Carotenoids, cancer, and clinical trials.
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Biomedical subjects
Publications and source records attributed to R G Ziegler.
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BACKGROUND: Breast cancer incidence rates have historically been 4-7 times higher in the United States than in China or Japan, although the reasons remain elusive. When Chinese, Japanese, or Filipino women migrate to the United States, breast cancer risk rises over several generations and approaches that among U.S. Whites. PURPOSE: Our objective was to quantify breast cancer risks associated with the various migration patterns of Asian-American women. METHODS: A population-based, case-control study of breast cancer among women of Chinese, Japanese, and Filipino ethnicities, aged 20-55 years, was conducted during 1983-1987 in San Francisco-Oakland, California, Los Angeles, California, and Oahu, Hawaii. We successfully interviewed 597 case subjects (70% of those eligible) and 966 control subjects (75%). RESULTS: A sixfold gradient in breast cancer risk by migration patterns was observed. Asian-American women born in the West had a breast cancer risk 60% higher than Asian-American women born in the East. Among those born in the West, risk was determined by whether their grandparents, especially grandmothers, were born in the East or the West. Asian-American women with three or four grandparents born in the West had a risk 50% higher than those with all grandparents born in the East. Among the Asian-American women born in the East, breast cancer risk was determined by whether their communities prior to migration were rural or urban and by the number of years subsequently lived in the West. Migrants from urban areas had a risk 30% higher than migrants from rural areas. Migrants who had lived in the West for a decade or longer had a risk 80% higher than more recent migrants. Risk was unrelated to age at migration for women migrating at ages less than 36 years. Ethnic-specific incidence rates of breast cancer in the migrating generation were clearly elevated above those in the countries of origin, while rates in Asian-Americans born in the West approximated the U.S. White rate. CONCLUSIONS: Exposure to Western lifestyles had a substantial impact on breast cancer risk in Asian migrants to the United States during their lifetime. There was no direct evidence of an especially susceptible period, during either menarche or early reproductive life. IMPLICATIONS: Because heterogeneity in breast cancer risk in these ethnic populations is similar to that in international comparisons and because analytic epidemiologic studies offer the opportunity to disentangle correlated exposures, this study should provide new insights into the etiology of breast cancer.
A liquid chromatographic (LC) method has been developed for the quantitative measurement of the six major carotenoids in human serum (lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, and beta-carotene) as well as retinol, retinyl palmitate, alpha-tocopherol, gamma-tocopherol, and delta-tocopherol. Several polar carotenoids, 2',3'-anhydrolutein, alpha-cryptoxanthin, and geometric isomers of lycopene and beta-carotene are also separated. Retinoids and carotenoids are monitored using a programmable ultraviolet-visible detector, while tocopherols are monitored using a fluorescence detector. The method uses a gradient containing acetonitrile, methanol, and ethyl acetate. Ammonium acetate is introduced with the methanol to minimize carotenoid losses on the LC column aggravated by the use of acetonitrile and ethyl acetate. The method is also applicable to the analysis of foods.
To identify systematically the nutrient and food group intakes associated with a low-fat diet, the authors used the detailed dietary information collected from 10,306 individuals aged 32-86 years in the 1982-1984 National Health Epidemiologic Follow-up Study. Intakes of vitamin C and percentages of calories from carbohydrates, dietary fiber, poultry, low-fat dairy products, fruits, vegetables, cereals, and whole grains were markedly higher, while intakes of protein, total fat, saturated fat, oleic and linoleic acids, cholesterol, sodium, all red meats, high-fat dairy products, eggs, nuts, white bread, fried potatoes, desserts, fats, and oils were much lower in the quartile with the lowest percentage of calories from fat. These dietary patterns associated with a low-fat diet were essentially constant across strata of age, sex, race, and socioeconomic status. This study suggests that individuals on a low-fat diet substitute certain carbohydrate-rich foods such as fruits and vegetables for fat. Given these associations between low-fat diets and other dietary factors independently associated with certain cancers, these dietary factors should be considered potential confounders in studies of dietary fat and these cancers.
