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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.

Objective: To estimate the relative risk of developing basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) after receiving therapeutic ionizing radiation., Design: Population-based case-control study., Setting: New Hampshire., Patients: A total of 592 cases of BCC and 289 cases of SCC identified through a statewide surveillance system and 536 age- and sex-matched controls selected from population lists., Main Outcome Measures: Histologically confirmed BCC and invasive SCC diagnosed between July 1, 1993, through June 30, 1995, among New Hampshire residents., Results: Information regarding radiotherapy and other factors was obtained through personal interviews. An attempt was made to review the radiation treatment records of subjects who reported a history of radiotherapy. Overall, an increased risk of both BCC and SCC was found in relation to therapeutic ionizing radiation. Elevated risks were confined to the site of radiation exposure (BCC odds ratio, 3. 30; 95% confidence interval, 1.60-6.81; SCC odds ratio, 2.94; 95% confidence interval, 1.30-6.67) and were most pronounced for those irradiated for acne exposure. For SCC, an association with radiotherapy was observed only among those whose skin was likely to sunburn with sun exposure., Conclusions: These results largely agree with those of previous studies on the risk of BCC in relation to ionizing radiation exposure. In addition, they suggest that the risk of SCC may be increased by radiotherapy, especially in individuals prone to sunburn with sun exposure. Arch Dermatol. 2000;136:1007-1011

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.

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.

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.

We conducted a study to estimate the current incidence rates of basal-cell carcinoma (BCC) and squamous-cell carcinoma (SCC) of the skin in the population of New Hampshire (NH), USA, and to quantify recent changes in the incidence rates of these malignancies. BCCs and SCCs diagnosed among NH residents were identified through physician practices and central pathology laboratories in NH and bordering regions from June 1979 through May 1980 and from July 1993 through June 1994. For each diagnosis period, we estimated the age-adjusted incidence rates for both BCC and SCC among both men and women and for separate anatomic sites. Between 1979-1980 and 1993-1994, incidence rates of SCC increased by 235% in men and by 350% in women. Incidence rates of BCC increased by more than 80% in both men and women. While the absolute increase was greatest for tumors of the head and neck, the relative change was most pronounced for tumors on the trunk in men and on the lower limb in women. Thus, there has been a marked rise in the incidence rates of BCC and SCC skin cancers in NH in recent years. The anatomic pattern of increase in BCC and SCC incidence is consistent with an effect of greater sunlight exposure. Studies of BCC and SCC occurrence are needed to identify possible behavioral and environmental factors and to assess possible changes in diagnostic practices that might account for the rise in incidence of these common malignancies.

Epidemiologic studies have suggested an increased risk for ovarian cancer associated with the use of talcum powder in genital hygiene, but the biologic credibility of the association has been questioned. We conducted a population-based case-control study in eastern Massachusetts and New Hampshire involving 563 women with newly diagnosed epithelial ovarian cancer and 523 control women selected either by random digit dialing or through lists of residents. Use of body powders was assessed through personal interview and the exposure odds ratio (OR) for the use of talc in genital hygiene was calculated. Cases were more likely than controls (45% vs. 36%) to have used talc as a body powder in some manner, and the excess was confined to patients who used talc on the perineum directly or as a dusting powder to underwear or sanitary napkins. Relative to women who never used body powder or used it only in non-genital areas, the OR (and 95% confidence interval) associated with genital exposure to talc was 1.60 (1.18 and 2. 15) after adjustment for age, study location, parity, oral contraceptive use, body mass index and family history of breast or ovarian cancer. Exposure prior to rather than after a first livebirth appeared to be more harmful, and the association was most apparent for women with invasive serous cancers and least apparent for those with mucinous tumors. We conclude that there is a significant association between the use of talc in genital hygiene and risk of epithelial ovarian cancer that, when viewed in perspective of published data on this association, warrants more formal public health warnings.

