胃肠外科领域文献阅读汇编

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.

Intraoperative image guidance has become a central component of modern surgical oncology, with near-infrared (NIR) fluorescence imaging emerging as a powerful platform for real-time visualization and precision intervention. Owing to its favorable optical characteristics, including reduced tissue autofluorescence, improved penetration depth, and excellent safety profile, NIR fluorescence imaging has rapidly evolved from experimental validation to clinical integration in gastrointestinal surgery. This review summarizes recent advances in both nonspecific and molecularly targeted NIR fluorescence imaging strategies for gastric tumors, with a particular emphasis on their integration with targeted drug delivery and theranostic applications. Preclinical studies demonstrate that NIR fluorophores conjugated to drugs, antibodies, or tumor-specific ligands enable high-contrast visualization of primary and metastatic lesions while supporting image-guided resection and localized phototherapy in gastric cancer (GC), gastrointestinal stromal tumors (GISTs), and neuroendocrine tumors. Large-animal models further validate the translational feasibility of NIR imaging for intraoperative assessment of vascular perfusion, anastomotic integrity, and sentinel lymph node (SLN) mapping. Clinically, NIR fluorescence imaging, most commonly using indocyanine green, enhances SLN detection, identifies metastatic lymphatic pathways beyond conventional dissection fields, and enables objective evaluation of tissue perfusion, thereby reducing postoperative complications. Collectively, NIR fluorescence imaging represents a versatile platform that bridges molecular imaging, drug delivery, and surgical intervention. Its integration into gastric tumor management has the potential to improve surgical precision, optimize therapeutic delivery, and accelerate the development of personalized and minimally invasive treatment strategies.

Generative indigo carmine chromoendoscopy (generative chromoendoscopy), produced using deep learning-based synthetic image transformation, is a novel image-enhanced endoscopic approach, whose clinical feasibility has not been validated. This proof-of-concept study evaluated whether generative chromoendoscopy improves the visibility of gastric neoplasms compared with conventional white-light imaging (WLI) and real chromoendoscopy. This prospective multicenter study was conducted at three Japanese institutions between January and August 2025. A deep neural network-based program converted WLI into generative chromoendoscopy images. Patients with early gastric cancer or adenoma sequentially underwent endoscopy using WLI, generative chromoendoscopy, and real chromoendoscopy. During live endoscopy, two endoscopists independently assessed lesion visibility using a 7-point Likert-type scale (-3 to +3). The primary end point was visibility of gastric neoplasms with generative chromoendoscopy relative to WLI, with comparison to real chromoendoscopy. Secondary end points included clinicopathologic factors associated with improved visibility. 60 patients were included. Mean (SD) visibility scores were 0.67 (0.93) for generative chromoendoscopy and 0.51 (1.00) for real chromoendoscopy. The mean difference was 0.16 (95%CI 0.01 to 0.30). Differentiated-type histology (odds ratio [OR] 2.19, 95%CI 1.03 to 4.62), current Helicobacter pylori infection (OR 2.14, 95%CI 1.02 to 4.46), and expert endoscopist status (OR 2.14, 95%CI 1.22 to 3.76) were significantly associated with higher visibility scores using generative chromoendoscopy. Generative chromoendoscopy was feasible during live endoscopic procedures. It improved visibility of pre-identified gastric neoplasms compared with WLI and achieved visibility comparable to real chromoendoscopy.

Extrachromosomal DNA (ecDNA), as a dynamic genetic vector, enables tumor cells to exhibit enhanced adaptability under chemotherapeutic stress. However, its functional role in tumor malignancy and the development of drug resistance in gastric cancer (GC) remains unclear. This study aims to investigate the relationship between chemotherapy and ecDNA in GC, and explore its potential as a novel therapeutic target. We first analyzed our clinical data to reveal associations between ecDNA induction by chemotherapy and metastatic progression. Then we investigated the role of ecDNA in mediating chemoresistance and malignant phenotypes in cisplatin-resistant cell models using WGS, SEM, western blot, qPCR, flow cytometry, and immunofluorescence. We found that neoadjuvant chemotherapy (NAC) promoted ecDNA formation from linear amplicons, which was associated with increased tumor mutational burden, poorer survival, and higher distant metastasis risk. The generation of ecDNA in GC was more likely to originate from chromosomes 5, 7, 8, 9, and 12. In cisplatin-resistant models, ecDNA emergence promoted various malignant phenotypes, including DNA damage repair, G1 arrest, autophagy, proliferation, migration, and invasion, which were attenuated by ecDNA inhibition. EcDNA inhibitors delayed acquired resistance in wild-type cells and showed combinatorial activity with cisplatin in resistant GC, supporting clinical potential. Our study revealed that cisplatin could promote ecDNA generation, which enhanced malignant phenotypes, including cell proliferation, motility and drug resistance, and was associated with poorer patient prognosis. Targeting ecDNA with inhibitors could reverse these effects, supporting further preclinical evaluation.

