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Association results between minor alleles of 467 variants incorportated in cross tissue gene expression prediction model for the gene of CRHR1.

Background: Emerging evidence from cohort studies indicates that adiposity is associated with greater incidence of head and neck cancer. However, most studies have used self-reported anthropometry which is prone to error.Methods: Among 363,094 participants in the European Prospective Investigation into Cancer and Nutrition study (EPIC) with measured anthropometry, there were 837 incident cases of head and neck cancer. Head and neck cancer risk was examined in relation to body mass index (BMI) [lean: 2, normal weight (reference): 22.5–24.9 kg/m2, overweight 25–29.9 kg/m2, obese: ≥30 kg/m2], waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR) using Cox proportional hazards models.Results: Among men, a BMI < 22.5 kg/m2 was associated with higher head and neck cancer risk [HR 1.62; 95% confidence interval (CI), 1.23–2.12)]; BMI was not associated with head and neck cancer among women. WC and WHR were associated with greater risk of head and neck cancer among women (WC per 5 cm: HR, 1.08; 95% CI, 1.02–1.15; WHR per 0.1 unit: HR, 1.64; 95% CI, 1.38–1.93). After stratification by smoking status, the association for WHR was present only among smokers (Pinteraction = 0.004). Among men, WC and WHR were associated with head and neck cancer only upon additional adjustment for BMI (WC per 5 cm: HR 1.16; 95% CI, 1.07–1.26; WHR per 0.1 unit: HR, 1.42; 95% CI, 1.21–1.65).Conclusions: Central adiposity, particularly among women, may have a stronger association with head and neck cancer risk than previously estimated.Impact: Strategies to reduce obesity may beneficially impact head and neck cancer incidence. Cancer Epidemiol Biomarkers Prev; 26(6); 895–904. ©2017 AACR.

PDF file - 71K, Spearman partial correlation coefficients between biomarkers among controls of a nested case-control study in the EPIC cohort.

Measures of adiposity and the risk of HNC among EPIC participants, by smoking status at baseline and second questionnaire

PDF file, 120KB, Supplemental Table 1. Study Descriptions, Design and Sample Size for 19 DENSNP Studies. Caucasian Women Only. Supplemental Table 2. Source and Timing of Reproductive and Anthropometric Variable Collection. Supplemental Table 3. Description of Mammogram View, Side, Film Digitizer and Density Estimation Software for DENSNP Studies. Supplemental Table 4. Genotyping Platform and SNP Call Rates Performed by Each Study.

Purpose: Renal cell carcinoma (RCC) has the potential for cure with surgery when diagnosed at an early stage. Kidney injury molecule-1 (KIM-1) has been shown to be elevated in the plasma of RCC patients. We aimed to test whether plasma KIM-1 could represent a means of detecting RCC prior to clinical diagnosis.Experimental Design: KIM-1 concentrations were measured in prediagnostic plasma from 190 RCC cases and 190 controls nested within a population-based prospective cohort study. Cases had entered the cohort up to 5 years before diagnosis, and controls were matched on cases for date of birth, date at blood donation, sex, and country. We applied conditional logistic regression and flexible parametric survival models to evaluate the association between plasma KIM-1 concentrations and RCC risk and survival.Results: The incidence rate ratio (IRR) of RCC for a doubling in KIM-1 concentration was 1.71 [95% confidence interval (CI), 1.44–2.03, P = 4.1 × 10−23], corresponding to an IRR of 63.3 (95% CI, 16.2–246.9) comparing the 80th to the 20th percentiles of the KIM-1 distribution in this sample. Compared with a risk model including known risk factors of RCC (age, sex, country, body mass index, and tobacco smoking status), a risk model additionally including KIM-1 substantially improved discrimination between cases and controls (area under the receiver-operating characteristic curve of 0.8 compared with 0.7). High plasma KIM-1 concentrations were also associated with poorer survival (P = 0.0053).Conclusions: Plasma KIM-1 concentrations could predict RCC incidence up to 5 years prior to diagnosis and were associated with poorer survival. Clin Cancer Res; 24(22); 5594–601. ©2018 AACR.

Scatterplots of the associations between BMI (kg/m2) and WC (Fig 1a) and between BMI (kg/m2) and WHR (Fig 1b).

Online Supplementary Documents

PDF file, 20KB, Supplemental Table 5a. Associations of Common Breast Cancer Susceptibility Variants with Adjusted Percent Mammographic Density. Supplemental Table 5b. Associations of Common Breast Cancer Susceptibility Variants with Adjusted Mammographic Dense Area. Supplemental Table 5c. Associations of Common Breast Cancer Susceptibility Variants with Adjusted Mammographic Non Dense Area.

PDF file - 100K, Odds Ratios with 95% Confidence Intervals (CI) of Lung Cancer for circulating levels of Tryptophan, Kynurenine and Kynurenine/Tryptophan ratio by histological type. P for trend were assessed by the base 2 logarithm of the circulating levels.

