Church, James M.

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.

Abstract It was not known whether the polygenic risk scores (PRSs) that predict colorectal cancer could predict colorectal cancer for people with inherited pathogenic variants in DNA mismatch repair genes—people with Lynch syndrome. We tested a PRS comprising 107 established single-nucleotide polymorphisms associated with colorectal cancer in European populations for 826 European-descent carriers of pathogenic variants in DNA mismatch repair genes (293 MLH1, 314 MSH2, 126 MSH6, 71 PMS2, and 22 EPCAM) from the Colon Cancer Family Registry, of whom 504 had colorectal cancer. There was no evidence of an association between the PRS and colorectal cancer risk, irrespective of which DNA mismatch repair gene was mutated, or sex (all 2-sided P > .05). The hazard ratio per standard deviation of the PRS for colorectal cancer was 0.97 (95% confidence interval = 0.88 to 1.06; 2-sided P = .51). Whereas PRSs are predictive of colorectal cancer in the general population, they do not predict Lynch syndrome colorectal cancer.

BACKGROUND: In selected patients with ulcerative colitis and pelvic pouch failure, redo pouch is an option. However, it is unknown whether selected patients with Crohn’s disease should be offered a chance to avoid permanent diversion after failure of IPAA. OBJECTIVE: The objective was to compare the outcomes of redo pouch for ulcerative colitis and Crohn’s disease. DESIGN: This was a retrospective analysis of a prospectively maintained pouch database (1983–2017). SETTINGS: The setting was the Cleveland Clinic. PATIENTS: This study included patients who underwent redo pouch with a primary surgical specimen diagnosis of ulcerative or Crohn’s colitis at the time of initial pouch. MAIN OUTCOME MEASURES: Pouch failure was defined as either pouch excision or indefinite pouch diversion. Patient characteristics, perioperative and functional outcomes, pouch survival, and quality of life were compared according to the diagnosis. RESULTS: Of 422 patients, 392 had ulcerative colitis and 30 had Crohn’s disease. Age and sex were comparable. The most common indications for redo pouch included anastomotic separation and fistulas (220 (56.1%) in ulcerative colitis and 21 (70%) in Crohn’s disease). The majority of redo pouches required mucosectomy with handsewn anastomosis (310 (79%) in ulcerative colitis and 30 (100%) in Crohn’s disease; p = 0.23). A new pouch was constructed in 160 patients (41%) with ulcerative colitis and repair of old pouch in 231 patients (59%) compared with 25 (83%) in Crohn’s disease, who had creation of new pouch; only in 5 (17%) was the old pouch re-anastomosed. Stool frequency, seepage, and fecal urgency were comparable between groups. Cumulative 5-year pouch survival was longer in ulcerative colitis versus Crohn’s disease (88% vs 55%; p = 0.008). Major causes of redo failure in Crohn’s disease were pouch fistulas and/or strictures occurring after ileostomy closure. These were more common in Crohn’s disease than in ulcerative colitis (p < 0.001). LIMITATIONS: This was a retrospective design. CONCLUSIONS: Redo pouch can be offered to selected patients with colonic Crohn’s disease diagnosed at the time of their primary pouch. See Video Abstract at http://links.lww.com/DCR/B206. Rehacer la Anastomosis Ileoanal con Reservorio Después de un Reservorio Ileal Fallido en Pacientes con Enfermedad de Crohn: ¿Vale la Pena Intentarlo? ANTECEDENTES: En pacientes seleccionados con colitis ulcerativa y falla del reservorio pélvico, rehacer el reservorio es una opción. Sin embargo, se desconoce si en los pacientes seleccionados con enfermedad de Crohn se debería ofrecer la oportunidad de evitar la derivación permanente después de la falla de la anastomosis ileoanal con reservorio ileal. OBJETIVO: El objetivo fue comparar los resultados de reservorios re-hechos en colitis ulcerosa y la enfermedad de Crohn. ESCENARIO: El escenario fue la Cleveland Clinic. DISEÑO: Análisis retrospectivo de una base de datos de reservorios ileales mantenida prospectivamente (1983-2017). PACIENTES: Este estudio incluyó a pacientes que se sometieron a cirugía para rehacer el reservorio ileal con un diagnóstico en el espécimen quirúrgico primario de colitis ulcerosa o de Crohn en el momento del reservorio inicial. PRINCIPALES MEDIDAS DE RESULTADO: La falla del reservorio se definió como la escisión del reservorio o la derivación indefinida del reservorio. Las características del paciente, los resultados perioperatorios y funcionales, la supervivencia del reservorio y la calidad de vida se compararon de acuerdo con el diagnóstico. RESULTADOS: De 422 pacientes, 392 tenían colitis ulcerativa y 30 tenían enfermedad de Crohn. La edad y el género fueron comparables. Las indicaciones más comunes para rehacer el reservorio incluyeron dehiscencia anastomótica y fístulas [220 (56,1%) en colitis ulcerosa y 21 (70%) en la enfermedad de Crohn]. La mayoría de los reservorios rehechos requirieron mucosectomía con anastomosis manual [310 (79%) en colitis ulcerosa y 30 (100%) en la enfermedad de Crohn, p = 0.23]. Se construyó un nuevo reservorio en 160 (41%) pacientes con colitis ulcerativa y se reparó el reservorio antiguo en 231 (59%) pacientes, en comparación con 25 (83%) en la enfermedad de Crohn, que requirieron creación de un nuevo reservorio, y solo 5 (17%) donde el reservorio antiguo se volvió a anastomosar. La frecuencia de las evacuaciones, el manchado fecal y la urgencia fecal fueron comparables entre grupos. La supervivencia acumulada del reservorio a 5 años fue mayor en la colitis ulcerativa frente a la enfermedad de Crohn (88% frente a 55%, p = 0.008). Las principales causas de falla del reservorio rehecho en la enfermedad de Crohn fueron las fístulas del reservorio y / o las estenosis que ocurrieron después del cierre de ileostomía. Estas fueron más comunes en la enfermedad de Crohn que en la colitis ulcerativa (p <0.001). LIMITACIONES: Este fue un diseño retrospectivo. CONCLUSIÓN: Rehacer el reservorio ileal se puede ofrecer a pacientes seleccionados con enfermedad de Crohn colónica diagnosticada en el momento de su reservorio primario. Consulte Video Resumen en http://links.lww.com/DCR/B206. (Traducción—Dr Jorge Silva Velazco)

