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Background: In two large, randomized prevention trials, supplementation with beta-carotene increased the risk of lung cancer. Subjects in these studies were predominantly cigarette smokers, and the adverse effects were concentrated among those who also drank alcohol. Although beta-carotene supplementation appeared not to increase the risk of cancer generally, it is not clear if smoking and/or alcohol use alters the effect of beta-carotene on carcinogenesis at sites outside the lung.Methods: We studied the effect of beta-carotene supplementation on colorectal adenoma recurrence among subjects in a multicenter double-blind, placebo-controlled clinical trial of antioxidants for the prevention of colorectal adenomas. A total of 864 subjects who had had an adenoma removed and were polyp-free were randomly assigned (in a factorial design) to receive beta-carotene (25 mg or placebo) and/or vitamins C and E in combination (1000 mg and 400 mg, respectively, or placebo), and were followed with colonoscopy for adenoma recurrence 1 year and 4 years after the qualifying endoscopy. A total of 707 subjects had two follow-up examinations and provided smoking and alcohol use data. Adjusted multivariate risk ratios (RRs) and 95% confidence intervals (CIs) were used to assess the effects of beta-carotene on adenoma recurrence.Results: Among subjects who neither smoked cigarettes nor drank alcohol, beta-carotene was associated with a marked decrease in the risk of one or more recurrent adenomas (RR = 0.56, 95% CI = 0.35 to 0.89), but beta-carotene supplementation conferred a modest increase in the risk of recurrence among those who smoked (RR = 1.36, 95% CI = 0.70 to 2.62) or drank (RR = 1.13, 95% CI = 0.89 to 1.43). For participants who smoked cigarettes and also drank more than one alcoholic drink per day, beta-carotene doubled the risk of adenoma recurrence (RR = 2.07, 95% CI = 1.39 to 3.08; P for difference from nonsmoker/nondrinker RR <.001).Conclusion: Alcohol intake and cigarette smoking appear to modify the effect of beta-carotene supplementation on the risk of colorectal adenoma recurrence. [ABSTRACT FROM AUTHOR]

Background: Human evidence that ionizing radiation is carcinogenic first came from reports of nonmelanoma skin cancers (NMSCs) on the hands of workers using early radiation devices. An increased risk of NMSC has been observed among uranium miners, radiologists, and individuals treated with x rays in childhood for tinea capitis (ringworm of the scalp) or for thymic enlargement; NMSC is one of the cancers most strongly associated with the atomic bombing of Hiroshima and Nagasaki. Although exposure to ionizing radiation is a known cause of NMSC, it is not yet clear whether therapeutic radiation causes both major histologic types of NMSC, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Additionally, the potentially modifying effects, such as latency, age when treated, and type of treatment, are not well understood.Purpose: We investigated the relative risks of BCC and SCC associated with previous radiation therapy and evaluated these risks in relation to age and time since initial treatment and the medical condition for which radiation therapy was given.Methods: The study group comprised individual diagnosed with at least one BCC or SCC from January 1980 through February 1986, who were recruited to participate in a skin cancer prevention trial designed to test whether oral beta-carotene supplementation would reduce the risk of new NMSCs. Patients were identified through the dermatology and pathology records of academic medical centers in Hanover, NH; Los Angeles, CA; San Francisco, CA; and Minneapolis, MN. Each participant completed a questionnaire detailing lifetime residence, pigmentary characteristics, occupational and recreational sun exposure, and history of radiation therapy. At enrollment, a study dermatologist assessed skin type (tendency to burn or tan) and extent of actinic skin damage. Participants were followed with an annual dermatologic examination for an average of 4 years. Of the 5232 potentially eligible individuals, 1805 were enrolled in the trial. We excluded 112 patients who reported previous radiation therapy for skin cancer only and three with missing information on whether they were ever treated with radiation therapy, leaving 1690 patients for the analysis. Approximately 4% of the patients died or discontinued participation for other reasons during each study year. We examined time to occurrence of first new histopathologically confirmed BCC and SCC during the follow-up period in relation to history of radiation therapy (for reasons other than NMSC) using a proportional hazards model. A multiple end points survival model was used to compare the rate ratios (RRs) for BCC and SCC. We also used a longitudinal method of analysis to compute the RR of total new BCC and SCC tumors per person per study year associated with radiation therapy. Using this method, we additionally assessed the potential modifying effects of age at treatment, latency, and type of therapy. All P values were derived from two-sided statistical tests of significance.Results: Among the participants we studied, 597 developed a new BCC (n = 1553 tumors) and 118 developed a new SCC (n = 179 tumors). The time to first new BCC, but not SCC, was associated with prior radiation therapy (RR = 1.7; 95% confidence interval [CI] = 1.4-2.0 and RR = 1.0; 95% CI = 0.6-1.7, respectively; P = .03 for the difference between the RRs). The RR of total BCC tumors was slightly higher (RR = 2.3; 95% CI = 1.7-3.1), but it was still unity for SCC (RR = 1.0; 95% CI = 0.5-1.9). BCC risk appeared to increase with younger age at exposure and time since initially treated, although these effects were only marginally statistically significant (P for trend = .06 and .07, respectively). Also, risk of BCC was more strongly related to treatment for acne (RR = 3.3; 95% CI = 2.1-5.2) than other conditions.Conclusions and Implications: Our data suggest that exposure to therapeutic radiation is associated with BCC but not with SCC. [ABSTRACT FROM AUTHOR]

Objective: To investigate the potential determinants of Helicobacter pylori infection between adults 21-65 years old., Methods: Data are from the initial screening visit of a randomized clinical trial of three antibiotic regimens to eradicate H. pylori, conducted in seven sites (Santiago-Chile, Túquerres-Colombia, Guanacaste-Costa Rica, Copán-Honduras, Obregón and Tapachula-México, León-Nicaragua). Thousand eight hundred and fifty-nine adults from the general population were screened for H. pylori infection using an urea breath test (UBT) and were interviewed to assess socioeconomic-, demographic-, and symptom-related characteristics. Logistic regression was used to assess the relationship between these characteristics and H. pylori positivity at enrollment., Results: Among the 1,852 eligible participants for whom a conclusive UBT result was obtained, H. pylori prevalence was 79.4 %, ranging from 70.1 to 84.7 % among the seven centers. Prevalence did not differ by sex (female: 78.4, male: 80.9; p = 0.20) or age (p = 0.08). H. pylori positivity increased with increasing number of siblings (p trend <0.0001). Participants with education beyond 12 years were less likely to be UBT-positive (OR 0.4: 0.3-0.6, compared to participants with 0-6 years of schooling) as were those employed outside the home (OR 0.7: 0.6-1.0). Odds of H. pylori infection increased with the presence of certain living conditions during childhood including having lived in a household with an earth floor (OR 1.8: 1.4-2.4), lack of indoor plumbing (OR 1.3: 1.0-1.8) and crowding (OR 1.4: 1.0-1.8, for having more than two persons per bedroom). Regarding current household conditions, living with more than 3 children in the household (OR 1.7: 1.2-2.5) and crowding (OR 1.8: 1.3-2.3) were associated with H. pylori infection., Conclusions: The prevalence of H. pylori in adults was high and differed significantly among the six Latin American countries studied (p < 0.001). Our findings confirm the strong link between poor socioeconomic conditions and H. pylori infection.

