Prospective clinical trial of disulfiram plus copper in men with metastatic castration-resistant prostate cancer.

BACKGROUND: In preclinical models of prostate cancer (PC), disulfiram (DSF) reduced tumor growth only when co-administered with copper (Cu), and Cu uptake in tumors is partially regulated by androgen-receptor signaling. However, prior trials of DSF in PC used DSF as monotherapy. OBJECTIVE: To assess the safety and efficacy of concurrent administration of DSF with Cu, we conducted a phase 1b clinical trial of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving Cu with DSF. DESIGN, SETTING, AND PARTICIPANTS: Patients with mCRPC were treated in two cohorts: mCRPC with nonliver/peritoneal metastases (A), and mCRPC with liver and/or peritoneal metastases (B). Baseline Cu avidity was measured by 64 CuCl2 PET scan. Intravenous (IV) CuCl2 was given weekly for three doses with oral daily DSF followed by daily oral Cu gluconate and DSF until disease progression. DSF and metabolite diethyldithiocarbamic acid methyl ester (Me-DDC) levels in plasma were measured. DSF and Me-DDC were then assessed for cytotoxicity in vitro. RESULTS: We treated nine patients with mCRPC (six on cohort A and three on cohort B). Bone and nodal metastases showed differential and heterogeneous Cu uptake on 64 CuCl2 PET scans. No confirmed PSA declines or radiographic responses were observed. Median PFS was 2.8 months and median OS was 8.3 months. Common adverse events included fatigue and psychomotor depression; no Grade 4/5 AEs were observed. Me-DDC was measurable in all samples (LOQ = 0.512 ng/ml), whereas DSF was not (LOQ = 0.032 ng/ml, LOD = 0.01 ng/ml); Me-DDC was not cytotoxic in vitro. CONCLUSIONS: Oral DSF is not an effective treatment for mCRPC due to rapid metabolism into an inactive metabolite, Me-DDC. This trial has stopped enrollment and further work is needed to identify a stable DSF formulation for treatment of mCRPC.

Recommended Musculoskeletal and Sports Medicine Model Curriculum for Emergency Medicine Residency Training.

ABSTRACT: Musculoskeletal and sports medicine conditions are common in the emergency department (ED). Emergency physicians may not be receiving adequate education to achieve clinical competency in musculoskeletal medicine during residency training. This article aims to provide a standardized musculoskeletal and sports medicine curriculum for emergency medicine training. Broad curriculum goals include proficiency in evaluating and managing patients presenting to the ED with acute and chronic musculoskeletal complaints and other medical conditions related to or affected by physical exertion, sports participation, or environmental exposure. Specific objectives focus on knowledge of these disorders, physical examination skills, procedural skills including musculoskeletal ultrasound, appropriate consultation and referral, and patient education for these conditions. Educational methods will consist of didactics; online self-directed learning modules; simulation; and supervised clinical experiences in the ED, primary care sports medicine clinics, and orthopedic clinics if available. Curriculum implementation is expected to vary across programs due to differences in residency program structure and resources.

High Sleep Disturbance and Longer Concussion Duration in Repeat Concussions.

Objectives: The relationship between repeated concussions and sleep disturbance is yet to be fully understood. The objective of this study was to examine the relationship between sleep disturbance, concussion duration, and repeated concussions by assessing postconcussive symptoms and cognition. Methods: Subjects (ages 13-33 years) underwent postconcussion cognitive function evaluation and reported postconcussion symptoms including severity of disturbed sleep (drowsiness, trouble falling asleep, sleeping more than usual, and sleeping less than usual), mood disturbance (sadness, irritability, nervousness, and emotional lability), and headache. Data on cognitive function and concussive symptoms were collected for 430 subjects after first concussion, 192 subjects after second concussion, and 118 subjects after three or more concussions. A subset of subjects (119) were monitored longitudinally to assess concussion duration. Analyses included group comparisons, regression, and correlation; data were adjusted for age and gender. Results: Sleep disturbance differed significantly by group (mean[SEM]: 1st concussion = 2.56[0.2]; 2nd concussion = 3.65[0.34]; 3+ concussions = 4.32[0.43]). Concussion history predicts concussion duration (R2 = 0.20, F[1,116] = 27.33, p < 0.001). Furthermore, trouble falling asleep (ß = 0.15) and sleeping less than usual (ß = 0.15) predicted concussion duration (R2 = 0.062, F[1,116] = 3.15, p = 0.047). Reported sleep disturbance after repeated concussions was higher in patients with higher headache (F[2,732] = 3.15, p = 0.043) and mood disturbance (F[2,733] = 3.35, p = 0.036) severity. In addition, after repeated concussions, the positive correlation between sleep disturbance and cognitive dysfunction strengthened. Conclusions: History of repeated concussion is associated with longer concussion duration and higher reported sleep disturbance. Furthermore, those with sleep disturbance after repeated concussion exhibit more severe headaches, mood disturbance, and cognitive dysfunction.Abbreviations: ImPACT: Immediate Postconcussion Assessment and Cognitive Assessment (ImPACT); this is a computer-based test that assesses an individual's cognitive function and cumulatively documents current concussion symptoms. PCSS: Post Concussion Symptom Scale; this scale assesses the severity of concussion symptoms. SPSS: Statistical Package for Social Sciences. This is a statistical software package.

