Publications by authors named "Zane Cohen"

63 Publications

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

Dis Colon Rectum 2020 12;63(12):1621-1627

Department of Surgery, University of Toronto, Toronto, Ontario, Canada.

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 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
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December 2020

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

Fam Cancer 2021 Apr 5;20(2):157-169. Epub 2020 Aug 5.

Zane Cohen Centre for Digestive Diseases, Sinai Health System, Box 24-60, Murray Street, Toronto, ON, M5T 3L9, Canada.

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.
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April 2021

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

Hered Cancer Clin Pract 2019 13;17:24. Epub 2019 Aug 13.

1Ryerson University, 350 Victoria Street, Toronto, ON M5B 2K3 Canada.

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 ( = 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.
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August 2019

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

Clin Transl Gastroenterol 2019 05;10(5):1-7

Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.

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.
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May 2019

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.

Int J Surg 2019 May 26;65:80-85. Epub 2019 Mar 26.

Mount Sinai Hospital, Zane Cohen Centre for Digestive Diseases, Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada. Electronic address:

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.
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May 2019

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

J Genet Couns 2019 06 14;28(3):495-506. Epub 2019 Jan 14.

Department of Psychology, Ryerson University, Toronto, ON, Canada.

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.
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June 2019

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

Dis Colon Rectum 2018 Mar;61(3):355-363

Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, University of Toronto, Toronto, Ontario, Canada.

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
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March 2018

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

Dig Dis Sci 2017 01 24;62(1):188-196. Epub 2016 Oct 24.

University of Toronto, Toronto, Canada.

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.
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January 2017

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.

Inflamm Bowel Dis 2016 10;22(10):2442-7

*Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; †Institute of Gastroenterology and Liver Diseases, Emek Medical Center, Afula, Israel; ‡Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; §Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Division of General Surgery, University of Toronto, Toronto, Ontario, Canada; and ‖Mount Sinai Hospital, Division of General Surgery, University of Toronto, Toronto, Ontario, Canada.

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.
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October 2016

Genetic testing for Lynch syndrome in the province of Ontario.

Cancer 2016 06 28;122(11):1672-9. Epub 2016 Mar 28.

Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada.

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.
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June 2016

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

J Clin Oncol 2016 07 21;34(19):2206-11. Epub 2016 Mar 21.

Eric Bouffet, Brittany B. Campbell, Daniele Merico, Richard de Borja, Carol Durno, Joerg Krueger, Vanja Cabric, Vijay Ramaswamy, Nataliya Zhukova, Peter Dirks, Michael Taylor, David Malkin, Cynthia E. Hawkins, Adam Shlien, and Uri Tabori, The Hospital for Sick Children, Toronto; Melyssa Aronson, and Zane Cohen, Zane Cohen Centre for Digestive Diseases, Mount Sinai, Ontario; Valérie Larouche and Rachel Laframboise, Université Laval, Quebec City; Jeffrey Atkinson, Montreal Children's Hospital; Steffen Albrecht, Roy W.R. Dudley, and Nada Jabado, McGill University, Montreal, Montreal, Quebec; Samina Afzal, IWK Health Centre, Halifax, Nova Scotia; Vanan Magimairajan, Cancer Care Manitoba and University of Manitoba, Winnipeg, Manitoba, Canada; Gary Mason, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA; Roula Farah, Saint George Hospital University Medical Center, Beirut, Lebanon; Michal Yalon and Gideon Rechavi, Sheba Medical Center, Tel Hashomer; Shlomi Constantini, Rina Dvir, and Ronit Elhasid, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Michael F. Walsh, Memorial Sloan Kettering Center, New York, NY; Alyssa Reddy, University of Alabama at Birmingham, Birmingham, AL; Michael Osborn, Women's and Children's Hospital, North Adelaide, South Australia; Michael Sullivan, Jordan Hansford, and Andrew Dodgshun, Royal Children's Hospital, Melbourne, Victoria, Australia; and Nancy Klauber-Demore, Lindsay Peterson, Sunil Patel, and Scott Lindhorst, Medical University of South Carolina, Charleston, SC.

