Journal of Gastroenterology最新文献

Pancreatic ductal adenocarcinoma (PDAC) remains a deadly malignancy owing to its late presentation and the limited sensitivity of current serum biomarkers and imaging for early detection. Extracellular vesicles (EVs), which carry proteins, nucleic acids, and lipids that reflect tumor-stromal interactions, have emerged as promising biomarkers for early diagnosis, disease monitoring, and treatment response. Several EV-derived proteins, microRNAs, long noncoding RNAs, and DNA alterations linked to early carcinogenesis and therapeutic resistance have been identified. However, variability in pre-analytical handling and analytical platforms has hindered reproducibility. Global standardization efforts, such as European Liquid Biopsy Society (ELBS), The Blood Profiling Atlas in Cancer (BloodPAC), International Liquid Biopsy Standardization Alliance (ILSA), and Minimal information for studies of extracellular vesicles (MISEV), are currently helping to unify methodologies for EV isolation and molecular profiling. Advances in analytical technologies have shifted the field from bulk EV measurements to high-resolution single-vesicle approaches. Techniques, such as nanoflow cytometry, super-resolution imaging, Raman spectroscopy, and surface-enhanced Raman scattering, enable the detection of rare, mutation-bearing, or functionally distinct EV subpopulations, which may enhance diagnostic precision. In gastroenterology, a major opportunity lies in integrating single-EV analytics with the endoscopic sampling of tumor-proximal fluids. EVs obtained from pancreatic juice, bile, duodenal fluid, or portal venous blood via endoscopic retrograde cholangiopancreatography (ERCP) or endoscopic ultrasound (EUS) provide spatially enriched molecular information beyond peripheral blood. Combining endoscopic access with particle-level EV characterization may allow real-time, mechanism-informed assessment of tumor biology and premalignant lesions, offering a promising strategy for early detection and risk stratification in PDAC. Together, these developments have positioned EV-based liquid biopsy as a rapidly maturing field with strong translational potential.

Background: Specific human leukocyte antigen (HLA) genotypes, particularly HLA-DQA1*05, have been proposed as predictors for infliximab (IFX) treatment response and immunogenicity in Western populations. However, the evidence regarding the effect of HLA-DQA1*05 remains limited in East Asian populations, including in Japan. Moreover, HLA-DQA1*05 frequency differs substantially from those in Western populations. Comprehensive analyses of the association between HLA alleles and IFX treatment outcomes may contribute to the identification of novel prognostic markers for IFX therapies.

Methods: We retrospectively analyzed 301 biologic-naïve Japanese patients with inflammatory bowel disease (IBD). IFX persistence was assessed at both 2-digit and 4-digit HLA allele resolutions, and associations with anti-drug antibody levels at 1 year after the initiation of IFX therapy were evaluated.

Results: At the 2-digit resolution analysis, HLA-DQB1*03 (hazard ratio [HR] = 2.39, p = 1.89E-06) and HLA-DQA1*05 (HR = 1.99, p = 3.91E-04) were significantly associated with early IFX discontinuation. At the 4-digit resolution analysis, HLA-DQB1*03:01 (HR = 2.03, p = 9.42E-05) and HLA-DQA1*05:05 (HR = 2.18, p = 4.42E-05) showed similar associations. All HLA-DQA1*05:05 alleles formed haplotypes with HLA-DQB1*03:01. Importantly, HLA-DQB1*03:01 was also associated with early discontinuation of IFX even when it formed haplotypes with alleles other than HLA-DQA1*05:05. Both HLA-DQB1*03:01 and HLA-DQA1*05:05 were significantly associated with elevated anti-drug antibody levels (p = 3.23E-03 and 3.54E-03, respectively).

Conclusions: HLA-DQB1*03:01 encompasses the information of HLA-DQA1*05:05 and serves as a strong genetic predictor of IFX treatment persistence and immunogenicity in Japanese patients with IBD, offering a potential biomarker for personalized therapy.

Background: This study aimed to investigate the impact of intestinal obstruction (IO) caused by colorectal cancer (CRC) on the cancer prognosis and recurrence patterns. We analyzed recurrence patterns in patients with stage II-III CRC and employed a murine model to elucidate the effects of IO on hepatic immunity.

