Physical activity levels of women with breast cancer during and after treatment, a comparison with the Dutch female population.

Background: Physical activity has been shown to reduce side-effects of breast cancer and its treatment. As physical activity levels of patients with breast cancer are largely unknown, we investigated these levels and compared them to women from the general population. Methods: In this prospective cohort study, physical activity levels of women with breast cancer participating in the UMBRELLA cohort were assessed at radiotherapy intake and thereafter every 6 months up to 3 years with the SQUASH questionnaire, which was also used in a random sample of the Dutch population. We compared physical activity levels (no activity, low, moderate or high levels of sports, leisure time or total activity) between patients and the Dutch female population using multinomial logistic regression. Standardized Prevalence Ratios (SPR) were calculated to compare adherence to Dutch physical activity guidelines. Results: Women with breast cancer (nbaseline = 1655, n6 months = 1414, n12 months = 1186, n18 months = 957, n24 months = 744, n30 months = 555, and n36 months = 377) were less likely to spend time in physical activity compared to the general population (n = 11,710) until 3 years post-diagnosis, especially after 6 months (ORhigh-vs.-no activity = 0.34, 95% CI: 0.28-0.41). From 12 months onwards, patients were more likely to perform sports compared to the general population, especially patients who underwent systemic therapy. Guideline adherence was significantly lower in patients at baseline and 6 months (SPRbaseline = 89, 95% CI: 82-97; SPR6 months = 88, 95% CI: 81-96), and comparable to the general population at 12-36 months, especially in older women. Conclusions: Physical activity levels in women with breast cancer during and after treatment were lower compared to the Dutch female population. Three years post-treatment, they were still less physically active, although they spend more time in sport activities. As about half of the patients did not perform any sports, physical activity needs to be stimulated during and after treatment.

Impact of prediagnostic smoking and smoking cessation on colorectal cancer prognosis: a meta-analysis of individual patient data from cohorts within the CHANCES consortium.

Background: Smoking has been associated with colorectal cancer (CRC) incidence and mortality in previous studies and might also be associated with prognosis after CRC diagnosis. However, current evidence on smoking in association with CRC prognosis is limited. Patients and methods: For this individual patient data meta-analysis, sociodemographic and smoking behavior information of 12 414 incident CRC patients (median age at diagnosis: 64.3 years), recruited within 14 prospective cohort studies among previously cancer-free adults, was collected at baseline and harmonized across studies. Vital status and causes of death were collected for a mean follow-up time of 5.1 years following cancer diagnosis. Associations of smoking behavior with overall and CRC-specific survival were evaluated using Cox regression and standard meta-analysis methodology. Results: A total of 5229 participants died, 3194 from CRC. Cox regression revealed significant associations between former [hazard ratio (HR) = 1.12; 95 % confidence interval (CI) = 1.04-1.20] and current smoking (HR = 1.29; 95% CI = 1.04-1.60) and poorer overall survival compared with never smoking. Compared with current smoking, smoking cessation was associated with improved overall (HR<10 years = 0.78; 95% CI = 0.69-0.88; HR≥10 years = 0.78; 95% CI = 0.63-0.97) and CRC-specific survival (HR≥10 years = 0.76; 95% CI = 0.67-0.85). Conclusion: In this large meta-analysis including primary data of incident CRC patients from 14 prospective cohort studies on the association between smoking and CRC prognosis, former and current smoking were associated with poorer CRC prognosis compared with never smoking. Smoking cessation was associated with improved survival when compared with current smokers. Future studies should further quantify the benefits of nonsmoking, both for cancer prevention and for improving survival among CRC patients, in particular also in terms of treatment response.

Reasons for (non)participation in supplemental population-based MRI breast screening for women with extremely dense breasts.

