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2.  Colon cancer lymph node evaluation among Military Health System beneficiaries: An analysis by race/ethnicity 
Annals of surgical oncology  2014;22(1):195-202.
The number of lymph nodes examined during colon cancer surgery falls below nationally recommended guidelines in the general population, with blacks and Hispanics less likely to have adequate nodal evaluation in comparison to whites. The Department of Defense’s (DoD’s) Military Health System (MHS) provides equal access to medical care for its beneficiaries, regardless of racial/ethnic background. This study aimed to investigate whether racial/ethnic treatment differences exist in the MHS, an equal access medical care system.
Linked data from the DoD cancer registry and administrative claims databases were used and included 2,155 colon cancer cases. Multivariate logistic regression assessed the association between race/ethnicity and the number of lymph nodes examined (<12 and ≥ 12) overall and for stratified analyses.
No overall racial/ethnic difference in the number of lymph nodes examined was identified. Further stratified analyses yielded similar results, except potential racial/ethnic differences were found among persons with poorly differentiated tumors, where non-Hispanic blacks (NHBs) tended to be less likely to have ≥12 lymph nodes dissected (OR: 0.34, 95% CI: 0.14-0.80, p-value: 0.01) compared to non-Hispanic whites.
Racial/ethnic disparities in the number of lymph nodes evaluated among patients with colon cancer were not apparent in an equal-access healthcare system. However, among poorly differentiated tumors, there might be racial/ethnic differences in nodal yield, suggesting the possible effects of factors other than access to healthcare.
PMCID: PMC4275347  PMID: 25059789
3.  Association between endogenous sex steroid hormones and inflammatory biomarkers in US men 
Andrology  2013;1(6):10.1111/j.2047-2927.2013.00129.x.
Sex steroid hormones and inflammatory biomarkers are both associated with the development and progression of chronic diseases, but their interrelationship is relatively uncharacterized. We examined the association of sex hormones and sex hormone binding globulin (SHBG) with biomarkers of inflammation, C-reactive protein (CRP) and white blood cell (WBC) count. The study included data from 809 adult men in the National Health and Nutrition Examination Survey 1999–2004. Geometric means and 95% confidence intervals were estimated separately for CRP and WBC concentrations by sex steroid hormones and SHBG using weighted linear regression models. Higher concentrations of total (slope per 1 quintile in concentration, −0.18; P-trend, 0.001) and calculated free (slope, −0.13; P-trend, 0.03) testosterone were statistically significantly associated with lower concentrations of CRP, but not with WBC count. Men in the bottom quintile of total testosterone (≤3.3 ng/mL), who might be considered to have clinically low testosterone, were more likely to have elevated CRP (≥ 3 mg/L) compared to men in the top four quintiles (OR, 1.61; 95% CI, 1.00 – 2.61). Total and calculated free estradiol (E2) were positively associated with both CRP (Total E2: slope, 0.14; P-trend, <0.001; Free E2: slope, 0.15; P-trend, <0.001) and WBC (Total E2: slope, 0.02; P-trend, 0.08; Free E2: slope, 0.02; P-trend, 0.02) concentrations. SHBG concentrations were inversely associated with WBC count (slope, −0.03; P-trend, 0.04), but not with CRP. These cross-sectional findings are consistent with the hypothesis that higher androgen and lower estrogen concentrations may have an anti-inflammatory effect in men.
PMCID: PMC3812341  PMID: 24124163
testosterone; estradiol; C-reactive protein; white blood cell; cross-sectional study
4.  Viral hepatitis markers in liver tissue in relation to serostatus in hepatocellular carcinoma 
Hepatocellular carcinoma (HCC) incidence is rising in the United States. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are major causes of HCC. Hepatitis infection in HCC patients is generally diagnosed by serology, which is not always consistent with the presence of HBV and HCV in the liver. The relationship of liver viral status to serostatus in hepatocarcinogenesis is not fully understood.
HBV and HCV were evaluated in formalin-fixed paraffin-embedded liver tissue specimens in a retrospective study of 61 U.S. HCC cases of known serologic status. HBV DNA and HCV RNA were detected by PCR, RT-PCR and pyrosequencing, and HBsAg and HBcAg were evaluated by immunohistochemistry.
Viral markers were detected in the liver tissue of 25 of 61 (41%) HCC cases. Tissue viral and serologic status were discordant in 27 (44%) cases, including those with apparent “occult” infection. Specifically, HBV DNA was detected in tissue of 4 of 39 (10%) serum HBsAg (−) cases, including 1 anti-HCV(+) case; and HCV RNA was detected in tissue of 3 of 42 (7%) anti-HCV seronegative cases, including 2 with serologic evidence of HBV.