A direct relation between body mass index (BMI) and risk of colorectal adenomas and cancer has been reported, but few studies have had adequate sample size for conducting stratified analyses by sex, family history, colorectal subsite, or features of metachronous lesions. Data from 8,213 participants in 7 prospective studies of metachronous colorectal adenomas were pooled to assess whether the association between BMI and metachronous neoplasia varied by these factors. A statistically significant direct association between BMI and the odds of nonadvanced adenomas (P(trend) < 0.001) was observed, while the relation for advanced adenomas was of marginal significance (P(trend) < 0.07). In sex-stratified analyses, obesity was statistically significantly associated with the odds of any metachronous lesion among men (odds ratio = 1.36, 95% confidence interval: 1.17, 1.58) but not among women (odds ratio = 1.10, 95% confidence interval: 0.89, 1.37). The associations with BMI appeared to be limited to proximal neoplasia, with statistically significant results for BMI and proximal (P(trend) < 0.001), but not distal (P(trend) < 0.85), neoplasia. Exploratory analyses indicated that BMI was significantly related to most histologic characteristics of metachronous adenomas among men but not among women. Our results provide further support for the association between BMI and metachronous colorectal adenomas, particularly among men, thereby indicating that body size may affect colorectal carcinogenesis at comparatively early stages.

Background & Aims: Limited data exist regarding the actual risk of developing advanced adenomas and cancer after polypectomy or the factors that determine risk., Methods: We pooled individual data from 8 prospective studies comprising 9167 men and women aged 22 to 80 with previously resected colorectal adenomas to quantify their risk of developing subsequent advanced adenoma or cancer as well as identify factors associated with the development of advanced colorectal neoplasms during surveillance., Results: During a median follow-up period of 47.2 months, advanced colorectal neoplasia was diagnosed in 1082 (11.8%) of the patients, 58 of whom (0.6%) had invasive cancer. Risk of a metachronous advanced adenoma was higher among patients with 5 or more baseline adenomas (24.1%; standard error, 2.2) and those with an adenoma 20 mm in size or greater (19.3%; standard error, 1.5). Risk factor patterns were similar for advanced adenomas and invasive cancer. In multivariate analyses, older age (P < .0001 for trend) and male sex (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.19-1.65) were associated significantly with an increased risk for metachronous advanced neoplasia, as were the number and size of prior adenomas (P < .0001 for trend), the presence of villous features (OR, 1.28; 95% CI, 1.07-1.52), and proximal location (OR, 1.68; 95% CI, 1.43-1.98). High-grade dysplasia was not associated independently with metachronous advanced neoplasia after adjustment for other adenoma characteristics., Conclusions: Occurrence of advanced colorectal neoplasia is common after polypectomy. Factors that are associated most strongly with risk of advanced neoplasia are patient age and the number and size of prior adenomas.

Background & Aims: Hypergastrinemia and Helicobacter pylori (Hp) infection have been associated with an increased risk for colorectal neoplasia in some studies. However, data from large prospective studies of both associations are lacking. The aim of this study was to evaluate whether serum gastrin levels and/or infection with Hp are associated with the subsequent development of colorectal adenomas., Methods: Subjects (all with a history of adenoma formation) were drawn from 2 previously completed adenoma chemoprevention trials. Participants underwent clearing colonoscopy at baseline with follow-up colonoscopy 1 and 4 years after enrollment. We used commercially available assays on fasting blood specimens to measure serum gastrin levels and Hp serologies 1 year after randomization. Risk ratios for adenoma and advanced adenoma development during the subsequent 3 years were computed by generalized linear regression., Results: Of the 1794 subjects randomized in the 2 trials, 685 had available serum and were included in the analyses. Gastrin levels were significantly higher in the 239 subjects with Hp titers indicating infection (mean, 88.3 pg/mL) than in those not infected (mean, 73.9 pg/mL; P < .001). In fully adjusted models, gastrin levels were not associated with incident adenoma development (risk ratio [RR], 1.10; 95% confidence interval [CI], 0.78-1.54) or advanced adenoma formation (RR, 0.82; 95% CI, 0.33-2.03). A positive Hp serology was associated with a decreased risk for adenoma formation (RR, 0.76; 95% CI, 0.60-0.96)., Conclusions: Neither hypergastrinemia nor serologic evidence of Hp infection were associated with an increased risk for recurrent adenoma development. These results do not support the notion that gastrin promotes colorectal carcinogenesis, at least at the stage of adenoma development.

Objective: Current standards of care for early-stage breast cancer include either breast-conserving surgery (BCS) with post-operative radiation or mastectomy. A variety of factors influence the type of treatment chosen. In northern, rural areas, daily travel for radiation can be difficult in winter. We investigated whether proximity to a radiation treatment facility (RTF) and season of diagnosis affected treatment choice for New Hampshire women with early-stage breast cancer., Methods: Using a population-based cancer registry, we identified all women residents of New Hampshire diagnosed with stage I or II breast cancer during 1998-2000. We assessed factors influencing treatment choices using multivariate logistic regression., Results: New Hampshire women with early-stage breast cancer were less likely to choose BCS if they live further from a RTF (P < 0.001). Of those electing BCS, radiation was less likely to be used by women living >20 miles from a RTF (P = 0.002) and those whose diagnosis was made during winter (P = 0.031)., Conclusion: Our findings indicate that a substantial fraction of women with early-stage breast cancer in New Hampshire receive suboptimal treatment by forgoing radiation because of the difficulty traveling for radiation in winter. Future treatment planning strategies should consider these barriers to care in cold rural regions.

Background: Prior studies suggest that histamines may modulate the development of colorectal neoplasia., Aim: To assess whether histamine receptor antagonist use was associated with adenoma formation., Methods: Patients (n = 2366) were drawn from three adenoma chemoprevention trials. All underwent baseline colonoscopy with removal of adenoma(s) and were deemed free of remaining lesions; they were followed with surveillance colonoscopy. Medication use was assessed by questionnaire. Adjusted risk ratios for adenoma formation related to histamine receptor antagonist use (histamine H1 and H2 receptor, H1RA and H2RA) were determined using log linear models., Results: In pooled analyses, H1RA exposure was not associated with subsequent adenoma risk (RR = 1.10; 95% CI 0.97-1.25) or multiple adenoma formation (RR = 0.85; 95% CI 0.67-1.07). H2RA use also was not associated with adenoma (RR = 0.90; 95% CI 0.77-1.06), or multiple adenoma (RR = 0.77; 95% CI 0.57-1.04) in the pooled analyses, but H2RA users in the first trial had a decreased risk of adenoma (RR = 0.70; 95% CI 0.48-1.03) and multiple adenoma (RR = 0.31; 95% CI 0.12-0.79)., Conclusion: H2RA use was associated with reduced risk for adenoma in one trial, but not in the pooled analyses. Further study would be warranted before undertaking randomized trials of H2RAs for adenoma chemoprevention.

Background & Aims: Colonoscopic polypectomy is considered effective for preventing colorectal cancer (CRC), but the incidence of cancer in patients under colonoscopic surveillance has rarely been investigated. We determined the incidence of CRC in patients under colonoscopic surveillance and examined the circumstances and risk factors for CRC and adenoma with high-grade dysplasia., Methods: Patients were drawn from 3 adenoma chemoprevention trials. All underwent baseline colonoscopy with removal of at least one adenoma and were deemed free of remaining lesions. We identified patients subsequently diagnosed with invasive cancer or adenoma with high-grade dysplasia. The timing, location, and outcome of all cases of cancer and high-grade dysplasia identified are described and risks associated with their development explored., Results: CRC was diagnosed in 19 of the 2915 patients over a mean follow-up of 3.7 years (incidence, 1.74 cancers/1000 person-years). The cancers were located in all regions of the colon; 10 were at or proximal to the hepatic flexure. Although most of the cancers (84%) were of early stage, 2 participants died of CRC. Seven patients were diagnosed with adenoma with high-grade dysplasia during follow-up. Older patients and those with a history of more adenomas were at higher risk of being diagnosed with invasive cancer or adenoma with high-grade dysplasia., Conclusions: CRC is diagnosed in a clinically important proportion of patients following complete colonoscopy and polypectomy. More precise and representative estimates of CRC incidence and death among patients undergoing surveillance examinations are needed.

