Comprehensive Impurity Profiling of mRNA: Evaluating Current Technologies and Advanced Analytical Techniques.

In vitro transcription (IVT) of mRNA is a versatile platform for a broad range of biotechnological applications. Its rapid, scalable, and cost-effective production makes it a compelling choice for the development of mRNA-based cancer therapies and vaccines against infectious diseases. The impurities generated during mRNA production can potentially impact the safety and efficacy of mRNA therapeutics, but their structural complexity has not been investigated in detail yet. This study pioneers a comprehensive profiling of IVT mRNA impurities, integrating current technologies with innovative analytical tools. We have developed highly reproducible, efficient, and stability-indicating ion-pair reversed-phase liquid chromatography and capillary gel electrophoresis methods to determine the purity of mRNA from different suppliers. Furthermore, we introduced the applicability of microcapillary electrophoresis for high-throughput (<1.5 min analysis time per sample) mRNA impurity profiling. Our findings revealed that impurities are mainly attributed to mRNA variants with different poly(A) tail lengths due to aborted additions or partial hydrolysis and the presence of double-stranded mRNA (dsRNA) byproducts, particularly the dsRNA 3'-loop back form. We also implemented mass photometry and native mass spectrometry for the characterization of mRNA and its related product impurities. Mass photometry enabled the determination of the number of nucleotides of different mRNAs with high accuracy as well as the detection of their size variants [i.e., aggregates and partial and/or total absence of the poly(A) tail], thus providing valuable information on mRNA identity and integrity. In addition, native mass spectrometry provided insights into mRNA intact mass, heterogeneity, and important sequence features such as poly(A) tail length and distribution. This study highlights the existing bottlenecks and opportunities for improvement in the analytical characterization of IVT mRNA, thus contributing to the refinement and streamlining of mRNA production, paving the way for continued advancements in biotechnological applications.

Evaluation of Porcine Psoas Major as a Scaffold Material for Engineered Heart Tissues.

Decellularized porcine myocardium is commonly used as scaffolding for engineered heart tissues (EHTs). However, structural and mechanical heterogeneity in the myocardium complicate production of mechanically consistent tissues. In this study, we evaluate the porcine psoas major muscle (tenderloin) as an alternative scaffold material. Head-to-head comparison of decellularized tenderloin and ventricular scaffolds showed only minor differences in mean biomechanical characteristics, but tenderloin scaffolds were less variable and less dependent on the region of origin than ventricular samples. The active contractile behavior of EHTs made by seeding tenderloin versus ventricular scaffolds with human-induced pluripotent stem cell-derived cardiomyocytes was also comparable, with only minor differences observed. Collectively, the data reveal that the behavior of EHTs produced from decellularized porcine psoas muscle is almost identical to those made from porcine left ventricular myocardium, with the advantages of being more homogeneous, biomechanically consistent, and readily obtainable.

Biophysical and mechanobiological considerations for T-cell-based immunotherapy.

Immunotherapies modulate the body's defense system to treat cancer. While these therapies have shown efficacy against multiple types of cancer, patient response rates are limited, and the off-target effects can be severe. Typical approaches in developing immunotherapies tend to focus on antigen targeting and molecular signaling, while overlooking biophysical and mechanobiological effects. Immune cells and tumor cells are both responsive to biophysical cues, which are prominent in the tumor microenvironment. Recent studies have shown that mechanosensing - including through Piezo1, adhesions, and Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) - influences tumor-immune interactions and immunotherapeutic efficacy. Furthermore, biophysical methods such as fluidic systems and mechanoactivation schemes can improve the controllability and manufacturing of engineered T cells, with potential for increasing therapeutic efficacy and specificity. This review focuses on leveraging advances in immune biophysics and mechanobiology toward improving chimeric antigen receptor (CAR) T-cell and anti-programmed cell death protein 1 (anti-PD-1) therapies.

Physiological calcium combined with electrical pacing accelerates maturation of human engineered heart tissue.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have wide potential application in basic research, drug discovery, and regenerative medicine, but functional maturation remains challenging. Here, we present a method whereby maturation of hiPSC-CMs can be accelerated by simultaneous application of physiological Ca2+ and frequency-ramped electrical pacing in culture. This combination produces positive force-frequency behavior, physiological twitch kinetics, robust ß-adrenergic response, improved Ca2+ handling, and cardiac troponin I expression within 25 days. This study provides insights into the role of Ca2+ in hiPSC-CM maturation and offers a scalable platform for translational and clinical research.