Background and Methods: Laboratory, clinical, and epidemiologic evidence suggests that calcium may help prevent colorectal adenomas. We conducted a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. We randomly assigned 930 subjects (mean age, 61 years; 72 percent men) with a recent history of colorectal adenomas to receive either calcium carbonate (3 g [1200 mg of elemental calcium] daily) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The primary end point was the proportion of subjects in whom at least one adenoma was detected after the first follow-up endoscopy but up to (and including) the second follow-up examination. Risk ratios for the recurrence of adenomas were adjusted for age, sex, lifetime number of adenomas before the study, clinical center, and length of the surveillance period., Results: The subjects in the calcium group had a lower risk of recurrent adenomas. Among the 913 subjects who underwent at least one study colonoscopy, the adjusted risk ratio for any recurrence of adenoma with calcium as compared with placebo was 0.85 (95 percent confidence interval, 0.74 to 0.98; P=0.03). The main analysis was based on the 832 subjects (409 in the calcium group and 423 in the placebo group) who completed both follow-up examinations. At least one adenoma was diagnosed between the first and second follow-up endoscopies in 127 subjects in the calcium group (31 percent) and 159 subjects in the placebo group (38 percent); the adjusted risk ratio was 0.81 (95 percent confidence interval, 0.67 to 0.99; P=0.04). The adjusted ratio of the average number of adenomas in the calcium group to that in the placebo group was 0.76 (95 percent confidence interval, 0.60 to 0.96; P=0.02). The effect of calcium was independent of initial dietary fat and calcium intake., Conclusions: Calcium supplementation is associated with a significant - though moderate - reduction in the risk of recurrent colorectal adenomas.

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.

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.

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: Evidence that aspirin and other non-steroidal anti-inflammatory drugs reduce risk for colorectal cancer has prompted interest in their ability to prevent other cancers. We aimed to find out what effect over-the-counter analgesics have on risk of ovarian cancer., Methods: In a case-control study we compared use of over-the-counter analgesics by 563 women from eastern Massachusetts and New Hampshire, USA, who had epithelial ovarian cancer with 523 women from the general population. We calculated exposure odds ratios to estimate the effect of over-the-counter analgesics on ovarian cancer risk. Use of over-the-counter analgesics was assessed through interviews and defined as use at least once a week continuously for at least 6 months., Findings: The odds ratio for risk of ovarian cancer for aspirin use was 0.75 (95% CI 0.52-1.10), that for ibuprofen was 1.03 (0.64-1.64), and that for paracetamol was 0.52 (0.31-0.86), after adjusting for age, study centre, education, religion, parity, oral contraceptive use, and menstrual, arthritic, or headache pain. Relative to no use, the lower risk of ovarian cancer associated with paracetamol was more apparent for use on a daily basis, 0.39 (0.21-0.74), for more than 10 years of use, 0.40 (0.19-0.88), or for more than 20 tablet years defined as (tablets per day x years of use), 0.45 (0.20-0.99)., Interpretation: In our data, there was a statistically significant inverse association between paracetamol use and ovarian cancer risk. There was a modest but non-significant inverse association with aspirin use and ovarian cancer and no association with ibuprofen use. Experimental studies in rodents demonstrating uterine and ovarian atrophy at high doses of paracetamol and decreased ovarian-cyst formation at lower doses suggest a biological basis for our observations.

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.

beta-Carotene has been studied widely as a potential cancer-preventing agent. Recent studies found that subjects who took beta-carotene supplements orally had increases in their serum concentrations of alpha-carotene and lycopene that were large (> 150% increase) and significantly greater than such increases in subjects who received placebo and that similar supplementation was associated with a decrease of approximately 37% in plasma lutein concentrations. A biologic interaction between beta-carotene and other carotenoids was suggested. We measured concentrations of retinol, alpha-tocopherol, and five carotenoids in serum specimens from a random sample of subjects enrolled in a clinical trial of the use of antioxidant vitamins in preventing colonic adenomas. We used serum specimens obtained at enrollment and after the subjects took placebo (n = 54) or 25 mg beta-carotene/d (n = 54) orally for 4 y. In a multivariate analysis, baseline serum concentrations of the analytes, sex, body mass index, diet, smoking status, and age were associated with variable changes in some analytes over the 4-y period but supplementation with beta-carotene was related only to a mean increase in serum beta-carotene itself of 151%. We excluded with 95% confidence an increase in lycopene > 4.9%, an increase in alpha-carotene > 17.6%, and a decrease in lutein > 14.7% in subjects given beta-carotene. These results confirm previous findings that supplementation with beta-carotene given orally does not alter serum concentrations of retinol or alpha-tocopherol. The findings also indicate that beta-carotene supplementation, which results in a moderate increase in serum beta-carotene concentration, does not significantly change serum concentrations of other carotenoids.