Background: In some studies, high calcium intake has been associated with an increased risk of prostate cancer, but no randomized studies have investigated this issue., Methods: We randomly assigned 672 men to receive either 3 g of calcium carbonate (1,200 mg of calcium), or placebo, daily for 4 years in a colorectal adenoma chemoprevention trial. Participants were followed for up to 12 years and asked periodically to report new cancer diagnoses. Subject reports were verified by medical record review. Serum samples, collected at randomization and after 4 years, were analyzed for 1,25-(OH)2 vitamin D, 25-(OH) vitamin D, and prostate-specific antigen (PSA). We used life table and Cox proportional hazard models to compute rate ratios for prostate cancer incidence and generalized linear models to assess the relative risk of increases in PSA levels., Results: After a mean follow-up of 10.3 years, there were 33 prostate cancer cases in the calcium-treated group and 37 in the placebo-treated group [unadjusted rate ratio, 0.83; 95% confidence interval (95% CI), 0.52-1.32]. Most cases were not advanced; the mean Gleason's score was 6.2. During the first 6 years (until 2 years post-treatment), there were significantly fewer cases in the calcium group (unadjusted rate ratio, 0.52; 95% CI, 0.28-0.98). The calcium risk ratio for conversion to PSA >4.0 ng/mL was 0.63 (95% CI, 0.33-1.21). Baseline dietary calcium intake, plasma 1,25-(OH)2 vitamin D and 25-(OH) vitamin D levels were not materially associated with risk., Conclusion: In this randomized controlled clinical trial, there was no increase in prostate cancer risk associated with calcium supplementation and some suggestion of a protective effect.

Background: Secondary analyses of data from a large randomized clinical trial have suggested that intake of the trace element selenium reduces risk of colorectal neoplasia, but epidemiologic studies have not shown a consistent protective association., Methods: We conducted a combined analysis of data from three randomized trials--the Wheat Bran Fiber Trial, the Polyp Prevention Trial, and the Polyp Prevention Study--which tested the effects of various nutritional interventions for colorectal adenoma prevention among participants who recently had an adenoma removed during colonoscopy. Selenium concentrations were measured from blood specimens from a total of 1763 trial participants, and quartiles of baseline selenium were established from the pooled data. To estimate the association between baseline selenium and colorectal adenoma risk, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression modeling. All statistical tests were two-sided., Results: Individual study results among participants whose blood selenium concentrations were in the highest versus the lowest quartile varied in magnitude (Polyp Prevention Trial: OR = 0.67, 95% CI = 0.43 to 1.05; P(trend) = .21; Wheat Bran Fiber Trial: OR = 0.66, 95% CI = 0.40 to 1.10; P(trend) = .13, and Polyp Prevention Study: OR = 0.57, 95% CI = 0.34 to 0.95, P(trend) = .04). Analyses of the pooled data showed that individuals whose blood selenium values were in the highest quartile (median = 150 ng/mL) had statistically significantly lower odds of developing a new adenoma compared with those in the lowest quartile (OR = 0.66, 95% CI = 0.50 to 0.87; P(trend) = .006)., Conclusions: The inverse association between higher blood selenium concentration and adenoma risk supports previous findings indicating that higher selenium status may be related to decreased risk of colorectal cancer.

Several studies have suggested that selenium may help to prevent colorectal neoplasia. To investigate the relation between prediagnostic serum selenium concentrations and colorectal adenomas, we conducted a nested case-control study using data from a large, multicenter, adenoma prevention trial. Cases comprised a total of 276 patients who developed a colorectal adenoma between the year 1 and year 4 follow-up exam. Controls were 276 patients who did not develop an adenoma during this time interval, matched to case subjects on age, sex, and clinical center. Total and bound selenium concentrations were measured from baseline or year 1 serum samples using instrumental neutron activation analysis. We estimated the odds ratios of colorectal adenoma in relation to serum selenium concentrations adjusting for age, clinical center, and sex. Compared with the lowest quintile, the odds ratio for the highest quintile was 0.76 (95% confidence interval, 0.44-1.30) for total selenium and 0.60 (95% confidence interval, 0.34-1.05) for bound selenium, and there was no apparent trend in risk (P for trend = 0.50 for total selenium and P for trend = 0.20 for bound selenium). Thus, our findings do not indicate a clear association between serum selenium concentrations and adenoma recurrence.

We evaluated the role of early life factors in a large, population-based, case-control study of breast cancer risk in postmenopausal women. Case women in Massachusetts, New Hampshire, and Wisconsin were ascertained through state cancer registries; control women were randomly selected from drivers license lists (50-65 years of age) or Medicare beneficiary lists (65-79 years of age). Information concerning factors of interest was obtained through structured telephone interviews. Overall, 83% of eligible cases and 78% of eligible controls participated, and data from more than 2900 women were available for this analysis. We observed a weak J-shaped relationship between birth weight and breast cancer risk; the increased risk was not statistically significant for either the lowest or the highest birth weight. Parental smoking during the pregnancy was not associated with risk of breast cancer in the adult daughter. Breast cancer risk increased significantly with father's education (P = 0.01). Risk also increased with greater age of the mother at the time of the subject's birth (P = 0.04). The subject's birth rank was inversely associated with risk (P = 0.03), as was the number of older sisters (P = 0.03), but the number of older brothers, number of younger siblings, sibship gender ratio, and total sibship size were unrelated to risk. Overall, our results are consistent with previous studies and suggest that these early life factors have a modest influence on breast cancer risk in postmenopausal women.

Objective: To clarify the hormonal context of breast cancer etiology we used data from a large, population-based case-control study to investigate the relationship between breast cancer risk and a history of diabetes mellitus, disorders associated with estrogen stimulation (uterine fibroids, endometriosis, gallstones), and disorders associated with androgen stimulation (acne, hirsutism, and polycystic ovaries)., Methods: Breast cancer patients between 50 and 75 years old were identified from state-wide tumor registries in Wisconsin, Massachusetts, and New Hampshire; controls were randomly selected from drivers' license lists (age less than 65) or Medicare enrollment files (age 65-74). Information on reproductive history, medical history, and personal habits was obtained by telephone interview. A total of 5659 cases and 5928 controls were interviewed and provided suitable data., Results: There was no overall association between breast cancer risk and reported history of diabetes mellitus, endometriosis, uterine fibroids, gallstones, or cholecystectomy. However, the disorders with androgenic associations all conferred an increased risk: the overall odds ratio (OR) for a history of acne was 1.4 (95% CI 1.0-1.9), that for hirsutism was 1.2 (95% CI 0.81-1.8), and that for polycystic ovaries 1.6 (95% CI 0.8-3.2). Diabetes mellitus diagnosed before age 35 conferred an odds ratio of 0.52 (95% 0.25-1.1), while diabetes diagnosed at a later age was associated with an increased risk (OR = 1.2, 95% CI 1.0-1.4)., Conclusions: Androgen-related phenomena are likely to be important in the etiology of breast cancer.

Non-melanoma skin cancer (NMSC) is an important cause of morbidity and long-term mortality in organ transplant recipients receiving immunosuppressive drugs such as azathioprine and cyclosporin, often combined with adrenocortical steroids (glucocorticoids). At lower doses, glucocorticoids alone are prescribed for other conditions including musculoskeletal, connective tissue and respiratory disorders. Presently, it is unknown whether patients taking glucocorticoids are at an increased risk of skin malignancies. In a population-based case-control study in New Hampshire, USA, we compared use of glucocorticoids in 592 basal cell carcinoma (BCC) and 281 squamous cell carcinoma (SCC) cases and in 532 age and gender matched controls; neither cases nor controls had a history of organ transplantation. Participants underwent a structured personal interview regarding history of medication use and skin cancer risk factors. We used unconditional logistic regression analysis to compute odds ratios associated with glucocorticoid use for 1 month or longer while controlling for potential confounding factors. Risk of SCC was increased among users of oral glucocorticoids (adjusted odds ratio = 2.31; 95% CI = 1.27, 4.18), and risk of BCC was elevated modestly (adjusted odds ratio = 1.49; 95% CI = 0.90, 2.47). In contrast, risk of both SCC and BCC were unrelated to use of inhaled steroids. Our data suggest that use of oral glucocorticoids may increase risk of NMSC, and SCC in particular, among patients other than organ transplant recipients. We hypothesize that immunosuppression induced by oral glucocorticoids may allow these cancers to emerge from immunosurveillance., (Copyright 2001 Cancer Research Campaign.)