Selenium deficiency is linked to gastric cancer, and p53 mutant tumors often acquire chemoresistance. To address this, we designed a camptothecin (CPT) dimeric prodrug with a hybrid -S-Se-S- linker (CPT-S-Se-S-CPT). It self-assembles into uniform nanoparticles (SSeSCPT NPs) with dual redox-responsive release triggered by glutathione and reactive oxygen species. Selenium plays dual synergistic roles: it enhances cellular uptake and pharmacokinetics while reducing systemic toxicity; it also acts as a redox-active center to amplify oxidative stress, activating p38/MAPK and unfolded protein response pathways, thereby inducing p53-independent apoptosis and overcoming drug resistance. In vivo, SSeSCPT NPs prolong plasma half-life, achieve efficient tumor accumulation via the EPR effect, and show potent antitumor activity in p53 mutant gastric cancer models. Surface selenium groups recognize Toll-like receptor 4 (TLR4) overexpressed on tumor cells, promoting clathrin/caveolin-mediated endocytosis and bypassing EPR size limitations. This nanoplatform integrates CPT chemotherapy, selenium intervention, and the p53 mutation background into a single system, establishing a toxicity-controlled, efficacy-enhanced strategy. It also reveals how selenium-based nanomaterials remodel redox homeostasis, bypass p53 deficiency, and reprogram apoptotic networks. This work provides mechanistic insights and translational directions for precision therapy of p53 mutant gastrointestinal malignancies.

Gastric cancer remains a leading cause of cancer mortality. The Correa cascade-stepwise progression from inflammation through atrophic gastritis, metaplasia and dysplasia to adenocarcinoma-has long defined its pathogenesis. Lineage tracing, single-cell multi-omics and organoid models now reveal marked cellular heterogeneity, plasticity and non-sequential trajectories. This review synthesises gastric stem-cell identity, niche architecture and precancerous progression. Homeostasis is sustained by cycling antral LGR5+ basal and IQGAP3+ isthmus progenitors and by quiescent corpus MIST1+/TROY+ chief-cell reserves, coordinated by Wnt/R-spondin, Notch, BMP, Hedgehog and EGFR signalling. Helicobacter pylori subverts this niche through type-IV-secretion-system delivery of cytotoxin-associated gene A and through BMP collapse, driving region-specific trajectories. In the antrum, hyperproliferation and CDX2-dependent intestinal metaplasia advance to TP53/KRAS/APC-mutant dysplasia. In the corpus, oxyntic atrophy triggers isthmus expansion via type-2 innate lymphoid cell (ILC2)-derived WNT5A and YAP signalling, alongside a tuft-cell-ILC2 interleukin-25/interleukin-13 circuit driving spasmolytic polypeptide-expressing metaplasia (SPEM). In lineage-tracing models, KrasG12D-mutant isthmus cells can also bypass SPEM to generate dysplasia directly. Further origins include ATOH1-deficient pit cells and bone-marrow-derived epithelial hybrids. Together, these findings support a regionally stratified, stem-cell-centred model in which metaplasia and dysplasia arise as parallel cellular fates. This refinement operates at the cellular level without displacing the tissue-level Correa sequence documented in long-term human cohorts. It nominates the remodelled stem-cell niche as a tractable pharmacological target and warrants molecular profiling of at-risk progenitor populations to complement, rather than replace, histopathological surveillance.