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Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.

Backgrounds: Multiple polymorphisms affecting smoking behavior have been identified through genome-wide association studies. Circulating levels of the nicotine metabolite cotinine is a marker of recent smoking exposure. Hence, genetic variants influencing smoking behavior are expected to be associated with cotinine levels.Methods: We conducted an analysis in a lung cancer case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We investigated the effects of single-nucleotide polymorphisms (SNP) previously associated with smoking behavior on (i) circulating cotinine and (ii) lung cancer risk. A total of 894 cases and 1,805 controls were analyzed for cotinine and genotyped for 10 polymorphisms on 7p14, 8p11, 10q23, 15q25, and 19q13.Results: Two variants in the nicotinic acetylcholine receptor subunit genes CHRNA5 and CHRNA3 on 15q25, rs16969968 and rs578776, were associated with cotinine (P = 0.001 and 0.03, respectively) in current smokers and with lung cancer risk (P < 0.001 and P = 0.001, respectively). Two 19q13 variants, rs7937 and rs4105144, were associated with increased cotinine (P = 0.003 and P < 0.001, respectively) but decreased lung cancer risk (P = 0.01 for both, after adjusting for cotinine). Variants in 7p14, 8p11, and 10q23 were not associated with cotinine or lung cancer risk.Conclusions: 15q25 and 19q13 SNPs were associated with circulating cotinine. The directions of association for 15q25 variants with cotinine were in accordance with that expected of lung cancer risk, whereas SNPs on 19q13 displayed contrasting associations of cotinine and lung cancer that require further investigation.Impact: This study is the largest to date investigating the effects of polymorphisms affecting smoking behavior on lung cancer risk using circulating cotinine measures as proxies for recent smoking behavior. Cancer Epidemiol Biomarkers Prev; 20(10); 2250–61. ©2011 AACR.

Background: Imbalances in tryptophan metabolism have been linked to cancer-related immune escape and implicated in several cancers, including lung cancer.Methods: We conducted a nested case–control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) that included 893 incident lung cancer cases and 1,748 matched controls. Circulating levels of tryptophan and six of its metabolites were measured and evaluated in relation to lung cancer risk.Results: Tryptophan (Ptrend = 2 × 10−5) and the kynurenine/tryptophan ratio (KTR; Ptrend = 4 × 10−5) were associated with lung cancer risk overall after adjusting for established risk factors. The ORs comparing the fifth and first quintiles (OR5th vs. 1st) were 0.52 [95% confidence interval (CI), 0.37–0.74] for tryptophan and 1.74 (95% CI, 1.24–2.45) for KTR. After adjusting for plasma methionine (available from previous work, which was strongly correlated with tryptophan), the associations of tryptophan (adjusted Ptrend = 0.13) and KTR (Ptrend = 0.009) were substantially attenuated. KTR was positively associated with squamous cell carcinoma, the OR5th vs. 1st being 2.83 (95% CI, 1.62–4.94, Ptrend = 3 × 10−5) that was only marginally affected by adjusting for methionine.Conclusions: This study indicates that biomarkers of tryptophan metabolism are associated with subsequent lung cancer risk. Although this result would seem consistent with the immune system having a role in lung cancer development, the overall associations were dependent on methionine, and further studies are warranted to further elucidate the importance of these metabolites in lung cancer etiology.Impact: This is the first prospective study investigating the tryptophan pathway in relation to lung cancer risk. Cancer Epidemiol Biomarkers Prev; 23(3); 461–8. ©2013 AACR.

PDF file, 133KB, Supplemental Table 6a. Per-Allele Association (SE) of Breast Cancer Susceptibility Variants with Mammographic Percent Density Stratifying by Case Status, BMI, Menopausal Status and PMH Use. Supplemental Table 6b. Per-Allele Associations (SE) of Breast Cancer Susceptibility Variants with Adjusted Mammographic Dense Area Stratifying by Case Status, BMI Menopausal Status and PMH Use. Supplemental Table 6c. Per-Allele Associations (SE) of Breast Cancer Susceptibility Variants with Adjusted Mammographic Non Dense Area Stratifying by Case Status, BMI Menopausal Status and PMH Use.

Measures of adiposity and the risk of HNC in the EPIC study, excluding Oxford participants with calibrated self-reported anthropometry

Background: Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biologic mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to interindividual differences in mammographic density measures.Methods: We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and nondense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, BMI, and menopausal status.Results: Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (P = 0.00005) and adjusted percent density (P = 0.001), whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (P = 0.003), but not with adjusted dense area (P = 0.07).Conclusion: We identified two common breast cancer susceptibility variants associated with mammographic measures of radiodense tissue in the breast gland.Impact: We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association. Cancer Epidemiol Biomarkers Prev; 21(7); 1156–. ©2012 AACR.

