Medication Trends in the Military: A Comparative Analysis of Prescribing Patterns Among Service Members Seen by a Pharmacist and Implications for Medical Readiness.

INTRODUCTION: Medications play a critical role supporting the health of military service members. Little is known about the broad use of medications prescribed to this population. Active duty service members (ADSMs), while often younger and having fewer diagnosed comorbid conditions, face unique health challenges that benefit from pharmacotherapy. Understanding prescribing patterns is instrumental to illuminate potential areas for research and to guide education so that military health care professionals can maintain competency, improve outcomes, and support medical readiness. This study aimed to characterize commonly dispensed medications among ADSMs and to compare these prescriptions with those of the general population. MATERIALS AND METHODS: A retrospective, cross-sectional analysis using data extracted contained in the Military Health System Information Platform focused on ADSMs who consulted with a clinical pharmacist during the 2019 fiscal year. Descriptive statistics were used to summarize patient and prescription data. The 100 most frequently prescribed medications and 20 most frequently prescribed therapeutic classes were identified. Analyses were performed using Statistical Analysis System (SAS) software, and a non-metric multidimensional scaling plot was generated in R to illustrate the relationships between the 20 most frequently used therapeutic classes and the branches of service. RESULTS: The study analyzed 719,788 prescriptions for 30,012 service members, revealing a high prescription rate for pain, inflammation, and psychiatric condition treatments. Antidepressants and nonsteroidal anti-inflammatory drugs were among the most commonly prescribed across all military branches. Some medication uses varied, which may indicate distinct needs within different service branches. CONCLUSIONS: Understanding medication patterns among ADSMs may be able to help health care professionals proactively address pharmacological challenges and optimize pharmaceutical use in this unique population. This knowledge can also aid in the development of training modules focused on medication side effects, interactions, counseling, and implications on military deployment for the most commonly used medications. Future examination into prescribing cascades and medication use related to proton-pump inhibitors, docusate, benzonatate, and muscle relaxants may identify opportunities to provide better care or lower cost.

Rates of Preeclampsia and Post-preeclamptic Cardiovascular Disease Among US Military Servicewomen: A Retrospective Case-cohort Study.

INTRODUCTION: Preeclampsia (PE), a hypertensive-inflammatory disorder of pregnancy, poses acute risks of seizures, stroke, and heart attack during pregnancy and up to 6 weeks post-delivery. Recent data suggest that residual increased risks for cardiovascular disease (CVD) linger for much longer, possibly decades, after PE pregnancies. In civilian studies, PE and the major vascular events resulting from it disproportionately affect women from minority groups, especially African American women. The Military Health System (MHS) provides equal access to care for all active-duty servicewomen (ADSW), thus theoretically mitigating disparities. Racial/ethnic breakdown for PE and post PE CVD has not been studied in the MHS. MATERIALS AND METHODS: We identified healthy pregnancies in the MHS electronic health records of ADSW in the years 2009/2010 and those with a PE diagnosis. Patients with preexisting conditions of PE or CVD based on a look-back period of two calendar years were excluded. Cases were matched to controls based on age at pregnancy within 5 years and race/ethnicity. Cohort was assessed for diagnosed CVDs, race, age, and service during 2011-2017. Time to first CVD event was assessed with Cox proportional hazards model, results reported as relative risks (95% CI). All variables were summarized using mean (SD) for normally distributed continuous variables; non-normal continuous variables were characterized by median [IQR] and categorical variables were summarized by counts and frequencies. All statistical testings were two-sided with a significance level of 5% and were completed using SAS-EG version 9.2 or R version 3.5.2. RESULTS: From an analysis of 106,808 inpatient ADSW records, PE incidence by race is 11.8% for White, 12% for African American, 11.4% for Asian/Pacific Islander, 11.2% for Native American, 9.5% for Other, and 7.6% for unknown (not documented) race. Thus, in the US Military, African American women have comparable (0.2% higher) PE rate than White women in contrast with civilian studies that often report much higher incidence in the African American population. Using Asians as referent group, PE increases the risk of CVD. White women have a hazard ratio (HR) of 1.47 95%CI (1.15-1.88), African Americans a HR of 1.51 95% CI (1.18-1.93), and Other a HR of 1.39 95% CI (1.01-1.91). CONCLUSION: In this study, we report overall higher incidence of PE in military women than what is published for civilian women in all races and across all services. Importantly, we do not find significantly higher numbers of PE and post-PE CVD for African American, compared to White women in the military. Our study is not designed to address differences between military and civilian PE epidemiology, but these results deserve further exploration. This study shines light on a health risk unique to women, which we found to be more prevalent in the US Military than published civilian population. Further study to determine the details of long-term morbidity, disability, and death attributable to PE (CVD, stroke, and kidney diseases) are needed to design optimal medical management protocols, ensure readiness for duty, and protect our Women Warfighters.

