Biomarker Testing, Treatment, and Outcomes in Patients With Advanced/Metastatic Non-Small Cell Lung Cancer Using a Real-World Database.

BACKGROUND: Little is known about the impact of up-front biomarker testing on long-term outcomes in patients with advanced or metastatic non-small cell lung cancer (a/mNSCLC). This study compared overall survival (OS) by biomarker testing status and by receipt of guideline-concordant therapy in a large real-world cohort of patients with a/mNSCLC in the United States. PATIENTS AND METHODS: This retrospective study used an a/mNSCLC database derived from real-world electronic healthcare records. Patients diagnosed with nonsquamous a/mNSCLC who initiated first-line therapy on or after January 1, 2015, were included. We describe the testing of patients for actionable biomarkers and whether they subsequently received guideline-recommended first-line treatment. OS was defined as the number of months from the initiation of first-line therapy to the date of death or end of follow-up, and was described using Kaplan-Meier analysis. Multivariable Cox proportional hazard modeling was conducted to compare OS between groups adjusting for baseline covariates; adjusted hazard ratios (HRs) were reported. RESULTS: A total of 21,572 patients with a median age of 69 years (IQR, 61-76 years) and follow-up of 9.5 months (IQR, 3.5-21.5 months) were included. Among patients in the database, 88% had a record of receiving testing for at least 1 biomarker at any time, and 69% of these patients received testing before or at the start of first-line treatment. The adjusted hazard of death was 30% higher in patients who never (vs ever) received biomarker testing in the database (HR, 1.30; 95% CI, 1.24-1.37), and 12% higher in patients who did not receive (vs did receive) biomarker testing before or at the start of first-line treatment (HR, 1.12; 95% CI, 1.08-1.16). The adjusted hazard of death was 25% higher in patients who did not receive guideline-concordant first-line treatment (vs those who did) after having a biomarker-positive disease (HR, 1.25; 95% CI, 1.13-1.40). CONCLUSIONS: Findings suggest that receipt of first-line treatment that is concordant with biomarker testing results and treatment guidelines is associated with improved survival outcomes in patients with a/mNSCLC in the United States.

Real-world characteristics and outcomes of advanced non-small-cell lung cancer patients with EGFR exon 19 deletions or exon 21 mutations.

Aim: To estimate real-world (rw) outcomes for first-line therapy in patients with advanced EGF receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), focusing on specific mutation types. Patients & methods: Retrospective observational study (n = 244 patients). Results: Univariate/multivariate analyses showed longer rw progression-free survival (rwPFS) and rwPFS2 in patients with ex19del versus Leu858Arg mutations. Median overall survival was 12.3 months longer with ex19del versus Leu858Arg mutations (HR: 1.47 [95% CI: 0.96-2.25]; p = 0.074). With EGFR-tyrosine kinase inhibitor monotherapy, unadjusted rwPFS for ex19del mutations was longer than for Leu858Arg mutations (HR: 1.62 [95% CI: 1.03-2.56]; p = 0.036). Conclusion: In this rw cohort of patients with advanced EGFR+ NSCLC, ex19del mutations conferred a prognostic advantage over Leu858Arg mutations, with significantly better rwPFS and rwPFS2.

Health and resource burden of a cancer diagnosis on the caregiver: an analysis of administrative claims data.

PURPOSE: Cancer diagnosis is known to affect the family; however, administrative claims data are not commonly used to evaluate the broader impact of cancer diagnosis. This study was designed to evaluate the feasibility of using claims data to explore the impact of cancer diagnosis on the caregiver. METHODS: IBM Marketscan data were used to identify eligible cancer patients, who were required to have a second adult over the age of 18 (defined as "caregiver" for this study) covered by the same the healthcare policy. Eligible control pairs included any two adults in the same policy with no evidence of cancer; for each pair one adult was randomly assigned to be the "patient control" while their partner was assigned as "caregiver control". Probabilistic stratified sampling was used select control pairs for analysis by matching the relative frequencies within sex and age group strata to those of patient/caregiver pairs. Eligible control pairs were probabilistically sampled without replacement until the stratum with at least 0.5 % relative frequency had been completely sampled. Caregiver and caregiver control healthcare resource utilization (HCRU), new diagnoses, and healthcare costs were compared during the 12-month post-diagnosis period. Subgroup analyses were conducted by cancer subtypes (breast, colorectal, lung, gastric, sarcoma) and by sex of the patient and caregiver. RESULTS: A total of 62,893 patient/caregiver pairs and 449,177 control pairs were included. Overall, caregivers used slightly fewer healthcare resources and expended less costs during the 12-month period after the cancer diagnosis than controls (physician visits; 85.8 % vs. 95.7 %; hospitalizations 5.4 % vs. 7.0 %; emergency room visits 15.7 % versus 16.2 %, all p ≤ 0.001). This finding was consistent in all subgroup analyses. New diagnoses were lower in the caregiver cohort, except for mental disorders, which were higher than controls (14.3 % vs. 9.9 %, p < 0.0001). Psychotherapeutic/antidepressant utilization occurred among 21.0 % of caregivers versus 17.2 % of caregiver controls during this period. CONCLUSIONS: It is feasible to use administrative claims data to evaluate the impact of a cancer diagnosis on the caregiver to evaluate outcomes such as HCRU, diagnoses and costs. These findings raise hypotheses about deferment of health care and increased mental distress during the caregiving period.

Randomized phase II study of the PDGFRα antibody olaratumab plus liposomal doxorubicin versus liposomal doxorubicin alone in patients with platinum-refractory or platinum-resistant advanced ovarian cancer.

