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Background: Large-scale international collaboration is essential to decipher relevant information in the context of omics-scale interrogations in cancer research. This is even more important for rare and fatal diseases like pancreas cancer (PC). Methods: The COST Action BM1204 is a unique platform to facilitate the collaboration of a broad range of European and international PC multidisciplinary research groups in order to: (1) integrate knowledge and experience in a multidisciplinary way ‘from cell to society', (2) promote the application of uniform study tools and protocols, (3) foster their optimal use by early-stage researchers, (4) enhance the mobility and training of researchers, and (5) disseminate the results produced to the broader society. Results: This Action will develop novel interdisciplinary tools for collaborative research to improve our understanding of PC and its prevention, diagnosis and treatment. It also aims to answer questions related to the etiology, early detection, evidence-based and personalized treatment, and health management for PC. Furthermore, the Action will contribute to new insights into PC personalized medicine and beyond as well as to the understanding of complex and rare diseases taking PC as a best practice example. The Action aims at attracting young scholars across a range of disciplines in collaboration with more experienced researchers and enhancing active European participation in the international scenario of PC research. Conclusion: The ultimate aim is to foster PC research in Europe and to coordinate this effort with other international initiatives to reduce disease mortality.

To investigate the role of selected medical conditions on the risk of ovarian cancer, we analysed data from a case-control study. Cases were 971 women below the age of 75 years with histologically confirmed epithelial ovarian cancer, admitted to a network of hospitals including the major teaching and general hospitals in the greater Milan area. Controls were 2758 women admitted to the same network of hospitals for acute, non-gynaecological, non-hormone related, non-neoplastic conditions. Obesity/severe overweight were inversely associated with the risk of ovarian cancer (multivariate relative risk, RR, 0.66, 95% confidence interval, CI, 0.52-0.85). Hyperlipidaemia was also inversely related to ovarian cancer risk, (RR 0.64, 95% CI 0.45-0.89). No relationship emerged between ovarian cancer risk and diabetes (RR 0.80, 95% CI 0.54-1.19), hypertension (RR 0.85, 95% CI 0.68-1.06), thyroid diseases (RR 0.89, 95% CI 0.63-1.13) and cholelithiasis (RR 0.86, 95% CI 0.66-1.12). A decreased frequency of ovarian cancer was seen in women with a history of uterine leiomyomas (RR 0.66, 95% CI 0.47-0.92) and benign ovarian cysts (RR 0.69, 95% CI 0.41-1.13). (C) 1997 Elsevier Science Ltd.

Background Menarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women.Methods Individual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression.Findings Breast cancer risk increased by a factor of 1.050 (95% CI 1.044-1.057; p < 0.0001) for every year younger at menarche, and independently by a smaller amount (1.029, 1.025-1.032; p < 0.0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45-54 years 1.43, 1.33-1.52, p < 0.001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p < 0.006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p < 0.01 for both comparisons).Interpretation The effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours.Funding Cancer Research UK.

Background Menarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women. Methods Individual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression. Findings Breast cancer risk increased by a factor of 1.050 (95% CI 1.044-1.057; p < 0.0001) for every year younger at menarche, and independently by a smaller amount (1.029, 1.025-1.032; p < 0.0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45-54 years 1.43, 1.33-1.52, p < 0.001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women’s year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p < 0.006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p < 0.01 for both comparisons). Interpretation The effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women’s total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours. Funding Cancer Research UK.

The relationship between various micronutrients and colorectal cancer risk was investigated using data from a case control study conducted between January 1992 and June 1996 in Italy. Cases were 1,953 incident, histologically confirmed colorectal cancers (1,225 of the colon and 728 of the rectum), admitted to the major teaching and general hospitals in the study areas, and 4,154 controls with no history of cancer, admitted to hospitals in the same catchment areas for acute, non-neoplastic diseases unrelated to the digestive tract and requiring no long-term modifications of the diet. Dietary habits were investigated using a validated food-frequency questionnaire. Odds ratio (ORs) were computed after allowance for age, sex and other potential confounding factors, including physical activity, total energy and fibre intake. For most micronutrients, ORs were below unity with increasing quintile of intake. The most consistent protective effects were for carotene, riboflavin and vitamin C (Multivariate ORs from the continuous model, with unit set as the difference between the upper cut-point of the 4th quintile and that of the Ist one, were 0.65, 0.73 and 0.80, respectively). Inverse relationships were observed also for calcium and vitamin D (ORs of 0.85 and 0.93, respectively). When the combined effect of calcium and vitamin D and selected anti-oxidants was considered, the OR reached 0.46 in subjects reporting high calcium/vitamin D and high anti-oxidant intake compared to those reporting tow intake of both groups of micronutrients. Most results were apparently stronger for colon cancer and among females. Our results provide further support for a protective effect of several micronutrients on colorectal cancer risk and some indications for a specific and stronger effect of selected anti-oxidants. (C) 1997 Wiley-Liss, Inc.

The relationship between breast cancer risk and family history of cancer in first-degree relatives was investigated using data from a multicentric case-control study conducted in Italy between lune 1991 and April 1994 an 2,569 women aged less than 75 years, with histologically confirmed incident breast cancer, and 2,588 control women admitted to hospital for acute, non-neoplastic, non-gynaecological conditions. Relative to women with no history, those with a family history of breast cancer had an odds ratio (OR) of 2.4 [95% confidence interval (CI) 1.9-3.0], and those with family history of intestinal cancer had an OR of 1.3 (95% CI 1.0-1.7). No significant relations emerged between breast cancer risk and family history of prostate (OR 1.1), ovarian (OR 1.3), cervical or endometrial (OR 1.2) or other cancers, except gallbladder (OR 8.6). The OR for family history of any type of cancer except breast cancer was 1.1. For family history of breast cancer the ORs were similar across strata of age of the proband, being 2.4 below age 45, 2.2 at age 45-59 and 2.7 above age 60, and whether the relative affected was the mother, sister(s) or both, while the risk appeared higher if the age at onset of breast cancer in the relative was lower than 40 years (OR 3.5), rather than higher (OR 2.2). Thus, our results, based on the investigation of all neoplasms in first-degree relatives, confirm that breast cancer risk is increased in women with a family history of breast cancer, while there was no material association with family history of cancer in general, excluding breast cancer. (C) 1997 Wiley-Liss, Inc.