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.

Epidemiologic evidence supports the concept that diet influences risk for breast cancer and suggests that prognosis after the diagnosis of breast cancer may also be related to modifiable nutritional factors. The purpose of this study was to investigate the feasibility of a randomized trial of a high-vegetable, reduced-fat, and increased-fiber diet intervention to reduce risk for recurrence among breast cancer survivors. This major change in dietary pattern was promoted through intensive telephone counseling. Participants were 93 women who had been diagnosed with breast cancer (stages I, II, and IIIA) within the previous four years and who had completed their initial treatment. We assessed adherence to the study diet using repeated 24-hour dietary recalls at 6 and 12 months and measurement of circulating carotenoid concentrations. Six months after randomization, the intervention group had significantly increased their mean intake of vegetables (+4.6 servings/day), fruit (+0.7 servings/day), and fiber (+6.4 g/1,000 kcal) and significantly reduced their intake of dietary fat (-9.9% of energy) compared with the control group. Circulating concentrations of carotenoids also increased in the intervention group. These changes persisted at the 12-month visit. Results of this study demonstrate that telephone counseling can be a useful approach in diet intervention and that breast cancer survivors can adopt and maintain a high-vegetable, reduced-fat dietary pattern.

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.

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.

Objective: To evaluate the association between pregnancy terminations and risk of breast cancer., Design and Setting: Population-based case-control study in Wisconsin, Massachusetts, Maine, and New Hampshire., Study Participants: Cases were women younger than 75 years with a new diagnosis of breast cancer (n = 6888), identified from statewide tumor registries. Controls younger than 65 years (n = 9529) were randomly selected from lists of licensed drivers, or for older subjects, from lists of Medicare beneficiaries. EXPOSURES AND OUTCOMES: Breast cancer risk in relation to spontaneous or induced abortions., Results: After adjustment for parity, age at first birth, and other risk factors, pregnancy termination (induced or spontaneous) was associated with a relative risk (RR) of breast cancer of 1.12 (95% confidence interval [CI], 1.04 to 1.21), compared with the risk among women who had never had a termination. Induced terminations were associated with a RR of 1.23 (95% CI, 1.00 to 1.51), which was somewhat greater than the risk associated with spontaneous terminations (RR, 1.11; 95% CI, 1.02 to 1.20). The association with induced abortions was stronger for those performed before legalization of abortion in 1973 (RR, 1.35; 95% CI, 1.01 to 1.80) than after this time (RR, 1.12; 95% CI, 0.84 to 1.49), suggesting a bias in reporting this sensitive procedure., Conclusions: A weak positive association was observed between abortion--whether induced or spontaneous--and risk of breast cancer. The increase in risk of breast cancer was somewhat greater among women with a history of induced terminations. However, this association may be due to reporting bias and was not significantly different than the slight risk for spontaneous terminations.

Several lines of evidence support the notion that aspirin and other nonsteroid anti-inflammatory drugs (NSAIDs) may prevent human cancer, particularly cancers of the large bowel. These drugs are potent inhibitors of cyclo-oxygenases, enzymes that catalyse the synthesis of prostaglandins from arachidonic acid. In rodent models, NSAIDs consistently inhibit chemically induced neoplasms of the colorectum. Case reports and randomized controlled trials are also consistent in showing a reduction in adenomas following administration of the NSAID sulindac to patients with familial adenomatous polyposis. Perhaps the most intriguing evidence, however, comes from epidemiological studies, which indicate a 30-50% reduction in risk of colorectal neoplasia among regular users of aspirin. These studies have employed both case-control and cohort approaches, and lower risk has been found for colon and rectal cancer mortality, invasive cancer incidence, and adenoma occurrence. The results of the epidemiological studies are not uniform, however, and a few studies found no benefit with aspirin use. Existing epidemiological studies are limited by a lack of information about dosage and duration of aspirin use. Moreover, questions remain about the mechanism through which NSAIDs might affect cancer occurrence. Thus, there is a clear need for focused clinical trials, as well as for further epidemiological study and laboratory investigation, to define better the potential of these agents to prevent cancers.