BACKGROUND: Olaratumab is a platelet-derived growth factor receptor-α (PDGFRα)-targeting monoclonal antibody blocking PDGFRα signaling. PDGFRα expression is associated with a more aggressive phenotype and poor ovarian cancer outcomes. This randomized, open label phase II study evaluated olaratumab plus liposomal doxorubicin compared with liposomal doxorubicin alone in advanced ovarian cancer patients. METHODS: Patients with platinum-refractory or platinum-resistant advanced ovarian cancer were randomized 1:1 to receive liposomal doxorubicin (40 mg/m2, intravenous infusion) administered every 4 weeks with or without olaratumab (20 mg/kg, IV infusion) every 2 weeks. Patients were stratified based on prior response to platinum therapy (refractory vs resistant). The primary efficacy endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, duration of response, and safety. RESULTS: A total of 123 patients were treated (62 olaratumab+liposomal doxorubicin; 61 liposomal doxorubicin). Median PFS was 4.2 months for olaratumab+liposomal doxorubicin and 4.0 months for liposomal doxorubicin (stratified hazard ratio [HR] = 1.043; 95% confidence interval [CI] 0.698-1.558; p = 0.837). Median OS was 16.6 months and 16.2 months in the olaratumab+liposomal doxorubicin and liposomal doxorubicin arms, respectively (HR = 1.098; 95% CI 0.71-1.71). In the platinum-refractory subgroup, median PFS was 5.5 months (95% CI 1.6-9.2) and 3.7 months (95% CI 1.9-9.2) in the olaratumab+liposomal doxorubicin (n = 15) and liposomal doxorubicin arms (n = 16), respectively (HR = 0.85; 95% CI 0.38-1.91). Overall, 59.7% (olaratumab+liposomal doxorubicin) and 65.6% (liposomal doxorubicin) of patients reported grade ≥ 3 adverse events regardless of causality. The most common treatment-emergent adverse events (all grades) regardless of causality were fatigue related (61%), nausea (57%), and constipation (52%) with olaratumab+liposomal doxorubicin and nausea (64%), fatigue related (62%), and mucositis (46%) with liposomal doxorubicin. CONCLUSIONS: The addition of olaratumab to liposomal doxorubicin did not result in significant prolongation of PFS or OS in platinum-resistant or platinum-refractory ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00913835 ; registered June 2, 2009.

Patient-reported pain and other quality of life domains as prognostic factors for survival in a phase III clinical trial of patients with advanced breast cancer.

BACKGROUND: Patient-reported outcomes have been associated with survival in numerous studies across cancer types, including breast cancer. However, the Brief Pain Inventory-Short Form (BPI-SF) and the Rotterdam Symptom Checklist (RSCL) have rarely been investigated in this regard in breast cancer. METHODS: Here we describe a post hoc analysis of the prognostic effect of baseline scores of these instruments on survival in a phase III trial of patients with advanced breast cancer who received gemcitabine plus paclitaxel or paclitaxel alone after anthracycline-based adjuvant or neoadjuvant therapy. The variables for this analysis were baseline BPI-SF "worst pain" and BPI-SF "pain interference" scores, and four RSCL subscales (each transformed to 0-100). Univariate and multivariate Cox models were used, the latter in the presence of 11 demographic/clinical variables. Kaplan-Meier curves and log-rank tests were used to compare survival for patients by BPI-SF or RSCL scores. RESULTS: Of 529 randomized patients, 286 provided BPI-SF data and 336 provided RSCL data at baseline. Univariate analyses identified BPI-SF worst pain and pain interference (both hazard ratios [HR], 1.07 for a 1-point increase; both p ≤ 0.0061) and three of four RSCL subscales [activity level, physical distress, and health-related quality of life (HRQOL) (HR, 0.86-0.91 for 10-point increase all p ≤ 0.0104)], to have significant prognostic effect for survival. BPI-SF worst pain (p = 0.0342) and RSCL activity level (p = 0.0004) were prognostic in the multivariate analysis. Median survival for patients categorized by BPI-SF worst pain score was 23.8 (n = 91), 17.9 (n = 94) and 14.6 (n = 94) months for scores 0, 1-4, and 5-10, respectively (log-rank p = 0.0065). Median survival was 23.8 and 14.6 months for patients (n = 330) with above- and below-median RSCL activity level scores respectively (log-rank p < 0.0001). CONCLUSION: Pretreatment BPI-SF worst pain and RSCL activity scores provide distinct prognostic information for survival in patients receiving paclitaxel or gemcitabine plus paclitaxel for advanced breast cancer even after controlling for multiple demographic and clinical factors. TRIAL REGISTRATION: Clinicaltrials.gov, NCT00006459.

Unsupervised Machine Learning in Countermovement Jump and Isometric Mid-Thigh Pull Performance Produces Distinct Combat and Physical Fitness Clusters in Male and Female U.S. Marine Corps Recruits.

