ABSTRACT
BACKGROUND: It is uncertain whether synchronous colorectal cancers (S-CRCs) preferentially develop through widespread DNA methylation and whether they have a prognosis worse than solitary CRC. As tumours with microsatellite instability (MSI) may confound the effect of S-CRC methylation on outcome, we addressed this issue in a series of CRC characterised by BRAF and MS status. METHODS: Demographics, clinicopathological records and disease-specific survival (DSS) were assessed in 881 consecutively resected CRC undergoing complete colonoscopy. All tumours were typed for BRAF(c.1799T>A) mutation and MS status, followed by search of germ-line mutation in patients with MSI CRC. RESULTS: Synchronous colorectal cancers (50/881, 5.7%) were associated with stage IV microsatellite-stable (MSS) CRC (19/205, 9.3%, P=0.001) and with HNPCC (9/32, 28%, P<0.001). BRAF mutation (60/881, 6.8%) was associated with sporadic MSI CRC (37/62, 60%, P<0.001) but not with S-CRC (3/50, 6.0%, P=0.96). Synchronous colorectal cancer (HR 1.82; 95% CI 1.15-2.87; P=0.01), synchronous advanced adenoma (HR 1.81; 95% CI 1.27-2.58; P=0.001), and BRAF(c.1799T>A) mutation (HR 2.16; 95% CI 1.25-3.73; P=0.01) were stage-independent predictors of death from MSS CRC. Disease-specific survival of MSI CRC patients was not affected by S-CRC (HR 0.74; 95% CI 0.09-5.75; P=0.77). CONCLUSION: Microsatellite-stable CRCs have a worse prognosis if S-CRC or synchronous advanced adenoma are diagnosed. The occurrence and the enhanced aggressiveness of synchronous MSS advanced neoplasia are not associated with BRAF mutation.
Subject(s)
Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Microsatellite Repeats , Adenoma/genetics , Aged , Colorectal Neoplasms/enzymology , Female , Germ-Line Mutation , Humans , Male , Microsatellite Instability , Middle Aged , Prognosis , Proto-Oncogene Proteins B-raf/geneticsABSTRACT
The role of nitric oxide and reactive oxygen species is well-demonstrated in inflammation. In this study, we evaluated the effect of aminoguanidine, a nitric oxide synthase inhibitor, in a rat model of periodontitis. We induced periodontitis in rats by placing a piece of 2/0 braided silk around the lower left 1st molar. At day 8, the gingivomucosal tissue encircling the mandibular 1st molar was removed for biochemical and histological analysis. Ligation significantly increased inducible nitric oxide synthase activity and expression, and damaged tissue revealed increased neutrophil infiltration, lipid peroxidation, and positive staining for nitrotyrosine formation and poly (ADP-ribose) polymerase activation. Ligation significantly increased Evans blue extravasation in gingivomucosal tissue and alveolar bone destruction. Aminoguanidine (100 mg/kg i.p., daily for 8 days) treatment significantly reduced all these inflammatory parameters, indicating that it protects against the tissue damage associated with periodontitis by reducing nitric oxide production and oxidative stress.