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Importance Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer. Combination sulindac and erlotinib was previously shown to reduce duodenal polyp burden but was associated with a relatively high adverse event (AE) rate. Objective: To evaluate if a once weekly dosing schedule for erlotinib intervention improves the AE profile, while still providing efficacy with respect to reduced polyp burden, in participants with FAP. Design, setting and participants: Single-arm trial, enrolling 46 participants with FAP, conducted from October 2017 to September 2019 in eight academic cancer centres. Exposures Participants self-administered 350 mg of erlotinib by mouth, one time per week for 6 months. Main outcomes and measures: Duodenal polyp burden (sum of polyp diameters) was assessed in the proximal duodenum by esophagogastroduodenoscopy performed at baseline and 6 months, with mean per cent change defined as the primary efficacy outcome of interest. Rate of grade 2–3 AEs was evaluated as a co-primary outcome. Secondary outcomes included changes in total duodenal polyp count, along with changes in lower gastrointestinal (GI) polyp burden and count (for participants examined by optional lower endoscopy). Results Forty-six participants (mean age, 44.1 years (range, 18–68); women, 22 (48%)) were enrolled; 42 participants completed 6 months of intervention and were included in the per-protocol analysis. Duodenal polyp burden was significantly reduced after 6 months of weekly erlotinib intervention, with a mean per cent change of −29.6% (95% CI, −39.6% to −19.7%; p<0.0001). Similar results were observed in subgroup analyses defined by participants with advanced duodenal polyposis (Spigelman 3) at baseline (mean, −27%; 95% CI, −38.7% to −15.2%; p<0.0001). Post-intervention Spigelman stage was downstaged in 12% of the participants. Lower GI polyp number was also decreased after 6 months of intervention (median, −30.8%; IQR, −47.4% to 0.0%; p=0.0256). Grade 2 or 3 AEs were reported in 71.7% of subjects, with only two experiencing grade 3 toxicity at least possibly related to intervention. Conclusion In this single-arm, multi-centre trial of participants with FAP, erlotinib one time per week resulted in markedly lower duodenal polyp burden, and modestly reduced lower GI polyp burden, after 6 months of intervention. While AEs were still reported by nearly three-quarters of all participants, these events were generally lower grade and well-tolerated. These findings support further investigation of erlotinib as an effective, acceptable cancer preventive agent for FAP-associated GI polyposis. Trial registration number NCT02961374 .

BACKGROUND: Colectomy and proctocolectomy are the initial standard of care for patients with familial adenomatous polyposis. Pharmacotherapy to prevent the progression of polyposis and surgeries in the lower GI tract would be beneficial to patients with this disease. OBJECTIVE: This analysis aimed to evaluate the impact of eflornithine-sulindac combination versus monotherapy in delaying time to disease progression in the lower GI tract of patients with familial adenomatous polyposis. DESIGN: This is a post hoc analysis of a randomized phase 3 trial. SETTING: This study was conducted in 21 hospitals in 7 countries treating patients with familial adenomatous polyposis. PATIENTS: Adults with familial adenomatous polyposis were randomly assigned 1:1:1 into 3 arms. INTERVENTIONS: Patients received either eflornithine (750 mg), sulindac (150 mg), or both once daily for up to 48 months. MAIN OUTCOME MEASURES: Efficacy was evaluated as the time from randomization to predefined primary disease progression end points. RESULTS: A total of 158 patients were included in the study. Disease progression was observed in 2 of 54 (3.7%), 9 of 53 (17.0%), and 10 of 51 (19.6%) patients with at least partial lower GI tract in the combination, sulindac, and eflornithine arms, corresponding to risk reductions of 80% (p = 0.02) and 83% (p = 0.01) between combination and sulindac or eflornithine. When endoscopic excision of adenomas ≥10 mm in size was censored, the need for major surgery was observed in 0 of 54, 7 of 53 (13.2%), and 8 of 51 (15.7%) patients in the combination, sulindac, and eflornithine arms, corresponding to risk reductions approaching 100% between combination and sulindac (p = 0.005) or combination and eflornithine (p = 0.003). LIMITATIONS: This was a post hoc analysis, the sample size was small, and there were fewer than expected events. CONCLUSIONS: Eflornithine-sulindac combination therapy was superior to either drug alone in delaying or preventing the need for lower GI tract surgery in patients with familial adenomatous polyposis. See Video Abstract at http://links.lww.com/DCR/B658. REGISTRATION: ClinicalTrials.gov, NCT01483144; EU Clinical Trials Register, EudraCT 2012-000427-41 LA COMBINACIÓN DE SULINDAC Y EFLORNITINA RETRASA LA NECESIDAD DE CIRUGÍA DEL TUBO DIGESTIVO BAJO EN PACIENTES CON PAF: ANÁLISIS POST-HOC DE UN ENSAYO CLÍNICO ALEATORIZADO ANTECEDENTES: La colectomía y la proctocolectomía