INTRODUCTION: Several challenges face the U.S. Marine Corps (USMC) and other services in their efforts to design recruit training to augment warfighter mobility and resilience in both male and female recruits as part of an integrated model. Strength and power underpin many of the physical competencies required to meet the occupational demands one might face in military. As the military considers adopting force plate technology to assess indices of strength and power, an opportunity presents itself for the use of machine learning on large datasets to deduce the relevance of variables related to performance and injury risk. The primary aim of this study was to determine whether cluster analysis on baseline strength and power data derived from countermovement jump (CMJ) and isometric mid-thigh pull (IMTP) adequately partitions men and women entering recruit training into distinct performance clusters. The secondary aim of this study is then to assess the between-cluster frequencies of musculoskeletal injury (MSKI). MATERIALS AND METHODS: Five hundred and sixty-five males (n = 386) and females (n = 179) at the Marine Corps Recruit Depots located at Parris Island and San Diego were enrolled in the study. Recruits performed CMJ and IMTP tests at the onset of training. Injury data were collected via medical chart review. Combat fitness test (CFT) and physical fitness test (PFT) results were provided to the study team by the USMC. A k-means cluster analysis was performed on CMJ relative peak power, IMTP relative peak force, and dynamic strength index. Independent sample t-tests and Cohen's d effect sizes assessed between-cluster differences in CFT and PFT performance. Differences in cumulative incidence of lower extremity %MSKIs were analyzed using Fisher's exact test. Relative risk and 95% confidence intervals (CIs) were also calculated. RESULTS: The overall effects of cluster designation on CMJ and IMTP outcomes ranged from moderate (relative peak power: d = -0.68, 95% CI, -0.85 to -0.51) to large (relative peak force: d = -1.69, 95% CI, -1.88 to -1.49; dynamic strength index: d = 1.20, 95% CI, 1.02-1.38), indicating acceptable k-means cluster partitioning. Independent sample t-tests revealed that both men and women in cluster 2 (C2) significantly outperformed those in cluster 1 (C1) in all events of the CFT and PFT (P < .05). The overall and within-gender effect of cluster designation on both CFT and PFT performance ranged from small (d > 0.2) to moderate (d > 0.5). Men in C2, the high-performing cluster, demonstrated a significantly lower incidence of ankle MSKI (P = .04, RR = 0.2, 95% CI, 0.1-1.0). No other between-cluster differences in MSKI were statistically significant. CONCLUSIONS: Our results indicate that strength and power metrics derived from force plate tests effectively partition USMC male and female recruits into distinct performance clusters with relevance to tactical and physical fitness using k-means clustering. These data support the potential for expanded use of force plates in assessing readiness in a cohort of men and women entering USMC recruit training. The ability to pre-emptively identify high and low performers in the CFT and PFT can aid in leadership developing frameworks for tailoring training to enhance combat and physical fitness with benchmark values of strength and power.

A Sex Comparison of the Physical and Physiological Demands of United States Marine Corps Recruit Training.

INTRODUCTION: The U.S. Marine Corps (USMC) recruit training is a 13-week preparatory period for military service men and women. Differences in absolute performance capabilities between sexes may impact physical and physiological responses to the demands of recruit training. The purpose of this study was to monitor U.S. Marine Corps recruits throughout recruit training to comparatively assess workload, sleep, stress, and performance responses in men and women. MATERIALS AND METHODS: A total of 281 recruits (men = 182 and women = 99; age = 19 ± 2 years) were monitored and tested. Workload, sleep, and stress assessments occurred at week 2, week 7/8, and week 11 of training. Workload (energy expenditure per kg body mass [EEREL], distance [DIS], steps) and sleep (continuity and duration) were tracked over 72-hour periods using wearable accelerometry and heart rate technology. Stress responses were determined through salivary cortisol analyses. Performance testing, consisting of countermovement vertical jump (CMJ) and isometric mid-thigh pull (IMTP) performance relative to body mass, occurred at weeks 2 and 11. Linear mixed models were used to test for sex, time, and sex-by-time interactions (α < .05). RESULTS: On average, recruits covered 13.0 ± 2.7 km/day, expended 3,762 ± 765 calories/day, and slept 6.2 ± 1.1 hours/night. Sex-by-time interactions were found for DIS, steps, sleep duration, cortisol, and CMJREL performance (P < .05). Planned contrasts revealed that men covered more DIS than women at week 7/8 (P < .001). Women experienced greater step counts compared to men at week 11 (P = .004). Women experienced no significant change in sleep duration (P > .05), whereas men increased sleep duration from week 2 to week 7/8 (P = .03). Women experienced greater sleep duration at week 2 (P = .03) and week 11 (P = .02) compared to men. Women exhibited higher cortisol levels than men at week 2 (P < .001) and week 11 (P < .001). Women experienced declines in cortisol at week 7 compared to week 2 (P < .001). Men experienced no changes in cortisol response at any timepoint (P > .05). Both sexes experienced declines in CMJREL from week 2 to week 11 (P > .001). Sex main effects were observed for EEREL, DIS, CMJREL, and IMTPREL (P < .05) with men experiencing greater overall workloads and producing greater strength and power metrics. Sex main effects were also found for sleep continuity and cortisol (P < .05), for which men experienced lower values compared to women. Time main effects were observed for EEREL, DIS, steps, cortisol, CMJREL, and IMTPREL (P < .05). CONCLUSIONS: This study not only highlights the known sex differences between men and women but also sheds light on the different physical and physiological responses of each sex to military training. Interestingly, the greatest physical demands incurred earlier in the training cycle. Despite declining workloads, the stress response was maintained throughout the training, which may have implications for adaptation and performance. In addition, average sleep duration fell notably below recommendations for optimizing health and recovery. Effectively monitoring the demands and performance outcomes during recruit training is essential for determining individual fitness capabilities, as well as establishing the effectiveness of a training program. Individual performance assessments and adequately periodized workloads may help to optimize recruit training for both men and women.

Neuromuscular Strength and Power Predict Musculoskeletal Injury and Attrition During Marine Corps Recruit Training.

