Katzka, D A

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.

ABSTRACT 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 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.

SummaryBackgroundPredictive models for eosinophilic oesophagitis (EoE) may not fully rule in the diagnosis.AimTo develop a reverse model that predicts against EoE to eliminate the need for oesophageal biopsies.MethodsIn this two‐centre study, a predictive model was developed (Mayo Clinic) and validated (University of North Carolina [UNC]). Cross‐sectional data from consecutive adult patients without prior EoE who underwent upper enoscopy with oesophageal biopsies were used. EoE cases had ≥15 eosinophils/high‐power field while controls had no eosinophils. Data were collected on patient clinical and endoscopic features. Multiple variable logistic regression was used to identify predictors of non‐EoE status while maintaining specificity ≥95%. A secondary model was developed to predict against the need for endoscopy in patients suspected of having EoE without alarm symptoms.ResultsThe Mayo and UNC cohorts consisted of 345 (EoE = 94, non‐EoE = 251) and 297 patients (EoE = 84, non‐EoE = 213), respectively. A primary model based on clinical and endoscopic features predicted against EoE with c‐statistic 0.92 (95% CI: 0.88–0.96), specificity 95%, and sensitivity 65%. This model was validated (UNC) with c‐statistic 0.87 (95% CI: 0.82–0.92). A simplified scoring system was created and a threshold of ≥12 points excluded EoE with 95% specificity and 50% sensitivity. A secondary model based on clinical characteristics alone predicted against EoE with c‐statistic 0.86 (95% CI: 0.82–0.90), specificity 95% and sensitivity 39% and validated (UNC) with c‐statistic 0.78 (95% CI: 0.71–0.85).ConclusionA simplified scoring system accurately identified a group of patients with a low likelihood of EoE where unnecessary oesophageal biopsies can be avoided, potentially resulting in resource and cost savings.

SummaryBackgroundAchalasia is a debilitating major motor disorder of the oesophagus. Hypervigilance and symptom‐specific anxiety substantially impact dysphagia symptom reporting, and quality of life is a critical patient outcome. Earlier achalasia symptom scales did not consider these constructs in their psychometric development.AimTo develop a new symptom measure, the Achalasia Patient‐Reported Outcomes (APRO) QuestionnaireMethodsFour gastroenterologists with achalasia expertise generated preliminary items. Patients reviewed items via cognitive interviews. Patients undergoing high‐resolution manometry completed the APRO with Oesophageal Hypervigilance and Anxiety Scale, Northwestern Oesophageal Quality of Life Scale, and three measures of reflux and dysphagia. Full APRO psychometric assessment (reliability, validity, factor structure) was done. Cluster analysis evaluated APRO + symptom‐anxiety/hypervigilance patient phenotypes.ResultsWe included 961 patients with normal motility and 296 with achalasia. The APRO yielded three subscales: dysphagia, reflux, chest pain with two items for weight change and diet modifications. Reliability and validity were excellent. Twenty‐five percent of achalasia patients may have high levels of anxiety/hypervigilance despite low symptoms, while 8% may report severe symptoms with low anxiety/hypervigilance. The APRO significantly predicted quality of life, but less cognitive‐affective processes.ConclusionsThe APRO is a reliable and valid measure of achalasia symptoms that addresses the limitations of existing questionnaires. Symptom anxiety and hypervigilance moderate the relationship between APRO and quality of life; 33% of patients with achalasia exhibit concerning patterns in symptom severity, anxiety and hypervigilance that may contribute to poorer outcomes.

Summary Background Optimal ambulatory reflux monitoring methodology in symptomatic reflux patients continues to be debated. Aims To utilise published literature and expert opinion to develop recommendation statements addressing use of ambulatory reflux monitoring in clinical practice Methods The RAND Appropriateness Method (RAM) was utilised among 17 experts with discussion, revision and two rounds of ranking of recommendation statements. Ambulatory reflux monitoring protocol, methodology and thresholds ranked as appropriate by ≥80% of panellists met the criteria for appropriateness. Results Prolonged (96‐h recommended) wireless pH monitoring off proton pump inhibitor (PPI) was identified as the appropriate diagnostic tool to assess the need for acid suppression in patients with unproven gastro‐oesophageal reflux disease (GERD) and persisting typical reflux symptoms despite once‐daily PPI. Acid exposure time (AET) <4.0% on all days of monitoring with negative reflux‐symptom association excludes GERD and does not support ongoing PPI treatment. Conversely, AET >6.0% across ≥2 days is conclusive evidence for GERD and supports treatment for GERD, while AET >10% across ≥2 days identifies severe acid burden that supports escalation of anti‐reflux treatment. In previously proven GERD, impedance‐pH monitoring on PPI is helpful in defining refractory GERD and mechanisms of continued symptoms; the presence of <40 reflux events, AET <2.0% and a negative reflux‐symptom association does not support escalation of anti‐reflux treatment. In contrast, AET > 4.0% and positive reflux‐symptom association support escalation of anti‐reflux treatment, including use of invasive therapeutics. Conclusions Statements meeting appropriateness for average clinical care have been identified when utilising reflux monitoring in patients with typical reflux symptoms and PPI non‐response.

Abstract Background: Discovery of methylated DNA markers (MDM) of esophageal squamous cell carcinoma (ESCC) has sparked interest in assessing these markers in tissue. We evaluated MDMs in ESCC from three geographically and ethnically distinct populations, and explored the feasibility of assaying MDMs from DNA obtained by swallowed balloon devices. Methods: MDMs were assayed in ESCC and normal tissues obtained from the populations of United States, Iran, and China, and from exfoliative cytology specimens obtained by balloons in a Chinese population. Areas under the receiver operating curve (AUC) of MDMs discriminating ESCC from normal tissues were calculated. Random forest prediction models were built, trained on U.S. cases and controls, and calibrated to U.S.-only controls (model 1) and three-country controls (model 2). Statistical tests were used to assess the relationship between dysplasia and MDM levels in balloons. Results: Extracted DNA from 333 ESCC and 322 normal tissues was analyzed, in addition to archival DNA from 98 balloons. For ESCC, model 1 validated in Iranian and Chinese tissues with AUCs of 0.90 and 0.87, and model 2 yielded AUCs of 0.99, 0.96, and 0.94 in tissues from the United States, Iran, and China, respectively. In Chinese balloons, MDMs showed a statistically significant trend of increasing levels with increasing grades of dysplasia (P &lt; 0.004). Conclusions: MDMs accurately discriminate ESCC from normal esophagus in tissues obtained from high- and low-incidence countries. Preliminary data suggest that levels of MDMs assayed in DNA from swallowed balloon devices increase with dysplasia grade. Larger studies are needed to validate these results. Impact: MDMs coupled with minimally invasive collection methods have the potential for worldwide application in ESCC screening.