胃肠外科领域文献阅读汇编

Endoscopic screening for gastric cancer reduces mortality, but the optimal upper age limit and modifying role of comorbidity remain unclear. This nationwide retrospective cohort study used the Korean National Health Insurance Service database linked to national mortality records. Individuals aged ≥40 years who underwent screening esophagogastroduodenoscopy between 2005 and 2010 were included and propensity score-matched to non-screened controls. The primary outcome was gastric cancer-specific mortality. Comorbidity was assessed using the Charlson Comorbidity Index (CCI). Hazard ratios (HRs) were estimated in the matched cohort. Among 555 904 propensity score-matched individuals (277 952 per group), gastric cancer-specific mortality HRs showed an age-dependent gradient: <1.0 at 50-59 years (HR 0.56, 95%CI 0.34-0.92), 60-64 (0.65, 0.40-1.07), and 65-69 (0.82, 0.58-1.17); close to 1.0 at 70-74 (0.99, 0.75-1.30) and 75-79 (0.92, 0.68-1.24); and elevated at ≥80 years (2.21, 1.49-3.27). Comorbidity further modified this association: HRs were <1.0 in individuals with CCI <3 (0.86, 0.74-1.01) but elevated in those with CCI ≥3 (1.88, 1.42-2.49). In age-CCI analyses, point estimates favored screening across age groups up to age 75-79 years among individuals with CCI 0, but HRs exceeded 1.0 in most age groups with CCI ≥3. Post-endoscopy respiratory or cerebrocardiovascular events increased with age and comorbidity. The mortality benefit of gastric cancer screening endoscopy diminished with advancing age and comorbidity burden, becoming questionable beyond age 70. At age ≥80 or in individuals with substantial comorbidity, potential harms may outweigh benefits.

Gastric cancer primarily originates from gastric stem/progenitor cells and is driven by somatic mutations. Although Helicobacter pylori is the main risk factor, how it drives malignancy is still not well understood. Analysis of single-cell RNA sequencing data reveals that human gastric cancer correlates with suppressed BMP signalling, a crucial niche signal for gastric stem cells, in stromal cells rather than epithelial cells. Genetic disruption of BMP signalling in Col1a2+ stromal cells or Acta2+ myocytes/pericytes alone, but not in gastric stem cells themselves, triggers mutations in gastric stem cells and initiates cancer development. Mechanistically, loss of BMP signalling increases stromal production of Wnt ligands, which dose-dependently drive transcription-replication collisions, R-loops, and DNA damage in gastric stem cells. The resulting DNA damage and carcinogenesis can be prevented by small-molecule inhibitors targeting Wnt pathway. Importantly, we identify inflammation as a key disruptor of stromal BMP signalling, as seen in patient samples with chronic atrophic gastritis and H. pylori-infected mouse gastric samples, which is associated with DNA damage. Together, these findings show how chronic inflammation derails niche signalling to drive stem cell mutations and gastric cancer and highlight promising avenues for early prevention.

Gastric cancer develops through a sequential carcinogenic process beginning with pyloric metaplasia, a key feature of which is the transdifferentiation of gastric chief cells into spasmolytic polypeptide-expressing metaplastic (SPEM) cells. We found that SOX9, a transcription factor, is highly expressed in SPEM cells in both human and murine metaplasia. We therefore investigated the impact of SOX9-mediated SPEM cell plasticity and function on metaplasia development and progression during gastric carcinogenesis. We utilized two Sox9 knock-out mouse models, GIFrtTA/+;TetO-CreTg/+; Sox9flox/flox (GCS) and GIFrtTA/+;TetO-CreTg/+;LSL-KrasG12DTg/+;Sox9flox/flox (GCKS) to examine the effects of SOX9 loss on metaplasia development following mucosal injury and carcinogenesis by immunofluorescence and single-cell RNA-sequencing. We also confirmed our findings in human patient tissue microarrays and utilized SPEM organoids to identify genes regulated by SOX9. Sox9 knock-out in chief cells resulted in the failure of metaplasia development in both acute and chronic injury as chief cells were unable to transdifferentiate into SPEM cells. The GCKS mouse failed to progress through carcinogenesis due to lack of a SPEM cell subpopulation responsible for metaplasia progression and fibroblast recruitment to gland bases. Instead, homeostatic gastric cell lineages were repopulated in the glands. We also identified a TOP2A-expressing SPEM cell subpopulation that contributes to metaplasia progression, and putative SOX9 downstream genes associated with lineage plasticity. These results demonstrate that SOX9 is a master regulator of SPEM cell lineage evolution and metaplasia progression. Therefore, SOX9-mediated SPEM cell plasticity is a central mechanism in carcinogenesis.