Naloxone Prescribing Associated With Reduced Emergency Department Visits in the Military Health System.

PURPOSE: The aim was to determine the association between the receipt of naloxone and emergency department (ED) visits within 60 days after the receipt of an opioid. METHODS: A retrospective cohort of individuals 18 years of age or above, enrolled in TRICARE, and were dispensed an opioid at any time from January 1, 2019, through September 30, 2020 was identified within the United States Military Health System. Individuals receiving naloxone within 5 days of the opioid dispensing date were propensity score matched with individuals receiving opioids only. A logistic regression was used to estimate the odds of an ED visit in the 60-day follow-up period after the index opioid dispense event among those co-dispensed naloxone and those receiving opioids only. RESULTS: Of the 2,136,717 individuals who received an opioid prescription during the study period, 800,071 (10.1%) met study inclusion criteria. Overall, 5096 (0.24%) of individuals who received an opioid prescription were co-dispensed naloxone. Following propensity score matching, those who received naloxone had a significantly lower odds of ED utilization in the 60 days after receiving an opioid prescription (odds ratio: 0.74, 95% CI: 0.68-0.80, P<0.001). CONCLUSION: This study highlights the importance of expanding access to naloxone in order to reduce ED utilization. Future research is needed to examine additional outcomes related to naloxone receipt and develop programs that make naloxone prescribing a routine practice.

Variability among Online Opioid Conversion Calculators Performing Common Palliative Care Conversions.

Introduction: Online opioid conversion calculators (OOCCs) are commonly used to aid conversion between opioids to overcome tolerance, reduce adverse effects, or challenges related to administration. The purpose of this study was to describe and characterize variability among OOCC used by health care practitioners when converting common opioids and doses encountered in the hospice and palliative care setting. Methods: We collected 58 quantitative surveys and performed sentiment analysis on 62 qualitative responses from adult learners primarily practicing in the palliative care setting and enrolled in an online palliative care Master of Science program through the University of Maryland, Baltimore, who were asked to perform opioid conversion calculations using realistic patient cases. Results: OOCC have substantial variability leading to a wide range of outputs, which may put patients at risk for opioid-related harm. Assessing participant sentiment toward OOCC showed most participants held a "Negative Sentiment" toward these calculators after the activity. Conclusion: Overall, findings reveal that given the same information, clinicians can come to widely different opioid doses and these differences can be amplified by OOCC. These differences can be particularly dangerous given the higher opioid doses commonly used in the palliative care setting. Considering the significant harm that can arise from an error when converting between opioids, clinicians should avoid the routine use of OOCC in real-world patient care settings. If an OOCC is used, organizations should endorse a specific calculator, provide training and education about the algorithm that supports the calculations, and encourage clinicians to use it only after their own manual calculation, which should be documented in the medical record.

Obstructive sleep apnea among survivors of combat-related traumatic injury: a retrospective cohort study.

