High Complication Rate After Early Ileostomy Closure: Early Termination of the Short Versus Long Interval to Loop Ileostomy Reversal After Pouch Surgery Randomized Trial.

BACKGROUND: In patients with ulcerative colitis who undergo IPAA, a diverting ileostomy is used to diminish the severity of anastomotic complications. Typically, the ileostomy is closed after an interval of 2 to 4 months. The safety of earlier closure of the ileostomy after pouch surgery is unknown. OBJECTIVE: This study aimed to compare postoperative outcomes in patients randomly assigned to early (7-12 days) or late (≥8 weeks) ileostomy closure after ileal pouch construction. DESIGN: This was a multicenter, prospective randomized trial. SETTING: The study was conducted at colorectal surgical units at select United States hospitals. PATIENTS: Adults with ulcerative colitis who underwent 2- or 3-stage proctocolectomy with IPAA were included. MAIN OUTCOME MEASURES: The primary outcomes included Comprehensive Complication Index at 30 days after ileostomy closure. The secondary outcomes included complications, severe complications, reoperations, and readmissions within 30 days of ileostomy closure. RESULTS: The trial was stopped after interim analysis because of a high rate of complications after early ileostomy closure. Among 36 patients analyzed, 1 patient (3%) had unplanned proctectomy with end-ileostomy. Of the remaining 35 patients, 28 patients (80%) were clinically eligible for early closure and underwent radiologic assessment. There were 3 radiologic failures. Of the 25 remaining patients, 22 patients (88%) were randomly assigned to early closure (n = 10) or late closure (n = 12), and 3 patients were excluded. Median Comprehensive Complication Index was 14.8 (0-54) and 0 (0-23) after early and late closure (p = 0.02). One or more complications occurred in 7 patients (70%) after early closure and in 2 patients (17%) after late closure (p = 0.01)' and complications were severe in 3 patients (30%) after early closure and 0 patients after late closure (p = 0.04). Reoperation was required in 1 patient (10%) and 0 patients (p = 0.26) after early closure and readmission was required in 7 patients (70%) and 1 patient (8%) after late closure (p = 0.003). LIMITATIONS: This study was limited by early study closure and selection bias. CONCLUSIONS: Early closure of a diverting ileostomy in patients with ulcerative colitis who underwent IPAA is associated with an unacceptably high rate of complications. See Video Abstract at http://links.lww.com/DCR/C68. ALTA TASA DE COMPLICACIONES DESPUS DEL CIERRE PRECOZ DE LA ILEOSTOMA TERMINACIN TEMPRANA DEL ENSAYO ALEATORIZADO DE INTERVALO CORTO VERSUS LARGO PARA LA REVERSIN DE LA ILEOSTOMA EN ASA DESPUS DE LA CIRUGA DE RESERVORIO ILEAL: ANTECEDENTES:En los pacientes con colitis ulcerosa que se someten a una anastomosis del reservorio ileoanal, se utiliza una ileostomía de derivación para disminuir la gravedad de las complicaciones de la anastomosis. Por lo general, la ileostomía se cierra después de un intervalo de 2 a 4 meses. Se desconoce la seguridad del cierre más temprano de la ileostomía después de la cirugía de reservorio.OBJETIVO:Comparar los resultados posoperatorios en pacientes asignados al azar al cierre temprano (7-12 días) o tardío (≥ 8 semanas) de la ileostomía después de la construcción de un reservorio ileal.DISEÑO:Este fue un ensayo aleatorizado prospectivo multicéntrico.ESCENARIO:El estudio se realizó en unidades quirúrgicas colorrectales en hospitales seleccionados de los Estados Unidos.PACIENTES:Se incluyeron adultos con colitis ulcerosa que se sometieron a proctocolectomía en 2 o 3 tiempos con anastomosis ileoanal con reservorio.PRINCIPALES MEDIDAS DE RESULTADO:Los resultados primarios incluyeron el Índice Integral de Complicaciones a los 30 días después del cierre de la ileostomía. Los resultados secundarios incluyeron complicaciones, complicaciones graves, reoperaciones y readmisiones dentro de los 30 días posteriores al cierre de la ileostomía.RESULTADOS:El ensayo se detuvo después del análisis interino debido a una alta tasa de complicaciones después del cierre temprano de la ileostomía. Entre los 36 pacientes analizados, 1 (3%) tuvo una proctectomía no planificada con ileostomía terminal. De los 35 pacientes restantes, 28 (80%) fueron clínicamente elegibles para el cierre temprano y se sometieron a una evaluación radiológica. Hubo 3 fracasos radiológicos. De los 25 pacientes restantes, 22 (88 %) se asignaron al azar a cierre temprano (n = 10) o tardío (n = 12) y 3 fueron excluidos. La mediana del Índice Integral de Complicaciones fue de 14,8 (0-54) y 0 (0-23) después del cierre temprano y tardío (p = 0,02). Una o más complicaciones ocurrieron en 7 pacientes (70%) después del cierre temprano y 2 (17%) pacientes después del cierre tardío (p = 0,01) y fueron graves en 3 (30%) y 0 pacientes, respectivamente (p = 0,04). Requirieron reintervención en 1 (10%) y 0 (p = 0,26) y reingreso en 7 (70%) y 1 (8%) pacientes (p = 0,003).LIMITACIONES:Este estudio estuvo limitado por el cierre temprano del estudio; sesgo de selección.CONCLUSIONES:El cierre temprano de una ileostomía de derivación en pacientes con colitis ulcerosa con anastomosis de reservorio ileoanal se asocia con una tasa inaceptablemente alta de complicaciones. Consulte Video Resumen en http://links.lww.com/DCR/C68. (Traducción-Dr. Felipe Bellolio).

