Autistic traits in youth with familial adenomatous polyposis: A Dutch-Canadian case-control study.

This study investigated the neurodevelopmental impact of pathogenic adenomatous polyposis coli (APC) gene variants in patients with familial adenomatous polyposis (FAP), a cancer predisposition syndrome. We hypothesized that certain pathogenic APC variants result in behavioral-cognitive challenges. We compared 66 FAP patients (cases) and 34 unaffected siblings (controls) to explore associations between APC variants and behavioral and cognitive challenges. Our findings indicate that FAP patients exhibited higher Social Responsiveness Scale (SRS) scores, suggesting a greater prevalence of autistic traits when compared to unaffected siblings (mean 53.8 vs. 47.4, Wilcoxon p = 0.018). The distribution of SRS scores in cases suggested a bimodal pattern, potentially linked to the location of the APC variant, with scores increasing from the 5' to 3' end of the gene (Pearson's r = 0.33, p = 0.022). While we observed a trend toward lower educational attainment in cases, this difference was not statistically significant. This study is the first to explore the connection between APC variant location and neurodevelopmental traits in FAP, expanding our understanding of the genotype-phenotype correlation. Our results emphasize the importance of clinical assessment for autistic traits in FAP patients, shedding light on the potential role of APC gene variants in these behavioral and cognitive challenges.

Routine diversion following delayed IPAA construction does not reduce the incidence of pouch-related sepsis or failure in patients with ulcerative colitis.

AIM: The aim of this study was to compare modified 2-stage and 3-stage IPAA construction techniques to evaluate the effect of diverting loop ileostomy following completion proctectomy and IPAA for ulcerative colitis. In addition, our overall institutional experience was reviewed to describe long-term outcomes and changes in staging trends over time. METHODS: Our institutional database was searched to identify all cases of IPAA for ulcerative colitis between 1981 and 2018. Patient, pouch and outcome characteristics were abstracted. Primary study outcomes were the incidence of primary pouch failure and pouch-related sepsis. Failure was evaluated by Kaplan-Meier estimates of survival over time. The adjusted effect of pouch stage was evaluated using multivariable Cox and logistic regression models. Exploratory analysis evaluated the effect of stage on failure in the pouch related sepsis subgroup. RESULTS: A total of 2105 patients underwent primary IPAA over the study period. The 5, 10 and 20-year pouch survival probabilities were 95.2%, 92.7% and 86.6%. The incidence of pouch related sepsis was 12.3%. Adjusted analysis demonstrated no difference in pouch failure (HR = 0.64: 95% 0.39-1.07, p = 0.09) or post-operative sepsis (aOR = 0.79: 95% CI 0.53-1.17, p = 0.24) by stage of construction. Among patients experiencing pouch sepsis, there was no difference in Kaplan-Meier estimates of pouch survival by stage (p = 0.90). CONCLUSIONS: Pouch related sepsis and IPAA failure did not differ between modified 2-stage and 3-stage construction techniques. Among the sub-group of patients experiencing pouch related sepsis, there was no difference in failure between groups. The results suggest diverting ileostomy may be safely avoided following delayed pouch reconstruction in appropriately selected patients.

Evaluating colonoscopy screening intervals in patients with Lynch syndrome from a large Canadian registry.

BACKGROUND: Lynch syndrome (LS) screening guidelines originally recommended colonoscopy every 1 to 2 years, beginning between the ages of 20 and 25 years. Recent studies have questioned the benefits of these short screening intervals in preventing colorectal cancer (CRC). Our goal is to determine how colonoscopy screening intervals impact CRC in patients with LS. METHODS: We analyzed the demographics, screening practices, and outcomes of patients with LS identified through the clinic based Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre, Sinai Health System, Toronto, Canada. RESULTS: A total of 429 patients with LS were identified with median follow-up of 9.2 years; 44 developed CRC. We found a positive trend between shorter screening intervals and the number of adenomas detected during colonoscopy. Any new adenoma detected at screening decreased 10-year CRC incidence by 11.3%. For MLH1 carriers, a screening interval of 1-2 years vs 2-3 years led to a 20-year cumulative CRC risk reduction of 28% and 14% in females and males, respectively. For MSH2 carriers, this risk reduction was 29% and 17%, respectively, and for male MSH6 carriers 18%. Individuals without any adenomas detected (53.4% of LS carriers) had an increased 20-year CRC risk of 25.7% and 57.2% for women and men, respectively, compared with those diagnosed with adenomas at screening. CONCLUSIONS: The recommended colonoscopy screening interval of 1-2 years is efficient at detecting adenomas and reducing CRC risk. The observation that 53.4% of LS patients never had an adenoma warrants further investigation about a possible adenoma-free pathway.

Transabdominal IPAA Revision: Does Indication Dictate Outcome?

