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1.  Breast cancer incidence in Mongolia 
Cancer causes & control : CCC  2012;23(7):1047-1053.
Purpose
Data on international variation in breast cancer incidence may help to identify additional risk factors. Substantially lower breast cancer rates in Asia than in North America and Western Europe are established, but differences within Asia have been largely ignored despite heterogeneity in lifestyles and environments. Mongolia’s breast cancer experience is of interest because of its shared genetics but vastly different diet compared with other parts of Asia.
Methods
Age-standardized breast cancer incidence and mortality rates obtained from the International Association of Cancer Registries are presented for several Asian countries. Mongolian incidence rates obtained from its cancer registry describe incidence within the country.
Results
Breast cancer incidence in Mongolia (age standardized 8.0/100,000) is almost a third of rates in China (21.6/100,000), and over five times that of Japan (42.7/100,000) and Russia (43.2/100,000). Rates within Mongolia appear to have increased slightly over the last decade and are higher in urban than rural areas (annual percentage increase of age-standardized rates from 1998 to 2005 was 3.60 and 2.57%, respectively). The increase in breast cancer incidence with age plateaus at menopause, as in other Asian populations.
Conclusions
Mongolia’s low breast cancer incidence is of particular interest because of their unusual diet (primarily red meat and dairy) compared with other Asian countries. More intensive study of potential dietary, reproductive and lifestyle factors in Mongolia with comparison to other Asian populations may provide more clarity in what drives the international breast cancer rate differences.
doi:10.1007/s10552-012-9973-2
PMCID: PMC3786577  PMID: 22543542
Mongolia; Breast cancer; Urban-rural; Asia; International
2.  Height at diagnosis and birth-weight as risk factors for osteosarcoma 
Cancer causes & control : CCC  2011;22(6):899-908.
OBJECTIVES
Osteosarcoma typically occurs during puberty. Studies of the association between height and/or birth-weight and osteosarcoma are conflicting. Therefore, we conducted a large pooled analysis of height and birth-weight in osteosarcoma.
METHODS
Patient data from 7 studies of height, and 3 of birth-weight were obtained, resulting in 1067 cases with height and 434 cases with birth-weight data. We compared cases to the 2000 US National Center for Health Statistics Growth Charts by simulating 1000 age and gender matched controls per case. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between height or birth-weight and risk of osteosarcoma for each study were estimated using logistic regression. All of the case data were combined for an aggregate analysis.
RESULTS
Compared to average birth-weight subjects (2665–4045g), individuals with high birth-weight (≥4046g) had an increased osteosarcoma risk (OR 1.35, 95%CI 1.01–1.79). Taller than average (51st–89th percentile) and very tall individuals (≥90th percentile) had an increased risk of osteosarcoma (OR 1.35, 95%CI 1.18–1.54, and OR 2.60, 95%CI 2.19–3.07, respectively; Ptrend <0.0001).
CONCLUSIONS
This is the largest analysis of height at diagnosis and birth-weight in relation to osteosarcoma. It suggests that rapid bone growth during puberty and in utero contributes to OS etiology.
doi:10.1007/s10552-011-9763-2
PMCID: PMC3494416  PMID: 21465145
osteosarcoma; height; birth-weight; meta-analysis; epidemiology
3.  Associations of Pregnancy Characteristics with Maternal and Cord Steroid Hormones, Angiogenic Factors, and Insulin-like Growth Factor Axis 
Cancer causes & control : CCC  2011;22(11):1587-1595.
Background
The objective of this study was to comprehensively profile biological factors in pregnancy that have been postulated to be important components of the in utero environment and may also have relevance to later susceptibility to cancer and other chronic diseases.
Methods
Steroid sex hormones, IGFs, and angiogenic factors were measured in maternal and cord serum from term, normotensive pregnancies. Spearman correlations and linear regression estimated relationships among the biological factors and clinical characteristics.
Results
The analytes were generally not correlated between maternal and fetal circulations. However, significant correlations were demonstrated among several analytes within maternal or cord samples. A few analytes were associated with clinical characteristics (e.g., maternal IGF-1and IGFBP-3 were inversely correlated with offspring birth weight, while maternal leptin and cord testosterone were positively correlated with this characteristic). Maternal androgens were higher in African-Americans than whites and maternal PlGF and soluble fms-like tyrosine kinase-1 (sFlt-1) were higher in male than female offspring.
