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Chronic lymphocytic leukemia (CLL) is preceded by monoclonal B-cell lymphocytosis (MBL), a CLL precursor state with a prevalence of up to 12% in aged individuals; however, the duration of MBL and the mechanisms of its evolution to CLL remain largely unknown. In this study, we sequenced the B-cell receptor (BcR) immunoglobulin heavy chain (IGH) gene repertoire of 124 patients with CLL and 118 matched controls in blood samples taken up to 22 years prior to diagnosis. Significant skewing in the BcR IGH gene repertoire was detected in the majority of patients, even before the occurrence of lymphocytosis and irrespective of the clonotypic IGH variable gene somatic hypermutation status. Furthermore, we identified dominant clonotypes belonging to major stereotyped subsets associated with poor prognosis up to 16 years before diagnosis in 14 patients with CLL. In 22 patients with longitudinal samples, the skewing of the BcR IGH gene repertoire increased significantly over time to diagnosis or remained stable at high levels. For 14 of 16 patients with available samples at diagnosis, the CLL clonotype was already present in the prediagnostic samples. Overall, our data indicate that the preclinical phase of CLL could be longer than previously thought, even in adverse-prognostic cases.

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further similar to 15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.

Background: Evidence is accumulating that immune cells play a prominent role in pancreatic cancer etiology but prospective investigations are missing. Methods: We conducted a nested case–control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) study with 502 pairs of incident pancreatic cancer cases and matched controls. Relative counts of circulating immune cells (neutrophils and lymphocyte sublineages: total CD3+, CD8+, CD4+, and FOXP3+ regulatory T cells (Tregs) relative to nucleated cells, (white blood cells) were measured by qRT-PCR. ORs with 95% confidence intervals were estimated using logistic regressions, modeling relative counts of immune cells on a continuous scale. Results: Neither relative counts of immune cell types taken individually, nor mutually adjusted for each other were associated with pancreatic cancer risks. However, in subgroup analyses by strata of lag-time, higher relative counts of Tregs and lower relative counts of CD8+ were significantly associated with an increased pancreatic cancer risks in participants diagnosed within the first 5 years of follow-up. Conclusions: These results might reflect reverse causation, due to higher relative counts of Tregs and lower counts of CD8+ cells among individuals with more advanced stages of latent pancreatic cancer, who are closer to the point of developing clinical manifest disease. Impact: We have shown, for the first time, that increased relative counts of regulatory T cells and lower relative counts of CD8+, cytotoxic T cells may be associated with pancreatic cancer risk or relatively late-stage tumor development. See related commentary by Michaud and Kelsey, p. 2176

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 the Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, and Institut National de la Santé et de la Recherche Médicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); the Sicilian Government, AIRE ONLUS Ragusa, AVIS Ragusa, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, 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), and Statistics Netherlands (the Netherlands); Nordic Centre of Excellence programme on Food, Nutrition and Health. (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia, Navarra, and the Catalan Institute of Oncology (Barcelona), Spain; Swedish Cancer Society, Swedish Scientific Council, and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (C864/A14136 to EPIC-Norfolk; C8221/A19170, C570/A16491 and C8221/ A290170 to EPIC-Oxford), Medical Research Council (MR/ N003284/1 and MC-UU_12015/1 to EPIC-Norfolk, MR/ M012190/1 to EPIC-Oxford (UK). The funding sources had no influence on the design of the study; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the paper for publication.Support for this study was also provided by the COST Action CA17118 supported by COST (European Cooperation in Science and Technology, www.cost.eu) to DJH., Experimental evidence has implicated genotoxic Escherichia coli (E. coli) and enterotoxigenic Bacteroides fragilis (ETBF) in the development of colorectal cancer (CRC). However, evidence from epidemiological studies is sparse. We therefore assessed the association of serological markers of E. coli and ETBF exposure with odds of developing CRC in the European Prospective Investigation into Nutrition and Cancer (EPIC) study. Serum samples of incident CRC cases and matched controls (n = 442 pairs) were analyzed for immunoglobulin (Ig) A and G antibody responses to seven E. coli proteins and two isoforms of the ETBF toxin via multiplex serology. Multivariable-adjusted conditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of sero-positivity to E. coli and ETBF with CRC. The IgA-positivity of any of the tested E. coli antigens was associated with higher odds of developing CRC (OR: 1.42; 95% CI: 1.05–1.91). Dual-positivity for both IgA and IgG to E. coli and ETBF was associated with >1.7-fold higher odds of developing CRC, with a significant association only for IgG (OR: 1.75; 95% CI: 1.04, 2.94). This association was more pronounced when restricted to the proximal colon cancers (OR: 2.62; 95% CI: 1.09, 6.29) compared to those of the distal colon (OR: 1.24; 95% CI: 0.51, 3.00) (pheterogeneity = 0.095). Sero-positivity to E. coli and ETBF was associated with CRC development, suggesting that co-infection of these bacterial species may contribute to colorectal carcinogenesis. These findings warrant further exploration in larger prospective studies and within different population groups., European Commission (DG-SANCO), International Agency for Research on Cancer, Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, and Institut National de la Santé et de la Recherche Médicale (INSERM) (France), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, and Federal Ministry of Education and Research (Germany), Hellenic Health Foundation (Greece), Sicilian Government, AIRE ONLUS Ragusa, AVIS Ragusa, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, 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), and Statistics Netherlands (the Netherlands), Nordic Centre of Excellence programme on Food, Nutrition and Health. (Norway), Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia, Navarra, and the Catalan Institute of Oncology (Barcelona), Spain, Swedish Cancer Society, Swedish Scientific Council, and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (C864/A14136 to EPIC-Norfolk; C8221/A19170, C570/A16491 and C8221/ A290170 to EPIC-Oxford), Medical Research Council (MR/ N003284/1 and MC-UU_12015/1 to EPIC-Norfolk, MR/ M012190/1 to EPIC-Oxford (UK), COST Action CA17118 supported by COST (European Cooperation in Science and Technology)

Aims The aim of this study was to develop, validate, and illustrate an updated prediction model (SCORE2) to estimate 10-year fatal and non-fatal cardiovascular disease (CVD) risk in individuals without previous CVD or diabetes aged 40-69 years in Europe.Methods and results We derived risk prediction models using individual-participant data from 45 cohorts in 13 countries (677 684 individuals, 30 121 CVD events). We used sex-specific and competing risk-adjusted models, including age, smoking status, systolic blood pressure, and total- and HDL-cholesterol. We defined four risk regions in Europe according to country-specific CVD mortality, recalibrating models to each region using expected incidences and risk factor distributions. Region-specific incidence was estimated using CVD mortality and incidence data on 10 776 466 individuals. For external validation, we analysed data from 25 additional cohorts in 15 European countries (1 133 181 individuals, 43 492 CVD events). After applying the derived risk prediction models to external validation cohorts, C-indices ranged from 0.67 (0.65-0.68) to 0.81 (0.76-0.86). Predicted CVD risk varied several-fold across European regions. For example, the estimated 10-year CVD risk for a 50-year-old smoker, with a systolic blood pressure of 140 mmHg, total cholesterol of 5.5 mmol/L, and HDL-cholesterol of 1.3 mmol/L, ranged from 5.9% for men in low- risk countries to 14.0% for men in very high-risk countries, and from 4.2% for women in low-risk countries to 13.7% for women in very high-risk countries.Conclusion SCORE2-a new algorithm derived, calibrated, and validated to predict 10-year risk of first-onset CVD in European populations-enhances the identification of individuals at higher risk of developing CVD across Europe. Acknowledgements We thank investigators and participants of the several studies that contributed data to the Emerging Risk Factors Collaboration (ERFC). This research has been conducted using the UK Biobank Resource under Application Number 26865. Data from the Clinical Practice Research Datalink (CPRD) were obtained under licence from the UK Medicines and Healthcare products Regulatory Agency (protocol 162RMn2). CPRD uses data provided by patients and collected by the NHS as part of their care and support. We thank all EPIC participants and staff for their contribution to the study, the laboratory teams at the Medical Research Council Epidemiology Unit for sample management and Cambridge Genomic Services for genotyping, Sarah Spackman for data management and the team at the EPIC-CVD Coordinating Centre for study co-ordination and administration. Funding The ERFC co-ordinating centre was underpinned by programme grants from the British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946), BHF Centre of Research Excellence (RE/18/1/34212), the UK Medical Research Council (MR/L003120/1), and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC1215-20014), with project-specific support received from the UK NIHR [*], British United Provident Association UK Foundation and an unrestricted educational grant from GlaxoSmithKline. A variety of funding sources have supported recruitment, follow-up, and laboratory measurements in the studies contributing data to the ERFC, which are listed on the ERFC website (www.phpc.cam.ac.uk/ceu/erfc/list-of-studies). *The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome. The MORGAM Project has received funding from EU projects MORGAM (Biomed BMH4-CT98-3183), GenomEUtwin (FP5, QLG2-CT-2002-01254), ENGAGE (FP7, HEALTH-F4-2007-201413),CHANCES (FP7, HEALTH-F3-2010-242244), BiomarCaRE (FP7,HEALTH-F2-2011-278913), euCanSHare (Horizon 2020, No. 825903) and AFFECT-EU (Horizon 2020, No. 847770); and Medical Research Council, London (G0601463, No. 80983: Biomarkers in the MORGAM Populations). This has supported central coordination, workshops and part of the activities of the MORGAM Data Centre, the MORGAM Laboratories and the MORGAM Participating Centres EPIC-CVD was funded by the European Research Council (268834), and the European Commission Framework Programme 7 (HEALTH-F2-2012-279233). This work was supported by the Estonian Research Council grant PUTs (PRG687, PUT1660, PUT1665, PRG184), by European Union through the European Regional Development Fund project no. MOBERA5 (Norface Network project no 462.16.107), by the Green ICT programme under Norway Grants 2014 – 2021 (grant number EU53928), by the European Union through Horizon 2020 grant no. 810645 and through the European Regional Development Fund (Project No. 2014-2020.4.01.16-0125) and by the PRECISE4Q consortium. PRECISE4Q project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Grant agreement 777107. This work was partly funded through the CoMorMent project. CoMorMent has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Grant agreement 847776. The KORA study was initiated and financed by the Helmholtz Zentrum Mu¨nchen—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. The KORA study was supported by a research grant from the Virtual Institute of Diabetes Research (Helmholtz Zentrum Mu¨nchen), the Clinical Cooperation Group Diabetes between Ludwig-Maximilians-Universita¨t Mu¨nchen and Helmholtz Zentrum Mu¨nchen, and by the German Diabetes Center (DDZ). The HAPIEE project, Institute, was supported by grants from the Wellcome Trust (064947/Z/01/Z; WT081081) and US National Institute on Aging (1R01 and AG23522). The co-ordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Ge´ne´rale de l’Education Nationale, Institut National de la Sante´ et de la Recherche Me´dicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch 2448 SCORE2 working group and ESC Cardiovascular Risk Collaboration 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); Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucı´a, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology—ICO (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Ska˚ne and Va¨sterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (United Kingdom)

