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Objectives: The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet has been associated with the risk of IBD, but its impact on clinical outcomes is uncertain. This study evaluated the association between MIND diet adherence and the risk of IBD-related surgery in a prospective cohort. Methods: This study included 2,288 participants with diagnosis of Crohn's disease (CD, n=777) or ulcerative colitis (UC, n=1,511) who completed valid WebQ 24-hour dietary recall from the UK Biobank. Dietary adherence was derived from a 15-component score based on 24-hour dietary recalls. Associations with IBD-related surgery were evaluated using Cox proportional hazards models, with nonlinear trends and examined via restricted cubic splines. Effect modification was explored in pre-specified subgroups, and multiple sensitivity analyses were conducted to assess robustness. Results: During 10.9 years of follow-up, 166 incident IBD-related surgery cases occurred. Higher MIND diet adherence was associated with reduced surgical risk. Compared with the lowest tertile of adherence, the highest tertile showed a 36% reduction in surgical risk in IBD (HR 0.64, 95% CI: 0.44-0.94, P = 0.024). Notably, this protective effect was pronounced in patients with CD, exhibiting a clear linear inverse association. In contrast, a reverse J-shaped association was observed in UC, with a steep initial decline in surgical risk followed by a plateau emerging at a MIND score of approximately 5, beyond which further adherence conferred minimal additional benefit. At the component level, higher vegetable consumption and lower intake of butter and fried foods were identified as independent protective factors against surgery. Stronger inverse associations were observed among patients with shorter disease duration and those with complicated disease behavior, including stricturing or penetrating phenotypes (all P interaction < 0.05). Conclusion: Greater MIND diet adherence is associated with reduced IBD-related surgery risk among patients with IBD and CD. These findings support the MIND diet as a feasible dietary strategy to improve IBD prognosis.

IntroductionHereditary diffuse gastric cancer (HDGC) associated with CDH1 germline pathogenic variants (GPV), carries a high lifetime risk of signet ring cell carcinoma (SRCC). Currently, there is uncertainty regarding to whom and when to recommend prophylactic total gastrectomy (PTG). We hypothesise a small number of early SRCC lesions correlates with low risk of progression to clinical gastric cancer. This study aimed to identify predictors of early SRCC burden and provide evidence to inform best surveillance intervals. MethodsWe analyzed data from 53 CDH1-GPV carriers who underwent PTG prospectively recruited between Aug 2004 and Aug 2024 (PTG dataset) and a separate cohort of 94 CDH1 CDH1-GPV carriers with [&ge;]2 surveillance endoscopies (endoscopy dataset). Targeted biopsies (TB) and systematic random biopsies (RB) were obtained using the Cambridge protocol. Multivariable negative binomial regression was used to assess the association of clinical (age, family history, CDH1 variant type) and endoscopic factors (mean number of positive TB and RB per endoscopy) with SRCC burden in PTG specimens. A logistic regression model with significant predictors was trained to classify patients into low and high SRCC burden. Temporal trends in biopsy findings were analyzed using linear mixed-effects models, and pathological outcomes at 6-, 12- and 24-month intervals were compared in endoscopy dataset. ResultsOf the 53 patients, 89% had early-stage cancer (pT1aN0M0) and 11% had no cancer (pT0N0M0). The number of SRCC foci ranged from 0 to 273 (median 33, IQR 2-37). The number of positive targeted (P = 0.003) and random biopsies (P < 0.001) during endoscopy surveillance were independent predictors of SRCC burden in the PTG specimen, whereas age, CDH1 mutation type (truncating vs. non-truncating), number of 1st and 2nd degree relatives (SDRs) were not significantly associated. In the endoscopy surveillance cohort, the number of positive biopsies remained largely stable over time, showing fluctuations rather than consistent progression; no significant temporal increase in biopsy positivity was detected over time (P = 0.177) with stable number of SRCC foci at follow-up. Extending surveillance intervals from 6 to 12 or 24 months did not significantly alter progression detection rates. ConclusionEndoscopic surveillance using targeted and random biopsies by experienced endoscopists provides a reliable estimate of SRCC burden in HDGC. Our findings suggest that extending surveillance intervals in patients with low early SRCC burden is clinically safe.