d-amino acids (D-AAs), the enantiomers of proteinogenic l-amino acids, are detectable in mammals, yet their biological roles in cancer immunity remain largely unexplored. Whether specific D-AAs modulate tumour progression or influence responsiveness to immunotherapy in gastrointestinal cancer is unknown. We aimed to determine how D-AAs, particularly d-serine (D-ser), shape the tumour immune microenvironment and affect clinical outcomes in gastrointestinal cancers. Mechanistic studies were conducted using murine MC38 tumours and orthotopic gastric cancer (GC) organoid allografts with or without D-AAs supplementation. Immune landscape alterations were assessed using single-cell RNA sequencing of tumour-infiltrating immune cells, flow cytometry, ex vivo macrophage-T cell co-culture assays, and microbiome manipulation experiments. D-AAs concentrations in plasma, urine, and stool were quantified in healthy controls (HCs; n = 87) and patients with GC across three cohorts (Cohort 1, n = 14; Cohort 2, n = 108; Cohort 3, n = 28). Associations between plasma D-ser levels, disease stage, immune cell infiltration, and clinical outcomes following anti-PD-1 antibody therapy were analysed. D-ser promoted tumour progression by suppressing CD8+ T cell immunity and enhancing SPP1-associated immunosuppressive macrophage signalling in murine model. Across all clinical cohorts, the plasma, urine, and stool levels of several D-AAs, most prominently D-ser, were significantly elevated in patients with GC compared to HCs. Plasma concentration of D-ser strongly correlated with disease stage (I-IV). Elevated plasma D-ser is associated with an immunosuppressive tumour microenvironment and poor response to anti-PD-1 monotherapy in patients with advanced gastric cancer. This study identifies D-ser as a previously unrecognised immunosuppressive metabolite that promotes tumour immune evasion by increased macrophages and reduced CD8+ T cell effector function, thereby shifting the tumour microenvironment toward an immunosuppressive phenotype. Clinically, D-ser is a potential metabolite to predict cancer progression and immunotherapy resistance. This work was supported by The Japan Science and Technology Agency (JST) Fusion Oriented Research for Disruptive Science and Technology (FOREST)[JPMJFR210P], Grants-in-Aid from the Japanese Society for the Promotion of Science (JSPS) (25K10430, 21K18272, 23H02899, 23K27590, 25K22627), KGRI challenge grant, Sakaguchi Memorial Foundation, Japan Agency for Medical Research and Development (CREST 21gm1510002h0001), and Miyarisan Pharmaceutical Grant.

Gastric cancer (GC) remains a major clinical challenge, with most patients exhibiting primary resistance to anti-programmed cell death protein-1 (anti-PD-1) immunotherapy and a lack of effective predictive biomarkers. Most advanced GC presents as immune-excluded "cold" tumors that respond poorly to immune checkpoint blockade. Traditional Chinese medicine (TCM) "Yong (abscess)" syndrome and the "treating GC as Yong" theory are widely applied in clinical practice, yet lack clear molecular and immunological mechanisms. Here, by translating these clinical observations into modern biological terms, we present an original, testable hypothesis proposing the "Yong" syndrome-cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) axis as the central molecular bridge connecting TCM syndrome subtypes, GC histological subtypes, and TME reprogramming. We hypothesize that heat-clearing and blood-activating TCM monomers activate cGAS-STING in a subtype-selective manner to convert "cold" tumors to "hot" immunogenic phenotypes, directly addressing the critical clinical dilemmas of primary anti-PD-1 resistance and insufficient biomarkers in GC immunotherapy. This hypothesis translates universal cGAS-STING mechanisms into a clinically actionable, syndrome-based precision strategy for GC.