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P

We thank the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands, for their contribution to, and ongoing support of, the EPIC Study. We thank Aude De Bruycker for her graphical support., (1) Background: Methyl-group donors (MGDs), including folate, choline, betaine, and methionine, may influence breast cancer (BC) risk through their role in one-carbon metabolism; (2) Methods: We studied the relationship between dietary intakes of MGDs and BC risk, adopting data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort; (3) Results: 318,686 pre- and postmenopausal women were followed between enrolment in 1992–2000 and December 2013–December 2015. Dietary MGD intakes were estimated at baseline through foodfrequency questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary intake of MGDs, measured both as a calculated score based on their sum and individually, and BC risk. Subgroup analyses were performed by hormone receptor status, menopausal status, and level of alcohol intake. During a mean follow-up time of 14.1 years, 13,320 women with malignant BC were identified. No associations were found between dietary intakes of the MGD score or individual MGDs and BC risk. However, a potential U-shaped relationship was observed between dietary folate intake and overall BC risk, suggesting an inverse association for intakes up to 350 µg/day compared to a reference intake of 205 µg/day. No statistically significant differences in the associations were observed by hormone receptor status, menopausal status, or level of alcohol intake; (4) Conclusions: There was no strong evidence for an association between MGDs involved in one-carbon metabolism and BC risk. However, a potential U-shaped trend was suggested for dietary folate intake and BC risk. Further research is needed to clarify this association., Research Foundation Flanders (FWO, 189019N), Research Foundation Flanders (FWO, V427019N), International Agency for Research on Cancer (IARC), Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, NIHR Imperial Biomedical Research Center (BRC), 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), German Institute of Human Nutrition Potsdam Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo 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), Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology—ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford), (United Kingdom)

This is the peer reviewed version of the following article: Stepien et.al (2021). Prediagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma. International Journal of Cancer, which has been published in final form at https://doi.org/10.1002/ijc.33885. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited. Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune-related processes. The liver is the primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case-control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow-up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/unconjugated) in prediagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (ORdoubling = 2.30, 95% confidence intervals [CI]: 1.76-3.00), and choline- and taurine-conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine-conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increase in BA concentration is accompanied by a shift in BA profile toward higher proportions of taurine-conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.

Background A quick and accurate case identification in the Emergency Department (ED) during the SARS-CoV-2 pandemic is crucial for clinical management and to prevent spread of infections. The gold standard for diagnosing SARS-CoV-2 infection is the real-time reverse transcription polymerase chain reaction (RT-PCR) test in upper airways swabs. However, the procedure is available in few specialized laboratories and requires an average sample processing time of about 6 hours from its inception. The development of reliable but cheaper and faster point-of-care tests was expected to be useful either for population-screening or as first aid tests in the ED. Rapid antigenic diagnostic tests (Ag-RDTs), directly detect SARS-CoV-2 proteins produced by the replicating virus in respiratory specimens, were proved to be candidates in both cases. However, data on their effectiveness are still few and controversial. The aim of the study is to establish the accuracy of antigen tests to identify SARS-CoV-2 in a high prevalence setting. Methods Results of 324 patients, consecutively admitted to the ED of San Luigi Gonzaga University Hospital in Orbassano (Turin, Italy) between 26 October and 10 November 2020 and subjected to both molecular and antigen tests, were compared. Results Using RT-PCR as gold standard, specificity and sensitivity of Ag-RDT were 0.94 (95%CI: 0.90-0.98) and 0.80 (95%CI: 0.75-0.85), respectively. The Ag-RDT positive predictive value was 0.96 (95%CI 0.93- 0.99), and the negative predictive value was 0.72 (95% CI: 0.65-0.79). Patients that tested negative to Ag-RDT but presented with fever and cough or had pneumonia at imaging were more likely to be false negatives. Ag-RDTs best performance occurs in the first days after symptom onset. Conclusions These results confirm the limits of antigenic tests as first line screening tests and suggest that the antigenic test should be integrated with clinical judgement, based on physical and instrumental examinations. Key messages Antigenic tests have a limited effectiveness as first line screening tests. In a high-prevalence setting these tests incorrectly judge as negative many COVID-19 symptomatic patients, making necessary to integrate their results with clinical judgement.

Background Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis. Methods and findings We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]–InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1–standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities. Conclusions Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D., Using both observational and genetic analyses, Ju-Sheng Zheng and colleagues investigate the relationship between vitamin D metabolites and type 2 diabetes among European individuals., Author summary Why was this study done? There is ongoing uncertainty on whether the body’s vitamin D status indicated by blood 25-hydroxyvitamin D (25(OH)D) is relevant to the prevention of type 2 diabetes. There are conflicting findings from observational studies and a limited number of randomised controlled trials. Prior research did not distinguish between different metabolites of total 25(OH)D, including 25(OH)D3 and C3-epi-25(OH)D3, an isomer of 25(OH)D3. It is not clear whether the associations of 25(OH)D metabolites with type 2 diabetes are causal, with conflicting findings from prior Mendelian randomisation studies of total 25(OH)D and no previous Mendelian randomisation studies appraising 25(OH)D metabolites. What did the researchers do and find? The current research compared observational estimates of the association between 25(OH)D metabolites and incident type 2 diabetes with Mendelian randomisation estimates based on genetic instruments. Using multiple data sources, we performed genome-wide association studies among 120,618 individuals for total 25(OH)D, and among 40,562 individuals for the other vitamin D metabolites. Among participants of European descent, 10 genetic loci were identified for total 25(OH)D, 7 loci for 25(OH)D3 and 3 loci for C3-epi-25(OH)D3. In meta-analysis of observational studies, we found that each 1–standard deviation higher level of total 25(OH)D was associated with 20% lower risk of type 2 diabetes. The result was similar for 25(OH)D3, but for C3-epi-25(OH)D3, a positive association with type 2 diabetes was found. With up to 80,983 type 2 diabetes cases and 842,909 controls, we assessed the association of genetically predicted differences in total 25(OH)D and its metabolites with type 2 diabetes. Neither genetically predicted higher total 25(OH)D level nor genetically predicted higher levels of 25(OH)D metabolites were significantly associated with type 2 diabetes. What do these findings mean? There were conflicting findings for a link with type 2 diabetes for the observational analysis of biochemically measured 25(OH)D metabolites versus the genetically predicted levels of these metabolites. The null findings based on Mendelian randomisation analysis indicate that blood levels of 25(OH)D or its metabolites are not likely to be causal factors for the development of type 2 diabetes. The current findings together with other evidence from randomised controlled trials do not support the use of vitamin D supplementation for the prevention of type 2 diabetes.

OBJECTIVE There is sparse evidence for the association of suitable food substitutions for red and processed meat on the risk of type 2 diabetes. We modeled the association between replacing red and processed meat with other protein sources and the risk of type 2 diabetes and estimated its population impact. RESEARCH DESIGN AND METHODS The European Prospective Investigation into Cancer (EPIC)-InterAct case cohort included 11,741 individuals with type 2 diabetes and a subcohort of 15,450 participants in eight countries. We modeled the replacement of self-reported red and processed meat with poultry, fish, eggs, legumes, cheese, cereals, yogurt, milk, and nuts. Country-specific hazard ratios (HRs) for incident type 2 diabetes were estimated by Prentice-weighted Cox regression and pooled using random-effects meta-analysis. RESULTS There was a lower hazard for type 2 diabetes for the modeled replacement of red and processed meat (50 g/day) with cheese (HR 0.90, 95% CI 0.83–0.97) (30 g/day), yogurt (0.90, 0.86–0.95) (70 g/day), nuts (0.90, 0.84–0.96) (10 g/day), or cereals (0.92, 0.88–0.96) (30 g/day) but not for replacements with poultry, fish, eggs, legumes, or milk. If a causal association is assumed, replacing red and processed meat with cheese, yogurt, or nuts could prevent 8.8%, 8.3%, or 7.5%, respectively, of new cases of type 2 diabetes. CONCLUSIONS Replacement of red and processed meat with cheese, yogurt, nuts, or cereals was associated with a lower rate of type 2 diabetes. Substituting red and processed meat by other protein sources may contribute to the prevention of incident type 2 diabetes in European populations.

