Atezolizumab for Advanced Alveolar Soft Part Sarcoma.

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported. METHODS: We conducted an investigator-initiated, multicenter, single-group, phase 2 study of the anti-programmed death ligand 1 (PD-L1) agent atezolizumab in adult and pediatric patients with advanced ASPS. Atezolizumab was administered intravenously at a dose of 1200 mg (in patients ≥18 years of age) or 15 mg per kilogram of body weight with a 1200-mg cap (in patients <18 years of age) once every 21 days. Study end points included objective response, duration of response, and progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as well as pharmacodynamic biomarkers of multistep drug action. RESULTS: A total of 52 patients were evaluated. An objective response was observed in 19 of 52 patients (37%), with 1 complete response and 18 partial responses. The median time to response was 3.6 months (range, 2.1 to 19.1), the median duration of response was 24.7 months (range, 4.1 to 55.8), and the median progression-free survival was 20.8 months. Seven patients took a treatment break after 2 years of treatment, and their responses were maintained through the data-cutoff date. No treatment-related grade 4 or 5 adverse events were recorded. Responses were noted despite variable baseline expression of programmed death 1 and PD-L1. CONCLUSIONS: Atezolizumab was effective at inducing sustained responses in approximately one third of patients with advanced ASPS. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03141684.).

Synthesis of polymer nanoparticles via electrohydrodynamic emulsification-mediated self-assembly.

HYPOTHESIS: Electrospray can rapidly produce fine, organic solvent-in-water emulsions in the absence of surfactant via electrohydrodynamic emulsification (EE), a reverse configuration of traditional electrospray. This paper investigates whether EE can produce high-quality nanocomposites comprised of block co-polymers and organic nanoparticles (NPs) via the interfacial instability (IS) self-assembly method. Surfactant-free approaches may increase encapsulation efficiency and product uniformity, process speed, and ease of downstream product purification. EXPERIMENTS: All particles were produced using EE-mediated self-assembly (SA) (EE-SA). Particles were produced using poly(lactic-co-glycolic acid) (PLGA) polymers as proof of concept. Then, block copolymer (BCP) micelles were synthesized from polystyrene-block-poly(ethylene oxide) (PS-b-PEO) (PS 9.5 kDa:PEO 18.0 kDa) in the presence and absence of superparamagnetic iron oxide nanoparticles (SPIONs) or quantum dots (QDs). Encapsulant concentration was varied, and the effect of encapsulant NP ligands on final particle size was investigated. FINDINGS: EE-SA generated both pure polymer NPs and nanocomposites containing SPIONs and QDs. PLGA particles spanned from sub- to super-micron sizes. PS-b-PEO NPs and nanocomposites were highly monodisperse, and more highly loaded than those made via a conventional, surfactant-rich IS process. Free ligands decreased the size of pure BCP particles. Increasing encapsulant levels led to a morphological transition from spherical to worm-like to densely loaded structures.

Phase I Study of Veliparib on an Intermittent and Continuous Schedule in Combination with Carboplatin in Metastatic Breast Cancer: A Safety and [18F]-Fluorothymidine Positron Emission Tomography Biomarker Study.

