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Background Endometrial cancer risk stratification may help target interventions, screening, or prophylactic hysterectomy to mitigate the rising burden of this cancer. However, existing prediction models have been developed in select cohorts and have not considered genetic factors. Methods We developed endometrial cancer risk prediction models using data on postmenopausal White women aged 45-85 years from 19 case-control studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Relative risk estimates for predictors were combined with age-specific endometrial cancer incidence rates and estimates for the underlying risk factor distribution. We externally validated the models in 3 cohorts: Nurses’ Health Study (NHS), NHS II, and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Results Area under the receiver operating characteristic curves for the epidemiologic model ranged from 0.64 (95% confidence interval [CI] = 0.62 to 0.67) to 0.69 (95% CI = 0.66 to 0.72). Improvements in discrimination from the addition of genetic factors were modest (no change in area under the receiver operating characteristic curves in NHS; PLCO = 0.64 to 0.66). The epidemiologic model was well calibrated in NHS II (overall expected-to-observed ratio [E/O] = 1.09, 95% CI = 0.98 to 1.22) and PLCO (overall E/O = 1.04, 95% CI = 0.95 to 1.13) but poorly calibrated in NHS (overall E/O = 0.55, 95% CI = 0.51 to 0.59). Conclusions Using data from the largest, most heterogeneous study population to date (to our knowledge), prediction models based on epidemiologic factors alone successfully identified women at high risk of endometrial cancer. Genetic factors offered limited improvements in discrimination. Further work is needed to refine this tool for clinical or public health practice and expand these models to multiethnic populations.

Aims This study aimed to evaluate the association between physical activity and the incidence of coronary heart disease (CHD) in individuals with and without CHD risk factors. Methods and results EPIC-CVD is a case-cohort study of 29 333 participants that included 13 582 incident CHD cases and a randomly selected sub-cohort nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Self-reported physical activity was summarized using the Cambridge physical activity index (inactive, moderately inactive, moderately active, and active). Participants were categorized into sub-groups based on the presence or the absence of the following risk factors: obesity (body mass index ≥30 kg/m2), hypercholesterolaemia (total cholesterol ≥6.2 mmol/L), history of diabetes, hypertension (self-reported or ≥140/90 mmHg), and current smoking. Prentice-weighted Cox regression was used to assess the association between physical activity and incident CHD events (non-fatal and fatal). Compared to inactive participants without the respective CHD risk factor (referent), excess CHD risk was highest in physically inactive and lowest in moderately active participants with CHD risk factors. Corresponding excess CHD risk estimates amongst those with obesity were 47% [95% confidence interval (CI) 32–64%] and 21% (95%CI 2–44%), with hypercholesterolaemia were 80% (95%CI 55–108%) and 48% (95%CI 22–81%), with hypertension were 80% (95%CI 65–96%) and 49% (95%CI 28–74%), with diabetes were 142% (95%CI 63–260%), and 100% (95%CI 32–204%), and amongst smokers were 152% (95%CI 122–186%) and 109% (95%CI 74–150%). Conclusions In people with CHD risk factors, moderate physical activity, equivalent to 40 mins of walking per day, attenuates but does not completely offset CHD risk.

Background Socio-economic inequalities in mortality are well established, yet the contribution of intermediate risk factors that may underlie these relationships remains unclear. We evaluated the role of multiple modifiable intermediate risk factors underlying socio-economic-associated mortality and quantified the potential impact of reducing early all-cause mortality by hypothetically altering socio-economic risk factors. Methods Data were from seven cohort studies participating in the LIFEPATH Consortium (total n = 179 090). Using both socio-economic position (SEP) (based on occupation) and education, we estimated the natural direct effect on all-cause mortality and the natural indirect effect via the joint mediating role of smoking, alcohol intake, dietary patterns, physical activity, body mass index, hypertension, diabetes and coronary artery disease. Hazard ratios (HRs) were estimated, using counterfactual natural effect models under different hypothetical actions of either lower or higher SEP or education. Results Lower SEP and education were associated with an increase in all-cause mortality within an average follow-up time of 17.5 years. Mortality was reduced via modelled hypothetical actions of increasing SEP or education. Through higher education, the HR was 0.85 [95% confidence interval (CI) 0.84, 0.86] for women and 0.71 (95% CI 0.70, 0.74) for men, compared with lower education. In addition, 34% and 38% of the effect was jointly mediated for women and men, respectively. The benefits from altering SEP were slightly more modest. Conclusions These observational findings support policies to reduce mortality both through improving socio-economic circumstances and increasing education, and by altering intermediaries, such as lifestyle behaviours and morbidities.

