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Background: Statins represent candidates for drug repurposing in Parkinson's disease (PD). Few studies examined the role of reverse causation, statin subgroups, and dose–response relations based on time‐varying exposures. Objectives: We examined whether statin use is associated with PD incidence while attempting to overcome the limitations described previously, especially reverse causation. Method: We used data from the E3N cohort study of French women (follow‐up, 2004–2018). Incident PD was ascertained using multiple sources and validated by experts. New statin users were identified through linked drug claims. We set up a nested case‐control study to describe trajectories of statin prescriptions and medical consultations before diagnosis. We used time‐varying multivariable Cox proportional hazards regression models to examine the statins–PD association. Exposure indexes included ever use, cumulative duration/dose, and mean daily dose and were lagged by 5 years to address reverse causation. Results: The case‐control study (693 cases, 13,784 controls) showed differences in case‐control trajectories, with changes in the 5 years before diagnosis in cases. Of 73,925 women (aged 54–79 years), 524 developed PD and 11,552 started using statins in lagged analyses. Ever use of any statin was not associated with PD (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.67–1.11). Alternatively, ever use of lipophilic statins was significantly associated with lower PD incidence (HR = 0.70, 95% CI = 0.51–0.98), with a dose–response relation for the mean daily dose (P‐linear trend = 0.02). There was no association for hydrophilic statins. Conclusion: Use of lipophilic statins at least 5 years earlier was associated with reduced PD incidence in women, with a dose–response relation for the mean daily dose. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Low‐dose aspirin has been hypothesized to prevent cancer risk by inhibiting platelet aggregation. However, the anti‐cancer effect of low‐dose aspirin has recently been questioned and its effect on breast cancer development remains unclear. The impact of other antiplatelet drugs on breast cancer risk has rarely been evaluated. Thus, this study aimed to investigate the associations between breast cancer risk and antiplatelet drug use in a nationwide nested case‐control study. From the Danish healthcare registries, we identified as cases all women with invasive breast cancer diagnosis between 2001 and 2018 (n = 68 852). The date of diagnosis corresponded to the index date. We matched cases to 10 population controls on age and calendar time, using risk set sampling. Controls were assigned the same index date as their matched case. We used the prescription registry to identify exposure to low‐dose aspirin, clopidogrel and dipyridamole. We defined ever use of antiplatelet drugs as at least two prescriptions filled up to 1 year before the index date. We applied conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals for breast cancer associated with the use of antiplatelet drugs, overall, by breast cancer subtype and by cumulative dose. Twelve percent of women had ever been exposed to low‐dose aspirin, 2% to clopidogrel and 2% to dipyridamole. In multivariable models, breast cancer risk was not associated with ever use of low‐dose aspirin (OR = 1.00 [0.97‐1.03]), clopidogrel (OR = 0.93 [0.87‐1.00]), and dipyridamole (OR = 1.02 [0.94‐1.10]), compared with never use, and there was no evidence of a dose‐response relation. However, we found an inverse association between dipyridamole use and breast cancer risk among women aged <55 years old, with suggestion of a dose‐response relationship (OR per 1000 Defined Daily Doses = 0.72 [0.54‐0.95]). Associations did not differ by breast cancer histological type, estrogen receptor status or clinical stage at diagnosis. Overall, the findings from this study do not support the use of antiplatelet drugs for breast cancer prevention. [ABSTRACT FROM AUTHOR]

Background: Available treatments for Parkinson's disease (PD) are only partially or transiently effective. Identifying existing molecules that may present a therapeutic or preventive benefit for PD (drug repositioning) is thus of utmost interest. Objective: We aimed at detecting potentially protective associations between marketed drugs and PD through a large‐scale automated screening strategy. Methods: We implemented a machine learning (ML) algorithm combining subsampling and lasso logistic regression in a case–control study nested in the French national health data system. Our study population comprised 40,760 incident PD patients identified by a validated algorithm during 2016 to 2018 and 176,395 controls of similar age, sex, and region of residence, all followed since 2006. Drug exposure was defined at the chemical subgroup level, then at the substance level of the Anatomical Therapeutic Chemical (ATC) classification considering the frequency of prescriptions over a 2‐year period starting 10 years before the index date to limit reverse causation bias. Sensitivity analyses were conducted using a more specific definition of PD status. Results: Six drug subgroups were detected by our algorithm among the 374 screened. Sulfonamide diuretics (ATC‐C03CA), in particular furosemide (C03CA01), showed the most robust signal. Other signals included adrenergics in combination with anticholinergics (R03AL) and insulins and analogues (A10AD). Conclusions: We identified several signals that deserve to be confirmed in large studies with appropriate consideration of the potential for reverse causation. Our results illustrate the value of ML‐based signal detection algorithms for identifying drugs inversely associated with PD risk in health‐care databases. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

