Formal Degree Programs in Physiology Promote Careers of Clinical Scientists and Benefit Basic Science Departments.

Physiologists may play critical roles in the development of clinician-scientists, who aspire to an academic career. The complexity of contemporary biomedical science and economic matters regarding post-graduate education pose real conundrums. We report a more than 22-year follow-up of surgical trainees pursuing bench laboratory science in Physiology and in Surgery Departments within a single public medical school. The sources and resources include selection, funding, physiology classroom work, and laboratory studies with personal involvement by faculty that have seldom been recorded, especially with longer-term career outcomes. These selected Ph.D. candidates have subsequently pursued several lines of activity, many with distinguished careers and major influences upon future generations of academic surgeons.

Systemic adiponectin levels in colorectal cancer and adenoma: a systematic review and meta-analysis.

BACKGROUND: Obesity is a well-established risk factor in the development of colorectal cancer; however, the mechanism mediating this relationship is not well understood. The adipokine, adiponectin, has an inverse relationship with obesity. Experimental studies have shown adiponectin to have dichotomous inflammatory and tumorigenic roles. Its role in the development of colorectal cancer, including the potential effect of its increase following bariatric surgery, is not yet clear. There are conflicting results from studies evaluating this relationship. This study sought to provide a systematic review and meta-analysis to examine the association between systemic adiponectin levels in patients with colorectal cancer and adenoma. METHODS: An electronic literature search was performed using PubMed, EMBASE, Web of Science as well as gray literature. Articles were screened for inclusion criteria and assessed for quality using the Newcastle-Ottawa Scale. Pooled mean differences were calculated using a random effects model. Subgroup and meta-regression analyses were performed to identify potential sources of heterogeneity. RESULTS: Thirty-two observational studies comparing systemic adiponectin in colorectal cancer vs healthy controls were included. Colorectal cancer cases had lower systemic adiponectin levels (overall pooled mean difference = -1.05 µg/ml [95% CI: -1.99; -0.12] p = 0.03); however, significant heterogeneity was present (I2 = 95% p < 0.01). Subgroup and meta- regression analyses results could not identify a source of the significant heterogeneity across the studies. CONCLUSIONS: Studies suggest a trend towards lower systemic adiponectin levels in colorectal cancer patients, but the heterogeneity observed showed current evidence is not sufficient to definitively draw any conclusions. These data, however, suggest rising adiponectin is unlikely to account for the reported observation of increased CRC following bariatric surgery. Further studies with prospective age, race, and BMI-matched cohorts, and standardized adiponectin measurements may provide a better understanding of this relationship.

State-of-the-art surgery for Crohn's disease: part III-perianal Crohn's disease.

PURPOSE: Diagnosis and treatment of perianal Crohn's disease is challenging and requires its own domain of therapy. Different types of perianal disease require a spectrum of treatment strategies. Treatment options range from conservative therapy, including immunosuppressives, biologics, or stem cell therapy, to surgical treatment with specific indications depending on the underlying lesion. This is part III of the series "state-of-the-art surgery for Crohn's disease," focusing on the management of perianal disease. We discuss the definition and diagnosis of perianal Crohn's disease, the treatment of perianal lesions, and specific surgical indications and techniques. RESULTS AND CONCLUSION: Pitfalls and complications play a substantial role in the treatment of perianal Crohn's disease, and surgical therapy may fail. Realistic treatment goals and an individual patient-oriented treatment approach are crucial in the treatment of perianal Crohn's disease.

Increased Expression of Long Non-coding RNA H19 is Associated With Colon Cancer Recurrence.

