poorer response to chemotherapy treatment than control mice. We therefore investigated whether dietary intervention could improve outcome from the most common pediatric cancer, ALL. Diet-induced obese (DIO) mice raised on a 60% calories from fat diet and control mice were implanted with syngeneic ALL cells. Some DIO mice were switched to the low-fat control diet. Survival from ALL was assessed without or with chemotherapy treatment starting at the time of the diet switch. Cells from DIO mice before and after diet switch were assessed by FACS for BrdU incorporation and phosphorylation status of AKT, S6K, and EIF2a. Similar experiments were done with human ALL xenografts. Mouse and human ALL cells were cultured in media with 10% or 5% fetal bovine serum, and sensitivity to chemotherapies assessed. DIO mice had poorer survival (17%) after vincristine monotherapy than control mice on a 10% low fat diet (42% We report herein that a dietary intervention can improve ALL outcome in a preclinical model. Further work is needed to identify the mechanisms of this effect and investigate potential impact on human leukemia in patients.

Personalized nanomedicine a rapid, sensitive, and selective UV-vis spectrophotometry method for the quantification of nanostructured PEG-asparaginase activity in childrens plasma.

PEGylated asparaginase (PEG-ASNase), which hydrolyzes asparagine to ammonia and aspartic acid, is an effective nanostructured antitumor agent for acute lymphoblastic leukemia (ALL). In order to monitor the activity of PEG-ASNase in plasma and design an individualization project, a rapid and sensitive method to determine PEG-ASNase activity in plasma using ultraviolet-visible spectrophotometry was established. PEG-ASNase is commonly used in acute lymphoblastic leukemia. With Nesslers reagent as the chromogenic reagent of ammonia, a stable yellow complex was produced. The units of enzyme activity were defined as micromoles of ammonia released per minute. Calibration curves fitted by plotting the OD at 450 nm of the Nessler product vs concentration were linear in the range of 27.8-1,111.0 IUL with This study proved that the Nessler method is well validated and can be successfully applied in the determination of plasma samples in the clinical setting for patients with ALL. It takes personalized nanomedicine to an entirely new level.

Incidence and survival of T-cell acute lymphoblastic leukemia in the United States.

T-cell acute lymphoblastic leukemia (T-ALL) is a curable malignancy in the pediatric population. However, population-level data on its incidence and outcomes among adults is sparse. Using SEER database, we identified 1141 patients aged ≥20 years with pathologically confirmed T-ALL diagnosed between the years 2001 and 2014 and actively followed. Incidence of T-ALL was 0.13 cases100,000 population with significant variations by age, gender, race, and period. The 5-year overall survival (OS) declined significantly with increasing age (age <40, 51.9% age 40-59, 37.3% age 60-79, 19.2% age ≥80, 0% p < .001) and varied by race (whites - 45.7%, blacks - 25.1%, others - 40.3% p < .001). Over time, OS has improved significantly in patients <60 years (2001-2007, 42.8% vs 2008-2014, 53.1% p .005), but not in patients older than 60 years (2001-2007, 18% vs 2008-2014, 22.8% p .71), highlighting the need for effective and safe treatments in this population.

Body Mass Index (BMI) and InfectiousFebrile Episodes in Children with Intermediate Risk Acute Lymphoblastic Leukemia (IR ALL).

The incidence of treatment related mortality in children with acute lymphoblastic leukemia (ALL) is reported to be between 2% and 4% with infections being the leading cause. To establish a relationship between body mass index at diagnosis (BMI 0), after protocol I therapy completion (BMI I) and the incidence rate ratio (IRR) of infectiousfebrile episodes in children with ALL intermediate risk. Thirty one consecutive patients (2-18 years old, with a male to female ratio of 1912) with newly diagnosed ALL that were treated uniformly according to ALL IC 2009 protocol were included in this analysis. A BMI decrease of at least 5% during protocol I therapy and BMI 1 under 15th percentile score corresponds significantly with higher IRR (with P-values 0.04 and 0.006 respectively) during the whole intensive therapy. Some relationships between BMI reduction and higher IRR in ALL patients were found, but their significance is limited by the size of the group analyzed.

Cytokine release syndrome and neurotoxicity after CD19 chimeric antigen receptor-modified (CAR-) T cell therapy.