son el estándar inicial de atención para los pacientes con poliposis adenomatosa familiar. La farmacoterapia para prevenir la progresión de la poliposis y las cirugías en el tracto gastrointestinal inferior sería beneficiosa para los pacientes con esta enfermedad. OBJETIVO: Este análisis tuvo como objetivo evaluar el impacto de la combinación de eflornitina-sulindac versus la monoterapia en el retraso del tiempo hasta la progresión de la enfermedad en el tracto gastrointestinal inferior de pacientes con poliposis adenomatosa familiar. DISEÑO: Este es un análisis posthoc de un ensayo de fase 3 aleatorizado. ENTORNO CLINICO: Veintiún hospitales en 7 países que tratan a pacientes con poliposis adenomatosa familiar. PACIENTES: Adultos con poliposis adenomatosa familiar fueron aleatorizados 1: 1: 1 en 3 brazos. INTERVENCIONES: Los pacientes recibieron eflornitina (750 mg), sulindac (150 mg) o ambos una vez al día durante un máximo de 48 meses. PRINCIPALES MEDIDAS DE VALORACION: La eficacia se evaluó como el tiempo desde la aleatorización hasta los criterios de valoración primarios predefinidos de progresión de la enfermedad. RESULTADOS: Los resultados se informan para la población de estudio excluyendo a los pacientes que se habían sometido a ileostomías permanentes (n = 158). Se observó progresión de la enfermedad en 2/54 (3,7%), 9/53 (17,0%) y 10/51 (19,6%) pacientes con al menos tracto gastrointestinal inferior parcial en los brazos de combinación, sulindac y eflornitina, respectivamente, correspondientes al riesgo de reducciones del 80% (p = 0,02) y del 83% (p = 0,01) entre la combinación y el sulindaco o la eflornitina, respectivamente. Cuando se censuró la escisión endoscópica de adenomas ≥10 mm de tamaño, se observó la necesidad de cirugía mayor en 0/54, 7/53 (13,2%) y 8/51 (15,7%) pacientes en la combinación, sulindac y eflornitina, respectivamente, correspondientes a reducciones de riesgo cercanas al 100% entre combinación y sulindac (p = 0,005) o combinación y eflornitina (p = 0,003). LIMITACIONES: Este fue un análisis posthoc, el tamaño de la muestra fue pequeño y hubo menos eventos de los esperados. CONCLUSIONES: La terapia de combinación de eflornitina-sulindac fue superior a cualquier fármaco solo para retrasar o prevenir la necesidad de cirugía del tracto gastrointestinal inferior en pacientes con poliposis adenomatosa familiar. Consulte Video Resumen en http://links.lww.com/DCR/B658.

INTRODUCTION: Endoscopy-related injury (ERI) is common in gastroenterologists (GI). The study aim was to assess the prevalence of self-reported ERI, patterns of injury, and endoscopist knowledge of preventative strategies in a nationally representative sample. METHODS: A 38-item electronic survey was sent to 15,868 American College of Gastroenterology physician members. The survey was completed by 1,698 members and was included in analyses. Descriptive, univariate, and multivariate analyses were conducted to evaluate the likelihood of ERI based on workload parameters and gender. RESULTS: ERI was reported by 75% of respondents. ERI was most common in the thumb (63.3%), neck (59%), hand/finger (56.5%), lower back (52.6%), shoulder (47%), and wrist (45%). There was no significant difference in the prevalence of ERI between men and women GI. However, women GI were significantly more likely to report upper extremity ERI while men were more likely to report lower-back pain-related ERI. Significant gender differences were noted in the reported mechanisms attributed to ERI. Most respondents did not discuss ergonomic strategies in their current practice (63%). ERI was less likely to be reported in GI who took breaks during endoscopy ( P = 0.002). DISCUSSION: ERI is highly prevalent in GI physicians. Significant gender differences regarding specific sites affected by ERI and the contributing mechanisms were observed. Results strongly support institution of training in ergonomics for all GI as a strategy to prevent its impact on providers of endoscopy. JOURNAL/ajgast/04.03/00000434-202103000-00021/inline-graphic1/v/2026-07-10T100418Z/r/image-tiff

Abstract Background: Familial adenomatous polyposis (FAP) is the most common hereditary polyposis syndrome. It is an autosomal dominant inherited disorder characterized by the early onset of hundreds to thousands of adenomatous polyps throughout the colon. If left untreated, nearly all individuals with this syndrome develop colorectal cancer (CRC) by the third decade of life. Prophylactic colectomy is the standard of care, but individuals remain at risk for malignant transformation of duodenal polyps, rectal polyps for those who have undergone rectal-sparing surgeries, and ileal pouch polyps for those with ileal pouch-anal anastomoses. Multiple studies with both nonselective and selective cyclooxygenase inhibitors (such as sulindac or celecoxib) have shown that anti-inflammatory agents may prevent the formation and inhibit the growth of colorectal adenomatous polyps. However, toxicities associated with these agents and their limited efficacy have prevented their further development. Therefore, there is a high unmet need for novel