Introduction

Diet is one of the most important factors contributing to the multistep process of carcinogenesis. The functional role of exogenous xeno-microRNAs (miRNAs) in this context is poorly understood. Recently, we reported the detectability of food-derived xeno miRNAs in various foods and in the gastrointestinal and colonic mucosa. However, little is known about the translational role of xeno-miRNA in the GI mucosa and specifically in GI diseases.

Aims & Methods

In this work, we aimed to evaluate the potential clinical relevance of the xeno-miRNA miR-168 in the gastric mucosa along the preneoplastic conditions and gastric carcinogenesis. To this end, we performed quantitative analysis of miR-168 in different settings: 1) samples from patients with normal mucosa (N), chronic non-atrophic (CNAG) and atrophic gastritis (CAG) and intestinal metaplasia (IM) (n=72); 2) matched non-tumorous (NT-) and tumorous (T-) gastric cancer (GC) tissues (n=82) and 3) matched NT- and T-colorectal cancer (CRC) tissues (n=40). Survival analysis was performed using Kaplan-Meyer analysis.

Results

MiR-168 was reproducibly detectable in the samples examined, with higher levels in stomach compared to colon tissue. In the stomach, a significantly higher level of miR-168 was observed in NT-GC compared to N, CNAG, AG/IM samples (p<0.01 each), but there was no difference related to H. pylori positivity or inflammation grade. Interestingly, miR-168 was higher in patients with moderate or severe AG/IM or OLGIM 3/4. Despite a significant correlation of miR-168 expression, paired sample analysis revealed a higher level of miR-168 in NT-GC compared to T-GC, with the highest level observed in the cardia and the lowest in the gastric mucosa of the antrum. Survival analysis showed only a small trend towards worse overall survival for patients with highest to lowest miR-168 levels, mostly during the first 3 years, but no long-term difference regardless of Lauren's classification. MiR-168 levels in normal mucosa were not associated with overall survival. In correlation with matched GC samples, NT-CRC showed higher miR-168 levels compared to T-CRC, although overall there was a positive correlation between matched tissues. No survival difference was observed for higher or lower miR-168 levels in CRC.

Conclusion

Food-derived xeno-miRNA are present in the gastric and colonic mucosa, with the highest levels in the stomach compared to the colon and in non-tumour compared to tumour tissues. While the potential impact of miR-168 on overall survival was weak, the higher level of miR-168 in patients with moderate and severe IM deserves further attention and further functional analyses are needed to better understand the functional role of xeno-miRNA in the GI tract.

Disclosure

Alexander Link received: speakers fee Janssen; consulting fee: Ferring. Reserach funds from EU/EFRE.

Introduction

Patients with gastric intestinal metaplasia (GIM) are at an increased risk of developing gastric cancer (GC). The histological Operative Link on Gastric Intestinal Metaplasia (OLGIM) classification aids in risk stratification. The recently developed endoscopic grading of GIM (EGGIM) may accurately predict the OLGIM stage. This study aimed to evaluate the diagnostic accuracy of EGGIM in assessing histological GIM using data from two large, prospective European consortia.

Aims & Methods

Interim data were derived from the Artificially Intelligent Diagnostic Assistant (AIDA) and Towards Gastric Cancer Screening Implementation in the European Union (TOGAS) consortia, both part of a European Horizon programme focused on gastric cancer prevention. Patients in AIDA underwent oesophagogastroduodenoscopy (OGD) for GIM surveillance or treatment of neoplastic lesions, while participants in TOGAS (aged 50–74) were offered an OGD during screening colonoscopy or polyp surveillance. Procedures were performed at eight academic centres by both expert and non-expert endoscopists, using high-resolution white-light endoscopy and virtual chromoendoscopy. The EGGIM score (range 0–10) was based on the extent of GIM (0: 0%, 1: ≤30%, 2: >30% of mucosa) across five anatomical sites: the lesser and greater curvatures of the antrum and corpus, and the incisura. Targeted biopsies were taken if GIM was suspected; otherwise, random biopsies were collected according to the Sydney system to determine the OLGIM stage. Healthy controls and GIM patients with an EGGIM score ≥1 but OLGIM stage 0 were also included. ROC curve and Spearman analyses assessed the diagnostic and ordinal correlation between EGGIM and OLGIM stages III–IV.

Results

A total of 252 patients were included (median age 60 years, IQR 9; 57.4% female): 91 from the TOGAS study (75 cancer screening, 16 polyp surveillance) and 161 from AIDA (117 GIM surveillance, 21 neoplasia treatment, 23 healthy controls). OLGIM staging identified 89 (35.3%) patients in stage 0, 74 (29.4%) in stage I, 49 (19.4%) in stage II, 35 (13.9%) in stage III, and 5 (2.0%) in stage IV. The area under the ROC curve for EGGIM in detecting OLGIM III/IV was 0.90 (95% CI 0.79–0.93, p < 0.001), with an optimal cut-off at EGGIM ≥5 (sensitivity 85%, specificity 89%).

Conclusion

Our findings prospectively validate the EGGIM score across two large European cohorts. This scoring system may serve as a practical tool to streamline gastric cancer surveillance by reducing the need for biopsies and enhancing endoscopic risk stratification.