STUDY OBJECTIVES: Obstructive sleep apnea is prevalent among military members despite fewer traditional risk factors. We sought to determine the incidence and longitudinal predictors of obstructive sleep apnea in a large population of survivors of combat-related traumatic injury and a matched control group. METHODS: Retrospective cohort study of military service members deployed to conflict zones from 2002-2016 with longitudinal follow-up in the Veterans Affairs and Military Health Systems. Two cohorts of service members were developed: (1) those who sustained combat injuries and (2) matched, uninjured participants. RESULTS: 17,570 service members were retrospectively analyzed for a median of 8.4 years. After adjustment, traumatic brain injury (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.20-1.60), posttraumatic stress disorder (HR 1.24, 95% CI 1.05-1.46), depression (HR 1.52, 95% CI 1.30-1.79), anxiety (HR 1.40, 95% CI 1.21-1.62), insomnia (HR 1.71, 95% CI 1.44-2.02), and obesity (HR 2.40, 95% CI 2.09-2.74) were associated with development of obstructive sleep apnea. While combat injury was associated with obstructive sleep apnea in the univariate analysis (HR 1.25, 95% CI 1.17-1.33), the direction of this association was reversed in the multivariable model (HR 0.74, 95% CI 0.65-0.84). In a nested analysis, this was determined to be due to the effect of mental health diagnoses. CONCLUSIONS: The incidence of obstructive sleep apnea is higher among injured service members (29.1 per 1,000 person-years) compared to uninjured service members (23.9 per 1,000 person-years). This association appears to be driven by traumatic brain injury and the long-term mental health sequelae of injury. CITATION: Haynes ZA, Stewart IJ, Poltavskiy EA, et al. Obstructive sleep apnea among survivors of combat-related traumatic injury: a retrospective cohort study. J Clin Sleep Med. 2022;18(1):171-179.

Risk factors of persistent insomnia among survivors of traumatic injury: a retrospective cohort study.

STUDY OBJECTIVES: Insomnia is a diagnosis with broad health and economic implications that has been increasingly recognized in military service members. This trend was concurrent with an increase in traumatic wartime injuries. Accordingly, we sought to determine longitudinal predictors of persistent insomnia in combat veterans who sustained traumatic injuries. METHODS: Retrospective cohort study of service members deployed to conflict zones from 2002 to 2016, with longitudinal follow-up in the Veterans Affairs and Military Health Systems. Two cohorts were derived: (1) service members who sustained traumatic injuries and (2) an age-, sex-, and service component-matched cohort of uninjured service members who deployed to a combat zone. Insomnia was defined using International Classification of Diseases, Ninth Revision or International Classification of Diseases, 10th Revision-Clinical Modification codes. RESULTS: The final population of 17,374 service members was followed from date of injury (or date of matched participant's injury) for a median of 8.4 (interquartile range, 5.3-10.7) years. Service members with traumatic injury were at significantly greater risk of developing insomnia than uninjured service members (hazard ratio = 1.43; 95% confidence interval, 1.30-1.58) after adjustment. Traumatic brain injury was associated with insomnia compared with patients without traumatic brain injury in the multivariable model: mild/unclassified traumatic brain injury (hazard ratio = 2.07; 95% confidence interval, 1.82-2.35) and moderate/severe/ penetrating traumatic brain injury (hazard ratio = 2.43; 95% confidence interval, 2.06-2.86). Additionally, burn injury (hazard ratio = 1.95; 95% confidence interval, 1.47-2.59) and amputation (hazard ratio = 1.61; 95% confidence interval, 1.26-2.06) significantly increased the risk of a diagnosis. CONCLUSIONS: Traumatic injuries significantly predicted a diagnosis of insomnia after controlling for mental health disorders. Our findings strongly suggest the need for long-term surveillance of sleep disorders in trauma survivors. CITATION: Haynes ZA, Collen JF, Poltavskiy EA, et al. Risk factors of persistent insomnia among survivors of traumatic injury: a retrospective cohort study. J Clin Sleep Med. 2021;17(9):1831-1840.

Longitudinal mental health outcomes of combat-injured service members.