The percent population attributable risk (AR) for kidney cancer was estimated in relation to smoking habits, beta-carotene intake, history of cystitis and family history of kidney cancer, using data from a case-control study conducted between 1985 and 1989 in Milan, northern Italy. The data comprised 133 histologically confirmed cases of incident kidney cancer and 392 controls, admitted to hospital for a wide range of acute, non-neoplastic, non-smoking-related diseases, On the basis of multivariate odds ratios (ORs), smoking habits accounted for about 26% of cases, a low beta-carotene intake for 18%, a history of cystitis for 7%, and a family history of kidney cancer in first-degree relatives for 3% of cases, Ever smoking and low beta-carotene intake combined explained 38% of all kidney cancers, and the combination of these two factors plus a history of cystitis and a family history of kidney cancer explained 45% of the incidence of the disease, Thus, even if available, dietary information was limited and the AR estimates were based on somewhat arbitrary assumptions, A considerable proportion of kidney cancers could be avoided simply by eliminating smoking and increasing consumption of fruit and vegetables in this Italian population, This would mean that about 1,500 kidney cancer deaths every year in the whole of Italy could be avoided.

The relation between family history of acute myocardial infarction (AMI) and the risk of AMI was analyzed using data of a case-control study conducted in Argentina between 1992 and 1994. Case patients were 1,060 subjects with AMI admitted to 35 coronary care units, and controls were 1,071 subjects admitted to the same network of hospitals where cases had been identified, for a wide spectrum of acute conditions unrelated to known or likely risk factors for AMI: 31% of cases versus 15% of controls reported greater than or equal to 1 first-degree relative with history of AMI. Compared with subjects without family history of AMI, the odds ratio (OR) of AMI, after allowance for age, sex, cholesterolemia, smoking, diabetes, hypertension, body mass index, education, social class, and physical exercise, was 2.18 (95% confidence interval [CI] 1.74 to 2.74) for those with family history of AMI. The OR was 2.04 (95% CI 1.60 to 2.60) for subjects with 1 relative, and 3.18 (95% CI 1.86 to 5.44) for those reporting greater than or equal to 2 relatives with AMI, in women the OR for any family history of AMI was 2.83, and in men 2.01. The association was of similar magnitude if the mother (OR 1.98), the father (OR 2.13), or a sibling (OR 2.48) had had an AMI. The association with family history was stronger at a younger age because the OR for subjects reporting greater than or equal to 2 more relatives with a history of AMI was 4.42 for subjects aged

BACKGROUND. Protection from thyroid carcinoma due to certain dietary factors was suggested by several studies, but the findings were relatively inconsistent. The role of micronutrients has not yet been systematically analyzed. To investigate the relationship between micronutrient intake and thyroid carcinoma risk, the authors used data from a case-control study conducted in northern Italy between 1986 and 1992. METHODS. The study included 399 incident, histologically confirmed thyroid carcinoma cases and 617 controls admitted to the hospital for acute, nonneoplastic, nonhormone-related diseases. RESULTS. Retinol intake showed a direct association with thyroid carcinoma risk, with odds ratios (ORs) of 1.39 (95% confidence interval [CI], 0.9-2.0) in the third quartile of consumption and 1.52 (95% CI, 1.0-2.3) in the highest quartile, whereas beta-carotene had an inverse relationship, with ORs of 0.63 (95% CI, 0.4-0.9) in the third quartile of consumption and 0.58 (95% CI, 0.4-0.9) in the highest quartile compared with the lowest quartile. Some protection was observed for measures of vitamin C intake (with an OR of 0.72) and vitamin E (with an OR of 0.67) for the highest quartile of consumption, although the estimates were not statistically significant, and were reduced after adjustment for beta-carotene intake. No clear pattern in risk appeared for vitamin D, folate, calcium, thiamin, or riboflavin. The inverse relationship between beta-carotene and thyroid carcinoma was observed in both papillary and follicular carcinomas. CONCLUSIONS. In this study, a significant inverse association between beta-carotene and thyroid carcinoma was observed, and some protection against thyroid carcinoma from vitamins C and E is as also suggested. (C) 1997 American Cancer Society.

There are indications that beta-carotene, but not pre-formed vitamin A, is protective on the risk of acute myocardial infarction (AMI). The relationship between nonfatal AMI and the intake of beta-carotene and retinol was investigated in a case-control study conducted between 1983 and 1992 in northern Italy on 433 women with nonfatal AMI and 869 controls in hospital for acute, non-cardiovascular, non-neoplastic, non-digestive, non-hormone related conditions. Odds ratios (OR), with their 95% confidence intervals (CI), were computed by unconditional multiple logistic regression analysis, including terms for age, education, body mass index, smoking, alcohol and coffee drinking, menopausal status, hormone replacement therapy and history of diabetes, hypertension and hyperlipidemia. The risk of AMI was inversely related to beta-carotene intake, with an OR of 0.5 (95% CI: 0.3 to 0.8) for the highest quintile of intake compared to the fewest (chi(2) trend = 10.53, p < 0.01). Retinol intake was not associated with AMI, with an OR of 0.9 (95% CI: 0.6 to 1.3) for the highest quintile of intake compared to the lowest. Analysis in separate strata of covariates indicated that the inverse association of beta-carotene intake with risk of AMI was appreciably stronger in younger, lean women with no history of diabetes or hypertension, and in current smokers. The results of this study indicate that the risk of nonfatal AMI in women is inversely related to intake of beta-carotene containing foods, but not foods containing retinol.

