Clinical Outcomes of Enzalutamide in Metastatic Hormone-sensitive Prostate Cancer in Patients Aged <75 and ≥75 Years: ARCHES Post Hoc Analysis.

BACKGROUND: In ARCHES, treatment intensification of androgen deprivation therapy (ADT) with enzalutamide versus placebo improved clinical outcomes in metastatic hormone-sensitive prostate cancer (mHSPC). Understanding the benefits and tolerability of enzalutamide for men aged ≥75 yr may inform disease management. OBJECTIVE: To determine whether age is associated with clinical outcomes in mHSPC. DESIGN, SETTING, AND PARTICIPANTS: A post hoc analysis of the multinational, double-blind, randomized, placebo-controlled, phase 3 ARCHES trial in 1150 men with mHSPC (median follow-up [mo]: <75 yr, 44.6; ≥75 yr, 44.3) was performed. INTERVENTION: Randomization 1:1 to enzalutamide (160 mg/d) plus ADT or placebo plus ADT; stratification by disease volume and prior docetaxel use. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS), radiographic progression-free survival (rPFS), safety, and other secondary endpoints were compared between age groups (<75 and ≥75 yr) and treatment arms (Cox proportional hazard models). RESULTS AND LIMITATIONS: Men aged <75 versus ≥75 yr had longer OS (enzalutamide plus ADT: hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.47-0.91; p = 0.02; placebo plus ADT: HR 0.81; 95% CI 0.60-1.09; p = 0.13) and rPFS (enzalutamide plus ADT: HR 0.78; 95% CI 0.58-1.04; p = 0.12; placebo plus ADT: HR 0.98; 95% CI 0.74-1.30; p = 0.007). Enzalutamide improved OS (<75 yr: HR 0.61; 95% CI 0.47-0.79; ≥75 yr: HR 0.76; 95% CI 0.54-1.09) and secondary efficacy endpoints without evidence of statistical heterogeneity, and was generally well tolerated in both age groups, with minimal quality-of-life impact. Older versus younger patients experienced more frequent dose interruptions (20.2% vs 10.9%) and treatment-emergent adverse events (95.2% vs 89.1%). Post hoc examination and small sample size preclude definitive conclusions. CONCLUSIONS: Enzalutamide plus ADT improved efficacy outcomes and was generally well tolerated despite shorter treatment exposure in older patients, indicating enzalutamide's utility in patients with mHSPC aged <75 and ≥75 yr. PATIENT SUMMARY: Enzalutamide is a drug approved to treat men with prostate cancer. In this report, we compared patients aged <75 and ≥75 yr treated with enzalutamide plus androgen deprivation therapy to determine whether age affected how long they lived without the cancer spreading to other parts of their body. We found that, although younger patients had more favorable survival outcomes, enzalutamide was associated with longer survival and reduced disease spread in both age groups.

Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer.

BACKGROUND: Patients with prostate cancer who have high-risk biochemical recurrence have an increased risk of progression. The efficacy and safety of enzalutamide plus androgen-deprivation therapy and enzalutamide monotherapy, as compared with androgen-deprivation therapy alone, are unknown. METHODS: In this phase 3 trial, we enrolled patients with prostate cancer who had high-risk biochemical recurrence with a prostate-specific antigen doubling time of 9 months or less. Patients were randomly assigned, in a 1:1:1 ratio, to receive enzalutamide (160 mg) daily plus leuprolide every 12 weeks (combination group), placebo plus leuprolide (leuprolide-alone group), or enzalutamide monotherapy (monotherapy group). The primary end point was metastasis-free survival, as assessed by blinded independent central review, in the combination group as compared with the leuprolide-alone group. A key secondary end point was metastasis-free survival in the monotherapy group as compared with the leuprolide-alone group. Other secondary end points were patient-reported outcomes and safety. RESULTS: A total of 1068 patients underwent randomization: 355 were assigned to the combination group, 358 to the leuprolide-alone group, and 355 to the monotherapy group. The patients were followed for a median of 60.7 months. At 5 years, metastasis-free survival was 87.3% (95% confidence interval [CI], 83.0 to 90.6) in the combination group, 71.4% (95% CI, 65.7 to 76.3) in the leuprolide-alone group, and 80.0% (95% CI, 75.0 to 84.1) in the monotherapy group. With respect to metastasis-free survival, enzalutamide plus leuprolide was superior to leuprolide alone (hazard ratio for metastasis or death, 0.42; 95% CI, 0.30 to 0.61; P<0.001); enzalutamide monotherapy was also superior to leuprolide alone (hazard ratio for metastasis or death, 0.63; 95% CI, 0.46 to 0.87; P = 0.005). No new safety signals were observed, with no substantial between-group differences in quality-of-life measures. CONCLUSIONS: In patients with prostate cancer with high-risk biochemical recurrence, enzalutamide plus leuprolide was superior to leuprolide alone with respect to metastasis-free survival; enzalutamide monotherapy was also superior to leuprolide alone. The safety profile of enzalutamide was consistent with that shown in previous clinical studies, with no apparent detrimental effect on quality of life. (Funded by Pfizer and Astellas Pharma; EMBARK ClinicalTrials.gov number, NCT02319837.).

