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Background: Urothelial carcinoma is the predominant (95%) bladder cancer subtype in industrialized nations. Animal and epidemiologic human studies suggest that hormonal factors may influence urothelial carcinoma risk. Methods: We used an analytic cohort of 333,919 women from the European Prospective Investigation into Cancer and Nutrition Cohort. Associations between hormonal factors and incident urothelial carcinoma (overall and by tumor grade, tumor aggressiveness, and non–muscle-invasive urothelial carcinoma) risk were evaluated using Cox proportional hazards models. Results: During a mean of 15 years of follow-up, 529 women developed urothelial carcinoma. In a model including number of full-term pregnancies (FTP), menopausal status, and menopausal hormone therapy (MHT), number of FTP was inversely associated with urothelial carcinoma risk (HR≥5vs1 ¼ 0.48; 0.25–0.90; Ptrend in parous women ¼ 0.010) and MHT use (compared with nonuse) was positively associated with urothelial carcinoma risk (HR ¼ 1.27; 1.03–1.57), but no dose response by years of MHT use was observed. No modification of HRs by smoking status was observed. Finally, sensitivity analyses in never smokers showed similar HR patterns for the number of FTP, while no association between MHT use and urothelial carcinoma risk was observed. Association between MHT use and urothelial carcinoma risk remained significant only in current smokers. No heterogeneity of the risk estimations in the final model was observed by tumor aggressiveness or by tumor grade. A positive association between MTH use and non–muscle-invasive urothelial carcinoma risk was observed. Conclusions: Our results support that increasing the number of FTP may reduce urothelial carcinoma risk. Impact: More detailed studies on parity are needed to understand the possible effects of perinatal hormone changes in urothelial cells. © 2020 American Association for Cancer Research.

Findings on the association between alcohol consumption and bladder cancer are inconsistent. We investigated that association in the European Prospective Investigation into Cancer and Nutrition cohort. We included 476,160 individuals mostly aged 35–70 years, enrolled in ten countries and followed for 13.9 years on average. Hazard ratios (HR) for developing urothelial cell carcinoma (UCC; 1,802 incident cases) were calculated using Cox proportional hazards models. Alcohol consumption at baseline and over the life course was analyzed, as well as different types of beverages (beer, wine, spirits). Baseline alcohol intake was associated with a statistically nonsignificant increased risk of UCC (HR 1.03; 95% confidence interval (CI) 1.00–1.06 for each additional 12 g/day). HR in smokers was 1.04 (95% CI 1.01–1.07). Men reporting high baseline intakes of alcohol (>96 g/day) had an increased risk of UCC (HR 1.57; 95% CI 1.03–2.40) compared to those reporting moderate intakes (6 to 24 g/day). Average lifelong alcohol intake was not associated with the risk of UCC, however intakes of spirits > 24 g/day were associated with an increased risk of UCC in men (1.38; 95% CI 1.01–1.91) and smokers (1.39; 95% CI 1.01–1.92), compared to moderate intakes. We found no association between alcohol and UCC in women and never smokers. In conclusion, we observed some associations between alcohol and UCC in men and in smokers, possibly because of residual confounding by tobacco smoking. © 2017 UICC

Experimental evidence shows cross-talk in mammary cells between estrogen, insulin-like growth factor I (IGF-I) and their respective receptors and possible synergistic effects of estrogen receptor (ER) activation and increased IGF-I signaling with regard to breast tumor development, and epidemiological evidence suggests that circulating IGF-I levels may be related more to the risk of ER-positive than ER-negative breast cancer. Using a case-control study nested within the prospective European EPIC cohort (938 breast cancer cases and 1,394 matched control subjects), we analyzed the relationships of prediagnostic serum IGF-I levels with the risk of estrogen and progesterone receptor-positive and -negative breast tumors. IGF-I levels were positively associated with the risk of ER+ breast tumors overall (pre- and postmenopausal women combined, odds ratio (OR)Q4-Q1 = 1.41 [95% confidence interval (CI) 1.01-1.98] for the highest vs. lowest quartile; OR = 1.17 [95% CI 1.04-1.33] per 1-standard deviation (SD) increase in IGF-I, ptrend = 0.01) and among women who were diagnosed with breast cancer at 50 years or older (ORQ3-Q1 = 1.38 [95% CI 1.01-1.89]; OR = 1.19 [95% CI 1.04-1.36] per 1-SD increase in IGF-I, ptrend = 0.01) but not with receptor-positive disease diagnosed at an earlier age. No statistically significant associations were observed for ER- breast tumors overall and by age at diagnosis. Tests for heterogeneity by receptor status of the tumor were not statistically significant, except for women diagnosed with breast cancer at 50 years or older (phet = 0.03 for ER+/PR+ vs. ER-/PR- disease). Our data add to a global body of evidence indicating that higher circulating IGF-I levels may increase risk specifically of receptor-positive, but not receptor-negative, breast cancer diagnosed at 50 years or older. What's new Both estrogen and insulin-like growth factor (IGF-I) promote breast cancer formation, and evidence suggests the two may work together. Some breast tumors express estrogen receptor, others don't. Does the presence of estrogen receptor allow IGF-I to stimulate tumor formation To address this question, the authors compared women's IGF-I levels before diagnosis with their risk of developing breast cancer, with or without estrogen receptor. They found a direct relationship between IGF levels and risk of ER-positive breast tumors diagnosed after age 50. They found no association with ER-positive tumors diagnosed at an earlier age, nor with ER-negative tumors. © 2013 UICC.