BACKGROUND: Colon cancer is a leading cause of cancer-related death. Long non-coding (Lnc) RNAs are critical mediators of tumor biology. H19 is a well-characterized lncRNA involved in p53 regulation and cancer progression. A specific colon cancer data set was utilized to determine if tumor H19 expression is associated with recurrence-free and overall survival. METHODS: Clinical patient data from The Cancer Genome Atlas colon adenocarcinoma data set was downloaded using FirebrowseR and normalized H19 expression from the associated RNA-seq data set downloaded using cBioportal. Univariable and multivariable Cox proportional regression analyses were used to identify an association between H19 expression in colon cancer tissue and recurrence-free, and overall survival. RESULTS: Three hundred eight patients were studied. Median age was 68 years (interquartile range: 58-77 years) and 156 patients (51%) were men. Increased H19 expression was associated with KRAS mutation status (P= 0.016). There was no difference in overall survival between the low and high H19 expression groups (log rank = 0.481); however, increased H19 expression was associated with reduced recurrence-free survival (Log-Rank = 0.012). On multivariable regression analysis, increased H19 expression (Hazard ratio  = 1.83, 95%CI: 1.02-3.27, P= 0.042), and stage III or IV disease (Hazard ratio  = 2.39, 95%CI: 1.34-4.27, P= 0.003) were risk factors for reduced recurrence-free survival. CONCLUSIONS: Colon cancer H19 expression is associated with advanced stage of tumor disease and is a significant risk factor for reduced recurrence-free survival. Tumor expression of H19 may have potential for both prognostic and therapeutic uses in the future.

State-of-the-art surgery for Crohn's disease: Part I-small intestine/ileal disease.

The management of Crohn's disease has evolved significantly over the past 20 years. The arrival of biologic therapies has altered not only the management and outcomes but also rates for refractory disease requiring surgery. New surgical techniques have paralleled these medical advances, and this article will provide an overview of these new modalities as well as their outcomes. This is the first of a three-part series and will focus on terminal ileal and ileocolic disease.

State-of-the-art surgery for Crohn's disease: Part II-colonic Crohn's disease and associated neoplasms.

Despite advances in medical therapy, surgery continues to play a vital role in the management of Crohn's disease and its complications. Continuing from Part I of this series (small intestine/ileal disease), we focus next on colonic Crohn's disease and associated neoplasms. We will first review the surgical management of medical-refractory Crohn's colitis and its complications and then examine cancer risk, surveillance, and surgical management of Crohn's-associated colorectal dysplasia and malignancy. We conclude with a discussion of restoration of gastrointestinal continuity following colonic surgery for Crohn's disease.

Decreased Tumoral Expression of Colon-Specific Water Channel Aquaporin 8 Is Associated With Reduced Overall Survival in Colon Adenocarcinoma.