In order to understand the determinants of oral contraceptive (OC) use in Italy, we analyzed data on 1577 women aged under age 60 (median age 50 years) admitted as controls in a case-control study of breast cancer. Included in this group were women with acute, non-neoplastic, non-gynecologic, non-hormone-related diseases, admitted between 1991 and 1994 to a network of hospitals in six Italian centres. A total of 275 (17.4%) women reported ever OC use. Oral contraceptive use was strongly related to the level of education: in comparison with women reporting7 years of schooling, the multivariate odds ratios (OR) of ever OC use were 2.2 and 3.5, respectively, in women reporting 7-11 andor = 12 years of schooling (chi 1(2) trend 40.87 p0.001). OC use was inversely related to body mass index (BMI): in comparison with leaner women (BMI, Kg/m2,25), the OR of being an ever OC user was 0.8 and 0.7, respectively, in women with BMI 25-30 andor = 30 (chi 1(2) trend 3.36, p = 0.07). Parous women more frequently tended to be OC users than nulliparous ones, the estimated OR being 2.4 and 2.3, respectively, in women reporting 1 or 2 and 3 or more births in comparison with nulliparae. Likewise, women with history of induced abortions were more frequently ever OC users (OR foror = 1 induced abortions vs no induced abortion, 1.8, 95% Cl 1.2-2.6). However, no relationship emerged between OC use and history of spontaneous abortions. Finally, there was no relation between pill use and history of hypertension, cholelithiasis, thyroid diseases, hyperlipidemia, family history of breast cancer, uterine fibroids and benign breast disease. Women with a history of diabetes were less likely to be OC users (OR 0.6), but the finding was not significant. The results of this analysis are comparable with those of a study conducted in the same population in the early 1980's, and suggest that sociodemographic and reproductive factors, rather than medical history, are major determinants of OC use in this population.In order to understand the determinants of oral contraceptive (OC) use in Italy, data were analyzed on 1577 women under age 60 (median age 50 years) admitted as controls in a case-control study of breast cancer. Women were included with acute, non-neoplastic, non-gynecologic, non-hormone-related diseases, admitted between 1991 and 1994 to a network of hospitals in 6 Italian centers. A total of 275 (17.4%) women reported ever use of OCs. OC use was strongly related to the level of education: the multivariate odds ratios (OR) of ever use were 2.2 and 3.5, respectively, in women reporting 7-11 and or= 12 years of schooling (p 0.001) compared to women reporting 7 years of schooling. OC use was inversely related to body mass index (BMI): the OR of ever use was 0.8 and 0.7, respectively, in women with BMI 25 - 30 and or= 30 (p = 0.07) compared to leaner women (BMI, Kg/m2, 25). Parous women more frequently tended to be OC users than nulliparous ones, the estimated OR being 2.4 and 2.3, respectively, in women reporting 1 or 2-3 or more births in comparison with nulliparae. Likewise, women with a history of induced abortions were more frequently ever users (OR for or= 1 induced abortions vs. no induced abortion, 1.8, (95% CI 1.2-2.6). However, no relationship emerged between OC use and history of spontaneous abortions. Finally, there was no relation between pill use and history of hypertension, cholelithiasis, thyroid diseases, hyperlipidemia, family history of breast cancer, uterine fibroids and benign breast disease. Women with a history of diabetes were less likely to be OC users (OR 0.6), but the finding was not significant. The results of this analysis are comparable with those of a study conducted in the same population in the early 1980's, and suggest that sociodemographic and reproductive factors, rather than medical history, are major determinants of OC use in this population.

The relation between breast feeding and breast cancer was investigated in a multicentric case-control study conducted in Italy on 2,167 parous women with histologically confirmed breast cancer, diagnosed within 1 year, and 2,208 parous control women admitted to hospitals in the same catchment areas of cases for acute, non-neoplastic, non-gynecological non-hormone-related diseases. Compared with women who had never tried to lactate, those who had always failed had a multivariate odds ratio (OR; adjusted for parity, education and several other potential confounding factors) of 0.94, and those who had lactated had an OR of 1.17. The multivariate ORs of women who had breast fed 1, 2 and 3 or more children were, respectively, 1.14, 1.18 and 1.32, compared with women who had never lactated. None of these ORs was statistically significant. Compared with women who had never breast fed, the multivariate ORs were 1.19 for women reporting less than 6 months of breast feeding, 1.15 for 6-11 months, 1.34 for 12-17 months, 1.10 for 18-23 months and 0.86 for 24 months or more. No appreciable difference was evident across strata of age, menopausal status, parity and age at first birth, while there was a hint of interaction with education. Our study therefore excluded any appreciable protective role for lactation in breast cancer risk, with the patterns of lactation in this European population, aside from the protective role of parity on breast carcinogenesis. (C) 1996 Wiley-Liss, Inc.

The relationship between spontaneous and induced abortions and breast cancer risk was analyzed using data from a case-control study conducted between June 1991 and February 1994 in 6 Italian centers on 2,569 histologically confirmed incident breast cancer cases and 2,588 controls admitted to hospital for a wide range of acute, non-neoplastic, non-hormone-related diseases. One or more abortions were reported by 31% of cases and 32% of controls, corresponding to a multivariate odds ratio (OR) of 1.0 (95% confidence interval [Cl], 0.8-1.1). No trend in risk was observed with increasing number of total abortions or spontaneous and induced abortions separately. No significant relationship was found between the risk of breast cancer and history of spontaneous or induced or total abortions in separate strata of age at diagnosis, number of children, time of abortion in relation to first birth and family history of breast cancer. When abortion was the outcome of the first pregnancy, the OR was 1.2 for spontaneous and 1.3 for induced abortion, in relation to women with birth as outcome of the first pregnancy, and 1.0 and 1.1, respectively, when the reference category was nulligravidae. Thus, our results indicate a lack of association between induced and spontaneous abortions and breast cancer risk. (C) 1996 Wiley-Liss, Inc.