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.
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July 2016

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

J Crohns Colitis 2016 Jul 7;10(7):766-72. Epub 2016 Mar 7.

Zane Cohen Centre for Digestive Disease, Mount Sinai Hospital, Toronto, ON, Canada, Division of General Surgery, University of Toronto, Toronto, ON, Canada.

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.
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July 2016

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

J Behav Med 2016 06 13;39(3):420-8. Epub 2016 Jan 13.

Department of Psychology, Ryerson University, 350 Victoria Street, Toronto, ON, M5B2K3, Canada.

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.
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June 2016

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

Am J Gastroenterol 2016 Feb 5;111(2):275-84. Epub 2016 Jan 5.

King Fahad Medical City, Riyadh, Saudi Arabia.

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.
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February 2016

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

J Crohns Colitis 2016 Apr 30;10(4):410-7. Epub 2015 Dec 30.

Division of Gastroenterology, University of Toronto, Mount Sinai Hospital, Toronto, Canada.

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.
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April 2016

Is there a role for prophylactic colectomy in Lynch syndrome patients with inflammatory bowel disease?

Int J Colorectal Dis 2016 Jan 28;31(1):9-13. Epub 2015 Sep 28.

Lunenfeld-Tanenbaum Research Institute, 60 Murray Street Box 31 Rm L6-304G, Toronto, ON, M5T3L9, Canada.

Purpose: Lynch syndrome and chronic inflammatory bowel disease are two important risk factors for colorectal cancer. It is unclear whether Lynch syndrome patients with inflammatory bowel disease are at sufficiently increased risk for colorectal cancer to warrant prophylactic colectomy. This study aims to identify all cases of Lynch syndrome and concurrent inflammatory bowel disease in a large familial gastrointestinal cancer registry, define incidence of colorectal cancer, and characterize mismatch repair protein gene mutation status and inflammatory bowel disease-associated colorectal cancer risk factors.

Methods: We retrospectively identified and collected clinical data for all cases with confirmed diagnoses of Lynch syndrome and inflammatory bowel disease in the Familial Gastrointestinal Cancer Registry at Mount Sinai Hospital in Toronto, Canada.

Results: Twelve cases of confirmed Lynch syndrome, and concurrent inflammatory bowel disease were identified. Four cases developed colorectal cancer. An additional five cases had colectomy; one was performed for severe colitis, and four were performed for low-grade dysplasia. None of these surgical specimens contained malignancy or high-grade dysplasia.

Conclusions: The presentation of Lynch syndrome with inflammatory bowel disease is uncommon and not well described in the literature. This small but important series of twelve cases is the largest reported to date. In this series, patients with Lynch syndrome and concurrent inflammatory bowel disease do not appear to have sufficiently increased risk for colorectal cancer to recommend prophylactic surgery. Therefore, the decision to surgery should continue to be guided by surgical indications for each disease. Further evaluation of this important area will require multi-institutional input.
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January 2016

DNA Mismatch Repair Status Predicts Need for Future Colorectal Surgery for Metachronous Neoplasms in Young Individuals Undergoing Colorectal Cancer Resection.

Dis Colon Rectum 2015 Jul;58(7):645-52

The Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.

Background: The treatment of colorectal cancer in young patients involves both management of the incident cancer and consideration of the possibility of Lynch syndrome and the development of metachronous colorectal cancers.

Objective: This study aims to assess the prognostic role of DNA mismatch repair deficiency and extended colorectal resection for metachronous colorectal neoplasia risk in young patients with colorectal cancer.

Design, Setting, And Patients: This is a retrospective review of 285 patients identified in our GI cancer registry with colorectal cancer diagnosed at 35 years or younger in the absence of polyposis.

Main Outcome Measures: Using univariate and multivariate analysis, we assessed the prognostic role of mismatch repair deficiency and standard clinicopathologic characteristics, including the extent of resection, on the rate of developing metachronous colorectal neoplasia requiring resection.

