The genomic basis of childhood T-lineage acute lymphoblastic leukaemia.

T-lineage acute lymphoblastic leukaemia (T-ALL) is a high-risk tumour1 that has eluded comprehensive genomic characterization, which is partly due to the high frequency of noncoding genomic alterations that result in oncogene deregulation2,3. Here we report an integrated analysis of genome and transcriptome sequencing of tumour and remission samples from more than 1,300 uniformly treated children with T-ALL, coupled with epigenomic and single-cell analyses of malignant and normal T cell precursors. This approach identified 15 subtypes with distinct genomic drivers, gene expression patterns, developmental states and outcomes. Analyses of chromatin topology revealed multiple mechanisms of enhancer deregulation that involve enhancers and genes in a subtype-specific manner, thereby demonstrating widespread involvement of the noncoding genome. We show that the immunophenotypically described, high-risk entity of early T cell precursor ALL is superseded by a broader category of 'early T cell precursor-like' leukaemia. This category has a variable immunophenotype and diverse genomic alterations of a core set of genes that encode regulators of hematopoietic stem cell development. Using multivariable outcome models, we show that genetic subtypes, driver and concomitant genetic alterations independently predict treatment failure and survival. These findings provide a roadmap for the classification, risk stratification and mechanistic understanding of this disease.

Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia.

PURPOSE: Although cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 90%, ALL remains a leading cause of cancer death in children. Half of relapses arise in children initially classified with standard-risk (SR) disease. MATERIALS AND METHODS: To identify genomic determinants of relapse in children with SR ALL, we performed genome and transcriptome sequencing of diagnostic and remission samples of children with SR (n = 1,381) or high-risk B-ALL with favorable cytogenetic features (n = 115) enrolled on Children's Oncology Group trials. We used a case-control study design analyzing 439 patients who relapsed and 1,057 who remained in complete remission for at least 5 years. RESULTS: Genomic subtype was associated with relapse, which occurred in approximately 50% of cases of PAX5-altered ALL (odds ratio [OR], 3.31 [95% CI, 2.17 to 5.03]; P = 3.18 × 10-8). Within high-hyperdiploid ALL, gain of chromosome 10 with disomy of chromosome 7 was associated with favorable outcome (OR, 0.27 [95% CI, 0.17 to 0.42]; P = 8.02 × 10-10; St Jude Children's Research Hospital validation cohort: OR, 0.22 [95% CI, 0.05 to 0.80]; P = .009), and disomy of chromosomes 10 and 17 with gain of chromosome 6 was associated with relapse (OR, 7.16 [95% CI, 2.63 to 21.51]; P = 2.19 × 10-5; validation cohort: OR, 21.32 [95% CI, 3.62 to 119.30]; P = .0004). Genomic alterations were associated with relapse in a subtype-dependent manner, including alterations of INO80 in ETV6::RUNX1 ALL, IKZF1, and CREBBP in high-hyperdiploid ALL and FHIT in BCR::ABL1-like ALL. Genomic alterations were also associated with the presence of minimal residual disease, including NRAS and CREBBP in high-hyperdiploid ALL. CONCLUSION: Genetic subtype, patterns of aneuploidy, and secondary genomic alterations determine risk of relapse in childhood ALL. Comprehensive genomic analysis is required for optimal risk stratification.

Integrated drug resistance and leukemic stemness gene-expression scores predict outcomes in large cohort of over 3500 AML patients from 10 trials.

