Risk of basal cell carcinoma in a randomized clinical trial of aspirin and folic acid for the prevention of colorectal adenomas.

BACKGROUND: Aspirin may reduce the risk of several types of cancer. OBJECTIVES: To evaluate if folic acid is associated with risk of basal cell carcinoma (BCC). METHODS: BCC incidence was evaluated in a randomized, double-blind, placebo-controlled clinical trial of aspirin (81 mg daily or 325 mg daily for ~3 years) and/or folic acid (1 mg daily for ~6 years) for the prevention of colorectal adenomas among 1121 participants with a previous adenoma. BCC was confirmed by blinded review of pathology reports. RESULTS: One hundred and four of 958 non-Hispanic white participants were diagnosed with BCC over a median follow-up of 13·5 years. Cumulative incidence of BCC was 12% [95% confidence interval (CI) 7-17] for placebo, 16% (95% CI 11-21) for 81 mg aspirin daily and 15% (95% CI 10-20) for 325 mg aspirin daily [hazard ratio (HR) for any aspirin 1·45 (95% CI 0·93-2·26); HR for 81 mg daily 1·57 (95% CI 0·96-2·56); HR for 325 mg daily 1·33 (95% CI 0·80-2·20)]. BCC risk was higher with aspirin use in those without previous skin cancer but lower with aspirin use in those with previous skin cancer (Pinteraction = 0·02 for 81 mg aspirin daily; Pinteraction = 0·03 for 325 mg aspirin daily). Folic acid supplementation was unrelated to BCC incidence (HR 0·85; 95% CI 0·57-1·27). CONCLUSIONS: Neither aspirin nor folic acid treatment had a statistically significant effect on risk of BCC. Subgroup analysis suggested that chemopreventive effects of nonsteroidal anti-inflammatory drugs may be specific to those at high risk for BCC.

Cross-sectional and prospective associations between proinsulin and cardiovascular disease risk factors in a population experiencing rapid cultural transition.

OBJECTIVE: To examine cross-sectional and prospective associations between proinsulin and cardiovascular disease risk factors using data from a population-based study of type 2 diabetes among Native Canadians. RESEARCH DESIGN AND METHODS: Between 1993 and 1995, 72% of eligible members of a Native Canadian community participated in a baseline diabetes prevalence survey. Fasting samples were collected for glucose, C-peptide, proinsulin, lipids, and apolipoproteins. A 75-g oral glucose tolerance test was administered, and a second sample for glucose was drawn after 120 min. Blood pressure and waist circumference were determined. In the present study, subjects with normal glucose tolerance (NGT) (n = 505) and impaired glucose tolerance (IGT) (n = 74) were included in cross-sectional analyses. In 1998, 95 individuals who had IGT or NGT at baseline with an elevated 2-h glucose concentration (> or = 7.0 mmol/l) participated in a follow-up evaluation using the protocol used at baseline. Cross-sectional and prospective associations between proinsulin and cardiovascular risk factors were assessed using correlation and multiple linear regression analyses. RESULTS: After adjustment for covariates including age, sex, C-peptide, waist circumference, and glucose tolerance status, fasting proinsulin concentration was significantly associated with concurrently measured lipid and apolipoprotein concentrations (triglycerides: r = 0.18, P < 0.0001; total cholesterol: r = 0.10, P = 0.02; LDL cholesterol: r = 0.11, P = 0.01; HDL cholesterol: r = -0.16, P = 0.0002; apolipoprotein (apo) B: r = 0.17, P < 0.0001; apoAI: r = -0.11, P = 0.008). In the adjusted prospective analysis, baseline triglycerides, HDL cholesterol, and apoB were associated with changes over time in proinsulin (r = 0.23, P = 0.04; r = -0.30, P = 0.01; r = 0.23, P = 0.04; respectively). CONCLUSIONS: These results confirm previously reported cross-sectional associations between proinsulin and lipid concentrations. In addition, an unexpected association between baseline lipids and proinsulin change was documented.