BackgroundHistomorphology is a strong prognostic biomarker correlated with basal-like and classical programs in surgically resected pancreatic ductal adenocarcinoma (PDAC). However, the spectrum of morphology and its biological associations remain poorly defined in advanced disease. ObjectivesWe explored the transcriptomic and genomic underpinnings and clinical relevance of morphological classes across localized and metastatic PDAC. DesignWe unified morphological classifications into four classes: glandular, cribriform, solid, and squamous. We integrated transcriptome and whole-genome sequencing following laser-capture microdissection with morphological classifications in 348 PDAC patients, where half of the cohort included locally advance and metastatic stages to uncover molecular associations. ResultsNon-glandular morphologies comprised three distinct classes that were enriched in metastatic disease. Transcriptomic profiling exhibited that glandular tumours predominantly expressed classical epithelial programs, although a subset displayed partial or full epithelial- mesenchymal transition signatures. In contrast, non-glandular morphologies showed basal-like transcriptional programs with subtype-specific pathways, including ciliogenesis in cribriform tumours, extracellular matrix remodelling and immune evasion in solid tumours, and keratinisation programs in squamous tumours. The solid class was significantly enriched in liver metastatic lesions and was associated with increased intra-tumoural morphological heterogeneity, whole-genome doubling, KRAS major allelic imbalance, and elevated KRAS-ERK signalling. ConclusionNon-glandular morphologies identify biologically distinct PDAC tumour states that are enriched in liver metastases and associated with subtype-specific transcriptional programs and KRAS-driven genomic alterations.

Background & aimsPancreatic ductal adenocarcinoma (PDAC) continues to be a devastating disease with late diagnosis and poor overall survival, complicated by clinical presentations similar to benign pancreatic diseases. We aimed to analyse clinical parameters with the goal of developing a prediction model for differentiating suspected PDAC from benign pancreatic conditions. Methods and resultsWe used a prospectively recruited cohort of patients with pancreatic disease (n=762) enrolled at the Barts Pancreas Tissue Bank between January 1, 2008 and September 21, 2021 to perform a case-control study examining the association of PDAC (n=340) with predictor variables including demographics, comorbidities, lifestyle factors, presenting symptoms and commonly performed blood tests. Using a machine learning approach, candidate PDAC risk-prediction algorithms were trained on 75% of the cohort, using a subset of the predictor variables identified from a preliminary observational association study. Models were assessed on the remaining 25%. Multiple imputed datasets were used for both training and validation to accommodate for unknown data. Age (over 55), weight loss in hypertensive patients, recent symptom of jaundice, high serum bilirubin, low serum creatinine, high serum alkaline phosphatase, low lymphocyte count and low serum sodium were the most important features when separating putative PDAC cases from less severe pancreatic conditions. A simple logistic regression model had the best performance with an area under the curve (AUC) of 0.88. Setting a probability threshold of 0.17 guided by the maximum F2 score, a sensitivity of 95.6% was reached in the full cohort which could lead to early detection of around 84% of the PDAC patients. ConclusionThe resultant prediction model significantly outperformed the current UK guidelines for suspected pancreatic cancer referral and could improve detection rates of PDAC in the community. After further work this approach could lead to an easy to understand, utilisable risk score to be applied in the primary and secondary care setting for referring patients to specialist hepato-pancreatico-biliary services.

Background and AimsPrior studies suggest an increased risk of non-alcoholic fatty liver disease (NAFLD) in patients with inflammatory bowel disease (IBD). We aimed to investigate the risk of cirrhosis in a nationwide cohort of IBD patients compared to a matched non-IBD population. MethodsPatients diagnosed with IBD without prior cirrhosis during 1998-2018 were identified in the Danish health registries and were matched 1:10 to persons without IBD. Cox regression was used to calculate hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). ResultsWithin the study population of 495,220 persons, a total of 2,741 cirrhosis cases were identified during follow-up, with a higher proportion of cases among patients with IBD (0.9%) compared to non-IBD persons (0.5%). Patients with IBD had a significantly higher risk of cirrhosis compared to non-IBD persons (adjusted HR (aHR) (95% CI): 1.84 (1.64-2.04)). The leading etiology of cirrhosis in IBD was NAFLD (51.6%), followed by alcohol (39.0%). The risk of cirrhosis among IBD patients (compared to non-IBD persons) was more pronounced among those diagnosed with IBD [&le;] 40 years of age (aHR (95% CI): 3.08 (2.45-3.87); vs. > 40 years of age, 1.63 (1.45-1.84); p-value <0.001) and CD patients (aHR (95% CI): 2.20 (1.80-2.67); vs. 1.72 (1.52-1.95) among UC; p-value 0.04). ConclusionIBD was associated with an increased risk of incident cirrhosis, especially in patients aged [&le;] 40 years at IBD diagnosis and in patients with CD. These findings point towards a need for focused screening for cirrhosis among IBD patients, especially in certain groups.

