Pregnancy outcomes and risk of endometrial cancer: A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium.

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

Body size and weight change over adulthood and risk of breast cancer by menopausal and hormone receptor status: a pooled analysis of 20 prospective cohort studies.

Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose-response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6-7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively-and nonlinearly-associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18-20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m2, respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18-20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associations with early adult BMI seemed stronger in receptor-negative subtypes of premenopausal and postmenopausal BC.

Global estimates of mortality associated with long-term exposure to outdoor fine particulate matter.

Exposure to ambient fine particulate matter (PM2.5) is a major global health concern. Quantitative estimates of attributable mortality are based on disease-specific hazard ratio models that incorporate risk information from multiple PM2.5 sources (outdoor and indoor air pollution from use of solid fuels and secondhand and active smoking), requiring assumptions about equivalent exposure and toxicity. We relax these contentious assumptions by constructing a PM2.5-mortality hazard ratio function based only on cohort studies of outdoor air pollution that covers the global exposure range. We modeled the shape of the association between PM2.5 and nonaccidental mortality using data from 41 cohorts from 16 countries-the Global Exposure Mortality Model (GEMM). We then constructed GEMMs for five specific causes of death examined by the global burden of disease (GBD). The GEMM predicts 8.9 million [95% confidence interval (CI): 7.5-10.3] deaths in 2015, a figure 30% larger than that predicted by the sum of deaths among the five specific causes (6.9; 95% CI: 4.9-8.5) and 120% larger than the risk function used in the GBD (4.0; 95% CI: 3.3-4.8). Differences between the GEMM and GBD risk functions are larger for a 20% reduction in concentrations, with the GEMM predicting 220% higher excess deaths. These results suggest that PM2.5 exposure may be related to additional causes of death than the five considered by the GBD and that incorporation of risk information from other, nonoutdoor, particle sources leads to underestimation of disease burden, especially at higher concentrations.

The Critical Importance of Molecular Biomarkers and Imaging in the Study of Electrohypersensitivity. A Scientific Consensus International Report.

Clinical research aiming at objectively identifying and characterizing diseases via clinical observations and biological and radiological findings is a critical initial research step when establishing objective diagnostic criteria and treatments. Failure to first define such diagnostic criteria may lead research on pathogenesis and etiology to serious confounding biases and erroneous medical interpretations. This is particularly the case for electrohypersensitivity (EHS) and more particularly for the so-called "provocation tests", which do not investigate the causal origin of EHS but rather the EHS-associated particular environmental intolerance state with hypersensitivity to man-made electromagnetic fields (EMF). However, because those tests depend on multiple EMF-associated physical and biological parameters and have been conducted in patients without having first defined EHS objectively and/or endpoints adequately, they cannot presently be considered to be valid pathogenesis research methodologies. Consequently, the negative results obtained by these tests do not preclude a role of EMF exposure as a symptomatic trigger in EHS patients. Moreover, there is no proof that EHS symptoms or EHS itself are caused by psychosomatic or nocebo effects. This international consensus report pleads for the acknowledgement of EHS as a distinct neuropathological disorder and for its inclusion in the WHO International Classification of Diseases.

Lung cancer mortality reduction by LDCT screening-Results from the randomized German LUSI trial.

In 2011, the U.S. National Lung Cancer Screening Trial (NLST) reported a 20% reduction of lung cancer mortality after regular screening by low-dose computed tomography (LDCT), as compared to X-ray screening. The introduction of lung cancer screening programs in Europe awaits confirmation of these first findings from European trials that started in parallel with the NLST. The German Lung cancer Screening Intervention (LUSI) is a randomized trial among 4,052 long-term smokers, 50-69 years of age, recruited from the general population, comparing five annual rounds of LDCT screening (screening arm; n = 2,029 participants) with a control arm (n = 2,023) followed by annual postal questionnaire inquiries. Data on lung cancer incidence and mortality and vital status were collected from hospitals or office-based physicians, cancer registries, population registers and health offices. Over an average observation time of 8.8 years after randomization, the hazard ratio for lung cancer mortality was 0.74 (95% CI: 0.46-1.19; p = 0.21) among men and women combined. Modeling by sex, however showed a statistically significant reduction in lung cancer mortality among women (HR = 0.31 [95% CI: 0.10-0.96], p = 0.04), but not among men (HR = 0.94 [95% CI: 0.54-1.61], p = 0.81) screened by LDCT (pheterogeneity = 0.09). Findings from LUSI are in line with those from other trials, including NLST, that suggest a stronger reduction of lung cancer mortality after LDCT screening among women as compared to men. This heterogeneity could be the result of different relative counts of lung tumor subtypes occurring in men and women.

