Journal of Gastroenterology最新文献

Background: We sought to evaluate the predictive value of protease-3 (PR3)-anti-neutrophil cytoplasmic antibodies (ANCAs) and myeloperoxidase (MPO)-ANCA for primary nonresponse (PNR) to biologic agents in patients with ulcerative colitis (UC).

Methods: A multicenter, prospective cohort study was conducted. Patients with UC who initiated biologic agents (anti-TNF, anti-integrin, or anti-IL12/23 agents) as their first-line therapy were enrolled. PNR was defined as failure to achieve a partial Mayo Score improvement of at least 2 points by weeks 14-16 or necessitating treatment modification. Logistic regression identified PNR predictors.

Results: Among 95 biologic-naïve UC patients, 38 received anti-TNF, 39 received anti-integrin, and 18 received anti-IL12/23 agents. PR3-ANCA positivity was observed in 47.4% of anti-TNF recipients. The PNR rate among PR3-ANCA-positive patients receiving anti-TNF therapy was 66.7%, significantly higher than in PR3-ANCA-negative patients (25.0%, P = 0.02). Multivariate logistic regression confirmed PR3-ANCA as an independent risk factor for PNR to anti-TNF therapy (OR 5.61; 95% CI 1.37-26.82; P = 0.02). By contrast, PR3-ANCA did not predict PNR to anti-integrin therapy, but the platelet-to-lymphocyte ratio (PLR) and the systemic immune-inflammatory index (SII) were identified as significant predictors. Only one of 95 patients tested positive for MPO-ANCA, precluding statistical analysis for its association with PNR.

Conclusion: In patients with UC, PR3-ANCA is a significant predictor of PNR to anti-TNF therapy, but not to anti-integrin therapy. PLR and SII may predict PNR to anti-integrin therapy. PR3-ANCA could aid biologic selection, optimizing personalized UC treatment and healthcare resource utilization.

Background: The long-term local control and effect of photodynamic therapy (PDT) using talaporfin sodium and a diode laser (talaporfin PDT) on overall survival (OS) for local failure after chemoradiotherapy (CRT) for esophageal cancer are unknown. Here, we present a 5-year survival analysis for talaporfin PDT.

Methods: This was a prospective follow-up analysis of an open-label, multicenter, phase 2 study of local failure after CRT or radiotherapy in patients who received talaporfin PDT. The primary endpoint was the overall OS. The secondary endpoints were progression-free survival (PFS), local progression-free survival (L-PFS) with local progression or recurrence and death as events, and local time to progression (L-TTP) with only local progression or recurrence as events.

Results: Between November 2012 and December 2013, 26 patients with oesophageal squamous cell carcinoma underwent talaporfin PDT. The baseline T stages were cT1 in 14 patients, cT2 in 6 patients, and cT3 in 6 patients. Pre-PDT T stages were cT1b for 19 and cT2 for 7 patients, and no lymph nodes or distant metastases were detected. At a median 6.8-year follow-up, the median OS and 5-year OS rates were 4.2 years (95% confidence interval [CI]: 1.6-7.3) and 40.6% (95% CI: 21.7-58.7), respectively. The median PFS and L-PFS were 1.1 and 2.1 years, respectively. The 5-year local progression-free rate was 84.9%. No treatment-related deaths occurred.

Conclusion: Talaporfin PDT for patients with oesophageal cancer with local failure after CRT can achieve long-term local complete response and long-term survival as a minimally invasive salvage treatment.

Trial registration number: UMIN000009184.

Background: Pancreaticobiliary maljunction (PBM) contributes to epithelial hyperplasia and, ultimately, the development of gallbladder cancer (GBC). Despite its clinical significance, the molecular and cellular mechanisms driving carcinogenesis in GBC with PBM remain poorly elucidated. This study investigated the oncogenic mechanisms, biomarkers, and performance associated with Erb-b2 receptor tyrosine kinase 2 (ERBB2)-targeted therapies in GBC with PBM.

Methods: Overall, 127 surgically treated patients were stratified as follows: Group A, normal gallbladder; Group B, PBM; Group C, GBC without PBM; and Group D, GBC with PBM. We performed whole-exome sequencing (WES) for Group D and human epidermal growth factor receptor 2 immunohistochemistry (HercepTest) for the entire cohort. Fluorescence in situ hybridization (FISH) was used to clarify human epidermal growth factor receptor 2 (HER2) expression in cases with equivocal HercepTest results.

Results: ERBB2 amplification was detected in 50% of Group D patients. The proportion of HER2 protein expression scores ≥ 2 + was highest in Group D compared with that in the other groups (50.0% vs. 0% in Groups A and B and 15.6% in Group C) (P = 0.006, chi-squared test). Finally, 37.5% and 13.3% of cases in Groups D and C, respectively, showed HER2 overexpression (P = 0.037, chi-squared test).

Conclusions: This is the first evaluation of HER2/ERBB2 expression in GBC with PBM based on WES, HercepTest, and FISH. The significant increase in ERBB2 expression, driven by the synergistic interplay between GBC and PBM, underscores a critical molecular interaction that may inform the development of targeted therapeutic strategies.

