Vázquez‐Roque, María I.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet their benefits remain limited to a subset of patients, underscoring the need for more reliable biomarkers and novel therapeutic strategies. The gut microbiome has emerged as a critical modulator of systemic immunity and a promising determinant of ICI response. Evidence links specific microbial features, taxa, and bioactive metabolites to enhanced antitumor immunity, whereas disruptions, such as antibiotic exposure, are associated with poorer outcomes. Advances in sequencing and multi-omics technologies have provided more profound insights into microbiome-immune crosstalk, though methodological heterogeneity continues to challenge reproducibility. Translational studies demonstrate that microbiome-based intervention, including fecal microbiota transplantation (FMT), biotics supplementation, and engineered microbial strains, can enhance ICI efficacy or mitigate immune-related toxicities. Despite encouraging early clinical signals, broader implementation requires methodological rigor, standardized protocols, and innovative trial designs that account for host and environmental factors. For clinicians, the most immediate strategies involve prudent antibiotic stewardship and patient enrollment in microbiome-focused clinical trials. Overall, the gut microbiome is a promising biomarker and a therapeutic target, representing a new frontier for personalizing immunotherapy and improving patient outcomes in oncology.

e24161 Background: Pertuzumab-induced gastrointestinal toxicities (PIGT), particularly diarrhea, is the most common adverse event reported in over 70% of patients receiving pertuzumab in combination with chemotherapy. PIGT can result in dose reduction, treatment delay, and discontinuation of chemotherapy. Rifaximin is a minimally absorbed oral antibiotic approved for gastrointestinal tract infections and bacterial overgrowth. Our aim was to evaluate the efficacy of rifaximin in reducing PIGT. Methods: Patients with stage I-III HER2-positive (HER2+) breast cancer who received pertuzumab in combination with docetaxel, carboplatin, and trastuzumab (TCHP) were enrolled. PIGT included diarrhea, abdominal distention, abdominal pain, dyspepsia, stomach pain, and typhlitis. Patients with any PIGT ≥ grade 2 after the first cycle of TCHP received rifaximin 550 mg orally twice daily on days 1-5 in all subsequent cycles of chemotherapy. Patients with PIGT grade < 2 were observed without rifaximin. Simon's Two-Stage design was used. Results: Between 2018-2022, a total of 21 patients were enrolled. One patient was excluded due to significant anemia not meeting the eligibility criteria to proceed with rifaximin after the first cycle of TCHP. Of 20 patients, the median age was 52.5 (39-69) years. 18/20 (90.0%) patients had PIGT ≥ grade 2 after 1 cycle of TCHP with PIGT grade 2 in 15 (83.3%) and grade 3 in 3 (16.7%). PIGT ≥ grade 2 included diarrhea in 14 (70.0%) with grade 2 in 12 (60.0%) and grade 3 in 2 (10.0%), abdominal pain in 9 (45.0%) with grade 2 in 8 (40.0%) and grade 3 in 1 (5.0%), abdominal distension in 3 (15.0%), dyspepsia in 5 (25.0%), and stomach pain in 4 (20.0%) patients. Among 18 patients who received rifaximin, 15 (83.3%; 95% CI 0.586-0.964) had at least 1 cycle with a maximum PIGT grade < 2. This result surpassed the threshold of the Two-Stage analysis. Reduction of individual PIGT symptoms for patients who experienced > grade 2 at baseline after the first cycle of rifaximin was reported in 2/3 (66.7%) for abdominal distention, 8/9 (88.9%) for abdominal pain, 6/14 (42.9%) for diarrhea, 3/4 (75.0%) for stomach pain, and 4/5 (80.0%) for dyspepsia. No patients experienced > grade 2 typhilitis at baseline and during treatment. Treatment is well tolerated, with no significant grade 3+ adverse event related to rifaximin observed. Among patients who received rifaximin, there was no treatment delay or discontinuation of pertuzumab related to PIGT. Conclusions: PIGT is a debilitating side effect observed in most patients receiving pertuzumab. A short course of rifaximin after each cycle of treatment is a well-tolerated treatment option that significantly reduces PIGT in patients receiving pertuzumab in combination with chemotherapy. Clinical trial information: NCT04249622 .