The specific etiology of meniscal tears, including the mechanism of lesion, location, and orientation, is considered for its contribution to subsequent joint cytokine responsiveness, healing outcomes, and by extension, appropriate lesion-specific surgical remediation. Meniscal repair is desirable to reduce the probability of development of posttraumatic osteoarthritis (PTOA) which is strongly influenced by the coordinate generation of pro- and anti-inflammatory cytokines by the injured cartilage. We now present biochemical data on variation in cytokine levels arising from two particular meniscal tears: bucket-handle (BH) and posterior horn (PH) isolated meniscal tears. We selected these two groups due to the different clinical presentations. We measured the concentrations of TNF-α, IL-1β, IL-6, IL-8, and IL-10 in knee synovial fluid of 45 patients with isolated meniscal lesions (BH tear, n = 12 ; PH tear, n = 33 ). TNF-α levels were significantly ( p < 0.05 ) greater in the BH group compared with the PH group, whereas IL-1β levels were significantly greater ( p < 0.05 ) in the PH group compared with the BH group. Both BH and PH groups were consistent in presenting a positive correlation between concentrations of IL-6 and IL-1β. A fundamental difference in IL-10 responsiveness between the two groups was noted; specifically, levels of IL-10 were positively correlated with IL-6 in the BH group, whereas in the PH group, levels of IL-10 were positively correlated with IL-1β. Collectively, our data suggest a possible influence of the meniscal tear pattern to the articular cytokine responsiveness. This differential expression of inflammatory cytokines may influence the risk of developing PTOA in the long term.

This work was supported by the French National Cancer Institute (INCa SHSESP17, grant No. 2017-127 to N. Murphy). The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition PotsdamRehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo 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); Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology-ICO (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Ska degrees ne and V_asterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (United Kingdom)., Background: Observational studies have consistently reported that postmenopausal hormone therapy use is associated with lower colon cancer risk, but epidemiologic studies examining the associations between circulating concentrations of endogenous estrogens and colorectal cancer have reported inconsistent results. Methods: We investigated the associations between circulating concentrations of estrone, estradiol, free estradiol, testosterone, free testosterone, androstenedione, dehydroepiandrosterone (DHEA), progesterone, and sex hormone–binding globulin (SHBG) with colon cancer risk in a nested case-control study of 1028 postmenopausal European women (512 colon cancer cases, 516 matched controls) who were noncurrent users of exogenous hormones at blood collection. Multivariable conditional logistic regression models were used to compute odds ratios and 95% confidence intervals to evaluate the association between circulating sex hormones and colon cancer risk. We also conducted a dose-response meta-analysis of prospective studies of circulating estrone and estradiol with colorectal, colon, and rectal cancer risk in postmenopausal women. All statistical tests were 2-sided. Results: In the multivariable model, a nonstatistically significantly positive relationship was found between circulating estrone and colon cancer risk (odds ratio per log2 1-unit increment¼1.17 [95% confidence interval¼1.00 to 1.38]; odds ratioquartile4-quartile1¼1.33 [95% confidence interval¼0.89 to 1.97], Ptrend¼.20). Circulating concentrations of estradiol, free estradiol, testosterone, free testosterone, androstenedione, DHEA, progesterone, and SHBG were not associated with colon cancer risk. In the doseresponse meta-analysis, no clear evidence of associations were found between circulating estradiol and estrone concentrations with colorectal, colon, and rectal cancer risk. Conclusion: Our observational and meta-analysis results do not support an association between circulating concentrations of endogenous sex hormones and colon or rectal cancer in postmenopausal women., French National Cancer Institute (INCa SHSESP17) 2017-127, World Health Organization, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue Contre le Cancer (France), Institut Gustave Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe German Cancer Research Center (DKFZ) (Germany) German Institute of Human Nutrition Potsdam Rehbruecke (DIfE) (Germany), Federal Ministry of Education & Research (BMBF), Fondazione AIRC per la ricerca sul cancro, Compagnia di San Paolo Consiglio Nazionale delle Ricerche (CNR), Netherlands Government, World Cancer Research Fund International (WCRF), Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII) (Spain) Junta de Andalucia Regional Government of Asturias (Spain) Regional Government of Basque Country (Spain) Regional Government of Murcia (Spain) Regional Government of Navarra (Spain) Catalan Institute of Oncology-ICO (Spain), Swedish Cancer Society Swedish Research Council County Council of Skane (Sweden) County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C8221/A29017 UK Research & Innovation (UKRI) Medical Research Council UK (MRC) 1000143 MR/M012190/1

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies.FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10–1·17), coronary disease excluding myocardial infarction (1·06, 1·00–1·11), heart failure (1·09, 1·03–1·15), fatal hypertensive disease (1·24, 1·15–1·33); and fatal aortic aneurysm (1·15, 1·03–1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91–0·97). In comparison to those who reported drinking >0–≤100 g per week, those who reported drinking >100–≤200 g per week, >200–≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1–2 years, or 4–5 years, respectively.INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Purpose Excess iron is involved in the development of non-communicable diseases such as cancer, type 2 diabetes and cardiovascular conditions. We aimed to describe the prevalence of excess iron and its determinants in healthy European adults. Methods Sociodemographic, lifestyle, iron status, dietary information, and HFE genotyping were obtained from controls from the nested case–control study EPIC-EurGast study. High sensitivity C-reactive protein (hsCRP) was measured to address possible systemic inflammation. Descriptive and multivariate analyses were used to assess iron status and its determinants. Results Out of the 828 participants (median age: 58.7 years), 43% were females. Median serum ferritin and prevalence of excess iron were 143.7 µg/L and 35.2% in males, respectively, and 77 µg/L and 20% in females, both increasing with latitude across Europe. Prevalence of HFE C282Y mutation was significantly higher in Northern and Central Europe (~ 11%) than in the South (5%). Overweight/obesity, age, and daily alcohol and heme iron intake were independent determinants for iron status, with sex differences even after excluding participants with hsCRP > 5 mg/L. Obese males showed a greater consumption of alcohol, total and red meat, and heme iron, compared with those normal weight. Conclusion Obesity, higher alcohol and heme iron consumption were the main risk factors for excess iron in males while only age was associated with iron overload in females. Weight control and promoting healthy lifestyle may help prevent iron overload, especially in obese people. Further research is needed to clarify determinants of excess iron in the healthy adult population, helping to reduce the associated comorbidities.

Systemic and local inflammation plays an important role in many cancers and colorectal liver metastases (CRLM). While the role of local immune response mediated by CD3+ tumour-infiltrating lymphocytes is well-established, new evidence on systemic inflammation and cancer, such as neutrophil-lymphocyte ratio (NLR), is emerging. The aim of this study is to seek an association between the CD3+ lymphocytes and NLR with patients’ prognosis and possibly stratifying it accordingly. From January 2005 to January 2013, 128 consecutive patients affected by CRLM and treated with chemotherapy and surgery were included in the study. Different cutoff levels were calculated with ROC curves for each of the biomarkers, and their relative outcome in terms of overall survival (OS) and recurrence-free survival (RFS) was determined. Associating the two biomarkers, three risk groups were determined: low risk (two protective biomarkers), intermediate risk (one protective biomarker) and high risk (no protective biomarker). After a median follow-up of 45 months, median OS and RFS were 44 and 9 months, respectively. For OS, 29 (22.66%), 59 (46.09%) and 40 (31.25%) patients were in the low, intermediate and high-risk groups, respectively. Adjusted Cox regression analysis showed an increased risk of death in the intermediate group (HR 2.67 p = 0.007 95% CI 1.31–5.42) and high-risk group (HR 2.86 p = 0.005 95% CI 1.37–5.99) compared to the low-risk group (reference). Systemic and local immune response index allows stratification of patients in different OS and RFS risk groups.

Aims/hypothesis Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. Methods GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. Results GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. Conclusions/interpretation Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.

This is a post-peer-review, pre-copyedit version of an article published in the European Journal of Epidemiology. The final authenticated version is available online at: https://doi.org/10.1007/s10654-019-00559-6. Pancreatic cancer (PC) is a highly fatal cancer with currently limited opportunities for early detection and effective treatment. Modifiable factors may offer pathways for primary prevention. In this study, the association between the Healthy Lifestyle Index (HLI) and PC risk was examined. Within the European Prospective Investigation into Cancer and Nutrition cohort, 1113 incident PC (57% women) were diagnosed from 400,577 participants followed-up for 15 years (median). HLI scores combined smoking, alcohol intake, dietary exposure, physical activity and, in turn, overall and central adiposity using BMI (HLIBMI) and waist-to-hip ratio (WHR, HLIWHR), respectively. High values of HLI indicate adherence to healthy behaviors. Cox proportional hazard models with age as primary time variable were used to estimate PC hazard ratios (HR) and 95% confidence intervals (CI). Sensitivity analyses were performed by excluding, in turn, each factor from the HLI score. Population attributable fractions (PAF) were estimated assuming participants’ shift to healthier lifestyles. The HRs for a one-standard deviation increment of HLIBMI and HLIWHR were 0.84 (95% CI: 0.79, 0.89; ptrend = 4.3e−09) and 0.77 (0.72, 0.82; ptrend = 1.7e−15), respectively. Exclusions of smoking from HLIWHR resulted in HRs of 0.88 (0.82, 0.94; ptrend = 4.9e−04). The overall PAF estimate was 19% (95% CI: 11%, 26%), and 14% (6%, 21%) when smoking was removed from the score. Adherence to a healthy lifestyle was inversely associated with PC risk, beyond the beneficial role of smoking avoidance. Public health measures targeting compliance with healthy lifestyles may have an impact on PC incidence.

