Camilleri, Michael

ABSTRACT Background Gastric emptying (GE) scintigraphy with 4‐h imaging and a radiolabeled chicken egg‐based meal (320 kcal, 30% fat) is the standard test for gastroparesis at Mayo Clinic, with an intraindividual coefficient of variation (COV intra ) of 23.8% for GE half emptying time (T 1/2 ). Alternative meals for patients with dietary restrictions, including egg allergies or vegan diets, are lacking, limiting test accessibility. The study aimed to establish a vegan, lactose‐, nut‐, and gluten‐free meal with similar caloric and fat content to the egg meal and to assess its performance in GE studies. Methods In Vitro: 99m Tc binding to egg meal over 4 h was compared to a calorically and nutritionally similar vegan alternative, JUST Egg, using a validated in vitro model simulating gastric conditions of pH, pepsin, and stirring. In Vivo: 10 healthy participants underwent randomized crossover GE scintigraphy with standard and vegan meals, spaced ≥ 3 days apart to measure GE% at 2 h, 4 h, and GE T 1/2 . Group comparisons and variance analysis included Rank Sum tests and Bland–Altman plots. Key Results In Vitro: A strong correlation ( R = 0.975, p ‐value < 0.01) between 99m Tc binding in the egg and vegan egg models was observed. Minimal variance (< 10%) was recorded at all time points. In Vivo: GE at 4 h and GE T 1/2 showed non‐statistically significant mean differences, < 2% and < 10 min respectively, between both meals. The intra‐individual variability was 18.8%. Conclusions and Inferences The vegan meal demonstrated in vitro stability, in vivo performance comparable to the egg meal, and a COV intra of 18.8%, which was lower than the 23.8% reported in repeat egg meal GE studies. Trial Registration ClinicalTrials.gov number NCT06991036 ( https://clinicaltrials.gov/study/NCT06991036?term=NCT06991036&rank=1 )

Abstract: Melanoma exhibits a broad spectrum of histopathologic variations, including rare forms with neural differentiation. Neurotropism in melanoma encompasses both perineural invasion and neural-like transformation, but the prognostic implications of these features remain uncertain. Although (peri)neural invasion is well documented, true neural differentiation in melanomas is exceedingly rare. In this study, we describe an unusual case of primary cutaneous malignant melanoma exhibiting extensive Wagner–Meissner-like bodies, a feature more commonly associated with benign neural tumors and nevi. In this case, histopathology revealed a dual-component lesion with a neurotized and an epithelioid melanocytic component, both showing PRAME expression and p16 loss. Chromosomal microarray identified heterozygous loss of 9p22.1p13.1 (including CDKN2A / CDKN2B ), and loss of 10q22.2q26.3 (including PTEN ), supporting malignancy. These findings suggest that in this case, Wagner–Meissner-like bodies likely represent neurotization rather than a benign or collision lesion, highlighting the need for integrated histopathologic, immunohistochemical, and molecular analysis in challenging melanocytic neoplasms.

This pilot, randomized, double-blind trial in a relatively small sample of patients with IBS-related pain shows rimegepant significantly reduced sensations of gas, urgency, and pain during rectal distention and decreased rectal compliance. Decrease in compliance implies that changes in physical properties or distensibility of rectum did not contribute to alterations in rectal sensation. Same dose of rimegepant did not significantly impact daily abdominal pain, BM frequency, or colonic transit. There were no serious adverse events.

INTRODUCTION: To perform a proof-of-concept study to evaluate the performance of individual and combined anorectal manometry and balloon expulsion testing (BET) parameters for diagnosing dyssynergic defecation (DD) using machine learning (ML). METHODS: A single gastrointestinal motility specialist assessed (2008–2018) 307 patients. A ML model was constructed on anorectal manometry/BET data. BET was weight-based in 235 patients and time-based in 72 patients. Missing data were imputed. Data were split 75% train/25% test with preprocessing performed. Five common ML models were trained, and performance was compared using receiver operating characteristic (ROC) area under the curve and accuracy based on 100 bootstrapped samples. The most accurate models were fine-tuned and evaluated on the test set. RESULTS: The median age was 40 years, body mass index 22.2 kg/m 2 , and 81% were women. Two-hundred and 22 (72.3%) patients had a clinical diagnosis of DD. Compared with patients without clinical diagnosis of DD, patients with DD had significantly lower rectoanal pressure gradient (RAG) (median −34.7 [IQR −57.1, −13.0] vs −24.6 [IQR −44.5, −2.4] mm Hg, P = 0.009) and more abnormal BET (59.5% vs 11.8%, P < 0.001). Four features were retained in the optimized model as predictors of DD: abnormal BET, greater resting anal pressure (RAP), and more negative RAG. The optimal parameter was abnormal BET ( P = 0.003), but combinations of 2 manometry results (RAP and RAG) yielded positive predictive values (PPVs) >80%. The optimized logistic regression model had an area under the curve of 0.878, with a sensitivity of 75.0% and specificity of 81.8% at a probability threshold of 0.704. DISCUSSION: Abnormal BET, or a combination of 2 manometric parameters (RAP and RAG), provides >80% positive predictive value for diagnosing DD in patients with chronic constipation.

