Journal of Gastroenterology最新文献

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: 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 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: CD44v6-positive extracellular vesicles (EVs) released by cancer cells drive tumor progression and liver metastasis. This study aimed to evaluate CD44v6-positive extracellular vesicles (EVs) as prognostic markers for pancreatic ductal adenocarcinoma (PDAC), a disease with poor prognosis.

Methods: Plasma samples from 100 patients with hepatobiliary and pancreatic diseases were retrospectively analyzed. Non-pancreatic and unresectable pancreatic cancer cases were included as control groups for cross-sectional comparisons, whereas prognostic analysis using preoperative plasma samples was limited to resected PDAC. EVs were defined based on CD9, CD63, and CD81 membrane antigens, and the proportion of CD44v6-positive EVs was measured using nano-flow cytometry. CD44v6 expression in resected PDAC tissues was assessed using immunohistochemistry.

Results: The proportion of CD44v6-positive EVs was significantly higher in patients with pancreatic cancer than in those without cancer (P = 0.0009). High CD44v6 expression in resected PDAC tissues correlated with elevated CD44v6-positive EVs in the plasma. Patients with CD44v6-positive EVs ≥ 31% had significantly poorer recurrence-free survival (P = 0.0008) and overall survival (P = 0.045) than those with < 31% EVs. Multivariate analysis confirmed CD44v6-positive EVs ≥ 31% were independent prognostic factors for recurrence-free (P = 0.005) and overall survival (P = 0.037), and a predictor of early liver metastasis (P = 0.001).

Conclusions: These findings highlight the potential of preoperative quantification of CD44v6-positive EVs as a biomarker for risk stratification and treatment optimization in PDAC.

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.

Background: Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) effectively treat metastatic colorectal cancer (CRC); however, predicting response to these therapies remains challenging. Here, we aimed to identify key regulators of EGFR internalization as predictive biomarkers for anti-EGFR mAb therapy in CRC.

Methods: CRC cell lines were treated with cetuximab and EGFR internalization was analyzed using siRNA knockdowns, inhibitors, and proteomic analyses. Key proteins mediating cetuximab-bound EGFR internalization were identified through immunoprecipitation and tandem mass spectrometry and validated using RT-PCR, co-immunoprecipitation, immunofluorescence, cell viability, and apoptosis assays. Immunohistochemistry was performed to correlate findings with clinical outcomes.

Results: Clathrin-dependent endocytosis mediated by Clathrin Heavy Chain was the primary pathway of cetuximab-bound EGFR internalization. Knockdown of clathrin-independent endocytosis genes or inhibition of macropinocytosis did not affect cetuximab-bound EGFR internalization. Ubiquitin Protein Ligase E3 Component N-Recognin 4 (UBR4) was identified as a critical mediator of EGFR degradation. UBR4 knockdown promoted EGFR recycling, enhanced cell proliferation, and reduced apoptosis in response to cetuximab. High UBR4 expression in CRC tissues correlated with better responses and longer progression-free survival in patients treated with anti-EGFR mAb therapy.

Conclusions: UBR4 promotes clathrin-dependent EGFR degradation, enhancing anti-EGFR therapeutic efficacy, and may serve as a predictive biomarker in metastatic CRC.

Background: Ulcerative colitis (UC) is an idiopathic chronic intestinal inflammation. It has been reported that macrophages are key cells mediating inflammation. Furthermore, Serpin family B member 5 (SerpinB5) plays a role in the regulation of macrophage phenotype conversion. However, the role and underlying mechanism of SerpinB5 in UC are still unclear.

Methods: Hematoxylin and eosin staining assay was used to assess colon pathological changes. GO enrichment and KEGG pathway enrichment analyses were conducted to assess the function of the DEGs from RNA-seq data. GSE224758 database, RNA-seq, and GeneCards database were applied to analyze the intersection targets. The mRNA and protein levels of the related genes were determined using RT-qPCR and western blot. The in vitro model of UC was established by stimulating colonic epithelial cells with tumor necrosis factor α (TNF-α). Cell viability, proliferation, and apoptosis were determined using CCK-8, EdU, and flow cytometry. Senescence-associated β-galactosidase (SA-β-Gal) staining and senescence-related proteins p53 and p16 were detected to evaluate the endothelial cell senescence. Inflammatory cytokines and oxidative stress were detected using ELISA and kits. Flow cytometry analysis assessed the percentage of CD11b⁺CD86⁺ and CD11b⁺CD206⁺ cells in mouse-derived macrophages. A mouse model of UC was constructed by injecting C57BL/6 mice with dextran sulfate sodium salt. The interaction of SerpinB5 and F-Box Protein 32 (FBXO32) was confirmed using GST pull-down and coimmunoprecipitation assays. Besides, MeRIP-qPCR, RNA pull-down, and RIP assays were used to examine the molecular mechanism underlying METTL3/m6A/YTHDF1 signaling axis in SerpinB5 expression.

Results: SerpinB5 expression was increased in UC patients, TNF-α-treated FUC cells, and a mouse model of UC. SerpinB5 silencing repressed TNF-α-induced cell apoptosis, cell senescence, inflammation response, oxidative stress, and M1 macrophage polarization. Meanwhile, SerpinB5 knockdown relieved symptoms of the mouse model of UC and repressed M1 macrophage polarization. SerpinB5 positively mediated the NF-κB pathway by regulating FBXO32. METTL3 improved the stability of SerpinB5 mRNA in an m6A-YTHDF1-dependent manner.

Conclusion: METTL3/YTHDF1 aggravated UC progression through promoting M1 macrophage polarization via SerpinB5 mRNA m6A modification and FBXO32/NF-κB pathway. These findings indicated that SerpinB5 might be a good and promising therapeutic target for UC treatment.