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.

Background: Although an association between alcohol consumption and risk of breast cancer has been observed in many studies, questions of major importance remain, including the nature of the dose-response relationship and the effects of drinking at various periods in life., Purpose: Our goal was to address the issues listed above with a large case-control study., Methods: We conducted a population-based case-control study in Maine, Massachusetts (excluding the four counties that include metropolitan Boston), New Hampshire, and Wisconsin. Case patients were eligible if their diagnosis of invasive breast cancer was first reported to one of the four statewide cancer registries during the period of 1988 through 1991. During the accrual period, 11,879 potentially eligible case patients and 16,217 control subjects were identified. After excluding ineligible women from the study, telephone interviews were obtained from 6888 case patients and 9424 control subjects. Complete data for recent alcohol consumption, and thus final eligibility for study participation, were determined for 6662 case patients and 9163 control subjects. The average age at time of interview was 58.7 years. The questions on alcohol use addressed average consumption during five periods of the subjects' lives: ages 16-19, 20-29, 30-39, 40-59, and 60-74 years. Similar responses from 211 control subjects upon reinterview 6-12 months later were taken to be indicative of the reliability of the questionnaire used in this study., Results: Lifetime average alcohol consumption (measured as the average grams per day consumed from age 16 to the recent past) and recent alcohol consumption (average grams per day consumed in the previous age interval) were associated with risk of developing breast cancer. The multivariate relative risk of breast cancer, in those who drink compared with abstainers, associated with average lifetime consumption of 12-18 g/day of alcohol (about one drink) was 1.39 (95% confidence interval [CI] = 1.16-1.67), of 19-32 g/day (about two drinks) was 1.69 (95% CI = 1.36-2.10), of 33-45 g/day (about three drinks) was 2.30 (95% CI = 1.51-3.51), and of greater than or equal to 46 g/day (four or more drinks) was 1.75 (95% CI = 1.16-2.64) (P for trend < .0001). The multivariate relative risk per 13 g/day (about one drink) of alcohol consumed before 30 years of age was 1.09 (95% CI = 0.95-1.24), whereas the relative risk associated with recent consumption of 13 g/day was 1.21 (95% CI = 1.09-1.34)., Conclusions: In these data, alcohol consumption was clearly related to breast cancer risk. Risk appeared to increase even at moderate levels of consumption. For women of all ages combined, consumption before 30 years of age was not an important determinant of risk.

Objective: To review the late sequelae of jejunoileal bypass (JIB) and the potential role of late surgical reversal in ameliorating morbidity and mortality following JIB., Design: Patients who underwent JIB between 1965 and 1977 were contacted and pertinent health-event information was gathered. Early sequelae were defined as disorders occurring within the first 2 years after JIB; late sequelae were those occurring after 2 years. Health events occurring between 0 and 23 years after JIB were documented., Setting: A private, tertiary referral center., Patients: Patients underwent JIB for morbid obesity that had failed medical and/or psychiatric interventions., Main Outcome Measures: Body mass index (BMI) (weight kilograms divided by the square of the height in meters), diarrhea, electrolyte imbalance, acute, and chronic liver disease, renal disease, JIB reversal, reason for JIB reversal, death, and cause of death., Results: A total of 453 morbidity obese patients underwent JIB. By 2 years following JIB, the mean (+/- SD) BMI dropped from 49.3 +/- 8.1 to 31.1 +/- 0.8 and remained at this level until year 15, after which weight gradually increased (BMI, 35.4 +/- 3.1). The most severe early complication was acute liver failure, which occurred in 7% of patients and caused seven deaths. At 15 years, the actuarial probability of the most common serious late complications related to JIB were renal disease (37%), with two deaths; diarrhea (29%); and liver disease (10%), with three deaths. One hundred thirty-eight patients (31%) had a bypass reversal. The most common indications for reversal were diarrhea and electrolyte disturbance (29%), renal disease (19%), and liver disease (17%). Fifty-six patients died more than 30 days after JIB: 64% before JIB reversal, 13% at the time of reversal, and 23% subsequently., Conclusions: Jejunoileal bypass is associated with progressive accrual of serious, sometimes life-threatening complications. Lifelong follow-up for early diagnosis and surgical reversal before life is threatened should reduce the morbidity and mortality associated with this procedure.

