The role of plasma microseminoprotein-beta in prostate cancer: an observational nested case-control and Mendelian randomization study in the European prospective investigation into cancer and nutrition.

BACKGROUND: Microseminoprotein-beta (MSP), a protein secreted by the prostate epithelium, may have a protective role in the development of prostate cancer. The only previous prospective study found a 2% reduced prostate cancer risk per unit increase in MSP. This work investigates the association of MSP with prostate cancer risk using observational and Mendelian randomization (MR) methods. PATIENTS AND METHODS: A nested case-control study was conducted with the European Prospective Investigation into Cancer and Nutrition (EPIC) with 1871 cases and 1871 matched controls. Conditional logistic regression analysis was used to investigate the association of pre-diagnostic circulating MSP with risk of incident prostate cancer overall and by tumour subtype. EPIC-derived estimates were combined with published data to calculate an MR estimate using two-sample inverse-variance method. RESULTS: Plasma MSP concentrations were inversely associated with prostate cancer risk after adjusting for total prostate-specific antigen concentration [odds ratio (OR) highest versus lowest fourth of MSP = 0.65, 95% confidence interval (CI) 0.51-0.84, Ptrend = 0.001]. No heterogeneity in this association was observed by tumour stage or histological grade. Plasma MSP concentrations were 66% lower in rs10993994 TT compared with CC homozygotes (per allele difference in MSP: 6.09 ng/ml, 95% CI 5.56-6.61, r2=0.42). MR analyses supported a potentially causal protective association of MSP with prostate cancer risk (OR per 1 ng/ml increase in MSP for MR: 0.96, 95% CI 0.95-0.97 versus EPIC observational: 0.98, 95% CI 0.97-0.99). Limitations include lack of complete tumour subtype information and more complete information on the biological function of MSP. CONCLUSIONS: In this large prospective European study and using MR analyses, men with high circulating MSP concentration have a lower risk of prostate cancer. MSP may play a causally protective role in prostate cancer.

[Spanish rare disease registries research network: first results of Spain-RDR's project in Navarre]. / Red española de registros de enfermedades raras para la investigación: primeros resultados del proyecto Spain-RDR en Navarra.

BACKGROUND: The Spanish Rare Disease Registries Research Network, Spain-RDR, was a project of the Carlos III Health Institute (2012-2015) in which all the Autonomous Communities participated. The initial results for Navarre are presented. METHODS: The Minimum Basic Data Set for 2010-2011 was explored to assess the collection of possible cases of rare diseases in Navarre (pilot study). The information was later extended in both time (the year 2012) and sources consulted (Mortality Statistics and Temporary Disability Registry). RESULTS: Navarre identified 9,420 possible cases amongst the 8,141 residents in the pilot study, reaching 13,494 cases amongst the 11,644 people obtained with the extension of time and sources. Thirty-eight percent of the cases corresponded to endocrine, metabolic and immune diseases, and congenital anomalies. CONCLUSIONS: It is necessary to expand the sources and the period of data collection, as well as to validate the cases registered in order to know the real magnitude of the problem as a whole and for each specific disease included in the registry.

Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study.

BACKGROUND: There is increasing evidence that folate, an important component of one-carbon metabolism, modulates the epigenome. Alcohol, which can disrupt folate absorption, is also known to affect the epigenome. We investigated the association of dietary folate and alcohol intake on leukocyte DNA methylation levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Leukocyte genome-wide DNA methylation profiles on approximately 450,000 CpG sites were acquired with Illumina HumanMethylation 450K BeadChip measured among 450 women control participants of a case-control study on breast cancer nested within the EPIC cohort. After data preprocessing using surrogate variable analysis to reduce systematic variation, associations of DNA methylation with dietary folate and alcohol intake, assessed with dietary questionnaires, were investigated using CpG site-specific linear models. Specific regions of the methylome were explored using differentially methylated region (DMR) analysis and fused lasso (FL) regressions. The DMR analysis combined results from the feature-specific analysis for a specific chromosome and using distances between features as weights whereas FL regression combined two penalties to encourage sparsity of single features and the difference between two consecutive features. RESULTS: After correction for multiple testing, intake of dietary folate was not associated with methylation level at any DNA methylation site, while weak associations were observed between alcohol intake and methylation level at CpG sites cg03199996 and cg07382687, with qval = 0.029 and qval = 0.048, respectively. Interestingly, the DMR analysis revealed a total of 24 and 90 regions associated with dietary folate and alcohol, respectively. For alcohol intake, 6 of the 15 most significant DMRs were identified through FL. CONCLUSIONS: Alcohol intake was associated with methylation levels at two CpG sites. Evidence from DMR and FL analyses indicated that dietary folate and alcohol intake may be associated with genomic regions with tumor suppressor activity such as the GSDMD and HOXA5 genes. These results were in line with the hypothesis that epigenetic mechanisms play a role in the association between folate and alcohol, although further studies are warranted to clarify the importance of these mechanisms in cancer.

