beta-carotene and Carcinoma

Lung cancer is the leading cause of cancer death in the United States, and advances in therapy have accounted for an improvement in five-year survival in this disease from 9% to 13% over the last three decades. Molecular genetic evidence has confirmed the epidemiologic link between tobacco and lung cancer causation, and has clarified the etiology of the persistent risk of lung cancer development in former smokers. Retinoids have shown promise in aerodigestive cancer chemoprevention, both in the reversal of preneoplastic lesions and in the prevention of second primary cancers. After initial epidemiologic and dietary studies had linked beta-Carotene with cancer risk reduction, large randomized phase III studies of this compound have shown no evidence of benefit and some evidence of heightened lung cancer risk in active smokers on high dose supplemental beta-Carotene. Therefore, careful clinical, epidemiologic, and basic studies of retinoids using intermediate end point markers are necessary to determine the definitive role of these compounds in the chemoprevention of respiratory tract cancer, with a particular focus on former smokers.

Topics: Aged; beta Carotene; Carcinoma; Clinical Trials as Topic; Female; Humans; Lung Neoplasms; Male; Middle Aged; Retinoids; Smoking

Dietary components may be both causal and protective in cases of pancreatic carcinoma, but the preventive potential of single constituents has not been evaluated. The authors report the effects of alpha-tocopherol and beta-carotene supplementations on the rates of incidence of and mortality from pancreatic carcinoma in a randomized, controlled trial.. The 29,133 participants in the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study were male smokers who were ages 50-69 years at the time they were randomized into 1 of the following 4 intervention groups: dl-alpha-tocopherol (AT; 50 mg/day), beta-carotene (BC; 20 mg/day), both AT and BC, and placebo. The daily supplementation lasted for 5-8 years. Incident cancers were identified through the national Finnish Cancer Registry and death certificates of the Statistics Finland. Results were analyzed by supplementation with Cox regression models.. Effects of both supplementations were statistically nonsignificant. The rate of incidence of pancreatic carcinoma was 25% lower for the men who received beta-carotene supplements (n = 38) compared with the rate for those who did not receive beta-carotene (n = 51) (95% CI, -51% to 14%). Supplementation with alpha-tocopherol (n = 51) increased the rate of incidence by 34% (95% CI, -12% to 105%) compared with the rate for those who did not receive alpha-tocopherol. Mortality from pancreatic carcinoma during the follow-up, adjusted for stage and anatomic location of the tumor, was 19% (95% CI, -47% to 26%) lower among those who received beta-carotene and 11% (95% CI, -28% to 72%) higher among those who received alpha-tocopherol as compared with those who did not receive supplementation.. Supplementation with beta-carotene or alpha-tocopherol does not have a statistically significant effect on the rate of incidence of pancreatic carcinoma or the rate of mortality caused by this disease.

Topics: Aged; Antioxidants; beta Carotene; Carcinoma; Chemoprevention; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Pancreatic Neoplasms; Registries; Smoking; Vitamin E

Higher blood levels of alpha-tocopherol, the predominant form of vitamin E, have been associated in some studies with a reduced risk of lung cancer, but other studies have yielded conflicting results. To clarify this association, we examined the relationship between prospectively collected serum alpha-tocopherol and lung cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort.. The ATBC Study was a randomized, clinical trial of 29 133 white male smokers from Finland who were 50-69 years old and who had received alpha-tocopherol (50 mg), beta-carotene (20 mg), both, or neither daily for 5-8 years. Data regarding medical histories, smoking, and dietary factors were obtained at study entry, as was a serum specimen for baseline alpha-tocopherol determination. alpha-Tocopherol measurements were available for 29 102 of the men, among whom 1144 incident cases of lung cancer were diagnosed during a median observation period of 7.7 years. The association between alpha-tocopherol and lung cancer was evaluated with the use of multivariate proportional hazards regression.. A 19% reduction in lung cancer incidence was observed in the highest versus lowest quintile of serum alpha-tocopherol (relative risk = 0.81; 95% confidence interval = 0. 67-0.97). There was a stronger inverse association among younger men (<60 years), among men with less cumulative tobacco exposure (<40 years of smoking), and possibly among men receiving alpha-tocopherol supplementation.. In the ATBC Study cohort, higher serum alpha-tocopherol status is associated with lower lung cancer risk; this relationship appears stronger among younger persons and among those with less cumulative smoke exposure. These findings suggest that high levels of alpha-tocopherol, if present during the early critical stages of tumorigenesis, may inhibit lung cancer development.