Results: Mismatch repair deficiency was identified in biospecimens from 44% of patients and was significantly associated with an increased risk for metachronous colorectal neoplasia requiring resection (10-year cumulative risk, 13.5% ± 4.2%) compared with 56% of patients with mismatch repair-intact colorectal cancer (10-year cumulative risk, 5.8% ± 3.3%; p = 0.011). In multivariate analysis, mismatch repair deficiency was associated with a HR of 3.65 (95% CI, 1.44-9.21; p = 0.006) for metachronous colorectal neoplasia, whereas extended resection with ileorectal or ileosigmoid anastomosis significantly decreased the risk of metachronous colorectal neoplasia (HR, 0.21; 95% CI, 0.05-0.90; p = 0.036).

Limitations: This study had a retrospective design, and, therefore, recommendations for colorectal cancer surgery and screening were not fully standardized. Quality of life after colorectal cancer surgery was not assessed.

Conclusions: Young patients with colorectal cancer with molecular hallmarks of Lynch syndrome were at significantly higher risk for the development of subsequent colorectal neoplasia. This risk was significantly reduced in those who underwent extended resection compared with segmental resection.
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July 2015

Predictors of Outcome in Ulcerative Colitis.

Inflamm Bowel Dis 2015 Sep;21(9):2097-105

*Zane Cohen Centre for Digestive Diseases, Division of Gastroenterology, Mount Sinai Hospital, Toronto, ON, Canada; †Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel; ‡Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Neuroscience Research, Toronto, ON, Canada; §University of Toronto, Toronto, ON, Canada; ||Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada; and ¶Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada.

Background: Approximately 80% of patients with ulcerative colitis (UC) have intermittently active disease and up to 20% will require a colectomy, but little data available on predictors of poor disease course. The aim of this study was to identify clinical and genetic markers that can predict prognosis.

Methods: Medical records of patients with UC with ≥5 years of follow-up and available DNA and serum were retrospectively assessed. Immunochip was used to genotype loci associated with immune mediated inflammatory disorders (IMIDs), inflammatory bowel diseases, and other single nucleotide polypmorphisms previously associated with disease severity. Serum levels of pANCA, ASCA, CBir1, and OmpC were also evaluated. Requirement for colectomy, medication, and hospitalization were used to group patients into 3 prognostic groups.

Results: Six hundred one patients with UC were classified as mild (n = 78), moderate (n = 273), or severe disease (n = 250). Proximal disease location frequencies at diagnosis were 13%, 21%, and 30% for mild, moderate, and severe UC, respectively (P = 0.001). Disease severity was associated with greater proximal extension rates on follow-up (P < 0.0001) and with shorter time to extension (P = 0.03) and to prednisone initiation (P = 0.0004). When comparing severe UC with mild and moderate UC together, diagnosis age >40 and proximal disease location were associated with severe UC (odds ratios = 1.94 and 2.12, respectively). None of the single nucleotide polypmorphisms or serum markers tested was associated with severe UC, proximal disease extension or colectomy.

Conclusions: Older age and proximal disease location at diagnosis, but not genetic and serum markers, were associated with a more severe course. Further work is required to identify biomarkers that will predict outcomes in UC.
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September 2015

Severity of inflammation as a risk factor for ileo-anal anastomotic leak after a pouch procedure in ulcerative colitis.

Int J Colorectal Dis 2015 Oct 25;30(10):1375-80. Epub 2015 Jun 25.

Department of Pathology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.

Purpose: The pelvic pouch procedure (PPP) carries significant post-operative complication risks including a 4-14 % risk of ileo-anal anastomotic (IAA) leak [1-4]. The aim of this study is to evaluate the severity of disease at the distal resection margin as an independent risk factor for an IAA leak following the PPP for patients with ulcerative colitis (UC).

Methods: A retrospective matched case-control study was undertaken. The distal margin of each subject's specimen was reviewed by a blinded pathologist and the degree of inflammation was scored using a modified histological activity index (mHAI)--a 0 to 5 graded scale with HAI of 5 representing ulcerations >25 % the depth of bowel wall.

Results: Forty-nine patients with perioperative IAA leaks (mean 11 days ±0.92) were identified and matched for gender, age and year of surgery. The case cohort had 33 males (67 %) of mean age at time of surgery of 36.3 years (±1.42). The severity of distal inflammation did not increase the risk of IAA leak. The presence of a diverting ileostomy was associated with a decreased incidence of an IAA leak (p = 0.01).