Night-shift work and breast and prostate cancer risk: updating the evidence from epidemiological studies.

It has been hypothesized that circadian disruption is related to higher cancer risk. Since the International Agency for Research on Cancer classified shift work involving circadian disruption as probably carcinogenic to humans (Group 2A), multiple studies have been conducted to test this hypothesis. The aim of this systematic review was to summarize the findings and evaluate the quality of existing epidemiological studies (case-control and cohort studies) on the relationship between night-shift work and breast and prostate cancer risk. Thirty-three epidemiological studies investigating the relationship between night-shift work and breast (n = 26) or prostate (n = 8) cancer risk were included (one paper included both sites). The Newcastle-Ottawa Scale for the quality of non-randomized studies was used to assess the risk of bias of the publications. The studies included were heterogeneous regarding population (general population, nurses working in rotating shifts, and other) and measurement of exposure to night-shift work (ever vs. never exposure, short vs. long-term, rotating vs. permanent) and, thus, a diversity of outcomes were observed even within the same type of cancer. In summary, 62.5% works found some type of association between night-shift work and increased risk of cancer, for both breast and prostate. The risk of bias scored an average of 7.5 over 9 stars. Due to the limitations inherent in these studies, the evidence of a possible association between night-shift work and breast or prostate cancer risk remains uncertain and more studies providing greater control of exposure and confounding factors are required. Despite the lack of conclusive evidence, application of the precautionary principle seems advisable.

Childhood and adolescent lymphoma in Spain: incidence and survival trends over 20 years.

BACKGROUND: Lymphoma is the third most common malignancy in children (0-14 years) and the first in adolescents (15-19 years). This population-based study-the largest ever done in Spain-analyses incidence and survival of lymphomas among Spanish children and adolescents. PATIENTS AND METHODS: 1664 lymphoma cases (1983-2007) for incidence and 1030 for survival (1991-2005) followed until 31/12/2010, were provided by 11 cancer registries. Age-adjusted incidence rates (ASRw) to the world standard population were obtained; incidence trends were modelled using the Joinpoint programme, observed survival (OS) was estimated with Kaplan-Meier and trends tested with a log-rank test. Results are presented according to the International Classification of Childhood Cancer-3. RESULTS: In Spain, the ASRw0-14 for lymphomas was 17.5 per 1.000.000 child-years and 50.0 the specific rate for adolescents. Overall incidence increased significantly during 1983-1997 with no increases thereafter. Patients over 9 years old showed significant rising trends for all subtypes, except for Burkitt lymphoma (BL) in adolescents. During 2001-2005 (age 0-19 years), 5-year OS was 94 (90-98), 73 (64-83) and 86 (78-94) for Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) and BL, respectively. No improvement in survival was found. The incidence in Spain was higher than overall European rates, but within the range of that in Southern Europe. Comparing OS in Spain 1991-1995 and 2001-2005 with results for Europe of the Automated Childhood Cancer Information System (ACCIS) (1988-1997) and the European cancer registry-based study on survival and care of cancer patients (EUROCARE) (2000-2007), it was similar for HL and lower for NHL and BL. CONCLUSIONS: Systematic monitoring and analysis of lymphoma paediatric data would provide clinical and epidemiological information to improve the health care of these patients and the outcomes for these malignancies in Spain.

