Although gastroesophageal reflux disease (GERD) and pancreatitis are both common gastrointestinal disorders, few studies have investigated their potential causal relationship. Clarifying whether GERD contributes to the development of acute pancreatitis (AP) and chronic pancreatitis (CP), and the possible mediating role of cholelithiasis, may provide new insights into shared pathogenic mechanisms. A univariable Mendelian randomization (UVMR) analysis was performed to assess the causal effects of GERD on AP and CP. To improve statistical power, the results from the discovery and replication cohorts were combined through meta-analysis. Multivariable Mendelian randomization (MVMR) was subsequently applied to adjust for the potential confounding effect of cholelithiasis. Finally, mediation analysis was conducted to evaluate the mediating role of cholelithiasis in the causal pathway from GERD to AP and CP. Multiple analyses, including heterogeneity analysis and horizontal pleiotropy analysis, were performed for sensitivity assessment. This study provides genetic evidence supporting a causal relationship between GERD and pancreatitis. The findings further highlight cholelithiasis as a partial mediator in this pathway, offering novel insights into shared mechanisms and potential preventive strategies for pancreatitis. UVMR suggested a positive causal association between GERD and both AP (discovery cohort: odds ratio [OR], 1.46; 95% confidence interval [CI], 1.29-1.65; P < .001; replication cohort: OR, 1.63; 95% CI, 1.37-1.93; P < .001) and CP (discovery cohort: OR, 1.47; 95% CI, 1.24-1.73; P < .001; replication cohort: OR, 1.50; 95% CI, 1.15-1.96; P = .003). Meta-analysis confirmed consistent and robust causal estimates across the discovery and replication datasets (AP: pooled OR, 1.52; 95% CI, 1.37-1.68; P < .001; CP: pooled OR, 1.48; 95% CI, 1.28-1.70; P < .001). After adjustment for cholelithiasis using MVMR, the causal effects were attenuated but remained statistically significant (AP: OR, 1.24; 95% CI, 1.06-1.44; P = .006; CP: OR, 1.39; 95% CI, 1.12-1.72; P = .003). Mediation analysis indicated that cholelithiasis partially mediated the causal effect of GERD on AP (mediation proportion [95% CI]: 42.4% [27.7-57.2%], P < .001) and CP (mediation proportion [95% CI]: 21.9% [0.1-43.7%], P = .048), suggesting that gallstone formation may be an important biological link between reflux disease and pancreatic inflammation. No significant evidence was detected in the sensitivity analyses (All P > .050).

The proton pump inhibitors are widely prescribed for the symptomatic treatment of chronic epigastric pain and heartburn in cancer patients, but they carry the potential for drug-drug interactions (DDI) with oral antineoplastic agents. In this retrospective cohort study, we examine the utility of 24-hour esophageal and gastric ambulatory pH monitoring off- or on-proton pump inhibitors (PPI) therapy as a guide in safely prescribing of PPI for cancer patients. We analyzed data from 189 consecutive non-cancer patients with chronic PPI-refractory gastroesophageal reflux disease (GERD) 146 (75F/71M) 'off' and 39 (21F/18M) 'on' PPIs; 4 (2F/2M) had atrophic gastritis and were used as controls. There were 69 with pathologic esophageal acid reflux and 74 patients with normal esophageal acid exposure. The 24-hour % gastric pH <4 in these two groups that exhibited median values of 92% and 89%, respectively (NS). Gastric acidity was highest in non-PPI users (median 92.8%), less in PPI users (median 40.8%), and near absent (median 1.65%) in patients with atrophic gastritis (P < .005). In 39 patients who underwent 24-hour intragastric pH monitoring 'on' PPI, the best times to administer a drug that needs acidity for optimal bioavailability are 3 pm-6 pm and 3 am-6 am, and better with daily v. twice- daily PPI. We conclude that dual esophageal and gastric pH monitoring, identifies (a) the presence of pathologic esophageal acid reflux, justifying long-term PPI use; (b) the absence of pathologic esophageal reflux negating PPI use; (c) the presence of variable levels of PPI-induced gastric hypochlorhydria; (d) time-windows of gastric pH < 4 that would optimize other drug coadministration for maximal oncologic drug bioavailability.