INTRODUCTION: Gastric-emptying scintigraphy (GES), routinely used to measure gastric emptying, is an essential tool to diagnose gastroparesis. An accurate diagnosis of gastroparesis relies upon the GES being performed according to a validated protocol. Jointly published protocol guidelines have been available for over a decade; however, the extent to which these guidelines are adhered to is unknown. This study aimed to assess national compliance with established GES protocol guidelines. METHODS: We developed a questionnaire addressing key protocol measures outlined in the published Procedure Guideline for Adult Solid-Meal Gastric Emptying Study 3.0. Survey questions addressed patient information collection (15), patient preparation and procedure protocol (16), meal content and preparation (7), imaging (3), interpretation (4), and reporting (7). Demographic data was also collected. The anonymous questionnaire was distributed electronically to members of the Society of Nuclear Medicine and Medical Imaging (SNMMI) and non-member recipients of the SNMMI daily email newsletter. One response per medical institution was permitted. Data were entered manually and statistically assessed using JMP®, Version 14.0. SAS Institute Inc., Cary, NC. RESULTS: 121 medical institutions (MI) responded; 49 (40.4%) were academic/teaching medical centers. The mean number of annual GES procedures was 199.9 (range, 5 to 2000 GES/year). On average, MI performed 64% (33.5/52) of protocol measures according to guidelines while academic medical centers performed 61% (31.5/52) of protocol measures according to guidelines. Only 59% of MI use the validated meal. 42% of MI reported stopping imaging prior to the validated 4-hour interval. Only 16% of MI test blood glucose levels prior to GES while 71% cancel or reschedule GES if blood glucose levels are above the validated cut-off. 68% of MI ask patients if they take narcotic pain medications; only 49% require that patients stop taking narcotic pain medications at least two days prior to the GES. Only 4.5% of MI perform GES while adhering to 3 critical measures: validated study duration; controlling blood glucose levels; and properly restricting medication use. CONCLUSION: Low compliance with GES protocol guidelines, even among academic medical centers, raises the likely possibility of misdiagnosis and thus improper management of upper gastrointestinal symptoms. These results highlight a need for increased awareness of protocol guidelines.

INTRODUCTION: High-resolution manometry using the Chicago Classification is standard in the evaluation of esophageal motility. When the relaxation of the esophagogastric junction is impaired and achalasia excluded, esophagogastric junction outflow obstruction (EGJ-OO) is diagnosed and the esophageal body is essentially ignored. We sought to characterize the function of the esophageal body in consecutive patients with EGJ-OO. METHODS: Retrospective review of the esophageal manometry findings in consecutive patients where there was computer recognition of EGJ-OO collected over a 2-month period. In each case, the esophageal body was reviewed manually and results reported independent of the suggested computer diagnosis. RESULTS: 116 patients underwent manometry over a 2-month period and 30 (26%) were identified as having EGJ-OO. The indications for testing included chronic cough (n = 5), GERD (n = 8), dysphagia (n = 9) and esophageal evaluation associated with severe lung disease or transplantation (n = 8). The mean IRP was 20.8 (range 16-33.6) and did not vary depending on indication ( P = 0.381). Computer interpretation was EGJ-OO in all patients without mention of the esophageal body. After review, 11 (37%) had an additional esophageal diagnosis. In effective esophageal motility (IEM) was the most prevalent among them (IEM-8, achalasia-2, jackhammer esophagus-1; P = 0.020). The frequency of an additional esophageal diagnosis was significantly different between GERD (0%) and dysphagia (66%; P = 0.004), but not between other groups (i.e. 40% in cough and 37.5% in transplant group). An esophageal body diagnosis was significantly more likely in patients with IRP > 25 (80%) compared with those with IRP < 25 (28%; P = 0.028). CONCLUSION: 1-EGJ-OO is common in patients referred for esophageal manometry. 2-An additional esophageal body diagnosis is common in those with EGJ-OO.3-Esophageal diagnoses are more common in patients with dysphagia and in those with a very high IRP. The body of the esophagus is important in cases of EGJ-OO and should be reported independent of the computer-generated interpretation of the Chicago Classification.

Abstract Although neurogastroenterology and motility ( NGM ) disorders are some of the most frequent disorders encountered by practicing gastroenterologists, a structured competency‐based training curriculum developed by NGM experts is lacking. The American Neurogastroenterology and Motility Society ( ANMS ) and the European Society of Neurogastroenterology and Motility ( ESNM ) jointly evaluated the components of NGM training in North America and Europe. Eleven training domains were identified within NGM , consisting of functional gastrointestinal disorders, visceral hypersensitivity and pain pathways, motor disorders within anatomic areas (esophagus, stomach, small bowel and colon, anorectum), mucosal disorders (gastro‐esophageal reflux disease, other mucosal disorders), consequences of systemic disease, consequences of therapy (surgery, endoscopic intervention, medications, other therapy), and transition of pediatric patients into adult practice. A 3‐tiered training curriculum covering these domains is proposed here and endorsed by all NGM societies. Tier 1 NGM knowledge and training is expected of all gastroenterology trainees and practicing gastroenterologists. Tier 2 knowledge and training is appropriate for trainees who anticipate NGM disorder management and NGM function test interpretation being an important part of their careers, which may require competency assessment and credentialing of test interpretation skills. Tier 3 knowledge and training is undertaken by trainees interested in a dedicated NGM career and may be restricted to specific domains within the broad NGM field. The joint ANMS and ESNM task force anticipates that the NGM curriculum will streamline NGM training in North America and Europe and will lead to better identification of centers of excellence where Tier 2 and Tier 3 training can be accomplished.

