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Active smoking and the A blood group are associated with pancreatic adenocarcinoma (PC) risk. However, potential interactions between those risk factors and the role of passive smoking have been little investigated. We aimed to explore specific and joint associations of passive and active smoking, and effect modification by the ABO blood group in French women. The study included 96,594 women from the E3N prospective cohort, mean age: 49 years (SD 6.7). Information on active and passive smoking was reported at inclusion and throughout follow‐up. Cases were classified according to the International Classification of Diseases 10. Associations with passive and active smoking and effect modification by the ABO blood group were investigated with multivariable Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI). During a 24‐year median follow‐up, 346 incident PC cases were identified. Current smoking compared with never and former smoking (HR 1.51 [95% CI 1.08–2.10]), and passive smoking in childhood compared with no childhood exposure (HR 1.47 [95% CI 1.08–2.00]) were associated with increased PC risk, but not passive exposure in adulthood (HR 1.16 [95% CI 0.91–1.47]). Exposure to both passive smoking in childhood and current smoking was associated with a stronger risk (HR 2.80 [95% CI 1.42–5.52]) than exposure to both current smoking and passive smoking only in adulthood (HR 1.68 [95% CI 1.10–2.57]) compared with neither passive nor active smoking. Associations between active smoking and PC risk were strongest in the O or B groups, while associations with passive smoking were strongest in the A or AB blood groups, but the interaction terms were not statistically significant. Both current smoking and passive smoking in childhood were associated with PC risk, with a maximal risk of current smokers exposed to passive smoking during childhood. Possible interactions between blood groups and active or passive smoking must be investigated in a larger series.

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.

Many patients affected by COVID-19 suffer from debilitating persistent symptoms whose risk factors remained poorly understood. This prospective study examined the association of depression and anxiety symptoms measured before and at the beginning of the COVID-19 pandemic with the incidence of persistent symptoms. Among 25,114 participants [mean (SD) age, 48.72 years (12.82); 51.1% women] from the SAPRIS and SAPRIS-Sérologie surveys nested in the French CONSTANCES population-based cohort, depression and anxiety symptoms were measured with the Center for Epidemiologic Studies-Depression scale and the 12-item General Health Questionnaire before the pandemic, and with the 9-item Patient Health Questionnaire and the 7-Item Generalized Anxiety Disorder scale at the beginning of the pandemic (i.e., between April 6, 2020 and May 4, 2020). Incident persistent symptoms were self-reported between December 2020 and January 2021. The following variables were also considered: gender, age, educational level, household income, smoking status, BMI, hypertension, diabetes, self-rated health, and SARS-CoV-2 infection according to serology/PCR test results. After a follow-up of seven to ten months, 2329 participants (9.3%) had been infected with SARS-CoV-2 and 4262 (17.0%) reported at least one incident persistent symptom that emerged from March 2020, regardless of SARS-CoV-2 infection. In multi-adjusted logistic regression models, participants in the highest (versus the lowest) quartile of depressive or anxiety symptom levels before or at the beginning of the pandemic were more likely to have at least one incident persistent symptom (versus none) at follow-up [OR (95%CI) ranging from 2.10 (1.89–2.32) to 3.01 (2.68–3.37)], with dose-response relationships (p for linear trend <0.001). Overall, these associations were significantly stronger in non-infected versus infected participants, except for depressive symptoms at the beginning of the pandemic. Depressive symptoms at the beginning of the pandemic were the strongest predictor of incident persistent symptoms in both infected and non-infected participants [OR (95%CI): 2.88 (2.01–4.14) and 3.03 (2.69–3.42), respectively]. In exploratory analyses, similar associations were found for each symptom taken separately in different models. Depression and anxiety symptoms should be tested as a potential target for preventive interventions against persistent symptoms after an infection with SARS-CoV-2.

ABSTRACTLifestyle-related phenotypes have been shown to be heritable and associated with DNA methylation. We aimed to investigate whether genetic predisposition to tobacco smoking, alcohol consumption, and higher body mass index (BMI) moderates the effect of these phenotypes on blood DNA methylation. We calculated polygenic scores (PGS) to quantify genetic predisposition to these phenotypes using training (N= 7,431) and validation (N= 4,307) samples. Using paired genetic-methylation data (N= 4,307), gene–environment interactions (i.e., PGS × lifestyle) were assessed using linear mixed-effects models with outcomes: 1) methylation at sites found to be strongly associated with smoking (1,061 CpGs), alcohol consumption (459 CpGs), and BMI (85 CpGs) and 2) two epigenetic ageing measures, PhenoAgeand GrimAge. In the validation sample, PGS explained ~1.4% (P= 1 × 10−14), ~0.6% (P= 2 × 10−7), and ~8.7% (P= 7 × 10−87) of variance in smoking initiation, alcohol consumption, and BMI, respectively. Nominally significant interaction effects (P< 0.05) were found at 61, 14, and 7 CpGs for smoking, alcohol consumption, and BMI, respectively. There was strong evidence that all lifestyle-related phenotypes were positively associated with PhenoAgeand GrimAge, except for alcohol consumption with PhenoAge. There was weak evidence that the association of smoking with GrimAgewas attenuated in participants genetically predisposed to smoking (interaction term: −0.022, standard error [SE] = 0.012, P= 0.058) and that the association of alcohol consumption with PhenoAgewas attenuated in those genetically predisposed to drink alcohol (interaction term: −0.030, SE = 0.015, P= 0.041). In conclusion, genetic susceptibility to unhealthy lifestyles did not strongly modify the association between observed lifestyle behaviour and blood DNA methylation. Potential associations were observed for epigenetic ageing measures, which should be replicated in additional studies.

