胃肠外科领域文献阅读汇编

There is currently no consensus on long-term risk stratification for metachronous gastric neoplasms (MGNs) occurring beyond 5 years following endoscopic submucosal dissection (ESD).This study aimed to investigate the time-dependent changes in predictive factors for MGN after curative ESD for early gastric cancer (EGC) and analyze the clinicopathological features of late MGNs. We retrospectively reviewed patients who underwent ESD for early gastric neoplasms between March 2005 and June 2020. MGN was defined as a new gastric neoplasm detected at a different site >12 months following ESD. Survival data were collected and analyzed using multivariable and time-split Cox hazard regression models. Among 5,571 patients treated with ESD, 876 were included with a median follow-up of 58 months. The cumulative incidence of MGN was 10.79% at 5 years and continued to accumulate beyond 5 years (26.65% at 10 years). All MGNs were stage I and there was no gastric cancer-related mortality. Cox regression analysis identified family history of gastric cancer (adjusted hazard ratio [aHR] 2.12, 95% confidence interval [CI] 1.32 - 3.41) and extensive intestinal metaplasia (aHR 6.50, 95% CI 3.73 - 11.36) as independent predictors of MGN. Histological upgrade was not associated with MGN during the first 5 years but emerged as a significant risk factor in the late period (interaction P value = 0.005). MGNs may develop even beyond 5 years following ESD with curative resection in patients with EGC. These findings highlight the long-term risk of MGN after ESD, providing a framework for clinical risk estimation.

Perioperative immunotherapy improves outcomes in locally advanced gastric or gastroesophageal junction cancer (GC/GEJC), but reliable predictive biomarkers remain elusive. In this biomarker-stratified, randomized, multicenter phase 2 Mountain-02 trail (NCT06374901), 136 patients with operable cT3-4aN + M0 GC/GEJC were enrolled and stratified by tumor-specific MHC class II (tsMHC-II) expression status and then randomized (1:1) to receive perioperative tislelizumab plus chemotherapy or chemotherapy alone. Among tsMHC-II-positive patients, adding tislelizumab to chemotherapy significantly increased the major pathological response (mPR) rate compared with chemotherapy alone (61.8% vs. 26.5%, p = 0.003), meeting the pre-specified primary endpoint. In contrast, no significant benefit was observed in the tsMHC-II-negative subgroup. Within the combination therapy arm, tsMHC-II-positive patients also achieved numerically higher mPR (61.8% vs. 23.5%, p = 0.001) and higher pathological complete response (pCR) rate (32.4% vs. 5.9%, p = 0.006) than tsMHC-II-negative patients. These findings support tsMHC-II as a promising predictive biomarker for perioperative immunotherapy and warrant further validation in larger studies.

The optimal surgical strategy for adenocarcinoma of oesophagogastric junction (AEG) remains debated, particularly regarding lymphadenectomy extent, gastrectomy type and surgical approach, with real-world prospective evidence being scarce. To map lymph node metastasis (LNM) patterns and assess surgical outcomes in a large multicentre cohort of patients with AEG undergoing radical resection. The Chinese League of Adenocarcinoma of Esophagogastric Junction (CLAEG) registry, initiated in 2022 across 44 high-volume Chinese centres, prospectively enrolled AEG patients. This analysis included 2044 radical resections, with LNM assessed by station, stratified by Siewert type and neoadjuvant therapy. Surgical outcomes were compared between total versus proximal gastrectomy and laparoscopic versus open resection. Most tumours were Siewert type II (64.6%) or III (33.4%). LNM was substantially higher in abdominal than mediastinal stations; category-1 nodes (metastasis, >10%) comprised stations 1, 2, 3, 4, 7, 8a, 9 and 11p. The LNM rates for mediastinal stations were 2.77% (No. 110), 0.71% (No. 111) and 0.68% (No. 112). Patients who received neoadjuvant therapy had lower LNM rates, indicating nodal downstaging. Among those undergoing gastrectomy, patients who underwent total gastrectomy had a lower postoperative complication rate than those who underwent proximal gastrectomy (14.8% vs 21.0%; p=0.001) and achieved more extensive lymphadenectomy. Compared with open surgery, patients who underwent laparoscopic resection experienced faster postoperative recovery without higher complication rates (16.5% vs 17.3%). No perioperative mortality occurred. The CLAEG study shows that abdominal lymphadenectomy should be prioritised in AEG, with neoadjuvant therapy, total gastrectomy and laparoscopy associated with favourable short-term outcomes.