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.

MicroRNAs (miRNAs) are promising biomarkers for cancer diagnosis due to their stability in body fluids and disease-specific expression profiles. However, current detection methods suffer from limitations including cumbersome workflows, heavy instrumentation for signal readout, or vulnerability in minimizing instrumentation. To address these challenges, we describe a novel point-of-care miRNA detection platform executable with "off-the-shelf", personal glucose meter (PGM), termed 'KEY-FACT (Kinases Ensemble-driven glucose phosphorYlation upon Fuel-Aided CRISPR acTivation)'. Upon recognition of target miRNA, a fuel-assisted toehold-mediated strand displacement reactions liberate guide RNAs (gRNAs) to activate Cas13a to cleave a chimeric reporter probe, producing 2',3'-cyclic adenosine monophosphates (cAMP). Subsequent dephosphorylation and kinases ensemble-mediated phosphorylation/dephosphorylation cycles lead cAMP to consume a large amount of glucose. A user can immediately measure resulting glucose level change with PGM on the spot. This strategy allows sensitive, prompt detection of miR-135b, a gastric cancer (GC) biomarker, with a limit of detection (LOD) of 1.4 pM within 2 h. KEY-FACT is specific to the target miRNA and is applicable to body fluids such as human serum with dilution (95.2% < recovery rates <104.3%, coefficients of variation ≤13%). Owing to its simple probe design, KEY-FACT was readily expanded to detect another GC biomarker, miR-21, with comparable sensitivity (LOD = 1.5 pM). The proposed platform fulfills minimal instrumentation and thus enables cost-effective, field-deployable analysis, paving the way for practical, on-demand miRNA diagnostics.

Metabolites sculpt the immunosuppressive tumor microenvironment (TME) that facilitates immune evasion. As a crucial signaling lysophospholipid, lysophosphatidylserine (LysoPS) correlates with advanced disease stages in multiple tumor types. However, the mechanisms by which LysoPS drives gastric cancer peritoneal metastasis remain undefined. Single-cell transcriptomic profiling of primary tumors, normal peritoneum, and metastatic lesions delineated mechanisms underlying LysoPS-mediated tumor-associated macrophages (TAMs) reprogramming. Immunohistochemistry and multiplex immunofluorescence validated GPR34-high TAMs infiltration in peritoneal metastases. Functional validation was performed using molecular assays and in vivo models. LysoPS accumulated in ascites from patients with gastric cancer peritoneal metastasis, establishing an immunosuppressive TME that drove malignant progression. Using single-cell transcriptome sequencing, we identified a distinct subset of TAMs highly expressing GPR34 enriched in gastric cancer peritoneal metastases, which correlates with tumor progression and immune evasion. Mechanistically, LysoPS engagement of GPR34 activated ERK/c-Jun signaling, transcriptionally upregulating AXL and CD36 to enhance efferocytosis. This effect drove TAMs toward an immunosuppressive phenotype, characterized by enhanced interleukin-10 and transforming growth factor-β secretion. GPR34 inhibitor attenuated M2-like TAMs infiltration while bolstering cytotoxic T cells recruitment and curtailing programmed cell death protein 1 (PD-1)+T cells accumulation. Furthermore, combination with anti-PD-1 therapy synergistically suppressed tumor growth beyond monotherapy efficacy. LysoPS-GPR34 axis synergized with efferocytosis to amplify TAMs immunosuppressive properties, fostering an immune-evasive microenvironment; GPR34 inhibitor thus represents a promising strategy to potentiate PD-1 blockade efficacy in gastric cancer peritoneal metastasis.

