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Background: Epidemiologic studies have reported that frequent consumption of quercetin-rich foods is inversely associated with lung cancer incidence. A quercetin-rich diet might modulate microRNA (miR) expression; however, this mechanism has not been fully examined.Methods: miR expression data were measured by a custom-made array in formalin-fixed paraffin-embedded tissue samples from 264 lung cancer cases (144 adenocarcinomas and 120 squamous cell carcinomas). Intake of quercetin-rich foods was derived from a food-frequency questionnaire. In individual-miR–based analyses, we compared the expression of miRs (n = 198) between lung cancer cases consuming high versus low quercetin-rich food intake using multivariate ANOVA tests. In family-miR–based analyses, we used Functional Class Scoring (FCS) to assess differential effect on biologically functional miR families. We accounted for multiple testing using 10,000 global permutations (significance at Pglobal < 0.10). All multivariate analyses were conducted separately by histology and by smoking status (former and current smokers).Results: Family-based analyses showed that a quercetin-rich diet differentiated miR expression profiles of the tumor suppressor let-7 family among adenocarcinomas (PFCS < 0.001). Other significantly differentiated miR families included carcinogenesis-related miR-146, miR-26, and miR-17 (PFCS < 0.05). In individual-based analyses, we found that among former and current smokers with adenocarcinoma, 33 miRs were observed to be differentiated between highest and lowest quercetin-rich food consumers (23 expected by chance; Pglobal = 0.047).Conclusions: We observed differential expression of key biologically functional miRs between high versus low consumers of quercetin-rich foods in adenocarcinoma cases.Impact: Our findings provide preliminary evidence on the mechanism underlying quercetin-related lung carcinogenesis. Cancer Epidemiol Biomarkers Prev; 21(12); 2176–84. ©2012 AACR.

PDF file - 80K, List of miRs (N=198) retained from chip array analysis

PDF file - 54K, All identified miR groups based on "seed" sequence (2-7nt)

PDF file - 47K, Food groups and individual food items

PDF file - 5418K, Hierarchical clustering heat map of miR expression levels for 25 miRs that displayed significant differential expression among former smokers with adenocarcinoma in the individual miR-based analysis. Average linkage was used to cluster miRs and samples with a distance metric of 1 minus centered correlation using BRB-ArrayTools version 4.2. Tertiles define subjects with low (Tertile 1) and high (Tertile 3) consumption of quercetin-rich food.

PDF file - 3580K, Hierarchical clustering heat map of miR expression levels for 10 miRs that displayed significant differential expression among former smokers with squamous cell carcinoma in the individual miR-based analysis. Average linkage was used to cluster miRs and samples with a distance metric of 1 minus centered correlation using BRB-ArrayTools version 4.2. Tertiles define subjects with low (Tertile 1) and high (Tertile 3) consumption of quercetin-rich food.

PDF file - 51K, Selected characteristics of included and excluded EAGLE cases

Introduction We compared the stage at diagnosis for non-small cell lung cancer (NSCLC) patients in the military healthcare system (MHS) and the general public to assess differences between these two groups as well as to assess the trends in stage at diagnosis in the recent past. Method This study was based on the non-identifiable data from the U.S. Department of Defense Automated Central Tumor Registry (ACTUR) and the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. Patients diagnosed with NSCLC between 1989 and 2012 were included. The distributions of tumor stage at diagnosis and trends in tumor stage were compared between the two populations. Results The cohorts were predominately male in both ACTUR (65.3%) and SEER (55.1%) and white patients accounted for greater than 80% of patients in both ACTUR and SEER. Among 21,031 patients in ACTUR and 773,356 patients in SEER, stage IV lung cancers predominated (ACTUR 33.6%, SEER 40.5%) followed by stage III (ACTUR 26.1%, SEER 26.4%) and stage I (ACTUR 24.7%, SEER 20.6%). Notable differences between the two populations were the higher percentage of stage I and lower percentage of stage IV, along with a lower rate of unknown stage patients after 2004, in ACTUR than SEER. Between 1989 and 2012, the percentage of stage IV disease increased in ACTUR and SEER coincident with a decrease in unknown stage disease. Conclusions The majority of NSCLC patients in the MHS and general population are diagnosed with stage IV NSCLC and the percentage is increasing. Compared to the general population, NSCLC patients in the MHS have a higher percentage of stage I, a lower percentage of stage IV, and of unknown stage cancer. Universal care along with more rigorous staging across the MHS may play a role in these findings.