Viral hepatitis, including HBV-HCV coinfection, may be unrecognized in up to 17% of HCC patients when based on serology alone. Further research is needed to understand the clinical significance of viral makers in liver tissue of HCC patients in the absence of serologic indices.
The contribution of HBV and HCV to the rising incidence of HCC in the United States may be underestimated.
PMCID: PMC3818344  PMID: 23983238
hepatitis; HBV; HCV; occult; hepatocellular carcinoma
5.  Congenital malformations and testicular germ cell tumors 
Cryptorchidism is one of the few known risk factors for testicular germ cell tumors (TGCT). It has been postulated that other congenital malformations, in particular hypospadias, are also associated with increased risk; however, associations with birth defects have not been extensively studied. Using Swedish population-based registries we evaluated the relationship between birth defects and risk of TGCT. TGCT cases (n=6,593) diagnosed between 15 and 65 years of age were identified from the Swedish Cancer Registry between 1964 and 2008. Five controls per case were randomly selected from the population register and matched on birth year and birth county. Congenital malformations were identified via linkage with the Hospital Discharge Register. Odds ratios (OR) and 95% confidence intervals (CI) for the association between each group of malformations and TGCT were estimated using conditional logistic regression. In addition to the expected association between cryptorchidism and TGCT risk [OR (95% CI): 3.18 (2.50 to 4.04)], hypospadias [2.41 (1.27 to 4.57)], inguinal hernia [1.37 (1.11–1.68)] and other genital malformations [2.19 (1.17 to 4.10)] were associated with an increased risk of TGCT. Mutual adjustment for cryptorchidism, hypospadias, inguinal hernia, and other genital malformations did not appreciably change the associations (ORs: 3.16; 2.25; 1.30; 1.90, respectively). The other (non-genital) malformations evaluated were not associated with TGCT. These data suggest that developmental urogenital abnormalities, specifically cryptorchidism, hypospadias, and inguinal hernia, are associated with an increased risk of TGCT; further supporting the hypothesis that prenatal exposure(s) related to proper genital development are related to this tumor.
PMCID: PMC4037852  PMID: 23580254
congenital malformations; testicular germ cell tumors; hypospadias; cryptorchidism
6.  Surveillance mammography among female DoD beneficiaries: a study by race and ethnicity 
Cancer  2013;119(19):3531-3538.
Annual surveillance mammography is recommended after breast cancer diagnosis. Previous studies have suggested that surveillance mammography varies by demographics and initial tumor characteristics, which are related to access to healthcare. The Department of Defense's Military Health System (MHS) provides beneficiaries with equal healthcare access and thus offers an excellent opportunity to assess whether racial differences in surveillance mammography persist when access to care is equal.
Among female beneficiaries with a history of breast cancer logistic regression was used to assess racial/ethnic variation in surveillance mammography during three 12-month periods, beginning one year after diagnosis adjusting for demographic, tumor and health characteristics.
Overall surveillance mammography decreased from 70% during the first year to 59% during the third year (p<0.01). Although there was an overall tendency for surveillance mammography to be higher among minority women compared to non-Hispanic white women, after adjusting for covariates, the difference was significant only during the first year among blacks (odds ratio (OR)=1.46; 95% Confidence Interval (CI)=1.10-1.95) and the second year among Asian Pacific Islanders (OR=2.29; 95%CI=1.52-3.44) and Hispanics (OR=1.92; 95%CI=1.17-3.18). When stratified by age at diagnosis and type of breast cancer surgery, significant racial differences tended to be observed among younger women (<50 years) and only among women who had mastectomies.
Minority women were equally or more likely than non-Hispanic white women to receive surveillance mammography within the MHS. The racial disparities in surveillance mammography reported in other studies were not observed in a system with equal access to care.
PMCID: PMC3787997  PMID: 23913448
breast cancer; mammography; surveillance; survivor; epidemiology; healthcare access
7.  Breast reconstruction after mastectomy among Department of Defense beneficiaries by race 
Cancer  2014;120(19):3033-3039.
Post-mastectomy breast reconstruction increased approximately 20% between 1998 and 2008 in the United States and has been found to improve body image, self-esteem and quality of life. These procedures, however, tend to be less common among minority women, which may be due to variations in healthcare access. The Department of Defense (DoD) provides equal healthcare access, thereby affording an exceptional environment to assess whether racial variations persist when access to care is equal.
Linked DoD cancer registry and medical claims data were used. The receipt of reconstruction was compared between white (n=2,974) and black women (n=708) who underwent mastectomies to treat incident, histologically-confirmed, breast cancer diagnosed from 1998 to 2007.