References

Esposito G, Pimentel-Nunes P, Angeletti S, et al. Endoscopic grading of gastric intestinal metaplasia (EGGIM): a multicenter validation study. Endoscopy. 2019;51(6):515-521. doi:10.1055/a-0808-3186

Introduction

Small intestinal bacterial overgrowth (SIBO) is frequent in patients with past or active upper GI cancer. SIBO is associated with clinical symptoms including, bloating and diarrhea that may impact negatively on quality of life. Current treatment of SIBO is empirical and relies on the cyclical use of antibiotics.

Aims & Methods

The aim of the present study was to characterize the microbiome composition of patient with upper GI cancer with or with no SIBO.
From April 2021 to May 2022, consecutive patients with past or active GI cancer attending our oncology outpatient department were enrolled in a prospective case control study. Treatment naïve patients with a first diagnosis of upper GI cancer but no SIBO-related symptoms served as controls. All included patients completed a standardised questionnaire about SIBO-related symptoms (bloating, diarrhoea), concomitant medications, and quality of life. They were offered upper endoscopy with duodenal aspirate, provided a 30-day period with no antibiotic intake. SIBO was defined as a bacterial count greater than 10³ colony forming units per millilitre in the duodenal aspirate. Using optimized protocol, the DNA from duodenal aspirate was extracted and the V1-V2 region of the 16S rRNA gene was amplified by PCR and sequencing using the Illumina platform. Dedicated bioinformatical approach was used for the multifactorial sample analysis.

Results

The microbiome composition was analyzed in 7 controls, 17 patients with SIBO and 12 with no SIBO.
We detected 513 phylotypes from 71 genera belonging to 11 phyla in the duodenal aspirate. The most abundant genera were Streptococcus, Veillonella and Prevotella. All three groups differed significantly in terms of their microbiome at phylum level (PERMANOVA p < 0.05). Based on the analysis of the individual phyla, we were able to show that the abundance of Proteobacteria was significantly higher in the SIBO group (Kruskal-Wallis test p < 0.05). Correlation analyses revealed an association between bacterial abundance and clinical phenotype. For instance, Proteobacteria, correlated positively with diarrhea intensity (Spearman r=0.35, p= 0.0362), and that Bacteroidetes correlated negatively with the reduction in quality of life (Spearman r=-0.4525, p=0.0056). Within the overall cohort, we were able to identify two clusters characterized by different microbial composition, underlying malignant diseases and clinical symptoms.

Conclusion

Among patients with upper GI cancer, the microbiome composition of the duodenal aspirate of patients with SIBO was different compared to patients with no SIBO and controls. Microbiome composition profiling may offer the opportunity for a personalized treatment in patients with SIBO.

Introduction

Gastric cancer is a multifactorial malignancy influenced by genetic and environmental factors. Cholecystectomy, the surgical removal of the gallbladder, may lead to bile reflux—backflow of duodenal contents into the stomach—potentially damaging gastric mucosa. hTERT and c-MYC play vital roles in cellular proliferation and cancer development. Although epidemiological data generally show no strong link between cholecystectomy and gastric cancer, existing studies are limited and may be influenced by other risk factors.

Aims & Methods

This study aimed to evaluate whether bile acid exposure post-cholecystectomy contributes to gastric cancer and to assess the expressions of hTERT and c-MYC in this context. We included 100 participants at Manisa Celal Bayar University Hospital between September 2021 and May 2023, divided into three groups: gastric cancer (n=32), cholecystectomy history (n=34), and control (n=34). Data on demographics, H. pylori, intestinal metaplasia, and gene expression levels were collected. Ethics approval and informed consent were obtained. Gene expression analysis was performed from endoscopic biopsy samples.

Results

Mean ages were 65.2 (cancer), 60.5 (cholecystectomy), and 59.9 (control), with no significant difference except for higher age in cancer patients. Females were predominant in the cholecystectomy group (p=0.021). Fourteen cancer patients had distant metastasis, but no significant differences in c-MYC or hTERT expression were observed based on metastasis status. No significant differences were found in H. pylori or intestinal metaplasia prevalence. However, c-MYC and hTERT levels were significantly lower in the cholecystectomy group compared to controls and cancer patients (p<0.001). Gender also affected gene expression: females had lower c-MYC and hTERT levels than males (p<0.05), though this effect was consistent across all groups. The presence of H. pylori or intestinal metaplasia did not significantly alter c-MYC or hTERT expression in any group.

Conclusion

Although cholecystectomy was not directly associated with increased gastric cancer risk, in individuals with a genetic predisposition, it may act as a contributing factor. Lower expressions of c-MYC and hTERT post-cholecystectomy suggest potential for these markers in cancer risk evaluation. Further research is necessary to clarify their roles in post-cholecystectomy follow-up.

Disclosure

Nothing to disclose.