Endoscopic Phenotype of the J Pouch in Patients With Inflammatory Bowel Disease: A New Classification for Pouch Outcomes.

BACKGROUND & AIMS: Pouchitis is a common complication of ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis who have undergone colectomy. Pouchitis has been considered a single entity despite a broad array of clinical and endoscopic patterns. We developed a novel classification system based on the pattern of inflammation observed in pouches and evaluated the contributing factors and prognosis of each phenotype. METHODS: We identified 426 patients (384 with ulcerative colitis) treated with proctocolectomy and IPAA who subsequently underwent pouchoscopies at the University of Chicago between June 1997 and December 2019. We retrospectively reviewed 1359 pouchoscopies and classified them into 7 main pouch phenotypes: (1) normal, (2) afferent limb involvement, (3) inlet involvement, (4) diffuse, (5) focal inflammation of the pouch body, (6) cuffitis, and (7) pouch with fistulas noted 6 months after ileostomy takedown. Logistic regression analysis was used to assess factors contributing to each phenotype. Pouch survival was estimated by the log-rank test and the Cox proportional hazards model. RESULTS: Significant contributing factors for afferent limb involvement were a body mass index of 25 or higher and hand-sewn anastomosis, for inlet involvement the significant contributing factor was male sex; for diffuse inflammation the significant contributing factors were extensive colitis and preoperative use of anti-tumor necrosis factor drugs, for cuffitis the significant contributing factors were stapled anastomosis and preoperative Clostridioides difficile infection. Inlet stenosis, diffuse inflammation, and cuffitis significantly increased the risk of pouch excision. Diffuse inflammation was associated independently with pouch excision (hazard ratio, 2.69; 95% CI, 1.34-5.41; P = .005). CONCLUSIONS: We describe 7 unique IPAA phenotypes with different contributing factors and outcomes, and propose a new classification system for pouch management and future interventional studies.

Using Wearable Biosensors to Predict Length of Stay for Patients with IBD After Bowel Surgery.

BACKGROUND AND AIMS: It remains unknown whether ambulation or sleep predicts postoperative length of stay for patients with IBD. We aim to identify the utility of wearable biosensors in predicting postoperative length of stay for patients with IBD. METHODS: Associations of postoperative length of stay with step count/sleep duration/sleep efficiency measured by wearable biosensors were examined. The best-fitting multivariable linear regression model predicting length of stay was constructed using stepwise model selection. RESULTS: Final sample included 37 patients. Shorter sleep duration on postoperative day 4 (r = 0.51, p = 0.043) or 5 (r = 0.81, p = 0.0045) or higher sleep efficiency on postoperative day 5 (r = - 0.77, p = 0.0098) was associated with a shorter length of stay. Additionally, a more positive change in sleep efficiency from postoperative day 4-5 was associated with a shorter length of stay (r = - 0.77, p = 0.024). The best-fitting multivariable linear regression model revealed Clavien-Dindo grade 1 (p = 0.045) and interaction between Clavien-Dindo grade 2/3a and mean daily steps (p = 0.00038) are significant predictors of length of stay. The following variables were not significantly associated with length of stay: mean daily steps/sleep duration/sleep efficiency, average rate of change in these three variables, and changes in step count between successive postoperative days 1-5, sleep duration between successive postoperative days 2-5, and sleep efficiency between successive postoperative days 2-4. CONCLUSION: We demonstrated the utility of activity and sleep data from wearable biosensors in predicting length of stay. Patients with more severe complications may benefit more (i.e., reduced postoperative length of stay) from increased ambulation. However, overall, sleep duration/efficiency did not predict length of stay.

Histopathology of Colectomy Specimens Predicts Endoscopic Pouch Phenotype in Patients with Ulcerative Colitis.

BACKGROUND: The endoscopic appearance in patients with "pouchitis" after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) can be quite heterogenous. Patients with an endoscopic phenotype resembling Crohn's disease (CD) are at high risk of pouch loss. AIMS: We aimed to assess how the histopathology of colectomy specimens predicts endoscopic pouch phenotypes in UC. METHODS: We retrospectively assessed pouchoscopies from patients with UC who underwent IPAA and classified pouch findings into 7 main phenotypes: (1) normal, (2) afferent limb involvement, (3) inlet involvement, (4) diffuse, (5) focal inflammation of the pouch body, (6) cuffitis, and (7) pouch with fistulas noted ≥ 6 months from ileostomy takedown. We assessed the clinical and pathological data including deep, focal inflammation, granulomas, and terminal ileal involvement in the colectomy specimens. Logistic regression analysis was performed to identify contributing factors to each phenotype. RESULTS: This study included 1,203 pouchoscopies from 382 patients with UC. On multivariable analysis, deep inflammation was significantly associated with pouch fistulas (Odds ratio 3.27; 95% confidence interval 1.65-6.47; P = 0.0007). Of the 75 patients with deep inflammation, only two patients (2.7%) were diagnosed with CD based on pathology review. Terminal ileal involvement significantly increased the risk of afferent limb involvement (Odds ratio 2.96; 95% confidence interval 1.04-8.47; P = 0.04). There were no significant associations between other microscopic features and phenotypes. CONCLUSIONS: We identify histologic features of colectomy specimens in UC that predict subsequent pouch phenotypes. Particularly, deep inflammation in the resected colon was significantly associated with pouch fistulas, a pouch phenotype with poor prognosis.