Topics: Adenocarcinoma; Aged; beta Carotene; Carcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Dietary Supplements; Finland; Humans; Lung Neoplasms; Male; Middle Aged; Prospective Studies; Risk; Risk Factors; Smoking; Treatment Outcome; Vitamin E

A major physiological role of retinoids is the regulation of epithelial and epidermal cell differentiation. A total of 285 patients with clinically and histopathologically confirmed diagnosis of various carcinomas (untreated) were selected for the study. The control values of serum beta-carotene and vitamin A levels were established from 50 subjects free of any known pathology. The controls were matched for age and sex. The mean serum levels of beta-carotene and vitamin A have shown a significant difference (p less than 0.001) in all the cancers compared with the controls. In cancer of the oral cavity, the males showed significantly lower levels (p less than 0.01) compared with their female counterparts. In cancer of the lung, however, the mean serum levels of beta-carotene and vitamin A were higher in males compared with females (p less than 0.02). Our results suggest a possible association between vitamin A and epithelial cancer, but whether the deficiency is the cause of the disease or if it is due to the tumor remains unknown.

Topics: beta Carotene; Carcinoma; Carotenoids; Female; Humans; Male; Sex Factors; Vitamin A; Vitamin A Deficiency

Some dietary factors could be involved as cofactors in cervical carcinogenesis, but evidence is inconclusive. There are no data about the effect of fruits and vegetables intake (F&V) on cervical cancer from cohort studies. We examined the association between the intake of F&V and selected nutrients and the incidence of carcinoma in situ (CIS) and invasive squamous cervical cancer (ISC) in a prospective study of 299,649 women, participating in the European Prospective Investigation into Cancer and Nutrition study. Cox proportional hazard models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (95% CI). A calibration study was used to control measurement errors in the dietary questionnaire. After a mean of 9 years of follow-up, 253 ISC and 817 CIS cases were diagnosed. In the calibrated model, we observed a statistically significant inverse association of ISC with a daily increase in intake of 100 g of total fruits (HR 0.83; 95% CI 0.72-0.98) and a statistically nonsignificant inverse association with a daily increase in intake of 100 g of total vegetables (HR 0.85: 95% CI 0.65-1.10). Statistically nonsignificant inverse associations were also observed for leafy vegetables, root vegetables, garlic and onions, citrus fruits, vitamin C, vitamin E and retinol for ISC. No association was found regarding beta-carotene, vitamin D and folic acid for ISC. None of the dietary factors examined was associated with CIS. Our study suggests a possible protective role of fruit intake and other dietary factors on ISC that need to be confirmed on a larger number of ISC cases.

Topics: Adult; Aged; Ascorbic Acid; beta Carotene; Carcinoma; Carcinoma, Squamous Cell; Diet; Europe; Female; Folic Acid; Follow-Up Studies; Fruit; Humans; Middle Aged; Neoplasm Invasiveness; Nutrition Surveys; Prospective Studies; Risk Factors; Uterine Cervical Neoplasms; Vegetables; Vitamin A; Vitamin D; Vitamin E

In this study, we evaluated the efficacy of lycopene against the growth of prostate cancer in vivo.. Athymic nude mice were implanted subcutaneously with human androgen-independent prostate carcinoma PC-3 cells. They were supplemented with a low or a high dose of lycopene (4 and 16 mg/kg) and a single dose of β-carotene (16 mg/kg) twice a week for 7 wk. At the end of the experiment, both lycopene and β-carotene strongly inhibited the tumor growth, as evidenced by the decrease in tumor volume and tumor weight. High-dosage lycopene and β-carotene significantly decreased the expression of proliferating cell nuclear antigen in tumor tissues and increased the levels of insulin-like growth factor-binding protein-3 in plasma. In addition, high-dosage lycopene supplementation significantly decreased the vascular endothelial growth factor (VEGF) levels in plasma. In contrast, β-carotene supplementation significantly increased the VEGF levels, as compared with tumor control group.. Lycopene and β-carotene supplementation suppressed the growth of prostate tumor cells, and the effects are likely associated with reduction of proliferation (attenuation of proliferating cell nuclear antigen expression) and with interference of the insulin-like growth factor 1 signaling (increased plasma insulin-like growth factor-binding protein-3 levels). Furthermore, the inhibition of VEGF by lycopene suggests that the antitumor mechanisms of lycopene also involve anti-angiogenesis.