There is growing evidence of the protective role of the Mediterranean diet (MD) on cancer. However, to date no epidemiological study has investigated the influence of the MD on bladder cancer. We evaluated the association between adherence to the MD and risk of urothelial cell bladder cancer (UCC), according to tumor aggressiveness, in the European Prospective Investigation into Cancer and Nutrition (EPIC). The analysis included 477,312 participants, recruited from ten European countries between 1991 and 2000. Information from validated dietary questionnaires was used to develop a relative Mediterranean diet score (rMED), including nine dietary components. Cox regression models were used to assess the effect of the rMED on UCC risk, while adjusting for dietary energy and tobacco smoking of any kind. Stratified analyses were performed by sex, BMI, smoking status, European region and age at diagnosis. During an average follow-up of 11 years, 1,425 participants (70.9% male) were diagnosed with a first primary UCC. There was a negative but non-significant association between a high versus low rMED score and risk of UCC overall (HR: 0.84 [95% CI 0.69, 1.03]) and risk of aggressive (HR: 0.88 [95% CI 0.61, 1.28]) and non-aggressive tumors (HR: 0.78 [95% CI 0.54, 1.14]). Although there was no effect modification in the stratified analyses, there was a significant 34% (p = 0.043) decreased risk of UCC in current smokers with a high rMED score. In EPIC, the MD was not significantly associated with risk of UCC, although we cannot exclude that a MD may reduce risk in current smokers. © 2013 UICC.

Carotenoids and vitamins A, C and E are possibly associated with a reduced colorectal cancer (CRC) risk through antioxidative properties. The association of prediagnostic plasma concentrations and dietary consumption of carotenoids and vitamins A, C and E with the risk of colon and rectal cancer was examined in this case-control study, nested within the European Prospective Investigation into Cancer and Nutrition study. Plasma concentrations of carotenoids (α- and β-carotene, canthaxanthin, β-cryptoxanthin, lutein, lycopene, zeaxanthin) and vitamins A (retinol), C and E (α-, β- and γ- and δ-tocopherol) and dietary consumption of β-carotene and vitamins A, C and E were determined in 898 colon cancer cases, 501 rectal cancer cases and 1,399 matched controls. Multivariable conditional logistic regression models were performed to estimate incidence rate ratios (IRR) and corresponding 95% confidence intervals (CIs). An association was observed between higher prediagnostic plasma retinol concentration and a lower risk of colon cancer (IRR for highest quartile = 0.63, 95% CI: 0.46, 0.87, p for trend = 0.01), most notably proximal colon cancer (IRR for highest quartile = 0.46, 95% CI: 0.27, 0.77, p for trend = 0.01). Additionally, inverse associations for dietary β-carotene and dietary vitamins C and E with (distal) colon cancer were observed. Although other associations were suggested, there seems little evidence for a role of these selected compounds in preventing CRC through their antioxidative properties.

We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp- and oral glucose tolerance test-based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs per allele [95% CI], -0.03 [-0.04, -0.01]; P = 0.004). This score was associated with lower BMI (-0.01 [-0.01, -0.0]; P = 0.02) and gluteofemoral fat mass (-0.03 [-0.05, -0.02; P = 1.4 × 10(-6)) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and γ-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (Pinteraction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (Pinteraction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.

