The risk of breast cancer among parous women increases with placental weight of pregnancies, and this association is strongest for premenopausal breast cancer.

Pregnancy characteristics and maternal risk of breast cancer.

CONTEXT During pregnancy, serum levels of estrogen, progesterone, and other hormones are markedly higher than during other periods of life. Pregnancy hormones primarily are produced in the placenta, and signs of placental impairment may serve as indirect markers of hormone exposures during pregnancy. During pregnancy, these markers have been inconsistently associated with subsequent risk of breast cancer in the mother. OBJECTIVE To examine associations between indirect markers of hormonal exposures, such as placental weight and other pregnancy characteristics, and maternal risk of developing breast cancer. DESIGN AND SETTING Population-based cohort study using data from the Swedish Birth Register, the Swedish Cancer Register, the Swedish Cause of Death Register, and the Swedish Register of Population and Population Changes. PARTICIPANTS Women included in the Sweden Birth Register who delivered singletons between 1982 and 1989, with complete information on date of birth and gestational age. Women were followed up until the occurrence of breast cancer, death, or end of follow-up (December 31, 2001). Cox proportional hazards models were used to estimate associations between hormone exposures and risks of breast cancer. MAIN OUTCOME MEASURE Incidence of invasive breast cancer. RESULTS Of 314,019 women in the cohort, 2216 (0.7%) developed breast cancer during the follow-up through 2001, of whom 2100 (95%) were diagnosed before age 50 years. Compared with women who had placentas weighing less than 500 g in 2 consecutive pregnancies, the risk of breast cancer was increased among women whose placentas weighed between 500 and 699 g in their first pregnancy and at least 700 g in their second pregnancy (or vice versa) (adjusted hazard ratio, 1.82; 95% confidence interval [CI], 1.07-3.08), and the corresponding risk was doubled among women whose placentas weighed at least 700 g in both pregnancies (adjusted hazard ratio, 2.05; 95% CI, 1.15-3.64). A high birth weight (> or =4000 g) in 2 successive births was associated with an increased risk of breast cancer before but not after adjusting for placental weight and other covariates (adjusted hazard ratio, 1.10; 95% CI, 0.76-1.59). CONCLUSIONS Placental weight is positively associated with maternal risk of breast cancer. These results further support the hypothesis that pregnancy hormones are important modifiers of subsequent maternal breast cancer risk.

Timing of menarche and first full-term birth in relation to breast cancer risk.

Ages at menarche and first birth are established risk factors for breast cancer. The interval between these ages may also affect risk, since the breast is more susceptible to carcinogenic insults during this period than during the parous period. However, few investigators have studied this relation. Using logistic regression, the authors evaluated associations between the timing of reproductive events and breast cancer risk among 4,013 cases and 4,069 controls enrolled in a multicenter, population-based US case-control study of White and African-American women (1994-1998). For White, parous premenopausal and postmenopausal women, those who had an interval of > or =16 years between the ages of menarche and first birth had 1.5-fold (95% confidence interval (CI): 1.0, 2.2) and 1.4-fold (95% CI: 1.1, 1.8) increased risks of breast cancer, respectively, in comparison with those who had < or =5 years between these ages. Adjusting for age at first birth altered these risk estimates somewhat, to odds ratios of 1.5 (95% CI: 0.8, 2.9) and 1.0 (95% CI: 0.6, 1.5), respectively. These associations were stronger for lobular and hormone-receptor-positive tumors but were absent among premenopausal African-American women. The authors conclude that the interval between age at menarche and age at first birth is associated with the risk of hormonally sensitive types of breast cancer, particularly among White women.

Intrauterine environments and breast cancer risk: meta-analysis and systematic review

INTRODUCTION Various perinatal factors, including birth weight, birth order, maternal age, gestational age, twin status, and parental smoking, have been postulated to affect breast cancer risk in daughters by altering the hormonal environment of the developing fetal mammary glands. Despite ample biologic plausibility, epidemiologic studies to date have yielded conflicting results. We investigated the associations between perinatal factors and subsequent breast cancer risk through meta-analyses. METHODS We reviewed breast cancer studies published from January 1966 to February 2007 that included data on birth weight, birth order, maternal age, gestational age, twin status, and maternal or paternal smoking. Meta-analyses using random effect models were employed to summarize the results. RESULTS We found that heavier birth weights were associated with increased breast cancer risk, with studies involving five categories of birth weight identifying odds ratios (ORs) of 1.24 (95% confidence interval [CI] 1.04 to 1.48) for 4,000 g or more and 1.15 (95% CI 1.04 to 1.26) for 3,500 g to 3,999 g, relative to a birth weight of 2,500 to 2,599 g. These studies provided no support for a J-shaped relationship of birthweight to risk. Support for an association with birthweight was also derived from studies based on three birth weight categories (OR 1.15 [95% CI 1.01 to 1.31] for > or =4,000 g relative to <3,000 g) and two birth weight categories (OR 1.09 [95% CI 1.02 to 1.18] for > or =3,000 g relative to <3,000 g). Women born to older mothers and twins were also at some increased risk, but the results were heterogeneous across studies and publication years. Birth order, prematurity, and maternal smoking were unrelated to breast cancer risk. CONCLUSION Our findings provide some support for the hypothesis that in utero exposures reflective of higher endogenous hormone levels could affect risk for development of breast cancer in adulthood.

Menstrual and reproductive factors in relation to mammographic density: the Study of Women’s Health Across the Nation (SWAN)

Menstrual and reproductive factors may increase breast cancer risk through a pathway that includes increased mammographic density. We assessed whether known or suspected menstrual and reproductive breast cancer risk factors were cross-sectionally associated with mammographic density, by measuring area of radiographic density and total breast area on mammograms from 801 participants in the Study of Women’s Health Across the Nation (SWAN), a multi-ethnic cohort of pre- and early perimenopausal women. From multivariable linear regression, the following menstrual or reproductive factors were independently associated with percent mammographic density (area of dense breast/breast area): older age at menarche (β = 10.3, P < 0.01, for >13 vs. <12 years), premenstrual cravings and bloating (β = −3.36, P = 0.02), younger age at first full-term birth (β = −8.12, P < 0.01 for ≤23 years versus no births), greater number of births (β = −6.80, P < 0.01 for ≥3 births versus no births), and premenopausal status (β = 3.78, P < 0.01 versus early perimenopausal). Only number of births remained associated with percent density after adjustment for age, race/ethnicity, study site, body mass index (BMI), and smoking. In addition, stratified analyses revealed that the association with number of births was confined to women within the lowest BMI tertile (β = −12.2, P < 0.01 for ≥3 births versus no births). Our data support a mechanism for parity and breast cancer that involves mammographic density among pre- and early perimenopausal women that may be modified by body size.

Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk.

The association between anthropometric indices and the risk of breast cancer was analyzed using pooled data from seven prospective cohort studies. Together, these cohorts comprise 337,819 women and 4,385 incident invasive breast cancer cases. In multivariate analyses controlling for reproductive, dietary, and other risk factors, the pooled relative risk (RR) of breast cancer per height increment of 5 cm was 1.02 (95% confidence interval (CI): 0.96, 1.10) in premenopausal women and 1.07 (95% CI: 1.03, 1.12) in postmenopausal women. Body mass index (BMI) showed significant inverse and positive associations with breast cancer among pre- and postmenopausal women, respectively; these associations were nonlinear. Compared with premenopausal women with a BMI of less than 21 kg/m2, women with a BMI exceeding 31 kg/m2 had an RR of 0.54 (95% CI: 0.34, 0.85). In postmenopausal women, the RRs did not increase further when BMI exceeded 28 kg/m2; the RR for these women was 1.26 (95% CI: 1.09, 1.46). The authors found little evidence for interaction with other breast cancer risk factors. Their data indicate that height is an independent risk factor for postmenopausal breast cancer; in premenopausal women, this relation is less clear. The association between BMI and breast cancer varies by menopausal status. Weight control may reduce the risk among postmenopausal women.

Breast cancer risk factors in relation to breast density (United States)

Evaluate known breast cancer risk factors in relation to breast density. We examined factors in relation to breast density in 144,018 New Hampshire (NH) women with at least one mammogram recorded in a statewide mammography registry. Mammographic breast density was measured by radiologists using the BI-RADS classification; risk factors of interest were obtained from patient intake forms and questionnaires. Initial analyses showed a strong inverse influence of age and body mass index (BMI) on breast density. In addition, women with late age at menarche, late age at first birth, premenopausal women, and those currently using hormone therapy (HT) tended to have higher breast density, while those with greater parity tended to have less dense breasts. Analyses stratified on age and BMI suggested interactions, which were formally assessed in a multivariable model. The impact of current HT use, relative to nonuse, differed across age groups, with an inverse association in younger women, and a positive association in older women (p < 0.0001 for the interaction). The positive effects of age at menarche and age at first birth, and the inverse influence of parity were less apparent in women with low BMI than in those with high BMI (p = 0.04, p < 0.0001 and p = 0.01, respectively, for the interactions). We also noted stronger positive effects for age at first birth in postmenopausal women (p = 0.004 for the interaction). The multivariable model indicated a slight positive influence of family history of breast cancer. The influence of age at menarche and reproductive factors on breast density is less evident in women with high BMI. Density is reduced in young women using HT, but increased in HT users of age 50 or more.

Predictors of mammographic density: insights gained from a novel regression analysis of a twin study.

Understanding which factors influence mammographically dense and nondense areas is important because percent mammographic density adjusted for age is a strong, continuously distributed risk factor for breast cancer, especially when adjusted for weight or body mass index. Using computer-assisted methods, we measured mammographically dense areas for 571 monozygotic and 380 dizygotic Australian and North American twin pairs ages 40 to 70 years. We used a novel regression modeling approach in which each twin's measure of dense and nondense area was regressed against one or both of the twin's and co-twin's covariates. The nature of changes to regression estimates with the inclusion of the twin and/or co-twin's covariates can be evaluated for consistency with causal and/or other models. By causal, we mean that if it were possible to vary a covariate experimentally then the expected value of the outcome measure would change. After adjusting for the individual's weight, the co-twin associations with weight were attenuated, consistent with a causal effect of weight on mammographic measures, which in absolute log cm(2)/kg was thrice stronger for nondense than dense area. After adjusting for weight, later age at menarche, and greater height were associated with greater dense and lesser nondense areas in a manner inconsistent with causality. The associations of dense and nondense areas with parity are consistent with a causal effect and/or within-person confounding. The associations between mammographic density measures and height are consistent with shared early life environmental factors that predispose to both height and percent mammographic density and possibly breast cancer risk.

Role of birthweight in the etiology of breast cancer.

Breast cancer may originate in utero. We reviewed the available evidence on the association between birthweight and the risk of breast cancer. To date, 26 research papers addressing this issue have been published. The majority of studies identified a positive link between birthweight and premenopausal, but not postmenopausal, breast cancer. The relative risk estimate for breast cancer comparing women with high birthweight to women with low birthweight combining all studies including both pre- and postmenopausal breast cancer was 1.23 (95% confidence interval 1.13-1.34). The mechanisms underlying this association likely include elevated levels of growth factors that may increase the number of susceptible stem cells in the mammary gland or initiate tumors through DNA mutations. Loss of imprinting (LOI) of growth hormone genes relevant for intrauterine growth, such as insulin-like growth factor 2 (IGF2), leads to abnormally high levels of these hormones evidenced by high birthweight. LOI of IGF2 has also been found in mammary tumor tissue. The role of environmental factors that stimulate such epigenetic regulation of gene expression remains to be elucidated.

Cancer after pre-eclampsia: follow up of the Jerusalem perinatal study cohort.

OBJECTIVE To compare the incidence of cancer among women with and without a history of pre-eclampsia. DESIGN Cohort study. SETTING Jerusalem perinatal study of women who delivered in three large hospitals in West Jerusalem during 1964-76. PARTICIPANTS 37 033 women. MAIN OUTCOME MEASURES Age adjusted and multivariable adjusted hazard ratios for cancer incidence for the entire cohort and for women who were primiparous at study entry. RESULTS Cancer developed in 91 women who had pre-eclampsia and 2204 who did not (hazard ratio 1.27, 95% confidence interval 1.03 to 1.57). The risk of site specific cancers was increased, particularly of the stomach, ovary epithelium, breast, and lung or larynx. The incidence of cancer of the stomach, breast, ovary, kidney, and lung or larynx was increased in primiparous women at study entry who had a history pre-eclampsia. CONCLUSIONS A history of pre-eclampsia is associated with increases in overall risk of cancer and incidence at several sites. This may be explained by environmental and genetic factors common to the development of pre-eclampsia and cancer in this population.

Breast cancer and obesity: an update.

Obesity has a complicated relationship to both breast cancer risk and the clinical behavior of the established disease. In postmenopausal women, particularly the elderly, various measures of obesity have been positively associated with risk. However, before menopause increased body weight is inversely related to breast cancer risk. In both premenopausal and postmenopausal breast cancer, the mechanisms by which body weight and obesity affect risk have been related to estrogenic activity. Obesity has also been related to advanced disease at diagnosis and with a poor prognosis in both premenopausal and postmenopausal breast cancer. Breast cancer in African-American women, considering its relationship to obesity, exhibits some important differences from those described in white women, although the high prevalence of obesity in African-American women may contribute to the relatively poor prognosis compared with white American women. Despite the emphasis on estrogens to explain the effects of obesity on breast cancer, other factors may prove to be equally or more important, particularly as they relate to expression of an aggressive tumor phenotype. Among these, this review serves to stress insulin, insulin-like growth factor-I, and leptin, and their relationship to angiogenesis, and transcriptional factors.

Intrauterine factors and risk of breast cancer: a systematic review and meta-analysis of current evidence.

BACKGROUND Emerging evidence suggests an association between female prenatal experience and her subsequent risk of developing breast cancer. Potential underlying mechanisms include variation in amounts of maternal endogenous sex hormones and growth hormones, germ-cell mutations, formation of cancer stem-cells, and other genetic or epigenetic events. We reviewed and summarised quantitatively the available data on intrauterine exposures and risk of breast cancer. METHODS We systematically searched for studies that assessed association between perinatal factors and risk of breast cancer. We reviewed separately each of the perinatal factors, including birthweight, birth length, parental age at delivery, gestational age, intrauterine exposure to diethylstilbestrol, twin membership, maternal pre-eclampsia or eclampsia, and other factors. FINDINGS We identified 57 studies published between Oct 1, 1980, and June 21, 2007. Increased risk of breast cancer was noted with increased birthweight (relative risk [RR] 1.15 [95% CI 1.09-1.21]), birth length (1.28 [1.11-1.48]), higher maternal age (1.13 [1.02-1.25]), and paternal age (1.12 [1.05-1.19]). Decreased risk of breast cancer was noted for maternal pre-eclampsia and eclampsia (0.48 [0.30-0.78]) and twin membership (0.93 [0.87-1.00]). No association was noted between risk of breast cancer and gestational age at birth (0.95 [0.71-1.26]) or maternal diethylstilbestrol treatment (1.40 [0.86-2.28]). INTERPRETATION The intrauterine environment contributes to the predisposition of women to breast cancer in adulthood. The in-utero mechanisms responsible for such predisposition need to be elucidated.

Diabetes, metabolic syndrome, and breast cancer: a review of the current evidence.

Incidences of breast cancer, type 2 diabetes, and metabolic syndrome have increased over the past decades with the obesity epidemic, especially in industrialized countries. Insulin resistance, hyperinsulinemia, and changes in the signaling of growth hormones and steroid hormones associated with diabetes may affect the risk of breast cancer. We reviewed epidemiologic studies of the association between type 2 diabetes and risk of breast cancer and the available evidence on the role of hormonal mediators of an association between diabetes and breast cancer. The combined evidence supports a modest association between type 2 diabetes and the risk of breast cancer, which appears to be more consistent among postmenopausal than among premenopausal women. Despite many proposed potential pathways, the mechanisms underlying an association between diabetes and breast cancer risk remain unclear, particularly because the 2 diseases share several risk factors, including obesity, a sedentary lifestyle, and possibly intake of saturated fat and refined carbohydrates, that may confound this association. Although the metabolic syndrome is closely related to diabetes and embraces additional components that might influence breast cancer risk, the role of the metabolic syndrome in breast carcinogenesis has not been studied and thus remains unknown.

Birth weight and mammographic density among postmenopausal women in Sweden.

Birth weight is a significant predictor of breast cancer risk in adult life and mammary gland mass could be an intermediate stage in this long process. We have studied the association of birth size measurements with mammographic density, a marker of mammary gland mass. For a population-based sample of 893 postmenopausal women without previous cancer in Sweden, we retrieved information on birth size from birth records and their most recent mammography. Film mammograms of the medio-lateral oblique view were digitized and the Cumulus software was used for computer-assisted semi-automated thresholding of mammographic density. Results were analyzed using generalized linear models controlling for possible confounders. Mean percent mammographic density increased when comparing the extreme categories of birth weight (from 15.6% to 18.6%) and head circumference (from 15.5% to 20.4%), and the corresponding linear trends were statistically significant (p values 0.02 and 0.007, respectively). The associations were particularly strong when the cutoff for high versus low mammographic density was set at the relatively high value of 50%. Compared to women weighing 3001-3500 grams at birth, women with birth weights >4000g were at almost 3-fold risk of developing high mammographic density (odds ratio: 2.9, 95% confidence interval 1.1 to 7.9). No association with mammographic density was evident with respect to birth length which, however, is known to be less accurately measured. These results indicate that adult breast density, a powerful predictor of breast cancer risk, has intrauterine roots, as reflected in birth size.

Prediagnostic levels of C-peptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer.

Conditions related to chronic hyperinsulinemia, such as obesity, noninsulin dependent diabetes mellitus and polycystic ovary syndrome, are associated with an increased risk of endometrial cancer. Elevated plasma IGF-I and decreased levels of IGF-binding proteins have been shown to be associated with increased risk of several cancer types that are frequent in affluent societies. We investigated for the first time in a prospective study the association of pre-diagnostic blood concentrations of C-peptide (a marker of pancreatic insulin production), IGF-I, IGFBP-1, -2 and -3 with endometrial cancer risk. A case-control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). It included 166 women with primary invasive endometrial cancer and 315 matched controls, of which 44 case and 78 control subjects were premenopausal at recruitment. Endometrial cancer risk increased with increasing levels of C-peptide (ptrend = 0.0002), up to an odds ratio (OR) of 4.76 [95% confidence interval (CI) = 1.91-11.8] for the highest quintile. This association remained after adjustment for BMI and other confounders [OR for the top quintile = 4.40 (1.65-11.7)]. IGFBP-1 levels were inversely related to endometrial cancer [ptrend = 0.002; OR in the upper quintile = 0.30 (0.15-0.62)], but the association was weakened and lost statistical significance after adjustment for confounders [ptrend = 0.06; OR in the upper quintile = 0.49 (0.22-1.07)]. Risk was unrelated to levels of IGF-I, IGFBP-2 and IGFBP-3. Chronic hyperinsulinemia, as reflected by increased circulating C-peptide, is associated with increased endometrial cancer risk. Decrease in the prevalence of chronic hyperinsulinemia, through changes in lifestyle or medication, is expected to prevent endometrial cancer.

