Mary E. Reid

Lack of Effect of a High-Fiber Cereal Supplement on the Recurrence of Colorectal Adenomas

BACKGROUND The risks of colorectal cancer and adenoma, the precursor lesion, are believed to be influenced by dietary factors. Epidemiologic evidence that cereal fiber protects against colorectal cancer is equivocal. We conducted a randomized trial to determine whether dietary supplementation with wheat-bran fiber reduces the rate of recurrence of colorectal adenomas. METHODS We randomly assigned 1429 men and women who were 40 to 80 years of age and who had had one or more histologically confirmed colorectal adenomas removed within three months before recruitment began to a supervised program of dietary supplementation with either high amounts (13.5 g per day) or low amounts (2 g per day) of wheat-bran fiber. The primary end point was the presence or absence of new adenomas at the time of follow-up colonoscopy. Subjects and physicians, including colonoscopists, were unaware of the group assignments. RESULTS Of the 1303 subjects who completed the study, 719 had been randomly assigned to the high-fiber group and 584 to the low-fiber group. The median times from randomization to the last follow-up colonoscopy were 34 months in the high-fiber group and 36 months in the low-fiber group. By the time of the last follow-up colonoscopy, at least one adenoma had been identified in 338 subjects in the high-fiber group (47.0 percent) and in 299 subjects in the low-fiber group (51.2 percent). The multivariate adjusted odds ratio for recurrent adenoma in tile high-fiber group, as compared with the low-fiber group, was 0.88 (95 percent confidence interval, 0.70 to 1.11; P=0.28), and the relative risk of recurrence according to the number of adenomas, in the high-fiber group as compared with the low-fiber group, was 0.99 (95 percent confidence interval, 0.71 to 1.36; P=0.93). CONCLUSIONS As used in this study, a dietary supplement of wheat-bran fiber does not protect against recurrent colorectal adenomas.

Effects of Long-Term Selenium Supplementation on the Incidence of Type 2 Diabetes: A Randomized Trial

