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 We show that the immunophenotypically described, high-risk entity of early T cell precursor ALL is superseded by a broader category of 'early T cell precursor-like' leukaemia.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.

The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21.

Intrachromosomal amplification of chromosome 21 defines a subtype of high-risk childhood acute lymphoblastic leukemia (iAMP21-ALL) characterized by copy number changes and complex rearrangements of chromosome 21. The genomic basis of iAMP21-ALL and the pathogenic role of the region of amplification of chromosome 21 to leukemogenesis remains incompletely understood. In this study, using integrated whole genome and transcriptome sequencing of 124 patients with iAMP21-ALL, including rare cases arising in the context of constitutional chromosomal aberrations, we identified subgroups of iAMP21-ALL based on the patterns of copy number alteration and structural variation. This large data set enabled formal delineation of a 7.8 Mb common region of amplification harboring 71 genes, 43 of which were differentially expressed compared with non-iAMP21-ALL ones, including multiple genes implicated in the pathogenesis of acute leukemia (CHAF1B, DYRK1A, ERG, HMGN1, and RUNX1). Using multimodal single-cell genomic profiling, including single-cell whole genome sequencing of 2 cases, we documented clonal heterogeneity and genomic evolution, demonstrating that the acquisition of the iAMP21 chromosome is an early event that may undergo progressive amplification during disease ontogeny. We show that UV-mutational signatures and high mutation load are characteristic secondary genetic features. Although the genomic alterations of chromosome 21 are variable, these integrated genomic analyses and demonstration of an extended common minimal region of amplification broaden the definition of iAMP21-ALL for more precise diagnosis using cytogenetic or genomic methods to inform clinical management.

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.

Comparative efficacy and safety of PD-1/PD-L1 inhibitors in triple negative breast cancer: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Triple-Negative Breast Cancer (TNBC) is a lethal subtype of breast cancer with limited treatment options. The purpose of this Network Meta-Analysis (NMA) is to compare the efficacy and safety of inhibitors of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in treating TNBC. METHODS: Our search strategy was used in six databases: PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature database, Embase, Scopus, and Web of Science up to November 2nd, 2022, as well as a thorough search in the most used trial registries. We included phase II and III randomized controlled trials that looked at the efficacy of PD-1/PD-L1 inhibitors in the treatment of TNBC and reported either Overall Survival (OS), Progression-Free Survival (PFS), or pathological Complete Response (pCR). The risk of bias was assessed utilizing Cochrane's risk of bias 2 tool, and the statistical analysis was performed using a frequentist contrast-based method for NMA by employing standard pairwise meta-analysis applying random effects model. RESULTS: 12 trials (5324 patients) were included in our NMA including seven phase III trials. Pembrolizumab in a neoadjuvant setting achieved a pooled OS of 0.82 (95% Confidence Interval (CI) 0.65 to 1.03), a PFS of 0.82 (95% CI 0.71 to 0.94) and a pCR 2.79 (95% CI 1.07 to 7.24) compared to Atezolizumab's OS of 0.92 (95% CI 0.74 to 1.15), PFS of 0.82 (95% CI 0.69 to 0.97), and pCR of 1.94 (95% CI 0.86 to 4.37). Atezolizumab had less grade ≥ 3 adverse events (OR 1.48, 95% CI 0.90 to 2.42) than Pembrolizumab (OR 1.90, 95% CI 1.08 to 3.33) in the neoadjuvant setting. CONCLUSIONS: PD-1/PD-L1 inhibitors exhibited varying efficacy in terms of OS, PFS, and pCR. They were associated with an increase in immune-related adverse effects. When used early in the course of TNBC, PD-1/PD-L1 inhibitors exert their maximum benefit. Durvalumab as a maintenance treatment instead of chemotherapy has shown promising outcomes. Future studies should focus on PD-L1 expression status and TNBC subtypes, since these factors may contribute to the design of individualized TNBC therapy regimens. Systematic review registration PROSPERO Identifier: CRD42022380712.

Symptom burden, fatigue, sleep quality and perceived social support in hemodialysis patients with musculoskeletal discomfort: a single center experience from Egypt.

