Gifu Municipal Hospital

Abstract Acute myeloid leukemia (AML) is an aggressive hematologic cancer characterized by proliferation of immature myeloblasts 1 . It shows profound molecular heterogeneity, which has been primarily studied through genetic abnormalities, providing the basis for disease classification, prognostication, and therapeutic choice 2–8 . However, genetic factors alone may not fully explain AML pathogenesis and diversity, while leaving the role of abnormal epigenome, particularly chromatin state, largely unexplored in a large cohort of patients. Here we show that AML is classified into 16 subgroups with distinct chromatin accessibility profiles based on ATAC-seq in 1,563 AML cases, derived from the encyclopedia of chromatin in AML (eCHROMA AML) dataset, including novel AML subgroups not previously recognized in conventional genomic classifications. By integrating multi-omics analyses of genome, transcriptome, and major histone marks, we show that these epigenetic subgroups exhibit unique features in clinical presentation, gene mutations, differentiation states, gene expression, and super-enhancer profiles, which are validated across independent cohorts. Single-cell sequencing demonstrates the presence of subgroup-specific ATAC signatures that are shared by all leukemic cells, confirming the key role of the epigenome in the ATAC-based classification. Mechanistically, each subgroup is associated with a distinct gene regulatory network centered on key transcription factors, where subgroup-specific super-enhancers play a pivotal role. These ATAC subgroups also have prognostic significance independent of genomic classification, and help reveal unexpected drug sensitivities. In summary, ATAC-based chromatin profiling in this large sample set, combined with multi-omics data, provides new insights into AML pathogenesis beyond genomic profiling and also serves as an invaluable resource for AML research.

The impact of each factor and the number of positive criteria on pathogenesis and the diagnostic performance of non-invasive tests (NITs) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. This study aimed to investigate the association between the cardiometabolic criteria and the clinical features. This retrospective study investigated clinicopathological characteristics and the diagnostic performance of the Enhanced Liver Fibrosis (ELF) test, fibrosis-4 (FIB-4) index, and nonalcoholic fatty liver disease fibrosis score (NFS) according to the factors and the number of positive cardiometabolic criteria in 1,038 patients with biopsy-proven MASLD. Hypertension is a significant risk factor for progression to advanced fibrosis and at-risk metabolic dysfunction-associated steatohepatitis (MASH) in male patients. In contrast, no significant risk factor was identified in female patients. The incidence of advanced fibrosis increased significantly in patients with three or more positive criteria. Similarly, the incidence of at-risk MASH increased significantly in a stepwise manner with the number of positive cardiometabolic criteria. The diagnostic performance of the ELF test for advanced fibrosis exceeded that of the FIB-4 index and NFS for all factors except hypertension. Regardless of the number of positive cardiometabolic criteria, the ELF test demonstrated a superior diagnostic performance for advanced fibrosis. MASLD with hypertension in male patients or a higher number of positive cardiometabolic criteria constitutes a significant risk for advanced fibrosis or at-risk MASH. The ELF test is a valuable tool for diagnosing advanced fibrosis progression regardless of individual factors or the number of positive cardiometabolic criteria.

The 3-dimensional (3D) volume of a pancreatic fluid collection (PFC) has not been fully investigated in EUS-guided treatment. In 372 patients, we examined the 3D volume in relation to the clinical outcomes. In walled-off necrosis, 3D volume was associated with time to clinical success and in-hospital mortality with a multivariable subdistribution hazard ratio of 0.43 (95% CI, 0.28-0.66; Ptrend = .010) and a multivariable odds ratio of 30.9 (95% CI, 4.31-222; Ptrend = .004), respectively (for ≥1000 cm3 vs < 250 cm3). In pseudocysts, 3D volume was associated with in-hospital mortality (Ptrend = .014) with a multivariable odds ratio of 12.5 (95% CI, 0.81-193; for ≥500 cm3 vs < 100 cm3). The maximum diameter represented a comparable model goodness-of-fit. PFC volume was associated with the outcomes of EUS-guided interventions, and the maximum diameter may be a reasonable surrogate.