BACKGROUND: Colon cancer survival is dependent on metastatic potential and treatment. Large RNA-sequencing data sets may assist in identifying colon cancer-specific biomarkers to improve patient outcomes. OBJECTIVE: This study aimed to identify a highly specific biomarker for overall survival in colon adenocarcinoma by using an RNA-sequencing data set. DESIGN: Raw RNA-sequencing and clinical data for patients with colon adenocarcinoma (n = 271) were downloaded from The Cancer Genome Atlas. A binomial regression model was used to calculate differential RNA expression between paired colon cancer and normal epithelium samples (n = 40). Highly differentially expressed RNAs were examined. SETTINGS: This study was conducted at the University of Louisville using data acquired by The Cancer Genome Atlas. PATIENTS: Patients from US accredited cancer centers between 1998 and 2013 were analyzed. MAIN OUTCOME MEASURES: The primary outcome measures were recurrence-free and overall survival. RESULTS: The median age was 66 years (147/271 men, 180/271 White patients). Thirty RNAs were differentially expressed in colon adenocarcinoma compared with paired normal epithelium, using a log-fold change cutoff of ±6. Using median expression as a cutoff, 4 RNAs were associated with worse overall survival: decreased ZG16 (log-rank = 0.023), aquaporin 8 (log-rank = 0.023), and SLC26A3 (log-rank = 0.098), and increased COL1A1 (log-rank = 0.105). On multivariable analysis, low aquaporin 8 expression (HR, 1.748; 95% CI, 1.016-3.008; p = 0.044) was a risk factor for worse overall survival. Our final aquaporin 8 model had an area under the curve of 0.85 for overall survival. On subgroup analysis, low aquaporin 8 was associated with worse overall survival in patients with high microsatellite instability and in patients with stage II disease. Low aquaporin 8 expression was associated with KRAS and BRAF mutations. Aquaporin 8 immunohistochemistry was optimized for clinical application. LIMITATIONS: This was a retrospective study. CONCLUSION: Aquaporin 8 is a water channel selectively expressed in normal colon tissue. Low aquaporin 8 expression is a risk factor for worse overall survival in patients who have colon cancer. Aquaporin 8 measurement may have a role as a colon-specific prognostic biomarker and help in patient risk stratification for increased surveillance. See Video Abstract at http://links.lww.com/DCR/B603. LA DISMINUCIN DE LA EXPRESIN TUMORAL DE LA ACUAPORINA DEL CANAL DE AGUA ESPECFICO DEL COLON SE ASOCIA CON UNA REDUCCIN DE LA SUPERVIVENCIA GENERAL EN EL ADENOCARCINOMA DE COLON: ANTECEDENTES:La supervivencia del cáncer de colon depende del potencial metastásico y del tratamiento. Grandes conjuntos de datos de secuenciación de ARN pueden ayudar a identificar biomarcadores específicos del cáncer de colon para mejorar los resultados de los pacientes.OBJETIVO:Identificar un biomarcador altamente específico para la supervivencia general en el adenocarcinoma de colon utilizando un conjunto de datos de secuenciación de ARN.DISEÑO:La secuenciación de ARN sin procesar y los datos clínicos para pacientes con adenocarcinoma de colon (n = 271) se descargaron de The Cancer Genome Atlas. Se utilizó un modelo de regresión binomial para calcular la expresión diferencial de ARN entre muestras de cáncer de colon emparejadas y muestras de epitelio normal (n = 40). Se examinaron los ARN expresados de forma altamente diferencial.ENTORNO CLINICO:Este estudio se realizó en la Universidad de Louisville utilizando datos adquiridos por The Cancer Genome Atlas.PACIENTES:Se analizaron pacientes de centros oncológicos acreditados en Estados Unidos entre 1998-2013.PRINCIPALES MEDIDAS DE VALORACION:Las principales medidas de valoración fueron la supervivencia general y libre de recurrencia.RESULTADOS:La mediana de edad fue de 66 años (147/271 hombres, 180/271 caucásicos). Treinta ARN se expresaron diferencialmente en el adenocarcinoma de colon en comparación con el epitelio normal emparejado, utilizando un límite de cambio logarítmico de ± 6. Utilizando la expresión mediana como punto de corte, cuatro ARN se asociaron con una peor supervivencia general: disminución de ZG16 (rango logarítmico = 0,023), acuaporina8 (rango logarítmico = 0,023) y SLC26A3 (rango logarítmico = 0,098) y aumento de COL1A1 (log -rango = 0,105). En el análisis multivariable, la baja expresión de acuaporina8 (HR = 1,748, IC del 95%: 1,016-3,008, p = 0,044) fue un factor de riesgo para una peor supervivencia global. Nuestro modelo de aquaporin8 final tuvo un AUC de 0,85 para la supervivencia global. En el análisis de subgrupos, la acuaporina8 baja se asoció con una peor supervivencia general en pacientes con MSI-H y en pacientes en estadio II. La baja expresión de acuaporina8 se asoció con mutaciones de KRAS y BRAF. La inmunohistoquímica de aquaporina8 se optimizó para su aplicación clínica.LIMITACIONES:Este fue un estudio retrospectivo.CONCLUSIÓN:La acuaporina8 es un canal de agua expresado selectivamente en el tejido normal del colon. La baja expresión de AQP8 es un factor de riesgo de peor supervivencia global en pacientes con cáncer de colon. La medición de aquaporina8 puede tener un papel como un biomarcador de pronóstico específico del colon y ayudar en la estratificación del riesgo del paciente para una mayor vigilancia. Consulte Video Resumen en http://links.lww.com/DCR/B603.

Interferon-gamma increases monocyte PD-L1 but does not diminish T-cell activation.