BACKGROUND AND AIMS: Musculoskeletal disorders (MSDs) are commonly encountered in hemodialysis (HD) patients. However, the causes linked to these disorders are still partially defined. The aim of this study was to determine the frequency of MSDs and their relationship to a variety of clinico-social characteristics such as sleep quality, mood disorders, fatigue, and social support, in addition to the patients' clinical and therapeutic profile. METHOD: The study included 94 patients on maintenance HD. Clinical and Sociodemographic data was gathered. To investigate the prevalence and trends of MSDs, the Nordic Musculoskeletal Questionnaire (NMQ-E) was employed. Patients completed the modified Edmonton Symptom Assessment System, Pittsburgh Sleep Quality Index (PSQI), multidimensional Fatigue Inventory (MFI-20), and Perceived Social Support from Family Scales. Univariate and multivariate regression analysis were used to assess the determinants of MSDs. RESULTS: The patients' mean age was 49.73 and 59.6% were males. Seventy-two percent of patients were afflicted by MSDs. Knee pain (48.9%), low back pain (43.6%), shoulder pain (41.6%), hip/thigh pain (35.1%), and neck pains (35.1%) were the most reported MSD domains. Pain (p = 0.001), fatigue (p = 0.01), depression (p = 0.015), and anxiety (p = 0.003) scores were substantially higher in patients with MSDs. Furthermore, patients with MSDs engaged in less physical activity (p = 0.02) and perceived less social support (p = 0.029). Patients with MSDs had lower subjective sleep quality, daytime dysfunction domains, and global PSQI scores (p = 0.02, 0.031, 0.036, respectively). Female gender (p = 0.013), fatigue (p = 0.012), depression (p = 0.014), anxiety (p = 0.004), lower activity (p = 0.029), and PSQI score (0.027), use of erythropoiesis-stimulating agents (ESAs), antihypertensive drugs, calcium and Iron supplementation were all significantly associated with MSDs. At the multivariable regression model, administration of ESAs (p = 0.017) and pain score (p = 0.040) were the only independent variables associated with the outcome. CONCLUSION: MSDs are quite common among HD patients. Female gender, pain, fatigue, depression, anxiety, reduced activity, poor sleep quality, and use of ESAs are all significantly associated with MSDs in HD patients. Patients with MSD perceived less social support compared to the other group. Patients treated with antihypertensive drugs, calcium and iron supplements were more likely to suffer MSDs.

Impact of Laparoscopic Sleeve Gastrectomy on Cardiovascular Pharmacotherapy in Left Ventricular Assist Device Patients.

ABSTRACT: Left ventricular assist device (LVAD) implantation is increasingly utilized in patients with advanced heart failure and morbid obesity. Laparoscopic sleeve gastrectomy (LSG) can facilitate weight loss in this population and can ultimately change the pharmacokinetics of heart failure therapeutics. In this study, we aimed to explore the changes in cardiovascular pharmacotherapy post LSG intervention. We conducted a retrospective observational cohort study of morbidly obese LVAD patients between 2013 and 2019 at the University of Florida with available pharmacotherapeutic data at 1 and 6 months. Thirteen post-LSG patients and 13 control subjects were included in the final analysis. In the post-LSG group, the mean body mass index decreased significantly (44 ± 5 vs. 34 ± 4.9, P < 0.001), and 7 patients were successfully bridged to cardiac transplantation. Only 3 patients required adjustment of their LVAD speed. Mean return to flow decreased by 8 mm Hg, despite a 45% reduction in the mean number of vasodilators per patient (1.2 vs. 0.7, P = 0.03). Mean weekly warfarin dose decreased by 35% after 6 months (32.9 ± 20.9 vs. 50.7 ± 26.6, P = 0.01). The use of diuretics, vasodilators, and beta-blockers was significantly reduced by 50%, 45%, and 35%, respectively. None of these changes were observed in the control group at 6-month follow-up post LVAD. In this single-center experience, weight loss post LSG is associated with decreased vasodilator, diuretic, and anticoagulant medication requirements in LVAD patients.

Conversion of RNA Aptamer into Modified DNA Aptamers Provides for Prolonged Stability and Enhanced Antitumor Activity.

Aptamers, synthetic single-strand oligonucleotides that are similar in function to antibodies, are promising as therapeutics because of their minimal side effects. However, the stability and bioavailability of the aptamers pose a challenge. We developed aptamers converted from RNA aptamer to modified DNA aptamers that target phospho-AXL with improved stability and bioavailability. On the basis of the comparative analysis of a library of 17 converted modified DNA aptamers, we selected aptamer candidates, GLB-G25 and GLB-A04, that exhibited the highest bioavailability, stability, and robust antitumor effect in in vitro experiments. Backbone modifications such as thiophosphate or dithiophosphate and a covalent modification of the 5'-end of the aptamer with polyethylene glycol optimized the pharmacokinetic properties, improved the stability of the aptamers in vivo by reducing nuclease hydrolysis and renal clearance, and achieved high and sustained inhibition of AXL at a very low dose. Treatment with these modified aptamers in ovarian cancer orthotopic mouse models significantly reduced tumor growth and the number of metastases. This effective silencing of the phospho-AXL target thus demonstrated that aptamer specificity and bioavailability can be improved by the chemical modification of existing aptamers for phospho-AXL. These results lay the foundation for the translation of these aptamer candidates and companion biomarkers to the clinic.