Chimeric antigen receptor-modified (CAR)-T cells have demonstrated impressive results in the treatment of haematological malignancies. However, cytokine release syndrome (CRS) and neurotoxicity are common toxicities which are potentially life-threatening in severe cases. Risk factors for CRS and neurotoxicity identified so far include disease burden, lymphodepletion intensity and CAR-T cell dose administered. Risk-adapted dosing, with lower CAR-T cell doses administered to B-cell acute lymphoblastic leukaemia patients with high marrow blast counts, has been successful at decreasing severe CRS rates in this population. Intervention with therapies, such as tocilizumab and corticosteroids, have been effective at ameliorating toxicity, enabling CAR-T cells to be administered safely to many patients without significantly compromising efficacy. Deeper understanding of the pathophysiology of underlying CRS and neurotoxicity will enable the development of novel approaches to reduce toxicity and improve outcomes.

An observational study of Chinese adults with relapsedrefractory Philadelphia-negative acute lymphoblastic leukemia.

Chinese adults with relapsedrefractory Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (Ph- ALL) have poor outcomes. We conducted a nationwide, retrospective, observational study to assess outcomes in this patient population. Of the 270 enrolled patients, 31% of patients at last salvage achieved complete remission (CR) or CR with partial hematologic recovery (CRh), with median time to CRCRh of 30 days and median CRCRh duration of 2.7 months. The CRCRh rate was more favorable with earlier versus later lines of salvage (41, 24 and 17% at first, second and third or later salvages, respectively). This dataset serves as an important reference of real-world outcomes using currently available chemotherapy regimens for high-risk Chinese adults with relapsedrefractory Ph- ALL.

Vitamin D and its receptor polymorphisms New possible prognostic biomarkers in leukemias.

Several factors such as chromosomal translocations, gene mutations, and polymorphisms are involved in the pathogenesis of leukemialymphoma. Recently, the role of vitamin D (VD) and vitamin D receptor (VDR) polymorphisms in hematologic malignancies has been considered. In this review, we examine the possible role of VD levels, as well as VDR polymorphisms as prognostic biomarkers in leukemialymphoma. Relevant English language literature were searched and retrieved from Google Scholar search engine (1985-2017). The following keywords were used

Nitric oxide functions in stromal cell-derived factor-1-induced cytoskeleton changes and the migration of Jurkat cells.

Stromal cell-derived factor-1 (SDF-1) regulates multiple cell signal pathways in a variety of cellular functions, including cell migration, proliferation, survival and angiogenesis. SDF-1-induced chemotaxis is an important step of lymphocyte migration. However, the molecular mechanisms that modulate SDF-1-mediated lymphocyte migration are not well identified. Nitric oxide (NO) has been found to function as a signaling molecule in a number of signaling pathways, including migration. In the present study, the potential role of NO in SDF-1-induced migration and the association between NO and the cytoskeletal changes of Jurkat cells was investigated. The present study demonstrated that Jurkat cells induced the production of NO by SDF-1 stimulation, using Griess reaction method and western blot analysis, and that NO was involved in SDF-1-induced rearrangement and polymerization of the cytoskeleton, using NOS inhibitor L-NMMA. Furthermore, NO was required for the migration of Jurkat cells. The research suggested that NO signaling pathways exerted a critical role in SDF-1-induced cytoskeleton changes and the migration of Jurkat cells. This work provides insight into the migration mechanism of acute lymphoblastic leukemia and provides an effective theoretical basis for therapy strategies for acute lymphoblastic leukemia.

Effect of Tyrosin Kinase Inhibitors on NK Cell and ILC3 Development and Function.

Tyrosin kinase inhibitors (TKI) sharply improved the prognosis of Chronic Myeloid Leukemia (CML) and of Philadelphia

Methotrexate-Induced Toxic Epidermal Necrolysis A Rare Case Report and Review of Literature.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in pediatric patients, and it is characterized by the presence of malignant lymphoblasts within the bone marrow and peripheral blood. The treatment of ALL involves induction, consolidation, reinduction, and maintenance therapy. Consolidation therapy in ALL-Berlin-Frankfurt-Münster 90 protocol involves the use of high-dose methotrexate (HDMTX, 5 gm

PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia.