treatment options to reduce polyp burden, delay or eliminate the need for colectomy and recurrent rectal surgery, and intercept the development of adenocarcinomas in individuals with FAP. Polyps from individuals with FAP display inflammatory features associated with the activation of the IL-23/IL-17/JAK/STAT3 pathway. This inflammation is thought to contribute to further carcinogenesis, culminating in tumor development. Specifically, IL-23 is linked to tumor growth and progression in CRC, and adenomas with high-grade dysplasia showed elevated levels of IL-17A and pSTAT3. Guselkumab, a human monoclonal antibody directed against the p19 subunit of IL-23, specifically targets IL-23 and inhibits its interaction with the IL-23 receptor. Pre-clinical models suggest that inhibition of IL-23 signaling will result in less inflammation and reduce tumor development. Methods: This randomized, blind, placebo-controlled study will evaluate the safety and efficacy of guselkumab in adults with FAP (genetic or clinical diagnosis) who have already undergone colectomy. Polyps with a sum of diameters ≥10 mm in the rectum or pouch are required. Subjects will be randomized equally to one of three study arms: 100 mg, 300 mg, or placebo given subcutaneously every 4 weeks for 6 doses. The primary efficacy endpoint is percentage change from baseline in rectal/pouch polyp burden after 24 weeks. Secondary efficacy endpoints include duodenal polyp burden change and changes in InSiGHT and Spigelman staging. Exploratory translational research objectives will explore changes in RNA expression profiles, epigenomic profiles, cytokine levels, and the microbiome. Exclusion criteria include prior IL-23 targeted therapies and any polyps &gt;1 cm that cannot be removed. While participating, subjects are required to stop any other FAP-directed drug therapy except for aspirin. As of January 2019, 18% of the planned 72 subjects have been enrolled. ClinicalTrials.gov Identifier: NCT03649971. Citation Format: Eduardo Vilar-Sanchez, Carol Burke, Marcia R. Cruz Correa, Evelien Dekker, William M. Grady, Philippe Grandval, Bryson W. Katona, Xavier Llor, Douglas L. Riegert-Johnson, Jean-Christophe Saurin, Peter Stanich, Daniel A. Sussman, David Weinberg, Edward F. Attiyeh, Devanand Joseph, Kelly Raybold, Gary V. Borzillo, Thomas J. Prior, Michael Smith, Hong Xie, Kurtis E. Bachman, Jeffrey R. Infante, Niloy Jewel Samadder. A phase 1b, multicenter, randomized, blinded, placebo-controlled study to evaluate the efficacy of guselkumab in subjects with familial adenomatous polyposis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT236.

INTRODUCTION: Endoscopy- related injury (ERI) is common in gastroenterologists. This study aimed to evaluate the prevalence of self-reported ERI, patterns of injury and knowledge of ergonomic strategies in endoscopists who are ACG physician members. METHODS: A 38-item survey was developed and initially piloted at three academic medical centers. Through the ACG Women in GI Committee and ACG Governing Board sponsorship, the survey was administered to ACG physician members. Statistical analysis was performed using SAS Enterprise Guide 7.0 (SAS Institute Inc., Cary, NC); chi-square tests and descriptive analysis evaluating associations between multiple variables and ERI. RESULTS: Of the 14759 total surveys sent, 5940 were opened, and only completed surveys were included (n = 1133). ERI was reported by 71% of the respondents including 49% of trainees. More than half of the respondents reported pain in the thumbs (64%), hand/fingers (59%), neck (57%), and lower back (54 %). The most common causes of ERI reported were torqueing with the right hand (64%), adjusting tip angulation with left hand (53%), standing for prolonged periods of time (59%), and standing in awkward positions while supporting an endoscope (58 %). While no differences were noted in characteristics associated with overall ERI, including sex ( P = 0.77), performance of interventional endoscopy or a focus in another GI domain ( P = 0.55) women were more likely to have upper extremity pain and upper back pain (see Table 2). There were statistically significant differences between genders in the mechanisms of ERI (see Table 3). Most respondents did not receive training during fellowship (68%), or discuss ergonomic strategies in their current practice (63%). Those without training in ergonomics were more likely to report ERI ( P = 0.02). 81 % of respondents noted a desire for more training in ergonomic strategies to reduce ERI. CONCLUSION: The results of this study show an overwhelming occurrence of ERI in all GI physicians and in nearly half of the trainee respondents. Preliminary analysis shows a significant difference between men and women with regards to specific areas of ERI and contributing mechanisms. Results strongly support training and a desire for continued education in ergonomic strategies as a preventative strategy. Education and prevention of ERI represent rich opportunities for improving key aspects of clinical practice, reducing burden on physicians, and decreasing interruptions to clinical care.