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.

Backgrounds Socio-economic position (SEP) is linked to many health outcomes but the link between SEP and breast cancer (BC) is complex. This study explores the relationship between SEP from early life and future risk of BC. Methods We used data from the Italian component of the European prospective investigation into cancer and nutrition: EPIC-Italy (up to 26,391 women). Cox proportional hazard models were used to estimate the association between measures of life course SEP (father’s occupation, educational level, highest household occupation) with risk of BC, adjusting for health behaviours (smoking, alcohol, physical activity, Mediterranean diet), height, weight and reproductive factors (postmenopausal status, age at first full term pregnancy). To mimic life course experiences, we analysed the relationship between father’s occupation and risk of BC, sequentially adjusting for SEP in young adulthood and adulthood, as well as the impact of social mobility. Results We observed a significant association between father’s occupation and risk of BC, where participant with low SEP had lower risk to develop BC (HR[95%CI] = 0.88[0.78; 0.99]). This association was borderline significant when we analysed educational level and highest household occupation. These associations were only slightly modified after adjustment for health behaviours, height and weight but more strongly affected by reproductive factors. However, the association between father’s occupation and BC remained borderline significant in the fully adjusted model (HR[95%CI] = 0.91[0.80; 1.03]). Stable low trajectory showed a lower risk of BC (HR[95%CI] = 0.82[0.71; 0.96]) slightly attenuated after adjusted for reproductive factors (HR[95%CI] = 0.88 [0.75; 1.03]). Conclusions Our findings suggest that low early-life SEP and stable low trajectory are associated with a lower risk of BC, which is partly explained by reproductive factors. Key messages Low early life socioeconomic position and stable low trajectory are associated with a lower risk of BC. Reproductive factors, especially age at the first full term pregnancy, explain part of these associations.

Background Breast cancer (BC) is the malignant tumor with the highest incidence in women in the world with an estimate of about 500,000 new cases per year in Europe. Guidelines for BC treatment include surgery followed by radiotherapy, hormonal therapy or chemotherapy. Several studies showed that BC treatment increases the risk of myocardial infarction (MI) while only few studies investigated the risk of stroke after BC. The aim of the present study was to assess the risk of MI and stroke in BC survivors, taking into account the possible influence of treatments. Methods Women included in the study are part of a longitudinal cohort including all residents in the Piedmont region linked to the 2011 census data and followed-up through administrative data on mortality, hospital admissions, drug prescriptions, and outpatient consultations. Validated algorithms to identify BC incident cases and their therapies as well as to identify MI and stroke were applied. The effect of BC on the risk of MI and stroke was tested using Cox models (adjusted for confounding variables) that allow to account for the competing risks. First, BC patients were compared to healthy women, then BC women that undertwent a specific therapy were compared with both healthy women and other BC patients. Results Women with BC showed an increased risk compared to healthy women for both MI (HR: 1.20; 95% CI: 1.05-1.38) and stroke (HR: 1.58; 95%CI: 1.38-1.82). Chemotherapy almost doubled the risk of MI, while radiotherapy did not seem to have a similar effect, even comparing with other BC patients. The high risk of stroke observed comparing BC (any therapy) with healthy women disappeared when comparing specific therapies among BC patients. Conclusions Chemotherapy increased the risk of MI in BC patients, while recent radiotherapy strategies had less impact, if any. Moreover, the mechanism for which BC patients have an increased risk of stroke seems not to be related to a late effect of therapies. Key messages Breast cancer women are at higher risk of developing cardio and cerebrovascular diseases and this should be taken into account when planning therapies and follow-up surveillance. Despite the increase in quality of the therapeutic approaches for breast cancer patients, chemotherapy increases the risk of myocardial infarction, while radiotherapy dangerousness recently decreased.