Topics: Androgens; Animals; Anticarcinogenic Agents; beta Carotene; Carcinoma; Carotenoids; Cell Line, Tumor; Dietary Supplements; Humans; Insulin-Like Growth Factor Binding Protein 3; Lycopene; Male; Mice; Mice, Nude; Proliferating Cell Nuclear Antigen; Prostatic Neoplasms; Random Allocation; Time Factors; Tumor Burden; Vascular Endothelial Growth Factors; Xenograft Model Antitumor Assays

Clinical trials have shown a significant increase in incidence of lung cancer among smokers and asbestos workers supplemented with beta-carotene, suggesting a tumor-promoting activity for this agent. We set out to test possible tumor-promoting and chemopreventive activities of dietary and topical beta-carotene in the two-stage 7,12-dimethylbenz[a]anthracene-12-O-tetradecanoylphorbol 13-acetate (TPA) model of mouse skin carcinogenesis. In the first study, the effects of three levels of dietary beta-carotene (6, 60, and 600 micrograms/g purified diet containing no other retinoid or carotenoid) were assessed over a period of 42 weeks. Carcinoma yield was reduced by approximately 50% in the 600 micrograms/g diet group (mean 0.22 carcinomas/mouse) compared with the 6 micrograms/g diet group (mean 0.44 carcinomas/mouse, p = 0.003). The 60 micrograms/g diet group showed a pattern of inhibition similar to the 600 micrograms/g diet group. A protective effect (25% reduction) of beta-carotene (in the 600 micrograms/g diet group) on papilloma formation was also found. However, the intermediate 60 micrograms/g diet group showed the same incidence as the low 6 micrograms/g diet group. This points to a lack of correlation between papilloma and carcinoma incidence, as we also found in previous work on dietary retinoids and carotenoids. The purpose of the second study was to assess whether topical beta-carotene (2 micrograms) has tumor-promoting or chemopreventive activity in the two-stage protocol. In the absence of TPA, beta-carotene had no significant tumor-promoting activity. Instead, papilloma yield induced by TPA was decreased by topical beta-carotene from an average of 20 to approximately 10 papillomas/mouse (p = 2.5 x 10(-7)). The effect of topical beta-carotene persisted beyond the treatment period (Week 24) until the termination of the study at Week 42. Western blot analysis of mouse skin extracts showed that topical beta-carotene upregulated retinoic acid receptor-alpha and -gamma expression in the dorsal skin. This finding suggests that beta-carotene may work as a chemopreventive agent by upregulating the expression of retinoid receptors in mouse skin. In conclusion, our data show that beta-carotene prevents skin carcinoma formation, induces retinoic acid receptor expression, and fails to act as a tumor promoter in the two-stage model of skin tumorigenesis.

Topics: Administration, Topical; Animals; beta Carotene; Blotting, Western; Carcinogens; Carcinoma; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Male; Mice; Mice, Inbred SENCAR; Papilloma; Pregnancy; Receptors, Retinoic Acid; Skin; Skin Neoplasms; Time Factors; Up-Regulation