We report the case of a middle childhood boy diagnosed with myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), who was resistant to initial steroid pulse therapy and plasma exchange but achieved long-term remission following rituximab (RTX) treatment. Over a 4-year follow-up, the patient experienced no relapse, serum anti-MOG antibodies were undetectable and steroids were successfully tapered and discontinued. This case highlights the potential efficacy of RTX not only as a relapse-preventing agent but also as an acute-phase therapy in paediatric-onset MOGAD.

Both anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) have shown prophylactic effects on graft-versus-host disease (GVHD) in multiple phase III studies. We conducted a comparative study of for low dose ATG (thymoglobulin) versus PTCy for GVHD prophylaxis in peripheral blood stem cell transplantation (PBSCT). The ATG (n = 67) and PTCy (n = 40) groups included patients enrolled in multicenter phase II studies (JSCT-ATG15 and JSCT-PTCY19, respectively). The probability of GVHD-free and relapse-free survival at 2 years as the primary endpoint was not significantly different between these two groups (57.9% for ATG vs. 67.8% for PTCy, P = 0.49). Both neutrophil and platelet engraftments were both significantly shorter in the ATG group than in the PTCy group (neutrophils: median 13 days vs. 15 days, P = 0.007; platelets: median 20 days vs. 27 days, P = 0.007). The cumulative incidences of acute and chronic GVHD, relapse, non-relapse mortality, and off-immunosuppressant use were similar between these two groups. The probabilities of overall and progression-free survival were 83.4% and 70.0% in the ATG group and 76.5% and 75.2% in the PTCy group, respectively, with no significant differences. These data indicate that low dose ATG and PTCy are equivalent for GVHD prophylaxis for PBSCT.

BackgroundUnresectable malignant bile duct stricture (often caused by unresectable pancreatic cancer and cholangiocarcinoma) can be drained via insertion of self-expandable metal stents (SEMS) during endoscopic retrograde cholangiopancreatography (ERCP). Because recurrent biliary obstruction (RBO) and complications following stent insertion can delay chemotherapy and other treatments, a longer time to RBO (TRBO) is desirable. Although a longer TRBO has been reported among patients who undergo insertion with larger diameter SEMS, patients who undergo insertion with smaller diameter fully covered SEMS (FCSEMS) may have a lower incidence of complications than those with larger diameter FCSEMS. The aim of this study is to determine the TRBO and incidence of complications with 6-mm FCSEMS vs 10-mm FCSEMS in patients with unresectable malignant distal bile duct stricture.MethodsIn this multicenter, open-label, randomized controlled, non-inferiority trial (COSMIC UNISON), a target of 250 patients over 23 locations in Japan will receive either the 6-mm FCSEM or the standard 10-mm FCSEM during ERCP, with 125 patients in each group. The observation period will be 24 months, and patients will be enrolled from 15 March 2024 and assessed until the date of RBO or the study end (31 March 2029). The primary endpoint is TRBO, with RBO defined as the coexistence of abnormal liver enzyme values and dilation of the common bile duct and intrahepatic bile duct upstream of the stent. The secondary endpoints are the incidence and rates (at 3, 6, and 12 months) of non-RBO events, overall survival, cause of RBO, and symptomatic stent deviation. Adverse events from endoscopic procedures will be classified by the Lexicon Classification from the American Society of Endoscopy, and all other adverse events will be classified per the Japanese translation of the Common Terminology Criteria for Adverse Events version 5.0.DiscussionThe COSMIC UNISON study is anticipated to provide evidence regarding the efficacy and safety of 6-mm vs 10-mm FCSEMS to inform the use of 6-mm FCSEMS for the treatment of unresectable malignant distal bile duct stricture.Trial registrationJapan Registry of Clinical Trials identifier: jRCT1042230170. Prospectively registered on 15 March 2024.