INTRODUCTION: Elevated rates of musculoskeletal injuries (MSIs) and attrition are documented in military recruit training. By identifying and addressing modifiable risk factors, the rate of successful training completion and military readiness can be enhanced. Despite their impact, the causes of MSIs and attrition among U.S. Marine Corps (USMC) recruits remain underexplored. This study investigates demographic, psychological, and physiological predictors of MSIs and attrition among USMC recruits. MATERIALS AND METHODS: In this prospective cohort study, we evaluated USMC recruits at Marine Corps Recruit Depot, Parris Island and San Diego. Recruits were briefed and invited to volunteer. All recruits who were medically cleared to participate in recruit training were eligible to participate in the study. We gathered baseline data on potential predictors at the start of training, with follow-up data on MSIs and attrition collected post-training. Analyzed predictors encompassed dynamic and static strength measures from countermovement jumps, isometric mid-thigh pulls; and participant surveys. We employed multiple logistic regression to discern risk factors for MSI and attrition. RESULTS: Our study comprised 584 USMC recruits (183 female recruits, 19.49 ± 1.88 years, 160.10 ± 7.17 cm, 61.19 ± 8.05 kg; 401 males, 18.94 ± 1.92 years, 172.97 ± 7.26 cm, 73.86 ± 11.04 kg). We observed 193 MSIs in 135 recruits, with 80.31% affecting the lower extremity (LE). Notably, lower relative peak power (odds ratio [OR] 0.91 [0.89, 0.94], P < .001) and shorter eccentric deceleration duration (OR 0.99 [0.99, 1.00], P = .005) were significant predictors of MSIs. Specifically, for LE MSIs, similar trends were noted for relative peak power and eccentric deceleration duration, with additional risks associated with lower body mass index (OR 0.93 [0.86, 0.99], P = .036) and previous LE MSIs (OR 2.25 [1.18, 4.27], P = .013). Attrition was more likely with a reduced eccentric deceleration impulse (OR 0.98 [0.97, 0.99], P < .001) and prolonged time to peak force (OR 1.36 [1.17, 1.59], P < .001) and cigarette use (OR 2.12 [1.01, 4.43], P = .046). CONCLUSIONS: MSIs and attrition during USMC recruit training significantly undermine force readiness and escalate costs. Our research has pinpointed several modifiable risk factors, chiefly reduced muscular power and cigarette smoking. We advocate for neuromuscular training programs to bolster strength and power, integrated nutrition and exercise strategies for optimal body composition, and support for smoking cessation to alleviate the incidence of MSIs and curtail attrition. Initiating training with a gradual increase in activity intensity can provide a critical window to correct pre-existing neuromuscular imbalances and weaknesses, particularly those stemming from prior MSIs. Effectively addressing these risk factors is pivotal for diminishing the rates of MSIs and attrition among recruits, thereby enhancing overall military readiness and operational efficiency.

United States Marine Corps Recruit Training Demands Associated With Performance Outcomes.

INTRODUCTION: United States Marine Corps' (USMC) recruit training is a 13-week program designed to maximize physical and mental performance adaptations. The purpose of this study was to evaluate the training demands and characteristics that are associated with performance outcomes during USMC recruit training. MATERIALS AND METHODS: A total of 196 recruits (M = 97 and W = 99) were monitored and tested throughout training. Laboratory-based performance testing occurred at the start of weeks 2 and 11 and consisted of body mass assessments, countermovement vertical jump, and isometric mid-thigh pull. Military-specific performance testing occurred twice within the first 8 weeks of training and included the physical fitness test (PFT) and combat fitness test (CFT) implemented by the USMC. Resilience data were collected at week 2 using the Connor-Davidson Resilience Scale. Workload, sleep, and stress responses were monitored at weeks 2, 7, and 11. Recruits were provided with a wearable tracking device which utilized heart rate and accelerometry-based technology to determine energy expenditure (EE), distances (DIS), and sleep metrics. Data were averaged over a 3-day period. Salivary cortisol testing occurred at the start of each monitoring week. Change scores were calculated for performance tests, and body mass was calculated from data obtained at week 2 to week 11. Area under the curve was calculated for the workload, sleep metrics, and cortisol responses using the trapezoidal method. Pearson product-moment correlations (r) were used to assess the relationships between training demands and performance. An α level of 0.05 was used to establish significance. RESULTS: A moderate positive correlation was found between changes in body mass and peak power (P < .001; r = 0.43). Weak positive correlations were found between changes in body mass and peak force (P = .002; r = 0.28), as well as body mass and resilience (P = .03; r = 0.19). A moderate negative correlation was observed between changes in body mass and PFT (P < .001; r = -0.49). A weak negative correlation was found between changes in body mass and EE (P = .003; r = -0.24). A weak negative correlation was found between changes in peak power and EE (P = .001; r = -0.29). A weak positive correlation was found between changes in peak power and changes in CFT (P = .05; r = 0.19) A weak negative correlation was found between changes in sleep continuity and CFT (P = .02; r = -0.20). A weak negative correlation was found between cortisol and changes in PFT (P = .05; r = -0.20). A weak negative correlation was found between cortisol and both EE (P = .001; r = -0.27) and DIS (P = .045; r = -0.16). A weak negative correlation was found between EE and sleep continuity (P < .001; r = -0.34). Weak negative correlations were found between sleep duration and both DIS (P = .01; r = -0.18) and steps (P = .003; r = -0.21). CONCLUSIONS: Increases in body mass throughout training were positively associated with strength and power changes, but negatively related to PFT scores. Changes in peak power related to improvements in CFT scores; however, higher workloads (i.e., EE) were negatively associated with peak power. The identification of the USMC physical and physiological training demands that are associated with performance outcomes may be a valuable resource to guide conditioning efforts to boost military readiness.

Design Considerations for a Multidisciplinary Approach to Provide Policy Recommendations on Gender-Integrated Recruit Training in the Marine Corps.