Conclusions
There were significant correlations among analytes but the patterns differed depending on whether they were measured in the maternal or fetal circulation. The number and magnitude of correlations among analytes, however, should affect the design and interpretation of future studies.
doi:10.1007/s10552-011-9835-3
PMCID: PMC3321929  PMID: 21947778
African-American; angiogenic factors; IGF; leptin; prolactin
4.  Maternal Angiogenic Profile in Pregnancies that Remain Normotensive 
Objective
We sought to determine if maternal characteristics are associated with angiogenic profile in the first and second trimester of normotensive pregnancies.
Study Design
Circulating levels of maternal placental like growth factor (PlGF), soluble fms-like tyrosine kinase receptor (sFlt1), and soluble endoglin (sEng) were measured in serum samples collected during the first (median 11.3 weeks) and second trimester (median 17.1 weeks) of 182 normotensive pregnancies. Diastolic blood pressure (DBP), systolic blood pressure (SBP), and mean arterial pressure (MAP) were measured at the same visits when samples were collected to measure angiogenic factors. Linear regression analysis was used to examine associations of the angiogenic measures with maternal characteristics. The association between blood pressure measures and concentrations of angiogenic factors was evaluated using Spearman correlation and linear regression analysis.
Results
In adjusted analyses, nulliparous women had higher sFlt1 concentrations in both first (P=0.06) and second (P=0.001) trimester. Higher BMI was associated with greater sFlt1 concentrations in both the first (P=0.004) and second trimester (P=0.008), but significantly lower sEng concentrations in both trimesters (P=0.002 for first trimester and P=0.0009 for second). Nulliparity and higher BMI also were associated with higher sFlt1/PLGF anti-angiogenic ratios in both first (p=0.05 and p=0.007, respectively) and second trimesters (p=0.003 and p=0.02, respectively). First trimester sFlt1 levels were weakly correlated with first trimester SBP (rs=0.18, p=0.03) and MAP (rs=0.16, p=0.04). Second trimester sEng levels were inversely associated with second trimester MAP (rs= −0.17, p=0.05). Including blood pressure measures in the linear regression models did not change the reported associations of angiogenic factors with maternal characteristics.
Conclusions
These results demonstrate that even early in normotensive pregnancies maternal characteristics are associated with variations in angiogenic profile across this population.
doi:10.1016/j.ejogrb.2011.05.001
PMCID: PMC3302581  PMID: 21641103
Pregnancy; angiogenic factors; sFlt1; PlGF; soluble endoglin; maternal
5.  Preterm Birth, Fetal Growth, and Age at Menarche among Women Exposed Prenatally to Diethylstilbestrol (DES) 
Diethylstilbestrol (DES), a synthetic estrogen used in pregnancy during the 1950s and 1960s, provides a model for potential health effects of endocrine disrupting compounds in the environment. We evaluated prenatal exposure to DES, based on medical record review, in relation to gestational length, fetal growth, and age at menarche in 4429 exposed and 1427 unexposed daughters. DES exposure was associated with an increase in preterm birth (odds ratio (OR) = 2.97; 95%CI=2.27, 3.87), and a higher risk of small for gestational age (SGA) (OR=1.61; 95% CI=1.31,1.98). The association between DES exposure and early menarche was borderline, with stronger effects when early menarche was defined as <= 10 years (OR = 1.41 95%CI=0.97, 2.03) than defined as <= 11 years (OR=1.16; 95%CI=0.97, 1.39). This study provides evidence that prenatal DES exposure was associated with fetal growth and gestational length, which may mediate associations between DES and health outcomes in later life.
doi:10.1016/j.reprotox.2010.11.006
PMCID: PMC3057340  PMID: 21130156
diethylstilbestrol; early life factors; birth weight; small for gestational age; gestational length; menarche; endocrine disruptors
6.  Autoimmune disease incidence among women prenatally exposed to Diethylstilbestrol 
The Journal of rheumatology  2010;37(10):2167-2173.
Objective
Animal studies have suggested that prenatal Diethylstilbestrol (DES) exposure may alter immune system development and function including antigen self-recognition. A cohort study was conducted to investigate whether prenatal DES exposure might influence the incidence of at least some specific autoimmune diseases in women.