BACKGROUND: Following IPAA failure, select patients are eligible for IPAA revision. Presently, there is limited evidence describing long-term revision outcomes and predictors of revision failure. This represents an important knowledge gap when selecting and counseling patients. OBJECTIVE: This study aimed to define long-term IPAA survival outcomes after transabdominal IPAA revision and identify preoperative clinical factors associated with revision failure. DESIGN: This was a retrospective cohort study. SETTINGS: This study was conducted at a tertiary referral center. PATIENTS: This study included all patients who underwent revisional IPAA surgery between 1982 and 2017 for pouch failure. INTERVENTION: Transabdominal IPAA revision was included. MAIN OUTCOME MEASURES: The primary outcome was pouch failure, defined as pouch excision or permanent pouch diversion, after IPAA revision. RESULTS: A total of 159 patients (64.2% women) were included with a median age of 36 years (interquartile range, 28.5-46.5) at revision. Eighty percent of patients had a primary diagnosis of ulcerative colitis. The most common indication for revision was leak/pelvic sepsis, representing 41% of the cohort, followed by pouch-vaginal fistula (22.2%), mechanical factors (20.4%), and poor pouch function (14.6%). During the study period, 56 patients (35.2%) experienced pouch failure. The 3-year pouch survival probability was 82.3% (95% CI, 75.5%-87.5%), 5-year pouch survival probability was 77.2% (95% CI, 69.8%-83.0%), and 10-year pouch survival probability was 70.6% (95% CI, 62.6%-77.2%). Compared to mechanical factors, pouch failure was significantly associated with pelvic sepsis (HR, 4.25; 95% CI, 1.50-12.0) and pouch-vaginal fistula (HR, 4.37; 95% CI, 1.47-12.99). No significant association was found between revision failure and previous revision, redo ileoanal anastomosis, or new pouch construction. LIMITATIONS: This study is limited by its retrospective design. CONCLUSIONS: Revisional IPAA can be undertaken with favorable long-term outcomes at high-volume centers. Consideration should be given to indication for revision when counseling patients regarding the risk of failure. Further research on risk stratifying patients before revision is required. See Video Abstract at http://links.lww.com/DCR/B966 . REVISIN DE LA ANASTOMOSIS ANAL DE LA BOLSA ILEAL TRANSABDOMINAL LA INDICACIN DICTA EL RESULTADO: ANTECEDENTES:Después de la falla en la anastomosis del reservorio ileoanal, los pacientes seleccionados son elegibles para la revisión de la anastomosis del reservorio ileoanal. Actualmente, hay evidencias limitadas que describen los resultados de la revisión a largo plazo y los predictores del fracaso de la revisión. Esto representa un importante vacío de investigación a la hora de seleccionar y asesorar a los pacientes.OBJETIVO:Definir los resultados de supervivencia a largo plazo de la IPAA después de la revisión de la anastomosis del reservorio ileoanal transabdominal e identificar los factores clínicos preoperatorios asociados con el fracaso de la revisión.DISEÑO:Este fue un estudio de cohorte retrospectivo.ENTORNO CLINICO:Este estudio se realizó en un centro de referencia terciario.PARTICIPANTES:Todos los pacientes que se sometieron a una cirugía de revisión de la anastomosis ileoanal del reservorio entre 1982 y 2017, por falla del reservorio.INTERVENCIÓN:Revisión de la anastomosis de reservorio ileoanal transabdominal.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario es el fracaso del reservorio, definido como escisión del reservorio o derivación permanente del reservorio, después de la revisión de la anastomosis del reservorio ileoanal.RESULTADOS:Se incluyeron un total de 159 pacientes (64,2% mujeres) con una mediana de edad a la revisión de 36 años (RIC: 28,5-46,5). El ochenta por ciento tenía un diagnóstico primario de colitis ulcerosa. La indicación más común para la revisión fue la fuga/sepsis pélvica, que representó el 41 % de la cohorte, seguida de la fístula vaginal del reservorio (22,2 %), factores mecánicos (20,4 %) y mala función del reservorio 14,6 %. Durante el período de estudio, 56 pacientes (35,2 %) experimentaron fallas en la bolsa. Las probabilidades de supervivencia de la bolsa a los 3, 5 y 10 años fueron del 82,3% (IC del 95%: 75,5%-87,5%), del 77,2% (IC del 95%: 69,8%-83,0%) y del 70,6% (IC del 95%: 62,6%- 77,2%), respectivamente. En comparación con los factores mecánicos, la falla de la bolsa se asoció significativamente con sepsis pélvica (HR = 4,25, IC del 95 %: 1,50 a 12,0) y fístula vaginal de la bolsa (HR = 4,37, IC del 95 %: 1,47 a 12,99). No hubo una asociación significativa entre el fracaso de la revisión y la revisión previa, el rehacer la anastomosis ileoanal o la construcción de una nueva bolsa.LIMITACIONES:El estudio está limitado por su diseño retrospectivo.CONCLUSIONES:La revisión de la anastomosis del reservorio ileoanal se puede realizar con resultados favorables a largo plazo en centros de alto volumen. Se debe considerar la indicación de revisión al asesorar a los pacientes sobre el riesgo de fracaso. Se requiere investigación adicional sobre la estratificación del riesgo de los pacientes antes de la revisión. Consulte Video Resumen en http://links.lww.com/DCR/B966 . (Traducción - Dr. Fidel Ruiz Healy ).