In this study, we leveraged machine-learning tools by evaluating expression of genes of pharmacological relevance to standard-AML chemotherapy (ara-C/daunorubicin/etoposide) in a discovery-cohort of pediatric AML patients (N = 163; NCT00136084 ) and defined a 5-gene-drug resistance score (ADE-RS5) that was predictive of outcome (high MRD1 positivity p = 0.013; lower EFS p < 0.0001 and OS p < 0.0001). ADE-RS5 was integrated with a previously defined leukemic-stemness signature (pLSC6) to classify patients into four groups. ADE-RS5, pLSC6 and integrated-score was evaluated for association with outcome in one of the largest assembly of ~3600 AML patients from 10 independent cohorts (1861 pediatric and 1773 adult AML). Patients with high ADE-RS5 had poor outcome in validation cohorts and the previously reported pLSC6 maintained strong significant association in all validation cohorts. For pLSC6/ADE-RS5-integrated-score analysis, using Group-1 (low-scores for ADE-RS5 and pLSC6) as reference, Group-4 (high-scores for ADE-RS5 and pLSC6) showed worst outcome (EFS: p < 0.0001 and OS: p < 0.0001). Groups-2/3 (one high and one low-score) showed intermediate outcome (p < 0.001). Integrated score groups remained an independent predictor of outcome in multivariable-analysis after adjusting for established prognostic factors (EFS: Group 2 vs. 1, HR = 4.68, p < 0.001, Group 3 vs. 1, HR = 3.22, p = 0.01, and Group 4 vs. 1, HR = 7.26, p < 0.001). These results highlight the significant prognostic value of transcriptomics-based scores capturing disease aggressiveness through pLSC6 and drug resistance via ADE-RS5. The pLSC6 stemness score is a significant predictor of outcome and associates with high-risk group features, the ADE-RS5 drug resistance score adds further value, reflecting the clinical utility of simultaneous testing of both for optimizing treatment strategies.

Pharmacogenomic Score Effectively Personalizes Treatment of Acute Myeloid Leukemia.

PURPOSE: Cytarabine (also known as ara-C) has been the backbone of acute myeloid leukemia (AML) chemotherapy for over five decades. Recent pharmacogenomics-based 10-SNP ara-C score (ACS10) showed low ACS10 (£0) to be associated with poor outcome in AML patients treated with standard chemotherapy. Here, we evaluated ACS10 score in the context of three different induction 1 regimens in pediatric AML patients. EXPERIMENTAL DESIGN: ACS10 score groups (low,£0 or high,>0) were evaluated for association with event-free survival (EFS) and overall survival (OS) by three randomized treatment arms in patients treated on the AML02 (NCT00136084) and AML08 (NCT00703820) clinical trials: AML02 low-dose cytarabine (LDAC arm, n=91), AML02+AML08 high-dose cytarabine (HDAC arm, n=194) and AML08 clofarabine+ cytarabine (Clo/Ara-C arm, n=105) induction 1 regimens. RESULTS: Within the low-ACS10 score (£0) group, significantly improved EFS and OS was observed among patients treated with Clo/Ara-C as compared to LDAC (EFS, HR=0.45, 95% CI, 0.23-0.88, p=0.020; OS, HR=0.44, 95% CI, 0.19-0.99, p=0.048). In contrast, within the high-ACS10 score group (score >0) augmentation with Clo/Ara-C was not favorable as compared to LDAC (Clo/Ara-C vs. LDAC, EFS, HR=1.95, 95% CI: 1.05-3.63, p=0.035; OS HR=2.17, 95%CI: 1.05-4.49; p=0.037). Personalization models predicted 9% improvement in outcome in ACS10 score-based tailored induction (Clo/Ara-C for low and LDAC for high-ACS10 groups) as compared to non-personalized approaches (p<0.002). CONCLUSIONS: Our findings suggest that tailoring induction regimens using ACS10 scores can significantly improve outcome in patients with AML. Given the SNPs are germline, preemptive genotyping can accelerate matching the most effective remission induction regimen.

CAR-T cell therapy: Efficacy in management of cancers, adverse effects, dose-limiting toxicities and long-term follow up.

Chimeric Antigen Receptor T-cell (CAR-T) therapy has emerged as a groundbreaking and highly promising approach for the management of cancer. This paper reviews the efficacy of CAR-T therapy in the treatment of various hematological malignancies, also, with a mention of its effect on solid tumors, for which they have not received FDA approval yet. Different common and uncommon side effects are also discussed in this paper, with attention to the effect of each drug separately. By reviewing the recommendations of the FDA for CAR-T therapy research, we have extensively discussed dose-limiting toxicities. This further highlights the need for precise dosing strategies, striking a balance between therapeutic benefits and potential risks. Additionally, we reviewed the long-term follow-up of patients receiving CAR-T therapy to gain valuable insights into response durability and late-onset effects.

Comparative effects of epidural analgesia and intramuscular morphine on maternal and neonatal outcomes: a retrospective cohort study.