During the study period, post-mastectomy reconstruction increased among both black (27.3% to 40.0%) and white (21.8% to 40.6%) female breast cancer patients. Receipt of reconstruction did not vary significantly by race (odds ratio: 0.93; 95% confidence interval 0.76-1.15). Reconstruction decreased significantly with increasing age, tumor stage and receipt of radiotherapy and was significantly more common in more recent years, among active servicewomen, Tricare Prime (HMO) beneficiaries and women whose sponsor was an officer.
The receipt of reconstruction did not vary by race within this equal access health system, indicating that the racial disparities reported in previous studies may have partially been due to variations in healthcare access. Additional research to determine why a large proportion of breast cancer patients do not undergo reconstruction might be beneficial, particularly because these procedures have been associated with non-cosmetic benefits.
PMCID: PMC4172542  PMID: 24965236
breast cancer; mastectomy; reconstruction; racial disparities; epidemiology; healthcare access
8.  Lung cancer survival among black and white patients in an equal access health system 
Racial disparities in lung cancer outcomes have been observed in the general population. However, it is unclear whether survival differences persist when patients have equal access to healthcare. Our objective was to determine if lung cancer survival differed among black and white patients in the U.S. Military Health System (MHS), an equal access healthcare system.
The study subjects were 10,181 black and white patients identified through the Department of Defense’s Automated Central Tumor Registry, who were ≥20 years old and diagnosed with lung cancer between 1990 and 2003. Racial differences in all-cause survival were examined using the Kaplan–Meier method and Cox proportional hazards regression models stratified by histology. For comparison, survival rates in the general population were calculated using Surveillance, Epidemiology and End Results (SEER)-9 data.
Analyses included 9,154 white and 1,027 black patients: 1,834 small cell lung cancers, 3,876 adenocarcinomas, 2,741 squamous cell carcinomas, and 1,730 large cell carcinomas. Although more favorable crude survival was observed among black patients than white patients with small cell lung cancer (p=0.04), survival was similar between the two groups after covariate adjustment. Racial differences in survival were non-significant for adenocarcinomas, squamous cell carcinomas and large cell carcinomas. Survival rates appeared to be better in the MHS than in the general population.
Conclusions and Impact
All-cause survival was similar among black and white lung cancer patients in the MHS. Providing equal access to healthcare may eliminate racial disparities in lung cancer survival while improving the outcome of all cases.
PMCID: PMC4151240  PMID: 22899731
equal access to healthcare; histologic subtypes; lung cancer; racial disparity; survival
9.  Trends in Testicular Germ Cell Tumors Among U.S. Military Servicemen, 1990–2003 
Military medicine  2011;176(10):1184-1187.
To determine the incidence of testicular germ cell tumors among active duty males and compare it with the incidence in the general U.S. population.
The Automated Cancer Tumor Registry and the Surveillance, Epidemiology, and End Results Program data from 1990 to 2003 were analyzed for men aged between 20 and 59 years by histology and stage at diagnosis. Rates were age adjusted using the male active duty military population as the standard.
Nonseminoma incidence was significantly lower in the military than in the general population (incidence rate ratio = 0.90, 95% confidence interval = 0.82-0.98). Trends in incidence tended to be similar in both the populations. Increases were observed for both histologic types but were only significant for seminoma (Automated Cancer Tumor Registry: 21% and Surveillance, Epidemiology, and End Results program: 16%; p < 0.05). Increases in incidence were only observed for localized tumors of both histologic types.
The lower incidence of nonseminoma in the military and the increased incidence of localized tumors in both populations remain unexplained.
PMCID: PMC4148906  PMID: 22128656
10.  Mammography Screening by Race/Ethnicity Among U.S. Servicewomen, 2009–2010 
Military medicine  2012;177(12):1513-1518.
Mammography screening has been shown to vary by race/ethnicity and is often thought to result from variations in access to healthcare. The objective of this study was to compare the prevalence of recent mammography screening among U.S. active duty servicewomen by race/ethnicity using administrative claim data from the Military Health System, which provides beneficiaries with equal access to medical care.
Mammography screening use during fiscal years 2009-2010 among non-Hispanic white, non-Hispanic black, Asian/Pacific Islander (API) and Hispanic servicewomen was analyzed using logistic regression.
Overall the prevalence of mammography screening during the study period was 61%. In comparison to non-Hispanic white servicewomen, API (OR=1.08; 95% CI=0.94-1.23) and Hispanic servicewomen (OR=0.97; 95% CI=0.85-1.11) were as likely and non-Hispanic black servicewomen were more likely to have a screening mammogram (OR=1.09; 95% CI=1.01-1.18). Screening mammography also increased with age, was highest in the Navy, was higher among officers than enlisted personnel, and did not differ by marital status.