Conclusion: Studies with greater power will be required to evaluate the association (if any) between histological severity of UC at the distal margin of a PPP procedure and IAA leak rate. This risk factor could influence preoperative management and post-operative outcome in patients requiring the PPP.
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October 2015

Proctocolectomy for colorectal cancer--is the ileal pouch anal anastomosis a safe alternative to permanent ileostomy?

Int J Colorectal Dis 2014 Dec 17;29(12):1485-91. Epub 2014 Oct 17.

Department of Surgery, University of Toronto, Toronto, ON, Canada.

Purpose: Ileal pouch anal anastomosis (IPAA) is the procedure of choice in patients requiring surgery for ulcerative colitis (UC) and familial adenomatous polyposis (FAP). There are few data on reconstruction with the IPAA in patients with colorectal cancer (CRC). This study assessed the outcomes of the IPAA compared to proctocolectomy and permanent ileostomy (PI) on these patients.

Methods: Between 1983 and 2013, over 2800 patients with CRC have been treated at the Mount Sinai Hospital (MSH). Demographic, surgical, pathological, and outcome data for all patients have been maintained in a database-73 patients were treated for CRC with proctocolectomy: 39 patients with IPAA and 34 patients with PI. Clinical features, pathologic findings, and survival outcomes were compared between these groups.

Results: Each group was similar with respect to gender, stage, and histologic grade. Patients undergoing IPAA were significantly younger. The diagnosis leading to proctocolectomy was more commonly UC or FAP in patients treated with IPAA (39/39 vs. 23/34, p = 0.001). Rectal cancer subgroups were similar in age, sex, TNM stage, T-stage, height of tumor, and histologic grade. There was no significant difference in overall or disease free survival between groups for colon or rectal primaries. Analysis using the Cochran-Armitage trend test suggests that utilization of IPAA has increased over time (p = 0.002).

Conclusions: The IPAA is a viable and safe option to select for patients who would otherwise require PI. Increased experience and improved outcomes following IPAA has led to its more liberal use in selected patients.
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December 2014

Progression and Management of Duodenal Neoplasia in Familial Adenomatous Polyposis: A Cohort Study.

Ann Surg 2015 Jun;261(6):1138-44

*Department of Surgery, McMaster University, Hamilton, Ontario, Canada †Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada ‡Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital, Toronto, Ontario, Canada §Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada ¶Department of Pathology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada; and ‖Division of Gastroenterology, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

Objective: To describe the natural history and outcomes of surveillance of duodenal neoplasia in familial adenomatous polyposis (FAP).

Background: Duodenal cancer is the most common cause of death in FAP.

Methods: Cohort study of patients prospectively enrolled in an upper endoscopic surveillance protocol from 1982 to 2012. The duodenum was assessed by side-viewing endoscopy and classified as stage 1 to 5 disease. Endoscopic and/or operative interventions were performed according to stage.

Results: There were 218 patients in the protocol (98 with advanced stage). They had a median of 9 endoscopies (range: 2-25) over a median of 11 years (range: 1-26). Median age at diagnosis of stage 3 disease (adenoma: 2.1-10 mm) was 41 years and stage 4 disease (adenoma >10 mm) was 45 years. Median time from first esophagogastroduodenoscopy to stage 4 disease was 22.4 years. The risk of stage 4 disease was 34.3% [95% confidence interval (CI) 23.8-43.4] at 15 years. In multivariate analysis, sex, type of colorectal surgery, years since colorectal surgery, and stage were significantly associated with risk of progression to stage 4 disease. Five of 218 (2.3%) patients developed duodenal cancer at median age of 58 years (range: 51-65). The risk of developing duodenal cancer was 2.1% (95% CI: 0-5.2) at 15 years.

Conclusions: Patients with advanced duodenal polyposis progress in the severity of disease (size and degree of dysplasia); however, the rate of progression to carcinoma is slow. Aggressive endoscopic and surgical intervention, especially in the presence of large polyps and high-grade dysplasia, appears to be effective in preventing cancer deaths in FAP.
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June 2015

Characterization of the gut-associated microbiome in inflammatory pouch complications following ileal pouch-anal anastomosis.