PURPOSE Linked cancer registry and medical claims data have increased the capacity for cancer research. However, few efforts have described methods to select information between data sources, which may affect data use. We developed a systematic process to evaluate and consolidate cancer diagnosis and treatment information between the linked Department of Defense Central Cancer Registry (CCR) and Military Health System Data Repository (MDR) administrative claims database, called Military Cancer Epidemiology Data System (MilCanEpi). METHODS MilCanEpi contains information on cancer diagnosis and treatment of patients receiving care from 1998 to 2014. We used an iterative process guided by knowledge of data features, current literature, and logical comparisons between the CCR and MDR data to evaluate and consolidate cancer diagnosis and treatment received (yes or no) and their dates. We applied the processes to breast cancer data as an example. Agreement between diagnosis and treatment dates in the two data sources was evaluated using Cohen’s κ with 95% CIs. RESULTS In MilCanEpi, we identified 15,965 patients with a breast cancer diagnosis and 15,145 patients who underwent breast cancer surgery; 97.9% and 84.1% of patients had records in both CCR and MDR for diagnosis and surgery, respectively. Exact agreement was 13.7% for diagnosis dates (Cohen’s κ = 0.14; 95% CI, 0.13 to 0.14) and 68.9% for surgery dates (Cohen’s κ = 0.69; 95% CI, 0.68 to 0.70) between the two data sources. After applying systematic processes, 98.1% of patients with a breast cancer diagnosis and 99.7% of patients with surgery had information selected for analytic data sets. CONCLUSION The developed processes resulted in high consolidation rates of breast cancer data in MilCanEpi and may serve as a data selection template for other tumor sites and linked data sources.

Background: Altered kinase localization is gaining appreciation as a mechanism of cardiovascular disease. Previous work suggests GSK-3β (glycogen synthase kinase 3β) localizes to and regulates contractile function of the myofilament. We aimed to discover GSK-3β’s in vivo role in regulating myofilament function, the mechanisms involved, and the translational relevance. Methods: Inducible cardiomyocyte-specific GSK-3β knockout mice and left ventricular myocardium from nonfailing and failing human hearts were studied. Results: Skinned cardiomyocytes from knockout mice failed to exhibit calcium sensitization with stretch indicating a loss of length-dependent activation (LDA), the mechanism underlying the Frank-Starling Law. Titin acts as a length sensor for LDA, and knockout mice had decreased titin stiffness compared with control mice, explaining the lack of LDA. Knockout mice exhibited no changes in titin isoforms, titin phosphorylation, or other thin filament phosphorylation sites known to affect passive tension or LDA. Mass spectrometry identified several z-disc proteins as myofilament phospho-substrates of GSK-3β. Agreeing with the localization of its targets, GSK-3β that is phosphorylated at Y216 binds to the z-disc. We showed pY216 was necessary and sufficient for z-disc binding using adenoviruses for wild-type, Y216F, and Y216E GSK-3β in neonatal rat ventricular cardiomyocytes. One of GSK-3β’s z-disc targets, abLIM-1 (actin-binding LIM protein 1), binds to the z-disc domains of titin that are important for maintaining passive tension. Genetic knockdown of abLIM-1 via siRNA in human engineered heart tissues resulted in enhancement of LDA, indicating abLIM-1 may act as a negative regulator that is modulated by GSK-3β. Last, GSK-3β myofilament localization was reduced in left ventricular myocardium from failing human hearts, which correlated with depressed LDA. Conclusions: We identified a novel mechanism by which GSK-3β localizes to the myofilament to modulate LDA. Importantly, z-disc GSK-3β levels were reduced in patients with heart failure, indicating z-disc localized GSK-3β is a possible therapeutic target to restore the Frank-Starling mechanism in patients with heart failure.

Purpose : The U.S. military health system provides universal health care access to beneficiaries. However, whether the universal access has translated into improved patient outcome is unknown. We compared survival of small-cell lung cancer patients in the military health system with that in the U.S. general population. Stage and receipt of cancer treatment were also compared to see if they could contribute to survival difference. Methods : The data were obtained from The Department of Defense's Automated Central Tumor Registry (ACTUR) and the national Surveillance, Epidemiology, and End Results (SEER) program, respectively. ACTUR (N = 3040) and SEER patients (N = 12,160) were matched on age, sex, race and diagnosis year. Multivariable Cox regression model was used to compare all-cause mortality between ACTUR and SEER. Multivariable logistic regression was performed to compare cancer stage and treatment. Results : ACTUR patients exhibited significantly better survival than SEER counterparts (HR = 0.77, 95% CI= 0.71–0.83). ACTUR and SEER patients had similar stage, but ACTUR patients were more likely to receive radiation treatment (OR = 1.26, 95% CI = 1.12–1.42). The survival advantage of ACTUR patients remained across all tumor stages and radiation groups. Conclusions : Survival of small-cell lung cancer patients with universal health care access had better survival than similar patients in the U.S. general population. Future studies are warranted to identify factors that may contribute to the improved survival.