PDF file - 113K, Odds ratios with 95% Confidence Intervals (CI) of lung cancer for circulating levels of Tryptophan, Kynurenine and Kynurenine/Tryptophan ratio by smoking status. P for trend were assessed by the base 2 logarithm of the circulating levels.

PDF file - 98K, Odds ratios with 95% Confidence Intervals (CI) of lung cancer for circulating levels of Kynurenic acid, 3-Hydroxykynurenine, Anthralinic acid, Xanthurenic acid, 3-Hydroxyantranilic acid and Neopterine. P for trend were assessed by the base 2 logarithm of the circulating levels.

Measures of adiposity and the risk of HNC among EPIC participants, including adjustment for weight change after baseline

Supplementary Table 1, Supplementary Figures 1 and 2

Background Skeletal muscle mass (SMM) loss is common in metastatic colorectal cancer (mCRC) patients and associated with poor clinical outcomes, including increased treatment‐related toxicities and reduced survival. Muscle loss may contribute to reduced health‐related quality of life (HRQoL), including fatigue. Our aim was to study associations between changes in SMM and concomitant changes in patient‐reported HRQoL. Methods This was a secondary analysis of mCRC patients in the CAIRO3 randomized clinical trial who were—after initial treatment—randomized between maintenance treatment with capecitabine plus bevacizumab (CAP‐B) and observation until first disease progression (PD1). Included patients had computed tomography images for SMM quantification, together with HRQoL assessments available at randomization and PD1. Changes in SMM (categorized as >2% loss, stable, and >2% gain) and HRQoL were computed between randomization and PD1. Changes in HRQoL score >10 points were considered clinically relevant. Associations between SMM and HRQoL changes were studied by multiple linear regression models. We also investigated whether associations differed by treatment arm for global health and the 13 other HRQoL subscales. Results Of 221 patients included (mean age 63.5 ± 8.4 years), 24% lost, 27% remained stable, and 49% gained SMM. At randomization, mean global health status was 73.5 ± 15.9 in the CAP‐B arm and 75.1 ± 17.5 in the observation arm (P = 0.48). A stable or gain in SMM was significantly associated with a clinically relevant improvement in global health status (9.9 and 14.7 points, respectively), compared with patients who lost SMM. From the subscales that did not show significant differences between the two treatment arms, we found significant and clinically relevant associations for stable or gain in SMM with improved role functioning (12.0 and 17.9, respectively) and with less fatigue (−10.0 and −15.0, respectively) and pain (−16.3 for SMM gain). From the subscales that did show significantly different associations with SMM between the two treatment arms, we only found significant results in the observation arm. Here, associations were found for stable or gain in SMM with clinically relevant improved physical (12.4 for SMM gain), cognitive (10.7 and 9.7, respectively), and social functioning (15.5 and 15.6, respectively) as well as reduced appetite loss (−28.5 and −30.7, respectively). Conclusions In mCRC, SMM preservation during CAP‐B and observation treatment is associated with significant and clinically relevant improvements in global health status and multiple functional and symptom scales. Studies are warranted to investigate whether interventions targeting SMM lead to improved HRQoL, fewer symptoms, and better functioning.

BackgroundAn efficient diagnostic pathway and early stage diagnosis for cancer patients is widely pursued. This study aims to chart the duration of the diagnostic pathway for patients with symptomatic oesophageal and gastric cancer, to identify factors associated with long duration and to assess the association of duration with tumour stage at diagnosis.MethodsThis was a retrospective cohort study, using electronic health records of six routine primary care databases covering about 640,000 patients, partly linked to the Netherlands Cancer Registry. Symptomatic patients with oesophageal and gastric cancer (2010-2015) that presented in primary care were included. Duration of four diagnostic intervals was determined: patient interval; first symptoms to primary care consultation, primary care interval; consultation to referral, secondary care interval; referral to diagnosis, and the diagnostic interval; consultation to diagnosis. Characteristics associated with 'long duration' (>= P75 duration) were assessed using log-binomial regression. Median durations were stratified for tumour stages.ResultsAmong 312 symptomatic patients with upper gastrointestinal cancer, median durations were: patient interval: 29 days (interquartile interval 15-73), primary care interval: 12 days (interquartile interval 1-43), secondary care interval: 13 days (interquartile interval 6-29) and diagnostic interval: 31 days (11-74). Patient interval duration was comparable for patients with and without alarm symptoms. Absence of cancer-specific alarm symptoms was associated with 'long duration' of primary care interval and secondary care interval: relative risk 5.0 (95% confidence interval 2.7-9.1) and 2.1 (95% confidence interval 1.3-3.7), respectively. Median diagnostic interval duration for local stage disease was 51 days (interquartile interval 13-135) versus 27 days (interquartile interval 11-71) for advanced stage (p = 0.07).ConclusionIn the diagnostic pathway of upper gastrointestinal cancers, the longest interval is the patient interval. Reducing time to diagnosis may be achieved by improving patients' awareness of alarm symptoms and by diagnostic strategies which better identify cancer patients despite low suspicion.