Preliminary Report From the Pelvic Floor Disorders Consortium: Large-Scale Data Collection Through Quality Improvement Initiatives to Provide Data on Functional Outcomes After Rectal Prolapse Repair.

BACKGROUND: The surgical management of rectal prolapse is constantly evolving, yet numerous clinical trials and meta-analyses studying operative approaches have failed to make meaningful conclusions. OBJECTIVE: The purpose of this study was to report on preliminary data captured during a large-scale quality improvement initiative to measure and improve function in patients undergoing rectal prolapse repair. DESIGN: This was a retrospective analysis of prospectively collected surgical quality improvement data. SETTINGS: This study was conducted at 14 tertiary centers specializing in pelvic floor disorders from 2017 to 2019. PATIENTS: A total of 181 consecutive patients undergoing external rectal prolapse repair were included. MAIN OUTCOME MEASURES: Preoperative and 3-month postoperative Wexner incontinence score and Altomare obstructed defecation score were measured. RESULTS: The cohort included 112 patients undergoing abdominal surgery (71 suture rectopexy/56% minimally invasive, 41 ventral rectopexy/93% minimally invasive). Those offered perineal approaches (n = 68) were older (median age, 75 vs 62 y; p < 0.01) and had more comorbidities (ASA 3-4: 51% vs 24%; p < 0.01) but also reported higher preintervention rates of fecal incontinence (Wexner 11.4 ± 6.4 vs 8.6 ± 5.8; p < 0.01). Patients undergoing perineal procedures had similar incremental improvements in function after surgery as patients undergoing abdominal repair (change in Wexner, -2.6 ± 6.4 vs -3.1 ± 5.6, p = 0.6; change in Altomare, -2.9 ± 4.6 vs -2.7 ± 4.9, p = 0.8). Similarly, patients undergoing posterior suture rectopexy and ventral mesh rectopexy had similar incremental improvements in overall scores; however, patients undergoing ventral mesh rectopexy had a higher decrease in the need to use pads after surgery. LIMITATIONS: The study was limited by its retrospective data analysis and 3-month follow-up. CONCLUSIONS: Functional outcomes improved in all of the patients undergoing prolapse surgery. Larger cohorts are necessary to show superiority among surgical procedures. Quality improvement methods may allow for systematic yet practical acquisition of information and data analysis. We call for the creation of a robust database to benefit this patient population. See Video Abstract at http://links.lww.com/DCR/B581. REPORTE PRELIMINAR DEL CONSORCIO DE TRASTORNOS DEL PISO PLVICO RECOLECCIN DE DATOS A GRAN ESCALA MEDIANTE INICIATIVAS DE MEJORAMIENTO DE LA CALIDAD PARA PROPORCIONAR INFORMACIN SOBRE LOS RESULTADOS FUNCIONALES: ANTECEDENTES:El tratamiento quirúrgico del prolapso rectal está evolucionando constantemente, sin embargo, numerosos estudios clínicos y metaanálisis que evalúan los tratamientos quirúrgicos no han logrado demostrar conclusiones significativas.OBJETIVO:Reportar datos preliminares obtenidos a gran escala durante una iniciativa de mejoramiento de la calidad para medir y mejorar la función en pacientes sometidos a reparación de prolapso rectal.DISEÑO:Análisis retrospectivo de datos recolectados prospectivamente de mejoramiento de la calidad quirúrgica.ENTORNO CLINICO:Este estudio se realizó en 14 centros terciarios especializados en trastornos del piso pélvico del 2017 al 2019.PACIENTES:Un total de 181 pacientes consecutivos sometidos a reparación de prolapso rectal externo.PRINCIPALES MEDIDAS DE VALORACION:Escala de incontinencia de Wexner y de defecación obstruida de Altomare preoperatoria y tres meses postoperatoria.RESULTADOS:El cohorte incluyó 112 pacientes sometidos a cirugía abdominal (71 rectopexia con sutura / 56% minimally invasive, 41 rectopexia ventral / 93% minimally invasive). Aquellos a los que se les realizaron abordajes perineales (n = 68) eran mayores (edad media de 75 vs. 62, p <0,01) y tenían mayorcomorbilidades (ASA 3-4: 51% vs. 24%, p <0,01), además reportaron una mayor tasa de incontinencia fecal previo a la intervención (Wexner 11,4 ± 6,4 vs. 8,6 +/- 5,8, p <0,01). Posterior a la cirugía, los pacientes sometidos a procedimientos perineales tuvieron mejoría progresiva en la función similar que los pacientes sometidos a reparación abdominal (cambio en Wexner -2,6 ± 6,4 vs. -3,1 ± 5,6, p = 0,6; cambio en Altomare -2,9 ± 4,6 vs. -2,7 ± 4,9, p = 0,8). De manera similar, los pacientes con rectopexia posterior con sutura y rectopexia ventral con malla tuvieron mejoría progresiva similares en las escalas generales; no obstante, pacientes con rectopexia ventral con malla tuvieron una mayor disminución en la necesidad de usar paños protectores después de la cirugía.LIMITACIONES:Análisis de datos retrospectivo y seguimiento de tres meses.CONCLUSIONES:Los resultados funcionales mejoraron en todos los pacientes sometidos a cirugía de prolapso. Se necesitan cohortes más grandes para demostrar superioridad entre los procedimientos quirúrgicos. Métodos de mejoramiento de la calidad pueden permitir la adquisición sistemática, pero práctica de información y análisis de datos. Hacemos un llamado para la creación de una base de datos sólida para beneficiar a esta población de pacientes. Consulte Video Resumen en http://links.lww.com/DCR/B581. (Traducción- Dr Francisco M. Abarca-Rendon).