Seasonal Trends in Emergency Department Visits for Mental and Behavioral Health Conditions Among Children and Adolescents Aged 5-17 Years - United States, January 2018-June 2023.

Mental and behavioral health conditions among school-aged children, including substance use disorders and overall emotional well-being, are a public health concern in the United States. Timely data on seasonal patterns in child and adolescent conditions can guide optimal timing of prevention and intervention strategies. CDC examined emergency department (ED) visit data from the National Syndromic Surveillance Program for 25 distinct conditions during January 2018-June 2023 among U.S. children and adolescents aged 5-17 years, stratified by age group. Each year, during 2018-2023, among persons aged 10-14 and 15-17 years, the number and proportion of weekly ED visits for eight conditions increased in the fall school semester and remained elevated throughout the spring semester; ED visits were up to twice as high during school semesters compared with the summer period. Among children aged 5-9 years, the number and proportion of visits increased for five mental and behavioral health conditions. Seasonal increases in ED visits for some conditions among school-aged children warrant enhanced awareness about mental distress symptoms and the challenges and stressors in the school environment. Systemic changes that prioritize protective factors (e.g., physical activity; nutrition; sleep; social, community, or faith-based support; and inclusive school and community environments) and incorporate preparedness for increases in conditions during back-to-school planning might improve child and adolescent mental health.

Anti-myeloma efficacy of CAR-iNKT is enhanced with a long-acting IL-7, rhIL-7-hyFc.

Multiple myeloma (MM), a malignancy of mature plasma cells, remains incurable. B-cell maturation antigen (BCMA) is the lead protein target for chimeric antigen receptor (CAR) therapy because of its high expression in most MM, with limited expression in other cell types, resulting in favorable on-target, off tumor toxicity. The response rate to autologous BCMA CAR-T therapy is high; however, it is not curative and is associated with risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome. Outcomes in patients treated with BCMA CAR-T cells (CAR-Ts) may improve with allogeneic CAR T-cell therapy, which offer higher cell fitness and reduced time to treatment. However, to prevent the risk of graft-versus-host disease (GVHD), allogenic BCMA CAR-Ts require genetic deletion of the T-cell receptor (TCR), which has potential for unexpected functional or phenotype changes. Invariant natural killer T cells (iNKTs) have an invariant TCR that does not cause GVHD and, as a result, can be used in an allogeneic setting without the need for TCR gene editing. We demonstrate significant anti-myeloma activity of BCMA CAR-iNKTs in a xenograft mouse model of myeloma. We found that a long-acting interleukin-7 (IL-7), rhIL-7-hyFc, significantly prolonged survival and reduced tumor burden in BCMA CAR-iNKT-treated mice in both primary and re-challenge settings. Furthermore, in CRS in vitro assays, CAR-iNKTs induced less IL-6 than CAR-Ts, suggesting a reduced likelihood of CAR-iNKT therapy to induce CRS in patients. These data suggest that BCMA CAR-iNKTs are potentially a safer, effective alternative to BCMA CAR-Ts and that BCMA CAR-iNKT efficacy is further potentiated with rhIL-7-hyFc.