Bij 10 tot 25% van de patiënten met darmkanker duurt het lang voordat de huisarts tot verwijzing overgaat. Dat moet beter, want de ziektelast neemt af wanneer kanker tijdig wordt herkend. Lange duur tot verwijzing kan teruggedrongen worden wanneer huisartsen valkuilen weten te vermijden en nieuwe diagnostische strategieën gaan toepassen.

Purpose The Trials within Cohorts (TwiCs) design aims to overcome problems faced in conventional RCTs. We evaluated the TwiCs design when estimating the effect of exercise on quality of life (QoL) and fatigue in inactive breast cancer survivors. Methods UMBRELLA Fit was conducted within the prospective UMBRELLA breast cancer cohort. Patients provided consent for future randomization at cohort entry. We randomized inactive patients 12–18 months after cohort enrollment. The intervention group (n = 130) was offered a 12-week supervised exercise intervention. The control group (n = 130) was not informed and received usual care. Six-month exercise effects on QoL and fatigue as measured in the cohort were analyzed with intention-to-treat (ITT), instrumental variable (IV), and propensity scores (PS) analyses. Results Fifty-two percent (n = 68) of inactive patients accepted the intervention. Physical activity increased in patients in the intervention group, but not in the control group. We found no benefit of exercise for dimensions of QoL (ITT difference global QoL: 0.8, 95% CI = − 2.2; 3.8) and fatigue, except for a small beneficial effect on physical fatigue (ITT difference: − 1.1, 95% CI = − 1.8; − 0.3; IV: − 1.9, 95% CI = − 3.3; − 0.5, PS: − 1.2, 95% CI = − 2.3; − 0.2). Conclusion TwiCs gave insight into exercise intervention acceptance: about half of inactive breast cancer survivors accepted the offer and increased physical activity levels. The offer resulted in no improvement on QoL, and a small beneficial effect on physical fatigue. Trial registration Netherlands Trial Register (NTR5482/NL.52062.041.15), date of registration: December 07, 2015.

Background Mediterranean diet (MD) adherence has been associated with reduced risks of esophageal and gastric cancer (subtypes) in a limited number of studies. We prospectively investigated associations between MD adherence and risks of esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), gastric cardia adenocarcinoma (GCA), and gastric non-cardia adenocarcinoma (GNCA) in a Dutch cohort. Methods Analyses were conducted using data from the 120852 participants of the Netherlands Cohort Study (NLCS), who were aged between 55 and 69 years at enrollment. Various MD scores, with and without alcohol, were calculated to estimate MD adherence. Using 20.3 years of follow-up, 133 ESCC, 200 EAC, 191 GCA, and 586 GNCA cases could be included in multivariable Cox regression analyses. Results Of the investigated scores, the alternate Mediterranean diet score without alcohol (aMEDr) performed best. aMEDr was inversely associated with risks of GCA and GNCA in men and women. However, statistical significance was only reached in men [ptrend: 0.019 (GCA), 0.016 (GNCA)]. Furthermore, higher aMEDr values were significantly associated with a reduced ESCC risk in men [HRper two−point increment (95% CI) = 0.57 (0.41–0.80), ptrend = 0.013], but not in women (pheterogeneity = 0.008). There was no evidence of an association between aMEDr and EAC risk. Educational level was a significant effect modifier for the association between aMEDr and GNCA risk (pheterogeneity = 0.0073). Conclusions Higher MD adherence was associated with reduced risks of ESCC, GCA, and GNCA in the NLCS. However, the decreased ESCC risk might be limited to men. Electronic supplementary material The online version of this article (10.1007/s10120-019-00927-x) contains supplementary material, which is available to authorized users.

Inleiding Het is niet bekend hoe lang de verschillende fases van het diagnostisch traject voor kanker in Nederland duren. Dit onderzoek brengt dit voor de vijf meest voorkomende kankersoorten in kaart. Methode Een retrospectief cohortonderzoek in geanonimiseerde huisartsdossiers en de Nederlandse kankerregistratie. De onderzoekers bepaalden de mediane duur van 1) het huisartsinterval (HI); de periode vanaf het eerste kankergerelateerde consult bij de huisarts tot de verwijzing; 2) het verwijzingsinterval (VI): de verwijzing tot de diagnosestelling; 3) het behandelinterval (BI): van de diagnosestelling tot de start van de behandeling; 4) het diagnostisch interval (DI): vanaf het eerste kankergerelateerde consult bij de huisarts tot de diagnosestelling en 5) het zorginterval (ZI): vanaf het eerste kankergerelateerde consult bij de huisarts tot de start van de behandeling. Resultaten Voor 301, 309, 197, 237 en 149 patienten met respectievelijk borst-, colorectale, long- en prostaatkanker, en melanoom was de mediane duur van HI, VI en DI het kortst voor borstkanker en melanoom (DI 7 en 21 dagen), middellang voor long- en colorectale kanker (DI 49 en 54 dagen) en het langst voor prostaatkanker (DI 137 dagen). Hoewel de duur van de diagnostische intervallen bij alle kankersoorten voor het grootste deel van de patienten beperkt was, was bij 10 tot 25% van de patienten de duur opvallend lang. Bij colorectale kanker werd bij stijgende DI-duur steeds meer tijd bij de huisarts gespendeerd. Conclusie De duur van het diagnostisch proces bij kanker lijkt voor het grootste deel van de patienten weinig ruimte voor substantiele verbetering te geven. Binnen de groep patienten met de langste diagnostische trajecten (10 tot 25%) zien we echter een sterke toename van de duur. Vooral voor colorectale kanker lijkt het relevant om te onderzoeken hoe de lengte van het huisartsinterval kan worden verkort.