Resistance to anti-programmed cell death protein-1 (PD-1) treatment in gastric cancer (GC) is closely associated with an immunosuppressive tumor microenvironment. However, the role of neutrophils in resistance to anti-PD-1 therapy remains unclear. Single-cell RNA sequencing was performed on tumor samples from patients with advanced GC receiving anti-PD-1 therapy to identify neutrophil subsets associated with neutrophil extracellular traps (NETs). Multilevel experimental validation was conducted using multiomics analysis, flow cytometry, multiplex immunofluorescence, and in vitro co-culture. Therapeutic strategies targeting NETs and CD8+ T-cell exhaustion were evaluated in a mouse model of YTN16 tumors. We identified a NETs-associated neutrophil subset enriched in patients with GC resistant to anti-PD-1 treatment. This subset was marked by CD177, and it exhibited a high potential for NETs release. Peripheral blood NETs levels and CD177+ neutrophil ratios in patients with GC act as markers for evaluating the efficacy of PD-1 inhibitors. Furthermore, transforming growth factor-β1 (TGF-β1), which was highly expressed in GC and spatially colocalized with CD177+ neutrophils, might induce neutrophils to release NETs via the Smad3-NFE2 axis. NETs promoted CD8+ T cell exhaustion by activating the MEK/ERK-c-Fos/JunB axis, as evidenced by increased PD-1/TIM3 expression and reduced interferon-gamma/tumor necrosis factor-alpha secretion. In vivo experiments confirmed that targeted inhibition of NETs formation using DNase I or TGF-β1 inhibitors significantly suppressed tumor growth and CD8+ T cell exhaustion. Notably, the MEK inhibitor trametinib reversed the immunosuppressive microenvironment associated with CD8+ T cell exhaustion and synergistically enhanced the antitumor efficacy with anti-PD-1 therapy. TGF-β1 drives CD177+ neutrophils to release NETs, which induce CD8+ T cell exhaustion via the ERK-c-Fos-JunB pathway, thereby mediating resistance to anti-PD-1 treatment in GC. Furthermore, targeting NETs formation and combining trametinib with PD-1 inhibitors can significantly reverse CD8+ T cell exhaustion, exert synergistic antitumor effects, and offer a potential therapeutic strategy for overcoming resistance to anti-PD-1 therapy in GC.

The early diagnosis of gastric cancer (GC) faces great challenges due to the lack of specific biomarkers. Therefore, it is crucial to discover effective markers and establish highly sensitive detection methods. This study validated the potential of BTN3A2 protein as an early GC biomarker by analyzing serum samples from patients with GC, benign gastritis, other digestive system cancers, and healthy controls across three clinical centers. Furthermore, a chemiluminescent (CL) imaging immunosensor based on copper-doped NiFe PBA (Cu-NiFe PBA) nanozyme probe was developed to achieve highly sensitive detection of BTN3A2 protein in serum of patients with GC and healthy controls. The high detection sensitivity for BTN3A2 was achieved by copper doping to enhance peroxidase-like activity of nanozyme for signal amplification. The proposed sensor exhibits a broad linear range from 0.5 to 5000 pg/mL, and achieves a detection limit of 0.15 pg/mL (S/N = 3). In addition, the established sensor is successfully utilized for BTN3A2 detection in serum samples from GC and healthy individuals across three clinical centers, and demonstrates perfect correlation with clinical outcomes when compared with traditional enzyme-linked immunosorbent assay. This study provides a candidate serum biomarker in the early stage of GC and offers a convenient, highly sensitive method for its detection.

Gastric cancer (GC) has shown relatively poor responses to existing immune therapies. The extensive infiltration of tissue-resident memory T cells (TRM) in tumor microenvironment (TME) is associated with better Overall Survival (OS) in patients treated with immune checkpoint inhibitors (ICIs). However, the precise roles of TRM cells in cancer immunity and responses to ICIs in GC remain poorly understood. We found that the TRM cells representing the majority of tumor-infiltrating lymphocytes and expressing high level of immune checkpoint TIGIT in GC tissue. This study aims to elucidate the mechanisms through which GC cells modulate TRM cells by PVR/TIGIT axis to facilitate immune evasion. The immune status of GC was evaluated by quantifying T cell subsets in GC tissues through flow cytometry. The biological functions and molecular mechanisms by which the oncogenic factor PRDM15 mediates tumor immune evasion were investigated through the PVR/TIGIT axis using transcriptome sequencing, Chromatin immunoprecipitation (ChIP) assay and Co-immunoprecipitation assay. The therapeutic potential of PRDM15/PVR/TIGIT was analyzed using tumor-bearing models. We confirmed that PRDM15 promotes the transcription of PVR which is the ligand of TIGIT in GC cells. Aberrantly high expression of PRDM15 in GC tissues was associated with higher TNM stages and T cell immunosuppressive state in GC patients. PRDM15 was found to upregulate the proliferation, invasion and migration of GC cells. When co-cultured with TRM cells with high TIGIT expression, PRDM15 activated the PVR/TIGIT axis to inhibit TRM cells activation by upregulating PVR expression in GC cells. Mechanistically, PRDM15 recruited the histone methyltransferase complex PRMT5/Mep50/WDR5 to activate PVR transcription. This study demonstrated that PRDM15 in GC cells could recruits the histone methyltransferase complex PRMT5/Mep50/WDR5 to promote PVR transcription, thereby activating the PVR/TIGIT axis, which inhibits TRM cells activation and mediates immune escape and GC progression.