AIM: To determine the willingness of women with extremely dense breasts to undergo breast cancer screening with magnetic resonance imaging (MRI) in a research setting, and to examine reasons for women to participate or not. MATERIALS AND METHODS: Between 2011 and 2015, 8,061 women (50-75 years) were invited for supplemental MRI as part of the Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial (ClinicalTrials.gov Identifier: NCT01315015), after a negative screening mammography in the national population-based mammography screening programme. Demographics of participants and non-participants were compared. All invitees were asked to report reasons for (non)participation. Ethical approval was obtained. Participants provided written informed consent. RESULTS: Of the 8,061 invitees, 66% answered that they were interested, and 59% eventually participated. Participants were on average 54-years old (interquartile range: 51-59 years), comparable to women with extremely dense breasts in the population-based screening programme (55 years). Women with higher socio-economic status (SES) were more often interested in participation than women with lower SES (68% versus 59%, p<0.001). The most frequently stated reasons for non-participation were "MRI-related inconveniences and/or self-reported contraindications to MRI" (27%) and "anxiety regarding the result of supplemental screening" (21%). "Expected personal health benefit" (68%) and "contribution to science" (43%) were the most frequent reasons for participation. CONCLUSION: Of women invited for MRI because of extremely dense breasts, 59% participated. Common reasons for non-participation were "MRI-related inconveniences" and "anxiety regarding the result of supplemental screening". In case of future implementation, availability of precise evidence on benefits and harms might reduce this anxiety.

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.

The Value of Ipsilateral Breast Tumor Recurrence as a Quality Indicator: Hospital Variation in the Netherlands.

PURPOSE: All Dutch hospitals are obliged to report their 5-year ipsilateral breast tumor recurrence (IBTR) rate after breast cancer surgery. Experts decided that these rates should not exceed 5 %. This study determined the value of IBTR as an indicator to compare quality of care between hospitals. METHODS: All patients with breast cancer (pT1-3, any N, M0) who underwent surgery in 1 of 92 Dutch hospitals from 2003 to 2006 were identified in the Netherlands Cancer Registry. Data of recurrence was retrieved from hospital records. Five-year IBTR rates for breast-conserving surgery (BCS) and mastectomy were calculated by using the Kaplan-Meier method. Hospital variation was presented in funnel plots. Multivariate analysis was used to assess hospital characteristics associated with IBTR rates. RESULTS: A total of 40,892 breast cancer patients were included. The overall 5-year IBTR rate was 2.85 % (95 % confidence interval 2.68-3.03) and was significantly lower for BCS than for mastectomy (2.38 vs. 3.45 %, p < 0.001). IBTR rates decreased over time in both groups. Rates varied between 0.77 and 5.70 % between hospitals. When random variation is taken into account, only extremely high IBTR rates can be detected as deviant from the target value of 5 %. Adjusting for tumor and patient characteristics, analyses showed that a higher volume of mastectomies is associated with lower IBTR rates. CONCLUSIONS: Our population-based findings show that IBTR rates in the Netherlands are low and have improved over time. The 5-year IBTR rate as an indicator for quality of care of individual hospitals is of limited value.

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.

Anti-Mullerian hormone is a more accurate predictor of individual time to menopause than mother's age at menopause.

STUDY QUESTION: In the prediction of time to menopause (TTM), what is the added value of anti-Müllerian hormone (AMH) when mother's age at natural menopause (ANM) is also known? SUMMARY ANSWER: AMH is a more accurate predictor of individual TTM than mother's age at menopause. WHAT IS KNOWN ALREADY: Mother's ANM is considered a proxy for daughter's ANM although studies on its predictive accuracy are non-existent. AMH is a biomarker with a known capacity to predict ANM. However, its added value on top of known predictors, like mother's ANM, is unknown. STUDY DESIGN, SIZE, DURATION: Population-based cohort studies were used. To assess any additive predictive value of mother's ANM, 164 mother-daughter pairs were used (Group 1). To assess the added value of AMH, a second group of 150 women in whom AMH and mother's ANM were recorded prior to a 12-year follow-up period during which daughter's ANM was assessed was used (Group 2). PARTICIPANTS/MATERIALS, SETTING, METHODS: Group 1 consisted of participants of the DOM cohort (an ongoing breast cancer study). Group 2 was a pooled cohort of women with regular menstrual cycles from two independent published studies. Cox proportional hazards analysis estimated uni- and multivariate regression coefficients for female age at study entry, mother's ANM and AMH in the prediction of TTM. Discrimination of models was assessed with C-statistics. Clinical added value of AMH was quantified with a net reclassification index (NRI). MAIN RESULTS AND THE ROLE OF CHANCE: A model with female age and mother's ANM had a c-statistic of 79 and 85% in groups 1 and 2, respectively. Both age and mother's ANM were significantly associated with TTM (HR 1.54 and HR 0.93 for age and mother's ANM in Cohort 1 and HR 1.59 and HR 0.89 in Group 2, respectively. P-value for all <0.001). In Group 2, the multivariate model with age, mother's ANM and AMH had a c-statistic of 92%, and only female age and AMH remained significantly associated with TTM (HR 1.41 P < 0.0001; HR 0.93 P = 0.08 and HR 0.06 P < 0.0001 for age, mother's ANM and AMH, respectively). The mean weighted NRI suggests that a 47% improvement in predictive accuracy is offered by adding AMH to the model of age and mother's ANM. In conclusion, AMH and mother's ANM both have added value in forecasting TTM for the daughter based on her age. In comparison, AMH is a more accurate added predictor of TTM than mother's ANM. LIMITATIONS, REASONS FOR CAUTION: The cohort of women is relatively small and different cohorts of women were pooled. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that AMH is a more accurate predictor of ANM than mother's ANM. However, before achieving clinical applicability, the certainty with which a woman's prediction is made must improve. The association between mother's ANM and TTM in daughters did not appear to be influenced by whether ANM was recorded by mothers or daughters--an important finding because in the clinical setting daughters usually provide this information. STUDY FUNDING/COMPETING INTEREST(S): No funding was received and there were no competing interests in direct relation to this study.

