Journal of Gastroenterology最新文献

Background: Carotegrast methyl is approved for treating patients with moderately active ulcerative colitis with inadequate response to 5-aminosalicylic acid agents. However, real-world evidence to guide optimal use is limited. This retrospective study aimed to characterise suitable patient profiles, identify biomarkers predictive of carotegrast methyl efficacy, and determine the appropriate timing for treatment evaluation.

Methods: We analysed data from 186 patients enrolled in a phase 3 trial of carotegrast methyl (96 carotegrast methyl, 90 placebo). We assessed biomarkers (leucine-rich α-2 glycoprotein, C-reactive protein, faecal calprotectin, and anti-integrin αvβ6 antibody titres) alongside clinical outcomes and assessed symptom diaries and maintenance therapies.

Results: Low disease activity at baseline (partial Mayo score ≤ 5) was associated with higher remission rates (56.1 vs. 33.3%). Anti-integrin αvβ6 antibody titres of < 44.6 U/mL at baseline predicted higher clinical remission rates (49.1 vs. 26.8%). Symptom improvement was detectable from week 2. Faecal calprotectin correlated with the endoscopic subscore at the end of treatment (ρ = 0.566); a faecal calprotectin level of < 387.5 µg/g predicted Mayo endoscopic subscore 0/1. Most patients maintained remission with oral 5-aminosalicylic acid alone; the 1-year maintenance rate was 56.5%.

Conclusions: Carotegrast methyl appears most effective in patients with moderately active ulcerative colitis with low disease activity, with week 2 and beyond as an appropriate time point for assessing efficacy. Anti-integrin αvβ6 antibody titre shows promise in predicting response to carotegrast methyl. Faecal calprotectin may serve as a non-invasive surrogate for evaluating endoscopic healing.

Background: Gastric cancer (GC) is a highly aggressive malignancy with limited therapeutic options and poor clinical outcomes. Aberrant regulation of the ubiquitin-proteasome system contributes to tumorigenesis by disrupting protein homeostasis and signal transduction. STAMBPL1, a JAMM family deubiquitinase (DUB) implicated in several cancers, remains poorly characterized in GC, and its mechanistic relevance to disease progression warrants investigation.

Methods: Transcriptomic analyses and clinical specimen profiling were conducted to assess STAMBPL1 expression and prognostic significance in GC. Functional effects were evaluated using in vitro assays, patient-derived organoids, and multiple mouse models. Mechanistic studies included mass spectrometry, co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis, and pharmacologic blockade of downstream signaling pathways.

Results: STAMBPL1 was significantly overexpressed in GC tissues and strongly associated with advanced T stage, distant metastasis, higher clinical stage, and unfavorable prognosis. Functionally, STAMBPL1 promotes GC cell proliferation, migration, invasion, and organoid growth in vitro, and drives subcutaneous tumor growth, peritoneal dissemination, and lung metastasis in vivo. Mechanistically, STAMBPL1 directly binds IQ-domain GTPase-activating protein 1 (IQGAP1), specifically catalyzing the removal of K48- and K63-linked ubiquitin chains at the 1368 lysine residue, thereby stabilizing IQGAP1 protein levels. Stabilized IQGAP1 subsequently activates the JAK2/STAT3 signaling axis, potentiating GC malignant progression. Notably, pharmacological blockade of JAK2 by AG490 markedly curtailed tumor progression and abrogated the oncogenic effects of STAMBPL1/IQGAP1, underscoring the functional dependency of this axis.

Conclusions: These findings identify STAMBPL1 as a novel oncogenic DUB that promotes GC progression through IQGAP1 stabilization and subsequent activation of JAK2/STAT3 signaling, providing a potential therapeutic target for GC.

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are bona fide cystic precursor lesions to pancreatic ductal adenocarcinoma (PDAC), which is the cancer type with the most dismal prognosis. Since IPMNs are detectable by imaging, they offer a rare window of opportunity for early intervention for PDAC development. Despite their clinical visibility, the molecular pathogenesis of IPMNs remained incompletely understood, and no effective non-surgical therapeutic strategies have been established to date. In the past few decades, however, substantial progress has been made in elucidating their molecular pathology. Next-generation sequencing technologies demonstrated the comprehensive genetic mutation profile of IPMNs in the early 2010s. Elucidation of these mutation profiles enabled the establishment of genetically engineered mouse models, successfully recapitulating the natural development of human IPMNs and their progression to invasive cancer. Rapid evolution of "omics" technologies in recent years has facilitated the application of mass spectrometry, single-cell sequencing and spatial transcriptomics to IPMNs, significantly advancing our understanding of their pathophysiology. These techniques elucidated the changes in transcriptome, proteome, metabolome, microbiome, and tumor microenvironment associated with IPMN development and progression. This review summarizes current insights into the molecular and cellular landscapes of IPMN tumorigenesis, with particular emphasis on the mechanisms driving malignant progression.

