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Increased Risk of Acute Lymphoblastic Leukemia in Adult Patients with GSTM1 Null Genetic Polymorphism.

Glutathione S-transferases (GSTT1 and GSTM1) detoxify various endogenous and exogenous compounds and provide cytoprotective role against reactive species. This study aimed to assess the frequency of This case-control study included 128 adult Sudanese, untreated newly diagnosed patients with ALL, aged 18 to 74 years and 128 age-gender matched healthy controls. Deletional polymorphisms of The genotypic frequency of Irrespective of age at diagnosis, gender, and phenotype of ALL, GSTM1 null polymorphism either alone or in combination with GSTT1 null polymorphism poses significantly increased risk of developing ALL in adults.

High BMP4 expression in lowintermediate risk BCP-ALL identifies children with poor outcomes.

Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) outcome has improved in the last decades, but leukemic relapses are still one of the main problems of this disease. Bone morphogenetic protein 4 (BMP4) was investigated as a new candidate biomarker with potential prognostic relevance, and its pathogenic role was assessed in the development of disease. A retrospective study was performed with 115 pediatric patients with BCP-ALL, and BMP4 expression was analyzed by quantitative reverse transcription polymerase chain reaction in leukemic blasts at the time of diagnosis. BMP4 mRNA expression levels in the third (upper) quartile were associated with a higher cumulative incidence of relapse as well as a worse 5-year event-free survival and central nervous system (CNS) involvement. Importantly, this association was also evident among children classified as having a nonhigh risk of relapse. A validation cohort of 236 patients with BCP-ALL supported these data. Furthermore, high BMP4 expression promoted engraftment and rapid disease progression in an NSG mouse xenograft model with CNS involvement. Pharmacological blockade of the canonical BMP signaling pathway significantly decreased CNS infiltration and consistently resulted in amelioration of clinical parameters, including neurological score. Mechanistically, BMP4 favored chemoresistance, enhanced adhesion and migration through brain vascular endothelial cells, and promoted a proinflammatory microenvironment and CNS angiogenesis. These data provide evidence that BMP4 expression levels in leukemic cells could be a useful biomarker to identify children with poor outcomes in the low-intermediate-risk groups of BCP-ALL and that BMP4 could be a new therapeutic target to blockade leukemic CNS disease.

Orthopaedic adverse events among adolescents and adults treated with asparaginase for acute lymphoblastic leukaemia.

Osteonecrosis (ON) is a complication of acute lymphoblastic leukaemia (ALL) treatment with patient- (age, female sex, genetic polymorphisms, presence of metabolic syndrome) and treatment-specific (glucocorticoid type and schedule) risk factors described. The potential role of asparaginase in increasing risk of ON via effects on coagulation, lipid metabolism, and steroid clearance is now also recognised. Paediatric studies consistently identify age as a key risk factor for ON, with adolescents at higher risk than young children. Fewer studies comprehensively report on risk of ON in adults, but available evidence suggests that adolescents and young adults (AYAs) treated with corticosteroid and asparaginase-containing paediatric-inspired regimens are more at risk than older adults treated with paediatric-inspired or traditional adult regimens. There are few proven strategies to prevent or mitigate the severity of ON and other orthopaedic complications of ALL therapy. Future clinical trials should carefully ascertain orthopaedic adverse events in adults. Evidence-based guidelines should be developed for management of orthopaedic adverse events in adults being treated for ALL, especially high-risk AYAs being treated with paediatric-inspired regimens.

Late Effects Screening of Acute Lymphoblastic Leukemia Survivors in the Military Healthcare System.

Pediatric acute lymphoblastic leukemia (ALL) survivors are a growing portion of the population with unique health screening needs. These survivors receive care within late effects oncology clinics and primary care clinics. Prior attempts to quantify compliance with follow-up recommendations have shown variable rates ranging from 28% to 73%. This study set out to assess rates of adherence to recommended health screening among pediatric ALL survivors within the U.S. DoD, identify potential risk factors contributing to patient compliance, and better define the prevalence of chronic health conditions. This Institutional Review Board-approved, retrospective cohort study used data from the U.S. DoD MHS database and identified incident cases of pediatric ALL during 2007-2011 using a conservative case identification algorithm. Minimum duration of follow-up was instituted in order to ensure the entire study population had sufficient time for the assessment of each screening exam according to recommended guidelines. Rates of adherence to recommended screening measures were calculated across the full study follow-up period, and regression analyses assessed protective factors for compliance. One hundred and forty-four incident ALL cases were identified. During the follow-up period, 31.3% developed a new mental health diagnosis. In terms of recommended screening, 94.4% had an annual complete blood count for the entire study period, 90.3% had a liver function screening, 81.9% had an echocardiogram, 34% had a bone density scan, and 54.2% had a mental health visit. Adolescents were less likely to have a bone density scan (odds ratio OR 0.32, 95% CI, 0.11-0.95) or a mental health visit (OR 0.28, 95% CI, 0.11-0.7). The MHS provides universal access to healthcare for all beneficiaries. In this population with universal access to care, there is increased compliance with screening recommendations. Our results reflect actual screening testing as opposed to general screening visits that have been previously reported in the literature. We also highlight the significant number of mental health diagnoses among pediatric ALL survivors.

Phosphorylation of SHP2 at Tyr62 Enables Acquired Resistance to SHP2 Allosteric Inhibitors in FLT3-ITD-Driven AML.

The protein tyrosine phosphatase SHP2 is crucial for oncogenic transformation of acute myeloid leukemia (AML) cells expressing mutated receptor tyrosine kinases. SHP2 is required for full RAS-ERK activation to promote cell proliferation and survival programs. Allosteric SHP2 inhibitors act by stabilizing SHP2 in its autoinhibited conformation and are currently being tested in clinical trials for tumors with overactivation of the RASERK pathway, alone and in various drug combinations. In this study, we established cells with acquired resistance to the allosteric SHP2 inhibitor SHP099 from two FLT3-ITD (internal tandem duplication)-positive AML cell lines. Label-free and isobaric labeling quantitative mass spectrometry-based phosphoproteomics of these resistant models demonstrated that AML cells can restore phosphorylated ERK (pERK) in the presence of SHP099, thus developing adaptive resistance. Mechanistically, SHP2 inhibition induced tyrosine phosphorylation and feedback-driven activation of the FLT3 receptor, which in turn phosphorylated SHP2 on tyrosine 62. This phosphorylation stabilized SHP2 in its open conformation, preventing SHP099 binding and conferring resistance. Combinatorial inhibition of SHP2 and MEK or FLT3 prevented pERK rebound and resistant cell growth. The same mechanism was observed in a FLT3-mutated B-cell acute lymphoblastic leukemia cell line and in the inv(16)KitD816Y AML mouse model, but allosteric inhibition of Shp2 did not impair the clonogenic ability of normal bone marrow progenitors. Together, these results support the future use of SHP2 inhibitor combinations for clinical applications. These findings suggest that combined inhibition of SHP2 and FLT3 effectively treat FLT3-ITD-positive AML, highlighting the need for development of more potent SHP2 inhibitors and combination therapies for clinical applications.

GLUT1 Immunohistochemistry Is a Highly Sensitive and Relatively Specific Marker for Erythroid Lineage in Benign and Malignant Hematopoietic Tissues.

Glucose transporter 1 (GLUT1), a glucose transporter, is an abundant protein in erythrocytes with expression beginning early in erythropoiesis. We sought to evaluate the utility of GLUT1 immunohistochemistry (IHC) as a diagnostic marker for identifying erythroid differentiation in hematopoietic tissues, including neoplastic erythroid proliferations. A variety of benign and neoplastic bone marrow biopsy specimens containing variable proportions of erythroid precursors were selected (n 46, including 36 cases of leukemia). GLUT1 IHC was performed using a commercially available polyclonal antibody. Each case was evaluated for staining of erythroid precursors, nonerythroid hematopoietic cells, and blasts. A GATA1GLUT1 double stain was performed on one case to confirm coexpression of GLUT1 on early erythroid precursors. Staining was compared with other erythroid markers, including glycophorin C. GLUT1 demonstrated strong membranous staining in erythroid precursors of all cases, which was restricted largely to the erythroid lineage. Of the 36 leukemia cases, all 6 cases of pure erythroid leukemia and both cases of therapy-related acute myeloid leukemia with erythroid differentiation showed positive GLUT1 staining in blasts. Otherwise, only lymphoblasts in B-lymphoblastic leukemia showed weak to moderate granular cytoplasmic staining (four of five cases). GLUT1 IHC is a highly sensitive and relatively specific marker for erythroid lineage in benign and neoplastic bone marrow biopsy specimens.

Targeting the lncRNA DUXAP8miR-29a

This study aimed to determine the expression profiles of long non-coding RNA (lncRNA), microRNA (miRNA), and mRNA in chemotherapy-resistant B-cell acute lymphoblastic leukemia (B-ALL). LncRNA, miRNA, and mRNA profiles were assessed by RNA-seq in diagnostic bone marrow samples from 6 chemotherapy-resistant and 6 chemotherapy-sensitive B-ALL patients. The lncRNA DUXAP8miR-29a 1,338 lncRNAs, 75 miRNAs, and 1620 mRNAs were found to be dysregulated in chemotherapy-resistant B-ALL in comparison to chemotherapy-sensitive B-ALL patient samples. Through bioinformatics analyses and RT-qPCR validation, the lncRNA DUXAP8miR-29a Targeting the lncRNA DUXAP8miR-29a

Case Report

Monitoring of Circulating CAR T Cells Validation of a Flow Cytometric Assay, Cellular Kinetics, and Phenotype Analysis Following Tisagenlecleucel.

Chimeric antigen receptor (CAR) T cell therapy is a potent new treatment option for relapsed or refractory hematologic malignancies. As the monitoring of CAR T cell kinetics can provide insights into the activity of the therapy, appropriate CAR T cell detection methods are essential. Here, we report on the comprehensive validation of a flow cytometric assay for peripheral blood CD19 CAR T cell detection. Further, a retrospective analysis (n 30) of CAR T cell and B cell levels over time has been performed, and CAR T cell phenotypes have been characterized. Serial dilution experiments demonstrated precise and linear quantification down to 0.05% of T cells or 22 CAR T cell events. The calculated detection limit at 13 events was confirmed with CAR T cell negative control samples. Inter-method comparison with real-time PCR showed appreciable correlation. Stability testing revealed diminished CAR T cell values already one day after sample collection. While we found long-term CAR T cell detectability and B cell aplasia in most patients (1217), some patients (517) experienced B cell recovery. In three of these patients the coexistence of CAR T cells and regenerating B cells was observed. Repeat CAR T cell infusions led to detectable but limited re-expansions. Comparison of CAR T cell subsets with their counterparts among all T cells showed a significantly higher percentage of effector memory T cells and a significantly lower percentage of naïve T cells and T EMRA cells among CAR T cells. In conclusion, flow cytometric CAR T cell detection is a reliable method to monitor CAR T cells if measurements start without delay and sufficient T cell counts are given.

Overview of the structure, side effects, and activity assays of l-asparaginase as a therapy drug of acute lymphoblastic leukemia.

l-Asparaginase (l-ASNase is the abbreviation, l-asparagine aminohydrolase, E.C.3.5.1.1) is an enzyme that is clinically employed as an antitumor agent for the treatment of acute lymphoblastic leukemia (ALL). Although l-ASNase is known to deplete l-asparagine (l-Asn), causing cytotoxicity in leukemia cells, the specific molecular signaling pathways are not well defined. Because of the deficiencies in the production and administration of current formulations, the l-ASNase agent in clinical use is still associated with serious side effects, so controlling its dose and activity monitoring during therapy is crucial for improving the treatment success rate. Accordingly, it is urgent to summarize and develop effective analytical methods to detect l-ASNase activity in treatment. However, current reports on these detection methods are fragmented and also have not been systematically summarized and classified, thereby not only delaying the investigations of specific molecular mechanisms, but also hindering the development of novel detection methods. Herein, in this review, we provided a detailed summary of the l-ASNase structures, antitumor mechanism and side effects, and current detection approaches, such as fluorescence assays, colorimetric assays, spectroscopic assays and some other assays. All of them possess unique advantages and disadvantages, so it has been difficult to establish clear criteria for clinical application. We hope that this review will be of some value in promoting the development of l-ASNase activity detection methods.

Atopy manifestations in pediatric patients with acute lymphoblastic leukemia correlation assessment with interleukin-4 (IL-4) and IgE level.

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in the age range of under 15 years old and accounts for 25-30% of all childhood cancers. Although conventional chemotherapy regimens are used to improve the overall survival rate, it has been associated with some complications, amongst which allergic manifestations with unknown mechanisms are more common. Our study compared serum IgE and IL-4 concentration, as a hallmark of allergic responses in pediatric ALL patients before and after 6 months of intensive (high-dose) chemotherapy, to show whether changes in the level of these markers may be associated with atopy. Serum level of IL-4 and IgE was measured using enzyme-linked immunosorbent assay (ELISA) method. The results showed that the level of IgE and IL-4 increased following chemotherapy in both ALL patients with and without atopy. In addition, post-chemotherapy treatment IgE and IL-4 levels were significantly elevated in patients with atopy compared to those without it. The difference between baseline and post-chemotherapy level of IgE and IL-4 was significantly higher in patients with atopy compared to those without it. To the best of our knowledge, this is the first study that showed a connection between post-chemotherapy allergic manifestations in pediatric ALL patients and IL-4 and IgE level. Flow cytometry analysis of the T-helper 2 (Th2) lymphocytes and other allergy-related T cell subsets like Tc2 and Th9 as well as the study of the genetic variations in atopy-related genes like IL-4IL-4R, IL-5, IL-9, IL-13, and high affinity FcεRI IgE receptor and also HLA genes is necessary to clearly define the underlying mechanism responsible for post-chemotherapy hypersensitivity reaction in pediatric ALL patients.

Allogeneic Hematopoietic Stem Cell Transplantation for Adult Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia in Second Complete Remission.