Multiple chemical sensitivity: discriminant validity of case definitions.

In this study, the authors used the University of Toronto's Health Survey self-administered questionnaire to determine discriminant validity of multiple chemical sensitivity definitions. The authors distributed a total of 4,126 questionnaires to adults who attended general, allergy, occupational, and environmental health practices. The authors then matched responses to features selected from existing case definitions posited by Thomson et al.; the National Research Council; Cullen; Ashford and Miller; Randolph; Nethercott et al.; and the 1999 Consensus (references 4-7, 2, 9, and 10, respectively, herein). The overall response rate was 61.7%. The prevalence of reported symptoms was lowest in general practices, was intermediate in occupational health and allergy practices, and was highest in environmental health practices. Features from the definitions presented by Nethercott et al. and the 1999 Consensus (references 9 and 10, respectively, herein) correctly identified more than 80% of environmental health practice patients and more than 70% of general practice patients. Combinations of 4 symptoms (i.e., having a stronger sense of smell than others, feeling dull/groggy, feeling "spacey," and having difficulty concentrating) also discriminated successfully. In summary, features from 2 of 7 case definitions assessed by the University of Toronto Health Survey achieved good discrimination and identified patients with an increased likelihood of multiple chemical sensitivity.

Ontario familial colon cancer registry: methods and first-year response rates.

The Ontario Familial Colon Cancer Registry (OFCCR) is a novel registry that collects family history information, epidemiologic data, blood samples and tumour specimens from a population-based sample of colorectal cancer patients and their families. Families are classified as either high familial risk, intermediate familial/other risk or low (sporadic) risk for colorectal cancer. Obtaining high response rates in genetic family studies is especially challenging because of both the time commitment required and issues of confidentiality. The first-year response rate was 61%, resulting in 1,395 participating probands. In an attempt to assess potential response bias, we compared participants with non-participants. The age and sex of participants did not differ from non-participating probands; however, cases in rural areas were somewhat more likely to participate. To date, 57% of 1,587 relatives participated; females were more likely to participate, and relatives of low familial risk were least likely to participate. The OFCCR is an excellent resource that will facilitate the study of genetic and environmental factors associated with colorectal cancer.

Reproducibility of the University of Toronto self-administered questionnaire used to assess environmental sensitivity.

Environmental sensitivity patients report symptoms provoked by low-level exposure to a wide range of substances. Features of published case definitions include nature of onset, chronicity, symptom provocation by multiple substances, symptom provocation by an escalating number of exposures, involvement of multiple body systems including the nervous system, provocation by unrelated substances, and addictive behaviors. This study assessed the reproducibility of a Canadian self-administered questionnaire, the University of Toronto Health Survey, designed to determine the prevalence of the features described in these case definitions. A total of 191 eligible respondents aged 16-70 years who attended several types of medical practices in 1994 were invited to complete a second questionnaire 5-7 months after the first; 134 (70.2%) complied. Total agreement on whether patients satisfied each of seven case definitions ranged from 80% to 90%. After adjustment for chance, major agreement was observed for three of the seven case definitions (kappa = 0.69, 0.68, and 0.78). The survey achieved good reproducibility regarding self-report of symptoms described in published case definitions of environmental sensitivity.

Insulin and related factors in premenopausal breast cancer risk.