Endoscopy generates aerosol droplets and fomites, thereby increasing the risk of SARS-CoV2 transmission to healthcare workers and uninfected patients within endoscopy departments. Despite the sharp rise in the incidence of COVID-19, authoritative recommendations to limit the spread of SARS-CoV2 within gastrointestinal endoscopy units are lacking. Therefore, with the primary aim of identifying best practice and scrutinizing its supporting evidence, we conducted a systematic review of literature for articles published between 1 January 2002 and 15 March 2020 in five databases relating to both the current SARS-CoV2 and the previous SARS-CoV outbreaks. Official websites for gastroenterology and endoscopy societies in the 15 most affected countries were also searched. Unfortunately, a paucity of high quality data and heterogeneity of recommendations between countries was observed. Interestingly, not all countries advocated the postponement of non-urgent or elective procedures. Recommendations for patient screening and personal protective equipment were commonly featured in all recommendations but specifics varied. Only 32% (9/28) of all gastroenterology and endoscopy societies issued guidance on endoscopy in the COVID-19 pandemic. In conclusion, stronger evidence to inform current practice and robust guidelines are urgently needed to prevent the transmission of SARS-CoV2 in gastrointestinal endoscopy departments worldwide.

MessageThe COVID-19 pandemic has severely curtailed the practice of endoscopy (as an exemplar for outpatient diagnostic procedures) worldwide. Restart and recovery processes will be influenced by the need to protect patients and staff from disease transmission, but data on the risk of COVID-19 transmission after endoscopy are sparse. This is of particular importance in later pandemic phases when the risk of harm from delayed or missed significant diagnoses is likely to far outweigh the risk of infection. The British Society of Gastroenterology (BSG) guidance for restarting endoscopy included stratification of diagnostic procedures according to aerosol generation or assessment of infectious risk as well as pragmatic guidance on the use of personal protective equipment (PPE). We sought to document the risk of COVID-19 transmission after endoscopy in this "COVID-minimised" environment. Prospective data were collected from 18 UK centres for n=6208 procedures. Pre-endoscopy, 3/2611 (0.11% [95% CI: 0.00-0.33%]) asymptomatic patients tested positive for SARS-CoV-2 on nasopharyngeal swab. Based on follow-up telephone symptom screening of patients at 7 and 14 days, no cases of COVID-19 were detected by any centre after endoscopy in either patients or staff. While these data cannot determine the relative contribution of each component of a COVID-minimised pathway, they provide clear support for such an approach. The rational use of PPE and infection control policies should be continued and will aid planning for outpatient diagnostics in the COVID-19 recovery phase.

ObjectivesHepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. Most cases occur in patients with an underlying cirrhosis. The French national guidelines recommend semiannual abdominal ultrasound surveillance for early HCC detection in patients with cirrhosis. The primary goal of our retrospective cohort study was to evaluate compliance with this recommendation. MethodsWe used 2007-2016 general public health insurance program (Regime General) data from the French National Health Data System (Systeme National des Donnees de Sante, or SNDS). Included patients were 18 to 75 years old, diagnosed with liver cirrhosis between 2009 and 2013, and underwent their first ultrasound >4 months after their index date. The number of annual ultrasounds was recorded over a 3-year follow-up period. Compliance was defined as having had at least 2 ultrasounds per year over the follow-up time. ResultsAmong the 66,464 patients included in the analysis, surveillance was optimal (no year with <2 ultrasounds) in 5,082 patients (7.6%), suboptimal (one year with <2 ultrasounds) in 3,928 (5.9%), and failed (remaining cases) in 57,454 (86.4%). Older age, male sex, a high Charlson index, frequent gastroenterologist/hepatologist visits, and viral etiology were associated with better surveillance, whereas low socioeconomic status, despite Frances universal health coverage, was linked to failed surveillance. ConclusionsIn French patients with cirrhosis, most of cancer surveillance is failing when considering recommendation in vigor. In order to improve surveillance, a better understanding of the social determinants of health equity is needed.