Immune dysfunction can occur during sepsis or following major trauma. Decreased monocyte HLA-DR expression and cytokine responses are associated with mortality. Recent studies have shown that adaptive immune system defects can also occur in such patients, characterised by increased PD-L1 expression and associated T-cell anergy. The aim of this study was to determine the effects of an immune adjuvant, interferon-gamma, on monocyte PD-L1 expression and T-cell activation in an ex-vivo human whole blood model of infection. We found that with interferon-gamma treatment, monocytes had increased HLA-DR expression and augmented TNF-α production in response to LPS stimulation, with a decrease in IL-10 levels. Both LPS and interferon-gamma increased the level of monocyte PD-L1 expression, and that a combination of both agents synergistically stimulated a further increase in PD-L1 levels as measured by flow cytometry. However, despite elevated PD-L1 expression, both CD4 and CD8 T-cell activation was not diminished by the addition of interferon-gamma treatment. These findings suggest that PD-L1 may not be a reliable marker for T-cell anergy, and that interferon-gamma remains an adjuvant of interest that can improve the monocyte inflammatory response while preserving T-cell activation.

A modified cholera toxin B subunit containing an ER retention motif enhances colon epithelial repair via an unfolded protein response.

Cholera toxin B subunit (CTB) exhibits broad-spectrum biologic activity upon mucosal administration. Here, we found that a recombinant CTB containing an endoplasmic reticulum (ER) retention motif (CTB-KDEL) induces colon epithelial wound healing in colitis via the activation of an unfolded protein response (UPR) in colon epithelial cells. In a Caco2 cell wound healing model, CTB-KDEL, but not CTB or CTB-KDE, facilitated cell migration via interaction with the KDEL receptor, localization in the ER, UPR activation, and subsequent TGF-ß signaling. Inhibition of the inositol-requiring enzyme 1/X-box binding protein 1 arm of UPR abolished the cell migration effect of CTB-KDEL, indicating that the pathway is indispensable for the activity. CTB-KDEL's capacity to induce UPR and epithelial restitution or wound healing was corroborated in a dextran sodium sulfate-induced acute colitis mouse model. Furthermore, CTB-KDEL induced a UPR, up-regulated wound healing pathways, and maintained viable crypts in colon explants from patients with inflammatory bowel disease (IBD). In summary, CTB-KDEL exhibits unique wound healing effects in the colon that are mediated by its localization to the ER and subsequent activation of UPR in epithelial cells. The results provide implications for a novel therapeutic approach for mucosal healing, a significant unmet need in IBD treatment.-Royal, J. M., Oh, Y. J., Grey, M. J., Lencer, W. I., Ronquillo, N., Galandiuk, S., Matoba, N. A modified cholera toxin B subunit containing an ER retention motif enhances colon epithelial repair via an unfolded protein response.

Reducing Patient Burden and Improving Data Quality With the New Cleveland Clinic Colorectal Cancer Quality of Life Questionnaire.