Objectives Patients who arrive at the emergency department (ED) with COVID-19, who test negative at the first real-time polymerase chain reaction (RT-PCR), represent a clinical challenge. This study aimed to evaluate if the clinical manifestation at presentation, the laboratory and imaging results, and the prognosis of COVID-19 differ in patients who tested negative at the first RT-PCR compared with those who tested positive and also to evaluate if comorbid conditions patient-related or the period of arrival are associated with negative testing. Study design We retrospectively collected clinical data of patients who accessed the ED from March 1 to May 15, 2020. Methods We compared clinical variables, comorbid conditions, and clinical outcomes in the two groups by univariate analysis and logistic regression. Results Patients who tested negative at the first RT-PCR showed a higher prevalence of cardiopathy, immunosuppression, and diabetes, as well as a higher leukocyte and lower lymphocyte counts compared with patients who tested positive. A bilateral interstitial syndrome and a typical pattern at computed tomography scan were prevalent in the test-negative group. Test-negative patients were more likely to be admitted to the hospital but less likely to need admission in a high level of care ward. The false-negative rate increased from March to May. Conclusion False-negative RT-PCR COVID-19 patients present a similar spectrum of symptoms compared with positive cohort, but more comorbidities. Imaging helps to identify them. True positives had a higher risk of serious complications.

No association between polymorphisms in CYP2E1, GSTM1, NAT1, NAT2 and the risk of gastric adenocarcinoma in the European prospective investigation into cancer and nutrition.

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), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy 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); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada; PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPICNorfolk, MR/M012190/1 to EPIC-Oxford) (UK). We thank the Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, and the National Institute for Public Health and the Environment (RIVM)-Bilthoven, the Netherlands, for their contribution and ongoing support to the EPIC Study., For information on how to submit an application for gaining access to EPIC data and/or biospecimens, please follow the instructions at http://epic.iarc.fr/ access/index.php., Informed consent was given by all study participants, and ethical approval for the entire EPIC cohort was obtained from the Institutional Review Board of the International Agency for Research on Cancer in Lyon, France, under protocol numbers SC/24/4 and SC/24/6, as well as from local ethics committees in the participating countries., The authors thank the EPIC participants and staff for their valuable contribution to this research and Bertrand Hemon (International Agency for Research on Cancer) for managing the data for the EPIC project., Background Trans fatty acids (TFAs) have been hypothesised to influence breast cancer risk. However, relatively few prospective studies have examined this relationship, and well-powered analyses according to hormone receptor-defined molecular subtypes, menopausal status, and body size have rarely been conducted. Methods In the European Prospective Investigation into Cancer and Nutrition (EPIC), we investigated the associations between dietary intakes of TFAs (industrial trans fatty acids [ITFAs] and ruminant trans fatty acids [RTFAs]) and breast cancer risk among 318,607 women. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, adjusted for other breast cancer risk factors. Results After a median follow-up of 8.1 years, 13,241 breast cancer cases occurred. In the multivariable-adjusted model, higher total ITFA intake was associated with elevated breast cancer risk (HR for highest vs lowest quintile, 1.14, 95% CI 1.06-1.23; P trend = 0.001). A similar positive association was found between intake of elaidic acid, the predominant ITFA, and breast cancer risk (HR for highest vs lowest quintile, 1.14, 95% CI 1.06-1.23; P trend = 0.001). Intake of total RTFAs was also associated with higher breast cancer risk (HR for highest vs lowest quintile, 1.09, 95% CI 1.01-1.17; P trend = 0.015). For individual RTFAs, we found positive associations with breast cancer risk for dietary intakes of two strongly correlated fatty acids (Spearman correlation r = 0.77), conjugated linoleic acid (HR for highest vs lowest quintile, 1.11, 95% CI 1.03-1.20; P trend = 0.001) and palmitelaidic acid (HR for highest vs lowest quintile, 1.08, 95% CI 1.01-1.16; P trend = 0.028). Similar associations were found for total ITFAs and RTFAs with breast cancer risk according to menopausal status, body mass index, and breast cancer subtypes. Conclusions These results support the hypothesis that higher dietary intakes of ITFAs, in particular elaidic acid, are associated with elevated breast cancer risk. Due to the high correlation between conjugated linoleic acid and palmitelaidic acid, we were unable to disentangle the positive associations found for these fatty acids with breast cancer risk. Further mechanistic studies are needed to identify biological pathways that may underlie these associations., European Commission European Commission Joint Research Centre, International Agency for Research on Cancer, Danish Cancer Society, Ligue Contre le Cancer (France), Institut Gustave Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe, German Cancer Research Center (DKFZ) (Germany), Federal Ministry of Education & Research (BMBF), Deutsches Krebsforschungszentrum (Germany), Hellenic Health Foundation (Greece), Associazione Italiana per la Ricerca sul Cancro (AIRC), Consiglio Nazionale delle Ricerche (CNR), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Netherlands Organization for Scientific Research (NWO), World Cancer Research Fund International (WCRF), Instituto de Salud Carlos III PI13/00061 PI13/01162, Junta de Andalucia, Catalan Institute of Oncology (Spain), Swedish Cancer Society Swedish Research Council, County Council of Skane (Sweden), County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C570/A16491 C8221/A19170, UK Research & Innovation (UKRI) Medical Research Council UK (MRC) 1000143 MR/M012190/1, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, National Institute for Public Health and the Environment (RIVM)-Bilthoven, the Netherlands, Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway), Regional Government of Asturias (Spain), Regional Government of Basque Country (Spain), Regional Government of Murcia (Spain), Regional Government of Navarra (Spain), ERC-2009-AdG 232997

BACKGROUND: Vitamin B6 insufficiency has been linked to increased risk of cancer and other chronic diseases. The circulating concentration of pyridoxal 5'-phosphate (PLP) is a commonly used measure of vitamin B6 status. Ratios of substrates indicating PLP coenzymatic function and metabolism may be useful complementary measures to further explore the role of vitamin B6 in health. OBJECTIVES: We explored the sensitivity of 5 outcomes, namely PLP concentration, homocysteine:cysteine (Hcy:Cys), cystathionine:cysteine (Cysta:Cys), the 3´-hydroxykynurenine ratio (HKr), and the 4-pyridoxic acid ratio (PAr) to vitamin B6 intake as well as personal and lifestyle characteristics. MEDTHODS: Dietary intake and biomarker data were collected from participants from 3 nested case-control studies within the European Prospective Investigation into Cancer and Nutrition (EPIC). Bayesian regression models assessed the associations of the 5 biomarker outcomes with vitamin B6 intake and personal and lifestyle covariates. Analogous models examined the relations of Hcy:Cys, Cysta:Cys, and HKr with PLP. RESULTS: In total, 4608 participants were included in the analyses. Vitamin B6 intake was most strongly associated with PLP, moderately associated with Hcy:Cys, Cysta:Cys, and HKr, and not associated with PAr (fold change in marker given a doubling of vitamin B6 intake: PLP 1.60 [95% credible interval (CrI): 1.50, 1.71]; Hcy:Cys 0.87 [95% CrI: 0.84, 0.90]; Cysta:Cys 0.89 [95% CrI: 0.84, 0.94]; HKr 0.88 [95% CrI: 0.85, 0.91]; PAr 1.00 [95% CrI: 0.95, 1.05]). PAr was most sensitive to age, and HKr was least sensitive to BMI and alcohol intake. Sex and menopause status were strongly associated with all 5 markers. CONCLUSIONS: We found that 5 different markers, capturing different aspects of vitamin B6-related biological processes, varied in their associations with vitamin B6 intake and personal and lifestyle predictors. ispartof: AMERICAN JOURNAL OF CLINICAL NUTRITION vol:114 issue:1 pages:338-347 ispartof: location:United States status: published

International audience; The role of chronic inflammation on breast cancer (BC) risk remains unclear beyond as an underlying mechanism of obesity and physical activity. We aimed to evaluate the association between the inflammatory potential of the diet and risk of BC overall, according to menopausal status and tumour subtypes. Within the European Prospective Investigation into Cancer and Nutrition cohort, 318,686 women were followed for 14 years, among whom 13,246 incident BC cases were identified. The inflammatory potential of the diet was characterized by an inflammatory score of the diet (ISD). Multivariable Cox regression models were used to assess the potential effect of the ISD on BC risk by means of hazard ratios (HR) and 95% confidence intervals (CI). ISD was positively associated with BC risk. Each increase of one standard deviation (1-Sd) of the score increased by 4% the risk of BC (HR = 1.04; 95% CI 1.01–1.07). Women in the highest quintile of the ISD (indicating a most pro-inflammatory diet) had a 12% increase in risk compared with those in the lowest quintile (HR = 1.12; 95% CI 1.04–1.21) with a significant trend. The association was strongest among premenopausal women, with an 8% increased risk for 1-Sd increase in the score (HR = 1.08; 95% CI 1.01–1.14). The pattern of the association was quite homogeneous by BC subtypes based on hormone receptor status. There were no significant interactions between ISD and body mass index, physical activity, or alcohol consumption. Women consuming more pro-inflammatory diets as measured by ISD are at increased risk for BC, especially premenopausal women.

