Faculty Bibliography

Background:It has been suggested that the relative importance of oestrogen-metabolising pathways may affect the risk of oestrogen-dependent tumours including endometrial cancer. One hypothesis is that the 2-hydroxy pathway is protective, whereas the 16alpha-hydroxy pathway is harmful.Methods:We conducted a case-control study nested within three prospective cohorts to assess whether the circulating 2-hydroxyestrone : 16alpha-hydroxyestrone (2-OHE1 : 16alpha-OHE1) ratio is inversely associated with endometrial cancer risk in postmenopausal women. A total of 179 cases and 336 controls, matching cases on cohort, age and date of blood donation, were included. Levels of 2-OHE1 and 16alpha-OHE1 were measured using a monoclonal antibody-based enzyme assay.Results:Endometrial cancer risk increased with increasing levels of both metabolites, with odds ratios in the top tertiles of 2.4 (95% CI=1.3, 4.6; P(trend)=0.007) for 2-OHE1 and 1.9 (95% CI=1.1, 3.5; P(trend)=0.03) for 16alpha-OHE1 in analyses adjusting for endometrial cancer risk factors. These associations were attenuated and no longer statistically significant after further adjustment for oestrone or oestradiol levels. No significant association was observed for the 2-OHE1 : 16alpha-OHE1 ratio.Conclusion:Our results do not support the hypothesis that greater metabolism of oestrogen via the 2-OH pathway, relative to the 16alpha-OH pathway, protects against endometrial cancer

Introduction: Prospective epidemiologic studies have consistently shown that levels of circulating androgens in postmenopausal women are positively associated with breast cancer risk. However, data in premenopausal women are limited. Methods: A case-control study nested within a prospective cohort, the NYU Women's Health Study, was conducted. A total of 356 cases (276 invasive and 80 in situ) and 683 individually-matched controls (1:2 matching) were included. Matching variables included age and date of blood donation, as well as phase and day of menstrual cycle. Testosterone, androstenedione, dehydroandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG) were measured using direct radioimmunoassays. Free testosterone was calculated. Samples from a second blood donation at a median of 2 years after the first blood donation were also analyzed for 138 cases and 268 controls. Results: Premenopausal serum testosterone and free testosterone concentrations were positively associated with subsequent breast cancer risk. In models adjusted for known risk factors of breast cancer (BMI, age at menarche, family history of breast cancer, parity/age at first birth, and history of breast biopsy), the odds ratios for increasing quintiles of testosterone were 1.0 (reference), 1.5 (95% confidence interval (CI), 0.9-2.3), 1.2 (95% CI, 0.7-1.9), 1.4 (95% CI, 0.9-2.3) and 1.8 (95% CI, 1.1-2.9) with the P value for trend of 0.04, and for free testosterone were 1.0 (reference), 1.2 (95% CI, 0.7-1.8), 1.5 (95% CI, 0.9-2.3), 1.5 (95% CI, 0.9-2.3), and 1.8 (95% CI, 1.1-2.8) with a P value for trend of 0.01). A marginally significant positive association was observed with androstenedione (p = 0.07), but no association with DHEAS or SHBG. Results were consistent in analyses stratified by tumor type (invasive, in situ), estrogen receptor status, age at blood donation, and menopausal status at diagnosis. Intra-class correlation coefficients (ICCs) for measurements of serial annual blood donations from the same !

The objective of this study was to comprehensively compare the genomic profiles in the breast of parous and nulliparous postmenopausal women to identify genes that permanently change their expression following pregnancy. The study was designed as a two-phase approach. In the discovery phase, we compared breast genomic profiles of 37 parous with 18 nulliparous postmenopausal women. In the validation phase, confirmation of the genomic patterns observed in the discovery phase was sought in an independent set of 30 parous and 22 nulliparous postmenopausal women. RNA was hybridized to Affymetrix HG_U133 Plus 2.0 oligonucleotide arrays containing probes to 54,675 transcripts, scanned and the images analyzed using Affymetrix GCOS software. Surrogate variable analysis, logistic regression, and significance analysis of microarrays were used to identify statistically significant differences in expression of genes. The false discovery rate (FDR) approach was used to control for multiple comparisons. We found that 208 genes (305 probe sets) were differentially expressed between parous and nulliparous women in both discovery and validation phases of the study at an FDR of 10% and with at least a 1.25-fold change. These genes are involved in regulation of transcription, centrosome organization, RNA splicing, cell-cycle control, adhesion, and differentiation. The results provide initial evidence that full-term pregnancy induces long-term genomic changes in the breast. The genomic signature of pregnancy could be used as an intermediate marker to assess potential chemopreventive interventions with hormones mimicking the effects of pregnancy for prevention of breast cancer. Cancer Prev Res; 4(9); 1457-64. (c)2011 AACR

BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk

Abstract This study evaluated in vitro immune responses to Escherichia coli lipopolysaccharide in maternal and fetal blood. Samples were concurrently obtained from maternal venipuncture and umbilical cord blood samples and cultured with the E. coli endotoxin, and cytokines were assayed. There were statistically significant correlations between maternal and fetal samples. This demonstrates maternal and fetal immune communication and mutual programming during pregnancy. Subclinical infection, which predisposes to premature labor, could be detectable from a maternal blood sample even if derived only from the fetal compartment. A maternal blood panel test might serve as a diagnostic screen for subclinical infection in patients at risk for preterm labor

Introduction: Myocardial perfusion imaging by single-energy computed tomography (SECT) is based on relative signal attenuation, and cannot directly quantify iodine density. True quantitative assessment of perfusion by direct measurement of specific materials such as iodinated contrast - as may be possible by projection-based dual-energy computed tomography (DECT) - may improve the accuracy and reproducibility of myocardial perfusion imaging by computed tomography. Methods: We determined the accuracy of DECT using material decomposition techniques to measure the absolute iodine density in a myocardial model with normal perfusion and a range of perfusion deficits using a projection-based DECT scanner (GE Discovery CT750HD, GE Healthcare, Waukesha, WI), using ground truth as the reference standard with 0-10% iopamidol concentrations (0-23.5 mg/ml) in 1% increments. Two blinded readers measured 20 consecutive slices for both helical and sequential acquisitions. Correlation and means were compared between DECT and ground truth, and between readers and scan acquisitions. Results: There was excellent correlation (r=0.99, p<0.01) and a small overestimation by DECT measurement of iodine density using the mean of the two acquisitions in comparison to ground truth (11.9+/-7.7 vs. 11.7+/-7.4 mg/dl, p<0.01; mean difference = 0.2+/-0.3 mg/dl) (Figure 1). Inter-scan correlation between acquisitions was excellent (r=0.99, p<0.01), with a higher density measured on sequential vs. helical acquisitions (12.0+/-7.7 vs. 11.8 +/-7.6, p<0.01; mean difference 0.2+/-0.2 mg/ml). Inter-reader correlation was excellent (r=0.99,p<0.01), with a small difference noted between readers (11.8+/-7.6 vs. 11.9+/-7.7 mg/dl, p<0.01; mean difference = 0.1+/-0.2 mg/dl). Conclusion: Projection-based DECT using material decomposition provides direct quantification of iodine density in an accurate and reproducible manner. This may permit true quantitative assessment of myocardial perfusion using DECT (Figure presented)

The association between serum levels of endogenous estrogens in postmenopausal women and the subsequent risk of coronary heart disease (CHD) was examined in a prospective case-control study nested within the New York University Women's Health Study (NYUWHS). The NYUWHS is a prospective cohort study of 14,274 healthy women enrolled between 1985 and 1991. A total of 99 women who were postmenopausal and free of cardiovascular disease at enrollment and who subsequently experienced CHD, defined as non-fatal myocardial infarction (MI), fatal CHD, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass grafting (CABG), were matched 1:2 by baseline age, blood sampling date, and postmenopausal status to controls who remained free of CHD as of the date of diagnosis of the matching case. Biochemical analyses for total estradiol, estrone, percent free estradiol, percent estradiol bound to sex hormone-binding globulin (SHBG), and SHBG were performed on pre-diagnostic stored serum samples. Participants had not used any hormone medications in the 6 months prior to blood collection. In the model adjusting only for matching factors, the risk of CHD in the top tertile of calculated bioavailable estradiol was elevated compared with the bottom tertile (OR=2.10; 95% CI=1.13-3.90, P for trend=0.03), and the risk in the top tertile of SHBG was reduced (OR=0.50, 95% CI=0.28-0.92, P for trend<0.01). However, these associations disappeared after adjusting for baseline hypertension status, body mass index, and serum cholesterol levels. These findings suggest that circulating estradiol and SHBG are not associated with CHD risk in postmenopausal women beyond what can be explained by the variation in hypertension status, BMI, and cholesterol