Item does not contain fulltext Carotenoids and vitamins A, C and E are possibly associated with a reduced colorectal cancer (CRC) risk through antioxidative properties. The association of prediagnostic plasma concentrations and dietary consumption of carotenoids and vitamins A, C and E with the risk of colon and rectal cancer was examined in this case-control study, nested within the European Prospective Investigation into Cancer and Nutrition study. Plasma concentrations of carotenoids (alpha- and beta-carotene, canthaxanthin, beta-cryptoxanthin, lutein, lycopene, zeaxanthin) and vitamins A (retinol), C and E (alpha-, beta- and gamma- and delta-tocopherol) and dietary consumption of beta-carotene and vitamins A, C and E were determined in 898 colon cancer cases, 501 rectal cancer cases and 1,399 matched controls. Multivariable conditional logistic regression models were performed to estimate incidence rate ratios (IRR) and corresponding 95% confidence intervals (CIs). An association was observed between higher prediagnostic plasma retinol concentration and a lower risk of colon cancer (IRR for highest quartile = 0.63, 95% CI: 0.46, 0.87, p for trend = 0.01), most notably proximal colon cancer (IRR for highest quartile = 0.46, 95% CI: 0.27, 0.77, p for trend = 0.01). Additionally, inverse associations for dietary beta-carotene and dietary vitamins C and E with (distal) colon cancer were observed. Although other associations were suggested, there seems little evidence for a role of these selected compounds in preventing CRC through their antioxidative properties.

Experimental evidence shows cross-talk in mammary cells between estrogen, insulin-like growth factor I (IGF-I) and their respective receptors and possible synergistic effects of estrogen receptor (ER) activation and increased IGF-I signaling with regard to breast tumor development, and epidemiological evidence suggests that circulating IGF-I levels may be related more to the risk of ER-positive than ER-negative breast cancer. Using a case-control study nested within the prospective European EPIC cohort (938 breast cancer cases and 1,394 matched control subjects), we analyzed the relationships of prediagnostic serum IGF-I levels with the risk of estrogen and progesterone receptor-positive and -negative breast tumors. IGF-I levels were positively associated with the risk of ER+ breast tumors overall (pre- and postmenopausal women combined, odds ratio (OR)Q4-Q1 = 1.41 [95% confidence interval (CI) 1.01-1.98] for the highest vs. lowest quartile; OR = 1.17 [95% CI 1.04-1.33] per 1-standard deviation (SD) increase in IGF-I, ptrend = 0.01) and among women who were diagnosed with breast cancer at 50 years or older (ORQ3-Q1 = 1.38 [95% CI 1.01-1.89]; OR = 1.19 [95% CI 1.04-1.36] per 1-SD increase in IGF-I, ptrend = 0.01) but not with receptor-positive disease diagnosed at an earlier age. No statistically significant associations were observed for ER- breast tumors overall and by age at diagnosis. Tests for heterogeneity by receptor status of the tumor were not statistically significant, except for women diagnosed with breast cancer at 50 years or older (phet = 0.03 for ER+/PR+ vs. ER-/PR- disease). Our data add to a global body of evidence indicating that higher circulating IGF-I levels may increase risk specifically of receptor-positive, but not receptor-negative, breast cancer diagnosed at 50 years or older.

The association of glycemic index (GI) and glycemic load (GL) with the risk of type 2 diabetes remains unclear. We investigated associations of dietary GI, GL, and digestible carbohydrate with incident type 2 diabetes. We performed a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition Study, including a random subcohort (n = 16,835) and incident type 2 diabetes cases (n = 12,403). The median follow-up time was 12 y. Baseline dietary intakes were assessed using country-specific dietary questionnaires. Country-specific HR were calculated and pooled using random effects meta-analysis. Dietary GI, GL, and digestible carbohydrate in the subcohort were (mean +/- SD) 56 +/- 4, 127 +/- 23, and 226 +/- 36 g/d, respectively. After adjustment for confounders, GI and GL were not associated with incident diabetes [HR highest vs. lowest quartile (HRQ4) for GI: 1.05 (95% CI = 0.96, 1.16); HRQ4 for GL: 1.07 (95% CI = 0.95, 1.20)]. Digestible carbohydrate intake was not associated with incident diabetes [HRQ4: 0.98(95% CI = 0.86, 1.10)]. In additional analyses, we found that discrepancies in the GI value assignment to foods possibly explain differences in GI associations with diabetes within the same study population. In conclusion, an expansion of the GI tables and systematic GI value assignment to foods may be needed to improve the validity of GI values derived in such studies, after which GI associations may need reevaluation. Our study shows that digestible carbohydrate intake is not associated with diabetes risk and suggests that diabetes risk with high-GI and -GL diets may be more modest than initial studies suggested. J. Nutr. 143: 93-99, 2013.