Abstract Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Carriers of germline mutations in DNA mismatch repair (MMR) genes are at increased risk of several cancers including colorectal and gynecologic cancers (Lynch syndrome). There is no substantial evidence that these mutations are associated with an increased risk of cervical cancer. A total of 369 families with at least one carrier of a mutation in a MMR gene (133 MLH1, 174 MSH2, 35 MSH6 and 27 PMS2) were ascertained via population cancer registries or via family cancer clinics in Australia, New Zealand, Canada, and USA. Personal and family histories of cancer were obtained from participant interviews. Modified segregation analysis was used to estimate the hazard ratio (incidence rates for carriers relative to those for the general population), and age‐specific cumulative risks of cervical cancer for carriers. A total of 65 cases of cervical cancer were reported (including 10 verified by pathology reports). The estimated incidence was 5.6 fold (95% CI: 2.3–13.8; p = 0.001) higher for carriers than for the general population with a corresponding cumulative risk to 80 years of 4.5% (95% CI: 1.9–10.7%) compared with 0.8% for the general population. The mean age at diagnosis was 43.1 years (95% CI: 40.0–46.2), 3.9 years younger than the reported USA population mean of 47.0 years (p = 0.02). Women with MMR gene mutations were found to have an increased risk of cervical cancer. Due to limited pathology verification we cannot be certain that a proportion of these cases were not lower uterine segment endometrial cancers involving the endocervix, a recognized cancer of Lynch syndrome.

AbstractThe association between thyroid cancer and familial adenomatous polyposis (FAP), albeit rare, is well known. It has been suggested that the thyroid tumors have unique histologic characteristics and may be follicular in origin. Because of their rarity, treatment and long‐term prognosis are uncertain. Twelve such patients (prevalence 399/100,000) seen during 1949–1995 were retrospectively reviewed. Histology was independently re‐reviewed by two pathologists. There were 11 female patients (two sisters) and 1 male patient, with a mean age of 28 years (range 15–61 years). Eight patients (66%) had multicentric tumors and five (42%) bilateral disease. Average tumor diameter was 1.8 cm (range 0.2–5.0 cm). Regional nodal metastases were present in two patients. All 12 thyroid cancers in this series were papillary. The one male patient demonstrated “typical” histology with variable papillary and follicular architecture, whereas the 11 female patients had tumors with unusual histology as described by Harach. Five patients (41%) were treated by total thyroidectomy, five with near‐total thyroidectomy, and two with lobectomy alone. Mean follow‐up was 142 months (range 7 months to 30 years). Regional recurrent disease occurred in two patients, one of whom died of the disease. The 5‐ and 20‐year survivals were 90% and 77%, respectively. The results indicated that all tumors in this study were papillary, although atypical histology was encountered in 91%. The mean age (28 years) is younger than that of patients with sporadic disease. Multicentricity and bilateral disease are common. In view of this finding, total thyroidectomy should be strongly considered. Long‐term prognosis is excellent. The finding of unusual histology in a young patient with papillary thyroid carcinoma should arouse the suspicion of FAP.