Identifying high-risk patients for recurrence after endoscopic resection (ER) of T1 colorectal cancer (CRC) remains challenging. This study aimed to identify recurrence-risk subtypes and develop an interpretable risk stratification framework. This retrospective study analyzed 1123 patients with T1 CRC treated with ER alone across 27 Japanese institutions (July 2009-December 2016). Patients were divided into development (68%) and evaluation (32%) cohorts based on institutional stratification. K-means clustering was applied to clinicopathological variables to identify recurrence-risk subtypes. A decision tree classifier was subsequently developed to generate transparent risk stratification rules. Three distinct subtypes were identified in the development cohort. Subtype 1 exhibited a numerically higher recurrence rate (5.4%) than subtype 2 (0.9%) and subtype 3 (1.4%). Although subtypes 2 and 3 showed comparable recurrence rates, they were clearly differentiated by morphology (flat vs. polypoid). In the evaluation cohort, subtype 1 continued to show a numerically higher recurrence (4.8%) compared with subtypes 2 (1.6%) and 3 (1.1%). The decision tree model stratified recurrence risk hierarchically: submucosal invasion <1,000μm indicated low risk, whereas invasion ≥1,000μm required morphological assessment, with polypoid lesions classified as high risk and flat lesions further stratified using a 2,000μm threshold. Three clinically distinct recurrence risk subtypes were identified in T1 CRC following ER, suggesting that morphological subclassification of T1b lesions may refine stratification beyond conventional depth-based criteria. The decision framework offers a preliminary exploratory basis for recurrence risk assessment in this population.

Peritoneal metastasis (PM) of colorectal cancer (CRC) remains a major therapeutic challenge due to the limited efficacy of current systemic and intraperitoneal treatments. To overcome these limitations, we developed an injectable, self-healing hydrogel constructed from a dual dynamic cross-linked network formed by borate ester and Schiff base bonds between phenylboronic acid-modified carboxymethyl chitosan (CMCS-PBA) and oxidized dextran (ODEX). This hydrogel was engineered for sustained intraperitoneal co-delivery of oxaliplatin (OXA) and resveratrol-loaded mesoporous silica nanoparticles (MSNs@RES). The system exhibited excellent biocompatibility and significantly inhibited cancer cell proliferation, migration, and invasion while inducing apoptosis and immunogenic cell death (ICD) in vitro. In a murine model of CRC peritoneal metastasis, the dual-drug-loaded hydrogel markedly suppressed tumor progression, reduced ascites formation, and prolonged survival. Proteomic analysis further revealed that treatment significantly modulated key signalling pathways, including HIF-1α-mediated angiogenesis, apoptosis-related cascades, and TGF-β-driven epithelial-mesenchymal transition (EMT). Collectively, this work presents a rationally designed localized delivery platform with significant potential for the treatment of colorectal cancer peritoneal metastasis.