Even in the era of high-intensity chemotherapy, disease recurrence remains a major cause of treatment failure in adult patients with Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (Ph-negative B-ALL). For patients who achieved second complete remission (CR2) with salvage chemotherapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be the best curative treatment. However, limited data are available on the outcomes of allo-HSCT for adult Ph-negative B-ALL in CR2 in the high-intensity chemotherapy era. We evaluated the transplantation outcomes of adult patients with Ph-negative B-ALL in CR2 compared with those in CR1. We also clarified the prognostic factors among adult allo-HSCT recipients with Ph-negative B-ALL in CR2. We conducted a nationwide retrospective study using the data form Japanese transplant registry database. Patients aged ≥16 years and underwent their first allo-HSCT between 2003 and 2017 were included. The 3-year overall survival (OS) rate of the patients in CR2 (n 382) was significantly lower than that in first complete remission (n 1375) (51.8% versus 68.1% P < .001), accompanied by a higher relapse rate (34.2% versus 17.6% at 3 years P < .001). In a multivariate analysis among CR2 patients, time from diagnosis to allo-HSCT (≤2 years) was a significant factor for OS (hazard ratio HR 1.87 P < .001) and relapse (HR 1.88 P < .001), whereas age at allo-HSCT (≥30 years) was a significant factor for OS (HR 2.10, P < .001) and nonrelapse mortality (HR 2.68 P < .001). By assigning a score of 1 to each factor, the 3-year OS rate of CR2 patients significantly stratified 70.7% in patients with score 0, 56.4% with score 1, and 28.4% with score 2 (P < .001). The survival outcomes of allo-HSCT in adult Ph-negative B-ALL patients in CR2 were inferior to those in CR1 in the high-intensity chemotherapy era, mainly because of the higher relapse rate. Among the CR2 patients, the short time between diagnosis and allo-HSCT was a significant risk factor for disease recurrence and overall mortality. Better disease control with novel treatment strategies may be needed for early relapse. In addition, the nonrelapse mortality rate in patients over 30 years of age was particularly high among CR2 patients, suggesting the need for improved supportive care for these patients. Further studies are warranted on the outcomes of allo-HSCT after achieving CR2 with novel drugs, such as inotuzumab ozogamicin and blinatumomab.

CRLF2 overexpression results in reduced B-cell differentiation and upregulated E2F signaling in the Dp16 mouse model of Down syndrome.

Children with Down syndrome (DS) are 10-fold more likely to develop B-cell acute lymphoblastic leukemia (B-ALL), with a higher frequency of rearrangements resulting in overexpression of cytokine receptor-like factor 2 (CRLF2). Here, we investigated the impact of CRLF2 overexpression on B-cell progenitor proliferation, immunophenotype, and gene expression profile in the Dp(16)1Yey (Dp16) mouse model of DS compared with wild-type (WT) mice. CRLF2 overexpression enhanced immature B-lymphoid colony development and increased the proportion of less differentiated pre-pro-B cells, with a greater effect in Dp16 versus WT. In CRLF2-rearranged (CRLF2-R) B-ALL patient samples, cells with higher CRLF2 expression exhibited a less differentiated B-cell immunophenotype. CRLF2 overexpression resulted in a gene expression signature associated with E2F signaling both in Dp16 B-progenitors and in DS-ALL patient samples, and PI3KmTOR and pan-CDK inhibitors, which reduce E2F-mediated signaling, exhibited cytotoxicity in CRLF2-R B-ALL cell lines and patient samples. CRLF2 overexpression alone in Dp16 stem and progenitor cells did not result in leukemic transformation in recipient mice. Thus, CRLF2 overexpression results in reduced B-cell differentiation and enhanced E2F signaling in Dp16 B-progenitor cells and DS-ALL patient samples. These findings suggest a functional basis for the high frequency of CRLF2-R in DS-ALL as well as a potential therapeutically targetable pathway.

A Systematic Review of Host Genomic Variation and Neuropsychological Outcomes for Pediatric Cancer Survivors.

Pediatric survivors of brain tumors and acute lymphoblastic leukemia (ALL) are at risk for long-term deficits in their neuropsychological functioning. Researchers have begun examining associations between germline single nucleotide polymorphisms (SNPs), which interact with cancer treatment, and neuropsychological outcomes. This review synthesizes the impact of treatment-related toxicity from germline SNPs by neuropsychological domain (i.e., working memory, processing speed, psychological functioning) in pediatric survivors. By focusing on specific neuropsychological domains, this review will examine outcome measurement and critique methodology. Fourteen studies were identified and included in this review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). All studies were published in peer-reviewed journals in English by November 24

The Historical Relationship Between Meis1 and Leukemia.

Acute leukemia (AL) is a poor progressive resistant hematological disease, which has different subtypes and immunophenotypic properties according to leukemic blasts. AL is caused by genetic changes and associated with leukemia stem cells (LSCs), which determine its prognosis and endurance. LSCs are thought to be hematopoietic progenitor and stem cell (HPSCs)-like cells that underwent a malignant transformation. In addition to their low number, LSCs have the characteristics of self-renewal, resistance to chemotherapy, and relapse of leukemia. The myeloid ecotropic integration site-1 (MEIS1) protein is a member of the three-amino acid loop extension (TALE) family of homeodomain (HD) proteins that can bind to DNA sequence-specific manner. Studies have shown that overexpression of MEIS1 and associated cofactors involves tumorigenesis of numerous cancers. Historically, increased expression of Meis1 transcript as well as protein has been determined in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients. Moreover, resistance to conventional chemotherapy was observed in leukemic blast samples with high Meis1 content. In this review article, the molecular mechanism of the oncological role of the MEIS1 protein in leukemia and LSC is discussed. In addition, it was suggested that MEIS1 protein could be utilized as a possible treatment target in leukemia with an emphasis on the inhibition of MEIS1, which is overexpressed in LSC.

Exposure to magnetic fields and childhood leukemia a systematic review and meta-analysis of case-control and cohort studies.

The association between childhood leukemia and extremely low frequency magnetic fields (ELF-MF) generated by power lines and various electric appliances has been studied extensively during the past 40 years. However, the conditions under which ELF-MF represent a risk factor for leukemia are still unclear. Therefore, we have performed a systematic review and meta-analysis to clarify the relation between ELF-MF from several sources and childhood leukemia. We have systematically searched Medline, Scopus, Cochrane Database of Systematic Review and DARE to identify each article that has examined the relationship between ELF-MF and childhood leukemia. We have performed a global meta-analysis that takes into account the different measures used to assess magnetic field exposure magnetic flux density measurements (<0.2 µT vs. >0.2 µT), distances between the childs home and power lines (>200 m vs. <200 m) and wire codings (low current configuration vs. high current configuration). Moreover, meta-analyses either based on magnetic flux densities, on proximity to power lines or on wire codings have been performed. The association between electric appliances and childhood leukemia has also been examined. Of the 863 references identified, 38 studies have been included in our systematic review. Our global meta-analysis indicated an association between childhood leukemia and ELF-MF (21 studies, pooled OR1.26 95% CI 1.06-1.49), an association mainly explained by the studies conducted before 2000 (earlier studies pooled OR1.51 95% CI 1.26-1.80 vs. later studies pooled OR1.04 95% CI 0.84-1.29). Our meta-analyses based only on magnetic field measurements indicated that the magnetic flux density threshold associated with childhood leukemia is higher than 0.4 µT (12 studies, >0.4 µT pooled OR1.37 95% CI 1.05-1.80 acute lymphoblastic leukemia alone seven studies, >0.4 µT pooled OR1.88 95% CI 1.31-2.70). Lower magnetic fields were not associated with leukemia (12 studies, 0.1-0.2 µT pooled OR1.04 95% CI 0.88-1.24 0.2-0.4 µT pooled OR1.07 95% CI 0.87-1.30). Our meta-analyses based only on distances (five studies) showed that the pooled ORs for living within 50 m and 200 m of power lines were 1.11 (95% CI 0.81-1.52) and 0.98 (95% CI 0.85-1.12), respectively. The pooled OR for living within 50 m of power lines and acute lymphoblastic leukemia analyzed separately was 1.44 (95% CI 0.72-2.88). Our meta-analyses based only on wire codings (five studies) indicated that the pooled OR for the very high current configuration (VHCC) was 1.23 (95% CI 0.72-2.10). Finally, the risk of childhood leukemia was increased after exposure to electric blankets (four studies, pooled OR2.75 95% CI 1.71-4.42) and, to a lesser extent, electric clocks (four studies, pooled OR1.27 95% CI 1.01-1.60). Our results suggest that ELF-MF higher than 0.4 µT can increase the risk of developing leukemia in children, probably acute lymphoblastic leukemia. Prolonged exposure to electric appliances that generate magnetic fields higher than 0.4 µT like electric blankets is associated with a greater risk of childhood leukemia.

Adolescent Medical Decisionmaking Rights Reconciling Medicine and Law.

Dennis Lindberg came into his aunts care when he was in the 4th grade because his parents struggled with drug addiction and could not provide for him. At thirteen, he was baptized in his aunts faith as a Jehovahs Witness. Just days after he turned fourteen, on November 6, he was diagnosed with acute lymphoblastic leukemia.The prognosis was that Dennis had a 75% chance of cure with standard oncology treatment. Consistent with the requirements of his new faith, however, Dennis told his doctors, I do not want to be treated if the requirement is that I would have to take a blood transfusion. His aunt, whose custodial rights seem not to have included medical decisionmaking, was adamant that this is Denniss decision.The hospital social worker assigned to Denniss case assured his aunt that having just turned 14, he could be considered mature enough to make his own decisions. But hospital psychologists declined to evaluate Denniss maturity because they did not have the tools for such an assessment. Established hospital policy described the failure to provide a minor with necessary, life-saving care as medical neglect. Hospital ethicists advised that Denniss autonomy interests were outweighed by the benefits associated with treatment. And, standard oncology practice norms are that doctors should push back against minors lifesaving treatment refusals. Still, Denniss doctor agreed with his social worker and aunt, saying, We owe respect to a 14-year-old. In this view, he was supported by colleagues on staff and by hospital counsel.A county judge got the case only at the eleventh hour, on an emergency motion filed by Denniss parents and Child Protective Services for a declaration of dependency and to compel the necessary transfusion. Although Dennis was degrading rapidly, his doctor testified that if a transfusion were ordered that day, Dennis still had a 70% chance of survival. The judge had no background in the applicable law and no time to research the issues nevertheless, he denied the motion concluding, It is time to do what Dennis has decided. Seven hours later, at 6 p.m., on Nov. 28, Dennis died.1.

Complete resolution of alopecia totalis following chemotherapy for B-cell acute lymphoblastic leukemia.

Alopecia totalis (AT) is a cosmetically debilitating chronic disease characterized by non-scarring hair loss of the entire scalp. The clinical course of AT is highly unpredictable, and effective durable treatment options are limited. The resolution of alopecia has been reported post-autologous and allogeneic hematopoietic stem cell transplantation however, no cases of AT remission following chemotherapy alone have been described. Herein, we present a case of complete remission of AT following chemotherapy for B-cell acute lymphoblastic leukemia in a pediatric patient.

A Novel Risk Defining System for Pediatric T-Cell Acute Lymphoblastic Leukemia From CCCG-ALL-2015 Group.

T-cell acute lymphoblastic leukemia (T-ALL) is a rare hematological malignancy with a poor prognosis. The present study aims to identify the precise risk grouping of children with T-ALL. We analyzed the outcomes for 105 consecutive patients treated using the Chinese Childrens Cancer Group ALL-2015 (CCCG-ALL-2015) protocol registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-14005706) between 2015 and 2020 in our center. Nine out of 21 clinical and biological indicators were selected for the new scoring system based on the analysis in this study. The 5-year overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) rates for the 105 patients were 83.1 ± 4.8%, 72.4 ± 5.6%, and 78.4 ± 3.6%, respectively. Based on the new scoring system, 90 evaluable children were regrouped into low-risk (n22), intermediate-risk (n50), and high-risk (n18) groups. The 5-year survival (OS, EFS, and RFS) rates for all patients in the low-risk group were 100%, significantly higher than the rates for those in the intermediate-risk group (91.2 ± 5.2%, 74.4 ± 8.6%, and 82.5 ± 6.2%, respectively) and high-risk group (59.0 ± 13.2%, 51.9 ± 12.4%, and 51.9 ± 12.4%, respectively) (all P values < 0.01). The CCCG-ALL-2015 program significantly improved the treatment outcomes for childhood T-ALL as compared with the CCCG-ALL-2008 protocol. Our new refined risk grouping system showed better stratification among pediatric T-ALL patients and better potential in evaluating therapeutic efficacy.

Contribution of imaging modalities to eosinophilic myocarditis diagnosis a case report.

Eosinophilic myocarditis (EM) is a relatively rare form of myocarditis that could progress to restrictive cardiomyopathy and might be fatal if left untreated. Although myocardial biopsy is considered to be the gold standard for the diagnosis of myocarditis, its use in paediatrics remains controversial and not easily applicable in routine practice. A 10-year-old girl with no prior medical history presented to the emergency department for fever, odynophagia, and gastrointestinal symptoms despite 48 h of antibiotics (Cefaclor). Physical examination revealed diffuse petechiae and abdominal tenderness but was otherwise unremarkable. Her vital signs were normal. She was found to have hypereosinophilia and increased cardiac markers on laboratory testing. Echocardiography showed diffuse left ventricular (LV) myocardial infiltrates, moderate LV dilatation, and mild systolic dysfunction. Bone marrow biopsy confirmed B cell acute lymphoblastic leukaemia. The diagnosis of EM was made. High doses of steroids and chemotherapy were initiated. Cardiac magnetic resonance imaging (MRI) identified eosinophilic infiltrates and sub-endocardial enhancement strongly suggestive of EM. Left ventricular function was slightly decreased. Intra-ventricular micro-thrombi were suspected, and warfarin was started. The outcome was favourable. Leucocyte and eosinophil counts were normalized within a month. At 6 months, cardiac MRI demonstrated a significant decrease in eosinophilic infiltration and micro-thrombi, normalization of LV function, and of sub-endocardial enhancement. This case demonstrates that non-invasive multi-modality imaging along with typical laboratory and clinical findings allow for appropriate diagnosis of EM while avoiding biopsy. It also highlights that an early diagnosis, timely treatment, and rigorous follow-up improve disease progression and outcome.

Hypercalcemia As the Sole Initial Presentation of Precursor B-cell Acute Lymphoblastic Leukemia.

A 24-year-old female presented with nausea, vomiting and abdominal pain. Physical examination was unremarkable. The patients laboratory studies showed calcium of 17.2 mgd, white cell count 9,000mcL with a normal peripheral blood smear. The patient had low PTH and PTHrp. She was hydrated, given calcitonin of four unitskg every 12 hours subcutaneously for 24 hours and zoledronate IV 4mg given once, with which calcium levels normalized and symptoms resolved. The patient returned one week later, with bone pain and bruises. Platelet count 51,000mcL, WBC count 9,000mcL, with lymphocytosis. A peripheral smear showed lymphoblasts. Flow cytometry confirmed precursor B-cell acute lymphoblastic leukemia (ALL) with 43% blasts. Hypercalcemic patients may have blasts at presentation, but can be aleukemic. Unexplained hypercalcemia with bone pain should lead to the suspicion of ALL, and a bone marrow exam should be performed even without peripheral blastosis to diagnose and treat ALL immediately.