Exposure to Anti-tumor Necrosis Factor Medications Increases the Incidence of Pouchitis After Restorative Proctocolectomy in Patients With Ulcerative Colitis.

BACKGROUND: Pouchitis is the most frequent complication after IPAA in patients with ulcerative colitis. Antibiotics represent the mainstay of treatment, suggesting a crucial role of dysbiosis in the pathogenesis of this condition. Anti-tumor necrosis factor agents have been shown to adversely impact the gut microbiome and local host immunity. OBJECTIVE: The aim of this study is to assess the effect of prior exposure to biologics on the development of pouchitis in patients who have ulcerative colitis. DESIGN: This is a retrospective case-control study. SETTINGS: This study was conducted at a tertiary-care IBD center. PATIENTS: Consecutive patients with ulcerative colitis who underwent restorative proctocolectomy between 2000 and 2010 were included. MAIN OUTCOME MEASURES: The primary outcome measured was the incidence of pouchitis. RESULTS: Four hundred seventeen patients with ulcerative colitis who underwent IPAA were included. The incidence of pouchitis was 40.4%. There were no differences in patient demographics, disease-specific factors, surgical approach, and short-term postoperative complications between patients who developed pouchitis compared to those that did not. Patients exposed to anti-tumor necrosis factor agents or preoperative steroids were significantly more likely to develop pouchitis (anti-tumor necrosis factor: 47.9% vs 36.5%, p = 0.027; steroids: 41.7% vs 23.3%, p = 0.048). However, on multivariable analysis, only anti-tumor necrosis factor therapy was an independent predictor for pouchitis (p = 0.05). Pouchitis was not associated with adverse long-term outcomes. LIMITATIONS: The retrospective design was a limitation of this study. CONCLUSION: In a large cohort of patients undergoing IPAA for ulcerative colitis with at least a 5-year follow-up, anti-tumor necrosis factor exposure was the only independent risk factor for the development of pouchitis. These agents may "precondition" the pouch to develop pouchitis through alterations in the microbiome and/or local host immunity of the terminal ileum. See Video Abstract at http://links.lww.com/DCR/B19. LA EXPOSICIÓN A MEDICAMENTOS ANTI-TNF AUMENTA LA INCIDENCIA DE POUCHITIS DESPUÉS DE LA PROCTOCOLECTOMÍA RESTAURADORA EN PACIENTES CON COLITIS ULCEROSA:: La pouchitis es la complicación más frecuente después de la anastomosis anal de bolsa ileal en pacientes con colitis ulcerosa. Los antibióticos representan el pilar del tratamiento, lo que sugiere un papel crucial de la disbiosis en la patogénesis de esta afección. Se ha demostrado que los agentes anti-TNF tienen un impacto adverso en la microbiota intestinal y en la inmunidad local del huésped.El objetivo de este estudio es evaluar el efecto de la exposición previa a terapía biológica sobre el desarrollo de la pouchitis en pacientes con colitis ulcerosa.Estudio retrospectivo de casos y controles.Centro de tercer nivel de atención en enfermedades inflamatorias intestinales.Pacientes consecutivos con colitis ulcerosa que se sometieron a proctocolectomía restaurativa entre 2000-2010.Incidencia de pouchitis.Cuatrocientos diecisiete pacientes con colitis ulcerativa se sometieron a anastomosis anal de bolsa ileal. La incidencia de pouchitis fue del 40.4%. No hubo diferencias en la demografía del paciente, los factores específicos de la enfermedad, el abordaje quirúrgico y las complicaciones postoperatorias a corto plazo entre los pacientes que desarrollaron pouchitis en comparación con los que no lo hicieron. Los pacientes expuestos a agentes anti-TNF o esteroides preoperatorios fueron significativamente más propensos a desarrollar pouchitis (anti-TNF: 47.9% vs 36.5%, p = 0.027; esteroides: 41.7% vs 23.3%, p = 0.048). Sin embargo, en el análisis multivariable, solo la terapia anti-TNF fue un predictor independiente para la pouchitis (p = 0.05). La pouchitis no se asoció con resultados adversos a largo plazo.Diseño retrospectivo.En una gran cohorte de pacientes sometidos a anastomosis anal de bolsa ileal para la colitis ulcerosa con al menos 5 años de seguimiento, la exposición a terapía anti-TNF fue el único factor de riesgo independiente para el desarrollo de pouchitis. Estos agentes pueden "precondicionar" la bolsa para desarrollar una pouchitis a través de alteraciones en el microbioma y / o inmunidad local del huésped del íleon terminal. Vea el Resumen del video en http://links.lww.com/DCR/B19.

Abnormal Pouchogram Predicts Pouch Failure Even in Asymptomatic Patients.