Introduction A number of studies have found an association between sickle cell trait (SCT) and exertional heat illnesses (EHIs) including heat stroke, a potentially fatal condition. The strength of this association varied across studies, limiting the ability to quantify potential benefits of SCT-screening policies for competitive athletics and military service members. We determined the relative rate and attributable risk of developing EHI associated with being SCT positive and the EHI health care utilization. Methods We conducted a retrospective cohort study among U.S. enlisted, active duty service members during 1992-2012 from the Department of Defense Military Healthcare System databases. All 15,081 SCT-positive individuals and a sample of 60,320 from those considered SCT negative were followed through 2013 for EHI outcomes ranging from mild heat illness to heat stroke. Results The adjusted hazard ratio for EHI in SCT-positive compared with SCT-negative individuals was 1.24 (95% confidence interval 1.06, 1.45). Risk factors for EHI included age over 30 yr at enlistment, female gender, Marine Corps, combat occupations, and enlistment between April and June. An estimated 216 Department of Defense enlistees (95% confidence interval: 147, 370) would need to be screened to identify and potentially prevent one case of EHI. The attributable risk of EHI due to SCT was 33% (95% confidence interval 19, 45%). Conclusion Our findings suggest that SCT screening will identify approximately a third of SCT individuals at risk for EHI, but does not provide definitive evidence for universal compared with selective (e.g., occupational based) in military enlistees. A cost-effectiveness analysis is needed for policy makers to assess the overall value of universal SCT screening to prevent morbidity and mortality in both the military and the collegiate athletic populations.

This study investigates transition rates between breast cancer diagnosis, recurrence, and death by insurance benefit type and care source in U.S. Military Health System (MHS). The MHS data repository and central cancer registry linked data were used to identify women aged 40–64 with histologically confirmed breast cancer between 2003 and 2007. Three-state continuous time Markov models were used to estimate transition rates and transition rate ratios (TRRs) by TRICARE benefit type (Prime or non-Prime) and care source (direct, purchased, or both), adjusted for demographic, tumor, and treatment variables. Analyses included 2668 women with transitions from diagnosis to recurrence (n = 832), recurrence to death (n = 79), and diagnosis to death without recurrence (n = 91). Compared to women with Prime within each care source, women with non-Prime using both care sources had higher transition rates (TRR 1.47, 95% CI 1.03, 2.10). Compared to those using direct care within each benefit type, women utilizing both care sources with non-Prime had higher transition rates (TRR 1.86, 95% CI 1.11, 3.13), while women with Prime utilizing purchased care had lower transition rates (TRR 0.82, 95% CI 0.68, 0.98). In the MHS, women with non-Prime benefit plans compared to Prime had higher transition rates along the breast cancer continuum among both care source users. Purchased care users had lower transition rates than direct care users among Prime beneficiaries. Benefit plan and care source may be associated with breast cancer progression. Further research is needed to demonstrate differences in survivorship.

Background Use of treatment for breast cancer is dependent on the patient’s cancer characteristics and willingness to undergo treatment and provider treatment recommendations. Receipt of breast cancer treatment varies by insurance status and type. It is not clear whether different benefit types and care sources differ in breast cancer treatment and outcomes among Department of Defense beneficiaries. Methods The objectives of this study are to assess whether receipt of breast cancer treatment varied by benefit type (TRICARE Prime vs non-Prime) or care source (direct care, purchased care, and both) and to examine whether survival and recurrence differed by benefit type and/or care source among female Department of Defense beneficiaries with the disease. Study subjects were women aged 40–64 yr, diagnosed with malignant breast cancer between 2003 and 2007. Multivariable logistic regression analyses were conducted to assess the likelihood of receiving treatment by benefit type or care source. Multivariable Cox proportional hazard models were used to investigate differences in survival and recurrence by benefit type or care source. Findings A total of 2,668 women were included in this study. Those with Prime were more likely to have chemotherapy, radiation, hormone therapy, breast-conserving surgery, surveillance mammography, and recurrence than women with non-Prime. Survival was high, with 94.86% of those with Prime and 92.58% with non-Prime alive at the end of the study period. Women aged 50–59 yr with non-Prime benefit type had better survival than women with Prime of the same age. No survival differences were seen by care source. In regard to recurrence, women aged 60–64 yr with TRICARE Prime were more likely to have recurrent breast cancer than women with non-Prime. Additionally, women aged 50–59 yr who used purchased care were less likely to have a recurrence than women who used direct care only. Discussion/Impact/Recommendations To our knowledge, this is the first study to examine breast cancer treatment and survival by care source and benefit type in the Military Health System. In this equal access health care system, no differences in treatment, except mastectomy, by benefit type, were observed. There were no overall differences in survival, although patients with non-Prime tended to have better survival in the age group of 50–59 yr. In regard to care source, women who utilized mostly purchased care or utilized both direct and purchased care were more likely to receive certain types of treatment, such as chemotherapy and radiation, as compared with women who used direct care only. However, survival did not differ between different care sources. Future research is warranted to further investigate variations in breast cancer treatment and its survival gains by benefit type and care source among Department of Defense beneficiaries.