Although screening was slightly higher for non-Hispanic blacks than non-Hispanic whites, in general, racial/ethnic differences in mammography screening were not substantial in an equal access system.
PMCID: PMC4148909  PMID: 23397698
11.  Melanoma incidence rates among whites in the U.S. military 
The U.S. Military and general populations may differ in the exposure to sunlight and other risk factors for melanoma, and therefore the incidence rates of melanoma may be different in these two populations. However, few studies have compared melanoma incidence rates and trends over time between the military and the general population.
Melanoma incidence rates from 1990 to 2004 among white active-duty military personnel and the general U.S. population were compared using data from the Department of Defense (DoD)’s Automated Central Tumor Registry (ACTUR) and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.
Age-adjusted melanoma rates overall were significantly lower in the military than in the general population; the incidence rate ratio (IRR) was 0.75 for men and 0.56 for women. Age-specific rates, however, were significantly lower among younger individuals aged <45 years but significantly higher among those aged 45 years or older (p-values<0.05). Melanoma incidence rose from 1990–1994 to 2000–2004 in both populations, with the most rapid increase (40%) among younger men in the military. Melanoma incidence rates also varied by branch of military service; rates were highest in the Air Force.
These results suggest that melanoma incidence rate patterns differ between the military and the general population.
Further studies of risk factors for melanoma in the military are needed to explain these findings.
PMCID: PMC4148910  PMID: 21148122
Melanoma; incidence rates; Active duty; military; SEER program
12.  Breast Conserving Surgery versus Mastectomy: The Influence of Comorbidities on Choice of Surgical Operation in the Department of Defense Healthcare System 
American journal of surgery  2013;206(3):393-399.
Studies on the effect of comorbidities on breast cancer operation have been limited and inconsistent. This study investigated whether pre-existing comorbidities influenced breast cancer surgical operation in an equal access healthcare system.
This study was based on linked Department of Defense cancer registry and medical claims data. The study subjects were patients diagnosed with stage I–III breast cancer during 2001 to 2007. Logistic regression was used to determine if comorbidity was associated with operation type and time between diagnosis and operation.
Breast cancer patients with comorbidities were more likely to receive mastectomy (OR=1.27, 95% CI, 1.14–1.42) than breast conserving surgery plus radiation. Patients with comorbidities were also more likely to delay having operation than those without comorbidities (OR=1.27, 95% CI, 1.14–1.41).
In an equal access healthcare system, comorbidity was associated with having a mastectomy and with a delay in undergoing operation.
PMCID: PMC4148911  PMID: 23866763
Breast cancer; breast conserving surgery; comorbidity; Department of Defense health system; mastectomy; military
13.  Changing hepatocellular carcinoma incidence and liver cancer mortality rates in the United States 
To describe Surveillance, Epidemiology and End Results (SEER) hepatocellular carcinoma (HCC) incidence trends and United States liver cancer mortality trends by geography, age, race/ethnicity and gender.
HCC incidence data from SEER 18 registries and liver cancer mortality data from the National Center for Health Statistics were analyzed. Rates and joinpoint trends were calculated by demographic subgroup. State-level liver cancer mortality rates and trends were mapped.
HCC incidence rates in SEER registries did not significantly increase during 2007–2010, however U.S. liver cancer mortality rates did increase. HCC incidence and liver cancer mortality rates increased among black, Hispanic and white men aged 50+ years and decreased among 35–49 year old men in all racial/ethnic groups including Asians/Pacific Islanders. Significantly increasing incidence and mortality rates among women were restricted to blacks, Hispanics and whites aged 50+ years. Asian/Pacific Islander liver cancer mortality rates decreased during 2000–2010 with decreasing rates among women aged 50–64 years and men 35–49 years and stable rates in other groups. During 2006–2010 among person 50–64 years of age, blacks and Hispanics had higher incidence and mortality rates than Asians/Pacific Islanders. Liver cancer mortality rates were highest in Louisiana, Mississippi, Texas and Washington, DC.
Decreasing HCC incidence and liver cancer mortality rates among Asian/Pacific Islanders, men aged 35–49 years, and the non-significant increase in overall HCC incidence rates suggest that the peak of the epidemic may be near or have passed. Findings of geographic variation in mortality rates can inform control efforts.
PMCID: PMC4148914  PMID: 24513805
hepatocellular carcinoma; liver cancer
14.  Histological classification of liver and intrahepatic bile duct cancers in SEER registries 
Journal of registry management  2011;38(4):201-205.