The tumor microenvironment, particularly the tumor stroma, plays a critical role in tumor progression, immune evasion, and therapeutic resistance. However, its interaction with the immune landscape in rectal cancer (RC) remains incompletely understood. This study aimed to comprehensively characterize the stromal-immune ecosystem associated with the tumor stroma ratio (TSR) in RC and to evaluate its clinical and therapeutic relevance. We analyzed a multicenter cohort of 498 patients with treatment-naïve RC in whom TSR was assessed on H&E-stained sections. Integrative multi-omics analyses were performed, including bulk RNA sequencing (n=118) and single-cell RNA/T-cell receptor (TCR) sequencing (n=10). Key findings were validated by immunohistochemistry (n=114) and multiplex immunofluorescence (n=20). Survival analyses and statistical comparisons were conducted to evaluate clinical associations and treatment responses. High TSR was an independent predictor of unfavorable disease-free survival and cancer-specific survival and was associated with aggressive clinicopathological features. Single-cell analyses revealed that TSR-high tumors exhibited a profoundly immunosuppressive microenvironment, characterized by clonally expanded terminally exhausted CD8+ T cells (CD8+ Tex-CXCL13) and activated CD4+ regulatory T cells (CD4+ Treg-TNFRSF4). Two LRRC15+ cancer-associated fibroblast (CAF) subsets (mCAF-CTHRC1 and mCAF-FAP) were enriched in TSR-high tumors. Among them, mCAF-CTHRC1 was associated with increased Treg abundance and activation features, with predicted interactions with CD4+ Treg-TNFRSF4 cells through the LGALS9-CD44 signaling axis. In addition, SPP1-expressing monocytes (Mon-SPP1) and malignant epithelial cells were prominent in TSR-high tumors and showed a predicted SPP1-CD44 interaction with T-cell subsets, suggesting potential involvement in immunosuppressive stromal-immune interactions. In patients receiving neoadjuvant therapy, pretreatment TSR-low tumors showed improved pathological response and survival outcomes compared with TSR-high tumors. In the neoadjuvant chemoradiotherapy plus immunotherapy cohort, TSR-low tumors were associated with a significantly higher major pathological response rate, whereas pathological complete response showed a non-significant trend in the same direction. High TSR identifies a clinically aggressive subtype of RC characterized by a profoundly immunosuppressive stromal-immune ecosystem enriched for exhausted T cells, immunosuppressive CAF programs, and SPP1-associated stromal-myeloid interactions. These findings highlight LGALS9-, LRRC15-, and SPP1-related stromal-immune pathways as candidate stromal-immune therapeutic vulnerabilities that warrant further mechanistic and preclinical validation.

Microsatellite stable (MSS) rectal cancer exhibits intrinsic resistance to immunotherapy. Although radiotherapy is frequently combined with immune checkpoint inhibitors (ICI) to augment immunotherapy responses, numerous immunologically cold tumors remain unresponsive. In this study, we observed a significant increase in electron transport chain activity, acetyl-CoA levels, and global lysine acetylation levels in patients achieving a pathologic complete response following immunotherapy administered after radiotherapy. Transcriptomic screening and in vivo experiments revealed that SIRT1, a key regulator of protein acetylation, restricted the immunostimulatory effects of radiotherapy. Mechanistically, SIRT1 deacetylated DDX5, promoting the unwinding of irradiation-induced R-loops and inhibiting the accumulation of cytoplasmic RNA:DNA hybrids to suppress cGAS/STING pathway activation and T-cell infiltration. Moreover, radiotherapy induced a tryptophan-SIRT1-SLC36A4 positive feedback loop that enhanced SIRT1 activity and promoted competitive tryptophan uptake from the microenvironment, thereby inhibiting tertiary lymphoid structure (TLS) formation and radioimmunotherapy efficacy. Finally, combining both an SIRT1 inhibitor and aspirin with radiotherapy converted ICI-unresponsive rectal cancer into immunogenic tumors that were sensitive to ICI. Together, this study identifies SIRT1 as a potential biomarker and therapeutic target to overcome radioimmunotherapy resistance in MSS rectal cancer. Radiotherapy activates a tryptophan-SIRT1 metabolic feedback loop in microsatellite stable rectal cancer that suppresses T cell infiltration and tertiary lymphoid structures formation, which can be overcome with SIRT1 inhibition and aspirin.