Prostate cancer incidence and mortality in Navarre (Spain).

BACKGROUND: Prostate cancer is one of the most commonly diagnosed malignancies among males worldwide. In this study, overall and age-specific incidence and mortality trends are analyzed in order to present the past and current epidemiological situation of the disease in Navarre (Spain). METHODS: Population-based incidence data from the 1975-2010 period, provided by the Cancer Registry of Navarre and prostate cancer specific mortality data for 1975-2013, provided by the Spanish Statistical Office, were used in the analysis. Age-standardized incidence and mortality rates, change-points and annual percentage changes (APC) were estimated by joinpoint regression analysis. One-dimensional P-spline models were used to estimate projections up to 2016. RESULTS: Considerable increases of cancer incidence rates in men aged 45-74 years were observed, with APC of +4.5% (p<0.001), +9.5% (p<0.001) and +2.4% (p<0.05) in the 1975-1990, 1990-2000 and 2000-2010 periods, respectively. In the older than 74 age-group, an increase of incidence rates in the 1975-1999 period was registered (APC +3.3%, p<0.001), followed by a significant decrease up to 2010 (APC -4.0%, p<0.01). Mortality rates rose until 1995 (APC +2.2%, p<0.001) whereas a decline occurred afterwards up to 2013 (APC -3.4%, p<0.001). CONCLUSION: Even though overall prostate cancer incidence rates seem to have stabilized in 2002-2010 in Navarra, trends were different by age groups: increased in men 45-74 years old and decreased in the 75+ year age-group. A decline in mortality rates was observed in both age groups since about 1995. Changes in the use of prostate specific antigen test for screening in oncoming years could affect future prostate cancer trends.

Cancer survival in adult patients in Spain. Results from nine population-based cancer registries.

INTRODUCTION: With the aim of providing cancer control indicators, this work presents cancer survival in adult (≥15 years) patients in Spain diagnosed during the period 2000-2007 from Spanish cancer registries participating in the EUROCARE project. METHODS: Cancer cases from nine Spanish population-based cancer registries were included and analysed as a whole. All primary malignant neoplasms diagnosed in adult patients were eligible for the analysis. Cancer patients were followed until 31 December 2008. For each type of cancer, 1-, 3- and 5-year observed and relative survival were estimated by sex, age and years from diagnosis. Furthermore, age-standardized 5-year relative survival for the period 2000-2007 has been compared with that of the period 1995-1999. RESULTS: Skin melanoma (84.6 95% CI 83.0-86.2), prostate (84.6% 95% CI 83.6-85.6) and thyroid (84.2% CI 95% 82.0-86.6) cancers showed the highest 5-year relative survival, whereas the worst prognosis was observed in pancreatic (6% 95% CI 5.1-7.0) and oesophageal (9.4% 95% CI 7.9-11.1) cancers. Overall, survival is higher in women (58.0%) than in men (48.9%). The absolute difference in relative survival between 2000-2007 and 1995-1999 was positive for all cancers as a whole (+4.8% in men, +1.6% in women) and for most types of tumours. Survival increased significantly for chronic myeloid leukaemia, non-Hodgkin's lymphoma and rectum cancer in both sexes, and for acute lymphoid leukaemia, prostate, liver and colon cancers in men and Hodgkin's lymphoma and breast cancer in women. Survival patterns by age were similar in Europe and Spain. A decline in survival by age was observed in all tumours, being more pronounced for ovarian, corpus uteri, prostate and urinary bladder and less for head and neck and rectum cancers. CONCLUSION: High variability and differences have been observed in survival among adults in Spain according to the type of cancer diagnosed, from above 84% to below 10%, reflecting high heterogeneity. The differences in prognosis by age, sex and period of diagnosis reveal opportunities for improving cancer care in Spain.

[Origin of newborn screening programs and their beginnings in Spain]. / Origen de los programas de cribado neonatal y sus inicios en España.