Barriers and facilitators to CDH1 carriers contemplating or undergoing prophylactic total gastrectomy.

Hereditary diffuse gastric cancer (HDGC) is an inherited cancer syndrome associated with high lifetime risk of diffuse-type gastric cancer. Current guidelines recommend individuals with HDGC undergo prophylactic total gastrectomy (PTG) to eliminate this risk. However, PTG is associated with significant lifestyle changes, post-surgical recovery, and symptom burden. This study examined factors related to decision-making about PTG in three groups of individuals who: (1) underwent PTG immediately after receiving genetic testing results; (2) delayed PTG by ≥ 1 year or; (3) declined PTG. Participants were recruited from a familial gastric cancer registry at a tertiary care hospital. Patients with CDH1 pathogenic or likely pathogenic variants who contemplated and/or underwent PTG were eligible. 24 individuals contemplated PTG: 9 had immediate surgery (within a year), 8 delayed surgery, and 7 declined surgery. Data on PTG barriers and facilitators were obtained on all participants using quantitative surveys (n = 7), qualitative interviews (n = 8) or both methods (n = 9). PTG barriers included age, positive beliefs about screening, close relatives with negative PTG experiences, fertility-related concerns, and life stress. Facilitators included social support, trust in healthcare providers, understanding risk, negative beliefs about screening, family-related factors, positive or abnormal screening results, and positive attitude toward PTG. This study highlights factors related to the PTG decision-making process among individuals with HDGC from three distinct groups. Future research should explore educational interventions aimed at addressing surgery-related concerns and the limitations of screening, and might also consider incorporating close relatives as informational supports.

Short-term and Long-term Outcomes Following Pelvic Pouch Excision: The Mount Sinai Hospital Experience.

BACKGROUND: Few studies have reported surgical outcomes following pouch excision and fewer have described the long-term sequelae. Given the debate regarding optimal surgical management following pouch failure, an accurate estimation of the morbidity associated with this procedure addresses a critical knowledge gap. OBJECTIVE: The objective of this study was to review our institutional experience with pouch excision with a focus on indications, short-term outcomes, and long-term reintervention rates. DESIGN: This was a retrospective cohort study. SETTING: This study was conducted at Mount Sinai Hospital, Toronto, Ontario Canada. PARTICIPANTS: Adult patients registered in the prospectively maintained IBD database with a diagnosis of pelvic pouch failure between 1991 and 2018 were selected. INTERVENTION: The patients had undergone pelvic pouch excision was measured. MAIN OUTCOMES AND MEASURES: Indications for excision, incidence of short-term and long-term complications, and long-term surgical reintervention were the primary outcomes. In addition, multivariable logistic regression models were fitted to identify predictors of chronic perineal wound complications and the effect of preoperative diversion. The positive predictive value of a clinical suspicion of Crohn's disease of the pouch was also evaluated. RESULTS: One hundred forty cases were identified. Fifty-nine percent of patients experienced short-term complications and 49.3% experienced delayed morbidity. Overall, one-third of patients required long-term reoperation related to perineal wound, stoma, and hernia complications. On multivariable regression, immunosuppression was associated with increased odds of perineal wound complications, and preoperative diversion was not associated with perineal wound healing. Crohn's disease was suspected in 24 patients preoperatively but confirmed on histopathology in only 6 patients. LIMITATIONS: This is a retrospective chart review of a single institution's experience, whereby complication rates may be underestimates of the true event rates. CONCLUSIONS: Pouch excision is associated with high postoperative morbidity and long-term reintervention due to nonhealing perineal wounds, stoma complications, and hernias. Further study is required to clarify risk reduction strategies to limit perineal wound complications and the appropriate selection of patients for diversion alone vs pouch excision in IPAA failure. See Video Abstract at http://links.lww.com/DCR/B348. RESULTADOS A CORTO Y LARGO PLAZO DESPUÉS DE LA EXTIRPACIÓN DE LA BOLSA PéLVICA: LA EXPERIENCIA DEL HOSPITAL MOUNT SINAÍ: Pocos estudios han informado resultados quirúrgicos después de la escisión de bolsa pélvica (reservorio ileoanal) y menos han descrito las secuelas a largo plazo. Dado el debate sobre el manejo quirúrgico óptimo después de la falla de la bolsa, una estimación precisa de la morbilidad asociada con este procedimiento aborda una brecha crítica de conocimiento.El objetivo de este estudio fue revisar nuestra experiencia institucional con la extirpación de la bolsa con un enfoque en las indicaciones, los resultados a corto plazo y las tasas de reintervención a largo plazo.Estudio de cohorte retrospectivo.Hospital Mt Sinaí, Toronto, Ontario, Canadá.Pacientes adultos registrados en la base de datos de EII mantenida prospectivamente con un diagnóstico de falla de la bolsa pélvica entre 1991 y 2018.Escisión de bolsa pélvica.Las indicaciones para la escisión, la incidencia de complicaciones a corto y largo plazo y la reintervención quirúrgica a largo plazo fueron los resultados primarios valorados. Además, se ajustaron modelos de regresión logística multivariable para identificar predictores de complicaciones de la herida perineal crónica y el efecto de la derivación preoperatoria. También se evaluó el valor predictivo positivo de una sospecha clínica de enfermedad de Crohn de la bolsa.Se identificaron 140 casos. El 59% de los pacientes desarrollaron complicaciones a corto plazo y el 49,3% con morbilidad tardía. En general, 1/3 de los pacientes requirieron una reoperación a largo plazo relacionada con complicaciones de herida perineal, estoma y hernia. En la regresión multivariable, la inmunosupresión se asoció con mayores probabilidades de complicaciones de la herida perineal y la derivación preoperatoria no se asoció con la cicatrización de la herida perineal. La enfermedad de Crohn se sospechó en 24 pacientes antes de la operación, pero se confirmó por histopatología en solo 6 pacientes.Revisión retrospectiva del cuadro de la experiencia de una sola institución por la cual las tasas de complicaciones pueden ser subestimadas de las tasas de eventos reales.La escisión de la bolsa se asocia con una alta morbilidad postoperatoria y una reintervención a largo plazo debido a complicaciones de heridas perineales, complicaciones del estoma y hernias. Se requieren más estudios para aclarar las estrategias de reducción de riesgos para limitar las complicaciones de la herida perineal y la selección adecuada de pacientes para la derivación sola versus la escisión de la bolsa en caso de falla de reservorio ileoanal. Consulte Video Resumen en http://links.lww.com/DCR/B348.