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. What's new? Sexually transmitted infections (STI) have been linked with pelvic inflammatory disease but their association with ovarian cancer remains unclear. In this large prospective study, serum antibodies against Chlamydia trachomatis were associated with higher epithelial ovarian cancer risk, though some associations were limited to select histotypes. Herpes simplex virus type 2 infection was associated with endometrioid ovarian cancer, a rarer ovarian cancer subtype. These findings underscore that STIs may be important in the etiology of ovarian cancer and may represent a target for primary prevention. [ABSTRACT FROM AUTHOR]

Endometrial cancer (EC) incidence rates vary ~10‐fold worldwide, in part due to variation in EC risk factor profiles. Using an EC risk model previously developed in the European EPIC cohort, we evaluated the prevention potential of modified EC risk factor patterns and whether differences in EC incidence between a European population and low‐risk countries can be explained by differences in these patterns. Predicted EC incidence rates were estimated over 10 years of follow‐up for the cohort before and after modifying risk factor profiles. Risk factors considered were: body mass index (BMI, kg/m2), use of postmenopausal hormone therapy (HT) and oral contraceptives (OC) (potentially modifiable); and, parity, ages at first birth, menarche and menopause (environmentally conditioned, but not readily modifiable). Modeled alterations in BMI (to all ≤23 kg/m2) and HT use (to all non‐HT users) profiles resulted in a 30% reduction in predicted EC incidence rates; individually, longer duration of OC use (to all ≥10 years) resulted in a 42.5% reduction. Modeled changes in not readily modifiable exposures (i.e., those not contributing to prevention potential) resulted in ≤24.6% reduction in predicted EC incidence. Women in the lowest decile of a risk score based on the evaluated exposures had risk similar to a low risk countries; however, this was driven by relatively long use of OCs (median = 23 years). Our findings support avoidance of overweight BMI and of HT use as prevention strategies for EC in a European population; OC use must be considered in the context of benefits and risks. What's new? Endometrial cancer rates vary considerably around the world, with incidence rates higher in Europe and North America than in parts of Asia and Africa. Here, the authors investigated how much of the risk disparity arises from modifiable factors, and how much modifying these factors could reduce cancer incidence. The 10% of European women with lowest risk had similar incidence to women in low‐risk countries, they found. Their model predicted that in European women, maintaining BMI below 23 kg/m2 and avoiding postmenopausal hormone use could reduce risk by 30%. Long‐term use of oral contraceptives could reduce risk by 42.5%. [ABSTRACT FROM AUTHOR]

Evidence suggests an influence of sex hormones on cutaneous melanoma risk, but epidemiologic findings are conflicting. We examined the associations between use of oral contraceptives (OCs) and menopausal hormone therapy (MHT) and melanoma risk in women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a prospective cohort study initiated in 1992 in 10 European countries. Information on exogenous hormone use at baseline was derived from country‐specific self‐administered questionnaires. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over 1992–2015, 1,696 melanoma cases were identified among 334,483 women, whereof 770 cases among 134,758 postmenopausal women. There was a positive, borderline‐significant association between OC use and melanoma risk (HR = 1.12, 95% CI = 1.00–1.26), with no detected heterogeneity across countries (phomogeneity = 0.42). This risk increased linearly with duration of use (ptrend = 0.01). Among postmenopausal women, ever use of MHT was associated with a nonsignificant increase in melanoma risk overall (HR = 1.14, 95% CI = 0.97–1.43), which was heterogeneous across countries (phomogeneity = 0.05). Our findings do not support a strong and direct association between exogenous hormone use and melanoma risk. In order to better understand these relations, further research should be performed using prospectively collected data including detailed information on types of hormone, and on sun exposure, which may act as an important confounder or effect modifier on these relations. What's new? Evidence suggests that sex hormones may influence melanoma risk. As part of a prospective study, the authors of this report found that women who had used oral contraceptives at any time had a moderately increased risk of melanoma, which increased linearly with longer usage. Menopausal hormone therapy (MHT), also increased risk somewhat. Further research is needed, in order to investigate potential confounding or effect‐modification of melanoma risk, for various types and formulations of hormones, and for UV exposure. [ABSTRACT FROM AUTHOR]

