Although duodenal cancer is a rare malignancy, its detection has been increasing with the widespread use of upper gastrointestinal endoscopy and advances in diagnostic modalities, and interest in its diagnosis and treatment is growing. Four years after the publication of the first edition of the clinical practice guidelines for duodenal cancer (2021 edition), we have prepared a revised edition that reflects the new findings accumulated during this period. In the field of diagnosis and endoscopic therapy, we further clarified the indications for treatment of non-ampullary duodenal epithelial tumors and provided specific recommendations for biopsy indications. For endoscopic treatment, the indication criteria for endoscopic submucosal dissection (ESD) were stratified according to lesion size and institutional experience, and specific techniques for the prevention of adverse events were presented. In surgical treatment, a new clinical question on minimally invasive surgery was established, and the current status and challenges of laparoscopic and robot-assisted surgery were summarized. In chemotherapy, we emphasized the importance of personalized medicine based on gene panel testing and biomarkers, and incorporated the latest treatment strategies, including immune checkpoint inhibitors. This revised edition is intended to serve as a practical reference in daily clinical practice and to contribute to further improving outcomes for patients with duodenal cancer.
There remains an unmet need for reliable biomarkers associated with therapeutic response to immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC). We retrospectively examined protein levels in serum-derived extracellular vesicles (EVs) as candidate biomarkers associated with treatment response in patients with advanced HCC. A total of 122 patients with advanced HCC treated with atezolizumab plus bevacizumab (ATZ/BEV) were retrospectively selected. The discovery group comprised 12 patients, whose serum-derived EV samples underwent comprehensive proteomic profiling by quantitative data-independent acquisition mass spectrometry. The remaining 110 patients comprised the validation group, in whom selected EV proteins were quantified by parallel reaction monitoring analysis. B cell receptor-associated protein 31 (BAP31) was identified as an exploratory biomarker associated with early treatment response. Receiver operating characteristic analysis of pretreatment log2 BAP31 levels for distinguishing non-progressive disease from progressive disease at the initial response in the validation group yielded an area under the curve of 0.719 and an optimal cut-off of −14.582. This threshold stratified overall survival (OS) in the entire cohort (44.8 vs 25.3 months for low- vs high-level groups, P = 0.039). Multivariable analysis showed that EV BAP31 levels were independently associated with OS (HR 1.78, P = 0.044); however, this association was attenuated and was no longer statistically significant after propensity score adjustment. No significant association with progression-free survival was observed. Pretreatment BAP31 levels in serum-derived EVs may represent an exploratory biomarker potentially associated with early treatment response and prognosis in patients with advanced HCC receiving ATZ/BEV. Further validation is warranted.
Upadacitinib is an oral Janus kinase inhibitor approved for the treatment of moderate-to-severe Crohn’s disease (CD). This post hoc analysis reports the efficacy and safety of upadacitinib for CD in patients in East Asia enrolled in the phase 3 clinical trials. In two induction studies (U-EXCEL [NCT03345849], U-EXCEED [NCT03345836]), adults with moderately to severely active CD were randomized 2:1 to once-daily upadacitinib 45 mg or placebo for 12 weeks. In the 52-week U-ENDURE maintenance study (NCT03345823), patients with clinical response to upadacitinib induction therapy were rerandomized 1:1:1 to once-daily upadacitinib 15 mg, upadacitinib 30 mg, or placebo. Data from patients in East Asia were evaluated. In the induction studies, achievement of clinical and endoscopic outcomes occurred at higher rates with upadacitinib vs placebo at week 12 among the 204 patients in East Asia. Clinical remission per CD Activity Index (CDAI) and endoscopic response were achieved by 50.7