BACKGROUND: The global practice of pain management during labor involves the use of epidural analgesia or intramuscular morphine. However, the impact of these methods on maternal and neonatal short-term outcomes remains uncertain. OBJECTIVE: This study aimed to evaluate the effect of labor exposure to epidural analgesia and intramuscular morphine on neonatal intensive care unit admission rates and other associated maternal and neonatal outcomes such as sepsis, respiratory distress, instrumental delivery, birth trauma, low Apgar score, and chorioamnionitis. STUDY DESIGN: A study at the Women's Wellness and Research Center in Qatar analyzed 7721 low-risk normal vaginal deliveries from January 2017 to April 2018. Results were analyzed using descriptive and backward stepwise multinomial regression analysis, categorizing outcomes on the basis of pain management during active labor. RESULTS: Of the 7607 participants in the final sample, 2606 received epidural analgesia, 1338 received intramuscular morphine, 286 received both, and 3304 received neither. Multinomial regression analysis revealed no difference in neonatal intensive care unit admission in the epidural analgesia group or in the intramuscular morphine group compared with the group that received neither intervention. However, the analysis showed a significant association between the combined use of epidural analgesia and intramuscular morphine and neonatal intensive care unit admission due to respiratory depression (adjusted odds ratio, 8.63; 95% confidence interval, 1.07-69.46; P=.04). Moreover, there was a significant association between prolonged duration of the second stage of labor and receiving epidural analgesia alone (adjusted odds ratio, 1.02; 95% confidence interval, 1.01-1.02; P<.001) or the combination of epidural analgesia and intramuscular morphine (adjusted odds ratio, 1.02; 95% confidence interval, 1.01-1.03; P<.001). In addition, the combined use of epidural analgesia and intramuscular morphine was associated with gestational age (adjusted odds ratio, 1.86; 95% confidence interval, 1.19-2.90; P=.01) and infant sex (adjusted odds ratio, 3.72; 95% confidence interval, 1.54-9.01; P=.003). Intramuscular morphine alone was only linked to low Apgar score at 1 minute (adjusted odds ratio, 6.29; 95% confidence interval, 1.33-29.83; P=.02). CONCLUSION: In low-risk mothers, combining epidural analgesia and intramuscular morphine during labor increases NICU admission risk due to respiratory depression. However, the individual use of either method shows distinct clinical profile. Further research is warranted to enhance understanding and optimize pain management protocols.

The Contemporary Role of Hematopoietic Stem Cell Transplantation in the Management of Chronic Myeloid Leukemia: Is It the Same in All Settings?

Hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) patients has transitioned from the standard of care to a treatment option limited to those with unsatisfactory tyrosine kinase inhibitor (TKI) responses and advanced disease stages. In recent years, the threshold for undergoing HSCT has increased. Most CML patients now have life expectancies comparable to the general population, and therefore, the goal of therapy is shifting toward achieving treatment-free remission (TFR). While TKI discontinuation trials in CML show potential for achieving TFR, relapse risk is high, affirming allogeneic HSCT as the sole curative treatment. HSCT should be incorporated into treatment algorithms from the time of diagnosis and, in some patients, evaluated as soon as possible. In this review, we will look at some of the recent advances in HSCT, as well as its indication in the era of aiming for TFR in the presence of TKIs in CML.

Male Fertility and Fatherhood in Chronic Myeloid Leukemia: Current Understanding and Future Perspectives.

Chronic myeloid leukemia (CML), while traditionally a disease of the elderly, has recently risen in incidence among younger patients. Hence, fertility concerns have emerged considering the disease process and treatments, especially with the current scarce and conflicting recommendations. This review explores the impact of CML treatments including the first-line tyrosine kinase inhibitors (TKIs) and other treatments on male fertility in chronic myeloid leukemia (CML) patients. The aim of this review was to compile the available evidence on male fertility to ultimately tailor treatment plans for male CML patients for whom fertility and future chances for conception pose a concern. The data available on the conventional and newer TKIs to address fertility concerns were reviewed, particularly the potential long- and short-term effects. Also, the possible side effects on subsequent generations were a crucial focus point of this review to reach a more comprehensive CML management approach. We found and compared the evidence on TKIs approved to treat CML. We also reported the effects of hydroxyurea, interferon, and transplantation, which are considered second-line treatments. Our findings suggest that these drugs might have an undiscovered effect on fertility. More research with larger sample sizes and longer follow-up periods is essential to solidify our understanding of these effects.

Balanced crystalloids versus isotonic saline in pediatric sepsis: a comprehensive systematic review and meta-analysis.