INTRODUCTION: Recruit training is designed to transform civilians into physically fit military service members, who embody their service's core values and possess military discipline and skills. At the time this research began, the U.S. Marine Corps (USMC) remained the only service that segregated recruits by gender at the lowest unit level (e.g., platoon) and employed gender-segregated drill instructor teams. USMC's Marine Corps Recruit Depots (MCRD) must comply with a 2020 Congressional Mandate to not segregate training by gender in Parris Island by 2025 and San Diego by 2028. In turn, USMC requested an independent scientific study to analyze current approaches to gender integration at recruit training to propose alternate models and other policy recommendations that increase gender integration while maintaining current USMC standards. The Marine Corps is currently evaluating alternate models and recommendations to optimize entry-level training. This article outlines considerations for choosing the optimal research study design, research methods, and types of data collected in a study intended to provide policy recommendations on gender-integrated recruit training for the USMC. MATERIALS AND METHODS: Research data were collected during visits to the MCRDs and selected recruit training locations for the Army, Air Force, Navy, and Coast Guard. Data collection on USMC recruits from three cohorts involved social science assessments (focus groups and surveys) and human performance testing (countermovement jumps and isometric mid-thigh pulls, sleep and activity wearables, and cortisol data) at multiple points in the training cycle. Data on recruits from the sister services were limited to social science assessments. Approximately 600 recruits between the two MCRDs and 160 recruits from the sister services participated in the study during a 7-month timeframe in 2021. The research team conducted extensive ethnographic observations of recruit training at all selected research sites and interviewed training cadre, drill instructors, and service leadership responsible for recruit training (∼90 interviews). Additionally, the research team interviewed 20 experts on gender integration or recruit training who possessed alternate viewpoints from the current USMC practice. RESULTS: The mixed methods study was designed to assess the current gender integration practices at recruit training across the services to generate alternative models of gender integration for USMC. The research team developed a set of multidisciplinary objectives and research questions serving as the foundation of the research study design and data collection process. The study was designed to collect qualitative, quantitative, and administrative data informed by social science and human performance disciplines. To ensure that all aspects and implications relevant to gender integration were considered, select data were collected across services and with stakeholders at all levels. CONCLUSIONS: This multidisciplinary research approach provided a comprehensive picture of the current USMC recruit training models. The research team captured multiple perspectives and data points for analysis through an expansive view on gender integration across all services, by interacting with participants at all levels of the institutions in varied ways. The information and data gathered enabled the research team to establish objective, data-driven alternate models, and recommendations for enhancing gender integration at recruit training for the USMC.

Increasing Gender Integration in U.S. Marine Corps Recruit Training: Policy Recommendations and Rationales From an Interdisciplinary Study.

INTRODUCTION: This article describes alternate models and policy recommendations created by an interdisciplinary team of researchers to increase gender integration at U.S. Marine Corps (USMC) recruit training. The USMC requested a study to analyze current approaches to gender integration at recruit training and provide alternate models that maximize integration, while continuing to train marines to established standards. USMC remains the only service that segregates recruits by gender at the lowest unit level (e.g., platoon) in recruit training and maintains gender-segregated drill instructor teams (i.e., same-gender teams train platoons of same-gender recruits). MATERIALS AND METHODS: A mixed-method, interdisciplinary approach was used to capture multiple perspectives and informed recommendations and alternate models for gender integration. The team studied select USMC, army, navy, air force, and coast guard recruit training locations, between June and November 2021. At each site, the team collected qualitative, quantitative, and administrative data as well as physical performance metrics and human performance outcomes. Study participants included recruits, drill instructors, training cadre, service leaders, and subject matter experts on gender integration in military services. Each alternate model was designed to maximize the feasibility of implementation within current USMC training conditions. RESULTS: The research team developed three alternate models and several policy recommendations. Alternate model 1 proposed a methodology for mixed-gender drill instructor teams within the Integrated Company model, USMC's current integrated training model. Alternate model 2 proposed an Integrated Company Plus model which increases the number and types of gender-integrated training events at or below the platoon level within the Integrated Company model. Alternate model 3 outlined an integrated platoon model where recruits fall out into integrated training platoons after their morning routine, with two options of varying integration based on USMC priorities for integration. The team also proposed a set of policy recommendations independent of the three alternate models to support current and future gender integration efforts at the Marine Corps Recruit Depots. CONCLUSIONS: Gender-integrated military training has been shown to positively alter perceptions and evaluations of women in military settings over detrimental aspects developed by gender-segregated training. The study team recommended USMC train recruits in the Integrated Company model with mixed-gender drill instructor teams (alternate model 1) and integrate more training events following the priority tiers outlined in the Integrated Company plus model (alternate model 2). The combined execution of these two alternate models would provide USMC recruits increased exposure to direct, sustained training from opposite-gender drill instructors and deliver intentional training opportunities for male and female recruits to work together and interact in meaningful ways. The integrated platoon model (alternate model 3) would offer USMC recruits the most direct exposure to training and working with members of the opposite gender, but it requires substantial changes to current logistics, accountability, and training procedures.

Results of a Randomized, Double-Blind, Placebo-Controlled, Phase 1b/2 Trial of Nabpaclitaxel + Gemcitabine ± Olaratumab in Treatment-Naïve Participants with Metastatic Pancreatic Cancer.

The efficacy and safety of olaratumab plus nabpaclitaxel and gemcitabine in treatment-naïve participants with metastatic pancreatic ductal adenocarcinoma was evaluated. An initial phase 1b dose-escalation trial was conducted to determine the olaratumab dose for the phase 2 trial, a randomized, double-blind, placebo-controlled trial to compare overall survival (OS) in the olaratumab arm vs. placebo arms. In phase 1b, 22 participants received olaratumab at doses of 15 and 20 mg/kg with a fixed dose of nabpaclitaxel and gemcitabine. In phase 2, 159 participants were randomized to receive olaratumab 20 mg/kg in cycle 1 followed by 15 mg/kg in the subsequent cycles (n = 81) or the placebo (n = 78) on days 1, 8, and 15 of a 28-day cycle, plus nabpaclitaxel and gemcitabine. The primary objective of the trial was not met, with a median OS of 9.1 vs. 10.8 months (hazard ratio [HR] = 1.05; 95% confidence interval [CI]: 0.728, 1.527; p = 0.79) and the median progression-free survival (PFS) was 5.5 vs. 6.4 months (HR = 1.19; 95% CI: 0.806, 1.764; p = 0.38), in the olaratumab vs. placebo arms, respectively. The most common treatment-emergent adverse event of any grade across both arms was fatigue. Olaratumab plus chemotherapy failed to improve the OS or PFS in participants with metastatic PDAC. There were no new safety signals.