Methods
Women who were and were not prenatally exposed to DES have been followed for more than 25 years for numerous health outcomes including autoimmune disease. To verify diagnoses, medical records or physician abstracts were requested for all women who reported a diagnosis of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), optic neuritis (ON) and idiopathic thrombocytopenic purpura (ITP). Incidence rates of these autoimmune diseases were compared between women who were or were not prenatally DES-exposed.
Results
Overall there was no increase in verified autoimmune disease among DES-exposed women relative to those who were not exposed (Relative Rate (RR) = 1.2; 95% Confidence Interval (CI): 0.7, 2.1). There was, however, a positive association between prenatal DES exposure and RA among women younger than 45 years (RR = 4.9; 95% CI: 1.1, 21.6) and an inverse association among women who were 45 years and older (RR = 0.1; 95% CI 0.01, 0.7).
Conclusions
Overall, these data provide little support for an association between prenatal DES exposure and development of autoimmune disease. The implication that such exposure may be related to RA in an unusual age-related manner is based on small numbers of cases and warrants further study.
doi:10.3899/jrheum.091092
PMCID: PMC2988471  PMID: 20634240
Diethylstilbestrol; Prenatal Exposure; Autoimmune Disease; Prospective study
7.  Birth Defects in the Sons and Daughters of Women who were Exposed in utero to Diethylstilbestrol (DES) 
Background
Prenatal exposure to diethylstilbestrol (DES) is associated with adverse health outcomes, including anatomic anomalies of the reproductive tract in women and of the genitourinary tract in men. The mouse model, which replicates many DES-related effects seen in humans, suggests that prenatal DES exposure causes alterations that may affect the next generation of offspring.
Methods
Women participating in a large multi-center study of prenatal DES exposure were asked to report birth defects occurring among 4,029 sons and 3,808 daughters (i.e., the third generation). A subcohort of 793 third generation daughters were also queried for birth defects. We used logistic regression models to generate odds ratios and 95% confidence intervals for the association between prenatal DES exposure in the mother and birth defects in the offspring.
Results
Based on the mothers’ reports, overall birth defects were elevated in the sons (OR = 1.53; 95% CI = 1.04, 2.23) and in the daughters (OR = 2.35; 95% CI = 1.44, 3.82). Most estimates of association were imprecise, but daughters appeared to have an excess of heart conditions (OR = 4.56; 95% CI = 1.27, 16.34.
Conclusions
. Our data suggest a possible association between the mother’s prenatal DES exposure and birth defects in their offspring, particularly in daughters. We cannot, however, rule-out the possible influence of reporting bias. In particular, the exposed daughters’ elevated risk of cardiac defects may be due to the underreporting of these conditions by unexposed mothers.
doi:10.1111/j.1365-2605.2009.01010.x
PMCID: PMC2874639  PMID: 20002218
Diethylstilbestrol; Prenatal exposure; Maternal exposure; Birth defects; Epigenetic alterations
8.  International osteosarcoma incidence patterns in children and adolescents, middle ages, and elderly persons 
Osteosarcoma incidence rates in the United States peak in adolescence and in the elderly. Whereas international patterns of osteosarcoma incidence in children have been described, those for young, middle age, or elderly adults have not. Using the Cancer Incidence in Five Continents, International Agency for Cancer Research (IARC) database we compared incidence rates for children and adolescents (age 0–24), the middle age group (25–59) and elderly (≥60) persons by world regions and individual countries. Overall, worldwide osteosarcoma incidence rates were quite similar in the younger age groups. The greatest variation in incidence rates was observed in the elderly.
doi:10.1002/ijc.24320
PMCID: PMC3048853  PMID: 19330840
osteosarcoma; bone cancer; epidemiology; incidence
9.  Osteosarcoma incidence and survival rates from 1973 to 2004: Data from the Surveillance, Epidemiology, and End Results Program 
Cancer  2009;115(7):1531-1543.
Background
Osteosarcoma, the most common primary bone tumor, occurs most frequently in adolescents, but a second incidence peak among individuals over age 60 exists. Most osteosarcoma epidemiology studies have been embedded in large analyses of all bone tumors, or focused on cases occurring in adolescence. Detailed descriptions of osteosarcoma incidence and survival specifically, with direct comparisons among subjects of all ages and ethnicities, are not available.
