Time filter

Source Type

Thompson B.A.,QIMR Berghofer Medical Research Institute | Thompson B.A.,University of Queensland | Spurdle A.B.,QIMR Berghofer Medical Research Institute | Plazzer J.-P.,Royal Melbourne Hospital | And 144 more authors.
Nature Genetics | Year: 2014

The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases. © 2014 Nature America, Inc.


Rosty C.,Royal Brisbane and Womens Hospital | Rosty C.,University of Queensland | Rosty C.,Queensland Institute of Medical Research | Buchanan D.D.,Queensland Institute of Medical Research | And 23 more authors.
American Journal of Surgical Pathology | Year: 2012

Serrated polyposis syndrome (SPS), also known as hyperplastic polyposis, is a syndrome of unknown genetic basis defined by the occurrence of multiple serrated polyps in the large intestine and associated with an increased risk of colorectal cancer (CRC). There are a variety of SPS presentations, which may encompass a continuum of phenotypes modified by environmental and genetic factors. To explore the phenotype of SPS, we recorded the histologic and molecular characteristics of multiple colorectal polyps in patients with SPS recruited between 2000 and 2010 from genetics clinics in Australia, New Zealand, Canada, and the United States. Three specialist gastrointestinal pathologists reviewed the polyps, which they classified into conventional adenomas or serrated polyps, with various subtypes, according to the current World Health Organization criteria. Mutations in BRAF and KRAS and mismatch repair protein expression were determined in a subset of polyps. A total of 100 patients were selected for the study, of whom 58 were female and 42 were male. The total polyp count per patient ranged from 6 to 150 (median 30). The vast majority of patients (89%) had polyposis affecting the entire large intestine. From this cohort, 406 polyps were reviewed. Most of the polyps (83%) were serrated polyps: microvesicular hyperplastic polyps (HP) (n=156), goblet cell HP (n=25), sessile serrated adenoma/polyps (SSA/P) (n=110), SSA/P with cytologic dysplasia (n=28), and traditional serrated adenomas (n=18). A further 69 polyps were conventional adenomas. BRAF mutation was mainly detected in SSA/P with dysplasia (95%), SSA/P (85%), microvesicular HP (76%), and traditional serrated adenoma (54%), whereas KRAS mutation was present mainly in goblet cell HP (50%) and in tubulovillous adenoma (45%). Four of 6 SSA/Ps with high-grade dysplasia showed loss of MLH1/PMS2 expression. CRC was diagnosed in 39 patients who were more often found to have a conventional adenoma compared with patients without CRC (P=0.003). Patients with SPS referred to genetics clinics had a pancolonic disease with a high polyp burden and a high rate of BRAF mutation. The occurrence of CRC was associated with the presence of conventional adenoma. © 2012 by Lippincott Williams & Wilkins.


Al-Sukhni E.,Mount Sinai Hospital | Al-Sukhni E.,Zane Cohen Center for Digestive Diseases | Al-Sukhni E.,University of Toronto | Messenger D.E.,Mount Sinai Hospital | And 12 more authors.
Annals of Surgical Oncology | Year: 2013

Purpose: This study was designed to elicit end-user opinions regarding the importance and diagnostic accuracy of MRI for T-category, threatened or involved circumferential margin (CRMi), and lymph node involvement (LNi) for preoperative staging of rectal cancer and to determine completeness of MRI reports for these elements on a population based level. Methods: The first part of this study was a mailed survey of surgeons, radiation oncologists, and medical oncologists to elicit their opinions regarding the importance and diagnostic accuracy of T-category, CRMi, and LNi on MRI. The second part of the study was an audit of MRI reports issued for pre-operative staging of rectal cancer to assess the completeness of these reports for T-category, CRMi, and LNi. Results: Although T-category, CRMi, and LNi were considered essential by 97, 94, and 77 % of respondents, respectively, the MRI report audit showed that only 40 % of MRI reports captured all of these elements. The majority of end users reported moderate diagnostic accuracy on MRI for T-category and CRMi and low diagnostic accuracy for LNi (52.3, 43, and 48.5 % respectively). Multivariate analysis showed that specialty was the only independent predictor of correct reporting of the diagnostic accuracy for each of the MRI elements. Conclusions: While end users consider T-category, CRMi and LNi essential for preoperative staging of rectal cancer, less than 40 % of MRI reports captured all of these elements. Therefore, strategies to improve communication between radiologists and end users are critical to improve the overall quality of care for rectal cancer patients. © 2012 Society of Surgical Oncology.