A Cross-sectional Survey to Assess Awareness of Syndromic Surveillance by Clinicians Practicing Emergency Medicine: An Opportunity for Education and Collaboration.

INTRODUCTION: Syndromic surveillance (SyS) is an important public health tool using de-identified healthcare discharge data from emergency department (ED) and urgent care settings to rapidly identify new health threats and provide insight into current community well-being. While SyS is directly fed by clinical documentation such as chief complaint or discharge diagnosis, the degree to which clinicians are aware their documentation directly influences public health investigations is unknown. The primary objective of this study was to evaluate the degree to which clinicians practicing in Kansas EDs or urgent care settings were aware that certain de-identified aspects of their documentation are used in public health surveillance and to identify barriers to improved data representation. METHODS: We distributed an anonymous survey August-November 2021 to clinicians practicing at least part time in emergency or urgent care settings in Kansas. We then compared responses from emergency medicine (EM)-trained physicians to non-EM trained physicians. Descriptive statistics were used for analysis. RESULTS: A total of 189 respondents across 41 Kansas counties responded to the survey. Of those surveyed, 132 (83%) were unaware of SyS. Knowledge did not differ significantly by specialty, practice setting, urban region, age, nor by experience level. Respondents were unaware of which aspects of their documentation were visible to public health entities, or how quickly records were retrievable. When asked about improving documentation for SyS, lack of clinician awareness (71.5%) was perceived as a greater barrier than electronic health record platform usability or time available to document (61% and 59%, respectively). CONCLUSION: This survey suggests that most practitioners in EM have not heard of SyS and are unaware of the invaluable role certain aspects of their documentation play in public health. Critical information that would be captured and coded into a key syndrome is often missing, but clinicians are unaware of what types of information may be most useful in their documentation, and where to document that information. Lack of knowledge or awareness was identified by clinicians as the single greatest barrier to enhancing surveillance data quality. Increased awareness of this important tool may lead to enhanced utility for timely and impactful surveillance through improved data quality and collaboration between EM practitioners and public health.

The Efficacy of Enzalutamide plus Androgen Deprivation Therapy in Oligometastatic Hormone-sensitive Prostate Cancer: A Post Hoc Analysis of ARCHES.

BACKGROUND: Few phase 3 studies have evaluated optimal systemic treatment strategies for patients with oligometastatic hormone-sensitive prostate cancer (HSPC), who may be at risk of undertreatment. OBJECTIVE: To evaluate outcomes for patients with oligometastatic and polymetastatic HSPC treated with enzalutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT. DESIGN, SETTING, AND PARTICIPANTS: This was a post hoc analysis of data for 927 patients with nonvisceral metastatic HSPC in the ARCHES trial (NCT02677896). INTERVENTION: Patients were randomized 1:1 to enzalutamide (160 mg/d orally) plus ADT or placebo plus ADT with HSPC categorized as oligometastatic (1-5 metastases) or polymetastatic (≥6 metastases). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The treatment effect on radiographic progression-free survival (rPFS), overall survival (OS), and secondary efficacy endpoints was evaluated in terms of the number of metastases. Safety was assessed. Cox proportional hazards models were used to generate hazard ratios (HRs). The Brookmeyer and Crowley method was used to generate 95% confidence intervals (CIs) for Kaplan-Meier median values. RESULTS AND LIMITATIONS: Enzalutamide plus ADT improved rPFS (HR 0.27, 95% CI 0.16-0.46; p < 0.001), OS (HR 0.59, 95% CI 0.40-0.87; p < 0.005), and secondary endpoints in patients with oligometastatic or polymetastatic disease (rPFS: HR 0.33, 95% CI 0.23-0.46; p < 0.001; OS: HR 0.55, 95% CI 0.41-0.74; p < 0.001). Safety profiles were generally similar across subgroups. Limitations include the small numbers of patients with fewer than three metastases. CONCLUSIONS: This post hoc analysis demonstrated the utility of enzalutamide, irrespective of metastatic burden or type of oligometastatic disease, and suggests that earlier treatment intensification with systemic potent androgen receptor inhibition is advantageous. PATIENT SUMMARY: This study considered two treatment options for metastatic hormone-sensitive prostate cancer in patients with one to five metastases or six or more metastases. Treatment with enzalutamide plus ADT improved survival and other outcomes over ADT alone, whether patients had few or many metastases.