3-T breast magnetic resonance imaging in patients with suspicious microcalcifications on mammography.

OBJECTIVE: To investigate the diagnostic value of 3-Tesla (T) breast MRI in patients presenting with microcalcifications on mammography. METHODS: Between January 2006 and May 2009, 123 patients with mammographically detected BI-RADS 3­5 microcalcifications underwent 3-T breast MRI before undergoing breast biopsy. All MRIs of the histopathologically confirmed index lesions were reviewed by two breast radiologists. The detection rate of invasive carcinoma and ductal carcinoma in situ (DCIS) was evaluated, as well as the added diagnostic value of MRI over mammography and breast ultrasound. RESULTS: At pathology, 40/123 (33%) lesions proved malignant; 28 (70%) DCIS and 12 (30%) invasive carcinoma. Both observers detected all invasive malignancies at MRI, as well as 79% (observer 1) and 86% (observer 2) of in situ lesions. MRI in addition to conventional imaging led to a significant increase in area under the receiver operating characteristic (ROC) curve from 0.67 (95% CI 0.56­0.79) to 0.79 (95% CI 0.70­0.88, observer 1) and to 0.80 (95% CI 0.71­0.89, observer 2), respectively. CONCLUSIONS: 3-T breast MRI was shown to add significant value to conventional imaging in patients presenting with suspicious microcalcifications on mammography. KEY POINTS: • 3-T MRI is increasingly used for breast imaging in clinical practice. • On 3-T breast MRI up to 86% of DCIS lesions are detected. • 3-T MRI increases the diagnostic value in patients with mammographically detected microcalcifications.

Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies.

BACKGROUND: Associations between circulating concentrations of oestrogens, progesterone, and androgens with breast cancer and related risk factors in premenopausal women are not well understood. We aimed to characterise these associations with a pooled analysis of data from seven studies. METHODS: Individual participant data for prediagnostic sex hormone and sex hormone-binding globulin (SHBG) concentrations were contributed from seven prospective studies. We restricted analyses to women who were premenopausal and younger than 50 years at blood collection, and to women with breast cancer diagnosed before age 50 years. We estimated odds ratios (ORs) with 95% CIs for breast cancer associated with hormone concentrations by conditional logistic regression in cases and controls matched for age, date of blood collection, and day of cycle, with stratification by study and further adjustment for cycle phase. We examined associations of hormones with risk factors for breast cancer in control women by comparing geometric mean hormone concentrations in categories of these risk factors, adjusted for study, age, phase of menstrual cycle, and body-mass index (BMI). All statistical tests were two-sided. FINDINGS: We included data for up to 767 women with breast cancer and 1699 controls in the risk analyses. Breast cancer risk was associated with a doubling in concentrations of oestradiol (OR 1·19, 95% CI 1·06-1·35), calculated free oestradiol (1·17, 1·03-1·33), oestrone (1·27, 1·05-1·54), androstenedione (1·30, 1·10-1·55), dehydroepiandrosterone sulphate (1·17, 1·04-1·32), testosterone (1·18, 1·03-1·35), and calculated free testosterone (1·08, 0·97-1·21). Breast cancer risk was not associated with luteal phase progesterone (doubling in concentration OR 1·00, 95% CI 0·92-1·09), and adjustment for other factors had little effect on any of these ORs. Cross-sectional analyses in control women showed several associations of sex hormones with breast cancer risk factors. INTERPRETATION: Circulating oestrogens and androgens are positively associated with the risk for breast cancer in premenopausal women.