We used data from a case-control study conducted in New Jersey between 1980 and 1983 to evaluate race and sex differences in associations of vegetable, fruit, and carotenoid consumption with lung cancer. Cases included 736 White males, 860 White females, 269 Black males, and 86 Black females with incident, histologically confirmed, primary cancer of the trachea, bronchus, or lung. Controls were identified through drivers' license and Health Care Financing Administration files and included 548 White males, 473 White females, 170 Black males, and 47 Black females. Usual intakes of vegetables (predominantly yellow/green) and fruit (predominantly yellow/orange) as well as other food sources of carotenoids were ascertained by a food frequency questionnaire. White females showed significant inverse associations of lung cancer with vegetables, fruit, and carotenoids. White males showed nonsignificant inverse associations with vegetables and carotenoids, and Black females just with vegetables. No inverse associations were found for Black males. Vegetable consumption was associated with risk of all histologic types of lung cancer, but the pattern of increasing risk with decreasing intake was limited to smokers. We infer that consumption of yellow/green vegetables and carotenoids may confer protection from lung cancer to White male and White female smokers. Further studies are needed to clarify the effect in Blacks.
We examined the relation of dietary diversity to subsequent all-cause mortality by using data from the First National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study, 1982-1987. The analytic cohort consisted of 4160 men and 6264 women (including 2556 deaths), 25-74 y at baseline (1971-1975). Twenty-four-hour dietary recalls were evaluated for variety among the five major food groups: dairy, meat, grain, fruit, and vegetable, with a dietary diversity score (DDS); consumption of each food group contributed 1 point to a maximum possible DDS of 5. Age-adjusted risk of mortality was inversely related to DDS (P < or = 0.0009) in men and women. The inverse diversity-mortality association was adjusted for potential confounders: education, race, smoking status, and dietary fiber intake; the relative risk of mortality in men and women consuming two or fewer food groups was 1.5 (95% CI 1.2-1.8) and 1.4 (95% CI 1.1-1.9), respectively. In conclusion, diets that omitted several food groups were associated with an increased risk of mortality.
A population-based, case-control study of laryngeal cancer was conducted in Shanghai, China, during 1988-1990, in which 201 incident cases (177 males, 24 females) and 414 controls (269 males, 145 females) were interviewed. Cigarette smoking was the major risk factor, accounting for 86% of the male and 54% of the female cases. After adjusting for smoking, there was little increase in risk associated with drinking alcoholic beverages. Among men, cases more often reported occupational exposures to asbestos and coal dust. A protective effect was associated with the intake of fruits (particularly oranges and tangerines), certain dark green/yellow vegetables, and garlic, but there was an increased risk with the intake of salt-preserved meat and fish. The findings suggest that risk factors for laryngeal cancer in Shanghai resemble those in Western countries, and they provide further evidence that dietary factors play an important etiologic role.
Increased intake of vegetables, fruits, and carotenoids and elevated blood levels of beta-carotene are consistently associated with reduced risk of lung cancer in epidemiologic studies. Epidemiologic research also suggests that carotenoids may reduce the risk of other cancers, although the evidence is less extensive and consistent. The simplest explanation is that beta-carotene is protective. However, the possible roles of other carotenoids, other constituents of vegetables and fruits, and associated dietary patterns have not been adequately explored. To evaluate these alternative hypotheses, we are undertaking three lines of research. (a) With dietary data from the 1987 National Health Interview Survey and the 1982-1984 Epidemiologic Follow-up of the first National Health and Nutrition Examination Study, we have determined which food groups and nutrients are highly correlated with vegetable and fruit intake. (b) We have developed and characterized a liquid chromatography method for optimal recovery and resolution of the common carotenoids in blood, specifically lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, and beta-carotene. (c) In a population-based case-control study of lung cancer in white men in New Jersey, we are assessing whether estimates of the intake of the individual carotenoids might produce stronger inverse associations than estimates of provitamin A carotenoids based on current food composition tables.
Sixty commercially available and five experimental liquid chromatography columns were evaluated for the separation and recovery of seven carotenoid compounds. Methanol- and acetonitrile-based solvents (either straight or modified with ethyl acetate or tetrahydrofuran) were compared to determine which solvent systems and which columns provided better selectivity and recovery. Methanol-based solvents typically provided higher recoveries than did acetonitrile-based solvents. Polymeric C18 phases generally provided better selectivity for the difficult separation of lutein and zeaxanthin than did monomeric C18 phases.