BACKGROUND: The Cleveland Clinic Colorectal Cancer Quality of Life Questionnaire was developed in response to the need for a new, fast, and comprehensive tool for evaluating quality of life in patients who have colorectal cancer. Available surveys such as the SF-12, SF-36, Functional Assessment of Cancer Therapy-Colorectal, and European Organization for Research and Treatment of Cancer are either too general to be informative or too lengthy to complete. OBJECTIVE: The aim was to validate the Cleveland Clinic Foundation Colorectal Quality of Life Questionnaire. DESIGN: Data were obtained as part of a prospective randomized controlled trial. SETTINGS: This was a worldwide multicenter study with 2 domestic and 5 international locations. PATIENTS: This study randomly assigned 190 patients between the ages of 18 and 80 undergoing surgery for low rectal cancer. Of those randomly assigned, 142 with partially complete surveys were analyzed for selection bias and acceptability, and 95 with complete surveys were analyzed for survey validity. INTERVENTIONS: Patients received either a J-pouch, side-to-end anastomosis, or straight anastomosis. MAIN OUTCOME MEASURE: The study evaluated survey validity measures such as standardized Cronbach α for internal consistency and Spearman correlation coefficients for construct validity, convergent validity, and responsiveness. Univariate analyses were used to assess discriminative validity. RESULTS: Sufficient acceptability, construct, and convergent validity and responsiveness were achieved. All scores showed great internal consistency (Cronbach α >0.8). Superior discriminative ability was demonstrated by significant differences (p < 0.05) in 2 of 7 scores between neoadjuvant treatment groups, and in 6 of 7 scores between complication groups, none of which were detected by the SF-12 or Functional Assessment of Cancer Therapy-Colorectal surveys. LIMITATIONS: Limitations included a small sample size, cultural differences, and failure to assess test-retest ability of the questionnaire. CONCLUSIONS: The Cleveland Clinic Colorectal Cancer Quality of Life Questionnaire is an efficient and reliable quality-of-life measure that better incorporates factors specific to colorectal cancer surgery. See Video Abstract at http://links.lww.com/DCR/B155. REDUCIENDO LA CARGA AL PACIENTE Y MEJORANDO LA CALIDAD DE DATOS CON EL NUEVO CUESTIONARIO DE CALIDAD DE VIDA EN CÁNCER COLORRECTAL DE CLEVELAND CLINIC (CCF-CAQL): El cuestionario de calidad de vida en cáncer colorrectal de Cleveland Clinic se desarrolló en respuesta a la necesidad de una herramienta nueva, rápida e integral para evaluar la calidad de vida en pacientes con cáncer colorrectal. Los cuestionarios disponibles como SF-12, SF-36, FACT-C y EORTC son demasiado generales para ser informativas o demasiado largas para completar.El objetivo fue validar el cuestionario de calidad de vida colorrectal de la Cleveland Clinic Foundation.Los datos se obtuvieron como parte de un ensayo prospectivo aleatorizado y controlado.Este fue un estudio multicéntrico mundial con dos sedes nacionales y cinco internacionales.Este estudio aleatorizó a 190 pacientes entre las edades de 18 y 80 sometidos a cirugía por cáncer rectal bajo. De aquellos aleatorizados, 142 con encuestas parcialmente completas se analizaron para determinar el sesgo de selección y la aceptabilidad, y 95 con encuestas completas se analizaron para determinar la validez de la encuesta.Los pacientes recibieron un reservorio en J, anastomosis latero-terminal o anastomosis termino-terminal.El estudio evaluó medidas de validez de la encuesta, como el Alfa de Cronbach estandarizado para la consistencia interna y los coeficientes de correlación de Spearman para la validez de construcción, la validez de convergencia y la capacidad de respuesta. Se utilizaron análisis univariados para evaluar la validez discriminativa.Se obtuvo suficiente aceptabilidad, construcción, validez de convergencia, y capacidad de respuesta. Todos los puntajes mostraron una gran consistencia interna (alfa de Cronbach > 0.8). Una capacidad discriminativa superior fue demostrada por diferencias significativas (p < 0.05) en dos de siete puntajes entre grupos de tratamiento neoadyuvante, y en seis de siete puntajes entre grupos de complicaciones, ninguno de los cuales fue detectado por SF-12 o FACT-C.Las limitaciones incluyeron un tamaño de muestra pequeño, diferencias culturales y la falta de evaluación de la confiabilidad test-retest del cuestionario.El Cuestionario de Calidad de Vida en Cáncer Colorrectal de Cleveland Clinic es una medida de calidad de vida eficiente y confiable que incorpora mejor factores específicos asociados a la cirugía de cáncer colorrectal. Consulte Video Resumen en http://links.lww.com/DCR/B155.

Preoperative Opioid Prescription Is Associated With Major Complications in Patients With Crohn's Disease Undergoing Elective Ileocolic Resection.

