Search

Purpose: Hysterectomy is associated with subsequent changes in circulating hormone levels, but the evidence of an association for tubal ligation is unclear. We evaluated whether circulating concentrations of androgens and estrogens differ by tubal ligation or hysterectomy status in postmenopausal women from the Women's Health Initiative (WHI)-Observational Study (OS)., Methods: Serum androgens and estrogens were measured in 920 postmenopausal women who did not use menopausal hormone therapy at the time of blood draw, of whom 139 self-reported a history of tubal ligation and 102 reported hysterectomy (with intact ovaries). Geometric mean hormone concentrations (GMs) and 95% confidence intervals (CIs) associated with a history of tubal ligation or hysterectomy (ever/never), as well as time since procedures, were estimated using adjusted linear regression with inverse probability of sampling weights to account for selection., Results: Circulating levels of 12 androgen/androgen metabolites and 20 estrogen/estrogen metabolites did not differ by tubal ligation status. Among women reporting prior hysterectomy compared to women without hysterectomy, we observed lower levels of several androgens (e.g., testosterone (nmol/L): GM yes 0.46 [95% CI:0.37-0.57] vs. GM no 0.62 [95% CI:0.53-0.72]) and higher levels of estrogen metabolites, for example, 2-hydroxyestrone-3-methyl ether (GM yes 11.1 [95% CI:8.95-13.9] pmol/L vs. GM no 8.70 [95% CI:7.38-10.3]) and 4-methoxyestrone (GM yes 6.50 [95% CI:5.05-8.37] vs. GM no 4.92 [95% CI:4.00-6.05])., Conclusion: While we did not observe associations between prior tubal ligation and postmenopausal circulating hormone levels, our findings support that prior hysterectomy was associated with lower circulating testosterone levels and higher levels of some estrogen metabolites, which may have implications for future hormone-related disease risks., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: The Fire service Organizational Culture of Safety (FOCUS) survey is an assessment tool comprised of psychometrically validated metrics of safety climate, safety behavior, and downstream outcomes (organizational and injury) that are specific to the U.S. fire and rescue service., Methods: This analysis consists of a descriptive summary of two independent survey waves (FOCUS 1.0 and 2.0). The fire departments included in these survey waves were from convenience sampling (n 1.0  = 275; n 2.0  = 170). In addition to department level characteristics, we examined individual level characteristics for firefighters and EMS providers in participating departments (n 1.0  = 22,719; n 2.0  = 16,882). We conducted regression analyses to examine the associations between safety climate and safety behaviors, organizational outcomes, and safety outcomes. All analyses were stratified by organization type (career, volunteer)., Results: Our analysis indicated that a majority of respondents were males (90.7% FOCUS 1.0 ; 90.4% FOCUS 2.0 ), non-officers (68.4% FOCUS 1.0 ; 66.4% FOCUS 2.0 ), and non-Hispanic Whites (70.8% FOCUS 1.0 ; 69.5% FOCUS 2.0 ). For both samples there was a higher prevalence of injuries among individuals in career departments (n FOCUS 1.0  = 3778 [17.5%]; n FOCUS 2.0  = 3072 [18.7%]) than volunteer departments (n FOCUS 1.0  = 103 [8.8%]; n FOCUS 2.0  = 34 [7.4%]). We observed an approximate 10-point difference between the mean scores of Management Commitment to Safety for career and volunteer departments in both samples. We observed associations for two organizational outcomes, Safety Behavior and Job Satisfaction, with Management Commitment to Safety and Supervisor Support for Safety overall and when stratified by organization type. We observed a decrease in the odds of injuries associated with a one-unit increase in Management Commitment to Safety (OR 1.0 overall : 0.98, 95% CI 0.97-0.99; OR 2.0 volunteer : 0.90, 95% CI 0.85-0.95) and Supervisor Support for Safety (OR 1.0 overall : 0.95, 95% CI 0.93-0.97; OR 1.0 career : 0.95, 95% CI 0.92-0.98)., Conclusions: From our current study, and a prior analysis of a geographically stratified random sample of U.S. fire departments, we identified that from all the organizational outcomes, job satisfaction was most consistently associated with FOCUS safety climate. Further, firefighters in our samples consistently rated Supervisor Support for Safety higher than Management Commitment to Safety. Future interventions should support fire departments in improving their departmental Management Commitment to Safety and maintaining their Supervisor for Safety., (© 2024. The Author(s).)