We assessed mortality risks associated with source-specific fine particles (PM2.5) in a pooled European cohort of 323,782 participants. Cox proportional hazard models were applied to estimate mortality hazard ratios (HRs) for source-specific PM2.5identified through a source apportionment analysis. Exposure to 2010 annual average concentrations of source-specific PM2.5components was assessed at baseline residential addresses. The source apportionment resulted in the identification of five sources: traffic, residual oil combustion, soil, biomass and agriculture, and industry. In single-source analysis, all identified sources were significantly positively associated with increased natural mortality risks. In multisource analysis, associations with all sources attenuated but remained statistically significant with traffic, oil, and biomass and agriculture. The highest association per interquartile increase was observed for the traffic component (HR: 1.06; 95% CI: 1.04 and 1.08 per 2.86 μg/m3increase) across five identified sources. On a 1 μg/m3basis, the residual oil-related PM2.5had the strongest association (HR: 1.13; 95% CI: 1.05 and 1.22), which was substantially higher than that for generic PM2.5mass, suggesting that past estimates using the generic PM2.5exposure response function have underestimated the potential clean air health benefits of reducing fossil-fuel combustion. Source-specific associations with cause-specific mortality were in general consistent with findings of natural mortality.

BackgroundTraditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted twostage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival. Methods We evaluated possible associations between overall survival after a breast cancer diagnosis and 10621 gerreline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26978 person-years at risk) that were genotyped previously in the SEARCH study with highdensity oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5' nuclease assay or mass spectrometry and overall survival information for up to 14096 patients with invasive breast cancer (including 2303 deaths and 70019 person-years at risk) from 15 international case-control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided. Results In the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gone at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor-negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 x [10.sup.-5]). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P = .03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P= 5 x [10.sup.4]). Conclusion The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer. DOI: 10.1093/jnci/djq057

Background: Some, but not all, published results have shown an association between circulating blood levels of some insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) and the subsequent risk for prostate cancer. Purpose: To assess the association between levels of IGFs and IGFBPs and the subsequent risk for prostate cancer. Data Sources: Studies identified in PubMed, Web of Science, and CancerLit. Study Selection: The principal investigators of all studies that published clata on circulating concentrations of sex steroids, IGFs, or IGFBPs and prostate cancer risk using prospectively collected blood samples were invited to collaborate. Data Extraction: Investigators provided individual participant data on circulating concentrations of IGF-I, IGF-II, IGFBP-II, and IGFBP-III and participant characteristics to a central data set in Oxford, United Kingdom. Data Synthesis: The study included data on 3700 men with prostate cancer and 5200 control participants. On average, case patients were 61.5 years of age at blood collection and received a diagnosis of prostate cancer 5 years after blood collection. The greater the serum IGF-I concentration, the greater the subsequent risk for prostate cancer (odds ratio [OR] in the highest vs. lowest quintile, 1.38 [95% Cl, 1.19 to 1.60]; P < 0.001 for trend). Neither IGF-II nor IGFBP-II concentrations were associated with prostate cancer risk, but statistical power was limited. Insulin-like growth factor I and IGFBP-III were correlated (r = 0.58), and although IGFBP-III concentration seemed to be associated with prostate cancer risk, this was secondary to its association with IGF-I levels. Insulin-like growth factor I concentrations seemed to be more positively associated with low-grade than high-grade disease; otherwise, the association between IGFs and IGFBPs and prostate cancer risk had no statistically significant heterogeneity related to stage or grade of disease, time between blood collection and diagnosis, age and year of diagnosis, prostate-specific antigen level at recruitment, body mass index, smoking, or alcohol intake. Limitations: Insulin-like growth factor concentrations were measured in only 1 sample for each participant, and the laboratory methods to measure IGFs differed in each study. Not all patients had disease stage or grade information, and the diagnosis of prostate cancer may differ among the studies. Conclusion: High circulating IGF-I concentrations are associated with a moderately increased risk for prostate cancer.

Background: The ELAC2 gene has been proposed to be a prostate cancer susceptibility gene and is being referred to as HPC2, in part because three case-control studies suggested that two common polymorphisms (Ser217Leu and Ala541Thr) are associated with risk. However, four subsequent larger studies have not confirmed this association. In five of the seven total studies, subject selection was influenced by prostate-specific antigen (PSA) levels. We examined the association and possible effect of subject selection in a larger study and a meta-analysis. Methods: In a population-based study in Australia, 825 case patients and 732 control subjects were genotyped for the Ser217Leu and Ala541Thr polymorphisms of ELAC2. Odds ratios (ORs) for prostate cancer were estimated by unconditional logistic and polytomous regression. A meta-analysis was conducted combining our data with those from seven published studies. The association of genotype with the logarithm of plasma PSA levels in control subjects was analyzed by linear regression. Results: The ORs for prostate cancer were 0.74 (95% confidence interval [CI] = 0.50 to 1.09) for Leu217 homozygotes and 1.01 (95% CI = 0.68 to 1.50) for Thr541 heterozygotes and homozygotes compared with Ser217 and Ala541 homozygotes, respectively. ORs were not changed by excluding control subjects with elevated PSA levels. Among control subjects, there were no statistically significant associations between genotype frequencies and PSA level for either polymorphism (both P>.4). The meta-analysis gave pooled OR estimates of 1.04 (95% CI = 0.85 to 1.26) for Leu217 homozygotes and 1.18 (OR = 0.98 to 1.42) for Thr541 homozygotes and heterozygotes. Conclusion: There is no evidence that either ELAC2 polymorphism is associated with prostate cancer or PSA level.

Long-term exposure to ambient air pollution has been associated with premature mortality, but associations at concentrations lower than current annual limit values are uncertain. We analysed associations between low-level air pollution and mortality within the multicentre study Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE).