Context Research suggests that selenium supplements may improve glucose metabolism. Contribution The investigators examined the incidence of type 2 diabetes among participants in a clinical trial designed to assess the effects of selenium supplementation on skin cancer. Participants randomly assigned to receive selenium were more likely to develop type 2 diabetes than were those assigned to placebo. Cautions Diabetes was a secondary outcome of the original trial. The diagnosis was self-reported, and most participants were older and white. Implication Long-term selenium supplementation appears to increase the risk for type 2 diabetes. The Editors Insulin resistance, impaired glucose tolerance, and type 2 diabetes are all linked to oxidative stress, which may be the pathogenic mechanism that links these conditions to cardiovascular disease (1). Observational epidemiologic studies show a protective association of dietary or plasma antioxidants against the development of type 2 diabetes (2, 3). However, the few clinical trials that have examined the efficacy of antioxidant supplementation in the prevention of type 2 diabetes or its complications have had negative results (46). Experimental evidence from animal models suggests that supplementation with low doses of the antioxidant selenium may exert beneficial effects on glucose metabolism, possibly through many insulin-like actions, and may delay complications of diabetes. The effects of high-dose selenium supplements, however, are less clear (710). Some studies in patients with diabetes suggest that selenium supplementation may help to prevent vascular complications (11) and that diabetic patients may be deficient in selenium relative to healthy persons (12). Conversely, recent findings from the SU.VI.MAX (Supplementation with Antioxidant Vitamins and Minerals) study (13) showed no effect of supplementation with a combination of antioxidants, including selenium (100 g/d), on fasting plasma glucose levels after 7.5 years of follow-up. Because no randomized, placebo-controlled clinical trials to date have tested the effect of long-term supplementation with selenium alone (200 g/d) on the risk for type 2 diabetes, we examined the efficacy of selenium supplementation in preventing new-onset type 2 diabetes in the NPC (Nutritional Prevention of Cancer) trial, a randomized, double-blind clinical trial designed primarily to evaluate the efficacy of selenium supplementation for prevention of cancer (14, 15). Specifically, we assessed the incidence of type 2 diabetes as a secondary end point throughout the blinded phase of the trial (19831996) among participants who did not have type 2 diabetes at baseline (n= 1202). Methods Design and Participants The rationale, design, and methods of the NPC trial are described in detail elsewhere (14). In brief, the NPC trial was a randomized, double-blind, placebo-controlled study of 1312 participants who were recruited in 1983 to 1991 from 7 dermatology clinics in areas of low selenium consumption of the eastern United States. Randomization was blocked by time and stratified by clinic. Persons were eligible if they had a confirmed history of nonmelanoma skin cancer in the year before randomization, had an estimated life expectancy of 5 years, and had no reported internal cancer in the previous 5 years. Participants with a history of clinically important liver or kidney disorders were excluded. Because the primary aim of the trial was to determine the effects of selenium supplementation on nonmelanoma skin cancer, we excluded nonwhite persons. This restriction served to control the effects of skin pigmentation on the risk for skin cancer recurrence. As a result, almost all participants in the NPC trial were non-Hispanic white persons; about 1.4% (n= 18) of persons who were randomly allocated were identified as Hispanic, and some persons were from other ethnic groups. Although recruitment was sex-neutral, about three quarters of the participants were male. Of the 1316 persons recruited, random assignment was successful for 1312. At the end of the blinded treatment period on 1 February 1996, no participant was lost to vital follow-up, generating a total of 9301 person-years of follow-up. Self-reported adherence indicated that 79.3% of participants (80.3% in the placebo group and 78.4% in the selenium group) adhered to the intervention (16). This was corroborated by the fact that plasma selenium levels remained constant throughout the trial in the placebo group but were substantially higher in the selenium group (Figure 1). Figure 1. Mean plasma selenium levels. We analyzed only participants with a valid baseline selenium value obtained within 4 days from the date of randomization (1250 of 1312 participants), a decision that is consistent with previously published studies from the NPC trial (1517). Baseline characteristics of the total NPC cohort of 1312 participants and the subsample of 1250 participants with valid baseline selenium levels did not statistically significantly differ (17), and our findings did not change substantially when analyses were expanded to include all 1312 participants (data not reported). We focus on the 1202 participants who did not have type 2 diabetes at baseline (600 selenium recipients and 602 placebo recipients). Ascertainment of prevalent type 2 diabetes at baseline was based on a self-reported diagnosis of type 2 diabetes before randomization, with subsequent evaluation of medical records (48 cases [21 in the selenium group and 27 in the placebo group]). Figure 2 shows the flow diagram of the NPC participants included in our analysis. Figure 2. Flow diagram of the Nutritional Prevention of Cancer Trial, 19831996. Clinical Examination and Laboratory Methods The intervention agent was 200 g of selenium daily, supplied in a 0.5-g, high-selenium bakers yeast tablet provided by Nutrition 21 (La Jolla, California) through 1995 and by Cypress Systems (Fresno, California) thereafter. The placebo group received a tablet containing yeast only. Selenium and placebo pills were coated with titanium oxide to ensure identical appearance and smell. Each patient was assigned a unique sequential treatment number. Treatment group assignment was made centrally by using sealed identical pill bottles that were distributed at the clinic. The coordinating center held all treatment information in blinded form (14). The selenium content of each batch of pills was determined in the laboratories of Dr. Combs and of I.S. Palmer, MD (South Dakota State University, Brookings, South Dakota), by the diaminonapthalene fluorometric procedure after nitricperchloric acid digestion (18). Plasma selenium level was determined in the laboratory of Dr. Combs by using an automated electrothermal atomic absorption spectrophotometer (Perkin Elmer 3030, Perkin-Elmer, Norwalk, Connecticut) equipped with an electrodeless discharge lamp and automatic Zeeman-effect background correction. Quality control included multiple aliquots of human plasma as external control samples. A coefficient of variation less than 7% (for duplicate analyses) was the criterion for acceptance (19). Participants visited their respective clinics biannually to provide blood samples and report new illnesses and medications. Patient medical records from both study and nonstudy visits were periodically reviewed to ensure completeness and accuracy. At the baseline interview, data were collected on sociodemographic, anthropometric, and behavioral characteristics, including education (0 to 18 years), body mass index (BMI), use of vitamin supplements, alcohol consumption (drinks consumed per day), smoking status (never, former, or current), and pack-years of smoking. For participants who became inactive, annual monitoring was attempted by using the National Death Index and ChoicePoint Services (formerly Equifax, Atlanta, Georgia) to determine vital status and identify diagnoses of new illnesses. Ascertainment of Type 2 Diabetes and Follow-up Participants who had a new diagnosis of type 2 diabetes during the blinded phase of the trial (15 September 1983 to 1 February 1996) were noted. The initial report of diabetes came from 3 sources: self-report during the clinical interview, reported use of drugs for diabetes, and reports in medical record documents. Medical record requests were then sent to the primary physicians for every patient with a report. This process of requesting and reviewing documentation was done in a blinded manner. About 92% of these reports, regardless of source, were corroborated with medical record documentation, as determined by registered nurse reviewers. Person-years of follow-up were accrued from the date of randomization as the start date to the date of an incident case of type 2 diabetes, the date of death, or the end of the blinded period of the trial. Statistical Analysis For continuous and categorical variables, we used t tests and chi-square tests, respectively, to determine the statistical significance of any difference in the distribution of baseline variables between treatment groups. Cumulative incidence curves of type 2 diabetes by treatment group were constructed by comparing NelsonAalen cumulative hazard function estimates that were calculated at different time points of the trial and by using the 2-sided log-rank test (20). In unadjusted analyses, incidence data were statistically analyzed by calculating relative risks as the ratios of the incidence density for the treatment groups, with corresponding 95% CIs. P values were derived from log-rank tests. In adjusted analyses, hazard ratios and 95% CIs were calculated by using the Cox proportional hazard model, which allowed adjustment for age, BMI (continuous variable), sex, and smoking status at baseline as covariates. We decided a priori to adjust for these diabetes risk factors regardless of whether they differed between treatment groups. Tests of proportional hazards assumptions were based on S

Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial

To present the results (to January 1996, the end of blinded treatment) of the Nutritional Prevention of Cancer (NPC) Trial, a randomized trial of selenium (200 µg daily) designed to test the hypothesis that selenium supplementation (SS) could reduce the risk of recurrent nonmelanoma skin cancer among 1312 residents of the Eastern USA.

Chronic Periodontitis and the Incidence of Head and Neck Squamous Cell Carcinoma

Substantial evidence supports an association between chronic infections/inflammation, and cancer. The aim of this study was to assess the effect of chronic periodontitis on head and neck squamous cell carcinoma (HNSCC). The study population consisted of new patients at the Department of Dentistry and Maxillofacial Prosthetics, Roswell Park Cancer Institute between 1999 and 2005. Cases were patients diagnosed with primary HNSCC. Controls were all patients seen during the same time period but negative for malignancy. Patients age <21 years, edentulous, immunocompromised, and those with history of cancer were excluded. Periodontitis was measured by alveolar bone loss (ABL) from panoramic radiographs by one examiner blind to cancer status. A total of 473 patients (266 cases and 207 controls) were included in the study. Each millimeter of ABL was associated with >4-fold increased risk of HNSCC (odds ratio, 4.36; 95% confidence interval, 3.16-6.01) after adjustment for age, gender, race/ethnicity, marital status, smoking status, alcohol use, and missing teeth. The strength of the association was greatest in the oral cavity, followed by oropharynx and larynx. The association persisted in subjects who never used tobacco and alcohol. There was a significant interaction between smoking and ABL (P = 0.03). Patients with periodontitis were more likely to have poorly differentiated oral cavity SCC than those without periodontitis (32.8% versus 11.5%; P = 0.038). This study suggests that chronic periodontitis is an independent risk factor for HNSCC and smoking modifies this association. These results have implications for practical and safe strategies for prevention, diagnosis, and treatment of HNSCC. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2406–12)

Smoking at diagnosis and survival in cancer patients.

The effect of smoking on survival in cancer patients is limited by the lack of structured prospective assessments of smoking at diagnosis. To assess the effect of smoking at diagnosis on survival, structured smoking assessments were obtained in a cohort of 5,185 cancer patients within 30 days of a cancer diagnosis between 1982 and 1998. Hazard ratios (HRs) or odds ratios were generated to analyze the effects of smoking at diagnosis on overall mortality (OM) and disease‐specific mortality (DSM) in a patient cohort from 13 disease sites containing at least 100 patients in each disease site. With a minimum of 12 years of follow‐up, current smoking increased OM risk versus recent quit (HR 1.17), former (HR 1.29) and never smokers (HR 1.38) in the overall cohort. Current smoking increased DSM risk versus former (HR 1.23) and never smokers (HR 1.18). In disease sites with proportionately large (>20%) recent quit cohorts (lung and head/neck), current smoking increased OM and DSM risks as compared with recent quit. Current smoking increased mortality risks in lung, head/neck, prostate and leukemia in men and breast, ovary, uterus and melanoma in women. Current smoking was not associated with any survival benefit in any disease site. Data using prospective structured smoking assessments demonstrate that current smoking increased long‐term OM and DSM. Standardized smoking assessment at diagnosis is an important variable for evaluating outcomes in cancer patients.

The Nutritional Prevention of Cancer: 400 Mcg Per Day Selenium Treatment

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.

Regular aspirin use and lung cancer risk.