BACKGROUND: Opioid use has grown exponentially over the last decade. The effect of preoperative opioid prescription in patients with Crohn's disease undergoing surgery is unknown. OBJECTIVE: The purpose of this study was to identify whether preoperative opioid prescription is associated with adverse postoperative outcomes in Crohn's disease. DESIGN: This is a single-institution retrospective observational study. SETTINGS: This study was performed at an academic tertiary care center. Details of preoperative opioid prescription were collected from the Kentucky All-Schedule Prescription Electronic Reporting database and the electronic databases of bordering states. PATIENTS: Consecutive patients undergoing ileocolic resection for Crohn's disease from 2014 to 2018 were included. MAIN OUTCOME MEASURES: The outcomes examined were major complications (Clavien-Dindo ≥3a), length of stay, and 30-day hospital readmission. RESULTS: Fifty one of 118 patients were prescribed opioids within 6 months preoperatively (range, 0-33,760 morphine milligram equivalents). Patients with preoperative opioid prescription compared with no preoperative opioid prescription required more daily opioids during hospital admission (p = 0.024). Nineteen patients had a major postoperative complication (preoperative opioid prescription: 26% (13/51) vs no preoperative opioid prescription: 9% (6/67)). On multivariable analysis, preoperative opioid prescription (OR = 2.994 (95% CI, 1.024-8.751); p = 0.045) was a significant risk factor for a major complication. Preoperative opioid prescription was associated with increased length of stay (p < 0.001) and was a risk factor for readmission (OR = 2.978 (95% CI, 1.075-8.246); p = 0.036). Twenty-four patients were readmitted. Using a cutoff for higher opioid prescription of 300 morphine milligram equivalents within 6 months preoperation (eg, 60 tablets of hydrocodone/acetaminophen 5/325), preoperative opioid prescription remained a risk factor for major postoperative complications (OR = 3.148 (95% CI, 1.110-8.928); p = 0.031). LIMITATIONS: This was a retrospective study and could not assess nonprescribed opioid use. CONCLUSIONS: Preoperative opioid prescription was a significant risk factor for adverse outcomes in patients with Crohn's disease undergoing elective ileocolic resection. See Video Abstract at http://links.lww.com/DCR/B113. LA PRESCRIPCIÓN PREOPERATORIA DE OPIOIDES SE ASOCIA CON COMPLICACIONES MAYORES EN PACIENTES CON ENFERMEDAD DE CROHN SOMETIDOS A RESECCIÓN ILEOCÓLICA ELECTIVA: El uso de opioides ha crecido exponencialmente en la última década. Se desconoce el efecto de la prescripción preoperatoria de opioides en pacientes con enfermedad de Crohn sometidos a cirugía.Identificar si la prescripción preoperatoria de opioides está asociada con resultados postoperatorios adversos en la enfermedad de Crohn.Este es un estudio observacional retrospectivo de una sola institución.Este estudio se realizó en un centro académico de atención terciaria. Los detalles de la prescripción preoperatoria de opiáceos se recopilaron de la base de datos de "Kentucky All-Schedule Prescription Electronic Reporting" y de las bases de datos electrónicas de los estados fronterizos.Pacientes consecutivos sometidos a resección ileocólica por enfermedad de Crohn entre 2014-2018.Los resultados examinados fueron complicaciones mayores (Clavien-Dindo ≥3a), duración de la estancia y el reingreso hospitalario de 30 días.A cincuenta y uno de 118 pacientes se le recetaron opioides dentro de los 6 meses preoperatorios (rango, 0 a 33,760 equivalentes de miligramos de morfina). Los pacientes con prescripción preoperatoria de opioides en comparación con ninguna prescripción preoperatoria de opioides requirieron más opioides diarios durante el ingreso hospitalario (p = 0,024). Diecinueve pacientes tuvieron una complicación postoperatoria importante (prescripción preoperatoria de opioides: 26% [13/51] frente a ninguna prescripción preoperatoria de opioides: 9% [6/67]). En el análisis multivariable, la prescripción de opioides preoperatorios (OR = 2.994, IC 95%: 1.024-8.751, p = 0.045) fueron factores de riesgo significativos para una complicación mayor. La prescripción preoperatoria de opioides se asoció con un aumento de la duración de la estadía (p <0.001) y fue un factor de riesgo para el reingreso (OR = 2.978, IC 95%: 1.075-8.246, p = 0.036). Veinticuatro pacientes fueron readmitidos. Utilizando un límite para una mayor prescripción de opioides de 300 miligramos equivalentes de morfina dentro de los 6 meses previos a la operación (p. Ej., 60 tabletas de hidrocodona / acetaminofén 5/325), la prescripción preoperatoria de opioides siguió siendo un factor de riesgo para complicaciones postoperatorias mayores (OR = 3.148 IC 95%: 1.110-8.928, p = 0.031).Este fue un estudio retrospectivo y no pudo evaluar el uso de opioides no prescritos.La prescripción preoperatoria de opioides fue un factor de riesgo significativo para los resultados adversos en pacientes con enfermedad de Crohn sometidos a resección ileocólica electiva. Consulte Video Resumen en http://links.lww.com/DCR/B113.