IMPORTANCE: After an infection by SARS-CoV-2, many patients present with persistent physical symptoms that may impair their quality of life. Beliefs regarding the causes of these symptoms may influence their perception and promote maladaptive health behaviors. OBJECTIVE: To examine the associations of self-reported COVID-19 infection and SARS-CoV-2 serology test results with persistent physical symptoms (eg, fatigue, breathlessness, or impaired attention) in the general population during the COVID-19 pandemic. DESIGN, SETTING, AND PARTICIPANTS: Participants in this cross-sectional analysis were 26 823 individuals from the French population-based CONSTANCES cohort, included between 2012 and 2019, who took part in the nested SAPRIS and SAPRIS-SERO surveys. Between May and November 2020, an enzyme-linked immunosorbent assay was used to detect anti–SARS-CoV-2 antibodies. Between December 2020 and January 2021, the participants reported whether they believed they had experienced COVID-19 infection and had physical symptoms during the previous 4 weeks that had persisted for at least 8 weeks. Participants who reported having an initial COVID-19 infection only after completing the serology test were excluded. MAIN OUTCOMES AND MEASURES: Logistic regressions for each persistent symptom as the outcome were computed in models including both self-reported COVID-19 infection and serology test results and adjusting for age, sex, income, and educational level. RESULTS: Of 35 852 volunteers invited to participate in the study, 26 823 (74.8%) with complete data for serologic testing and self-reported infection were included in the present study (mean [SD] age, 49.4 [12.9] years; 13 731 women [51.2%]). Self-reported infection was positively associated with persistent physical symptoms, with odds ratios ranging from 1.44 (95% CI, 1.08-1.90) to 16.61 (95% CI, 10.30-26.77) except for hearing impairment (odds ratio, 1.38; 95% CI, 0.76-2.51), joint pain (odds ratio, 1.32; 95% CI, 0.98-1.80) and sleep problems (odds ratio, 1.12; 95% CI, 0.87-1.44). A serology test result positive for SARS-COV-2 was positively associated only with persistent anosmia (odds ratio, 2.59; 95% CI, 1.57-4.28), even when restricting the analyses to participants who attributed their symptoms to COVID-19 infection. Further adjusting for self-rated health or depressive symptoms yielded similar results. There was no significant interaction between belief and serology test results. CONCLUSIONS AND RELEVANCE: The findings of this cross-sectional analysis of a large, population-based French cohort suggest that persistent physical symptoms after COVID-19 infection may be associated more with the belief in having been infected with SARS-CoV-2 than with having laboratory-confirmed COVID-19 infection. Further research in this area should consider underlying mechanisms that may not be specific to the SARS-CoV-2 virus. A medical evaluation of these patients may be needed to prevent symptoms due to another disease being erroneously attributed to “long COVID.”

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.

Unhealthy diets, the rise of non-communicable diseases, and the declining health of the planet are highly intertwined, where food production and consumption are major drivers of increases in greenhouse gas emissions, substantial land use, and adverse health such as cancer and mortality. To assess the potential co-benefits from shifting to more sustainable diets, we aimed to investigate the associations of dietary greenhouse gas emissions and land use with all-cause and cause-specific mortality and cancer incidence rates.

ABSTRACTWe conducted a genome-wide association study of blood DNA methylation and smoking, attempted replication of previously discovered associations, and assessed the reversibility of smoking-associated methylation changes. DNA methylation was measured in baseline peripheral blood samples for 5,044 participants in the Melbourne Collaborative Cohort Study. For 1,032 participants, these measures were repeated using blood samples collected at follow-up, a median of 11 years later. A cross-sectional analysis of the association between smoking and DNA methylation and a longitudinal analysis of changes in smoking status and changes in DNA methylation were conducted. We used our cross-sectional analysis to replicate previously reported associations for current (N = 3,327) and former (N = 172) smoking. A comprehensive smoking index accounting for the biological half-life of smoking compounds and several aspects of smoking history was constructed to assess the reversibility of smoking-induced methylation changes. This measure of lifetime exposure to smoking allowed us to detect more associations than comparing current with never smokers. We identified 4,496 cross-sectional associations at P < 10−7, including 3,296 annotated to 1,326 genes that were not previously implicated in smoking-associated DNA methylation changes at this significance threshold. We replicated the majority of previously reported associations (P < 10−7) for current and former smokers. In our data, we observed for former smokers a substantial degree of return to the methylation levels of never smokers, compared with current smokers (median: 74%, IQR = 63-86%), corresponding to small values (median: 2.75, IQR = 1.5–5.25) for the half-life parameter of the comprehensive smoking index. Longitudinal analyses identified 368 sites at which methylation changed upon smoking cessation. Our study demonstrates the usefulness of the comprehensive smoking index to detect associations between smoking and DNA methylation at CpGs across the genome, replicates the vast majority of previously reported associations, and quantifies the reversibility of smoking-induced methylation changes.

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale= 1.71 × 10−8compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90–1.07], Pfemale= 0.68) and 12q23.3 (intergenic, ORmale= 0.75 [95% CI = 0.68-0.83], Pmale= 1.59 × 10−8compared with ORfemale= 0.93 [95% CI = 0.82–1.06], Pfemale= 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.

•During the first wave of the pandemic in France, the estimated overall infection hospitalization ratio (IHR, probability of hospitalization in infected adults) was 2.7%.•At that time, the estimated overall infection fatality ratio (IFR, probability of death in infected adults) was 0.49%.•Both IHR and IFR were higher in men.•IHR approximately doubled every 10 years while IFR doubled every 5 years.•IFR should not be neglected, even in young and middle-aged adults (0.042% in individuals aged 40-50 years).