Physiological characteristics predictive of passing military physical employment standard tasks for ground close combat occupations in men and women.

Challenges for some women meeting the physical employment standards (PES) for ground close combat (GCC) roles stem from physical fitness and anthropometric characteristics. The purpose of this study was to identify the modifiable and nonmodifiable characteristics predictive of passing GCC-based PES tasks and determine the modifiable characteristics suitable to overcome nonmodifiable limitations. 107 adults (46 women) underwent multiday testing assessing regional and total lean mass (LM), percent body fat (BF%), aerobic capacity (V̇O2peak), strength, power, and PES performance. Predictors with p-value <0.200 were included in stepwise logistic regression analysis or binary logistic regression when outcomes among sexes were insufficient. Relative and absolute arm LM (OR: 4.617-8.522, p < 0.05), leg LM (OR: 2.463, p < 0.05), and upper body power (OR: 2.061, p < 0.05) predicted medicine ball chest throw success. Relative and absolute arm LM (OR: 3.734-11.694, p < 0.05), absolute trunk LM (OR: 2.576, p < 0.05), and leg LM (OR: 2.088, p < 0.05) predicted casualty drag success. Upper body power (OR: 3.910, p < 0.05), absolute trunk LM (OR: 2.387, p < 0.05), leg LM (OR: 2.290, p < 0.05), and total LM (OR: 1.830, p < 0.05) predicted maximum single lift success. Relative and absolute arm LM (OR: 3.488-7.377, p < 0.05), leg LM (OR: 1.965, p < 0.05), and upper body power (OR: 1.957, p < 0.05) predicted water can carry success. %BF (OR: 0.814, p = 0.007), V̇O2peak (OR: 1.160, p = 0.031), and lower body strength (OR: 1.059, p < 0.001) predicted repeated lift and carry success. V̇O2peak (OR: 1.540, p < 0.001) predicted 2-km ruck march success. Modifiable characteristics were the strongest predictors for GCC-based PES task success to warrant their improvement for enhancing PES performance for women.

Quality of life in patients with advanced non-small-cell lung cancer given maintenance treatment with pemetrexed versus placebo (H3E-MC-JMEN): results from a randomised, double-blind, phase 3 study.

BACKGROUND: Pemetrexed maintenance therapy significantly improved overall survival and progression-free survival compared with placebo, and had a good safety profile in a phase 3 placebo-controlled study in patients with advanced non-small-cell lung cancer (NSCLC). Results for quality of life, symptom palliation, and tolerability are presented here. METHODS: After four cycles of platinum-based induction therapy, 663 patients with stage IIIB or stage IV NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (in a 2:1 ratio) from March 15, 2005, to July 20, 2007, using the Pocock and Simon minimisation method to receive pemetrexed (500 mg/m(2) every 21 days; n=441) or placebo (n=222) plus best supportive care until disease progression. The primary efficacy data have been reported previously. Patients completed the Lung Cancer Symptom Scale (LCSS) at baseline, after each cycle, and post-discontinuation. Worsening of symptoms was defined as an increase of 15 mm or more from baseline on a 100 mm scale for each LCSS item. The primary outcome for these quality-of-life analyses was time to worsening of symptoms, analysed for all randomised patients. This study is registered with ClinicalTrials.gov, number NCT00102804. FINDINGS: Baseline characteristics, including LCSS scores, were well balanced between groups. Baseline LCSS scores were low, indicating low symptom burden for patients without disease progression after completion of first-line treatment. Longer time to worsening was recorded for pain (hazard ratio [HR] 0·76, 95% CI 0·59-0·99; p=0·041) and haemoptysis (HR 0·58, 95% CI 0·34-0·97; p=0·038) with pemetrexed than with placebo; no other significant differences in analyses of time to worsening were noted. Additional longitudinal analyses showed a greater increase in loss of appetite in the pemetrexed group than in the placebo group (4·3 mm vs 0·2 mm; p=0·028). Rates of resource use were statistically higher for pemetrexed than for placebo: admissions to hospital for drug-related adverse events (19 [4%] vs none; p=0·001), transfusions (42 [10%] vs seven [3%]; p=0·003), and erythropoiesis-stimulating agents (26 [6%] vs four [2%]; p=0·017). INTERPRETATION: Quality of life during maintenance therapy with pemetrexed is similar to placebo, except for a small increase in loss of appetite, and significantly delayed worsening of pain and haemoptysis. In view of the improvements in overall and progression-free survival noted with pemetrexed maintenance therapy, such treatment is an option for patients with advanced non-squamous NSCLC who have not progressed after platinum-based induction therapy. FUNDING: Eli Lilly.

Initial versus early switch to targeted therapy during first-line treatment among patients with biomarker-positive advanced or metastatic non-small cell lung cancer in the United States.