Pyoderma Gangrenosum in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Pyoderma gangrenosum (PG) is an uncommon but severe extra-intestinal manifestation (EIM) of inflammatory bowel disease (IBD). The incidence and risk factors for PG are disputed. AIMS: To assess the incidence of PG and identify factors associated with PG in IBD patients. METHODS: A search of electronic databases (Ovid and PubMed) was conducted between 1966 and 2019. Studies that calculated the incidence of PG in IBD patient cohorts were included. Patient demographics, IBD subtype, and EIM presence were recorded. A review of our institutional database of 1057 IBD patients was conducted. A multivariate regression model and meta-analysis were conducted to identify risk factors for PG. A random effects model was used to combine the data of included studies. RESULTS: Fourteen studies were included in addition to 1057 IBD patients and 26 PG cases from the Louisville cohort. In total, there were 379 cases of PG in the cumulative cohort of 61,695 IBD patients. The PG incidence in individual studies ranged from 0.4 to 2.6%. In the institutional cohort, ocular EIMs and a permanent stoma were significant risk factors for PG. In the meta-analysis, PG was associated with female gender (RR = 1.328, 95% CI 1.161-1.520), Crohn's disease (RR = 1.193, 95% CI 1.001-1.422), erythema nodosum (RR = 9.281, 95% CI 6.081-14.164), and ocular EIM (RR = 4.55, 95% CI 3.04-6.81). There was study heterogeneity when assessing IBD subtype, ocular, and joint EIMs. CONCLUSIONS: There are conflicting data on the incidence and risk factors for PG. This meta-analysis confirms an association between PG and female gender, Crohn's disease, erythema nodosum, and ocular EIM that have been described in smaller studies.

Better Function With a Colonic J-Pouch or a Side-to-end Anastomosis?: A Randomized Controlled Trial to Compare the Complications, Functional Outcome, and Quality of Life in Patients With Low Rectal Cancer After a J-Pouch or a Side-to-end Anastomosis.

BACKGROUND INFORMATION: We aimed to compare prospectively the complications and functional outcome of patients undergoing a J-Pouch (JP) or a side-to-end anastomosis (SE) for treatment of low rectal cancer at a 2-year time point after resection for rectal cancer. METHODS: A multicenter study was conducted on patients with low rectal cancer who were randomized to receive either a JP or SE and were followed for 24 months utilizing SF-12 and FACT-C surveys to evaluate the quality of life (QOL). Fecal incontinence was evaluated using the Fecal Incontinence Severity Index (FISI). Bowel function, complications, and their treatments were recorded. RESULTS: Two hundred thirty-eight patients (165 males) were randomized with 167 final eligible patients, 80 in the JP group and 87 in the SE group for evaluation. The mean age at surgery was 61 (range 29 to 82) years. The overall mean recurrence rate was 12 of 238, 5% and similar in both groups. COMPLICATIONS: Overall, 37 of 190 (19%) patients reported complications, 14 of these were Clavien Dindo Grade 3b and 2 were 3a: leak 3 (2 JP,1 SE), fistula 4 (1 JP, 3 SE), small bowel obstruction 4 (3JP, 1 SE), stricture 4 (3 SE, 1 SA), pouch necrosis 2 (JP), and wound infection 5 (2 JP, 3 SE). QOL scores using either instrument between the 2 groups at 12 and 24 months were similar (P > 0.05). Bowel movements, clustering, and FISI scores were similar. CONCLUSION: At time points of 1 and 2 years after a JP or a SE for low rectal cancer, QOL, functional outcome, and complications are comparable between the groups. Although choosing a particular procedure may depend on surgeon/patient choice or anatomical considerations at the time of surgery, SE functions similar to JP and may be chosen due to the ease of construction.