Background and ObjectivesThe etiology of biliary obstruction has undergone notable shifts over recent decades, yet long-term epidemiological studies addressing these changes remain scarce. With the widespread clinical adoption of endoscopic ultrasound (EUS), its role in altering diagnostic patterns warrants investigation. This study aimed to characterize the evolving disease patterns of biliary obstruction and specifically evaluate the impact of EUS adoption on driving these perceived etiological shifts over a 15-year period. MethodsThis retrospective, single-center study analyzed data from patients with biliary obstruction over a 15-year period. Time-series analysis was employed to characterize evolving disease patterns. To investigate the drivers underlying the observed trends, we applied a difference-in-differences (DID) analytical framework, uniquely treating the widespread clinical adoption of EUS as a natural experiment. Furthermore, multivariable logistic regression was utilized to identify independent predictors for malignant biliary obstruction of pancreatic origin. ResultsAmong 5,672 patients with pathological diagnoses, the disease spectrum shifted significantly toward malignant etiologies, particularly pancreatic and ampullary cancers, over the study period. The DID analysis confirmed that the broad adoption of EUS was associated with a significant relative increase in the precise diagnosis of malignancies detectable by this modality. Multivariable analysis further identified the EUS promotion era and calendar year as independent predictors for the pancreatic origin of malignancy. ConclusionsThe observed increase in pancreatic and ampullary cancers among patients with biliary obstruction is significantly associated with the enhanced diagnostic capabilities brought by EUS. This suggests that the diagnostic evolution driven by the widespread adoption of EUS, alongside potential epidemiological changes, is a major contributing factor to the perceived etiological shifts in biliary obstruction.

"Long COVID" (LC) remains an ongoing issue and one which has created a substantial burden of disease. Gastrointestinal LC is relatively poorly understood. In this study we characterize a syndrome of persistent SARS-CoV2 viral material via clinical and histologic data, and RNA sequencing MethodsWe reviewed patients aged 5-22 years with an esophagogastroduodenoscopy (EGD) for gastrointestinal (GI) symptoms from 6/2020-6/2023, excluding patients with known histologic disease. Biopsies were sent for immunohistochemical staining. Clinical data was collected. Duodenal, ileal, cecal, and sigmoid colon samples were stained for SARS-CoV-2 using a SARS-CoV-2 nucleocapsid antibody. Slides were reviewed by a blinded pathologist. 8 patients with known duodenal SARS-CoV-2 nucleocapsid antigen (SC-NA) positivity and 8 demographically matched IBS matched patients from prior to 2020 were identified for RNA sequencing comparison. Results were compared with public data from the Gene Expression Omnibus (GEO) data repository for intestinal tissue with IBS and epithelial tissues with active SARS-CoV2 infection. ResultsOf 30 patients, fifteen (50%) were identified to have positive SC-NA. 3 (20%) had received at least a single SARS-CoV2 vaccine in the + cohort, and 8 (53.3%) in the - (P=0.05). Primary symptoms were pain (86%, nausea (66.6%), and weight loss (60%). 37.5% of patients with colonic SC-NA displayed hematochezia. 33% of + patients showed elevated ESR/CRP. Mean + calprotectin was 317.3 vs. 156.4 (p=0.2). 11/15 (73.3%) +SC-NA had large lymphoid aggregates (LLA) (p = 0.00338). RNA expression was consistent with known acute SARS-CoV2 infection. Hub network analysis showed a tight shift in RNA expression centered around HSPE-1p26, with involvement of known SARS-CoV2 immune mediators like NEAT1. DGE comparative analysis with IBS and acute SARS-CoV2 infection showed higher overlap with acute infection vs. IBS. FGSEA analysis with the same source data demonstrated the same. ConclusionsOur findings establish a syndrome mediated by persistent viral infection (SARS-CoV2 Persistent Intestinal Epithelial Syndrome (SPIES)). We hypothesize that persistent sparse infection drives ongoing immune signaling altering movement and function, creating epithelial and movement effects overlapping with DGBI and IBD