Methods: We examined the clinical outcomes of CRC patients with IO and utilized a murine IO model to assess alterations in hepatic immunity, focusing on natural killer (NK) cell function.

Results: IO was significantly associated with poor prognosis and an increased incidence of liver metastases. In the murine model, IO induced hepatic inflammation and impaired the antitumor activity of liver-resident NK cells, whereas its effects on conventional splenic and pulmonary NK cells were minimal. These findings, consistent between human clinical data and murine experiments, suggest that IO promotes a microenvironment conducive to liver metastasis by compromising hepatic immunity.

Conclusions: IO exerts a detrimental effect on hepatic immunity by impairing NK cell-mediated antitumor responses, thereby facilitating liver metastasis in CRC.

Several similarities and differences have been reported in the epidemiology and clinical characteristics of adult eosinophilic esophagitis (EoE) between Japan and Western countries. To review the similarities and differences in adult EoE between Japan and Western countries with respect to asymptomatic cases, the efficacy of proton pump inhibitors (PPIs) and potassium-competitive acid blockers (P-CABs), gene profiles, and disease severity. A PubMed search was performed to identify relevant publications using the following search terms: "eosinophilic esophagitis," "esophageal eosinophilia," "epidemiology," "natural history," "asymptomatic," "PPI," "P-CAB," "Japan," and "Japanese." Asymptomatic EoE has been reported only in Japan, primarily during gastric cancer screening and routine health check-ups, and progression from asymptomatic EoE to symptomatic EoE is uncommon. The efficacy of PPIs and P-CABs for the treatment of EoE appears to be higher in Japan than in Western countries. Severe fibrostenotic cases requiring emergency visits or endoscopic dilation are rare in Japan. The gene expression profile of EoE in Japan is similar to that reported in the United States, and no differences in gene expression have been observed between patients with EoE and those with asymptomatic EoE in Japan. We hypothesize that early detection and diagnosis of adult EoE in Japan may contribute to the high efficacy of PPIs and P-CABs and that early therapeutic intervention may prevent the development of fibrostenosis and severe disease.

Background: In pancreatic ductal adenocarcinoma (PDAC), activation of Yes-associated protein 1 (YAP1) is linked to increased extracellular matrix (ECM) stiffness, yet how YAP1 interacts with cancer-associated fibroblasts (CAFs) and their subtypes to promote stromal remodeling remains unclear.

Methods: Utilizing single-cell RNA sequencing (scRNA-seq) data to identify CAF subsets; validating the role of a specific subset, tumor-like CAFs (tCAFs), in YAP1-dependent promotion of ECM stiffness, epithelial-mesenchymal transition (EMT) combining the YAP1 inhibitor verteporfin with gemcitabine in KPC mouse models to assess effects on tCAF function, stromal stiffness, and survival; and employing magnetic resonance elastography (MRE) to quantify tumor stiffness in PDAC patients and mouse models.

Results: scRNA-seq identified a novel CAF subset (tCAFs) enriched in tumors with high YAP1 activity; tCAFs and mCAFs can mutually differentiate, and this process is regulated by YAP1 activity; in KPC mice, the combination of verteporfin and gemcitabine suppressed tCAF function, reduced stromal stiffness, and improved survival; MRE can accurately quantify tumor stiffness in PDAC patients; elevated YAP1 activity induces a stiffer, more highly cross-linked ECM, which is associated with increased tumor aggressiveness and shortened survival.

Conclusions: YAP1 and tumor-like CAFs (tCAFs) play a pivotal role in driving desmoplasia in PDAC. YAP1 mediates the conversion of mCAFs to tCAFs and remodels the extracellular matrix (ECM), while high YAP1 activity in tCAFs regulates EMT induction to propel disease progression. Targeting the YAP1-tCAF axis can suppress desmoplasia and improve therapeutic outcomes. Magnetic resonance elastography (MRE) holds significant potential for non-invasive monitoring of stromal mechanics, offering a new perspective for stromal therapies in PDAC.