BACKGROUND: Anastomotic complications after restorative total proctocolectomy with IPAA for ulcerative colitis alter functional outcomes and quality of life and may lead to pouch failure. Routine contrast enema of the pouch assesses anastomotic integrity before ileostomy reversal, but its clinical use is challenged. OBJECTIVE: The purpose of this research was to assess the relationship among preoperative clinical characteristics, abnormal pouchography, and long-term pouch complications. DESIGN: This was a retrospective chart review. SETTINGS: The study was conducted at a tertiary care center between 2000 and 2010. PATIENTS: Ulcerative colitis patients with IPAA undergoing pouchography before ileostomy closure were included. MAIN OUTCOME MEASURES: Patient demographics, incidence of pouch-related complications, and findings on pouchogram were recorded. Primary outcome was pouch failure, defined as excision or permanent diversion of the ileoanal pouch. Independent predictors of pouch failure were determined by multivariate regression. RESULTS: A total of 262 patients with ulcerative colitis were included. Contrast extravasation was seen in 27 patients (10.3%): 14 (51.9%) were clinically asymptomatic at the time of pouchogram. Six (22.2%) of 27 patients with extravasation developed pouch failure despite normalization of the pouchogram before ileostomy closure. Forty patients (15.3%) were found to have pouch-anal anastomotic stenosis; only 1 developed pouch failure. Pre-IPAA serum albumin and hemoglobin levels were inversely associated with contrast extravasation (serum albumin: OR = 0.42; hemoglobin: OR = 0.77; p < 0.05). Contrast extravasation was associated with delayed takedown operation (average = 67 d), increased risk (OR = 5.25; p < 0.01), and shorter time (median = 32.0 vs 72.5 mo; HR = 5.88; p < 0.05) to pouch failure, as well as increased risk of pouch-related complications (p < 0.05). LIMITATIONS: The study was limited by its retrospective nature and small number of patients who developed pouch failure. CONCLUSIONS: Pouchography before ileostomy takedown is useful in identifying patients with ulcerative colitis at risk for postoperative complications. Radiologic resolution of IPAA-related leak does not reliably predict healing; caution is warranted in this subgroup. See Video Abstract at http://links.lww.com/DCR/A818.

Oral Polyphosphate Suppresses Bacterial Collagenase Production and Prevents Anastomotic Leak Due to Serratia marcescens and Pseudomonas aeruginosa.

OBJECTIVE: The objective of this study was to determine the effect of polyphosphate on intestinal bacterial collagenase production and anastomotic leak in mice undergoing colon surgery. BACKGROUND: We have previously shown that anastomotic leak can be caused by intestinal pathogens that produce collagenase. Because bacteria harbor sensory systems to detect the extracellular concentration of phosphate which controls their virulence, we tested whether local phosphate administration in the form of polyphosphate could attenuate pathogen virulence and prevent leak without affecting bacterial growth. METHODS: Groups of mice underwent a colorectal anastomosis which was then exposed to collagenolytic strains of either Serratia marcescens or Pseudomonas aeruginosa via enema. Mice were then randomly assigned to drink water or water supplemented with a 6-mer of polyphosphate (PPi-6). All mice were sacrificed on postoperative day 10 and anastomoses assessed for leakage, the presence of collagenolytic bacteria, and anastomotic PPi-6 concentration. RESULTS: PPi-6 markedly attenuated collagenase and biofilm production, and also swimming and swarming motility in both S. marcescens and P. aeruginosa while supporting their normal growth. Mice drinking PPi-6 demonstrated increased levels of PPi-6 and decreased colonization of S. marcescens and P. aeruginosa, and collagenase activity at anastomotic tissues. PPi-6 prevented anastomotic abscess formation and leak in mice after anastomotic exposure to S. marcescens and P. aeruginosa. CONCLUSIONS: Polyphosphate administration may be an alternative approach to prevent anastomotic leak induced by collagenolytic bacteria with the advantage of preserving the intestinal microbiome and its colonization resistance.

Consolidation mFOLFOX6 Chemotherapy After Chemoradiotherapy Improves Survival in Patients With Locally Advanced Rectal Cancer: Final Results of a Multicenter Phase II Trial.

BACKGROUND: Adding modified FOLFOX6 (folinic acid, fluorouracil, and oxaliplatin) after chemoradiotherapy and lengthening the chemoradiotherapy-to-surgery interval is associated with an increase in the proportion of rectal cancer patients with a pathological complete response. OBJECTIVE: The purpose of this study was to analyze disease-free and overall survival. DESIGN: This was a nonrandomized phase II trial. SETTINGS: The study was conducted at multiple institutions. PATIENTS: Four sequential study groups with stage II or III rectal cancer were included. INTERVENTION: All of the patients received 50 Gy of radiation with concurrent continuous infusion of fluorouracil for 5 weeks. Patients in each group received 0, 2, 4, or 6 cycles of modified FOLFOX6 after chemoradiation and before total mesorectal excision. Patients were recommended to receive adjuvant chemotherapy after surgery to complete a total of 8 cycles of modified FOLFOX6. MAIN OUTCOME MEASURES: The trial was powered to detect differences in pathological complete response, which was reported previously. Disease-free and overall survival are the main outcomes for the current study. RESULTS: Of 259 patients, 211 had a complete follow-up. Median follow-up was 59 months (range, 9-125 mo). The mean number of total chemotherapy cycles differed among the 4 groups (p = 0.002), because one third of patients in the group assigned to no preoperative FOLFOX did not receive any adjuvant chemotherapy. Disease-free survival was significantly associated with study group, ypTNM stage, and pathological complete response (p = 0.004, <0.001, and 0.001). A secondary analysis including only patients who received ≥1 cycle of FOLFOX still showed differences in survival between study groups (p = 0.03). LIMITATIONS: The trial was not randomized and was not powered to show differences in survival. Survival data were not available for 19% of the patients. CONCLUSIONS: Adding modified FOLFOX6 after chemoradiotherapy and before total mesorectal excision increases compliance with systemic chemotherapy and disease-free survival in patients with locally advanced rectal cancer. Neoadjuvant consolidation chemotherapy may have benefits beyond increasing pathological complete response rates. See Video Abstract at http://links.lww.com/DCR/A739.