Background: Although research suggests that type II diabetes mellitus (DM-2) is associated with overall and breast cancer–specific decreased survival, most prior studies of breast cancer survival investigated the effect of preexisting DM-2 without assessing the effect of DM-2 diagnosed at or after breast cancer diagnosis. This study examined the relationship between DM-2 diagnosed before and after breast cancer diagnosis and overall survival. Methods: This study uses linked Department of Defense cancer registry and medical claims data from 9,398 women diagnosed with breast cancer between 1998 and 2007. Cox proportional hazards models were used to assess the association between DM-2 and overall survival. Results: Our analyses showed that women with DM-2 diagnosed before breast cancer diagnosis tended to have a higher risk of mortality compared with women without diabetes [HR = 1.17; 95% confidence interval (CI), 0.95–1.44] after adjustment for potential confounders. Similarly, patients diagnosed with DM-2 at or after breast cancer diagnosis had increased mortality compared with women without DM-2 (HR = 1.39; 95% CI, 1.16–1.66). The similar tendency was also observed among most subgroups when results were stratified by race, menopausal status, obesity, tumor hormone receptor status, and stage. Conclusions: Using data from a health system that provides universal health care to its beneficiaries, this study showed an increased risk of death associated with DM-2, regardless of whether it was diagnosed before or at/after breast cancer diagnosis. Impact: These results suggest the potential effects of factors independent of the timing of DM-2 clinical diagnosis on the association of DM-2 with overall survival. Cancer Epidemiol Biomarkers Prev; 27(1); 50–57. ©2017 AACR.

Breast tumors from young women under the age of 40 account for approximately 7% of cases and have a poor prognosis independent of established prognostic factors. We evaluated the patient population served by the Military Health System, where a disproportionate number of breast cancer cases in young women are seen and treated in a single universal coverage healthcare system.The Military Health System Repository and the DoD Central Registration databases were used to identify female breast cancer patients diagnosed or treated at military treatment facilities from 1998 to 2007.10,066 women were diagnosed with invasive breast cancer at DoD facilities from 1998 to 2007, of which 11.3% (1139), 23.4% (2355) and 65.2% (6572) were 40, 40-49 and 50 years old (yo), respectively, at diagnosis. 53% in the 40 yo cohort were white, 25% were African American (AA) and 8% were Hispanic, with 14% undisclosed. Breast cancer in women diagnosed 40 yo was more high grade (p 0.0001), Stage II (p 0.0001) and ER negative (p 0.0001). There was a higher rate of bilateral mastectomies among the women 40 compared to those 40-49 and 50 (18.4% vs. 9.1% and 5.0%, respectively). Independent of disease stage, chemotherapy was given more frequently to 40 yo (90.43%) and 40-49 yo (81.44%) than ≥ 50 yo (53.71%). The 10-year overall survival of younger women was similar to the ≥ 50 yo cohort. Outcomes in the African American and Hispanic subpopulations were comparable to the overall cohort.Younger women had a similar overall survival rate to older women despite receiving more aggressive treatment.

Background While the incidence of bladder cancer is twice as high among whites than among blacks, mortality is higher among blacks than whites. Unequal access to medical care may be an important factor. Insufficient access to care could delay cancer detection and treatment, which can result in worse survival. The purpose of this study was to evaluate whether survival differed between black and white bladder cancer patients in the Department of Defense (DoD), which provides universal healthcare to all beneficiaries regardless of racial background. Methods This study was based on data from the U.S. DoD Automated Central Tumor Registry (ACTUR). White and black patients histologically diagnosed with bladder cancer between 1990 and 2004 were included in the study and followed to the end of 2007. The outcomes were all-cause mortality and recurrence. We assessed the relationship between race and outcomes of interest using Cox proportional hazard ratios (HRs) for all, non-muscle invasive (NMIBC), and muscle invasive (MIBC) bladder cancers, separately. Results The survival of black and white individuals did not differ statistically. No significant racial differences in survival (HR: 0.96, 95% CI: 0.76–1.22) or recurrence-free survival (HR: 0.94, 95% CI: 0.69–1.30) were observed after adjustment for demographic variables, tumor characteristics, and treatment. Similar findings were observed for NMIBC and MIBC patients, respectively. Conclusion Black patients were more likely to present with MIBC than white patients. However, white and black patients with bladder cancer were not significantly different in overall and recurrence-free survival regardless of muscle invasion. Our study suggests the importance of equal access to healthcare in reducing racial disparities in bladder cancer survival.