The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondrial apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components (

Application of minimal residual disease monitoring in pediatric patients with acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a malignant neoplastic disease characterized by abnormal hyperplasia of immature lymphatic cells and has become the most common tumor in children. Although the efficacy of acute lymphoblastic leukemia in children was significantly increased with the adjustment of chemotherapy regimen, there were still a few patients who failed in treatment. The main reasons were relapse and drug resistance. Minimal residual disease (MRD) refers to a state in which there remain traces of leukemia cells that could not be detected using morphological methods in leukemia patients who are in complete remission after receiving the induction chemotherapy or bone marrow transplantation, which is considered to be the main cause of recurrence. The most commonly used methods for detection of MRD include flow cytometry (FCM), real-time quantitative polymerase chain reaction (RQ-PCR) and next-generation sequencing (NGS). MRD evaluation plays an important role in evaluating prognosis, predicting recurrence, guiding risk stratify and individualized therapy for children with ALL. In this paper, we reviewed the progresses in major detection methods for MRD that have been made in the clinical application of pediatric ALL.

Assessment of Health-Related Quality of Life in Pediatric Acute Lymphoblastic Leukemia Survivors Perceptions of Children, Siblings, and Parents.

We investigated the health-related quality of life (HRQL) in survivors of pediatric acute lymphoblastic leukemia (ALL) and evaluated the perceptions of the children, their siblings, and their parents. Seventy ALL survivors, who were between 7 and 17 years of age and had completed therapy ≥2 years, were included. The control group consisted of their healthy siblings. HRQL was assessed by the age-specific KINDL No significant differences could be found among HRQL scores of ALL survivors with respect to variables such as sex, risk group, and having chronic illness. HRQL scores for physical well-being, emotional well-being, family, and social functioning of the patient and sibling self-reports and parent proxy reports were lower than the expected values for healthy and chronically ill children. These results demonstrate that both ALL survivors and their families need help via psychological counseling programs to improve their HRQL even after completion of therapy. Çocukluk çağı akut lenfoblastik lösemi (ALL) sağ kalanlarında sağlıkla ilişkili yaşam kalitesinin (HRQL) araştırılması ve çocukların, kardeşlerinin ve ebeveynlerinin bununla ilgili algılamalarının değerlendirilmesi amaçlandı. Çalışma grubu 7-17 yaş arası, kemoterapisi en az 2 yıl önce tamamlanmış 70 ALL’li çocuktan oluşturuldu. Kontrol grubu hastaların sağlıklı kardeşlerini (n32) içerdi. HRQL ölçümü için yaşa uygun KINDL ALL sağ kalanlarında HRQL skorları cinsiyet, risk grubu, kronik hastalığı olma ve relaps öyküsü açısından istatistiksel anlamlı fark göstermedi. Hastalar ve kardeşlerinin HRQL skorlarıyla ebeveynlerin hasta çocuklarının durumuna bakış açısı skorları değerlendirildiğinde fiziksel iyilik, duygusal iyilik, aile ve sosyal ilişkiler ile ilgili HRQL skorları sağlıklı ve kronik hastalığa sahip çocuklara göre düşük bulundu. Hasta ve ebeveynlerin HRQL skorlarının düşük saptanması çocukluk çağı ALL sağ kalanları ve ebeveynlerinin tedavi bitimi sonrasında da psikolojik danışmanlık programlarına ihtiyacı olduğunu göstermektedir.

Late Effects of Therapy in Childhood Acute Lymphoblastic Leukemia Survivors.