Insights into the pathogenesis of ulcerative colitis from a murine model of stasis-induced dysbiosis, colonic metaplasia, and genetic susceptibility.

Gut dysbiosis, host genetics, and environmental triggers are implicated as causative factors in inflammatory bowel disease (IBD), yet mechanistic insights are lacking. Longitudinal analysis of ulcerative colitis (UC) patients following total colectomy with ileal anal anastomosis (IPAA) where >50% develop pouchitis offers a unique setting to examine cause vs. effect. To recapitulate human IPAA, we employed a mouse model of surgically created blind self-filling (SFL) and self-emptying (SEL) ileal loops using wild-type (WT), IL-10 knockout (KO) (IL-10), TLR4 KO (T4), and IL-10/T4 double KO mice. After 5 wk, loop histology, host gene/protein expression, and bacterial 16s rRNA profiles were examined. SFL exhibit fecal stasis due to directional motility oriented toward the loop end, whereas SEL remain empty. In WT mice, SFL, but not SEL, develop pouchlike microbial communities without accompanying active inflammation. However, in genetically susceptible IL-10-deficient mice, SFL, but not SEL, exhibit severe inflammation and mucosal transcriptomes resembling human pouchitis. The inflammation associated with IL-10 required TLR4, as animals lacking both pathways displayed little disease. Furthermore, germ-free IL-10 mice conventionalized with SFL, but not SEL, microbiota populations develop severe colitis. These data support essential roles of stasis-induced, colon-like microbiota, TLR4-mediated colonic metaplasia, and genetic susceptibility in the development of pouchitis and possibly UC. However, these factors by themselves are not sufficient. Similarities between this model and human UC/pouchitis provide opportunities for gaining insights into the mechanistic basis of IBD and for identification of targets for novel preventative and therapeutic interventions.

Evidence against a systemic arterial defect in patients with inflammatory bowel disease.

BACKGROUND: Despite increasing interest in local microvascular alterations associated with inflammatory bowel disease (IBD), the potential contribution of a primary systemic vascular defect in the etiology of IBD is unknown. We compared reactivity of large diameter mesenteric arteries from segments affected by Crohn disease (CD) or ulcerative colitis (UC) to an uninvolved vascular bed in both IBD and control patients. METHODS: Mesenteric and omental arteries were obtained from UC, CD, and non-IBD patients. Isometric arterial contractions were recorded in response to extracellular potassium (K(+)) and cumulative additions of norepinephrine (NE). In addition, relaxation in response to pinacidil, an activator of adenosine triphosphate-sensitive K(+) channels was examined. RESULTS: Contraction to K(+) and sensitivity to NE were not significantly different in arteries from CD, UC, and controls. Relaxation to pinacidil was also similar between groups. CONCLUSIONS: Potassium-induced contractions and sensitivity to NE and pinacidil were not significantly different in large diameter mesenteric and omental arteries obtained from IBD patients. Furthermore, there was no significant difference in the sensitivity to K(+), NE, and pinacidil between mesenteric and omental arteries of CD and UC patients and those from non-IBD patients. Our results suggest an underlying vascular defect systemic to CD or UC patients is unlikely to contribute to the etiology of IBD.

Endoscopic Normalization and Transition of J-Pouch Phenotypes Over Time in Patients With Inflammatory Bowel Disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) who undergo proctocolectomy with ileal pouch-anal anastomosis may develop pouchitis. We previously proposed a novel endoscopic classification of pouchitis describing 7 phenotypes with differing outcomes. This study assessed phenotype transitions over time. METHODS: We classified pouch findings into 7 main phenotypes: (1) normal, (2) afferent limb (AL) involvement, (3) inlet (IL) involvement, (4) diffuse, (5) focal inflammation of the pouch body, (6) cuffitis, and (7) pouch-related fistulas noted more than 6 months after ileostomy takedown. Among 2 endoscopic phenotypes, the phenotype that was first identified was defined as the primary phenotype, and the phenotype observed later was defined as the subsequent phenotype. RESULTS: We retrospectively reviewed 1359 pouchoscopies from 426 patients (90% preoperative diagnosis of ulcerative colitis). The frequency of primary phenotype was 31% for AL involvement, 42% for IL involvement, 28% for diffuse inflammation, 72% for focal inflammation, 45% for cuffitis, 18% for pouch-related fistulas, and 28% for normal pouch. The most common subsequent phenotype was focal inflammation (64.8%), followed by IL involvement (38.6%), cuffitis (37.8%), AL involvement (25.6%), diffuse inflammation (23.8%), normal pouch (22.8%), and pouch-related fistulas (11.9%). Subsequent diffuse inflammation, pouch-related fistulas, and AL or IL stenoses significantly increased the pouch excision risk. Patients who achieved subsequent normal pouch were less likely to have pouch excision than those who did not (8.1% vs 15.7%; P = .15). CONCLUSIONS: Pouch phenotype and the risk of pouch loss can change over time. In patients with pouch inflammation, subsequent pouch normalization is feasible and associated with favorable outcome.