INTRODUCTION: Colorectal cancer (CRC) is one of the leading causes of cancer death for both men and women in the United States. Several factors can increase one’s risk of CRC, including a personal or family history of CRC, a diagnosis or family history of a hereditary colon cancer syndrome, or a diagnosis of chronic inflammatory bowel disease. The purpose of this project was to create a colorectal cancer registry (Co-Care) for individuals with a personal or family history of CRC, and those with disorders of the colon or rectum that are associated with an increased risk for developing CRC. METHODS: To be eligible for the registry, patients either had a personal or family history of CRC, a diagnosis or family history of Lynch syndrome, familial adenomatous polyposis, or a diagnosis of Crohn’s colitis or ulcerative colitis with dysplasia. Participants were recruited after seeing their gastroenterologist or genetic counselor, or after undergoing a full or partial colectomy at Mount Sinai Hospital in New York City. Eligible patients who agreed to participate were interviewed by a member of the research staff and asked a wide range of questions pertaining to CRC risk. RESULTS: A total of 224 patients were enrolled in the registry. Participants are mostly white, born in the United States, and married, with a bachelor’s or graduate degree, reporting an annual household income of $100,000 or more. The largest portion have a family history of CRC (27.2%), and almost half of participants are of Jewish descent (46.2%) and have undergone full or partial colectomy (48.2%). More than half of participants have neither received genetic counseling (54.5%) nor undergone genetic testing (59.7%). Only 3.6% report that they currently smoke cigarettes, and 41.1% consume alcohol at least once per week. Lastly, 18.3%, 10.3%, and 27.7% of participants report that they currently take aspirin, folic acid/folate pills or tablets, or calcium pills/tablets, respectively. CONCLUSIONS: This registry can improve our understanding of CRC and related diseases, and be used to design future interventions related to disease risk, prognosis, and prevention of CRC.

Introduction Sickle cell trait (SCT), the heterozygous carrier state for hemoglobin S, is present in an estimated 1.6% of all newborns and 7.3% in black individuals in the USA. SCT has long been considered a benign condition with anticipated normal life expectancy and no increased risk for chronic diseases. The medical literature is inconclusive on the potential association between SCT and chronic medical conditions (CMC) including chronic kidney disease, venous thromboembolism, and stroke. Studies addressing these questions are lacking particularly in non-Black young adults. Materials and methods We conducted a retrospective cohort study among U.S. active duty, enlisted, service members who entered from 1992 to 2012 using existing Department of Defense (DoD Military Healthcare System databases). SCT positive subjects (1,323) were matched by demographic characteristics to SCT negative subjects (3,136) and followed through 2013 for CMC that included deep vein thrombosis, diabetes mellitus and hematologic, pulmonary, and renal conditions. Results The rate of developing any of the included CMC was higher for those with SCT (incidence rate ratio = 1.71 95% CI 1.61-1.81) compared with those who were SCT negative and their healthcare utilization rate for any of CMC studied was higher for SCT positive compared with negative individuals (URR = 2.45 95% CI 2.41-2.50), with the highest rate ratios observed for hematologic and renal conditions. SCT positive compared with negative individuals were more likely to have encounter diagnoses of sickle cell disease and diabetes Type II and were less likely to have encounter diagnoses of other hemoglobinopathies and diabetes type I. Conclusion SCT in these racially diverse, young adults increased both the incidence of and healthcare utilization for thromboembolism, diabetes mellitus type II, sickle cell disease, pulmonary, and chronic renal conditions. These findings suggest that clinicians treating young adults with SCT should exercise heightened surveillance for these CMC to ensure both early diagnosis and access to treatments.

Introduction Breast cancer care imposes a significant financial burden to U.S. healthcare systems. Health services factors, such as insurance benefit type and care source, may impact costs to the health system. Beneficiaries in the U.S. Military Health System (MHS) have universal healthcare coverage and access to a network of military facilities (direct care) and private practices (purchased care). This study aims to quantify and compare breast cancer care costs to the MHS by insurance benefit type and care source. Materials and Methods We conducted a retrospective analysis of data linked between the MHS data repository administrative claims and central cancer registry databases. The institutional review boards of the Walter Reed National Military Medical Center, the Defense Health Agency, and the National Institutes of Health Office of Human Subjects Research reviewed and approved the data linkage. We used the linked data to identify records for women aged 40-64 yr who were diagnosed with breast cancer between 2003 and 2007 and to extract information on insurance benefit type, care source, and cost to the MHS for breast cancer treatment. We estimated per capita costs for breast cancer care by benefit type and care source in 2008 USD using generalized linear models, adjusted for demographic, pathologic, and treatment characteristics. Results The average per capita (n = 2,666) total cost for breast cancer care was $66,300 [standard error (SE) $9,200] over 3.31 (1.48) years of follow-up. Total costs were similar between benefit types, but varied by care source. The average per capita cost was $34,500 ($3,000) for direct care (n = 924), $96,800 ($4,800) for purchased care (n = 622), and $60,700 ($3,900) for both care sources (n = 1,120), respectively. Care source differences remained by tumor stage and for chemotherapy, radiation, and hormone therapy treatment types. Conclusions Per capita costs to the MHS for breast cancer care were similar by benefit type and lower for direct care compared with purchased care. Further research is needed in breast and other tumor sites to determine patterns and determinants of cancer care costs between benefit types and care sources within the MHS.