Arsenic is a known carcinogen specifically linked to skin cancer occurrence in regions with highly contaminated drinking water or in individuals who took arsenic-containing medicines. Presently, it is unknown whether such effects occur at environmental levels found in the United States. To address this question, the authors used data collected on 587 basal cell and 284 squamous cell skin cancer cases and 524 controls interviewed as part of a case-control study conducted in New Hampshire between 1993 and 1996. Arsenic was determined in toenail clippings using instrumental neutron activation analysis. The odds ratios for squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) were close to unity in all but the highest category. Among individuals with toenail arsenic concentrations above the 97th percentile, the adjusted odds ratios were 2.07 (95% confidence interval (CI): 0.92, 4.66) for SCC and 1.44 (95% CI: 0.74, 2.81) for BCC, compared with those with concentrations at or below the median. While the risks of SCC and BCC did not appear elevated at the toenail arsenic concentrations detected in most study subjects, the authors cannot exclude the possibility of a dose-related increase at the highest levels of exposure experienced in the New Hampshire population.

We assessed menstrual and reproductive factors in relation to ovarian cancer risk in a large, population-based, case-control study. 563 cases in Massachusetts and New Hampshire were ascertained from hospitals and statewide tumour registries; control women (n = 523) were selected through random digit dialing and matched to case women by age and telephone sampling unit. We used multivariate logistic regression to evaluate factors in relation to risk of ovarian cancer and the major tumour histologic subtypes. Ovarian cancer risk was reduced among parous women, relative to nulliparous women (OR = 0.4; 95% CI = 0.3-0.6). Among parous women, higher parity (P = 0.0006), increased age at first (P = 0.03) or last (P = 0.05) birth, and time since last birth (P = 0.04) were associated with reduced risk. Early pregnancy losses, abortions, and stillbirths were unrelated to risk, but preterm, term, and twin births were protective. Risk was lower among women who had breast-fed, relative to those who had not (OR = 0.7; 95% CI = 0.5-1.0), but the average duration of breast-feeding per child was unrelated to risk (P for trend = 0.21). Age at menarche and age at menopause were unrelated to risk overall, although increasing menarcheal age was protective among premenopausal women (P = 0.02). Menstrual cycle characteristics and symptoms were generally unrelated to risk, although cycle-related insomnia was associated with decreased risk (OR = 0.5; 95% CI = 0.3-0.8). We found no association between the type of sanitary product used during menstruation and ovarian cancer risk. In analyses by histologic subtype, reproductive and menstrual factors had most effect on risk of endometrioid/clear cell tumours, and least influential with regard to risk of mucinous tumours. Overall, our findings offer some support to current hypotheses of ovarian pathogenesis, and show aetiologic differences among the tumour subtypes., (Copyright 2001 Cancer Research Campaign.)

From 1940 through the 1960s, diethylstilbestrol (DES), a synthetic oestrogen, was given to pregnant women to prevent pregnancy complications and losses. Subsequent studies showed increased risks of reproductive tract abnormalities, particularly vaginal adenocarcinoma, in exposed daughters. An increased risk of breast cancer in the DES-exposed mothers was also found in some studies. In this report, we present further follow-up and a combined analysis of two cohorts of women who were exposed to DES during pregnancy. The purpose of our study was to evaluate maternal DES exposure in relation to risk of cancer, particularly tumours with a hormonal aetiology. DES exposure status was determined by a review of medical records of the Mothers Study cohort or clinical trial records of the Dieckmann Study. Poisson regression analyses were used to estimate relative risks (RR) and 95% confidence intervals (CI) for the relationship between DES and cancer occurrence. The study results demonstrated a modest association between DES exposure and breast cancer risk, RR = 1.27 (95% CI = 1.07-1.52). The increased risk was not exacerbated by a family history of breast cancer, or by use of oral contraceptives or hormone replacement therapy. We found no evidence that DES was associated with risk of ovarian, endometrial or other cancer., (Copyright 2001 Cancer Research Campaign.)

Both body iron stores and dietary iron intake have been reported to increase risk of colorectal neoplasms. We assessed whether serum ferritin concentration was associated with recurrence of colorectal adenomas among 733 individuals with baseline determinations of ferritin as part of a multicenter clinical trial of antioxidant supplements for adenoma prevention. All study participants had at least one adenoma removed within 3 months before enrollment, and 269 of them developed one or more adenomas between follow-up colonoscopies conducted 1 and 4 years after enrollment. Baseline serum ferritin concentrations were analyzed both as a log-transformed continuous variable and as a categorical variable, defined as whether iron stores were nonreplete and low (ferritin < or =30 microg/liter), nonreplete and borderline (31-70 microg/liter), replete and adequate (71-160 microg/liter), or replete and high (>160 microg/liter). Analyses were based on multiple logistic regression models, including age, sex, study center, energy, alcohol, fiber, folate, and total fat intake, number of months between colonoscopic examinations, smoking status, and aspirin use. Overall, there was no statistically significant linear association between log ferritin concentration and adenoma recurrence (P = 0.33). Risk of adenoma recurrence was modestly increased among participants with ferritin concentrations >70 microg/liter relative to those with lower ferritin (odds ratio, 1.39; 95% confidence interval, 0.96-2.02). This result seemed more pronounced among women than men. Dietary intake of iron and red meat was inversely associated with adenoma recurrence among participants with replete iron stores but not consistently associated among those with nonreplete stores. Our findings suggest that any role of iron stores and dietary iron in influencing risk of colorectal adenoma recurrence is likely complex.

It is not yet known whether early-life physical activity reduces the risk of developing breast cancer. Subgroup analyses according to menopausal status and body mass may help clarify this association. Data from a population-based case-control study of female residents of Wisconsin, Massachusetts, Maine, and New Hampshire were used to examine associations between body mass and breast cancer risk. Cases (n = 4614) were identified by each state's tumor registry; controls (n = 5817) were randomly selected from population lists. Frequency of participation in strenuous physical activity when 14-22 years of age, weight at age 18 and 5 years before interview, height, and other factors were ascertained through structured telephone interviews. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using logistic regression. Reductions in postmenopausal breast cancer risk associated with strenuous physical activity were greatest for women in the fourth quartile of body mass index at age 18; the OR for women with the highest activity frequency on average (> or =once/day) was 0.45 (95% CI = 0.26-0.79). Associations with frequency of activity also varied by weight change. Compared to women with no activity and little adult weight gain, frequent physical activity was associated with reduced postmenopausal breast cancer risk in women who had lost weight since age 18 (OR = 0.19, 95% CI = 0.05-0.70) or had gained little or modest amounts of weight (weight gain: first tertile, OR = 0.36, 95% CI = 0.05-0.85; second tertile, OR = 0.31, 95% CI = 0.14-0.66). Weighted MET score analyses yielded similar but less inverse results. These findings suggest that the reduced risk of postmenopausal breast cancer associated with frequent, early-life physical activity may be greatest in women who, over the adult years, either lost weight or gained only modest amounts.