Clear definitions of histological groups are essential for studies of liver and intrahepatic bile duct cancers. Thus, we developed a classification system based on abstracted information on histologies of liver and intrahepatic bile duct cancers diagnosed during 1978–2007 within all Surveillance, Epidemiology, and End Results (SEER) registries. Of 61,990 reported primary liver and intrahepatic bile duct cancers, 108 distinct ICD-O histology codes were identified. During the five recent years of diagnosis, 2003–2007, the leading histological groups were hepatocellular carcinoma (75%) and cholangiocarcinoma (12%). The remaining categories were other specified (3%) and poorly specified carcinomas (3%), hepatoblastomas (1%), sarcomas (1%), embryonal sarcomas (0.1%), other specified malignancies (0.05%), and poorly specified malignancies (5%). During 2003–2007, only 68% of diagnoses were microscopically confirmed. Factors contributing to incomplete histological classification may include reluctance to obtain diagnostic specimens from late stage cases and administration of therapy in lieu of histological confirmation after positive diagnostic imaging.
The proposed histological classification in this report may facilitate studies of primary liver cancers. This is of value because the inconsistent characterization of some cancers, particularly cholangiocarcinomas, may affect interpretation of incidence trends. Incomplete histological characterization of hepatocellular carcinomas was noted in this report. It is likely to be explained by guidelines affirming the use of non-invasive diagnostic and treatment procedures for this cancer.
PMCID: PMC4148005  PMID: 23270094
Hepatocellular carcinoma; cholangiocarcinoma; microscopic confirmation; trends
16.  Race and Colon Cancer Survival in an Equal-Access Healthcare System 
Studies have shown that whites have a higher colorectal cancer survival rate than blacks. However, it is unclear whether racial disparities result from unequal access to medical care or factors other than healthcare access or both. This study assessed whether non-Hispanic Whites (NHWs) and non-Hispanic Blacks (NHBs) differ in colon cancer (CC) survival in an equal-access healthcare system and examined whether racial differences varied by demographic and tumor characteristics. The study included 2,537 Military Health System patients diagnosed with CC between 1998 and 2007. Median follow-up time was 31.4 months. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) for race, overall and stratified by age at diagnosis, sex, and tumor stage. No difference in overall survival (OS) between NHWs and NHBs was observed in general. However, among patients younger than 50 years old, NHBs experienced significantly worse OS than NHWs (HR: 2.27, 95% CI: 1.48–3.49). Further stratification by sex and tumor stage showed that this racial disparity was confined to women (HR: 2.80, 95% CI: 1.30–6.00) and patients with distant stage disease (HR: 2.65, 95% CI: 1.38–5.08) in this age group. When medical care is equally available to NHWs and NHBs, similar overall CC survival was observed; however, evidence of racial differences in survival was apparent for patients younger than 50 years old. This study suggests that factors other than access to care may be related to racial disparities in CC survival among younger, but not older, patients.
PMCID: PMC4143979  PMID: 23576691
race; colon cancer; survival; equal-access
17.  Metabolic syndrome increases the risk of primary liver cancer in the United States: a population-based case-control study 
Hepatology (Baltimore, Md.)  2011;54(2):463-471.
Incidence rates of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) have increased in the United States. Metabolic syndrome is recognized as a risk factor for HCC and a postulated one for ICC. The magnitude of risk, however, has not been investigated on a population level in the U.S. We therefore examined the association between metabolic syndrome and the development of these cancers. All persons diagnosed with HCC and ICC between 1993 and 2005 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. For comparison, a 5% sample of individuals residing in the same regions as the SEER registries of the cases was selected. The prevalence of metabolic syndrome as defined by the U.S. National Cholesterol Education Program Adult Treatment Panel III criteria, and other risk factors for HCC (hepatitis B virus, hepatitis C virus, alcoholic liver disease, liver cirrhosis, biliary cirrhosis, hemochromatosis, Wilson’s disease) and ICC (biliary cirrhosis, cholangitis, cholelithiasis, choledochal cysts, hepatitis B virus, hepatitis C virus, alcoholic liver disease, cirrhosis, inflammatory bowel disease) were compared among persons who developed cancer and those who did not. Logistic regression was used to calculate odds ratios and 95% confidence intervals. The inclusion criteria were met by 3649 HCC cases, 743 ICC cases and 195,953 comparison persons. Metabolic syndrome was significantly more common among persons who developed HCC (37.1%) and ICC (29.7%) than the comparison group (17.1%, p<0.0001). In adjusted multiple logistic regression analyses, metabolic syndrome remained significantly associated with increased risk of HCC (odds ratio=2.13; 95%CI=1.96–2.31, p<0.0001) and ICC (odds ratio=1.56; 95% CI= 1.32–1.83, p<0.0001).