Clinical and Laboratory Diagnosis of Cryptosporidiosis among Children with Acute Gastroenteritis at a Tertiary Hospital, Cairo, Egypt.

BACKGROUND: Most studies on gastroenteritis have focused on viral and bacterial infections, while gastroenteritis where intestinal protozoan parasites may have played a role has not been well studied. This study was therefore, designed to assess the frequency and several potential risk factors for Cryptosporidium infection among children suffering from acute gastroenteritis and presented to a tertiary hospital in Cairo, Egypt. Effectiveness of modified Ziehl-Neelsen (MZN) and nested polymerase chain reaction (nPCR) for Cryptosporidium detection were evaluated as well. METHODS: A cross-sectional study was performed during the period from July 2018 to December 2018, where 100 human diarrheic stool samples were collected from children aged 3 months up to 12 years old presented to Ain Shams University Pediatrics Hospital, Cairo, Egypt with acute gastroenteritis. Demographic and clinical data were obtained from the participants. Initial parasite screening was done using the MZN staining method, and microscopically examined for Cryptosporidium infection, while genotyping was based on molecular diagnostic assays using nPCR and sequencing for selected samples. RESULTS: The overall frequency of Cryptosporidium infection was 5% using light microscopy, while 19% of samples were positive by nPCR. Cryptosporidium hominis was the only detected genotype. Clinical picture among cases were not significant in comparison to patients with other causes of gastroenteritis. CONCLUSION: Cryptosporidium infection is more common below 5 years of age; however, clinical data are not enough for suspicion of infection. Nucleic acid-based methods are more sensitive and specific despite the high cost in developing countries. However, real estimation of Cryptosporidium disease burden is of an outmost importance to achieve prevention and detection of the Cryptosporidium species genetic diversity. Lay summaryCryptosporidium is a protozoan, which causes gastroenteritis in humans. It is most common below 5 years of age; however, diarrhea and vomiting characteristics are not different from other causes of gastroenteritis. General diagnostic methods are inadequate for detection of these infections. Nested polymerase chain reaction (nPCR) and sequencing are accurate methods for pathogen detection and species verification. Our study included 100 Egyptian children with acute gastroenteritis. The overall frequency of Cryptosporidium infection was 5% using light microscopy, while 19% of samples were positive by nPCR. The clinical picture of the children presenting with this disease was not significantly different from those presenting with gastroenteritis due to other causes. This emphasizes the importance of proper diagnosis to know the true burden of the disease.

PRKAR1B-AS2 Long Noncoding RNA Promotes Tumorigenesis, Survival, and Chemoresistance via the PI3K/AKT/mTOR Pathway.

Many long noncoding RNAs have been implicated in tumorigenesis and chemoresistance; however, the underlying mechanisms are not well understood. We investigated the role of PRKAR1B-AS2 long noncoding RNA in ovarian cancer (OC) and chemoresistance and identified potential downstream molecular circuitry underlying its action. Analysis of The Cancer Genome Atlas OC dataset, in vitro experiments, proteomic analysis, and a xenograft OC mouse model were implemented. Our findings indicated that overexpression of PRKAR1B-AS2 is negatively correlated with overall survival in OC patients. Furthermore, PRKAR1B-AS2 knockdown-attenuated proliferation, migration, and invasion of OC cells and ameliorated cisplatin and alpelisib resistance in vitro. In proteomic analysis, silencing PRKAR1B-AS2 markedly inhibited protein expression of PI3K-110α and abrogated the phosphorylation of PDK1, AKT, and mTOR, with no significant effect on PTEN. The RNA immunoprecipitation detected a physical interaction between PRKAR1B-AS2 and PI3K-110α. Moreover, PRKAR1B-AS2 knockdown by systemic administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with PRKAR1B-AS2-specific small interfering RNA enhanced cisplatin sensitivity in a xenograft OC mouse model. In conclusion, PRKAR1B-AS2 promotes tumor growth and confers chemoresistance by modulating the PI3K/AKT/mTOR pathway. Thus, targeting PRKAR1B-AS2 may represent a novel therapeutic approach for the treatment of OC patients.

Blockade of CDK7 Reverses Endocrine Therapy Resistance in Breast Cancer.