This subgroup analysis assessed the efficacy and safety of semaglutide in the Japanese subgroup versus the overall trial population of ESSENCE (part 1) and evaluated the impact of baseline characteristics. ESSENCE is an ongoing, phase 3, multicenter, randomized, double-blind, placebo-controlled trial that includes 1197 participants with biopsy-defined metabolic dysfunction-associated steatohepatitis and liver fibrosis stage 2 or 3 randomized 2:1 to receive once-weekly subcutaneous semaglutide 2.4 mg or placebo for 240 weeks (NCT04822181). The results of an interim analysis for efficacy conducted at week 72 involving the first 800 randomized participants are reported here (part 1). One hundred and sixteen of the first 800 randomized participants included in the interim analysis for efficacy were Japanese and received semaglutide (n = 78) or placebo (n = 38). Compared with the overall population, Japanese participants were older and had a lower body mass index. Resolution of steatohepatitis and no worsening of liver fibrosis was achieved by 63.1 and 36.8 https://clinicaltrials.gov/study/NCT04822181
Dihydroorotate dehydrogenase (DHODH) is a critical enzyme involved in pyrimidine biosynthesis anda key suppressor of ferroptosis. This enzyme is commonly overexpressed in colorectal cancer (CRC), and itsupregulation facilitates the malignant progression of CRC tumors. This study explored the endogenous degradation mechanism of DHODH in CRC.Mechanistically, DHODH is eliminated through KCTD10-mediated selective autophagy. As a substrate-specifi cadaptor for the CUL3–RBX1 E3 ubiquitin ligase complex, KCTD10 induces K63-linked ubiquitination of DHODH. Theautophagy receptor SQSTM1/p62 subsequently recognizes the ubiquitinated DHODH and mediates its lysosomal-dependent degradation. Based on this molecular regulatory axis, we constructed DH-AUTAC, a novel autophagy-targeting chimera designed to specifi cally recruit endogenous DHODH to the autophagy system for targeteddegradation. In vitro cell experiments and in vivo animal model assays consistently verifi ed the functional effi cacy ofDH-AUTAC. DH-AUTAC treatment effi ciently degraded DHODH protein, triggered robust ferroptosis, and therebymarkedly suppressed the proliferation of CRC cells and the growth of subcutaneous tumors. Pharmacologicalintervention experiments further showed that inhibiting ferroptosis completely abrogated the antitumor eff ects ofDH-AUTAC, whereas combined treatment with the autophagy and ferroptosis activator ATA194 signifi cantlyaugmented its therapeutic effi cacy. Moreover, animal model observations confi rmed that DH-AUTAC possessed agood in vivo safety profi le with no obvious adverse eff ects. This study identifi es a previously unreported molecular regulatory axis governing DHODH degradationin CRC. It also establishes an innovative AUTAC-based targeted protein degradation strategy to selectively activateferroptosis. Collectively, these fi ndings highlight the promising translational potential of targeted ferroptosisinduction as a novel therapeutic approach for clinical CRC treatment.
Secondary sclerosing cholangitis (SSC) has emerged as a severe complication in critically ill COVID-19 patients. This study outlines the clinical course, prognostic markers, and liver transplantation (LT) outcomes of COVID-19-associated SSC. This retrospective multicenter study included 36 COVID-19-associated SSC patients from three Swiss tertiary centers. Clinical, laboratory, imaging, and histopathological data were analyzed with respect to outcomes defined as survival without LT versus LT or death. Post-transplant outcomes were assessed. All 36 critically ill patients developed acute respiratory distress syndrome. SSC was diagnosed post-ICU in 80.6
While animal studies suggest that intestinal inflammation can remodel glymphatic function, glymphatic alterations in Crohn’s disease (CD) remain poorly understood. This study aims to characterize glymphatic activity in CD patients and explore its associations with systemic inflammation and neuropsychiatric symptoms. In this prospective study, we enrolled 89 patients with CD and 48 age- and sex-matched healthy controls (HCs). Glymphatic function was assessed using advanced MRI metrics including free water in white matter (FW-WM), diffusion tensor image analysis along the perivascular space (DTI-ALPS), and global coupling of blood-oxygen-level-dependent with cerebrospinal fluid signals (gBOLD–CSF coupling). General linear models were applied to compare group differences, and partial correlation analyses were conducted to examine the associations of these metrics with inflammatory levels and neuropsychological scores. Compared with HCs, patients with CD showed significantly higher FW-WM, lower DTI-ALPS index, and weaker gBOLD–CSF coupling. Within the CD group, elevated FW-WM was associated with higher CRP levels (r = 0.308, p = 0.021), SAS scores (r = 0.355, p = 0.018), and SDS scores (r = 0.290, p = 0.029), whereas a lower DTI-ALPS index correlated with higher ESR levels (r = − 0.271, p = 0.042) and MFI scores (r = − 0.312, p = 0.021). Furthermore, weaker gBOLD–CSF coupling was significantly associated with higher PSQI scores (r = 0.329, p = 0.021). This study provides noninvasive MRI evidence of glymphatic alterations in patients with CD that are associated with systemic inflammation and neuropsychiatric symptoms.