To examine the protective role of dietary antioxidants (carotenoids, vitamin C, vitamin E, glutathione, and flavonoids) in lung cancer risk, a case-control study involving 541 cases of lung cancer and 540 hospitalized controls was carried out in Uruguay. The relevant variables were energy adjusted using the residuals method and then categorized in quartiles. Adjusted odds ratios (ORs) for antioxidants were calculated through unconditional logistic regression. With the exception of lycopene and vitamin C, the remaining antioxidants were associated with significant reductions in risk of lung cancer. Of particular interest was the inverse association between dietary glutathione and lung cancer [OR of quartile with highest intake compared with lowest quartile = 0.42, 95% confidence interval (CI) = 0.27-0.63]. Also, carotenoids and vitamin E were associated with significant reductions in risk of lung cancer (OR = 0.43, 95% CI = 0.29-0.64 for total carotenoids and OR = 0.50, 95% CI = 0.39-0.85 for vitamin E). A joint effect for high vs. low intakes of beta-carotene and glutathione was associated with a significant reduction in risk (OR = 0.32, 95% CI = 0.22-0.46). It could be concluded that dietary antioxidants are associated with a significant protective effect in lung carcinogenesis and that the inverse association for glutathione persisted after controlling for total vegetables and fruits.

Topics: Adenocarcinoma; Adult; Age Distribution; Aged; Aged, 80 and over; Antioxidants; beta Carotene; Carcinoma; Carcinoma, Large Cell; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Case-Control Studies; Diet; Glutathione; Humans; Logistic Models; Lung Neoplasms; Male; Middle Aged; Odds Ratio; Risk Factors; Surveys and Questionnaires; Uruguay

The aim of the present study was to elucidate the influence of social, dietary and environmental factors on the incidence of malignant epithelial tumours in the upper digestive tract and on the prognosis of patients with these cancers.. A population-based case-control study was carried out, and the patients in the study were included in a survival analysis.. The study was carried out at the Department of Otorhinolaryngology at Ullevål University Hospital, Oslo, Norway.. In the case-control study, 84 patients and 89 controls were included. Only the patients were included in the survival analysis.. Smoking showed the highest odds ratio (OR) for morbidity (OR = 29). The patients had in general a lower social status, and a higher alcohol intake (OR = 6.6). For both beta-carotene and vitamin C, the ORs decreased with increasing intake (OR = 0.2 and 0.3, respectively). Increased ORs were associated with low values for haemoglobin, iron, TIBC, folic acid, magnesium and especially for albumin (OR = 14), and with high values for ferritin, vitamin B12 and thiocyanate (a marker for smoking). Stage of the disease was an important prognostic factor. The relative risk (RR) of dying for disseminated vs localised tumours being 3.2. A poorer prognosis was linked to higher age, to smoking vs no smoking (RR = 2.3), and to lower levels of haemoglobin, albumin, magnesium and thiocyanate.. Strong beer, liquor, consumption of milk and table fat, low social status and smoking seemed to have a negative impact on both disease and survival. Fruit and vegetables might, however, reduce the risk. Whereas low serum albumin, iron and magnesium indicated a high OR for cancer, vitamin C and beta-carotene had the opposite implication. No significant implications on survival could be detected in blood chemistry beyond the stage of disease.

Topics: Adult; Aged; Alcohol Drinking; Ascorbic Acid; beta Carotene; Carcinoma; Case-Control Studies; Diet; Dietary Fats; Digestive System Neoplasms; Female; Humans; Male; Middle Aged; Norway; Prognosis; Smoking; Social Class; Survival Analysis

Using 7,12-dimethylbenz[a]anthracene as the initiator and 12-O-tetradecanoyl-13-acetate as the tumor promoter on the dorsal skin of Sencar mice, we previously showed that pharmacological dietary all-trans-retinoic acid and beta-carotene inhibit the conversion of papillomas to carcinomas in a two-stage system of chemical carcinogenesis. The purpose of this study was to determine the influence of dietary retinoic acid and beta-carotene on retinoid and beta-carotene concentrations in skin and other tissues. We were unable to measure tissue retinoic acid because of the relatively limited amount of tissue available for analysis and the fast rate of metabolism. Different dietary levels of retinoic acid or beta-carotene did not influence total retinol of skin, papilloma, and carcinoma tissues, which all showed a concentration of approximately 1 +/- 0.5 microgram/g wet wt. Equally refractory to dietary retinoic acid or beta-carotene was serum retinol concentration. In contrast, dietary retinoic acid protected loss of liver retinol and retinyl palmitate, and beta-carotene caused an increase in beta-carotene and retinyl palmitate in liver but did not affect serum and liver retinol. We further investigated metabolic and functional aspects of retinoic acid in cultured mouse epidermal keratinocytes (LC-8 cells) and found that these cells actively metabolized [10,11-14C]retinoic acid to polar compounds. Isomers of retinoic acid were a minor product in the presence of cells and the major product when incubated in serum-containing medium in the absence of cells. From the functional point of view, exposure of LC-8 cells to 3 x 10(-6) M all-trans-retinoic acid (RA) caused a 75-fold induction in tissue transglutaminase and an approximately 9-fold induction in 10(-6) M RA at three days of culture. We conclude that retinoic acid spares endogenous retinol and that beta-carotene greatly enhances liver retinyl palmitate levels. Moreover we show that although mouse epidermal cells metabolize retinoic acid at a very high rate, they respond functionally by induction of tissue transglutaminase activity. Because this enzyme has been suggested to be involved in programmed cell death, we are presently investigating the possibility that it may be involved in the inhibition of carcinogenesis in mice fed pharmacological doses of RA.