Over the last 50 years, the survival rates in children with acute lymphoblastic leukemia (ALL) have increased remarkably. The optimal use of antileukemic agents in cooperative group protocols, central nervous system-directed treatment, improvements in supportive care, and recognition of biological, clinical, and treatment response characteristics that predict patients with a higher or a lower risk of treatment failure have improved 5-year event-free survival rates, reaching more than 85%, and 5-year overall survival rates, reaching more than 90%. Consequently, it has become increasingly important to characterize the occurrence of long-term late effects. ALL treatments have been associated with increased risks for adverse outcomes such as late mortality, secondary malignancies, and neurological, cardiac, endocrine, and socialpsychological disorders. In recent decades, cooperative groups in Europe and in the United States have provided essential information about the long-term effects of ALL therapy, giving recommendations for screening as well as facilitating new approaches for reducing late-term morbidity and mortality. Current frontline protocols continue to examine ways to lower the intensity and amount of therapy to reduce late effects, whereas survivorship studies attempt to predict such adverse effects precisely and develop targeted prevention and treatment strategies. Son 50 yıldaki gelişmeler ile akut lenfoblastik lösemili (ALL) çocuklardaki tedavi sonrası sağkalım oranında belirgin derecede artış saptandı. Antilösemik ilaçların akılcı kullanımı, santral sinir sistemini hedefleyen lokal tedaviler ve destek tedavisindeki gelişmeler ile 5 yıllık olaysız sağkalım %85’e ve 5 yıllık genel sağkalım %90’a ulaştı. Uzamış sağkalım süreleri, tedavinin uzun dönem yan etkilerine olan farkındalığı da arttırdı. Geç dönem mortalite, ikincil maligniteler, nörolojik, kardiyak, endokrin ve psikososyal bozukluklar ALL tedavisi sonrası sık görülen yan etkilerdir. Son yıllarda Avrupa ve Amerika Birleşik Devletleri’ndeki birçok grup ALL tedavisi sonrası uzun dönem yan etkiler konusunda çalışmalar yaptı, takip için ve uzun dönem mortalite ve morbiditeyi azaltmak için yeni yaklaşımlar önerdiler. Günümüzde kullanımda olan protokoller uzun dönem yan etkileri önlemek için tedavinin yoğunluğunu azaltmaya çalışırken, sağkalımla iligili çalışmalarda da yan etkilerin öngörülmesi ve gerekli önlem ve tedavilerin sağlanması konusu irdeleniyor.

The Landscape of Protein Tyrosine Phosphatase (Shp2) and Cancer.

Role of Shp2 The dysregulation of cell signaling cascades associated with the cell differentiation and growth, due to the deletion, insertion or point mutation in specific amino acids which alters the intrinsic conformation of the protein, can ultimately lead to a fatal cancer disease. The protein tyrosine phosphatase has been recognized as a key regulator of extracellular stimuli such as cytokine receptor and receptor tyrosine kinase signaling. In the last era, the PTPN11 gene (encode a Shp2 protein) and its association with acute myeloid, juvenile myelomonocytic, and B-cell acute lymphoblastic leukemia, Noonan syndrome, and myelodysplastic have been recognized as the cause of such deadly disease due to the occurrence of germline mutations in the interface of PTP and SH2 domain. Conclusion The current study was designed to focus on the allosteric regulation (autoinhibition) of the of Shp2 protein. Subsequently, it will cover the last 10-year recap of Shp2 protein, their role in cancer, and regulation in numerous ways (allosteric regulation).

Hedgehog (HH), WNT, NOTCH, and mechanistic target of rapamycin (mTOR) signalling pathways are known to regulate the progression of cancer however, their interaction in leukaemia cells is not fully clarified. Myeloid and T-lymphoblastic leukaemia cell lines (NB4, THP-1, Jurkat, and DND-41) were transfected with small interfering RNAs targeting the glioma-associated oncogene homolog 1 (GLI1) and catenin beta-1 (CTNNB1) genes involved in the regulation of HH and WNT pathways, respectively, and we examined cell proliferation and gene expression. The knockdown of GLI1 and CTNNB1 did not significantly affect proliferation of any cell line however, it up-regulated the expression of NOTCH1, cleaved NOTCH1 fragment, and phosphorylated mTOR in NB4 cells, but not in the other cell lines. Our data suggest that HH and WNT act upstream of NOTCH and mTOR pathways and negatively regulate them in myeloid NB4 cells. Further studies are required to determine the biological significance of this signalling crosstalk in leukaemia.

T-cell lymphoblastic lymphoma involving the ocular adnexa report of two cases and review of the current literature.

The majority of ocular adnexal lymphomas are B-cell in origin. We report two cases of T-cell lymphoblastic lymphoma (T-LBL) involving the ocular adnexa. One patient presented with a painless pink conjunctival lesion and inferior orbital fullness. The second patient presented with a painless orbital mass. The diagnoses were confirmed by histopathology and immunohistochemistry. Both patients had extensive multifocal lesions during staging. Prompt intensified chemotherapy regimens were initiated. T-LBL is an aggressive disease with poor prognosis. This report emphasizes the importance of timely diagnosis by the ophthalmologist with co-management and treatment with an oncologist.