Epicardial adipose tissue (EAT) is a metabolically active visceral fat depot implicated in cardiometabolic disease. Although EAT reductions are commonly attributed to weight loss, the extent to which EAT change is explained by body mass index (BMI) reduction versus intervention-specific effects remains unclear. We performed a systematic review and multilevel meta-regression of interventional studies reporting pre- and post-intervention changes in EAT and BMI. MEDLINE, Embase, and Cochrane CENTRAL were searched from inception to April 2026. Standardized mean change using pre-test standardization (SMCR) was calculated for both outcomes. Multilevel meta-regression assessed the association between BMI and EAT change while adjusting for intervention class, follow-up duration, and imaging modality. BMI-adjusted residual analyses were used descriptively to evaluate deviations from model-predicted EAT responses. Forty-two studies comprising 50 intervention arms and 1,890 participants were included. Across all interventions, both EAT and BMI decreased significantly. In the multivariable meta-regression model, BMI reduction was associated with EAT reduction (β = 0.19, p = 0.03), although BMI explained only a limited proportion of variability in EAT response. Intervention class remained a significant moderator of EAT change (p < 0.001). Larger observed reductions in EAT were seen with dietary interventions, GLP-1 receptor agonists, and bariatric surgery. In descriptive residual analyses, dietary interventions and GLP-1 receptor agonists demonstrated greater-than-predicted reductions in EAT relative to the overall study-level BMI-EAT relationship. These findings should be interpreted cautiously because intervention-specific comparisons were exploratory and do not constitute formal comparative efficacy estimates. EAT reduction is only partially explained by systemic weight loss, and substantial heterogeneity exists across intervention classes. These findings support the concept that EAT remodeling may be influenced by factors beyond generalized adiposity reduction. However, intervention-specific patterns observed in this study are descriptive and hypothesis-generating and require confirmation in adequately powered comparative studies. Moreover, overall certainty of evidence was low for pooled EAT reduction and very low for intervention-specific comparative patterns. PROSPERO (CRD420261367140).

Pathological complete response (pCR) following neoadjuvant therapy is associated with favorable prognosis in esophageal adenocarcinoma. However, whether long-term outcomes differ by neoadjuvant modality among patients achieving pCR remains uncertain. To compare survival outcomes and recurrence patterns in patients with esophageal or gastroesophageal junction adenocarcinoma achieving pCR after perioperative 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy vs the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study protocol (CROSS). This cohort study was conducted at 14 high-volume European esophagogastric cancer centers between January 2018 and December 2024 with follow-up from surgery to death or last contact among patients with esophageal or junctional adenocarcinoma treated with neoadjuvant therapy followed by curative esophagectomy. Patients with squamous carcinoma, noncurative resection, incomplete pathological response, or 90-day mortality were excluded. Neoadjuvant perioperative FLOT chemotherapy or CROSS chemoradiotherapy followed by curative-intent esophagectomy. The primary outcome was overall survival. Secondary outcomes included disease-free survival, recurrence patterns, and nodal stage-stratified survival. Survival was estimated using Kaplan-Meier methods and multivariable Cox proportional hazards models. Among 2717 eligible patients, 297 achieved pCR and were analyzed (mean [SD] age, 64.4 [9.7] years; 256 [79.5%] men). Of these, 150 received CROSS and 147 FLOT. FLOT patients were younger and more frequently clinically node-positive at baseline, while postoperative outcomes were similar. On unadjusted analysis, FLOT was associated with better overall survival (hazard ratio [HR], 0.32; 95% CI, 0.17-0.60; P < .001) and disease-free survival (HR, 0.32; 95% CI, 0.19-0.55; P < .001). After adjustment, FLOT remained independently associated with better overall survival (HR, 0.34; 95% CI, 0.16-0.69; P = .003) and disease-free survival (HR, 0.35; 95% CI, 0.19-0.62; P < .001). Recurrence occurred in 13 of 147 patients receiving FLOT (8.8%) compared with 37 of 150 receiving CROSS (24.7%). Distant metastases predominated in the CROSS group (27 of 37 recurrences [70.3%]), whereas recurrence patterns were more heterogeneous after FLOT (locoregional, 2 of 13 recurrences [15.4%]; distant, 2 of 13 recurrences [38.5%]; both, 6 of 13 recurrences [30.8%]). The median (IQR) time to recurrence was longer after FLOT than CROSS (16.8 [12.3-21.5] vs 12.8 [7.1-26.7] months). In subgroup analyses, FLOT was associated with better survival in cN0 or 1 disease (HR, 0.32; 95% CI, 0.15-0.67; P = .002). In this cohort study, perioperative FLOT in patients achieving pCR for esophageal adenocarcinoma was associated with superior survival, lower recurrence risk, and later recurrence compared with CROSS. These findings suggest the prognostic significance of pCR may vary by neoadjuvant modality and should be interpreted in the context of treatment strategy.