BACKGROUND: Factors contributing to chronic inflammation appear to be associated with increased risk of ovarian cancer. The purpose of this study was to assess the association between circulating levels of inflammation mediators and subsequent risk of ovarian cancer.METHODS: We conducted a case-control study of 230 cases and 432 individually-matched controls nested within three prospective cohorts to evaluate the association of pre-diagnostic circulating levels of inflammation-related biomarkers (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-13, TNFalpha, IL-1Ra, sIL-1RII, sIL-2Ra, sIL-4R, sIL-6R, sTNF-R1, and sTNF-R2) measured using Luminex xMap technology with risk of ovarian cancer. RESULTS: We observed a trend across quartiles for IL-2 (OR(Q4 vs. Q1): 1.57, 95% CI: 0.98, 2.52, p= 0.07), IL-4 (OR(Q4 vs. Q1): 1.50, 95% CI: 0.95, 2.38, p= 0.06), IL-6 (OR(Q4 vs. Q1): 1.63, 95% CI: 1.03, 2.58, p= 0.03), IL-12p40 (OR(Q4 vs. Q1): 1.60, 95% CI: 1.02, 2.51, p= 0.06), and IL-13 (OR(Q4 vs. Q1): 1.42, 95% CI: 0.90, 2.26, p= 0.11). Trends were also observed when cytokines were modeled on the continuous scale for IL-4 (p-trend=0.01), IL-6 (p-trend=0.01), IL-12p40 (p-trend=0.01), and IL-13 (p-trend=0.04). Odds ratios were not materially different after excluding cases diagnosed less than five years after blood donation or when limited to serous tumors.Conclusions and Impact: This study provides the first direct evidence that multiple inflammation markers, specifically IL-2, IL-4, IL-6, IL-12, and IL-13, may be associated with risk of epithelial ovarian cancer, and adds to the evidence that inflammation is involved in the development this disease

BACKGROUND: Subjects with non-O ABO blood group alleles have increased risk of pancreatic cancer. Glycosyltransferase activity is greater for the A(1) versus A(2) variant, whereas O01 and O02 variants are nonfunctioning. We hypothesized: 1) A(1) allele would confer greater risk than A(2) allele, 2) protective effect of the O allele would be equivalent for O01 and O02 variants, 3) secretor phenotype would modify the association with risk. METHODS: We determined ABO variants and secretor phenotype from single nucleotide polymorphisms in ABO and FUT2 genes in 1,533 cases and 1,582 controls from 12 prospective cohort studies. Adjusted odds ratios (OR) for pancreatic cancer were calculated using logistic regression. RESULTS: An increased risk was observed in participants with A(1) but not A(2) alleles. Compared with subjects with genotype O/O, genotypes A(2)/O, A(2)/A(1), A(1)/O, and A(1)/A(1) had ORs of 0.96 (95% CI, 0.72-1.26), 1.46 (95% CI, 0.98-2.17), 1.48 (95% CI, 1.23-1.78), and 1.71 (95% CI, 1.18-2.47). Risk was similar for O01 and O02 variant O alleles. Compared with O01/O01, the ORs for each additional allele of O02, A(1), and A(2) were 1.00 (95% CI, 0.87-1.14), 1.38 (95% CI, 1.20-1.58), and 0.96 (95% CI, 0.77-1.20); P, O01 versus O02 = 0.94, A(1) versus A(2) = 0.004. Secretor phenotype was not an effect modifier (P-interaction = 0.63). CONCLUSIONS: Among participants in a large prospective cohort consortium, ABO allele subtypes corresponding to increased glycosyltransferase activity were associated with increased pancreatic cancer risk. IMPACT: These data support the hypothesis that ABO glycosyltransferase activity influences pancreatic cancer risk rather than actions of other nearby genes on chromosome 9q34