Effect of Previous Miscarriage on Depressive Symptoms During Subsequent Pregnancy and Postpartum in the First Baby Study

Our objective was to test the hypothesis that nulliparous women with a history of miscarriage have an increased risk of depression during late pregnancy, and at 1, 6, and 12 months postpartum compared to women without a history of miscarriage. We conducted secondary analysis of a longitudinal cohort study, the First Baby Study, and compared 448 pregnant women with a history of miscarriage to 2,343 pregnant women without a history of miscarriage on risk of probable depression (score >12 on the Edinburgh Postnatal Depression Scale). Logistic regression models were used to estimate odds ratios at each time point and generalized estimating equations were used to obtain estimates in longitudinal analysis. Women with a history of miscarriage were not more likely than woman without a history of miscarriage to score in the probable depression range during the third trimester or at 6 or 12 months postpartum but were more likely at 1 month postpartum, after adjustment for sociodemographic factors (OR 1.66, 95 % CI 1.03–2.69). Women with a history of miscarriage may be more vulnerable to depression during the first month postpartum than women without prior miscarriage, but this effect does not appear to persist beyond this time period. We support the promotion of awareness surrounding this issue and recommend that research is planned to identify risk factors that may position a woman with a history of miscarriage to be at higher risk for depression.

Prepregnancy BMI and the risk of gestational diabetes: a systematic review of the literature with meta-analysis.

The objective of this study is to assess and quantify the risk for gestational diabetes mellitus (GDM) according to prepregnancy maternal body mass index (BMI). The design is a systematic review of observational studies published in the last 30 years. Four electronic databases were searched for publications (1977-2007). BMI was elected as the only measure of obesity, and all diagnostic criteria for GDM were accepted. Studies with selective screening for GDM were excluded. There were no language restrictions. The methodological quality of primary studies was assessed. Some 1745 citations were screened, and 70 studies (two unpublished) involving 671 945 women were included (59 cohorts and 11 case-controls). Most studies were of high or medium quality. Compared with women with a normal BMI, the unadjusted pooled odds ratio (OR) of an underweight woman developing GDM was 0.75 (95% confidence interval [CI] 0.69 to 0.82). The OR for overweight, moderately obese and morbidly obese women were 1.97 (95% CI 1.77 to 2.19), 3.01 (95% CI 2.34 to 3.87) and 5.55 (95% CI 4.27 to 7.21) respectively. For every 1 kg m(-2) increase in BMI, the prevalence of GDM increased by 0.92% (95% CI 0.73 to 1.10). The risk of GDM is positively associated with prepregnancy BMI. This information is important when counselling women planning a pregnancy.

Type 2 diabetes and subsequent incidence of breast cancer in the Nurses' Health Study.

OBJECTIVE Hyperinsulinemia may promote mammary carcinogenesis. Insulin resistance has been linked to an increased risk of breast cancer and is also characteristic of type 2 diabetes. We prospectively evaluated the association between type 2 diabetes and invasive breast cancer incidence in the Nurses' Health Study. RESEARCH DESIGN AND METHODS A total of 116,488 female nurses who were 30-55 years old and free of cancer in 1976 were followed through 1996 for the occurrence of type 2 diabetes and through 1998 for incident invasive breast cancer, verified by medical records and pathology reports. RESULTS During 2.3 million person-years of follow-up, we identified 6,220 women with type 2 diabetes and 5,189 incident cases of invasive breast cancer. Women with type 2 diabetes had a modestly elevated incidence of breast cancer (hazard ratio [HR] = 1.17; 95% CI 1.01-1.35) compared with women without diabetes, independent of age, obesity, family history of breast cancer, history of benign breast disease, reproductive factors, physical activity, and alcohol consumption. This association was apparent among postmenopausal women (1.16; 0.98-1.62) but not premenopausal women (0.83; 0.48-1.42). The association was predominant among women with estrogen receptor-positive breast cancer (1.22; 1.01-1.47). CONCLUSIONS Women with type 2 diabetes may have a slightly increased risk of breast cancer.

Birth Size and Breast Cancer Risk: Re-analysis of Individual Participant Data from 32 Studies

BACKGROUND Birth size, perhaps a proxy for prenatal environment, might be a correlate of subsequent breast cancer risk, but findings from epidemiological studies have been inconsistent. We re-analysed individual participant data from published and unpublished studies to obtain more precise estimates of the magnitude and shape of the birth size-breast cancer association. METHODS AND FINDINGS Studies were identified through computer-assisted and manual searches, and personal communication with investigators. Individual participant data from 32 studies, comprising 22,058 breast cancer cases, were obtained. Random effect models were used, if appropriate, to combine study-specific estimates of effect. Birth weight was positively associated with breast cancer risk in studies based on birth records (pooled relative risk [RR] per one standard deviation [SD] [= 0.5 kg] increment in birth weight: 1.06; 95% confidence interval [CI] 1.02-1.09) and parental recall when the participants were children (1.02; 95% CI 0.99-1.05), but not in those based on adult self-reports, or maternal recall during the woman's adulthood (0.98; 95% CI 0.95-1.01) (p for heterogeneity between data sources = 0.003). Relative to women who weighed 3.000-3.499 kg, the risk was 0.96 (CI 0.80-1.16) in those who weighed < 2.500 kg, and 1.12 (95% CI 1.00-1.25) in those who weighed > or = 4.000 kg (p for linear trend = 0.001) in birth record data. Birth length and head circumference from birth records were also positively associated with breast cancer risk (pooled RR per one SD increment: 1.06 [95% CI 1.03-1.10] and 1.09 [95% CI 1.03-1.15], respectively). Simultaneous adjustment for these three birth size variables showed that length was the strongest independent predictor of risk. The birth size effects did not appear to be confounded or mediated by established breast cancer risk factors and were not modified by age or menopausal status. The cumulative incidence of breast cancer per 100 women by age 80 y in the study populations was estimated to be 10.0, 10.0, 10.4, and 11.5 in those who were, respectively, in the bottom, second, third, and top fourths of the birth length distribution. CONCLUSIONS This pooled analysis of individual participant data is consistent with birth size, and in particular birth length, being an independent correlate of breast cancer risk in adulthood.

Case-control study of endogenous steroid hormones and endometrial cancer.

BACKGROUND It has been suggested that identified risk factors for endometrial cancer operate through a single etiologic pathway, i.e., exposure to relatively high levels of unopposed estrogen (estrogen in the absence of progestins). Only a few studies, however, have addressed this issue directly. PURPOSE We assessed the risk of developing endometrial cancer among both premenopausal and postmenopausal women in relation to the circulating levels of steroid hormones and sex hormone-binding globulin (SHBG). The independent effect of hormones was assessed after adjustment for other known risk factors. METHODS The data used in the analysis are from a case-control study conducted in five geographic regions in the United States. Incident cases were newly diagnosed during the period from June 1, 1987, through May 15, 1990. The case patients, aged 20-74 years, were matched to control subjects by age, race, and geographic region. The community control subjects were obtained by random-digit-dialing procedures (for subjects 20-64 years old) and from files of the Health Care Financing Administration (for subjects > or = 65 years old). Additional control subjects who were having a hysterectomy performed for benign conditions were obtained from the participating centers. Women reporting use of exogenous estrogens or oral contraceptives within 6 months of interview were excluded, resulting in 68 case patients and 107 control subjects among premenopausal women and 208 case patients and 209 control subjects among postmenopausal women. The hormone analyses were performed on blood samples obtained from case patients or from hysterectomy control subjects before surgery. The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by use of an unconditional logistic regression analysis after we controlled for matching variables and potential confounders. All P values were two-sided. RESULTS High circulating levels of androstenedione were associated with 3.6-fold and 2.8-fold increased risks among premenopausal and postmenopausal women, respectively, after adjustment for other factors (P for trend = .01 and < .001, respectively). Risks related to other hormone fractions varied by menopausal status. Among postmenopausal women, a reduced risk was associated with high SHBG levels and persisted after adjustment was made for obesity and other factors (OR = 0.51; 95% CI = 0.27-0.95). High estrone levels were associated with increased risk (OR = 3.8; 95% CI = 2.2-6.6), although adjustment for other risk factors (particularly body mass index) diminished the effect (OR = 2.2; 95% CI = 1.2-4.4). Albumin-bound estradiol (E2), a marker of the bioavailable fraction, also remained an important risk factor after adjustment was made for other factors (OR = 2.0; 95% CI = 1.0-3.9). In contrast, high concentrations of total, free, and albumin-bound E2 were unrelated to increased risk in premenopausal women. In both premenopausal and postmenopausal groups, risks associated with obesity and fat distribution were not affected by adjustment for hormones. CONCLUSION High endogenous levels of unopposed estrogen are related to increased risk of endometrial cancer, but their independence from other risk factors is inconsistent with being a common underlying biologic pathway through which all risk factors for endometrial cancer operate. IMPLICATIONS Further research should focus on alternative endocrinologic mechanisms for risk associated with obesity and body fat distribution and for the biologic relevance of the increased risk associated with androstenedione in both premenopausal and postmenopausal disease.

Mammographic density and the risk and detection of breast cancer.

BACKGROUND Extensive mammographic density is associated with an increased risk of breast cancer and makes the detection of cancer by mammography difficult, but the influence of density on risk according to method of cancer detection is unknown. METHODS We carried out three nested case-control studies in screened populations with 1112 matched case-control pairs. We examined the association of the measured percentage of density in the baseline mammogram with risk of breast cancer, according to method of cancer detection, time since the initiation of screening, and age. RESULTS As compared with women with density in less than 10% of the mammogram, women with density in 75% or more had an increased risk of breast cancer (odds ratio, 4.7; 95% confidence interval [CI], 3.0 to 7.4), whether detected by screening (odds ratio, 3.5; 95% CI, 2.0 to 6.2) or less than 12 months after a negative screening examination (odds ratio, 17.8; 95% CI, 4.8 to 65.9). Increased risk of breast cancer, whether detected by screening or other means, persisted for at least 8 years after study entry and was greater in younger than in older women. For women younger than the median age of 56 years, 26% of all breast cancers and 50% of cancers detected less than 12 months after a negative screening test were attributable to density in 50% or more of the mammogram. CONCLUSIONS Extensive mammographic density is strongly associated with the risk of breast cancer detected by screening or between screening tests. A substantial fraction of breast cancers can be attributed to this risk factor.

Risk for breast cancer development determined by mammographic parenchymal pattern.

A classification of risk for developing breast cancer has been devised based solely on the appearance of the breast parenchyma by mammography. Four groups of patients were isolated. The study encompassed a five-year period and was done by reviewing the mammograms of all women over the age of 30 who had been examined at Hutzel Hospital, Detroit. The average time of followup would be approximately 2 1/2 years. Four groups had an incidence of developing breast cancer of 0.1, 0.4, 1.7, and 2.2. These parenchymal patterns are described and criteria for their identification are given.

Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk.

Epidemiologic studies suggest that ovarian hormones contribute to the development of breast cancer at all stages. Early menopause and premenopausal obesity reduces the risk while postmenopausal obesity and menopausal estrogen replacement therapy increases the risk. Combined oral contraceptives and Depo-Provera do not reduce the risk. It appears that estrogens and progestogens act through and with proto-oncogenes and growth factors to affect breast cell proliferation and breast cancer etiology. Animal studies suggest that estrogen causes interlobular ductal cell division and progesterone causes increased terminal duct lobular unit cell division in the luteal phase. Most breast carcinomas originate from terminal duct lobular unit cells. During pregnancy, these cells fully multiply. Their reproduction is also increased during the luteal phase. Yet, there is considerable interpersonal variation. No studies examining breast cell division have compared cell division rates with serum hormone concentrations, however. The peak of mitosis occurs about 3 days before breast cell death in the late luteal and very early follicular phases. Other research suggests that breast stem cell proliferation is linked to breast cancer development. Endocrine therapy reduces mitotic activity, indicating the estrogen and progesterone receptor content of breast cancers. Hormone-dependent breast cancer cell lines are all estrogen-dependent. Progesterone can block the estrogen-dependent cell lines which act like endometrial cells. The results of the various breast cell proliferation studies in relation to breast cancer are unclear and research identifying a molecular explanation would help in understanding the different findings.

Serum high-density lipoprotein cholesterol, metabolic profile, and breast cancer risk.

BACKGROUND The prevalence of metabolic syndrome (obesity, glucose intolerance, low serum high-density lipoprotein cholesterol [HDL-C], high serum triglycerides, hypertension) is high and increasing in parallel with an increasing breast cancer incidence worldwide. HDL-C represents an important aspect of the syndrome, yet its role in breast cancer is still undefined. METHODS In two population-based screening surveys during 1977-1983 and 1985-1987, serum HDL-C was assayed enzymatically among 38,823 Norwegian women aged 17-54 years at entry. Height, weight, blood pressure, serum lipids, fat and energy intake, physical activity, parity, oral contraceptive use, hormone therapy use, alcohol intake, and tobacco use were also assessed. We used Cox proportional hazards modeling to estimate the relative risk (RR) of breast cancer associated with serum HDL-C levels and to adjust for potential confounding variables. We performed stratified analyses to evaluate effect modification by body mass index (BMI) and menopausal status. All statistical tests were two-sided. RESULTS During a median follow-up of 17.2 years, we identified 708 cases of invasive breast cancer. In multivariable analysis, the risk of postmenopausal breast cancer was inversely related to quartile of HDL-C (P(trend) =.02). Among women with HDL-C above 1.64 mmol/L (highest quartile) versus below 1.20 mmol/L (lowest quartile), the relative risk was 0.75 (95% confidence interval [CI] = 0.58 to 0.97). The HDL-C association was confined to women in the heavier subgroup (BMI > or =25 kg/m2), for whom the relative risk of postmenopausal breast cancer in those with HDL-C above 1.64 mmol/L versus below 1.20 mmol/L was 0.43 (95% CI = 0.28 to 0.67; P(trend)<.001; P(interaction) =.001). CONCLUSION Low HDL-C, as part of the metabolic syndrome, is associated with increased postmenopausal breast cancer risk.

Gene–environment interactions in 7610 women with breast cancer: prospective evidence from the Million Women Study

BACKGROUND Information is scarce about the combined effects on breast cancer incidence of low-penetrance genetic susceptibility polymorphisms and environmental factors (reproductive, behavioural, and anthropometric risk factors for breast cancer). To test for evidence of gene-environment interactions, we compared genotypic relative risks for breast cancer across the other risk factors in a large UK prospective study. METHODS We tested gene-environment interactions in 7610 women who developed breast cancer and 10 196 controls without the disease, studying the effects of 12 polymorphisms (FGFR2-rs2981582, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, 2p-rs4666451, 5p12-rs981782, CASP8-rs1045485, LSP1-rs3817198, 5q-rs30099, TGFB1-rs1982073, and ATM-rs1800054) in relation to prospectively collected information about ten established environmental risk factors (age at menarche, parity, age at first birth, breastfeeding, menopausal status, age at menopause, use of hormone replacement therapy, body-mass index, height, and alcohol consumption). FINDINGS After allowance for multiple testing none of the 120 comparisons yielded significant evidence of a gene-environment interaction. By contrast with previous suggestions, there was little evidence that the genotypic relative risks were affected by use of hormone replacement therapy, either overall or for oestrogen-receptor-positive disease. Only one of the 12 polymorphisms was correlated with any of the ten other risk factors: carriers of the high-risk C allele of MAP3K1-rs889312 were significantly shorter than non-carriers (mean height 162.4 cm [95% CI 162.1-162.7] vs 163.1 cm [162.9-163.2]; p=0.01 after allowance for multiple testing). INTERPRETATION Risks of breast cancer associated with low-penetrance susceptibility polymorphisms do not vary significantly with these ten established environmental risk factors. FUNDING Cancer Research UK and the UK Medical Research Council.

Management of women who have a genetic predisposition for breast cancer.

The management of women who have a genetic predisposition for breast cancer requires careful planning. Women who have BRCA 1 and BRCA 2 mutations are at increased risk for breast cancer and for other cancers as well, particularly ovarian cancer. Screening, prophlyactic surgery, and chemoprevention are commonly utilized strategies in the management of these patients, and women may choose more than one of these strategies. No randomized prospective trials have assessed the impact of these strategies specifically in mutation carriers. All patients should be informed that screening, prophylactic surgery, and chemoprevention have the potential for harm as well as benefit.

Human papillomavirus and Papanicolaou tests to screen for cervical cancer.

BACKGROUND Screening for cervical cancer based on testing for human papillomavirus (HPV) increases the sensitivity of detection of high-grade (grade 2 or 3) cervical intraepithelial neoplasia, but whether this gain represents overdiagnosis or protection against future high-grade cervical epithelial neoplasia or cervical cancer is unknown. METHODS In a population-based screening program in Sweden, 12,527 women 32 to 38 years of age were randomly assigned at a 1:1 ratio to have an HPV test plus a Papanicolaou (Pap) test (intervention group) or a Pap test alone (control group). Women with a positive HPV test and a normal Pap test result were offered a second HPV test at least 1 year later, and those who were found to be persistently infected with the same high-risk type of HPV were then offered colposcopy with cervical biopsy. A similar number of double-blinded Pap smears and colposcopies with biopsy were performed in randomly selected women in the control group. Comprehensive registry data were used to follow the women for a mean of 4.1 years. The relative rates of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected at enrollment and at subsequent screening examinations were calculated. RESULTS At enrollment, the proportion of women in the intervention group who were found to have lesions of grade 2 or 3 cervical intraepithelial neoplasia or cancer was 51% greater (95% confidence interval [CI], 13 to 102) than the proportion of women in the control group who were found to have such lesions. At subsequent screening examinations, the proportion of women in the intervention group who were found to have grade 2 or 3 lesions or cancer was 42% less (95% CI, 4 to 64) and the proportion with grade 3 lesions or cancer was 47% less (95% CI, 2 to 71) than the proportions of control women who were found to have such lesions. Women with persistent HPV infection remained at high risk for grade 2 or 3 lesions or cancer after referral for colposcopy. CONCLUSIONS The addition of an HPV test to the Pap test to screen women in their mid-30s for cervical cancer reduces the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected by subsequent screening examinations. (ClinicalTrials.gov number, NCT00479375 [ClinicalTrials.gov].).