The authors analyzed data from two multistate, population-based case-control studies to investigate the association between age at any full-term pregnancy (FP) and breast cancer risk. Study subjects included breast cancer cases aged 20-79 years identified from four statewide cancer registries and randomly selected controls interviewed from 1988 to 1996. Complete information on a comprehensive set of risk factors for breast cancer was available for 9,891 cases and 12,271 controls. The large number of subjects enabled simultaneous adjustment of the covariates and efficient application of various modeling approaches. Overall, each 5-year increase in age at first FP was associated with an odds ratio of 1.07 (95% confidence interval (CI): 1.01, 1.13) for breast cancer. The corresponding estimates were odds ratio = 1.02 (95% CI: 1.00, 1.05) for age at second through ninth FPs. For age at last FP, the effect estimate (odds ratio = 1.01, 95% CI: 0.97, 1.06) was indistinguishable from that for other FPs after the first. In this analysis, a modest and transient increase in breast cancer risk after childbirth was also observed. The relatively greater effect of age at first FP is consistent with the existence of a long-term effect of early first FP on the differentiation of mammary cells, causing them to become less susceptible to carcinogenesis.

Breast cancer risk may be influenced by intrauterine exposure to steroid hormones. We evaluated left-handedness, a marker of intrauterine hormone exposure, in relation to breast cancer risk in our population-based, case-control study. Case women 50-79 years of age with a first diagnosis of invasive breast cancer were ascertained through statewide cancer registries in Wisconsin, Massachusetts, and New Hampshire. Control women were identified in each state through lists of licensed drivers (for ages 50-64) and Medicare beneficiaries (for ages 65-79), and selected at random to correspond with the age distribution of case women. Exposure information, including handedness, was obtained through a telephone interview. Our results indicated a modest association between left-handedness and breast cancer risk (OR = 1.42; 95% CI = 1.10-1.83). The effect of left-handedness was modified by age; we observed the greatest risk ratio in the oldest age group. Left-handedness was not associated with breast tumor laterality. Our results are consistent with the hypothesis that intrauterine hormone exposures play a role in the development of breast cancer.

Consumption or metabolism of dairy sugar and ovarian cancer have been linked based on evidence that galactose may be toxic to ovarian germ cells and that ovarian cancer is induced in animals by depletion of oocytes. We assessed consumption of dairy products and obtained blood for biochemical and molecular genetic assessment of galactose metabolism in 563 women with newly diagnosed epithelial ovarian cancer and 523 control women selected either by random digit dialing or through lists of residents in eastern Massachusetts and New Hampshire. We observed no significant differences between cases and controls in usual consumption of various types of dairy products or total daily lactose (the principal source of galactose in the diet); nor did we find that RBC activity of either galactose-1-phosphate uridyl transferase (GALT) or galactokinase differed. The mean (and SE) activity of uridine diphospho-galactose 4'-epimerase (in micromoles per hour per gram of hemoglobin) was, however, significantly lower (P < 0.005) in cases compared with controls, 20.32 (0.31) versus 21.64 (0.36). Ovarian cancer cases were also more likely to carry the N314D polymorphism of the GALT gene, generally predisposing to lower GALT activity. The difference was most evident for endometrioid and clear cell types of ovarian cancer, in which 3.9% of cases were found to be homozygous for N314D compared with 0.4% of controls, yielding an odds ratio and 95% confidence interval of 14.17 (2.62-76.60). We conclude that, whereas adult consumption of lactose carries no clear risk for the disease, certain genetic or biochemical features of galactose metabolism may influence disease risk for particular types of ovarian cancer.

A modest inverse association between lactation and breast cancer risk has most consistently been observed in premenopausal women, and certain breastfeeding patterns, such as prolonged duration and early age at first lactation, may be important determinants of risk. However, these associations have not generally been observed in relation to postmenopausal breast cancer. As part of a multicenter population-based case-control study, the authors examined postmenopausal breast cancer risk according to breastfeeding characteristics. Breast cancer patients aged 50-79 years were identified from statewide tumor registries in Massachusetts, New Hampshire, and Wisconsin from July 1992 through July 1995. Similarly aged control women were randomly selected from population lists. Information regarding lactation history and breast cancer risk factors was obtained through telephone interviews. This analysis included only data on parous postmenopausal women (3,633 cases and 3,790 controls). After adjustment for age, parity, age at first birth, and other breast cancer risk factors, breastfeeding for at least 2 weeks was associated with a slightly reduced risk of breast cancer in comparison with women who had never lactated (relative risk = 0.87, 95% confidence interval 0.78-0.96). There was only a modest suggestion that increasing cumulative duration of lactation was inversely associated with breast cancer risk; the relative risk for women who had breastfed for > or =24 months was 0.73 (95% confidence interval 0.56-0.94) (p-trend for duration = 0.10). Age at first lactation was not consistently associated with risk. Modest inverse associations appeared to persist even up to 50 years since first lactation. Use of hormones to suppress lactation was not associated with postmenopausal breast cancer, nor was inability to breastfeed related to risk. These results suggest that lactation may have a slight and perhaps long-lasting protective effect on postmenopausal breast cancer risk.

We evaluated menstrual factors in relation to breast cancer risk in a large, population-based, case-control study. Case women were ascertained through state-wide registries covering Wisconsin, Western Massachusetts, Maine, and New Hampshire; control women were randomly selected from driver's license and Medicare lists in each state. Information regarding menstrual characteristics was obtained through a telephone interview. The study population comprised 6888 breast cancer cases and 9529 control women. Because exogenous hormones influence menstrual cycle patterns, we repeated our analyses in a subgroup of women who had never used oral contraceptives or hormone replacement therapy. Our results indicate decreased breast cancer risk with menarcheal age of 15 years or more, relative to menarche at age 13; the relation was stronger among premenopausal [odds ratio (OR), 0.72; 95% confidence interval (CI), 0.57-0.91] as opposed to postmenopausal women (OR, 0.90; 95% CI, 0.80-1.03). Risk was slightly reduced among premenopausal women whose menstrual cycles did not become regular until at least 5 years after onset of menses, relative to those whose cycles became regular within 1 year (OR, 0.80; 95% CI, 0.63-1.02). There was no clear relation between breast cancer risk and irregular menstrual cycles, episodes of amenorrhea, or menstrual cycle length. Early menopause, whether natural or surgical, was associated with decreased breast cancer risk; surgical menopause before age 40 conferred the strongest protective effect (OR, 0.57; 95% CI, 0.47-0.71). We found no evidence of increased risk with late natural menopause (OR, 0.92; 95% CI, 0.80-1.06). Results in the subgroup of women who never used exogenous hormones were similar to those for the entire group.

Intake of dairy products and major dairy constituents (e.g., calcium) has been proposed to reduce the risk of colorectal cancer, although epidemiological studies have yielded inconclusive results. We conducted a randomized cross-over trial to test the effects of high- and low-dairy consumption diets on rectal mucosal proliferation, a possible intermediary marker for large bowel cancer. From a gastroenterology clinic at an academic medical center, we recruited 40 patients, ages 25-79 years, who had either a history of a large bowel adenoma or a first-degree relative with large bowel cancer. Participants completed a baseline questionnaire covering demographic characteristics, health history, and habits and a food frequency questionnaire. They were randomized to a 12-week diet of either high dairy intake (six dairy servings/day) or low dairy intake (<0.5 serving of dairy products/day), with an intervening 12-week washout period in which they were asked to resume their usual diet before crossing over to the alternate study diet for the last 12-week period of the study. Adherence to the study diets was monitored by a daily dairy intake checklist and periodic, unscheduled 24-h dietary recalls. Biopsies of the rectal mucosa were obtained at the beginning and end of each intervention phase. Two assays of rectal mucosal cell proliferation were performed: immunohistochemical determination of proliferating cell nuclear antigen and whole crypt mitotic count. We found no statistically significant changes in either of these proliferation measures as a result of high or low dairy intake. There was no correlation between the labeling index for proliferating cell nuclear antigen and whole crypt mitotic count; however, measures of the location and intensity of cell proliferation within the rectal crypt were highly correlated between the two assays. Thus, our study indicates that greater consumption of dairy products over a 12-week period does not change rectal mucosal cell proliferation.