Alcohol consumption is associated with higher risk of breast cancer (BC); however, the biological mechanisms underlying this association are not fully elucidated, particularly the extent to which this relationship is mediated by sex hormone levels. Circulating concentrations of estradiol, testosterone, their free fractions and sex‐hormone binding globulin (SHBG), were examined in 430 incident BC cases and 645 matched controls among alcohol‐consuming postmenopausal women nested within the European Prospective Investigation into Cancer and Nutrition. Mediation analysis was applied to assess whether individual hormone levels mediated the relationship between alcohol intake and BC risk. An alcohol‐related hormonal signature, obtained by partial least square (PLS) regression, was evaluated as a potential mediator. Total (TE), natural direct and natural indirect effects (NIE) were estimated. Alcohol intake was positively associated with overall BC risk and specifically with estrogen receptor‐positive tumors with respectively TE = 1.17(95%CI: 1.01,1.35) and 1.36(1.08,1.70) for a 1‐standard deviation (1‐SD) increase of intake. There was no evidence of mediation by sex steroids or SHBG separately except for a weak indirect effect through free estradiol where NIE = 1.03(1.00,1.06). However, an alcohol‐related hormonal signature negatively associated with SHBG and positively with estradiol and testosterone was associated with BC risk (odds ratio [OR] = 1.25 [1.07,1.47]) for a 1‐SD higher PLS score, and had a statistically significant NIE accounting for a mediated proportion of 24%. There was limited evidence of mediation of the alcohol‐BC association by individual sex hormones. However, a hormonal signature, reflecting lower levels of SHBG and higher levels of sex steroids, mediated a substantial proportion of the association. What's new? Alcohol consumption is associated with an increased risk of breast cancer (BC). However, the mechanisms underlying this association are not yet fully understood. For example, do sex‐hormone levels play a role? In this study, the authors assessed a number of alcohol‐related hormonal signatures. They found that lower levels of sex‐hormone binding globulin (SHBG), combined with higher levels of sex steroids, mediate a substantial proportion of the observed alcohol‐BC association. It is likely that the mechanism involves the interplay of multiple hormones, rather than the action of individual hormones. [ABSTRACT FROM AUTHOR]

Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n = 864), very aggressive (death in 1 to < 3 years, n = 1,390), moderately aggressive (death in 3 to < 5 years, n = 639), and less aggressive (lived 5+ years, n = 1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet = 0.01), family history of ovarian cancer (phet = 0.02), body mass index (BMI; phet ≤ 0.04) and smoking (phet < 0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58–0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92–1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47–2.55]). High BMI (≥35 vs. 20 to < 25 kg/m2, 1.93 [1.46–2.56] and current smoking (vs. never, 1.30 [1.07–1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted. What's new? In ovarian cancer, risk factor profiles may be associated with disease subtypes defined by aggressiveness independent of histology, according to this new analysis. In this large consortium‐based prospective study, the authors classified ovarian tumors according to aggressiveness, based on years between diagnosis and death. They hypothesized that pre‐diagnosis exposure to risk factors, such as smoking, BMI, family history, and pregnancy, would influence whether an ovarian cancer developed on a path toward more aggressive or less aggressive disease. Indeed, in clustering analysis, risk factor associations tracked by tumor aggressiveness rather than histotypes. Smoking and BMI, two modifiable risk factors, were associated with highly aggressive disease. [ABSTRACT FROM AUTHOR]

Experimental studies have shown a protective effect of nonsteroidal anti‐inflammatory drugs (NSAIDs) on breast cancer development. However, results from epidemiological cohort studies are less consistent. Our objective was to assess the association between NSAID use and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a prospective cohort study initiated in 1992 in 10 European countries. Self‐reported information on NSAID use at baseline has been collected in five EPIC countries. Multivariable Cox regression models were used to estimate hazard ratios for the association of NSAID use with breast cancer incidence with adjustment for potential confounders. We also assessed effect modification by breast cancer risk factors and examined the associations within specific breast cancer subtypes. Among the 140,981 women included in the analysis, 7% were regularly using NSAIDs at baseline. During a median follow‐up time period of 13 years, 7,379 incident breast cancer cases were diagnosed (816 in situ and 6,563 invasive). There were no statistically significant associations between NSAID use and breast cancer risk, overall and by subtypes. However, a statistically significant interaction was observed for invasive cases between NSAID use and ever use of menopausal hormonal therapy (MHT) among postmenopausal women [MHT users: HRNSAID use = 0.84 (0.73–0.96); non MHT users: HRNSAID use = 1.08 (0.93–1.25); pinteraction = 0.05]. Our results indicate potential effect modification of MHT use on the association between use of NSAIDs and breast cancer risk which deserves in‐depth investigation in studies with accurate data on both NSAID and MHT use. [ABSTRACT FROM AUTHOR]