Mapping biopsy (MB) can evaluate superficial ductal spread (SDS) through the histopathological diagnosis of cholangiocarcinoma, enabling the selection of an appropriate surgical procedure. This retrospective study evaluated the efficacy of MB using a novel sheath system in distal cholangiocarcinoma (dCCA) cases. A total of 199 cholangiocarcinoma cases underwent preoperative diagnosis. Among them, 40, 21, and 26 cases underwent direct, sheath, and peroral cholangioscopy (POCS) MB, respectively, for dCCA. Each group was compared regarding their technical success rate and the diagnostic accuracy for SDS. Although all cases achieved technical success, the median procedure time of POCS (48-min) tended to be longer than direct (33-min) and sheath MB (30-min) (p overall = .092). Diagnostic specificity and accuracy were significantly higher in the sheath group (95.2%, 95.2%) compared to the direct (71.0%, 70.0%) and POCS (60.9%, 57.7%) MB groups (p overall = .019 and .0094). Multivariate analysis revealed that the sheath MB group was an independent significant factor for the accurate margin diagnosis (OR 0.11; 95% CI: 0.01-0.86, p = .0358). The sheath MB method provided the most accurate histopathological diagnosis of SDS in dCCA. To obtain a larger tissue sample and avoid tumor cell contamination, sheath MB is worth performing to assess the accuracy of the preoperative SDS diagnosis.

We investigated whether miR143#12, a synthesized chemically modified miR-143-3p derivative, exerts therapeutic effects on acute myocardial infarction (AMI). Sprague–Dawley rats and Japanese white rabbits underwent 30 min of coronary occlusion followed by 2 weeks of reperfusion. The rat AMI model was intravenously administered with control miRNA (9 μg/kg), 3 μg/kg or 9 μg/kg of miR143#12 1 h after reperfusion, while the rabbit AMI model was intravenously administered with control miRNA (9 μg/kg) or 9 μg/kg of miR143#12. In the rat and rabbit AMI models, 9 μg/kg of miR143#12 significantly reduced infarct sizes and significantly improved cardiac function including LVEF and LVFS at 2 weeks. The tissue miR143 levels in infarct areas significantly decreased after AMI in both models. Electron microscopic study and immunohistochemistry suggested that miR143#12 suppressed autophagic cell death caused by AMI and induced neoangiogenesis in the infarct border. In cultured rat H9c2 cells, miR143#12 significantly inhibited H2O2-induced autophagic cell death by decreasing ROS levels and increased viable cell numbers more than the control by silencing COX-1, -2, and ATG7. Replacement treatment with miR143#12 in the infarct areas, where the expression levels of miR143 were significantly decreased, has a beneficial effect on AMI by silencing COX-1 and -2.

TO THE EDITOR: der(1;7)(q10;p10) is an unbalanced translocation recurrently found in a variety of myeloid neoplasms, where +1q and −7q are the common consequences [1] [2] [3] [4] [5] [6] . Although it represents one of the most frequent chromosomal abnormalities in myeloid neoplasms among Asian populations, the molecular characteristics of der(1;7) (q10;p10)(+) myeloid neoplasms have not been fully elucidated. In this retrospective study, we enrolled 3,385 myeloid neoplasm cases to identify a total of 148 cases with der(1;7)(q10;p10) on the basis of conventional cytogenetics and/or sequencing-based copy number analysis [7] and investigated their clinical features and mutational profiles in comparison with those cases having −7/ del(7q) (n = 376) and 1q trisomy (+1q) (n = 54) alone, using whole-exome sequencing (WES) and/or targeted-capture sequencing. The remaining 2,808 cases were collectively analyzed as "OTHER" cases (Supplementary Methods and Supplementary Table 1 ). Through these analyses, we demonstrated that der(1;7) (q10;p10)(+) myeloid neoplasms were characterized by unique clinical and mutational features and therefore, represented a distinct subset of myeloid neoplasms.