There is limited evidence on the association between dietary folate intake and the risk of breast cancer (BC) by hormone receptor expression in the tumors. We investigated the relationship between dietary folate and BC risk using data from the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 367993 women age 35 to 70 years were recruited in 10 European countries. During a median follow-up of 11.5 years, 11575 women with BC were identified. Dietary folate intake was estimated from country-specific dietary questionnaires. Cox proportional hazards regression models were used to quantify the association between dietary variables and BC risk. BC tumors were classified by receptor status. Subgroup analyses were performed by menopausal status and alcohol intake. Intake of other B vitamins was considered. All statistical tests were two-sided. A borderline inverse association was observed between dietary folate and BC risk (hazard ratio comparing top vs bottom quintile [HRQ5-Q1] = 0.92, 95% CI = 0.83 to 1.01, P (trend) = .037). In premenopausal women, we observed a statistically significant trend towards lower risk in estrogen receptor-negative BC (HRQ5-Q1 = 0.66, 95% CI = 0.45 to 0.96, P (trend) = .042) and progesterone receptor-negative BC (HRQ5-Q1 = 0.70, 95% CI = 0.51 to 0.97, P (trend) = .021). No associations were found in postmenopausal women. A 14% reduction in BC risk was observed when comparing the highest with the lowest dietary folate tertiles in women having a high (> 12 alcoholic drinks/week) alcohol intake (HRT3-T1 = 0.86, 95% CI = 0.75 to 0.98, P (interaction) = .035). Higher dietary folate intake may be associated with a lower risk of sex hormone receptor-negative BC in premenopausal women.

STUDY QUESTION: Do women who have diabetes before menopause have their menopause at an earlier age compared with women without diabetes? SUMMARY ANSWER: Although there was no overall association between diabetes and age at menopause, our study suggests that early-onset diabetes may accelerate menopause. WHAT IS KNOWN ALREADY: Today, more women of childbearing age are being diagnosed with diabetes, but little is known about the impact of diabetes on reproductive health. STUDY DESIGN, SIZE, DURATION: We investigated the impact of diabetes on age at natural menopause (ANM) in 258 898 women from the European Prospective Investigation into Cancer and Nutrition (EPIC), enrolled between 1992 and 2000. PARTICIPANTS/MATERIALS, SETTING, METHODS: Determinant and outcome information was obtained through questionnaires. Time-dependent Cox regression analyses were used to estimate the associations of diabetes and age at diabetes diagnosis with ANM, stratified by center and adjusted for age, smoking, reproductive and diabetes risk factors and with age from birth to menopause or censoring as the underlying time scale. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, no association between diabetes and ANM was found (hazard ratio (HR) = 0.94; 95% confidence interval (CI) 0.89-1.01). However, women with diabetes before the age of 20 years had an earlier menopause (10-20 years: HR = 1.43; 95% CI 1.02-2.01

Prospective studies examining the association between coffee and tea consumption and gastric cancer risk have shown inconsistent results. We investigated the association between coffee (total, caffeinated and decaffeinated) and tea consumption and the risk of gastric cancer by anatomical site and histological type in the European Prospective Investigation into Cancer and Nutrition study. Coffee and tea consumption were assessed by dietary questionnaires at baseline. Adjusted hazard ratios (HRs) were calculated using Cox regression models. During 11.6 years of follow up, 683 gastric adenocarcinoma cases were identified among 477,312 participants. We found no significant association between overall gastric cancer risk and consumption of total coffee (HR 1.09, 95%-confidence intervals [CI]: 0.84-1.43; quartile 4 vs. non/quartile 1), caffeinated coffee (HR 1.14, 95%-CI: 0.82-1.59; quartile 4 vs. non/quartile 1), decaffeinated coffee (HR 1.07, 95%-CI: 0.75-1.53; tertile 3 vs. non/tertile 1) and tea (HR 0.81, 95%-CI: 0.59-1.09; quartile 4 vs. non/quartile 1). When stratified by anatomical site, we observed a significant positive association between gastric cardia cancer risk and total coffee consumption per increment of 100 mL/day (HR 1.06, 95%-CI: 1.03-1.11). Similarly, a significant positive association was observed between gastric cardia cancer risk and caffeinated coffee consumption (HR 1.98, 95%-CI: 1.16-3.36, p-trend=0.06; quartile 3 vs. non/quartile 1) and per increment of 100 mL/day (HR 1.09, 95%-CI: 1.04-1.14). In conclusion, consumption of total, caffeinated and decaffeinated coffee and tea is not associated with overall gastric cancer risk. However, total and caffeinated coffee consumption may be associated with an increased risk of gastric cardia cancer. Further prospective studies are needed to rule out chance or confounding. What's New? Can drinking coffee or tea lead to cancer? Can they protect against cancer? These popular drinks certainly contain antioxidants, but despite many investigations into the question, we still have no clear answer. A new study has plied the data from the European Prospective Investigation into Cancer and Nutrition (EPIC) in search of a link. Participants self-reported their coffee and tea consumption by questionnaire. The authors found no link between drinking tea or coffee - with or without caffeine - and overall risk of gastric cancer; they did discern a slight increase in gastric cardia cancer with consumption of caffeinated coffee.