Expression of immune checkpoints on circulating tumor cells in men with metastatic prostate cancer.

BACKGROUND: A subset of men with metastatic prostate cancer (mPC) responds to immune checkpoint inhibitors, and there is an unmet need to predict those most likely to benefit. We characterized circulating tumor cells (CTCs) for expression of immune checkpoint ligands in men with mPC as a non-invasive biomarker of immune evasion and immunotherapy benefit. METHODS: Three cohorts of patients were enrolled: 1) men with mCRPC starting abiraterone acetate/prednisone or enzalutamide (pre-ARSI), 2) men with mCRPC who were progressing on enzalutamide or abiraterone acetate/prednisone (post-ARSI), and 3) men with newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) starting androgen deprivation therapy. CTCs were captured using the CellSearch® system and stained for PD-L1, PD-L2, B7-H3, and CTLA-4 at baseline, on treatment, and disease progression. Summary statistics on mean CTCs per cohort, as well as rates of ligand positivity were used to analyze CTCs by cohort and by timepoint. RESULTS: Men in all cohorts and timepoints had prevalent CTC B7-H3 expression (> 80%). We found evidence for CTC PD-L1 expression across disease states, in which > 1 positive CTC or > 50% of CTCs were positive for PD-L1 in 40 and 30% of men with mHSPC, respectively, 60 and 20% of men with mCRPC pre-ARSI, and 70 and 30% of men with mCRPC post-ARSI. CTC PD-L2 expression was present in 20-40% of men in each disease state, while CTC CTLA-4 expression was rare, present in 20% of men with mCRPC pre-ARSI and 10% of men with mCRPC post-ARSI or with mHSPC. CTC immune checkpoint expression was heterogeneous within/between men and across disease states. CONCLUSIONS: We have identified that CTCs from men with mPC heterogeneously express immune checkpoints B7-H3, PD-L1, PD-L2, and CTLA-4, and the detection of these immune checkpoints may enable monitoring on immunotherapy.

Postconcussive Symptoms After Single and Repeated Concussions in 10- to 20-Year-Olds: A Cross-Sectional Study.

The objective was to characterize cognitive deficits and postconcussive symptoms in a pediatric population with no concussion, a single concussion, and ≥2 concussions, using a cross-sectional design. Cognitive function and postconcussive symptoms were assessed in participants (age 10-20) with no concussion (n = 1118), single concussion (n = 368), and repeated (≥2) concussions (n = 252). Analyses were adjusted for age and gender. Individuals with ≥2 concussions exhibited more total postconcussive symptoms; more loss of consciousness, amnesia and confusion; more headaches; and poorer cognitive function compared to no concussion and single concussion. Postconcussive symptoms may play a modulatory role in cognitive dysfunction after repeated concussions as those with loss of consciousness, amnesia, confusion, or headaches exhibited worse verbal memory, visual memory, visual-motor processing, and poorer impulse control compared to those without these symptoms. This analysis demonstrates that repeated concussions is associated with poorer cognitive function and postconcussive symptoms compared to a single concussion.

Gender differences in sleep symptoms after repeat concussions.

OBJECTIVES: There are notable gender differences in concussion as well as sleep. Sleep disturbance is a major symptom of post-concussive syndrome. The interplay between sleep disturbance, concussion, and gender has yet to be examined. The objective of this study was to determine whether sleep disturbance plays a role in the known gender differences associated with concussion. METHODS: Males and females (ages 10-35 years) completed a pre-concussion and post-concussion evaluation. Levels of sleep disturbance were assessed at baseline (N = 1284), after first concussion (N = 432) and after repeated concussions (one or more concussions, N = 296). Sleep disturbance levels were also compared among males and females with headaches, mood changes, and cognitive dysfunction. Analyses included group comparisons and correlations of post-concussive symptoms and cognitive dysfunction, respectively. Data was adjusted for age. RESULTS: Compared to males, females reported higher levels of sleep disturbance after a single concussion; however, levels of sleep disturbance equalized after repeated concussions. Females with higher levels of sleep disturbance had more headaches and more mood changes requiring medical treatment, compared to males. In addition, sleep disturbance was more strongly correlated with cognitive dysfunction in females compared to males. CONCLUSION: Gender differences in concussion recovery after repeat concussions may be primarily due to a difference in sleep disturbance between the genders. This difference in sleep appears to moderate the levels of other post-concussive symptoms. This indicates that sleep disturbance should be closely monitored and treated in females after a concussion. Further studies are required to determine the underlying reasons for these gender differences.