International audience; Epidemiologic studies examining the association between specific fatty acids and colorectal cancer (CRC) risk are inconclusive. We investigated the association between dietary estimates and plasma levels of individual and total saturated (SFA), monounsaturated (MUFA), industrial-processed trans (iTFA), and ruminant-sourced trans (rTFA) fatty acids, and CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Baseline fatty acid intakes were estimated in 450 112 participants (6162 developed CRC, median follow-up = 15 years). In a nested case-control study, plasma phospholipid fatty acids were determined by gas chromatography in 433 colon cancer cases and 433 matched controls. Multivariable-adjusted hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were computed using Cox and conditional logistic regression, respectively. Dietary total SFA (highest vs lowest quintile, HRQ5vsQ1 = 0.80; 95%CI:0.69-0.92), myristic acid (HRQ5vsQ1 = 0.83, 95%CI:0.74-0.93) and palmitic acid (HRQ5vsQ1 = 0.81, 95%CI:0.70-0.93) were inversely associated with CRC risk. Plasma myristic acid was also inversely associated with colon cancer risk (highest vs lowest quartile, ORQ4vsQ1 = 0.51; 95%CI:0.32-0.83), whereas a borderline positive association was found for plasma stearic acid (ORQ4vsQ1 = 1.63; 95%CI:1.00-2.64). Dietary total MUFA was inversely associated with colon cancer (per 1-SD increment, HR1-SD = 0.92, 95%CI: 0.85-0.98), but not rectal cancer (HR1-SD = 1.04, 95%CI:0.95-1.15, Pheterogeneity = 0.027). Dietary iTFA, and particularly elaidic acid, was positively associated with rectal cancer (HR1-SD = 1.07, 95%CI:1.02-1.13). Our results suggest that total and individual saturated fatty acids and fatty acids of industrial origin may be relevant to the aetiology of CRC. Both dietary and plasma myristic acid levels were inversely associated with colon cancer risk, which warrants further investigation.

Increasing evidence points to a role for inflammation in lung carcinogenesis. A small number of circulating inflammatory proteins have been identified as showing elevated levels prior to lung cancer diagnosis, indicating the potential for prospective circulating protein concentration as a marker of early carcinogenesis. To identify novel markers of lung cancer risk, we measured a panel of 92 circulating inflammatory proteins in 648 prediagnostic blood samples from two prospective cohorts in Italy and Norway (women only). To preserve the comparability of results and protect against confounding factors, the main statistical analyses were conducted in women from both studies, with replication sought in men (Italian participants). Univariate and penalized regression models revealed for the first time higher blood levels of CDCP1 protein in cases that went on to develop lung cancer compared with controls, irrespective of time to diagnosis, smoking habits, and gender. This association was validated in an additional 450 samples. Associations were stronger for future cases of adenocarcinoma where CDCP1 showed better explanatory performance. Integrative analyses combining gene expression and protein levels of CDCP1 measured in the same individuals suggested a link between CDCP1 and the expression of transcripts of LRRN3 and SEM1. Enrichment analyses indicated a potential role for CDCP1 in pathways related to cell adhesion and mobility, such as the WNT/β-catenin pathway. Overall, this study identifies lung cancer–related dysregulation of CDCP1 expression years before diagnosis. Significance: Prospective proteomics analyses reveal an association between increased levels of circulating CDCP1 and lung carcinogenesis irrespective of smoking and years before diagnosis, and integrating gene expression indicates potential underlying mechanisms. See related commentary by Itzstein et al., p. 3441.

Purpose: Rhabdomyosarcoma (RMS) has a worse prognosis in adults than in children, but there is evidence of a better outcome in the former if treated using a pediatric-like approach. This study desc...

Gender equity and gender medicine are opportunities not to be missed, and this Expert Group Opinion Paper on pain in women aims to review the treatment of pain conditions mainly affecting women, as well as the fundamental aspects of the different clinical response to drug treatment between the genders, and what can be done for gender-specific rehabilitation. Perspective review. Genotypic and phenotypic differences in pain between the sexes are conditioned by anatomical, physiological, neural, hormonal, psychological, social, and cultural factors, such as the response to pharmacological treatment to control pain. The examination of these factors shows that women are affected by pain diseases more frequently and severely than men and that they report pain more frequently and with a lower pain threshold than men. Some forms of pain are inherently related to gender differences, such as pain related to the genitourinary system. However, other forms of chronic pain are seen more frequently in women than men, such as migraine, rheumatological, and musculoskeletal pain, in particular fibromyalgia. Research is needed into the pathophysiological basis for gender differences in the generation of acute pain and maintenance of chronic pain, including the factors that put women at higher risk for developing chronic pain. In addition, different specialties need to collaborate to develop gender-related diagnostic and therapeutic guidelines, and healthcare professionals need to upskill themselves in the appropriate management of pain using existing diagnostic tools and therapeutic options.

Background Randomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalisability of results to individuals with low vitamin D status is unclear. We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks. Methods Observational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline. Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died. Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality. Findings Observational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations. In population-wide genetic analyses, there were no associations of genetically-predicted 25(OH)D with coronary heart disease, stroke, or all-cause mortality. However, for the participants with vitamin D deficiency (25[OH]D concentration Interpretation Stratified Mendelian randomisation analyses suggest a causal relationship between 25(OH)D concentrations and mortality for individuals with low vitamin D status. Our findings have implications for the design of vitamin D supplementation trials, and potential disease prevention strategies. Funding British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer.

Background Even though in situ breast cancer (BCIS) accounts for a large proportion of the breast cancers diagnosed, few studies have investigated potential risk factors for BCIS. Their results suggest that some established risk factors for invasive breast cancer have a similar impact on BCIS risk, but large population-based studies on lifestyle factors and BCIS risk are lacking. Thus, we investigated the association between lifestyle and BCIS risk within the European Prospective Investigation into Cancer and Nutrition cohort. Methods Lifestyle was operationalized by a score reflecting the adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations. The recommendations utilized in these analyses were the ones pertinent to healthy body weight, physical activity, consumption of plant-based foods, energy-dense foods, red and processed meat, and sugary drinks and alcohol, as well as the recommendation on breastfeeding. Cox proportional hazards regression was used to assess the association between lifestyle score and BCIS risk. The results were presented as hazard ratios (HR) and corresponding 95% confidence intervals (CI). Results After an overall median follow-up time of 14.9 years, 1277 BCIS cases were diagnosed. Greater adherence to the WCRF/AICR cancer prevention recommendations was not associated with BCIS risk (HR = 0.98, 95% CI 0.93–1.03; per one unit of increase; multivariable model). An inverse association between the lifestyle score and BCIS risk was observed in study centers, where participants were recruited mainly via mammographic screening and attended additional screening throughout follow-up (HR = 0.85, 95% CI 0.73–0.99), but not in the remaining ones (HR = 0.99, 95% CI 0.94–1.05). Conclusions While we did not observe an overall association between lifestyle and BCIS risk, our results indicate that lifestyle is associated with BCIS risk among women recruited via screening programs and with regular screening participation. This suggests that a true inverse association between lifestyle habits and BCIS risk in the overall cohort may have been masked by a lack of information on screening attendance. The potential inverse association between lifestyle and BCIS risk in our analyses is consistent with the inverse associations between lifestyle scores and breast cancer risk reported from previous studies.

Background Existing evidence for the prospective association of vitamin D status with type 2 diabetes (T2D) is focused almost exclusively on circulating total 25-hydroxyvitamin D [25(OH)D] without distinction between its subtypes: nonepimeric and epimeric 25(OH)D3 stereoisomers, and 25(OH)D2, the minor component of 25(OH)D. We aimed to investigate the prospective associations of circulating levels of the sum and each of these three metabolites with incident T2D. Methods This analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC)–InterAct case-cohort study for T2D included 9671 incident T2D cases and 13,562 subcohort members. Plasma vitamin D metabolites were quantified by liquid chromatography–mass spectrometry. We used a multivariable Prentice-weighted Cox regression to estimate hazard ratios (HRs) of T2D for each metabolite. Analyses were performed separately within country, and estimates were combined across countries using random-effects meta-analysis. Results The mean concentrations (SD) of total 25(OH)D, nonepimeric 25(OH)D3, epimeric 25(OH)D3, and 25(OH)D2 were 41.1 (17.2), 40.7 (17.3), 2.13 (1.31), and 8.16 (6.52) nmol/L, respectively. Plasma total 25(OH)D and nonepimeric 25(OH)D3 were inversely associated with incident T2D [multivariable-adjusted HR per 1 SD = 0.81 (95% CI, 0.77, 0.86) for both variables], whereas epimeric 25(OH)D3 was positively associated [per 1 SD HR = 1.16 (1.09, 1.25)]. There was no statistically significant association with T2D for 25(OH)D2 [per 1 SD HR = 0.94 (0.76, 1.18)]. Conclusions Plasma nonepimeric 25(OH)D3 was inversely associated with incident T2D, consistent with it being the major metabolite contributing to total 25(OH)D. The positive association of the epimeric form of 25(OH)D3 with incident T2D provides novel information to assess the biological relevance of vitamin D epimerization and vitamin D subtypes in diabetes etiology., We examined the prospective association of plasma vitamin D metabolites with type 2 diabetes and found that the epimeric form of plasma 25(OH)D3 was positively associated with type 2 diabetes risk.