Management of pediatric esophageal disease has traditionally relied on static anatomic endpoints including luminal diameter, endoscopic findings, and histologic features to guide diagnosis and therapeutic decision-making. However, these measures incompletely capture esophageal function and the biomechanical consequences of chronic inflammation, fibrosis, injury, and extrinsic compression. In adult gastroenterology, esophageal distensibility assessment using the functional lumen imaging probe (FLIP) has emerged as an adjunctive marker of disease severity and treatment response in conditions such as achalasia and eosinophilic esophagitis. This work reviews pediatric and adult literature examining esophageal distensibility, compliance, and biomechanical remodeling, with emphasis on FLIP-based assessment, disease-specific remodeling patterns, and implications for therapeutic endoscopy. Available evidence demonstrates that esophageal distensibility provides physiologic information beyond static luminal diameter and may help explain discordance between anatomic findings and symptoms. Pediatric studies support the feasibility of FLIP-based functional assessment and suggest that altered distensibility trajectories reflect disease-related remodeling in eosinophilic esophagitis, caustic injury, postsurgical strictures, and vascular compression. Functional measurements may also help interpret dilation response and identify situations in which additional size escalation alone may yield diminishing functional benefit. This review also proposes a pediatric framework integrating FLIP-derived biomechanics into interpretation of dysphagia, dilation response, and therapeutic decision-making. Esophageal distensibility and biomechanical remodeling represent underutilized actionable concepts in pediatric esophageal disease. Integrating functional assessment with anatomic evaluation may improve interpretation of disease severity, explain discordance between symptoms and luminal diameter, and inform therapeutic decision-making. Pediatric-specific interpretive frameworks are needed to determine how distensibility and compliance metrics can guide management in children.

Rome V represents a major conceptual and clinical evolution in the field of disorders of gut-brain interaction (DGBI). Its most important contribution is the deliberate move away from the term "functional", a label that has often implied that symptoms are less real, less biological, or merely psychological. By emphasizing DGBI, Rome V reframes these conditions as positive diagnoses arising from altered gut-brain regulation, visceral sensitivity, motility, mucosal and immune mechanisms, microbiota, autonomic function, and central processing. Beyond terminology, Rome V introduces greater diagnostic precision. In esophageal disorders, the exclusion of gastroesophageal reflux disease and major motor disorders is aligned with Lyon Consensus 2.0 and Chicago Classification v4.0, while globus and functional chest pain are refined to avoid unnecessary interventions. In gastroduodenal disorders, functional dyspepsia is better phenotyped according to meal-related symptoms, with clearer distinctions from chronic nausea and vomiting syndrome, gastroparesis, cyclic vomiting syndrome, cannabinoid hyperemesis syndrome, rumination, and inability to belch. In bowel disorders, Rome V reintroduces abdominal discomfort into IBS criteria, changes the symptom frequency threshold, renames functional constipation as chronic constipation, and redefines abdominal bloating/distension. The anorectal section is particularly relevant because it operationalizes fecal incontinence, defines dyssynergic defecation using objective testing, and formally recognizes rectal hypo- and hypersensitivity, which may guide biofeedback therapy. Rome V also raises future challenges: implementation in clinical practice, patient-centered communication, avoidance of reductionism, development of mechanism-based research, and interpretation of forthcoming epidemiological data. Overall, Rome V promotes precision, reduces stigma, and supports more rational, mechanism-based care.

Esophageal motility disorders are an important and uncommon cause of dysphagia when structural abnormalities are absent. We present a case of a 77-year-old woman with dysphagia and regurgitation whose barium esophagram demonstrated a characteristic "nutcracker" appearance of the distal esophagus. Despite this striking radiographic finding, peristalsis was preserved, and a barium tablet traversed the segment without obstruction. These features argue against classic diffuse esophageal spasm and instead suggest a hypercontractile motility disorder. This case highlights the role of barium esophagram as a complementary diagnostic tool while emphasizing that definitive classification of esophageal motility disorders requires high-resolution manometry.

Third-space endoscopy refers to a set of endoscopic techniques that allow access to the submucosal space or "third space" between the mucosa and muscularis propria, enabling therapeutic intervention while preserving mucosal integrity. The unifying concept across all third-space endoscopy procedures is the creation of a submucosal tunnel with a mucosal flap acting as a safety valve, allowing separation of access from therapy. This principle is the key factor underlying its rapid adoption across diverse indications. The evolution of third-space endoscopy began with the submucosal endoscopy with mucosal flap technique, followed by the first porcine per-oral endoscopic myotomy and its clinical application in humans nearly two decades ago. Per-oral endoscopic myotomy has not only transformed the management of achalasia but also established a platform that has since been extended to multiple gastrointestinal disorders, including per-oral endoscopic myotomy for refractory gastroparesis, submucosal tunneling endoscopic resection for sub-epithelial tumors, Zenker's per-oral endoscopic myotomy, and per-oral endoscopic myotomy for epiphrenic diverticula. Although some procedures, such as per-oral endoscopic myotomy and tunneling resection for subepithelial tumors, have matured with well-defined roles in clinical algorithms, others, including per-oral endoscopic myotomy in refractory gastroparesis and Zenker's per-oral endoscopic myotomy, demonstrate promising safety and efficacy but continue to face unresolved questions regarding patient selection, durability, and comparative effectiveness. Despite these limitations, third-space endoscopy has emerged as a minimally invasive alternative for several conditions traditionally managed surgically. Its standardized core principles allow broad adaptability across disease phenotypes. This narrative review discusses the evolution, technical framework, clinical outcomes, and current limitations of key third-space endoscopy procedures.