The impact of enzalutamide on quality of life in men with metastatic hormone-sensitive prostate cancer based on prior therapy, risk, and symptom subgroups.

BACKGROUND: Enzalutamide plus androgen deprivation therapy (ADT) improved radiographic progression-free survival versus ADT alone in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in ARCHES (NCT02677896). While health-related quality of life (HRQoL) was generally maintained in the intent-to-treat population, we further analyzed patient-reported outcomes (PROs) in defined subgroups. METHODS: ARCHES was a randomized, double-blind, placebo-controlled, phase 3 study. Patients with mHSPC received enzalutamide (160 mg/day) plus ADT (n = 574) or placebo plus ADT (n = 576). Questionnaires, including the Functional Assessment of Cancer Therapy-Prostate, Brief Pain Inventory-Short Form, and EuroQol 5-Dimension, 5-Level (EQ-5D-5L), were completed at baseline, Week 13, and every 12 weeks until disease progression. PRO endpoints were time to first confirmed clinically meaningful deterioration (TTFCD) in HRQoL or pain. Subgroups included prognostic risk, pain/HRQoL, prior docetaxel, and local therapy (radical prostatectomy [RP] and/or radiotherapy [RT]). RESULTS: There were several between-treatment differences in TTFCD for pain and functioning/HRQoL PROs. Enzalutamide plus ADT delayed TTFCD for worst pain in the prior RT group (not reached vs. 14.06 months; hazard ratio [HR]: 0.56 [95% confidence interval: 0.34-0.94]) and pain interference in low-baseline-HRQoL group (19.32 vs. 11.20 months; HR: 0.64 [0.44-0.94]) versus placebo plus ADT. In prior/no prior RP, prior RT, prior local therapy, no prior docetaxel, mild baseline pain, and low-risk subgroups, TTFCD was delayed for the EQ-5D-5L visual analog scale. CONCLUSION: Enzalutamide plus ADT provides clinical benefits in defined patient subgroups versus ADT alone, while maintaining lack of pain and high HRQoL, with delayed deterioration in several HRQoL measures.

CS1 CAR-T targeting the distal domain of CS1 (SLAMF7) shows efficacy in high tumor burden myeloma model despite fratricide of CD8+CS1 expressing CAR-T cells.

Despite improvement in treatment options for myeloma patients, including targeted immunotherapies, multiple myeloma remains a mostly incurable malignancy. High CS1 (SLAMF7) expression on myeloma cells and limited expression on normal cells makes it a promising target for CAR-T therapy. The CS1 protein has two extracellular domains - the distal Variable (V) domain and the proximal Constant 2 (C2) domain. We generated and tested CS1-CAR-T targeting the V domain of CS1 (Luc90-CS1-CAR-T) and demonstrated anti-myeloma killing in vitro and in vivo using two mouse models. Since fratricide of CD8 + cells occurred during production, we generated fratricide resistant CS1 deficient Luc90- CS1- CAR-T (ΔCS1-Luc90- CS1- CAR-T). This led to protection of CD8 + cells in the CAR-T cultures, but had no impact on efficacy. Our data demonstrate targeting the distal V domain of CS1 could be an effective CAR-T treatment for myeloma patients and deletion of CS1 in clinical production did not provide an added benefit using in vivo immunodeficient NSG preclinical models.

Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In primary analysis, enzalutamide plus androgen deprivation therapy (ADT) improved radiographic progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC); however, overall survival data were immature. In the phase III, double-blind, global ARCHES trial (ClinicalTrials.gov identifier: NCT02677896), 1,150 patients with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg once daily) plus ADT or placebo plus ADT, stratified by disease volume and prior docetaxel use. Here, we report the final prespecified analysis of overall survival (key secondary end point) and an update on rPFS, other secondary end points, and safety. After unblinding, 180 (31.3%) progression-free patients randomly assigned to placebo plus ADT crossed over to open-label enzalutamide plus ADT. As of May 28, 2021 (median follow-up, 44.6 months), 154 of 574 patients randomly assigned to enzalutamide plus ADT and 202 of 576 patients randomly assigned to placebo plus ADT had died. Enzalutamide plus ADT reduced risk of death by 34% versus placebo plus ADT (median not reached in either group; hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P < .001). Enzalutamide plus ADT continued to improve rPFS and other secondary end points. Adverse events were generally consistent with previous reports of long-term enzalutamide use. In conclusion, enzalutamide plus ADT significantly prolongs survival versus placebo plus ADT in patients with mHSPC.

Effect of enzalutamide on PK of P-gp and BCRP substrates in cancer patients: CYP450 induction may not always predict overall effect on transporters.

Drug-drug interaction (DDI) is an important consideration for clinical decision making in prostate cancer treatment. The objective of this study was to evaluate the effect of enzalutamide, an oral androgen receptor inhibitor, on the pharmacokinetics (PK) of digoxin (P-glycoprotein [P-gp] probe substrate) and rosuvastatin (breast cancer resistance protein [BCRP] probe substrate) in men with metastatic castration-resistant prostate cancer (mCRPC). This was a phase I, open-label, fixed-sequence, crossover study (NCT04094519). Eligible men with mCRPC received a single dose of transporter probe cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin plus enzalutamide placebo-to-match on day 1. On day 8, patients started 160 mg enzalutamide once daily through day 71. On day 64, patients also received a single dose of the cocktail. The primary end points were digoxin and rosuvastatin plasma maximum concentration (Cmax ), area under the concentration-time curve from the time of dosing to the last measurable concentration (AUClast ), and AUC from the time of dosing extrapolated to time infinity (AUCinf ). Secondary end points were enzalutamide and N-desmethyl enzalutamide (metabolite) plasma Cmax , AUC during a dosing interval, where tau is the length of the dosing interval (AUCtau ), and concentration immediately prior to dosing at multiple dosing (Ctrough ). When administered with enzalutamide, there was a 17% increase in Cmax , 29% increase in AUClast , and 33% increase in AUCinf of plasma digoxin compared to digoxin alone, indicating that enzalutamide is a "mild" inhibitor of P-gp. No PK interaction was observed between enzalutamide and rosuvastatin (BCRP probe substrate). The PK of enzalutamide and N-desmethyl enzalutamide were in agreement with previously reported data. The potential for transporter-mediated DDI between enzalutamide and digoxin and rosuvastatin is low in men with prostate cancer. Therefore, concomitant administration of enzalutamide with medications that are substrates for P-gp and BCRP does not require dose adjustment in this patient population.

Enzalutamide versus bicalutamide in patients with nonmetastatic castration-resistant prostate cancer: a prespecified subgroup analysis of the STRIVE trial.

BACKGROUND: In the phase 2, randomized, double-blind STRIVE trial, enzalutamide significantly reduced the risk of prostate cancer progression or death versus bicalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) and nonmetastatic CRPC (nmCRPC). The objective of this protocol-specified subgroup analysis of STRIVE was to investigate the benefit of enzalutamide versus bicalutamide specifically in patients with nmCRPC. METHODS: Patients (N = 139) were stratified by disease stage and randomized to enzalutamide 160 mg/day plus androgen deprivation therapy (ADT; n = 70) or bicalutamide 50 mg/day plus ADT (n = 69). RESULTS: Baseline characteristics of patients with nmCRPC were comparable between groups. At a median of 17 months follow-up, enzalutamide reduced the risk of progression or death by 76% versus bicalutamide in patients with nmCRPC (hazard ratio [HR], 0.24; 95% CI 0.14-0.42). Enzalutamide reduced risk of prostate-specific antigen progression by 82% versus bicalutamide in patients with nmCRPC (HR, 0.18; 95% CI 0.10-0.34). The most frequently reported adverse events by patients receiving enzalutamide were fatigue (36.2%), hot flush (20.3%), decreased appetite (17.4%), dizziness (17.4%), and nausea (17.4%). CONCLUSIONS: This STRIVE subgroup analysis of patients with nmCRPC illustrates the benefit of enzalutamide in reducing the risk of progression or death versus bicalutamide in patients with nmCRPC. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01664923.