Introduction Advances in paediatric oncology led to the increase in long-term survival, revealing the burden of therapy-related long-term side effects. We evaluated overall and cause-specific mortality in a large cohort of Italian childhood cancer survivors (CCSs) and adolescent cancer survivors identified through the off-therapy registry. Materials and methods CCSs alive 5 years after cancer diagnosis occurring between 1960 and 1999 were eligible; the last follow-up was between 2011 and 2014. Outcomes were reported as standardised mortality ratios (SMRs) and absolute excess risks (AERs). Results Among 12,214 CCSs, 1113 (9.1%) deaths occurred. Survival at 35 years since diagnosis was 87% (95% confidence interval [CI]: 86–88) and at 45 years was 81% (95% CI: 77–84). CCSs had an 11-fold increased risk of death (SMR 95% CI: 10.7–12), corresponding to an AER of 48 (95% CI: 45–51). Mortality decreased by 60% for survivors treated most recently (1990–1999). The most frequent causes of death were recurrence of the original cancer (56%), a subsequent neoplasm (19%) and cardiovascular diseases (5.8%). Among those who survived at least 15 years after diagnosis, a secondary malignancy was the leading cause of death. Conclusions This study confirms the impact of recent advances in anticancer therapy in reducing mortality, mainly attributable to recurrence but also to other causes. However, overall mortality continues to be higher than in the general population. A long-term follow-up is needed to prevent late mortality due to secondary neoplasms and non-neoplastic causes in CCSs.

Funder: European Union FP6 programme grant number LSHM_CT_2006_037197, Type 2 diabetes (T2D) is a global public health challenge. Whilst the advent of genome-wide association studies has identified >400 genetic variants associated with T2D, our understanding of its biological mechanisms and translational insights is still limited. The EPIC-InterAct project, centred in 8 countries in the European Prospective Investigations into Cancer and Nutrition study, is one of the largest prospective studies of T2D. Established as a nested case-cohort study to investigate the interplay between genetic and lifestyle behavioural factors on the risk of T2D, a total of 12,403 individuals were identified as incident T2D cases, and a representative sub-cohort of 16,154 individuals was selected from a larger cohort of 340,234 participants with a follow-up time of 3.99 million person-years. We describe the results from a genome-wide association analysis between more than 8.9 million SNPs and T2D risk among 22,326 individuals (9,978 cases and 12,348 non-cases) from the EPIC-InterAct study. The summary statistics to be shared provide a valuable resource to facilitate further investigations into the genetics of T2D.

Objective Treatment of pain associated with osteoarthritis (OA) is unsatisfactory and innovative approaches are needed. The secretome from human adipose-derived mesenchymal stem cells (hASC-Conditioned Medium, CM) has been successfully used to relieve painful symptoms in models of chronic pain. The aim of this study was to explore the efficacy of the hASC-CM to control pain and neuroinflammation in an animal model of OA. Methods OA was induced in mice by intra-articular monosodium-iodoacetate (MIA) injection. Thermal hyperalgesia and mechanical allodynia were assessed. Once hypersensitivity was established (7 days after MIA), hASC-CM was injected by IA, IPL and IV route and its effect monitored over time. Neuroinflammation in nerve, dorsal root ganglia and spinal cord was evaluated measuring proinflammatory markers and mediators by RT-qPCR. Protein content analysis of secretome by Mass Spectrometry was performed. Results A single injection with hASC-CM induced a fast and long lasting antihyperalgesic and antiallodynic effect. The IV route of administration appeared to be the most efficacious although all the treatments were effective. The effect on pain correlated with the ability of hASC-CM to reduce the neuroinflammatory condition in both the peripheral and central nervous system. Furthermore, the secretome analysis revealed 101 factors associated with immune regulation. Conclusion We suggest that hASC-CM is a valid treatment option for controlling OA-related hypersensitivity, exerting a rapid and long lasting pain relief. The mechanisms underpinning its effects are likely linked to the positive modulation of neuroinflammation in peripheral and central nervous system that sustains peripheral and central sensitization.

To better understand the role of individual and lifestyle factors in human disease, an exposome‐wide association study was performed to investigate within a single‐study anthropometry measures and lifestyle factors previously associated with B‐cell lymphoma (BCL). Within the European Prospective Investigation into Cancer and nutrition study, 2402 incident BCL cases were diagnosed from 475 426 participants that were followed‐up on average 14 years. Standard and penalized Cox regression models as well as principal component analysis (PCA) were used to evaluate 84 exposures in relation to BCL risk. Standard and penalized Cox regression models showed a positive association between anthropometric measures and BCL and multiple myeloma/plasma cell neoplasm (MM). The penalized Cox models additionally showed the association between several exposures from categories of physical activity, smoking status, medical history, socioeconomic position, diet and BCL and/or the subtypes. PCAs confirmed the individual associations but also showed additional observations. The PC5 including anthropometry, was positively associated with BCL, diffuse large B‐cell lymphoma (DLBCL) and MM. There was a significant positive association between consumption of sugar and confectionary (PC11) and follicular lymphoma risk, and an inverse association between fish and shellfish and Vitamin D (PC15) and DLBCL risk. The PC1 including features of the Mediterranean diet and diet with lower inflammatory score showed an inverse association with BCL risk, while the PC7, including dairy, was positively associated with BCL and DLBCL risk. Physical activity (PC10) was positively associated with DLBCL risk among women. This study provided informative insights on the etiology of BCL., What's new? The “exposome” includes all non‐genetic exposures (e.g. diet, viral, environmental, etc.), with the goal of understanding how those exposures may affect an individual's health. In this study, the authors used a technique called “EWAS” (exposome‐wide association study) to identify multiple factors that are associated with B‐cell lymphoma (BCL) risk. Their results confirm both previously reported risk factors and protective factors. In addition, they identify several previously unknown associations. These new insights, gained via the analysis of multiple exposures, suggest that traditional single‐factor approaches may be suboptimal compared with an EWAS approach.

PURPOSE We evaluated the prevalence of coronary stenosis on coronary computed tomography angiography (CCTA) in patients aged 18 to 30 years, who presented to the emergency department with chest pain. We also examined the risk factors potentially associated with abnormal coronary findings on CCTA in this age group. MATERIALS AND METHODS A total of 884 patients were retrospectively evaluated. Indication for CCTA was guided by our hospital's chest pain protocol based on ACC/AHA guidelines. These were performed using the standard technique and interpreted based on CAD-RADS guidelines. Scans were identified as abnormal if atherosclerotic coronary artery disease (CAD), myocardial bridging (MB), or any anatomic coronary artery anomaly were present. RESULTS Twenty-two percent of patients had a coronary abnormality on CCTA. The most common abnormality was MB (17.3%), followed by CAD (4.4%) and coronary anomalies (1.5%). A small minority had stenosis (2.8%), most commonly caused by CAD. Most cases with stenosis were minimal to mild (72%) with 0.8% having coronary stenosis ≥50%. Age and male sex were risk factors for both coronary artery stenosis (odds ratio: 1.32 and 4.50, 95% confidence interval: 1.03-1.69, and 1.23-16.46, P=0.028 and 0.023, respectively) and CAD (odds ratio: 1.52 and 3.67, 95% confidence interval: 1.14-2.04, and 1.26-10.66, P=0.005 and 0.017, respectively). CONCLUSIONS Epicardial coronary stenosis is rarely the cause of chest pain among young adult patients presenting to the emergency department. Age and male sex were both risk factors for coronary artery stenosis/disease in this age group.

Background: Age-related epigenetic dysregulations are associated with several diseases, including cancer. The number of stochastic epigenetic mutations (SEM) has been suggested as a biomarker of life-course accumulation of exposure-related DNA damage; however, the predictive role of SEMs in cancer has seldom been investigated. Methods: A SEM, at a given CpG site, was defined as an extreme outlier of DNA methylation value distribution across individuals. We investigated the association of the total number of SEMs with the risk of eight cancers in 4,497 case–control pairs nested in three prospective cohorts. Furthermore, we investigated whether SEMs were randomly distributed across the genome or enriched in functional genomic regions. Results: In the three-study meta-analysis, the estimated ORs per one-unit increase in log(SEM) from logistic regression models adjusted for age and cancer risk factors were 1.25; 95% confidence interval (CI), 1.11–1.41 for breast cancer, and 1.23; 95% CI, 1.07–1.42 for lung cancer. In the Melbourne Collaborative Cohort Study, the OR for mature B-cell neoplasm was 1.46; 95% CI, 1.25–1.71. Enrichment analyses indicated that SEMs frequently occur in silenced genomic regions and in transcription factor binding sites regulated by EZH2 and SUZ12 (P < 0.0001 and P = 0.0005, respectively): two components of the polycomb repressive complex 2 (PCR2). Finally, we showed that PCR2-specific SEMs are generally more stable over time compared with SEMs occurring in the whole genome. Conclusions: The number of SEMs is associated with a higher risk of different cancers in prediagnostic blood samples. Impact: We identified a candidate biomarker for cancer early detection, and we described a carcinogenesis mechanism involving PCR2 complex proteins worthy of further investigations.

Aim: Inflammation represents a potential pathway through which socioeconomic position (SEP) is biologically embedded. Materials & methods: We analyzed inflammatory biomarkers in response to life course SEP by integrating multi-omics DNA-methylation, gene expression and protein level in 178 European Prospective Investigation into Cancer and Nutrition-Italy participants. Results & conclusion: We identified 61 potential cis acting CpG loci whose methylation levels were associated with gene expression at a Bonferroni correction. We examined the relationships between life course SEP and these 61 cis-acting regulatory methylation sites individually and jointly using several scores. Less-advantaged SEP participants exhibit, later in life, a lower inflammatory methylome score, suggesting an overall increased expression of the corresponding inflammatory genes or proteins, supporting the hypothesis that SEP impacts adult physiology through inflammation.