Background: Epidemiological studies suggest that haem iron, which is found predominantly in red meat and increases endogenous formation of carcinogenic N-nitroso compounds, may be positively associated with lung cancer. The objective was to examine the relationship between haem iron intake and lung cancer risk using detailed smoking history data and serum cotinine to control for potential confounding. Methods: In the European Prospective Investigation into Cancer and Nutrition (EPIC), 416,746 individuals from 10 countries completed demographic and dietary questionnaires at recruitment. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident lung cancer (n?=?3731) risk relative to haem iron, non-haem iron, and total dietary iron intake. A corresponding analysis was conducted among a nested subset of 800 lung cancer cases and 1489 matched controls for whom serum cotinine was available. Results: Haem iron was associated with lung cancer risk, including after adjustment for details of smoking history (time since quitting, number of cigarettes per day): as a continuous variable (HR per 0.3?mg/1000?kcal 1.03, 95% CI 1.00–1.07), and in the highest versus lowest quintile (HR 1.16, 95% CI 1.02–1.32; trend across quintiles: P?=?0.035). In contrast, non-haem iron intake was related inversely with lung cancer risk; however, this association attenuated after adjustment for smoking history. Additional adjustment for serum cotinine did not considerably alter the associations detected in the nested case–control subset. Conclusions: Greater haem iron intake may be modestly associated with lung cancer risk.

ObjectiveTo systematically identify and validate published colorectal cancer risk prediction models that do not require invasive testing in two large population-based prospective cohorts.DesignModels were identified through an update of a published systematic review and validated in the European Prospective Investigation into Cancer and Nutrition (EPIC) and the UK Biobank. The performance of the models to predict the occurrence of colorectal cancer within 5 or 10 years after study enrolment was assessed by discrimination (C-statistic) and calibration (plots of observed vs predicted probability).ResultsThe systematic review and its update identified 16 models from 8 publications (8 colorectal, 5 colon and 3 rectal). The number of participants included in each model validation ranged from 41 587 to 396 515, and the number of cases ranged from 115 to 1781. Eligible and ineligible participants across the models were largely comparable. Calibration of the models, where assessable, was very good and further improved by recalibration. The C-statistics of the models were largely similar between validation cohorts with the highest values achieved being 0.70 (95% CI 0.68 to 0.72) in the UK Biobank and 0.71 (95% CI 0.67 to 0.74) in EPIC.ConclusionSeveral of these non-invasive models exhibited good calibration and discrimination within both external validation populations and are therefore potentially suitable candidates for the facilitation of risk stratification in population-based colorectal screening programmes. Future work should both evaluate this potential, through modelling and impact studies, and ascertain if further enhancement in their performance can be obtained.

Monozygotic twins have long been studied to estimate heritability and explore epigenetic influences on phenotypic variation. The phenotypic and epigenetic similarities of monozygotic twins have been assumed to be largely due to their genetic identity. Here, by analyzing data from a genome-scale study of DNA methylation in monozygotic and dizygotic twins, we identified genomic regions at which the epigenetic similarity of monozygotic twins is substantially greater than can be explained by their genetic identity. This “epigenetic supersimilarity” apparently results from locus-specific establishment of epigenotype prior to embryo cleavage during twinning. Epigenetically supersimilar loci exhibit systemic interindividual epigenetic variation and plasticity to periconceptional environment and are enriched in sub-telomeric regions. In case-control studies nested in a prospective cohort, blood DNA methylation at these loci years before diagnosis is associated with risk of developing several types of cancer. These results establish a link between early embryonic epigenetic development and adult disease. More broadly, epigenetic supersimilarity is a previously unrecognized phenomenon that may contribute to the phenotypic similarity of monozygotic twins.

Information on sunscreens should warn against excessive sun exposure EDITOR--We approve of Diffey's proposition to clarify the information about sunscreens by abandoning numerical labelling and instead using measures focusing more [...]

IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

In 2011, WHO member states signed up to the 25 × 25 initiative, a plan to cut mortality due to non-communicable diseases by 25% by 2025. However, socioeconomic factors influencing non-communicable diseases have not been included in the plan. In this study, we aimed to compare the contribution of socioeconomic status to mortality and years-of-life-lost with that of the 25 × 25 conventional risk factors.

Objective:To present long‐term survival data from the Victorian Radical Prostatectomy Register (VRPR), 1995–2000, and analyse the effect of rural residence on survival.

Epidemiological studies on statin use in relation to skin cancer risk are scarce and yielded conflicting results. We explored this association in Etude Epidémiologique auprès de femmes de l’Education Nationale, a prospective cohort of French women born in 1925–1950. Health and lifestyle data were self-reported biennially and matched with drug reimbursement data, allowing the identification of participants’ statin use since 2004. Multivariable cause-specific hazards regression models adjusted for skin cancer risk factors estimated hazard ratios with 95% confidence intervals. Over 2004–2014, 455 cutaneous melanoma, 1,741 basal cell carcinoma, and 268 squamous cell carcinoma cases were ascertained among 62,473 women. Compared with never use, there were no associations between ever use of statins and melanoma (hazard ratio = 1.16, 95% confidence interval = 0.94–1.44) or squamous cell carcinoma (hazard ratio = 0.89, 95% confidence interval = 0.66–1.19) risks and a decrease in basal cell carcinoma risk with ever use of statins (hazard ratio = 0.89, 95% confidence interval = 0.79–0.996). We found no trend of increasing or decreasing risks with dose, duration of use, time since first use, or age at first use and no statistically significant effect modification by pigmentary traits or residential UVR exposure. Because of the limited number of studies evaluating the associations between the use of statins and the risks of melanoma, basal cell carcinoma, and squamous cell carcinoma, these findings would deserve further investigation in other settings.