Patient-physician relationships, health self-efficacy, and gynecologic cancer screening among women with Lynch syndrome.

BACKGROUND: Lynch syndrome, a hereditary cancer syndrome, predisposes women to colorectal, endometrial, and ovarian cancer. Current guidelines recommend that women with Lynch syndrome undergo risk-reducing gynecological surgery to reduce their chances of developing endometrial or ovarian cancer. Little is known about how women with Lynch syndrome perceive gynecological cancer screening, or the psychosocial factors associated with screening attitudes and behaviour. METHODS: This study used a cross-sectional, quantitative design. Using self-report questionnaire data from a sample of women with Lynch syndrome (N = 50) who had not undergone risk-reducing surgery, the current study sought to: 1) describe the gynecological cancer screening behaviours of women with Lynch syndrome, as well participant-reported sources of information about Lynch syndrome; 2) examine the extent to which women believe gynecological cancer screening is effective and provides them with reassurance and; 3) assess to what extent relationships with one's family physician were associated with gynecological cancer screening, perceptions about screening, and health self-efficacy. Data were analyzed using descriptive statistics and Spearman rank-ordered correlations. RESULTS: Data analyses showed that transvaginal ultrasound was the most common screening behaviour (57%) followed by pelvic ultrasound (47%). Only 22% of participants underwent endometrial biopsy. Patient-physician relationships were related to greater health self-efficacy to manage Lynch syndrome and greater perceived effectiveness of gynecological screening. However, health self-efficacy and better patient-physician relationships were not associated with increased engagement in gynecological cancer screening. CONCLUSIONS: The data suggest that feeling efficacious about managing one's Lynch syndrome and screening is related to positive interactions and communication with one's family physician. While this is encouraging, future research should examine educating both family physicians and patients about current guidelines for Lynch syndrome gynecological screening recommendations.

Mucosa-Associated Microbiota in Ileoanal Pouches May Contribute to Clinical Symptoms, Particularly Stool Frequency, Independent of Endoscopic Disease Activity.