Long-term use of psychotropic medication may increase the risk for epithelial ovarian cancer through increased gonadotropin secretion or direct ovarian stimulation of adrenergic receptors, effects which may affect ovarian cancer pathogenesis. An earlier case-control study found that prior use of antidepressants or benzodiazepine tranquilizers was associated with a 2-fold increase in risk of epithelial ovarian cancer. However, that study lacked details on all types of psychotropic medications, length of use, and the categorization of the specific action of these medications on the hypothalamic-pituitary-ovarian axis. In a new case-control study conducted in eastern Massachusetts (MA) and all of New Hampshire (NH), we identified all women with newly diagnosed ovarian cancer between May 1992 and March 1997. We interviewed 563 women diagnosed with malignant or borderline epithelial ovarian tumors and 523 controls identified through random digit dialing and the use of Town Books (residential listings by name, age, and precinct). Participants were asked to provide the name of medications used for 6 months or longer, the age at first use, and total months or years of use. Psychotropic medications included amphetamines, sedatives, barbiturates/anticonvulsants, antidepressants, and antipsychotics. Self-reported use of psychotropic medication for 6 months or longer was associated with a statistically significant increase in risk of invasive ovarian cancer [odds ratio (OR), 1.6; 95% confidence interval (CI), 1.1-2.3]. Relative to nonusers, risk was greatest in those whose first use occurred premenopausally for more than 2 years (OR, 2.9; CI, 1.3-6.6). The association was largely confined to use of medications that operate through dopaminergic mechanisms (OR, 2.9; CI, 1.3-6.4) or gabaergic pathways (OR, 1.5; CI, 0.9-2.5) as opposed to serotoninergic pathways (OR, 1.0; CI, 0.4-2.1). These results are consistent with the hypothesis that psychotropic medications induce gonadotropin secretion, which in turn may increase ovarian cancer risk. However, until other studies confirm our findings and determine whether they apply to medications with specific neuroendocrine actions, it is premature to advise a change in clinical practice and conclude that these medications indeed play a role in the etiology of ovarian cancer.

Background: There is considerable interest in the possibility of an infectious etiology for human breast cancer. Although studies have shown that certain strains of mice transmit mammary tumor virus via breast milk, few epidemiologic studies have addressed this topic in humans., Methods: We evaluated the relationship between having been breast-fed as an infant and breast cancer risk among 8299 women who participated in a population-based, case-control study of breast cancer in women aged 50 years or more. Case women were identified through cancer registries in three states (Massachusetts, New Hampshire, and Wisconsin); control women were identified through statewide driver's license lists (age <65 years) or Medicare lists (ages 65-79 years). Information on epidemiologic risk factors was obtained through telephone interview. We used multiple logistic regression to assess having been breast-fed and maternal history of breast cancer in relation to breast cancer occurrence both in premenopausal women (205 case women; 220 control women) and in postmenopausal women (3803 case women; 4071 control women)., Results: We found no evidence that having been breast-fed increased breast cancer risk in either premenopausal women (odds ratio [OR] = 0.65; 95% confidence interval [CI] = 0.41-1.04) or postmenopausal women (OR = 0.95; 95% CI = 0.85-1.07). In addition, breast cancer risk was not increased by having been breast-fed by a mother who later developed breast cancer., Conclusion: Our results do not support the hypothesis that a transmissible agent in breast milk increases breast cancer risk. Because premenopausal women were not well represented in our study population, our findings with regard to this group may not be generalizable and should be viewed with caution.

Family history (FH) is an important indicator of a woman's future risk of developing breast cancer. Using data collected in a large population-based case-control study (6705 cases and 9341 controls), we examined the associations of breast cancer with known risk factors in women reporting a first-degree FH (mother or sister), with an emphasis on lifestyle determinants that may be altered to reduce risk. First-degree FH was reported by 18.4% (n = 1234) of cases and 11.3% (n = 1058) of controls; the overall relative risk (RR) for breast cancer associated with a positive history was 1.70 [95% confidence interval (CI), 1.55-1.87] and 2.34 (95% CI, 1.80-3.02) for breast cancer at age 45 years or younger. Among women with a FH, statistically significant inverse associations were observed for increasing parity (RR per birth = 0.90; P < 0.0001), intake of carotene-rich foods (RR for >2000 IU/day = 0.73; P = 0.02), and strenuous activity as a young adult (RR per episode/week = 0.93; P = 0.02). Recent alcohol consumption increased risk (RR per 13 g/week = 1.21; P = 0.02), as did weight gain during adult life in postmenopausal women (RR per 5 kg = 1.08; P = 0.001). Breast-feeding for any duration was associated with a lower RR in parous, premenopausal women (RR = 0.59; P = 0.04). Associations for most risk factors with breast cancer were similar among women with and without a FH of breast cancer; however, a stronger inverse association was observed for parity in women with a positive history (P for interaction = 0.04). Based on these data, women with a FH may reduce their excess risk of breast cancer through adjustments in lifestyle and reproductive choices. The risk associated with FH of breast cancer seems to be largely independent of other known risk factors.

The association between calcium intake and the risk of colorectal neoplasia remains controversial. This analysis prospectively investigated the association between dietary and supplemental calcium intake and recurrent colorectal adenomas. Participants were part of a multicenter, randomized clinical trial of antioxidant vitamins. The study endpoints were adenomas detected between surveillance colonoscopies conducted at approximately 1 year and 4 years after study entry. Baseline intake of energy-adjusted calcium derived from a food frequency questionnaire was used as the main exposure of interest. Calcium supplement use was assessed by semiannual questionnaires. Logistic regression was used to compute odds ratios and 95% confidence limits, and Poisson regression was used to estimate rate ratios. Subjects in the fifth quintile of dietary calcium had an adjusted odds ratio of 0.72 (95% confidence interval, 0.43-1.22) compared to those in the lowest quintile. Investigation of the numbers of adenomas yielded stronger findings: the rate ratio for the fifth quintile versus the first was 0.63 (95% confidence interval, 0.39-1.02). Dietary calcium seemed to have a greater effect among individuals with a high-fat diet than among those with a low-fat diet; however, the interaction was not statistically significant. Use of calcium supplements was not related to adenoma recurrence. These results suggest that a high calcium intake may be associated with a reduction in risk of recurrent adenomas, especially among individuals on a high-fat diet.

Epidemiological studies suggest that individuals with basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin are more likely to develop other malignancies; however, the factors responsible for this are unknown. To clarify the risk of other cancers following the occurrence of BCC and SCC, we followed participants in a multicenter skin cancer prevention trial for subsequent malignancies. The study group consisted of 1805 BCC and SCC patients who had enrolled in a trial testing the efficacy of oral beta-carotene. Medical confirmation was sought for all cancers (other than BCC or SCC), which were reported by participants or their next-of-kin over a follow-up period of 10 years. We computed the rate ratio (RR) and 95% confidence interval (CI) of time to first new, primary cancer in relation to history of BCC and SCC, using a proportional hazards model. A total of 235 participants had a new primary invasive cancer during 13,887 person-years of follow up. The risk of other cancers was modestly elevated in patients with one or more previous SCCs compared with those who only had a history of BCC (adjusted RR, 1.37; 95% CI, 0.91-2.07). Risk of other cancers also appeared to be increased among those who had multiple prior BCCs relative to those who had only one prior BCC (adjusted RR, 1.21; 95% CI, 0.91-1.61). Further adjustment for smoking history, Quetelet index, radiotherapy, extent of actinic skin damage, treatment assignment, or baseline beta-carotene concentrations did not appreciably alter the results. Cancer of the respiratory system was most strongly related to previous SCC or multiple BCC [RRs (95% CI), 2.20 (1.05-4.62) and 2.34 (1.14-4.83), respectively]. Our data suggest that unidentified exposures or inherited risk factors may play a common etiological role in the pathogenesis of nonmelanoma skin cancer and other cancers, especially respiratory cancers, although larger studies would be necessary to exclude the role of chance in these findings.