The quiescence-activation transition of cancer stem cells regulated by environmental stimuli has been shown to potentially contribute to cancer maintenance and regrowth after therapy. However, little is known about how the neoplastic niche couples with neighboring signals to control the activation of quiescent rectal cancer stem cells during radiotherapy. Lineage-tracing experiments were performed usingHopxCreERT2;RosatdTomato mice and organoids to visualize the dynamics and radioresistance ofHopx-expressing cells in vivo. BrdU pulse-chase assays and cell cycle analysis were used to identify whether Hopx+ stem cells were label-retaining cells (LRCs). The paracrine pro-survival effect of radiotherapy-induced dying cancer cells on neighboring Hopx+ quiescent stem cells was analyzed in the context of both apoptosis and necroptosis blockade. Human rectal cancer organoids and patient-derived xenografts (PDXs) were used to assess the radiotherapy-enhanced efficacy of Hopx targeting. Lineage tracing experiments revealed that Hopx+ quiescent stem cell subpopulation exhibited an enhanced regeneration, which functionally drove the recurrence of rectal cancer after irradiation. Mechanistically, iron released from radiotherapy-induced tumor cell death triggered a Stat3-dependent pro-survival program in neighbor-surviving Hopx+ quiescent stem cells. Interestingly, we demonstrated activated Hopx+ cancer stem cells antagonized ferroptosis that should be caused by iron-overload via the inhibition of de novo lipid synthesis. Collectively, quiescent cancer stem cells could establish a new dependency on anti-apoptotic programs in their dying neighbors. This study highlights targeting and regulating Hopx+ quiescent stem cells could be a promising therapeutic approach to overcome the refractoriness of human rectal cancer.

Helicobacter pylori infection is the principal cause of peptic ulcer disease, mucosa-associated lymphoid tissue lymphoma, and noncardia gastric cancer. The major advances in diagnostics and treatment and eradication success are threatened by rising antimicrobial resistance and concerns about disruption of the normal microbiome. This review summarizes current unresolved issues in H pylori treatment, with a focus on resistance, optimal regimens, ecological impact, and emerging therapies. Extensive review of randomized controlled trials, meta-analyses, international consensus guidelines, molecular epidemiology studies, microbiome analyses, and translational research related to H pylori eradication, resistance, microbiome effects, and novel therapies. Global resistance to clarithromycin, metronidazole, and fluoroquinolones significantly undermines the performance of traditionally effective antimicrobial therapies. The corner stone of successful antimicrobial therapy is susceptibility-guided therapy but remains of limited use with H pylori because of lack of infrastructure. Eradication regimens potentially induce substantial alterations in gut and gastric microbiota and expand the antimicrobial resistome. Probiotics and N-acetylcysteine offer at best very modest improvements in eradication and tolerability. Novel and still experimental platforms, including engineered phage therapy, antimicrobial peptides, nanoparticle-delivered urease inhibitors, biofilm-targeting agents, and vaccines show promise. Implementation gaps, persistent use of suboptimal regimens, and global inequities constrain the impact of available therapies. Optimizing H pylori treatment requires evidence-based regimen selection, precision-guided strategies, antimicrobial stewardship, and equitable access to essential medications. Advances in molecular diagnostics, antimicrobial development, and implementation science are all critical to reducing the global burden of H pylori-associated disease and gastric cancer.