Background The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed the worldwide epidemiological evidence on the relation between breast cancer risk and use of hormonal contraceptives. Methods Individual data on 53297 women with breast cancer and 100 239 women without breast cancer from 54 studies conducted in 25 countries were collected, checked, and analysed centrally. Estimates of the relative risk for breast cancer were obtained by a modification of the Mantel-Haenszel method. All analyses were stratified by study, age at diagnosis, parity, and, where appropriate, the age a woman was when her first child was born, and the age she was when her risk of conception ceased. Findings The results provide strong evidence for two main conclusions. First, while women are taking combined oral contraceptives and in the 10 years after stopping there is a small increase in the relative risk of having breast cancer diagnosed (relative risk [95% CI] in current users 1.24 [1.15-1.33], 2p

The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed the worldwide epidemiological evidence on breast cancer risk and use oi hormonal contraceptives. Original data from 54 studies, representing about 90% of the information available on the topic, were collected, checked and analysed centrally. The 54 studies were performed in 26 countries and include a total of 53,297 women with breast cancer and 100,239 women without breast cancer. The studies were varied in their design, setting and timing. Most information came from case-control studies with controls chosen from the general population; most women resided in Europe or North America and most cancers were diagnosed during the 1980s. Overall 41% of the women with breast cancer and 40% of the women without breast cancer had used oral contraceptives at some time: the median age at first use was 26 years, the median duration of use was 3 years, the median year of first use was 1968, the median time since first use was 16 years, and the median time since last use was 9 years. The main findings, summarised elsewhere,I are that there is a small increase in the risk of having breast cancer diagnosed in current users of combined oral contraceptives and in women who had stopped use in the past 10 years but that there is no evidence of an increase in the risk more than 10 years after stopping use. In addition, the cancers diagnosed in women who had used oral contraceptives tended to be less advanced clinically than the cancers diagnosed in women who had not used them. Despite the large number of possibilities investigated, few factors appeared to modify the main findings either in recent or in past users. For recent users who began use before age 20 the relative risks are higher than for recent users who began at older ages. For women whose use of oral contraceptives ceased more than 10 years before there was some suggestion of a reduction in breast cancer risk in certain subgroups, with a deficit of tumors that had spread beyond the breast, especially among women who had used preparations containing the highest doses of oestrogen and progestogen. These findings are unexpected and need to be confirmed. Although these data represent most of the epidemiologi cal evidence on the topic to date, there is still insufficient information to comment reliably about the effects of specific types of oestrogen or of progestogen. What evidence there is suggests, however, no major differences in the effects for specific types of oestrogen or of progestogen and that the pattern of risk associated with use of hormonal contraceptives containing progestogens alone may be similar to that observed for preparations containing both oestrogens and progestogens. On the basis of these results, there is little difference between women who have and have not used combined oral contraceptives in terms of the estimated cumulative number of breast cancers diagnosed during the period from starting use up to 20 rears after stopping. The cancers diagnosed in women who have used oral contraceptives are, however, less advanced clinically than the cancers diag nosed in never users. Further research is needed to establish whether the associations described here are due to earlier diagnosis of breast cancer in women who have used oral contraceptives, to the biological effects of the hormonal contraceptives or to a combination of both. Little information is as yet available about the effects on breast cancer risk of oral contraceptive use that ceased more than 20 years before and as such data accumulate it will be necessary to reexamine the worldwide evidence. RI Ranstam, Jonas/A-4386-2009; Colditz, Graham/A-3963-2009

Epidemiologic evidence on the relation between nutrition and bladder cancer is reviewed. A role of diet and nutrition in bladder carcinogenisis is plausible since most substances or metabolites, including carcinogens, are excreted through the urinary tract. Ecologic studies on populations have found positive correlations between fats and oils and bladder cancer, but these are reflected only partly in the international differences in bladder cancer rates,which are systematically higher in Europe than in the United States. Ten case-control and three cohort studies of bladder cancer published in English between 1979 and 1994, and including some information on dietary factors,were reviewed. Of seven studies which considered various types and measures of fruit and vegetable consumption, six found a reduced risk with increasing consumption, which was more consistent for vegetables, with relative risk (RR) estimates between 0.5 and 0.7 for the highest cf the lowest consumption level. There is, therefore, suggestive evidence that a diet rich in fresh fruit and vegetables is a correlate - or an indicator - of reduced bladder cancer risk. No clear association emerged for other foods investigated, including meat and milk. With reference to nutrients, total fat intake was related to bladder cancer risk in three case-control studies,with relative risks between 1.4 and 1.7 for the highest cf the lowest consumption level. However, no relationship between fats and bladder cancer emerged in a cohort study on Japanese-Americans in Hawaii. No consistent association emerged between protein or carbohydrate consumption and bladder cancer risk. Among micronutrients, vitamin A, and particularly carotenoids, showed an inverse association with bladder cancer risk in four case-control studies, including one allowing for a measure of total caloric intake, but were not related consistently in two other studies. There were only scattered and inconclusive data on vitamin C and E. Finally, two studies suggested that calcium and sodium may be related to bladder cancer risk. Thus, available data on diet and bladder cancer are still inconclusive. This is at least partly attributable to the limited number of cohort studies and the paucity of case-control studies, including satisfactorily detailed and validated dietary questionnaires. Despite these limitations, available data suggest that a diet rich in fresh fruit and vegetables, and, hence, possibly in carotenoids, is a correlate of reduced bladder cancer risk.

To evaluate the relationship between smoking and uterine myomas requiring surgery.We conducted a case-control study in Milan between 1986 and 1992. Cases were 476 patients under 55 years of age with histologically confirmed myomas. Controls were 1,283 women admitted to the hospital for a spectrum of acute, other-than-gynecologic, hormonal or neoplastic conditions (30% trauma, 25% nontraumatic orthopedic conditions, 25% surgical, 20% other miscellaneous).Cases were less frequently current smokers (22%) than controls (32%). In comparison with never smokers, the multivariate relative risk (RR) for myomas was 0.5 (95% confidence interval [CI], 0.4-0.7) in smokers. Ex-smokers were 10% of cases versus 7% of controls (RR 1.2, 95% CI 0.9-1.8). No clear trend in risk was observed with the number of cigarettes smoked per day or duration of smoking and risk of fibroids. The estimated RRs were largely consistent when separate analyses were performed in strata of age and other selected covariates, including indices of body weight.Current smoking seems to reduce the risk of myomas.