A hotspot mutation targeting the R-RAS2 GTPase acts as a potent oncogenic driver in a wide spectrum of tumors.

A missense change in RRAS2 (Gln

In Utero Development and Immunosurveillance of B Cell Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the most frequent type of pediatric cancer with a peak incidence at 2-5 years of age. ALL frequently begins in utero with the emergence of clinically silent, preleukemic cells. Underlying leukemia-predisposing germline and acquired somatic mutations define distinct ALL subtypes that vary dramatically in treatment outcomes. In addition to genetic predisposition, a second hit, which usually occurs postnatally, is required for development of overt leukemia in most ALL subtypes. An untrained, dysregulated immune response, possibly due to an abnormal response to infection, may be an important co-factor triggering the onset of leukemia. Furthermore, the involvement of natural killer (NK) cells and T helper (Th) cells in controlling the preleukemic cells has been discussed. Identifying the cell of origin of the preleukemia-initiating event might give additional insights into potential options for prevention. Modulation of the immune system to achieve prolonged immunosurveillance of the preleukemic clone that eventually dies out in later years might present a future directive. Herein, we review the concepts of prenatal origin as well as potential preventive approaches to pediatric B cell precursor (BCP) ALL.

Sedation Practices for Lumbar Punctures in Patients With Acute Lymphoblastic Leukemia A Multicenter Retrospective Study Using Pediatric Health Information Systems.

Sedation is often used to reduce pain and anxiety in pediatric patients with acute lymphoblastic leukemia (ALL) undergoing lumbar punctures (LPs). There is a potential for long-term effects on neurocognition with repeat sedative exposures in young children. The purpose of this study is to determine the practice habits regarding sedation for LPs in pediatric patients with ALL among multiple institutions. This is a retrospective study of 48 hospitals in the Pediatric Health Information Systems (PHIS) between October 2015 and December 2019. Children 1 to 18 years old with ALL who received intrathecal chemotherapy in an outpatient setting were included. We analyzed the prevalence of anesthesia usage and the types of anesthetics used. Of the 16,785 encounters with documented use of anesthetic medications, intravenous and inhaled anesthetics were used in 16,486 (98.2%) and local anesthetics alone in 299 (1.8%). The most commonly used medications used for sedation were propofol (n13,279 79.1%), midazolam (n4228 25.2%), inhaled fluranes (n3169 18.9%), and ketamine (n2100 12.5%). The majority of childrens hospitals in the United States use intravenous and inhaled anesthetics for routine therapeutic LPs in pediatric patients with ALL. Propofol is one of the most common medications used for sedation.

Direct CNS administration of rituximab and epratuzumab in a pediatric patient with relapsed refractory CNS B-cell acute lymphoblastic leukemia.

Relapsed central nervous system (CNS) leukemia presents a therapeutic challenge to pediatric oncologists. Systemic monoclonal antibody therapy has shown recent promise in patients with relapsed acute lymphoblastic leukemia, however its effect on CNS disease in this population is not well established. We describe a case of multiply relapsed and refractory CNS leukemia in an adolescent patient who responded to the intra-CNS delivery of rituximab (anti-CD20) and epratuzumab (anti-CD22) therapy, demonstrating the practical use and potential efficacy of a novel route of monoclonal antibody administration in difficult-to-treat CNS leukemia.

Evaluation of the efficacy of ursodiol for prevention of hepatotoxicity in patients receiving gemtuzumab ozogamicin and inotuzumab ozogamicin.

Gemtuzumab ozogamicin (GO) and inotuzumab ozogamicin (InO) are indicated for newly diagnosed or relapsedrefractory CD33-positive acute myeloid leukemia and relapsedrefractory B-cell precursor acute lymphoblastic leukemia respectively. Patients undergoing therapy with these agents are at increased risk for hepatotoxicity. Forty-nine patients received either GO or InO with concomitant ursodiol (n14) or no ursodiol (n35) for hepatotoxicity prophylaxis. Hepatotoxicity occurred in 2 (14%) patients in the ursodiol group compared to 15 (43%) patients in the no ursodiol group (p0.10). Median days (17 versus 11 p0.66) and doses (4 versus 2 p0.28) to development of hepatotoxicity were higher in the ursodiol versus no ursodiol group. After adjusting for concomitant hepatotoxic medications and prior chemotherapy, ursodiol did not significantly reduce the incidence of hepatotoxicity. Ursodiol prophylaxis was associated with a similar incidence of hepatotoxicity compared to no ursodiol, but may delay the time to occurrence.

The role of

This retrospective study aimed to evaluate the role of metabolic parameters of Thirty patients with LBL underwent 42 scans. Metabolic parameters including maximum standardized uptake value (SUV Patients with stage Ⅳ had a higher TMTV than those with stage III (p 0.031). Besides, patients with T-LBL or mediastinal involvement had a high TMTV and TLG (p < 0.05). There was no significant difference in PETCT metabolic parameters between patients with different outcomes (p > 0.05). Children with a low TMTV (<242.91 cm³) had a better 3-year EFS compared with those with a high TMTV (88.9% vs. 56.3% p 0.036). SUV Metabolic parameters of baseline PETCT were not predictive of outcomes in children with LBL. PETCT done after the reinduction regime had better sensitivity and NPV than CT alone, and a negative scan could be a reliable indicator for sustained remission.

More Related Gene Pathways to Vincristine-Induced Death Events in a Human T-Acute Lymphoblastic Leukemia Cell Line.

Acute lymphoblastic leukemia (ALL) is common in children but rare in adults. Vincristine (VCR) is one of the drugs used at the beginning of treatment. Some genes are resistant to VCR in B-ALL. Here, we examined the effect of VCR on gene expression changes in a T-ALL cell line, Jurkat. The MTT method was used to determine the IC We identified 66 differentially expressed genes as comparison to untreated cells. The response to VCR-induced apoptotic events was remarkable in the pathways of heat shock protein, topoisomerases, protein kinases, cathepsins and cell cycle. In other pathways, there were resistant genes as well as sensitive genes to VCR treatment. Some proteins like HSP90AA1 and ESR1 had determining associations with other proteins. The results suggest VCR target genes in T-ALL cells may be beneficial biomarkers for ALL treatment and can be used to select appropriate synergistic drugs for VCR.

Immunophenotypic characteristics of T lineage acute lymphoblastic leukemia absence of immaturity markers-TdT, CD34 and HLADR is not uncommon.

T ALL may show variable morphological features and immunophenotypic analysis for characterisation of immature nature of these cells is needed to establish a diagnosis and distinguish from reactive conditions and mature T cell leukemias. Sometimes immaturity markers-CD34, TdT and HLA DR may not be expressed by blasts. The aim of the present study was to analyse immunophenotype of T ALLs especially with respect to absence of immaturity markers. Thirty-eight cases of T ALL diagnosed over a period of two and half years were analysed retrospectively with respect to clinical features, haematological features and flow cytometric immunophenotyping for T, B, Myeloid and immaturity markers. Students The most common T-lineage marker expressed was cCD3 and CD7 which were expressed in 100% cases followed by CD5 in 86.8% cases. The most common immaturity marker expressed was TdT (39.5% cases) followed by CD34 (34.2% cases). Thirteen cases (34.2%) were negative for all three of the immaturity markers i.e. TdT-CD34-HLADR. Absence of CD34 was associated with absence of expression of HLA DR (P<0.05) and aberrant expression of B lineage markers (P<0.05). T-ALL is a rare and aggressive disease. Many cases lack immaturity markers viz, TdT, CD34 and HLADR. In such cases a comprehensive approach taking into account the clinical presentation, cytomorphology and immunophenotyping is diagnostic in experienced hands. Further, molecular studies may be needed to aid diagnosis.

Monitoring of Leukemia Clones in B-cell Acute Lymphoblastic Leukemia at Diagnosis and During Treatment by Single-cell DNA Amplicon Sequencing.

Acute lymphoblastic leukemia (ALL) is characterized by the presence of chromosomal changes, including numerical changes, translocations, and deletions, which are often associated with additional single-nucleotide mutations. In this study, we used single cell-targeted DNA sequencing to evaluate the clonal heterogeneity of B-ALL at diagnosis and during chemotherapy treatment. We designed a custom DNA amplicon library targeting mutational hotspot regions (in 110 genes) present in ALL, and we measured the presence of mutations and small insertionsdeletions (indels) in bone marrow or blood samples from 12 B-ALL patients, with a median of 7973 cells per sample. Nine of the 12 cases showed at least 1 subclonal mutation, of which cases with

Effect of virtual reality-based exercise intervention on sleep quality in children with acute lymphoblastic leukemia and healthy siblings A randomized controlled trial.

Sleep is one of the important measurements of the quality of life for children especially suffering from a chronic illness such as cancer. Our aim was to determine the changes in sleep quality and to investigate the effect of virtual reality-based exercise (VRBE) approaches on sleep in patients with acute lymphoblastic leukemia (ALL) off treatment. The participants (ALL and healthy siblings) were evaluated for sleep quality with polysomnography and Childrens Sleep Habit Questionnaire before and after 12 weeks. The study randomized into two groups an exercise group who received VRBE in two days in a week, 45 min of each session for 12 weeks and an control group who were managed with supportive measures. The VRBE comprised of aerobic exercise in four different games by Nintendo Wii Fit Plus®. This randomized controlled trial was carried out on 38 participants. Before intervention, ALL patients ( Patients with ALL off treatment had similar values of sleep quality with healthy siblings. Novel types of exercises like VRBE have positive effects on sleep disorders in children with ALL and also healthy siblings. Future studies are needed comparing the different types of interventions.

Venous thromboembolism in pediatric patients with acute lymphoblastic leukemia under chemotherapy treatment. Risk factors and usefulness of thromboprophylaxis. Results of LAL-SEHOP-PETHEMA-2013.

Symptomatic venous thromboembolism (VTE) is diagnosed in 3%-14% of patients during pediatric acute lymphoblastic leukemia (ALL) therapy. There are well-known risk factors, but the role of others as inherited thrombophilia is still controversial. Prophylaxis with low molecular weight heparin (LMWH) has been described, but its use is not globally accepted. A retrospective multicentric study in ALL patients 1-18 years old following SEHOP-PETHEMA-2013 treatment guideline was performed to evaluate VTE rate, anticoagulant treatment, outcome, risk factors, and safety and usefulness of LMWH administration as primary thromboprophylaxis in children with inherited thrombophilia. A total of 652 patients were included in the study. VTE incidence was 8.7%. Most of the cases occurred during induction therapy associated with central venous catheter. Univariant analysis showed that family history of thrombosis, presence of mediastinal mass, high-risk treatment group, and inherited thrombophilia were statistically significant risk factors. LMWH administration seemed to decrease VTE rate in patients with inherited thrombophilia and those with T-cell ALL phenotype. Most of the VTE cases occurred in patients without inherited thrombophilia, but when it is present, the VTE risk is higher. LMWH administration was useful to decrease VTE in these patients.

Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia.

KMT2A-rearranged infant ALL is an aggressive childhood leukemia with poor prognosis. Here, we investigated the developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia (B-ALL) using bulk messenger RNA (mRNA) meta-analysis and examination of single lymphoblast transcriptomes against a developing bone marrow reference. KMT2A-rearranged infant B-ALL was uniquely dominated by an early lymphocyte precursor (ELP) state, whereas less adverse NUTM1-rearranged infant ALL demonstrated signals of later developing B cells, in line with most other childhood B-ALLs. We compared infant lymphoblasts with ELP cells and revealed that the cancer harbored hybrid myeloid-lymphoid features, including nonphysiological antigen combinations potentially targetable to achieve cancer specificity. We validated surface coexpression of exemplar combinations by flow cytometry. Through analysis of shared mutations in separate leukemias from a child with infant KMT2A-rearranged B-ALL relapsing as AML, we established that KMT2A rearrangement occurred in very early development, before hematopoietic specification, emphasizing that cell of origin cannot be inferred from the transcriptional state.

A novel IgG-based FLT3xCD3 bispecific antibody for the treatment of AML and B-ALL.

In lymphoid malignancies, the introduction of chimeric antigen receptor T (CAR-T) cells and bispecific antibodies (bsAbs) has achieved remarkable clinical success. However, such immunotherapeutic strategies are not yet established for acute myeloid leukemia (AML), the most common form of acute leukemia in adults. Common targets in AML such as CD33, CD123, and CLEC12A are highly expressed on both AML blasts and on normal myeloid cells and hematopoietic stem cells (HSCs), thereby raising toxicity concerns. In B-cell acute lymphoblastic leukemia (B-ALL), bsAbs and CAR-T therapy targeting CD19 and CD22 have demonstrated clinical success, but resistance via antigen loss is common, motivating the development of agents focused on alternative targets. An attractive emerging target is FLT3, a proto-oncogene expressed in both AML and B-ALL, with low and limited expression on myeloid dendritic cells and HSCs. We developed and characterized CLN-049, a T cell-activating bsAb targeting CD3 and FLT3, constructed as an IgG heavy chainscFv fusion. CLN-049 binds the membrane proximal extracellular domain of the FLT3 protein tyrosine kinase, which facilitates the targeting of leukemic blasts regardless of FLT3 mutational status. CLN-049 was evaluated for preclinical safety and efficacy in vitro and in vivo. CLN-049 induced target-restricted activation of CD4 and CD8 T cells. AML cell lines expressing a broad range of surface levels of FLT3 were efficiently lysed on treatment with subnanomolar concentrations of CLN-049, whereas FLT3-expressing hematopoietic progenitor cells and dendritic cells were not sensitive to CLN-049 killing. Treatment with CLN-049 also induced lysis of AML and B-ALL patient blasts by autologous T cells at the low effector-to-target ratios typically observed in patients with overt disease. Lysis of leukemic cells was not affected by supraphysiological levels of soluble FLT3 or FLT3 ligand. In mouse xenograft models, CLN-049 was highly active against human leukemic cell lines and patient-derived AML and B-ALL blasts. CLN-049 has a favorable efficacy and safety profile in preclinical models, warranting evaluation of its antileukemic activity in the clinic.

T cell receptor engineering of primary NK cells to therapeutically target tumors and tumor immune evasion.