Immuno‐proteomic screening has identified several tumor‐associated autoantibodies (AAb) that may have diagnostic capacity for invasive epithelial ovarian cancer, with AAbs to P53 proteins and cancer‐testis antigens (CTAGs) as prominent examples. However, the early detection potential of these AAbs has been insufficiently explored in prospective studies. We performed ELISA measurements of AAbs to CTAG1A, CTAG2, P53 and NUDT11 proteins, for 194 patients with ovarian cancer and 705 matched controls from the European EPIC cohort, using serum samples collected up to 36 months prior to diagnosis under usual care. CA125 was measured using electrochemo‐luminiscence. Diagnostic discrimination statistics were calculated by strata of lead‐time between blood collection and diagnosis. With lead times ≤6 months, ovarian cancer detection sensitivity at 0.98 specificity (SE98) varied from 0.19 [95% CI 0.08–0.40] for CTAG1A, CTAG2 and NUDT1 to 0.23 [0.10–0.44] for P53 (0.33 [0.11–0.68] for high‐grade serous tumors). However, at longer lead‐times, the ability of these AAb markers to distinguish future ovarian cancer cases from controls declined rapidly; at lead times >1 year, SE98 estimates were close to zero (all invasive cases, range: 0.01–0.11). Compared to CA125 alone, combined logistic regression scores of AAbs and CA125 did not improve detection sensitivity at equal level of specificity. The added value of these selected AAbs as markers for ovarian cancer beyond CA125 for early detection is therefore limited. [ABSTRACT FROM AUTHOR]

Other than the influence of ionizing radiation and benign thyroid disease, little is known about the risk factors for differentiated thyroid cancer (TC) which is an increasing common cancer worldwide. Consistent evidence shows that body mass is positively associated with TC risk. As excess weight is a state of chronic inflammation, we investigated the relationship between concentrations of leptin, adiponectin, C‐reactive protein, interleukin (IL)‐6, IL‐10 and tumor necrosis factor (TNF)‐α and the risk of TC. A case‐control study was nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study and included 475 first primary incident TC cases (399 women and 76 men) and 1,016 matched cancer‐free cohort participants. Biomarkers were measured in serum samples using validated and highly sensitive commercially available immunoassays. Odds ratios (ORs) of TC by levels of each biomarker were estimated using conditional logistic regression models, adjusting for BMI and alcohol consumption. Adiponectin was inversely associated with TC risk among women (ORT3vs.T1 = 0.69, 95% CI: 0.49–0.98, Ptrend = 0.04) but not among men (ORT3vs.T1 = 1.36, 95% CI: 0.67–2.76, Ptrend = 0.37). Increasing levels of IL‐10 were positively associated with TC risk in both genders and significantly so in women (ORT3vs.T1 = 1.59, 95% CI: 1.13–2.25, Ptrend = 0.01) but not in men (ORT3vs.T1 = 1.78, 95% CI: 0.80–3.98, Ptrend = 0.17). Leptin, CRP, IL‐6 and TNF‐α were not associated with TC risk in either gender. These results indicate a positive association of TC risk with IL‐10 and a negative association with adiponectin that is probably restricted to women. Inflammation may play a role in TC in combination with or independently of excess weight. [ABSTRACT FROM AUTHOR]

Endometrial cancer risk prediction models including lifestyle, anthropometric and reproductive factors have limited discrimination. Adding biomarker data to these models may improve predictive capacity; to our knowledge, this has not been investigated for endometrial cancer. Using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we investigated the improvement in discrimination gained by adding serum biomarker concentrations to risk estimates derived from an existing risk prediction model based on epidemiologic factors. Serum concentrations of sex steroid hormones, metabolic markers, growth factors, adipokines and cytokines were evaluated in a step-wise backward selection process; biomarkers were retained at p < 0.157 indicating improvement in the Akaike information criterion (AIC). Improvement in discrimination was assessed using the C-statistic for all biomarkers alone, and change in C-statistic from addition of biomarkers to preexisting absolute risk estimates. We used internal validation with bootstrapping (1000-fold) to adjust for over-fitting. Adiponectin, estrone, interleukin-1 receptor antagonist, tumor necrosis factor-alpha and triglycerides were selected into the model. After accounting for over-fitting, discrimination was improved by 2.0 percentage points when all evaluated biomarkers were included and 1.7 percentage points in the model including the selected biomarkers. Models including etiologic markers on independent pathways and genetic markers may further improve discrimination. [ABSTRACT FROM AUTHOR]