Background: Although impaired intestinal barrier function is implicated in type 2 diabetes (T2D), its direct in vivo assessment in humans remains challenging, limiting our understanding of the underlying mechanisms. We utilized a novel endoscopic real-time, in situ impedance measurement technique to investigate how hyperglycemia and the intestinal microbiota contribute to intestinal barrier dysfunction in T2D.

Methods: We validated this impedance-based approach against ex vivo transepithelial electrical resistance (TEER) (r = 0.64, p = 0.011) and applied it to 137 patients undergoing colonoscopy. A mechanistic study (22 T2D, 19 controls) analyzed mucosal microbiota, short-chain fatty acid (SCFA) levels, and tight junction protein gene expression. In vitro assays with Caco-2 monolayers evaluated Bacteroides vulgatus (B. vulgatus) supernatant and high-glucose exposure effects on TEER.

Results: Patients with T2D had significantly lower ileal impedance (20.9 Ω·cm²) compared to controls (24.2 Ω·cm²; p < 0.001). Lower Bacteroides abundance correlated with decreased SCFA biosynthesis gene expression and ZO-1 levels. B. vulgatus supernatant counteracted lipopolysaccharide-induced barrier disruption. High-glucose exposure reduced transepithelial electrical resistance (p < 0.05), indicating a direct detrimental effect. Impedance negatively correlated with HbA1c (r = - 0.49, p < 0.001), and metformin use was associated with preserved barrier function.

Conclusions: To our knowledge, this study provides the first direct, in situ evidence that intestinal barrier function is impaired in T2D, a condition associated with concurrent microbial and metabolic alterations. Our findings establish intestinal barrier dysfunction as a key pathophysiological feature of T2D, suggesting that interventions aimed at the intestinal barrier function may represent a novel therapeutic strategy.

Background: Mismatch repair (MMR) testing is recommended for all colorectal cancer (CRC) patients, but this assay necessitates the involvement of specialized institutions and is time-consuming. This study aims to develop a deep learning model for MMR prediction using macroscopic images to provide a rapid and cost-free screening tool.

Methods: This diagnostic study enrolled 809 CRC patients who underwent surgical resection without neoadjuvant therapy at Peking University Third Hospital (from January 2020 to July 2025). Macroscopic images of surgical specimens were captured immediately after resection. MMR status was confirmed by postoperative immunohistochemical staining for MMR proteins (MLH1, MSH2, MSH6, and PMS2). Deep learning models were developed by a two-step approach: automated lesion segmentation using DeepLabV3 + , followed by MMR classification using vision transformer (ViT). MMR prediction performance was mainly evaluated utilizing area under the curve (AUC). Gradient-weighted Class Activation Mapping (Grad-CAM) appraisal and principal component analysis (PCA) were performed to assess the explainability of the model.

Results: The proposed model achieved an average AUC of 0.896 (95% CI, 0.763-0.959) on internal test and 0.860 (95% CI, 0.644-0.921) on independent test for MMR prediction. High NPVs of 0.987 (95% CI, 0.928-0.999) and 0.978 (95% CI, 0.925-0.994) were observed in internal and independent testing, respectively, using a threshold of 0.323. Grad-CAM analysis and PCA demonstrated that the deep-learning model was of explainability.

Conclusions: The new deep-learning model accurately identified MMR status using macroscopic specimen images and showed potential for MMR screening among CRC patients, particularly in a rapid-response scenario.

Background: Tyrosine kinase inhibitors (TKIs) targeting KIT and PDGFRA mutations are the mainstay of treatment for gastrointestinal stromal tumors (GISTs). Comprehensive genomic profiling (CGP) has recently been incorporated into routine practice for various solid tumors, facilitating personalized treatment strategies. We elucidated the current status and clinical significance of CGP in patients with advanced GISTs.

Methods: In this multicenter retrospective cohort study, we analyzed 36 patients with unresectable or recurrent GISTs who underwent CGP testing between November 2019 and February 2025. Specimen details, genomic alterations, expert panel assessments, and treatment implementations were collected. Turnaround time and overall survival (OS) were evaluated.

Results: Among the patients, 75% underwent CGP during or post-third-line treatment. Actionable and druggable alterations were identified in 97.2% and 52.8%, respectively. Expert panel-recommended treatment was proposed for 12 patients (33.3%); however, only one received CGP-guided therapy. The median turnaround time and OS from CGP were 63 days (range, 41-100) and 19.9 months (range, 0.8-68.0), respectively. Most patients were microsatellite-stable with low tumor mutational burden. Among non-KIT genes, CDKN2A and CDKN2B alterations were the most frequently identified. Furthermore, patients harboring these alterations showed poorer OS post-recurrence (CDKN2A: HR 3.09, 95% CI 1.17-8.18, p = 0.017; CDKN2B: HR 2.55, 95% CI 0.86-8.18, p = 0.081).

Conclusions: CGP revealed actionable alterations in most patients with advanced GISTs; however, its impact on treatment decisions remains limited under current practice. Early CGP implementation may facilitate access to matched therapies or clinical trials, enabling prognostic stratification in patients with advanced GISTs.