The role of the miR-200 family in epithelial-mesenchymal transition in colorectal cancer: a systematic review.

Colorectal cancer (CRC) is associated with significant morbidity and mortality as many patients are diagnosed with advanced stage disease. MicroRNAs are small, noncoding RNA molecules that have a major role in gene expression regulation and are dysregulated in CRC. The miR-200 family is involved in epithelial-mesenchymal transition (EMT). This systematic review describes the roles of the miR-200 family in EMT in CRC. A search of electronic databases (PubMed and Embase) was conducted between January 2000 and July 2017. Both in vitro and human studies reporting on the miR-200 family and CRC were included. Studies describing molecular pathways and the role of the miR-200 family in the diagnostic and therapeutic management of CRC were analyzed. Thirty-four studies (22 in vitro and 18 human studies) were included. miR-200 family expression is regulated epigenetically and via transcriptional factor regulation. In vitro studies show that transfection of miR-200 family members into chemo-resistant colon cancer cell lines results in improved chemo-sensitivity and epithelial phenotype restoration. There is intra-tumoral variability in the tissue expression of miR-200 family members with decreased expression at the invasive front. Clinical studies in CRC patients have shown decreased primary tumor tissue expression of miR-429, miR-200a and miR-200c may be associated with worse survival. Conversely, increased blood levels of miR-141, miR-200a and miR-200c may be associated with worse outcomes. The miR-200 family has a central role in EMT. The miR200 family has potential for both prognostic and therapeutic management of CRC.

Blood-based microRNAs as biomarkers for the diagnosis of colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: Colorectal cancer (CRC) is common and associated with significant mortality. Current screening methods for CRC lack patient compliance. microRNAs (miRNAs), identified in body fluids, are negative regulators of gene expression and are dysregulated in many cancers, including CRC. This paper summarises studies identifying blood-based miRNAs dysregulated in CRC compared with healthy controls in an attempt to evaluate their use as a screening tool for the diagnosis of CRC. METHODS: A search of electronic databases (PubMed and EMBASE) and grey literature was performed between January 2002 and April 2016. Studies reporting plasma or serum miRNAs in the diagnosis of CRC compared with healthy controls were selected. Patient demographics, type of patient sample (serum or plasma), method of miRNA detection, type of normalisation, and the number of significantly dysregulated miRNAs identified were recorded. Statistical evaluation of dysregulated miRNAs using sensitivity, specificity, and area under the curve (AUC) was performed. RESULTS: Thirty-four studies investigating plasma or serum miRNAs in the diagnosis of CRC were included. A total of 31 miRNAs were found to be either upregulated (n=17) or downregulated (n=14) in CRC cases as compared with controls. Fourteen studies identified panels of ⩾2 dysregulated miRNAs. The highest AUC, 0.943, was identified using a panel of 4 miRNAs with 83.3% sensitivity and 93.1% specificity. Meta-analysis of studies identifying a single dysregulated miRNA in CRC cases compared with controls was performed. Overall sensitivity and specificity of 28 individual miRNAs in the diagnosis of CRC were 76% (95% CI 72%-80%) and 76% (95% CI 72%-80%), respectively, indicating good discriminative ability of miRNAs as biomarkers for CRC. These data did not change with sensitivity analyses. CONCLUSIONS: Blood-based miRNAs distinguish patients with CRC from healthy controls with high sensitivity and specificity comparable to other common and invasive currently used screening methods for CRC. In future, miRNAs may be used as a relatively non-invasive blood-based marker for detection of CRC.