Methods
Frequency, incidence and survival rates for 3,482 patients with osteosarcoma from the National Cancer Institute’s population-based Surveillance, Epidemiology, and End Results (SEER) program between 1973 and 2004 are presented by age (0–24, 25–59, and 60–85+ years), race, sex, pathology subtype, stage, and anatomic site.
Results
There were large differences in incidence and survival rates by age. Osteosarcoma incidence in the youngest cases was greatest in the Other race designation, while it was greatest in Blacks and Whites in the middle age and elderly patients, respectively. There was a high percentage of osteosarcoma with Paget’s disease and osteosarcoma as a second or greater cancer among the elderly. Tumor site differences among age groups were noted. Survival rates varied by anatomic site and disease stage, and have not significantly improved from 1984 to 2004.
Conclusions
This comprehensive, population-based description of osteosarcoma, identified important differences in incidence, survival, pathologic subtype, and anatomic site among age groups, and quantified the impact of osteosarcoma in Paget’s disease or as a second cancer on incidence and mortality rates. These findings may have implications in understanding osteosarcoma biology and epidemiology.
doi:10.1002/cncr.24121
PMCID: PMC2813207  PMID: 19197972
osteosarcoma; bone cancer; epidemiology; SEER; incidence; survival
10.  Breast Cancer Screening in Women Exposed In Utero to Diethylstilbestrol 
Journal of Women's Health  2009;18(4):547-552.
Abstract
Purpose
To determine if women exposed in utero to diethylstilbestrol (DES) are more likely than unexposed women to receive recommended or additional breast cancer screening examinations.
Methods
1994 Diethylstilbestrol-Adenosis (DESAD) cohort data are used to assess the degree of recommended compliance of breast cancer screenings found in 3140 DES-exposed and 826 unexposed women. Participants were enrolled at four sites: Houston, Boston, Rochester, and Los Angeles. Logistic regression modeling was used to analyze mailed questionnaire data that included reported frequency over the preceding 5 years (1990–1994) of breast-self examinations (BSEs), clinical breast examinations (CBEs), and mammograms.
Results
DES-exposed women exceeded annual recommendations for CBEs (aOR 2.20, 95% CI, 1.04-4.67) among women without a history of benign breast disease (BBD) compared with unexposed women. There were no other statistically significant differences between exposed and unexposed women who reported performing BSEs, CBEs (<40 years of age), and mammographies, regardless of BBD history.
Conclusions
The majority of DES-exposed women receive breast cancer screenings at least at recommended intervals, but over two thirds do not perform monthly BSEs. Future efforts should be focused on further educating this and other at-risk populations through mailed reminders and during patient consultations on the benefits of screening examinations.
doi:10.1089/jwh.2007.0580
PMCID: PMC2857514  PMID: 19361323
11.  Pregnancy weight gain is not associated with maternal or mixed umbilical cord estrogen and androgen concentrations 
Cancer causes & control : CCC  2008;20(2):263-267.
The association of maternal weight gain with serum hormone concentrations was explored in 75 women who had healthy, singleton pregnancies. Estradiol, estriol, estrone, androstenedione, testosterone, dehydroepiandrosterone (DHEA) and DHEA sulfate concentrations were measured both in maternal and mixed umbilical cord serum to assess hormone levels in both the maternal and fetal circulation at delivery. Our data show no association of maternal or cord steroid hormone concentrations with pregnancy weight gain. Increased exposure to steroid hormones, especially estrogens, during pregnancy has been hypothesized to play a role in subsequent breast cancer risk for both mother and female offspring. Our results are not consistent with an effect of pregnancy weight gain being mediated by this pathway as reflected by hormone concentrations at the end of pregnancy.
doi:10.1007/s10552-008-9235-5
PMCID: PMC2631613  PMID: 18830676
Pregnancy; breast cancer; estrogens; androgens
12.  Blood pressure augmentation and maternal circulating concentrations of angiogenic factors at delivery in preeclamptic and uncomplicated pregnancies 
Objective
The objective of the study was to determine whether blood pressure increases are associated with maternal angiogenic factors in uncomplicated and preeclamptic pregnancies.
Study Design
Associations of blood pressure increases from mid- to late pregnancy with maternal serum concentrations of soluble fms-like tyrosine kinase receptor (sFlt1), soluble endoglin (sEng), and placental growth factor (PlGF) at delivery were analyzed in 43 uncomplicated and 44 preeclamptic pregnancies.