BackgroundSurvivors of childhood cancer are at risk of subsequent primary neoplasms (SPNs), but the risk of developing specific digestive SPNs beyond age 40 years remains uncertain. We investigated risks of specific digestive SPNs within the largest available cohort worldwide.MethodsThe PanCareSurFup cohort includes 69 460 five-year survivors of childhood cancer from 12 countries in Europe. Risks of digestive SPNs were quantified using standardised incidence ratios (SIRs), absolute excess risks and cumulative incidence.Results427 digestive SPNs (214 colorectal, 62 liver, 48 stomach, 44 pancreas, 59 other) were diagnosed in 413 survivors. Wilms tumour (WT) and Hodgkin lymphoma (HL) survivors were at greatest risk (SIR 12.1; 95% CI 9.6 to 15.1; SIR 7.3; 95% CI 5.9 to 9.0, respectively). The cumulative incidence increased the most steeply with increasing age for WT survivors, reaching 7.4% by age 55% and 9.6% by age 60 years (1.0% expected based on general population rates). Regarding colorectal SPNs, WT and HL survivors were at greatest risk; both seven times that expected. By age 55 years, 2.3% of both WT (95% CI 1.4 to 3.9) and HL (95% CI 1.6 to 3.2) survivors had developed a colorectal SPN—comparable to the risk among members of the general population with at least two first-degree relatives affected.ConclusionsColonoscopy surveillance before age 55 is recommended in many European countries for individuals with a family history of colorectal cancer, but not for WT and HL survivors despite a comparable risk profile. Clinically, serious consideration should be given to the implementation of colonoscopy surveillance while further evaluation of its benefits, harms and cost-effectiveness in WT and HL survivors is undertaken.

Bladder cancer (BC) is the tenth most frequent cancer worldwide. Due to the need for recurrent cystoscopies and the lack of non-invasive biomarkers, BC is associated with a high management burden. In this respect, small non-coding RNAs (sncRNAs) have been investigated in urine as possible biomarkers for BC, but in plasma their potential has not yet been defined. The expression levels of sncRNAs contained in plasma extracellular vesicles (EVs) from 47 men with BC and 46 healthy controls were assessed by next-generation sequencing. The sncRNA profiles were compared with urinary profiles from the same subjects. miR-4508 resulted downregulated in plasma EVs of muscle-invasive BC patients, compared to controls (adj-p = 0.04). In World Health Organization (WHO) grade 3 (G3) BC, miR-126-3p was upregulated both in plasma EVs and urine, when compared to controls (for both, adj-p &lt, 0.05). Interestingly, two sncRNAs were associated with the risk class: miR-4508 with a downward trend going from controls to high risk BC, and piR-hsa-5936 with an upward trend (adj-p = 0.04 and adj-p = 0.05, respectively). Additionally, BC cases with low expression of miR-185-5p and miR-106a-5p or high expression of miR-10b-5p showed shorter survival (adj-p = 0.0013, adj-p = 0.039 and adj-p = 0.047, respectively). SncRNAs from plasma EVs could be diagnostic biomarkers for BC, especially in advanced grade.

Background Cancer stage is a determinant of survival of childhood central nervous system (CNS) cancers and could help the interpretation of survival variability among countries. Consensus guidelines to stage childhood malignancies in population cancer registries ("Toronto Childhood Cancer Stage Guidelines") have been recently proposed with the goal of data comparability. Indeed, stage is not systematically recorded in all registries and, when it is, different classification systems are used. We applied the Toronto Childhood Cancer Stage Guidelines to CNS cancer cases of three population-based cancer registries with the aim of evaluating the feasibility of staging this type of cancer and the critical points in the classification of CNS tumors. Procedures The Toronto Childhood Cancer Stage Guidelines were applied to 175 CNS patients, diagnosed from January 1, 2002 to December 31, 2014 in three cancer registries in Italy, and the percentage of cases that could be staged was assessed. Results One hundred eight of 126 (86%) medulloblastomas and other embryonal CNS cancers and 22 of 49 (45%) ependymomas were staged. Using these guidelines, survival of children with localized tumors could be discriminated from that of children with metastatic disease. Conclusions The use of the Toronto Childhood Cancer Stage Guidelines is feasible for staging medulloblastoma in Italian population-based cancer registries, whereas it is more difficult for ependymomas. In Italy, cerebrospinal fluid examination, one of the decisive tests to stage CNS tumors, is not routinely performed as a first-line diagnosis procedure in ependymoma pediatric patients. A similar exercise by a larger number of cancer registries in different countries could suggest improvements in the childhood cancer staging system.

•Our patient is a 63-year-old African American female with medical history significant for hypertension, class 1 obesity, osteoarthritis of knees who initially presented to the adult ambulatory clinic on 9/19/2013 with complaints of body aches and bone pain. Labs were remarkable for a serum calcium level of 9.8 mg/dl, serum phosphorous of 4.7 mg/dl, and serum parathyroid hormone level of 166 pg/ml (15-65 pg/ml), normal GFR and serum vitamin 25-OH D of 62. A DEXA scan was performed which showed mild osteopenia wof 1.0 (0.8-1.8), serum 1,25 - OH vitamin D of

Chronic lymphocytic leukemia (CLL) is an incurable disease accounting for almost one-third of leukemias in the Western world. Aberrant expression of microRNAs (miRNAs) is a well-established characteristic of CLL, and the robust nature of miRNAs makes them eminently suitable liquid biopsy biomarkers. Using a nested case–control study within the European Prospective Investigation into Cancer and Nutrition (EPIC), the predictive values of five promising human miRNAs (hsa-miR-16-5p, hsa-miR-29a-3p, hsa-miR-150-5p, hsa-miR-155-5p and hsa-miR-223-3p), identified in a pilot study, were examined in serum of 224 CLL cases (diagnosed 3 months to 18 years after enrollment) and 224 matched controls using Taqman based assays. Conditional logistic regressions were applied to adjust for potential confounders. The median time from blood collection to CLL diagnosis was 10 years (p25–p75: 7–13 years). Overall, the upregulation of hsa-miR-150-5p, hsa-miR-155-5p and hsa-miR-29a-3p was associated with subsequent risk of CLL [OR1∆Ct-unit increase (95%CI) = 1.42 (1.18–1.72), 1.64 (1.31–2.04) and 1.75 (1.31–2.34) for hsa-miR-150-5p, hsa-miR-155-5p and hsa-miR-29a-3p, respectively] and the strongest associations were observed within 10 years of diagnosis. However, the predictive performance of these miRNAs was modest (area under the curve

Citrus intake has been suggested to increase the risk of skin cancer. Although this relation is highly plausible biologically, epidemiologic evidence is lacking. We aimed to examine the potential association between citrus intake and skin cancer risk. EPIC is an ongoing multi-center prospective cohort initiated in 1992 and involving ~ 520,000 participants who have been followed-up in 23 centers from 10 European countries. Dietary data were collected at baseline using validated country-specific dietary questionnaires. We used Cox proportional hazards regression models to compute hazard ratios (HR) and 95% confidence intervals (CI). During a mean follow-up of 13.7 years, 8448 skin cancer cases were identified among 270,112 participants. We observed a positive linear dose–response relationship between total citrus intake and skin cancer risk (HR = 1.10, 95% CI 1.03–1.18 in the highest vs. lowest quartile; Ptrend = 0.001), particularly with basal cell carcinoma (BCC) (HR = 1.11, 95% CI 1.02–1.20, Ptrend = 0.007) and squamous cell carcinoma (SCC) (HR = 1.23, 95% CI 1.04–1.47, Ptrend = 0.01). Citrus fruit intake was positively associated with skin cancer risk (HR = 1.08, 95% CI 1.01–1.16, Ptrend = 0.01), particularly with melanoma (HR = 1.23, 95% CI 1.02–1.48; Ptrend = 0.01), although with no heterogeneity across skin cancer types (Phomogeneity = 0.21). Citrus juice was positively associated with skin cancer risk (Ptrend = 0.004), particularly with BCC (Ptrend = 0.008) and SCC (Ptrend = 0.004), but not with melanoma (Phomogeneity = 0.02). Our study suggests moderate positive linear dose–response relationships between citrus intake and skin cancer risk. Studies with available biomarker data and the ability to examine sun exposure behaviors are warranted to clarify these associations and examine the phototoxicity mechanisms of furocoumarin-rich foods.