NKX3.1 is a tumor suppressor down-regulated in early prostate cancers. A SNP (rs2228013), which represents a polymorphic NKX3.1(C154T) coding for a variant protein NKX3.1(R52C), is present in 10% of the population and is related to prostatic enlargement and prostate cancer. We investigated rs2228013 in prostate cancer risk for 937 prostate cancer cases and 1,086 age-matched controls from a nested case-control study within the prospective Physicians’ Health Study (PHS) and among 798 cases and 527 controls retrospectively collected in the Risk Factors for Prostate Cancer Study of the Victoria Cancer Council (RFPCS). We also investigated the interaction between serum IGF-I levels and NKX3.1genotype in the populations from PHS and RFPCS. In the PHS, we found no overall association between the variant T allele in rs2228013 in NKX3.1and prostate cancer risk (odd ratio = 1.25; 95% confidence interval = 0.92-1.71). A subgroup analysis for cases diagnosed before age 70 showed an increased risk (relative risk = 1.55; 95% confidence interval = 1.04-2.31) of overall prostate cancer. In this age-group, the risk of metastatic cancer at diagnosis or of fatal cancer was even higher in carriers of the T allele (relative risk = 2.15; 95% confidence interval = 1.00-4.63). These associations were not replicated in the RFPCS. Serum IGF-I levels were found to be a risk factor for prostate cancer in both study populations. The wild type NKX3.1 protein can induce IGFBP-3 expression in vitro. We report that variant NKX3.1 cannot induce IGFBP-3 expression, but the NKX3.1genotype does not modify the association between serum IGF-I levels and prostate cancer risk.

Insulin-like growth factor-1 (IGF-1), insulin, and IL-6 are dysregulated in multiple myeloma pathogenesis and may also contribute to multiple myeloma etiology. To examine their etiologic role, we prospectively analyzed concentrations of serologic markers in 493 multiple myeloma cases and 978 controls from 8 cohorts in the Multiple Myeloma Cohort Consortium. We computed odds ratios (ORs) and 95% confidence intervals (CIs) for multiple myeloma per 1-SD increase in biomarker concentration using conditional logistic regression. We examined heterogeneity by time since blood collection (≤ 3, 4- ≤ 6, and > 6 years) in stratified models. Fasting IGF binding protein-1 concentration was associated with multiple myeloma risk within 3 years (OR, 95% CI per 1-SD increase: 2.3, 1.4-3.8, P= .001) and soluble IL-6 receptor level was associated within 6 years after blood draw (OR ≤ 3 years, 95% CI, 1.4, 1.1-1.9, P= .01; OR4- ≤ 6 years, 95% CI, 1.4, 1.1-1.7, P= .002). No biomarker was associated with longer-term multiple myeloma risk (ie, > 6 years). Interactions with time were statistically significant (IGF binding protein-1, P-heterogeneity = .0016; sIL6R, P-heterogeneity = .016). The time-restricted associations probably reflect the bioactivity of tumor and microenvironment cells in transformation from monoclonal gammopathy of undetermined significance or smoldering multiple myeloma to clinically manifest multiple myeloma.

Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium. We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects. These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar. The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified.

UDP glucuronosyltransferase 2B17 is present in the prostate, where it catalyzes the addition of glucuronic acid to testosterone and dihydrotestosterone and their metabolites androsterone and androstane-3α,17β-diol. Hence, changes in UGT2B17 gene expression may affect the capacity of the prostate to inactivate and eliminate male sex hormones. In this work, we identify a prevalent polymorphism, –155G/A, in the proximal promoter of the UGT2B17 gene. This polymorphism modulates UGT2B17 promoter activity, because luciferase-gene reporter constructs containing the –155A allele were 13-fold more active than those containing the –155G allele in prostate cancer LNCaP cells. The –155G/A polymorphism is contained within a putative binding site for the transcription factor Forkhead Box A1 (FOXA1). Using gene reporter, electromobility shift, and chromatin immunoprecipitation analyses, we show that FOXA1 binds to this site and stimulates the UGT2B17 promoter. Furthermore, down-regulation of FOXA1 in LNCaP cells substantially reduces UGT2B17 mRNA levels. The binding of FOXA1 and subsequent stimulation of the UGT2B17 promoter is greatly reduced in the presence of the –155G allele compared with the –155A allele. Consonant with its capacity to be stimulated by FOXA1, the UGT2B17 –155A allele, compared with the –155G allele, is associated with higher levels of circulating androstane-3α,17β-diol glucuronide. Although the initial phases of prostate cancer are androgen-dependent and UGT2B17 inactivates androgens, there was no association of the UGT2B17 –155G/A polymorphism with prostate cancer risk. In summary, this work identifies FOXA1 as an important regulator of UGT2B17 expression in prostate cancer LNCaP cells and identifies a polymorphism that alters this regulation.

Objective:Radical prostatectomy (RP) as a first line treatment of prostate cancer was rare prior to the advent of prostate specific antigen (PSA) testing, yet little is known of its use and outcomes in a population setting. We described baseline characteristics of cases in the Victorian Radical Prostatectomy Register (VRPR), investigated possible associations between demographic characteristics and characteristics at diagnosis and at surgery and trends over time. Methods:The VRPR is a population‐based series of all RPs performed in Victoria from July 1995 to December 2000 (n=2,154). Results:On average, socio‐economic status for cases was higher than for the general Victorian population (34% vs 20% in the highest quintile respectively, p<0.0001). The proportion of PSA‐detected cases increased from 53% in 1995 to 79% in 2000 (pfor linear trend=0.0004). Age at surgery and PSA levels at diagnosis decreased over time (p=0.006 and p=0.04 respectively). The proportion of cases with Gleason score ≤5 from RP decreased from 35% in 1995 to 14% in 2000, while cases with Gleason score 6‐7 increased from 60% to 79%. Similar trends were observed for Gleason score from biopsy. We found little evidence of significant trends over time in other pathological characteristics relevant to prognosis. Conclusion and Implications:The VRPR provides a unique whole of population based description of radical prostatectomy in Victoria, confirms findings previously reported in single institution clinical series overseas such as migration to younger age at surgery and to Gleason scores 6 to 7, and provides a resource for evaluating RP outcomes in the future.