Endoscopic pouch phenotypes can change over time and subsequent development of diffuse inflammation, pouch-related fistulas, and afferent limb/inlet stenoses significantly worsen pouch outcomes. In patients with pouch inflammation, subsequent pouch normalization is feasible and associated with favorable outcomes.

Role of the Microbiome in Malignancy.

The conceptual underpinning of carcinogenesis has been strongly influenced by an expanded understanding of the human microbiome. Malignancy risks in diverse organs have been uniquely tied to aspects of the resident microbiota in different organs and systems including the colon, lungs, pancreas, ovaries, uterine cervix, and stomach; other organs are increasingly linked to maladaptive aspects of the microbiome as well. In this way, the maladaptive microbiome may be termed an oncobiome. Microbe-driven inflammation, anti-inflammation, and mucosal protection failure, as well as diet-induced microbiome derangement are all mechanisms that influence malignancy risk. Therefore, they also offer potential avenues of diagnostic and therapeutic intervention to modify malignancy risk, and to perhaps interrupt progression toward cancer in different sites. Each of these mechanisms will be explored using colorectal malignancy as a prototype condition to demonstrate the microbiome's role in carcinogenesis.

A comparison of the quality of life of ulcerative colitis patients after IPAA vs ileostomy.

BACKGROUND: Total proctocolectomy with IPAA is frequently considered the procedure of choice for surgical patients with ulcerative colitis, presumably owing to an expectation of improved quality of life in comparison with an ileostomy. OBJECTIVE: The goal of our study was to determine whether long-term quality of life among patients with a pelvic pouch is better than those who chose a permanent stoma. DESIGN: This investigation is a cross-sectional observational study using a prospective database. SETTING: This study was conducted at an academic medical center. PATIENTS: Consecutive patients who had undergone IPAA or a permanent ileostomy for ulcerative colitis by a single surgeon, presenting for their annual follow-up visit from July through September 2011, were offered participation in the study. A randomly chosen group of subjects who did not have scheduled appointments during the study period were sent a letter inviting them to participate in the study. MAIN OUTCOME MEASURES: The primary outcome measures used were EQ-5D-3L, the Short Quality of Life in Inflammatory Bowel Disease questionnaire, the Cleveland Global Quality of Life instrument, the Fecal Incontinence Quality of Life scale, and the Stoma Quality of Life scale. RESULTS: Thirty-five patients with a pelvic pouch and 24 ostomates were accrued and comprehensively studied. Global quality-of-life scores were virtually identical for the 2 groups. Patients with a pelvic pouch had better subscores in current quality of health and energy level, Fazio score, sexuality/body image, and work/social function. LIMITATIONS: This study was limited by its small sample size, and some of our patients were enrolled through mailed surveys and, hence, nonresponse bias may be present. The follow-up time since surgery was longer in the pelvic pouch group than in the ileostomy group. CONCLUSION: Informed patients with ulcerative colitis choosing an ileostomy have a health-related global quality of life very similar to patients with a pelvic pouch. Better outcomes in patients with an ileal pouch were most evident in the areas of sexuality/body image and work/social function.

Is Previous Postoperative Infection an Independent Risk Factor for Postoperative Infection after Second Unrelated Abdominal Operation?

BACKGROUND: Infections after abdominal surgery remain a significant problem. Although preoperative antibiotic prophylaxis is a primary strategy used to reduce postoperative infections, it is typically prescribed based on standardized protocols, without attention to previous infection or antibiotic history. Patients with a previous infection after surgery may be at higher risk for infectious complications after subsequent operations owing to antibiotic resistance. We hypothesized that a previous postoperative infection is a significant risk factor for the development of infection after a second unrelated surgery. STUDY DESIGN: We performed a retrospective study of patients who had undergone 2 unrelated abdominal operations at a tertiary care center from 2012 to 2018. Clinical variables and microbiological culture results were abstracted. Univariate and multivariable regression models were constructed. RESULTS: Of 758 patients, 15.0% (n = 114) developed an infection after the first operation. After the second operation, 22.8% (n = 26) of those with a previous infection developed another infection, whereas the incidence of an infection after the second operation was only 9.5% (n = 61) in patients who did not develop an infection after the first operation. Multivariable analysis demonstrated that previous infection (odds ratio 2.49, 95% CI 1.46 to 4.25) was associated with future infection risk. Microbiological analysis found that infections after the second surgery were significantly more likely to be antibiotic resistant than infections after the first surgery (82.3% vs 64.1%; p = 0.036). Strikingly, 49% of infections after the second surgery were resistant to the antibiotic prophylaxis given at the time of incision. CONCLUSIONS: Previous postoperative infection is an independent risk factor for a subsequent postoperative infection and is associated with resistance to standard prophylaxis. Individualization of antibiotic prophylaxis in patients with a previous postoperative infection is warranted.

Factors associated with anti-tumor necrosis factor effectiveness to prevent postoperative recurrence in Crohn's disease.