T cell receptor (TCR)-engineered cells can be powerful tools in the treatment of malignancies. However, tumor resistance by Human Leukocyte antigen (HLA) class I downregulation can negatively impact the success of any TCR-mediated cell therapy. Allogeneic natural killer (NK) cells have demonstrated efficacy and safety against malignancies without inducing graft-versus-host-disease, highlighting the feasibility for an off the shelf cellular therapeutic. Furthermore, primary NK cells can target tumors using a broad array of intrinsic activation mechanisms. In this study, we combined the antitumor effector functions of NK cells with TCR engineering (NK-TCR), creating a novel therapeutic strategy to avoid TCR-associated immune resistance. BOB1, is a transcription factor highly expressed in all healthy and malignant B cell lineages, including multiple myeloma (MM). Expression of an HLA-B0702 restricted BOB1-specifc TCR in peripheral blood-derived NK cells was achieved following a two-step retroviral transduction protocol. NK-TCR was then compared with TCR-negative NK cells and CD8-T cells expressing the same TCR for effector function against HLA-B0702 B-cell derived lymphoblastoid cell lines (B-LCL), B-cell acute lymphoblastic leukemia and MM cell lines in vitro and in vivo. Firstly, TCR could be reproducibly expressed in NK cells isolated from the peripheral blood of multiple healthy donors generating pure NK-TCR cell products. Secondly, NK-TCR demonstrated antigen-specific effector functions against malignancies which were previously resistant to NK-mediated lysis and enhanced NK efficacy in vivo using a preclinical xenograft model of MM. Moreover, antigen-specific cytotoxicity and cytokine production of NK-TCR was comparable to CD8 T cells expressing the same TCR. Finally, in a model of HLA-class I loss, tumor cells with B2M KO were lysed by NK-TCR in an NK-mediated manner but were resistant to T-cell based killing. NK-TCR cell therapy enhances NK cell efficacy against tumors through additional TCR-mediated lysis. Furthermore, the dual efficacy of NK-TCR permits the specific targeting of tumors and the associated TCR-associated immune resistance, making NK-TCR a unique cellular therapeutic.

Late effects of high-dose methotrexate treatment in childhood cancer survivors-a systematic review.

High-dose methotrexate (HD-MTX) is used in the treatment of different childhood cancers, including leukemia, the most common cancer type and is commonly defined as an intravenous dose of at least 1 gm We conducted a systematic literature search in PubMed, including studies published in English or German between 1985 and 2020. The population of each study had to consist of at least 75% childhood cancer survivors (CCSs) who had completed the cancer treatment at least twelve months before late effects were assessed and who had received HD-MTX. The literature search was not restricted to specific cancer diagnosis or organ systems at risk for late effects. We excluded case reports, case series, commentaries, editorial letters, poster abstracts, narrative reviews and studies only reporting prevalence of late effects. We followed PRISMA guidelines, assessed the quality of the eligible studies according to GRADE criteria and registered the protocol on PROSPERO (ID CRD42020212262). We included 15 out of 1731 identified studies. Most studies included CCSs diagnosed with acute lymphoblastic leukemia (n 12). The included studies investigated late effects of HD-MTX on central nervous system (n 10), renal (n 2) and bone health (n 3). Nine studies showed adverse outcomes in neuropsychological testing in exposed compared to non-exposed CCSs, healthy controls or reference values. No study revealed lower bone density or worse renal function in exposed CCSs. As a limitation, the overall quality of the studies per organ system was low to very low, mainly due to selection bias, missing adjustment for important confounders and low precision. CCSs treated with HD-MTX might benefit from neuropsychological testing, to intervene early in case of abnormal results. Methodological shortcomings and heterogeneity of the tests used made it impossible to determine the most appropriate test. Based on the few studies on renal function and bone health, regular screening for dysfunction seems not to be justified. Only screening for neurocognitive late effects is warranted in CCSs treated with HD-MTX.

Feasibility of ovarian stimulation for fertility preservation during and after blinatumomab treatment for Ph-negative B-cell acute lymphoblastic leukemia.

It is challenging to preserve the fertility of female patients with B-cell acute lymphoblastic leukemia (B-ALL) before allogeneic hematopoietic stem cell transplantation (allo-HSCT) while maintaining treatment intensity. We report two cases of female patients with Philadelphia chromosome-negative (Ph -) B-ALL whose oocytes were retrieved after controlled ovarian stimulation during and after blinatumomab treatment. The first patient was a 30-year-old woman with relapsed Ph-B-ALL who received prednisolone (PSL) and cytoreductive chemotherapy with cyclophosphamide, vincristine, doxorubicin, and dexamethasone, followed by three courses of blinatumomab bridging to allo-HSCT. Ovarian stimulation was performed twice during blinatumomab administration, and two oocytes were retrieved during each course. The second patient was a 26-year-old woman with newly diagnosed Ph-B-ALL who received PSL, one course of conventional chemotherapy, and one course of high-dose methotrexate and cytarabine followed by two courses of blinatumomab bridging to allo-HSCT. Immediately after completion of the first course of blinatumomab, ovarian stimulation was performed, and three oocytes were retrieved. Use of a 2-week rest period enabled ovarian stimulation and oocyte retrieval to be performed without delaying treatment. Blinatumomab may be an option for preserving fertility while maintaining treatment intensity.

A Curious Case of Morphologically Deceptive Pediatric B-Lymphoblastic Leukemia with Granular Blebbed Blasts and DLBCL-Like Biopsy Findings.

Thyroid and Breast Cancer in 2 Sisters With Monoallelic Mutations in the Ataxia Telangiectasia Mutated (

The presence of a bidirectional risk for metachronous carcinomas among women with thyroid and breast cancer is well established. However, the underlying risk factors remain poorly understood. Two sisters developed papillary thyroid cancer (PTC) at age 32 and 34 years, followed by ductal carcinoma of the breast at 44 and 42 years. The 2 children of the younger sister developed ataxia-telangiectasia the son also developed lymphoblastic lymphoma and his sister died secondary to acute lymphoblastic leukemia (ALL). They were found to be compound heterozygous for ataxia telangiectasia mutated (

Diagnostic Value of

Cancer refers to a massive number of diseases distinguished by the development of abnormal cells that divide uncontrollably and have the capability of infiltration and destroying the normal body tissue. It is critical to detect biomarkers that are early detectable and noninvasive to save millions of lives. The aim of the present work is to use NMR as a noninvasive diagnostic tool for cancer diseases. This study included 30 plasma and 21 urine samples of patients diagnosed with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), 25 plasma and 17 urine samples of patients diagnosed with breast cancer (BC), and 9 plasma and urine samples obtained from healthy individuals as controls. They were prepared for NMR measurements then, the metabolites were identified and the data were analyzed using multivariate statistical procedures. The OPLS-DA score plots clearly discriminated ALL, AML, and BC from healthy controls. Plots of the PLS-DA loadings and S-line plots showed that all metabolites in plasma were greater in BC than in the healthy controls, whereas lactate,

Integrin α6-Targeted Molecular Imaging of Central Nervous System Leukemia in Mice.

Central nervous system leukemia (CNS-L) is caused by leukemic cells infiltrating into the meninges or brain parenchyma and remains the main reason for disease relapse. Currently, it is hard to detect CNS-L accurately by clinically available imaging models due to the relatively low amount of tumor cells, confined blood supply, and the inferior glucose metabolism intensity. Recently, integrin α6-laminin interactions have been identified to mediate CNS-L, which suggests that integrin α6 may be a promising molecular imaging target for the detection of CNS-L. The acute lymphoblastic leukemia (ALL) cell line NALM6 stabled and transfected with luciferase was used to establish the CNS-L mouse model. CNS-L-bearing mice were monitored and confirmed by bioluminescence imaging. Three of our previously developed integrin α6-targeted peptide-based molecular imaging agents, Cy5-S5 for near-infrared fluorescence (NIRF), Gd-S5 for magnetic resonance (MR), and

A case of therapy-related acute lymphoblastic leukemia following the treatment of acute myeloid leukemia.

Therapy-related acute lymphoblastic leukemia represents a distinct entity associated with inferior survival compared with de novo acute lymphoblastic leukemia. It consists of a subset of patients who have had exposure to chemotherapy or radiation for a previous malignancy. Here, we describe a case of acute myeloid leukemia who later developed precursor B cell acute lymphoblastic leukemia and discuss the current relevant literature. Our case highlights the importance of classifying therapy-related acute lymphoblastic leukemia as a separate as entity based on its biologic and clinical features.

True hyponatremia in the setting of pegasparagase-induced hypertriglyceridemia A case report.

Pegasparagase (PEG-Asparaginase) induced hypertriglyceridemia is rare in the treatment of lymphoblastic lymphoma in children. We present a case of PEG-asparaginase induced hypertriglyceridemia that was incidentally identified and suspicion of its interference with sodium measurement in the clinical laboratory. The use of a direct ion selective method clarified the presence of true hyponatremia. The patient was treated with an oral Fenofibrate therapy which resolved the hypertriglyceridemia. This case highlights that PEG-asparaginanse and Olazanpine can induce hypertriglyceridemia in acute lymphoblastic leukemia and it may be useful to obtain baseline triglyceride measurements for these patients.

Chronic Kidney Disease in Patients After Allogeneic Hematopoietic Cell Transplant.

Hematopoietic stem cell transplant (HSCT) is used in advanced hematologic diseases to restart the immune system. Kidney damage remains significant complication of hematopoietic cell transplant (HCT) affecting the mortality of transplant recipients. The aim of the study was to assess the advancement of chronic kidney disease (CKD) in patients after HSCT. We studied 150 patients who underwent allo-HSCT treatment in our center in years 1995 to 2020 because of acute myeloid leukemia in 47% of patients, acute lymphoblastic leukemia in 19%, and lymphoma in 32%. The mean age of patients with acute leukemia is 48 years (including acute myeloid leukemia it is 47 years, and including acute lymphoblastic leukemia it is 32 years). The mean age of lymphoma patients is 34 years. We studied the prevalence and stages of CKD. CKD stage 3a and 3b was found in 24.6%. None of the patients studied had CKD stage 4 or 5. In patients after HSCT because of both acute myeloid leukemia and acute lymphoblastic leukemia, CKD stage 3a was found in 19% and stage 3b in 7.3%. Estimated glomerular filtration rate (eGFR) >90 mLmin1.73 m

Role and Mechanism of lncRNA-pvt1 in the Pathogenesis of Acute Lymphoblastic Leukemia in Children.

To investigate the role and mechanism of lncRNA-pvt1 in the pathogenesis of childhood acute lymphoblastic leukemia (ALL). The expression of lncRNA-pvt1 in bone marrow tissues of ALL patients after initial diagnosis and complete remission was detected by RT-PCR to explore its possible involvement in the pathogenesis of ALL. The proliferation and apoptosis of Jurkat cells transfected with lncRNA-pvt1 were observed by MTT and flow cytometry. lncRNA-pvt1 expression was upregulated in bone marrow of ALL patients. Knockdown of lncRNA-pvt1 inhibited Jurkat cell proliferation and increased its apoptosis rate. Silencing lncRNA-pvt1 expression can inhibit the development of ALL.

Novel Insights into Pediatric Acute Lymphoblastic Leukemia Ophthalmic Relapses from a Nationwide Cohort Study.

Ten to fifteen percent of children with acute lymphoblastic leukemia (ALL) relapse following treatment. Of these, less than 2% display ophthalmic relapses, which owing to their scarcity, are largely undocumented, leaving clinicians with few diagnostic and therapeutic recommendations, despite serious functional sequelae. We conducted a French multicenter retrospective study to collect all clinical, radiological, biological, and therapeutic data, and outcomes for children with ALL ophthalmic relapses. From 2000 to 2020, 20 ophthalmic relapses occurring after first-line therapy performed before January 1

The Missing LNK Evolution from Cytosis to Chronic Myelomonocytic Leukemia in a Patient with Multiple Sclerosis and Germline SH2B3 Mutation.

Chronic myelomonocytic leukemia (CMML) is a rare but distinct hematological neoplasm with overlapping features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). Individuals with CMML have persistent monocytosis and bone marrow dyspoiesis associated with various constitutional symptoms like fevers, unintentional weight loss, or night sweats. It is established that there is a strong association of CMML with preceding or coexisting autoimmune diseases and systemic inflammatory syndromes affecting around 20% of patients. Various molecular abnormalities like

Inhibition of Protein Kinase CK2 Affects Thymidylate Synthesis Cycle Enzyme Level and Distribution in Human Cancer Cells.

Thymidylate synthase (TS), dihydrofolate reductase (DHFR), and serine hydroxymethyltransferase (SHMT) constitute the thymidylate synthesis cycle providing thymidylate for DNA synthesis and repair. Our previous studies indicated that TS and DHFR are the substrates of protein kinase CK2. This work has been aimed at the elucidation of the effect of CK2 activity on cell cycle progression, thymidylate synthesis enzyme expression and localization, and the role of CK2-mediated TS phosphorylation in

Acute Lymphoblastic Leukaemia in the Youngest Haematopoietic Stem Cell Transplantation and Beyond.

The ALL SCTped 2012 FORUM (For Omitting Radiation Under Majority age) trial compared outcomes for children ≥4 years of age transplanted for acute lymphoblastic leukaemia (ALL) who were randomised to myeloablation with a total body irradiation (TBI)-based or chemotherapy-based conditioning regimen. The TBI-based preparation was associated with a lower rate of relapse compared with chemoconditioning. Nevertheless, the age considered suitable for TBI was progressively raised over time to spare the most fragile youngest patients from irradiation-related complications. The best approach to use for children <4 years of age remains unclear. Children diagnosed with ALL in their first year of life, defined as infants, have a remarkably poorer prognosis compared with older children. This is largely explained by the biology of their ALL, with infants often carrying a

Prognostic Significance of Comprehensive Gene Mutations and Clinical Characteristics in Adult T-Cell Acute Lymphoblastic Leukemia Based on Next-Generation Sequencing.

Adult T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous malignant tumor with poor prognosis. However, accurate prognostic stratification factors are still unclear. Data from 90 adult T-cell acute lymphoblastic leukemialymphoma (T-ALLLBL) patients were collected. The association of gene mutations detected by next-generation sequencing and clinical characteristics with the outcomes of T-ALLLBL patients were retrospectively analyzed to build three novel risk stratification models through Cox proportional hazards model. Forty-seven mutated genes were identified. Here, 73.3% of patients had at least one mutation, and 36.7% had ≥3 mutations. The genes with higher mutation frequency were Our risk stratification models exhibited good prognostic roles in adult T-ALLLBL patients and might guide individualized treatment and ultimately improve their outcomes.

LMO1 Plays an Oncogenic Role in Human Glioma Associated With NF-kB Pathway.

LIM domain only protein1(LMO1), a nuclear transcription coregulator, is implicated in the pathogenesis of T-cell acute lymphoblastic leukemia and neuroblastoma. However, the clinical significance and potential mechanism of LMO1 in human gliomas remain to be determined. In this study, expression level data and clinical information were obtained High LMO1 expression was associated with a high tumor grade and a poor prognosis in patients. High levels of LMO1 mRNA were correlated with poor prognosis in patients with isocitrate dehydrogenase (IDH)-wild-type (wt) and 1p19q non-codeletion gliomas. Gene silencing of LMO1 significantly inhibited tumor growth, invasion and migration This study provides new insights and evidences that high level expression of LMO1 is significantly correlated with progression and prognosis in human gliomas. LMO1 played a critical role in tumorigenesis and progression. The present study first investigated the LMO1-NGFR-NF-kB axis regulate cell growth and invasion in human glioma cells, whereby targeting this pathway may be a therapeutic target for glioma.