RUNX1 Mutations Can Lead to Aberrant Expression of CD79a and PAX5 in Acute Myelogenous Leukemias A Potential Diagnostic Pitfall.

RUNX1 is a crucial transcription factor for hematological stem cells and well-known for its association with acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML). Besides the translocation t(8 21) that leads to the RUNX1-RUNX1T1 fusion, somatic mutations of RUNX1 have been discovered. Four bone marrow trephine biopsies of patients with CD79a-positive andor PAX5-positive acute leukemias were investigated by immunohistochemistry (IHC), karyotyping, and next-generation sequencing-based genetic analysis. Data were then compared to a historical collective of AML (n 42) and 42 cases of AML newly diagnosed at our institution between June 2017 and May 2018. We report on 4 cases of acute leukemia with an equivocal immunophenotype showing expression of CD79a andor PAX5, which led to a preliminary histopathologic classification as probable ALLunclassifiable acute leukemia. All cases were positive for CD34 and TdT but negative for several myeloid markers on IHC. Mutational analysis revealed point mutations and indels of RUNX1 and further mutations typical for AML such as TET2, DNMT3A, and SRSF2, and 2 cases had tetrasomy 13 characteristic of RUNX1 mutant AML. Aberrant CD79a andor PAX5 expression can be found in AML cases with RUNX1 mutations even without the translocation t(8 21). Our series shows the expression of CD79a and PAX5 to be a potential pitfall in the classification of RUNX1 mutant acute leukemia.

Recommendations for the assessment and management of measurable residual disease in adults with acute lymphoblastic leukemia A consensus of North American experts.

Measurable residual disease (MRD) that persists after initial therapy is a powerful predictor of relapse and survival in acute lymphoblastic leukemia (ALL). However, the optimal use of this information to influence therapeutic decisions is controversial. Herein, we comprehensively review the role of MRD assessment in adults with ALL, including methods to quantify residual leukemia cells during remission, prognostic impact of MRD across ALL subtypes, and available therapeutic approaches to eradicate MRD. This review presents consensus statements and provides an evidence-based framework for practicing hematologists and oncologists to use MRD information to make rational treatment decisions in adult patients with ALL.

A Syngeneic Mouse B-Cell Lymphoma Model for Pre-Clinical Evaluation of CD19 CAR T Cells.

The astonishing clinical success of CD19 chimeric antigen receptor (CAR) T-cell therapy has led to the approval of two second generation chimeric antigen receptors (CARs) for acute lymphoblastic leukemia (ALL) andnon-Hodgkin lymphoma (NHL). The focus of the field is now on emulating these successes in other hematological malignancies where less impressive complete response rates are observed. Further engineering of CAR T cells or co-administration of other treatment modalities may successfully overcome obstacles to successful therapy in other cancer settings. We therefore present a model in which others can conduct pre-clinical testing of CD19 CAR T cells. Results in this well tested B-cell lymphoma model are likely to be informative CAR T-cell therapy in general. This protocol allows the reproducible production of mouse CAR T cells through calcium phosphate transfection of Plat-E producer cells with MP71 retroviral constructs and pCL-Eco packaging plasmid followed by collection of secreted retroviral particles and transduction using recombinant human fibronectin fragment and centrifugation. Validation of retroviral transduction, and confirmation of the ability of CAR T cells to kill target lymphoma cells ex vivo, through the use of flow cytometry, luminometry and enzyme-linked immunosorbent assay (ELISA), is also described. Protocols for testing CAR T cells in vivo in lymphoreplete and lymphodepleted syngeneic mice, bearing established, systemic lymphoma are described. Anti-cancer activity is monitored by in vivo bioluminescence and disease progression. We show typical results of eradication of established B-cell lymphoma when utilizing 1

MicroRNA expression profiles discriminate childhood T- from B-acute lymphoblastic leukemia.