Objective: The US fire service experienced increased demands due to COVID-19. This qualitative study explored the pandemic's impact on work-life balance and safety., Methods: Five interviews and 10 focus groups were conducted with 15 fire departments in the COVID-19 RAPID Mental Health Assessment. Coding and multilevel content analysis were conducted in NVivo., Results: Four department support themes were identified: emotional/social (33.1%), policy (28.4%), instrumental (22.9%), and informational (15.5%). Four work-life balance themes were identified: life (51.2%), children (18.1%), physiological (16.5%), and work (14.2%). We observed more departmental resources to help mitigate job demands within the work environment compared with those for work-life demands., Conclusions: Job resources are needed to mitigate demands and improve safety culture and mental well-being of the fire service under normal conditions, and for the next pandemic, natural disaster, or long-term emergency., Competing Interests: Conflict of interest: None declared., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Occupational and Environmental Medicine.)

Background: Hair relaxers and skin lighteners have been commonly used by African women, with suggestions that they may have hormonal activity., Objectives: To investigate the relationship of hair relaxer and skin lightener use to serum estrogen/estrogen metabolite levels., Methods: We utilized the postmenopausal population-based controls of the Ghana Breast Health Study to estimate adjusted geometric means (GM) and 95% confidence intervals of individual circulating estrogen levels by hair relaxer/skin lightener exposure categories., Results: Of the 585 postmenopausal women included in our analysis, 80.2% reported hair relaxer use and 29.4% skin lightener use. Ever hair relaxer use was positively associated with estriol (adjusted GM 95.4 pmol/L vs. never 74.5, p value = 0.02) and 16-epiestriol (20.4 vs. 16.8, p value = 0.05) particularly among users of lye-based hair relaxers. Positive associations between scalp burns and unconjugated estrogens were observed (e.g., unconjugated estrone: 5+ scalp burns 76.9 [59.6-99.2] vs. no burns 64.0 [53.7-76.3], p-trend = 0.03). No association was observed between use of skin lighteners and circulating estrogens., Significance: This study presents evidence that circulating 16-pathway estrogens (i.e., estriol and 16-epiestriol) may be increased in users of lye-based hair relaxer products. Among hair relaxer users, unconjugated estrogen levels were elevated in women with a greater number of scalp burns., Impact Statement: In this population-based study of hair relaxer and skin lightener use among postmenopausal women in Ghana, altered estrogen metabolism was observed with hair relaxer use, particularly among women using lye-based products or with a greater number of scalp burns. In contrast, skin lightener use was not associated with differences in estrogen metabolism in this population. Continued investigation of the potential biological impact on breast cancer risk of hair relaxer use is warranted., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Purpose: The American Cancer Society (ACS) published an updated Guideline for Cancer Prevention (ACS Guideline) in 2020. Research suggests that adherence to the 2012 ACS Guideline might lower breast cancer risk, but there is limited evidence that this applies to women at increased familial and genetic risk of breast cancer., Methods: Using the Breast Cancer Family Registry (BCFR), a cohort enriched for increased familial and genetic risk of breast cancer, we examined adherence to three 2020 ACS Guideline recommendations (weight management (body mass index), physical activity, and alcohol consumption) with breast cancer risk in 9615 women. We used Cox proportional hazard regression modeling to calculate hazard ratios (HRs) and 95% confidence intervals (CI) overall and stratified by BRCA1 and BRCA2 pathogenic variant status, family history of breast cancer, menopausal status, and estrogen receptor-positive (ER +) breast cancer., Results: We observed 618 incident invasive or in situ breast cancers over a median 12.9 years. Compared with being adherent to none (n = 55 cancers), being adherent to any ACS recommendation (n = 563 cancers) was associated with a 27% lower breast cancer risk (HR = 0.73, 95% CI: 0.55-0.97). This was evident for women with a first-degree family history of breast cancer (HR = 0.68, 95% CI: 0.50-0.93), women without BRCA1 or BRCA2 pathogenic variants (HR = 0.71, 95% CI: 0.53-0.95), postmenopausal women (HR = 0.63, 95% CI: 0.44-0.89), and for risk of ER+ breast cancer (HR = 0.63, 95% CI: 0.40-0.98)., Discussion: Adherence to the 2020 ACS Guideline recommendations for BMI, physical activity, and alcohol consumption could reduce breast cancer risk for postmenopausal women and women at increased familial risk., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Safety climate