3w?>Studies investigating the association of Mediterranean diet (MD) adherence with pancreatic cancer risk are limited and had inconsistent results. We examined the association between MD adherence and pancreatic cancer incidence by pooling data from the Netherlands Cohort Study (NLCS, 120,852 subjects) and the Dutch cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC‐NL, 40,011 subjects). MD adherence was assessed using alternate and modified Mediterranean diet scores (aMED and mMED, respectively), including and excluding alcohol. After median follow‐ups of 20.3 (NLCS) and 19.2 (EPIC‐NL) years, 449 microscopically confirmed pancreatic cancer (MCPC) cases were included in study‐specific multivariable Cox models. Study‐specific estimates were pooled using a random‐effects model. MD adherence was not significantly associated with MCPC risk in pooled and study‐specific analyses, regardless of sex and MD score. Pooled hazard ratios (95% confidence interval) for high (6–8) compared to low (0–3) values of mMED excluding alcohol were 0.66 (0.40–1.10) in men and 0.94 (0.63–1.40) in women. In never smokers, mMED excluding alcohol seemed to be inversely associated with MCPC risk (nonsignificant). However, no association was observed in ever smokers (p heterogeneity = 0.03). Hazard ratios were consistent across strata of other potential effect modifiers. Considering MD scores excluding alcohol, mMED‐containing models generally fitted better than aMED‐containing models, particularly in men. Although associations somewhat differed when all pancreatic cancers were considered instead of MCPC, the overall conclusion was similar. In conclusion, MD adherence was not associated with pancreatic cancer risk in a pooled analysis of two Dutch cohorts., What's new? Adherence to the Mediterranean diet, characterized primarily by a high intake of plant‐based foods, is associated with reduced risks of several cancers. In the case of pancreatic cancer, however, in which dietary factors are suspected of playing a significant role, evidence remains inconclusive. In this pooled analysis of two Dutch cohorts, no association was found between Mediterranean diet adherence and risk of microscopically confirmed pancreatic cancer (MCPC). The outcome was unaffected by sex and type of Mediterranean diet score used. MCPC risk may be inversely related to Mediterranean diet adherence in never smokers, though statistical analysis did not reach significance.

Contains fulltext : 220990.pdf (Publisher’s version ) (Closed access) PURPOSE: Fatigue is a common and potentially disabling symptom in patients with cancer. It can often be effectively reduced by exercise. Yet, effects of exercise interventions might differ across subgroups. We conducted a meta-analysis using individual patient data of randomized controlled trials (RCT) to investigate moderators of exercise intervention effects on cancer-related fatigue. METHODS: We used individual patient data from 31 exercise RCT worldwide, representing 4366 patients, of whom 3846 had complete fatigue data. We performed a one-step individual patient data meta-analysis, using linear mixed-effect models to analyze the effects of exercise interventions on fatigue (z score) and to identify demographic, clinical, intervention- and exercise-related moderators. Models were adjusted for baseline fatigue and included a random intercept on study level to account for clustering of patients within studies. We identified potential moderators by testing their interaction with group allocation, using a likelihood ratio test. RESULTS: Exercise interventions had statistically significant beneficial effects on fatigue (beta = -0.17; 95% confidence interval [CI], -0.22 to -0.12). There was no evidence of moderation by demographic or clinical characteristics. Supervised exercise interventions had significantly larger effects on fatigue than unsupervised exercise interventions (betadifference = -0.18; 95% CI -0.28 to -0.08). Supervised interventions with a duration