Patients with gastric cancer face substantial risk of recurrence after surgical resection. Molecular profiling of primary tumors may improve risk stratification to guide postoperative management. To identify genomic features of primary gastric tumors associated with disease recurrence and patterns of metastatic spread. This single-center cohort study took place at an academic quaternary referral center and included patients who underwent curative-intent resection of gastric adenocarcinoma from 2010 to 2024. Patients were classified by recurrence status and pattern of metastatic spread. Patients with gastric cancer (stages I to III) who underwent a margin-negative resection and had genomic sequencing of their primary tumor were included. Primary analysis excluded patients who had no evidence of disease with less than 2 years of follow-up. These data were analyzed from June 2025 through March 2026. Primary tumor specimens were sequenced using a targeted panel of cancer-associated genes (MSK-IMPACT). Correlation of disease-free survival and patterns of metastatic spread (hematogenous, peritoneal, or lymphatic) with primary tumor genomic profile. Among 438 patients who underwent complete oncologic resection, 377 had sufficient clinical follow-up or developed recurrence (median [IQR] age, 64 [55-71] years; 113 female [30%] and 264 male [70%]). Recurrence was identified in 179 patients, whereas 198 patients had no evidence of disease. In a multivariable analysis, alterations in KRAS (hazard ratio [HR], 1.54; 95% CI, 1.04-2.28; P = .03) and PIK3CA (HR, 2.15; 95% CI, 1.25-3.69; P = .006) were independently associated with worse disease-free survival. Tumors of patients with hematogenous recurrence had greater chromosomal instability (fraction genome altered, 0.11 vs 0.03; P = .001), whole-genome duplication (47% vs 15%; P = .02), and more frequent alterations of genes modulating cell cycle regulation (39% vs 6%; P < .001) compared with peritoneal recurrence. Bone metastasis arose from more genomically stable primary tumors (fraction genome altered, 0.005 vs 0.114; P < .001) and tumors with Lauren diffuse-type histology (36% vs 3%; P < .001) compared with other sites of hematogenous spread. This study identifies genomic alterations associated with disease-free survival and patterns of recurrence after resection of gastric cancer. These clinicogenomic risk factors may personalize postoperative surveillance strategies and inform perioperative treatment decisions.

Cell-Cell adhesion maintained by tight junctions (TJs) is essential for epithelial integrity; loss of TJs correlates with poor prognosis, metastasis, and adverse clinical outcome in gastric cancer (GC). Restoring TJ integrity is therefore considered a promising therapeutic strategy in GC. The study identifies the stomach renin angiotensin system (stRAS) as a crucial regulator of TJ function in GC. Using integrative analysis of GC patient tissues, human GC cell lines, and orthotopic GC xenograft models, here we show that angiotensin II (ATII), the principal effector peptide of stRAS, drives TJ disassembly through an autocrine loop involving angiotensin receptor type 1 (AT1R) expressed on GC cells. Both ATII and AT1R are overexpressed in GC, where they suppress the expression of key TJ proteins. By analyzing global RNA-sequencing (RNA-seq) data and performing CRISPR/Cas9 gene deletion, chromatin immunoprecipitation, and functional assays, we mechanistically reveal that ATII, which is predominantly produced by cancer cells within the tumor microenvironment (TME), inhibits the expression of krüppel-like factor 4 (KLF4), a transcription factor crucial for the transcription of key TJ genes (CLDN1, 3, 4, and TJP1), leading to reduced synthesis of TJ proteins via AT1R expressed on cancer cells. Notably, the study demonstrates the effectiveness of pharmacological inhibition of AT1R with clinically established AT1R antagonists in preventing GC growth and metastasis by restoring TJ stability in vivo. These findings delineate a previously unrecognized role for ATII in governing TJ disassembly in GC and highlight the ATII/AT1R axis as a promising therapeutic target.

Interleukin-10 (IL-10) is an essential regulator of intestinal immune homeostasis. Neutralising autoantibodies against IL-10 (anti-IL-10) have been identified in children and also adult patients with IBD. Positivity for anti-IL-10 autoantibodies was associated with carriage of HLA-DRB1*01:03 allele. To determine the prevalence of anti-IL-10 in paediatric IBD and assess the associated clinical phenotype. We conducted a cross-sectional multicentre study across paediatric IBD cohorts from four countries. Anti-IL-10 antibodies were investigated in serum and plasma from paediatric patients with IBD (mean age of IBD onset 11.2±3.8 years). IL-10-neutralisation capacity was confirmed by functional IL-10 reporter assay, competitive ELISA and cytokine release assay. Clinical data were analysed to evaluate disease phenotype and treatment outcomes, with comparison with matched controls. HLA-DRB1*01:03 analysis was performed. Anti-IL-10 positivity was identified in 26/1045 paediatric patients with IBD (2.5%) (Crohn's disease n=6, UC n=19, IBD unclassified n=1; IBD diagnosis age of 13±3 years). Anti-IL-10 autoantibodies were of the IgG class and amplified pro-inflammatory cytokine responses in vitro. Anti-IL-10-positive patients exhibited more severe disease compared with matched controls, including an increased prevalence of difficult-to-treat disease (23% vs 6%, p=0.03), higher rate of acute severe UC (26% vs 6%; p=0.038) and higher rates of colectomy (27% vs 6%, p=0.01). Eighty percent (16/20) of anti-IL-10-positive patients with available HLA data carried the HLA-DRB1*01:03 allele, compared with 1.5% in the anti-IL-10-negative group. Anti-IL-10 autoantibodies are present in a subgroup of paediatric patients with IBD and are associated with difficult-to-treat disease.