Experimental evidence shows cross-talk in mammary cells between estrogen, insulin-like growth factor I (IGF-I) and their respective receptors and possible synergistic effects of estrogen receptor (ER) activation and increased IGF-I signaling with regard to breast tumor development, and epidemiological evidence suggests that circulating IGF-I levels may be related more to the risk of ER-positive than ER-negative breast cancer. Using a case-control study nested within the prospective European EPIC cohort (938 breast cancer cases and 1,394 matched control subjects), we analyzed the relationships of prediagnostic serum IGF-I levels with the risk of estrogen and progesterone receptor-positive and -negative breast tumors. IGF-I levels were positively associated with the risk of ER+ breast tumors overall (pre- and postmenopausal women combined, odds ratio (OR)Q4-Q1 = 1.41 [95% confidence interval (CI) 1.01-1.98] for the highest vs. lowest quartile; OR = 1.17 [95% CI 1.04-1.33] per 1-standard deviation (SD) increase in IGF-I, ptrend = 0.01) and among women who were diagnosed with breast cancer at 50 years or older (ORQ3-Q1 = 1.38 [95% CI 1.01-1.89]; OR = 1.19 [95% CI 1.04-1.36] per 1-SD increase in IGF-I, ptrend = 0.01) but not with receptor-positive disease diagnosed at an earlier age. No statistically significant associations were observed for ER- breast tumors overall and by age at diagnosis. Tests for heterogeneity by receptor status of the tumor were not statistically significant, except for women diagnosed with breast cancer at 50 years or older (phet = 0.03 for ER+/PR+ vs. ER-/PR- disease). Our data add to a global body of evidence indicating that higher circulating IGF-I levels may increase risk specifically of receptor-positive, but not receptor-negative, breast cancer diagnosed at 50 years or older. What's new Both estrogen and insulin-like growth factor (IGF-I) promote breast cancer formation, and evidence suggests the two may work together. Some breast tumors express estrogen receptor, others don't. Does the presence of estrogen receptor allow IGF-I to stimulate tumor formation To address this question, the authors compared women's IGF-I levels before diagnosis with their risk of developing breast cancer, with or without estrogen receptor. They found a direct relationship between IGF levels and risk of ER-positive breast tumors diagnosed after age 50. They found no association with ER-positive tumors diagnosed at an earlier age, nor with ER-negative tumors. © 2013 UICC.

Dietary flavanols and flavonols, flavonoid subclasses, have been recently associated with a lower risk of type 2 diabetes (T2D) in Europe. Even within the same subclass, flavonoids may differ considerably in bioavailability and bioactivity. We aimed to examine the association between individual flavanol and flavonol intakes and risk of developing T2D across European countries. The European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study was conducted in 8 European countries across 26 study centers with 340,234 participants contributing 3.99 million person-years of follow-up, among whom 12,403 incident T2D cases were ascertained and a center-stratified subcohort of 16,154 individuals was defined. We estimated flavonoid intake at baseline from validated dietary questionnaires using a database developed from Phenol-Explorer and USDA databases. We used country-specific Prentice-weighted Cox regression models and random-effects meta-analysis methods to estimate HRs. Among the flavanol subclass, we observed significant inverse trends between intakes of all individual flavan-3-ol monomers and risk of T2D in multivariable models (all P-trend < 0.05). We also observed significant trends for the intakes of proanthocyanidin dimers (HR for the highest vs. the lowest quintile. 0.81; 95% Cl: 0.71, 0.92; P-trend = 0.003) and trimers (HR: 0.91; 95% Cl: 0.80, 1.04; P-trend = 0.07) but not for proanthocyanidins with a greater polymerization degree. Among the flavonol subclass, myricetin (HR: 0.77; 95% Cl: 0.64, 0.93; P-trend = 0.001) was associated with a lower incidence of T2D. This large and heterogeneous European study showed inverse associations between all individual flavan-3-ol monomers, proanthocyanidins with a low polymerization degree, and the flavonol myricetin and incident T2D. These results suggest that individual flavonoids have different roles in the etiology of T2D.