Experimental studies suggest protective effects of vitamin D on breast carcinogenesis, but epidemiological evidence is not conclusive. Body mass index (BMI) has been shown to modulate the effect of supplementation on the vitamin D status, but its potential influence on the relationship with breast cancer risk has been little studied. We investigated a potential interaction between BMI and vitamin D supplementation on breast cancer risk while considering an already reported interaction between vitamin D supplementation and menopausal hormone therapy (MHT) use. Vitamin D supplementation was prospectively investigated in 57,403 postmenopausal women from the French E3N cohort including 2,482 incident breast cancer cases diagnosed between 1995 and 2008. Multivariable hazard ratios (HR) for primary invasive breast cancer and 95% confidence intervals (CI) were estimated using Cox models. Among MHT ever users, vitamin D supplementation was associated with decreased breast cancer risk, similarly across BMI strata ( Phomogeneity = 0.83). Among MHT never users, ever vitamin D supplementation was associated with increased postmenopausal breast cancer risk in women with baseline BMI <25 kg/m2 (HR = 1.51, 95% CI: 1.13, 2.02), but not in women with higher BMI (0.98, 95% CI: 0.62, 1.56), Phomogeneity = 0.12. In conclusion, our findings suggest that vitamin D supplementation may reduce the excess breast cancer risk in MHT users, but draw attention on a potential risk in postmenopausal women not exposed to high exogenous or endogenous hormones, i.e. non-overweight MHT-non users, especially in the present context of increasing vitamin D supplement use and decreasing MHT use. [ABSTRACT FROM AUTHOR]

Laying hens are likely to be exposed to a wide range of persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs). To improve the safety of poultry farming systems in terms of POPs, the present research focused on assessing the impact of physiological characteristics of the hen on the transfer of ingested PCBs to eggs. Modeling was used as a research tool to explore the impact of some physiological characteristics on the transfer of PCBs in the laying hen. The mathematical model simulates the dynamics of the size of the lipid compartments in the animal and the frequency of laying, with the PCB concentrations in egg yolk and adipose tissue being model outputs. Simulations were run to assess effects of animal characteristics on the transfer of PCBs to eggs. Laying rate proportionally influenced the PCB level of eggs and adipose tissue at steady state. Body fat diluted absorbed PCBs in the absence of laying and significantly influenced the decontamination rate of tissues during depuration after an exposure period. Application of the present model to actual exposure cases highlights its value in improving the support of risk management in livestock farming. Environ Toxicol Chem 2015;34:173-183. © 2014 SETAC [ABSTRACT FROM AUTHOR]

The relative bioavailability of sediment-bound polychlorinated biphenyls (PCBs 138, 153, and 180) from a local contaminated site was examined using an in vivo carp model. Surface sediment from the PCB-contaminated site and spiked canola oil containing equivalent masses of PCBs were respectively incorporated in the sediment-dosed diets and oil-dosed diets at 3 dose levels resulting in 6 experimental diets. Juvenile carps ( n = 90) were divided in 18 tanks (5 fish × 6 treatments × 3 tanks). Fish were fed the control diet during the adaptation period (15 d). Next, 1 fish was sampled in each tank and muscle tissues were combined in control groups. During the exposure period (15 d), the remaining fish were fed with 1 of the 6 experimental diets. At the end of the experiment, fish were sampled and muscle tissues were combined for each tank. The PCBs were monitored in feed and fish muscle. For both the contaminated sediment and spiked canola oil groups, concentrations of PCBs 138, 153, and 180 in muscle linearly increased with concentrations in food, with similar intercepts and slopes. In the present study, the sediment-bound PCBs were as bioavailable as those spiked into canola oil and fed to carp in a standard diet. Environ Toxicol Chem 2014;33:1324-1330. © 2014 SETAC [ABSTRACT FROM AUTHOR]