INTRODUCTION: Pouchitis is a common complication after ileal pouch-anal anastomosis (IPAA). However, there is a poor correlation between symptoms and endoscopic appearance of the pouch, and many patients can have debilitating symptoms in the absence of overt inflammation. It is unknown whether these clinical symptoms are independently associated with the microbiota. The objective of this work was to examine whether the individual clinical components of the pouch activity scoring systems are associated with specific microbiota. METHODS: Pouch biopsies from 233 patients (50% male, 100% IPAA/ulcerative colitis) post-IPAA were included. Clinical phenotyping was performed, and patients were classified using both clinical and endoscopic components of the Pouch Activity Scale. Scoring for symptoms examined 24-hour stool frequency, urgency, incontinence, and rectal bleeding as described by the Pouchitis Disease Activity Index Score. RESULTS: In the absence of inflammation, an increase in stool frequency reported over 24 hours was associated with a decrease in Bacteroidetes relative abundance, and this was the strongest association found. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis in inflamed groups showed that an increase in 24-hour stool frequency was associated with an increase in biofilm formation. DISCUSSION: These findings indicate that in patients with IPAA, the composition of mucosa-associated microbiota of the pouch may contribute to clinical symptoms, particularly stool frequency, independent of endoscopic disease activity.

Preoperative exposure to anti-tumor necrosis factor therapy in ulcerative colitis patients undergoing ileal pouch-anal anastomosis (IPAA) is not associated with histological fibrosis: A case control study.

BACKGROUND: We sought to determine whether preoperative exposure to anti-TNF therapy affects objective histological measures of fibrosis in the colorectum. METHODS: Ulcerative colitis (UC) patients who received infliximab as maintenance therapy pre IPAA surgery were identified and compared to anti-TNF-naïve matched controls by age, sex, BMI, disease duration, albumin levels, and post-operative leak outcome. Hematoxylin and eosin- (H&E) and trichrome-stained slides from the most distal, well-oriented, full-thickness section of colorectum from each patient's total colectomy specimen were evaluated. Blinded histopathological assessment of the degree of fibrosis was performed using a semi-quantitative pictorial scale. RESULTS: Histological fibrosis in 65 patients from the therapy group was compared to 65 patients from the matched control group. There were no statistically significant differences in the degree of fibrosis observed in any of the bowel layers. In the lamina propria, 29% of the control group and 28% of the treatment group had fibrosis scores ≥3. Fibrosis scores were higher in the submucosa, with both groups having 66% of patients showing scores ≥3. Similarly, in the region above the muscularis propria, 77% of the control group and 80% of the treatment group had fibrosis scores ≥3. In the subserosa, fibrosis scores were lower, with 25% of the control group and 32% of the treatment group having fibrosis scores ≥3. CONCLUSION: Resection specimens from UC patients treated with maintenance anti-TNF therapy who underwent IPAA surgery showed no significant differences in the degree of histologic fibrosis in any of the bowel layers compared to a matched control group.

The impact of health anxiety on perceptions of personal and children's health in parents with Lynch syndrome.

This study examined the differences in perceptions of one's health and one's child's health between parents with Lynch syndrome (LS) characterized with high versus low health anxiety. Twenty-one parents completed semistructured telephone interviews about their perceptions of their own health and the health of their children. Qualitative content analysis using a template coding approach examined the differences between parents with high and low health anxiety. Findings revealed that the most prevalent difference emerged on perceptions of personal health, showing individuals with high health anxiety reported more extreme worries, were more hypervigilant about physical symptoms, experienced the emotional and psychological consequences of LS as more negative and severe, and engaged in more dysfunctional coping strategies than those with low health anxiety. Unexpectedly, with regards to perceptions of their children, parents in the high and low health anxiety groups exhibited similar worries. However, high health anxiety parents reported using dysfunctional coping about their children's health more frequently than those with low health anxiety. The findings suggest that health anxiety is of clinical significance for individuals with LS. Accurately identifying and treating health anxiety among this population may be one avenue to reduce the distress experienced by LS carriers.

Symptom Severity and Quality of Life Among Long-term Colorectal Cancer Survivors Compared With Matched Control Subjects: A Population-Based Study.

BACKGROUND: Data are lacking regarding physical functioning, psychological well-being, and quality of life among colorectal cancer survivors >10 years postdiagnosis. OBJECTIVE: The purpose of this study was to examine self-reported physical functioning, quality of life, and psychological well-being in long-term colorectal cancer survivors compared with age- and sex-matched unaffected control subjects. DESIGN: Participants completed a cross-sectional survey. SETTINGS: The colorectal cancer survivors and unaffected control subjects were recruited from the Ontario Familial Colorectal Cancer Registry. PATIENTS: A population-based sample of colorectal cancer survivors (N = 296) and their age- and sex-matched unaffected control subjects (N = 255) were included. Survivors were, on average, 15 years postdiagnosis. MAIN OUTCOME MEASURES: Quality of life was measured with the Functional Assessment of Cancer Therapy-General scale, bowel dysfunction with the Memorial Sloan-Kettering Cancer Center scale, urinary dysfunction with the International Consultation on Incontinence Questionnaire-Short Form, fatigue with the Functional Assessment of Chronic Illness Therapy-Fatigue scale, and depression with the Center for Epidemiologic Studies-Depression scale. RESULTS: In linear mixed-model analyses adjusting for income, education, race, and comorbid medical conditions, survivors reported good emotional, functional, physical, and overall quality of life, comparable to control subjects. Fatigue and urinary functioning did not differ significantly between survivors and control subjects. Survivors reported significantly higher social quality of life and lower depression compared with unaffected control subjects. The only area where survivors reported significantly worse deficits was in bowel dysfunction, but the magnitude of differences was relatively small. LIMITATIONS: Generalizability is limited by moderately low participation rates. Findings are likely biased toward healthy participants. No baseline assessment was available to examine change in outcomes over time. CONCLUSIONS: Long-term colorectal cancer survivors appear to have comparable quality of life and, in some areas, better well-being than their unaffected peers. Bowel dysfunction may continue to be an ongoing issue even 15 years after colorectal cancer diagnosis. Overall quality of life can be expected to be good in this group of older survivors. See Video Abstract at http://links.lww.com/DCR/A476.