There is growing evidence of the protective role of the Mediterranean diet (MD) on cancer. However, to date no epidemiological study has investigated the influence of the MD on bladder cancer. We evaluated the association between adherence to the MD and risk of urothelial cell bladder cancer (UCC), according to tumor aggressiveness, in the European Prospective Investigation into Cancer and Nutrition (EPIC). The analysis included 477,312 participants, recruited from ten European countries between 1991 and 2000. Information from validated dietary questionnaires was used to develop a relative Mediterranean diet score (rMED), including nine dietary components. Cox regression models were used to assess the effect of the rMED on UCC risk, while adjusting for dietary energy and tobacco smoking of any kind. Stratified analyses were performed by sex, BMI, smoking status, European region and age at diagnosis. During an average follow-up of 11 years, 1,425 participants (70.9% male) were diagnosed with a first primary UCC. There was a negative but non-significant association between a high versus low rMED score and risk of UCC overall (HR: 0.84 [95% CI 0.69, 1.03]) and risk of aggressive (HR: 0.88 [95% CI 0.61, 1.28]) and non-aggressive tumors (HR: 0.78 [95% CI 0.54, 1.14]). Although there was no effect modification in the stratified analyses, there was a significant 34% (p = 0.043) decreased risk of UCC in current smokers with a high rMED score. In EPIC, the MD was not significantly associated with risk of UCC, although we cannot exclude that a MD may reduce risk in current smokers. What’s new? Urothelial cell carcinoma (UCC) is the most common form of bladder cancer. Previous studies suggested that plasma carotenoids, antioxidants found in fruit and vegetables, were associated with a decreased risk of UCC while a high intake of animal protein was associated with an increased cancer risk. Here, the authors conducted the first study to investigate the association between the Mediterranean diet, a diet rich in fresh fruits and vegetables and low in animal products, and UCC in Europe. They found that adherence to a Mediterranean diet was not significantly associated with UCC, regardless of level of tumour aggressiveness. They point out that these findings are in line with the rather weak evidence for questionnaire-based associations between dietary factors and bladder cancer risk.

Background: There is growing evidence of the protective role of dietary intake of flavonoids and lignans on cancer, but the association with bladder cancer has not been thoroughly investigated in epidemiological studies. We evaluated the association between dietary intakes of total and subclasses of flavonoids and lignans and risk of bladder cancer and its main morphological type, urothelial cell carcinoma (UCC), within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Methods: A cohort of 477 312 men and women mostly aged 35-70 years, were recruited in 10 European countries. At baseline, dietary flavonoid and lignan intakes were estimated using centre-specific validated questionnaires and a food composition database based on the Phenol-Explorer, the UK Food Standards Agency and the US Department of Agriculture databases. Results: During an average of 11 years of follow-up, 1575 new cases of primary bladder cancer were identified, of which 1425 were UCC (classified into aggressive (n = 430) and non-aggressive (n = 413) UCC). No association was found between total flavonoid intake and bladder cancer risk. Among flavonoid subclasses, significant inverse associations with bladder cancer risk were found for intakes of flavonol (hazard ratio comparing fifth with first quintile (HRQ5-Q1) 0.74, 95% confidence interval (CI): 0.61-0.91; P-trend = 0.009) and lignans (HRQ5-Q 10.78, 95% CI: 0.62-0.96; P-trend = 0.046). Similar results were observed for overall UCC and aggressive UCC, but not for non-aggressive UCC. Conclusions: Our study suggests an inverse association between the dietary intakes of flavonols and lignans and risk of bladder cancer, particularly aggressive UCC.

Evidence on associations between self-reported diabetes mellitus, diabetes duration, age at diabetes diagnosis, insulin treatment, and risk of biliary tract cancer (BTC) and hepatocellular carcinoma (HCC), independent of general and abdominal obesity is scarce. We conducted a prospective analysis in the EPIC-cohort study among 363 426 participants with self-reported diabetes data. Multivariable adjusted relative risks and 95% confidence intervals were estimated from Cox regression models. In a nested case-control subset, analyses were carried out in HCV/HBV-negative individuals. During 8.5 years of follow-up, 204 BTC cases [including 75 gallbladder cancer (GBC) cases], and 176 HCC cases were identified. Independent of body mass index and waist-to-height ratio diabetes status was associated with higher risk of BTC and HCC [1.77 (1.00-3.13) and 2.17 (1.36-3.47)]. For BTC, the risk seemed to be higher in participants with shorter diabetes duration and those not treated with insulin. Regarding cancer subsites, diabetes was only associated with GBC [2.72 (1.17-6.31)]. The risk for HCC was particularly higher in participants treated with insulin. The results were not appreciably different in HCV/HBV-negative individuals. This study supports the hypothesis that diabetes is a risk factor for BTC (particularly GBC) and HCC. Further research is required to establish whether diabetes treatment or duration is associated with these cancers.