Physical activity is associated with reduced risks of invasive breast cancer. However, whether this holds true for breast cancer subtypes defined by the estrogen receptor (ER) and the progesterone receptor (PR) status is controversial. The study included 257,805 women from the multinational EPIC-cohort study with detailed information on occupational, recreational and household physical activity and important cofactors assessed at baseline. During 11.6 years of median follow-up, 8,034 incident invasive breast cancer cases were identified. Data on ER, PR and combined ER/PR expression were available for 6,007 (67.6%), 4,814 (54.2%) and 4,798 (53.9%) cases, respectively. Adjusted hazard ratios (HR) were estimated by proportional hazards models. Breast cancer risk was inversely associated with moderate and high levels of total physical activity (HR = 0.92, 95% confidence interval (CI): 0.86-0.99, HR = 0.87, 95%-CI: 0.79-0.97, respectively; p-trend = 0.002), compared to the lowest quartile. Among women diagnosed with breast cancer after age 50, the largest risk reduction was found with highest activity (HR = 0.86, 95%-CI: 0.77-0.97), whereas for cancers diagnosed before age 50 strongest associations were found for moderate total physical activity (HR = 0.78, 95%-CI: 0.64-0.94). Analyses by hormone receptor status suggested differential associations for total physical activity ( p-heterogeneity = 0.04), with a somewhat stronger inverse relationship for ER+/PR+ breast tumors, primarily driven by PR+ tumors (p-heterogeneity < 0.01). Household physical activity was inversely associated with ER-/PR- tumors. The results of this largest prospective study on the protective effects of physical activity indicate that moderate and high physical activity are associated with modest decreased breast cancer risk. Heterogeneities by receptor status indicate hormone-related mechanisms. [ABSTRACT FROM AUTHOR]

ABSTRACT Purpose To estimate the number of deaths from valvular insufficiency caused by the use of the fenfluramine-derivative benfluorex during the period 1976-2009 in France. Methods Our calculation was based on (i) the exposure level to benfluorex in the French population, derived from sales figures for the period 1976-2009 and from the main characteristics of benfluorex use provided by the French health products safety agency; (ii) the relative risk of hospitalization for valvular insufficiency among exposed compared with unexposed individuals with diabetes, originating from a cohort study based on a French medico-administrative database, with benfluorex exposure assessed in 2006; (iii) the incidence of hospitalization for valvular insufficiency among exposed individuals, originating from the same database; and (iv) the mortality associated with valvular heart disease. Results In France, use of benfluorex during the period 1976-2009 is likely to be responsible for around 3100 hospitalizations and 1300 deaths due to valvular insufficiency. These figures may be underestimations. Conclusions The grave consequences benfluorex use have had for many people lend support to the public investigation, which has been set to understand the reasons that have contributed to the delay in withdrawing benfluorex from the French market. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated the association between menopausal hormone therapy (HT) and colorectal cancer risk in postmenopausal women enrolled in the European Prospective Investigation into Cancer and Nutrition. Cox proportional hazards models were use to estimate hazard ratios and 95 percent confidence intervals. The study revealed no significant association between colorectal cancer risk and estrogen-only or estrogen plus progestin HT.

Menopausal hormone therapy (MHT) is characterized by use of different constituents, regimens and routes of administration. We investigated the association between the use of different types of MHT and breast cancer risk in the EPIC cohort study. The analysis is based on data from 133,744 postmenopausal women. Approximately 133,744 postmenopausal women contributed to this analysis. Information on MHT was derived from country-specific self-administered questionnaires with a single baseline assessment. Incident breast cancers were identified through population cancer registries or by active follow-up (mean: 8.6 yr). Overall relative risks (RR) and 95% confidence interval (CI) were derived from country-specific Cox proportional hazard models estimates. A total of 4312 primary breast cancers were diagnosed during 1,153,747 person-years of follow-up. Compared with MHT never users, breast cancer risk was higher among current users of estrogen only (RR: 1.42, 95% CI 1.23-1.64) and higher still among current users of combined MHT (RR: 1.77, 95% CI 1.40-2.24; p = 0.02 for combined vs. estrogen-only). Continuous combined regimens conferred a 43% (95% CI: 19-72%) greater risk compared with sequential regimens. There was no significant difference between progesterone and testosterone derivatives in sequential regimens. There was no significant variation in risk linked to the estrogenic component of MHT, neither for oral vs. cutaneous administration nor for estradiol compounds vs. conjugated equine estrogens. Estrogen-only and combined MHT uses were associated with increased breast cancer risk. Continuous combined preparations were associated with the highest risk. Further studies are needed to disentangle the effects of the regimen and the progestin component. [ABSTRACT FROM AUTHOR]