Results
In uncomplicated pregnancies, increases in diastolic and mean arterial pressure were inversely associated with PlGF at delivery and positively associated with sEng and sFlt1/PlGF ratio. There were no significant associations between blood pressure increases and angiogenic factor concentrations in preeclampsia.
Conclusion
These data suggest that angiogenic factors are involved in blood pressure modulation in normotensive pregnancy and are consistent with the hypothesis that angiogenic balance plays a role in maternal breast cancer risk reduction associated with mid- to late blood pressure increases in uncomplicated pregnancies.
doi:10.1016/j.ajog.2008.06.030
PMCID: PMC2646178  PMID: 18722574
angiogenic factors; blood pressure; breast cancer; preeclampsia; pregnancy
13.  Urogenital abnormalities in men exposed to diethylstilbestrol in utero: a cohort study 
Environmental Health  2009;8:37.
Background
Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women during the 1940s-70s, has been shown to cause reproductive problems in the daughters. Studies of prenatally-exposed males have yielded conflicting results.
Methods
In data from a collaborative follow-up of three U.S. cohorts of DES-exposed sons, we examined the relation of prenatal DES exposure to occurrence of male urogenital abnormalities. Exposure status was determined through review of prenatal records. Mailed questionnaires (1994, 1997, 2001) asked about specified abnormalities of the urogenital tract. Risk ratios (RR) were estimated by Cox regression with constant time at risk and control for year of birth.
Results
Prenatal DES exposure was not associated with varicocele, structural abnormalities of the penis, urethral stenosis, benign prostatic hypertrophy, or inflammation/infection of the prostate, urethra, or epididymus. However, RRs were 1.9 (95% confidence interval 1.1-3.4) for cryptorchidism, 2.5 (1.5-4.3) for epididymal cyst, and 2.4 (1.5-4.4) for testicular inflammation/infection. Stronger associations were observed for DES exposure that began before the 11th week of pregnancy: RRs were 2.9 (1.6-5.2) for cryptorchidism, 3.5 (2.0-6.0) for epididymal cyst, and 3.0 (1.7-5.4) for inflammation/infection of testes.
Conclusion
These results indicate that prenatal exposure to DES increases risk of male urogenital abnormalities and that the association is strongest for exposure that occurs early in gestation. The findings support the hypothesis that endocrine disrupting chemicals may be a cause of the increased prevalence of cryptorchidism that has been seen in recent years.
doi:10.1186/1476-069X-8-37
PMCID: PMC2739506  PMID: 19689815
14.  Secondary Sex Ratio among Women Exposed to Diethylstilbestrol in Utero 
Environmental Health Perspectives  2007;115(9):1314-1319.
Background
Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women during the mid-1900s, is a potent endocrine disruptor. Previous studies have suggested an association between endocrine-disrupting compounds and secondary sex ratio.
Methods
Data were provided by women participating in the National Cancer Institute (NCI) DES Combined Cohort Study. We used generalized estimating equations to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the relation of in utero DES exposure to sex ratio (proportion of male births). Models were adjusted for maternal age, child’s birth year, parity, and cohort, and accounted for clustering among women with multiple pregnancies.
Results
The OR for having a male birth comparing DES-exposed to unexposed women was 1.05 (95% CI, 0.95–1.17). For exposed women with complete data on cumulative DES dose and timing (33%), those first exposed to DES earlier in gestation and to higher doses had the highest odds of having a male birth. The ORs were 0.91 (95% C, 0.65–1.27) for first exposure at ≥ 13 weeks gestation to < 5 g DES; 0.95 (95% CI, 0.71–1.27) for first exposure at ≥ 13 weeks to ≥ 5 g; 1.16 (95% CI, 0.96–1.41) for first exposure at < 13 weeks to < 5 g; and 1.24 (95% CI, 1.04–1.48) for first exposure at < 13 weeks to ≥ 5 g compared with no exposure. Results did not vary appreciably by maternal age, parity, cohort, or infertility history.
Conclusions
Overall, no association was observed between in utero DES exposure and secondary sex ratio, but a significant increase in the proportion of male births was found among women first exposed to DES earlier in gestation and to a higher cumulative dose.
doi:10.1289/ehp.10246
PMCID: PMC1964903  PMID: 17805421
diethylstilbestrol; estrogens; endocrine-disrupting chemicals; females; sex ratios

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