The CDKN2A p.A148T variant is associated with cutaneous melanoma in Southern Brazil.

Several germline mutations and sequence variants in cancer predisposition genes have been described. Among these, the CDKN2A p.A148T variant appears to be frequent in patients with melanoma, at least in certain ethnic groups. In this case-control study, we evaluated 127 patients with cutaneous melanoma and 128 controls from Southern Brazil, the region with the highest melanoma incidence rates in the country. Using PCR-RFLP, we demonstrate that CDKN2A p.A148T variant was significantly more frequent in patients with melanoma than in controls (12.6% vs 3.9%; P=0.009). There was no association between presence of the polymorphism and tumor thickness, site of the primary tumor, melanoma subtype, age at diagnosis, quantitative and qualitative number of nevi. Patients with a positive family of history for other cancers were particularly prone to carry the CDKN2A p.A148T allele. All patients with p.A148T-positive melanoma reported European ancestry, especially German, and this was confirmed using a panel of ancestry-informative INDELs. Our data suggest that CDKN2A p.A148T is a melanoma susceptibility allele in Southern Brazil and is particularly common in patients with melanoma of predominantly European ancestry.

Role of probucol in inhibiting intimal hyperplasia after coronary stent implantation: a randomized study.

BACKGROUND: Oxygen-free radicals can stimulate smooth muscle cell proliferation and may therefore be involved in the genesis of in-stent restenosis. Thus, treatment with probucol, a potent antioxidant agent that has been shown to reduce restenosis after balloon angioplasty, may be an effective strategy to prevent intimal hyperplasia after stenting. METHODS: In a prospective double-blind study, 59 patients submitted to coronary stent implantation were randomly assigned to treatment with either probucol (1 g/d) or placebo, starting two weeks before the procedure and continued for 6 months. The primary end point was the intimal hyperplasia volume at 6 months measured by intravascular ultrasound (IVUS) imaging. RESULTS: Of the 59 randomized patients, 54 underwent successful stent implantation, completed the follow-up period, and underwent repeat angiography, 6.1 +/- 1.1 months after the procedure. Volumetric IVUS analysis revealed similar intimal hyperplasia volumes (403 +/- 26.7 mm3 for probucol vs 44.8 +/- 28.3 mm3 for placebo) and percent volume obstruction of the lumen (30.4% +/- 14.5% for probucol versus 30.7% +/- 17.2% for placebo) in both groups. In addition, quantitative coronary angiography showed no differences in late loss (1.0 +/- 0.8 mm vs 1.1 +/- 0.8 mm), loss index (0.5 +/- 0.4 for both groups), or angiographic restenosis rates (19.4% vs 18.5%) between the probucol and placebo groups, despite the observation of significant changes in the lipid profile and in the plasma antioxidant defenses in patients receiving probucol. CONCLUSIONS: Treatment with the antioxidant probucol failed to reduce neointimal formation after coronary stent implantation as assessed by IVUS volumetric analysis.

Superoxide dismutase activity in adriamycin-induced cardiotoxicity in humans: a potential novel tool for risk stratification.

BACKGROUND: Oxidative stress has been implicated in Adriamycin cardiotoxicity experimentally. We evaluated whether changes in systemic markers of antioxidant reserve occur and are associated with left ventricular (LV) dysfunction during Adriamycin use in humans. METHODS AND RESULTS: We prospectively evaluated oncology patients eligible for Adriamycin chemotherapy. Blood samples for enzymatic (erythrocyte superoxide dismutase activity [SOD-U SOD/mg protein]) and nonenzymatic antioxidants (total radical trapping antioxidant potential [TRAP-U of Trolox/microL plasma]) were collected at baseline (B), intermediate (I), and final (F) cycles. LV ejection fraction (LVEF) was assessed by radionuclide ventriculography. Fifty-one patients (49 +/- 12 years, 90% female) underwent 5.9 +/- 0.9 chemotherapy cycles and received 301 +/- 52 mg/m 2 of Adriamycin. LVEF decreased from 61 +/- 6% (B) to 56 +/- 7% (F) ( P < .001), but only 6 (12%) patients developed significant LV systolic dysfunction (LVEF < 50%). SOD activity increased significantly during treatment (4.5 +/- 1.8 [B], 6.0 +/- 2.1 [I], 5.6 +/- 2.2 [F]; P < .01), whereas TRAP values were unchanged. Baseline SOD activity from patients who developed LV systolic dysfunction was significantly higher than from those who maintained normal LVEF (5.9 +/- 1.8 versus 4.3 +/- 1.7; P < .05). In multivariate analysis, baseline SOD levels remained independently associated with LV dysfunction ( P = .05). CONCLUSION: Erythrocyte SOD activity increases after Adriamycin treatment and high baseline levels predicts Adriamycin-induced cardiotoxicity in humans.