The obesity paradox, in which obese patients experience improved outcomes following immune checkpoint inhibitor (ICI) therapy, has been reported in several malignancies. However, its clinical relevance in advanced biliary tract cancer (BTC) remains unclear. We retrospectively analyzed patients with advanced BTC who received first-line gemcitabine and cisplatin with ICI (ICI cohort; n = 68) or without ICI (non-ICI cohort; n = 179). Obesity was evaluated using body mass index (BMI) and computed tomography (CT)–based adipose tissue parameters, including total adipose tissue index (TATI), visceral adipose tissue index, and subcutaneous adipose tissue index (SATI). Skeletal muscle mass was quantified on CT images. Progression-free survival (PFS) and overall survival (OS) were assessed using Cox proportional hazards models. High TATI was associated with a lower prevalence of sarcopenia in both cohorts. In the ICI cohort, high SATI was independently associated with prolonged PFS (hazard ratio [HR], 0.45; P = 0.004) and OS (HR, 0.27; P = 0.001), whereas BMI and sarcopenia were not. High SATI showed a trend toward improved survival in both sarcopenic (P = 0.16) and non-sarcopenic subgroups (P < 0.001). In contrast, no significant associations between adipose tissue parameters and survival outcomes were observed in the non-ICI cohort. Higher subcutaneous adiposity was independently associated with improved survival outcomes in patients with advanced BTC receiving ICI therapy, but not in those treated without ICI, suggesting that it may serve as a clinically relevant prognostic factor in this setting.
Primary biliary cholangitis (PBC) is a chronic, progressive, cholestatic liver disease caused by autoimmune reactions. A previous international meta-analysis of a genome-wide association study (GWAS) reported a robust association of the human chr.11q23.3 locus including C-X-C motif chemokine receptor 5 (CXCR5) with susceptibility to PBC. However, the molecular mechanism by which CXCR5 confers disease susceptibility in PBC remains unclear. Cutting-edge post-GWAS analyses were conducted using in silico and in vitro functional approaches, including multi-omics analysis, machine-learning-based transcription factor prediction, and prime editor as a genome-editing technology. Expression data for CXCR5 and correlated genes were obtained by RNA-seq and immunohistochemistry analyses. Among the variants around CXCR5, rs57494551 was identified as a disease-causal variant for PBC. rs57494551 regulates endogenous CXCR5 expression in B-cells through binding to the transcription repressor TEA domain transcription factor 3 (TEAD3). CXCR5 expression was correlated with disease activity, as identified by hierarchical clustering of mRNA expression patterns, and portal inflammation markers, such as serum IgM, Aspartate Transferase (AST), and Mac-2 binding protein glycosylation isomer (M2BPGi). The number of IgM+ CXCR5+ B-cells was increased in the portal area of PBC with high-disease activity. Immune dysregulation and portal inflammation are affected by increased expression of CXCR5 on IgM+ B-cells in PBC patients who have the risk allele of rs57494551, indicating that CXCR5 is a potential therapeutic target for PBC.