Rates and Predictors of Endoscopic and Clinical Recurrence After Primary Ileocolic Resection for Crohn's Disease.

BACKGROUND AND AIMS: The utility of postoperative medical prophylaxis (POMP) and the treatment of mild endoscopic recurrence remain controversial. METHODS: This study is a retrospective review of patients undergoing a primary ileocolic resection for CD at a single academic center. Endoscopic recurrence (ER) was defined using the Rutgeerts score (RS), and clinical recurrence (CR) was defined as symptoms of CD with endoscopic or radiologic evidence of neo-terminal ileal disease. RESULTS: There were 171 patients who met inclusion criteria. The cumulative probability of ER (RS ≥ i-1) at 1, 2, and 5 years was 29, 51, and 77 %, respectively. The only independent predictors of ER were the absence of POMP (HR 1.50; P = 0.03) and penetrating disease behavior (HR 1.50; P = 0.05). The cumulative probability of CR at 1, 2, and 5 years was 8, 13, and 27 %, respectively. There was a higher rate of clinical recurrence in patients with RS-2 compared to RS-1 on the initial postoperative endoscopy (HR 2.50; P = 0.02). In 11 patients not exposed to POMP with i-1 on initial endoscopy, only 2 patients (18 %) progressed endoscopically during the study period while 5 patients (45 %) regressed to i-0 on subsequent endoscopy without treatment. CONCLUSIONS: Postoperative medical prophylaxis decreased the likelihood of ER while certain phenotypes of CD appear to increase the risk of developing ER and CR. There may be a role for watchful waiting in patients with mild endoscopic recurrence on the initial postoperative endoscopy.

Preoperative Anti-tumor Necrosis Factor Therapy in Patients with Ulcerative Colitis Is Not Associated with an Increased Risk of Infectious and Noninfectious Complications After Ileal Pouch-anal Anastomosis.

BACKGROUND: There are conflicting data regarding the effect of previous exposure to anti-tumor necrosis factor (anti-TNF) therapy on complication rates after pelvic pouch surgery for patients with ulcerative colitis (UC). In particular, there is concern surrounding the rates of pouch leaks and infectious complications, including pelvic abscesses, in anti-TNF-treated subjects who require ileal pouch-anal anastomosis (IPAA) surgery. METHODS: A retrospective study was performed in UC subjects who underwent IPAA between 2002 and 2013. Demographic data, clinical data, use of anti-TNF therapy, steroids, immunosuppressants, and surgical outcomes were assessed. RESULTS: Seven hundred seventy-three patients with UC/IPAA were reviewed. Fifteen patients were excluded from the analysis because of missing data. There were 196 patients who were exposed to anti-TNF therapy and 562 patients who were not exposed to anti-TNF therapy preoperatively. There were no significant differences in the postoperative IPAA leak rate between those exposed to anti-TNF therapy and the control group (n = 26 [13.2%] versus 66 [11.7%], respectively, P = 0.44). In addition, there were no significant differences in the postoperative 2-stage IPAA leak rate in those who had been operated on within 15 days from the last anti-TNF dose (n = 10), within 15 to 30 days (n = 17), or 31 to 180 days (n = 54) (10%, 5.9%, and 14.8% respectively, P = 0.43) nor were there differences based on the presence of detectable infliximab serum levels. CONCLUSIONS: Preoperative anti-TNF therapy in patients with UC is not associated with an increased risk of infectious and noninfectious complications after IPAA including pelvic abscesses, leaks, and wound infections.

Modified Two-stage Ileal Pouch-Anal Anastomosis Results in Lower Rate of Anastomotic Leak Compared with Traditional Two-stage Surgery for Ulcerative Colitis.