The first newborn screening programs to detect congenital errors of the metabolism and other endocrinal diseases started in the late 1950s and, one decade later, were introduced in Spain. Since then they have evolved considerably, but in a very heteroge-neous way, at both the international level and the regional level. The continuous scientific and technological advances, basically since the year 2000, have accentuated these inequalities, making this question into an inexhaustible subject of review, debate and argument up until the present. This review aims to gather, in summarized fashion, the origins of the newborn screening programs and their beginnings in Spain as a first step in analyzing their development, evolution and current situation. This year updating is expected to take place in all the Spanish autonomous regions following publication in November 2014 of a state order that regulates and attempts to homogenize these programs.

Survival of 86,690 patients with thyroid cancer: A population-based study in 29 European countries from EUROCARE-5.

BACKGROUND: Incidence rates of thyroid cancer (TC) increased in several countries during the last 30 years, while mortality rates remained unchanged, raising important questions for treatment and follow-up of TC patients. This study updates population-based estimates of relative survival (RS) after TC diagnosis in Europe by sex, country, age, period and histology. METHODS: Data from 87 cancer registries in 29 countries were extracted from the EUROCARE-5 dataset. One- and 5-year RS were estimated using the cohort approach for 86,690 adult TC patients diagnosed in 2000-2007 and followed-up to 12/31/2008. RS trends in 1999-2007 and 10-year RS in 2005-2007 were estimated using the period approach. RESULTS: In Europe 2000-2007, 5-year RS after TC was 88% in women and 81% in men. Survival rates varied by country and were strongly correlated (Pearson ρ = 75%) with country-specific incidence rates. Five-year RS decreased with age (in women from >95% at age 15-54 to 57% at age 75+), from 98% in women and 94% in men with papillary TC to 14% in women and 12% in men with anaplastic TC. Proportion of papillary TC varied by country and increased over time, while survival rates were similar across areas and periods. In 1999-2007, 5-year RS increased by five percentage points for all TCs but only by two for papillary and by four for follicular TC. Ten-year RS in 2005-2007 was 89% in women and 79% in men. CONCLUSIONS: The reported increasing TC survival trend and differences by area are mainly explained by the varying histological case-mix of cases.

Cancer incidence in Spain, 2015.

PURPOSE: Periodic cancer incidence estimates of Spain from all existing population-based cancer registries at any given time are required. The objective of this study was to present the current situation of cancer incidence in Spain. METHODS: The Spanish Network of Cancer Registries (REDECAN) estimated the numbers of new cancer cases occurred in Spain in 2015 by applying the incidence-mortality ratios method. In the calculus, incidence data from population-based cancer registries and mortality data of all Spain were used. RESULTS: In 2015, nearly a quarter of a million new invasive cancer cases were diagnosed in Spain, almost 149,000 in men (60.0%) and 99,000 in women. Globally, the five most common cancers were those of colon-rectum, prostate, lung, breast and urinary bladder. By gender, the four most common cancers in men were those of prostate (22.4%), colon-rectum (16.6%), lung (15.1%) and urinary bladder (11.7%). In women, the most common ones were those of breast (28.0%), colon-rectum (16.9%), corpus uteri (6.2%) and lung (6.0%). In recent years, cancer incidence in men seems to have stabilized due to the fact that the decrease in tobacco-related cancers compensates for the increase in other types of cancer like those of colon and prostate. In women, despite the stabilization of breast cancer incidence, increased incidence is due, above all, to the rise of colorectal and tobacco-related cancers. CONCLUSION: To reduce these incident cancer cases, improvement of smoking control policies and extension of colorectal cancer screening should be the two priorities in cancer prevention for the next years.

Incidence and survival time trends for Spanish children and adolescents with leukaemia from 1983 to 2007.