Al-Sukhni E.,Mount Sinai Hospital | Al-Sukhni E.,University of Toronto | Al-Sukhni E.,Zane Cohen Center for Digestive Diseases | Milot L.,University of Toronto | And 13 more authors.
Annals of Surgical Oncology | Year: 2012

Background. Magnetic resonance imaging (MRI) is increasingly being used for rectal cancer staging. The purpose of this study was to determine the accuracy of phased array MRI for T category (T1-2 vs. T3-4), lymph node metastases, and circumferential resection margin (CRM) involvement in primary rectal cancer. Methods. Medline, Embase, and Cochrane databases were searched using combinations of keywords relating to rectal cancer and MRI. Reference lists of included articles were also searched by hand. Inclusion criteria were: (1) original article published January 2000-March 2011, (2) use of phased array coil MRI, (3) histopathology used as reference standard, and (4) raw data available to create 2 × 2 contingency tables. Patients who underwent preoperative long-course radiotherapy or chemoradiotherapy were excluded. Two reviewers independently extracted data. Sensitivity, specificity, and diagnostic odds ratio were estimated for each outcome using hierarchical summary receiver-operating characteristics and bivariate random effects modeling. Results. Twenty-one studies were included in the analysis. There was notable heterogeneity among studies. MRI specificity was significantly higher for CRM involvement [94%, 95% confidence interval (CI) 88-97] than for T category (75%, 95% CI 68-80) and lymph nodes (71%, 95% CI 59-81). There was no significant difference in sensitivity between the three elements as a result of wide overlapping CIs. Diagnostic odds ratio was significantly higher for CRM (56.1, 95% CI 15.3-205.8) than for lymph nodes (8.3, 95% CI 4.6-14.7) but did not differ significantly from T category (20.4, 95% CI 11.1-37.3). Conclusions. MRI has good accuracy for both CRM and T category and should be considered for preoperative rectal cancer staging. In contrast, lymph node assessment is poor on MRI. © 2012 Society of Surgical Oncology.


Ryan P.,King Edward Memorial Hospital for Women | Ferguson S.E.,University of Toronto | Aronson M.,Zane Cohen Center for Digestive Diseases | Semotiuk K.,Zane Cohen Center for Digestive Diseases | And 9 more authors.
American Journal of Surgical Pathology | Year: 2014

Women with Lynch syndrome (LS) are at increased risk for the development of epithelial ovarian cancer (OC). Analogous to previous studies on BRCA1/2 mutation carriers, there is evidence to suggest a histotype-specific association in LS-associated OCs (LS-OC). Whereas the diagnosis of high-grade serous carcinoma is an indication for BRCA1/2 germline testing, in contrast, there are no screening guidelines in place for triaging OC patients for LS testing based on histotype. We performed a centralized pathology review of tumor subtype on 20 germline mutation-confirmed LS-OCs, on the basis of morphologic assessment of hematoxylin and eosin-stained slides, with confirmation by immunohistochemistry when necessary. Results from mismatch-repair immunohistochemistry (MMR-IHC) and microsatellite instability (MSI) phenotype status were documented, and detailed pedigrees were analyzed to determine whether previously proposed clinical criteria would have selected these patients for genetic testing. Review of pathology revealed all LS-OCs to be either pure endometrioid carcinoma (14 cases), mixed carcinoma with an endometrioid component (4 cases), or clear cell carcinoma (2 cases). No high-grade or low-grade serous carcinomas or mucinous carcinomas of intestinal type were identified. Tumor-infiltrating lymphocytes were prominent (â‰140 per 10 high-powered fields) in 2 cases only. With the exception of 1 case, all tumors tested for MMR-IHC or MSI had an MMR-deficient phenotype. Within this cohort, 50%, 55%, 65%, and 85% of patients would have been selected for genetic workup by Amsterdam II, revised Bethesda Guidelines, SGO 10% to 25%, and SGO 5% to 10% criteria, respectively, with <60% of index or sentinel cases detected by any of these schemas. To further support a subtype-driven screening strategy, MMR-IHC reflex testing was performed on all consecutive non-serous OCs diagnosed at 1 academic hospital over a 2-year period; MMR deficiency was identified in 10/48 (21%) cases, all with endometrioid or clear cell histology. We conclude that there is a strong association between endometrioid and clear cell ovarian carcinomas and hereditary predisposition due to MMR gene mutation. These findings have implications for the role of tumor subtype in screening patients with OC for further genetic testing and support reflex MMR-IHC and/or MSI testing for newly diagnosed cases of endometrioid or clear cell ovarian carcinoma. © 2014 by Lippincott Williams and Wilkins.


