Defects in mismatch repair occur after APC mutations in the pathogenesis of sporadic colorectal tumours

The roles of the intrinsic mutation rate and genomic instability in tumorigenesis are currently controversial. In most colorectal tumours, it is generally supposed that the first mutations occur at the adenomatous polyposis coli (APC) locus; APC mutations are thought to provide cells with a selective advantage but have no known effect on the mutation rate. It has also been suggested that genomic instability is the initiating event in colorectal tumorigenesis and, if this is true, mutations of DNA mismatch repair (MMR) genes (or at similar loci) are the most likely candidates. If defective MMR precedes APC mutations, the APC mutations of colon tumours with defective MMR and hence replication errors (RER+) should differ from those of RER- tumours, in at least three specific ways: (1) a higher frequency of allele loss at APC in RER- tumours; (2) more frameshift than nonsense mutations in RER+ tumours; and (3) APC mutations in simple repeat sequences [(N)_n, (N₁N₂)_n, or (N₁N₂N₃)_n] in RER+ tumours. We found no evidence that sporadic RER+ and RER- colon cancers (including cell lines) differ in any of these three ways. Although it remains possible that MMR is abnormal in tumours from HNPCC families before APC mutations occur, it is likely that in sporadic colon tumours, APC mutations, rather than genomic instability, are the initiating events in tumorigenesis. Hum Mutat 11:114–120, 1998. © 1998 Wiley-Liss, Inc.     

Visual outcomes after pars plana vitrectomy for epiretinal membranes associated with pars planitis.

OBJECTIVE: To evaluate the results of pars plana vitrectomy and membrane stripping for visually significant macular epiretinal membranes associated with chronic idiopathic pars planitis. DESIGN: Consecutive noncomparative case series. PARTICIPANTS AND METHODS: The records of all patients who underwent pars plana vitrectomy for pars planitis from 1988 through 1997 were retrospectively reviewed. Seven eyes of five patients who were diagnosed with visually significant epiretinal membranes associated with pars planitis and who underwent vitrectomy and membrane stripping were analyzed. Patients were diagnosed with pars planitis based on characteristic clinical signs and pertinent negative laboratory test results. INTERVENTION: Pars plana vitrectomy and epiretinal membrane stripping. MAIN OUTCOME MEASURES: Visual acuity and inflammatory grade were compared between the last preoperative visit and the most recent follow-up visit. Intraoperative and postoperative complications were also analyzed. RESULTS: The mean patient age was 31 years (range, 6 to 45 years). The mean duration of uveitis was 6.4 years (range, 6 months to 13 years). All patients were treated with combinations of periocular, topical, and oral corticosteroids before surgery. Five eyes had laser retinopexy, and two eyes had cryopexy to the inferior retina at the time of surgery. Five eyes had at least 3 Snellen lines of visual acuity improvement, and visual acuity in one eye worsened by 2 lines. Mean preoperative visual acuity was 20/73 (range, 20/50 to 20/300), and mean final visual acuity was 20/37 (range, 20/25 to 20/70). Five eyes had a final visual acuity of 20/40. Vitritis improved in all cases. Mean follow-up was 23 months (range, 3 to 54 months). Six of seven eyes had progressive cataract development, four of which underwent cataract extraction. No other intraoperative or postoperative complications occurred. CONCLUSIONS: Removal of epiretinal membranes associated with pars planitis can be safely performed and may result in improved visual acuity. Patients often require subsequent cataract extraction to obtain the best long-term final acuity.