Very rare near-haploid acute lymphoblastic leukemia resistant to immunotherapy and CAR-T therapy in 19-year-old male patient.

Near-haploid acute lymphoblastic leukemia is rare subgroup of the disease, which is very important due to very poor prognosis and resistance to treatment including novel monoclonal antibodies and CAR-T therapy.

Efficacy analysis of Venetoclax combined with TKI and dexamethasone-containing low-dose chemotherapy for relapsedrefractory Ph

The clinical data of five cases of relapsedrefractory (RR) Philadelphia chromosome-positive acute B-lymphocytic leukaemia (Ph 分析郑州大学附属肿瘤医院采用Bcl-2抑制剂维奈托克联合酪氨酸激酶抑制剂（TKI）及含地塞米松小剂量化疗方案治疗5例复发难治（RR）费城染色体阳性急性B淋巴细胞白血病（Ph

Optimized outcome prediction of oncogenetic mutations in non-early T-cell precursor acute lymphoblastic leukemia.

Early biomarkers allowing effective treatment stratification in adult T-cell acute lymphoblastic leukemia (T-ALL) patients remain elusive. The mutation spectrum of 116T-ALL adult patients enrolled in the Shanghai Institute of Hematology (SIH)-based hospital network or Multicenter Hematology-Oncology Protocols Evaluation System (M-HOPES) in China were studied by using RNA-sequencing or targeted next generation sequencing. A comprehensive survival analysis based on clinical characteristics, immunophenotype and oncogenetic classifier was performed. Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) has higher mutation rates of NK-RAS and lower mutation rates of FBXW7 compared to non-ETP ALL, but the survival probability of ETP-ALL patients is similar to that of non-ETP ALL patients. T-ALLs with a NOTCH1FBXW7 (NF) mutation in the absence of RAS or PTEN abnormalities (NFRP class I) show a more favorable outcome compared to T-ALLs with no NF mutation andor with the presence of RASPTEN alterations (NFRP class II). A survival analysis of T-ALL, taking into account both the ETP-ALLnon-ETP T-ALL groups and the NFRP oncogenetic classifier, demonstrates that, within the non-ETP T-ALL subtype, NFRP class II identifies a group with poor prognosis and significant decreases of both OS (14.8% versus 50.9%, P 0.019) and EFS (11.4% versus 42.4%, P 0.001). In contrast, no survival difference is observed within ETP-ALL between the NFRP class I or class II (OS 37.9% versus 33%, P 0.876 EFS 39.8% versus 33.7%, P 0.969). In summary, the oncogenetic classifier based on the NFRP classes is particularly useful to improve the stratification of non-ETP ALL.

Design of a targeted next-generation DNA sequencing panel for pediatric T-cell lymphoblastic lymphoma to unravel biology and optimize treatment.

Low incidence and molecular heterogeneity of pediatric T-cell lymphoblastic lymphoma (T-LBL) require an international, large-scale effort to identify novel clinical biomarkers. The ongoing international clinical trial LBL2018 (NCT04043494) represents an ideal opportunity to implement a common analytic approach. Targeted next-generation sequencing is well-suited for this purpose however, selection of relevant target genes for T-LBL remains subject of ongoing debates. Our group has recently designed and evaluated a first target panel of 80 candidate genes for T-LBL. The present study aimed at developing a novel optimized gene panel for large-scale application and to promote an international agreement on a common core panel. Small sequence variants obtained from our former study were systematically analyzed and classified with regards to pathogenic relevance, to prioritize candidate genes. Additional genes were curated from literature and online databases for a more comprehensive analysis of relevant functions and signaling pathways. The new target panel TGP-T-LBL entails 84 candidate genes which are key actors in NOTCH, PI3K-AKT, JAK-STAT, RAS signaling, epigenetic regulation, transcription, DNA repair, cell cycle regulation, and ribosomal function. From our former gene panel, 35 out of 80 candidate genes were selected for the novel panel. Forty-six out of 84 genes are currently being analyzed in the ongoing international trial LBL2018. Exploratory analysis of prognostic relevance on mutation-level suggested a potential association of PIK3CA variants c.1624G>A(p.Glu542Lys) and c.1633G>A(p.Glu545Lys) to occurrence of relapse, emphasizing particular relevance of mutation analysis in PI3K-AKT signaling. Our approach promotes comprehensive and clinically relevant mutational profiling of pediatric T-LBL.

Distinct outcomes, ABL1 mutation profile, and transcriptome features between p190 and p210 transcripts in adult Philadelphia-positive acute lymphoblastic leukemia in the TKI era.

The differential signaling and outcome of patients with p190 or p210 transcripts of BCR-ABL1 have been systematically investigated in chronic myeloid leukemia rather than in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph We analyzed the outcomes and ABL1 mutation profiles in 305 consecutive adult patients with Ph P190 and p210 were found in 199 (65%) and 106 (35%) patients, respectively. Compared to patients with p190, a higher white blood cell count (p 0.05), platelet count (p 0.047), BCR-ABL1 transcript level (p < 0.001), and lower bone marrow blasts (p 0.003) were found in patients with p210. Patients with p210 had fewer types of ABL1 mutations (4 vs. 16) and a higher prevalence of T315I and E225KV mutations (91.3% vs. 68.6% p 0.031). Patients with p210 had a similar complete remission rate (91.0% vs. 90.1% p 0.805) but a lower complete molecular remission rate at 1 month (9.9% vs. 22.0% p 0.031) compared with p190. Patients with p210 had lower 3-year overall survival (OS) and disease-free survival (DFS) rates than those with p190 (3-year DFS 10.4% vs. 9.2%, p 0.069, 3-year OS 44.3% vs. 38.2%, p 0.018, respectively). Multivariate analysis revealed that p210 was independently associated with worse OS HR 1.692 (95% CI 1.009-2.838), p 0.046. Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) was associated with a better prognosis in patients with p210 (p < 0.0001). In addition, scRNA-seq data showed distinct molecular and cellular heterogeneity between bone marrow cells of the two transcripts. Ph

Combining nilotinib and PD-L1 blockade reverses CD4 T-cell dysfunction and prevents relapse in acute B-cell leukemia.

Patients with acute lymphoblastic leukemia have experienced significantly improved outcomes due to the advent of chimeric antigen receptor (CAR) T cells and bispecific T-cell engagers, although a proportion of patients still relapse despite these advances. T-cell exhaustion has been recently suggested to be an important driver of relapse in these patients. Indeed, phenotypic exhaustion of CD4 T cells is predictive of relapse and poor overall survival in B-cell acute lymphoblastic leukemia (B-ALL). Thus, therapies that counter T-cell exhaustion, such as immune checkpoint blockade, may improve leukemia immunosurveillance and prevent relapse. Here, we used a murine model of Ph B-ALL as well as human bone marrow biopsy samples to assess the fundamental nature of CD4 T-cell exhaustion and the preclinical therapeutic potential for combining anti-PD-L1 based checkpoint blockade with tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein. Single-cell RNA-sequence analysis revealed that B-ALL induces a unique subset of CD4 T cells with both cytotoxic and helper functions. Combination treatment with the tyrosine kinase inhibitor nilotinib and anti-PD-L1 dramatically improves long-term survival of leukemic mice. Depletion of CD4 T cells prior to therapy completely abrogates the survival benefit, implicating CD4 T cells as key drivers of the protective anti-leukemia immune response. Indeed, treatment with anti-PD-L1 leads to clonal expansion of leukemia-specific CD4 T cells with the aforementioned helpercytotoxic phenotype as well as reduced expression of exhaustion markers. These findings support efforts to use PD1PD-L1 checkpoint blockade in clinical trials and highlight the importance of CD4 T-cell dysfunction in limiting the endogenous anti-leukemia response.

Near-Haploid B-Cell Acute Lymphoblastic Leukemia in a Patient with Rubinstein-Taybi Syndrome.

Rubinstein-Taybi syndrome (RSTS) is a rare disorder characterized by developmental delay, short stature, dysmorphic facies and skeletal abnormalities. RSTS has been linked to a variety of malignant and benign tumors, but the frequency and characteristics of RSTS-related neoplasms remain unclear. We describe a unique case of near haploid B-cell lymphoblastic leukemia (B-ALL) in a 6-year-old girl with RSTS who harbors a likely pathogenic variant in

Gross motor disorders in pediatric patients with acute lymphoblastic leukemia and survivors A systematic review.

Acute Lymphoblastic Leukemia (ALL) is the most common cancer in children and toxicities related to treatment are common. One of these adverse effects is related to the musculoskeletal system and especially to gross motor skills that allow body movements walking, running, jumping, and balance. This systematic review aims to describe gross motor impairments in pediatric patients with ALL during and after chemotherapeutic treatment and to identify the most commonly used tools for their assessment. Multiple electronic databases were searched for observational studies describing gross motor skills in children with ALL and the assessment tool used. The STROBE checklist was used to assess the reporting quality of each study. Ten studies were included in this review with assessments of gross motor skills in children with ALL undergoing treatment and survivors. Evidence suggests impairments in the performance of daily life activities during intensification and maintenance and persists up to 5 to 6 years after treatment´s cessation. Balance problems are noted at the start of treatment when the cumulative dose of vincristine is low and, in the survivors, it was the most reported alteration. These skills are essential for an adequate performance of children in daily life activities, recreation and leisure. We emphasize the need to assess gross motor skills and implement interventions that include physiotherapy and occupational rehabilitation in children with ALL.

Unrelated cord blood transplantation for adult-onset EBV-associated T-cell and NK-cell lymphoproliferative disorders.

Adult-onset EBV-associated T-cell and NK-cell lymphoproliferative disorders (EBV-TNK-LPDs) often progress rapidly, and require allogeneic stem cell transplantation early in the course of treatment. Unrelated cord blood transplantation (UCBT) is a readily available option for patients without HLA-matched donors. We retrospectively analyzed the outcomes of 12 UCBT in adult patients with chronic active EBV infection (CAEBV, n 8), EBV-positive hemophagocytic lymphohistiocytosis following primary EBV infection (n 2), hydroa vacciniforme-like lymphoproliferative disorder (n 1), and systemic EBV-positive T-cell lymphoma of childhood (STCLC, n 1). The median age at transplantation was 31.5 years (range 19-58). At the median follow-up time for survivors, which was 6.3 years (range 0.3-11.3), 3-year overall survival (OS) rates in all patients and 8 CAEBV patients were 68.2% (95% CI 28.6-88.9) and 83.3% (95% CI 27.3-97.5), respectively. Graft failure occurred in 4 of 8 CAEBV patients, requiring a second UCBT to achieve neutrophil engraftment. The cumulative incidence of grade II-IV acute GVHD was 33.3% (95% CI 9.1-60.4%). The EBV-DNA load became undetectable or very low after UCBT in all cases. UCBT may be a promising treatment option for adult-onset EBV-TNK-LPDs.

Recalcitrant Optic Nerve and Retinal Infiltration in a Relapse of Acute Lymphoblastic Leukaemia.

Isolated ocular relapse of leukaemia is rare. We present the case of a 20-year-old male with T-cell acute lymphoblastic leukaemia (ALL) who reported sudden blurring of vision in both eyes 6 months after documentation of ALL remission. Ocular examination showed bilateral infiltrative optic neuropathies and serous retinal detachments. Cerebrospinal fluid and bone marrow samples were negative for blast cells. Systemic work-up did not reveal any other sites of involvement. The ocular infiltration partially responded to reinduction chemotherapy, intraconal steroids, and radiotherapy. This report demonstrates a challenging case of isolated ocular ALL relapse presenting as bilateral optic nerve and retinal infiltration.

High CD34 surface expression in BCP-ALL predicts poor induction therapy response and is associated with altered expression of genes related to cell migration and adhesion.

Minimal residual disease (MRD) constitutes the most important prognostic factor in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Flow cytometry is widely used in MRD assessment, yet little is known regarding the effect of different immunophenotypic subsets on outcome. In this study of 200 BCP-ALL patients, we found that a CD34-positive, CD38 dim-positive, nTdT dim-positive immunophenotype on the leukemic blasts was associated with poor induction therapy response and predicted an MRD level at the end of induction therapy (EOI) of ≥ 0.001. CD34 expression was strongly and positively associated with EOI MRD, whereas CD34-negative patients had a low relapse risk. Further, CD34 expression increased from diagnosis to relapse. CD34 is a stemness-associated cell-surface molecule, possibly involved in cell adhesionmigration or survival. Accordingly, genes associated with stemness were overrepresented among the most upregulated genes in CD34-positive leukemias, and protein-protein interaction networks showed an overrepresentation of genes associated with cell migration, cell adhesion, and negative regulation of apoptosis. The present work is the first to demonstrate a CD34-negative immunophenotype as a good prognostic factor in ALL, whereas high CD34 expression is associated with poor therapy response and an altered gene expression profile reminiscent of migrating cancer stem-like cells.

Childrens Oncology Group Trial AALL1231 A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma.

To improve the outcomes of patients with T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL), the proteasome inhibitor bortezomib was examined in the Childrens Oncology Group phase III clinical trial AALL1231, which also attempted to reduce the use of prophylactic cranial radiation (CRT) in newly diagnosed T-ALL. Children and young adults with T-ALLT-LL were randomly assigned to a modified augmented Berlin-Frankfurt-Münster chemotherapy regimen withwithout bortezomib during induction and delayed intensification. Multiple modifications were made to the augmented Berlin-Frankfurt-Münster backbone used in the predecessor trial, AALL0434, including using dexamethasone instead of prednisone and adding two extra doses of pegaspargase in an attempt to eliminate CRT in most patients. AALL1231 accrued 824 eligible and evaluable patients from 2014 to 2017. The 4-year event-free survival (EFS) and overall survival (OS) for arm A (no bortezomib) versus arm B (bortezomib) were 80.1% ± 2.3% versus 83.8% ± 2.1% (EFS, Patients with T-LL had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. Systemic therapy intensification allowed elimination of CRT in more than 90% of patients with T-ALL without excess relapse.

Genetic Biomarkers and Their Clinical Implications in B-Cell Acute Lymphoblastic Leukemia in Children.

Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies characterized by abnormal proliferation of immature lymphoid cells. It is the most commonly diagnosed childhood cancer with an almost 80% cure rate. Despite favorable survival rates in the pediatric population, a significant number of patients develop resistance to therapy, resulting in poor prognosis. ALL is a heterogeneous disease at the genetic level, but the intensive development of sequencing in the last decade has made it possible to broaden the study of genomic changes. New technologies allow us to detect molecular changes such as point mutations or to characterize epigenetic or proteomic profiles. This process made it possible to identify new subtypes of this disease characterized by constellations of genetic alterations, including chromosome changes, sequence mutations, and DNA copy number alterations. These genetic abnormalities are used as diagnostic, prognostic and predictive biomarkers that play an important role in earlier disease detection, more accurate risk stratification, and treatment. Identification of new ALL biomarkers, and thus a greater understanding of their molecular basis, will lead to better monitoring of the course of the disease. In this article, we provide an overview of the latest information on genomic alterations found in childhood ALL and discuss their impact on patients clinical outcomes.

Immunoproteasome Activity in Chronic Lymphocytic Leukemia as a Target of the Immunoproteasome-Selective Inhibitors.

Targeting proteasome with proteasome inhibitors (PIs) is an approved treatment strategy in multiple myeloma that has also been explored pre-clinically and clinically in other hematological malignancies. The approved PIs target both the constitutive and the immunoproteasome, the latter being present predominantly in cells of lymphoid origin. Therapeutic targeting of the immunoproteasome in cells with sole immunoproteasome activity may be selectively cytotoxic in malignant cells, while sparing the non-lymphoid tissues from the on-target PIs toxicity. Using activity-based probes to assess the proteasome activity profile and correlating it with the cytotoxicity assays, we identified B-cell chronic lymphocytic leukemia (B-CLL) to express predominantly immunoproteasome activity, which is associated with high sensitivity to approved proteasome inhibitors and, more importantly, to the immunoproteasome selective inhibitors LU005i and LU035i, targeting all immunoproteasome active subunits or only the immunoproteasome β5i, respectively. At the same time, LU102, a proteasome β2 inhibitor, sensitized B-CLL or immunoproteasome inhibitor-inherently resistant primary cells of acute myeloid leukemia, B-cell acute lymphoblastic leukemia, multiple myeloma and plasma cell leukemia to low doses of LU035i. The immunoproteasome thus represents a novel therapeutic target, which warrants further testing with clinical stage immunoproteasome inhibitors in monotherapy or in combinations.

A natural history study of nitrous oxide versus propofol-assisted intrathecal therapy in the treatment of acute lymphoblastic leukemia.

Childhood acute lymphoblastic leukemia (ALL) treatment requires numerous lumbar punctures (LPs) with intrathecal (IT) chemotherapy to prevent and treat central nervous system disease. Historically, LPs in this setting are performed using propofol sedation at most institutions. At our center, LPs are often alternatively performed under nitrous oxide (N Retrospective cohort study of patients aged 0-31 years with ALL treated between January 1, 2013 and December 31, 2018 at the Childrens Minnesota Cancer and Blood Disorders Center, including all therapeutic LPs performed in the clinic setting under either propofol or N Among 215 patients and 2677 therapeutic LPs, 56.6% (n 1515) occurred under N N

Population genetics of PDE4B (phosphodiesterase-4B) in neglected Native Americans Implications for cancer pharmacogenetics.

PDE4B (phosphodiesterase-4B) has an important role in cancer and in pharmacology of some disorders, such as inflammatory diseases. Remarkably in Native Americans, PDE4B variants are associated with acute lymphoblastic leukemia (ALL) relapse, as this gene modulates sensitivity of glucocorticoids used in ALL chemotherapy. PDE4B allele rs6683977.G, associated with genomic regions of Native American origin in US-Hispanics (admixed among Native Americans, Europeans, and Africans), increases ALL relapse risk, contributing to an association between Native American ancestry and ALL relapse that disappeared with an extra-phase of chemotherapy. This result insinuates that indigenous populations along the Americas may have high frequencies of rs6683977.G, but this has never been corroborated. We studied ancestry and PDE4B diversity in 951 healthy individuals from nine Latin American populations. In non-admixed Native American populations rs6683977.G has frequencies greater than 90%, is in linkage disequilibrium with other ALL relapse associated and regulatory variants in PDE4B-intron-7, conforming haplotypes showing their highest worldwide frequencies in Native Americans (>0.82). Our findings inform the discussion on the pertinence of an extra-phase of chemotherapy in Native American populations, and exemplifies how knowledge generated in US-Hispanics is relevant for their even more neglected and vulnerable Native American ancestors along the American continent.

High tumor burden before blinatumomab has a negative impact on the outcome of adult patients with B-cell precursor acute lymphoblastic leukemia. A real-world study by the GRAALL.

Blinatumomab is a bispecific T-cell engager approved for B-cell precursor acute lymphoblastic leukemia (B-ALL) with persistent minimal residual disease (MRD) or in relapse. The prognostic impact of tumor load has been suggested before other immunotherapies but remains poorly explored before blinatumomab. We retrospectively analyzed the outcome of 73 patients who received blinatumomab either in first complete remission (CR) with MRD (n35) or at relapse (n38). Among MRD patients, 91% had MRD >0.01% before blinatumomab, and 89% achieved complete MRD response after blinatumomab. High pre-blinatumomab MRD levels were associated with shorter relapse-free survival (P0.049) and overall survival (OS) (P0.011). At 3 years, OS was 33%, 58% and 86% for pre-blinatumomab MRD >1%, between MRD 0.1- 1% and <0.1% respectively. Among relapsed patients, 23 received blinatumomab with overt relapse and 15 were in complete response (CR) after bridging chemotherapy. At 3 years, overall CR rate was 68% and complete MRD response rate was 84%. Patients who directly received blinatumomab had shorter relapse-free survival (P0.033) and OS (P0.003) than patients bridged to blinatumomab. Three-year OS was 66% in the latter group compared to 16% in the former group. Our observations suggest that pre-blinatumomab tumor burden should help to design more tailored strategies including tumor load reduction in relapsed patients.

Trends in Grade 5 Toxicity and Response in Phase I Trials in Hematologic Malignancy 20-Year Experience From the Cancer Therapy Evaluation Program at the National Cancer Institute.

Cancer drug development has largely shifted from cytotoxic chemotherapy to targeted treatment in the past two decades. Although previous studies have highlighted improvement in response rates in recent phase I trials, disease-focused reporting is limited. We integrated patient-level data for patients with hematologic malignancies who participated in phase I trials sponsored by the National Cancer Institute Cancer Therapy Evaluation Program between January 2000 and May 2019 and estimated the trend of grade 5 toxicity and response by disease subtype over time. We analyzed 161 trials involving 3,308 patients, all of whom were assessed for toxicity and 2,404 of whom were evaluable for response to therapy. The overall rate of grade 5 toxicities was 1.81% (95% CI, 1.36 to 2.27), with no significant change in the rate over time. Baseline characteristics associated with higher risk of grade 5 toxicity were age and performance status ≥ 2 at enrollment. Overall response rate (ORR) and complete response (CR) rate for all trials during the study period were 25.1% and 14.7%, respectively. A significant increase in both ORR and CR rate was observed over time (ORR, 18.5% in 2000-2005, 25.9% in 2006-2012, and 50.6% in 2013-2019, Over time, the ORR and CR rates in phase I trials for hematologic malignancy have improved meaningfully, whereas the rate of toxicity-related death remains stable. This study provides broad experience that physicians can use when discussing the potential outcomes for patients with hematologic malignancy considering participation in phase I trials.

Measurable Residual Disease Detection in B-Acute Lymphoblastic Leukemia The Childrens Oncology Group (COG) Method.

Measurable (minimal) residual disease (MRD) in B-acute lymphoblastic leukemia (B-ALL), as assessed by flow cytometry, is an established prognostic factor used to adjust treatment in most pediatric therapeutic protocols. MRD in B-ALL has been standardized by the Childrens Oncology Group in North America and more recently in a multicenter Foundation for the National Institutes of Health-funded study. This article outlines the reagents, instrument setup, and analysis protocols required for the reproducible detection of residual leukemic cells in patients following induction therapy for B-ALL. © 2022 Wiley Periodicals LLC. Basic Protocol 1 Staining and flow cytometry for B-acute lymphoblastic leukemia (B-ALL) measurable residual disease detection Support Protocol Specimen collection, handling, storage, and shipping Basic Protocol 2 Analysis and interpretation of data for B-ALL measurable residual disease detection Basic Protocol 3 Analysis of samples lacking sufficient CD19 events.

Large-cohort humanized NPI mice reconstituted with CD34

Cancer immunotherapy has achieved impressive therapeutic effects in many cancers, while only a small subset of patients benefit from it and some patients even have experienced severe toxicity. It is urgent to develop a feasible large-cohort humanized mouse model to evaluate the pre-clinical efficacy and safety of cancer immunotherapy. Furthermore, developing potentially effective combination therapy between cancer immunotherapy and other therapies also needs humanized mouse model to adequately mimic clinical actual setting. Herein, we established a humanized mouse model engrafted with less human CD34

Residence in a Latinx enclave and end-induction minimal residual disease positivity among children with acute lymphoblastic leukemia.

Racial and ethnic inequities in survival persist for children with acute lymphoblastic leukemia (ALL). In the US, there are strong associations between SES, raceethnicity, and place of residence. This is evidenced by ethnic enclaves neighborhoods with high concentrations of ethnic residents, immigrants, and language isolation. The Latinx enclave index (LEI) can be used to investigate how residence in a Latinx enclave is associated with health outcomes. We studied the association between LEI score and minimal residual disease (MRD) in 142 pediatric ALL patients treated at Texas Childrens Hospital. LEI score was associated with end-induction MRD positivity (OR per unit increase 1.63, CI 1.12-2.46). There was also a significant trend toward increased odds of MRD positivity among children living in areas with the highest enclave index scores. MRD positivity at end of induction is associated with higher incidence of relapse and lower overall survival among children with ALL future studies are needed to elucidate the exact causes of these findings and to improve ALL outcomes among children residing within Latinx enclaves.Supplemental data for this article is available online at httpsdoi.org10.108008880018.2022.2047850.

PTENPI3KAkt pathway alters sensitivity of T-cell acute lymphoblastic leukemia to L-asparaginase.

Childhood T-cell acute lymphoblastic leukemia (T-ALL) still remains a therapeutic challenge due to relapses which are resistant to further treatment. L-asparaginase (ASNase) is a key therapy component in pediatric T-ALL and lower sensitivity of leukemia cells to this drug negatively influences overall treatment efficacy and outcome. PTEN protein deletion andor activation of the PI3KAkt signaling pathway leading to altered cell growth and metabolism are emerging as a common feature in T-ALL. We herein investigated the relationship amongst PTEN deletion, ASNase sensitivity and glucose metabolism in T-ALL cells. First, we found significant differences in the sensitivity to ASNase amongst T-ALL cell lines. While cell lines more sensitive to ASNase were PTEN wild type (WT) and had no detectable level of phosphorylated Akt (P-Akt), cell lines less sensitive to ASNase were PTEN-null with high P-Akt levels. Pharmacological inhibition of Akt in the PTEN-null cells rendered them more sensitive to ASNase and lowered their glycolytic function which then resembled PTEN WT cells. In primary T-ALL cells, although P-Akt level was not dependent exclusively on PTEN expression, their sensitivity to ASNase could also be increased by pharmacological inhibition of Akt. In summary, we highlight a promising therapeutic option for T-ALL patients with aberrant PTENPI3KAkt signaling.

Investigation of the function of the PI3-Kinase AKT signaling pathway for leukemogenesis and therapy of acute childhood lymphoblastic leukemia (ALL).

Acute lymphoblastic leukemia is the most common cause of cancer-related death in children and, especially for patients in a high-risk group, still represents a poor prognosis. The PI3KAKTmTOR signaling pathway has been identified as a frequently constitutively activated switching point in the disease of ALL. Despite the knowledge of the therapeutic importance of the signaling pathway, the results of clinically effective treatment strategies have so far been extremely sobering. In particular, monotherapy approaches represent a major problem with regard to cell resistance. In this work, the PI3KAKTmTOR signaling pathway was examined as a therapeutic target for the treatment of childhood acute lymphoblastic leukemia (ALL) with a new therapeutic approach to avoid cell resistance. Therefore, we used a combined therapeutic approach with inhibitors directed against AKT (MK2206), mTOR (RAD001) and the most prominent and aberrantly activated tyrosine kinase. In case of BCR-ABL-positive B-ALL cells we used a combination with the classic inhibitor Imatinib and in case of MLL-AF4-positive B-ALL cells we used a combination with Quizartinib (directed against FLT3). We show, in particular compared to the monotherapies, a highly significant inhibition of the growth of these cells after this new specific triple combination therapy. Furthermore, we show that inhibiting AKT alone leads to a feedback mechanism and an upregulation of the phosphorylation of a number of receptor-tyrosine-kinases. After isoform-specific knockdown of the three AKT isoforms in ALL cells we identified that especially ErbB2Her2 is most strongly phosphorylated in cells with AKT2 knockdown. AKT isoform 1 and 2 knockdown cells show, in contrast to AKT isoform 3 knockdown cells, a weak proliferation and are presumably kept alive among others by the increased phosphorylation of the receptor-tyrosine-kinase ErbB2. This work provides first indications for a new combination therapy of B-ALL cells, which is directed against AKT, mTOR and a predominantly highly activated kinase.

JACLS ALL-02 SR protocol reduced-intensity chemotherapy produces excellent outcomes in patients with low-risk childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. As overall cure rates of childhood ALL have improved, reduction of overall treatment intensity while still ensuring excellent outcomes is imperative for low-risk patients. We report the outcomes of patients treated following the standard-risk protocol from the prospective Japan Association of Childhood Leukemia Study (JACLS) ALL-02 study, which was conducted between 2002 and 2008 for patients with newly diagnosed ALL aged 1-18 years. Of 1138 patients with B-cell precursor ALL, 388 (34.1%) were allocated to this protocol. Excellent outcomes were achieved despite the overall treatment intensity being lower than that of most contemporary protocols 4 years event-free survival (EFS) was 92.3% and 4 years overall survival 98.2%. Patients with high hyperdiploidy (HHD) involving triple trisomy (trisomy of chromosomes 4, 10, and 17) or ETV6-RUNX1 had even better outcomes (4 years EFS 97.6% and 100%, respectively). Unique characteristics of this protocol include a selection of low-risk patients with a low initial WBC count and good early treatment response and reduction of cumulative doses of chemotherapeutic agents while maintaining dose density. In Japan, we are currently investigating the feasibility of this protocol while incorporating minimal residual disease into the patient stratification strategy.

Excess morbidity and mortality among survivors of childhood acute lymphoblastic leukaemia 25 years of follow-up from the United Kingdom Childhood Cancer Study (UKCCS) population-based matched cohort.