Topics: Animals; beta Carotene; Carcinoma; Carotenoids; Cell Division; Chromatography, High Pressure Liquid; Diet; Female; Keratinocytes; Liver; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Papilloma; Skin; Skin Neoplasms; Transglutaminases; Tretinoin; Tumor Cells, Cultured; Vitamin A

Selenium has been suggested to be anticarcinogenic and to play a role in the cellular defense against oxidative stress. The association between toenail selenium (a marker of long-term selenium status) and lung cancer was investigated in a cohort study of diet and cancer that started in 1986 among 120,852 Dutch men and women aged 55-69 years. After 3.3 years of follow-up, 550 incident cases of lung carcinoma were detected. Toenail selenium data were available for 370 lung cancer cases and 2459 members of a randomly selected subcohort. The rate ratio of lung cancer for subjects in the highest compared to the lowest quintile of toenail selenium, after controlling for age, gender, smoking, and education, was 0.50 (95% confidence interval, 0.30-0.81), with a significant inverse trend across quintiles (P = 0.006). The protective effect of selenium was concentrated in subjects with a relatively low dietary intake of beta-carotene or vitamin C. The rate ratio in the highest compared to the lowest quintile of selenium was 0.45 in the low beta-carotene group (95% confidence interval, 0.22-0.92; trend P = 0.028) and 0.36 in the low vitamin C group (95% confidence interval, 0.17-0.75; trend P < 0.001). The results of this study support an inverse association between selenium status and lung cancer and suggest a modification of the effect of selenium by the antioxidants beta-carotene and vitamin C.

Topics: Adenocarcinoma; Age Factors; Aged; Ascorbic Acid; beta Carotene; Carcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Carotenoids; Cohort Studies; Education; Feeding Behavior; Female; Follow-Up Studies; Humans; Incidence; Lung Neoplasms; Male; Middle Aged; Nails; Netherlands; Prospective Studies; Risk Factors; Selenium; Sex Factors; Smoking; Surveys and Questionnaires; Time Factors; Toes; Vitamin A

SENCAR mice were used to determine the effects of the provitamin A compound beta-carotene on papilloma formation and the conversion of papillomas to carcinomas in a two-stage protocol with one application of the initiator 7,12-dimethylbenz[a]anthracene (DMBA, 20 micrograms) and 20 weekly applications of the promotor 12-O-tetradecanoylphorbol-13-acetate (TPA, 2 micrograms). A purified vitamin A-free diet was supplemented with beta-carotene at four levels (0.6, 6, 60 and 600 micrograms/g of diet) for female mice and two levels (60 and 600 micrograms/g) for male mice. Dietary supplementations of beta-carotene did not result in significant changes in body weight and survival of female and male mice. However, papillomas developed more rapidly and papilloma incidence (% mice with papillomas) reached its maximum (100%) sooner in male mice fed 600 micrograms of beta-carotene/g of diet than those fed 60 micrograms/g. There were smaller differences in papilloma incidence among the dietary groups in female mice, but the papilloma incidence again reached 100% sooner in mice fed 600 micrograms of beta-carotene/g of diet. Female and male mice fed 600 micrograms of beta-carotene/g of diet had significantly higher papilloma yields (average number of papillomas/mouse) than other dietary groups and a very low percentage of these papillomas converted to carcinomas in these mice. Thus, beta-carotene at 600 micrograms/g inhibited the conversion of papillomas to carcinomas in both sexes. In addition, papilloma yields were higher in female mice and these papillomas regressed more quickly than those in the corresponding groups of male mice. In conclusion, dietary beta-carotene caused differential effects on papilloma and carcinoma yields and sex-dependent differences in papilloma formation in female and male SENCAR mice treated with DMBA and TPA in a two-stage carcinogenesis protocol.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Carcinoma; Carotenoids; Cocarcinogenesis; Dose-Response Relationship, Drug; Female; Incidence; Male; Mice; Neoplasms, Multiple Primary; Papilloma; Pregnancy; Sex Factors; Skin Neoplasms; Tetradecanoylphorbol Acetate