Metabolic syndrome is a significant risk factor for development of HCC and ICC in the general U.S. population.
PMCID: PMC4141525  PMID: 21538440
Hepatocellular Carcinoma; Intrahepatic Cholangiocarcinoma; Metabolic Syndrome; SEER-Medicare-linked database
18.  The Global Epidemiology of Hepatocellular Carcinoma, Present and Future 
Clinics in liver disease  2011;15(2):223-x.
PMCID: PMC4141529  PMID: 21689610
incidence rate; hepatitis B virus; hepatitis C virus; aflatoxin; alcohol; diabetes
19.  Trends in sex hormone concentrations in U.S. males: 1988–1991 to 1999–2004 
Previous studies suggest that male testosterone concentrations have declined over time. To explore this in a large US population, we examined testosterone and free testosterone concentrations in National Health and Nutrition Examination Surveys (NHANES) from 1988–1991 and 1999–2004. We also examined sex hormone-binding globulin (SHBG), estradiol, and androstanediol glucuronide (3α-diol-G) over the same period. Non-Hispanic white, non-Hispanic black, and Mexican-American men from 1988–1991 and 1999–2004 NHANES surveys who were ≥ 20 years old and had serum from morning blood draws were included in this analysis (1988–1991: N=1,413; 1999–2004: N=902). Testosterone, estradiol, and SHBG were measured by competitive electrochemiluminescence immunoassays and 3α-diol-G was measured by enzyme immunoassay. Free testosterone was calculated using testosterone and SHBG values. Adjusted mean hormone concentrations were estimated using linear regression, accounting for NHANES sampling weights and design, age, race/ethnicity, body mass index, waist circumference, alcohol use, and smoking. Differences in adjusted mean concentrations (Δ) and two-sided P-values were calculated; P<0.05 was statistically significant. Overall, 3α-diol-G and estradiol declined between 1988–1991 and 1999–2004, but there was little change in testosterone, free testosterone, or SHBG (Δ: 3α-diol-G =−1.83 ng/mL, P<0.01; estradiol=−6.07 pg/mL, P<0.01; testosterone=− 0.03 ng/mL, P=0.75; free testosterone=−0.001 ng/mL, P=0.67; SHBG=−1.17 nmol/L, P=0.19). Stratification by age and race revealed that SHBG and 3α-diol-G declined among whites 20–44 years old (Δ: SHBG=−5.14 nmol/L, P<0.01; 3α-diol-G =−2.89 ng/mL, P<0.01) and free testosterone increased among blacks 20–44 years old (Δ: 0.014, P=0.03). Estradiol declined among all ages of whites and Mexican-Americans. In conclusion, there was no evidence for testosterone decline between 1988–1991 and 1999–2004 in the US general population. Subgroup analyses suggest that SHBG and 3α-diol-G declined in young white men, estradiol declined in white and Mexican-American men, and free testosterone increased in young black men. These changes may be related to the increasing prevalence of reproductive disorders in young men.
PMCID: PMC4137971  PMID: 22150314
testosterone; androstanediol glucuronide; estradiol; sex hormone-binding globulin; epidemiology; National Health and Nutrition Examination Survey
20.  Diabetes mellitus as a risk factor for gastrointestinal cancers among postmenopausal women 
Cancer causes & control : CCC  2012;24(3):577-585.
While diabetes has been linked to several cancers in the gastrointestinal (GI) tract, findings have been mixed for sites other than colorectal and liver cancer. We used the Women's Health Initiative (WHI) data and conducted a comprehensive assessment of associations between diabetes and GI malignancy (esophagus, stomach, liver, biliary, pancreas, colon and rectal).
145,765 postmenopausal women ages 50-79 enrolled in the WHI were followed for a mean 10.3 years. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between GI cancers and diagnosed diabetes, including its duration and treatment.
Diabetes at enrollment was associated with increased risk for liver (HR = 3.00 95% CI 1.68-5.36), pancreatic (HR=1.64 95% CI: 1.16-2.33), colon (HR=1.37 95% CI: 1.13-1.65) and rectal (HR=1.90, 95%CI: 1.24-2.90) cancer. Diabetes severity, assessed by duration or need for pharmacotherapy, appeared to have stronger links to risk of liver, pancreatic and rectal cancer, but not colon cancer. There was no statistically significant association of diabetes with biliary, esophageal and stomach cancers.