The clinical landscape of chronic liver disease has changed with effective antiviral therapies, enabling the eradication of hepatitis C virus and the durable suppression of hepatitis B virus replication. Despite these advances, patients remain at risk for hepatocellular carcinoma (HCC) and other liver-related complications, but the growing burden of metabolic dysfunction-associated steatotic liver disease (MASLD) has created new challenges for clinical practice. These trends emphasize the need for reliable, noninvasive biomarkers that can stratify risk and guide long-term management across diverse etiologies. Growth differentiation factor 15 (GDF15), a stress-inducible cytokine, has attracted increasing interest as a promising biomarker. Its expression is induced by metabolic, oxidative, and inflammatory stress, and circulating levels increase with disease progression. Elevated serum GDF15 is consistently associated with fibrosis severity, HCC risk, hepatic decompensation, and mortality. Importantly, GDF15 is not merely a surrogate of fibrosis; rather, it integrates hepatocellular and stromal stress pathways and captures residual risk beyond fibrosis stage, liver function scores, and conventional biomarkers. In addition to its prognostic association, GDF15 has diverse biological effects. It may act as a protective response by limiting inflammation and cellular injury; yet, in other contexts, it contributes to fibrogenesis, tumor progression, immunosuppression, and cachexia. These dual roles highlight both the potential and the complexity of targeting GDF15 in therapeutic strategies. Collectively, the results of the current study indicate that GDF15 represents a promising biomarker in chronic hepatic diseases and is clinically independent of hepatic fibrosis. Further work is needed to clarify the underlying mechanisms, validate the prognostic utility, and determine whether GDF15 can be developed as a therapeutic target within precision medicine approaches.

Background and aims: The potential for recompensation and its defining criteria in patients with decompensated cirrhosis due to primary biliary cholangitis (PBC) remain poorly defined. Therefore, our study aimed to explore the criteria for etiological suppression and provide preliminary insights into PBC recompensation.

Methods: In this retrospective-prospective study, we enrolled hospitalized patients with PBC cirrhosis from January 2014 to June 2023. Recompensation was defined according to the Baveno VII criteria. In addition, expanded recompensation criteria were evaluated for patients on low-dose diuretics and/or lactulose/rifaximin with resolution of decompensation and stable improvement of liver function. We explored whether the biochemical responses to UDCA could serve as surrogates for etiological suppression.

Results: We enrolled 240 patients with PBC cirrhosis (122 compensated and 118 decompensated). With a median follow-up of 50.0 (31.0, 72.0) months, 18 (15.3%) out of 118 decompensated patients achieved recompensation and 31 (26.3%) achieved the expanded recompensation. Both recompensated and expanded recompensated patients showed similar long-term outcomes to compensated patients (recompensation: hazard ratio [HR]: 0.70, p = 0.735; expanded recompensation: HR: 0.83, p = 0.814). Patients with variceal hemorrhage as index decompensation had higher potential of recompensation. Fulfillment of the Paris II and Momah/Lindor criteria was linked to better further decompensation-free survival and long-term stabilization of liver function reserve.

Conclusion: Regression to a recompensated stage is possible in PBC patients with decompensated cirrhosis, especially when portal hypertension is the main driver of index decompensation. The Paris II and Momah/Lindor criteria are potentially useful as surrogate indicators for etiological suppression.

Background: Peutz-Jeghers syndrome (PJS), a rare genetic disorder characterized by hamartomatous gastrointestinal polyps, poses increased risks of various cancers. Despite the importance of early intervention, the optimal timing for jejunal-ileal polypectomy remains unclear owing to the limited number of comparative studies.

Methods: Herein, we conducted a nationwide survey in Japan and analyzed data from 184 patients with PJS identified through a two-stage sampling process. The initial screening of 2912 medical institutions yielded 1748 facilities, of which 1077 responded to the survey. Time-dependent Cox proportional hazards models and logistic regression analyses were used to examine the association between the timing of jejunal-ileal polypectomy and the risk of surgery for intussusception.

Results: Among 184 patients (47.0% women; mean age, 33.5 years), intussusception was the most common complication (67.7%). In the Cox proportional hazards analysis excluding surgeries within 1 year of diagnosis, early jejunal-ileal polypectomy was associated with a reduced risk of surgery for intussusception (adjusted hazard ratio, 0.17; 95% confidence interval [CI] 0.04-0.74, p = 0.018). Logistic regression analysis showed higher odds of surgery in the late treatment group compared with the early treatment group (adjusted odds ratio, 4.26; 95% CI 1.38-13.16, p = 0.012).

Conclusions: Early jejunal-ileal polypectomy may reduce the risk of intussusception in patients with PJS. However, the need for frequent endoscopic procedures must be balanced considering patient burden. These findings support the importance of early intervention and highlight the need for optimized surveillance strategies that consider clinical effectiveness and patients' quality of life.