Background: The U.S. military health system (MHS) provides universal health care access to its beneficiaries. However, whether the universal access has translated into improved patient outcome is unknown. This study compared survival of non–small cell lung cancer (NSCLC) patients in the MHS with that in the U.S. general population. Methods: The MHS data were obtained from The Department of Defense's (DoD) Automated Central Tumor Registry (ACTUR), and the U.S. population data were drawn from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. The study subjects were NSCLC patients diagnosed between January 1, 1987, and December 31, 2012, in ACTUR and a sample of SEER patients who were matched to the ACTUR patients on age group, sex, race, and year of diagnosis group with a matching ratio of 1:4. Patients were followed through December 31, 2013. Results: A total of 16,257 NSCLC patients were identified from ACTUR and 65,028 matched patients from SEER. Compared with SEER patients, ACTUR patients had significantly better overall survival (log-rank P < 0.001). The better overall survival among the ACTUR patients remained after adjustment for potential confounders (HR = 0.78, 95% confidence interval, 0.76–0.81). The survival advantage of the ACTUR patients was present regardless of cancer stage, grade, age group, sex, or race. Conclusions: The MHS's universal care and lung cancer care programs may have translated into improved survival among NSCLC patients. Impact: This study supports improved survival outcome among NSCLC patients with universal care access. Cancer Epidemiol Biomarkers Prev; 27(6); 673–9. ©2018 AACR.

INTRODUCTION: Sickle cell trait (SCT) affects an estimated 5.02% of non-Hispanic blacks, 1.08% of Hispanics, and 0.1% of Whites in the U.S. military. Policies for SCT screening and occupational restrictions vary by service. Population-based studies of SCT with quantification of military-relevant outcomes are lacking. METHODS: The study design was a retrospective cohort of 15,081 SCT-positive versus 60,320 SCT-negative U.S. active duty personnel enlisted from 1992 to 2012 and followed through 2013. Military-relevant outcome included number and days of deployment, length of service, and cause of death. RESULTS: SCT-positive versus SCT-negative service members experienced more deployments (p < 0.01) and longer number of days deployed for all services, especially the Army (p < 0.001). The median length of service was longer for SCT-positive service members stratified by service and by gender (p < 0.05). The adjusted risk of length of service greater than 5 yr by SCT status was 1.37 (95% confidence interval 1.31–1.43) with greater than a three-fold higher risk in the Navy and Air Force compared with the Army. Crude mortality rate was not significantly different by SCT status, although deaths due to suicide, self-directed violence, and other non-specific causes were more common in SCT-positive service members. CONCLUSION: We found that SCT-positive service members deployed more frequently, for greater lengths of time, and remained in service longer. No significant difference in crude mortality ratio was discovered. Additional research on military-relevant outcomes and a cost-effectiveness analysis of SCT screening practices are needed to inform evidence-based SCT enlistment policies.

Population-based estimates of sickle cell trait (SCT) prevalence in the U.S. military across services and over time are lacking.SCT prevalence by service, race/ethnicity, and gender in 5-year time intervals was estimated using demographic, ambulatory, and hospital SCT encounter (International Classification of Diseases, 9th Revision, Clinical Modification 282.5) data for active duty, enlisted between 1992 and 2012 and limited SCT laboratory results.Our study identified 15,081 SCT subjects. SCT prevalence varied significantly by race, year, gender, and service branch. SCT prevalence was highest for non-Hispanic blacks (5.02%; prevalence ratio = 56.33, confidence interval [CI] = 52.14-60.85; compared to non-Hispanic white) in 2005-2009 (0.40%; prevalence ratio = 10.04, CI = 9.21-10.94; compared to 1992-1994), for women (2.97%; prevalence ratio = 3.14, CI = 3.04-3.25; compared to men), and in the Navy (2.26%; prevalence ratio = 2.96, CI = 2.84-3.02; compared to Army). Among foreign born, Africans were more likely to be SCT+ (prevalence ratio = 1.68, CI = 1.39-2.04; compared to non-U.S. North American).This study estimated the prevalence of SCT within U.S. military enlisted force and describes variability across services for race, time intervals, gender, and foreign-born region and will support investigation into the health effects of SCT in young adult populations.