Introduction

Esophageal cancer (EC) exhibits a disproportionate burden in low- and middle-income regions. Magnesium, a critical regulator of metabolic and inflammatory pathways, has been implicated in chronic diseases such as diabetes and cardiovascular disorders. Preclinical studies suggest that magnesium deficiency promotes oxidative stress and systemic inflammation, processes central to cancer progression. However, evidence directly linking magnesium metabolism disorders with esophageal cancer risk remains limited. The Magnesium Depletion Score (MDS), a validated tool integrating diuretic use, proton pump inhibitors, renal dysfunction, and heavy alcohol consumption, offers a novel approach to evaluate magnesium status. The study aims to elucidate the potential mechanisms by which magnesium metabolism may influence the development of esophageal cancer and to provide a scientific basis for future preventive and intervention strategies.

Aims & Methods

This prospective cohort study included 450,700 UK Biobank participants. The Magnesium Depletion Score (MDS) incorporated diuretic use, proton pump inhibitors, renal function (eGFR-based), and heavy alcohol consumption, categorized as low (0–1), moderate (2), or high (3–5). Multivariable Cox proportional hazards models, adjusted for demographics, socioeconomic factors, BMI, smoking, and alcohol use, assessed associations between MDS and esophageal cancer (EC) incidence (ICD-10: C15) and subtypes. Sensitivity analyses excluded participants with <1–3 years of follow-up. Mediation analyses evaluated inflammatory/metabolic biomarkers (e.g., CRP, HbA1c). Subgroup analyses explored effect modification by age, sex, and lifestyle factors, while restricted cubic splines tested nonlinear relationships. Analyses adhered to STROBE guidelines and utilized R v4.2.3.

Results

Among 450,700 participants (54% female, mean age 56.6 years), 1,572 developed esophageal cancer (EC: 645 adenocarcinomas [EAC], 275 squamous cell carcinomas [ESCC], 905 lower EC). EC cases were predominantly male, older (mean +4.8 years vs. non-EC), and exhibited higher Magnesium Depletion Score (MDS), BMI, smoking rates, and socioeconomic deprivation. EAC patients were more likely overweight/obese (BMI >25), while ESCC patients had higher smoking rates and normal BMI.
Higher MDS was significantly associated with increased EC risk (continuous MDS: HR=1.186, 95% CI:1.102–1.277, P<0.001). Compared to low MDS (0–1), moderate (2) and high MDS (3–5) groups showed 29.6% (HR=1.296, P=0.001) and 63.5% (HR=1.635, P<0.001) higher EC risk, respectively. Similar trends were observed for EAC (HR=1.277, P<0.001) and lower EC (HR=1.158, P=0.003). Sensitivity analyses excluding early-diagnosis cases (1–3 years) confirmed robustness. Associations persisted after adjusting for diabetes, hypertension, and H. pylori.
Stratified analyses revealed stronger MDS-EC associations in males, smokers, alcohol consumers, and overweight/obese individuals (BMI>25). MDS did not correlate with all-cause mortality in EC patients (HR=0.963, P=0.370). Mediation analyses identified inflammatory (C-reactive protein: 1.40%, P=0.013; neutrophils: 4.50%, P=0.003) and metabolic biomarkers (HbA1c: 0.91%, P=0.033; glucose: 0.38%, P=0.047) as partial mediators.

Conclusion

In summary, this study demonstrates a significant positive association between MDS and the risk of esophageal cancer, with an especially pronounced impact observed among overweight or obese individuals, males, and alcohol consumers. The findings support the hypothesis that magnesium metabolism may influence esophageal cancer through multiple mechanisms, including inflammation, metabolic abnormalities, and immune dysfunction.

Introduction

The incidence of early-onset gastric cancer (EOGC) has been rising globally. While homologous recombination deficiency (HRD) is increasingly recognized as a molecular hallmark in various solid tumors, its clinical and prognostic significance in young adults with gastric cancer remains poorly defined. This study aimed to assess the influence of HRD on tumor biology and treatment outcomes specifically in younger patients.

Aims & Methods

We retrospectively analyzed clinical and genomic data from 140 patients aged ≤39 years with advanced or recurrent gastric or gastroesophageal junction cancer, registered in the Japanese nationwide Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database between 2019 and 2023. HRD was defined as the presence of pathogenic variants in homologous recombination repair (HRR) genes. Tumor mutation burden (TMB), microsatellite instability (MSI), and treatment efficacy—measured as time to treatment failure (TTF) and overall survival (OS)—were compared between HRD-positive and HRD-negative patients. Only patients treated with first-line platinum-doublet chemotherapy were included in outcome analyses.

Results

Among the 140 younger patients, HRD was identified in 23 (16.4%). No cases of MSI-high status were observed, and median TMB was uniformly low (2.0 Muts/Mb) irrespective of HRD status. However, HRD-positive patients had significantly shorter TTF (8.6 vs. 15.9 months, P = 0.041) and OS (13.6 vs. 22.0 months, P = 0.033) than HRD-negative patients. These findings suggest that HRD does not confer the favorable treatment response often seen in older cohorts or other cancer types.

Conclusion

In younger patients with gastric cancer, HRD is not associated with elevated TMB or MSI-high status and may instead indicate poor prognosis and reduced chemotherapy efficacy. These findings underscore the need for age-specific therapeutic strategies and potential development of targeted therapies for HRD-positive EOGC.