BACKGROUND/AIMS: We assessed the effectiveness of anti-TNF agents and its associated factors to prevent endoscopic and clinical postoperative recurrence (POR) in Crohn's disease (CD). METHODS: From a prospectively-maintained database, we retrieved 316 CD patients who underwent intestinal resection (2011-2017). Endoscopic (Rutgeerts index ≥ i2 at 6 months) and clinical (recurrence of symptoms leading to hospitalization or therapeutic escalation) POR were assessed. RESULTS: In 117 anti-TNF-naïve patients, anti-TNF therapy was more effective than immunosuppressive agents (odds ratio [OR], 8.8; 95% confidence interval [CI], 1.8-43.9; P= 0.008) and no medication/5-aminosalicylates (OR, 5.2; 95% CI, 1.0-27.9; P= 0.05) to prevent endoscopic POR. In 199 patients exposed to anti-TNF prior to the surgery, combination with anti-TNF and immunosuppressive agents was more effective than anti-TNF monotherapy (OR, 2.32; 95% CI, 1.02-5.31; P= 0.046) to prevent endoscopic POR. Primary failure to anti-TNF agent prior to surgery was predictive of anti-TNF failure to prevent endoscopic POR (OR, 2.41; 95% CI, 1.10-5.32; P= 0.03). When endoscopic POR despite anti-TNF prophylactic medication (n = 55), optimizing anti-TNF and adding an immunosuppressive drug was the most effective option to prevent clinical POR (hazard ratio, 7.38; 95% CI, 1.54-35.30; P= 0.012). Anti-TNF therapy was the best option to prevent clinical POR (hazard ratio, 3.10; 95% CI, 1.09-8.83; P= 0.034) in patients with endoscopic POR who did not receive any biologic to prevent endoscopic POR (n = 55). CONCLUSIONS: Anti-TNF was the most effective medication to prevent endoscopic and clinical POR. Combination with anti-TNF and immunosuppressive agents should be considered in patients previously exposed to anti-TNF.

Outcomes of Ileoanal Pouch Anastomosis in Pediatric Ulcerative Colitis Are Worse in the Modern Era: A Time Trend Analysis Outcomes Following Ileal Pouch-Anal Anastomosis in Pediatric Ulcerative Colitis.

BACKGROUND: Despite significant differences in surgical outcomes between pediatric and adult patients with ulcerative colitis (UC) undergoing colectomy, counseling on pediatric outcomes has largely been guided by data from adults. We compared differences in pouch survival between pediatric and adult patients who underwent total proctocolectomy with ileal pouch-anal anastomosis (IPAA). METHODS: This was a retrospective single-center study of patients with UC treated with IPAA who subsequently underwent pouchoscopy between 1980 and 2019. Data were collected via electronic medical records. We stratified the study population based on age at IPAA. Differences between groups were assessed using t tests and chi-square tests. Kaplan-Meier curves were used to compare survival probabilities. Differences between groups were assessed using a log-rank test. RESULTS: We identified 53 patients with UC who underwent IPAA before 19 years of age and 329 patients with UC who underwent IPAA at or after 19 years of age. Subjects who underwent IPAA as children were more likely to require anti-tumor nerosis factor (TNF) postcolectomy compared with adults (41.5% vs 25.8%; P < .05). Kaplan-Meier estimates revealed that pediatric patients who underwent IPAA in the last 10 years had a 5-year pouch survival probability that was 28% lower than that of those who underwent surgery in the 1990s or 2000s (72% vs 100%; P < .001). Further, children who underwent IPAA and received anti-TNF therapies precolectomy had the most rapid progression to pouch failure when compared with anti-TNF-naive children and with adults who were either exposed or naive precolectomy (P < .05). CONCLUSIONS: There are lower rates of pouch survival for children with UC who underwent IPAA following the uptake of anti-TNF therapy compared with both historical pediatric control subjects and contemporary adults.

Ileal pouch­anal anastomosis is the most common surgical approach for patients with ulcerative colitis undergoing total proctocolectomy. Outcomes are informed by heterogeneous adult data cohorts often predating anti-tumor necrosis factor uptake. We find that for children in the modern era pouch loss occurs at higher rates.

Mucosal serotonin signaling is altered in chronic constipation but not in opiate-induced constipation.

OBJECTIVES: Changes in mucosal serotonin (5-HT) signaling have been detected in a number of functional and inflammatory disorders of the gastrointestinal (GI) tract. This study was undertaken to determine whether chronic constipation (CC) is associated with disordered 5-HT signaling and to evaluate whether constipation caused by opiate use causes such changes. METHODS: Human rectal biopsy samples were obtained from healthy volunteers, individuals with idiopathic CC, and individuals taking opiate medication with or without occurrence of constipation. EC cells were identified by 5-HT immunohistochemistry. 5-HT content and release levels were determined by enzyme immunoassay, and mRNA levels for the synthetic enzyme tryptophan hydroxylase-1 (TpH-1) and serotonin-selective reuptake transporter (SERT) were assessed by quantitative real-time reverse transcription PCR. RESULTS: CC was associated with increases in TpH-1 transcript, 5-HT content, and 5-HT release under basal and stimulated conditions, whereas EC cell numbers and SERT transcript levels were not altered. No changes in these elements of 5-HT signaling were detected in opiate-induced constipation (OIC). CONCLUSIONS: These findings demonstrate that CC is associated with a pattern of altered 5-HT signaling that leads to increased 5-HT availability but does not involve a decrease in SERT expression. It is possible that increased 5-HT availability due to increased synthesis and release contributes to constipation due to receptor desensitization. Furthermore, the finding that elements of 5-HT signaling were not altered in the mucosa of individuals with OIC indicates that constipation as a condition does not lead to compensatory changes in 5-HT synthesis, release, or signal termination.