BACKGROUND: The relationship between traumatic injury and subsequent mental health diagnoses is not well understood and may have significant implications for patient screening and clinical intervention. We sought to determine the adjusted association between traumatic injury and the subsequent development of post-traumatic stress disorder (PTSD), depression, and anxiety. METHODS: Using Department of Defense and Veterans Affairs datasets between February 2002 and June 2016, we conducted a retrospective cohort study of 7,787 combat-injured United States service members matched 1:1 to combat-deployed, uninjured service members. The primary exposure was combat injury versus no combat injury. Outcomes were diagnoses of PTSD, depression, and anxiety, defined by International Classification of Diseases 9th and 10th Revision Clinical Modification codes. RESULTS: Compared to noninjured service members, injured service members had higher observed incidence rates per 100 person-years for PTSD (17.1 vs. 5.8), depression (10.4 vs. 5.7), and anxiety (9.1 vs. 4.9). After adjustment, combat-injured patients were at increased risk of development of PTSD (HR 2.92, 95%CI 2.68-3.17), depression (HR 1.47, 95%CI 1.36-1.58), and anxiety (HR 1.34, 95%CI 1.24-1.45). CONCLUSIONS: Traumatic injury is associated with subsequent development of PTSD, depression, and anxiety. These findings highlight the importance of increased screening, prevention, and intervention in patients with exposure to physical trauma.

The Enduring Health Consequences of Combat Trauma: a Legacy of Chronic Disease.

BACKGROUND: A better understanding of the long-term health effects of combat injury is important for the management of veterans' health in the Department of Defense (DoD) and Veterans Affairs (VA) health care systems and may have implications for primary care management of civilian trauma patients. OBJECTIVE: To determine the impact of traumatic injury on the subsequent development of hypertension (HTN), diabetes mellitus (DM), and coronary artery disease (CAD) after adjustment for sociodemographic, health behavior, and mental health factors. DESIGN: Retrospective cohort study of current and former US military personnel with data obtained from both the DoD and VA health care systems. PARTICIPANTS: Combat injured (n = 8727) service members between 1 February 2002 and 14 June 2016 randomly selected from the DoD Trauma Registry matched 1:1 based on year of birth, sex, and branch of service to subjects that deployed to a combat zone but were not injured. MAIN MEASURES: Traumatic injury, stratified by severity, compared with no documented injury. Diagnoses of HTN, DM, and CAD defined by International Classification of Diseases 9th or 10th Revision Clinical Modification codes. KEY RESULTS: After adjustment, severe traumatic injury was significantly associated with HTN (HR 2.78, 95% CI 2.18-3.55), DM (HR 4.45, 95% CI 2.15-9.18), and CAD (HR 4.87, 95% CI 2.11-11.25), compared with no injury. Less severe injury was associated with HTN (HR 1.14, 95% CI 1.05-1.24) and CAD (HR 1.62, 95% CI 1.11-2.37). CONCLUSIONS: Severe traumatic injury is associated with the subsequent development of HTN, DM, and CAD. These findings have profound implications for the primary care of injured service members in both the DoD/VA health systems and may be applicable to civilian trauma patients as well. Further exploration of pathophysiologic, health behavior, and mental health changes after trauma is warranted to guide future intervention strategies.

Dental Caries Risk in the U.S. Air Force: 2009 to 2017.