Intrinsic genetic characteristics determine tumor-modifying capacity of fibroblasts: matrix metalloproteinase-3 5A/5A genotype enhances breast cancer cell invasion

Stromal fibroblasts can contribute to tumor invasion through the release of matrix metalloproteinases (MMPs). Population studies have suggested that single nucleotide polymorphisms (SNPs) in MMP genes influence levels of expression and may be associated with breast cancer risk and with disease progression. This study directly examined the impact of MMP SNP genotype on the ability of host fibroblasts to promote tumor cell invasion. Primary breast fibroblasts were isolated from patients with (n = 13) or without (n = 19) breast cancer, and their ability to promote breast cancer cell invasion was measured in in vitro invasion assays. Fibroblast invasion-promoting capacity (IPC) was analyzed in relation to donor type (tumor or non-tumor patient), MMP-1, MMP-3, and MMP-9 SNP genotype and MMP activity using independent samples t test and analysis of variance. All statistical tests were two-sided. Tumor-derived fibroblasts promoted higher levels of invasion than normal fibroblasts (p = 0.041). When IPC was related to genotype, higher levels of IPC were generated by tumor fibroblasts with the high-expressing MMP-3 5A/5A genotype compared with the 5A/6A and 6A/6A genotypes (p = 0.05 and 0.07, respectively), and this was associated with enhanced MMP-3 release. The functional importance of MMP-3 was demonstrated by enhanced invasion in the presence of recombinant MMP-3, whereas reduction occurred in the presence of a specific MMP-3 inhibitor. An inverse relationship was demonstrated between fibroblast IPC and the high-expressing MMP-1 genotype (p = 0.031), but no relationship was seen with MMP-9 SNP status. In contrast, normal fibroblasts showed no variation in IPC in relation to MMP genotype, with MMP-3 5A/5A fibroblasts exhibiting significantly lower levels of IPC than their tumor-derived counterparts (p = 0.04). This study has shown that tumor-derived fibroblasts exhibit higher levels of IPC than normal fibroblasts and that the MMP-3 5A/5A genotype contributes to this through enhanced MMP-3 release. Despite a high-expressing genotype, normal fibroblasts do not exhibit higher IPC or enhanced MMP release. This suggests that more complex changes occur in tumor-derived fibroblasts, enabling full expression of the MMP SNP genotype and these possibly are epigenetic in nature. The results do suggest that, in women with breast cancer, a high-expressing MMP-3 genotype may promote tumor progression more effectively.

Weight gain during pregnancy: reexamining the guidelines.

As women of childbearing age have become heavier, the trade-off between maternal and child health created by variation in gestational weight gain has become more difficult to reconcile. Weight Gain During Pregnancy responds to the need for a reexamination of the 1990 Institute of Medicine guidelines for weight gain during pregnancy. It builds on the conceptual framework that underscored the 1990 weight gain guidelines and addresses the need to update them through a comprehensive review of the literature and independent analyses of existing databases. The book explores relationships between weight gain during pregnancy and a variety of factors (e.g., the mother's weight and height before pregnancy) and places this in the context of the health of the infant and the mother, presenting specific, updated target ranges for weight gain during pregnancy and guidelines for proper measurement. New features of this book include a specific range of recommended gain for obese women. Weight Gain During Pregnancy is intended to assist practitioners who care for women of childbearing age, policy makers, educators, researchers, and the pregnant women themselves to understand the role of gestational weight gain and to provide them with the tools needed to promote optimal pregnancy outcomes.

Female Gender and Reproductive Factors Affecting Risk, Relapses and Progression in Multiple Sclerosis

Multiple sclerosis (MS), a chronic inflammatory demyelina-ting and degenerative disease of the central nervous system, is a frequent cause of neurological disability in young adults. Female predominance has increased over the last decades. Although female gender carries a higher risk of developing relapsing remitting MS, being female and at child-bearing age also appears to provide some protection against cognitive decline and against progressive onset MS, an adverse predictive factor when considering long-term disability in MS. The risk of MS in women has been associated with an earlier age at menarche. In most studies, parity did not impact MS risk. However, the recently published association of higher parity and offspring number with a reduced risk of a first demyelinating event suggests a potential suppressive effect. Pregnancy in MS patients has been associated with a reduced relapse rate and a reduction of neurological symptoms, especially in the third trimester. Despite the increased relapse risk in the postpartum period, there is no indication of an adverse effect of childbirth on the long-term course of MS. Fertility treatment in MS has been associated with an increased relapse risk in the following 3-month period, especially when the procedure did not result in pregnancy and gonadotrophin-releasing hormone agonists were used. Altogether, there is substantial evidence to support a regulatory role of sex steroid hormones in MS. In the absence of correlations with single hormone blood levels, we can only speculate about the underlying mechanisms. In conclusion, the increased MS risk in women and the changes in relapse and progression risk in association with reproductive events suggest significant and complex interactions between immune, neuroendocrine and reproductive systems in MS.

Breast cancer clusters in the northeast United States: a geographic analysis.

High breast cancer mortality rates have been reported in the northeastern part of the United States, with recent attention focused on Long Island, New York. In this study, the authors investigate whether the high breast cancer mortality is evenly spread over the Northeast, in the sense that any observed clusters of deaths can be explained by chance alone, or whether there are clusters of statistical significance. Demographic data and age-specific breast cancer mortality rates for women were obtained for all 244 counties in 11 northeastern states and for the District of Columbia for 1988-1992. A recently developed spatial scan statistic is used, which searches for clusters of cases without specifying their size or location ahead of time, and which tests for their statistical significance while adjusting for the multiple testing inherent in such a procedure. The basic analysis is adjusted for age, with further analyses examining how the results are affected by incorporating race, urbanicity, and parity as confounding variables. There is a statistically significant and geographically broad cluster of breast cancer deaths in the New York City-Philadelphia, Pennsylvania, metropolitan area (p = 0.0001), which has a 7.4% higher mortality rate than the rest of the Northeast. The cluster remains significant when race, urbanicity, and/or parity are included as confounding variables. Four smaller subclusters within this area are also significant on their own strength: Philadelphia with suburbs (p = 0.0001), Long Island (p = 0.0001), central New Jersey (p = 0.0001), and northeastern New Jersey (p = 0.0001). The elevated breast cancer mortality on Long Island might be viewed less as a unique local phenomenon and more as part of a more general situation involving large parts of the New York City-Philadelphia metropolitan area. The several known and hypothesized risk factors for which we could not adjust and that may explain the detected cluster are most notably age at first birth, age at menarche, age at menopause, breastfeeding, genetic mutations, and environmental factors.

Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus.

The environment in which the fetus develops is critical for its survival and long-term health. The regulation of normal human fetal growth involves many multidirectional interactions between the mother, placenta, and fetus. The mother supplies nutrients and oxygen to the fetus via the placenta. The fetus influences the provision of maternal nutrients via the placental production of hormones that regulate maternal metabolism. The placenta is the site of exchange between mother and fetus and regulates fetal growth via the production and metabolism of growth-regulating hormones such as IGFs and glucocorticoids. Adequate trophoblast invasion in early pregnancy and increased uteroplacental blood flow ensure sufficient growth of the uterus, placenta, and fetus. The placenta may respond to fetal endocrine signals to increase transport of maternal nutrients by growth of the placenta, by activation of transport systems, and by production of placental hormones to influence maternal physiology and even behavior. There are consequences of poor fetal growth both in the short term and long term, in the form of increased mortality and morbidity. Endocrine regulation of fetal growth involves interactions between the mother, placenta, and fetus, and these effects may program long-term physiology.

Independent Association of Lobular Involution and Mammographic Breast Density With Breast Cancer Risk

BACKGROUND Lobular involution, or age-related atrophy of breast lobules, is inversely associated with breast cancer risk, and mammographic breast density (MBD) is positively associated with breast cancer risk. METHODS To evaluate whether lobular involution and MBD are independently associated with breast cancer risk in women with benign breast disease, we performed a nested cohort study among women (n = 2666) with benign breast disease diagnosed at Mayo Clinic between January 1, 1985, and December 31, 1991 and a mammogram available within 6 months of the diagnosis. Women were followed up for an average of 13.3 years to document any breast cancer incidence. Lobular involution was categorized as none, partial, or complete; parenchymal pattern was classified using the Wolfe classification as N1 (nondense), P1, P2 (ductal prominence occupying <25%, or >25% of the breast, respectively), or DY (extremely dense). Hazard ratios (HRs) and 95% confidence intervals (CIs) to assess associations of lobular involution and MBD with breast cancer risk were estimated using adjusted Cox proportional hazards model. All tests of statistical significance were two-sided. RESULTS After adjustment for MBD, having no or partial lobular involution was associated with a higher risk of breast cancer than having complete involution (none: HR of breast cancer incidence = 2.62, 95% CI = 1.39 to 4.94; partial: HR of breast cancer incidence = 1.61, 95% CI = 1.03 to 2.53; P(trend) = .002). Similarly, after adjustment for involution, having dense breasts was associated with higher risk of breast cancer than having nondense breasts (for DY: HR of breast cancer incidence = 1.67, 95% CI = 1.03 to 2.73; for P2: HR of breast cancer incidence = 1.96, 95% CI = 1.20 to 3.21; for P1: HR of breast cancer incidence = 1.23, 95% CI = 0.67 to 2.26; P(trend) = .02). Having a combination of no involution and dense breasts was associated with higher risk of breast cancer than having complete involution and nondense breasts (HR of breast cancer incidence = 4.08, 95% CI = 1.72 to 9.68; P = .006). CONCLUSION Lobular involution and MBD are independently associated with breast cancer incidence; combined, they are associated with an even greater risk for breast cancer.

Reproductive and lifestyle determinants of anti-Müllerian hormone in a large population-based study.

CONTEXT Anti-müllerian hormone (AMH) is an ovarian reserve marker that is increasingly applied in clinical practice as a prognostic and diagnostic tool. Despite increased use of AMH in clinical practice, large-scale studies addressing the influence of possible determinants on AMH levels are scarce. OBJECTIVE We aimed to address the role of reproductive and lifestyle determinants of AMH in a large population-based cohort of women. DESIGN In this cross-sectional study, age-specific AMH percentiles were calculated using general linear modeling with CG-LMS (Cole and Green, Lambda, Mu, and Sigma model, an established method to calculate growth curves for children). SETTING Women from the general community participating in the Doetinchem Cohort study were assessed. PARTICIPANTS Two thousand three hundred twenty premenopausal women were included. MAIN OUTCOME MEASURE The effect of female reproductive and lifestyle factors on shifts in age-specific AMH percentiles was studied. RESULTS In comparison to women with a regular menstrual cycle, current oral contraceptive (OC) users, women with menstrual cycle irregularity, and pregnant women had significantly lower age-specific AMH percentiles (for OC use, 11 percentiles lower; for cycle irregularity, 11 percentiles lower; and for pregnancy, 17 percentiles lower [P value for all <.0001]). Age at menarche and age at first childbirth were not associated with the age-specific AMH percentile. Higher parity was associated with 2 percentiles higher age-specific AMH (P = .02). Of the lifestyle factors investigated, current smoking was associated with 4 percentiles lower age-specific AMH percentiles (P = .02), irrespective of the smoking dose. Body mass index, waist circumference, alcohol consumption, physical exercise, and socioeconomic status were not significantly associated with age-specific AMH percentiles. CONCLUSIONS This study demonstrates that several reproductive and lifestyle factors are associated with age-specific AMH levels. The lower AMH levels associated with OC use and smoking seem reversible, as effects were confined to current use of OC or cigarettes. It is important to give careful consideration to the effect of such determinants when interpreting AMH in a clinical setting and basing patient management on AMH.

Effects of interventions in pregnancy on maternal weight and obstetric outcomes: meta-analysis of randomised evidence

OBJECTIVE To evaluate the effects of dietary and lifestyle interventions in pregnancy on maternal and fetal weight and to quantify the effects of these interventions on obstetric outcomes. DESIGN Systematic review and meta-analysis. DATA SOURCES Major databases from inception to January 2012 without language restrictions. STUDY SELECTION Randomised controlled trials that evaluated any dietary or lifestyle interventions with potential to influence maternal weight during pregnancy and outcomes of pregnancy. DATA SYNTHESIS Results summarised as relative risks for dichotomous data and mean differences for continuous data. RESULTS We identified 44 relevant randomised controlled trials (7278 women) evaluating three categories of interventions: diet, physical activity, and a mixed approach. Overall, there was 1.42 kg reduction (95% confidence interval 0.95 to 1.89 kg) in gestational weight gain with any intervention compared with control. With all interventions combined, there were no significant differences in birth weight (mean difference -50 g, -100 to 0 g) and the incidence of large for gestational age (relative risk 0.85, 0.66 to 1.09) or small for gestational age (1.00, 0.78 to 1.28) babies between the groups, though by itself physical activity was associated with reduced birth weight (mean difference -60 g, -120 to -10 g). Interventions were associated with a reduced the risk of pre-eclampsia (0.74, 0.60 to 0.92) and shoulder dystocia (0.39, 0.22 to 0.70), with no significant effect on other critically important outcomes. Dietary intervention resulted in the largest reduction in maternal gestational weight gain (3.84 kg, 2.45 to 5.22 kg), with improved pregnancy outcomes compared with other interventions. The overall evidence rating was low to very low for important outcomes such as pre-eclampsia, gestational diabetes, gestational hypertension, and preterm delivery. CONCLUSIONS Dietary and lifestyle interventions in pregnancy can reduce maternal gestational weight gain and improve outcomes for both mother and baby. Among the interventions, those based on diet are the most effective and are associated with reductions in maternal gestational weight gain and improved obstetric outcomes.

Prospective study of body fat distribution and the risk of endometrial cancer.

BACKGROUND Epidemiologic studies have found that overall obesity is positively related to endometrial cancer (EC) risk. However, data assessing the association between body fat distribution and risk of EC are still limited. METHODS We followed 51,948 women who first reported waist circumference (WC) and hip circumference in 1986 in the Nurses' Health Study. Waist-to-hip ratio (WHR) was calculated. RESULTS During 24 years of follow-up, 449 incident invasive EC cases were diagnosed. In a multivariate analysis without adjusting for body mass index (BMI), the relative risks (RRs) for EC comparing extreme categories were 2.44 (95% confidence interval [CI] 1.72-3.45) for WC and 1.69 (95% CI=1.20-2.40) for WHR. However, after adjustment of BMI, those positive associations were substantially attenuated and no longer significant; RR=1.08 (95% CI=0.69-1.67) for WC and 1.15 (95% CI=0.81-1.64) for WHR, respectively. CONCLUSION In our prospective cohort study, we found no independent association between body fat distribution and the risk of EC after adjustment for BMI.

Role of DNA Methylation and Epigenetic Silencing of HAND2 in Endometrial Cancer Development

BACKGROUND Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development. METHODS AND FINDINGS Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression. CONCLUSIONS HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies. Please see later in the article for the Editors' Summary.

Life course breast cancer risk factors and adult breast density (United Kingdom)

Objective To determine whether risk factors in childhood and early adulthood affect later mammographic breast density. Methods: Subjects were 628 women who attended a medical examination at the University of Glasgow Student Health Service (1948–1968), responded to a questionnaire (2001) and had a screening mammogram in Scotland (1989–2002). Mammograms (median age of 59years) were classified using a six category classification (SCC) of breast density percent. Logistic regression was used to determine associations between risk factors and having a high-risk mammogram (≥25 dense). Results: In multi-variable analyses, high-risk mammograms were associated with parity (adjusted odds ratio (OR) per child: 0.77 (95 confidence interval (CI) 0.61–0.99)), age at first birth, OR per year: 1.05 (0.99–1.11), smoking at university, OR smokers versus non-smokers: 0.58 (0.36–0.92) and body mass index (BMI) while at university, OR per 1kg/m20.75 (0.69–0.82). No associations with SCC were found for age at menarche, birth weight, oral contraceptive (OC) use, height, leg length or exercise at age 20. Conclusions: We confirm previous findings that breast density is affected by reproductive events and some anthropometric measures, however most of the risk factors acting throughout the life course which we examined were not closely related to adult breast density.

Plasma lipids and prolactin in patients with breast cancer.

In a comparative study of pre- and postmenopausal women with benign and malignant breast disease, a number of differences were observed in circulating plasma prolactin and lipid concentrations. Plasma lipids, phospholipids, triglycerides, cholesterol and free fatty acids were all higher in blood obtained from breast cancer patients prior to surgery. HDL-Cholesterol levels were significantly lower in these patients. These differences remained when the patient groups were sub-divided according to menopausal status. Plasma prolactin concentrations were also found to be higher in cancer compared with non-cancer patients, this effect being more marked in premenopausal than in postmenopausal patients. Premenopausal patients with invasive or poorly differentiated disease had significantly higher prolactin levels than those with non-invasive disease. No correlations were found between plasma prolactin and any of the lipid fractions.

Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5·24 million UK adults

BACKGROUND High body-mass index (BMI) predisposes to several site-specific cancers, but a large-scale systematic and detailed characterisation of patterns of risk across all common cancers adjusted for potential confounders has not previously been undertaken. We aimed to investigate the links between BMI and the most common site-specific cancers. METHODS With primary care data from individuals in the Clinical Practice Research Datalink with BMI data, we fitted Cox models to investigate associations between BMI and 22 of the most common cancers, adjusting for potential confounders. We fitted linear then non-linear (spline) models; investigated effect modification by sex, menopausal status, smoking, and age; and calculated population effects. FINDINGS 5·24 million individuals were included; 166,955 developed cancers of interest. BMI was associated with 17 of 22 cancers, but effects varied substantially by site. Each 5 kg/m(2) increase in BMI was roughly linearly associated with cancers of the uterus (hazard ratio [HR] 1·62, 99% CI 1·56-1·69; p<0·0001), gallbladder (1·31, 1·12-1·52; p<0·0001), kidney (1·25, 1·17-1·33; p<0·0001), cervix (1·10, 1·03-1·17; p=0·00035), thyroid (1·09, 1·00-1·19; p=0·0088), and leukaemia (1·09, 1·05-1·13; p≤0·0001). BMI was positively associated with liver (1·19, 1·12-1·27), colon (1·10, 1·07-1·13), ovarian (1·09, 1.04-1.14), and postmenopausal breast cancers (1·05, 1·03-1·07) overall (all p<0·0001), but these effects varied by underlying BMI or individual-level characteristics. We estimated inverse associations with prostate and premenopausal breast cancer risk, both overall (prostate 0·98, 0·95-1·00; premenopausal breast cancer 0·89, 0·86-0·92) and in never-smokers (prostate 0·96, 0·93-0·99; premenopausal breast cancer 0·89, 0·85-0·94). By contrast, for lung and oral cavity cancer, we observed no association in never smokers (lung 0·99, 0·93-1·05; oral cavity 1·07, 0·91-1·26): inverse associations overall were driven by current smokers and ex-smokers, probably because of residual confounding by smoking amount. Assuming causality, 41% of uterine and 10% or more of gallbladder, kidney, liver, and colon cancers could be attributable to excess weight. We estimated that a 1 kg/m(2) population-wide increase in BMI would result in 3790 additional annual UK patients developing one of the ten cancers positively associated with BMI. INTERPRETATION BMI is associated with cancer risk, with substantial population-level effects. The heterogeneity in the effects suggests that different mechanisms are associated with different cancer sites and different patient subgroups. FUNDING National Institute for Health Research, Wellcome Trust, and Medical Research Council.

Plasma vitamin D metabolites and risk of colorectal cancer in women.