is an upstream predictor of safety behaviors (e.g., safety compliance), organizational outcomes (e.g., burnout, engagement), and safety outcomes (e.g., injuries). The Fire Service Organizational Culture of Safety (FOCUS) survey, which was psychometrically validated, measures the industry-specific safety climate of the US fire and rescue service. It is expressed by two factors, Management Commitment to Safety and Supervisor Support for Safety., Methods: The FOCUS beta-test included a random sample of 132 fire departments stratified by Federal Emergency Management Agency region and organization type (career, combination, volunteer). We conducted descriptive analysis with the responses from 8414 firefighters nested within 611 stations in 125 fire departments. We reported descriptive statistics to assess the distribution of all continuous [mean ± standard deviation (SD)] and categorical variables (counts, percentages) stratified by organization type. Regression analyses were conducted to investigate the associations between safety climate, safety behaviors, organizational outcomes, and safety outcomes stratified by organization type., Results: The mean age of the analytic sample was 40.2 years, and the mean years of experience was 16.1 years. This sample included 53.6% career, 27.2% combination (career and volunteer), and 19.2% volunteer fire departments. The mean Management Commitment score was 71.4 (SD =  ± 10.4), and the mean Supervisor Support score was 81.7 (± 5.2). The mean Management Commitment scores were 67.1 (± 8.4), 72.2 (± 10.7), and 82.1 (± 6.1), respectively, for career, combination, and volunteer fire departments. The mean Supervisor Support scores were not notably different by organization type. Regression analyses generally supported the beneficial role of safety climate, while suggesting organization type as a potential effect modifier. Specifically, we observed a more negative association between Management Commitment as departments became more career., Conclusions: Analysis of nationally representative data from the US fire and rescue service indicates safety climate is positively associated with safety behavior, organizational outcomes, and safety outcomes reflecting employee well-being. The findings also suggest that this association varies by organization type. In fact, a dose-response relationship was observed, with Management Commitment to safety lowest among career departments. Thus, our results suggest that it is not just being busy that decreases Management Commitment., (© 2022. The Author(s).)

Background: Several anthropometric measures have been associated with hormone-related cancers, and it has been shown that estrogen metabolism in postmenopausal women plays an important role in these relationships. However, little is known about circulating estrogen levels in African women, and the relevance to breast cancer or breast cancer risk factors. To shed further light on the relationship of anthropometric factors and estrogen levels in African women, we examined whether measured body mass index (BMI), waist-to-hip ratio (WHR), height, and self-reported body size were associated with serum estrogens/estrogen metabolites in a cross-sectional analysis among postmenopausal population-based controls of the Ghana Breast Health Study., Methods: Fifteen estrogens/estrogen metabolites were quantified using liquid chromatography-tandem mass spectrometry in serum samples collected from postmenopausal female controls enrolled in the Ghana Breast Health Study, a population-based case-control study conducted in Accra and Kumasi. Geometric means (GMs) of estrogens/estrogen metabolites were estimated using linear regression, adjusting for potential confounders., Results: Measured BMI (≥ 30 vs. 18.5-24.9 kg/m 2 ) was positively associated with parent estrogens (multivariable adjusted GM for unconjugated estrone: 78.90 (66.57-93.53) vs. 50.89 (43.47-59.59), p-value < 0.0001; and unconjugated estradiol: 27.83 (21.47-36.07) vs. 13.26 (10.37-16.95), p-value < 0.0001). Independent of unconjugated estradiol, measured BMI was associated with lower levels of 2-pathway metabolites and higher levels of 16-ketoestradriol. Similar patterns of association were found with WHR; however, the associations were not entirely independent of BMI. Height was not associated with postmenopausal estrogens/estrogen metabolite levels in African women., Conclusions: We observed strong associations between measured BMI and parent estrogens and estrogen metabolite patterns that largely mirrored relations that have previously been associated with higher breast cancer risk in postmenopausal White women. The consistency of the BMI-estrogen metabolism associations in our study with those previously noted among White women suggests that estrogens likely explain part of the BMI-postmenopausal breast cancer risk in both groups. These findings merit evaluation in Black women, including prospective studies., (© 2022. The Author(s).)