BACKGROUND: Poly(ADP-ribose) polymerase inhibitors (PARPis) are U.S. Food and Drug Administration (FDA) approved for treatment of BRCA-mutated metastatic breast cancer. Furthermore, the BROCADE studies demonstrated benefit of adding an oral PARPi, veliparib, to carboplatin and paclitaxel in patients with metastatic breast cancer harboring BRCA mutation. Given multiple possible dosing schedules and the potential benefit of this regimen for patients with defective DNA repair beyond BRCA, we sought to find the recommended phase II dose (RP2D) and schedule of veliparib in combination with carboplatin in patients with advanced breast cancer, either triple-negative (TNBC) or hormone receptor (HR)-positive, human epidermal growth receptor 2 (HER2) negative with defective Fanconi anemia (FA) DNA-repair pathway based on FA triple staining immunofluorescence assay. MATERIALS AND METHODS: Patients received escalating doses of veliparib on a 7-, 14-, or 21-day schedule with carboplatin every 3 weeks. Patients underwent [18]fluoro-3'-deoxythymidine (18 FLT) positron emission tomography (PET) imaging. RESULTS: Forty-four patients (39 TNBC, 5 HR positive/HER2 negative with a defective FA pathway) received a median of 5 cycles (range 1-36). Observed dose-limiting toxicities were grade (G) 4 thrombocytopenia (n = 4), G4 neutropenia (n = 1), and G3 akathisia (n = 1). Common grade 3-4 toxicities included thrombocytopenia, lymphopenia, neutropenia, anemia, and fatigue. Of the 43 patients evaluable for response, 18.6% achieved partial response and 48.8% had stable disease. Median progression-free survival was 18.3 weeks. RP2D of veliparib was established at 250 mg twice daily on days 1-21 along with carboplatin at area under the curve 5. Patients with partial response had a significant drop in maximum standard uptake value (SUVmax ) of target lesions between baseline and early in cycle 1 based on 18 FLT-PET (day 7-21; ptrend = .006). CONCLUSION: The combination of continuous dosing of veliparib and every-3-week carboplatin demonstrated activity and an acceptable toxicity profile. Decrease in SUVmax on 18 FLT-PET scan during the first cycle of this therapy can identify patients who are likely to have a response. IMPLICATIONS FOR PRACTICE: The BROCADE studies suggest that breast cancer patients with BRCA mutation benefit from addition of veliparib to carboplatin plus paclitaxel. This study demonstrates that a higher dose of veliparib is tolerable and active in combination with carboplatin alone. With growing interest in imaging-based early response assessment, the authors demonstrate that decrease in [18]fluoro-3'-deoxythymidine positron emission tomography (FLT-PET) SUVmax during cycle 1 of therapy is associated with response. Collectively, this study established a safety profile of veliparib and carboplatin in advanced breast cancer while also providing additional data on the potential for FLT-PET imaging modality in monitoring therapy response.

Effects of Weighted Vest Loading During Daily Living Activities on Countermovement Jump and Sprint Performance.

PURPOSE: Wearing a weighted vest (WV) during daily living and training can enhance jump and sprint performance; however, studies examining the efficacy of this method in female populations is limited. This study examined the effect of wearing a WV during daily living and training on countermovement jump (CMJ), change-of-direction, and sprint performance. METHODS: Trained females were separated into intervention (n = 9) and control (n = 10) groups. The intervention group wore WVs of ∼8% body mass 4 days per week for 8 hours per day (32 h/wk total), and 3 training sessions per week for the first 3 weeks. Subsequently, 3 weeks of regular training without WV stimulus was completed. The control group received no intervention and continued normal training for 6 weeks. Average and best performance was assessed on the single CMJ, four continuous CMJ, t-test change-of-direction drill, and a 25-m sprint at baseline, week 3, and week 6. RESULTS: No significant interactions or group effects were found. However, significant time main effects revealed increases in average rate of force development during the CMJ from baseline to week 3 (P = .048) and week 6 (P = .013), whereas peak vertical ground reaction force increased during the four continuous CMJ from baseline to week 3 (P = .048) and week 6 (P = .025) for both groups. CONCLUSIONS: The lower relative WV load used in this study failed to elicit significant improvements in jump and sprint performance in comparison with routine training, or that which have been found in past investigations with elite male athletes completing high-intensity performance tasks with greater WV loads.

The Interaction of Cognitive Interference, Standing Surface, and Fatigue on Lower Extremity Muscle Activity.

BACKGROUND: Performing cognitive tasks and muscular fatigue have been shown to increase muscle activity of the lower extremity during quiet standing. A common intervention to reduce muscular fatigue is to provide a softer shoe-surface interface. However, little is known regarding how muscle activity is affected by softer shoe-surface interfaces during static standing. The purpose of this study was to assess lower extremity muscular activity during erect standing on three different standing surfaces, before and after an acute workload and during cognitive tasks. METHODS: Surface electromyography was collected on ankle dorsiflexors and plantarflexors, and knee flexors and extensors of fifteen male participants. Dependent electromyography variables of mean, peak, root mean square, and cocontraction index were calculated and analyzed with a 2 × 2 × 3 within-subject repeated measures analysis of variance. RESULTS: Pre-workload muscle activity did not differ between surfaces and cognitive task conditions. However, greater muscle activity during post-workload balance assessment was found, specifically during the cognitive task. Cognitive task errors did not differ between surface and workload. CONCLUSIONS: The cognitive task after workload increased lower extremity muscular activity compared to quite standing, irrespective of the surface condition, suggesting an increased demand was placed on the postural control system as the result of both fatigue and cognitive task.

Ground reaction forces during a drop vertical jump: Impact of external load training.