To examine morbidity and mortality among teenagers and young adults (TYAs) previously diagnosed with acute lymphoblastic leukaemia (ALL) in childhood, and compare to the general TYA population. National population-based sex-matched and age-matched case-control study converted into a matched cohort, with follow-up linkage to administrative healthcare databases. The study population comprised all children (0-14 years) registered for primary care with the National Health Service (NHS) in England 1992-1996. 1082 5-year survivors of ALL diagnosed<15 years of age (1992-1996) and 2018 unaffected individuals followed up to 15 March 2020. Associations with hospital activity, cancer and mortality were assessed using incidence rate ratios (IRR) and differences. Mortality in the 5-year ALL survivor cohort was 20 times higher than in the comparison cohort (rate ratio 21.3, 95% CI 11.2 to 45.6), and cancer incidence 10 times higher (IRR 9.9 95% CI 4.1 to 29.1). Hospital activity was increased for many clinical specialties, the strongest associations being for endocrinology outpatient IRR 36.7, 95% CI 17.3 to 93.4 and inpatient 19.7, 95% CI 7.9 to 63.2 for males, and 11.0, 95% CI 6.2 to 21.1 and 6.2 95% CI 3.1 to 13.5, respectively, for females. Notable excesses were also evident for cardiology, neurology, ophthalmology, respiratory medicine and general medicine. Males were also more likely to attend gastroenterology ear, nose and throat urology and dermatology, while females were more likely to be seen in plastic surgery and less likely in midwifery. Adding to excess risks of death and cancer, survivors of childhood ALL experience excess outpatient and inpatient activity across their TYA years, which is not related to routine follow-up monitoring. Involving most clinical specialties, associations are striking, showing no signs of diminishing over time. Recognising that all survivors are potentially at risk of late treatment-associated effects, our findings underscore the need to take prior ALL diagnosis into account when interpreting seemingly unrelated symptoms later in life.

CAR1922 T cell cocktail therapy for B-ALL relapsed after allogeneic hematopoietic stem cell transplantation.

B cell acute lymphocytic leukemia (B-ALL) patients who have relapsed after hematopoietic stem cell transplantation (HSCT) have a poor prognosis, and there is currently no standard approach available. Chimeric antigen receptor (CAR)-T cells induce high rates of initial response and long-term remission among patients with B-cell malignancies, especially B-ALL. Meanwhile, sequential infusion of CAR1922 T cells has been proven to be effective at preventing tumor immune escape. In the present study, we retrospectively analyzed 23 B-ALL patients who relapsed after allogeneic (allo)-HSCT and underwent sequential infusion of CAR1922 T cells, including nine donor-derived and 14 recipient-derived, in our center from July 2016 to July 2020, to evaluate the safety and efficacy of the cocktail of two single-specific CAR-T cells in B-ALL patients relapsed after transplantation. Except for one patient refusing evaluation, the remaining 22 patients achieved minimal residual disease (MRD)-negative complete remission within 30 days after CAR-T infusion. Most toxicities were slight and reversible. The estimated 12-month progression-free survival (PFS) rate was 59.2% (95% confidence interval CI, 35.9% to 76.5%), and the estimated 12-month overall survival (OS) rate was 67.4% (95% CI, 43.2% to 83.1%). Only two patients had CD19-negative recurrence. In addition, early recurrence after transplantation, graft-versus-host disease (GVHD) and severe infection after CAR-T infusion were poor prognostic factors. Our results indicate that sequential infusion of CAR1922 T cells is safe and effective for relapsed ALL patients after HSCT. This trial was registered at www.chictr.org.cn as ChiCTR-OPN-16008526.

Allogeneic Hematopoietic Stem Cell Transplant for Acute Lymphoblastic Leukemia in a Pediatric Patient After COVID-19 Infection Complicated by MIS-C.

The COVID-19 pandemic has impacted the care of countless individuals, including pediatric oncology patients. The initial lack of knowledge about the disease course and implications of infection led to delays in treatment to minimize additional harm. In pediatric oncology, unnecessary delays in chemotherapy or hematopoietic stem cell transplantation may increase the risk of disease relapse. This case report describes one high-risk pediatric oncology patients clinical course through hematopoietic stem cell transplantation immediately following COVID-19 infection complicated by multisystem inflammatory syndrome in children. The disease course, monitoring, long-term outcome, and recommendations for future research are reviewed.

Results of ARI-0001 CART19 cell therapy in patients with relapsedrefractory CD19-positive acute lymphoblastic leukemia with isolated extramedullary disease.

We evaluated outcomes of 18 patients with isolated extramedullary disease (iEMD) relapsedrefractory (RR) B-cell acute lymphoblastic leukemia (B-ALL) treated with the CD19-directed CAR T cells ARI-0001 in two centers (adult and pediatric), including patients treated in the CART19-BE-01 trial and the consecutive compassionate use program. iEMD was detected by PET-CT in 78% (1418), andor by cerebrospinal fluid analysis in 28% (518). Patients received cyclophosphamide and fludarabine followed by 1 × 10

The impact of the COVID-19 pandemic on the future incidence of acute lymphoblastic leukaemia in children Projections for Germany under a COVID-19 related scenario.

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CRLF2 overexpression defines an immature-like subgroup which is rescued through restoration of the PRC2 function in T-cell precursor acute lymphoblastic leukemia.

CRLF2 overexpression has been described as a biomarker of poor prognosis in T-cell acute lymphoblastic leukemia (T-ALL). In the present study, we aimed to unravel the genomic profile underlying CRLF2 overexpression (CRLF2-high) by analyzing RNA-seq, WES, and SNP-array data from 264 T-ALL patients and five cell lines deposited on the TARGET initiative, Cancer Cell Line Encyclopedia and Gene Expression Omnibus. These data allowed us to delineate the genomic landscape of CRLF2-high in T-ALL, which was associated with PTEN, JAK3, PHF6, EZH2, and RUNX1 mutations. We also observed an enrichment of CRLF2-high in early T-precursor (ETP)-ALL (23.08% vs. 4.02%, P 7.579e

Bispecific Antibodies and Other Non-CAR Targeted Therapies and HSCT Decreased Toxicity for Better Transplant Outcome in Paediatric ALL

This review will address the place of innovative, non-chemotherapy, non-CAR-T targeted therapies in the treatment of Acute Lymphoblastic Leukaemia (ALL), focusing on their use in the hematopoietic stem cell transplant (HSCT) context. The focus will be on the agent with the most experience to date, namely the bispecific T-cell engater (BiTE) blinatumomab, but references to antibody-drug conjugates (ADCs) such as inotuzumab ozogamicin and monoclonal antibodies such as daratumamab will be made as well. Specific issues to be addressed include (1) The use of these agents to reduce measurable residual disease (MRD) prior to HSCT and their potential for improved transplant outcomes due to reduced toxicity compared to traditional chemotherapy salvage, as well as potentially increased toxicity with HSCT with particular agents (2) the appropriate sequencing of innovative therapies, i.e., when to use BiTEs or antibodies versus CARs pre- andor post-HSCT this will include also the potential for impact on response of one group of agents on response to the other (3) the role of these agents particularly in the post-HSCT relapse setting, or as maintenance to prevent relapse in this setting (4) special populations in which these agents may substitute for traditional chemotherapy during induction or consolidation in patients with predisposing factors for toxicity with traditional therapy (e.g., Trisomy 21, infants), or those who develop infectious complications precluding delivery of full standard-of-care (SOC) chemotherapy during inductionconsolidation (e.g., fungal infections) (5) the evidence we have to date regarding the potential for substitution of blinatumomab for some of the standard chemotherapy agents used pre-HSCT in patients without the above risk factors for toxicity, but with high risk disease going into transplant, in an attempt to decrease current rates of transplant-related mortality as well as morbidity (6) the unique toxicity profile of these agents and concerns regarding particular side effects in the HSCT context. The manuscript will include both the data we have to date regarding the above issues, ongoing studies that are trying to explore them, and suggestions for future studies to further refine our knowledge base.

Management of Chronic Graft-vs.-Host Disease in Children and Adolescents With ALL Present Status and Model for a Personalised Management Plan.

Herein we review current practice regarding the management of chronic graft-vs.-host disease (cGvHD) in paediatric patients after allogeneic haematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukaemia (ALL). Topics covered include (i) the epidemiology of cGvHD (ii) an overview of advances in our understanding cGvHD pathogenesis (iii) current knowledge regarding risk factors for cGvHD and prevention strategies complemented by biomarkers (iii) the paediatric aspects of the 2014 National Institutes for Health-defined diagnosis and grading of cGvHD and (iv) current options for cGvHD treatment. We cover topical therapy and newly approved tyrosine kinase inhibitors, emphasising the use of immunomodulatory approaches in the context of the delicate counterbalance between immunosuppression and immune reconstitution as well as risks of relapse and infectious complications. We examine real-world approaches of response assessment and tapering schedules of treatment. Furthermore, we report on the optimal timepoints for therapeutic interventions and changes in relation to immune reconstitution and risk of relapseinfection. Additionally, we review the different options for anti-infectious prophylaxis. Finally, we put forth a theory of a holistic view of paediatric cGvHD and its associated manifestations and propose a checklist for individualised risk evaluation with aggregated considerations including site-specific cGvHD evaluation with attention to each individuals GvHD history, previous medical history, comorbidities, and personal tolerance and psychosocial circumstances. To complement this checklist, we present a treatment algorithm using representative patients to inform the personalised management plans for patients with cGvHD after HSCT for ALL who are at high risk of relapse.

Clinical outcomes of patients with acute lymphoblastic leukemia receiving the hyper-CVAD regimen and assessment of the risk of hepatitis flares due to hepatitis B virus reactivation after chemotherapy.

Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone) has become a popular regimen for adults with acute lymphoblastic leukemia (ALL). We assessed the efficacy and tolerability of hyper-CVAD in the treatment of adult ALL. We retrospectively reviewed ALL patients aged 18 or above receiving the hyper-CVAD regimen. We assessed complete remission rate and overall survival, as well as hepatitis B carrier rate and hepatitis flare due to hepatitis B virus (HBV) reactivation. Fifty-two patients were treated with the hyper-CVAD regimen. The median age at diagnosis was 42 years 27% of patients were Philadelphia (Ph) chromosome positive. The complete remission (CR) rate was 90.4% after the first cycle of chemotherapy. The induction mortality rate was 1.9%. Three patients required two cycles of hyper-CVAD to achieve CR. The median overall survival was 39.6 months and the 5-year overall survival was 50%. Age over 30 years and white blood cell count of more than 30 × 10 Hyper-CVAD is feasible and tolerable with a good CR rate in the treatment of adult ALL patients. It is an option for the treatment of ALL. Antiviral prophylaxis should be considered in ALL patients with HBV infection to reduce the risk of HBV reactivation.

Novel Compound, ND-17, Regulates the JAKSTAT, PI3KAKT, and MAPK Pathways and Restrains Human T-lymphoid Leukemia Development.

T cell acute lymphoblastic leukemia (T-ALL) is an invasive hematological malignant disorder of T cell progenitors. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway plays an important role in the development of T-ALL and in the inhibition of the key molecule, JAK2, and could suppress T-ALL cell proliferation. The objective of this study was to investigate the in vitro anti-tumor effects of a novel nilotinib derivative, ND-17, on cancer cell lines via its interactions with JAK2. The effects of ND-17 on cell proliferation and on cell cycle and apoptosis were evaluated using the tetrazolium assay and flow cytometry, respectively. In addition, the ND-17JAK2 binding interactions were evaluated using surface plasmon resonance and western blot analyses. ND-17 exerted the greatest inhibitory effects on T-ALL cells amongst all hematological cancer cell lines tested. Flow cytometric analysis indicated that ND-17 blocked the cell cycle at the S phase in T-ALL cells. Nilotinib did not significantly inhibit T-ALL cell growth or regulate the cell cycle. Preliminary investigations revealed that the regulation of cyclin-dependent kinasescyclins was attributed to ND-17-induced cell cycle arrest. Furthermore, ND-17 could bind to JAK2 with strong affinity, and more importantly, ND-17 bound to the ATP pocket of JAK2 in a manner similar to the potent inhibitor. Thus, ND-17 treatment exhibited a prominent effect in inhibiting the phosphorylation of JAK2 in T-ALL cells. An increase in the phosphorylation of JAK2 was observed in interleukin-6- stimulated Jurkat cells, which was reversed by ND-17 treatment. Meanwhile, the combination of TG- 101348 and ND-17 led to further improvement in inhibiting the phosphorylation of JAK2. Moreover, the transfection and knockdown of JAK2 altered the inhibitory effect of ND-17 on Jurkat cell viability. In addition, ND-17 treatment suppressed the JAKSTAT, phosphatidylinositol-3-kinaseprotein kinase Bmechanistic target of rapamycin, and mitogen-activated protein kinaseextracellular signal-regulated protein kinases 1 and 2 signaling pathways. These findings suggest that ND-17 could be a promising JAK2 inhibitor for the treatment of T-ALL.

mTOR inhibition downregulates glucose-6-phosphate dehydrogenase and induces ROS-dependent death in T-cell acute lymphoblastic leukemia cells.

mTOR activation is a hallmark of T-cell acute lymphoblastic leukemia (T-ALL) and is associated with resistance to glucocorticoid (GC)-based chemotherapy. We previously showed that altering redox homeostasis primes T-ALL cells to GC-induced apoptosis. Here we investigated the connection between the mTOR pathway and redox homeostasis using pharmacological inhibitors and gene silencing. In vitro studies performed on T-ALL cell lines and CG-resistant patient-derived T-ALL xenograft (PDX) cells showed that the mTOR inhibitor everolimus increased reactive oxygen species (ROS) levels, augmented lipid peroxidation, and activated the ROS-controlled transcription factor NRF2. These effects were accompanied by a decrease in the levels of NADPH and of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), which is a major source of cytosolic NADPH needed for maintaining the cellular ROS-scavenging capacity. The mTOR inhibitor everolimus induced mitochondrial inner membrane depolarization and dose-dependent apoptosis of T-ALL cells, but did not kill normal T-cells. Importantly, the combination of everolimus and the GC dexamethasone had a synergistic effect on killing T-ALL cells. The effects of mTOR inhibition were blunted by ROS scavengers and phenocopied by siRNA-mediated G6PD silencing. In vivo studies of NODSCID mice inoculated with refractory T-ALL PDX demonstrated that everolimus overcame dexamethasone resistance in conditions of high tumor burden that mimicked the clinical setting of acute leukemia. These findings provide insight into the crosstalk between mTOR and ROS homeostasis in T-ALL cells and furnish mechanistic evidence to support the combination of glucocorticoids with mTOR inhibitors as a therapeutic avenue for treating refractory T-ALL.