Laminin-111-Enriched Fibrin Hydrogels Enhance Functional Muscle Regeneration Following Trauma.

Volumetric muscle loss (VML) is the surgical or traumatic loss of skeletal muscle, which can cause loss of limb function or permanent disability. VML injuries overwhelms the endogenous regenerative capacity of skeletal muscle and results in poor functional healing outcomes. Currently, there are no approved tissue engineering treatments for VML injuries. In this study, fibrin hydrogels enriched with laminin-111 (LM-111; 50-450 µg/mL) were used for the treatment of VML of the tibialis anterior in a rat model. Treatment with fibrin hydrogel containing 450 µg/mL of LM-111 (FBN450) improved muscle regeneration following VML injury. FBN450 hydrogel treatment increased the relative proportion of contractile to fibrotic tissue as indicated by the myosin: collagen ratio on day 28 post-VML injury. FBN450 hydrogels also enhanced myogenic protein expression and increased the quantity of small to medium size myofibers (500-2000 µm2) as well as innervated myofibers. Improved contractile tissue deposition due to FBN450 hydrogel treatment resulted in a significant improvement (∼60%) in torque production at day 28 postinjury. Taken together, these results suggest that the acellular FBN450 hydrogels provide a promising therapeutic strategy for VML that is worthy of further investigation. Impact statement Muscle trauma accounts for 50-70% of total military injuries and complications involving muscle result in ∼80% of delayed amputations. The lack of a clinical standard of care for volumetric muscle loss (VML) injuries presents an opportunity to develop novel regenerative therapies and improve healing outcomes. Laminin-111-enriched fibrin hydrogel may provide a promising therapy for VML that is worthy of further investigation. The acellular nature of these hydrogels will allow for easy off the shelf access to critically injured patients and fewer regulatory hurdles during commercialization.

Efficacy of enzalutamide in subgroups of men with metastatic hormone-sensitive prostate cancer based on prior therapy, disease volume, and risk.

BACKGROUND: While enzalutamide plus androgen deprivation therapy (ADT) significantly reduces the risk of radiographic progression-free survival (rPFS) and improves overall survival in metastatic hormone-sensitive prostate cancer (mHSPC), the efficacy in clinically relevant subgroups of patients based on prior local and systemic therapy, disease volume, and risk has not been analyzed to date. These post hoc analyses of the phase 3 ARCHES trial (NCT02677896) evaluated the efficacy of enzalutamide plus ADT according to prior local and systemic treatment, disease volume, and risk, assessed at trial baseline. METHODS: In ARCHES, a global, double-blind, placebo-controlled, phase 3 study, 1150 patients with mHSPC were randomized 1:1 to receive enzalutamide (160 mg/day) plus ADT or placebo plus ADT, stratified by prior docetaxel therapy and disease volume. Primary endpoint was rPFS. Secondary endpoints included time to prostate-specific antigen progression, symptomatic skeletal events, and prostate-specific antigen and radiographic responses. Analyses of clinical endpoints were completed by prior local therapy, prior docetaxel exposure, CHAARTED (NCT00309985)-defined disease volume, and LATITUDE (NCT01715285)-defined risk groups. RESULTS: Patients were randomized to enzalutamide plus ADT (n = 574) and placebo plus ADT (n = 576). Enzalutamide plus ADT significantly improved rPFS (hazard ratio: 0.39; p < 0.0001), with similar improvements reported in all subgroups based on prior local and docetaxel treatment, disease volume, and risk. Treatment benefits were observed with enzalutamide plus ADT in multiple secondary clinical endpoints in the overall population and all subgroups. CONCLUSIONS: Enzalutamide plus ADT demonstrated clinical benefit across all patients with mHSPC, irrespective of prior local and systemic treatment, disease volume, and risk.

