Journal of Gastroenterology最新文献

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: 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.

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.

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: Existing pancreatic cancer prediction models still have significant limitations until now. This multicenter retrospective study aimed to identify clinical features and develop machine learning models for predicting overall survival (OS) in patients with pancreatic cancer.

Methods: Clinicopathological and survival data from patients with pancreatic cancer who underwent radical surgery between 2012 and 2023 were collected at two major pancreatic centers in China. A total of 704 patients from the National Cancer Center of China (NCC) formed the training and internal validation cohort, while 131 patients from Sun Yat-sen Memorial Hospital constituted the external validation cohort. Five predictive machine learning models were developed and validated, and the optimal predictive model was determined by comparing area under the receiver operating characteristic curve (AUC) values. The SHapley Additive exPlanation (SHAP) method was employed to provide interpretability for the machine learning model.

Results: The median OS for 704 postoperative pancreatic cancer patients in NCC was 24 months (21-26 months), with 1-year, 3-year, and 5-year survival rates of 72.8%, 34.0%, and 22.1%, respectively. Perioperative chemotherapy was significantly associated with improved survival (P = 0.0026). Survival data for NCC were generally consistent with Japan and the United States. Among the five predictive models, the Random Survival Forest (RSF) model exhibited superior performance, achieving AUC values of 0.81, 0.76 and 0.78 in the training, internal and external validation sets. The most influential variables contributing to the model predictions were identified using the SHAP method, with those of particular importance including chemotherapy, CA19-9, abdominal pain, the number of lymph node resection and TNM stage.

Conclusions: The 5-year survival rate for postoperative pancreatic cancer patients is 22.1% in NCC, which is comparable with the United States and Japan. Based on multicenter clinical data, we developed and validated an interpretable survival prediction model, which can guide clinical management and personalized treatment for pancreatic cancer patients.

Background: Long-term follow-up is essential after a sustained virologic response (SVR) to direct-acting antivirals (DAAs) in patients with chronic hepatitis C. However, real-world continuity of care and determinants of disengagement are poorly characterized at the national level. Here, we quantified the follow-up continuity within Japan's government-designated regional core centers and identified independent factors associated with transfer and self-discontinuation.

Methods: We conducted a retrospective multicenter cohort study of 3702 patients with chronic hepatitis C who achieved SVR at 16 regional core centers (2015-2018). Continuation was assessed using Kaplan-Meier analysis and competing-risk analysis, and Fine-Gray regression identified determinants of transfer and discontinuation.

Results: At 5 years, 56% of the patients were followed up, 24% were transferred, and 18% self-discontinued. Older age was significantly associated with transfer (subdistribution hazard ratio [sHR] 1.41, 95% CI 1.23-1.61), whereas hepatocellular carcinoma (HCC) and other malignancies favored continuous follow-up. Self-discontinuation was more frequent with hepatitis C virus (HCV) serotype 2 (sHR 1.36, 95% CI 1.18-1.57) and less common among patients with advanced disease or prior hospitalization.

Conclusions: Within Japan's core-center network, long-term continuation after SVR is high but not universal. Follow-up was generally maintained for patients with severe comorbidities, while disengagement was more likely among those with lower perceived risk. Strengthening low-intensity, structured support for such patients may improve the continuity and equity of post-SVR care. These findings provide a foundation for optimizing post-SVR care pathways in national liver disease networks.

Background: Sphincter of Oddi dysfunction (SOD) can cause unexplained biliary pain and idiopathic pancreatitis. Although Rome IV criteria recommend sphincter of Oddi manometry (SOM) for diagnosis, SOM is invasive and carries pancreatitis risk. We hypothesized that cine-dynamic magnetic resonance cholangiopancreatography (MRCP) could non-invasively visualize bile and pancreatic juice flow, enabling functional papillary assessment.

Methods: In this prospective observational study, 40 participants were enrolled, and 29 were included in the final analysis after excluding 11 participants who did not meet the Rome IV criteria (10 healthy controls, 7 with suspected biliary-type SOD [BSOD], and 12 with suspected pancreatic-type SOD [PSOD]). Cine-dynamic MRCP was performed with 20 sequential frames over 5 min. Two quantitative indices were assessed: flow frequency and secretion grade (distance traveled by bile or pancreatic juice).