Background: People who consume a diet high in vegetables and fruits have a lower risk of cancer of the large bowel. Antioxidant vitamins, which are present in vegetables and fruits, have been associated with a diminished risk of cancers at various anatomical sites. We conducted a randomized, controlled clinical trial to test the efficacy of beta carotene and vitamins C and E in preventing colorectal adenoma, a precursor of invasive cancer., Methods: We randomly assigned 864 patients, using a two-by-two factorial design, to four treatment groups, which received placebo; beta carotene (25 mg daily); vitamin C (1 g daily) and vitamin E (400 mg daily); or the beta carotene plus vitamins C and E. In order to identify new adenomas, we performed complete colonoscopic examinations in the patients one year and four years after they entered the study. The primary end points for analyses were new adenomas identified after the first of these two follow-up examinations., Results: Patients adhered well to the prescribed regimen, and 751 completed the four-year clinical trial. There was no evidence that either beta carotene or vitamins C and E reduced the incidence of adenomas; the relative risk for beta carotene was 1.01 (95 percent confidence interval, 0.85 to 1.20); for vitamins C and E, it was 1.08 (95 percent confidence interval, 0.91 to 1.29). Neither treatment appeared to be effective in any subgroup of patients or in the prevention of any subtype of polyp defined by size or location., Conclusions: The lack of efficacy of these vitamins argues against the use of supplemental beta carotene and vitamins C and E to prevent colorectal cancer. Although our data do not prove definitively that these antioxidants have no anticancer effect, other dietary factors may make more important contributions to the reduction in the risk of cancer associated with a diet high in vegetables and fruits.

We examined time trends and geographical variations in the detection and treatment of prostate cancer in USA, based on information from white men aged 50 to 79 who resided in areas covered by the Surveillance, Epidemiology, and End Results (SEER) program of the United States National Cancer Institute. Prostate-cancer incidence and treatment rates were determined for the 9 population-based cancer registries which participate in the SEER program. Prostate-cancer mortality rates were assessed from data compiled by the National Center for Health Statistics. Prostate cancer incidence rates increased by 6.4% per year between 1983 and 1989. The increase appeared to be due to detection of early-stage disease; there was no increase in the incidence rate of metastatic cancer. Incidence rates varied widely among the SEER program areas: in 1989 from 267.9 per 100,000 in Connecticut to 606.8 in Seattle. Radical prostatectomy rates more than tripled between 1983 and 1989 in the SEER areas as a whole. Among men aged 70-79, the rate of prostatectomy increased by nearly 35% per year. There was a five-fold variation among SEER areas in radical prostatectomy rates in 1989, with a low of 43.4 per 100,000 in Connecticut and a high of 224.4 in Seattle. Prostate cancer mortality rates did not increase during the period of study; there was little variation among areas in prostate-cancer mortality rates, and no apparent correlation between the incidence and mortality rates for an area. Increases in rates of prostate cancer incidence and prostate surgery have occurred in the United States without clear evidence that screening and prostectomy are effective in reducing mortality. Moreover, much of the growth in incidence and radical prostatectomy rates has occurred among older men, who appear least likely to benefit from early detection and surgery of occult prostate cancer.

Background: The antioxidants beta carotene and vitamin E may play a role in cancer prevention. However, some studies have suggested that oral supplements of beta carotene may cause a decrease in serum levels of alpha tocopherol (vitamin E)., Purpose: We conducted this study to determine if beta carotene supplements affect serum levels of vitamin E and vice versa., Methods: Five hundred five patients in a clinical trial of antioxidant vitamins, used to prevent recurrences of colonic polyps, received either a placebo, 25 mg of beta carotene per day, 1 g ascorbic acid plus 400 mg alpha tocopherol per day, or all three agents combined. Serum levels of beta carotene and vitamin E were measured before and after 9 months of supplementation, using high-performance liquid chromatography., Results: Vitamin E levels changed very little among the groups receiving placebo or beta carotene and went up substantially and equally in the groups receiving vitamin E plus ascorbic acid or all three agents together. Conversely, beta carotene levels changed very little for the groups receiving placebo or ascorbic acid plus vitamin E but went up substantially and equally for the groups receiving beta carotene alone or all three agents., Conclusions: We conclude that oral supplementation with beta carotene for 9 months does not alter serum concentration of vitamin E and that supplementation with vitamin E plus ascorbic acid does not alter serum beta carotene levels.