Diets high in vegetables and fruits have been suggested to be inversely associated with risk of gastric cancer. However, the evidence of the effect of variety of consumption is limited. We therefore investigated whether consumption of a variety of vegetables and fruit is associated with gastric and esophageal cancer in the European Prospective Investigation into Cancer and Nutrition study. Data on food consumption and follow-up on cancer incidence were available for 452,269 participants from 10 European countries. After a mean follow-up of 8.4 years, 475 cases of gastric and esophageal adenocarcinomas (180 noncardia, 185 cardia, gastric esophageal junction and esophagus, 110 not specified) and 98 esophageal squamous cell carcinomas were observed. Diet Diversity Scores were used to quantify the variety in vegetable and fruit consumption. We used multivariable Cox proportional hazard models to calculate risk ratios. Independent from quantity of consumption, variety in the consumption of vegetables and fruit combined and of fruit consumption alone were statistically significantly inversely associated with the risk of esophageal squamous cell carcinoma (continuous hazard ratio per 2 products increment 0.88; 95% CI 0.790.97 and 0.76; 95% CI 0.620.94, respectively) with the latter particularly seen in ever smokers. Variety in vegetable and/or fruit consumption was not associated with risk of gastric and esophageal adenocarcinomas. Independent from quantity of consumption, more variety in vegetable and fruit consumption combined and in fruit consumption alone may decrease the risk of esophageal squamous cell carcinoma. However, residual confounding by lifestyle factors cannot be excluded.

BACKGROUND: Insulin-like growth factors (IGFs) and their binding proteins (BPs) regulate cell differentiation, proliferation and apoptosis, and may have a role in the aetiology of various cancers. Information on their role in pancreatic cancer is limited and was examined here in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition. METHODS: Serum concentrations of IGF-I and IGFBP-3 were measured using enzyme-linked immunosorbent assays in 422 cases and 422 controls matched on age, sex, study centre, recruitment date, and time since last meal. Conditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI) adjusted for confounding variables. RESULTS: Neither circulating levels of IGF-I (OR = 1.21, 95% CI 0.75-1.93 for top vs bottom quartile, P-trend 0.301), IGFBP-3 (OR = 1.00, 95% CI 0.66-1.51, P-trend 0.79), nor the molar IGF-I/IGFBP-3 ratio, an indicator of free IGF-I level (OR = 1.22, 95% CI 0.75-1.97, P-trend 0.27), were statistically significantly associated with the risk of pancreatic cancer. In a cross-classification, however, a high concentration of IGF-I with concurrently low levels of IGFBP-3 was related to an increased risk of pancreatic cancer (OR = 1.72, 95% CI 1.05-2.83; P-interaction = 0.154). CONCLUSION: On the basis of these results, circulating levels of components of the IGF axis do not appear to be the risk factors for pancreatic cancer. However, on the basis of the results of a subanalysis, it cannot be excluded that a relatively large amount of IGF-1 together with very low levels of IGFBP-3 might still be associated with an increase in pancreatic cancer risk. British Journal of Cancer (2012) 106, 1004-1010. doi:10.1038/bjc.2012.19 www.bjcancer.com Published online 7 February 2012 (C) 2012 Cancer Research UK

Recent research does not show an association between fruit and vegetable consumption and bladder cancer risk. None of these studies investigated variety in fruit and vegetable consumption, which may capture different aspects of consumption. We investigated whether a varied consumption of vegetables and fruits is associated with bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Detailed data on food consumption and complete follow-up for cancer incidence were available for 452,185 participants, who were recruited from ten European countries. After a mean follow-up of 8.7 years, 874 participants were diagnosed with bladder cancer. Diet diversity scores (DDSs) were used to quantify the variety in fruit and vegetable consumption. Multivariable Cox proportional hazard models were used to assess the effect of the DDSs on bladder cancer risk. There was no evidence of a statistically significant association between bladder cancer risk and any of the DDSs when these scores were considered as continuous covariates. However, the hazard ratio (HR) for the highest tertile of the DDS for combined fruit and vegetable consumption was marginally significant compared to the lowest (HR = 1.30, 95% confidence interval: 1.00-1.69, p-trend = 0.05). In EPIC, there is no clear association between a varied fruit and vegetable consumption and bladder cancer risk. This finding provides further evidence for the absence of any strong association between fruit and vegetable consumption as measured by a food frequency questionnaire and bladder cancer risk. © 2010 UICC.

Background: Previous epidemiologic studies found inconsistent results for the association between red meat intake, nitrosamines [NDMA: N-nitrosodimethylamine, and ENOC (endogenous nitroso compounds)], and the risk of bladder cancer. We investigated the association between red meat consumption, dietary nitrosamines, and heme iron and the risk of bladder cancer among participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods: Data on food consumption and complete follow-up for cancer occurrence were available for a total of 481,419 participants, recruited in 10 European countries. Estimates of HRs were obtained by proportional hazard models, stratified by age at recruitment, gender, and study center and adjusted for total energy intake, smoking status, lifetime intensity of smoking, duration of smoking, educational level, and BMI. Results: After a mean follow-up of 8.7 years, 1,001 participants were diagnosed with bladder cancer. We found no overall association between intake of red meat (log2 HR: 1.06; 95% CI: 0.99-1.13), nitrosamines (log2 HR: 1.09; 95% CI: 0.92-1.30 and HR: 0.98; 95% CI: 0.92-1.05 for ENOC and NDMA, respectively) or heme iron (log2 HR: 1.05; 95 CI: 0.99-1.12) and bladder cancer risk. The associations did not vary by sex, high- versus low-risk bladder cancers, smoking status, or occupation (high vs. low risk). Conclusions: Our findings do not support an effect of red meat intake, nitrosamines (endogenous or exogenous), or heme iron intake on bladder cancer risk. ©2011 AACR.