PLoS One 2013 24;8(9):e66934. Epub 2013 Sep 24.

Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada ; Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital Inflammatory Bowel Disease Group, Toronto, Ontario, Canada.

Introduction: Inflammatory complications following ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) are common and thought to arise through mechanisms similar to de novo onset inflammatory bowel disease. The aim of this study was to determine whether specific organisms in the tissue-associated microbiota are associated with inflammatory pouch complications.

Methods: Patients having previously undergone IPAA were recruited from Mount Sinai Hospital. Clinical and demographic information were collected and a pouchoscopy with biopsy of both the pouch and afferent limb was performed. Patients were classified based on post-surgical phenotype into four outcome groups: familial adenomatous polyposis controls (FAP), no pouchitis, pouchitis, and Crohn's disease-like (CDL). Pyrosequencing of the 16S rRNA V1-V3 hypervariable region, and quantitative PCR for bacteria of interest, were used to identify organisms present in the afferent limb and pouch. Associations with outcomes were evaluated using exact and non-parametric tests of significance.

Results: Analysis at the phylum level indicated that Bacteroidetes were detected significantly less frequently (P<0.0001) in the inflammatory outcome groups (pouchitis and CDL) compared to both FAP and no pouchitis. Conversely, Proteobacteria were detected more frequently in the inflammatory groups (P=0.01). At the genus level, organisms associated with outcome were detected less frequently among the inflammatory groups compared to those without inflammation. Several of these organisms, including Bacteroides (P<0.0001), Parabacteroides (P≤2.2x10(-3)), Blautia (P≤3.0x10(-3)) and Sutterella (P≤2.5x10(-3)), were associated with outcome in both the pouch and afferent limb. These associations remained significant even following adjustment for antibiotic use, smoking, country of birth and gender. Individuals with quiescent disease receiving antibiotic therapy displayed similar reductions in these organisms as those with active pouch inflammation.

Conclusions: Specific genera are associated with inflammation of the ileal pouch, with a reduction of typically ubiquitous organisms characterizing the inflammatory phenotypes.
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July 2014

Ileal pouch symptoms do not correlate with inflammation of the pouch.

Clin Gastroenterol Hepatol 2014 May 27;12(5):831-837.e2. Epub 2013 Sep 27.

Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Department of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.

Background & Aims: Pouchitis is the most common complication after ileal pouch-anal anastomosis (IPAA). However, symptoms are not specific. The Pouchitis Disease Activity Index (PDAI) and the Pouchitis Activity Score (PAS) have been used to diagnose pouchitis. We evaluated the correlation between the clinical components of these scores and endoscopic and histologic findings.

Methods: We performed a cross-sectional study, analyzing data from 278 patients from Mount Sinai Hospital (Toronto, Canada) who had an IPAA. Patients underwent pouchoscopy with a biopsy, and data were collected on patients' clinical status. The PDAI and PAS were calculated for each subject. The Spearman rank correlation (ρ) statistical test was used to evaluate correlations between the PDAI scores and PAS, and between total scores and subscores.

Results: The total PDAI scores and PAS scores were correlated; the clinical components of each correlated with the total score (ρ = 0.59 and ρ = 0.71, respectively). However, we observed a low level of correlation between clinical and endoscopic or histologic subscores, with ρ of 0.20 and 0.10, respectively, by PDAI, and ρ of 0.19 and 0.04, respectively, by PAS.

Conclusions: There is a low level of correlation between clinical and endoscopic and histologic subscores of patients with IPAA; clinical symptoms therefore might not reflect objective evidence of inflammation. These findings, along with evidence of correlation between total scores and clinical symptoms, indicate that these indices do not accurately identify patients with pouch inflammation. Further research is required to understand additional factors that contribute to clinical symptoms in the absence of objective signs of pouch inflammation.
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May 2014

Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer.

Eur Urol 2013 Feb 2;63(2):379-85. Epub 2012 Aug 2.

Department of Surgical Oncology, Urology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.

