effects of treatment overall and within subgroups of baseline prostate-specific antigen (PSA) and plasma selenium concentrations were examined using incidence rate ratios and Cox proportional hazards models. RESULTSSS continued to significantly reduce the overall incidence (relative risk and 95% confidence interval) of prostate cancer (0.51, 0.29-0.87). The protective effect of SS appeared to be confined to those with a baseline PSA level of £ 4 ng/mL (0.35, 0.13-0.87), although the interaction of baseline PSA and treatment was not statistically significant. Participants with baseline plasma selenium concentrations only in the lowest two tertiles (< 123.2 ng/mL) had significant reductions in prostate cancer incidence. A significant interaction between baseline plasma selenium and treatment was detected. CONCLUSIONTo the end of the blinded treatment the NPC trial continued to show a significant protective effect of SS on the overall incidence of prostate cancer, although the effect was restricted to those with lower baseline PSA and plasma selenium concentrations.

Selenium status has been inversely associated with colorectal cancers (CRC) and adenomas. This investigation evaluates the association between selenium supplementation and prevalent and incident colorectal adenomas and CRC detected during the Nutritional Prevention of Cancer trial follow-up. Of the 1,312 randomized to 200 mcg of selenized yeast of matching placebo, 598 participants underwent endoscopic screening (flexible sigmoidoscopy or colonoscopy) for CRC sometime during the follow-up period, which ended in February 1, 1996. There was no colorectal screening performed at baseline. Of those screened, 77% were male (with a mean age of 62.8 years), 42% were former and 25% were current smokers. Adenomas were classified as prevalent (identified at the first endoscopic examination postrandomization during the follow-up period) or incident (identified at the second or subsequent examination). Ninety-nine prevalent and 61 incident adenomas were ascertained. Logistic regression odds ratios (OR) and 95% confidence intervals (CI) were calculated, adjusting for age, gender and smoking status. For prevalent adenomas, there was a suggestive but nonsignificant decrease in risk associated with selenium treatment (OR 5 0.67, 95% CI 5 0.43-1.05). Subjects in the lowest tertile of baseline selenium (OR 5 0.27, 95% CI 5 0.09-0.77) and current smokers (OR 5 0.27, 95% CI 5 0.11-0.66) had significant reductions in risk. The OR for incident adenomas was 0.98 (95% CI 5 0.57-1.68). In addition to being associated with a reduced risk of incident CRC, selenium supplementation was associated with a significantly reduced risk of prevalent adenomas, but only among subjects with either a low baseline selenium level or among current smokers. ' 2005 Wiley-Liss, Inc.Key words: selenium; colorectal cancer; colorectal adenomas The Nutritional Prevention of Cancer (NPC) study 1 was a placebo-controlled, randomized clinical trial designed to prevent the recurrence of nonmelanoma skin cancer (NMSC) in men and women living in the low soil selenium areas of the Eastern Coastal plain of the US. The results indicated that selenium led to a significant increase in the recurrence of squamous cell carcinoma of the skin.2 The secondary endpoints of the trial (total cancer mortality, total cancer incidence, prostate, colon and lung cancer incidence), defined in 1993, were found to be inversely associated with selenium supplementation, with the greatest reduction in risk seen among subjects in the lower third of the distribution of baseline plasma selenium levels. 1,3,4 Since the trial began, patients were interviewed at each clinical visit for new illnesses, tests and new medications. These reports included cancer screening procedures and newly diagnosed colorectal polyps, cancers and other gastrointestinal conditions. Starting in 1989, specific questions were added to the clinical interview on general cancer screening practices and exam results, focusing on breast, cervical, colorectal and prostate cancers. Patients were asked repeatedly about their perso...

The Nutritional Prevention of Cancer Trial was a double-blind, randomized, placebo-controlled clinical trial designed to test whether selenium as selenized yeast (200 microg daily) could prevent nonmelanoma skin cancer among 1312 patients from the Eastern United States who had previously had this disease. Results from September 15, 1983, through December 31, 1993, showed no association between treatment and the incidence of basal and squamous cell carcinomas of the skin. This report summarizes the entire blinded treatment period, which ended on January 31, 1996. The association between treatment and time to first nonmelanoma skin cancer diagnosis and between treatment and time to multiple skin tumors overall and within subgroups, defined by baseline characteristics, was evaluated. Although results through the entire blinded period continued to show that selenium supplementation was not statistically significantly associated with the risk of basal cell carcinoma (hazard ratio [HR] = 1.09, 95% confidence interval [CI] = 0.94 to 1.26), selenium supplementation was associated with statistically significantly elevated risk of squamous cell carcinoma (HR = 1.25, 95% CI = 1.03 to 1.51) and of total nonmelanoma skin cancer (HR = 1.17, 95% CI = 1.02 to 1.34). Results from the Nutritional Prevention of Cancer Trial conducted among individuals at high risk of nonmelanoma skin cancer continue to demonstrate that selenium supplementation is ineffective at preventing basal cell carcinoma and that it increases the risk of squamous cell carcinoma and total nonmelanoma skin cancer.

Nonexperimental studies suggest that individuals with higher selenium (Se) status are at decreased risk of cancer. The Nutritional Prevention of Cancer (NPC) study randomized 1,312 high-risk dermatology patients to 200-mcg/day of Se in selenized yeast or a matched placebo; selenium supplementation decreased the risk of lung, colon, prostate, and total cancers but increased the risk of nonmelanoma skin cancer. In this article, we report on a small substudy in Macon, GA, which began in 1989 and randomized 424 patients to 400-mcg/day of Se or to matched placebo. The subjects from both arms had similar baseline Se levels to those treated by 200 mcg, and those treated with 400-mcg attained plasma Se levels much higher than subjects treated with 200 mcg. The 200-mcg/day Se treatment decreased total cancer incidence by a statistically significant 25%; however, 400-mcg/day of Se had no effect on total cancer incidence.

Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) play a role in inflammation and carcinogenesis. Biomarkers that reflect tobacco smoke-induced tissue injury are needed. In this study, levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E 4 (LTE 4 ), biomarkers of the COX and 5-LO pathways, were compared in never smokers, former smokers, and current smokers. The effects of celecoxib, a selective COX-2 inhibitor, on levels of PGE-M and LTE 4 were determined. Baseline levels of PGE-M and LTE 4 were positively associated with smoking status; levels of PGE-M and LTE 4 were higher in current versus never smokers. Treatment with 200 mg celecoxib twice daily for 6 ± 1 days led to a reduction in urinary PGE-M levels in all groups but exhibited the greatest effect among subjects with high baseline PGE-M levels. Thus, high baseline PGE-M levels in smokers reflected increased COX-2 activity. In individuals with high baseline PGE-M levels, treatment with celecoxib led to a significant increase in levels of urinary LTE 4 , an effect that was not found in individuals with low baseline PGE-M levels. In conclusion, increased levels of urinary PGE-M and LTE 4 were found in human smokers, a result that may reflect subclinical lung inflammation. In individuals with high baseline levels of PGE-M (elevated COX-2 activity), celecoxib administration shunted arachidonic acid into the proinflammatory 5-LO pathway. Because 5-LO activity and LTE 4 have been suggested to play a role in cardiovascular disease, these results may help to explain the link between use of COX-2 inhibitors and cardiovascular complications.