Background: This study assessed the degree of diagnostic agreement among community-based general pathologists reading slides of representative breast tissue specimens and tested whether diagnostic variability is associated with type of breast specimen (e.g., core needle or excisional biopsy) or slide quality., Methods: Twenty-six of the 44 eligible pathologists working at community-based pathology practices in New Hampshire participated. Each pathologist evaluated slides of breast tissue obtained from 30 case subjects randomly selected from a statewide breast pathology database. The diagnostic categories used were benign, benign with atypia, noninvasive malignant, and invasive malignant. The levels of agreement (i.e., kappa coefficients) for the diagnoses were assessed., Results: Agreement was high among pathologists for assignment of diagnostic category (kappa coefficient = 0.71) and was nearly perfect for their selection of benign versus malignant categories (kappa coefficient = 0.95). There was less agreement for the categories of noninvasive malignant and benign with atypia (kappa coefficients of 0.59 and 0.22, respectively). There was no apparent relationship between levels of diagnostic agreement and specimen type or perceived slide quality., Conclusions: Diagnostic agreement for breast tissue specimens is high overall among community-based pathologists, but clinically relevant disagreements may occur in the assessment of noninvasive malignant diagnoses. The establishment of reread policies for certain diagnostic categories may reduce the possibility that diagnostic misclassification will lead to overtreatment or undertreatment. The high degree of diagnostic reproducibility for invasive cancerous lesions of the breast suggests that it is unnecessary for a central review of these lesions in national cancer trials.

Background: Recent evidence suggests that folic acid (and derivatives) could contribute to the protective effect of fruits and vegetables against the risk of large-bowel cancer. Other evidence indicates that alcohol drinking and cigarette smoking may impair the biologic actions of folate. We used data from an adenoma prevention trial to investigate the occurrence of colorectal adenomas (possible precursors of colorectal cancer) in association with folate intake, alcohol consumption, and cigarette smoking., Methods: Patients with at least one recent large-bowel adenoma were followed with colonoscopy 1 year and 4 years after their qualifying colon examinations. Adenomas detected after the year 1 examination were used as end points. A food-frequency questionnaire was administered at study entry and at study completion; nutrient intake at study entry was used in this analysis. All statistical tests were two-sided., Results: After adjustment for caloric intake, dietary folate had a significant protective association with the risk of recurrence of large-bowel adenoma (P for trend = .04). However, this inverse association was attenuated by further adjustment for intake of dietary fiber and fat. Use of folate supplements was not associated with a reduction in risk. Alcohol intake (seven or more drinks/week) was associated with increased risk (odds ratio = 2.04; 95% confidence interval = 1.28-3.26). Cigarette smoking, even smoking for long duration, was not related to adenoma recurrence., Conclusions: These data provide only modest support for previous findings suggesting beneficial effects of folate on colorectal adenoma risk. We find no evidence that cigarette smoking increases risk. These findings do suggest a substantial increase in risk with alcohol consumption.

Previous research suggests that iron acts as a prooxidant to increase the risk of colorectal neoplasia. This study examined effects of dietary intake of iron on colorectal adenoma recurrence using data from an antioxidant clinical trial. All subjects were free of polyps at study entry but had at least one adenoma removed within the 3 months before enrollment. Follow-up colonoscopies were conducted after 1 and 4 years. Patients who developed one or more adenomatous polyps between years 1 and 4 were classified as cases; all others were controls. Dietary iron intake at baseline and at the end of the study was estimated from self-administered food frequency questionnaires and averaged together for each subject, energy-adjusted, and categorized into quartiles. Odds ratios were adjusted for age, center, sex, calories, treatment group, and alcohol, fiber, folate, and fat intakes in unconditional logistic regression analysis. Dietary iron was inversely associated with adenoma risk, although risk did not decrease monotonically with increasing intake. Odds ratios comparing second, third, and fourth quartiles to the lowest quartile were 0.61 [95% confidence interval (CI), 0.37-1.02], 0.80 (95% CI, 0.45-1.44), and 0.37 (95% CI, 0.19-0.73), respectively. A limited examination showed no clear evidence that use of iron supplements affected risk of recurrence in this study population. This study provides evidence against the hypothesis that recent dietary intake of iron increases risk for colorectal adenomas. However, these results may reflect the presence of other dietary factors found in combination with iron.

Intake of fruits, vegetables, vitamin A, and related compounds are associated with a decreased risk of breast cancer in some studies, but additional data are needed. To estimate intake of beta-carotene and vitamin A, the authors included nine questions on food and supplement use in a population-based case-control study of breast cancer risk conducted in Maine, Massachusetts, New Hampshire, and Wisconsin in 1988-1991. Multivariate-adjusted models were fit to data for 3543 cases and 9406 controls. Eating carrots or spinach more than twice weekly, compared with no intake, was associated with an odds ratio of 0.56 (95% confidence interval 0.34-0.91). Estimated intake of preformed vitamin A from all evaluated foods and supplements showed no trend or monotonic decrease in risk across categories of intake. These data do not allow us to distinguish among several potential explanations for the protective association observed between intake of carrots and spinach and risk of breast cancer. The findings are, however, consistent with a diet rich in these foods having a modest protective effect.

The relation between body size and breast cancer remains uncertain, particularly with regard to differences between pre- and postmenopausal women. The authors examined whether height, weight, body mass index, and weight change were associated with breast cancer risk among pre- and postmenopausal women. This population-based case-control study included women aged 20-74 years (n = 6,548) who were diagnosed with invasive breast cancer during 1988-1991 in Maine, Massachusetts, New Hampshire, and Wisconsin. Similarly aged control women (n = 9,057) were selected at random from driver's license files and Health Care Financing Administration files. Height, weight, and information on other breast cancer risk factors were ascertained by telephone interview, and logistic regression was used to estimate multivariate-adjusted odds ratios and 95% confidence intervals. Among premenopausal women, the adjusted odds ratio for the upper quintile group of height relative to the lowest was 1.36 (95% confidence interval (CI) 1.05-1.76). The heaviest premenopausal women had a lower risk (odds ratio (OR) = 0.87, 95% CI 0.70-1.10). Among postmenopausal women, the adjusted odds ratios were higher for the upper quintile categories of both height (OR = 1.27, 95% CI 1.11-1.45) and weight (OR = 1.57, 95% CI 1.37-1.79). Weight gain since ages 18 and 35 years was associated with increased postmenopausal breast cancer risk, and risk was lower in women who had lost weight. These findings suggest that programs to avoid weight gain merit study as a means to reduce risk of postmenopausal breast cancer.

We conducted a nested case-control study of squamous cell skin cancer (SCC) to determine whether risk was related to plasma concentrations of selenium, alpha-tocopherol, beta-carotene, and retinol. We derived the study sample from participants in our Skin Cancer Prevention Study, all of whom had at least one basal cell or squamous cell skin cancer before study entry. Those who developed a new squamous cell skin cancer during the 3-5-year follow-up period were selected as cases (n = 132). Controls (n = 264) were chosen at random, with matching by age, sex, and study center, from among those who did not develop SCC but were being followed actively at the time the SCC case was diagnosed. Prediagnostic plasma samples were analyzed for alpha-tocopherol, beta-carotene, and retinol using high-performance liquid chromatography. Selenium determinations were made using instrumental neutron activation analysis. Odds ratios were computed using conditional logistic regression for matched samples. We found no consistent pattern of SCC risk associated with any of the nutrients examined. The odds ratios (95% confidence intervals) for the highest versus the lowest quartiles of beta-carotene, retinol, alpha-tocopherol, and selenium were 0.73 (0.38-1.41), 1.43 (0.77-2.64), 0.89 (0.43-1.85), and 0.86 (0.47-1.58), respectively. Thus, our data add to the growing body of evidence that these nutrients, at the concentrations we evaluated, are not related strongly to SCC risk.