Background: Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is caused by mutations in mismatch repair (MMR) genes. An increased risk for upper tract urothelial carcinoma (UTUC) has been described in this population; however, data regarding the risk for bladder cancer (BCa) are sparse.

Objective: To assess the risk of BCa in MMR mutation carriers and suggest screening and management recommendations.

Design, Setting, And Participants: Cancer data from 1980 to 2007 were obtained from the Familial Gastrointestinal Cancer Registry in Toronto for 321 persons with known MMR mutations: mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1); mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2); mutS homolog 6 (E. coli) (MSH6); and PMS2 postmeiotic segregation increased 2 (S. cerevisiae) (PMS2).

Outcome Measurements And Statistical Analysis: Standardized incidence ratios from the Ontario Cancer Registry, using the Surveillance Epidemiology and End Results public database, were used to compare cancer risk in patients with MMR mutations with the Canadian population. Microsatellite instability analysis and immunohistochemistry (IHC) of the MMR proteins were also performed and the results compared with matched sporadic bladder tumors.

Results And Limitations: Eleven of 177 patients with MSH2 mutations (6.21%, p<0.001 compared with the Canadian population) were found to have BCa, compared with 3 of 129 patients with MLH1 mutations (2.32%, p>0.05). Of these 11 tumors, 81.8% lacked expression of MSH2 on IHC, compared with the matched sporadic cases, which all displayed normal expression of MSH2 and MLH1. The incidence of UTUC among MSH2 carriers was 3.95% (p<0.001), and all tumors were found to be deficient in MSH2 expression on IHC. Mutations in the intron 5 splice site and exon 7 of the MSH2 gene increased the risk of urothelial cancer. Limitations include possible inflated risk estimates due to ascertainment bias.

Conclusions: LS patients with MSH2 mutations are at an increased risk for not only UTUC but also BCa and could be offered appropriate screening.
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February 2013

The NOD2insC polymorphism is associated with worse outcome following ileal pouch-anal anastomosis for ulcerative colitis.

Gut 2013 Oct 9;62(10):1433-9. Epub 2012 Aug 9.

Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.

Background: Inflammatory complications after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) are common.

Objective: To investigate whether genetic factors are associated with adverse pouch outcomes such as chronic pouchitis (CP) and a Crohn's disease-like (CDL) phenotype.

Design: 866 patients were recruited from three centres in North America: Mount Sinai Hospital (Toronto, Ontario, Canada), the Cleveland Clinic (Cleveland, Ohio, USA) and Penn State Milton S Hershey Medical Center (Hershey, Pennsylvania, USA). DNA and clinical and demographic information were collected. Subjects were classified into post-surgical outcome groups: no chronic pouchitis (NCP), CP and CDL phenotype.

Results: Clinical and genetic data were available on 714 individuals. 487 (68.2%) were classified as NCP, 118 (16.5%) CP and 109 (15.3%) CDL. The presence of arthritis or arthropathy (p=0.02), primary sclerosing cholangitis (p=0.009) and duration of time from ileostomy closure to recruitment (p=0.001) were significantly associated with outcome. The NOD2insC (rs2066847) risk variant was the single nucleotide polymorphism (SNP) most significantly associated with pouch outcome (p=7.4×10(-5)). Specifically, it was associated with both CP and CDL in comparison with NCP (OR=3.2 and 4.3, respectively). Additionally, SNPs in NOX3 (rs6557421, rs12661812), DAGLB (rs836518) and NCF4 (rs8137602) were shown to be associated with pouch outcome with slightly weaker effects. A multivariable risk model combining previously identified clinical (smoking status, family history of inflammatory bowel disease), serological (anti-Saccharomyces cerevisiae antibody IgG, perinuclear antineutrophil cytoplasmic antibody and anti-CBir1) and genetic markers was constructed and resulted in an OR of 2.72 (p=8.89×10(-7)) for NCP versus CP/CDL and 3.22 (p=4.11×10(-8)) for NCP versus CDL, respectively.

Conclusion: Genetic polymorphisms, in particular, the NOD2insC risk allele, are associated with chronic inflammatory pouch outcomes among patients with UC and IPAA.
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October 2013

Strictureplasty in selected Crohn's disease patients results in acceptable long-term outcome.