OBJECTIVES: This study compared outcomes between patients with biomarker-positive advanced/metastatic non-small cell lung cancer (a/mNSCLC) who initiated treatment with targeted therapy versus those who initiated chemotherapy-based treatment and switched to targeted therapy during the first ∼3 cycles (defined as the first 56 days) of first-line treatment. MATERIALS AND METHODS: This was an observational study of patients with a/mNSCLC who received targeted therapy from a nationwide electronic health record (EHR)-derived de-identified database. Outcomes were compared between those who initiated targeted therapy versus those who switched from chemotherapy to a targeted agent. Time-to-event outcomes were evaluated using Kaplan-Meier method; Cox proportional hazards models (adjusted for baseline covariates) were used to compare outcomes between groups. RESULTS: Of the 4,244 patients in this study, 3,107 (73.2%) initiated the first line with targeted therapy and 346 (8.2%) switched to targeted therapy. Patients who received initial targeted therapy were significantly more likely to be non-smokers, treated in an academic practice setting, and of slightly older age (all p < 0.05). Patients who received initial targeted therapy also had a significantly longer time to start of first-line treatment (35.8 vs 25.3 days, p < 0.001). No significant differences were observed for clinical outcomes between groups. CONCLUSION: In both unadjusted and adjusted analyses, there were no differences in the clinical outcomes observed among patients with a/mNSCLC in this study. This study found that initiating chemotherapy with an early switch to targeted therapy (within 56 days) of receiving biomarker positive results may be an acceptable strategy for a patient for whom immediate care is needed.

Results of an Open-label, Phase Ia/b Study of Pembrolizumab plus Olaratumab in Patients with Unresectable, Locally Advanced, or Metastatic Soft-Tissue Sarcoma.

PURPOSE: The study evaluated safety and efficacy of olaratumab + pembrolizumab in patients with unresectable locally advanced/metastatic soft-tissue sarcoma (STS) with disease progression on standard treatment. PATIENTS AND METHODS: This was open-label, multicenter, nonrandomized, phase Ia/Ib dose-escalation study followed by cohort expansion (olaratumab + pembrolizumab intravenous infusion). Primary objectives were safety and tolerability. RESULTS: The majority of patients enrolled (n = 41) were female [phase Ia: 9 of 13, phase Ib/dose-expansion cohort (DEC), 17 of 28], aged < 65 years. In phases Ia and Ib, 13 and 26 patients received prior systemic therapy, respectively. Patients received olaratumab 15 mg/kg (phase Ia; cohort 1) or 20 mg/kg (phase Ia; cohort 2 and phase Ib) and pembrolizumab 200 mg (phase Ia/Ib). The median (Q1-Q3) duration of therapy (olaratumab) was 6.0 (3.0-11.9; cohort 1), 14.4 (12.4-20.9; cohort 2), and 14.0 (6.0-21.8) weeks (DEC). No dose-limiting toxicities and few grade ≥ 3 treatment-emergent adverse events [TEAE; 15 mg/kg: 2 (increased lipase); 20 mg/kg: 1 (increased lipase), 1 (colitis), 2 (diarrhea), 3 (anemia)] were reported. Two TEAEs (increased lipase) were related to study discontinuations. Twenty-one patients reported mild (grade ≤ 2) TEAEs [phase Ia, disease control rate (DCR):14.3% (1/7, cohort 1); 66.7% (4/6, cohort 2); no responses were reported; phase Ib, DCR: 53.6% (15/28); objective response rate: 21.4% (6/28; RECIST and irRECIST criteria)]. No response was observed in patients with programmed death ligand-1-positive tumors. CONCLUSIONS: Antitumor activity was observed in some patients in DEC, and combination was well tolerated with manageable safety profile. Further studies are warranted to evaluate the efficacy and mechanistic impact of platelet-derived growth factor receptor inhibitors with immune checkpoint modulator coadministration.

Randomized Phase 2 Clinical Trial of Olaratumab in Combination with Gemcitabine and Docetaxel in Advanced Soft Tissue Sarcomas.

Gemcitabine plus docetaxel is an effective treatment regimen for advanced soft tissue sarcomas (STSs). However, the prognosis for patients remains poor, and thus there is an urgent medical need for novel and effective therapies to improve long-term outcomes. The aim of the ANNOUNCE 2 trial was to explore the addition of olaratumab (O) to gemcitabine (G) and docetaxel (D) for advanced STS. Adults with unresectable locally advanced/metastatic STS, ≤2 prior lines of systemic therapy, and ECOG PS 0-1 were eligible. In Phase 2, patients were randomized 1:1 from two cohorts (O-naïve and O-pretreated) to 21-day cycles of olaratumab (20 mg/kg Cycle 1 and 15 mg/kg other cycles, Days 1 and 8), gemcitabine (900 mg/m2, Days 1 and 8), and docetaxel (75 mg/m2, Day 8). The primary objective was overall survival (OS) in the O-naïve population (α level = 0.20). Secondary endpoints included OS (O-pretreated), other efficacy parameters, patient-reported outcomes, safety, pharmacokinetics, and immunogenicity. A total of 167 and 89 patients were enrolled in the O-naïve and O-pretreated cohorts, respectively. Baseline patient characteristics were well balanced. No statistically significant difference in OS was observed between the investigational vs. control arm for either cohort (O-naïve cohort: HR = 0.95 (95% CI: 0.64-1.40), p = 0.78, median OS, 16.8 vs. 18.0 months; O-pretreated cohort: HR = 0.67 (95% CI: 0.39-1.16), p = 0.15, median OS 19.8 vs. 17.3 months). Safety was manageable across treatment arms. There was no statistically significant difference in the primary endpoint of OS between the two arms in the O-naïve population, and therefore based on hierarchical evaluation no other outcomes in this study can be considered statistically significant. No new safety signals were observed.

Twelve weeks of concurrent resistance and interval training improves military occupational task performance in men and women.