Kennedy E.D.,Mount Sinai Hospital | Kennedy E.D.,University of Toronto | Milot L.,University of Toronto | Milot L.,Sunnybrook Health Science Center | And 11 more authors.
Diseases of the Colon and Rectum | Year: 2014

BACKGROUND: Colorectal cancer physician champions across the province of Ontario, Canada, reported significant concern about appropriate selection of patients for preoperative chemoradiotherapy because of perceived variation in the completeness and consistency of MRI reports. OBJECTIVE: The purpose of this work was to develop, pilot test, and implement a synoptic MRI report for preoperative staging of rectal cancer. DESIGN: This was an integrated knowledge translation project. SETTINGS: This study was conducted in Ontario, Canada. PATIENTS: Surgeons, radiologists, radiation oncologists, medical oncologists, and pathologists treating patients with rectal cancer were included in this study. INTERVENTIONS: A multifaceted knowledge translation strategy was used to develop, pilot test, and implement a synoptic MRI report. This strategy included physician champions, audit and feedback, assessment of barriers, and tailoring to the local context. A radiology webinar was conducted to pilot test the synoptic MRI report. MAIN OUTCOME MEASURES: Seventy-three (66%) of 111 Ontario radiologists participated in the radiology webinar and evaluated the synoptic MRI report. RESULTS: A total of 78% and 90% radiologists expressed that the synoptic MRI report was easy to use and included all of the appropriate items; 82% noted that the synoptic MRI report improved the overall quality of their information, and 83% indicated they would consider using this report in their clinical practice. An MRI report audit after implementation of the synoptic MRI report showed a 39% improvement in the completeness of MRI reports and a 37% uptake of the synoptic MRI report format across the province. LIMITATIONS: Radiologists evaluating the synoptic MRI report and participating in the radiology webinar may not be representative of gastroenterologic radiologists in other geographic jurisdictions. The evaluation of completeness and uptake of the synoptic MRI reports is limited because of unmeasured differences that may occur before and after the MRI. CONCLUSIONS: A synoptic MRI report for preoperative staging of rectal cancer was successfully developed and pilot tested in the province of Ontario, Canada.© The ASCRS 2014.


Spiegle G.,University of Toronto | Spiegle G.,Samuel Lunenfeld Research Institute | Al-Sukhni E.,University of Toronto | Al-Sukhni E.,Samuel Lunenfeld Research Institute | And 14 more authors.
Cancer | Year: 2013

Background: Although patient decision aids (pDAs) are effective, widespread use of pDAs for cancer treatment has not been achieved. The objectives of this study were to perform a systematic review to identify alternate types of decision support interventions (DSIs) for cancer treatment and a meta-analysis to compare the effectiveness of these DSIs to pDAs. Methods: The inclusion criteria for the study were: 1) all published studies using a randomized, controlled trial design, and 2) DSIs involving treatment decision-making for breast, prostate, colorectal, and/or lung cancer. For this analysis, DSIs were classified as pDAs if: 1) one reported outcome measure mapped onto the International Patient Decision Aids Standards Collaboration effectiveness criterion, and 2) the DSI was evaluated relative to standard consultation. Random effects models were used to compare the effectiveness of pDAs relative to other identified DSIs for reported outcomes. Results: A total of 71 studies were reviewed, and 24 met the inclusion criteria. Overall, there were no significant differences in knowledge, satisfaction, anxiety, or decisional conflict scores between pDAs and other DSIs. Conclusions: This study showed that the effectiveness of other DSIs, including question prompt lists and audiorecording of the consultation, is similar to pDAs. This is important because it may be that these less complex DSIs may be all that is necessary to achieve similar outcomes as pDAs for cancer treatment. © 2012 American Cancer Society.


Waterman M.,Sinai University | Waterman M.,Zane Cohen Center for Digestive Diseases | Xu W.,Lana | Xu W.,University of Toronto | And 24 more authors.
Gut | Year: 2013

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.

Loading Zane Cohen Center for Digestive Diseases collaborators
Loading Zane Cohen Center for Digestive Diseases collaborators