To investigate reasons for the higher rates of invasive squamous-cell cervical carcinoma among Blacks than Whites in the United States, we examined data from a case-control study of cervical cancer conducted in five geographic areas of the US, supplemented by incidence data from the Surveillance, Epidemiology, and End Results (SEER) Program, and hysterectomy prevalence data from the Cancer and Steroid Hormone Study. We observed only minor differences between Blacks and Whites in the magnitude of relative risks associated with a long interval since last Pap smear, multiple sexual partners, cigarette smoking, a higher number of births, and low levels of income and education. Thus, differences in the strength of associations contributed little to the higher incidence rare in Blacks, but the prevalence of these risk factors, except for cigarette smoking, was higher in Blacks than Whites. The SEER incidence rate ratio of 2.3 for Blacks compared to whites was increased to 2.7 when incidence rates utilized denominators corrected for prevalence of hysterectomy, while the rate difference increased from 14.9 to 25.8 cases per 100,000 person-years (PY). We estimated further that, after adjustment for prevalence of hysterectomy, the incidence rate for women at the lowest levels of exposure to the risk factors evaluated was 2.2 times higher in Blacks than Whites, but that the corresponding rate difference was only 2.2 cases per 100,000 PYs. Thus, our results suggest that racial differences in the prevalence of exposure to identified risk factors account for most of the difference in incidence rates. It remains to be determined what, as yet unidentified, aspects of lower socioeconomic status contribute to the higher incidence rate in Blacks.
A case-control study of women with incident in situ and invasive cervical cancer was conducted during 1982-83 in five US areas reporting to the Comprehensive Cancer Patient Data System: Birmingham, AL; Chicago, IL; Denver, CO; Miami, FL; and Philadelphia, PA. Controls were selected by random-digit dialing and matched to invasive cases on age, race, and telephone exchange. Of the white non-Hispanic in situ cases and controls identified, 229 (78 percent) and 502 (74 percent) were successfully interviewed. Diet was assessed by asking about the usual adult frequency of consumption of 75 food items and the use of vitamin supplements. Included were the major sources of the four micronutrients postulated to reduce the risk of cervical cancer: carotenoids, vitamin A, vitamin C, and folate. Weak inverse associations between risk of in situ disease and intake of carotenoids, vitamin C, folate, fruit, and vegetables/fruits were noted but, with further analysis, these seemed attributable to residual confounding by the multiple lifestyle-related risk factors for this disease and possibly to selection bias. Vitamin A and vegetable intake were unrelated to risk. Dark yellow-orange vegetable consumption and duration of multivitamin use were each strongly related to reduced risk of in situ disease (P for trend = 0.02 and 0.002, respectively) and need to be evaluated in other studies. The absence of persuasive protective effects for the four micronutrients and the similar findings from our analysis of invasive cervical cancer do not concur with other epidemiologic studies and suggest that the role of diet and nutrition in the etiology of cervical cancer is not yet resolved.
In this case-control study, 201 case patients with vulvar cancer and 342 community control subjects responded to a 61-item food frequency questionnaire. Risk was unrelated to intake of dark green vegetables, citrus fruits, legumes, and vitamins A and C and folate. Risk increased modestly with decreased intake of dark yellow-orange vegetables; the relative risk for the lowest versus the highest quartile was 1.6. Analyses using preliminary determinations of the major carotenoids in common fruits and vegetables suggested that alpha carotene might be the protective constituent in dark yellow-orange vegetables. Intake of beta carotene and provitamin A carotenoids was unrelated to risk. Multivitamin users were at lower risk, compared to nonusers, but no trend was observed with increasing years of use, suggesting that this association was due to unmeasured differences in life-style factors. Risk increased irregularly with the number of cups of coffee consumed per week whereas consumption of alcohol was unrelated to risk.
Low intake of vegetables, fruits, and carotenoids is consistently associated with increased risk of lung cancer in both prospective and retrospective studies. In addition, low levels of beta-carotene in serum or plasma are consistently associated with the subsequent development of lung cancer. The simplest explanation is that beta-carotene is protective. Since retinol (preformed vitamin A) is not related in a similar manner to lung cancer risk, beta-carotene appears to function through a mechanism that does not require conversion into vitamin A. However, the importance of other carotenoids and other constituents of vegetables and fruit has not been adequately explored. Both prospective and retrospective studies suggest that vegetable and fruit intake may reduce the risk of cancers of the mouth, pharynx, larynx, esophagus, stomach, colon, rectum, bladder, and cervix. But because of fewer studies and less consistency among studies, the epidemiologic evidence is at present less persuasive than for lung cancer.
Plasma supplemented with ascorbic acid was prepared; the stability of these samples was characterized and the accuracy of the supplementation was established. Studies on the accuracy, precision, and sources of methodological bias in the measurement of ascorbic acid were summarized. Measurements of the ratio of ascorbic acid to dehydroascorbic acid in clinical samples was evaluated and was shown to be relatively constant in plasma taken from blood stored at 12 degrees C for 6 h. These results imply that whole blood has the capacity to maintain a constant ascorbic-dehydroascorbic acid ratio and suggest that this ratio may be of physiological significance.