The contributions of gastric emptying (GE) and gastric accommodation (GA) to satiation, satiety, and postprandial symptoms remain unclear. We aimed to evaluate the relationships between GA or GE with satiation, satiety, and postprandial symptoms in healthy overweight or obese volunteers (total n = 285, 73% women, mean BMI 33.5 kg/m 2 ): 26 prospectively studied obese, otherwise healthy participants and 259 healthy subjects with previous similar GI testing. We assessed GE of solids, gastric volumes, calorie intake at buffet meal, and satiation by measuring volume to comfortable fullness (VTF) and maximum tolerated volume (MTV) by using Ensure nutrient drink test (30 ml/min) and symptoms 30 min after MTV. Relationships between GE or GA with satiety, satiation, and symptoms were analyzed using Spearman rank ( r s ) and Pearson ( R) linear correlation coefficients. We found a higher VTF during satiation test correlated with a higher calorie intake at ad libitum buffet meal ( r s = 0.535, P < 0.001). There was a significant inverse correlation between gastric half-emptying time (GE T 1/2 ) and VTF ( r s = −0.317, P < 0.001) and the calorie intake at buffet meal ( r s = −0.329, P < 0.001), and an inverse correlation between GE Tlag and GE25% emptied with VTF ( r s = −0.273, P < 0.001 and r s = −0.248, P < 0.001, respectively). GE T 1/2 was significantly associated with satiation (MTV, R = −0.234, P < 0.0001), nausea ( R = 0.145, P = 0.023), pain ( R = 0.149, P = 0.012), and higher aggregate symptom score ( R = 0.132, P = 0.026). There was no significant correlation between GA and satiation, satiety, postprandial symptoms, or GE. We concluded that GE of solids, rather than GA, is associated with postprandial symptoms, satiation, and satiety in healthy participants. NEW & NOTEWORTHY A higher volume to comfortable fullness postprandially correlated with a higher calorie intake at ad libitum buffet meal. Gastric emptying of solids is correlated to satiation (volume to fullness and maximum tolerated volume) and satiety (the calorie intake at buffet meal) and symptoms of nausea, pain, and aggregate symptom score after a fully satiating meal. There was no significant correlation between gastric accommodation and either satiation or satiety indices, postprandial symptoms, or gastric emptying.

ObjectiveTo examine the association of gene variants of uncoupling proteins (UCP)‐2 and −3 with obesity and gastrointestinal (GI) traits.MethodsIn 255 overweight or obese adults, the associations of gene variants in UCP‐2 (−3474, rs659366) and UCP‐3 (rs1626521, rs2075577, rs15763) with body weight (BW) and GI traits were studied. Gene variants were genotyped by TaqMan® assay. The associations of genotypes with BW and GI traits (gastric emptying, gastric volume, satiety by buffet meal, satiation by nutrient drink test and GI hormones) were assessed using ANOVA corrected for false detection rate (FDR).ResultsA novel UCP‐3 gene variant, rs1626521, was identified; it was associated with BW (P = 0.039), waist circumference (P = 0.035), and significantly higher postprandial gastric volume (P = 0.003) and calories ingested at buffet meal (P = 0.006, both significant with FDR). In a subgroup of 11 participants, rs1626521 was also associated with reduced mitochondrial bioenergetics efficiency in skeletal muscle (P = 0.051). In an in vitro study in HEK293 cells, rs1626521 reduced UCP‐3 protein expression (P = 0.049). Associations detected between other genotypes and GI traits were nonsignificant with FDR.ConclusionsA newly identified functional variant (rs1626521) in UCP‐3 affects postprandial gastric functions and satiety and may contribute to weight gain and alter human mitochondrial function.