BACKGROUND: Insulin and insulin-like growth factor I (IGF-I) are important mitogens in vitro and in vivo. It has been hypothesized that these factors may play an important role in the development of breast cancer. METHODS: A case-control study comparing plasma insulin levels in 99 premenopausal women with newly diagnosed node-negative invasive carcinoma of the breast and 99 age-matched controls with incident biopsied non-proliferative breast disease (NP) was conducted. Women with known diabetes were excluded. RESULTS: For the entire study group, mean age was 42.6 +/- 5.1 years and mean weight was 62.9 +/- 10.3 kg. After adjustment for age and weight, elevated insulin levels were significantly associated with breast cancer, Odds Ratio (OR) for women in the highest insulin quintile versus the lowest quintile = 2.83 (95% Confidence Interval [CI] 1.22-6.58). There were no statistically significant differences between cases and controls for IGF-I and IGFBP-1 levels. However, after adjustment for age, the association between plasma levels of insulin-like growth factor binding protein 3 (IGFBP-3) and breast cancer approached statistical significance; OR for highest quintile versus lowest quintile of IGFBP-3 being 2.05 (95% CI, 0.93-4.53). All results were independent of diet and other known risk factors for breast cancer. CONCLUSION: Circulating insulin levels and possibly IGFBP-3 levels are elevated in women with premenopausal breast cancer. This association may reflect an underlying syndrome of insulin resistance that is independent of obesity.

Impact of menstrual phase on false-negative mammograms in the Canadian National Breast Screening Study.

BACKGROUND: The efficacy of breast carcinoma screening should be enhanced if false-negative mammography were reduced. Prospectively collected data from the Canadian National Breast Screening Study were used to examine whether menstrual cycle phase was associated with false-negative outcomes for mammographic screening. METHODS: Of 8887 women ages 40-44 years at the onset of screening, randomized to receive annual mammography and clinical breast examination, reporting menstruation no more than 28 days prior to their screening examination, and with a valid radiologic report, 1898 had never used oral contraceptives or replacement estrogen with or without progesterone. The remainder were past (6573) and current (416) estrogen users. Similar selection criteria were applied at subsequent screens. The distribution of false-negative and false-positive mammography in relation to true-negative and true-positive mammography was examined with respect to the follicular (Days 1 to 14) and luteal (Days 15-28) menstrual phases. RESULTS: Comparing luteal with follicular mammograms in 6989 patients who ever used estrogen, the unadjusted odds ratio (2-sided P-values) for false-negatives versus true-negatives was 2.16 (0.05) and the adjusted odds ratio was 1.47 (0.05). In 1898 never-users, parallel odds ratios for luteal false-negatives were 0.55 (1.0) and 0.74 (1.0), respectively. CONCLUSIONS: These results suggest that menstruating women who have used hormones may have an increased risk of false-negative results for screening mammograms performed in the luteal phase of the menstrual cycle. An increased risk of false-negative mammography might adversely affect screening efficacy. The impact of menstrual phase on mammographic interpretation, especially for women who ever used hormones, requires further investigation.

Research initiatives at the University of Toronto Environmental Hypersensitivity Research Unit.

The Environmental Hypersensitivity Research Unit at the University of Toronto is following a research strategy to develop and evaluate diagnostic methods for environmental hypersensitivity. These methods will be used to identify cases for inclusion in studies of disease etiology and therapy. The Research Unit has actively sought consultation and collaboration with researchers at the University of Toronto, clinicians from a variety of specialties, and patients. It is hoped that such a multidisciplinary approach will lead to the generation and testing of innovative hypothesis with rigorous methodology and, ultimately, to increased understanding of the complex conditions known as environmental hypersensitivity.

Epidemiology of colorectal cancer revisited: are serum triglycerides and/or plasma glucose associated with risk?