The extent of diversity in the diets of black and white adults (n = 11,658) aged 19 to 74 years was evaluated from 24-hour dietary recalls obtained in the second National Health and Nutrition Examination Survey. Each 24-hour recall was evaluated for the consumption of items from the dairy, meat, grain, fruit, and vegetable groups (Food Group Score). A second scoring method (Serving Score) evaluated every recall for consumption of at least two servings each from dairy, meat, fruit, and vegetable groups and four servings from the grain group. Only a third of the population surveyed reported consuming foods from all the food groups on the survey day; less than 3% reported consuming foods from all food groups in at least the recommended amount. Blacks scored lower on both types of diet diversity scores than whites. Both types of diversity scores showed a significant trend to increase with increasing income and level of education. Failure to consume any foods from the dairy, meat, grain, fruit, and vegetable groups was reported by 24%, 6%, 5%, 46%, and 18%, respectively, of the population on the survey day. The proportion of the population consuming at least the desired number of servings from each of these food groups was 51%, 71%, 29%, 29%, 61%, respectively. The results emphasize the need for major public campaigns directed at increasing the diversity of US diets. Special target groups include minorities and those with limited income and formal education.
We developed a method for evaluating food group intake patterns using dietary recall data (n = 11,529) from the second National Health and Nutrition Examination Survey. We used this method to examine the relationship of these food group intake patterns to nutrient intake and to selected biochemical indexes of nutritional status. We evaluated each 24-hour dietary intake recall for the presence or omission of five broad food groups--dairy, meat, grain, fruit, and vegetable. The five most prevalent patterns and the proportion of the population reporting them was as follows: all food groups, 33.6%; no fruit, 23.9%; no dairy and fruit, 9.0%; no dairy, 8.0%; and no fruit and vegetable, 5.6%. In the most prevalent pattern, all food groups were consumed; this was the only pattern that provided mean amounts of all of the key vitamins and minerals at levels greater than or equal to the Recommended Dietary Allowances (RDAs). This pattern also was reported by the lowest proportion of individuals consuming less than 100% RDA of the key nutrients. Patterns in which both fruit and vegetables were consumed were associated with highest levels of serum vitamin C. The consistency of these results indicates that screening diets for food group consumption can quickly provide meaningful information about their quality.
The relation between serum vitamin A measurements made at baseline examination (1971-1975) and subsequent development of prostate cancer was examined in the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study (1981-1984). The analytic cohort consisted of 2440 men 50 years of age or older who were followed for a median of 10 years. A total of 84 men developed prostate cancer. The mean level of serum vitamin A was significantly lower (P less than 0.01) in prostate cancer cases than in noncases. Considered as a continuous variable or in quartiles, a statistically significant (P less than 0.005 or P less than 0.02, respectively) trend was observed for increased risk of prostate cancer with decreasing levels of serum vitamin A. Adjusted for age and race, men in the lowest quartile had a relative risk of 2.2 (95% confidence intervals, 1.1, 4.3) compared to those in the highest quartile. The elevated risk of prostate cancer associated with the lowest quartile of serum vitamin A levels did not attenuate with increasing time between blood drawing and diagnosis, suggesting that metabolic effects of early disease are an unlikely explanation of these results. The inverse association between serum vitamin A and prostate cancer incidence was independent of age at examination and several other possible confounding variables. This is the first prospective study of serum vitamin A and prostate cancer to include a large (84) number of cases.
A case-control study of incident invasive cervical cancer was conducted in Birmingham, Alabama; Chicago, Illinois; Denver, Colorado; Miami, Florida; and Philadelphia, Pennsylvania, during 1982-1983. Controls were selected by random-digit dialing and were matched to cases by age, race, and telephone exchange. Of the white, non-Hispanic cases and controls identified, 271 (73%) and 502 (74%), respectively, were successfully interviewed. Diet was assessed by asking about the usual adult frequency of consumption of 75 food items and the use of vitamin supplements. Included were the major sources of the four micronutrients believed to reduce the risk of cervical cancer: carotenoids, vitamin A, vitamin C, and folate. Women in the highest quartiles of intake of each of these micronutrients had adjusted relative risks of invasive squamous cell cervical cancer comparable to those of women in the lowest quartiles, although their micronutrient intake was estimated to be 3-4 times as high. Risk was not affected by increased consumption of vegetables, dark green vegetables, dark yellow-orange vegetables, fruits, or legumes, or by high intake of the basic food groups. These generally negative findings stand in contrast to findings in previous epidemiologic studies, and the discrepancy is not readily explained by bias, uncontrolled confounding, or inadequate power. The question of the role of diet and nutrition in the etiology of cervical cancer is not yet resolved.