Type of insurance and out-of-pocket costs influence the use of medical care. Specifically, type of insurance can impact an individual's likelihood of receiving a screening mammogram. Additionally, variation in tumor stage at diagnosis exists for patients with different types of insurance. It is not clear whether different benefit types and care sources differ in breast cancer care and outcomes among Department of Defense (DoD) beneficiaries.The objective of this study was to examine differences in screening mammography and tumor stage at diagnosis between different benefit types (TRICARE Prime vs. non-Prime) and among different care sources (direct care, purchased care, and both) in the DoD Military Health System. Study subjects were women 40 to 64 years of age, diagnosed with malignant breast cancer between 2003 and 2007. Multivariable logistic regression analyses were conducted to assess differences by benefit type and care source in receipt of screening mammography before diagnosis and tumor stage at diagnosis.A total of 2,668 women were included in this study. Patients with Prime were more likely to receive a screening mammography and have an earlier tumor stage than those with non-Prime. Women with direct care were more likely to have an earlier tumor stage but less likely to receive a screening mammogram than those with purchased care.In an equal access health care system, the use of mammography screening and tumor stage at diagnosis may differ by benefit type and care source among DoD beneficiaries. To our knowledge, this was the first study to assess mammography screening and tumor stage differences by benefit type and care source in the Military Health System. Although underlying reasons for the differences are not clear, they may be related to out-of-pocket costs, distance from medical treatment facilities, and frequency of doctor visits for other medical problems. Further research is needed to assess these differences and related factors among DoD beneficiaries.

Background: Serum proteomic biomarkers offer a promising approach for early detection of cancer. In this study, we aimed to identify proteomic profiles that could distinguish colon cancer cases from controls using serial prediagnostic serum samples. Methods: This was a nested case–control study of active duty military members. Cases consisted of 264 patients diagnosed with colon cancer between 2001 and 2009. Controls were matched to cases on age, gender, race, serum sample count, and collection date. We identified peaks that discriminated cases from controls using random forest data analysis with a 2/3 training and 1/3 validation dataset. We then included epidemiologic data to see whether further improvement of model performance was obtainable. Proteins that corresponded to discriminatory peaks were identified. Results: Peaks with m/z values of 3,119.32, 2,886.67, 2,939.23, and 5,078.81 were found to discriminate cases from controls with a sensitivity of 69% and a specificity of 67% in the year before diagnosis. When smoking status was included, sensitivity increased to 76% while histories of other cancer and tonsillectomy raised specificity to 76%. Peaks at 2,886.67 and 3,119.32 m/z were identified as histone acetyltransferases while 2,939.24 m/z was a transporting ATPase subunit. Conclusions: Proteomic profiles in the year before cancer diagnosis have the potential to discriminate colon cancer patients from controls, and the addition of epidemiologic information may increase the sensitivity and specificity of discrimination. Impact: Our findings indicate the potential value of using serum prediagnostic proteomic biomarkers in combination with epidemiologic data for early detection of colon cancer. Cancer Epidemiol Biomarkers Prev; 26(5); 711–8. ©2016 AACR.

Background While differences in CPM use between White and Black patients are well known, it is not clear whether CPM use differs by estrogen/progesterone receptor (ER/PR) status of tumors and whether racial/ethnic differences in the use are affected by ER/PR status, which varies between racial groups. The purpose of this study was to investigate whether CPM usage differs by racial/ethnic group and ER/PR status among patients in the Surveillance, Epidemiology, and End Results (SEER) data. Methods The study subjects were women with histologically confirmed unilateral breast cancer who underwent breast surgery between 1998 and 2011. Age-adjusted CPM use as a proportion of all surgically treated patients or all patients who had mastectomy was analyzed by racial/ethnic group, tumor behavior, and ER/PR status. Temporal trends in age-adjusted CPM use were presented by ER/PR status and racial/ethnic group. Results The analyses stratified by ER/PR status showed significant racial/ethnic differences in age-adjusted CPM use with non-Hispanic White and non-Hispanic Asian/Pacific Islander (API) patients having the most and least CPM use. Age-adjusted CPM use was significantly higher for ER+/PR+ tumors than ER⿿/PR⿿ ones for each race/ethnicity group among patients with mastectomy. However, among patients with any breast surgeries, the only difference was a higher proportion of CPM use for ER⿿/PR⿿ tumors (8.6%) than ER+/PR+ tumors (8.0%) in non-Hispanic Whites. CPM use has increased over time in all racial/ethnic groups despite ER/PR status. Conclusion CPM usage was lower not only in non-Hispanic Blacks, but also in non-Hispanic API and Hispanic patients compared to non-Hispanic White patients. CPM usage tended to be higher for ER+/PR+ tumors, but the results varied when different denominators (all mastectomies vs. all breast surgeries) were used.