So far, studies on dietary antioxidant intake, including β-carotene, vitamin C and vitamin E, and breast cancer risk are inconclusive. Thus, we addressed this question in the European Prospective Investigation into Cancer and Nutrition. During a median follow-up time of 8.8 years, 7,502 primary invasive breast cancer cases were identified. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). All analyses were run stratified by menopausal status at recruitment and, additionally, by smoking status, alcohol intake, use of exogenous hormones and use of dietary supplements. In the multivariate analyses, dietary intake of β-carotene, vitamin C and E was not associated with breast cancer risk in premenopausal [highest vs. lowest quintile: HR, 1.04 (95% CI, 0.85-1.27), 1.12 (0.92-1.36) and 1.11 (0.84-1.46), respectively] and postmenopausal women [0.93 (0.82-1.04), 0.98 (0.87-1.11) and 0.92 (0.77-1.11), respectively]. However, in postmenopausal women using exogenous hormones, high intake of β-carotene [highest vs. lowest quintile; HR 0.79 (95% CI, 0.66-0.96), P trend 0.06] and vitamin C [0.88 (0.72-1.07), P trend 0.05] was associated with reduced breast cancer risk. In addition, dietary β-carotene was associated with a decreased risk in postmenopausal women with high alcohol intake. Overall, dietary intake of β-carotene, vitamin C and E was not related to breast cancer risk in neither pre- nor postmenopausal women. However, in subgroups of postmenopausal women, a weak protective effect between β-carotene and vitamin E from food and breast cancer risk cannot be excluded. © 2009 Springer Science+Business Media, LLC.

Previous epidemiologic studies found inconsistent associations between vegetables and fruit consumption and the risk of bladder cancer. We therefore investigated the association between vegetable and fruit consumption and the risk of bladder cancer among participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Data on food consumption and complete follow-up for cancer occurrence was available for a total of 478,533 participants, who were recruited in 10 European countries. Estimates of rate ratios were obtained by Cox proportional hazard models, stratified by age at recruitment, gender and study centre, and adjusted for total energy intake, smoking status, duration of smoking and lifetime intensity of smoking. A calibration study in a subsample was used to control for dietary measurement errors. After a mean follow-up of 8.7 years, 1015 participants were newly diagnosed with bladder cancer. Increments of 100 g/day in fruit and vegetable consumption combined did not affect bladder cancer risk (i.e., calibrated HR = 0.98; 95%CI: 0.95-1.01). Borderline statistically significant lower bladder cancer risks were found among never smokers with increased consumption of fruit and vegetables combined (HR = 0.94 95%CI: 0.87-1.00 with increments of 100 g/day; calibrated HR = 0.92 95%CI 0.79-1.06) and increased consumption of apples and pears (hard fruit; calibrated HR 5 0.90 95%CI: 0.82-0.98 with increments of 25 g/day). For none of the associations a statistically significant interaction with smoking status was found. Our findings do not support an effect of fruit and vegetable consumption, combined or separately, on bladder cancer risk. © 2009 UICC.

Background: Dietary supplement use is increasing, but there are few comparable data on supplement intakes and how they affect the nutrition and health of European consumers. The aim of this study was to describe the use of dietary supplements in subsamples of the 10 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods: Specific questions on dietary supplement use were asked as a part of single 24-h recalls performed on 36 034 men and women aged 35-74 years from 1995 to 2000. Results: Between countries, the mean percentage of dietary supplement use varied almost 10-fold among women and even more among men. There was a clear north-south gradient in use, with a higher consumption in northern countries. The lowest crude mean percentage of use was found in Greece (2.0% among men, 6.7% among women), and the highest was in Denmark (51.0% among men, 65.8% among women). Use was higher in women than in men. Vitamins, minerals or combinations of them were the predominant types of supplements reported, but there were striking differences between countries. Conclusions: This study indicates that there are wide variations in supplement use in Europe, which may affect individual and population nutrient intakes. The results underline the need to monitor consumption of dietary supplements in Europe, as well as to evaluate the risks and benefits. European Journal of Clinical Nutrition (2009) 63, S226-S238; doi: 10.1038/ejcn.2009.83