The relationship between oral contraceptives (OC) and breast-cancer risk was analysed using data from a case-control study conducted between lune 1991 and February 1994 in 6 Italian centres on 1,991 patients below age 65 with histologically confirmed incident breast cancer and 1,899 controls admitted to hospital for a wide range of acute, non-neoplastic, non-hormone-related diseases, ''Ever OC use'' was reported by 18% of cases versus 14% of controls, corresponding to a multivariate odds ratio (OR) of 1.1 (95% confidence interval, CI 0.9 to 1.4). The ORs were 1.3 for use lasting < 1 year, 1.1 for 1 to 4 years, 0.9 for 5 to 8 years, and 1.2 for over 8 years. With reference to age at first use, there was some indication that the OR was elevated in women who had started use before age 30, but not in those starting at a later age. With reference to time since last OC use, the OR was above unity for women who had stopped for less than 10 years (1.6 for 1 to 4 years; 1.7 for 5 to 9 years), but the OR declined to unity for women who had stopped OC use for 10 years or longer. The OR for women who had stopped OC use for less than 10 years was consistently elevated across strata of selected covariates, and was directly related to the duration of use (OR 1.3 for < 5 years, 1.7, for greater than or equal to 5 years). In contrast, the OR was 0.6, for use lasting greater than or equal to 5 years in women who had stopped for 10 years or more. The elevated OR for women who had recently stopped OC use, together with the absence of association (or the suggestion of some protection) for those who had stopped for 10 years or more is consistent with the pattern of breast-cancer risk observed after a full-term pregnancy, and provides important reassurance on a public health level on the long-term impact of OCs on breast carcinogenesis. (C) 1995 Wiley-Liss, Inc.

Background. A case-control study was conducted to analyze the association between body mass, selected indicator food intake, and vulvar cancer risk. Methods. The patients included in this report were 125 women aged 80 years or younger with histologically confirmed diagnosis of invasive vulvar cancer who were admitted to a network of general and teaching hospitals in the greater Milan area. Control subjects were 541 patients admitted to teaching and general hospitals in Milan for acute conditions. Results. The risk of vulvar cancer was inversely related to green vegetable and carrot consumption, the corresponding multivariate relative risks for lowest versus highest levels of intake being 2.0 (95% confidence interval [CI], 1.2-3.4) and 1.4 (95% CI, 0.9-2.2). The trend in risk was significant for green vegetables. No consistent association emerged between milk, meat, liver, alcohol and coffee consumption and risk of vulvar cancer. In comparison with leaner women, the relative risks of vulvar cancer were 1.8, 1.9, 2.8, and 2.9 in progressively higher quintiles of the body mass index, and the trend in risk was significant. Conclusions. These data indicate that the risk of vulvar cancer is related to a number of nutritional and dietary factors. This is of particular interest, because vulvar cancer is a relatively rare neoplasm, whose etiology is still poorly understood, and on which only a few epidemiologic studies have been conducted.

The proportions of gastric cancer cases attributable (or attributable risks, AR) to consumption of traditional foods (i.e., pasta, rice and maize), low intake of beta-carotene and vitamin C, short duration of use of an electric refrigerator, low educational level, and family history of gastric cancer were computed using data from a case-control study conducted in Northern Italy. Between 1985 and lune 1993 a total of 746 incident, histologically confirmed gastric cancer cases and 2,053 controls admitted to the same network of hospitals for acute, nonneoplastic, non-digestive-tract diseases, unrelated to long-term modifications of diet, were interviewed. The ARs were 48% for low intake of beta-carotene, 40% for high consumption of traditional foods, and 16% for low intake of vitamin C. Overall, these 3 dietary factors explained 73% of the gastric cancer cases in the population. Five percent of all cases were attributable to less than 30 years' use of an electric refrigerator, 15% to low educational level, and 5% to family history of gastric cancer. In individuals over age 60, a greater proportion of cases was attributable to traditional foods, low education and late adoption of electric refrigeration (58% vs. 32% aged under 60), suggesting that correlates of lower social class, influenced lifestyle and dietary habits more markedly in earlier than in more recent generations. According to our estimates, over 3 quarters of the gastric cancer cases in this area are explainable in terms of the risk factors considered. Increased consumption of vitamin C and beta-carotene, and reduced consumption of traditional foods, would help to avoid over 10,000 out of 14,000 stomach-cancer deaths in Italy every year. Consequently, stomach cancer, which is still the third leading cause of cancer death in Italy, would represent only about 2% of all cancer deaths. (C) 1995 Wiley-Liss, Inc.

All ages and truncated (35 to 64 years) mortality rates from all neoplasms and from cancers of the lung, stomach, intestines, and breast for the six calendar quinquennia from 1960-1964 to 1985-1989 were computed from official death certification data and population estimates obtained from the World Health Organization database for total Europe (excluding former Soviet Union) and for three broad European areas: (a) member countries of the European Economic Community for the last period of the study; (b) other Western European countries; and (c) Eastern European countries. In Europe, mortality rates for all neoplasms increased for men and decreased for women. The increase in men can be largely explained by the major tobacco-related lung cancer epidemic throughout Europe. Lung cancer mortality rates rose steeply in Eastern Europe, where the truncated rates reached the highest levels ever observed, and there is no evidence of a leveling off. Stomach cancer mortality decreased in all Europe for both sexes, although rates remained higher in Eastern Europe, while intestinal cancer rates tended to level off around the highest values in various areas of the continent. Breast cancer showed a moderate but steady increase. Overall, the most unfavorable trends were in Eastern Europe, due to major epidemics in tobacco-related neoplasms and in other common cancers related to diet and other lifestyle habits.