Background: The evidence of an association of lactation with a reduction in the risk of breast cancer among women has been limited and inconsistent. The effect of lactation appears to be confined to premenopausal women with a history of long lactation, but most studies of this relation have been limited in statistical power. We conducted a multicenter, population-based, case-control study with a sample large enough for us to describe more precisely the association between lactation and the risk of breast cancer., Methods: Patients less than 75 years old who had breast cancer were identified from statewide tumor registries in Wisconsin, Massachusetts, Maine, and New Hampshire. Controls were randomly selected from lists of licensed drivers if the case subjects were less than 65 years old, and from lists of Medicare beneficiaries if they were 65 through 74 years old. Information on lactation, reproductive history, and family and medical history was obtained by means of telephone interviews. After the exclusion of nulliparous women, 5878 case subjects and 8216 controls remained for analysis., Results: After adjustment for parity, age at first delivery, and other risk factors for breast cancer, lactation was associated with a slight reduction in the risk of breast cancer among premenopausal women, as compared with the risk among women who were parous but had never lactated (relative risk, 0.78; 95 percent confidence interval, 0.66 to 0.91); the relative risk of breast cancer among postmenopausal women who had lactated, as compared with those who had not, was 1.04 (95 percent confidence interval, 0.95 to 1.14). With an increasing cumulative duration of lactation, there was a decreasing risk of breast cancer among premenopausal women (P for trend < 0.001) but not among postmenopausal, parous women (P for trend = 0.51). A younger age at first lactation was significantly associated with a reduction in the risk of premenopausal breast cancer (P for trend = 0.003). As compared with parous women who did not lactate, the relative risk of breast cancer among women who first lactated at less than 20 years of age and breast-fed their infants for a total of six months was 0.54 (95 percent confidence interval, 0.36 to 0.82)., Conclusions: There is a reduction in the risk of breast cancer among premenopausal women who have lactated. No reduction in the risk of breast cancer occurred among postmenopausal women with a history of lactation.

Both retinoids and carotenoids decrease cancer occurrence in selected animal models of carcinogenesis, but the retinoids appear to have more potent activity against a wider variety of tumors. Further use of retinoids for cancer prevention will be limited, however, because of their toxic effects on bone and skin (among other organs). In contrast to retinoids, carotenoids seem to be free of important toxicity and this fact makes them more promising for use in the general adult population. However, the idea that carotenoids have a cancer-preventive effect in humans is based almost entirely on epidemiological studies of diet and serum which could simply reflect the effects of some other dietary constituents. In the search to explain the profoundly lower risk of death associated with eating a diet high in fruits, vegetables, and grains, there is a place for clinical trials testing one specific nutrient, such as beta-carotene, against one disease, such as lung cancer, but we should not rely exclusively on these narrowly focused studies. In addition, careful analyses of cohort studies may reveal broad patterns of diet that are associated with lower mortality. These diets can then be tested in clinical trials for their efficacy against a variety of causes of death and disability. For now, the most rational and prudent choice would be to consume a diet high in fruits, vegetables, and grains and not to take either supplemental antioxidants or retinoids until there is clear evidence of their effectiveness and safety.