Objectives: The oncologic outcomes of pedunculated-type T1 colorectal cancer (CRC) remain unknown. We determined the risk factors for lymph node metastasis (LNM) and recurrence and evaluated the survival according to the treatment method.

Methods: In this multicenter retrospective study involving 4673 patients with T1 CRC, we analyzed 444 patients with pedunculated-type T1 CRC treated between 2009 and 2016. Treatment included local resection (LR) alone (n = 169), surgery with lymph node (LN) dissection alone (n = 83), and LR followed by additional surgery with LN dissection (n = 192). Factors associated with LNM and recurrence, relapse-free survival (RFS) and overall survival (OS) by treatment were analyzed. The median follow-up period was 64 months.

Results: LNM and recurrence were observed in 25 (5.6%) and 13 (2.9%) cases, respectively. Submucosal invasion depth ≥ 1000 μm (p = 0.0036), positive lymphovascular invasion (p = 0.0007), and budding grade 2/3 (p = 0.0171) were risk factors for LNM. The risk factor for recurrence was tumor size ≥ 20 mm (HR 5.488; 95% CI 1.199-25.12; p = 0.028) in a multivariate analysis. The 5-year RFS rates were 92.5% for LR alone, 94.3% for LR+ surgery, and 90.5% for surgery alone; the 5-year OS rates were 93.1%, 97.1%, and 94.0%, respectively, with no significant difference.

Conclusion: Even in the specific subset of pedunculated-type T1 CRC, submucosal invasion depth ≥ 1000 μm and budding grade 2/3 are risk factors for LNM. Tumors ≥ 20 mm require careful surveillance for recurrence risk. High RFS and OS rates in LR-alone and LR+ surgery groups suggest LR is appropriate for pedunculated lesions.

Background: Owing to the rarity of metastatic tumors in the small bowel, their clinicopathological features, and prognostic factors remain poorly understood. This study aimed to clarify the clinicopathological features and factors associated with the prognosis of patients with small bowel metastasis from other organs in Japan.

Methods: We retrospectively examined 253 patients who were histopathologically diagnosed with small bowel metastases between January 2008 and December 2017 at multiple institutions in Japan. We identified the clinicopathological features of the condition and determined the factors associated with the prognosis of these patients.

Results: Obstructive symptoms were the most frequent clinical presentations (39% abdominal pain and 18% vomiting), while gastrointestinal bleeding was observed in 27% of patients. The diagnostic modalities included enteroscopy (33%), balloon-assisted enteroscopy (30%), and capsule endoscopy (13%). The most common primary tumor was lung cancer (38%), followed by colorectal cancer (18%), gastric cancer (9%), and malignant melanoma (6%). Surgical intervention, including tumor resection or bypass surgery, was performed in 79% of patients. The cumulative survival rates of patients at 12, 24, and 60 months were 49%, 36%, and 22%, respectively. Multivariate analysis identified surgery as a significant factor for improving overall survival (HR = 0.56, 95% CI 0.35-0.89, p = 0.01).

Conclusions: The lung cancer is the most frequent primary tumor of metastatic tumors in the small bowel. Surgical intervention was associated with improved survival outcomes.

Objectives: Sedation is increasingly essential for gastrointestinal endoscopy. Remimazolam, an ultra-short-acting benzodiazepine, has a shorter pharmacokinetic half-life than midazolam. The aim of this study was to determine whether remimazolam provides superior procedural sedation in Japanese patients.

Methods: The cohort of this prospective, multicenter, randomized, single-blind controlled trial comprised adults (18-80 years) scheduled for sedated upper gastrointestinal endoscopy. Participants were randomized to remimazolam and midazolam groups. The primary outcome was the proportion of ambulatory patients 5 min after endoscopy. Secondary outcomes were successful pre-procedure sedation (Modified Observer's Assessment of Alertness/Sedation ≤ 4), dose of sedative to achieve sedation, time to ambulation, and adverse events.

Results: From October 2024 to January 2025, 40 patients were enrolled. After excluding two outliers 38 were analyzed (remimazolam, n = 20; midazolam, n = 18). Ambulation at 5 min occurred in 85.0% (17/20) of the remimazolam versus 0.0% (0/18) of the midazolam group (p < 0.0001). Mean time from procedure end to walking was 4.25 min (range 0.0-10.0) for remimazolam and 35.56 min (10.0-60.0) for midazolam (p < 0.0001). Pre-procedure sedation was successful (MOAA/S ≤ 4) in 100% of both groups. Mean doses to achieve sedation were 4.30 mg (3.0-7.0) for remimazolam and 3.11 mg (2.0-5.0) for midazolam (p = 0.003). Hypoxemia occurred in 5.0% of the remimazolam and 33.3% of the midazolam group (p = 0.038).

Conclusions: In upper gastrointestinal endoscopy, remimazolam achieved markedly faster recovery and a lower incidence of hypoxemia than midazolam. Rates of achieving target sedation were equivalent. These findings indicate remimazolam is an effective and potentially safer sedative option for Japanese patients undergoing endoscopy.

Trial registration: This research was registered with the Japan Registry of Clinical Trials (trial number jRCTs071240062) on September 26, 2024.