BackgroundAlthough a large number of epidemiological studies have examined the role of aspirin in the chemoprevention of colon cancer and other solid tumors, there is a limited body of research focusing on the association between aspirin and lung cancer risk.MethodsWe conducted a hospital-based case-control study to evaluate the role of regular aspirin use in lung cancer etiology. Study participants included 868 cases with primary, incident lung cancer and 935 hospital controls with non-neoplastic conditions who completed a comprehensive epidemiological questionnaire. Participants were classified as regular aspirin users if they had taken the drug at least once a week for at least one year.ResultsResults indicated that lung cancer risk was significantly lower for aspirin users compared to non-users (adjusted OR = 0.57; 95% CI 0.41–0.78). Although there was no clear evidence of a dose-response relationship, we observed risk reductions associated with greater frequency of use. Similarly, prolonged duration of use and increasing tablet years (tablets per day × years of use) was associated with reduced lung cancer risk. Risk reductions were observed in both sexes, but significant dose response relationships were only seen among male participants. When the analyses were restricted to former and current smokers, participants with the lowest cigarette exposure tended to benefit most from the potential chemopreventive effect of aspirin. After stratification by histology, regular aspirin use was significantly associated with reduced risk of small cell lung cancer and non-small cell lung cancer.ConclusionsOverall, results from this hospital-based case-control study suggest that regular aspirin use may be associated with reduced risk of lung cancer.

Plasma levels of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and the risk of prostate cancer

In the US, prostate cancer (PCa) has the highest incidence rate of all cancers in males, with few known modifiable risk factors. Some studies support an association between the Vitamin D metabolites, 1,25-dihydroxyvitamin D (1alpha,25(OH)(2)D(3)) and/or 25-hydroxyvitamin D (25(OH)D(3)), and prostate cancer, while others have yielded conflicting results. 1alpha,25(OH)(2)D(3) has anti-proliferative and pro-differentiating effects in prostate cancer cell lines, and levels of circulating 25(OH)D(3) may be important as PCa cells possess 1-alpha-hydroxylase activity. Using a nested case-control design, we evaluated whether plasma levels of 25(OH)D(3) and 1alpha,25(OH)(2)D(3) were associated with prostate cancer risk in participants from the Nutritional Prevention of Cancer (NPC) trial. With 83 cases and 166 matched controls, we calculated the adjusted odds ratios for increasing plasma levels of 25(OH)D(3) and 1alpha,25(OH)(2)D(3). Compared to the lowest tertile of plasma 25(OH)D(3) levels, the adjusted odds ratios were 1.71 (0.68-4.34) and 0.75 (0.29-1.91); the corresponding odds ratios for 1alpha,25(OH)(2)D(3) were 1.44 (0.59-3.52) and 1.06 (0.42-2.66). Given the pivotal effects of the Vitamin D receptor on gene transcription, it is likely that the anti-carcinogenic effects of Vitamin D that have previously been described are related to the activity and expression of the Vitamin D receptor and should be investigated further.

Selenium supplementation and colorectal adenomas: An analysis of the nutritional prevention of cancer trial

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 = 0.67, 95% CI = 0.43–1.05). Subjects in the lowest tertile of baseline selenium (OR = 0.27, 95% CI = 0.09–0.77) and current smokers (OR = 0.27, 95% CI = 0.11–0.66) had significant reductions in risk. The OR for incident adenomas was 0.98 (95% CI = 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.

Human papillomavirus types 16 and 18 in epithelial dysplasia of oral cavity and oropharynx: A meta-analysis, 1985–2010

Human papillomavirus (HPV) types 16 and 18 are causally related to a sub-set of oral cavity and oropharyngeal squamous cell cancers. However, a clear estimate of the prevalence of HPV-16/18 in oral cavity and oropharyngeal dysplasia (OOPD) is not available. This literature review and meta-analysis was conducted to provide a prevalence estimate for HPV-16/18 in OOPD. Twenty-two studies that reported prevalence of HPV-16 and/or 18 in 458 OOPD lesions were analyzed. Meta-analysis was used to evaluate the prevalence of HPV-16/18 and logistic regression was used for stratified analysis by age, gender, and histological grade. The overall prevalence of HPV-16/18 in OOPD lesions was 24.5% [95% confidence interval (CI), 16.4-36.7%)]. The individual prevalence for HPV-16 alone was 24.4%. The prevalence of HPV-16/18 in oral cavity lesions alone was 25.3% (95% CI, 14.2-45.2%). The odds of detection of HPV-16/18 in dysplastic lesions in males were twice that of females [odds ratio (OR), 2.44]. HPV-16/18 were 3 times more common in dysplastic lesions (OR, 3.29; 95% CI, 1.95-5.53%) and invasive cancers (OR, 3.43; 95% CI, 2.07-5.69%), when compared to normal biopsies. There was no significant difference in HPV-16/18 rates between dysplastic lesions and cancers or between mild, moderate or severe dysplastic lesions. This meta-analysis provides a quantification of the prevalence of HPV types 16/18 in OOPD lesions. These results also support the assumption that HPV-16/18 infection occurs during the early phase of the oral cavity and oropharyngeal carcinogenesis.