INTRODUCTION: The Air Force uses dental caries risk assessments (CRA) to determine which active duty Air Force (ADAF) members are at high caries risk (HCR) and will benefit from additional preventive and restorative dental care. The purpose of this study is to describe the caries risk of ADAF from 2009 to 2017 and determine how demographic, military, and tobacco-use characteristics affect caries risk. MATERIALS AND METHODS: Data from ~300,000 ADAF annual dental examinations from 2009 to 2017 were used. The outcome variable investigated was dental caries risk (high, moderate, or low). Independent variables analyzed were: age, sex, race, education, marital status, military rank, service years, flying status, and tobacco use. Descriptive and multivariable analyses were performed to explore associations between potential risk indicators and caries risk outcomes. RESULTS: From 2009 to 2013, there was a steady decline in ADAF that were diagnosed as low caries risk (LCR), from 80.3% to 67.7%. Since 2013, the prevalence of ADAF that are LCR has remained unchanged at about two-thirds of the force. The proportion of the ADAF that are moderate caries risk (MCR) increased from 15.7% in 2009 to 25.3% in 2013 and remained unchanged affecting about a quarter of the force since then. The proportion that was diagnosed as HCR increased from 3.9% in 2009 to 7.1% in 2013 and declined slightly in 2017 (6.0%). After controlling for other covariates, younger age (<20 years old: odds ratio [OR], 4.4; 95% confidence interval [CI], 3.3-5.8), less time in service (≤4 years: OR, 2.1; 95% CI, 1.7-2.6), junior rank (E-1-E-4: OR, 1.6; 95% CI, 1.3-1.8), less education (high-school graduate: OR, 2.3; 95% CI, 2.0-2.6), using tobacco (Smoker: OR, 1.6; 95% CI, 1.5-1.7), being a nonflyer (OR, 1.2; 95% CI, 1.1-1.3), being male (OR, 1.1; 95% CI, 1.1-1.2), or being black (OR, 1.2; 95% CI, 1.1-1.2) were each associated with being HCR. Among the cohort of Airmen who were LCR at baseline, the majority (75.9%) remained at low risk, but for nearly a quarter (24.1%), their risk of caries increased over 9 years. Among those who were originally MCR in 2009, 61.5% improved to LCR, whereas 4.6% progressed to HCR; among those identified as high risk for caries in 2009, a substantial majority (89.1%) improved over 9 years, but 10.9% remained unchanged. CONCLUSIONS: The prevalence of HCR and MCR service members increased from 2009 to 2013 but has remained consistent since 2013. Overall caries risk in the Air Force is lower compared to previously published findings from 2001 to 2004. This suggests that CRA and prevention programs have been effective at helping to reduce caries prevalence among Airmen. Smoking prevalence among ADAF has also declined substantially over the past 16 years which may contribute to overall caries risk reductions. Using a CRA approach may be an effective tool for helping to identify and develop strategies to manage dental caries risk in patients.

Effect of Military Deployment on Diabetes Mellitus in Air Force Personnel.

Introduction: Military deployments relocate service members to austere locations with limited medical capabilities, raising uncertainties whether members with diabetes can participate safely. Military regulations require a medical clearance for service members with diabetes prior to deployment, but there is a dearth of data that can guide the provider in this decision. To alleviate the lack of evidence in this area, we analyzed the change in glycated hemoglobin (HbA1c) and body mass index (BMI) before and after a deployment among active duty U.S. Air Force personnel who deployed with diabetes. Materials and Methods: A retrospective analysis was conducted using HbA1c and BMI values obtained within 3 mo before and within 3 mo after repatriation from a deployment of at least 90 d between January 1, 2004 through December 31, 2014. The study population consisted of 103 and 195 subjects who had an available pre- and post-deployment HbA1c and BMI values, respectively. Paired t-tests were conducted to determine significant differences in HbA1C and BMI values. Results: The majority (73.8%) of members had a HbA1c <7.0% (53 mmol/mol) prior to deployment. For the overall population, HbA1c before and after deployment decreased from 6.7% (50 mmol/mol) to 6.5% (40 mmol/mol) (p = 0.03). Subgroup analysis demonstrated a significant decline in HbA1c among males, those aged 31-40 yr, and those with a pre-deployment HbA1c of >7%. BMI declined for the overall population (28.3 kg/m2 vs. 27.7 kg/m2, p < 0.0001) and for most of the subgroups. Conclusion: Air Force service members who deployed with diabetes, including those with a HbA1c > 7%, experienced a statistically significant improvement in HbA1c and BMI upon repatriation. A prospective study design in the future can better reconcile the effect of a military deployment on a more comprehensive array of diabetes parameters.