The aim of the Tyrol study was to monitor the impact of screening in a natural experiment by comparing prostate cancer mortality in Tyrol, where prostate-specific antigen (PSA) testing was introduced at no charge, with the rest of Austria, where it was not strictly organized and not free of charge. In 1993, PSA testing was made freely available to men between the ages of 45 and 75 years in the Federal State of Tyrol, Austria. At least 70% of all of the men in this age range have been tested at least once during the first 10 years of the study. Initially, only total PSA was measured, but free PSA measurement was added in 1995. Since 2001, complexed PSA also has been measured. Digital rectal examination was not part of the screening examination. Significant migration to lower clinical and pathological stages has been observed since the introduction of this screening program. These findings are consistent with the hypothesis that the policy of making PSA testing freely available, and the wide acceptance by men in the population, is associated with a reduction in prostate cancer mortality in an area in which urology services and radiotherapy are available freely to all patients. It is our opinion that most of this decline is likely a result of aggressive downstaging and successful treatment and that any contribution from detecting and treating early cancers will become apparent in the years to come.

Objective: To examine the risk of prostate cancer associated with foods and nutrients, including individual fatty acids and carotenoids. Methods: Population-based case–control study of 858 men aged <70 years at diagnosis with histologically confirmed prostate cancer of Gleason Grade 5 or greater, and 905 age-frequency-matched men, selected at random from the electoral rolls. Dietary intakes were assessed with a 121-item food frequency questionnaire. Results: Inverse associations with prostate cancer were observed for (Odds ratio, OR, 95% confidence intervals, 95% CI for tertile III compared with tertile I) allium vegetables 0.7, 0.5–0.9; ptrend 0.01, tomato-based foods 0.8, 0.6–1.0; ptrend 0.03 and total vegetables 0.7, 0.5–1.0; ptrend 0.04. Margarine intake was positively associated with prostate cancer 1.3, 1.0–1.7; ptrend 0.04. The only statistically significant associations observed with nutrients were weak inverse associations for palmitoleic acid (ptrend 0.04), fatty acid 17:1 (ptrend 0.04), and 20:5 n-6 (ptrend 0.05); and a non-significant trend for oleic acid (ptrend 0.09). Neither total, nor beverage-specific, intake of alcohol was associated with risk. Conclusions: Based on these findings, diets rich in olive oil (a source of oleic acid), tomatoes and allium vegetables might reduce the risk of prostate cancer.

A Phase II trial in children with advanced neuroblastoma was carried out in five Italian institutions to evaluate the antitumor activity and tolerability of topotecan followed by vincristine and doxorubicin. Children older than age 1 year with Stage III or Stage IV neuroblastoma, all of whom had been treated previously with chemotherapy and were diagnosed with either refractory or recurrent disease, were treated with topotecan at an intravenous dose of 1.5 mg/m² (the dose was 0.75 mg/m² for patients who were treated within 1 year of previous megatherapy) per day for 5 days followed by 48-hour intravenous infusions of 2 mg/m² vincristine and 45 mg/m² doxorubicin. Cycles of therapy were repeated every 3 weeks. Twenty-five patients (2 with Stage III disease and 23 with Stage IV disease; 19 with refractory disease and 6 with recurrent disease) were treated with a total of 115 cycles. Four patients had complete responses, 12 patients had partial responses, 4 patients had minor responses or stable disease, and 5 patients had tumor progression. The overall response rate (including complete and partial responses) was 64% (95% confidence interval, 43–82%). Fifteen patients were alive at the time of the current report and were progression free at 4–16 months (median, 9 months) after the first course of this treatment. Toxicity generally was limited to the hematopoietic system. Dose-limiting toxicity was observed in only 1 patient (Grade 4 liver toxicity). There were no deaths due to infectious or toxic causes. The topotecan-vincristine-doxorubicin combination was active and well tolerated in previously treated patients with advanced neuroblastoma. Cancer 2003. © 2003 American Cancer Society.

Objective: The solar wavelength involved in melanoma occurrence remains unknown. Sunburns and latitude gradient are indicators of greater exposure to the ultraviolet B radiation. We examined the associations between the components of holiday sun exposure with numbers of small (2–4.9 mm) and large nevi (≥5 mm) in young children. Methods: Information about each holiday period from birth to interview was recorded from parents of 628 6–7-year-old children in four European countries. Sun exposure was characterized using four different components: cumulative duration of holidays, number of holiday periods, sunburn episodes and latitude gradient between habitual living place and holiday places. Results: Individual susceptibility to sunlight, cumulative duration and number of holiday periods were moderately associated with increasing number of small but not of large nevi. The number of small nevi together with sunburn history and latitude gradient were strong predictors of large nevi number. In contrast, sunburn history and latitude gradient were not associated with small nevi. Conclusions: Exposure to high doses of ultraviolet B radiation would be implicated in the formation of large nevi, while solar radiation other than the ultraviolet B could be implicated in the development of small nevi in children. Given that numbers of large nevi are strong predictors of melanoma in children and adolescents, these results agree with the hypothesis that high ultraviolet B doses are needed for melanoma occurrence, but probably not for nevi formation.

The role of growth from birth through puberty and through adult life has been the subject of epidemiologic investigation in regard to the risk of prostate cancer but the evidence remains weak and inconsistent. We investigated associations between prostate cancer risk and a number of markers of body growth, size and changes to size in a population-based, case-control study in Australia from 1994 to 1998. We analyzed data obtained in face-to-face interviews from 1,476 cases and 1,409 controls. The main outcomes of interest were the timing of the growth spurt in adolescence, the experience of acne and interviewer observation of facial acne scarring, body size at age 21, body size in reference year, maximum body weight and rate of body size change since age 21 years. Analysis was performed on all cases and also by tumour grade. We found no associations with measures of body size including body mass index and lean body mass at age 21 or later in adult life. Having a growth spurt later than friends reduced risk (odds ratio [OR] 0.79 [0.63–0.97]) and some measures of acne also gave odds ratios less than 1, for example, having facial acne scarring gave an OR of 0.67 (0.45–1.00). We conclude that markers of delayed androgen action, such as delayed growth spurt in puberty, and markers of other androgen-dependent activity in puberty, such as facial acne scarring, are associated with prostate cancer risk but we could detect no associations with markers of adult body size and growth including lean body mass. © 2002 Wiley-Liss, Inc.