Purpose: We conducted a comprehensive meta-analysis to compare the effects of balanced crystalloids (BC) and isotonic saline (IS) in pediatric sepsis. Methods: A systematic search was performed for studies comparing BC and IS in pediatric sepsis. Outcomes included mortality, acute kidney injury (AKI), need for renal replacement therapy (RRT), hospital length of stay (LOS), and pediatric intensive care unit (PICU) LOS. A random-effect models was used to calculated pooled odds ratios (OR) and mean differences (MD) with 95% confidence intervals (CIs). Results: The analysis included six studies with 8753 children. BC demonstrated significant reductions in overall mortality (OR 0.84, 95% CI 0.71 to 0.98, P = 0.03, I2 = 0%) and AKI (OR 0.74, 95% CI 0.57 to 0.96, P = 0.03, I2 = 37%) compared to IS. RRT need was similar between the BC and IS groups (OR 0.79, 95% CI 0.60 to 1.02, P = 0.07, I2 = 0%). Hospital and PICU LOS did not differ significantly. However, subgroup analysis of randomized controlled trials revealed significantly shorter hospital LOS in the BC group (mean difference -0.66 days, 95% CI -1.10 to -0.23, P = 0.003, I2 = 0%). Conclusion: Our meta-analysis demonstrates that using BC in pediatric sepsis is associated with reduced mortality, AKI, and hyperchloremia rates compared to IS, while maintaining similar hospital and PICU LOS. Large-scale randomized controlled trials are needed to validate these findings.

Phenotypic switching of vascular smooth muscle cells in atherosclerosis, hypertension, and aortic dissection.

Vascular smooth muscle cells (VSMCs) play a critical role in regulating vasotone, and their phenotypic plasticity is a key contributor to the pathogenesis of various vascular diseases. Two main VSMC phenotypes have been well described: contractile and synthetic. Contractile VSMCs are typically found in the tunica media of the vessel wall, and are responsible for regulating vascular tone and diameter. Synthetic VSMCs, on the other hand, are typically found in the tunica intima and adventitia, and are involved in vascular repair and remodeling. Switching between contractile and synthetic phenotypes occurs in response to various insults and stimuli, such as injury or inflammation, and this allows VSMCs to adapt to changing environmental cues and regulate vascular tone, growth, and repair. Furthermore, VSMCs can also switch to osteoblast-like and chondrocyte-like cell phenotypes, which may contribute to vascular calcification and other pathological processes like the formation of atherosclerotic plaques. This provides discusses the mechanisms that regulate VSMC phenotypic switching and its role in the development of vascular diseases. A better understanding of these processes is essential for the development of effective diagnostic and therapeutic strategies.

Predictors of perioperative bleeding in left ventricular assist device implantation.

Study objective: Early bleeding is a common source of morbidity associated with left ventricular assist device (LVAD) implantation. Our objective was to identify potential predictors of peri-implant bleeding. Methods: We conducted a retrospective cohort study of LVAD implants at our institution between January 2010 and November 2018. A total of 210 patients were included. Data were collected for the duration of implant hospitalization, including perioperative invasive hemodynamics, echocardiography and operative details, antiplatelet and anticoagulant use, bleeding events and blood product use, and thromboembolic events. Peri-operative bleeding was defined as a transfusion requirement of >4 units of packed red blood cells in the intraoperative and first 7 days postoperative period, or a major 7-day post-implant overt bleeding event requiring procedural intervention. Results: Perioperative bleeding occurred in 32% of patients and required surgical re-exploration in 9%. Multivariable logistic regression analysis identified history of previous sternotomy (OR 2.63, 95% CI 1.29 to 5.35, p-value 0.008), preoperative glomerular filtration rate <60 ml/min (OR 2.58, 95% CI 1.34 to 4.94, p-value 0.004), preoperative right atrial pressure >13 mm Hg (OR 2.36, 95% CI 1.19 to 4.67, p-value 0.014) and concomitant tricuspid valve repair (OR 2.48, 95% CI 1.23 to 5.01, p-value 0.011) as independent predictors of perioperative bleeding. In-hospital thromboembolic events occurred in 5% of patients, but there were no significant predictors for them. Conclusions: Elevated right atrial pressure appears to be a reversible risk factor for early bleeding that should be targeted during pre-implant optimization of LVAD candidates.