Acute myeloid leukaemia (AML) is an aggressive blood cancer characterized by the unregulated proliferation of immature myeloblasts. Gene mutations have been shown to have a large effect on pathogenesis, inter-tumour heterogeneity and clinical outcomes in AML1-8; however, the role of epigenetic alterations in these respects has been investigated less extensively. Here we use ATAC-seq (assay for transposase-accessible chromatin with sequencing) in a cohort of 1,563 individuals with a recent diagnosis of AML (the 'eCHROMA' cohort) to show that AML can be classified into 16 subgroups on the basis of chromatin accessibility profiles. Multiomics analyses of gene mutations, the transcriptome, DNA methylation and histone marks show that these ATAC subgroups exhibit distinct driver mutations, differentiation states, gene expression, DNA methylation and super-enhancer profiles, and are also associated with clinical outcomes. These findings were validated in independent cohorts. Single-cell ATAC sequencing reveals that all leukaemic cells in each subgroup share a common chromatin accessibility profile, which suggests that subgroup-specific epigenomic fingerprints underlie the ATAC-based classification. Mechanistically, the subgroups have distinct gene-regulatory networks that are driven by the activities of key transcription factors in haematopoiesis, and in which subgroup-specific super-enhancers have a pivotal role. Multiomics single-cell analysis further reveals deregulated trajectories of differentiation coupled with chromatin accessibility and gene expression. Notably, ATAC subgroups have an independent prognostic effect, compared with genomic classification, and are associated with particular drug sensitivities. In summary, ATAC-based chromatin profiling, combined with multiomics data, provides insights into AML pathogenesis beyond genomics and constitutes a valuable resource for AML research.
A 59-year-old woman was diagnosed with symptomatic Bence Jones protein, lambda (λ) type, associated with multiple myeloma (BJP-λ MM). Considering her renal dysfunction, she initially received bortezomib and dexamethasone. After renal function improved, she received one cycle of bortezomib, lenalidomide, and dexamethasone (BLD) therapy and achieved stringent complete response. She presented with general fatigue and jaundice before the second cycle of BLD. Laboratory testing revealed: total bilirubin, 4.8 mg/dl; indirect bilirubin, 4.1 mg/dl; lactate dehydrogenase, 978 U/l; hemoglobin, 7.4 g/dl; haptoglobin, <10 mg/dl; platelet count, 23,000/µl; and creatinine, 0.96 mg/dl. A hemogram revealed 1% schistocytes. ADAMTS13 activity was undetectable and the ADAMTS13 inhibitor level was 1.8 Bethesda units. A diagnosis of acquired thrombotic thrombocytopenic purpura (aTTP) was made, and treatment was initiated with prednisolone and rituximab. Plasma exchange was not performed because thrombocytopenia did not progress. The first dose of rituximab restored platelet count, and ADAMTS13 inhibitor became undetectable. The clinical course in this case was consistent with drug-induced aTTP.
347 Background: In Japan, the standard treatment for resectable gastric cancer is primary gastrectomy followed by adjuvant chemotherapy based on S-1. However, the survival benefit of adjuvant chemotherapy in elderly patients, particularly those considered vulnerable, remains uncertain. Methods: JCOG1507 (BIRDIE trial) was a phase III randomized controlled trial to confirm the superiority of dose-modified S-1 adjuvant chemotherapy to surgery alone for vulnerable elderly patients with pathological stage II/III gastric cancer. The trial was conducted at 45 institutions of the Stomach Cancer Study Group of the Japan Clinical Oncology Group. Vulnerability to S-1 was defined as: (1) weight loss <15% and creatinine clearance (Ccr) ≥30 mL/min after total gastrectomy, or (2) weight loss <15% and 30 ≤ Ccr <80 mL/min after the other gastrectomy. Patients in the control arm were followed without S-1, while those in the experimental arm received one year of dose-modified S-1 monotherapy at a reduced dose according to the Ccr and type of gastrectomy. The primary endpoint was overall survival (OS). Secondary endpoints included relapse-free survival (RFS), time-to-treatment-failure, treatment continuity, dose intensity, and safety. Assuming a 3-year OS of 55% in the control arm and a 10% improvement with the experimental arm, the sample size was set at 370 (one-sided α=0.05, power 75%). This trial was registered with UMIN (000025742). Results: Patient accrual began in January 2017, but the planned sample size was reduced to 170 due to slow accrual (α=0.1, power 70%), and enrollment was closed to 167 patients in January 2024. At the second planned interim analysis, conducted after completion of protocol treatment for all enrolled patients on June 21, 2025, the 3-year OS was 63.8% (95% CI, 51.0–74.1) in the control arm and 63.4% (95% CI, 50.6–73.7) in the experimental arm (stratified HR, 1.272; 95% CI, 0.768–2.107). As the probability of demonstrating superiority at the final analysis was considered low, the trial was terminated early due to futility. For RFS, the 3-year RFS was 52.5% (95% CI, 40.6–63.1) in the control arm and 57.9% (95% CI, 45.5–68.4) in the experimental arm (HR, 0.888; 95% CI, 0.567–1.389). Conclusions: Dose-modified S-1 adjuvant therapy did not improve OS in vulnerable elderly patients with pStage II/III gastric cancer. Surgery alone remains the standard treatment for this population. Clinical trial information: 000025742 .
BACKGROUND:Acute pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP), known as post-ERCP pancreatitis (PEP), is a major adverse event. Although risk factors for PEP incidence have been widely studied, factors associated with severe PEP remain unclear. AIM:To identify risk factors, including body composition, associated with severe PEP. METHODS:A retrospective cohort study was conducted in patients who underwent ERCP at two tertiary care centers in Japan between January 2013 and October 2021. PEP severity was defined according to the American Society of Gastrointestinal Endoscopy Workshop criteria (2010). Patients were divided into mild and moderate-to-severe groups. Body composition parameters, including skeletal muscle index, subcutaneous adipose tissue, and visceral adipose tissue (VAT), were assessed using CT. Multivariate analysis was performed to identify factors associated with severe PEP. RESULTS:Among 3087 patients who underwent ERCP for biliary disease, 85 (2.75%) developed PEP. VAT was significantly higher in the severe than mild group (132.7 vs. 80.1 cm2, p < 0.01). VAT > 95 cm2 was the only independent risk factor for severe PEP (OR 2.79, p = 0.04). CONCLUSION:VAT may be associated with severe PEP. ERCP should be performed with awareness of the increased risk of severe PEP in patients with high visceral adiposity.