Aims and Background The aim of the study was to assess the usefulness of virtual simulation in postoperative radiotherapy treatment planning of early-stage breast cancer and to evaluate its potential to reduce the volume of critical structures exposed compared to treatment plans produced by a conventional 2D system.Methods and Study Design Eighteen patients undergoing breast radiotherapy following conservative surgery for small breast carcinomas were studied. Scans from spiral CT equipment (with the patient in the treatment position) were transferred to a virtual simulator. From the screen images the operator contoured breast, lung and heart. Calculations were made of the extent to which the heart and lung were included in the irradiation fields (50% isodose line of tangential fields).Results Manual contouring was time-consuming, but when virtual simulation was used, the mean volume of the lung included in the radiation fields was significantly reduced compared to the 2D treatment plan (4.5% vs 5.4%, P = 0.034); in addition, a slight reduction was observed for the heart (0.5% to 1.2%), but this was not statistically significant.Conclusions With a 3D system we obtained optimal target coverage and a reduction of the dose to critical structures (statistically significant only for the lung). From a clinical point of view, this 0.9% reduction in the mean irradiated lung volume is probably not significant, as the percentage irradiated with a 2D system is considerably below the recommended value. Furthermore, our analysis was performed in a relatively small group of patients; for a reliable estimate larger series would be required. Consequently, the 3D system should not be considered in routine treatment after breast conserving surgery for early stage carcinomas; for the time being it should be reserved for selected cases.

The national breast cancer screening programme in Luxembourg, the Mammography Programme (MP), was launched in 1992. Its primary goal was to set up an organised breast cancer screening with biennial invitation-reinvitation of women 50–64 years, 2-view mammography, technical quality assurance, double-reading procedures and close monitoring of performance. In 1994, the decision was taken by health authorities to only reimburse screening mammograms done within the MP. We evaluated the performance of 3 screening rounds that took place in 1992–1997. In 1992, 4,815 women had opportunistic screening and 4,790 attended the MP. In 1997, 861 women had opportunistic screening and 8,603 attended the MP. In 1997, the participation rate in the MP reached 50%. The referral rate in the MP was 10% for initial screening and 5% for subsequent screening. Echographic examinations accounted for 71% of referrals. Per 1,000 screened women, biopsy and cancer rates were 18.0 and 8.0 for initial screening and 10.3 and 5.8 for subsequent screening. Twenty-one percent of the breast cancers diagnosed in screened women were interval cancers. The age-adjusted proportion of tumours >20 mm was 56.1% before 1992, 45.1% for women not (yet) screened by the MP, 27.0% for interval cancers, 26.6% for initial screening and 12.0% for subsequent screenings. Tumour size distribution was similar to that observed in the Dutch Breast Cancer Screening Programme, 1990–1993, except that in the latter programme, no difference was observed between initial and subsequent screening. The Luxembourg experience shows that in a liberal health care system, a policy of organising the screening process by reimbursing only those mammograms done within the context of the organised screening programme can drastically reduce opportunistic screening. Further efforts in the Mammography Programme will aim at increasing participation and look at ways to decrease referrals to echography. © 2001 Wiley-Liss, Inc.

In absolute terms, prostate cancer is a public health problem of major and increasing importance particularly as the population ages. Prostate cancer control comprises a series of actions ranging from primary prevention, through screening to improvements in therapy for prostate cancer. An exciting approach lies in the possibility of chemoprevention to reverse the process of carcinogenicity and prevent prostate cancer by this route. Indeed, there are several very interesting ideas being tested at this moment. One major difficulty is the long length of time which can elapse between exposure and the time at which clinical cancer can be found and diagnosed. In cases where delays are long, then preventative treatment should be initiated at an early age. This, and many other issues, current in prostate cancer, are rendered problematic by the age distribution of prostate cancer in the population. Although it is decreasing now, around the early 1990s, the median age of diagnosis of prostate cancer was around 75 in some European countries although considerably lower in population groups in the United States. The median age at death is between 77 and 80 in most countries. These special circumstances must be taken into account when discussing clinical trials of chemoprevention of prostate cancer. The importance of developing reliable intermediate endpoints which can be used in such studies in highlighted.

Prolonged administration of natural or synthetic retinoids has been associated with significant skeletal abnormalities, including osteoporosis. We studied the effects of the synthetic retinoid fenretinide (N-4-hydroxyphenylretinamide, or 4-HPR) administered for a mean of 40 months on bone mineral density and metabolism in 66 consecutive women with early breast cancer belonging to a secondary prevention trial. The mean (±SD) bone mineral density at the distal and ultradistal forearm were, respectively, 0.61±0.08 and 0.30±0.05 g/cm2 in 33 treated women and 0.62±0.07 and 0.29±0.07 g/cm2 in 33 control women (p = ns for both). Also, no significant difference was observed in markers of bone formation such as bone alkaline phosphatase and osteocalcin, nor in urinary bone resorption markers such as calcium, hydroxyproline, and type I bone collagen cross-linked N-telopeptide (NTx). However, a border-line higher excretion of urinary calcium and NTx was found in the 4-HPR group after adjustment for menopausal status. We conclude that prolonged administration of 4-HPR is not associated with significant alterations of bone mineral density of the forearm. However, a trend towards an increase in bone resorption markers suggests the need for further assessment at different skeletal sites.