Prescription stimulant misuse in a military population.

BACKGROUND: Increased prescription drug misuse has been reported in veterans, yet there has not been a focused look at stimulant misuse in the military community or correlation with deployment injuries and illnesses. Our objective was to identify rates of stimulant misuse and any correlation with deployment in the military population. METHODS: A prospective, anonymous institutional review board-approved survey in the emergency department waiting room of a military tertiary care hospital using a 12-item questionnaire created with fixed response and multiple-choice questions. Stimulant misuse was defined as taking more than prescribed, obtaining stimulants from others, and taking it for a nonprescribed reason. Proportions were assessed by Chi-square test and Fisher's exact test. RESULTS: 26/498 (5%) of respondents reported misusing stimulants in the last 5 years. Misusers were more likely to have a mental health diagnosis, and they suffered either a deployment-related injury or another injury, as compared to those who used stimulants properly (p<0.05). The stimulant misuse did not correlate with age, gender, active duty status, education, location of deployment, number of times deployed, traumatic brain injury diagnosis, or enlistment status. CONCLUSION: Stimulant drug misuse in the military community is associated with mental health conditions, deployment-related injuries, or new physical injuries.

A laparoscopic swine model of noncompressible torso hemorrhage.

BACKGROUND: Hemorrhage persists as the leading cause of potentially preventable civilian and military death. Noncompressible torso hemorrhage (NCTH) is a particularly lethal injury complex, with few contemporary prehospital interventions available. Various porcine models of hemorrhage have been developed for civilian and military trauma research. However, the predominant contemporary models lack key physiologic characteristics including the natural tamponade provided by an intact abdominal wall.To improve physiologic and clinical relevance, we developed a laparoscopic model of NCTH. This approach maintains both the integrity of the peritoneum and the natural tamponade effect of an intact abdominal wall while preserving the intrinsic physiologic responses to hemorrhage. Furthermore, we present data quantifying the contribution of the swine contractile spleen in the context of uncontrolled hemorrhage. METHODS: Anesthetized adult male Yorkshire swine underwent a laparoscopic Grade V liver injury, with or without open preinjury splenectomy. Animals were observed without intervention for a total of 120 minutes after injury to simulate point of injury, transport time, and arrival at hospital. RESULTS: Shed blood-to-body weight ratio did not differ among groups; however, mortality was higher in splenectomized animals (67% vs. 33%). Cox regression modeling demonstrated a critical time point of 45 minutes and blood pressure as significant predictors of mortality. CONCLUSION: This study describes a model of NCTH that reflects clinically relevant physiology in trauma and uncontrolled hemorrhage. In addition, it quantitatively assesses the role of the swine contractile spleen in the described model.

Lineage of origin in rhabdomyosarcoma informs pharmacological response.

Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1.

Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma.

BACKGROUND: Alveolar rhabdomyosarcoma (aRMS) is a myogenic childhood sarcoma frequently associated with a translocation-mediated fusion gene, Pax3:Foxo1a. METHODS: We investigated the complementary role of Rb1 loss in aRMS tumor initiation and progression using conditional mouse models. RESULTS: Rb1 loss was not a necessary and sufficient mutational event for rhabdomyosarcomagenesis, nor a strong cooperative initiating mutation. Instead, Rb1 loss was a modifier of progression and increased anaplasia and pleomorphism. Whereas Pax3:Foxo1a expression was unaltered, biomarkers of aRMS versus embryonal rhabdomyosarcoma were both increased, questioning whether these diagnostic markers are reliable in the context of Rb1 loss. Genome-wide gene expression in Pax3:Foxo1a,Rb1 tumors more closely approximated aRMS than embryonal rhabdomyosarcoma. Intrinsic loss of pRb function in aRMS was evidenced by insensitivity to a Cdk4/6 inhibitor regardless of whether Rb1 was intact or null. This loss of function could be attributed to low baseline Rb1, pRb and phospho-pRb expression in aRMS tumors for which the Rb1 locus was intact. Pax3:Foxo1a RNA interference did not increase pRb or improve Cdk inhibitor sensitivity. Human aRMS shared the feature of low and/or heterogeneous tumor cell pRb expression. CONCLUSIONS: Rb1 loss from an already low pRb baseline is a significant disease modifier, raising the possibility that some cases of pleomorphic rhabdomyosarcoma may in fact be Pax3:Foxo1a-expressing aRMS with Rb1 or pRb loss of function.