We studied the relation between the alcohol drinking and gallstone disease, using data from the 1983 Italian National Health Survey. This survey included information on 58,462 adults age 25 years and over (27,912 males and 30,550 females), randomly selected within strata of geographical area, size of the municipality of residence, and size of the household. The prevalence of gallstone disease or cholecystectomy was 2.4% among males and 4.8% among females. Compared with alcohol abstainers, the relative risk of gallstone disease, controlling for age, sex, education, smoking, and body mass index, was 0.83% [95% confidence interval (CI) = 0.73-0.92] for occasional and regular moderate drinkers (

The report of an increase of ovarian cancer risk among women who had used fertility drugs prompted us to analyse the relationship between fertility drugs and ovarian cancer in a case-control study which has been ongoing in four areas of Italy since 1992. The present analysis is based on 195 epithelial ovarian cancer cases and 1339 controls admitted to hospital for diseases other than gynaecological or malignant conditions. Fewer ovarian cancer cases than controls reported use of fertility drugs (odds ratio, after allowance for potential confounding factors: 0.7, 95% confidence interval: 0.2-3.3). Among nulligravid women, 5/177 control women compared with 0/36 cancer cases reported having ever used fertility drugs. Although only based on small numbers of women who were suffering from ovarian cancer and who had also used fertility drugs, the present study indicated that a role of ovarian stimulation in the aetiology of epithelial ovarian cancer is not established, although it is worth investigating.

Study objective - The study aimed to investigate the relationship between years since stopping smoking and the risk of acute myocardial infarction. Design - This was a hospital based, multicentre, case-control study conducted in Italy between September 1988 and June 1989 within the framework of the GISSI-2 clinical trial. Setting - Over 80 coronary care units in various Italian regions participated. Subjects - A total of 916 incident cases of acute myocardial infarction, below age 75 years, and with no history of ischaemic heart disease, and 1106 control subjects admitted to the same hospitals for acute, non-neoplastic, cardiovascular or cerebrovascular conditions that were not known or suspected to be related to cigarette smoking took part in the study. Main outcome measures and results - Measures were relative risk (RR) estimates of acute myocardial infarction according to the time since stopping smoking and adjusted for identified potential confounding factors. Compared with never smokers, the multivarlate RRs were 1.6 (95% confidence interval (CI) 0.8,3.2) for subjects who had given up smoking for one year; 1.4 (95% CI0.9,2.1) for those who had stopped for two to five years; 1.2 (95% CI0.7,2.1) for six to 10 years; and 1.1 (95% CI0.8,1.8) for those who had not smoked for over 10 years. The estimated RR for current smokers was 2.9 (95% CI 2.2,3.9). The risks of quitters were higher for heavier smokers and those below age 50 years, while no difference emerged in relation to the duration of smoking, sex, and other risk factors for myocardial infarction. Conclusions - These results indicate that there is already a substantial drop in the risk of acute myocardial infarction one year after stopping. The risk in ex-smokers, however, seemed higher (although not significantly) than that of those who had never smoked, even more than 10 years after quitting. This could support the existence of at least two mechanisms linking cigarette smoking with acute myocardial infarction - one involving thrombogenesis or spasms that occurs over the short term, and another involving atherosclerosis that is a long term effect.

Trends in death certification rates from lung cancer in broad Italian geographical areas (north/centre/south) were analysed over the period 1969-1987. In northern Italy, lung cancer rates in young and middle-aged males reached a peak between the mid and late 1970s, and tended to decline afterwards; only above age 60 was mortality still rising in the 1980s. A similar pattern of age-specific rates was observed in central areas, while in the South rates tended to level off in the early 1980s only below age 55, but were still upwards in subsequent age groups. Consequently, the north/south ratio for the overall age-standard rate increased slightly between the late 1960s and mid 1970s, from 1.68 (corresponding to a world standardised rate of 47.1/100 000 in the north vs. 28.1 in the south) to 1.73, but declined to 1.55 between 1985 and 1987 (for a rate of 69.1/100 000 males in the north vs. 44.6 in south). In the younger age groups a diverging pattern was observed: at ages of 25-34 rates in 1985 and 1987 were apparently higher in the south (1.0 vs. 0.9/100 000 in the north), and in the 35-44 age group the north/south ratio decreased from 1.7 to 1.2 (with rates of 12.9 and 10.7, respectively, in 1985 and 1987). Among females, lung cancer rates increased in all geographical areas and age groups except the youngest (25-34 years). Under the age of 50, the rises were proportionally similar in various geographical areas, thus widening the north/south difference in absolute terms. Above the age of 50, the north/south difference tended to be wider in relative terms too, reaching a factor of 2 in the 65-74 age group. The overall age-standardised north/south ratio for females increased from 1.51 in 1969-1974 (5.6 vs. 3.7/100 000) to 1.87 in 1985-1987 (8.4 vs. 4.5/100 000). These trends reflect changes in smoking habits in subsequent generations of Italian males and females from different areas of the country, and confirm the central role of cigarette smoking in lung cancer rates in various populations, although this does not exclude some influence by other, mainly occupational, lung carcinogens on the substantial differences in lung cancer rates in various Italian geographical areas.

The relationship between beer consumption and the risk of colon and rectal cancer was considered in a case-control study conducted in northern Italy. The study was based on 828 histologically confirmed incident cases of colon cancer, 498 of rectal cancer, and 2,024 controls in hospital for a wide spectrum of acute, nonneoplastic, nonalcohol-related diseases. Beer drinking was reported by 6% of colon cancer cases, 7% of rectal cancer cases, and 10% of controls: regular beer drinkers (greater-than-or-equal-to 1 drinks/day) made up 2.6% of colon cancer cases, 3.2% of rectal cancer cases, and 4.1% of controls. Thus the multivariate relative risks (RR) for irregular drinkers were 0.6 [95% confidence interval (CI) 0.4-1.0] for colon and 0.7 (95% CI 0.4-1.2) for rectum. Corresponding values for regular drinkers were 0. 7 (95% CI 0.4-1.2) for colon and 0. 9 (95% CI 0.5-1.5) for rectal cancer. Despite the low frequency of beer drinking in this study, and hence its limited statistical power, the originality of the population in terms of colorectal cancer incidence, patterns of risk factor exposure, and the large dataset pro vide interesting and useful confirmation that moderate beer drinking is not associated with elevated colon or rectal cancer risk.