Background and AimsEmergency admission with foreign body in the oesophagus (FBO) commonly requires endoscopic removal. Oesophageal food bolus obstruction is often due to eosinophilic oesophagitis (EoE). Patients with food bolus obstruction should undergo endoscopy and multilevel oesophageal biopsies to exclude EoE. This national retrospective study examined the management, including endoscopy and follow-up, of patients presenting as an emergency with FBO. MethodsThe Hospital Episode Statistics database was used to identify patients over 18 with FBO presenting as an emergency in England using the ICD-10 code T18.1 between 2008 and 2019. Logistic regression analysis was used to assess factors associated with undergoing endoscopy and biopsy. Results27,063 patients were identified: 65.5% male; median age 57(IQR 41-73) years; and 47.2% were admitted under Ear, Nose & Throat (ENT). 75.7% underwent endoscopy (94% within a week of admission) but only 19.8% had biopsies taken within 6 months of admission. 0.4% were coded with a perforation related to endoscopy for FBO. 70% of ENT patients underwent endoscopy but only 11.9% had biopsy to exclude EOE, compared with 83% of patient admitted under General Medicine undergoing endoscopy and 29.5% biopsy. Endoscopy and biopsy was associated with: older age (e.g. 61-70 OR 1.42 (95% CI 1.26-1.61)), males (females 0.67(0.62-0.72)), the least deprived (1.25 (1.13-1.38)), later diagnosis year (2019 1.42 (1.21-1.66)), and admission under General Medicine (2.68(2.48-2.88)) or Gastroenterology (3.03(2.61-3.51)) but not with NHS trust FBO volume. 33.4% received relevant outpatient follow-up within 12 months of FBO admission: 26% of patients admitted under General Medicine were referred to gastroenterology for follow-up, but only 12.1% of those admitted under ENT. Conclusions75.7% of patients presenting with FBO undergo endoscopy but few (19.8%) had biopsies taken to exclude this common presentation of EOE. Pathways for the management of food bolus obstruction require re-design and unless the airway is impaired, this condition should be managed under General Medicine.

ObjectivesTo identify factors associated with outcomes of Kasai portoenterostomy (KPE), and predictors of 2- and 5- year native liver survival (NLS) for infants achieved jaundice clearance (JC) within 6 months of KPE. MethodsThis retrospective cohort study was conducted on 151 patients with type III biliary atresia (BA) who underwent KPE at our center. Univariate analysis and logistic regression analyses were performed to identify factors associated with NLS in infants achieved JC. Kaplan-Meier curves and log-rank tests were used to estimate the NLS, and the Cox proportional hazards regression model identified variables most associated with 2- and 5-year NLS at 6 months post-KPE. A receiver operating characteristic (ROC) curve was used to evaluate the predictive value of these factors. ResultsThe 2- and 5-year NLS of infants achieved JC at 3 months post-KPE were not different from those achieved JC earlier. Operation age and total bile acid (TBA) were factors associated with JC. For infants who have achieved JC, DB was the only factor associated with 2-year NLS, the AUC was 0.872, the cutoff value was 14 mol/L; ALB and DB were factors associated with 5-year NLS, the AUCs were 0.894 and 0.95, and the cutoff values were 39 g/L and 14 mol/L, respectively. ConclusionsNLS should be estimated at 6 months post-KPE. Preoperative factors are not predictive of NLS. For infants cleared jaundice, DB and ALB can predict NLS with good performance. Whats Known on This SubjectAge, liver stiffness, and CMV infections are factors associated with outcomes of Kasai portoenterostomy. Jaundice clearance is directly associated with native liver survival; however, even with successful surgery, liver pathology in most cases will progress to end-stage cirrhosis. What This Study AddsNo preoperative factors are predictive of native liver survival (NLS). Infants cleared jaundice after 3 months of KPE can achieve the same NLS as those cleared jaundice earlier. For infants cleared jaundice, 6-month postoperative DB and Albumin are predictive of NLS. How this study might affect research, practice or policyIn this study, we argued that 6 months post-KPE was the appropriate timing for predicting NLS; direct bilirubin (DB) and albumin (ALB) at 6 months post-KPE can be used to predict 2- and 5-year NLS with good performance. Article SummaryRetrospective analysis revealed its difficult to predict outcomes of Kasai portoenterostomy (KPE) preoperatively; jaundice clearance should be evaluated at 6 months after KPE, for infants cleared jaundice, 6-month postoperative DB and Albumin are predictive of NLS.

