ABSTRACT
Identifying colorectal cancers (CRCs) with high levels of microsatellite instability (MSI-H) is clinically important. MSI-H is a positive prognostic marker for CRC, a predictive marker for resistance to standard 5-fluorouracil-based adjuvant chemotherapy, and an important feature for identifying individuals and families with Lynch syndrome. Our aim was to compare and improve upon the existing predictive pathology models for MSI-H CRCs. We tested 2 existing models used to predict MSI-H tumors, (1) Revised Bethesda Guidelines and (2) MsPath, in our population-based cohort of CRCs diagnosed less than 75 years from Newfoundland (N=710). We also scored additional histologic features not described in the other models. From this analysis, we developed a model for the prediction of MSI-H CRCs; Pathologic Role in Determination of Instability in Colorectal Tumors (PREDICT). An independent pathologist validated this model in a second cohort of all CRCs (N=276). Tumor histology was a better predictor of MSI status than was personal and family history of cancer. MsPath identified MSI-H CRCs with a sensitivity of 92.1% and a specificity of 37.8%, whereas the Revised Bethesda Guidelines had a sensitivity of 81.3% and a specificity of 39.5%. PREDICT included some new histology features, including peritumoral lymphocytic reaction and increased proportion of plasma cells in the tumor stroma. PREDICT was superior to both existing models in the development cohort with a sensitivity of 97.4% and a specificity of 53.9%. In the validation cohort, sensitivity was 96.9% and specificity 76.6%. We conclude that PREDICT is a good predictor of MSI-H CRC.
Subject(s)
Adenocarcinoma/genetics , Adenocarcinoma/pathology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Microsatellite Instability , Adult , Aged , Aged, 80 and over , Family Health , Female , Humans , Male , Middle Aged , Models, Genetic , Predictive Value of Tests , Young AdultABSTRACT
BACKGROUND: The serrated pathway represents a distinct molecular pathway of colorectal carcinogenesis and is associated with the p.V600E BRAF mutation. The objective of this study is to characterize the cancer family history and clinicopathologic features of colorectal cancer (CRC) patients according to the microsatellite instability (MSI) and BRAF mutation status of their tumors. METHODS: The tumors from 558 population-based CRC patients underwent pathologic examination and molecular analysis for MSI, BRAF, and germline mutations in mismatch repair genes MUTYH and APC. The cancer history in first-degree relatives (FDR) of index patients was ascertained. RESULTS: The risk of CRC in FDRs of index patients with MSI-H BRAF mutation [hazard ratio (HR) = 2.49; 95% confidence interval (95% CI), 1.57- 3.93] and microsatellite-stable BRAF mutation tumors (HR = 1.64; 95% CI, 1.01-2.66) was significantly elevated compared with FDRs of index patients with microsatellite-stable BRAF wild-type tumors. The incidence of nonmelanoma skin cancer was also significantly elevated in FDRs of patients with BRAF mutation CRC (HR = 2.52; 95% CI, 1.31-4.86). Furthermore, BRAF mutation CRC was associated with a distinct clinical, molecular, and pathologic phenotype. CONCLUSIONS: The increased incidence of cancer in FDRs of index CRC patients with the p.V600E BRAF mutation may be explained by a genetic predisposition to develop cancer through the serrated pathway of colorectal carcinogenesis. IMPACT: Family members of BRAF CRC patients have an increased predisposition to develop cancer. Future work should aim to identify the causative genetic factors.
Subject(s)
Colorectal Neoplasms/genetics , Germ-Line Mutation , Proto-Oncogene Proteins B-raf/genetics , Adult , Colorectal Neoplasms/enzymology , Colorectal Neoplasms/pathology , DNA Glycosylases/genetics , DNA Mutational Analysis , Family Health , Female , Genes, APC , Genetic Predisposition to Disease , Humans , Male , Microsatellite Instability , Middle AgedABSTRACT
The authors explore the complexity of challenges facing the public health community in an era increasingly defined by terrorism. The public health and associated political structure in this country has much to do to better coordinate its' efforts in an effective way. Solutions will ultimately come from partnerships between government agencies, community organizations, the business community, and international interests.
Subject(s)
Public Health Administration , Terrorism , Humans , United StatesABSTRACT
Videoconferencing has been used to provide distance education for medical students, physicians and other health-care professionals, such as nurses, physiotherapists and pharmacists. The Dalhousie University Office of Continuing Medical Education (CME) has used videoconferencing for CME since a pilot project with four sites in 1995-6. Since that pilot project, videoconferencing activity has steadily increased; in the year 1999-2000, a total of 64 videoconferences were provided for 1059 learners in 37 sites. Videoconferencing has been well accepted by faculty staff and by learners, as it enables them to provide and receive CME without travelling long distances. The key components of the development of the videoconferencing programme include planning, scheduling, faculty support, technical support and evaluation. Evaluation enables the effect of videoconferencing on other CME activities, and costs, to be measured.