There are substantial variations in incidence and mortality from oral and pharyngeal cancer in Europe, with systematic tendencies towards increasing rates in most European countries, particularly in younger males. Most of the geographical differences are due to tobacco and alcohol consumption, which explain over three quarters of approximately 20 000 deaths from oral cancer registered every year in Europe, excluding the former Soviet Union. Nonetheless, dietary factors have an established and quantifiable role in oral carcinogenesis in Europe. Two studies showed a significant protective effect by vegetables and fresh fruit, which appeared particularly strong and consistent for fruit, but were not explained by measures of intake of beta-carotene or other micro-nutrients. Although it is not clear whether the observed associations simply reflected a generally poorer nutritional status of oral cancer cases, they open interesting perspectives for aetiological research and prevention, since about one in six oral cancers in European populations can be attributed to dietary deficiencies or imbalances.

Objective-To analyse the relation between tar and nicotine yield of cigarettes smoked in the recent past and the risk of myocardial infarction. Design-Multicentre case-control study conducted between September 1988 and June 1989. Setting-Over 80 coronary care units in various Italian regions. Subjects-916 patients with acute myocardial infarction without history of ischaemic heart disease and 1106 controls admitted to hospital for acute conditions not related to known or suspected risk factors for ischaemic heart disease. Main outcome measures-Relative risk of myocardial infarction according to type of cigarette smoked adjusted for identified potential confounding factors. Brands of cigarettes classified according to yield of tar and nicotine. Results-Patients with acute myocardial infarction were more often smokers and among smokers they tended to smoke more cigarettes. Compared with non-smokers their estimated relative risks were 3.8, 4.3, 3.2, and 3.7 in the four categories of tar yield (< 10, 10-15, > 15-20, and > 20 mg, respectively). No trend in risk across yields was evident when analysis was restricted to smokers and allowance was made for number of cigarettes. Compared with risks in subjects in the lowest category of tar yield the relative risks were 1.2, 0.8, and 1.0 for the subsequent yields. Compared with risks in non-smokers the relative risks ranged from 9.3 to 12.6 below the age of 50 but no trend was observed with increasing yield. Conclusions-Changing to cigarettes with a lower tar yield is not an effective means of reducing tobacco related morbidity from myocardial infarction.

We conducted a study on 91 women with thyroid cancer and 306 controls in hospital for acute nonneoplastic, non-hormone-related disorders in order to investigate the role of reproductive and hormonal factors in the etiology of epithelial thyroid cancer in the Canton of Vaud, Switzerland. Non-significant increases in cancer risk with an increasing number of full-term pregnancies (odds ratio, OR, after allowance for age and previous benign thyroid disease = 1.6, for greater-than-or-equal-to 3 vs. 0 full-term pregnancies, 95% confidence interval, CI: 0.7-3.6) and spontaneous abortions (OR = 2.0 for greater-than-or-equal-to 2 vs. 0 spontaneous abortions, 95% CI: 0.7-5.2) were seen. A significantly elevated OR (2.8,95% CI: 1. 1-7.2) was found in those women whose first pregnancy ended with an abortion. Whereas most other reproductive, menstrual and hormonal factors examined did not seem to affect the risk of thyroid cancer significantly, a clue emerged of an association between thyroid cancer and artificial menopause (OR = 6.3, for women who underwent artificial menopause vs. premenopausal women, 95% CI: 1.7-23.2). Although not necessarily causal, the relationship between the risk of epithelial thyroid cancer and the occurrence of spontaneous abortions and artificial menopause deserves attention in future studies, in the light of the high incidence of thyroid cancer in young and middle-aged women.

The relationship between dietary factors and the risk of breast cancer was investigated in a case-control study conducted in the Canton of Vaud, Switzerland as a pilot phase for a larger cooperative study within the SEARCH Programme of the International Agency for Research on Cancer (Lyon, France). A total of 107 incident, histologically confirmed cases of breast cancer and 318 controls admitted to hospital for acute, nonhormone-related, gynecological, metabolic, or neoplastic disorders were interviewed Significant direct trends in risk were observed with total energy intake [relative risk (RR) for highest vs. lowest intake tertile = 1.9] and, after allowance for energy intake, with frequency of consumption of various types of meat (RR = 2.1 for the highest tertile), cheese (RR = 2.7), and alcohol (RR = 2.1). Significant protections, on the order of 40-60% reductions for the highest vs. lowest consumption tertile, were conferred by total green vegetable consumption, selected types of vegetables and fruits (cucumbers, onions, pears), and a summary index of beta-carotene intake (RR = 0.4 for highest consumption tertile). Thus the present study confirmed the existence of an unfavorable dietary pattern for breast cancer risk (characterized by high-calorie, selected sources of animal fat and alcohol intake). Moreover, a significant protection could be gained by consuming a diet rich in vegetables and perhaps fruits.