OBJECTIVE: We have analysed incidence and survival trends of children and adolescents with leukaemia registered in Spanish population-based cancer registries during the period 1983-2007. METHODS: Childhood and adolescent leukaemia cases were drawn from the 11 Spanish population-based cancer registries. For survival, registries with data for the period 1991-2005 and follow-up until 31-12-2010 were included. Overall incidence trends were evaluated using joinpoint analysis. Observed survival rates were estimated using Kaplan-Meier, and trends were tested using the log-rank test. RESULTS: Based on 2606 cases (2274 children and 332 adolescents), the overall age-adjusted incidence rate (ASRw) of leukaemia was 47.9 cases per million child-years in children and 23.8 in adolescents. The ASRw of leukaemia increased with an annual percentage change of 9.6 % (95 % CI: 2.2-17.6) until 1990 followed by a stabilisation of rates. In adolescents, incidence did not increase. Five-year survival increased from 66 % in 1991-1995 to 76 % in 2001-2005. By age, survival was dramatically lower in infants (0) and adolescents (15-19) than in the other age groups and no improvement was observed. In both children and adolescents, differences in 5-year survival rates among major subgroups of leukaemias were significant. CONCLUSIONS: The increasing incidence trends observed in childhood leukaemias during the study period were confined to the beginning of the period. Remarkable improvements in survival have been observed in Spanish children with leukaemias. However, this improvement was not observed in infants and adolescents.

Unprocessed red meat and processed meat consumption and risk of stroke in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC).

BACKGROUND/OBJECTIVES: High intakes of unprocessed red or processed meat may increase the risk of stroke. We aimed to examine the association between unprocessed red meat, processed meat and total red meat consumption and risk of total stroke and ischaemic stroke. SUBJECTS/METHODS: Cox proportional hazards regression analyses were conducted based on the data for 41,020 men and women aged 29-69 years at baseline. RESULTS: During a mean follow-up of 13.8 years, 674 incident cases of stroke (531 ischaemic strokes, 79 haemorrhagic strokes, 42 subarachnoid haemorrhages and 22 mixed or unspecified events) were identified. After multiple adjustment, unprocessed red meat, processed meat and total red meat consumption were not correlated with incidence of total stroke or ischaemic stroke in either men or women. The hazard ratios (HRs) for unprocessed red meat and processed meat and risk of total stroke comparing the highest with the lowest quintiles were, respectively, 0.81 (95% confidence interval (CI) 0.54-1.21; P-trend=0.15) and 0.92 (95% CI 0.64-1.32; P-trend=0.82) in men and 1.21 (95% CI 0.79-1.85; P-trend=0.10) and 0.81 (95% CI 0.51-1.27; P-trend=0.17) in women. The HRs for unprocessed red meat and processed meat and risk of ischaemic stroke were, respectively, 0.80 (95% CI 0.51-1.25; P-trend=0.51) and 0.86 (95% CI 0.57-1.29; P-trend=0.77) in men and 1.24 (95% CI 0.74-2.05; P-trend=0.13) and 0.82 (95% CI 0.47-1.42; P-trend=0.31) in women. CONCLUSIONS: In the Spanish European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, unprocessed red meat and processed meat consumption were not associated with risk of stroke in men or women.

Levels and predictors of persistent organic pollutants in an adult population from four Spanish regions.

This research aimed to assess serum concentrations of a group of persistent organic pollutants (POPs) in a sample of adults recruited in four different regions from Spain and to assess socio-demographic, dietary, and lifestyle predictors of the exposure. The study population comprised 312 healthy adults selected from among controls recruited in the MCC-Spain multicase-control study. Study variables were collected using standardized questionnaires, and pollutants were analyzed by means of gas chromatography with electron capture detection. Multivariable analyses were performed to identify predictors of log-transformed pollutant concentrations, using combined backward and forward stepwise multiple linear regression models. Detection rates ranged from 89.1% (hexachlorobenzene, HCB) to 93.6% (Polychlorinated biphenyl-153 [PCB-153]); p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) showed the highest median concentrations (1.04ng/ml), while HCB showed the lowest (0.24ng/ml). In the multivariable models, age was positively associated with HCB, p,p'-DDE, and PCB-180. BMI was associated positively with p,p'-DDE but negatively with PCB-138. Total accumulated time residing in an urban area was positively associated with PCB-153 concentrations. The women showed higher HCB and lower p,p'-DDE concentrations versus the men. Notably, POP exposure in our study population was inversely associated with the breastfeeding received by participants and with the number of pregnancies of their mothers but was not related to the participants' history of breastfeeding their children or parity. Smoking was negatively associated with HCB and PCB-153 concentrations. Consumption of fatty foods, including blue fish, was in general positively associated with POP levels. Although POP environmental levels are declining worldwide, there is a need for the continuous monitoring of human exposure in the general population. The results of the present study confirm previous findings and point to novel predictors of long-term exposure to persistent organic pollutants.

