David A. Katzka

Background & Aims: Eosinophilic esophagitis (EoE) patients deemed treatment‐refractory are frequently referred to tertiary centres. We aimed to characterize expert perspectives on patients referred for refractory EoE, including its causes, prevalence, and evaluation. Methods: We conducted an anonymous and blinded cross‐sectional survey of international EoE experts ( n = 52) assessing provider characteristics, referral patterns, perceived causes of treatment failure, diagnostic approaches, and prior therapies. Descriptive statistics and subgroup analyses were performed. Results: Respondents were predominantly gastroenterologists (77%) and practiced in academic settings (87%) with high EoE volume. Experts estimated that true refractoriness to medical and diet therapy was 15% [IQR 10–25], median 31% [20–50], respectively. Patients referred for perceived refractory EoE had been treated with PPIs (80%), topical steroids (55%), and elimination diets (45%); dupilumab (10%) was infrequently trialled. Half of the patients referred had been on combination therapy. After referral, experts focused on assessing medication adherence (98%), dosing (92%), and administration technique (90%), with most repeating endoscopy (85%) and performing oesophageal dilation (42%). The causes of perceived refractory disease were subtherapeutic dosing (34%), incorrect medication administration (30.5%), inappropriate medication choice (26.5%), and dietary non‐adherence (26%). Functional and behavioural contributors including co‐existing oesophageal hypersensitivity (20%), ARFID (9%), and rumination syndrome (5%) were also reported. Experience in treating EoE patients assessed by less than or greater than 10 years did not affect most results. Conclusions: Among international experts, most referred EoE patients labelled as refractory had received suboptimal medical and dilation therapy. This highlights opportunities to optimize care along guideline recommendations prior to referral.

Background: Obesity affects over 40% of the US population and contributes to worse outcomes in a variety of diseases and disorders. Glucagon‐like peptide‐1 receptor agonists have drawn attention for their impact on obesity. With a dense population of receptors throughout the gastrointestinal tract, it is critical to understand the way that glucagon‐like peptide‐1 receptor agonists impact gastrointestinal diseases and disorders. Aims: To evaluate the expanding role of glucagon‐like peptide‐1 receptor agonists in the management of obesity and gastrointestinal disease, with a focus on therapeutic applications, impact on gastrointestinal cancers, safety profile, and implications for gastroenterology practice. Methods: We conducted a narrative review of recent clinical trials, cohort studies, and guideline updates through 2025. Evidence was synthesised on efficacy, safety, and clinical implications across gastrointestinal disorders including steatotic liver disease, gastroesophageal reflux, inflammatory bowel disease, short bowel syndrome, and obesity‐associated cancers. Results: Glucagon‐like peptide‐1 receptor agonists induce substantial and durable weight loss and improve obesity‐related gastrointestinal outcomes. They are approved for steatotic liver disease, with demonstrated histologic and biochemical benefits. Evidence suggests a reduced incidence of several gastrointestinal cancers. The most common adverse events include nausea, vomiting, diarrhoea, constipation, and delayed gastric emptying, which may affect peri‐endoscopic management. Discontinuation rates remain substantial but can be mitigated by careful titration and specialist oversight. Conclusions: Glucagon‐like peptide‐1 receptor agonists are a critical therapy for obesity and several related gastrointestinal conditions. Gastroenterologists are uniquely positioned to optimize their use, manage adverse events, coordinate multidisciplinary care, and ensure safe and effective integration into practice.

Background There is a gap of knowledge with regards to the optimal biopsy sampling procedure as well as the technical and temporal aspects of endoscopic dilation for eosinophilic oesophagitis (EoE). Current guidelines lack specific recommendations. Methods The Swiss Network for Eosinophilic Gastrointestinal Diseases, together with members from The International Gastrointestinal Eosinophil Researchers, assembled a topical review consensus group. After a systematic literature review, two rounds of voting in a Delphi-style process were performed. Statements were rated on an even Likert scale ranging from 1 (strong disagreement) to 4 (strong agreement). Statements were accepted if they achieved an agreement of >80%. Results The experts agreed on a total of 10 statements, 5 statements about biopsy sampling and 5 statements about endoscopic dilation. There was agreement about the need for separately collecting biopsies from at least two segments of the oesophagus, standardised endoscopic and histological disease assessment and the optimal biopsy technique (one biopsy per attempt using the turn and suction technique). The experts further agreed on the early use of endoscopic dilation whenever fibrostenosis is present and an interval of 6–12 months between dilations in most cases. In the absence of fibrostenosis and dysphagia symptoms, empiric dilation for non-dysphagia symptoms cannot be recommended. Conclusion These current practice positions summarise the recommended approach to oesophageal biopsy sampling and endoscopic dilation in adult patients with EoE. Given the lack of randomised controlled data, the statements made in this topical review consensus are largely based on expert opinion and should be seen as guidance in clinical practice that will evolve in the future as newer data emerge.