OBJECTIVE Experimental evidence suggests that 1,25-dihydroxyvitamin D and its precursor, 25-hydroxyvitamin D [25(OH)D], may aid in the prevention of colorectal cancer. We therefore examined risk in relation to plasma concentrations of these vitamin D metabolites. METHODS In a nested case-control study among women in the Nurses' Health Study, we identified 193 colorectal cancer cases, ages 46 to 78 years, diagnosed up to 11 years after blood collection. Two controls were matched per case on year of birth and month of blood draw. Odds ratios (OR) for risk of colorectal cancer were calculated using conditional logistic regression adjusted for body mass index, physical activity, smoking, family history, use of hormone replacement therapy, aspirin use, and dietary intakes. RESULTS We found a significant inverse linear association between plasma 25(OH)D and risk of colorectal cancer (P = 0.02). Among women in the highest quintile, the OR (95% confidence interval) was 0.53 (0.27-1.04). This inverse association remained strong when limited to women > or =60 years at blood collection (P = 0.006) but was not apparent among the younger women (P = 0.70). Benefit from higher 25(OH)D concentrations was observed for cancers at the distal colon and rectum (P = 0.02) but was not evident for those at the proximal colon (P = 0.81). In contrast to 25(OH)D, we did not observe an association between 1,25-dihydroxyvitamin D and colorectal cancer, although risk was elevated among the women in the highest quintile if they were also in the lower half of the 25(OH)D distribution (OR, 2.52; 95% confidence interval, 1.04-6.11). CONCLUSION From these results and supporting evidence from previous studies, we conclude that higher plasma levels of 25(OH)D are associated with a lower risk of colorectal cancer in older women, particularly for cancers at the distal colon and rectum.

Risk of gestational hypertension in relation to folic acid supplementation during pregnancy.

The authors investigated the association between folic acid supplementation and gestational hypertension. The study population included women with nonmalformed infants in the United States and Canada who were participating in the Slone Epidemiology Center Birth Defects Study between 1993 and 2000. Women were interviewed within 6 months after delivery about sociodemographic and medical factors, the occurrence of hypertension with or without preeclampsia, and multivitamin use in pregnancy. Relative risks, adjusted for weight, parity, twin pregnancy, diabetes, smoking, education, and family income, were estimated using Cox regression models. Of 2,100 women, 204 (9.7%) reported gestational hypertension (onset after the 20th week of gestation). The multivariate-adjusted relative risk of developing gestational hypertension during the month after folic acid supplementation, compared with not using folic acid during that same month, was 0.55 (95% confidence interval: 0.39, 0.79). This finding suggests that folic acid-containing multivitamins may reduce the risk of gestational hypertension.

Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid.

PURPOSE Three large, randomized trials of patients with bone metastases recently demonstrated that zoledronic acid reduces the risk of skeletal-related events. These trials provide an opportunity for investigating the correlation between bone metabolism and clinical outcome during bisphosphonate therapy. PATIENTS AND METHODS Urinary measurements of N-telopeptide (Ntx) and serum bone alkaline phosphatase (BAP) were obtained in 1,824 bisphosphonate-treated patients-1,462 with zoledronic acid (breast, 490; prostate, 411; myeloma, 210; non-small-cell lung, 183; other, 168) and 362 with pamidronate (breast, 254; myeloma, 108). This exploratory cohort analysis grouped patients by baseline and most recent levels of Ntx as low (< 50 nmol/mmol creatinine), moderate (50 to 99 nmol/mmol creatinine), or high (> or = 100 nmol/mmol creatinine), and BAP as low (< 146 U/L) or high (> or = 146 U/L). The relative risks for negative clinical outcomes were estimated for each group using multiple-event and Cox regression models with time-varying covariates. RESULTS Patients with high and moderate Ntx levels had 2-fold increases in their risk of skeletal complications and disease progression compared with patients with low Ntx levels (P < .001 for all). High Ntx levels in each solid tumor category were associated with a 4- to 6-fold increased risk of death on study, and moderate Ntx levels a 2- to 4-fold increased risk compared with low Ntx levels (P < .001 for all). Bone alkaline phosphatase also showed some correlation with risk of negative clinical outcomes. CONCLUSION The bone resorption marker Ntx provides valuable prognostic information in patients with bone metastases receiving bisphosphonates.

Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database.

The importance of genetic factors in etiology of chronic lymphocytic leukemia (CLL) is suggested by family and population studies. However, the spectrum of malignancies sharing common genetic factors with CLL and the effects of sex and age on familial risk are unknown. We used the Swedish Family-Cancer Database to test for increased familial risks of CLL and other lymphoproliferative tumors. Cancer diagnoses from 1958 to 1998 were assessed in 14 336 first-degree relatives of 5918 CLL cases and in 28 876 first-degree relatives of 11 778 controls. Cancer risks in relatives of cases were compared with those in relatives of controls using marginal survival models. Relatives of cases were at significantly increased risk for CLL (relative risk [RR] = 7.52; 95% confidence interval [CI], 3.63-15.56), for non-Hodgkin lymphoma (RR = 1.45; 95% CI, 0.98-2.16), and for Hodgkin lymphoma (RR = 2.35; 95% CI, 1.08-5.08). CLL risks were similar in parents, siblings, and offspring of cases, in male and female relatives, and were not affected by the case's age at diagnosis. Anticipation was not significant when analyzed using life table methods. We conclude that the familial component of CLL is shared with other lymphoproliferative malignances, suggesting common genetic pathways. However, because clinically diagnosed CLL is uncommon, absolute excess risk to relatives is small.

Mammographic density, plasma vitamin D levels and risk of breast cancer in postmenopausal women.

Mammographic density is a strong risk factor for breast cancer, but the underlying biology for this association is unknown. Studies suggest that vitamin D may reduce breast cancer risk and dietary vitamin D intake has been associated with reduced breast density. We conducted a case-control study nested within the Nurses' Health Study cohort consisting of 463 and 497 postmenopausal cases and controls, respectively. We examined the association between mammographic density and plasma levels of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. We assessed whether plasma vitamin D metabolites modify the association between breast density and breast cancer. Percent mammographic density was measured from digitized film mammograms. Generalized linear models were used to determine mean percent breast density per quartile of vitamin D metabolite. Logistic regression models were used to calculate relative risks and confidence intervals. All models were adjusted for matching variables and potential confounders. We found no cross-sectional association between circulating levels of 25(OH)D or 1,25(OH)(2)D with mammographic density. Women in the highest tertile of mammographic density and lowest tertile of plasma 25(OH)D had 4 times greater risk of breast cancer than women with the lowest mammographic density and highest plasma 25(OH)D levels (RR = 3.8; 95% CI: 2.0-7.3). The overall interaction between mammographic density and plasma 25(OH)D was nonsignificant (p-het = 0.20). These results indicate that the association between mammographic density and breast cancer is independent of plasma vitamin D metabolites in postmenopausal women. Further research examining vitamin D, mammographic density and breast cancer risk is warranted.

Cerebral palsy among term and postterm births.

CONTEXT Although preterm delivery is a well-established risk factor for cerebral palsy (CP), preterm deliveries contribute only a minority of affected infants. There is little information on the relation of CP risk to gestational age in the term range, where most CP occurs. OBJECTIVE To determine whether timing of birth in the term and postterm period is associated with risk of CP. DESIGN, SETTING, AND PARTICIPANTS Population-based follow-up study using the Medical Birth Registry of Norway to identify 1,682,441 singleton children born in the years 1967-2001 with a gestational age of 37 through 44 weeks and no congenital anomalies. The cohort was followed up through 2005 by linkage to other national registries. MAIN OUTCOME MEASURES Absolute and relative risk of CP for children surviving to at least 4 years of age. RESULTS Of the cohort of term and postterm children, 1938 were registered with CP in the National Insurance Scheme. Infants born at 40 weeks had the lowest risk of CP, with a prevalence of 0.99/1000 (95% confidence interval [CI], 0.90-1.08). Risk for CP was higher with earlier or later delivery, with a prevalence at 37 weeks of 1.91/1000 (95% CI, 1.58-2.25) and a relative risk (RR) of 1.9 (95% CI, 1.6-2.4), a prevalence at 38 weeks of 1.25/1000 (95% CI, 1.07-1.42) and an RR of 1.3 (95% CI, 1.1-1.6), a prevalence at 42 weeks of 1.36/1000 (95% CI, 1.19-1.53) and an RR of 1.4 (95% CI, 1.2-1.6), and a prevalence after 42 weeks of 1.44 (95% CI, 1.15-1.72) and an RR of 1.4 (95% CI, 1.1-1.8). These associations were even stronger in a subset with gestational age based on ultrasound measurements: at 37 weeks the prevalence was 1.17/1000 (95% CI, 0.30-2.04) and the relative risk was 3.7 (95% CI, 1.5-9.1). At 42 weeks the prevalence was 0.85/1000 (95% CI, 0.33-1.38) and the relative risk was 2.4 (95% CI, 1.1-5.3). Adjustment for infant sex, maternal age, and various socioeconomic measures had little effect. CONCLUSION Compared with delivery at 40 weeks' gestation, delivery at 37 or 38 weeks or at 42 weeks or later was associated with an increased risk of CP.

The body-mass index of twins who have been reared apart.

To assess the relative importance of genetic and environmental effects on the body-mass index (weight in kilograms divided by the square of the height in meters), we studied samples of identical and fraternal twins, reared apart or reared together. The samples consisted of 93 pairs of identical twins reared apart, 154 pairs of identical twins reared together, 218 pairs of fraternal twins reared apart, and 208 pairs of fraternal twins reared together. The intrapair correlation coefficients of the values for body-mass index of identical twins reared apart were 0.70 for men and 0.66 for women. These are the most direct estimates of the relative importance of genetic influences (heritability) on the body-mass index, and they were only slightly lower than those for twins reared together in this and earlier studies. Similar estimates were derived from maximum-likelihood model-fitting analyses--0.74 for men and 0.69 for women. Nonadditive genetic variance made a significant contribution to the estimates of heritability, particularly among men. Of the potential environmental influences, only those unique to the individual and not those shared by family members were important, contributing about 30 percent of the variance. Sharing the same childhood environment did not contribute to the similarity of the body-mass index of twins later in life. We conclude that genetic influences on body-mass index are substantial, whereas the childhood environment has little or no influence. These findings corroborate and extend the results of earlier studies of twins and adoptees.

A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection.

BACKGROUND Human papillomavirus (HPV) has been associated with cervical intraepithelial neoplasia, but the temporal relation between the infection and the neoplasia remains unclear, as does the relative importance of the specific type of HPV, other sexually transmitted diseases, and other risk factors. METHODS We studied prospectively a cohort of 241 women who presented for evaluation of sexually transmitted disease and had negative cervical cytologic tests. The women were followed every four months with cytologic and colposcopic examinations of the uterine cervix and tests for HPV DNA and other sexually transmitted diseases. RESULTS Cervical intraepithelial neoplasia grade 2 or 3 was confirmed by biopsy in 28 women. On the basis of survival analysis, the cumulative incidence of cervical intraepithelial neoplasia at two years was 28 percent among women with a positive test for HPV and 3 percent among those without detectable HPV DNA: The risk was highest among those with HPV type 16 or 18 infection (adjusted relative risk as compared with that in women without HPV infection, 11; 95 percent confidence interval, 4.6 to 26; attributable risk, 52 percent). All 24 cases of cervical intraepithelial neoplasia grade 2 or 3 among HPV-positive women were detected within 24 months after the first positive test for HPV. After adjustment for the presence of HPV infection, the development of cervical intraepithelial neoplasia was also associated with younger age at first intercourse, the presence of serum antibodies to Chlamydia trachomatis, the presence of serum antibodies to cytomegalovirus, and cervical infection with Neisseria gonorrhoeae. CONCLUSIONS Cervical intraepithelial neoplasia is a common and apparently early manifestation of cervical infection by HPV, particularly types 16 and 18.

Antioxidant Defenses in the Rat Placenta in Late Gestation: Increased Labyrinthine Expression of Superoxide Dismutases, Glutathione Peroxidase 3, and Uncoupling Protein 21

Placental oxidative stress plays a key role in the pathophysiology of placenta-related disorders, most notably preeclampsia (PE) and intrauterine growth restriction (IUGR). Oxidative stress occurs when accumulation of reactive oxygen species (ROS) damages DNA, proteins and lipids, an outcome that is limited by antioxidant enzymes; mitochondrial uncoupling protein 2 (UCP2) may also limit oxidative stress by reducing ROS production. Here we characterized placental antioxidant defenses during normal gestation and following glucocorticoid-induced IUGR. Placentas were collected on Days 16 and 22 of normal rat pregnancy (term = Day 23) and at Day 22 after dexamethasone treatment from Day 13. Expression of several genes encoding antioxidant enzymes (Sod1, Sod2, Sod3, Cat, Gpx3, Txn1, Txnrd1, Txnrd2, and Txnrd3) and Ucp2 was measured by quantitative RT-PCR in the labyrinth (LZ) and junctional zones (JZ) of the placenta. Expression of Sod1 and Ucp2 mRNAs and the activity of xanthine oxidase, a source of ROS, all increased from Days 16 to 22 in both placental zones, whereas Sod2 and Gpx3 increased only in the rapidly growing LZ. In contrast, Sod3 and Txnrd1 expression fell in the LZ over this period, whereas total superoxide dismutase activity remained stable. Dexamethasone treatment reduced fetal-placental growth and LZ expression of Ucp2 but increased JZ expression of Txn1. Indices of placental oxidative damage (TBARS, F2-isoprostanes, and 8-OHdG) did not change with gestational age or dexamethasone, indicative of adequate antioxidant protection. Overall, our data suggest that the rat placenta is protected from oxidative stress by the dynamic zone- and stage-dependent expression of antioxidant defense genes.

Body-mass index and mortality in Korean men and women.

BACKGROUND Obesity is associated with diverse health risks, but the role of body weight as a risk factor for death remains controversial. METHODS We examined the association between body weight and the risk of death in a 12-year prospective cohort study of 1,213,829 Koreans between the ages of 30 and 95 years. We examined 82,372 deaths from any cause and 48,731 deaths from specific diseases (including 29,123 from cancer, 16,426 from atherosclerotic cardiovascular disease, and 3362 from respiratory disease) in relation to the body-mass index (BMI) (the weight in kilograms divided by the square of the height in meters). RESULTS In both sexes, the average baseline BMI was 23.2, and the rate of death from any cause had a J-shaped association with the BMI, regardless of cigarette-smoking history. The risk of death from any cause was lowest among patients with a BMI of 23.0 to 24.9. In all groups, the risk of death from respiratory causes was higher among subjects with a lower BMI, and the risk of death from atherosclerotic cardiovascular disease or cancer was higher among subjects with a higher BMI. The relative risk of death associated with BMI declined with increasing age. CONCLUSIONS Underweight, overweight, and obese men and women had higher rates of death than men and women of normal weight. The association of BMI with death varied according to the cause of death and was modified by age, sex, and smoking history.

Multipoint Kras oncogene mutations potentially indicate mucinous carcinoma on the entire spectrum of mucinous ovarian neoplasms

Kras mutation is a common phenomenon in many human neoplasms. We aimed to assess the Kras mutational status along the histological continuum from normal ovaries to the development of benign, borderline and malignant ovarian mucinous neoplasms. We analyzed 41 cases of malignant, 10 cases of borderline, 7 cases of benign mucinous ovarian tumors and 7 cases of normal ovarian tissue. The prevalence of Kras mutations in the normal ovary was 0.00% (n=0/7), while the prevalence in benign, borderline and malignant mucinous neoplasms was 57.14% (n=4/7), 90.00% (n=9/10) and 75.61% (n=31/41), respectively. Multiple Kras mutations were detected in 6 cases of mucinous carcinoma, including 5 double mutations with G13D/V14I (n=1), G12V/G13S (n=1), G12D/G13S (n=3) and one triple mutation with A11V/G13N/V14I (n=1). We identified six cases with 3 novel Kras mutations not previously described in the COSMIC database, which included A11V (n=3) and V14I (n=2) in mucinous carcinomas, and A11T (n=1) in a mucinous borderline tumor. In conclusion, Kras mutation appears to be one of the imperative events in the ovarian mucinous adenoma-borderline tumor-carcinoma sequence, as increased numbers of Kras mutations have been shown to be the strongest predictor of unequivocal malignancy in ovarian mucinous neoplasms.

Interaction between broad-spectrum antibiotics and the combined oral contraceptive pill. A literature review.

There is considerable variation in opinion about the importance of drug interactions between the combined oral contraceptive pill (COCP) and broad-spectrum antibiotics. Clinical practice varies widely, especially between doctors in Europe and those in the US. Rifampicin and griseofulvin induce hepatic enzymes and do appear to have a genuine interaction with the COCP, leading to reduced efficacy. The situation with the broad-spectrum antibiotics is less clear. There are relatively few prospective studies of the pharmacokinetics of concurrent COCP and antibiotic use and few, if any, demonstrate a convincing basis for any reduced contraceptive efficacy. There is evidence, however, that variable contraceptive steroid handling could make some women, at some times, more susceptible to COCP failure. Given the serious consequences of unwanted pregnancy, the cautious approach of using additional or alternative contraception during short courses of broad-spectrum antibiotics and the initial weeks of long-term antibiotic administration may be justified to safeguard the few unidentifiable women who may be at risk. Conflicting opinion and advice is potentially confusing to both professionals and patients, and instructions for additional precautions during and after concurrent COCP and antibiotic use are complicated. Many women are ignorant of, or confused about, the circumstances that can cause OC to fail. Health professionals who prescribe the COCP must continue to strive to educate women about the mode of action and about the times when there is the greatest danger of failure. Professionals who feel that concurrent antibiotic use represents a real threat to contraceptive efficacy of the COCP should be prepared to present the advice for additional contraceptive precautions in a simple and consistent way, backed up with written information and reinforced at regular intervals.

Effect of women's nutrition before and during early pregnancy on maternal and infant outcomes: a systematic review.

Current understanding of biologic processes indicates that women's nutritional status before and during early pregnancy may play an important role in determining early developmental processes and ensuring successful pregnancy outcomes. We conducted a systematic review of the evidence for the impact of maternal nutrition before and during early pregnancy (<12 weeks gestation) on maternal, neonatal and child health outcomes and included 45 articles (nine intervention trials and 32 observational studies) that were identified through PubMed and EMBASE database searches and examining review articles. Intervention trials and observational studies show that periconceptional (<12 weeks gestation) folic acid supplementation significantly reduced the risk of neural tube defects. Observational studies suggest that preconceptional and periconceptional intake of vitamin and mineral supplements is associated with a reduced risk of delivering offspring who are low birthweight and/or small-for-gestational age (SGA) and preterm deliveries (PTD). Some studies report that indicators of maternal prepregnancy size, low stature, underweight and overweight are associated with increased risks of PTD and SGA. The available data indicate the importance of women's nutrition prior to and during the first trimester of pregnancy, but there is a need for well-designed prospective studies and controlled trials in developing country settings that examine relationships with low birthweight, SGA, PTD, stillbirth and maternal and neonatal mortality. The knowledge gaps that need to be addressed include the evaluation of periconceptional interventions such as food supplements, multivitamin-mineral supplements and/or specific micronutrients (iron, zinc, iodine, vitamin B-6 and B-12) as well as the relationship between measures of prepregnancy body size and composition and maternal, neonatal and child health outcomes.