Background Low skeletal muscle index (SMI) in metastatic colorectal cancer (mCRC) patients is associated with poor outcomes. The prognostic impact of SMI changes during consecutive palliative systemic treatments is unknown. Methods This is a retrospective analysis of the phase 3 CAIRO3 study. The CAIRO3 study randomized 557 patients between maintenance capecitabine + bevacizumab (CAP‐B) or observation, after six cycles capecitabine + oxaliplatin + bevacizumab (CAPOX‐B). Upon first disease progression (PD1), CAPOX‐B was reintroduced until second progression (PD2). SMI was assessed by computed tomography (CT) (total 1355 scans). SMI and body mass index (BMI) changes were analyzed for three time‐periods; p1: during initial CAPOX‐B, p2: randomization to PD1, and p3: PD1 to PD2. The association between absolute and change in SMI and BMI (both per 1 standard deviation) during p1‐p3, with PD1, PD2, and survival was studied by Cox regression models. Results This analysis included 450 of the 557 patients randomized in the CAIRO3 study. Mean SMI decreased during p1: mean −0.6 SMI units [95% CI −1.07;‐0.26] and p3: −2.2 units [−2.7;‐1.8], whereas during p2, SMI increased + 1.2 units [0.8‐1.6]. BMI changes did not reflect changes in SMI. SMI loss during p2 and p3 was significantly associated with shorter survival (HR 1.19 [1.09‐1.35]; 1.54 [1.31‐1.79], respectively). Sarcopenia at PD1 was significantly associated with early PD2 (HR 1.40 [1.10‐1.70]). BMI loss independent of SMI loss was only associated with shorter overall survival during p3 (HR 1.35 [1.14‐1.63]). Conclusions In mCRC patients, SMI loss during palliative systemic treatment was related with early disease progression and reduced survival. BMI did not reflect changes in SMI and could not identify patients at risk of poor outcome during early treatment lines.

Background Having a physically active lifestyle after cancer diagnosis is beneficial for health, and this needs to be continued into survivorship to optimize long-term benefits. We found that patients, who participated in an 18-week exercise intervention, reported significant higher physical activity (PA) levels 4 years after participation in a randomized controlled trial of supervised exercise delivered during chemotherapy (PACT study). This study aimed to identify social-ecological correlates of PA levels in breast and colon cancer survivors 4 years after participation in the PACT study. Methods Self-reported PA levels and potential correlates (e.g. physical fitness, fatigue, exercise history, and built environment) were assessed in 127 breast and colon cancer survivors shortly after diagnosis (baseline), post-intervention and 4 years later. Multivariable linear regression analyses were performed to identify social-ecological correlates of PA 4 years post-baseline. Results The final model revealed that lower baseline physical fatigue (β = -0.25, 95% CI -0.26; -0.24) and higher baseline total PA (0.06, 95% CI, 0.03; 0.10) were correlated with higher total PA levels 4 years post-baseline. Higher baseline leisure and sport PA (0.02, 95% CI 0.01; 0.03), more recreational facilities within a buffer of 1 km (4.05, 95% CI = 1.28; 6.83), lower physical fatigue at 4-year follow-up (-8.07, 95% CI -14.00; -2.13), and having a positive change in physical fatigue during the intervention period (0.04, 95% CI 0.001; 0.07) were correlates of sport and leisure PA levels 4 years post-baseline. Conclusions This study suggests that baseline and 4-year post-baseline physical fatigue, and past exercise behaviour, were significant correlates of PA 4 years after participation in an exercise trial. Additionally, this study suggests that the built environment should be taken into account when promoting PA. Understanding of socio-ecological correlates of PA can provide insights into how future exercise interventions should be designed to promote long-term exercise behaviour. Trial registration Current Controlled Trials ISRCTN43801571, Dutch Trial Register NTR2138. Trial registered on 9 December 2009, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2138.

© 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Higher-educated people often have healthier diets, but it is unclear whether specific dietary patterns exist within educational groups. We therefore aimed to derive dietary patterns in the total population and by educational level and to investigate whether these patterns differed in their composition and associations with the incidence of fatal and non-fatal CHD and stroke. Patterns were derived using principal components analysis in 36 418 participants of the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort. Self-reported educational level was used to create three educational groups. Dietary intake was estimated using a validated semi-quantitative FFQ. Hazard ratios were estimated using Cox Proportional Hazard analysis after a mean follow-up of 16 years. In the three educational groups, similar ‘Western’, ‘prudent’ and ‘traditional’ patterns were derived as in the total population. However, with higher educational level a lower population-derived score for the ‘Western’ and ‘traditional’ patterns and a higher score on the ‘prudent’ pattern were observed. These differences in distribution of the factor scores illustrate the association between education and food consumption. After adjustments, no differences in associations between population-derived dietary patterns and the incidence of CHD or stroke were found between the educational groups (Pinteraction between 0·21 and 0·98). In conclusion, although in general population and educational groups-derived dietary patterns did not differ, small differences between educational groups existed in the consumption of food groups in participants considered adherent to the population-derived patterns (Q4). This did not result in different associations with incident CHD or stroke between educational groups.