Results: Bile flow frequency and secretion grade were significantly lower in both BSOD and PSOD than in controls: frequency (median [range], 13.5 [6-19] in controls vs. 2.0 [1-17] in BSOD, p = 0.006; vs. 8.0 [3-14] in PSOD, p = 0.008) and secretion grade (1.6 [0.3-2.05] in controls vs. 0.2 [0.1-1.3] in BSOD, p = 0.001; vs. 0.5 [0.15-1.75] in PSOD, p = 0.03). Pancreatic juice flow showed no significant difference between BSOD and controls but was significantly reduced in PSOD: frequency (16 [14-19] in controls vs. 9.5 [4-17] in PSOD, p < 0.001) and secretion grade (2.15 [0.7-3.25] in controls vs. 0.98 [0.25-2.9] in PSOD, p = 0.003). Cine-dynamic MRCP parameters improved after sphincterotomy in six patients.

Conclusions: Cine-dynamic MRCP enables non-invasive visualization and quantification of bile and pancreatic juice flow, providing functional assessment of the sphincter of Oddi.

Background: Studies investigating the incidence of extra-intestinal cancer (EIC) in Asian inflammatory bowel disease (IBD) patients are limited. The impact of thiopurines and anti-tumor necrosis factor (anti-TNF) antibodies on the development of EIC remains unclear.

Methods: In this multicenter retrospective cohort study, we analyzed data from 4604 IBD patients (1864 with Crohn's disease [CD] and 2740 with ulcerative colitis [UC]) with a history of hospital visits between 2008 and 2020. The standardized incidence ratio (SIR) of EIC was calculated. To identify predictors of the presence of EIC, clinical characteristics and medication were evaluated. The cumulative probability of EIC was compared based on exposure to thiopurines and anti-TNF antibodies.

Results: EIC was identified in 65 CD patients and 97 UC patients. A higher incidence of leukemia was observed in CD patients (SIR 5.21). Gallbladder/bile duct cancer was more prevalent in UC patients (SIR 2.65), while gastric cancer was less common (SIR 0.46). Independent predictors of EIC in CD patients included female sex, age, disease duration, and complicated disease behavior, while in UC patients, predictors included age, primary sclerosing cholangitis, and current steroid use. Use of thiopurines in CD patients and anti-TNF antibodies in UC patients appeared protective against the presence of EIC. However, the duration of exposure to thiopurines and anti-TNF antibodies did not affect the development of EIC.

Conclusions: Japanese CD and UC patients seem to have a higher incidence of leukemia and gallbladder/bile duct cancer, respectively. Thiopurines and anti-TNF antibodies were not associated with an increased risk of EIC.

Background: No diagnostic criteria have been established to specifically evaluate the activity of intestinal lesions in Behçet's disease (BD). We aimed to identify intestinal ultrasound (IUS) parameters that were correlated with endoscopic ulcer activity, as well as develop and prospectively validate an IUS activity score for patients with intestinal BD.

Methods: Patients who underwent colonoscopy and IUS within 2 weeks during 2007-2019 were retrospectively included in the development phase. Correlations between corresponding endoscopic activity and seven IUS parameters [bowel wall thickness (BWT), vascularity, bowel wall stratification, white-plaque sign, mesenteric lymphadenopathy, extramural phlegmons, and fistulas] based on 73 examinations and were assessed. We created an IUS activity score with a multivariate logistic regression model and inter-observer assessment. This score was prospectively validated in a new cohort (2020-2024).

Results: Among seven IUS parameters, only BWT (p = 0.001) and vascularity (p = 0.004) were significantly associated with endoscopically active disease, with high inter-observer agreement confirmed (intraclass correlation = 0.98, weighted kappa = 0.83, respectively) in the development phase. The IUS score for ileocecal ulcers in intestinal BD (IUS-BD) was developed based on 2*BWT + 5*vascularity. With a cutoff ≥ 16 points, IUS-BD could detect active ileocecal ulcers (sensitivity 84.6%, specificity 91.2%, and accuracy 87.7%). In the validation cohort including 17 IUS examinations, the IUS-BD was significantly increased in the endoscopically active disease (p = 0.024), with high diagnostic performance (sensitivity 84.6%, specificity 100%).

Conclusions: We developed and preliminarily validated a novel ultrasonographic score for intestinal BD to identify endoscopically active disease.