Background: Postmenopausal pregnenolone and/or progesterone levels in relation to endometrial and ovarian cancer risks have been infrequently evaluated. To address this, we utilized a sensitive and reliable assay to quantify prediagnostic levels of seven markers related to endogenous hormone metabolism., Methods: Hormones were quantified in baseline serum collected from postmenopausal women in a cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (B∼FIT). Women using exogenous hormones at baseline (1992-1993) were excluded. Incident endometrial ( n = 65) and ovarian ( n = 67) cancers were diagnosed during 12 follow-up years and compared with a subcohort of 345 women (no hysterectomy) and 413 women (no oophorectomy), respectively. Cox models with robust variance were used to estimate cancer risk., Results: Circulating progesterone levels were not associated with endometrial [tertile (T)3 vs. T1 HR (95% confidence interval): 1.87 (0.85-4.11); P trend = 0.17] or ovarian cancer risk [1.16 (0.58-2.33); 0.73]. Increasing levels of the progesterone-to-estradiol ratio were inversely associated with endometrial cancer risk [T3 vs. T1: 0.29 (0.09-0.95); 0.03]. Increasing levels of 17-hydroxypregnenolone were inversely associated with endometrial cancer risk [0.40 (0.18-0.91); 0.03] and positively associated with ovarian cancer risk [3.11 (1.39-6.93); 0.01]., Conclusions: Using sensitive and reliable assays, this study provides novel data that endogenous progesterone levels are not strongly associated with incident endometrial or ovarian cancer risks. 17-hydroxypregnenolone was positively associated with ovarian cancer and inversely associated with endometrial cancer., Impact: While our results require replication in large studies, they provide further support of the hormonal etiology of endometrial and ovarian cancers., (©2021 American Association for Cancer Research.)

Background: The role of progestogens in colorectal cancer development is poorly characterized. To address this, our group developed a highly sensitive assay to measure concentrations of seven markers of endogenous progestogen metabolism among postmenopausal women., Methods: The markers were measured in baseline serum collected from postmenopausal women in a case-cohort study within the breast and bone follow-up to the fracture intervention trial (B∼FIT). We followed women not using exogenous hormones at baseline (1992-1993) for up to 12 years: 187 women with incident colorectal cancer diagnosed during follow-up and a subcohort of 495 women selected on strata of age and clinical center. We used adjusted Cox regression models with robust variance to estimate risk for colorectal cancer [hazard ratios (HR), 95% confidence intervals (CI)]., Results: High concentrations of pregnenolone and progesterone were not associated with colorectal cancer [quintile(Q)5 versus Q1: pregnenolone HR, 0.71, 95% CI, 0.40-1.25; progesterone HR, 1.25; 95% CI, 0.71-2.22]. A trend of increasing risk was suggested, but statistically imprecise across quintiles of 17-hydroxypregnenolone (Q2 to Q5 HRs, 0.75-1.44; P trend , 0.06)., Conclusions: We used sensitive and reliable assays to measure multiple circulating markers of progestogen metabolism. Progestogens were generally unassociated with colorectal cancer risk in postmenopausal women., Impact: Our findings are consistent with most prior research on circulating endogenous sex hormones, which taken together suggest that sex hormones may not be major drivers of colorectal carcinogenesis in postmenopausal women., (©2021 American Association for Cancer Research.)