An epidemiologic risk prediction model for ovarian cancer in Europe: the EPIC study.

BACKGROUND: Ovarian cancer has a high case-fatality ratio, largely due to late diagnosis. Epidemiologic risk prediction models could help identify women at increased risk who may benefit from targeted prevention measures, such as screening or chemopreventive agents. METHODS: We built an ovarian cancer risk prediction model with epidemiologic risk factors from 202,206 women in the European Prospective Investigation into Cancer and Nutrition study. RESULTS: Older age at menopause, longer duration of hormone replacement therapy, and higher body mass index were included as increasing ovarian cancer risk, whereas unilateral ovariectomy, longer duration of oral contraceptive use, and higher number of full-term pregnancies were decreasing risk. The discriminatory power (overall concordance index) of this model, as examined with five-fold cross-validation, was 0.64 (95% confidence interval (CI): 0.57, 0.70). The ratio of the expected to observed number of ovarian cancer cases occurring in the first 5 years of follow-up was 0.90 (293 out of 324, 95% CI: 0.81-1.01), in general there was no evidence for miscalibration. CONCLUSION: Our ovarian cancer risk model containing only epidemiological data showed modest discriminatory power for a Western European population. Future studies should consider adding informative biomarkers to possibly improve the predictive ability of the model.

Fruit and vegetable consumption in relation to hepatocellular carcinoma in a multi-centre, European cohort study.

BACKGROUND: Vegetable and/or fruit intakes in association with hepatocellular carcinoma (HCC) risk have been investigated in case-control studies conducted in specific European countries and cohort studies conducted in Asia, with inconclusive results. No multi-centre European cohort has investigated the indicated associations. METHODS: In 486,799 men/women from the European Prospective Investigation into Cancer and nutrition, we identified 201 HCC cases after 11 years median follow-up. We calculated adjusted hazard ratios (HRs) for HCC incidence for sex-specific quintiles and per 100 g d(-1) increments of vegetable/fruit intakes. RESULTS: Higher vegetable intake was associated with a statistically significant, monotonic reduction of HCC risk: HR (100 g d(-1) increment): 0.83; 95% CI: 0.71-0.98. This association was consistent in sensitivity analyses with no apparent heterogeneity across strata of HCC risk factors. Fruit intake was not associated with HCC incidence: HR (100 g d(-1) increment): 1.01; 95% CI: 0.92-1.11. CONCLUSIONS: Vegetable, but not fruit, intake is associated with lower HCC risk with no evidence for heterogeneity of this association in strata of important HCC risk factors. Mechanistic studies should clarify pathways underlying this association. Given that HCC prognosis is poor and that vegetables are practically universally accessible, our results may be important, especially for those at high risk for the disease.

Diabetes and onset of natural menopause: results from the European Prospective Investigation into Cancer and Nutrition.

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, <10 years: HR = 1.59; 95% CI 1.03-2.43) compared with non-diabetic women, whereas women with diabetes at age 50 years and older had a later menopause (HR = 0.81; 95% CI 0.70-0.95). None of the other age groups were associated with ANM. LIMITATIONS, REASONS FOR CAUTION: Strengths of the study include the large sample size and the broad set of potential confounders measured. However, results may have been underestimated due to survival bias. We cannot be sure about the sequence of the events in women with a late age at diabetes, as both events then occur in a short period. We could not distinguish between type 1 and type 2 diabetes. WIDER IMPLICATIONS OF THE FINDINGS: Based on the literature, an accelerating effect of early-onset diabetes on ANM might be plausible. A delaying effect of late-onset diabetes on ANM has not been reported before, and is not in agreement with recent studies suggesting the opposite association. STUDY FUNDING/COMPETING INTERESTS: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ) and Federal Ministry of Education and Research (BMMF) (Germany); Ministry of Health and Social Solidarity, Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC) and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skåne and Västerbotten (Sweden); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and Wellcome Trust (UK). None of the authors reported a conflict of interest.