Several aspects of Western diets, alcohol use, and exercise patterns which are related to the risk of colorectal cancer have systemic effects in common. Those which increase the risk of colorectal cancer are positively associated with serum triglycerides and plasma glucose; those which decrease risk are negatively associated with serum triglycerides and plasma glucose. These observations suggest the hypothesis that serum triglycerides and/or plasma glucose may themselves be associated with colorectal cancer risk. Evidence for associations between colorectal neoplasia and triglycerides and glucose comes from two recent studies of adenomatous polyps, presumed precursors for colorectal cancer, and from previous studies of diabetes and cancer. In addition, three randomized trials, one in humans and two in animal models, suggest that diets which would be expected to increase serum triglycerides and plasma glucose increase the levels of cellular indicators of colorectal cancer risk. Biological mechanisms explaining associations between colorectal neoplasia and serum triglycerides and/or plasma glucose might involve luminal or circulatory effects: (a) triglycerides and/or glucose may be associated with fecal bile acids, acids which are positively associated with colorectal cancer risk in epidemiological studies and which promote colorectal cancer in animal models; (b) serum triglycerides and/or plasma glucose might influence circulating hormones, such as insulin, which might themselves be involved in cancer development; (c) serum triglycerides and/or plasma glucose might be indicators of energy available through the circulation for neoplastic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized trial of a low fat high fibre diet in the recurrence of colorectal polyps. Toronto Polyp Prevention Group.

After polypectomy for adenomatous colorectal polyps, 201 persons were randomized to receive counselling on a diet low in fat (the lesser of 50 g/day or 20% of energy) and high in fibre (50 g/day) (LFHF), or to follow a normal western diet (ND), high in fat and low in fibre. After 12 months of counselling, fat consumption was about 25% of energy in the LFHF group and 33% in the ND group; fibre consumption was 35 g and 16 g respectively. After an average of two years of follow-up, an intention to treat analysis led to a ratio of cumulative incidence rates of 1.2 (95% CL 0.6-2.2) for recurrence of neoplastic polyps, a finding which suggests no significant difference between dietary groups over the period of observation. An exploratory analysis conducted among 142 persons with substantial diet counselling indicated a reduced risk of neoplastic polyp recurrence in women (RR = 0.5), associated with reduced concentrations of faecal bile acids while on the LFHF diet, but indicated an increased risk of recurrence in men (RR = 2.1), associated with increased faecal bile acids. Although a larger study would be needed to rule out the role of chance, these findings of gender-specific associations between diet counselling and both faecal bile acid concentrations and recurrence of colorectal neoplasia are consistent with recently published evidence of differences between genders.

High-molecular-weight cytokeratin and cytokeratin-19 in the diagnosis of thyroid tumors.

The pathologic diagnosis of thyroid tumors is often difficult and subjective. Immunohistochemical markers including high molecular weight cytokeratin (HMW-CK), cytokeratin-19 (CK-19) and epithelial membrane antigen have been suggested to be helpful in the distinction of various types of thyroid neoplasia. We collected frozen and/or paraffin-embedded tissues from a total of 116 surgically resected thyroids including 31 nodular hyperplasias, 18 follicular adenomas, 48 papillary carcinomas and 19 follicular carcinomas, stained them for HMW-CK, CK-19 and epithelial membrane antigen, and graded the results on a scale from 0 to 3+. Although little staining for HMW-CK was seen in paraffin-embedded tissues, different results were obtained when both HMW-CK and CK-19 were tested on frozen tissues. In papillary carcinomas, including the follicular variant of papillary carcinoma, diffuse positivity for these antigens was seen immunohistochemically, and these antigens significantly distinguished papillary carcinomas from follicular neoplasms and nodular hyperplasias. Focal staining for epithelial membrane antigen was found in all pathological processes; thus this marker was not useful. We conclude that HMW-CK and CK-19 are useful in the distinction of papillary carcinomas from follicular adenomas, follicular carcinomas, and nodular hyperplasias when applied to frozen tissues. We recommend that samples of thyroid follicular nodules be frozen, and retrieved if necessary to aid in the differential diagnosis of these tumors.

Implications of measurement error in exposure for the sample sizes of case-control studies.

In this paper, recent results describing the effects of measurement error on estimation of the association between an exposure and a disease are applied to sample size calculation in case-control studies. Models of the relation between true exposure and a surrogate exposure measure assessed with error are used to derive equations for sample size determination. The results show that the sample size of a study based on an exposure variable which is measured with error must be larger by a factor of 1/rho 2 than if exposure were measured without error, where rho is the correlation between the true exposure and the surrogate exposure measure. Review of the magnitude of measurement error in dietary assessments suggests that failure to account for measurement error in sample size determination for case-control studies of diet and disease could lead to marked underestimation of the required sample size.