The aim of this study was to evaluate the potential role of intestinal ultrasound scan (IUS) in predicting short-term treatment outcomes in pediatric acute severe ulcerative colitis (ASUC). This prospective longitudinal study was conducted across 10 European centers. Biologic-naïve children with ASUC were included. Each patient underwent 2 IUS, the first within 48 hours of initiating intravenous corticosteroids, and the second between day 5 and 7 of treatment. Key metrics assessed included colonic wall thickness (CWT), colonic wall stratification (CWS), and colonic wall blood flow via power Doppler. The Milan ultrasound score was also calculated for each colonic quadrant. The study prospectively enrolled 60 patients (61.7% girls; median age at enrollment, 13.5 years). Escalation to infliximab was required in 39 patients (65%) who were corticosteroid nonresponders. Nonresponders had significantly higher CWT assessed in the left-lower quadrant (LLQ) (6 vs 4.2 mm, P < .001) and left upper quadrant (5 vs 4 mm, P = .003) and had more frequent hypervascularity (Limberg's score ≥3) assessed in the same sections. Receiver operator characteristic curve analysis identified LLQ CWT >5 mm (area under the curve [AUC] = 0.819) and Milan Ultrasound Criteria >7.8 (AUC = 0.834) as optimal cutoffs for predicting steroid resistance. Ten patients (16.7%) who did not respond to medical therapy underwent colectomy within the 8-week period of the study. At the second IUS, CWT >4.8 mm and Milan Ultrasound Criteria >8.7 in LLQ were associated with medical therapy failure (AUC = 0.844 and 0.878, respectively). Patients in steroid-free clinical remission at week 8 had lower CWT (3.5 vs 5 mm, P = .037) and Milan Ultrasound Criteria (5.3 vs 8.7, P < .001) at the second IUS. IUS is an effective noninvasive tool to predict first-line therapy failure and the need for colectomy in patients with ASUC.

Understanding how skeletal muscle responds to weight loss is crucial for developing targeted strategies to manage obesity and promote sustained improvement in metabolic health. Here, we investigated the molecular mechanisms underlying skeletal muscle reprogramming of gene expression and metabolic activity following Roux-en-Y gastric bypass (RYGB). Forty-one women were studied before and one year after RYGB surgery. We leveraged multi-omics (DNA methylomics and transcriptomics) and machine learning approaches to complement muscle metabolic analyses and clinical data to identify mechanisms underlying RYGB-induced muscle metabolic reprogramming. RYGB markedly decreased body weight and fat mass and improved metabolic health. Integrative analysis of vastus lateralis muscle identified 8233 genes with differentially methylated regions and 2173 differentially expressed genes post-RYGB surgery, of which 1197 genes were both differentially methylated and differentially expressed. Promoter hypomethylation was associated with the enhanced expression of transcription factors involved in skeletal muscle development and ribosomal subunits. In contrast, expression of genes encoding mitochondrial proteins decreased despite increases in mitochondrial content and enhanced mitochondrial function in skeletal muscle post-RYGB. Pre-operative muscle OXPHOS capacity, and expression of skeletal muscle hypertrophy and differentiation genes MYOC and EHMT2 were associated with weight loss success. RYGB improves systemic metabolic health and induces sustained skeletal muscle bioenergetic reprogramming characterised by enhanced expression of genes involved in myogenesis and protein translation, but decreased expression of genes involved in mitochondrial metabolism, which may reflect improved mitochondrial quality and function. These findings advance our understanding of skeletal muscle metabolic responses to weight loss and of individual variability in metabolic phenotypes. Canadian Institutes of Health Research (CIHR PJT183651-M-EH, 201709FDN-CEBA-116200-GRS), Diabetes Canada Investigator Award grant OG-3-22-5645-GS (GRS), J. Bruce Duncan Endowed Chair in Metabolic Diseases (GRS), Tier 1 Canada Research Chair in Mitochondrial Bioenergetics and Metabolic Health (M-EH), Tier 1 Canada Research Chair in Metabolic Diseases (GRS).