Cancer epidemiology update, following the 2011 IARC evaluation of radiofrequency electromagnetic fields (Monograph 102).

Epidemiology studies (case-control, cohort, time trend and case studies) published since the International Agency for Research on Cancer (IARC) 2011 categorization of radiofrequency radiation (RFR) from mobile phones and other wireless devices as a possible human carcinogen (Group 2B) are reviewed and summarized. Glioma is an important human cancer found to be associated with RFR in 9 case-control studies conducted in Sweden and France, as well as in some other countries. Increasing glioma incidence trends have been reported in the UK and other countries. Non-malignant endpoints linked include acoustic neuroma (vestibular Schwannoma) and meningioma. Because they allow more detailed consideration of exposure, case-control studies can be superior to cohort studies or other methods in evaluating potential risks for brain cancer. When considered with recent animal experimental evidence, the recent epidemiological studies strengthen and support the conclusion that RFR should be categorized as carcinogenic to humans (IARC Group 1). Opportunistic epidemiological studies are proposed that can be carried out through cross-sectional analyses of high, medium, and low mobile phone users with respect to hearing, vision, memory, reaction time, and other indicators that can easily be assessed through standardized computer-based tests. As exposure data are not uniformly available, billing records should be used whenever available to corroborate reported exposures.

Impact of screening mammography on breast cancer mortality.

The degree to which observed reductions in breast cancer mortality is attributable to screening mammography has become increasingly controversial. We examined this issue with three fundamentally different approaches: (i) Chronology--the temporal relationship of the onset of breast cancer mortality decline and the national implementation of screening mammography; (ii) Magnitude--the degree to which breast cancer mortality declined relative to the amount (penetration) of screening mammography; (iii) Analogy--the pattern of mortality rate reductions of other cancers for which population screening is not conducted. Chronology and magnitude were assessed with data from Europe and North America, with three methods applied to magnitude. A comparison of eight countries in Europe and North America does not demonstrate a correlation between the penetration of national screening and either the chronology or magnitude of national breast cancer mortality reduction. In the United States, the magnitude of the mortality decline is greater in the unscreened, younger women than in the screened population and regional variation in the rate of breast cancer mortality reduction is not correlated with screening penetrance, either as self-reported or by the magnitude of screening-induced increase in early-stage disease. Analogy analysis of United States data identifies 14 other cancers with a similar distinct onset of mortality reduction for which screening is not performed. These five lines of evidence from three different approaches and additional observations discussed do not support the hypothesis that mammography screening is a primary reason for the breast cancer mortality reduction in Europe and North America.

Long-term exposure to fine particulate matter air pollution and the risk of lung cancer among participants of the Canadian National Breast Screening Study.

Recently, air pollution has been classified as a carcinogen largely on the evidence of epidemiological studies of lung cancer. However, there have been few prospective studies that have evaluated associations between fine particulate matter (PM2.5 ) and cancer at lower concentrations. We conducted a prospective analysis of 89,234 women enrolled in the Canadian National Breast Screening Study between 1980 and 1985, and for whom residential measures of PM2.5 could be assigned. The cohort was linked to the Canadian Cancer Registry to identify incident lung cancers through 2004. Surface PM2.5 concentrations were estimated using satellite data. Cox proportional hazards models were used to characterize associations between PM2.5 and lung cancer. Hazard ratios (HRs) and 95% confidence intervals (CIs) computed from these models were adjusted for several individual-level characteristics, including smoking. The cohort was composed predominantly of Canadian-born (82%), married (80%) women with a median PM2.5 exposure of 9.1 µg/m(3) . In total, 932 participants developed lung cancer. In fully adjusted models, a 10 µg/m(3) increase in PM2.5 was associated with an elevated risk of lung cancer (HR: 1.34; 95% CI = 1.10, 1.65). The strongest associations were observed with small cell carcinoma (HR: 1.53; 95% CI = 0.93, 2.53) and adenocarcinoma (HR: 1.44; 95% CI = 1.06, 1.97). Stratified analyses suggested increased PM2.5 risks were limited to those who smoked cigarettes. Our findings are consistent with previous epidemiological investigations of long-term exposure to PM2.5 and lung cancer. Importantly, they suggest associations persist at lower concentrations such as those currently found in Canadian cities.