Recent evidence suggested a weak relationship between alcohol consumption and pancreatic cancer (PC) risk. In our study, the association between lifetime and baseline alcohol intakes and the risk of PC was evaluated, including the type of alcoholic beverages and potential interaction with smoking. Within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, 1,283 incident PC (57% women) were diagnosed from 476,106 cancer-free participants, followed up for 14 years. Amounts of lifetime and baseline alcohol were estimated through lifestyle and dietary questionnaires, respectively. Cox proportional hazard models with age as primary time variable were used to estimate PC hazard ratios (HR) and their 95% confidence interval (CI). Alcohol intake was positively associated with PC risk in men. Associations were mainly driven by extreme alcohol levels, with HRs comparing heavy drinkers (>60 g/day) to the reference category (0.1-4.9 g/day) equal to 1.77 (95% CI: 1.06, 2.95) and 1.63 (95% CI: 1.16, 2.29) for lifetime and baseline alcohol, respectively. Baseline alcohol intakes from beer (>40 g/day) and spirits/liquors (>10 g/day) showed HRs equal to 1.58 (95% CI: 1.07, 2.34) and 1.41 (95% CI: 1.03, 1.94), respectively, compared to the reference category (0.1-2.9 g/day). In women, HR estimates did not reach statistically significance. The alcohol and PC risk association was not modified by smoking status. Findings from a large prospective study suggest that baseline and lifetime alcohol intakes were positively associated with PC risk, with more apparent risk estimates for beer and spirits/liquors than wine intake.

Background: A low vitamin D status has been put forward as a potential risk factor for the development of inflammatory bowel disease (IBD). This study investigated the association between prediagnostic circulating vitamin D concentrations and dietary intakes of vitamin D, and the risk of Crohn’s disease (CD) and ulcerative colitis (UC).Methods: Among 359,728 participants of the European Prospective Investigation into Cancer and Nutrition cohort, individuals who developed CD or UC after enrollment were identified. Each case was matched with2 controls by center, gender, age, date of recruitment, and follow-up time. At cohort entry, blood samples were collected and dietary vitamin D intakes were obtained from validated food frequency questionnaires. Serum 25-hydroxyvitamin D levels were measured using liquid chromatography-tandem mass spectrometry. Conditional logistic regression was performed to determine the odds of CD and UC.Results: Seventy-two participants developed CD and 169 participants developed UC after a median follow-up of 4.7 and 4.1 years, respectively. Compared with the lowest quartile, no associations with the 3 higher quartiles of vitamin D concentrations were observed for CD (p trend = 0.34) or UC (p trend = 0.66). Similarly, no associations were detected when serum vitamin D levels were analyzed as a continuous variable. Dietary vitamin D intakes were not associated with CD (p trend = 0.39) or UC (p trend = 0.83).Conclusions: Vitamin D status was not associated with the development of CD or UC. This does not suggest a major role for vitamin D deficiency in the etiology of IBD, although larger studies are needed to confirm these findings.

Objectives: This study evaluates the risk of cardiovascular disease (CVD) following breast cancer, accounting for baseline CVD risk. Methods: Within the EPIC-NL (Dutch part of the European Prospective Investigation into Nutrition and Cancer) cohort, 1103 women were diagnosed with breast cancer. For every breast cancer patient, 3–4 women without breast cancer (n = 4328) were selected matched for age, year, and time since cohort enrollment. Based on CVD risk factors at cohort enrollment, 10-year risk of CVD was calculated and categorized: low ( 20%). Cox proportional hazard models assessed the risk of CVD events (hospitalization or mortality) and CVD mortality of women with versus without breast cancer, adjusted for baseline CVD risk. Results: After median follow-up of 5 and 6 years, 92 (8.3%) and 325 (7.5%) CVD events occurred in women with and without breast cancer, respectively. In the low CVD risk group, women with breast cancer had 1.44 (95% CI 1.00–2.06) times higher risk of CVD events than women without breast cancer. In the intermediate and high CVD risk categories, risk of CVD events was similar in women with and without breast cancer. Overall, women with breast cancer had 1.77 (95% CI 1.10–2.86) times higher risk of CVD mortality than women without breast cancer. Conclusions: Among women with low CVD risk, women with breast cancer have a higher risk of CVD event than women without breast cancer. Overall, women with breast cancer have a higher risk of CVD mortality than women without breast cancer.

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.

Other than the influence of ionizing radiation and benign thyroid disease, little is known about the risk factors for differentiated thyroid cancer (TC) which is an increasing common cancer worldwi ...

CA125 is the best ovarian cancer early detection marker to date; however, sensitivity is limited and complementary markers are required to improve discrimination between ovarian cancer cases and no ...