Background: Epidemiological studies have indicated that aspirin consumption can lower the risk of large-bowel cancer. These studies are not entirely consistent, however, and their interpretation has been complicated by the possibility that cancer symptoms may have led patients to avoid aspirin or that aspirin may have influenced cancer diagnosis and treatment., Purpose: Our purpose was to determine the effect of aspirin on risk of large-bowel neoplasms in a study in which aspirin use would not be expected to affect tumor detection and tumor-related symptoms would not likely influence aspirin use. A less complicated assessment of the relationship between aspirin and large-bowel tumors should thus be possible., Methods: We studied 793 patients enrolled in a clinical trial of nutrient supplements to prevent large-bowel adenomas. Unlike invasive cancers, adenomas usually do not cause symptoms or detectable gastrointestinal bleeding; thus, adenomas are unlikely to influence aspirin use. Each patient had at least one large-bowel adenoma diagnosed and removed shortly before study entry and had been judged to be free of further tumors by colonoscopy. Use of aspirin was assessed by responses on questionnaires administered 6 and 12 months after enrollment. We performed complete colonoscopies on all patients 1 year after they entered the study and removed all polyps., Results: Patients who reported taking aspirin on both questionnaires (consistent users) had a lower risk of new adenomas at their 1-year follow-up colonoscopy (odds ratio = 0.52; 95% confidence interval = 0.31-0.89) compared with patients who did not report using aspirin on either of the questionnaires. The apparent protective effect of consistent aspirin use was present among both men and women and did not appear to be influenced by the number of prior adenomas., Conclusions: These data further support the hypothesis that aspirin has an antineoplastic effect in the large bowel. Nevertheless, the question of whether aspirin should be used to prevent large-bowel tumors would be best answered by a randomized controlled clinical trial specifically designed to address this issue.

Objective: Further assessment of the long-term risk of breast cancer associated with diethylstilbestrol (DES) during pregnancy., Design: Follow-up continuation through June 1, 1989, of a historical cohort of DES-exposed and unexposed mothers ascertained by review of obstetric records., Participants: Totals of 3029 each of DES-exposed and unexposed mothers who had delivered live babies at four centers in the United States during 1940 through 1960. Questionnaires were returned for 92.6% of the DES-exposed and 88.8% of the unexposed women., Main Outcome Measures: Breast cancer incidence and mortality assessed from returned questionnaires and review of medical records and death certificates., Main Results: The relative rate of breast cancer associated with DES exposure, after adjustment for demographic and reproductive variables, was 1.35 (95% confidence interval, 1.05 to 1.74). For 30 years or more following exposure, the relative rate was not appreciably higher (relative rate, 1.33; 95% confidence interval, 0.95 to 1.87) than that in earlier periods. Surveillance and increased detection seemed unlikely explanations for the increased risk, since DES-exposed women had excesses of both large and small breast cancers and the two cohorts reported similar breast cancer detection practices. A history of miscarriage before first term delivery was not associated with breast cancer occurrence., Conclusion: Exposure to DES during pregnancy is associated with a modest but statistically significant increased risk of breast cancer. Contrary to prior indications, the risk does not appear to increase greatly over time. The findings are sufficient to exclude the possibility of a doubling of risk for the period of 30 or more years following exposure.

Objective: The primary aims of this study were to assess risk of subsequent basal and squamous cell skin cancer among patients with a prior history of these tumors and to examine these risks in relation to patient characteristics and life-style factors., Design: Follow-up of participants in a randomized trial of betacarotene as a possible skin cancer preventive agent., Setting: Clinical centers in Los Angeles, Calif, San Francisco, Calif, Minneapolis, Minn, and Hanover, NH., Participants: Patients (n = 1805) who were diagnosed as having a basal or squamous cell skin cancer between January 1980 and February 1986 and were free of skin cancer at study entry., Main Outcome Measure: Time from study entry to first new occurrence of basal and squamous cell skin cancer., Results: The estimated risk of developing one or more new skin cancers was 35% at 3 years and 50% at 5 years. New skin cancers tended to be of the same cell type as the previous skin cancers. For both basal and squamous cell skin cancer, risk was higher among patients who were male, were over the age of 60 years, had more prior skin cancers, had severe actinic skin damage, or who burned easily with sun exposure. Compared with those who had never smoked, the rate of subsequent squamous cell skin cancer was higher among current smokers (rate ratio, 2.01; 95% confidence interval, 1.21 to 3.34) and former smokers (rate ratio, 1.62; 95% confidence interval, 1.07 to 2.47) and increased with both duration and amount smoked. There was no clear relationship between smoking and basal cell skin cancer; the rate appeared lower among heavy smokers but was unrelated to duration of smoking., Conclusions: Persons with a prior nonmelanoma skin cancer had a substantial 5-year risk of developing another tumor of the same histologic type. Number of previous skin cancers, solar damage, and skin sensitivity to sun exposure were particularly related to this risk. The increased risk of squamous cell skin cancer associated with cigarette smoking merits further study.