In a case-control study to determine the risk of developing lung cancer, the serum levels of vitamins A and E, carotene and selenium were determined in 31 patients, newly diagnosed as having lung cancer, and in matched controls, the said controls being selected from outpatients with no cancer. A significant, inverse association was found between serum vitamins A and E and lung cancer. The relative risk for the low vs high tertiles were, respectively, 5.94 for serum vitamin A and 8.44 for serum vitamin E. Taking histological cancer subtype into account, no relation was revealed between the microelements and squamous cell carcinoma of the lung. The relative risk for lung cancer was 6.50, however, when three, or all four, microelement levels were in the lowest tertile, compared with there being fewer than three in the lowest tertile. Even when three microelements, excluding vitamin E which had the most significant inverse association with lung cancer, were considered, the relative risk was 7.50 when any two or all three were in the lowest tertile, compared with there being just one microelement or none at all in the lowest tertile. A combined effect of vitamins A and E, carotene and selenium on the development of lung cancer has, therefore, been suggested. Further studies will thus be necessary to elucidate the cumulative effect of the serum micronutrients and trace elements, as well as the effect of single elements, on the development of lung cancer.

Topics: Adenocarcinoma; Adult; Aged; beta Carotene; Carcinoma; Carcinoma, Squamous Cell; Carotenoids; Case-Control Studies; Female; Humans; Lung Neoplasms; Male; Middle Aged; Risk Factors; Selenium; Smoking; Vitamin A; Vitamin E

In a hospital-based case-control study, consumption of lactose-containing (dairy) foods and foods containing beta-carotene by 71 women with epithelial cancer of the ovary and 141 matched controls was investigated. No significant differences were found between cases and controls in the frequency of consumption of dairy foods or in the amount of lactose consumed. Consumption of carrots was found to decrease risk. Logistic regression analyses indicated a protective effect of high beta-carotene intake (odds ratio = 0.3, 95% confidence interval = 0.1-0.8), after adjusting for body mass, smoking, and lactose consumption.

Topics: Administration, Oral; Adult; Aged; beta Carotene; Carcinoma; Carotenoids; Diet; Female; Humans; Lactose; Middle Aged; Nutritional Physiological Phenomena; Ovarian Neoplasms; Regression Analysis; Risk Factors

The dietary importance of beta-carotene as a factor in health maintenance has recently attracted considerable interest. Previously, total carotene content was estimated in a limited number of human tissues by means of spectrophotometric methods. In this study the levels of beta-carotene were measured by high-pressure liquid chromatography in tissue samples of uterine leiomyomas and adjacent normal myometrium obtained at hysterectomy from uteri of 18 patients. beta-Carotene concentration was significantly (p = 0.0013) lower in fibroid tissue than in normal myometrium. In addition, levels of beta-carotene were assayed in tissue samples of cancers of the cervix, endometrium, ovary, breast, colon, lung, liver, and rectum and were compared with levels of respective adjacent normal sites. The concentrations of beta-carotene were found to be lower in all cancer tissues. The decreased levels of beta-carotene suggest that beta-carotene deficiency may have a role in the cause and/or pathogenesis of leiomyomas and cancers of the organs that were investigated. The mechanism of action, however, remains unknown.

Topics: Adult; Aged; beta Carotene; Breast Neoplasms; Carcinoma; Carotenoids; Female; Humans; Leiomyoma; Middle Aged; Ovarian Neoplasms; Uterine Neoplasms