BackgroundA major unmet need in gastric cancer prevention is the lack of biomarkers to predict precancerous lesion progression, and the potential of chromosomal instability (CIN) for this role, particularly regarding early cancer and recurrence, remains unclear. ObjectiveTo assess the predictive role of CIN in lesion progression and postoperative recurrence following endoscopic submucosal dissection (ESD). DesignWe enrolled 106 patients from Taizhou Hospital Affiliated to Wenzhou Medical University (2011-2025) and collected 1,045 temporally continuous pathological samples. Copy number variations were profiled using low-coverage whole-genome sequencing (LC-WGS), and CIN scores were calculated. Associations between CIN and clinical outcomes were analyzed using survival analysis and ROC curves. ResultsCIN was detectable up to two years before gastric cancer diagnosis, with positivity rates increasing alongside lesion severity: 25.5% in intestinal metaplasia, 39.7% in low-grade dysplasia, and 83.0% in gastric cancer. CIN positivity independently predicted lesion progression (hazard ratio [HR] = 2.55, 95% CI: 1.19-5.47, p = 0.016), with the greatest risk for progression to carcinoma (HR = 16.61, p < 0.001). The predictive AUC was 0.81, improving to 0.88 when combined with age. Among 84 patients who underwent ESD, CIN positivity significantly increased recurrence risk (HR = 19.57, 95% CI: 2.59 - 147.61, p = 0.004; AUC = 0.80). Chromosomal arms 7p/q, 8p/q, and 20p/q showed high CIN frequencies, with MYC being the most frequently mutated oncogene. ConclusionCIN represents a reliable biomarker for early prediction of lesion progression and postoperative recurrence, enabling proactive surveillance and precision management of gastric cancer. Single Sentence SummaryChromosomal instability (CIN) acts as a reliable biomarker for predicting the progression of gastric precancerous lesions and postoperative recurrence.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid tumors. Based on transcriptomic classifiers, basal-like and classical PDAC subtypes can be defined that differ in prognosis. Single-cell sequencing has recently revealed that these subtypes coexist in individual tumors. However, the contribution of either clonal heterogeneity or microenvironmental cues to subtype heterogeneity is unclear. Here, we report the tumor phenotype dynamics in a cohort of patients in whom PDAC infiltrated the duodenal wall. Using multiplex immunohistochemistry, we show that PDAC cells revert to non-destructive growth and undergo differentiation towards the classical subtype upon integration into the duodenal epithelium. Our results tightly link microenvironmental cues to the PDAC molecular subtype and open the door to a systematic investigation of microenvironmental control in human pancreatic cancer.

IBD is characterized by altered immune reactions and infections are thought to trigger the chronic inflammatory response in IBD. The gut represents a productive reservoir for SARS-CoV-2 and the aforementioned factors together with immunosuppression used to treat IBD are likely influencing the outcomes of IBD patients in COVID-19. We used large and small intestinal organoids from IBD patients and controls to comparatively assess the transcriptional response of the gut epithelium during SARS- CoV-2 infection. Our analysis showed that IBD epithelia exhibit reduced viral loads compared to controls associated with a reduced expression of SARS-CoV-2 entry factors including the host receptor ACE2. Moreover, several genes implicated in the epithelial response to viral infection are intrinsically altered in IBD likely counteracting viral propagation. Notably, differences between IBD phenotypes exist wherein ulcerative colitis represents with induced cell death pathways and an induction of IL-1{beta} despite overall lower viral loads suggestive of increased epithelial stress in this IBD phenotype. Altogether our analysis shows that IBD epithelia are not more prone to SARS-CoV-2 infection but epithelia from ulcerative colitis and Crohns disease exhibit specific differences which might explain the differing COVID-19 outcomes between IBD phenotypes.