Revised estimates of overdiagnosis from the Canadian National Breast Screening Study.

We have re-estimated overdiagnosis of breast cancer from mammography screening by age group in the Canadian National Breast Screening Study (CNBSS), a randomized screening trial. In the CNBSS, participants were recruited in 15 centers. 89,835 women were randomized with informed consent, 50,430 age 40-49 and 39,405 age 50-59. Women aged 40-49 received annual mammography and physical examination (MA+PX) versus a single physical examination and usual care in the community (UC). Women aged 50-59 received (MA+PX) versus (PX-alone) annually. Individual randomization resulted in 44 almost identically distributed demographic and risk factors. Annual compliance over the five or four scheduled screens was 86-95%. The cumulative numbers of invasive and in situ breast cancers ascertained by year during screening and subsequent follow-up to 25 years post entry to the CNBSS in the mammography arm have been compared to those in the control arm. Estimates of overdiagnosis were derived using post-screening cessation cut-off points from 1 to 20years.⋯Overdiagnosis of invasive breast cancer at five years post cessation of screening for women aged 40-49 was estimated to be 32%, and 16% for women aged 50-59; 20years post cessation of screening 48% for women 40-49 and 5% for those 50-59. Including ductal carcinoma in situ with invasive cancer, estimates were 41%, 25%, 55% and 16%, respectively. We conclude that approximately 30% of invasive screen-detected breast cancers in women age 40-49 were overdiagnosed, and 20% of those screen-detected in women age 50-59. Including ductal carcinoma in situ, the estimates are 40% and 30%, respectively.

Did death certificates and a death review process agree on lung cancer cause of death in the National Lung Screening Trial?

BACKGROUND/AIMS: Randomized controlled trials frequently use death review committees to assign a cause of death rather than relying on cause of death information from death certificates. The National Lung Screening Trial, a randomized controlled trial of lung cancer screening with low-dose computed tomography versus chest X-ray for heavy and/or long-term smokers ages 55-74 years at enrollment, used a committee blinded to arm assignment for a subset of deaths to determine whether cause of death was due to lung cancer. METHODS: Deaths were selected for review using a pre-determined computerized algorithm. The algorithm, which considered cancers diagnosed during the trial, causes and significant conditions listed on the death certificate, and the underlying cause of death derived from death certificate information by trained nosologists, selected deaths that were most likely to represent a death due to lung cancer (either directly or indirectly) and deaths that might have been erroneously assigned lung cancer as the cause of death. The algorithm also selected deaths that might be due to adverse events of diagnostic evaluation for lung cancer. Using the review cause of death as the gold standard and lung cancer cause of death as the outcome of interest (dichotomized as lung cancer versus not lung cancer), we calculated performance measures of the death certificate cause of death. We also recalculated the trial primary endpoint using the death certificate cause of death. RESULTS: In all, 1642 deaths were reviewed and assigned a cause of death (42% of the 3877 National Lung Screening Trial deaths). Sensitivity of death certificate cause of death was 91%; specificity, 97%; positive predictive value, 98%; and negative predictive value, 89%. About 40% of the deaths reclassified to lung cancer cause of death had a death certificate cause of death of a neoplasm other than lung. Using the death certificate cause of death, the lung cancer mortality reduction was 18% (95% confidence interval: 4.2-25.0), as compared with the published finding of 20% (95% confidence interval: 6.7-26.7). CONCLUSION: Death review may not be necessary for primary-outcome analyses in lung cancer screening trials. If deemed necessary, researchers should strive to streamline the death review process as much as possible.