Rozemary Karamatic

Features of Colorectal Cancers with High-Level Microsatellite Instability Occurring in Familial and Sporadic Settings : Parallel Pathways of Tumorigenesis

High-level microsatellite instability (MSI-H) is demonstrated in 10 to 15% of sporadic colorectal cancers and in most cancers presenting in the inherited condition hereditary nonpolyposis colorectal cancer (HNPCC). Distinction between these categories of MSI-H cancer is of clinical importance and the aim of this study was to assess clinical, pathological, and molecular features that might be discriminatory. One hundred and twelve MSI-H colorectal cancers from families fulfilling the Bethesda criteria were compared with 57 sporadic MSI-H colorectal cancers. HNPCC cancers presented at a lower age (P < 0.001) with no sporadic MSI-H cancer being diagnosed before the age of 57 years. MSI was less extensive in HNPCC cancers with 72% microsatellite markers showing band shifts compared with 87% in sporadic tumors (P < 0.001). Absent immunostaining for hMSH2 was only found in HNPCC tumors. Methylation of hMLH1 was observed in 87% of sporadic cancers but also in 55% of HNPCC tumors that showed loss of expression of hMLH1 (P = 0.02). HNPCC cancers were more frequently characterized by aberrant beta-catenin immunostaining as evidenced by nuclear positivity (P < 0.001). Aberrant p53 immunostaining was infrequent in both groups. There were no differences with respect to 5q loss of heterozygosity or codon 12 K-ras mutation, which were infrequent in both groups. Sporadic MSI-H cancers were more frequently heterogeneous (P < 0.001), poorly differentiated (P = 0.02), mucinous (P = 0.02), and proximally located (P = 0.04) than HNPCC tumors. In sporadic MSI-H cancers, contiguous adenomas were likely to be serrated whereas traditional adenomas were dominant in HNPCC. Lymphocytic infiltration was more pronounced in HNPCC but the results did not reach statistical significance. Overall, HNPCC cancers were more like common colorectal cancer in terms of morphology and expression of beta-catenin whereas sporadic MSI-H cancers displayed features consistent with a different morphogenesis. No individual feature was discriminatory for all HNPCC cancers. However, a model based on four features was able to classify 94.5% of tumors as sporadic or HNPCC. The finding of multiple differences between sporadic and familial MSI-H colorectal cancer with respect to both genotype and phenotype is consistent with tumorigenesis through parallel evolutionary pathways and emphasizes the importance of studying the two groups separately.

The efficacy of training insertion skill on a physical model colonoscopy simulator

Background and study aims: Prior research supports the validity of performance measures derived from the use of a physical model colonoscopy simulator – the Kyoto Kagaku Colonoscope Training Model (Kyoto Kagaku Co. Ltd., Kyoto, Japan) – for assessing insertion skill. However, its use as a training tool has received little research attention. We assessed the efficacy of a brief structured program to develop basic colonoscope insertion skill through unsupervised practice on the model. Participants and methods: This was a training study with pretesting and post-testing. Thirty-two colonoscopy novices completed an 11-hour training regime in which they practiced cases on the model in a colonoscopy simulation research laboratory. They also attempted a series of test cases before and after training. For each outcome measure (completion rates, time to cecum and peak force applied to the model), we compared trainees’ post-test performance with the untrained novices and experienced colonoscopists from a previously-reported validation study. Results: Compared with untrained novices, trained novices had higher completion rates and shorter times to cecum overall (Ps < .001), but were out-performed by the experienced colono-scopists on these metrics (Ps < .001). Nevertheless, their performance was generally closer to that of the experienced group. Overall, trained novices did not differ from either experience-level comparison group in the peak forces they applied (P > .05). We also present the results broken down by case. Conclusions: The program can be used to teach trainees basic insertion skill in a more or less self-directed way. Individuals who have completed the program (or similar training on the model) are better prepared to progress to supervised live cases.