Randomized trial of the effect of calcium supplementation on fecal risk factors for colorectal cancer.

Newmark et al. (J Natl Cancer Inst 1984; 72:1323-8) hypothesized that supplementation with calcium would decrease the concentration of bile acids in aqueous phase feces and that such a reduction would reduce the risk of malignant disease in the bowel. A randomized trial was therefore undertaken to examine the effects of calcium supplementation on fecal biochemistry. A total of 68 men between 40 and 60 years of age volunteered to participate after having been selected randomly from population lists in Scarborough, a city in the Toronto area, Ontario, Canada. Participants were randomly assigned to receive a daily supplement of 3 g of calcium carbonate or a sucrose placebo for a period of 1 week. Fecal samples were collected for 2 days prior to supplementation and for the last 2 days of supplementation. Records of all foods consumed were kept throughout the study period. The average concentration of total soluble bile acids fell in the placebo group (-11.2 g/ml) but increased slightly in the calcium group (1.4 g/ml). Similar patterns of change were observed for deoxycholic acid (placebo, -3.0 g/ml; calcium, 4.5 g/ml). The distribution of changes in total bile acids and deoxycholic acid differed between randomization groups at the 10 percent level of significance in univariate analysis. After adjustment for initial stool chemistry and initial levels and changes in nutrient intake, no reduction in fecal bile acid levels was observed in association with calcium supplementation. In fact, a statistically significant (p = 0.05) increase in deoxycholic acid concentration remained in the calcium supplemental group. Thus, this study was unable to support the hypothesis that calcium supplementation alters aqueous phase bile acids in the manner hypothesized to be consistent with protection from colorectal cancer.

Comparisons of diet and biochemical characteristics of stool and urine between Chinese populations with low and high colorectal cancer rates.

In an investigation of the roles of diet and stool biochemistry in human colorectal carcinogenesis, 24-hour food, urine, and stool samples were collected from randomly selected participants from two populations with a fourfold difference in colorectal cancer risk: Chinese in Sha Giao, People's Republic of China (low risk), and Chinese-Americans of similar ages in San Francisco County, Calif, in the United States (high risk). The findings supported the hypotheses that colorectal cancer risk is increased by the consumption of high-fat, high-protein, and low-carbohydrate diets and is associated with high levels of cholesterol in stool as well as increased daily outputs of 3-methyl-histidine and malonaldehyde in urine. However, risk does not increase with low stool bulk and low total stool fibers.

Validity and reproducibility of a screening examination for neurological abnormality in persons exposed to methylmercury.

The validity and reliability of methods of screening for neurologic abnormality were assessed as part of an investigation of an outbreak of methylmercury exposure in two northern Canadian communities. Four hundred and forty-five Cree Indians were examined by one of five neurologists in a complete neurologic examination and by a trained paramedical observer in a short screening examination which included a selection of tests from the complete examination. The screening examinations were recorded on videotape and those for 176 men were reviewed by the five neurologists and the paramedical observer 1 year after the field studies. The prevalence of abnormality assessed in the field screening examination was greater than that assessed during the complete neurologic examination, for neurologic features included in both examinations. However, agreement between examinations in identifying individuals with abnormality was poor with the sensitivity of the screening examination falling under 50% for half of the neurologic features examined. In contrast, specificity was over 80% for 14 of 18 features. Review of the videotapes revealed marked interobserver variation in the assessment of the prevalence of neurologic abnormality and poor agreement with the neurologic examinations in the identification of abnormality in individuals, with kappa less than 0.2 for most neurologic features. The levels of agreement between the neurologic examinations and the screening examinations conducted in the field and by videotape review suggest that neither screening examination provides equivalent information in the identification of the presence of abnormality to that obtained in the neurologic examination.