Autoimmune gastritis (AIG) has been traditionally recognised as a precursor to type I gastric neuroendocrine tumours and non-cardia gastric adenocarcinoma. However, emerging but scattered evidence suggests that its oncogenic footprint may extend beyond the gastric body to the cardia, gastro-oesophageal junction (GOJ) and oesophagus. In this review, we synthesise the available epidemiological and clinical studies linking AIG and its late manifestation, pernicious anaemia, to cardia/GOJ adenocarcinoma and oesophageal cancers. We discuss putative histopathological, immunological and other mechanisms, including corpus-predominant atrophy, intestinal metaplasia and vitamin B12 deficiency that may create a carcinogenic microenvironment not only in the distal stomach but also at the GOJ and beyond. We highlight diagnostic and epidemiologic challenges that have obscured these associations, including the difficulties in defining the gastric cardia, disentangling autoimmune versus other potential pathways and the under-recognition of AIG in routine practice. Finally, we outline a research agenda aimed at clarifying the malignancy risk across the stomach-cardia-oesophagus continuum, emphasising the need for well-phenotyped cohorts, biomarker-driven risk stratification and refined surveillance strategies. By reframing AIG as a potential hidden gateway to junctional and oesophageal malignancies, we argue that its true oncological significance may be broader than previously appreciated.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, highlighting the need for improved non-invasive biomarkers for early detection and prognostic evaluation. tRNA-derived fragments (tRFs) have emerged as regulatory non-coding RNAs in cancer, but their biological and clinical significance in GC remains unclear. To evaluate the diagnostic, prognostic, and biological significance of tRF-28-ZJ47D112Z4DZ (tRF-28) in GC and investigate its underlying molecular mechanism. tRF-28 was identified using a stepwise screening strategy, and an absolute quantification assay was established for plasma detection. Receiver operating characteristic (ROC) analysis, survival analysis, and Cox regression models were used to evaluate its clinical significance. Gain- and loss-of-function studies in GC cells, together with xenograft overexpression models, were performed to investigate its biological functions. RNA immunoprecipitation, dual-luciferase reporter assays, rescue experiments, and immunohistochemistry were used to explore the underlying mechanism. Plasma tRF-28 levels progressively decreased from healthy controls to precancerous lesions and GC patients. tRF-28 demonstrated diagnostic value for precancerous lesions (AUC = 0.713) and showed moderate but reproducible diagnostic performance for GC in both the training and validation cohorts (AUC = 0.762 in the training cohort). Reduced plasma tRF-28 levels were associated with poor differentiation, deeper invasion, and unfavorable overall survival, and multivariate Cox analysis identified tRF-28 as an independent protective prognostic factor. Functionally, tRF-28 inhibited GC cell proliferation, colony formation, invasion, migration, and cell cycle progression while promoting apoptosis. Mechanistically, tRF-28 associated with Argonaute 2 (Ago2) and directly targeted the 3' untranslated region of CCND1, thereby suppressing the Cyclin D1/CDK4/p-Rb signaling pathway. Xenograft studies further confirmed its tumor-suppressive effect in vivo. tRF-28 suppresses GC progression through regulation of the CCND1-associated cell cycle pathway and may serve as a complementary plasma biomarker for GC diagnosis and prognostic assessment.