Background: In the USA, it is unknown whether metastatic prostate cancer incidence has continued to increase and whether racial differences have persisted., Objective: Combining multiple imputation with age and delay adjustment, we provide an up-to-date, comprehensive assessment of US prostate cancer incidence trends by stage and race., Design, Setting, and Participants: From Surveillance Epidemiology and End Results (SEER)-18, 774 240 prostate cancer cases were diagnosed during 2004-2017., Outcome Measurements and Statistical Analysis: Multiple imputation assigned prostate cancer stage to the 4.7% of cases with missing stage, which varied by year and race-ethnicity. SEER delay factors adjusted case counts to anticipated future data corrections. Twenty datasets were imputed, and Rubin's rules were used for summary estimation. Overall and stage-specific rates were estimated and stratified by race and age group. Joinpoint software identified significant temporal changes and estimated annual percentage changes. We compared these estimates without multiple imputation and delay adjustment., Results and Limitations: Metastatic prostate cancer incidence increased during 2011-2017, with an annual percentage change of 5.5. This was followed by increases in localized and regional disease since 2014. Non-Hispanic black men continued to have the highest incidence, especially for metastatic disease. The increasing rate of metastatic prostate cancer in non-Hispanic white men aged 50-74 yr accelerated recently, and the incidence was 56% higher in 2017 than in 2004. Rates without multiple imputation and delay adjustment were quantitatively and qualitatively different. This observational study is unable to assign causes to observed changes in prostate cancer incidence., Conclusions: Multiple imputation and delay adjustment are essential for portraying accurately stage- and race-specific prostate cancer incidence as clinical practice evolves., Patient Summary: In the USA, diagnosis of prostate cancer that has spread to distant sites (metastatic disease) continues to increase. Black men continue to have higher risks of being diagnosed with metastatic prostate cancer than other race-ethnicities., (Published by Elsevier B.V.)

Background: Despite the high incidence and mortality of prostate cancer (PCa) in the Unites States, few risk factors have been consistently linked with these PCa outcomes. Assessing proxies of reproductive factors may offer insights into PCa pathogenesis. In this study, we examined fatherhood status as a proxy of fertility in relation to total, nonaggressive, aggressive, and fatal PCa., Methods: We examined participants of two cohorts, the NIH-AARP Diet and Health (NIH-AARP) Study and Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals of associations between fatherhood status and number of children sired in relation to PCa incidence., Results: Fatherhood status (one or more children vs. childless) was positively associated with total PCa risk in NIH-AARP or PLCO, but was not statistically significant (p = 0.06 and 0.55, respectively). Number of children sired indicated a slightly elevated risk of total PCa, but HRs were rarely significant and were of a fairly constant magnitude with no discernable trend relative to the childless referent group. Associations were similar for nonaggressive and aggressive PCa. The trend test for fatal PCa was statistically significant in NIH-AARP (p trend  < 0.01), despite none of the individual categorical point estimates reaching this threshold., Conclusion: This study provides tentative evidence that fathering children is associated with a slightly increased PCa risk. Future research should strive to assess better proxies of reproductive function in relation to aggressive and fatal PCa to provide more specific evidence for this putative relationship., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Importance: The role of endogenous progesterone in the development of breast cancer remains largely unexplored to date, primarily owing to assay sensitivity limitations and low progesterone concentrations in postmenopausal women. Recently identified progesterone metabolites may provide insights as experimental data suggest that 5α-dihydroprogesterone (5αP) concentrations reflect cancer-promoting properties and 3α-dihydroprogesterone (3αHP) concentrations reflect cancer-inhibiting properties., Objective: To evaluate the association between circulating progesterone and progesterone metabolite levels and breast cancer risk., Design, Setting, and Participants: Using a sensitive liquid chromatography-tandem mass spectrometry assay, prediagnostic serum levels of progesterone and progesterone metabolites were quantified in a case-cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (n = 15 595). Participation was limited to women not receiving exogenous hormone therapy at the time of blood sampling (1992-1993). Incident breast cancer cases (n = 405) were diagnosed during 12 follow-up years and a subcohort of 495 postmenopausal women were randomly selected within 10-year age and clinical center strata. Progesterone assays were completed in July 2017; subsequent data analyses were conducted between July 15, 2017, and December 20, 2018., Exposures: Circulating concentrations of pregnenolone, progesterone, and their major metabolites., Main Outcomes and Measures: Development of breast cancer, with hazard ratios (HRs) and 95% CIs was estimated using Cox proportional hazards regression adjusted for key confounders, including estradiol. Evaluation of hormone ratios and effect modification were planned a priori., Results: The present study included 405 incident breast cancer cases and a subcohort of 495 postmenopausal women; the mean (SD) age at the time of the blood draw was 67.2 (6.2) years. Progesterone concentrations were a mean (SD) of 4.6 (1.7) ng/dL. Women with higher circulating progesterone levels were at an increased risk for breast cancer per SD increase in progesterone levels (HR, 1.16; 95% CI, 1.00-1.35; P = .048). The association with progesterone was linear in a 5-knot spline and stronger for invasive breast cancers (n = 267) (HR, 1.24; 95% CI, 1.07-1.43; P = .004). Among women in the lowest quintile (Q1) of circulating estradiol (<6.30 pg/mL) elevated progesterone concentrations were associated with reduced breast cancer risk per SD increase in progesterone levels (HR, 0.38; 95% CI, 0.15-0.95; P = .04) and increased risk among women in higher quintiles of estradiol (Q2-Q5; ≥6.30 pg/mL) (HR, 1.18; 95% CI, 1.04-1.35; P = .01; P = .04 for interaction)., Conclusions and Relevance: In this case-cohort study of postmenopausal women, elevated circulating progesterone levels were associated with a 16% increase in the risk of breast cancer. Additional research should be undertaken to assess how postmenopausal breast cancer risk is associated with both endogenous progesterone and progesterone metabolites and their interactions with estradiol.

Our knowledge of epidemiologic risk factors for ovarian cancer supports a role for androgens in the pathogenesis of this disease; however, few studies have examined associations between circulating androgens and ovarian cancer risk. Using highly sensitive LC-MS/MS assays, we evaluated associations between pre-diagnostic serum levels of 12 androgens, including novel androgen metabolites that reflect androgen activity in tissues, and ovarian cancer risk among postmenopausal women in a nested case-control study in the Women's Health Initiative (WHI) Observational Study (OS). We frequency-matched 169 ovarian cancer cases to 410 controls from women enrolled in WHI-OS who were not using menopausal hormones at enrollment/blood draw. We estimated associations overall and by subtype (n = 102 serous/67 non-serous) using multivariable adjusted logistic regression. Androgen/androgen metabolite levels were not associated with overall ovarian cancer risk. In analyses by subtype, women with increased levels of androsterone-glucuronide (ADT-G) and total 5-α reduced glucuronide metabolites (markers of tissue-level androgenic activity) were at increased risk of developing non-serous ovarian cancer: ADT-G tertile (T)3 versus T1 odds ratio [OR] (95% confidence interval [CI]) 4.36 (1.68-11.32), p-heterogeneity 0.002; total glucuronide metabolites 3.63 (1.47-8.95), 0.002. Risk of developing serous tumors was unrelated to these markers. ADT-G and total glucuronide metabolites, better markers of tissue-level androgenic activity in women than testosterone, were associated with an increased risk of developing non-serous ovarian cancer. Our work demonstrates that sex steroid metabolism is important in the etiology of non-serous ovarian cancers and supports a heterogeneous hormonal etiology across histologic subtypes of ovarian cancer., (© 2019 UICC.)

Frequent detection of serous tubal intraepithelial carcinoma (STIC) among BRCA1/ 2 mutation carriers undergoing risk-reducing surgery prompted the hypothesis that many adnexal high-grade serous carcinomas (HGSCs) arise from the fallopian tube, rather than the ovary, as supposed. The changing paradigm has important implications for HGSC prevention. Most data related to the frequency of STIC are derived from case series and estimates vary widely. Therefore, we analyzed population-based data from 10 523 surgeries including salpingectomy (Jan 2014-Dec 2016) that were examined using the "Sectioning and Extensively Examining the Fimbria" protocol, which optimizes STIC detection. Overall, STIC was detected in 40 (0.38%) specimens, including 32 diagnosed with concurrent gynecologic cancer. STIC was detected in 8 (<0.01%) of 9392 cases with benign diagnoses. We conclude that the relative rarity of STIC diagnoses in routine pathology practice has critical implications for research aiming to elucidate the pathogenesis of HGSC and developing prevention strategies.