Dis Colon Rectum 2012 Aug;55(8):864-9

Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.

Background: Strictureplasty is an alternative to resection in patients with Crohn's disease.

Objective: The objective of this study was to evaluate the long-term results of patients who have undergone strictureplasty.

Design: This is a retrospective cohort study.

Setting: This study was conducted at a tertiary referral center, Mount Sinai Hospital, Toronto, Ontario, Canada.

Patients: All patients who had a strictureplasty of the small bowel between 1985 and 2010 were identified from a prospective database.

Main Outcome Measures: The main outcomes were short-term complications, need for further surgery, and surgery-free survival. Multivariate analysis was performed to determine factors affecting the need for further surgery. Quality of life was measured by use of the short version of the Inflammatory Bowel Disease Questionnaire.

Results: Ninety-four patients (42 women; age at first strictureplasty, 33.4 ± 9.7 years) underwent 119 operations (range per patient, 1-4). The number of strictureplasties was 278 (range, 1-11), including 9 in the duodenum and 269 in the jejunum-ileum. The most common type of procedure was the Heineke-Mickulicz (258, 92.8%). Median follow-up of the patients was 94 months (interquartile range, 27-165 months). The surgery-free survival at 5 and 10 years was 70.7% (95% CI 59.8, 81.7) and 26.6% (95% CI 13.6, 39.6). In multivariate analysis, only age at the time of first strictureplasty was associated with the need for further surgery. Fifty-seven (64.8%) patients returned the questionnaire. The average score was 5.2 ± 1.2 (range, 2.2-7.0) with no significant differences between patients with or without previous surgery (p = 0.22), with or without simultaneous resection (p = 0.71) or with or without further surgery (p = 0.11).

Limitations: This study was limited by its sample size and retrospective design.

Conclusions: Strictureplasty is a safe procedure with acceptable long-term outcomes. The risk of needing further surgery is high, which reflects the complexity of this disease. Younger age is associated with a higher risk of need for further surgery. However, most patients have a satisfactory quality of life.
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August 2012

A tribute to Nils G. Kock, 1924-2011.

Zane Cohen

Can J Surg 2012 Jun;55(3):153-4

Division of General Surgery, Department of Surgery, University of Toronto, Toronto, Ont.

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June 2012

Preoperative biological therapy and short-term outcomes of abdominal surgery in patients with inflammatory bowel disease.

Gut 2013 Mar 22;62(3):387-94. Epub 2012 May 22.

Division of Gastroenterology, Mount Sinai Hospital, 600 University Ave., Toronto, ON, Canada.

Objective: Previous investigations of short-term outcomes after preoperative exposure to biological therapy in inflammatory bowel disease (IBD) were conflicting. The authors aimed to assess postoperative outcomes in patients who underwent abdominal surgery with recent exposure to anti-tumour necrosis factor therapy.

Design: A retrospective case-control study with detailed matching was performed for subjects with IBD with and without exposure to biologics within 180 days of abdominal surgery. Postoperative outcomes were compared between the groups.

Results: 473 procedures were reviewed consisting of 195 patients with exposure to biologics and 278 matched controls. There were no significant differences in most postoperative outcomes such as: length of stay, fever (≥ 38.5°C), urinary tract infection, pneumonia, bacteraemia, readmission, reoperations and mortality. On univariate analysis, procedures on biologics had more wound infections compared with controls (19% vs 11%; p=0.008), but this was not significant in multivariate analysis. Concomitant therapy with biologics and thiopurines was associated with increased frequencies of urinary tract infections (p=0.0007) and wound infections (p=0.0045). Operations performed ≤ 14 days from last biologic dose had similar rates of infections and other outcomes when compared with those performed within 15-30 days or 31-180 days. Patients with detectable preoperative infliximab levels had similar rates of wound infection compared with those with undetectable levels (3/10 vs 0/9; p=0.21).

Conclusion: Preoperative treatment with TNF-α antagonists in patients with IBD is not associated with most early postoperative complications. A shorter time interval from last biological dose is not associated with increased postoperative complications. In most cases, surgery should not be delayed, and appropriate biological therapy may be continued perioperatively.
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March 2013