A randomized trial of vitamins C and E in the prevention of recurrence of colorectal polyps.

Because supplements of vitamins C and E had been associated with reduction of fecal mutagen levels, a double-blind randomized trial was designed to examine the effects of these vitamins on the rate of recurrence of colorectal polyps, presumed precursors for colorectal cancer. Two hundred patients believed to be free of polyps after removal of at least one colorectal polyp were randomized to receive a supplement of 400 mg each of ascorbic acid and alpha-tocopherol, or a placebo. Fifteen patients had to be excluded because a review of pathology indicated that their polyps were not adenomatous. A second colonoscopic examination was planned after 2 yr of supplementation. One hundred thirty-seven people (75% of eligible subjects) completed the study; polyps were observed in the second colonoscopy in 41.4% of 70 subjects on vitamin supplements and in 50.7% of 67 subjects on placebos. After adjustment for differences between groups in demographic and dietary factors before study entry, the relative risk of polyp occurrence was 0.86, with 95% confidence limits from 0.51 to 1.45, in an analysis of 129 subjects with complete information on demographic and dietary factors who had completed the trial. Of the 48 patients who had not completed the study, 7 had died, 33 had not returned to their physician for an examination, and 8 had had a follow-up colonoscopy or sigmoidoscopy. Inclusion of the three polyps found in these eight examinations led to an estimate of relative risk of 0.86 (95% confidence limits, 0.51 to 1.43). The findings of this investigation suggest that any reduction in the rate of polyp recurrence associated with vitamin supplementation is small, and a larger study would be required to ensure that an effect of this size was not a chance finding.

Fiber intake in different populations and colon cancer risk.

It has been suggested that consumption of fiber may reduce the risk for colon cancer. A negative association has been reported between national rates of mortality from colon cancer and estimates of dietary fiber from cereals, based on the fiber content of foods available in the national diets. Total dietary fiber consumption estimated from dietary surveys also was negatively associated with bowel cancer rates in a comparison of four regions of Denmark and Finland, and nonstarch polysaccharides were negatively associated with regional cancer rates in Britain. However, no association with estimates of fiber consumption has been observed in three case-control studies, and one case-control study reported a positive association between fiber intake and colorectal cancer among women. Other epidemiological investigations have examined the relationship between bowel cancer and use of cereals, fruit, and vegetables, foods that contain fiber as well as other nutrients but have failed to produce consistent results among investigations employing different study designs. The National Academy of Sciences found in 1982 that there was "no conclusive evidence to indicate that dietary fiber exerts a protective effect against colorectal cancer in humans," and the present data still do not satisfy the epidemiological criteria required to establish beyond doubt a protective effect of fiber. Nevertheless, dietary guidelines, such as those from the National Academy of Sciences, which recommend reduced fat consumption and increased consumption of cereals, fruit, and vegetables represent the current state of knowledge and form the basis of a diet that is unlikely to do harm and may have the potential for reducing cancer rates in North America.

Assessment of past diet in epidemiologic studies.

The reproducibility of recall of diet was examined for 44 men in Toronto, Ontario, Canada, by comparing estimates of consumption obtained from a dietary questionnaire in 1982 with estimates of consumption made by recalling the original diet at an interview conducted one year later in 1983. Estimates of average consumption obtained by recall were significantly lower than those originally reported for most foods and nutrients, but the magnitude of the differences was never greater than 20% of the original estimate. Correlations between individuals' levels of consumption were greater than 0.7 for nine of the 13 foods and nutrients studied. Current diet, assessed from two-day food records, was also associated with consumption originally reported for some nutrients. Fecal levels of hemicellulose were associated with fiber consumption originally reported and with current fiber consumption, and urine levels of 3-methylhistidine were associated with past meat consumption. The best prediction of past consumption of fiber and fat, however, was obtained from the recalled diet. No significant additional contribution to the prediction was made from estimates of current consumption or from biochemical measures.