Linkage Disequilibrium Mapping of       CHEK2: Common Variation and Breast Cancer Risk

Background Checkpoint kinase 2 (CHEK2) averts cancer development by promoting cell cycle arrest and activating DNA repair in genetically damaged cells. Previous investigation has established a role for the CHEK2 gene in breast cancer aetiology, but studies have largely been limited to the rare 1100delC mutation. Whether common polymorphisms in this gene influence breast cancer risk remains unknown. In this study, we aimed to assess the importance of common CHEK2 variants on population risk for breast cancer by capturing the majority of diversity in the gene using haplotype tagging single nucleotide polymorphisms (tagSNPs). Methods and Findings We analyzed 14 common SNPs spanning 52 kilobases (kb) of the CHEK2 gene in 92 Swedish women. Coverage evaluation indicated that these typed SNPs would efficiently convey association signal also from untyped SNPs in the same region. Six of the 14 SNPs predicted well both the haplotypic and single SNP variations within CHEK2. We genotyped these six tagSNPs in 1,577 postmenopausal breast cancer cases and 1,513 population controls, but found no convincing association between any common CHEK2 haplotype and breast cancer risk. The 1100delC mutation was rare in our Swedish population—0.7% in cases and 0.4% in controls— with a corresponding odds ratio for carriers versus noncarriers of 2.26 (95% confidence interval, 0.99–5.15). Estimates of the population frequency and the odds ratio of 1100delC indicate that our sample is representative of a Northern European population.

The ATM missense mutation p.Ser49Cys (c.146C>G) and the risk of breast cancer.

Homozygous mutation in the ATM gene causes ataxia telangiectasia and heterozygous mutation carriers may be at increased risk of breast cancer. We studied a total of 22 ATM variants; 18 variants were analyzed in one of two large population-based studies from the U.S. and Poland, and four variants were analyzed in all 2,856 breast cancer cases and 3,344 controls from the two studies. The missense mutation Ser49Cys (c.146C>G, p. S49C), carried by approximately 2% of subjects, was more common in cases than controls in both study populations, combined odds ratio (OR) 1.69 (95% CI, 1.19-2.40; P=0.004). Another missense mutation at approximately 2% frequency, Phe858Leu (c.2572T>C, p. F858L), was associated with a significant increased risk in the U.S. study but not in Poland, and had a combined OR of 1.44 (95% CI, 0.98-2.11; P=0.06). These analyses provide the most convincing evidence thus far that missense mutations in ATM, particularly p. S49C, may be breast cancer susceptibility alleles. Because of their low frequency, even larger sample sizes are required to more firmly establish these associations.

Vaginal progesterone, cerclage or cervical pessary for preventing preterm birth in asymptomatic singleton pregnant women with a history of preterm birth and a sonographic short cervix.

OBJECTIVE To compare the outcome of pregnancy in cohorts of women with singleton pregnancy and history of preterm birth and sonographic short cervix managed with different treatment protocols, namely cerclage, vaginal progesterone or cervical pessary. METHODS This was a comparison of three management protocols for women with singleton pregnancy and a high risk of preterm birth because of a prior spontaneous preterm birth before 34 weeks and a shortened cervical length detected by transvaginal ultrasound. The study included 142 women who were initially treated with cerclage (USA), 59 with vaginal progesterone (UK) and 42 with cervical pessary (Spain). Perinatal outcomes were compared between the three cohorts. RESULTS There were no statistically significant differences in perinatal losses, neonatal morbidity and preterm births among the three groups, apart from a higher rate of preterm birth before 34 weeks' gestation after treatment with vaginal progesterone in comparison with treatment with cervical pessary (32% vs 12%; relative risk (RR) = 2.70; 95% CI, 1.10-6.67). When only the subgroups of women with cervical length < 25 mm, irrespective of gestational age, were compared, the difference between these two cohorts was not statistically significant (RR = 2.21; 95% CI, 0.83-5.89). CONCLUSION Cerclage, vaginal progesterone and pessary appear to have similar effectiveness as management strategies in women with singleton pregnancy, previous spontaneous preterm birth and short cervix. Direct randomized comparisons of these strategies, or combinations thereof, are needed to determine optimal management.

Evaluation of human papillomavirus testing in primary screening for cervical abnormalities: comparison of sensitivity, specificity, and frequency of referral.

CONTEXT Human papillomavirus (HPV) DNA testing of women having Papanicolaou (Pap) smears showing atypical squamous cells of undetermined significance (ASCUS) has clinical usefulness. Whether HPV DNA testing alone is useful in primary screening remains to be determined. OBJECTIVE To determine the accuracy of HPV DNA testing for detecting cervical intraepithelial neoplasia (CIN) grade 3 or cancer (the criterion standard). DESIGN, SETTING, AND PARTICIPANTS Between December 1997 and October 2000, 4075 women who attended Planned Parenthood clinics in Washington State were screened simultaneously using thin-layer Pap and HPV DNA testing by a polymerase chain reaction (PCR)-based method and by a liquid-based RNA-DNA hybridization capture with signal amplification assay (signal amplification). Women who were positive for high-risk HPV types, or had Pap results of ASCUS or higher, were considered to have positive screening test results and were referred for colposcopy and biopsy. Additionally, a random sample of women with negative screening test results was referred for colposcopy. Based on individual and combined thin-layer Pap, HPV PCR, and HPV signal amplification test results from the screening and the colposcopy visits, 7 colposcopy triage strategies were defined and evaluated. MAIN OUTCOME MEASURE Sensitivity and specificity for detecting cervical lesions graded CIN 3 or higher for each of the 7 triage strategies. RESULTS The estimated prevalence of CIN 3 or higher was 3.2%. The sensitivity (95% confidence interval) of thin-layer Pap (with a result of > or = ASCUS) for identifying women with CIN 3 or higher was only 61.3% (48.5%-70.9%) compared with 88.2% (78.9%-93.8%) for HPV testing by PCR and 90.8% (83.1%-95.8%) by signal amplification. Differences in specificities were also observed: 82.4% (81.8%-83.1%) for thin-layer Pap (with a result of > or = ASCUS), 78.8% (77.9%-79.7%) for PCR, and 72.6% (69.4%-75.0%) for signal amplification. Compared with referral for colposcopy of all women with ASCUS or higher, signal amplification testing of women with ASCUS and referral of those with a positive result was about as sensitive (61.3% vs 60.3%, respectively) and significantly more specific (82.4% vs 88.9%, respectively). The strategy requiring repeat positive PCR tests on 2 visits had a sensitivity of 84.2% (75.3%-91.0%) and a specificity of 86.2% (85.1%-87.3%). All tests were more specific and less sensitive in older (> or = 30 years) vs younger women. CONCLUSIONS Testing for HPV has higher sensitivity but lower specificity than thin-layer Pap screening. In some settings, particularly where screening intervals are long or haphazard, screening for HPV DNA may be a reasonable alternative to cytology-based screening of reproductive-age women.

A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability

Inherited mutations in the gene BRCA2 predispose carriers to early onset breast cancer, but such mutations account for fewer than 2% of all cases in East Anglia. It is likely that low penetrance alleles explain the greater part of inherited susceptibility to breast cancer; polymorphic variants in strongly predisposing genes, such as BRCA2, are candidates for this role. BRCA2 is thought to be involved in DNA double strand break-repair. Few mice in which Brca2 is truncated survive to birth; of those that do, most are male, smaller than their normal littermates and have high cancer incidence. Here we show that a common human polymorphism (N372H) in exon 10 of BRCA2 confers an increased risk of breast cancer: the HH homozygotes have a 1.31-fold (95% CI, 1.07–1.61) greater risk than the NN group. Moreover, in normal female controls of all ages there is a significant deficiency of homozygotes compared with that expected from Hardy-Weinberg equilibrium, whereas in males there is an excess of homozygotes: the HH group has an estimated fitness of 0.82 in females and 1.38 in males. Therefore, this variant of BRCA2 appears also to affect fetal survival in a sex-dependent manner.

Preconception Care and the Risk of Congenital Anomalies in the Offspring of Women With Diabetes Mellitus: A Meta-Analysis

Preconception care (PCC) and strict periconceptional glycemic control are both used to minimize the risk of congenital birth defects in offspring of women with type 1 or type 2 diabetes mellitus (DM). These malformations are ascribed in large measure to poor periconceptional control. This study evaluated PCC by a meta-analysis of published studies of PCC in women with DM, published from 1970 to 2000. Two reviewers independently abstracted the data, and the rate and relative risk (RR) of major and minor malformations were pooled from eligible studies using a random effects model. Early first-trimester values of glycosylated hemoglobin were recorded. Eight retrospective and eight prospective cohort studies were included; they were carried out in Europe, the United Kingdom, the United States, and Israel. Most participants had type 1 DM, but three studies included women with type 2 DM. Women given PCC tended to be about 2 years older on average than the others. Methods of PCC were quite variable, although most centers provided some maternal education about the pregnancy risks associated with poor glycemic control. In seven studies reporting early gestational glycosylated hemoglobin values, mean levels were consistently lower in PCC patients. Among 2104 offspring, the pooled rate for major and minor anomalies was 2.4% in the PCC group and 7.7% in non-PCC recipients, for a pooled RR of 0.32. Among 2651 offspring, major malformations were less prevalent in the PCC group (2.1 vs. 6.5%; pooled RR = 0.36). Comparable results were obtained when only prospective studies were analyzed and in studies where the infant examiners were unaware of the mothers' PCC status. The lowest risk of major anomalies was in a study that administered folic acid periconceptionally to its PCC recipients; the RR was 0.11. This meta-analysis, which included both retrospective and prospective studies, demonstrates an association of PCC with a significantly lower risk of congenital anomalies in the offspring of women with established DM. The lowered risk was accompanied by significantly lower glycosylated hemoglobin values in the first trimester in recipients of PCC.

Lipid-based nutrient supplement increases the birth size of infants of primiparous women in Ghana.

BACKGROUND The International Lipid-Based Nutrient Supplements Project developed a small-quantity (20 g/d) lipid-based nutrient supplement (LNS) for pregnant and lactating women. OBJECTIVE We evaluated the effects of prenatal LNS supplementation on fetal growth. DESIGN In a community-based, partially double-blind, individually randomized controlled trial, 1320 women ≤20 wk pregnant received 60 mg Fe/400 μg folic acid (IFA), or 1-2 Recommended Dietary Allowances of 18 micronutrients, including 20 mg Fe (MMN), or LNS with the same micronutrients as the MMN group, plus 4 minerals and macronutrients contributing 118 kcal (LNS) daily until delivery. Fetal growth was compared across groups by using intention-to-treat analysis. The primary outcome was birth length. RESULTS This analysis included 1057 women (IFA = 349, MMN = 354, LNS = 354). Groups did not differ significantly in mean birth length, length-for-age z score (LAZ), head circumference, or percentage low birth length but differed in mean birth weight (P = 0.044), weight-for-age z score (WAZ; P = 0.046), and BMI-for-age z score (BMIZ; P = 0.040), with a trend toward differences in low birth weight (P = 0.069). In pairwise comparisons, the LNS group had greater mean birth weight (+85 g; P = 0.040), WAZ (+0.19; P = 0.045), and BMIZ (+0.21; P = 0.035) and a lower risk of low birth weight (RR: 0.61, 95% CI: 0.39, 0.96; P = 0.032) than did the IFA group. The other group differences were not significant. The effect of intervention was modified by mother's parity, age, height, baseline hemoglobin, household food insecurity, and child sex, with parity being the most consistent modifier. Among primiparous women (IFA = 131; MMN = 110; LNS = 128), the LNS group had greater mean birth length (+0.91 cm; P = 0.001), LAZ (+0.47; P = 0.001), weight (+237 g; P < 0.001), WAZ (+0.56; P < 0.001), BMIZ (+0.52; P < 0.001), head circumference (0.50 cm; P = 0.017), and head circumference-for-age z score (+0.40; P = 0.022) than did the IFA group; similar differences were found when comparing the LNS and MMN groups among primiparous women, and no group differences were found among multiparous women. CONCLUSION Prenatal LNS supplementation can improve fetal growth among vulnerable women in Ghana, particularly primiparous women. This trial was registered at clinicaltrials.gov as NCT00970866.

Obesity occurring in apolipoprotein E-knockout mice has mild effects on fertility.

The Apolipoprotein (Apo) family is implicated in lipid metabolism. There are five types of Apo: Apoa, Apob, Apoc, Apod, and Apoe. Apoe has been demonstrated to play a central role in lipoprotein metabolism and to be essential for efficient receptor-mediated plasma clearance of chylomicron remnants and VLDL remnant particles by the liver. Apoe-deficient (Apoe(-/-)) mice develop atherosclerotic plaques spontaneously, followed by obesity. In this study, we investigated whether lipid deposition caused by Apoe knockout affects reproduction in female mice. The results demonstrated that Apoe(-/-) mice were severely hypercholesterolemic, with their cholesterol metabolism disordered, and lipid accumulating in the ovaries causing the ovaries to be heavier compared with the WT counterparts. In addition, estrogen and progesterone decreased significantly at D 100. Quantitative PCR analysis demonstrated that at D 100 the expression of cytochromeP450 aromatase (Cyp19a1), 3β-hydroxysteroid dehydrogenase (Hsd3b), mechanistic target of rapamycin (Mtor), and nuclear factor-κB (Nfkb) decreased significantly, while that of BCL2-associated agonist of cell death (Bad) and tuberous sclerosis complex 2 (Tsc2) increased significantly in the Apoe(-/-) mice. However, there was no difference in the fertility rates of the Apoe(-/-) and WT mice; that is, obesity induced by Apoe knockout has no significant effect on reproduction. However, the deletion of Apoe increased the number of ovarian follicles and the ratio of ovarian follicle atresia and apoptosis. We believe that this work will augment our understanding of the role of Apoe in reproduction.

Relation between Medicare screening reimbursement and stage at diagnosis for older patients with colon cancer.

CONTEXT Medicare's reimbursement policy was changed in 1998 to provide coverage for screening colonoscopies for patients with increased colon cancer risk, and expanded further in 2001 to cover screening colonoscopies for all individuals. OBJECTIVE To determine whether the Medicare reimbursement policy changes were associated with an increase in either colonoscopy use or early stage colon cancer diagnosis. DESIGN, SETTING, AND PARTICIPANTS Patients in the Surveillance, Epidemiology, and End Results Medicare linked database who were 67 years of age and older and had a primary diagnosis of colon cancer during 1992-2002, as well as a group of Medicare beneficiaries who resided in Surveillance, Epidemiology, and End Results areas but who were not diagnosed with cancer. MAIN OUTCOME MEASURES Trends in colonoscopy and sigmoidoscopy use among Medicare beneficiaries without cancer were assessed using multivariate Poisson regression. Among the patients with cancer, stage was classified as early (stage I) vs all other (stages II-IV). Time was categorized as period 1 (no screening coverage, 1992-1997), period 2 (limited coverage, January 1998-June 2001), and period 3 (universal coverage, July 2001-December 2002). A multivariate logistic regression (outcome = early stage) was used to assess temporal trends in stage at diagnosis; an interaction term between tumor site and time was included. RESULTS Colonoscopy use increased from an average rate of 285/100,000 per quarter in period 1 to 889 and 1919/100,000 per quarter in periods 2 (P<.001) and 3 (P vs 2<.001), respectively. During the study period, 44,924 eligible patients were diagnosed with colorectal cancer. The proportion of patients diagnosed at an early stage increased from 22.5% in period 1 to 25.5% in period 2 and 26.3% in period 3 (P<.001 for each pairwise comparison). The changes in Medicare coverage were strongly associated with early stage at diagnosis for patients with proximal colon lesions (adjusted relative risk period 2 vs 1, 1.19; 95% confidence interval, 1.13-1.26; adjusted relative risk period 3 vs 2, 1.10; 95% confidence interval, 1.02-1.17) but weakly associated, if at all, for patients with distal colon lesions (adjusted relative risk period 2 vs 1, 1.07; 95% confidence interval, 1.01-1.13; adjusted relative risk period 3 vs 2, 0.97; 95% confidence interval, 0.90-1.05). CONCLUSIONS Expansion of Medicare reimbursement to cover colon cancer screening was associated with an increased use of colonoscopy for Medicare beneficiaries, and for those who were diagnosed with colon cancer, an increased probability of being diagnosed at an early stage. The selective effect of the coverage change on proximal colon lesions suggests that increased use of whole-colon screening modalities such as colonoscopy may have played a pivotal role.

A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction.

CONTEXT Maternal depressive symptoms during pregnancy have been reported in some, but not all, studies to be associated with an increased risk of preterm birth (PTB), low birth weight (LBW), and intrauterine growth restriction (IUGR). OBJECTIVE To estimate the risk of PTB, LBW, and IUGR associated with antenatal depression. DATA SOURCES AND STUDY SELECTION We searched for English-language and non-English-language articles via the MEDLINE, PsycINFO, CINAHL, Social Work Abstracts, Social Services Abstracts, and Dissertation Abstracts International databases (January 1980 through December 2009). We aimed to include prospective studies reporting data on antenatal depression and at least 1 adverse birth outcome: PTB (<37 weeks' gestation), LBW (<2500 g), or IUGR (<10th percentile for gestational age). Of 862 reviewed studies, 29 US-published and non-US-published studies met the selection criteria. DATA EXTRACTION Information was extracted on study characteristics, antenatal depression measurement, and other biopsychosocial risk factors and was reviewed twice to minimize error. DATA SYNTHESIS Pooled relative risks (RRs) for the effect of antenatal depression on each birth outcome were calculated using random-effects methods. In studies of PTB, LBW, and IUGR that used a categorical depression measure, pooled effect sizes were significantly larger (pooled RR [95% confidence interval] = 1.39 [1.19-1.61], 1.49 [1.25-1.77], and 1.45 [1.05-2.02], respectively) compared with studies that used a continuous depression measure (1.03 [1.00-1.06], 1.04 [0.99-1.09], and 1.02 [1.00-1.04], respectively). The estimates of risk for categorically defined antenatal depression and PTB and LBW remained significant when the trim-and-fill procedure was used to correct for publication bias. The risk of LBW associated with antenatal depression was significantly larger in developing countries (RR = 2.05; 95% confidence interval, 1.43-2.93) compared with the United States (RR = 1.10; 95% confidence interval, 1.01-1.21) or European social democracies (RR = 1.16; 95% confidence interval, 0.92-1.47). Categorically defined antenatal depression tended to be associated with an increased risk of PTB among women of lower socioeconomic status in the United States. CONCLUSIONS Women with depression during pregnancy are at increased risk for PTB and LBW, although the magnitude of the effect varies as a function of depression measurement, country location, and US socioeconomic status. An important implication of these findings is that antenatal depression should be identified through universal screening and treated.

Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells

A long-standing hypothesis on tumorigenesis is that cell division failure, generating genetically unstable tetraploid cells, facilitates the development of aneuploid malignancies. Here we test this idea by transiently blocking cytokinesis in p53-null (p53-/-) mouse mammary epithelial cells (MMECs), enabling the isolation of diploid and tetraploid cultures. The tetraploid cells had an increase in the frequency of whole-chromosome mis-segregation and chromosomal rearrangements. Only the tetraploid cells were transformed in vitro after exposure to a carcinogen. Furthermore, in the absence of carcinogen, only the tetraploid cells gave rise to malignant mammary epithelial cancers when transplanted subcutaneously into nude mice. These tumours all contained numerous non-reciprocal translocations and an 8–30-fold amplification of a chromosomal region containing a cluster of matrix metalloproteinase (MMP) genes. MMP overexpression is linked to mammary tumours in humans and animal models. Thus, tetraploidy enhances the frequency of chromosomal alterations and promotes tumour development in p53-/- MMECs.

Epidemiology of surgically managed pelvic organ prolapse and urinary incontinence.

OBJECTIVE To determine the incidence of surgically managed pelvic organ prolapse and urinary incontinence in a population-based cohort, and to describe their clinical characteristics. METHODS Our retrospective cohort study included all patients undergoing surgical treatment for prolapse and incontinence during 1995; all were members of Kaiser Permanente Northwest, which included 149,554 women age 20 or older. A standardized data-collection form was used to review all inpatient and outpatient charts of the 395 women identified. Variables examined included age, ethnicity, height, weight, vaginal parity, smoking history, medical history, and surgical history, including the preoperative evaluation, procedure performed, and details of all prior procedures. Analysis included calculation of age-specific and cumulative incidences and determination of the number of primary operations compared with repeat operations performed for prolapse or incontinence. RESULTS The age-specific incidence increased with advancing age. The lifetime risk of undergoing a single operation for prolapse or incontinence by age 80 was 11.1%. Most patients were older, postmenopausal, parous, and overweight. Nearly half were current or former smokers and one-fifth had chronic lung disease. Reoperation was common (29.2% of cases), and the time intervals between repeat procedures decreased with each successive repair. CONCLUSION Pelvic floor dysfunction is a major health issue for older women, as shown by the 11.1% lifetime risk of undergoing a single operation for pelvic organ prolapse and urinary incontinence, as well as the large proportion of reoperations. Our results warrant further epidemiologic research in order to determine the etiology, natural history, and long-term treatment outcomes of these conditions.

Risk of breast cancer in relation to blood lipids: a prospective study of 31,209 Norwegian women

In this prospective study, the relationship between blood lipids and breast cancer risk was examined. Between 1977 and 1983, 31,209 Norwegian women, 20 to 54 years of age, attended a health screening carried out by the Norwegian National Health Screening Services. The screening consisted of a questionnaire, anthropometric measurements, and nonfasting blood drawn for analysis of total serum cholesterol (TC), triglyceride (TG), and high density lipoprotein (HDL) cholesterol. Low density lipoprotein (LDL) cholesterol was calculated by the Friedewald's formula. During the seven to 13 years of follow-up, 302 breast cancer cases were identified by linkage to the Norwegian Cancer Registry. After adjustment for some of the known risk factors of breast cancer, the relative risk of women in the highest quartile of TC compared with women in the lowest quartile was 0.87 (95 percent confidence interval [CI]=0.61–1.23). The corresponding relative risks and CIs were 0.82 (CI=0.58–1.16) for TG, 1.02 (CI=0.73–1.42) for HDL, and 0.93 (CI=0.67–1.29) for LDL. No association between breast cancer risk and blood lipids was found in the total population, nor when the data were divided into those diagnosed before or after the age of 50 as a dividing line between pre- and postmenopausal diagnosis.

Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population.

Most multiple case families of young onset breast cancer and ovarian cancer are thought to be due to highly penetrant mutations in the predisposing genes BRCA1 and BRCA2. However, these mutations are uncommon in the population and they probably account for only a few percent of all breast cancer incidence. A much larger fraction of breast cancer might, in principle, be due to common variants which confer more modest individual risks. There are several common polymorphisms in the BRCA1 gene which generate amino acid substitutions. We have examined the frequency of four of these polymorphisms: Gln356Arg, Pro871Leu, Glu1038Gly and Ser1613Gly in large series of breast and ovarian cancer cases and matched controls. Due to strong linkage disequilibrium, these four sites generate only three haplotypes with a frequency > 1.3%. The most common haplotypes, defined by the alleles Gln356Pro871Glu1038Ser1613 and Gln356Leu871Gly1038Gly1613, have frequencies of 0.57 and 0.32 respectively, and these frequencies do not differ significantly between patient and control groups. Thus the most common polymorphisms of the BRCA1 gene do not make a significant contribution to breast or ovarian cancer risk. However, our data suggest that the Arg356 allele may have a different genotype distribution in breast cancer patients from that in controls (Arg356 homozygotes are more frequent in the control groups, P = 0.01), indicating that it may be protective against breast cancer. If this finding can be confirmed, it may provide an insight into the structural features of the BRCA1 protein that are important for its function.

Comparison of survival between cerebellar and supratentorial glioblastoma patients: surveillance, epidemiology, and end results (SEER) analysis.

BACKGROUND Cerebellar glioblastoma multiforme (cGBM) is rare, and although there is a general belief that these tumors have a worse prognosis than supratentorial GBM (sGBM), few studies have been published to support this belief. OBJECTIVE To investigate the effect of cerebellar location on survival through a case-control design comparing overall survival time of cGBM and sGBM patients. METHODS The Surveillance, Epidemiology, and End Results (SEER) registry was used to identify 132 patients with cGBM (1973-2008). Each cGBM patient was matched with an sGBM patient from among 20,848 sGBM patients on the basis of age, extent of resection, decade of diagnosis, and radiation therapy using propensity score matching. RESULTS Within the cGBM, 37% were older than 65 years of age, 62% were men, and 87% were white. Most patients underwent surgery and radiation (74%), whereas only 26% underwent surgical resection only. The median survival time for the cGBM and sGBM matched cohort was 8 months; however, the survival distributions differed (log-rank P = .04). Survival time for cGBM vs sGBM at 2 years was 21.5% vs 8.0%, and 12.7% vs 5.3% at 3 years. Multivariate analysis of survival among cGBM patients showed that younger age (P < .0001) and having radiation therapy (P < .0001) were significantly associated with reduced hazard of mortality. Among all patients, multivariate analysis showed that tumor location (P = .03), age (P < .0001), tumor size (P = .009), radiation (P < .0001), and resection (P < .0001) were associated with survival time in the unmatched cohort. CONCLUSION Median survival time for cGBM and sGBM patients was 8 months, but cGBM patients had a survival time advantage as the study progressed. These findings suggest that cGBM patients should be treated as aggressively as sGBM patients with surgical resection and radiation therapy.

Prognostic impact of minimal pleural effusion in non-small-cell lung cancer.

PURPOSE Minimal (< 10 mm thick) pleural effusion (PE) may represent an early phase of malignant PE, but its clinical relevance has rarely been studied. Therefore, we examined the proportion of minimal PE in patients with non-small-cell lung cancer (NSCLC) and its impact on survival. We also considered possible accumulation mechanisms in our data set. PATIENTS AND METHODS On the basis of PE status from chest computed tomography scans at diagnosis, 2,061 patients were classified into three groups: no PE, minimal PE, and malignant PE. Twenty-one variables associated with four factors-patient, stage migration, tumor, and treatment-were investigated for correlation with survival. RESULTS Minimal PE presented in 272 patients (13.2%). Of 2,061 patients, the proportion of each stage was the following: 5.2% stage I, 10.9% stage II, 13.2% stage IIIA, 23.8% stage IIIB, and 13.9% stage IV. Minimal PE correlated significantly with shorter survival time than did no PE (median survival time, 7.7 v 17.7 months; log-rank P < .001), even after full adjustment with all variables (adjusted hazard ratio, 1.40; 95% CI, 1.21 to 1.62). Prognostic impact of minimal PE was higher in early versus advanced stages (Pinteraction = .001). In 237 patients (87.8%) with minimal PE, pleural invasion or attachment as a direct mechanism was observed, and it was an independent factor predicting worse survival (P = .03). CONCLUSION Minimal PE is a commonly encountered clinical concern in staging NSCLCs. Its presence is an important prognostic factor of worse survival, especially in early-stage disease.

Molecular characterization of endometrial cancer: a correlative study assessing microsatellite instability, MLH1 hypermethylation, DNA mismatch repair protein expression, and PTEN, PIK3CA, KRAS, and BRAF mutation analysis.

Endometrial cancer is associated with numeric and structural chromosomal abnormalities, microsatellite instability (MSI), and alterations that activate oncogenes and inactivate tumor suppressor genes. The aim of this study was to characterize a set of endometrial cancers using multiple molecular genetic and immunohistochemical techniques. Ninety-six cases were examined for genomic alterations by MSI, MLH1 promoter hypermethylation, p53 and mismatch repair protein expression (MLH1, MSH2, MSH6, PMS2), and PTEN, PIK3CA, KRAS, and BRAF mutation analysis. At least 1 alteration was identified in 48 of 87 (55%) specimens tested for PTEN, making it the most common abnormality in this study. A PIK3CA alteration was observed in 16 (17%) specimens. Twenty-nine of 94 (31%) MSI tested tumors exhibited an MSI-H phenotype. Of the 29 MSI-H cases, 24 (83%) were positive for methylation of the MLH1 promoter region. Twenty-three (82%) of the 28 MSI-H cases with immunohistochemistry results showed loss of expression of MLH1/PMS2 (n=19), MSH2/MSH6 (n=2), or MSH6 only (n=2). Of the 19 MSI-H cases with loss of MLH1/PMS2 on immunohistochemistry, 18 were positive, and 1 was equivocal for MLH1 promoter hypermethylation. Twelve of 94 cases (13%) analyzed for KRAS mutations were found to have a mutation. No BRAF V600E mutations were indentified. This study provides a comprehensive molecular genetic analysis of commonly analyzed targets in a large cohort of endometrial cancers.

Mismatch repair status and clinical outcome in endometrial cancer: a systematic review and meta-analysis.

BACKGROUND The association between the deficiency in mismatch repair (MMR) genes and prognosis in women with endometrial cancer is unclear. Here we report a systematic review and meta-analysis exploring this association. METHODS We searched literature databases (MEDLINE, EMBASE, and Cochrane) from 1980 until December 2011 to identify studies evaluating the association between MMR status and clinical outcome in endometrial cancer. The main outcome measures were overall survival (OS) and disease-free survival (DFS). RESULTS Twenty-three studies met the inclusion criteria. The median sample size of studies was 112, 74% were retrospective case-series and 70% performed microsatellite instability (MSI) analysis to evaluate the status of MMR. Only 22% of studies used the panel of five microsatellite markers recommended by the National Cancer Institute. Seven studies used immunohistochemistry to define MMR deficiency, but only two of them determined the expression of all four MMR proteins. Overall, significant associations between MMR and outcome were observed in 32% of studies. There was marked inter-study heterogeneity for estimates of OS and DFS. Pooled analysis did not show any significant association between deficiency in MMR and worse OS (6 studies, hazard ratio [HR] 2.0, p=0.11) or DFS (4 studies, HR ratio 1.31, p=0.66). CONCLUSION There is no definitive evidence of a significant association between MMR status and detrimental survival in endometrial cancer.

The prognostic impact of the platelet distribution width-to-platelet count ratio in patients with breast cancer

Activated platelets promote tumor cell growth, angiogenesis, and invasion. Platelet activity can be inferred by platelet volume indices (PVIs), which include platelet distribution width (PDW), mean platelet volume (MPV), platelet distribution width-to-platelet count ratio (PDW/P), and mean platelet volume-to-platelet count ratio. Platelets and platelet-related markers, such as the platelet-to-lymphocyte ratio, have been found to be significant prognostic factors in patients with breast cancer. However, the role of PVIs for predicting survival in breast cancer remains unknown; hence, we performed this retrospective analysis of 275 patients with breast cancer. PVIs were compared with clinicopathological variables, and were assessed to identify independent indicators associated with disease-free survival (DFS) using the Cox proportional hazards model. An elevated PDW/P significantly correlated with age and HER2 status. Univariate analysis revealed that elevated PDW, MPV, and PDW/P as well as tumor size, nuclear grade, and lymph node involvement were significantly associated with inferior DFS rates (tumor size: p<0.01; nuclear grade, lymph node involvement, PDW, MPV, and PDW/P: p<0.05). On multivariate analysis, a large tumor size and elevated PDW/P were significant prognostic factors for DFS, with hazard ratios of 3.24 (95% confidence interval [CI]: 1.24-8.47) and 2.99 (95% CI: 1.18-7.57), respectively (p<0.05). Our study is the first to reveal that an elevated PDW/P significantly reduces DFS in patients with breast carcinoma. Measuring the PDW/P is simple, relatively inexpensive, and almost universally available using routine blood counts; this makes it an attractive biomarker for improved risk assessment.

Longitudinal changes in maternal corin and mid-regional proatrial natriuretic peptide in women at risk of pre-eclampsia

Objectives Corin, an atrial natriuretic peptide-converting enzyme, has been found to promote trophoblast invasion and spiral artery remodeling. Reduced maternal plasma atrial natriuretic peptide (ANP) levels and elevated corin levels have been reported in pregnancies complicated by PE. The aim of this study was to investigate longitudinal changes in maternal plasma levels of corin and midregional proatrial natriuretic peptide (MR-PANP) in pregnancies that develop preeclampsia (PE) and gestational hypertension (GH). Methods Nested case control study drawn from a larger prospective longitudinal study in singleton pregnancies identified by screening at 11 + 0 − 13 + 6 weeks’ gestation as being at high risk for PE. Blood samples were taken every four weeks until delivery. Values were compared in pregnancies that developed preterm-PE (requiring delivery before 37 weeks), term-PE, GH, and those that remained normotensive. The distribution of maternal plasma corin and PANP were made Gaussian after log 10 transformation. Analysis of repeated measures with multilevel mixed-effects linear model (fixed effects and random effects) was performed. The multilevel model was compared to one-level model by the likelihood radio (LR) test. Results A total of 471 samples were analyzed from 122 women, including 85 that remained normotensive, 12 that developed GH, 13 term-PE and 12 preterm-PE. In the normotensive group, log10corin levels were associated with gestational age ( p p  = 0.001). In the GH and term-PE groups, corin did not differ significantly from the normotensive group ( p  = 0.64 and p  = 0.16, respectively). Compared to the normotensive group, MR-PANP levels were significantly higher in the pregnancies that developed preterm-PE and GH ( p  = 0.046 and p  = 0.019, respectively), but not term-PE ( p  = 0.47). Conclusions Maternal plasma corin and MR-PANP could potentially be useful biomarkers for the prediction of preterm-PE. Disclosures A. Khalil: Research Support Recipient; Commercial Interests: USCOM, Roche, Alere, NICOM, Q-fFN; Speaker: Roche.

Dietary fat and obesity: evidence from epidemiology.

The epidemiological evidence that a high-fat diet promotes the development of obesity is considered suggestive but not definitive. The purpose of this paper is to provide a review of various epidemiological methods that have been used to address this issue as well as an updated summary of the existing evidence. Ecological studies describing dietary fat intake and obesity at the population level provide mixed results and are likely to be biased by both confounding and unknown data quality factors that differ systematically across the populations studied. Cross-sectional studies are generally in agreement that the concentration of fat in the diet is positively associated with relative weight. Prospective studies of diet in relation to subsequent weight change give inconsistent results. This may be due to behavioural factors such as dieting in response to weight gain; in addition, this type of study rarely takes into account the possible interaction between genetic predisposition and dietary fat in promoting weight gain. Finally, intervention studies in free-living subjects are considered, providing evidence of a consistent but short-lived period of active weight loss on low-fat diets. The experimental evidence on this relationship is more conclusive than the epidemiological evidence, although biological mechanisms remain controversial. Some areas for future epidemiological research involve: longitudinal studies of dietary fat intake as a predictor of growth in children; observational studies relating total dietary fat and specific types of fat to overall as well as regional adiposity; and randomized intervention studies of the effect of low-fat diets with particular emphasis on and familial predisposition to obesity and other possible modifying factors.

Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes.

IMPORTANCE Studies suggest pioglitazone use may increase risk of cancers. OBJECTIVE To examine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additional cancers. DESIGN, SETTING, AND PARTICIPANTS Cohort and nested case-control analyses among persons with diabetes. A bladder cancer cohort followed 193,099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders. A cohort analysis of 10 additional cancers included 236,507 persons aged 40 years or older in 1997-2005 and followed until June 2012. Cohorts were from Kaiser Permanente Northern California. EXPOSURES Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent. MAIN OUTCOMES AND MEASURES Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma. RESULTS Among 193,099 persons in the bladder cancer cohort, 34,181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer. Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100,000 person-years, respectively. Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26). Results were similar in case-control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78-1.80). In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71). Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100,000 person-years, respectively. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose. CONCLUSIONS AND RELEVANCE Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded. The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality.

Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies.

BACKGROUND The main associations of body-mass index (BMI) with overall and cause-specific mortality can best be assessed by long-term prospective follow-up of large numbers of people. The Prospective Studies Collaboration aimed to investigate these associations by sharing data from many studies. METHODS Collaborative analyses were undertaken of baseline BMI versus mortality in 57 prospective studies with 894 576 participants, mostly in western Europe and North America (61% [n=541 452] male, mean recruitment age 46 [SD 11] years, median recruitment year 1979 [IQR 1975-85], mean BMI 25 [SD 4] kg/m(2)). The analyses were adjusted for age, sex, smoking status, and study. To limit reverse causality, the first 5 years of follow-up were excluded, leaving 66 552 deaths of known cause during a mean of 8 (SD 6) further years of follow-up (mean age at death 67 [SD 10] years): 30 416 vascular; 2070 diabetic, renal or hepatic; 22 592 neoplastic; 3770 respiratory; 7704 other. FINDINGS In both sexes, mortality was lowest at about 22.5-25 kg/m(2). Above this range, positive associations were recorded for several specific causes and inverse associations for none, the absolute excess risks for higher BMI and smoking were roughly additive, and each 5 kg/m(2) higher BMI was on average associated with about 30% higher overall mortality (hazard ratio per 5 kg/m(2) [HR] 1.29 [95% CI 1.27-1.32]): 40% for vascular mortality (HR 1.41 [1.37-1.45]); 60-120% for diabetic, renal, and hepatic mortality (HRs 2.16 [1.89-2.46], 1.59 [1.27-1.99], and 1.82 [1.59-2.09], respectively); 10% for neoplastic mortality (HR 1.10 [1.06-1.15]); and 20% for respiratory and for all other mortality (HRs 1.20 [1.07-1.34] and 1.20 [1.16-1.25], respectively). Below the range 22.5-25 kg/m(2), BMI was associated inversely with overall mortality, mainly because of strong inverse associations with respiratory disease and lung cancer. These inverse associations were much stronger for smokers than for non-smokers, despite cigarette consumption per smoker varying little with BMI. INTERPRETATION Although other anthropometric measures (eg, waist circumference, waist-to-hip ratio) could well add extra information to BMI, and BMI to them, BMI is in itself a strong predictor of overall mortality both above and below the apparent optimum of about 22.5-25 kg/m(2). The progressive excess mortality above this range is due mainly to vascular disease and is probably largely causal. At 30-35 kg/m(2), median survival is reduced by 2-4 years; at 40-45 kg/m(2), it is reduced by 8-10 years (which is comparable with the effects of smoking). The definite excess mortality below 22.5 kg/m(2) is due mainly to smoking-related diseases, and is not fully explained.