Photodynamic therapy (PDT) demonstrates remarkable versatility by activating diverse non-apoptotic cell death pathways, effectively circumventing apoptosis resistance and enhancing tumor eradication. Key mechanisms include autophagic cell death, regulated necrosis-driven immune activation, ferroptosis-mediated oxygen replenishment, pyroptosis-induced immunogenic cell death (ICD), and paraptosis. These pathways collectively highlight PDT's capacity to disrupt tumor survival mechanisms and stimulate systemic anti-tumor immunity. However, several challenges remain, including precise spatiotemporal control of ROS, hypoxia mitigation, and selective photosensitizer delivery. Advances in nanotechnology, hypoxia-responsive agents, and combination therapies (e.g., immune checkpoint inhibitors or chemotherapy) hold promise for overcoming these limitations. In this review, we discuss multiple types of non-apoptotic cell death pathways activated by PDT and the underlying mechanisms of each distinct cell death process. We also review the clinical applications and current challenges of leveraging these pathways to enhance tumor treatment in PDT. Future research should prioritize the development of subcellular-targeted photosensitizers, deeper light-penetration technologies, and biomarker-guided personalized regimens for more precise and effective PDT.

Alcohol use disorder (AUD) is characterized by high relapse rates, necessitating novel interventions. Continuous theta-burst stimulation (cTBS) targeting the right dorsolateral prefrontal cortex (rDLPFC) has been proposed to reduce relapse risk by modulating prefrontal control networks implicated in craving and self-regulation, but its efficacy and mechanisms remain to be established. In a randomized, double-blind, sham-controlled trial at the First Special Hospital of Harbin, 50 AUD patients (aged 18-60 years) received active cTBS or sham stimulation over 2 weeks (10 treatment days; two applications/day). Alcohol Use Disorders Identification Test (AUDIT) scores were assessed before and after intervention, and relapse status was monitored during the 1-year follow-up. Resting-state fMRI data were analyzed using non-negative matrix factorization (NMF) and Tabular Prior-data Fitted Network (TabPFN) to identify relapse-associated neural patterns. Network control theory (NCT) was used to quantify the control energy required to regulate frontoparietal network (FPN) to subcortical network (SUB) transitions, constrained by structural connectomes. Transcriptomic analysis and TransBrain-based cross-species phenotype mapping were used to link control energy changes to gene expression and investigate the evolutionary conservation of the identified network-control targets. Compared with sham treatment, active cTBS was associated with a lower risk of relapse over one year (hazard ratio = 0.426, 95% CI [0.189, 0.964], p = 0.041). NMF revealed an abstinence-associated pattern in the prefrontal-subcortical regions, enhanced by cTBS (p = 0.042). NCT showed a reduction in FPN-to-SUB control energy (p = 0.003), mediating changes in AUDIT-assessed alcohol-use severity (95% CI [-0.302, -0.014]). Changes in the control energy correlated with gene expression profiles enriched for genes related to neuroplasticity (p < 0.001, FDR corrected) and mapped specifically to the murine infralimbic and prelimbic areas. rDLPFC-targeted cTBS may be associated with lower relapse risk through modulation of FPN-to-SUB regulation, a network-level effect linked to neuroplasticity-related gene expression and evolutionarily conserved prefrontal circuits. These findings support further evaluation of network-informed neuromodulation strategies for AUD.

Obesity is an alarmingly growing global epidemic strongly associated with type 2 diabetes, cardiovascular disease, metabolic syndrome, and chronic kidney disease. Metabolic dysfunction-associated steatotic liver disease (MASLD) is considered an important contributor within this interconnected spectrum, representing a new component of the broader cardio-kidney-metabolic (CKM) syndrome, now more aptly labelled as the cardio-kidney-liver-metabolic (CKLM) syndrome. This narrative review synthesizes evidence from epidemiological studies, clinical trials, and ongoing scientific research to explore the multifaceted associations, complex interplay and shared pathophysiological mechanisms among these disorders. The clinical implications of this interplay are substantial, underscoring the need for a holistic approach encompassing early detection, comprehensive risk assessment, and multi-targeted interventions. Therapeutic strategies discussed include lifestyle modification, anti-diabetic, anti-obesity, lipid-lowering agents, and bariatric surgery. Given MASLD's potential role in the CKLM spectrum, future research should deepen the understanding of shared mechanisms and develop integrated clinical management strategies to improve outcomes and reduce their global burden.

