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Cancer cohorts are now known to be associated with increased rates of clonal hematopoiesis (CH). We sort to characterize the hematopoietic compartment of patients with melanoma and non-small cell lung cancer (NSCLC) given our recent population level analysis reporting evolving rates of secondary leukemias. The advent of immune checkpoint blockade (ICB) has dramatically changed our understanding of cancer biology and has altered the standards of care for patients. However, the impact of ICB on hematopoietic myeloid clonal expansion remains to be determined. We studied if exposure to ICB therapy affects hematopoietic clonal architecture and if their evolution contributed to altered hematopoiesis. Blood samples from patients with melanoma and NSCLC ( n = 142) demonstrated a high prevalence of CH. Serial samples (or post ICB exposure samples; n = 25) were evaluated in melanoma and NSCLC patients. Error-corrected sequencing of a targeted panel of genes recurrently mutated in CH was performed on peripheral blood genomic DNA. In serial sample analysis, we observed that mutations in DNMT3A and TET2 increased in size with longer ICB exposures in the melanoma cohort. We also noted that patients with larger size DNMT3A mutations with further post ICB clone size expansion had longer durations of ICB exposure. All serial samples in this cohort showed a statistically significant change in VAF from baseline. In the serial sample analysis of NSCLC patients, we observed similar epigenetic expansion, although not statistically significant. Our study generates a hypothesis for two important questions: (a) Can DNMT3A or TET2 CH serve as predictors of a response to ICB therapy and serve as a novel biomarker of response to ICB therapy? (b) As ICB-exposed patients continue to live longer, the myeloid clonal expansion may portend an increased risk for subsequent myeloid malignancy development. Until now, the selective pressure of ICB/T-cell activating therapies on hematopoietic stem cells were less known and we report preliminary evidence of clonal expansion in epigenetic modifier genes (also referred to as inflammatory CH genes).

There has been a widespread adoption of hypomethylating agents (HMA: 5-Azacytidine (5-Aza)/decitabine) and venetoclax (Ven) for the treatment of acute myeloid leukemia (AML); however, the mechanisms behind the combination's synergy are poorly understood. Monotherapy often encounters resistance, leading to suboptimal outcomes; however, the combination of HMA and Ven has demonstrated substantial improvements in treatment responses. This study elucidates multiple synergistic pathways contributing to this enhanced therapeutic effect. Key mechanisms include HMA-mediated downregulation of anti-apoptotic proteins, notably MCL-1, and the priming of cells for Ven through the induction of genes encoding pro-apoptotic proteins such as Noxa. Moreover, Ven induces sensitization to HMA, induces overcoming resistance by inhibiting the DHODH enzyme, and disrupts antioxidant pathways (Nrf2) induced by HMA. The combination further disrupts oxidative phosphorylation in leukemia stem cells, amplifying the therapeutic impact. Remarkably, clinical studies have revealed a favorable response, particularly in patients harboring specific mutations, such as IDH1/2 , NPM1 , CEBPA , or ASXL1 . This prompts future studies to explore the nuanced underpinnings of these synergistic mechanisms in AML patients with these molecular signatures.