Biomimetic sponges improve functional muscle recovery following composite trauma.

There is a dearth of therapies that are safe and effective for the treatment of volumetric muscle loss (VML), defined as the surgical or traumatic loss of muscle tissue, resulting in functional impairment. To address this gap in orthopedic care, we developed a porous sponge-like scaffold composed of extracellular matrix (ECM) proteins (e.g., gelatin, collagen, and laminin-111) and an immunosuppressant drug, FK-506. While the majority of VML injuries occur in orthopedic trauma cases, preclinical models typically study muscle injuries in isolation without a concomitant bone fracture. The goal of this study was to investigate the extent to which FK506 loaded biomimetic sponges support functional muscle regeneration and fracture healing in a composite trauma model involving VML injury to the tibialis anterior muscle and osteotomy (OST) to the tibia. In this model, implantation of the FK-506 loaded biomimetic sponges limited the extent of inflammation while increasing the total number of myofibers, mean myofiber cross-sectional area, myosin-to-collagen ratio, and peak isometric torque compared to untreated VML+OST muscles on Day 28. Although all tibia fractures were bridged by Day 28 post-injury, fracture healing was impaired in response to an adjacent VML injury. Sponge treatment increased bone callus volume, yet the bridged mineralized bone volume was not significantly different. Taken together, these results suggest that biomimetic sponges primarily benefitted muscle repair and may provide a promising therapy for traumatized muscle.

A phase 3 randomised study of enzalutamide plus leuprolide and enzalutamide monotherapy in high-risk non-metastatic hormone-sensitive prostate cancer with rising PSA after local therapy: EMBARK study design.

INTRODUCTION: Limited data from controlled clinical trials are available for men who experience biochemical recurrence after definitive therapy for prostate cancer. In the absence of overt metastases, patients with non-metastatic castration-sensitive prostate cancer (nmCSPC) often receive androgen deprivation therapy (ADT). There is no standard-of-care consensus on optimal ADT timing, although most men are treated prior to metastases, especially those with high-risk features (Gleason score 8-10 or prostate-specific antigen doubling time (PSADT) <9-12 months). Given data that ADT plus novel hormonal agents improve survival in men with metastatic CSPC, there is a desire to evaluate these agents earlier in the disease course. The main objective of EMBARK is the comparative assessment of enzalutamide plus leuprolide (luteinising hormone-releasing hormone agonist (LHRHa)) or enzalutamide monotherapy versus monotherapy LHRHa to improve metastasis-free survival (MFS) in patients with high-risk nmCSPC PSA recurrence after definitive therapy. METHODS AND ANALYSIS: EMBARK is a randomised, phase 3 study of high-risk patients with nmCSPC, a PSADT of ≤9 months and a screening PSA of ≥2 ng/mL above the nadir after radiotherapy (RT) or ≥1 ng/mL after radical prostatectomy (RP) with or without postoperative RT. Men (n=1050) are randomised 1:1:1 to enzalutamide 160 mg/day plus LHRHa or placebo plus LHRHa (double-blind arms) or enzalutamide monotherapy (open-label arm). Treatment is suspended at week 37 if PSA concentrations are <0.2 ng/mL and reinstated if levels rise to ≥2.0 ng/mL with RP or ≥5.0 ng/mL without RP. Patients with PSA ≥0.2 ng/mL at week 37 continue until treatment discontinuation criteria are met. The primary endpoint is MFS comparing enzalutamide plus LHRHa versus placebo plus LHRHa. ETHICS AND DISSEMINATION: The study is conducted under the guiding principles of the World Medical Association Declaration of Helsinki. The results will be disseminated at research conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02319837.

Biomimetic sponges improve muscle structure and function following volumetric muscle loss.