BackgroundPatients with disorders of gastrointestinal function may undergo unnecessary treatment if misdiagnosed as motility disorders.ObjectiveTo report on clinical features, medical, surgical, and psychiatric comorbidities, and prior treatments of a patient cohort diagnosed concurrently with nonpsychogenic rumination syndrome and pelvic floor dysfunction (also termed rectal evacuation disorder).MethodsFrom a consecutive series (1994–2013) of 438 outpatients with rectal evacuation disorders in the practice of a single gastroenterologist at a tertiary care centre, 57 adolescents or adults were diagnosed with concomitant rumination syndrome. All underwent formal psychological assessment or completed validated questionnaires.ResultsAll 57 patients (95% female) fulfilled Rome III criteria for rumination syndrome; rectal evacuation disorder was confirmed by testing of anal sphincter pressures and rectal balloon evacuation. Prior to diagnosis, most patients underwent multiple medical and surgical treatments (gastrostomy, gastric fundoplication, other gastric surgery, ileostomy, colectomy) for their symptoms. Psychological comorbidity was identified in 93% of patients. Patients were managed predominantly with psychological and behavioural approaches: diaphragmatic breathing for rumination and biofeedback retraining for pelvic floor dysfunction.ConclusionsAwareness of concomitant rectal evacuation disorder and rumination syndrome and prompt identification of psychological comorbidity are keys to instituting behavioural and psychological methods to avoid unnecessary treatment.

Genetic variations in metabolism of endocannabinoids and in CNR1 (gene for cannabinoid 1 receptor) are associated with symptom phenotype, colonic transit, and left colon motility in irritable bowel syndrome (IBS). Our aim was to evaluate associations between two variations in CNR1 genotype (rs806378 and [AAT]n triplets) with symptom phenotype, small bowel and colonic transit, and rectal sensations in 455 patients with IBS and 228 healthy controls. Small bowel and colonic transit were measured by scintigraphy, rectal sensation by isobaric distensions. Associations with genotype were assessed by χ2test (symptom phenotype) and ANCOVA (quantitative traits) based on a dominant genetic model. Significant association of CNR1 rs806378 (but not CNR1 [AAT]n) genotype and symptom phenotype was observed (χ2P = 0.028). There was significant association of CNR1 rs806378 ( P = 0.014; CC vs. CT/TT) with colonic transit in IBS-diarrhea (IBS-D) group; the TT group had the fastest colonic transit at 24 and 48 h. There was significant overall association of CNR1 rs806378 with sensation rating of gas ( P = 0.025), but not pain; the strongest associations for gas ratings were in IBS-D ( P = 0.002) and IBS-alternating ( P = 0.025) subgroups. For CNR1 (AAT)n, gene-by-phenotype interactions were observed for colonic transit at 24 ( P = 0.06) and 48 h ( P = 0.002) and gas ( P = 0.046, highest for IBS-D, P = 0.034), but not pain sensation; the strongest association with transit was in controls, not in IBS. These data support the hypothesis that cannabinoid receptors may play a role in control of colonic transit and sensation in humans and deserve further study as potential mediators or therapeutic targets in lower functional gastrointestinal disorders.

Patients with irritable bowel syndrome (IBS) with diarrhea (IBS-D) carrying human leukocyte antigen (HLA)-DQ2/8 genotypes benefit from gluten withdrawal. Our objective was to compare gastrointestinal barrier function, mucosal inflammation, and transit in nonceliac IBS-D patients and assess association with HLA-DQ2/8 status. In 45 IBS-D patients who were naive to prior exclusion of dietary gluten, we measured small bowel (SB) and colonic mucosal permeability by cumulative urinary lactulose and mannitol excretion (0–2 h for SB and 8–24 h for colon), inflammation on duodenal and rectosigmoid mucosal biopsies (obtained in 28 of 45 patients), tight junction (TJ) protein mRNA and protein expression in SB and rectosigmoid mucosa, and gastrointestinal and colonic transit by validated scintigraphy. SB mucosal biopsies were stained with hematoxylin-eosin to assess villi and intraepithelial lymphocytes, and immunohistochemistry was used to assess CD3, CD8, tryptase, and zonula occludens 1 (ZO-1); colonic biopsy intraepithelial lymphocytes were quantitated. Associations of HLA-DQ were assessed using Wilcoxon's rank-sum test. Relative to healthy control data, we observed a significant increase in SB permeability ( P < 0.001), a borderline increase in colonic permeability ( P = 0.10), and a decrease in TJ mRNA expression in rectosigmoid mucosa in IBS-D. In HLA-DQ2/8-positive patients, ZO-1 protein expression in the rectosigmoid mucosa was reduced compared with that in HLA-DQ2/8-negative patients and colonic transit was slower than in HLA-DQ2/8-negative patients. No other associations with HLA genotype were identified. There is abnormal barrier function (increased SB permeability and reduced mRNA expression of TJ proteins) in IBS-D relative to health that may be, in part, related to immunogenotype, given reduced ZO-1 protein expression in rectosigmoid mucosa in HLA-DQ2/8-positive relative to HLA-DQ2/8-negative patients.