Analyses were supported by the UK Medical Research Council (MR/M012190/1), Cancer Research UK (C8221/A19170 and 570/A16491) and the Wellcome Trust (Our Planet Our Health, Livestock Environment and People 205212/Z/16/Z). A.P.C. is supported by a Cancer Research UK Population Research Fellowship (C60192/A28516) and by the World Cancer Research Fund (WCRF UK), as part of the Word Cancer Research Fund International grant programme (2019/1953). EPIC-CVD has been supported by the European Union Framework 7 (HEALTH-F2-2012-279233), the European Research Council (268834), the UK Medical Research Council (G0800270 and MR/L003120/1), the British Heart Foundation (SP/09/002 and RG/08/014 and RG13/13/30194) and the UK National Institute of Health Research. The InterAct project was funded by the EU FP6 programme (grant number LSHM_CT_2006_037197) and provided the biomarker data in the sub-cohort that was used in the current study. The coordination of EPIC is financially supported by the European Commission (DGSANCO) 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 Ge ' ne ' rale de l'Education Nationale, Institut National de la Sante ' et de la Recherche Me ' dicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy 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); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andaluci ' a, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Ska degrees ne and Va sterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), UK Medical Research Council [1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford, MC_UU_12015/1 (N.J.W.), MC_UU_12015/5 (NGF), and MC_UU_12015/520], and NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014) to the MRC Epidemiology Unit Cambridge (N.J.W., N.G.F.). J.D. holds a British Heart Foundation Chair and an NIHR Senior Investigator Award. K.E.B. holds a Girdlers' New Zealand Health Research Council Fellowship. J.D. is funded by the National Institute for Health Research [Senior Investigator Award] [*]. A.W is supported by a BHF-Turing Cardiovascular Data Science Award and by the ECInnovative Medicines Initiative (BigData@Heart).M.S.reports funding from the Alpro Foundation whilst at the Cardiovascular Epidemiology Unit (up to 15-08-2016), and Core MRC Unit support through the Nutritional Epidemiology Programme (MC_UU_12015/5) whilst at the MRC Epidemiology Unit (15-08-2016 until now), during the conduct of the study., The authors thank all participants in the EPIC cohort for their invaluable contribution to the study., Epidemiological evidence indicates that diets rich in plant foods are associated with a lower risk of ischaemic heart disease (IHD), but there is sparse information on fruit and vegetable subtypes and sources of dietary fibre. This study examined the associations of major plant foods, their subtypes and dietary fibre with risk of IHD in the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods We conducted a prospective analysis of 490 311 men and women without a history of myocardial infarction or stroke at recruitment (12.6 years of follow-up, n cases = 8504), in 10 European countries. Dietary intake was assessed using validated questionnaires, calibrated with 24-h recalls. Multivariable Cox regressions were used to estimate hazard ratios (HR) of IHD. Results There was a lower risk of IHD with a higher intake of fruit and vegetables combined [HR per 200 g/day higher intake 0.94, 95% confidence interval (CI): 0.90–0.99, P-trend = 0.009], and with total fruits (per 100 g/day 0.97, 0.95–1.00, P-trend = 0.021). There was no evidence for a reduced risk for fruit subtypes, except for bananas. Risk was lower with higher intakes of nuts and seeds (per 10 g/day 0.90, 0.82–0.98, P-trend = 0.020), total fibre (per 10 g/day 0.91, 0.85–0.98, P-trend = 0.015), fruit and vegetable fibre (per 4 g/day 0.95, 0.91–0.99, P-trend = 0.022) and fruit fibre (per 2 g/day 0.97, 0.95–1.00, P-trend = 0.045). No associations were observed between vegetables, vegetables subtypes, legumes, cereals and IHD risk. Conclusions In this large prospective study, we found some small inverse associations between plant foods and IHD risk, with fruit and vegetables combined being the most strongly inversely associated with risk. Whether these small associations are causal remains unclear., UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MR/M012190/1 G0800270 MR/L003120/1 1000143 MC_UU_12015/1 MC_UU_12015/5 MC_UU_12015/520, Cancer Research UK C8221/A19170 570/A16491 14136 C570/A16491, Wellcome Trust (Our Planet Our Health, Livestock Environment and People) 205212/Z/16/Z, Cancer Research UK Population Research Fellowship C60192/A28516, World Cancer Research Fund (WCRF UK), as part of the Word Cancer Research Fund International grant programme 2019/1953, European Commission HEALTH-F2-2012-279233, European Research Council (ERC) European Commission 268834, British Heart Foundation SP/09/002 RG/08/014 RG13/13/30194, National Institute for Health Research (NIHR), European Commission LSHM_CT_2006_037197, European Commission European Commission Joint Research Centre, International Agency for Research on Cancer, Danish Cancer Society, Ligue Contre le Cancer (France), Institut Gustave Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe, German Cancer Research Center (DKFZ) (Germany), Federal Ministry of Education & Research (BMBF), Hellenic Health Foundation (Greece), Associazione Italiana per la Ricerca sul Cancro (AIRC), Consiglio Nazionale delle Ricerche (CNR), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Netherlands Organization for Scientific Research (NWO), World Cancer Research Fund International (WCRF), Instituto de Salud Carlos III PI13/00061 PI13/01162, Junta de Andalucia, Regional Government of Asturias (Spain), Regional Government of Basque Country (Spain), Regional Government of Murcia (Spain) 6236, Regional Government of Navarra (Spain), Instituto de Salud Carlos III RD06/0020, Swedish Cancer Society, Swedish Research Council, County Council of Skane (Sweden), County Council of Vasterbotten (Sweden), NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme IS-BRC-1215-20014, British Heart Foundation, NIHR Senior Investigator Award, Girdlers' New Zealand Health Research Council Fellowship, BHF-Turing Cardiovascular Data Science Award, ECInnovative Medicines Initiative (BigData@Heart), Alpro Foundation 15-08-2016, Core MRC Unit support through the Nutritional Epidemiology Programme MC_UU_12015/5

Background: While Helicobacter pylori (H. pylori) is the major cause of gastric cancer, it has also been suggested to be involved in colorectal cancer development. However, prospective studies addressing H. pylori and colorectal cancer are sparse and inconclusive. We assessed the association of antibody responses to H. pylori proteins with colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods: We applied H. pylori multiplex serology to measure antibody responses to 13 H. pylori proteins in prediagnostic serum samples from 485 colorectal cancer cases and 485 matched controls nested within the EPIC study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable conditional logistic regression to estimate the association of H. pylori overall and protein-specific seropositivity with odds of developing colorectal cancer. Results: Fifty-one percent of colorectal cancer cases were H. pylori seropositive compared with 44% of controls, resulting in an OR of 1.36 (95% CI, 1.00–1.85). Among the 13 individual H. pylori proteins, the association was driven mostly by seropositivity to Helicobacter cysteine-rich protein C (HcpC; OR: 1.66; 95% CI, 1.19–2.30) and Vacuolating cytotoxin A (VacA) (OR: 1.34; 95% CI, 0.99–1.82), the latter being nonstatistically significant only in the fully adjusted model. Conclusions: In this prospective multicenter European study, antibody responses to H. pylori proteins, specifically HcpC and VacA, were associated with an increased risk of developing colorectal cancer. Impact: Biological mechanisms for a potential causal role of H. pylori in colorectal carcinogenesis need to be elucidated, and subsequently whether H. pylori eradication may decrease colorectal cancer incidence.

Emerging evidence suggests that a metabolic profile associated with obesity may be a more relevant risk factor for some cancers than adiposity per se. Basal metabolic rate (BMR) is an indicator of overall body metabolism and may be a proxy for the impact of a specific metabolic profile on cancer risk. Therefore, we investigated the association of predicted BMR with incidence of 13 obesity-related cancers in the European Prospective Investigation into Cancer and Nutrition (EPIC). BMR at baseline was calculated using the WHO/FAO/UNU equations and the relationships between BMR and cancer risk were investigated using multivariable Cox proportional hazards regression models. A total of 141,295 men and 317,613 women, with a mean follow-up of 14 years were included in the analysis. Overall, higher BMR was associated with a greater risk for most cancers that have been linked with obesity. However, among normal weight participants, higher BMR was associated with elevated risks of esophageal adenocarcinoma (hazard ratio per 1-standard deviation change in BMR [HR 1-SD]: 2.46; 95% CI 1.20; 5.03) and distal colon cancer (HR 1-SD: 1.33; 95% CI 1.001; 1.77) among men and with proximal colon (HR 1-SD: 1.16; 95% CI 1.01; 1.35), pancreatic (HR 1-SD: 1.37; 95% CI 1.13; 1.66), thyroid (HR 1-SD: 1.65; 95% CI 1.33; 2.05), postmenopausal breast (HR 1-SD: 1.17; 95% CI 1.11; 1.22) and endometrial (HR 1-SD: 1.20; 95% CI 1.03; 1.40) cancers in women. These results indicate that higher BMR may be an indicator of a metabolic phenotype associated with risk of certain cancer types, and may be a useful predictor of cancer risk independent of body fatness.

International audience; A substantial proportion of epithelial ovarian cancer (EOC) arises in the fallopian tube and other epithelia of the upper genital tract; these epithelia may incur damage and neoplastic transformation after sexually transmitted infections (STI) and pelvic inflammatory disease. We investigated the hypothesis that past STI infection, particularly Chlamydia trachomatis, is associated with higher EOC risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort including 791 cases and 1669 matched controls. Serum antibodies against C. trachomatis, Mycoplasma genitalium, herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) 16, 18 and 45 were assessed using multiplex fluorescent bead-based serology. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) comparing women with positive vs. negative serology. A total of 40% of the study population was seropositive to at least one STI. Positive serology to C. trachomatis Pgp3 antibodies was not associated with EOC risk overall, but with higher risk of the mucinous histotype (RR = 2.30 [95% CI = 1.22-4.32]). Positive serology for chlamydia heat shock protein 60 (cHSP60-1) was associated with higher risk of EOC overall (1.36 [1.13-1.64]) and with the serous subtype (1.44 [1.12-1.85]). None of the other evaluated STIs were associated with EOC risk overall; however, HSV-2 was associated with higher risk of endometrioid EOC (2.35 [1.24-4.43]). The findings of our study suggest a potential role of C. trachomatis in the carcinogenesis of serous and mucinous EOC, while HSV-2 might promote the development of endometrioid disease.

The hypothesis that pain can predispose to frailty development has been recently investigated in several clinical studies suggesting that frailty and pain may share some mechanisms. Both pain and frailty represent important clinical and social problems and both lack a successful treatment. This circumstance is mainly due to the absence of in-depth knowledge of their pathological mechanisms. Evidence of shared pathways between frailty and pain are preliminary. Indeed, many clinical studies are observational and the impact of pain treatment, and relative pain-relief, on frailty onset and progression has never been investigated. Furthermore, preclinical research on this topic has yet to be performed. Specific researches on the pain-frailty relation are needed. In this narrative review, we will attempt to point out the most relevant findings present in both clinical and preclinical literature on the topic, with particular attention to genetics, epigenetics and inflammation, in order to underline the existing gaps and the potential future interventional strategies. The use of pain and frailty animal models discussed in this review might contribute to research in this area.