BackgroundPost-discharge morbidity and mortality is high in acute pancreatitis (AP) and pathophysiological mechanisms remain poorly understood. ObjectivesWe aim to investigate the composition of gut microbiota and clinical long-term outcomes of prospectively enrolled AP patients to predict post-discharge complications. DesignIn this long-term follow-up study, we analysed clinical and microbiome data of 277 patients from the prospective multi-centre P-MAPS trial. Primary endpoint was the association of the microbial composition with post-discharge mortality, recurrent AP (RAP), progression to chronic pancreatitis (CP), pancreatic exocrine insufficiency (PEI), diabetes mellitus (DM) and pancreatic ductal adenocarcinoma (PDAC). ResultsBuccal (n=238) and rectal (n=249) swabs were analysed by 16S rRNA and metagenomics sequencing using Oxford Nanopore Technologies. Median follow-up was 2.8 years. Distance-based redundancy analysis (dbRDA) with canonical analysis of principle coordinates (CAP) showed significant differences for {beta}-diversity (Bray-Curtis) for post-discharge mortality (p=0.04), RAP (p=0.02), and DM (p=0.03). A ridge regression model including 11 differentially abundant species predicted post-discharge DM with an area under the receiving operating characteristic (AUROC) of 94.8% and 86.2% in the matched and entire cohort, respectively. Using this classifier, a positive predictive value of 66.6%, a negative predictive value of 96% and an accuracy of 95% was achieved. ConclusionOur data indicate that the admission microbiome of AP patients correlates with post-discharge complications independent from multiple risk factors such as AP severity, smoking or alcohol. Microbiota at admission show excellent discriminative capacity to predict post-discharge DM and may thus open new stratification tools for a tailored risk assessment in the future.

IntroductionMedical complications of malnutrition and refeeding account for approximately half of deaths in anorexia nervosa (AN). The AN Care Pathway (ANCP) was introduced at our institution in 2016 to improve quality of care of patients admitted for medical observation and management. We report results from our review of medical complications and report the impact and adoption of the ANCP. MethodsThe ANCP was developed in response to a need to improve quality of medical monitoring of patients with severe AN using Squire Guidelines and the Plan-Do-Study-Act cycle. All patients admitted to a medical hospital with AN between 2010-2020 were included after hospital inpatient enquiry and medical records were reviewed. Descriptive statistics were calculated using Stata (Statcorp). ResultsFifty-one patients (63 admissions) were included. Median BMI was 13.8 kg/m (11.9-22.5). After ANCP implementation in 2016, compliance with recommended daily ECG, thiamine and blood tests improved from 30% (n=8/27) to 86% (n=21/36). We report a high rate of medical complications of severe AN including anaemia (n=24, 47%), neutropoenia (n=18, 35%), abnormal liver bloods (n=15, 29%) and half developed refeeding syndrome. One-third patients had cardiovascular compromise including reduced cardiac contractility (n=13, 25%), pericardial effusion (n=7, 14%) and one death. Low BMI was associated with cardiovascular complications (mean BMI 13.5 kg/m vs 15.5 kg/m, p=0.01) and neutropoenia (mean BMI 13.4 kg/m vs 15.4 kg/m, p=0.02). ConclusionIntroduction of the ANCP improved quality of care during medical stabilisation. We report a high rate of medical complications of severe AN in patients admitted to a medical hospital. Use of multidisciplinary care protocols may contribute to quality improvement and improved consistency of care for this vulnerable population.

Background: Gastric cancer surveillance in CDH1 pathogenic variant carriers is challenging, as predictors of localized (stage T1a) and advanced (stage >T1a) signet ring cell carcinoma (SRCC) are not well defined. We established the Group of investigAtors STriving toward Research In CDH1 (GASTRIC) consortium to identify clinicopathological factors associated with localized and advanced SRCC. Methods: A retrospective observational study (1998-2025) of CDH1 carriers across twelve academic centers was performed. Clinical, endoscopic, and pathological data were compared between carriers with and without SRCC on endoscopy, and between those with advanced versus localized or no cancer on gastrectomy specimens. Results: Overall, 390 CDH1 carriers from 235 families were included. Presence of SRCCs on endoscopy was significantly associated with thickened folds, nodularity, masses, and intestinal metaplasia, while gastritis was negatively associated. Of 196 carriers (52.4%) undergoing gastrectomy, 11 (5.6%) had advanced cancers, 10(90.9%) of which showed endoscopic abnormalities. Identification of SRCC on baseline endoscopy was the most sensitive feature for advanced disease (0.81) but had moderate specificity (0.74), whereas masses and thickened folds were highly specific (0.99 and 0.96, respectively) but less sensitive. Negative predictive values were high (0.94-1.0), while positive predictive values were modest (0.13-0.66). On multivariate analysis, masses and SRCC foci on baseline endoscopy were independent predictors of advanced disease. Conclusion: Among CDH1 carriers, absence of endoscopic findings was reassuring, whereas significance of detected endoscopic and pathological abnormalities was less certain. Advanced cancer occurred in a small number of carriers, with endoscopic abnormalities in nearly all cases. Endoscopic surveillance might be an alternative to surgery in carriers without worrisome mucosal findings.