Type 2 diabetes is associated with a significantly increased risk of cancers of the liver, pancreas, colon and rectum in postmenopausal women. Diabetes severity may further increase risk of pancreatic, liver and rectal cancer.
This study confirmed that diabetes increases risk of cancers of the liver, pancreas, colon and rectum. The suggestion that diabetes severity further increases these cancer risks requires future studies.
PMCID: PMC4135433  PMID: 22622863
21.  Dichlorodiphenyltrichloroethane (DDT) and risk of hepatocellular carcinoma 
Dichlorodiphenyltrichloroethane (p,p’-DDT), an organochlorine pesticide known to have deleterious health effects in humans, has been linked to hepatocellular carcinoma (HCC) in rodents. A recent study has reported that p,p’-DDT and its most persistent metabolite, dichlorodiphenyldichloroethylene (p,p’-DDE), may also be associated with HCC in humans.
To examine whether there is an association between p,p’-DDT and/or p,p’-DDE in a population at high-risk of developing HCC.
A nested case-control study was conducted within the 83,794 person Haimen City Cohort in China. Sera and questionnaire data were collected from all participants between 1992 and 1993. The current study included 473 persons who developed HCC and 492 who did not, frequency matched on sex, age and area of residence. p,p’-DDT and p,p’-DDE levels were determined by mass spectrometry. Hepatitis B viral infection status (based on hepatitis B virus surface antigen; HBsAg) was also determined. Adjusting for age, sex, area of residence, HBsAg, family history of HCC, history of acute hepatitis, smoking, alcohol, occupation (farmers) and levels of p,p’-DDT or p,p’-DDE, odds ratios (OR) and 95% confidence intervals (CI) were calculated via unconditional logistic regression,
p,p’-DDT and/or p,p’-DDE serum levels were significantly associated with sex, area of residence, occupation, alcohol consumption and cigarette smoking. Overall, the highest quintile of p,p’-DDT was associated with an increased risk of HCC, OR= 2.96 95% CI; 1.19–7.40. There were no statistically significant associations with p,p’-DDE.
Overall, these results suggest that recent exposure to p,p’-DDT may increase risk of HCC.
PMCID: PMC4127991  PMID: 22290210
DDT; DDE; hepatocellular carcinoma; cohort study; China; epidemiology
22.  Racial variation in breast cancer treatment among Department of Defense beneficiaries 
Cancer  2011;118(3):812-820.
Although the overall age-adjusted incidence rates for female breast cancer are higher among whites than blacks, mortality rates are higher among blacks. Many attribute this discrepancy to disparities in healthcare access and to blacks presenting with later stage disease. Within the Department of Defense (DoD) Military Health System all beneficiaries have equal access to healthcare. The aim of this study was to determine if breast cancer treatment varied between white and black female breast cancer patients in the DoD system.
The study data were drawn from the DoD cancer registry and medical claims databases. Study subjects included 2,308 white and 391 black female beneficiaries diagnosed with breast cancer between 1998 and 2000. Multivariate logistic regression analyses that controlled for demographic factors, tumor characteristics, and comorbidities were used to assess racial differences in the receipt of surgery, chemotherapy and hormonal therapy.
There was no significant difference in surgery type, particularly when mastectomy was compared to breast conserving surgery plus radiation (blacks vs. whites: OR=1.1; 95% CI=0.8–1.5). Among those with local stage tumors, blacks were as likely as whites to receive chemotherapy (OR=1.2; 95% CI=0.9–1.8) and hormonal therapy (OR=1.0; 95% CI=0.7–1.4). Among those with regional stage tumors, blacks were significantly less likely than whites to receive chemotherapy (OR=0.4; 95% CI=0.2–0.7) and hormonal therapy (OR=0.5; 95% CI=0.3–0.8).
Even within an equal access healthcare system, stage-related racial variations in breast cancer treatment are evident. Studies that identify driving factors behind these within-stage racial disparities are warranted.
PMCID: PMC4123115  PMID: 21766298
23.  Population-Attributable Fractions of Risk Factors for Hepatocellular Carcinoma in the United States 
Risk factors for hepatocellular carcinoma (HCC) include hepatitis B and C viruses (HBV, HCV), excessive alcohol consumption, rare genetic disorders and diabetes/obesity. The population attributable fractions (PAF) of these factors, however, have not been investigated in population-based studies in the United States.
Persons ≥ 68 years diagnosed with HCC (n = 6,991) between 1994 and 2007 were identified in the SEER-Medicare database. A 5 % random sample (n = 255,702) of persons residing in SEER locations were selected for comparison. For each risk factor, odds ratios (ORs), 95 % confidence intervals (95 % CI) and PAFs were calculated.