The tumor microbiota critically shapes responses to immunotherapy; however, the mechanisms by which specific microbial species drive immune checkpoint blockade (ICB) resistance in gastric cancer (GC) remain poorly defined. Streptococcus anginosus enrichment was assessed in ICB-unresponsive GC tissues from patients and multiple preclinical models. Orthotopic, subcutaneous, and germ-free mono-colonized mouse models were employed to evaluate the impact of S. anginosus on antitumor immunity and programmed cell death protein 1 (PD-1) blockade efficacy. Integrated multi-omics analyses were performed to identify microbiota-derived metabolites, and mechanistic studies investigated their effects on CD8+ T-cell function. Therapeutic targeting of integrin α2 (ITGA2) was tested to assess restoration of cytotoxic T-cell activity and sensitization to PD-1 blockade. S. anginosus was markedly enriched in ICB-non-responsive GC tissues. Colonization with S. anginosus impaired antitumor immunity and promoted PD-1 blockade resistance by suppressing CD8+ T-cell effector function. Multi-omics analyses identified kynurenic acid (KA) as a microbiota-derived metabolite selectively enriched following S. anginosus colonization. KA induced ITGA2 expression and inhibited an mTOR-dependent signaling cascade, sustaining cathepsin V expression and attenuating interferon-γ and granzyme B production in CD8+ T cells. Therapeutic inhibition of ITGA2 restored CD8+ T-cell cytotoxicity and sensitized tumors to PD-1 blockade. A microbiota-metabolite-immune signaling axis involving S. anginosus, KA, and ITGA2 drives immunotherapy resistance in GC. Therapeutic inhibition of ITGA2 represents a potential strategy to overcome ICB resistance in GC.

Gastrointestinal (GI) adenocarcinomas pose a significant therapeutic challenge due to highly immunosuppressive tumor microenvironments that limit effective antitumor immune responses. Dense stromal fibrosis, immune exclusion and poor responses to immune checkpoint inhibitors are hallmarks of treatment-resistant malignancies, most notably pancreatic ductal adenocarcinoma (PDAC) and subsets of gastric cancer. In this regard, IL-15 superagonists such as N-803, NIZ985, RLI, and NKTR-255 have emerged as promising immunotherapeutic candidates, as they selectively expand natural killer (NK) cells and CD8+ T-cells without the systemic toxicity and regulatory T-cell activation observed with IL-2 therapy. IL-15 superagonists have emerged as more effective therapeutic agents when used in conjunction with local inhibitors of TGF-β and IL-10, stromal remodelling, and vascular normalization. They are supported by increasingly conclusive mechanistic, preclinical and early clinical data. A combination of these interventions circumvents extracellular matrix-provoked immune barriers, reverses VEGF-induced endothelial dysfunction, and enhances the trafficking of lymphocytes into tumor cores. Moreover, several localized therapeutic delivery strategies, such as endoscopic delivery, implantable depots, biomaterial scaffolds, and nanocarriers, can improve intratumoral cytokine retention and reduce systemic inflammatory toxicity. Together, these advances define a new paradigm for cytokine-immunotherapy, with IL-15 superagonists serving as key mediators of reprogramming of the tumor microenvironment. Therapeutic strategies targeting IL-15 have the potential to restore cytotoxic immunity, improve access to immune cells, and promote responsiveness to the checkpoint blockade, making them a promising yet investigational approach to converting immune-cold GI malignancies into more treatment-responsive disease states, though further clinical validation is required.