Feasibility of video-assisted thoracoscopic surgery lobectomy in Veterans Administration patients.

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) pulmonary lobectomy has been associated with decreased complication rates and length of stay compared with lobectomy by thoracotomy. No studies have addressed VATS lobectomy in Veterans Administration (VA) patients. METHODS: A retrospective review was undertaken of 50 VATS lobectomies performed between August 2007 and June 2009 by one surgeon in a VA hospital, a university-affiliated county hospital, and a private community hospital. RESULTS: VA patients had more medical comorbidities, poorer lung function, greater current smoker status, and fewer preoperative biopsies. Pleural adhesions or hilar lymphadenopathy were encountered more commonly in VA than nonfederal patients. Surgical times and number of procedures performed were greater in VA patients. There was no statistically significant difference in the risk of postoperative complications or chest tube duration although length of stay was longer for VA patients. CONCLUSIONS: VATS lobectomy is feasible in a VA setting. The evidence strongly suggests that veterans can benefit from VATS lobectomy in terms of improved outcomes and diminished length of stay compared with thoracotomy.

Toxic epidermal necrolysis: five years of treatment experience from a burn unit.

BACKGROUND: Toxic epidermal necrolysis (TEN) is a serious drug eruption that results in death in approximately 25% to 50% of patients. There is controversy over whether SCORTEN accurately predicts mortality or if treatment interventions such as intravenous immunoglobulin (IVIg) can alter mortality. OBJECTIVES: We sought to determine whether SCORTEN accurately predicts mortality in this cohort, whether IVIg improved survival, and which drugs and medical comorbidities impacted mortality. METHODS: We summarize our experience prospectively over 5 years and 82 patients. Patients either received supportive care, intravenous immunoglobulin, or cyclosporine as treatment. All patients had a SCORTEN on admission, an offending drug on record, and a list of medical comorbidities. RESULTS: Of the 82 patients, 29% died from TEN. SCORTEN accurately predicted mortality in this cohort with an area under the curve (AUC) of 0.83 in a receiver operator curve (ROC) analysis. A Kaplan-Meier curve did not show improved mortality if patients received IVIg versus supportive care (P = .9). Medications most often responsible for TEN were trimethoprim/sulfamethoxazole, followed by anticonvulsants, nonsteroidal anti-inflammatories, and allopurinol. LIMITATIONS: This prospective cohort study design is not as ideal as patients presenting for a randomized controlled trial. CONCLUSIONS: SCORTEN was an accurate predictor of mortality in this cohort. Age older than 40 years, the presence of metabolic syndrome and/or gout, higher body surface area involvement, higher SCORTEN, and higher number of medical comorbidities statistically significantly increased risk of death. IVIg did not significantly alter mortality. Although the highest number of cases was due to trimethoprim/sulfamethoxazole, the greatest proportion of deaths was due to allopurinol.

18F-FDG microPET imaging detects early transient response to an IGF1R inhibitor in genetically engineered rhabdomyosarcoma models.