Outcomes of a population-based series of early breast cancer patients with micrometastases and isolated tumour cells in axillary lymph nodes.

BACKGROUND: Axillary lymph node staging is traditionally important to provide prognostic information to guide further treatment. However, the relevance of isolated tumour cells (ITC) or micrometastases in axillary nodes and the need for adjuvant treatment remain uncertain. PATIENTS AND METHODS: Data from 18 370 patients with pT1-2 breast cancer with pN0, pN0i+ or pN1mi were analysed. The primary end point was 5-year disease-free survival (locoregional recurrence, distant metastases or contralateral breast cancer). RESULTS: Five-year disease-free survival was 89.9% [95% confidence interval 89.5% to 90.4%]; and did not differ significantly between groups. After adjusting for prognostic factors (including treatment), patients with ITC had a comparable risk (hazard ratio = 1.12) as patients with node-negative disease, while patients with micrometastases had a 38% higher risk of recurrence. CONCLUSION(S): Patients with ITC and node-negative breast cancer appear to have similar prognosis, and those with micrometastases have a 38% higher risk of tumour recurrence. However, considering that disease-free survival is already high, we are reluctant to advise chemotherapy in all patients with ITC or micrometastases. In future, genomic tumour characteristics might predict the propensity of dissemination from the primary cancer better than the status of the axillary lymph nodes.

Mediterranean diet and incidence of hip fractures in a European cohort.

UNLABELLED: Prevention of hip fractures is of critical public health importance. In a cohort of adults from eight European countries, evidence was found that increased adherence to Mediterranean diet, measured by a 10-unit dietary score, is associated with reduced hip fracture incidence, particularly among men. INTRODUCTION: Evidence on the role of dietary patterns on hip fracture incidence is scarce. We explored the association of adherence to Mediterranean diet (MD) with hip fracture incidence in a cohort from eight European countries. METHODS: A total of 188,795 eligible participants (48,814 men and 139,981 women) in the European Prospective Investigation into Cancer and nutrition study with mean age 48.6 years (±10.8) were followed for a median of 9 years, and 802 incident hip fractures were recorded. Diet was assessed at baseline through validated dietary instruments. Adherence to MD was evaluated by a MD score (MDs), on a 10-point scale, in which monounsaturated were substituted with unsaturated lipids. Association with hip fracture incidence was assessed through Cox regression with adjustment for potential confounders. RESULTS: Increased adherence to MD was associated with a 7 % decrease in hip fracture incidence [hazard ratio (HR) per 1-unit increase in the MDs 0.93; 95 % confidence interval (95 % CI) = 0.89-0.98]. This association was more evident among men and somewhat stronger among older individuals. Using increments close to one standard deviation of daily intake, in the overall sample, high vegetable (HR = 0.86; 95 % CI = 0.79-0.94) and high fruit (HR = 0.89; 95 % CI = 0.82-0.97) intake was associated with decreased hip fracture incidence, whereas high meat intake (HR = 1.18; 95 % CI = 1.06-1.31) with increased incidence. Excessive ethanol consumption (HR high versus moderate = 1.74; 95 % CI = 1.32-2.31) was also a risk factor. CONCLUSIONS: In a prospective study of adults, increased adherence to MD appears to protect against hip fracture occurrence, particularly among men.

Dietary patterns derived from principal component- and k-means cluster analysis: long-term association with coronary heart disease and stroke.

BACKGROUND AND AIMS: Studies comparing dietary patterns derived from different a posteriori methods in view of predicting disease risk are scarce. We aimed to explore differences between dietary patterns derived from principal component- (PCA) and k-means cluster analysis (KCA) in relation to their food group composition and ability to predict CHD and stroke risk. METHODS AND RESULTS: The study was conducted in the EPIC-NL cohort that consists of 40,011 men and women. Baseline dietary intake was measured using a validated food-frequency questionnaire. Food items were consolidated into 31 food groups. Occurrence of CHD and stroke was assessed through linkage with registries. After 13 years of follow-up, 1,843 CHD and 588 stroke cases were documented. Both PCA and KCA extracted a prudent pattern (high intakes of fish, high-fiber products, raw vegetables, wine) and a western pattern (high consumption of French fries, fast food, low-fiber products, other alcoholic drinks, soft drinks with sugar) with small variation between components and clusters. The prudent component was associated with a reduced risk of CHD (HR for extreme quartiles: 0.87; 95%-CI: 0.75-1.00) and stroke (0.68; 0.53-0.88). The western component was not related to any outcome. The prudent cluster was related with a lower risk of CHD (0.91; 0.82-1.00) and stroke (0.79; 0.67-0.94) compared to the western cluster. CONCLUSION: PCA and KCA found similar underlying patterns with comparable associations with CHD and stroke risk. A prudent pattern reduced the risk of CHD and stroke.