BACKGROUND AND AIMS: There is a paucity of evidence in ulcerative colitis [UC] comparing the traditional two-stage [total proctocolectomy with ileal pouch-anal anastomosis [IPAA] and diverting ileostomy, followed by ileostomy closure] vs the modified two-stage restorative proctocolectomy [subtotal colectomy with end ileostomy, followed by completion proctectomy and IPAA, without diverting ileostomy]. This study examines the risk of anastomotic leak following IPAA in traditional vs modified two-stage IPAA for UC patients. METHODS: This was a single-institution, retrospective study of all UC patients who underwent a traditional or modified two-stage IPAA between 2002 and 2013. The primary outcome was anastomotic leak following IPAA. RESULTS: In all, 460 patients had a two-stage IPAA procedure; 223 [48.5%] patients underwent traditional two-stage IPAA and 237 [51.5%] patients received the modified two-stage procedure. There was more preoperative enteral corticosteroid use [44.7% vs 33.2%, p = 0.04] before the first surgery in the modified two-stage group compared with the traditional two-stage group. The modified two-stage group had higher UC disease severity at presentation [86.9% patients with moderate/severe UC vs 73.1%, p < 0.01]. However, the modified two-stage group had a lower rate of anastomotic leak following IPAA [4.6% vs 15.7%, p < 0.01] and was associated with a lower risk of anastomotic leak on univariate (odds ratio [OR] 0.26, 95% confidence interval [CI] 0.13, 0.52] and multivariate analysis [OR 0.27, 95% CI 0.12, 0.57]. CONCLUSIONS: Patients with ulcerative colitis who received the modified two-stage IPAA had a significantly lower rate of anastomotic leak following pouch creation, compared with the traditional two-stage procedure.

Genetic testing for Lynch syndrome in the province of Ontario.

BACKGROUND: In November 2001, genetic testing for Lynch syndrome (LS) was introduced by the Ministry of Health and Long-Term Care (MOH) in Ontario for individuals at high risk for LS cancers according to either tumor immunohistochemistry staining or their family history. This article describes the outcomes of the program and makes recommendations for improving it and informing other public health care programs. METHODS: Subjects were referred for molecular testing of the mismatch repair (MMR) genes MutL homolog 1, MutS homolog 2, and MutS homolog 6 if they met 1 of 7 MOH criteria. Testing was conducted from January 2001 to March 2015 at the Molecular Diagnostic Laboratory of Mount Sinai Hospital in Toronto. RESULTS: A total of 1452 subjects were tested. Of the 662 subjects referred for testing because their tumor was immunodeficient for 1 or more of the MMR genes, 251 (37.9%) carried a germline mutation. In addition, 597 subjects were tested for a known family mutation, and 298 (49.9%) were positive; 189 of these 298 subjects (63.4%) were affected with cancer at the time of testing. An additional 193 subjects were referred because of a family history of LS, and 34 of these (17.6%) had a mutation identified. CONCLUSIONS: These results indicate that the provincial criteria are useful in identifying LS carriers after an MMR-deficient tumor is identified. Placing greater emphasis on testing unaffected relatives in families with a known mutation may identify more unaffected carriers and facilitate primary prevention in those individuals. Cancer 2016;122:1672-9. © 2016 American Cancer Society.

Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency.

PURPOSE: Recurrent glioblastoma multiforme (GBM) is incurable with current therapies. Biallelic mismatch repair deficiency (bMMRD) is a highly penetrant childhood cancer syndrome often resulting in GBM characterized by a high mutational burden. Evidence suggests that high mutation and neoantigen loads are associated with response to immune checkpoint inhibition. PATIENTS AND METHODS: We performed exome sequencing and neoantigen prediction on 37 bMMRD cancers and compared them with childhood and adult brain neoplasms. Neoantigen prediction bMMRD GBM was compared with responsive adult cancers from multiple tissues. Two siblings with recurrent multifocal bMMRD GBM were treated with the immune checkpoint inhibitor nivolumab. RESULTS: All malignant tumors (n = 32) were hypermutant. Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations (mean, 17,740 ± standard deviation, 7,703), all other high-grade tumors were hypermutant (mean, 1,589 ± standard deviation, 1,043), similar to other cancers that responded favorably to immune checkpoint inhibitors. bMMRD GBM had a significantly higher mutational load than sporadic pediatric and adult gliomas and all other brain tumors (P < .001). bMMRD GBM harbored mean neoantigen loads seven to 16 times higher than those in immunoresponsive melanomas, lung cancers, or microsatellite-unstable GI cancers (P < .001). On the basis of these preclinical data, we treated two bMMRD siblings with recurrent multifocal GBM with the anti-programmed death-1 inhibitor nivolumab, which resulted in clinically significant responses and a profound radiologic response. CONCLUSION: This report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and other hypermutant cancers arising from primary (genetic predisposition) or secondary MMRD.