Preoperative analysis of body composition is critical for anticipating metabolic changes and optimizing outcomes after bariatric surgery (BS). This study assessed agreement between dual-energy X-ray absorptiometry (DXA)-derived fat-free mass (FFM) and lean soft tissue (LST) and estimates from anthropometric equations in individuals with class-II obesity or greater. FFM and LST were measured by DXA in 123 participants with class-II obesity or greater before and approximately 1 month after BS. Six equations were used to estimate FFM and five to estimate LST. The estimates were calculated at both time points, and changes from pre- to post-BS were compared with the DXA-derived values. Paired t-tests were used to evaluate differences between the predicted and measured values. At the group level, the Li et al. equation for higher body mass index (BMI) values demonstrated the highest agreement with DXA-FFM before surgery (mean-difference, 0.01 kg; 95% confidence interval [CI], -0.74 to 0.74), whereas the Li et al. equation for normal BMI values showed the greatest agreement at follow-up (mean-difference, 1.71 kg; 95% CI, 1.30 to 2.13). For LST estimation, the Salamat et al. equation provided the greatest accuracy before BS (mean-difference, 0.03 kg; 95% CI, -1.35 to 1.40), and the Kulkarni et al. equation achieved the best performance in capturing group-level changes during follow-up (mean-difference, 0.48 kg; 95% CI, 0.05 to 0.92). Although certain predictive equations yielded acceptable group-level agreement with DXA, their individual-level performance was inconsistent, limiting their clinical utility. Further research is warranted to develop predictive models with enhanced precision and reliability.

Post-endoscopy upper gastrointestinal cancer (PEUGIC) is defined as cancer diagnosed 6-36 months after a prior index endoscopy during which cancer was not diagnosed. Few studies have examined PEUGIC survival. We describe survival in PEUGIC patients compared with upper gastrointestinal cancer (UGIC) patients who did not undergo endoscopy without a cancer diagnosis prior to their diagnosis. This was a population-based retrospective survival analysis of UGIC patients diagnosed between January 2009 and December 2018 in England. Patients were categorized into "detected UGIC" (without prior endoscopy) and "PEUGIC" diagnosed 6-12, 12-18, 18-24, or 24-36 months after index endoscopy. PEUGIC survival was analyzed according to pre-existing Barrett's esophagus (BE), esophageal cancer histological, and gastric cancer. Kaplan-Meier all-cause survival curves investigated survival from both diagnosis and index endoscopy date. 98710 UGIC patients (9068 PEUGIC [9.2%]) were studied. Pre-existing BE was recorded for 9975 UGIC patients (10.1%), including 2583 PEUGIC (25.9%). PEUGIC survival was better than detected UGIC survival but the difference decreased as time between index endoscopy and diagnosis increased. Patients with pre-existing BE and PEUGIC had much better survival, with more stage 1 cancer (39.5% versus 8.4% for PEUGIC without BE; P < 0.001). Survival in PEUGIC and detected UGIC patients was similar when BE patients were excluded. Survival in PEUGIC patients with squamous cell carcinoma and gastric cancer was the same as for detected UGIC. Better survival in patients with PEUGIC compared with detected UGIC appeared to be related to BE surveillance. Epidemiological biases, including selection, lead time, and immortal time, should be considered when reporting PEUGIC survival outcomes.

Consensus on abdominal hernia treatment with biological meshes remains elusive, largely due to variable and dynamic responses that dictate extracellular matrix (ECM) remodeling outcomes. Matrix-bound nanovesicles (MBVs) are ECM-embedded bioactive cues that govern cell-mesh crosstalk, whereas their tissue-specific functions in immunomodulatory repair remain poorly understood. Herein, MBVs were isolated from clinically used small intestinal submucosa (SIS) and urinary bladder matrix (UBM)-SIS (UBM-SIS) meshes to investigate their differential immunomodulation during hernia repair. SIS MBVs promoted angiogenesis via ERK1/2 activation, while UBM MBVs favored anti-inflammatory macrophage polarization through transforming growth factor-β1(TGF-β1) signaling pathways, showing synergistic effects in combination. In the repair of a full-thickness rat model, UBM-SIS meshes elicited milder early inflammation than SIS meshes. However, the superior immunomodulation of UBM was compromised with the progressive exposure of SIS interlayer. Conversely, SIS meshes initially triggered pronounced inflammation but switched to an anti-inflammatory state after 4 weeks, facilitating tissue integration over 8 weeks through prevailing neovascularization. The ECM-driven response in distinct microenvironments closely aligned with the spatiotemporal release of respective MBVs, with mechanistic analyses corroborating their functional relevance in orchestrating reciprocal pro/anti-inflammatory and remodeling signals. Investigating tissue-specific MBVs offers insights into their roles in hernia repair and highlights emerging therapeutic potential in regenerative applications.