Genetic susceptibility to sporadic ovarian cancer: a systematic review.

Ovarian cancer is a highly lethal disease. Many researchers have, therefore, attempted to identify high risk populations. In this perspective, numerous genetic association studies have been performed to discover common ovarian cancer susceptibility variants. Accordingly, there is an increasing need to synthesize the evidence in order to identify true associations. A comprehensive and systematic assessment of all available data on genetic susceptibility to sporadic ovarian cancer was carried out. The evidence of statistically significant findings was evaluated based on the number of positive replications, the ratio of positive and negative studies, and the false-positive report probability (FPRP). The authors reviewed three genome-wide association studies (GWAS) and 147 candidate gene studies, published from 1990 to October 2010, including around 1100 genetic variants in more than 200 candidate genes and 20 intergenic regions. Genetic variants with the strongest evidence for an association with ovarian cancer include the rs2854344 in the RB1 gene and SNPs on chromosomes 9p22.2, 8q24, 2q31, and 19p13. Promising genetic pathways for ovarian cancer include the cell cycle, DNA repair, sex steroid hormone and oncogenic pathway. Concluding, this review shows that many genetic association studies have been performed, but only a few genetic variants show strong evidence for an association with ovarian cancer. More research is needed to elucidate causal genetic variants, taking into consideration gene-gene and gene-environment interactions, combined effects of common and rare variants, and differences between histological subtypes of this cancer.

Variety in vegetable and fruit consumption and the risk of gastric and esophageal cancer in the European Prospective Investigation into Cancer and Nutrition.

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 0.79-0.97 and 0.76; 95% CI 0.62-0.94, 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.

Concentrations of IGF-I and IGFBP-3 and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition.

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.

Inflammation marker and risk of pancreatic cancer: a nested case-control study within the EPIC cohort.

BACKGROUND: Established risk factors for pancreatic cancer include smoking, long-standing diabetes, high body fatness, and chronic pancreatitis, all of which can be characterised by aspects of inflammatory processes. However, prospective studies investigating the relation between inflammatory markers and pancreatic cancer risk are scarce. METHODS: We conducted a nested case-control study within the European Prospective Investigation into Cancer and Nutrition, measuring prediagnostic blood levels of C-reactive protein (CRP), interleukin-6 (IL-6), and soluble receptors of tumour necrosis factor-α (sTNF-R1, R2) in 455 pancreatic cancer cases and 455 matched controls. Odds ratios (ORs) were estimated using conditional logistic regression models. RESULTS: None of the inflammatory markers were significantly associated with risk of pancreatic cancer overall, although a borderline significant association was observed for higher circulating sTNF-R2 (crude OR=1.52 (95% confidence interval (CI) 0.97-2.39), highest vs lowest quartile). In women, however, higher sTNF-R1 levels were significantly associated with risk of pancreatic cancer (crude OR=1.97 (95% CI 1.02-3.79)). For sTNF-R2, risk associations seemed to be stronger for diabetic individuals and those with a higher BMI. CONCLUSION: Prospectively, CRP and IL-6 do not seem to have a role in our study with respect to risk of pancreatic cancer, whereas sTNF-R1 seemed to be a risk factor in women and sTNF-R2 might be a mediator in the risk relationship between overweight and diabetes with pancreatic cancer. Further large prospective studies are needed to clarify the role of proinflammatory proteins and cytokines in the pathogenesis of exocrine pancreatic cancer.

Helicobacter pylori infection assessed by ELISA and by immunoblot and noncardia gastric cancer risk in a prospective study: the Eurgast-EPIC project.