Cyclin-dependent kinase (CDK)-7 inhibitors are emerging as promising drugs for the treatment of different types of cancer that show chemotherapy resistance. Evaluation of the effects of CDK7 inhibitor, THZ1, alone and combined with tamoxifen is of paramount importance. Thus, in the current work, we assessed the effects of THZ1 and/or tamoxifen in two estrogen receptor-positive (ER+) breast cancer cell lines (MCF7) and its tamoxifen resistant counterpart (LCC2) in vitro and in xenograft mouse models of breast cancer. Furthermore, we evaluated the expression of CDK7 in clinical samples from breast cancer patients. Cell viability, apoptosis, and genes involved in cell cycle regulation and tamoxifen resistance were determined. Tumor volume and weight, proliferation marker (Ki67), angiogenic marker (CD31), and apoptotic markers were assayed. Bioinformatic data indicated CDK7 expression was associated with negative prognosis, enhanced pro-oncogenic pathways, and decreased response to tamoxifen. Treatment with THZ1 enhanced tamoxifen-induced cytotoxicity, while it inhibited genes involved in tumor progression in MCF-7 and LCC2 cells. In vivo, THZ1 boosted the effect of tamoxifen on tumor weight and tumor volume, reduced Ki67 and CD31 expression, and increased apoptotic cell death. Our findings identify CDK7 as a possible therapeutic target for breast cancer whether it is sensitive or resistant to tamoxifen therapy.

Poor Outcome of Surgical Management of Acute Malfunctioning Mechanical Mitral Valve During Pregnancy. Should Centers with Limited Resources Find Different Options?

BACKGROUND: Rheumatic heart disease (RHD) is the most common cardiac disease in pregnancy in developing countries with the mitral valve being the most affected. In this study, the results of surgical intervention in pregnant women presented with acute malfunctioning mechanical mitral valve were discussed. METHODS: All patients underwent emergency redo mitral valve replacement due to acute malfunctioning mechanical mitral valve during pregnancy in a single center between January 2005 and December 2017. These patients were retrospectively analyzed. Additionally, anticoagulation strategy before the event and outcomes for the mother and the fetus were outlined. RESULTS: Between 2005 and 2017, 16 pregnant women arrived in a single tertiary center with acute malfunctioning mechanical mitral valves. The mean gestational age at the time of presentation was 13.19 ± 2.6 weeks. Fifteen out of the 16 patients changed their anticoagulation regimen either with or without medical advice. After replacing the valve, cardiopulmonary bypass successfully was weaned in 12 patients, who were transferred to the ICU sedated and ventilated with variable doses of chemical Inotropes. The remaining 4 patients died on the table after failure of weaning from bypass. In one case, the patient developed immediate postoperative stroke with the Glasgow Coma Scale (GCS) of 7, CT brain revealed massive infarction, her fetus was not viable, she remained sedated and ventilated, and she passed away on post-operative Day 12, due to pneumonia and sepsis. Another patient, with a viable fetus, passed away on post-operative Day 1, due to low cardiac output. CONCLUSION: Acute malfunctioning MHV during pregnancy represents a real dilemma to patients and caregivers. It carries high fetal and maternal morbidity and mortality, especially in centers with limited resources. We believe that an alternative plane must be formulated for such patients to avoid devastating complications, including maternal and fetal deaths.

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.

Thrombopoietin Receptor Agonists in Post-Hematopoietic Cell Transplantation Complicated by Prolonged Thrombocytopenia: A Comprehensive Review.

Hematopoietic cell transplantation (HCT) is a well-established procedure that has become a therapeutic mainstay for various hematological conditions. Prolonged thrombocytopenia following HCT is associated with a significant risk of morbidity and mortality, yet no universally recognized treatment protocol exists for such a complication. First-generation thrombopoietin receptor (TpoR) agonists as well as second-generation agents are known for their role in enhancing platelet production, and their use is expanding across various thrombocytopenic conditions. Therefore, we conducted this comprehensive review of the literature to provide an updated evaluation of the use of TpoR agonists and explore their efficacy and safety in the treatment of extended post-HCT thrombocytopenia. The literature search was conducted using PubMed database from 1996 through December 2023, using a predefined strategy with medical subject headings terms. We identified 64 reports on the utility of TpoR agonists, five of them were randomized controlled trials and the rest were retrospective observational studies and case series, with a total number of 1730 patients. Second-generation TpoR agonists appear more convenient than subcutaneous recombinant human thrombopoietin (rhTpo) as they can be orally administered and exhibit similar efficacy in platelet recovery, as indicated by recent trial results. Among these agents, avatrombopag, unlike eltrombopag, does not require any dietary restrictions, which could be more favorable for patients. However, eltrombopag remains the most extensively studied agent. TpoR agonists had promising effects in the treatment of post-HCT thrombocytopenia with a good safety profile so far, highlighting the potential benefit of their use.

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.

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.

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.

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.

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.

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.

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.