ABSTRACT Background In the United States, metoclopramide is the only medication approved for gastroparesis. There is a need to reappraise the main considerations involved in the approval of pharmacological treatments of gastroparesis. Objectives and Methods We conducted a literature review to address issues that might impact the approval of medications for gastroparesis. We appraised the epidemiology, clinical presentations, variations in diagnostic tests, and their thresholds for identification of gastroparesis. Based on the review, we proposed trial designs for proof of efficacy and safety of novel medications for gastroparesis. Results Based on epidemiological studies, the age‐adjusted prevalence in US population is 152,005 for all categories (definite, probable and possible) of gastroparesis. The major symptoms of gastroparesis are nausea, vomiting, early satiety and postprandial fullness and may lead to hospitalisation or emergency department visits. It is essential to appraise gastric emptying with a solid meal over at least 3 h using scintigraphy or a stable isotope breath test. Diagnostic thresholds have been established for these diagnostic tests and at present, reproducibility, normative data, and coefficient of variation are well established for the 320‐kcal real egg solid meal. Based on published guidelines on clinical efficacy of medications used in gastroparesis, we propose targeting the gastroparesis symptom subscales, such as nausea and vomiting, with pharmacological agents specifically directed at their causative mechanisms rather than targeting the underlying dysmotility. Conclusion The evidence documented here justifies consideration of gastroparesis as an orphan disease, as well as an innovative approach to supplement the regulatory bodies' recommendations and guidance to industry. We propose treatment trials of 4‐weeks duration and considering the use of specific symptoms of gastroparesis as clinical endpoints based on a pharmaceutical agent's mechanism of action, rather than using a total gastroparesis symptom score. Such an approach would include evidence of safety and efficacy of new medications targeting gastroparesis subscales, and approval for marketing would be based on the symptoms specifically ameliorated in robust trials.

Summary Esophageal high-resolution manometry (HRM) is the gold standard for evaluating esophageal motility disorders but can be limited by patient intolerance. With increasing use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) for obesity and type 2 diabetes, delayed gastric emptying raises concerns for HRM feasibility and safety. This study assessed HRM tolerability in patients on GLP-1RAs. We conducted a retrospective case–control study of adult patients who underwent HRM at our tertiary care center between January 2014 and November 2024. Patients actively taking GLP-1RAs during HRM were identified as cases, while an equal number of consecutive eligible patients not on GLP-1RAs served as controls. Patients with established gastrointestinal dysmotility, prior foregut surgery, esophageal mechanical obstruction, large hiatal hernias, malignancy, or recent opioid use were excluded. From a prospective database of 7194 HRM attempts, 83 cases and 83 matched controls were identified. Among 166 patients, 15 (9.0%) had incomplete HRM due to intolerance, with similar rates between GLP-1RA users and controls (10.84% vs. 7.2%, P = 0.59). Predictors of incomplete HRM included younger age (44.9 ± 17.4 vs. 60.4 ± 13.7 years, P &lt; 0.01), globus (P = 0.02), dyspepsia (P = 0.02), and depression (P = 0.04). No aspiration or adverse events occurred in either group. Duration of HRM before abortion was similar between cases and controls. GLP-1RA use was not associated with increased risk of HRM abortion or adverse events, suggesting these medications do not significantly impact HRM feasibility or safety.

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.

ABSTRACT Background Microbial overgrowth (MO) in the small intestine can cause gastrointestinal symptoms and may arise from stasis, such as dysmotility. Microtypes of MO include small intestinal bacterial overgrowth (SIBO) and intestinal methanogen overgrowth (IMO). Dyssynergic defecation (DD) is associated with constipation and slow colonic transit (STC). Our aim was to assess the relationship between DD and MO. Methods We retrospectively identified patients who underwent both anorectal manometry (ARM) and balloon expulsion testing (BET) for DD, and MO testing using either small intestinal aspirate culture or breath testing. SIBO was analyzed using two culture thresholds: ≥ 10 5 CFU/mL and ≥ 10 3 CFU/mL. Chi‐square tests compared positive vs. negative results. Key Results 436 patients underwent culture of SB aspirates. At the ≥ 10 5 CFU/mL threshold, 41.7% were diagnosed with SIBO, and 87.4% at ≥ 10 3 CFU/mL. At ≥ 10 5 CFU/mL, percent anal relaxation was significantly lower in SIBO‐positive patients. SIBO patients were more likely to have reduced anal relaxation ( p = 0.032), but no other ARM parameters or BET > 60 s. At ≥ 10 3 CFU/mL, a more negative recto‐anal pressure differential (RAPD) was observed, along with a combination of RAPD < −45 mmHg and resting anal pressure > 90 mmHg. 637 patients underwent breath testing for MO, with 174 positive results, predominantly showing IMO (73%). In this group, BET was significantly longer, and anal relaxation was significantly lower. SIBO at ≥ 10 3 CFU/mL was more prevalent in DD than STC (85.5% vs. 64.7%, p = 0.002). IMO was more common in DD than STC ( p = 0.021). Conclusion/Inferences DD may be a risk factor for MO, often with evidence of methanogenesis.

INTRODUCTION: Indomethacin is often used experimentally to induce intestinal hyperpermeability, enabling evaluation of interventions targeting barrier function. METHODS: We conducted a randomized, double-blind, placebo-controlled study (NCT05538247) in healthy volunteers to assess whether a supplement could mitigate indomethacin-induced hyperpermeability. Participants received 150 mg/d of indomethacin for 6 days, either before or during placebo/supplement administration. Permeability was measured using 13 C-mannitol and lactulose urinary excretion. RESULTS: Contrary to expectations, indomethacin failed to increase 13 C-mannitol excretion in either group. No meaningful elevations in serum (zonulin, claudins) or fecal (calprotectin) biomarkers were observed. DISCUSSION: Our findings suggest that the expected increase in intestinal permeability after indomethacin administration may not be consistently observed in healthy volunteers. These results highlight the need to carefully consider the reproducibility and sensitivity of this model in future clinical studies aiming to investigate gut barrier function.