Consumption of coffee has been associated with a reduction in the risk of cancer of the colon, and (less consistently) drinking tea has been associated with a reduction in the risk of rectal cancer. The effect of these beverages on the risk of colorectal adenomas, however, has not been well investigated. We used data from an adenoma prevention trial to investigate these associations. Patients with at least one recent large bowel adenoma were followed with colonoscopy 1 and 4 years after their qualifying examinations. Adenomas detected at the year 4 colonoscopy were used as end points. A food frequency questionnaire was administered at study entry and study completion; average intake over the study period was used to estimate the exposures of interest. There was no apparent association between the intake of regular coffee, decaffeinated coffee, or tea and the risk of recurrent colorectal adenomas. The relative risks and 95% confidence intervals per cup daily were 0.96 (0.87-1.05) for regular coffee, 0.97 (0.84-1.12) for decaffeinated coffee, and 1.02 (0.83-1.25) for tea. These negative findings were present both overall and for adenomas of the right and left large bowel.

We conducted a pilot study to assess the utility of toenail arsenic concentrations as an indicator of ingestion of arsenic-containing water. We enrolled 21 individuals whose household drinking water supply was provided by a private well, including 10 individuals who lived in areas of New Hampshire where elevated water levels of arsenic had been reported previously. Participants were interviewed regarding use of their private (unregulated) wells for drinking and cooking, and each provided a sample of water and toenail clippings. All specimens were analyzed using instrumental neutron activation analysis with a sensitivity of approximately 0.001 parts per million (ppm). Trace concentrations of arsenic were detected in 15 of the 21 well water samples and in all toenail clipping samples. Among the 10 individuals who lived in areas with reportedly high arsenic levels in the water supply, the geometric mean toenail concentration was 0.39 ppm (SE, 0.12 ppm); among the other 11 persons, the geometric mean was 0.14 ppm (SE, 0.02 ppm; P = 0.005 for the difference between the two means). The overall Spearman correlation between toenail and well water arsenic was 0.67 (P = 0.009), and among those with detectable well water levels of arsenic, the Spearman correlation was 0.83 (P = 0.0001). Based on the regression analysis of those who had detectable water levels of arsenic, a 10-fold increase in well water concentrations of arsenic was reflected by about a 2-fold increase in toenail concentrations. These results indicate that concentrations of arsenic in toenails reflect use of arsenic-containing drinking water.

We conducted a reliability study of whole crypt mitotic count, a measure of cellular proliferation with potential use as an intermediate marker in studies of colorectal cancer risk and prevention. The study involved biopsies taken from two distinct locations at 8-10 cm from the anal verge for 20 subjects scheduled to undergo routine endoscopy. In addition to the overall count of mitoses per crypt (mitotic count), we investigated two novel measures based on the percentages of heights of mitotic cells within crypts: the mean height, and the maximum minus minimum (max - min) height of mitoses. The max - min height was positively correlated with mitotic count (r = 0.64); however, there was little correlation between mitotic count and the mean height of mitotic cells (r = 0.12). Components of variance were estimated for the three measures; for mitotic count and max - min height, the variability between persons was substantially greater than that between locations within an individual. For mean height, the between-person and between-location variabilities were roughly equal. These results suggest that whole crypt mitotic count has promise as a reliable measure of rectal cellular proliferation, but further studies will be necessary to assess the utility of this assay.

Greater use of mammography in the United States in recent years has increased the detection of early neoplasms of the breast, including carcinoma in situ. However, the occurrence and treatment of diagnosed carcinoma in situ of the breast has not been fully described. Our goal was to examine temporal, geographic, and demographic patterns in the incidence and treatment of in situ breast cancer. The study included data from all women with in situ breast cancer that had been detected in the nine Surveillance, Epidemiology, and End Results areas of the United States from 1975 through 1990 (Surveillance Program, Cancer Statistics Branch, Bethesda, MD: National Cancer Institute, November, 1993). We calculated age-adjusted incidence rates (1970 United States standard) using data on histology and treatment from the Surveillance, Epidemiology, and End Results data tape. We assessed predictors of treatment by mastectomy using multiple logistic regression. From 1975-1979 to 1986-1990, the age-adjusted incidence rate of in situ breast cancer increased from 4.7 to 16.9/100,000 women. The increase occurred in all age groups and among both white and black women. However, there was nearly a 2-fold difference in incidence rates across geographic areas in 1986-1990, ranging from < 12/100,000 in Iowa and New Mexico to > 20/100,000 in San Francisco and Seattle. Geographic variability in treatment was also evident, with mastectomy, rather than breast-conserving therapy, performed on 46% of the women with in situ breast cancer in San Francisco and on 66% of those in Iowa. The incidence of diagnosed in situ breast cancer increased markedly during the 1980s, and there was substantial geographic variability in the rates of detection of these tumors and in the type of therapy received. Although mastectomy became a less common treatment over time, it was still performed on a high proportion of women with in situ breast cancer during the latter part of the decade.

The epidemiologic data on the relation between strenuous physical activity and breast cancer are limited and inconsistent. Because risk of breast cancer may be influenced by ovarian function which, in turn is modulated by physical activity, the hypothesis that exercise may be associated with a reduced risk of breast cancer merits further investigation. We, therefore, conducted a large case-control study in 1988-1991, and interviewed 6,888 women (17 to 74 years of age) with breast cancer in Maine, Massachusetts, New Hampshire, and Wisconsin (United States). Interviewed controls (9,539 women, 18 to 74 years of age) were selected randomly from lists of licensed drivers (for younger women) or from a roster of Medicare enrollees (for older women). We used multivariate adjusted odds ratios (OR) and 95 percent confidence intervals (CI) from logistic regression models to estimate relative risks between self-reported physical activity when 14 to 22 years of age and breast cancer. When compared with sedentary controls, women who reported any strenuous physical during ages 14 to 22 years had a modest reduction in the risk of breast cancer (OR = 0.95, CI = 0.93-0.97). However, those who exercised vigorously at least once a day had a 50 percent reduction in risk of breast cancer (OR = 0.5, CI = 0.4-0.7). These data support the hypothesis that women who are physically active have a reduced risk of breast cancer.

We examined the reliability of self-reported alcohol consumption in past age periods of women's lives. As part of a case-control study of breast cancer conducted in Massachusetts and Wisconsin in 1988-1991, the same questionnaire was administered for a second time to 211 controls (mean age = 54 years) after an interval of 6-12 months. The Spearman correlation coefficients between the average number of grams of alcohol consumed daily reported in the two interviews, by age period of consumption, were: 16-19 years, r = 0.81; 20-29 years, r = 0.84; 30-39 years, r = 0.75; and for recent consumption, r = 0.77. Self-reported alcohol consumption throughout adult life was reported with precision sufficient to make the ranking of subjects' intake consistent between interviews.

Data on breast surgery from national samples of patients discharged from hospital in the United States and in England and Wales were reviewed for the years 1970-80. In the United States the rate of breast surgery increased dramatically in 1974 and 1975, but in Britain it remained constant and well below the level in the United States. In both countries the proportion of radical mastectomies declined and the proportion of less extensive procedures rose. The increase in mastectomy rates in the United States probably resulted from increased public concern about breast cancer and from the promotion of breast screening in the mid-1970s. The costs, morbidity, and early mortality associated with a higher rate of mastectomy are substantial and the advantages unclear.