Background: Eosinophilic oesophagitis (EoE) is a food allergen-induced inflammatory disorder characterised by interleukin (IL)-13-mediated oesophageal inflammation and epithelial basal cell hyperplasia (BCH). The role of mitochondria in EoE pathogenesis remains elusive. Design: Prompted by single cell transcriptomics data, we interrogated the role of mitochondria in EoE pathobiology using patient biopsies, EoE-mouse models and oesophageal epithelial cells grown in monolayer and three-dimensional (3D) organoid cultures treated with EoE-relevant cytokines. 3D organoids and EoE-bearing mice were treated with omeprazole—a proton-pump inhibitor used as first-line EoE therapy. We performed CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) interference in mouse organoids to identify the key mitochondrial regulatory genes whose depletion may lead to BCH. We analysed mitochondrial membrane potential, mass and superoxide production by flow cytometry, cellular oxygen consumption by respirometry, mitochondrial structures and perturbation of cellular energy homeostasis by immunoblotting. Results : Mitochondrial dysfunction appeared to be a hallmark of EoE-related BCH where mitochondrial structural damage was associated with impaired oxidative respiratory capacity, elevation of mitochondrial superoxide and decreased adenosine triphosphate (ATP) production, as corroborated by activation of the adenosine monophosphate (AMP) -activated protein kinase and suppression of mammalian target-of-rapamycin signalling. Depletion of PGC1A, the master regulator of mitochondria biogenesis, recapitulated EoE-related BCH, suggesting that mitochondrial dysfunction drives BCH. Further, omeprazole alleviated mitochondrial damage and dysfunction in EoE-related BCH modelled in mice and patient-derived organoids. Conclusion: Mitochondrial dysfunction is tightly linked to perturbation of redox homeostasis in EoE-related BCH, which is promoted by IL-13 and reversible with omeprazole treatment.

INTRODUCTION: The risk of progression to esophageal adenocarcinoma in Barrett's esophagus (BE) increases with advancing degrees of dysplasia. There is a critical need to improve the diagnosis of BE dysplasia, given substantial interobserver variability and overcalls of dysplasia during manual community pathologist reads. We aimed to externally validate a previously cross-validated BE dysplasia diagnosis deep learning model (BEDDLM) that predicts dysplasia grade on whole slide images (WSIs). METHODS: We digitized nondysplastic BE (NDBE), low-grade (LGD), and high-grade dysplasia (HGD) histology slides from 3 external academic centers. A consensus read by 2 expert study pathologists was used as the criterion standard. Slide stain characteristics were normalized using cycle-generative adversarial networks. WSIs were assessed by BEDDLM using an ensemble approach, combining a “You Only Look Once” model followed by a ResNet101 classifier model. RESULTS: We included 489 WSIs. Consensus histopathology revealed 232 NDBE, 117 LGD, and 140 HGD WSIs. The mean age (SD) was 66.9 (11.4) years; 413 (84.7%) were men. Using the BEDDLM ensemble model, sensitivity and specificity for NDBE were 73.3% (95% confidence interval [CI]: 67.09%–78.85%) and 93.4% (95% CI: 89.62%–96.10%); for LGD, 84.6% (95% CI: 76.78%–90.62%) and 80.6% (95% CI: 76.26%–84.54%); and for HGD, 80.7% (95% CI: 73.19%–86.89%) and 94.8% (95% CI: 91.97%–96.91%), respectively. The F1 score was 0.81, 0 0.69, and 0.83 for NDBE, LGD, and HGD, respectively. DISCUSSION: Our externally validated deep learning model demonstrates substantial accuracy for the diagnosis of BE dysplasia grade on WSIs.

Purpose of Review Supragastric belching (SGB), rumination syndrome (RS), and abdominophrenic dyssynergia are often misunderstood and underdiagnosed syndromes. Better understanding of these conditions is needed to increase recognition and guide treatment. Recent Findings Diagnosis is typically made by history and physical examination though supplementary evaluations can be considered in difficult to diagnose cases. These diseases are unique in that their optimal therapies are behavioral and focused entirely on the basic physiology of breathing techniques. Summary Once one of these syndromes is recognized, the change in life for these patients can be formidable. As a result, recognition and proper treatment of these syndromes is essential for the gastroenterologist.

INTRODUCTION: The adjunctive use of p53 immunohistochemistry has been proposed as a potential tool to improve risk stratification in Barrett's esophagus (BE) with conflicting results. We performed a systematic review and meta-analysis to evaluate the performance of p53 in predicting progression to advanced neoplasia (high-grade dysplasia [HGD] and esophageal adenocarcinoma [EAC]) among patients with BE. METHODS: We searched multiple databases for studies that evaluated the use of aberrant p53 in esophageal biopsies among patients with BE and reported progression rates to HGD/EAC. The outcomes were p53 test characteristics and incidence and risk ratio (RR) for progression to HGD/EAC in patients with and without aberrant p53 using random effects models. RESULTS: Among the 27 included studies, the proportion of patients with aberrant p53 expression at baseline was 20% (95% CI: 14%, 27%). The rate of progression with and without aberrant p53 was 8 per 100 person-years (95% CI: 6, 11) and 0.3 per 100 person-years (95% CI: 0.1, 0.6), respectively. Compared with patients without aberrant p53 expression, those with aberrant p53 had a higher risk for progression to HGD/EAC in cohort studies (RR = 10.2 [95% CI: 6.9, 15.0]) and case control studies (RR = 3.3 [95% CI: 2.5, 4.4]). The sensitivity for progression for non-dysplastic Barrett's esophagus and low-grade dysplasia/indefinite for dysplasia was 42% and 77% and specificity was 96% and 76%, respectively. DISCUSSION: While aberrant p53 expression has been associated with an increased risk of progression to advanced neoplasia in patients with BE undergoing surveillance, the diagnostic characteristics are suboptimal precluding uniform clinical adoption. Prospective studies with standardized grading protocols are needed to determine whether p53-guided surveillance strategies can meaningfully improve patient outcomes.