GSK-3ß Localizes to the Cardiac Z-Disc to Maintain Length Dependent Activation.

BACKGROUND: Altered kinase localization is gaining appreciation as a mechanism of cardiovascular disease. Previous work suggests GSK-3ß (glycogen synthase kinase 3ß) localizes to and regulates contractile function of the myofilament. We aimed to discover GSK-3ß's in vivo role in regulating myofilament function, the mechanisms involved, and the translational relevance. METHODS: Inducible cardiomyocyte-specific GSK-3ß 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-3ß. Agreeing with the localization of its targets, GSK-3ß 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-3ß in neonatal rat ventricular cardiomyocytes. One of GSK-3ß'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-3ß. Last, GSK-3ß 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-3ß localizes to the myofilament to modulate LDA. Importantly, z-disc GSK-3ß levels were reduced in patients with heart failure, indicating z-disc localized GSK-3ß is a possible therapeutic target to restore the Frank-Starling mechanism in patients with heart failure.

Comparative study of survival among small cell lung cancer patients in the U.S. military health system and those in the surveillance, epidemiology, and end results (SEER) program.

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.

Consolidation of Cancer Registry and Administrative Claims Data on Cancer Diagnosis and Treatment in the US Military Health System.

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.

Comparative Trends in the Distribution of Lung Cancer Stage at Diagnosis in the Department of Defense Cancer Registry and the Surveillance, Epidemiology, and End Results data, 1989-2012.

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.

Race and overall survival in men diagnosed with prostate cancer in the Department of Defense Military Health System, 1990-2010.

BACKGROUND: In the U.S. general population, black men experience poorer survival after prostate cancer (CaP) diagnosis compared to white men, and findings may be impacted by unequal access to healthcare. The objective of the study is to investigate racial differences in overall survival (OS) among Department of Defense beneficiaries diagnosed with CaP. METHODS: A retrospective cohort study was conducted utilizing the Automated Central Tumor Registry within the Military Healthcare System, a system designed to provide equal access. Men diagnosed with primary prostate adenocarcinomas between 1990 and 2010 [n = 18,484; 24% Non-Hispanic black (NHB), 76% Non-Hispanic white (NHW)] were followed through 2013 for vital status. Unadjusted Kaplan-Meier estimation curves and multivariable Cox proportional hazards (PH) regression models were used to examine racial differences in OS. RESULTS: Age-specific Kaplan-Meier analyses showed equivalent OS for NHW and NHB men in all age groups, except for 75+, where NHB had poorer OS (p = 0.0048). Multivariable Cox PH models revealed no significant differences in OS for race (HR 1.02; 95% CI 0.95-1.08), except in men aged ≥ 75 years, where NHB men had poorer OS (HR 1.27; 95% CI 1.08-1.49). CONCLUSIONS: Findings suggest that in a healthcare system designed for equal access, disparities in OS among men diagnosed with CaP may not exist.

Association Between Sickle Cell Trait With Selected Chronic Medical Conditions in U.S. Service Members.

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.

Costs for Breast Cancer Care in the Military Health System: An Analysis by Benefit Type and Care Source.

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.

Survival among Lung Cancer Patients in the U.S. Military Health System: A Comparison with the SEER Population.

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.

The Association Between Sickle Cell Trait in U.S. Service Members with Deployment, Length of Service, and Mortality, 1992-2012.

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.

The continuum of breast cancer care and outcomes in the U.S. Military Health System: an analysis by benefit type and care source.

PURPOSE: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. IMPLICATIONS FOR CANCER SURVIVORS: Benefit plan and care source may be associated with breast cancer progression. Further research is needed to demonstrate differences in survivorship.

Risk of Exertional Heat Illnesses Associated with Sickle Cell Trait in U.S. Military.

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.

Breast Cancer Treatment and Survival Among Department of Defense Beneficiaries: An Analysis by Benefit Type and Care Source.

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.

Diabetes and Overall Survival among Breast Cancer Patients in the U.S. Military Health System.

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.

Analysis of breast cancer in young women in the Department of Defense (DOD) database.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Younger women had a similar overall survival rate to older women despite receiving more aggressive treatment.

Benefit Type and Care Source in Relation to Mammography Screening and Breast Cancer Stage at Diagnosis Among DoD Beneficiaries.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. DISCUSSION: 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.

Sickle Cell Trait Prevalence Among U.S. Military Service Members: 1992-2012.

BACKGROUND: Population-based estimates of sickle cell trait (SCT) prevalence in the U.S. military across services and over time are lacking. METHODS: 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. 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). CONCLUSION: 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.