Background. The incidence of esophageal cancer in women in Italy is low, and its risk factors have not been studied extensively. Methods. The relationship between risk of esophageal cancer and frequency of consumption of tobacco, alcohol, and a few selected dietary items was studied in 57 Italian women with histologically confirmed incident cancers of the esophagus and 344 hospital control patients, using data from a case-control study conducted in Milan, Italy, 1984-1991. Results. The major risk factor for cancer of the esophagus in Italian women was cigarette smoking (relative risk [RR], 1.5 for < 15 cigarettes/day, 95% confidence interval [CI], 0.6-3.8; and RR, 4.8 for greater-than-or-equal-to 15 cigarettes/day, 95% Cl, 2.2-10.3; compared with those who never smoked), followed by elevated alcohol consumption (RR, 2.3; 95% Cl, 1.0-5.4 for three or more drinks/day, relative to teetotalers), which together explained more than 50% of cases. Among dietary items, high intake of fresh fruit showed a statistically significant protective effect (RR, 0.4; 95% CI, 0.2-0.9 for the highest versus the lowest tertile of intake). There was an inverse relationship with an estimate of beta-carotene intake (RR, 0.5; 95%) Cl, 0.2-1.0 for the highest versus the lowest level of intake). No association was evident with preformed vitamin A (retinol). Conclusion. On a population scale, tobacco is the major risk factor for esophageal cancer in Italian women. Although the incidence of esophageal cancer is much lower in women than in men, major risk and protective factors are similar for both sexes.

The association between oral contraceptive (OC) use and the risk of uterine fibroids was analyzed in a case-control study conducted between 1986-1990. The subjects were 390 patients under 55 years of age with histologically confirmed fibroids and 1136 controls in hospitals for a spectrum of acute conditions (other than gynecologic, hormonal, or neoplastic) apparently unrelated to OC use. A total of 78 cases (20%) and 200 controls (18%) reported OC use. Compared with never-users, the multivariate relative risk for ever-users was 1.1 (95% confidence interval [CI] 0.8-1.5). No direct relationship emerged with duration of use, the estimated relative risk being 1.3 (95% CI 0.9-2.0) in users of OCs for less than 3 years and 0.8 (95% CI 0.5-1.3) in users for 3 years or more. The risk of fibroids was apparently (though not significantly) greater with longer recency of use: The estimated relative risks were 0.9 and 1.5, respectively, in women reporting last OC use less than 10 years before and 10 or more years before diagnosis of the disease. No relationship emerged with latency of use. There was no noteworthy interaction regarding risk of fibroids between OC use and potential covariates. These findings suggest that fibroids are unrelated to the use of OCs.

Differences in the frequency of consumption of 30 selected foods and in the estimated intake of total calories and selected nutrients in relation to alcohol drinking, tobacco smoking, and education were described using information obtained from 1,774 controls of a case-control study of digestive tract cancers conducted in northern Italy. Heavy alcohol consumption, tobacco smoking, and lower level of education were associated with a diet poorer in several aspects, including lower consumption of fresh fruit and green vegetables and higher intake of specific indicator foods, such as sausages and canned meat. For instance, the mean number of portions of fresh fruit per week was 10.5 among male nondrinkers vs. 9.0 among heavy drinkers, 10.4 among male nonsmokers vs. 8.1 among heavy smokers, and 8.8 in less educated individuals vs. 10.7 among those more educated. Consequently, intake of beta-carotene, ascorbic acid, and calcium tended to be inversely related to alcohol and tobacco and directly related to education. Most associations were stronger in males, for whom alcohol consumption was also more common in less educated individuals. Calorie intake was directly related to alcohol consumption, largely reflecting calories provided by alcohol itself. However, alcohol drinking was also directly related to fat consumption. In both sexes, there was a strong positive correlation between cigarette smoking and coffee drinking. These results provide quantitative documentation that alcohol drinking, tobacco smoking, and education, three of the major determinants of cancer risks, were also correlates of dietary patterns and, hence, may exert an important confounding or modifying effect on the diet and cancer relationship.

The relation between meal frequency and the risk of colorectal cancer was investigated in a case-control study conducted in North Italy on 889 cases of colon cancer, 581 cases of rectal cancer, and 2475 controls admitted to hospital for acute, nonneoplastic, or digestive disorders. As compared to individuals who reported 2 or fewer meals per day, the multivariate colon cancer odds ratios were 1.7 [95% confidence interval (95% CI), 1.5-2.1] for 3, and 1.9 (95% CI, 1.1-3.3) for 4 meals or more. Corresponding rectal cancer odds ratios were 1.4 (95% CI, 1.1-1.7) for 3, and 1.9 (95% CI, 1.1-3.5) for 4 meals or more. The direct trends in risk of colorectal cancer with frequency of eating were not substantially modified by allowance for various dietary and nondietary potential confounding factors, including an approximate measure of total energy intake, and did not show significant effect modification across strata of age, sex, education, and other major risk covariates. A role of meal frequency in the etiology of colorectal cancer is biologically plausible, since when a meal is eaten, the gallbladder contracts and releases bile acids. Thus, eating patterns can influence the enterohepatic circulation and, consequently, the exposure time of intestinal mucosa to bile acids.

Background. The role of tobacco and alcohol consumption and the frequency of intake of a selected number of indicator foods as causes of cancer were investigated in a case-control study conducted in northern italy. Methods. One hundred two men with cancer of the tongue, 104 patients with cancer of the mouth, and 726 control subjects (the latter admitted to the hospital for acute nonneoplastic disease without respiratory illness) were interviewed. Results. Similarly strong associations were observed with cigarette smoking (odds ratio [OR], 10.5 and 11.8 for current smokers versus never smokers in cancer of the tongue and mouth, respectively) and alcohol (OR, 3.4 and 3.0 for greater-than-or-equal-to 60 versus less-than-or-equal-to 19 drinks/week). The risk conferred by pipe or cigar smoking, although based on only 12 smokers who did not smoke cigarettes, seemed, however, to be lower for cancer of the tongue (OR, 3.4) than cancer of the mouth (OR, 21.9). Selected indicator foods and beverages, including green vegetables, carrots, fresh fruits, whole-grain bread and pasta, coffee, and tea also affected the cancer risk similarly in the two sites. The beneficial influence of such foods and beverages seemed, however, to be more marked for cancer of the mouth than for cancer of the tongue. Conclusions. This study suggested that, although none of the differences in the effects between cancer sites was statistically significant, tobacco from pipes and cigars and the cleansing effect of some foods of plant origin and nonalcoholic beverages may influence the risk of cancer of the tongue less strongly than the risk of cancer of the mouth.