BACKGROUND: In humans, low socioeconomic status (SES) across the life course is associated with greater diurnal cortisol production, increased inflammatory activity and higher circulating antibodies for several pathogens, all suggesting a dampened immune response. Recent evidence suggests that DNA methylation of pro-inflammatory genes may be implicated in the biological embedding of the social environment. METHODS: The present study examines the association between life-course SES and DNA methylation of candidate genes, selected on the basis of their involvement in SES-related inflammation, in the context of a genome-wide methylation study. Participants were 857 healthy individuals sampled from the EPIC Italy prospective cohort study. RESULTS: Indicators of SES were associated with DNA methylation of genes involved in inflammation. NFATC1, in particular, was consistently found to be less methylated in individuals with low vs high SES, in a dose-dependent manner. IL1A, GPR132 and genes belonging to the MAPK family were also less methylated among individuals with low SES. In addition, associations were found between SES and CXCL2 and PTGS2, but these genes were consistently more methylated among low SES individuals. CONCLUSIONS: Our findings support the hypothesis that the social environment leaves an epigenetic signature in cells. Although the functional significance of SES-related DNA methylation is still unclear, we hypothesize that it may link SES to chronic disease risk.

In this study, the relation between fruit and vegetable consumption and mortality was investigated within the European Prospective Investigation Into Cancer and Nutrition. Survival analyses were performed, including 451,151 participants from 10 European countries, recruited between 1992 and 2000 and followed until 2010. Hazard ratios, rate advancement periods, and preventable proportions to respectively compare risk of death between quartiles of consumption, to estimate the period by which the risk of death was postponed among high consumers, and to estimate proportions of deaths that could be prevented if all participants would shift their consumption 1 quartile upward. Consumption of fruits and vegetables was inversely associated with all-cause mortality (for the highest quartile, hazard ratio = 0.90, 95% confidence interval (CI): 0.86, 0.94), with a rate advancement period of 1.12 years (95% CI: 0.70, 1.54), and with a preventable proportion of 2.95%. This association was driven mainly by cardiovascular disease mortality (for the highest quartile, hazard ratio = 0.85, 95% CI: 0.77, 0.93). Stronger inverse associations were observed for participants with high alcohol consumption or high body mass index and suggested in smokers. Inverse associations were stronger for raw than for cooked vegetable consumption. These results support the evidence that fruit and vegetable consumption is associated with a lower risk of death.

Contains fulltext : 167299.pdf (Publisher’s version ) (Closed access) Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 x 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 x 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 x 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC. info:eu-repo/grantAgreement/EC/FP7/018827 info:eu-repo/grantAgreement/EC/FP7/218071 Radboud University Nijmegen Medical Centre (RUNMC) Prinses Beatrix Fonds VSB Fonds National Institute of Mental Health (NIH/NIMH) MH078075 Cancer Research UK Yorkshire Cancer Research European Union 513943 Compagnia di San Paolo-Human Genetics Foundation (HuGeF) Italian Association for Cancer Research, Italy Piedmont Region Progetti di Ricerca Sanitaria Finalizzata Flemish government Belgian province of Limburg Swedish Cancer Society Swedish Research Council Shiraz Institute for Cancer Research Shiraz, Iran ICR-87-502 Red Tematica de Investigacion Cooperativa en Cancer RD06/0020/1054

Udgivelsesdato: 2010-Oct-20 Estrogen-only menopausal hormone therapy (HT) increases the risk of endometrial cancer, but less is known about the association with other types of HT. Using Cox proportional hazards regression, the authors examined the association of various types of HT with the risk of endometrial cancer among 115,474 postmenopausal women recruited into the European Prospective Investigation into Cancer and Nutrition between 1992 and 2000. After a mean follow-up period of 9 years, 601 incident cases of endometrial cancer were identified. In comparison with never users of HT, risk of endometrial cancer was increased among current users of estrogen-only HT (hazard ratio (HR) = 2.52, 95% confidence interval (CI): 1.77, 3.57), tibolone (HR = 2.96, 95% CI: 1.67, 5.26), and, to a lesser extent, estrogen-plus-progestin HT (HR = 1.41, 95% CI: 1.08, 1.83), although risks differed according to regimen and type of progestin constituent. The association of HT use with risk was stronger among women who were older, leaner, or had ever smoked cigarettes. The finding of a strong increased risk of endometrial cancer with estrogen-only HT and a weaker association with combined HT supports the hypothesis that progestins have an attenuating effect on endometrial cancer risk. The increased risk associated with tibolone use requires further investigation.