General and abdominal adiposity and risk of death in Europe.

BACKGROUND Previous studies have relied predominantly on the body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) to assess the association of adiposity with the risk of death, but few have examined whether the distribution of body fat contributes to the prediction of death. METHODS We examined the association of BMI, waist circumference, and waist-to-hip ratio with the risk of death among 359,387 participants from nine countries in the European Prospective Investigation into Cancer and Nutrition (EPIC). We used a Cox regression analysis, with age as the time variable, and stratified the models according to study center and age at recruitment, with further adjustment for educational level, smoking status, alcohol consumption, physical activity, and height. RESULTS During a mean follow-up of 9.7 years, 14,723 participants died. The lowest risks of death related to BMI were observed at a BMI of 25.3 for men and 24.3 for women. After adjustment for BMI, waist circumference and waist-to-hip ratio were strongly associated with the risk of death. Relative risks among men and women in the highest quintile of waist circumference were 2.05 (95% confidence interval [CI], 1.80 to 2.33) and 1.78 (95% CI, 1.56 to 2.04), respectively, and in the highest quintile of waist-to-hip ratio, the relative risks were 1.68 (95% CI, 1.53 to 1.84) and 1.51 (95% CI, 1.37 to 1.66), respectively. BMI remained significantly associated with the risk of death in models that included waist circumference or waist-to-hip ratio (P<0.001). CONCLUSIONS These data suggest that both general adiposity and abdominal adiposity are associated with the risk of death and support the use of waist circumference or waist-to-hip ratio in addition to BMI in assessing the risk of death.

Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung.

The mechanisms by which a primary tumor affects a selected distant organ before tumor cell arrival remain to be elucidated. This report shows that Gr-1+CD11b+ cells are significantly increased in lungs of mice bearing mammary adenocarcinomas before tumor cell arrival. In the premetastatic lungs, these immature myeloid cells significantly decrease IFN-gamma production and increase proinflammatory cytokines. In addition, they produce large quantities of matrix metalloproteinase 9 (MMP9) and promote vascular remodeling. Deletion of MMP9 normalizes aberrant vasculature in the premetastatic lung and diminishes lung metastasis. The production and activity of MMP9 is selectively restricted to lungs and organs with a large number of Gr-1+CD11b+ cells. Our work reveals a novel protumor mechanism for Gr-1+CD11b+ cells that changes the premetastatic lung into an inflammatory and proliferative environment, diminishes immune protection, and promotes metastasis through aberrant vasculature formation. Thus, inhibition of Gr-1+CD11b+ cells could normalize the premetastatic lung environment, improve host immunosurveillance, and inhibit tumor metastasis.

Association between smoking and risk of bladder cancer among men and women.

CONTEXT Previous studies indicate that the population attributable risk (PAR) of bladder cancer for tobacco smoking is 50% to 65% in men and 20% to 30% in women and that current cigarette smoking triples bladder cancer risk relative to never smoking. During the last 30 years, incidence rates have remained stable in the United States in men (123.8 per 100,000 person-years to 142.2 per 100,000 person-years) and women (32.5 per 100,000 person-years to 33.2 per 100,000 person-years); however, changing smoking prevalence and cigarette composition warrant revisiting risk estimates for smoking and bladder cancer. OBJECTIVE To evaluate the association between tobacco smoking and bladder cancer. DESIGN, SETTING, AND PARTICIPANTS Men (n = 281,394) and women (n = 186,134) of the National Institutes of Health-AARP (NIH-AARP) Diet and Health Study cohort completed a lifestyle questionnaire and were followed up between October 25, 1995, and December 31, 2006. Previous prospective cohort studies of smoking and incident bladder cancer were identified by systematic review and relative risks were estimated from fixed-effects models with heterogeneity assessed by the I(2) statistic. MAIN OUTCOME MEASURES Hazard ratios (HRs), PARs, and number needed to harm (NNH). RESULTS During 4,518,941 person-years of follow-up, incident bladder cancer occurred in 3896 men (144.0 per 100,000 person-years) and 627 women (34.5 per 100,000 person-years). Former smokers (119.8 per 100,000 person-years; HR, 2.22; 95% confidence interval [CI], 2.03-2.44; NNH, 1250) and current smokers (177.3 per 100,000 person-years; HR, 4.06; 95% CI, 3.66-4.50; NNH, 727) had higher risks of bladder cancer than never smokers (39.8 per 100,000 person-years). In contrast, the summary risk estimate for current smoking in 7 previous studies (initiated between 1963 and 1987) was 2.94 (95% CI, 2.45-3.54; I(2) = 0.0%). The PAR for ever smoking in our study was 0.50 (95% CI, 0.45-0.54) in men and 0.52 (95% CI, 0.45-0.59) in women. CONCLUSION Compared with a pooled estimate of US data from cohorts initiated between 1963 and 1987, relative risks for smoking in the more recent NIH-AARP Diet and Health Study cohort were higher, with PARs for women comparable with those for men.

Risk factors at medical school for subsequent professional misconduct: multicentre retrospective case-control study

OBJECTIVE To determine whether there are risk factors in a doctor's time at medical school that are associated with subsequent professional misconduct. DESIGN Matched case-control study. Setting Records from medical schools and the General Medical Council (GMC). PARTICIPANTS 59 doctors who had graduated from any one of eight medical schools in the United Kingdom in 1958-97 and had a proved finding of serious professional misconduct in GMC proceedings in 1999-2004 (cases); 236 controls (four for each case) were selected by systematic sampling from matching graduation cohorts. Case-control status was revealed by the GMC after completion of data entry. MAIN OUTCOME MEASURE Odds ratios for being a "case," with multivariable conditional logistic regression of potential risk factors including pre-admission characteristics and progress during the course. These data were obtained from anonymised copies of the students' progress files held by their original medical schools. RESULTS Univariate conditional logistic regression analysis found that cases were more likely to be men, to be of lower estimated social class, and to have had academic difficulties during their medical course, especially in the early years. Multivariable analysis showed that male sex (odds ratio 9.80, 95% confidence interval 2.43 to 39.44, P=0.001), lower social class (4.28, 1.52 to 12.09, P=0.006), and failure of early or preclinical examinations (5.47, 2.17 to 13.79, P<0.001) were independently associated with being a case. CONCLUSIONS This small study suggests that male sex, a lower socioeconomic background, and early academic difficulties at medical school could be risk factors for subsequent professional misconduct. The findings are preliminary and should be interpreted with caution. Most doctors with risk factors will not come before the GMC's disciplinary panels.

Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.

IMPORTANCE Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES Breast and ovarian cancer risks. RESULTS Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

Contemporary type 1 diabetes pregnancy outcomes: impact of obesity and glycaemic control.

OBJECTIVE To compare contemporary pregnancy outcomes in women with and without type 1 diabetes, and to examine the effects of obesity and glycaemic control on these outcomes. DESIGN AND SETTING Historical cohort study in a specialist diabetes and maternity network in Victoria. PARTICIPANTS All singleton births (at least 20 weeks' gestation), 2010-2013, were analysed: 107 pregnancies to women with type 1 diabetes and 27 075 pregnancies to women without diabetes. Women with type 2 diabetes or gestational diabetes were excluded. METHODS Data were extracted from the Birthing Outcomes System database; associations between type 1 diabetes and pregnancy outcomes were analysed by multivariable regression. MAIN OUTCOME MEASURES Mode of birth; maternal and neonatal outcomes. RESULTS The mean body mass index was higher for women with type 1 diabetes than for women without diabetes (mean, 27.3 kg/m(2) [SD, 5.0] v 25.7 kg/m(2) [SD, 5.9]; P = 0.01); the median gestation period for their babies was shorter (median, 37.3 weeks [IQR, 34.6-38.1] v 39.4 weeks [IQR, 38.4-40.4]; P < 0.001) and they were more likely to be large for gestational age (LGA) (adjusted odds ratio [aOR], 7.9; 95% CI, 5.3-11.8). Women with type 1 diabetes were more likely to have had labour induced (aOR, 3.0; 95% CI, 2.0-4.5), a caesarean delivery (aOR, 4.6; 95% CI, 3.1-7.0), or a pre-term birth (aOR, 6.7; 95% CI, 4.5-10.0); their babies were more likely to have shoulder dystocia (aOR, 8.2; 95% CI, 3.6-18.7), hypoglycaemia (aOR, 10.3; 95% CI, 6.8-15.6), jaundice (aOR, 5.1; 95% CI, 3.3-7.7), respiratory distress (aOR, 2.5; 95% CI, 1.4-4.4) or to suffer perinatal death (aOR, 4.3; 95% CI, 1.9-9.9). In women with type 1 diabetes, greater obesity was associated with increased odds for an LGA baby or congenital malformation, and increased HbA1c levels were associated with pre-term birth and perinatal death. CONCLUSION Women with type 1 diabetes, even when managed in a specialist setting, still experience adverse obstetric and neonatal outcomes. Poor glycaemic control is not wholly responsible for adverse outcomes, reinforcing the importance of other risk factors, such as obesity and weight gain.

The nuclear receptors SF1 and LRH1 are expressed in endometrial cancer cells and regulate steroidogenic gene transcription by cooperating with AP-1 factors.

Excessive exposure to estradiol represents the main risk factor for endometrial cancer. The abnormally high estradiol levels in the endometrium of women with endometrial cancer are most likely due to overproduction by the tumour itself. Endometrial cancer cells express the genes encoding the steroidogenic enzymes involved in estradiol synthesis. Here we used RT-PCR and Western blot to show that the nuclear receptors SF1 and LRH1, two well-known regulators of steroidogenic gene expression in gonadal and adrenal cells, are also expressed in endometrial cancer cell lines. By transient transfections, we found that SF1 and LRH1, but not the related nuclear receptor NUR77, can activate the promoters of three human steroidogenic genes: STAR, HSD3B2, and CYP19A1 PII. Similarly, forskolin but not PMA, could activate all three promoters. In addition, we found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. All together, our data provide novel insights into the mechanisms of steroidogenic gene expression in endometrial cancer cells and thus in the regulation of estradiol biosynthesis by tumour cells.

Endometrial carcinoma risk among women diagnosed with endometrial hyperplasia: the 34-year experience in a large health plan

Classifying endometrial hyperplasia (EH) according to the severity of glandular crowding (simple hyperplasia (SH) vs complex hyperplasia (CH)) and nuclear atypia (simple atypical hyperplasia (SAH) vs complex atypical hyperplasia (CAH)) should predict subsequent endometrial carcinoma risk, but data on progression are lacking. Our nested case–control study of EH progression included 138 cases, who were diagnosed with EH and then with carcinoma (1970–2003) at least 1 year (median, 6.5 years) later, and 241 controls, who were individually matched on age, date, and follow-up duration and counter-matched on EH classification. After centralised pathology panel and medical record review, we generated rate ratios (RRs) and 95% confidence intervals (CIs), adjusted for treatment and repeat biopsies. With disordered proliferative endometrium (DPEM) as the referent, AH significantly increased carcinoma risk (RR=14, 95% CI, 5–38). Risk was highest 1–5 years after AH (RR=48, 95% CI, 8–294), but remained elevated 5 or more years after AH (RR=3.5, 95% CI, 1.0–9.6). Progression risks for SH (RR=2.0, 95% CI, 0.9–4.5) and CH (RR=2.8, 95% CI, 1.0–7.9) were substantially lower and only slightly higher than the progression risk for DPEM. The higher progression risks for AH could foster management guidelines based on markedly different progression risks for atypical vs non-atypical EH.

Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial.

BACKGROUND Human papillomavirus (HPV) testing is known to be more sensitive, but less specific than cytology for detecting cervical intraepithelial neoplasia (CIN). We assessed the efficacy of cervical-cancer screening policies that are based on HPV testing. METHODS Between March, 2004, and December, 2004, in two separate recruitment phases, women aged 25-60 years were randomly assigned to conventional cytology or to HPV testing in combination with liquid-based cytology (first phase) or alone (second phase). Randomisation was done by computer in two screening centres and by sequential opening of numbered sealed envelopes in the remaining seven centres. During phase one, women who were HPV-positive and aged 35-60 years were referred to colposcopy, whereas women aged 25-34 years were referred to colposcopy only if cytology was also abnormal or HPV testing was persistently positive. During phase two, women in the HPV group were referred for colposcopy if the HPV test was positive. Two rounds of screening occurred in each phase, and all women had cytology testing only at the second round. The primary endpoint was the detection of grade 2 and 3 CIN, and of invasive cervical cancers during the first and second screening rounds. Analysis was done by intention to screen. This trial is registered, number ISRCTN81678807. FINDINGS In total for both phases, 47,001 women were randomly assigned to the cytology group and 47,369 to HPV testing. 33,851 women from the cytology group and 32,998 from the HPV-testing group had a second round of screening. We also retrieved the histological diagnoses from screening done elsewhere. The detection of invasive cervical cancers was similar for the two groups in the first round of screening (nine in the cytology group vs seven in the HPV group, p=0.62); no cases were detected in the HPV group during round two, compared with nine in the cytology group (p=0.004). Overall, in the two rounds of screening, 18 invasive cancers were detected in the cytology group versus seven in the HPV group (p=0.028). Among women aged 35-60 years, at round one the relative detection (HPV vs cytology) was 2.00 (95% CI 1.44-2.77) for CIN2, 2.08 (1.47-2.95) for CIN3, and 2.03 (1.60-2.57) for CIN2 and 3 together. At round two the relative detection was 0.54 (0.23-1.28) for CIN2, 0.48 (0.21-1.11) for CIN3, and 0.51 (0.28-0.93) for CIN2 and 3 together. Among women aged 25-34 years, there was significant heterogeneity between phases in the relative detection of CIN3. At round one the relative detection was 0.93 (0.52-1.64) in phase one and 3.91 (2.02-7.57) in phase two. At round two the relative detection was 1.34 (0.46-3.84) in phase one and 0.20 (0.04-0.93) in phase two. Pooling both phases, the detection ratio of CIN2 for women aged 25-34 years was 4.09 (2.24-7.48) at round one and 0.64 (0.23-1.27) at round two. INTERPRETATION HPV-based screening is more effective than cytology in preventing invasive cervical cancer, by detecting persistent high-grade lesions earlier and providing a longer low-risk period. However, in younger women, HPV screening leads to over-diagnosis of regressive CIN2. FUNDING European Union, Italian Ministry of Health, Regional Health Administrations of Piemonte, Tuscany, Veneto and Emilia-Romagna, and Public Health Agency of Lazio.

The relation between past exposure to fine particulate air pollution and prevalent anxiety: observational cohort study

OBJECTIVE To determine whether higher past exposure to particulate air pollution is associated with prevalent high symptoms of anxiety. DESIGN Observational cohort study. SETTING Nurses' Health Study. PARTICIPANTS 71,271 women enrolled in the Nurses' Health Study residing throughout the contiguous United States who had valid estimates on exposure to particulate matter for at least one exposure period of interest and data on anxiety symptoms. MAIN OUTCOME MEASURES Meaningfully high symptoms of anxiety, defined as a score of 6 points or greater on the phobic anxiety subscale of the Crown-Crisp index, administered in 2004. RESULTS The 71,271 eligible women were aged between 57 and 85 years (mean 70 years) at the time of assessment of anxiety symptoms, with a prevalence of high anxiety symptoms of 15%. Exposure to particulate matter was characterized using estimated average exposure to particulate matter <2.5 μm in diameter (PM2.5) and 2.5 to 10 μm in diameter (PM2.5-10) in the one month, three months, six months, one year, and 15 years prior to assessment of anxiety symptoms, and residential distance to the nearest major road two years prior to assessment. Significantly increased odds of high anxiety symptoms were observed with higher exposure to PM2.5 for multiple averaging periods (for example, odds ratio per 10 µg/m(3) increase in prior one month average PM2.5: 1.12, 95% confidence interval 1.06 to 1.19; in prior 12 month average PM2.5: 1.15, 1.06 to 1.26). Models including multiple exposure windows suggested short term averaging periods were more relevant than long term averaging periods. There was no association between anxiety and exposure to PM2.5-10. Residential proximity to major roads was not related to anxiety symptoms in a dose dependent manner. CONCLUSIONS Exposure to fine particulate matter (PM2.5) was associated with high symptoms of anxiety, with more recent exposures potentially more relevant than more distant exposures. Research evaluating whether reductions in exposure to ambient PM2.5 would reduce the population level burden of clinically relevant symptoms of anxiety is warranted.

An adoption study of human obesity.

We examined the contributions of genetic factors and the family environment to human fatness in a sample of 540 adult Danish adoptees who were selected from a population of 3580 and divided into four weight classes: thin, median weight, overweight, and obese. There was a strong relation between the weight class of the adoptees and the body-mass index of their biologic parents - for the mothers, P less than 0.0001; for the fathers, P less than 0.02. There was no relation between the weight class of the adoptees and the body-mass index of their adoptive parents. Cumulative distributions of the body-mass index of parents showed similar results; there was a strong relation between the body-mass index of biologic parents and adoptee weight class and no relation between the index of adoptive parents and adoptee weight class. Furthermore, the relation between biologic parents and adoptees was not confined to the obesity weight class, but was present across the whole range of body fatness - from very thin to very fat. We conclude that genetic influences have an important role in determining human fatness in adults, whereas the family environment alone has no apparent effect.

Maternal and child undernutrition: consequences for adult health and human capital

In this paper we review the associations between maternal and child undernutrition with human capital and risk of adult diseases in low-income and middle-income countries. We analysed data from five long-standing prospective cohort studies from Brazil, Guatemala, India, the Philippines, and South Africa and noted that indices of maternal and child undernutrition (maternal height, birthweight, intrauterine growth restriction, and weight, height, and body-mass index at 2 years according to the new WHO growth standards) were related to adult outcomes (height, schooling, income or assets, offspring birthweight, body-mass index, glucose concentrations, blood pressure). We undertook systematic reviews of studies from low-income and middle-income countries for these outcomes and for indicators related to blood lipids, cardiovascular disease, lung and immune function, cancers, osteoporosis, and mental illness. Undernutrition was strongly associated, both in the review of published work and in new analyses, with shorter adult height, less schooling, reduced economic productivity, and--for women--lower offspring birthweight. Associations with adult disease indicators were not so clear-cut. Increased size at birth and in childhood were positively associated with adult body-mass index and to a lesser extent with blood pressure values, but not with blood glucose concentrations. In our new analyses and in published work, lower birthweight and undernutrition in childhood were risk factors for high glucose concentrations, blood pressure, and harmful lipid profiles once adult body-mass index and height were adjusted for, suggesting that rapid postnatal weight gain--especially after infancy--is linked to these conditions. The review of published works indicates that there is insufficient information about long-term changes in immune function, blood lipids, or osteoporosis indicators. Birthweight is positively associated with lung function and with the incidence of some cancers, and undernutrition could be associated with mental illness. We noted that height-for-age at 2 years was the best predictor of human capital and that undernutrition is associated with lower human capital. We conclude that damage suffered in early life leads to permanent impairment, and might also affect future generations. Its prevention will probably bring about important health, educational, and economic benefits. Chronic diseases are especially common in undernourished children who experience rapid weight gain after infancy.