We studied within-person variation over time in serum concentrations of five carotenoids. In a diurnal study involving 33 subjects, only the 1700 h blood samples demonstrated carotenoid concentrations different from the original 0800 values. Correlations between serum concentrations of the same carotenoids drawn 1 d apart ranged from 0.93 to 0.98. In a seasonal study involving 29 subjects, no systematic trends were observed for serum concentrations of these carotenoids. Correlations between concentrations of the same carotenoids drawn 1 y apart ranged from 0.57 to 0.82. Concentrations of different carotenoids within an individual tended to be correlated with each other. Obtaining one blood sample from subjects is a relatively imprecise way to estimate their usual serum concentrations of carotenoids. If an epidemiological study was to be based on only one determination of serum carotenoids, within-person variability in serum concentrations would attenuate true regression coefficients by 4-13% and would increase the required numbers of study subjects by 19-65%.

A survey of skin cancer occurrence between June 1979 and May 1980 among residents of New Hampshire and Vermont identified 277 cases of squamous cell carcinoma and 1761 cases of basal cell carcinoma. The age-adjusted incidence rates for squamous cell carcinoma (32 per 100,000 in men, 8 per 100,000 in women) and for basal cell carcinoma (159 per 100,000 in men, 87 per 100,000 in women) were similar to those reported in other populations in the northern United States. Skin cancer incidence was particularly high among men more than 70 years of age and a large proportion (greater than 30%) of patients 55 years or older had a history of at least one previous skin cancer.

We investigated differences in lung cancer care and outcome between academic and community settings for all lung cancer patients diagnosed during 1973-1976 in New Hampshire and Vermont. Trained abstracters reviewed hospital charts to record personal, diagnostic, and clinical information, and survival was determined for all patients through the end of 1979. Patients diagnosed in university hospital cancer centers underwent more staging procedures and tended to be assigned to a higher stage than similar patients diagnosed in community hospitals. When tumor stage was considered as a covariable in a survival analysis, these patients appeared to have a lower mortality rate both for non-small cell tumors (mortality rate ratio, 95% confidence interval = 0.81, 0.71-0.91) and for small cell tumors (0.71, 0.55-0.91). When functional status rather than tumor stage was used to adjust for disease severity, there was no apparent survival advantage for university patients with non-small cell cancer (0.96, 0.85-1.09) and the lower mortality for small cell cancers (0.76, 0.59-0.97) was attenuated, although still statistically significant. We conclude that inconsistently-collected data on clinical stage can complicate comparisons of prognosis between cancer patients from different types of hospitals and that measures of performance status may be more useful indicators of disease severity in population based studies.

Background: Beta carotene has been associated with a decreased risk of human cancer in many studies employing dietary questionnaires or blood measurements, and it has had protective effects in some animal models of carcinogenesis., Methods: We tested the possible cancer-preventing effects of beta carotene by randomly assigning 1805 patients who had had a recent nonmelanoma skin cancer to receive either 50 mg of beta carotene or placebo per day and by conducting annual skin examinations to determine the occurrence of new nonmelanoma skin cancer., Results: Adherence to the prescribed treatment was good, and after one year the actively treated group's median plasma beta carotene level (3021 nmol per liter) was much higher than that of the control group (354 nmol per liter). After five years of follow-up, however, there was no difference between the groups in the rate of occurrence of the first new nonmelanoma skin cancer (relative rate, 1.05; 95 percent confidence interval, 0.91 to 1.22). In subgroup analyses, active treatment showed no efficacy either in the patients whose initial plasma beta carotene level was in the lowest quartile or in those who currently smoked. There was also no significant difference between treated and control groups in the mean number of new nonmelanoma skin cancers per patient-year., Conclusions: In persons with a previous nonmelanoma skin cancer, treatment with beta carotene does not reduce the occurrence of new skin cancers over a five-year period of treatment and observation.