PLATFORM is a prospective, open-label, multicentre, adaptive phase II trial assessing maintenance therapy in patients with advanced HER2-negative oesophagogastric adenocarcinoma after platinum-based first-line chemotherapy. After 18 weeks of platinum-based chemotherapy, patients with response or stable disease were randomised to surveillance (4 weekly visits) or rucaparib 600 mg tablet twice daily every 28 days. The primary endpoint was progression-free survival (PFS) (prespecified P value of 0.025). Secondary endpoints were safety and overall survival (OS). Exploratory translational analyses of homologous recombination deficiency (HRD) and somatic gene profiling are also reported. A total of 125 patients were randomised (surveillance: 62, rucaparib: 63). The median follow-up was 41 months. Median PFS was 2.8 months for surveillance and 4.2 months for rucaparib [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.49-1.02, P = 0.031]. There was no difference in OS (HR 1.15, 95% CI 0.77-1.72, P = 0.247). Grade ≥3 adverse events (AEs) occurred in 23% of surveillance and 32% of rucaparib patients. Treatment-related AEs were reported in 84% of patients in the rucaparib arm; 22% of which were grade 3-4. Most frequent grade 3-4 AEs were anaemia, fatigue, infection, and neutropenia. Adequate tissue for HRD analysis was available in 51/125 (40.8%) patients (surveillance: 20, rucaparib: 31). Five patients (9.8%) were HRD-positive, 41 (80.4%) HRD-negative, and 5 (9.8%) had inconclusive results. Among HRD-positive patients, four were treated with rucaparib and had PFS durations of 2.6, 3.0, 8.3, and 10.6 months, respectively. TP53 was the most frequently detected somatic alteration, followed by SMARCA4 and ARID1A. Compared with surveillance, maintenance rucaparib following first-line chemotherapy in patients with advanced HER2-negative OGA did not significantly improve PFS with no observed difference in OS. Translational analyses were limited by small sample size, and no clear associations with clinical outcomes were identified.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related mortality worldwide. This study was aimed at estimating regional and national variations in lifetime CRC risk worldwide. CRC data were extracted from GLOBOCAN 2022, including 185 countries, and population and all-cause mortality data were sourced from the United Nations. The world was divided into 20 geographical regions and categorized by Human Development Index (HDI). Lifetime CRC risk was estimated with the life table method, adjusted for multiple primary cancers. In 2022, the lifetime risks of developing and dying from CRC were 2.69% [95% confidence interval (CI): 2.68-2.70] and 1.39% (95% CI: 1.39-1.40), respectively. Men had a higher risk of colon cancer than rectal cancer, and higher CRC risk than women. Lifetime risk varied by region and HDI: regions with very high, high, moderate, and low HDI had incidence risks of 5.17%, 2.75%, 0.72%, and 0.57%, respectively, and mortality risks of 2.48%, 1.50%, 0.44%, and 0.41%, respectively. Australia/New Zealand had the highest incidence risk (7.41%, 95% CI: 7.30-7.52), and Northern Europe the highest mortality risk (3.28%, 95% CI: 3.24-3.32). Risks were stable before 40 years of age, peaked in middle age, and declined after 70 years of age. Temporally, Thailand had the highest increasing trend in lifetime risk, whereas the United States and Austria showed a decreasing trend. Lifetime CRC risk differs by subtype, sex, HDI, and geography, and residual risk gradually decreases with age. Targeted primary prevention strategies should be implemented in various countries and regions to mitigate CRC burden.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Current tyrosine kinase inhibitors (TKIs) targeting oncogenic KIT and PDGFRA have improved patient outcomes, yet off-target toxicities and drug resistance mutations remain major clinical challenges. Many approved TKIs, often repurposed from other cancer indications, harbor diverse hinge-binding motifs that limit activity against resistance mutations clustering in the ATP-binding pocket of the kinase domain. Here, we describe a structure-based scaffold-hopping strategy to design kinase inhibitors with selectivity for mutant KIT/PDGFRA. Using structure-activity relationship (SAR) studies and 14 determined co-crystal structures, including a structure of the PDGFRA-G680R solvent-front mutation, we define key molecular interactions underlying resistance and inhibitor selectivity. Our lead 6,7-quinazoline-based inhibitors show high potency against clinically relevant KIT/PDGFRA mutations and effectively suppress downstream signaling. These compounds provide selective chemical tools to interrogate resistance mechanisms, and the PDGFRA-G680R structure shows the molecular basis for targeting solvent-front mutations across oncogenic kinases.

Excessive postoperative inflammation is associated with multisystem complications after surgery, culminating in morbidity, mortality and increased healthcare costs. Epigenetic modifications regulate gene transcription without altering DNA sequences and can augment powerful inflammatory responses. Translational studies have emerged, investigating how epigenetic mechanisms influence perioperative inflammation and complications. This scoping review consolidates studies in this expanding field and provides informed recommendations for future research. The protocol for this scoping review was created using best-practice guidelines and was prospectively registered and published. Searches were conducted using Medline and Embase and included studies published in English between 1946 and 2025. Two reviewers independently screened titles and abstracts, then full texts of studies before data extraction. Included studies investigated postoperative complications alongside epigenetic mechanisms and inflammation. Studies (n=15 451) were assessed for title and abstract screening, and 26 articles were included in the review. Included studies were published between 2016 and 2025. Cardiac surgery was investigated most often, followed by general and colorectal surgery. Several surgical specialities were not represented. Most studies investigated microRNA mechanisms, investigating either a small number of microRNAs (≤8) or using whole transcriptome approaches. DNA methylation and histone modifications were investigated less commonly. Complications were variably defined in the included studies, and most studies focused on a small number of complications. Inflammation was heterogeneously assessed, with most studies using C-reactive protein and interleukin-6 or both, whereas other studies used broader proteomic approaches to quantify inflammation. DNA methylation and histone modifications are less researched epigenetic mechanisms in perioperative inflammation. Future studies should recruit patients with homogeneous surgical insults. Studies should use standard measures of inflammation to enhance generalisability, whereas experimental approaches (including transcriptomics and proteomics) could advance mechanistic understanding in exploratory studies. Future research would benefit from consistent use of validated definitions of postoperative complications to enable comparison between studies.