As anticipated, the risk of HCC was increased in relationship to each factor: HCV (OR 39.89, 95 % CI: 36.29–43.84), HBV (OR 11.17, 95 % CI: 9.18–13.59), alcohol-related disorders (OR 4.06, 95 % CI: 3.82–4.32), rare metabolic disorders (OR 3.45, 95 % CI: 2.97–4.02), and diabetes and/or obesity (OR 2.47, 95 % CI: 2.34–2.61). The PAF of all factors combined was 64.5 % (males 65.6 % ; females 62.2 %). The PAF was highest among Asians (70.1 %) and lowest among black persons (52.4 %). Among individual factors, diabetes/obesity had the greatest PAF (36.6 %), followed by alcohol-related disorders (23.5 %), HCV (22.4 %), HBV (6.3 %) and rare genetic disorders (3.2 %). While diabetes/obesity had the greatest PAF among both males (36.4 %) and females (36.7 %), alcohol-related disorders had the second greatest PAF among males (27.8 %) and HCV the second greatest among females (28.1 %). Diabetes/obesity had the greatest PAF among whites (38.9 %) and Hispanics (38.1 %), while HCV had the greatest PAF among Asians (35.4 %) and blacks (34.9 %). The second greatest PAF was alcohol-related disorders in whites (25.6 %), Hispanics (30.1 %) and blacks (and 18.5 %) and HBV in Asians (28.5 %).
The dominant risk factors for HCC in the United States among persons ≥68 years differ by sex and race/ethnicity. Overall, eliminating diabetes/obesity could reduce the incidence of HCC more than the elimination of any other factor.
PMCID: PMC4105976  PMID: 23752878
24.  Second to fourth digit ratio, handedness and testicular germ cell tumors 
Early human development  2013;89(7):463-466.
Research on early life exposures and testicular germ cell tumors (TGCT) risk has focused on a possible perinatal etiology with a well-known hypothesis suggesting that hormonal involvement during fetal life is associated with risk. Second-to-fourth digit ratio (2D:4D) and left hand dominance have been proposed as markers of prenatal hormone exposure.
To evaluate associations between 2D:4D digit ratio, right minus left 2D:4D (ΔR-L), and left-hand dominance and TGCT in the U.S. Servicemen’s Testicular Tumor Environmental and Endocrine Determinants (STEED) Study.
A total of 246 TGCT cases and 236 non-testicular cancer controls participated in the current study, and completed a self-administered questionnaire. Associations between digit ratio, hand dominance and TGCT were estimated using unconditional logistic regression adjusting for identified covariates.
Right 2D:4D was not associated with TGCT [OR for a one-standard deviation (SD) increase in right hand 2D:4D: 1.12, 95% CI: 0.93–1.34]. The results were consistent when evaluating the association based on the left hand. The difference between right and left hand 2D:4D was also not associated with TGCT risk [OR for a one-SD increase in ΔR-L: 1.03, 95% CI: 0.87–1.23]. Compared to men who reported right-hand dominance, ambidexterity [OR (95% CI) = 0.65 (0.30–1.41)] and left-hand dominance [OR (95% CI) = 0.79 (0.44–1.44)] were not associated with risk.
These results do not support the hypothesis that prenatal hormonal imbalance is associated with TGCT risk. Given the limited sample size, further evaluation of the relationship between TGCT and prenatal hormonal factors using digit ratio, ΔR-L, or left-hand dominance and larger sample size are warranted.
PMCID: PMC3684556  PMID: 23623693
case-control; testicular cancer; hand pattern; left-handed dominance; digit ratio
25.  Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23 
Human Molecular Genetics  2013;22(13):2748-2753.
Genome-wide association studies (GWASs) have identified multiple common genetic variants associated with an increased risk of testicular germ cell tumors (TGCTs). A previous GWAS reported a possible TGCT susceptibility locus on chromosome 1q23 in the UCK2 gene, but failed to reach genome-wide significance following replication. We interrogated this region by conducting a meta-analysis of two independent GWASs including a total of 940 TGCT cases and 1559 controls for 122 single-nucleotide polymorphisms (SNPs) on chromosome 1q23 and followed up the most significant SNPs in an additional 2202 TGCT cases and 2386 controls from four case–control studies. We observed genome-wide significant associations for several UCK2 markers, the most significant of which was for rs3790665 (PCombined = 6.0 × 10−9). Additional support is provided from an independent familial study of TGCT where a significant over-transmission for rs3790665 with TGCT risk was observed (PFBAT = 2.3 × 10−3). Here, we provide substantial evidence for the association between UCK2 genetic variation and TGCT risk.
PMCID: PMC3674801  PMID: 23462292

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