Healthy lifestyle index and risk of gastric adenocarcinoma in the EPIC cohort study.

Several modifiable lifestyle factors, including smoking, alcohol, certain dietary factors and weight are independently associated with gastric cancer (GC); however, their combined impact on GC risk is unknown. We constructed a healthy lifestyle index to investigate the joint influence of these behaviors on GC risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The analysis included 461,550 participants (662 first incident GC cases) with a mean follow-up of 11.4 years. A healthy lifestyle index was constructed, assigning 1 point for each healthy behavior related to smoking status, alcohol consumption and diet quality (represented by the Mediterranean diet) for assessing overall GC and also body mass index for cardia GC and 0 points otherwise. Risk of GC was calculated using Cox proportional hazards regression models while adjusting for relevant confounders. The highest versus lowest score in the healthy lifestyle index was associated with a significant lower risk of GC, by 51% overall (HR 0.49 95% CI 0.35, 0.70), by 77% for cardia GC (HR 0.23 95% CI 0.08, 0.68) and by 47% for noncardia GC (HR 0.53 (95% CI 0.32, 0.87), p-trends<0.001. Population attributable risk calculations showed that 18.8% of all GC and 62.4% of cardia GC cases could have been prevented if participants in this population had followed the healthy lifestyle behaviors of this index. Adopting several healthy lifestyle behaviors including not smoking, limiting alcohol consumption, eating a healthy diet and maintaining a normal weight is associated with a large decreased risk of GC.

Brain and central nervous system cancer incidence in navarre (Spain), 1973-2008 and projections for 2014.

Different studies have pointed out Navarre as one of the regions of Spain with the highest incidence rates of brain and other central nervous system (CNS) cancer. Trend analysis for cancer incidence rates for long periods of time, might help determining risk factors as well as, assessing prevention actions involved in this disease. The objective of this study was to describe the incidence of brain and CNS cancer using data from the population-based cancer registry of Navarre, (Spain) during the period 1973-2008 and provide forecast figures up to-2014. Crude and age-standardized (world population) incidence rates of brain cancer per 100,000 person-years were calculated by the direct method separately by gender, area (Pamplona and others), and age-groups. Penalized splines for smoothing rates in the temporal dimensions were applied in order to estimate and forecast cancer incidence rates. Age-adjusted incidence rates showed an increase over the study and forecast periods in both sexes more marked in women than in men. Higher incidence rates were observed in men compared with women but the differences became smaller with time. The increase was due to the rise of rates in the oldest age groups since the rates for younger age groups remained stable or decreased over time. As the entire aetiology of brain and other CNS cancer is not still clear, keep promoting healthful lifestyles for cancer primary prevention among the whole population is necessary.

Insulin-like growth factor I and risk of epithelial invasive ovarian cancer by tumour characteristics: results from the EPIC cohort.

BACKGROUND: Prospective studies on insulin-like growth factor I (IGF-I) and epithelial ovarian cancer (EOC) risk are inconclusive. Data suggest risk associations vary by tumour characteristics. METHODS: We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate IGF-I concentrations and EOC risk by tumour characteristics (n=565 cases). Multivariable conditional logistic regression models were used to estimate associations. RESULTS: We observed no association between IGF-I and EOC overall or by tumour characteristics. CONCLUSIONS: In the largest prospective study to date was no association between IGF-I and EOC risk. Pre-diagnostic serum IGF-I concentrations may not influence EOC risk.

Flavonoid and lignan intake in relation to bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

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-Q1 0.78, 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.