BACKGROUND: In epidemiological studies, Helicobacter pylori infection is usually detected by enzyme-linked immunosorbent assay (ELISA). However, infection can spontaneously clear from the mucosa during the progression of atrophy and could lead to substantial under-detection of infection and underestimation of its effect on gastric cancer (GC) risk. Antibodies detected by western blot are known to persist longer after the loss of the infection. METHODS: In a nested case-control study from the Eurogast-EPIC cohort, including 88 noncardia GC cases and 338 controls, we assessed the association between noncardia GC and H. pylori infection comparing antibodies detected by western blot (HELICOBLOT2.1) to those detected by ELISA (Pyloriset EIA-GIII(®)). RESULTS: By immunoblot, 82 cases (93.2%) were H. pylori positive, 10 of these cases (11.4%) were negative by ELISA and only 6 cases (6.8%) were negative by both ELISA and immunoblot. Multivariable odds ratio (OR) for noncardia GC comparing immunoglobulin G positive versus negative by ELISA was 6.8 [95% confidence interval (CI) 3.0-15.1], and by immunoblot, the OR was 21.4 (95% CI 7.1-64.4). CONCLUSIONS: Using a western blot assay, nearly all noncardia GC were classified as H. pylori positive and the OR was more than threefold higher than the OR assessed by ELISA, supporting the hypothesis that H. pylori infection is a necessary condition for noncardia GC.

Diabetes mellitus, glycated haemoglobin and C-peptide levels in relation to pancreatic cancer risk: a study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

AIMS/HYPOTHESIS: There has been long-standing debate about whether diabetes is a causal risk factor for pancreatic cancer or a consequence of tumour development. Prospective epidemiological studies have shown variable relationships between pancreatic cancer risk and blood markers of glucose and insulin metabolism, overall and as a function of lag times between marker measurements (blood donation) and date of tumour diagnosis. METHODS: Pre-diagnostic levels of HbA(1c) and C-peptide were measured for 466 participants with pancreatic cancer and 466 individually matched controls within the European Prospective Investigation into Cancer and Nutrition. Conditional logistic regression models were used to estimate ORs for pancreatic cancer. RESULTS: Pancreatic cancer risk gradually increased with increasing pre-diagnostic HbA(1c) levels up to an OR of 2.42 (95% CI 1.33, 4.39 highest [≥ 6.5%, 48 mmol/mol] vs lowest [≤ 5.4%, 36 mmol/mol] category), even for individuals with HbA(1c) levels within the non-diabetic range. C-peptide levels showed no significant relationship with pancreatic cancer risk, irrespective of fasting status. Analyses showed no clear trends towards increasing hyperglycaemia (as marked by HbA(1c) levels) or reduced pancreatic beta cell responsiveness (as marked by C-peptide levels) with decreasing time intervals from blood donation to cancer diagnosis. CONCLUSIONS/INTERPRETATION: Our data on HbA(1c) show that individuals who develop exocrine pancreatic cancer tend to have moderate increases in HbA(1c) levels, relatively independently of obesity and insulin resistance-the classic and major risk factors for type 2 diabetes. While there is no strong difference by lag time, more data are needed on this in order to reach a firm conclusion.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

General and abdominal adiposity and risk of death in Europe.

BACKGROUND: Previous studies have relied predominantly on the body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) to assess the association of adiposity with the risk of death, but few have examined whether the distribution of body fat contributes to the prediction of death. METHODS: We examined the association of BMI, waist circumference, and waist-to-hip ratio with the risk of death among 359,387 participants from nine countries in the European Prospective Investigation into Cancer and Nutrition (EPIC). We used a Cox regression analysis, with age as the time variable, and stratified the models according to study center and age at recruitment, with further adjustment for educational level, smoking status, alcohol consumption, physical activity, and height. RESULTS: During a mean follow-up of 9.7 years, 14,723 participants died. The lowest risks of death related to BMI were observed at a BMI of 25.3 for men and 24.3 for women. After adjustment for BMI, waist circumference and waist-to-hip ratio were strongly associated with the risk of death. Relative risks among men and women in the highest quintile of waist circumference were 2.05 (95% confidence interval [CI], 1.80 to 2.33) and 1.78 (95% CI, 1.56 to 2.04), respectively, and in the highest quintile of waist-to-hip ratio, the relative risks were 1.68 (95% CI, 1.53 to 1.84) and 1.51 (95% CI, 1.37 to 1.66), respectively. BMI remained significantly associated with the risk of death in models that included waist circumference or waist-to-hip ratio (P<0.001). CONCLUSIONS: These data suggest that both general adiposity and abdominal adiposity are associated with the risk of death and support the use of waist circumference or waist-to-hip ratio in addition to BMI in assessing the risk of death.