The importance of miRNA-630 in human diseases with an especial focus on cancers.

miR-630 is encoded by MIR630 gene (NC000015.10) on 15q24.1. This miRNA is mostly associated with cytokine signaling in immune system. Several neoplastic as well as non-neoplastic conditions have been linked with dysregulation of miR-630. It is an oncogenic miRNA in renal cell carcinoma, multiple myeloma, colorectal cancer, acute lymphoblastic leukemia, ovarian cancer and prostate cancer. On the other hand, it is a putative tumor suppressor miRNA in lung, cervical, breast, thyroid and esophageal tissues. In a number of other tissues, data regarding the role of miR-630 in the carcinogenesis is conflicting. Expression levels of miR-630 can be used as markers for prediction of cancer course. Moreover, miR-630 can influence response to chemoradiotherapy. This miRNA is also involved in the pathoetiology of IgA nephropathy, obstructive sleep apnea, age-related nuclear cataract and vitiligo. In the present review, we discuss the role of miR-630 in these conditions.

Cancer Epidemiology in Hispanic Populations What Have We Learned and Where Do We Need to Make Progress

The HispanicLatino(x) population (HL) in the United States of America is heterogeneous and fast growing. Cancer is the number one cause of death among HLs, accounting for 21% of deaths. Whereas for the most common cancers, incidence rates are lower in HLs compared with non-HL White (NHW) individuals, HLs have a higher incidence of liver, stomach, cervical, penile, and gallbladder cancers. HL patients tend to be diagnosed at more advanced stages for breast, colorectal, prostate, and lung cancers, and melanoma compared with NHW individuals. Etiologic and cancer outcomes research among HLs lags other populations. In this review, we provide a summary of challenges, opportunities, and research priorities related to cancer etiology, cancer outcomes, and survivorship to make progress in addressing scientific gaps. Briefly, we prioritize the need for more research on determinants of obesity, nonalcoholic fatty liver disease and its progression to liver cancer, stomach and gallbladder cancers, and pediatric acute lymphoblastic leukemia. We emphasize the need to improve cancer screening, early detection of cancer, and survivorship care. We highlight critical resources needed to make progress in cancer epidemiologic studies among HL populations, including the importance of training the next generation of cancer epidemiologists conducting research in HLs.

Automated identification of cell populations in flow cytometry data with transformers.

Acute Lymphoblastic Leukemia (ALL) is the most frequent hematologic malignancy in children and adolescents. A strong prognostic factor in ALL is given by the Minimal Residual Disease (MRD), which is a measure for the number of leukemic cells persistent in a patient. Manual MRD assessment from Multiparameter Flow Cytometry (FCM) data after treatment is time-consuming and subjective. In this work, we present an automated method to compute the MRD value directly from FCM data. We present a novel neural network approach based on the transformer architecture that learns to directly identify blast cells in a sample. We train our method in a supervised manner and evaluate it on publicly available ALL FCM data from three different clinical centers. Our method reaches a median F

Distinct power of bone marrow microRNA signatures and tumor suppressor genes for early detection of acute leukemia.

Acute leukemia involving lymphocytic and myeloid cells is cancer with a high mortality rate. Swift and timely diagnosis might be a potential approach to improving patient prognosis and survival. The microRNA (miRNA) signatures are emerging nowadays for their promising diagnostic potential. MiRNA levels from bone marrow can be used as prognostic biomarkers. The current study was designed to evaluate if the microRNAs and tumor suppressor genes (TSGs) profiling of hematopoietic bone marrow could help in acute leukemia early detection. Also, we assessed the DNA methyltransferase 3A (DNMT3A) expression and its possible epigenetic effects on miRNAs plus TSGs expression levels. The expression levels of ten miRNAs and four TSGs involved in acute lymphocytic leukemia (ALL) as well as acute myeloid leukemia (AML) were quantified in 43 and 40 bone marrow samples of ALL and AML patients in comparison with cancer-free subjects via real-time quantitative PCR (RT-qPCR). The receiver-operating-characteristic (ROC) analysis of miRNAs was performed in the study groups. Further, the correlation between the DNMT3A and TSGs was calculated. Significant differences were detected in the bone marrow expression of miRNAs and TSGs (P < 0.05) between acute leukemia patients and healthy group. ROC analysis confirmed the ability of miR-30a, miR-101, miR-132, miR-129, miR-124, and miR-143 to discriminate both ALL and AML patients with an area under the ROC curve of ≥ 0.80 (P < 0.001) and high accuracy. The correlation between DNMT3A and P15P16 TSGs revealed that DNMT3A plays a vital role in epigenetic control of TSGs expression. Our findings indicated that the downregulation of bone marrow miRNAs and TSGs was accompanied by acute leukemia development. The authors conclude that this study could contribute to introducing useful biomarkers for acute leukemia diagnosis.

Low back pain as an unusual presentation in a child with acute lymphoblastic leukaemia.

Acute leukaemia is the most common childhood cancer. The clinical presentation of acute leukaemia includes fever, pallor, bleeding tendencies, hepatosplenomegaly, lymphadenopathy and bone pains. This case is about a 7-year-old boy who presented with 2 months of progressive low back pain after jumping into the sea. Radiologic workup showed compression fractures in the T6-L5 regions of the spine. Trauma and osteogenesis imperfecta were considered initially until the patient developed the classic features of leukaemia. Analysis of the bone marrow aspirate, 2 months after the sea incident, revealed B cell acute lymphoblastic leukaemia (ALL). The low back pain subsided after a week of chemotherapy. A symptom that involves bone pain in a child needs thorough evaluation because a delay in diagnosis affects the outcome of treatment. ALL has been lingering at the time of his accident and this has caused weakening of his spine that resulted in much more severe injury than would have occurred in the absence of the ALL.

Selumetinib in combination with dexamethasone for the treatment of relapsedrefractory RAS-pathway mutated paediatric and adult acute lymphoblastic leukaemia (SeluDex) study protocol for an international, parallel-group, dose-finding with expansion phase III trial.

Event-free survival rates at 15 years for paediatric patients with relapsedrefractory acute lymphoblastic leukaemia (ALL) are 30%-50%, with 5-year survival for adult patients only 20%. Many patients with newly diagnosed and relapsed ALL harbour somatic RAS-signalling activation mutations. Induction therapy for ALL involves steroids, with preclinical data suggesting the combination of dexamethasone with the MEK12 inhibitor, selumetinib (ARRY-142886) has a synergistic anticancer effect. The SeluDex trial is an international, parallel-group, dose-finding with expansion, phase III trial to assess the selumetinibdexamethasone combination in adult and paediatric patients with relapsedrefractory, RAS pathway mutant ALL. The Cancer Research UK Clinical Trials Unit at University of Birmingham is the UK Coordinating Centre, with national hubs in Copenhagen, Denmark Monza, Italy Münster, Germany Paris, France and Utrecht, Netherlands. Patients with morphologically proven relapsedrefractory or progressive B-cell precursor or T-cell ALL, with demonstrated RAS pathway activating mutations are eligible. Adult patients are Medical ethical committees of all the participating countries have approved the study protocol initial (UK) ethics approval (17YH0123) was granted by Yorkshire The Humber-Leeds West Research Ethics Committee. Participants are required to provide written informed consentassent. Results will be disseminated through national and international presentations and peer-reviewed publications. ISRCTN92323261.

A novel bi-alleleic DDX41 mutations in B-cell lymphoblastic leukemia case report.

The germline mutations of DDX41, also known as DEAD box RNA helicase 41, have been found in about 1.5% of myeloid neoplasms (MNs). Development of MDSAML is relatively common in germline DDX41 mutations. However, a variety of hematological malignancies (HMs) have been reported. We report a novel case of bi-alleleic DDX41 mutations in B-cell lymphoblastic leukemia (B-ALL), with unusual location of DDX41 mutations. The gene expression profile (GEP) of Ph B-ALL with bi-alleleic DDX41 mutations showed heterogeneously transitional GEP and altered gene expression levels of genes involved in the process essential for red blood cells and myeloid cell differentiation were noted. We report that DDX41 mutations are unusual but can be an underlying event in Ph B-ALL and screening DDX41 mutations can be also informative for patients awaiting for haploidentical stem cell transplantation and choosing the therapy.

How to resist Notch-targeted T-leukemia therapy Lineage- and MYC enhancer switch.

Gain-of-function NOTCH1 mutations drive oncogenic MYC expression in T-ALL cells. Zhou et al. (2022) reveal that Notch-targeted therapy-resistant T-ALL cells activate EBF1, which promotes a T-to-B lineage shift and maintains oncogenic MYC expression in the absence of Notch signaling.

Outcome of donor-derived TAA-T cell therapy in patients with high-risk or relapsed acute leukemia post allogeneic BMT.

Patients with hematologic malignancies relapsing after allogeneic blood or marrow transplantation (BMT) have limited response to conventional salvage therapies, with an expected 1-year overall survival (OS) of <20%. We evaluated the safety and clinical outcomes following administration of a novel T-cell therapeutic targeting 3 tumor-associated antigens (TAA-T) in patients with acute leukemia who relapsed or were at high risk of relapse after allogeneic BMT. Lymphocytes obtained from the BMT donor were manufactured to target TAAs WT1, PRAME, and survivin, which are over-expressed and immunogenic in most hematologic malignancies. Patients received TAA-T infusions at doses of 0.5 to 4 × 107m2. Twenty-three BMT recipients with relapsedrefractory (n 11) andor high-risk (n 12) acute myeloid leukemia (n 20) and acute lymphoblastic leukemia (n 3) were infused posttransplant. No patient developed cytokine-release syndrome or neurotoxicity, and only 1 patient developed grade 3 graft-versus-host disease. Of the patients who relapsed post-BMT and received bridging therapy, the majority (n 911) achieved complete hematologic remission before receiving TAA-T. Relapsed patients exhibited a 1-year OS of 36% and 1-year leukemia-free survival of 27.3% post-TAA-T. The poorest prognosis patients (relapsed <6 months after transplant) exhibited a 1-year OS of 42.8% postrelapse (n 7). Median survival was not reached for high-risk patients who received preemptive TAA-T posttransplant (n 12). Although as a phase 1 study, concomitant antileukemic therapy was allowed, TAA-T were safe and well tolerated, and sustained remissions in high-risk and relapsed patients were observed. Moreover, adoptively transferred TAA-T detected by T-cell receptor V-β sequencing persisted up to at least 1 year postinfusion. This trial was registered at clinicaltrials.gov as NCT02203903.

The KRAS-G12D mutation induces metabolic vulnerability in B-cell acute lymphoblastic leukemia.

Mutations in RAS pathway genes are highly prevalent in acute lymphoblastic leukemia (ALL). However, the effects of RAS mutations on ALL cell growth have not been experimentally characterized, and effective RAS-targeting therapies are being sought after. Here, we found that Reh ALL cells bearing the KRAS-G12D mutation showed increased proliferation rates

Inotuzumab ozogamicin and blinatumomab sequential therapy for relapsedrefractory Philadelphia chromosome-positive acute lymphoblastic leukemia.

To overcome the unfavorable outcome of refractoryrelapsed (RR) Philadelphia chromosome-positive acute lymphoblastic leukemia (PhALL) and conduct allogeneic stem cell transplantation (allo-SCT) safely, we designed a sequential therapy involving a single cycle of Inotuzumab ozogamicin (InO) and Blinatumomab (Blina). Two heavily treated and aged patients with RR PhALL were treated with the therapy. Both of them achieved complete molecular remission without cytokine release syndrome and underwent allo-SCT without veno-occlusive diseasesinusoidal obstruction syndrome. Although appropriate central nervous system prophylaxis should be added, the InO-Blina sequential therapy is a promising strategy for treating RR PhALL as a bridging regimen before allo-SCT.

Capillary hyperpermeability syndrome A fatal complication of acute leukaemia Case report and review.

The capillary hyperpermeability syndrome is a rare disease that should be suspected in the presence of recurrent generalized edema without obvious cause, which may be idiopathic or secondary. In this case, we report a Clarkson syndrome secondary to an acute leukemia affecting a 4-year-old child admitted to the emergency room in respiratory and hemodynamic distress with a generalized oedematous syndrome and a bone marrow failure syndrome. Laboratory tests concluded that the patient was suffering from an acute lymphoblastic leukemia, hypoalbuminemia, pericardial effusion, and the absence of any other cause that is in favor of a capillary leak syndrome.In spite of the filling and the introduction of drugs, the cardio respiratory arrest could not be recovered and the child died 24h after his admission. It is a rare pathology described for the first time in 1960, generally secondary to a pathological state and more rarely idiopathic, to be evoked in front of clinical and biological parameters which are hypoalbuminemia, hemiconcentration and hypoperfusion, after having eliminated a sepsis in the first place.The treatment is based on the management of the acute phase by filling with crystalloids, drugs or even steroids, and as a preventive treatment of relapses immunoglobulins or theophylline are used. The evolution can be quickly fatal, thats why it is necessary to know how to evoke this syndrome in front of a similar clinical presentation.

Tumor Genomic Profiling and

To describe the frequency of use of tumor genomic profiling and functional A retrospective chart review was conducted to analyze the frequency of tumor genomic profiling and functional drug sensitivity screening in our institution in pediatric patients with hematologic malignancies and to ask if the results were used to direct treatment. A case series of patients for whom these testing recommendations resulted in therapeutic interventions is reported. Thirty-three patients underwent tumor genomic profiling assays, functional This retrospective case series demonstrates that precision medicine techniques such as genomic profiling and drug sensitivity testing can positively inform treatment selection in pediatric patients with relapsed or refractory leukemia and lymphoma.

Obesity-induced galectin-9 is a therapeutic target in B-cell acute lymphoblastic leukemia.

The incidence of obesity is rising with greater than 40% of the worlds population expected to be overweight or suffering from obesity by 2030. This is alarming because obesity increases mortality rates in patients with various cancer subtypes including leukemia. The survival differences between lean patients and patients with obesity are largely attributed to altered drug pharmacokinetics in patients receiving chemotherapy whereas, the direct impact of an adipocyte-enriched microenvironment on cancer cells is rarely considered. Here we show that the adipocyte secretome upregulates the surface expression of Galectin-9 (GAL-9) on human B-acute lymphoblastic leukemia cells (B-ALL) which promotes chemoresistance. Antibody-mediated targeting of GAL-9 on B-ALL cells induces DNA damage, alters cell cycle progression, and promotes apoptosis in vitro and significantly extends the survival of obese but not lean mice with aggressive B-ALL. Our studies reveal that adipocyte-mediated upregulation of GAL-9 on B-ALL cells can be targeted with antibody-based therapies to overcome obesity-induced chemoresistance.