Going Retro In a year celebrating Darwin, the question of how new functional genes arise during evolution is of particular interest. Through a multibreed genetic analysis of the domestic dog, Parker et al. (p. 995 , published online 16 July; see the Perspective by Kaessmann ) find that the short-legged phenotype that characterizes at least 19 common dog breeds, including the corgi, dachshund, and basset hound, is specifically associated with the expression in developing bone of a gene encoding fibroblast growth factor 4 ( fgf4 ), a member of a gene family previously implicated in dwarfism in humans. Interestingly, the culprit fgf4 gene in dogs has the hallmarks of a “retrogene,” a gene that arises when a parental gene is duplicated through an RNA-based copying mechanism.

The U.S. military health system (MHS) provides universal access to its beneficiaries. However, little is known about whether the universal access has translated into improved patient outcomes. We compared survival among non-small cell lung cancer (NSCLC) cases in MHS with that of NSCLC cases from the general U.S. population. The MHS data were obtained from The Department of Defense’s (DoD) Automated Central Tumor Registry (ACTUR). The U.S. population data were drawn from the National Cancer Institute’s (NCI) Surveillance, Epidemiology, and End Results (SEER) program18 registries (1973- 2012) which represents 27.8% of the U.S. population. NSCLC patients in ACTUR and SEER who were diagnosed between January 1, 1987 and December 31, 2012 were included. The ACTUR and SEER cases were then matched by age group, sex, race, and year of diagnosis group at a matching ratio of 1:4, which comprised of 16,257 cases from ACTUR and 65,028 cases from SEER. Kaplan-Meir curves and log-rank test were used to compare overall survival between the two populations. Multivariable Cox proportional hazards models for matched data were used to estimate hazard ratios (HRs) and 95% CI with adjustment for potential confounders. Compared to the SEER cases, the ACTUR cases were more likely to be diagnosed at stage I or stage II (P Citation Format: Jie Lin, Christine Kamamia, Derek Brown, Stephanie Shao, Katherine A. McGlynn, Joel A. Nations, Corey A. Carter, Craig D. Shriver, Kangmin Zhu. Survival among lung cancer patients in the U.S. Military Health System: a comparison with the SEER population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3296. doi:10.1158/1538-7445.AM2017-3296

Epidemiologic studies have previously reported an association between high fat intake and colon cancer risk. However, findings have generally been inconclusive. This study aimed to investigate the association between fat as a percentage of energy intake and colon cancer risk. Study subjects included 215 cases and 215 matched controls identified by the Defense Medical Surveillance System. Percentage energy from fat (Pfat) was estimated using a short dietary screener developed by the National Cancer Institute for two time periods: the year before the first blood draw and the year before colon cancer diagnosis. Conditional logistic regression analysis was used to assess the relationship between colon cancer risk and Pfat. Odds ratios and 95% confidence intervals (CIs) were calculated. Compared with the lowest quartile of Pfat, the adjusted odds of having colon cancer were 2.00 (95% CI 0.96-4.18), 2.83 (95% CI 1.41-5.66), and 3.37 (95% CI 1.58-7.17), respectively, for the second, third, and highest quartiles in the year before cancer diagnosis. Similar results were observed for Pfat at an earlier time point. Our findings suggest a positive association between Pfat and colon cancer in the US military population.

Background: Epidemiologic studies have reported that frequent consumption of quercetin-rich foods is inversely associated with lung cancer incidence. A quercetin-rich diet might modulate microRNA (miR) expression; however, this mechanism has not been fully examined. Methods: miR expression data were measured by a custom-made array in formalin-fixed paraffin-embedded tissue samples from 264 lung cancer cases (144 adenocarcinomas and 120 squamous cell carcinomas). Intake of quercetin-rich foods was derived from a food-frequency questionnaire. In individual-miR–based analyses, we compared the expression of miRs (n = 198) between lung cancer cases consuming high versus low quercetin-rich food intake using multivariate ANOVA tests. In family-miR–based analyses, we used Functional Class Scoring (FCS) to assess differential effect on biologically functional miR families. We accounted for multiple testing using 10,000 global permutations (significance at Pglobal < 0.10). All multivariate analyses were conducted separately by histology and by smoking status (former and current smokers). Results: Family-based analyses showed that a quercetin-rich diet differentiated miR expression profiles of the tumor suppressor let-7 family among adenocarcinomas (PFCS < 0.001). Other significantly differentiated miR families included carcinogenesis-related miR-146, miR-26, and miR-17 (PFCS < 0.05). In individual-based analyses, we found that among former and current smokers with adenocarcinoma, 33 miRs were observed to be differentiated between highest and lowest quercetin-rich food consumers (23 expected by chance; Pglobal = 0.047). Conclusions: We observed differential expression of key biologically functional miRs between high versus low consumers of quercetin-rich foods in adenocarcinoma cases. Impact: Our findings provide preliminary evidence on the mechanism underlying quercetin-related lung carcinogenesis. Cancer Epidemiol Biomarkers Prev; 21(12); 2176–84. ©2012 AACR.