Skeletal muscle is inept in regenerating after traumatic injuries such as volumetric muscle loss (VML) due to significant loss of various cellular and acellular components. Currently, there are no approved therapies for the treatment of muscle tissue following trauma. In this study, biomimetic sponges composed of gelatin, collagen, laminin-111, and FK-506 were used for the treatment of VML in a rodent model. We observed that biomimetic sponge treatment improved muscle structure and function while modulating inflammation and limiting the extent of fibrotic tissue deposition. Specifically, sponge treatment increased the total number of myofibers, type 2B fiber cross-sectional area, myosin: collagen ratio, myofibers with central nuclei, and peak isometric torque compared to untreated VML injured muscles. As an acellular scaffold, biomimetic sponges may provide a promising clinical therapy for VML.

Efficacy of Enzalutamide plus Androgen Deprivation Therapy in Metastatic Hormone-Sensitive Prostate Cancer by Pattern of Metastatic Spread: ARCHES Post Hoc Analyses.

PURPOSE: Enzalutamide plus androgen deprivation therapy has previously been shown to improve clinical outcomes in men with metastatic hormone-sensitive prostate cancer (ARCHES; NCT02677896). Here, we assessed if and how the pattern of metastatic spread impacts efficacy of enzalutamide plus androgen deprivation therapy in men enrolled in ARCHES. MATERIALS AND METHODS: Men with metastatic hormone-sensitive prostate cancer were randomized 1:1 to enzalutamide (160 mg/day) plus androgen deprivation therapy or placebo plus androgen deprivation therapy, stratified by disease volume and prior docetaxel treatment. The primary end point was radiographic progression-free survival. Secondary end points included time to prostate specific antigen progression, initiation of new antineoplastic therapy, first symptomatic skeletal event and castration resistance. Post hoc analyses were performed by pattern of metastatic spread based on study entry imaging. RESULTS: Of the overall population with metastases identified at enrollment (1,146), the largest patient subgroups were those with bone metastases only (513) and those with bone plus lymph node metastases (351); there were fewer men with lymph node metastases only (154) and men with visceral±bone or lymph node metastases (128). Enzalutamide plus androgen deprivation therapy reduced the risk of radiographic progression vs placebo plus androgen deprivation therapy in men with bone metastases only (HR 0.33) and bone plus lymph node metastases (HR 0.31). Similar improvements in secondary end points were also observed in these subgroups. CONCLUSIONS: These findings indicate that treatment with enzalutamide plus androgen deprivation therapy provides improvements in men with bone and/or lymph node metastases but may be less effective in men with visceral patterns of spread.

Probiotic treatment (Bifidobacterium longum subsp. longum 35624™) affects stress responsivity in male rats after chronic corticosterone exposure.

Mounting evidence suggests that gut microbiota do not only regulate intestinal function and health, but that they also play a role in mental health via the gut-brain axis. Previous research further suggests that probiotics may have beneficial health effects, but more research is needed to confirm these beneficial effects and better understand the underlying mechanisms and potential sex differences in the response to probiotics. Therefore, the current study investigates the effects of chronic administration of the commercially available probiotic Bifidobacterium longum subsp. longum 35624™(B. 35624) to male and female rats under control or "stressed" conditions. For this, 24 male and 24 female Sprague-Dawley rats were either given daily corticosterone injections (40 mg/kg; to induce depressive-like behavior and a "stressed" condition) or oil injections (controls) together with oral administration of B.35624 or vehicle for 21 days (n = 5-7/group). Animals performed the Open Field Test (OFT) and Forced Swim Test (FST) and several blood samples were collected to investigate basal as well as stress-induced corticosterone levels. Rats were sacrificed on day 22 and their brains sliced and stained with doublecortin, a marker of immature neurons. Results showed that B.35624 was not able to rescue depressive-like behavior or induce changes in neurogenesis in males or females, but the probiotic impacted hypothalamic-pituitary-adrenal axis functioning in male animals and tended to reduce anxiolytic behavior in the OFT. More research is needed to further elucidate the potential health effects of probiotics especially in regard to possible sex differences.