BACKGROUND: Alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) are among the most common and most treatment resistant soft tissue sarcomas of childhood. Here, we evaluated the potential of (18)F-Fluorodeoxyglucose (FDG) as a marker of therapeutic response to picropodophyllin (PPP), an IGF1R inhibitor, in a conditional mouse model of ARMS and a conditional model of ERMS/undifferentiated pleomorphic sarcoma (UPS). PROCEDURE: Primary tumor cell cultures from Myf6Cre,Pax3:Fkhr,p53 and Pax7CreER,Ptch1,p53 conditional models of ARMS and ERMS/UPS were found to be highly sensitive to PPP (IC(50) values 150 and 200 nM, respectively). Animals of each model were then treated with 80 mg/kg/day PPP by intraperitoneal injection for 12 days and imaged by (18)F-FDG microPET. RESULTS: Tumor volumes on day 4 for PPP-treated ARMS and ERMS mice were lower than untreated control mouse tumor volumes, although treated tumors were larger than day 0. However, tumor FDG uptake was significantly reduced on day 4 for PPP-treated mice compared to pretreatment baseline or untreated control mice on day 4 (P < 0.05). Nevertheless, by day 12 tumor volumes and FDG uptake for treated mice had increased significantly, indicating rapidly evolving resistance to therapy. CONCLUSIONS: (18)F-FDG PET imaging is a potential imaging biomarker of molecular susceptibility to targeted agents early in treatment for this aggressive form of sarcoma, but may find best use serially for Phase I/II studies where chemotherapy and targeted agents are combined to cytoreduce tumors and abrogate Igf1r inhibitor resistance.

Preclinical testing of erlotinib in a transgenic alveolar rhabdomyosarcoma mouse model.

Rhabdomyosarcoma is an aggressive childhood malignancy, accounting for more than 50% of all soft-tissue sarcomas in children. Even with extensive therapy, the survival rate among alveolar rhabdomyosarcoma patients with advanced disease is only 20%. The receptor tyrosine kinase Epidermal Growth Factor Receptor (EGFR) has been found to be expressed and activated in human rhabdomyosarcomas. In this study we have used a genetically engineered mouse model for alveolar rhabdomyosarcoma (ARMS) which faithfully recapitulates the human disease by activating the pathognomic Pax3:Fkhr fusion gene and inactivating p53 in the maturing myoblasts. We have demonstrated that tumors from our mouse model of alveolar rhabdomyosarcoma express EGFR at both the mRNA and protein levels. We then tested the EGFR inhibitor, Erlotinib, for its efficacy in this mouse model of alveolar rhabdomyosarcoma. Surprisingly, Erlotinib had no effect on tumor progression, yet mice treated with Erlotinib showed 10-20% loss of body weight. These results suggest that EGFR might not be an a priori monotherapy target in alveolar rhabdomyosarcoma.

IL-4R drives dedifferentiation, mitogenesis, and metastasis in rhabdomyosarcoma.

PURPOSE: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. The alveolar subtype of rhabdomyosarcoma (ARMS) is a paradigm for refractory and incurable solid tumors because more than half of the children at diagnosis have either regional lymph node or distant metastases. These studies follow our previous observation that Interleukin-4 receptor α (IL-4Rα) is upregulated in both human and murine ARMS, and that the IL-4R signaling pathway may be a target for abrogating tumor progression. EXPERIMENTAL DESIGN: By in vitro biochemical and cell biology studies as well as preclinical studies using a genetically engineered mouse model, we evaluated the role of IL-4 and IL-13 in IL-4R-mediated mitogenesis, myodifferentiation, and tumor progression. RESULTS: IL-4 and IL-13 ligands accelerated tumor cell growth and activated STAT6, Akt, or MAPK signaling pathways in the human RMS cell lines, RD and Rh30, as well as in mouse primary ARMS cell cultures. IL-4 and IL-13 treatment also decreased protein expression of myogenic differentiation factors MyoD and Myogenin, indicating a loss of muscle differentiation. Using a genetically engineered mouse model of ARMS, we have shown that inhibition of IL-4R signaling pathway with a neutralizing antibody has a profound effect on the frequency of lymph node and pulmonary metastases, resulting in significant survival extension in vivo. CONCLUSIONS: Our results indicate that an IL-4R-dependent signaling pathway regulates tumor cell progression in RMS, and inhibition of this pathway could be a promising adjuvant therapeutic approach.