Common variants in DGKK are strongly associated with risk of hypospadias

Hypospadias is a common congenital malformation of the male external genitalia. We performed a genome-wide association study using pooled DNA from 436 individuals with hypospadias (cases) and 494 controls of European descent and selected the highest ranked SNPs for individual genotyping in the discovery sample, an additional Dutch sample of 133 cases and their parents, and a Swedish series of 266 cases and 402 controls. Individual genotyping of two SNPs (rs1934179 and rs7063116) in DGKK, encoding diacylglycerol kinase κ, produced compelling evidence for association with hypospadias in the discovery sample (allele-specific odds ratio (OR) = 2.5, P = 2.5 × 10−11 and OR = 2.3, P = 2.9 × 10−9, respectively) and in the Dutch (OR = 3.9, P = 2.4 × 10−5 and OR = 3.8, P = 3.4 × 10−5) and Swedish (OR = 2.5, P = 2.6 × 10−8 and OR = 2.2, P = 2.7 × 10−6) replication samples. Expression studies showed expression of DGKK in preputial tissue of cases and controls, which was lower in carriers of the risk allele of rs1934179 (P = 0.047). We propose DGKK as a major risk gene for hypospadias.

Emerging role of bisphosphonates in the clinic--antitumor activity and prevention of metastasis to bone.

Bisphosphonates are currently used for the treatment of bone metastases, and emerging data suggest that they may also have antitumor properties. Preclinical studies have demonstrated that zoledronic acid can inhibit angiogenesis, invasion and adhesion of tumor cells, and overall tumor progression, and emerging evidence suggests that the use of these agents may impede the development of skeletal metastases. In a recent clinical study in patients with metastatic bone disease, basal levels of vascular endothelial growth factor, a factor essential for angiogenesis, were significantly reduced in patients receiving zoledronic acid, suggesting that zoledronic acid may have clinically relevant antiangiogenic properties. Early clinical data on prevention of bone metastases by the early-generation bisphosphonate clodronate have yielded promising results in patients with breast cancer, and trials are currently ongoing to assess the efficacy of clodronate in this setting. Similarly, the new-generation bisphosphonate zoledronic acid has demonstrated activity in the prevention of bone metastases in small, 18-month pilot studies in patients with high-risk solid tumors (N=40; P=0.0002). Similarly, in a separate 5-year trial, the overall survival of patients with multiple myeloma was greater in patients whose standard treatment regimens included zoledronic acid compared with standard treatment alone (P<0.01). These encouraging early clinical results supported the initiation of larger randomized trials that are currently ongoing.

Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening.

BACKGROUND Primary cervical screening with both human papillomavirus (HPV) DNA testing and cytological examination of cervical cells with a Pap test (cytology) has been evaluated in randomized clinical trials. Because the vast majority of women with positive cytology are also HPV DNA positive, screening strategies that use HPV DNA testing as the primary screening test may be more effective. METHODS We used the database from the intervention arm (n = 6,257 women) of a population-based randomized trial of double screening with cytology and HPV DNA testing to evaluate the efficacy of 11 possible cervical screening strategies that are based on HPV DNA testing alone, cytology alone, and HPV DNA testing combined with cytology among women aged 32-38 years. The main outcome measures were sensitivity for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) within 6 months of enrollment or at colposcopy for women with a persistent type-specific HPV infection and the number of screening tests and positive predictive value (PPV) for each screening strategy. All statistical tests were two-sided. RESULTS Compared with screening by cytology alone, double testing with cytology and for type-specific HPV persistence resulted in a 35% (95% confidence interval [CI] = 15% to 60%) increase in sensitivity to detect CIN3+, without a statistically significant reduction in the PPV (relative PPV = 0.76, 95% CI = 0.52 to 1.10), but with more than twice as many screening tests needed. Several strategies that incorporated screening for high-risk HPV subtypes were explored, but they resulted in reduced PPV compared with cytology. Compared with cytology, primary screening with HPV DNA testing followed by cytological triage and repeat HPV DNA testing of HPV DNA-positive women with normal cytology increased the CIN3+ sensitivity by 30% (95% CI = 9% to 54%), maintained a high PPV (relative PPV = 0.87, 95% CI = 0.60 to 1.26), and resulted in a mere 12% increase in the number of screening tests (from 6,257 to 7,019 tests). CONCLUSIONS Primary HPV DNA-based screening with cytology triage and repeat HPV DNA testing of cytology-negative women appears to be the most feasible cervical screening strategy.

Survival analysis: time-dependent effects and time-varying risk factors.

In traditional Kaplan-Meier or Cox regression analysis, usually a risk factor measured at baseline is related to mortality thereafter. During follow-up, however, things may change: either the effect of a fixed baseline risk factor may vary over time, resulting in a weakening or strengthening of associations over time, or the risk factor itself may vary over time. In this paper, short-term versus long-term effects (so-called time-dependent effects) of a fixed baseline risk factor are addressed. An example is presented showing that underweight is a strong risk factor for mortality in dialysis patients, especially in the short run. In contrast, overweight is a risk factor for mortality, which is stronger in the long run than in the short run. In addition, the analysis of how time-varying risk factors (so-called time-dependent risk factors) are related to mortality is demonstrated by paying attention to the pitfall of adjusting for sequelae. The proper analysis of effects over time should be driven by a clear research question. Both kinds of research questions, that is those of time-dependent effects as well those of time-dependent risk factors, can be analyzed with time-dependent Cox regression analysis. It will be shown that using time-dependent risk factors usually implies focusing on short-term effects only.

Association Between Biomarkers of Ovarian Reserve and Infertility Among Older Women of Reproductive Age

Importance Despite lack of evidence of their utility, biomarkers of ovarian reserve are being promoted as potential markers of reproductive potential. Objective To determine the associations between biomarkers of ovarian reserve and reproductive potential among women of late reproductive age. Design, Setting, and Participants Prospective time-to-pregnancy cohort study (2008 to date of last follow-up in March 2016) of women (N = 981) aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, recruited from the community in the Raleigh-Durham, North Carolina, area. Exposures Early-follicular-phase serum level of antimüllerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B and urinary level of FSH. Main Outcomes and Measures The primary outcomes were the cumulative probability of conception by 6 and 12 cycles of attempt and relative fecundability (probability of conception in a given menstrual cycle). Conception was defined as a positive pregnancy test result. Results A total of 750 women (mean age, 33.3 [SD, 3.2] years; 77% white; 36% overweight or obese) provided a blood and urine sample and were included in the analysis. After adjusting for age, body mass index, race, current smoking status, and recent hormonal contraceptive use, women with low AMH values (<0.7 ng/mL [n = 84]) did not have a significantly different predicted probability of conceiving by 6 cycles of attempt (65%; 95% CI, 50%-75%) compared with women (n = 579) with normal values (62%; 95% CI, 57%-66%) or by 12 cycles of attempt (84% [95% CI, 70%-91%] vs 75% [95% CI, 70%-79%], respectively). Women with high serum FSH values (>10 mIU/mL [n = 83]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (63%; 95% CI, 50%-73%) compared with women (n = 654) with normal values (62%; 95% CI, 57%-66%) or after 12 cycles of attempt (82% [95% CI, 70%-89%] vs 75% [95% CI, 70%-78%], respectively). Women with high urinary FSH values (>11.5 mIU/mg creatinine [n = 69]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (61%; 95% CI, 46%-74%) compared with women (n = 660) with normal values (62%; 95% CI, 58%-66%) or after 12 cycles of attempt (70% [95% CI, 54%-80%] vs 76% [95% CI, 72%-80%], respectively). Inhibin B levels (n = 737) were not associated with the probability of conceiving in a given cycle (hazard ratio per 1-pg/mL increase, 0.999; 95% CI, 0.997-1.001). Conclusions and Relevance Among women aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, biomarkers indicating diminished ovarian reserve compared with normal ovarian reserve were not associated with reduced fertility. These findings do not support the use of urinary or blood follicle-stimulating hormone tests or antimüllerian hormone levels to assess natural fertility for women with these characteristics.

Circulating adiponectin, leptin and adiponectin-leptin ratio and endometrial cancer risk: Evidence from a meta-analysis of epidemiologic studies.

We performed this meta-analysis of epidemiologic studies to investigate the associations between circulating adiponectin, leptin and adiponectin-leptin (A/L) ratio and endometrial cancer risk. Relevant manuscripts were identified by searching PubMed and ISI Web of Science databases as well as by manual searching the references cited in retrieved manuscripts. Random-effects models were used to estimate summary odds ratio (SOR) and 95% confidence intervals (CIs) for aforementioned associations. Fourteen manuscripts with 13 studies (five nested case-control and eight case-control studies) cumulatively involving a total of 1,963 endometrial cancer cases and 3,503 noncases were included in the analyses. Overall, comparing persons with circulating concentrations of adiponectin, leptin and A/L ratio in the top tertile with persons with concentrations of these biomarkers in the bottom tertile yielded SORs of 0.47 (95% CI: 0.34-0.65; I(2)  = 63.7%; n = 13), 2.19 (95% CI: 1.44-3.31; I(2)  = 64.2%; n = 7),and 0.45 (95% CI: 0.24-0.86; I(2)  = 90.1%; n = 5), respectively. Notably, there was an 18% reduction in risk for per each 5 μg/mL increment in circulating adiponectin concentrations (SOR = 0.82; 95% CI: 0.74-0.90; I(2)  = 49%; n = 8). Stratifying by study characteristics and whether these studies considered or adjusted for potential confounders, the findings were robust in the analyses of circulating adiponectin and leptin. No evidence of publication bias was detected. In conclusion, the findings from this meta-analysis suggest that increased circulating adiponectin and A/L ratio or decreased leptin concentrations were associated with reduced risk of endometrial cancer. Further prospective designed studies are warranted to confirm our findings.

Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer

Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case–control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10−5), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10−4) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10−9). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.

Short term persistence of human papillomavirus and risk of cervical precancer and cancer: population based cohort study

OBJECTIVE To evaluate the cumulative incidence of cervical intraepithelial neoplasia II or worse (grade II+) or cervical intraepithelial neoplasia grade III+ after short term persistence of prevalently detected carcinogenic human papillomavirus (HPV). DESIGN Population based cohort study. SETTING Guanacaste, Costa Rica. PARTICIPANTS 2282 sexually active women actively followed after enrolment. MAIN OUTCOME MEASURES Primary end points: three year and five year cumulative incidence of histologically confirmed cervical intraepithelial neoplasia grade II+ (n=70). Cervical specimens collected at each visit tested for more than 40 HPV genotypes. HPV 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, and 82 were considered the primary carcinogenic genotypes. RESULTS Women who tested positive for a carcinogenic HPV at enrolment and after about one year (9-21 months) (positive/positive) had a three year cumulative incidence of cervical intraepithelial neoplasia grade II+ of 17.0% (95% confidence interval 12.1% to 22.0%). Those who tested negative/positive (3.4%, 0.1% to 6.8%), positive/negative (1.2%, -0.2% to 2.5%), and negative/negative (0.5%, 0.1% to 0.9%) were at a significantly lower risk. There was little difference in the cumulative incidence of cervical intraepithelial neoplasia grade II+ between testing positive twice for any carcinogenic HPV genotype (same genotype or different genotypes) v testing positive twice for the same carcinogenic genotype (17.0% v 21.3%, respectively). Short term persistence of HPV 16 strongly predicted cervical intraepithelial neoplasia grade II+, with a three year cumulative incidence of 40.8% (26.4% to 55.1%). Similar patterns were observed for the five year cumulative incidence of grade II+ and for three year and five year cumulative incidence of grade III+. CONCLUSIONS Short term persistence of a prevalently detected carcinogenic HPV infection, especially HPV 16, strongly predicts a subsequent diagnosis of cervical intraepithelial neoplasia II+ over the next few years.

Genetic variability in GLP-1 receptor is associated with inter-individual differences in weight lowering potential of liraglutide in obese women with PCOS: a pilot study

The weight lowering potential of glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) is inter-individually different and clinically unpredictable. The potential role of genetic variability of GLP-1R on body weight response to GLP-1 RAs in obese women with polycystic ovary syndrome (PCOS) has not yet been evaluated. Fifty-seven obese women with PCOS (aged 30.7 ± 7.0, BMI 38.6 ± 5.3 kg/m2) were assigned to liraglutide 1.2 mg QD s.c. for 12 weeks and classified as strong responders regarding weight loss if they lost 5 % or more of their initial body weight. They were genotyped for common GLP-1R single nucleotide polymorphisms (SNPs) rs6923761 and rs10305420. Changes of measures of obesity were measured before and at the end of the treatment. Twenty out of 57 subjects were strong responders and lost 7.38 ± 1.74 compared to 2.11 ± 2.17 kg lost in poor responders. Carriers of at least one polymorphic rs10305420 allele had poor treatment response compared to carriers of two wild type alleles (OR = 0.27, 95 % CI = 0.09–0.85, P = 0.025). Carriers of at least one polymorphic rs6923761 allele tended to have stronger treatment response compared to carriers of two wild type alleles (OR = 3.06, 95 % CI = 0.96–9.74, P = 0.058). Fasting glucose and glucose after oral glucose tolerance test (OGTT) comparably decreased in both groups when compared to baseline, whereas no within treatment differences were found in androgen profile. Gastrointestinal adverse events were transit and balanced between strong and poor responders. GLP-1R rs10305420 polymorphism explained some of the inter-individual differences in response to liraglutide regarding weight loss in obese PCOS women.

A comparison of cancer screening practices in cancer survivors and in the general population: the Korean national health and nutrition examination survey (KNHANES) 2001–2007

This study aimed to describe cancer screening rates for second primary cancer among cancer survivors in Korea, and to compare these rates with those of two control groups: individuals without a history of cancer but with other chronic diseases, and individuals without a history of cancer and without other chronic diseases. The study is a cross-sectional analysis of 15,556 adults ≥30 years old who participated in the 2001, 2005, and 2007 Korean National Health and Nutrition Examination Surveys (KNHANES). The prevalence of breast, cervical, gastric, and colorectal cancer screening examinations according to national guidelines was assessed and compared to two control groups. Screening rates among cancer survivors were 48.5, 54.7, 34.7, and 28.6% for breast, cervical, gastric, and colorectal cancer screening, respectively. Cancer survivors showed higher screening rates for all four cancer sites compared with both control groups, but breast cancer screening was only statistically significant after adjusting gender, age, marital status, education, income, working status, health insurance, smoking and drinking status, and self-reported health status. Cancer survivors were more likely than individuals without a cancer history to obtain screening examinations according to recommended guidelines. Still, screening rates even among survivors were suboptimal, emphasizing the need for a more systematic approach to second primary cancer screening and prevention.

Geographical access to healthcare in Northern England and post-mortem diagnosis of cancer.

BACKGROUND There is some previous evidence that diagnosis of cancer at death, recorded as registry death certificate only records, is associated with problems of access to care. METHODS Records from the Northern and Yorkshire Cancer Registry for patients registered with breast, colorectal, lung, ovarian or prostate cancer between 1994 and 2002 were supplemented with measures of travel time to general practitioner and hospital services, and social deprivation. Logistic regression was used to identify predictors of records where diagnosis was at death. RESULTS There was no association between the odds diagnosis at death and access to primary care. For all sites except breast, the highest odds of being a cancer diagnosed at death fell among those living in the highest quartile of hospital travel time, although it was only statistically significant for colorectal and ovary tumours. Those in the most deprived and furthest travel time to hospital quartile were 2.6 times more likely to be a diagnosis at death case compared with those in the most affluent and proximal areas. CONCLUSIONS There is some evidence that poorer geographical access to tertiary care, in particular when coupled with social disadvantages, may be associated with increased odds of diagnosis at death.

Suicides after pregnancy in Finland, 1987-94: register linkage study.

OBJECTIVE To determine rates of suicide associated with pregnancy by the type of pregnancy. DESIGN Register linkage study. Information on suicides in women of reproductive age was linked with the Finnish birth, abortion, and hospital discharge registers to find out how many women who committed suicide had had a completed pregnancy during her last year of life. SETTING Nationwide data from Finland. SUBJECTS Women who committed suicide in 1987-94. RESULTS There were 73 suicides associated with pregnancy, representing 5.4% of all suicides in women in this age group. The mean annual suicide rate was 11.3 per 100,000. The suicide rate associated with birth was significantly lower (5.9) and the rates associated with miscarriage (18.1) and induced abortion (34.7) were significantly higher than in the population. The risk associated with birth was higher among teenagers and that associated with abortion was increased in all age groups. Women who had committed a suicide tended to come from lower social classes and were more likely to be unmarried than other women who had had a completed pregnancy. CONCLUSIONS The increased risk of suicide after an induced abortion indicates either common risk factors for both or harmful effects of induced abortion on mental health.

Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies.

OBJECTIVE To assess the effect of 25-hydroxyvitamin D (25-OHD) levels on pregnancy outcomes and birth variables. DESIGN Systematic review and meta-analysis. DATA SOURCES Medline (1966 to August 2012), PubMed (2008 to August 2012), Embase (1980 to August 2012), CINAHL (1981 to August 2012), the Cochrane database of systematic reviews, and the Cochrane database of registered clinical trials. STUDY SELECTION Studies reporting on the association between serum 25-OHD levels during pregnancy and the outcomes of interest (pre-eclampsia, gestational diabetes, bacterial vaginosis, caesarean section, small for gestational age infants, birth weight, birth length, and head circumference). DATA EXTRACTION Two authors independently extracted data from original research articles, including key indicators of study quality. We pooled the most adjusted odds ratios and weighted mean differences. Associations were tested in subgroups representing different patient characteristics and study quality. RESULTS 3357 studies were identified and reviewed for eligibility. 31 eligible studies were included in the final analysis. Insufficient serum levels of 25-OHD were associated with gestational diabetes (pooled odds ratio 1.49, 95% confidence interval 1.18 to 1.89), pre-eclampsia (1.79, 1.25 to 2.58), and small for gestational age infants (1.85, 1.52 to 2.26). Pregnant women with low serum 25-OHD levels had an increased risk of bacterial vaginosis and low birthweight infants but not delivery by caesarean section. CONCLUSION Vitamin D insufficiency is associated with an increased risk of gestational diabetes, pre-eclampsia, and small for gestational age infants. Pregnant women with low 25-OHD levels had an increased risk of bacterial vaginosis and lower birth weight infants, but not delivery by caesarean section.