Nanoscale phase transformations at interfaces enable unprecedented control over the structure and functionalities of low-dimensional materials. Flexoelectric polarization, universally produced by the strain gradient in all dielectrics, can be directly coupled to an external electric field and amplified at nanoscale interfaces. Here, we show that this coupling leads to an electromechanical response and a reversible phase transformation at a nanoscale flexoelectric layer between morphotropic phases. In epitaxial BiFeO3-BaTiO3 thin films, the external electric field triggers a transient structural transition from an interfacial flexoelectric layer to crystalline phases, as revealed by in situ time-resolved X-ray microdiffraction. When the electric field exceeds the built-in flexoelectric field, the net interfacial electrical polarization is reconstructed inversely, resulting in a change in the electromechanical response and phase transformation. These results establish flexoelectric coupling at nanoscale interfaces as an alternative, electrically controllable pathway for dynamic phase engineering in complex material systems.

Lactylation is a recently identified metabolism-associated post-translational modification that provides a mechanistic link between tumor metabolic reprogramming and epigenetic regulation. Although aberrant lactate accumulation in tumor tissues has long been recognized, a comprehensive and unified understanding of how lactate-derived modifications contribute to tumor initiation and progression remains lacking. Here, we use lactate metabolism as a conceptual framework to systematically review the biogenesis and regulatory networks of lactylation, with a particular focus on its functions and underlying molecular mechanisms in key malignant processes, including tumor proliferation, invasion and metastasis, angiogenesis, immune evasion, radiotherapy resistance and systemic therapy resistance. Furthermore, we review emerging anti-tumor therapeutic strategies targeting lactate metabolism and tumor lactylation, highlighting that glucose metabolism-driven lactate accumulation and lactylation play a pivotal role in sustaining tumor cell survival and immunosuppressive phenotypes. Inhibition of lactate metabolism markedly attenuates tumor-associated lactylation and exhibits substantial synergistic efficacy when combined with other anti-tumor therapies. Overall, this work advances a systematic understanding of the roles of lactylation in tumor malignant progression and provides an important conceptual and theoretical foundation for the development of novel cancer therapeutic strategies targeting protein lactylation.

Extracellular tumor-derived DNA (tDNA) has emerged as an important biomarker for cancer diagnosis and monitoring. A better understanding of the mechanisms controlling the abundance of tDNA could help improve biomarker and treatment strategies. In this study, we identified oncogenic KRAS as a critical regulator of tDNA levels. Mutant KRAS promoted tDNA clearance by inducing the tetraspanin CD9, which recruited FXR1 to remodel the actin cortex, lower plasma membrane tension, and promote endocytic uptake of extracellular tDNA. The reduction in tDNA dampened ZBP1-dependent DNA sensing in tumor-associated macrophages (TAM), shifting them toward an immunosuppressive state. Blockade of CD9 restored extracellular tDNA and DNA sensing, reprogrammed TAMs, and synergized with PD-1 blockade in KRAS-mutant cancer models. These findings delineate a KRAS-CD9-FXR1 pathway that couples membrane mechanics to extracellular DNA clearance and immune evasion, providing a strong rationale for targeting CD9 to augment the efficacy of immune checkpoint blockade therapy. KRAS activates CD9-FXR1 signaling that reduces membrane tension to promote extracellular tumor DNA uptake and reduce innate DNA sensing, reshaping the immune landscape and opening opportunities for KRAS-mutant cancer diagnosis and treatment. See related commentary by McAndrews, p. 3371.