The associations of dietary total carbohydrates, overall glycemic index, total dietary glycemic load, total sugars, total starch, and total fiber with endometrial cancer risk were analyzed among 288,428 women in the European Prospective Investigation into Cancer and Nutrition cohort (1992-2004), including 710 incident cases diagnosed during a mean 6.4 years of follow-up. Cox proportional hazards models were used to estimate relative risks and 95% confidence intervals. There were no statistically significant associations with endometrial cancer risk for increasing quartile intakes of any of the exposure variables. However, in continuous models calibrated by using 24-hour recall values, the multivariable relative risks were 1.61 (95% confidence interval: 1.06, 2.45) per 100 g/day of total carbohydrates, 1.40 (95% confidence interval: 0.99, 1.99) per 50 units/day of total dietary glycemic load, and 1.36 (95% confidence interval: 1.05, 1.76) per 50 g/day of total sugars. These associations were stronger among women who had never used postmenopausal hormone therapy compared with ever users (total carbohydrates P-heterogeneity = 0.04). Data suggest no association of overall glycemic index, total starch, and total fiber with risk, and a possible modest positive association of total carbohydrates, total dietary glycemic load, and total sugars with risk, particularly among never users of hormone replacement therapy.

We have conducted a randomized trial which investigated the ability of dietary changes (in particular diets rich in cruciferous vegetables and flavonoids), to increase urinary antimutagenicity and inhibit DNA damage in smokers. Ninety heavy smokers were recruited and randomly assigned to three groups, and were given three different diets. The first diet was based on flavonoid-rich foods, particularly cruciferous vegetables, but not based on supplementation; the second was a normal isocaloric diet (with an adequate administration of fruits and vegetables); and the third was based on supplementation of flavonoids in the form of green tea and soy products. DNA adducts were measured by (32)P-postlabelling in exfoliated bladder cells at different times since the start of the trial. In spite of randomization, subjects in the control group smoked more than those in the experimental groups, and this can explain the higher adduct levels at baseline. A slight decrease in bulky DNA adducts in exfoliated bladder cells was observed after 1 year since the end in the supplementation group and after 1 month in white blood cells. The only statistically significant association was found in a regression model that adjusted for smoking, in which the increase in flavonoid intake was associated with a decrease in adducts after 1 year (P = 0.02). These data suggest that adherence to a diet rich in cruciferous vegetables and flavonoids might reduce genotoxicity in the human urinary bladder of smokers, but they should be interpreted with caution owing to small numbers and the uneven distribution of smoking habits in the experimental groups. Smoking is the most important single preventable cause of cancer; at the present stage of knowledge it is totally unlikely that certain dietary habits can seriously counteract the effects of tobacco smoking.

Background In humans, low socioeconomic status across the lifecourse is associated with greater diurnal cortisol production, increased inflammatory activity, and higher circulating antibodies for several pathogens, all suggesting a dampened immune response. Recent evidence suggests that DNA methylation of pro-inflammatory genes may be implicated in the …

Helicobacter pylori has been suggested as a cause of gastric carcinoma and gastric non-Hodgkin's lymphoma (NHL). In a previous cohort study, a relative risk of six for gastric NHL was reported among subjects who tested positive for anti-H.pylori antibodies. The association between peptic ulcer and NHL has been studied in a population-based case-control investigation on hemato-lymphopoietic malignancies in Italy, based on face-to-face interviews to 2671 cases and 1718 controls (refusal rates 10 and 19%, respectively). Subjects who reported a diagnosis of peptic ulcer had a relative risk of 5.6 [95% confidence interval (CI) 3.8-8.0] for gastric NHL, whereas the estimate for non-gastric NHL was 1.3 (1.0-1.6). The association with recent diagnosis of ulcer was stronger, but the odds ratio (OR) was as high as 2.1 (95% CI 1.1-4.2) after/=20 years since such diagnosis. After exclusion of the last 2 years before the diagnosis of NHL, and of ulcers diagnosed before 1978 (when gastroscopy became common in Italy), the OR was still 5.3 (95% CI 3.0-9.2). We found a strong effect modification by educational level, with ORs for ulcer more elevated in higher social groups. Gender was an effect modifier (OR = 4.1 in males, 9.2 in females; P = 0.03 for heterogeneity). The association with other gastrointestinal pathologies was much lower and statistically not significant. Almost all gastric lymphomas were B-cell NHLs of intermediate grade according to the working formulation; the majority belonged to the mucosa-associated lymphoid tissue (MALT) type. The association with ulcer was much stronger among MALT lymphomas, but only for recent ulcer diagnoses (2-10 years). Our study shows an increased risk for gastric NHL, very similar to the estimate reported in a previous cohort study. The risk was higher among more educated subjects.