Background: Despite advances, immunotherapy has shown limited efficacy in pancreatic ductal adenocarcinoma (PDAC). The profoundly immunosuppressive tumor microenvironment (TME) of PDAC restricts effective antitumor immune responses, necessitating the development of novel therapeutic approaches. Emerging evidence suggests that modulating the TME could enhance immunotherapy outcomes, with glucocorticoid-induced TNFR-related protein (GITR) presenting as a promising target.

Methods: We performed in vivo studies using the Pan02 mouse model of PDAC, where we activated GITR. Complementary analyses were performed on human PDAC samples that were obtained from surgical resections, both from treatment-naive patients and those undergoing neoadjuvant chemotherapy. Human PDAC samples were assessed using scRNA-seq, spatial transcriptomics, and immunofluorescence.

Results: GITR was found to be significantly overexpressed in PDAC tissues compared to normal adjacent pancreatic tissue, with further upregulation observed following neoadjuvant chemotherapy. These findings were corroborated in Pan02 mouse model. GITR activation in vivo led to a reduction in regulatory T cells (Tregs) and an increase in activated cytotoxic effector cells within the TME, resulting in suppressed tumor growth and extended survival. Spatial transcriptomic analysis revealed that GITR expression was predominantly localized to lymphocytes in close proximity to tumor cells in human PDAC. Additionally, long-term survival PDAC patients showed high levels of GITR⁺ lymphocytes, underscoring its clinical relevance.

Conclusions: This study identifies GITR as a key regulator of the immunosuppressive TME in PDAC. By promoting T cell activation and effector functions, GITR represents a promising target for immunotherapeutic treatment in PDAC. Combining GITR activation with standard chemotherapy may offer a promising strategy to improve outcomes for PDAC patients.

Background: Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) are distinct gastrointestinal disorders with overlapping symptoms and pathophysiological background. The long-term risk of IBD is unclear in IBS patients.

Methods: Overall, 447,631 participants free of IBD at baseline (2006-2010) and 76,992 individuals who completed Digestive Health Questionnaire (2017-2018) from UK Biobank were enrolled in longitudinal cohort and cross-sectional analysis, respectively. The primary outcome was incident IBD in the cohort design, and Cox proportional hazards model was conducted to estimate the associated hazard ratio (HR). Prevalent IBD was defined as primary outcome in the cross-sectional design, and logistic regression was performed to estimate the associated odds ratio (OR).

Results: In the cohort design, 2,916 incident IBD cases were identified during a median 14.2 years' follow-up, with 2,097 ulcerative colitis (UC) and 1,015 Crohn's disease (CD), respectively. IBS patients had a 68%, 60%, and 104% increased risk of IBD (HR = 1.68, 95% CI:1.47-1.92), UC (HR = 1.60, 1.36-1.89), and CD (HR = 2.04, 1.66-2.51) versus non-IBS participants. Moreover, a greater risk of incident IBD persisted in IBS patients even after 10 years' duration (HR = 1.55, 1.27-1.89). In cross-sectional analysis, IBS patients exhibited significantly elevated odds of IBD (OR = 2.40, 2.14-2.70), UC (OR = 2.18, 1.92-2.48), and CD (OR = 3.15, 2.68-3.70). A greater odds of IBD was observed among all IBS subtypes, with IBS-D showing the highest odds (OR = 3.72, 3.24-4.28).

Conclusions: The risk of incident IBD, either UC or CD, is significantly higher in IBS patients compared with the general population, especially in IBS-D patients.

Background: The transient receptor potential cation channel subfamily V member 6 (TRPV6) gene, encoding a calcium-selective ion channel, was recently identified as a susceptibility gene for pancreatitis. This study aimed to clarify the natural history of TRPV6-related pancreatitis and the impact of pancreas-specific deletion of Trpv6 on pancreatitis in mice.

Methods: Clinical information of the patients carrying functionally impaired TRPV6 variants, defined by Ca²⁺ imaging and minigene assays, was collected from six international centers. Cumulative rates were assessed using Kaplan-Meier analysis. As controls, Japanese patients with alcohol-unrelated pancreatitis carrying pathogenic variants in PRSS1 or SPINK1, as well as those without pathogenic variants in pancreatitis susceptibility genes, were enrolled. A pancreas-specific Trpv6 conditional knockout mouse was established by crossing the Trpv6 floxed mouse and the Pdx-1-Cre mouse. Pancreatitis was induced by repeated intraperitoneal injections of caerulein.

Results: Ninety-four patients with functionally impaired TRPV6 variants, including six splice-site variants, were enrolled. The median age at symptom onset was 16 years. The cumulative rates of pancreatic calcification, pancreatic exocrine insufficiency, diabetes mellitus, and interventions for pancreatitis were 55.5%, 20.1%, 10.8%, and 41.6% at 30 years, and 81.5%, 49.6%, 45.4%, and 69.9% at 50 years, respectively. Pancreas-specific Trpv6 knockout mice developed more severe acute and chronic pancreatitis than the control mice. Caerulein treatment increased the TRPV6 expression in pancreatic acinar cells.

Conclusions: Functionally impaired TRPV6 variants significantly influenced the clinical outcomes of chronic pancreatitis. TRPV6 in pancreatic acinar cells might play a protective role against pancreatitis in mice.