ObjectiveTo investigate the associations between air pollution and mortality, focusing on associations below current European Union, United States, and World Health Organization standards and guidelines.DesignPooled analysis of eight cohorts.SettingMulticentre project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) in six European countries.Participants325 367 adults from the general population recruited mostly in the 1990s or 2000s with detailed lifestyle data. Stratified Cox proportional hazard models were used to analyse the associations between air pollution and mortality. Western Europe-wide land use regression models were used to characterise residential air pollution concentrations of ambient fine particulate matter (PM2.5), nitrogen dioxide, ozone, and black carbon.Main outcome measuresDeaths due to natural causes and cause specific mortality.ResultsOf 325 367 adults followed-up for an average of 19.5 years, 47 131 deaths were observed. Higher exposure to PM2.5, nitrogen dioxide, and black carbon was associated with significantly increased risk of almost all outcomes. An increase of 5 µg/m3in PM2.5was associated with 13% (95% confidence interval 10.6% to 15.5%) increase in natural deaths; the corresponding figure for a 10 µg/m3increase in nitrogen dioxide was 8.6% (7% to 10.2%). Associations with PM2.5, nitrogen dioxide, and black carbon remained significant at low concentrations. For participants with exposures below the US standard of 12 µg/m3an increase of 5 µg/m3in PM2.5was associated with 29.6% (14% to 47.4%) increase in natural deaths.ConclusionsOur study contributes to the evidence that outdoor air pollution is associated with mortality even at low pollution levels below the current European and North American standards and WHO guideline values. These findings are therefore an important contribution to the debate about revision of air quality limits, guidelines, and standards, and future assessments by the Global Burden of Disease.

Asthma control is suboptimal in nearly half of adults with asthma. Household exposure to disinfectants and cleaning products (DCP) has been associated with adverse respiratory effects, but data on their association with asthma control are scant.

ABSTRACTExperimental 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. coliand 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. coliproteins 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. coliand ETBF with CRC.The IgA-positivity of any of the tested E. coliantigens 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. coliand 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. coliand 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.

ObjectivesTo conduct a comprehensive analysis of prospectively measured circulating high sensitivity C reactive protein (hsCRP) concentration and risk of lung cancer overall, by smoking status (never, former, and current smokers), and histological sub-type.DesignNested case-control study.Setting20 population based cohort studies in Asia, Europe, Australia, and the United States.Participants5299 patients with incident lung cancer, with individually incidence density matched controls.ExposureCirculating hsCRP concentrations in prediagnostic serum or plasma samples.Main outcome measureIncident lung cancer diagnosis.ResultsA positive association between circulating hsCRP concentration and the risk of lung cancer for current (odds ratio associated with a doubling in hsCRP concentration 1.09, 95% confidence interval 1.05 to 1.13) and former smokers (1.09, 1.04 to 1.14) was observed, but not for never smokers (P<0.01 for interaction). This association was strong and consistent across all histological subtypes, except for adenocarcinoma, which was not strongly associated with hsCRP concentration regardless of smoking status (odds ratio for adenocarcinoma overall 0.97, 95% confidence interval 0.94 to 1.01). The association between circulating hsCRP concentration and the risk of lung cancer was strongest in the first two years of follow-up for former and current smokers. Including hsCRP concentration in a risk model, in addition to smoking based variables, did not improve risk discrimination overall, but slightly improved discrimination for cancers diagnosed in the first two years of follow-up.ConclusionsFormer and current smokers with higher circulating hsCRP concentrations had a higher risk of lung cancer overall. Circulating hsCRP concentration was not associated with the risk of lung adenocarcinoma. Circulating hsCRP concentration could be a prediagnostic marker of lung cancer rather than a causal risk factor.

IMPORTANCE: There is an urgent need to improve lung cancer risk assessment because current screening criteria miss a large proportion of cases. OBJECTIVE: To investigate whether a lung cancer risk prediction model based on a panel of selected circulating protein biomarkers can outperform a traditional risk prediction model and current US screening criteria. DESIGN, SETTING, AND PARTICIPANTS: Prediagnostic samples from 108 ever-smoking patients with lung cancer diagnosed within 1 year after blood collection and samples from 216 smoking-matched controls from the Carotene and Retinol Efficacy Trial (CARET) cohort were used to develop a biomarker risk score based on 4 proteins (cancer antigen 125 [CA125], carcinoembryonic antigen [CEA], cytokeratin-19 fragment [CYFRA 21-1], and the precursor form of surfactant protein B [Pro-SFTPB]). The biomarker score was subsequently validated blindly using absolute risk estimates among 63 ever-smoking patients with lung cancer diagnosed within 1 year after blood collection and 90 matched controls from 2 large European population-based cohorts, the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Northern Sweden Health and Disease Study (NSHDS). MAIN OUTCOMES AND MEASURES: Model validity in discriminating between future lung cancer cases and controls. Discrimination estimates were weighted to reflect the background populations of EPIC and NSHDS validation studies (area under the receiver-operating characteristics curve [AUC], sensitivity, and specificity). RESULTS: In the validation study of 63 ever-smoking patients with lung cancer and 90 matched controls (mean [SD] age, 57.7 [8.7] years; 68.6% men) from EPIC and NSHDS, an integrated risk prediction model that combined smoking exposure with the biomarker score yielded an AUC of 0.83 (95% CI, 0.76-0.90) compared with 0.73 (95% CI, 0.64-0.82) for a model based on smoking exposure alone (P = .003 for difference in AUC). At an overall specificity of 0.83, based on the US Preventive Services Task Force screening criteria, the sensitivity of the integrated risk prediction (biomarker) model was 0.63 compared with 0.43 for the smoking model. Conversely, at an overall sensitivity of 0.42, based on the US Preventive Services Task Force screening criteria, the integrated risk prediction model yielded a specificity of 0.95 compared with 0.86 for the smoking model. CONCLUSIONS AND RELEVANCE: This study provided a proof of principle in showing that a panel of circulating protein biomarkers may improve lung cancer risk assessment and may be used to define eligibility for computed tomography screening.

With population aging, further asthma research is needed in the elderly.