Evidence from in vivo, in vitro and ecological studies are suggestive of a protective effect of vitamin D against pancreatic cancer (PC). However, this has not been confirmed by analytical epidemiological studies. We aimed to examine the association between pre-diagnostic circulating vitamin D concentrations and PC incidence in European populations. We conducted a pooled nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nord-Trondelag Health Study's second survey (HUNT2) cohorts. In total, 738 primary incident PC cases (EPIC n = 626; HUNT2 n = 112; median follow-up = 6.9 years) were matched to 738 controls. Vitamin D [25(OH)D2 and 25(OH)D3 combined] concentrations were determined using isotope-dilution liquid chromatography-tandem mass spectrometry. Conditional logistic regression models with adjustments for body mass index and smoking habits were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95%CI). Compared with a reference category of >50 to 75 nmol/L vitamin D, the IRRs (95% CIs) were 0.71 (0.42-1.20); 0.94 (0.72-1.22); 1.12 (0.82-1.53) and 1.26 (0.79-2.01) for clinically pre-defined categories of ≤25; >25 to 50; >75 to 100; and >100 nmol/L vitamin D, respectively (p for trend = 0.09). Corresponding analyses by quintiles of season-standardized vitamin D concentrations also did not reveal associations with PC risk (p for trend = 0.23). Although these findings among participants from the largest combination of European cohort studies to date show increasing effect estimates of PC risk with increasing pre-diagnostic concentrations of vitamin D, they are not statistically significant.

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five-year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share a consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639, rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (ORhomozygous = 1.19, 95% CI 1.02-1.38, p = 0.023). Additionally all the SNPs confirmed statistically significant associations with risk of developing CP, the strongest being PRSS1-PRSS2-rs10273639 (ORheterozygous = 0.51, 95% CI 0.39-0.67, p = 1.10 × 10-6 ) and MORC4-rs 12837024 (ORhomozygous = 2.07 (1.55-2.77, ptrend = 0.7 × 10-11 ). Taken together, the results from our study do not support variants rs11988997, rs379742, rs10273639, rs2995271 and rs12688220 as strong predictors of PDAC risk, but further support the role of these SNPs in CP susceptibility. Our study suggests that CP and PDAC probably do not share genetic susceptibility, at least in terms of high frequency variants.

Fruit and vegetable (FV 95% CI: 0.68-1.15; p-trend = 0.44), vegetables (HR: 0.89; 95% CI: 0.69-1.14; p-trend = 0.56), or fruit (HR: 1.00; 95% CI: 0.79-1.26; p-trend = 0.64). No significant association was observed with any individual type of vegetable or fruit. However, there was a positive borderline trend with fruit juice intake (HR: 1.23; 95% CI: 0.98-1.53; p-trend = 0.06). This study did not find any significant association between FV however a positive trend with fruit juice intake was observed, possibly related to its high sugar content.

Hepcidin is the main regulator of iron homeostasis and dysregulation of proteins involved in iron metabolism has been associated with tumorogenesis. However, to date, no epidemiological study has researched the association between hepcidin levels and gastric cancer risk. To further investigate the relationship between hepcidin levels and gastric cancer risk, we conducted a nested case-control study (EURGAST) within the multicentric European Prospective Investigation into Cancer and Nutrition study. The study included 456 primary incident gastric adenocarcinoma cases and 900 matched controls that occurred during an average of 11 years of follow-up. We measured serum levels of hepcidin-25, iron, ferritin, transferrin and C-reactive protein. Odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of gastric cancer by hepcidin levels were estimated from multivariable conditional logistic regression models. Mediation effect of the ferritin levels on the hepcidin-gastric cancer pathway was also evaluated. After adjusting for relevant confounders, we observed a statistically significant inverse association between gastric cancer and hepcidin levels (OR 5 ng/l = 0.96, 95% CI = 0.93–0.99). No differences were found by tumor localization or histological type. In mediation analysis, we found that the direct effect of hepcidin only represents a nonsignificant 38% (95% CI: −69%, 91%). In summary, these data suggest that the inverse association of hepcidin levels and gastric cancer risk was mostly accounted by ferritin levels. Further investigation including repeated measures of hepcidin is needed to clarify their role in gastric carcinogenesis.

Noninvasive biomarkers for early pancreatic ductal adenocarcinoma (PDAC) diagnosis and disease risk stratification are greatly needed. We conducted a nested case-control study within the Prospective Investigation into Cancer and Nutrition (EPIC) cohort to evaluate prediagnostic microRNAs (miRs) as biomarkers of subsequent PDAC risk. A panel of eight miRs (miR-10a, -10b, -21-3p, -21-5p, -30c, -106b, -155 and -212) based on previous evidence from our group was evaluated in 225 microscopically confirmed PDAC cases and 225 controls matched on center, sex, fasting status and age/date/time of blood collection. MiR levels in prediagnostic plasma samples were determined by quantitative RT-PCR. Logistic regression was used to model levels and PDAC risk, adjusting for covariates and to estimate area under the receiver operating characteristic curves (AUC). Plasma miR-10b, -21-5p, -30c and -106b levels were significantly higher in cases diagnosed within 2 years of blood collection compared to matched controls (all p-values