In the British Army, ground close combat roles have opened to women, however, they must pass the newly developed, gender-neutral Role Fitness Tests for Soldiers (RFT(S)). Due to physiological differences between sexes, training that optimally prepares both sexes for military occupational demands and the RFT(S) is needed. The purpose of this study was to determine the efficacy of a 12-week periodized strength and power programme with concurrent interval training on RFT(S) performance and determine if performance adaptations differed between sexes. 39 recruit-aged (18-35 yrs) participants, including 21 men (29 ± 1 yrs) and 18 women (27 ± 1 yrs), completed the study. Participants performed 3 training sessions per week that included strength and power resistance training followed by interval training. Pre- to post-training, improvements were observed for seated medicine ball throw (4.5%, p < 0.001), casualty drag (29.8%, p < 0.001), single lift (8.9%, p < 0.001), water can carry (13.8%, p = 0.012), repeated lift and carry (6.5%, p < 0.001), 2-km load carriage (7.2%, p < 0.001) and 2-km run (3.2%, p = 0.021). Pre- to post-training improvements were also observed for maximal squat (27.0%, p < 0.001), bench press (8.9%, p < 0.001) and deadlift (24.6%, p < 0.001) maximal strength, but not upper body power or aerobic capacity. No differences in RFT(S) improvements were observed between sexes, however men performed better than women in all RFT(S) and physical performance measures. Concurrent resistance and interval training improves military occupational performance in men and women; however, women may need more training than men to pass the gender-neutral RFT(S).

Twelve weeks of concurrent resistance and interval training improved seated medicine ball throw, casualty drag, single lift, water can carry, repeated lift and carry, 2-km load carriage and 2-km run performance, military occupational performance measures that comprise the British Army Role Fitness Test for Soldiers (RFT(S)).Men and women demonstrated similar military occupational performance improvements from pre- to post-training, however, men performed better than women in all measures.Simple linear regression analyses between improvements in RFT(S) tasks and measures of physical fitness (one-repetition maximal strength, upper body power, lower body power, aerobic capacity) demonstrated limited significant associations suggesting that military occupational performance improvement relies on simultaneous development of multiple fitness domains.

Exploratory Analysis of Patients With Gastric/Gastroesophageal Junction Adenocarcinoma With or Without Liver Metastasis From the Phase 3 RAINBOW Study.

PURPOSE: Liver metastasis (LM) is reported in approximately 40% of patients with advanced/metastatic gastric/gastroesophageal junction adenocarcinoma (metastatic esophagogastric adenocarcinoma; mGEA) and is associated with a worse prognosis. This post-hoc analysis from the RAINBOW trial reported the efficacy, safety, and biomarker outcomes of ramucirumab and paclitaxel combination treatment (RAM+PAC) in patients with (LM+) and without (LM-) LM at baseline. MATERIALS AND METHODS: Patients (n=665) were randomly assigned on a 1:1 basis to receive either RAM+PAC (LM+: 150, LM-: 180) or placebo and paclitaxel (PL+PAC) (LM+: 138, LM-: 197). The overall survival (OS) and progression-free survival (PFS) were evaluated using stratified Kaplan-Meier and Cox regression models. The correlation of dichotomized biomarkers (VEGF-C, D; VEGFR-1,2) with efficacy in the LM+ versus LM- subgroups was analyzed using the Cox regression model with reported interaction P-values. RESULTS: The presence of LM was associated with earlier progression than those without LM, particularly in patients receiving PL+PAC (hazard ratio [HR], 1.68). RAM+PAC treatment improved OS and PFS irrespective of LM status but showed greater improvement in LM+ than that in LM- (OS HR, 0.71 [LM+] vs. 0.88 [LM-]; PFS HR, 0.47 [LM+] vs. 0.76 [LM-]). Treatment-emergent adverse events were similar between patients with and without LM. No predictive relationship was observed between biomarker levels (VEGF-C, D; VEGFR-1,2) and efficacy outcome (OS, PFS) (all interaction P-values >0.05). CONCLUSIONS: RAM provided a significant benefit, irrespective of LM status; however, its effect was numerically stronger in patients with LM. Therefore, RAM+PAC is a clinically meaningful therapeutic option for patients with mGEA and LM. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01170663.

Overall Survival and Safety With Pemetrexed/Platinum ± Anti-VEGF Followed by Pemetrexed ± Anti-VEGF Maintenance in Advanced Nonsquamous Non-Small-Cell Lung Cancer: A Pooled Analysis of 4 Randomized Studies.

BACKGROUND: Before immune checkpoint blockade therapy, chemotherapy with pemetrexed maintenance was the standard of care for patients with advanced nonsquamous non-small-cell lung cancer (NSQ-NSCLC) and remains such where immunotherapy is not applicable. This pooled analysis aimed to characterize overall survival (OS) and safety of pemetrexed ± anti-VEGF maintenance, by treatment duration. PATIENTS AND METHODS: Data from 4 randomized clinical trials (PARAMOUNT, PRONOUNCE, PointBreak, JVBL) of patients with NSQ-NSCLC receiving pemetrexed ± anti-VEGF maintenance therapy were pooled as 2 groups (Group A: pemetrexed-only maintenance, n = 486; and Group B: pemetrexed + anti-VEGF maintenance, n = 329). OS and treatment-emergent adverse events (TEAEs) were analyzed in both groups by treatment duration. RESULTS: Baseline characteristics were well balanced between both groups. Median OS did not significantly differ between Group A (16.1 months) and Group B (18.4 months; hazard ratio: 1.17, P= .1417). A correlation between median OS and treatment duration was numerically stronger in Group A (r = 0.72) versus B (r = 0.62). Across treatment groups, TEAEs were largely grade 1 to 2 and, with few exceptions, did not increase with increased treatment duration. CONCLUSION: There was no significant OS difference between pemetrexed-only and pemetrexed ± anti-VEGF maintenance in patients with NSQ-NSCLC. Patients receiving pemetrexed + anti-VEGF experienced a slightly less favorable safety profile with more reported TEAEs compared to pemetrexed monotherapy. Pemetrexed ± anti-VEGF maintenance therapy may be considered in NSQ-NSCLC, based on an individualized patient approach, particularly where immunotherapy is not clinically indicated.