Since Barrett’s esophagus (BE) is an established precancerous condition for esophageal adenocarcinoma, understanding the natural history of BE is crucial for effective endoscopic surveillance. We aimed to elucidate temporal changes in BE status over a 10-year period using a database derived from repeated endoscopies. A total of 9,741 subjects who underwent screening esophagogastroduodenoscopy in 2014 and at least one follow-up examination by December 2025 were included. Transitions in BE status between the index and final examinations were classified as progression, regression, or no change based on differences in BE length. Logistic regression analyses were performed to investigate factors associated with BE progression. The median follow-up period from the index to final examination was 8.8 years. Overall, BE ≥ 1 cm or BE ≥ 2 cm was newly identified at the final examination in 4.87
S1P receptor modulators are emerging oral therapies for moderate-to-severe ulcerative colitis (UC); however, a comprehensive synthesis incorporating the largest number of RCTs to date, alongside Trial Sequential Analysis (TSA) and GRADE-based certainty assessment, remains lacking. We aim to evaluate the efficacy and safety of S1P receptor modulators in moderate-to-severe UC and assess the conclusiveness and certainty of the evidence. PubMed, Cochrane Library, Europe PMC, and Google Scholar were searched from inception through February 28, 2026. Eligible studies were RCTs comparing any S1P receptor modulator with placebo in adults (≥ 18 years) with UC. Pooled risk ratios (RRs) with 95
Early intravenous crystalloid resuscitation is central to acute pancreatitis (AP) management; however, whether normal saline (NS) or balanced Ringer's solutions (RS) are superior for reducing mortality remains unsettled. Using the Japanese Diagnosis Procedure Combination database (July 2010–March 2022), we identified adults admitted to general medical wards with AP who had a hospital stay longer than 3 days and received sufficient fluid resuscitation within three days of admission. Patients were classified by predominant crystalloid exposure during the first three days (NS vs. RS). Propensity score matching was used to balance measured confounders and compare in-hospital mortality and total hospitalization costs between the two groups. Among 43,247 eligible patients, 1,652 (4.0
Lean metabolic dysfunction-associated steatotic liver disease (MASLD) is often treated as a single entity despite substantial heterogeneity. We assessed whether body mass index (BMI) strata, cardio-metabolic risk factor (CMRF) phenotype, and CMRF burden stratify the risk of clinical outcomes. Using the TriNetX Global Network, we identified adults with MASLD from 2005 to 2024. Lean MASLD was defined by BMI less than 25 kg/m2 and stratified into underweight and normal-weight groups. Underweight and normal-weight MASLD were compared after 1:1 propensity score matching. Within normal-weight MASLD, phenotypes were defined as hypertension-only, type 2 diabetes (T2D)-only, dyslipidemia-only, and multi-factor burden, categorized as 2 CMRF or 3 CMRF. Outcomes were major adverse liver outcomes (MALO), major adverse cardiovascular events (MACE), extrahepatic cancer, and all-cause mortality. We identified 40,456 patients with lean MASLD, including 2121 underweight and 38,335 normal weight. After matching, 2115 patients remained in each group. Underweight MASLD had higher risks of all-cause mortality (HR 2.03; 95
The proportion of elderly patients with pancreatic ductal adenocarcinoma (PDAC) is increasing. This study aimed to investigate whether neoadjuvant treatment (NAT) and adjuvant therapy (AT) are effective in PDAC patients over 80 years of age. Patients over 80 years of age who underwent pancreatectomy for PDAC in 2012–2020 and were recorded in the Japan Society for Gastroenterological Surgery and Japan Pancreas Society databases were included. Propensity score matching (PSM) analysis was performed to determine whether NAT and AT contribute to survival. In patients treated from 2017 onward, resectability status was incorporated into the PSM model. Of the 3438 patients in the study population, the primary resectability-adjusted PSM analysis of NAT among patients treated from 2017 onward compared 274 matched pairs. The MST was 30.5 (95
BACKGROUND:The main risk factor for gastric carcinogenesis is infection with Helicobacter pylori (H. pylori) that injects the bacterial oncoprotein cytotoxin-associated gene A (CagA). Aberrant cartilage oligomeric protein (COMP) expression is implicated in tumorigenesis and cancer development. However, the critical mediators participating in regulation of COMP and how COMP contributes to the progression of gastric cancer (GC) have not been elucidated. METHODS:To evaluate H. pylori-mediated transcriptional changes, RNA-seq was performed. The clinical relevance and prognostic potential of COMP in GC were examined via Western blot and IHC assays. Functional roles of COMP were further probed using in vitro cellular models and in vivo animal studies. Putative mechanistic networks were elucidated through chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (Co-IP) experiments. RESULTS:In GC cell lines and mouse models, both H. pylori colonization and its virulence factor CagA upregulated COMP at transcriptional and translational levels. COMP expression is markedly elevated in H. pylori-related GC and is associated with poor prognosis. The inhibition of COMP curtailed the pro-proliferative, metastatic, and epithelial-mesenchymal transition (EMT) capacities of the CagA in GC cells. H. pylori infection enhances COMP expression via the activation of KLF5. COMP binding to NOTCH2 and JAG1 facilitates the interaction between NOTCH2 and JAG1, hence activating downstream SMAD3, which promotes EMT in GC. CONCLUSIONS:H. pylori infection depends on CagA/KLF5 to induce COMP expression and highlights the COMP/NOTCH2/SMAD3/EMT axis in modulating GC progression, which may reveal actionable targets for GC therapy.