MicroRNAs (miRNAs) play a critical role on biological and cellular processes the search for functional markers may be of importance for differential diagnosis, prognosis, and development of new therapeutic regimens. In this context, we evaluated the bone marrow miRNA profile of Brazilian children exhibiting T- or B-cell acute lymphoblastic leukemia (T-ALL or B-ALL), using massive parallel sequencing, using the HiSeq 2500 platform (Illumina). The differential expression analysis was conducted considering a leave-one-out approach and FDR ≤ 0.05. Machine learning algorithms were applied to search for the disease subset biomarkers. Target prediction, functional enrichment, and classification of biological categories were also performed. Sixteen miRNAs were differentially expressed between T- and B-ALL, of which 10 (miR-708-5p, miR-497-5p, miR-151a-5p, miR-151b, miR-371b-5p, miR-455-5p, miR-195-5p, miR-1266-5p, miR-574-5p, and miR-425-5p) were downregulated and six (miR-450b-5p, miR-450a-5p, miR-542-5p, miR-424-5p, miR-629-5p, and miR-29c-5p) were upregulated in childhood T-ALL. These miRNAs may be used for distinguishing childhood lymphoblastic leukemia subtypes, since it provided the clear separation of patients in these two distinct groups. Six relevant biological pathways were identified according to their role in leukemia, namely, viral carcinogenesis, cell cycle, and B-cell receptor signaling pathways for induced miRNAs and TGF-beta signaling, apoptosis, and NF-kappa B signaling for the repressed miRNAs, of which several miRNA gene targets participate in cell differentiation and hematopoiesis processes. Machine learning analysis pointed out miR-29c-5p expression as the best discriminator between childhood T- and B-ALL, which is involved in calcium signaling, critical for B-cell lymphocyte fate. Further studies are needed to assure the role of the 16 miRNAs and miR-29c-5p on acute lymphoblastic leukemia subtypes and on disease prognosis.

Acquired Platythorax, or Anteroposterior Flattening of the Chest Wall, as a Late Complication of Cyclophosphamide Treatment for Childhood Acute Lymphoblastic Leukemia, Presenting in a Young Man with Respiratory Failure.

BACKGROUND Acquired platythorax, or flattening of the chest with a reduction in the anteroposterior (AP) diameter, is very rare and the prognosis depends on the degree of the deformity, respiratory function, and on any underlying disease. Drug-induced pulmonary fibrosis is associated with pulmonary hypoplasia. A case of acquired platythorax is presented in a young man previously treated with cyclophosphamide in childhood. CASE REPORT A 20-year-old man began to experience cough, chest pain, and mild exertional dyspnea. He was admitted to the hospital at 23 years of age with respiratory failure. Chest imaging showed pleural thickening and platythorax. He had been successfully treated for acute lymphoblastic leukemia (ALL), at 3 years of age, with chemotherapy that included a cumulative dose of cyclophosphamide of 15.6 gm². His ALL relapsed six years later and he was the treated again with cyclophosphamide and underwent a second and complete remission. A clinical diagnosis of late-onset cyclophosphamide-induced lung disease with progressive platythorax was made on the basis of his clinical history and on imaging findings of the ratio of the AP to lateral chest wall diameter when compared with age-matched controls. Despite continued remission of his ALL, he died of progressive cardiopulmonary failure at 25 years of age. CONCLUSIONS This report described a rare case of acquired platythorax, or flattening of the chest, in a young adult. The use of the ratio of the chest wall AP diameter to lateral diameter may be used in the early detection of this rare chemotherapy-induced complication in children and adults.

Clinical and prognostic significance of ABO promotor methylation level in adult leukemia and myelodydysplastic syndrome.

Dysregulation of miR-125b predicts poor response to therapy in pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most well-known sort of leukemia in children. In spite of favorable survival rates, some patients relapse and achieve a poor outcome. We analyzed miR-125b and Bcl-2 expressions in pediatric patients with ALL and evaluated their clinical utility as molecular markers for the prediction of disease outcomes. Downregulation of miR-125b and increased Bcl-2 expression levels in pediatric patients with ALL were associated with poor prognosis at diagnosis. At day 28 of induction, miR-125b was significantly increased, whereas Bcl-2 was downregulated. Loss of miR-125b during diagnosis and its elevation after therapy are strongly correlated with short leukemia-free survival and worse survival. Moreover, the combination of miR-125b with Bcl-2 markers can clearly enhance the prediction of the disease outcome. Finally, a univariate analysis highlighted the independent prognostic value of miR-125 in a pediatric patient with ALL. miR-125b and Bcl-2 together are potent predictors for the prognosis and, therefore, can be used as therapeutic targets in childhood ALL.