PurposeIncidental detection of pancreas lesions (IPLs) is common and creates an opportunity to intercept pancreatic ductal adenocarcinoma (PDAC). However, identifying patients at risk for progression who can benefit from surgical resection remains challenging. The current role of blood tests for risk stratification in patients with IPLs is limited. MethodsWe evaluated the performance of circulating glycoproteins (CA19-9, CEA and CA125), plasma DNA fragmentation analysis, and their combination, in 99 asymptomatic patients with IPLs, for detection of advanced pathology (high-grade dysplasia or invasive carcinoma). Plasma DNA fragmentation was analyzed using a machine learning model, adapted to detect PDAC in 242 patients with cancer and 300 healthy individuals. ResultsDuring 18.8 months of median follow-up by a multidisciplinary clinical team, 11 of 99 patients with IPLs were diagnosed with advanced pathology. We observed area under the receiver operating characteristic curves (AUROCs) of 0.78, 0.63, 0.54 and 0.74 using CA19-9, CEA, CA125 and plasma DNA fragmentation, respectively. Combined analysis of CA19-9, CA125 and plasma DNA fragmentation showed an AUROC of 0.93, with 91% sensitivity and 53% positive predictive value (PPV) at 90% specificity. In a subset of 25 patients with histologically confirmed diagnoses, AUROC improved to 0.96 and PPV improved to 91%. In one patient with an equivocal initial endoscopy, multi-analyte blood analysis predicted cancer 3 months before diagnosis of stage IA cancer. ConclusionOur results demonstrate a multianalyte blood test combining glycoprotein biomarkers with plasma DNA fragmentation could complement current clinical workflows for cancer detection in patients with IPLs.

BackgroundA resemblance of pancreatic tumors to their native tissue architecture remains largely unexplored, while it may reveal novel insights into the healthy and diseased tissue. ObjectiveThis study aims at generating a spatially resolved map of human pancreatic duct cell populations in the native tissue and in tumors, i.e. pancreatic ductal adenocarcinoma (PDAC) and adenosquamous cancer of the pancreas (ASCP). DesignNew datasets were acquired with several spatial transcriptomics platforms and were integrated with public single-cell RNAseq datasets and validated by multiplex immunofluorescence. Cell lines and primary human cell cultures were genetically manipulated. ResultsGroups of Keratin-5+ cells in larger ducts have a gene signature reminiscent of stem cells and (supra)basal cells from other tissues. At single cell resolution, this group comprises {Delta}Np63+ basal cells (BAS) and {Delta}Np63- supra-basally residing luminal-B cells (LUM-B). The latter express previously unreported MUC4 and MUC16. Additionally, we identified three other luminal cell populations in the ducts (LUM-A, -C, -D). In cancer, BAS and LUM-B signatures associate with basal-like (BL) PDAC, and correlate with lower survival. However, PDAC exhibits a random spatial pattern and fragmented native expression programs while ASCP preserve the identity of LUM-B and BAS in a spatially unmixed pattern. {Delta}Np63 drives cell plasticity to BAS, conserved from the native tissue to cancer. ConclusionSpatially distinct duct cell populations are revealed, and the extent of preservation of the native cell identities in pancreatic cancer underpins distinct tumor identities. This warrants a separate consideration in research and therapy. What is already known on this topicWhile tumors in the pancreas can exhibit basal-like and squamous features resembling tumors of other tissues, their resemblance to the native duct cells, and possible subpopulations thereof, had not been studied in detail. What this study addsOne basal and four luminal spatially distinct cell populations exist in human pancreatic ducts. These are best conserved in ASCP while PDAC shows loss of the native cell identity program. How this study might affect research, practice or policyOur study demonstrates fundamental differences between the tumor cells of the BL PDAC versus the rare ASCP, highlighting the necessity for a clear distinction between them in research and in tumor-specific treatments. Meanwhile, the research community should acknowledge the spatial and functional heterogeneity of human duct cells, including in their experimental models.