Infliximab to Treat Refractory Inflammation After Pelvic Pouch Surgery for Ulcerative Colitis.

BACKGROUND: Inflammatory pouch complications refractory to first-line therapies remain problematic following ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC). We evaluated infliximab efficacy and associations with therapeutic response. METHODS: Data from individuals who underwent colectomy and IPAA for UC (2000-2014) were reviewed. Patients with chronic refractory pouchitis (CP) and Crohn's disease (CD)-like outcomes treated with infliximab were included. Pre-treatment parameters and response at median 8 (initial) and 48 weeks (sustained) were measured. Complete response was defined as symptomatic and endoscopic resolution with modified Pouchitis Disease Activity Index (mPDAI) <5. Partial response included mPDAI improvement >2. Serum was analysed for Anti-Saccharomyces cerevisiae antibodies (ASCA), anti-OmpC, anti-CBir1 and perinuclear Anti-Neutrophil Cytoplasmic Antibodies (pANCA). RESULTS: One hundred and fifty-two patients with CP or a CD-like phenotype were identified. Forty-two were treated with infliximab (33% male; age 32.6±2.6 years, 28.5% CD-like). Post-induction response was achieved in 74% (48% complete) and sustained response in 62.6% (29.6% complete). Mean mPDAI and C-reactive protein declined from 8.5±0.3 to 2±3.4 (p < 0.002) and from 29.48±6.2 to 5.76±1.6mg/L (p < 0.001), respectively. Female gender, smoking and presence of anti-CBir1 were associated with infliximab use (p < 0.01) but not response. Pre-treatment mPDAI <10 (p < 0.01), resolution of rectal bleeding (p < 0.001 ) and week 8 endoscopic activity were associated with sustained response (p = 0.04; odds ratio [OR] 2.2; 95% confidence interval [CI] 1.1-16.5]). More than 2 positive antimicrobial antibody titres were associated with non-response (p < 0.05), but did not retain significance in multivariate analysis (p = 0.197; OR 0.632; 95% CI 0.31-1.2). CONCLUSIONS: Infliximab can effectively treat inflammatory pouch complications. Pre-treatment mPDAI <10 and early endoscopy may identify responders.

Gastrointestinal Findings in the Largest Series of Patients With Hereditary Biallelic Mismatch Repair Deficiency Syndrome: Report from the International Consortium.

OBJECTIVES: Hereditary biallelic mismatch repair deficiency (BMMRD) is caused by biallelic mutations in the mismatch repair (MMR) genes and manifests features of neurofibromatosis type 1, gastrointestinal (GI) polyposis, and GI, brain, and hematological cancers. This is the first study to characterize the GI phenotype in BMMRD using both retrospective and prospective surveillance data. METHODS: The International BMMRD Consortium was created to collect information on BMMRD families referred from around the world. All patients had germline biallelic MMR mutations or lack of MMR protein staining in normal and tumor tissue. GI screening data were obtained through medical records with annual updates. RESULTS: Thirty-five individuals from seven countries were identified with BMMRD. GI data were available on 24 of 33 individuals (73%) of screening age, totaling 53 person-years. The youngest age of colonic adenomas was 7, and small bowel adenoma was 11. Eight patients had 19 colorectal adenocarcinomas (CRC; median age 16.7 years, range 8-25), and 11 of 18 (61%) CRC were distal to the splenic flexure. Eleven patients had 15 colorectal surgeries (median 14 years, range 9-25). Four patients had five small bowel adenocarcinomas (SBC; median 18 years, range 11-33). Two CRC and two SBC were detected during surveillance within 6-11 months and 9-16 months, respectively, of last consecutive endoscopy. No patient undergoing surveillance died of a GI malignancy. Familial clustering of GI cancer was observed. CONCLUSIONS: The prevalence and penetrance of GI neoplasia in children with BMMRD is high, with rapid development of carcinoma. Colorectal and small bowel surveillance should commence at ages 3-5 and 8 years, respectively.

Physician trust moderates the relationship between intolerance of uncertainty and cancer worry interference among women with Lynch syndrome.

This study investigated the extent to which intolerance of uncertainty was associated with cancer worry interference, anxiety and depression among women with Lynch syndrome (LS), and whether having greater trust in one's physician moderated those relationships. Women with confirmed LS (N = 128) were recruited from a high-risk of cancer registry and completed a one-time self-report questionnaire. Women who reported greater intolerance of uncertainty and more trust in their physician reported less cancer worry interference compared to women who had greater intolerance of uncertainty and less trust in their physician, who reported the highest worry interference, b = -1.39, t(99) = -2.27, p = .03. No moderation effect of trust in physician was found for anxiety or depression. Trust in one's physician buffered the impact of high intolerance of uncertainty on cancer worry interference, underscoring the need for supportive provider-patient relationships, particularly for LS patients.