Introduction: The use of high fraction of inspired oxygen (FiO 2 ) intraoperatively for the prevention of surgical site infection (SSI) remains controversial. Promising results of early randomised controlled trials (RCT) have been replicated with varying success and subsequent meta-analysis are equivocal. Recent advancements in perioperative care, including the increased use of laparoscopic surgery and pneumoperitoneum and shifts in fluid and temperature management, can affect peripheral oxygen delivery and may explain the inconsistency in reproducibility. However, the published data provides insufficient detail on the participant level to test these hypotheses. The purpose of this individual participant data meta-analysis is to assess the described benefits and harms of intraoperative high FiO 2 compared with regular (0.21-0.40) FiO 2 and its potential effect modifiers., Methods and Analysis: Two reviewers will search medical databases and online trial registries, including MEDLINE, Embase, CENTRAL, CINAHL, ClinicalTrials.gov and WHO regional databases, for randomised and quasi-RCT comparing the effect of intraoperative high FiO 2 (0.60-1.00) to regular FiO 2 (0.21-0.40) on SSI within 90 days after surgery in adult patients. Secondary outcome will be all-cause mortality within the longest available follow-up. Investigators of the identified trials will be invited to collaborate. Data will be analysed with the one-step approach using the generalised linear mixed model framework and the statistical model appropriate for the type of outcome being analysed (logistic and cox regression, respectively), with a random treatment effect term to account for the clustering of patients within studies. The bias will be assessed using the Cochrane risk-of-bias tool for randomised trials V.2 and the certainty of evidence using Grading of Recommendations, Assessment, Development and Evaluation methodology. Prespecified subgroup analyses include use of mechanical ventilation, nitrous oxide, preoperative antibiotic prophylaxis, temperature (<35°C), fluid supplementation (<15 mL/kg/hour) and procedure duration (>2.5 hour)., Ethics and Dissemination: Ethics approval is not required. Investigators will deidentify individual participant data before it is shared. The results will be submitted to a peer-review journal., Prospero Registration Number: CRD42018090261., Competing Interests: Competing interests: SWdJ reports receipt of grants from Photonics in Healthcare, Integra LifeSciences and Ethicon outside the submitted. PM reports receipt of grants or contracts from the Australian National Health and Medical Research Council (NHMRC), Practitioner Fellowship and Projects Grants, payment of expert testimony from Avant Medical Indemnity, and participation on a Data Safety Monitoring Board of Advisory Board for the SNAP, TOPIC-2 and BONANZA trials. AF reports receipt of institutional grants from the Australian Research Council Discovery Project and National Health and Medical Research Council Ideas outside the submitted work and participation on a Data Safety Monitoring Board or Advisory Board for the Australian Kidney Trials Research Network (INCH-HD, IMPEDE, TEQCH-PD, PHOSPHATE, BEST Fluids, N3RO trial, CKD-FIX, IMPROVE-FIX). RG reports participation on Steering Committee for the IntuBot Innosuisse Projekt and has a leadership role as ERC Director of Guidelines and ILCOR, and ILCOR Task Force Chair on Education, Implementation and Team, and Treasurer of European Airway Management society, and reports receipt without any payment of airway equipment for the research of the following: Intersurgical, Karl Storz, Verathon, Aircraft Medical, Prodol Meditec, Venner Medical, Kingsystems, Medtronic, Ambu, VBM, Radiometer, Sentec and Fisher & Paykel. AK reports receipt of grants or contracts from Potrero Medical, Rehabtronics and The 37Company outside the submitted work and participation on a Data Safety Monitoring Board of Advisory Board in Directed systems, Potrero Medical and BioAgel Laboratories. JM-O reports voluntary participation as a panellist in the updated WHO Guidelines on high versus low FiO2 in 2018 and voluntary coinvestigator in the PENGUIN trial of high versus low FiO2 for SSI prevention in abdominal surgery in low-income and middle-income settings with GlobalSurg Collaborative. MGWD reports participation on a Data Safety Monitoring Board or Advisory Board for the following trials: DANCE, SPHINX, ICONIC, SAFE, PACER, LEARNS, RECAP and BIOPEX2. CF reports receipt fees for lectures and educational events from Getinge and Medtronic outside the submitted work. CMS reports receipts of institutional grants from NICHD outside the submitted work. MB reports receipt of institutional grants from KCI/3M, Johnson & Johnson, New Compliance, BD Bard, Gore, Telabio, GDM, Medtronic and Smith & Nephew outside the submitted work, and participation on the Data Monitoring Committee of the EXTEND trial. MWH reports receipt of institutional grants from ZonMw outside the submitted work, consulting institutional fees from IDD Pharma outside the submitted work, institutional payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from CSL Behring outside the submitted work and has a leadership role in DGAI, ISAP and IARS (Anaesthesia and Analgesia). The other authors declare no conflict of interest., (© World Health Organization 2023. Licensee BMJ.)