External load training (ELT) is a supplemental training method used to potentially improve high intensity task performance. However, biomechanical parameters such as ground reaction forces (GRF), ground contact time, and time to peak GRF during a drop vertical jump (DVJ) following an ELT intervention have yet to be examined. Therefore, this study investigated the impact of ELT on certain biomechanical parameters of a DVJ task. Well-trained females stratified into two groups (ELT = 9, Control = 10) completed a DVJ from a 45.72 cm box onto a force platform at baseline, post-ELT, and post-detraining (DET). ELT consisted of wearing weight vests (WV) with 8% body mass for 32 h/week during daily living and 3 training sessions/week for 3 weeks. After ELT, a 3 week DET phase was completed. The control group replicated procedures without ELT intervention. The vertical, medial/lateral, and anterior/posterior components of the GRF were assessed during the initial contact, minimum force following initial contact, push-off, and second landing periods. Dependent variables were analyzed using a 2 (group) × 3 (time) mixed model ANOVA (p < .05). Significantly greater peak vertical GRF during the initial contact period was identified for the ELT group. Significant increases in the minimum vertical GRF following the initial contact period from baseline to post-ELT following the were observed for the ELT group, while significant increases in peak vertical GRF during the second landing period at post-ELT and post-DET in comparison to baseline was observed for both groups. The combination of greater vertical GRF during the initial contact period and the period following initial contact suggests that ELT may increase GRFs during a DVJ in comparison to routine training without a weighted vest.

External load training does not alter balance performance in well-trained women.

This study investigated the influence of external load training (ELT) on static and dynamic balance. Nineteen females stratified into two groups (ELT = 9, control = 10) completed three testing sessions over 6 weeks. The ELT group wore weighted vests (WV) of ~8% body mass for 32 h/week during daily living and three training sessions/week for 3 weeks. Following completion of ELT, a 3 week detraining (DET) phase was completed. Bilateral and unilateral static balance were assessed with eyes open and closed. Dynamic balance was assessed using the star excursion balance test (SEBT). Static and dynamic balance variables were analysed using a 2 (group) x 3 (time) between participants repeated measures ANOVA (p < 0.05). Results revealed significant reductions in average centre of pressure (COP) velocity in the control group on the non-dominant limb with eyes closed, and significantly greater reach distances in the ELT group on the SEBT for the posteromedial and medial directions on the dominant limb (p < 0.05). These findings suggest the ELT group did not significantly improve their balance in comparison to the control group. However, future research should further examine this unique, supplemental training method and the impact on balance performance.

Isolation and analysis of rare cells in the blood of cancer patients using a negative depletion methodology.

A variety of enrichment/isolation technologies exist for the characterization of rare cells in the blood of cancer patients. In this article, a negative depletion process is presented and discussed which consists of red blood cell (RBC) lysis and the subsequent removal of CD45 expressing cells through immunomagnetic depletion. Using this optimized assembly on 120 whole blood specimens, from 71 metastatic breast cancer patients, after RBC lysis, the average nucleated cell log depletion was 2.56 with a 77% recovery of the nucleated cells. The necessity of exploring different anti-CD45 antibody clones to label CD45 expressing cells in this enrichment scheme is also presented and discussed. An optimized, four-color immunofluorescence staining is conducted on the cells retained after the CD45-based immunomagnetic depletion process. Different types of rare non-hematopoietic cells are found in these enriched peripheral blood samples and a wide range of external and internal markers have been characterized, which demonstrates the range and heterogeneity of the rare cells.

On-chip magnetic separation and encapsulation of cells in droplets.

Single cell study is gaining importance because of the cell-to-cell variation that exists within cell population, even after significant initial sorting. Analysis of such variation at the gene expression level could impact single cell functional genomics, cancer, stem-cell research, and drug screening. The on-chip monitoring of individual cells in an isolated environment would prevent cross-contamination, provide high recovery yield, and enable study of biological traits at a single cell level. These advantages of on-chip biological experiments is a significant improvement for a myriad of cell analyses methods, compared to conventional methods, which require bulk samples and provide only averaged information on cell structure and function. We report on a device that integrates a mobile magnetic trap array with microfluidic technology to provide the possibility of separation of immunomagnetically labeled cells and their encapsulation with reagents into picoliter droplets for single cell analysis. The simultaneous reagent delivery and compartmentalization of the cells immediately following sorting are all performed seamlessly within the same chip. These steps offer unique advantages such as the ability to capture cell traits as originated from its native environment, reduced chance of contamination, minimal use of the reagents, and tunable encapsulation characteristics independent of the input flow. Preliminary assay on cell viability demonstrates the potential for the device to be integrated with other up- or downstream on-chip modules to become a powerful single-cell analysis tool.

Assessment of γ-H2AX levels in circulating tumor cells from patients receiving chemotherapy.

Circulating tumor cells (CTCs) are prognostic markers in a variety of solid tumor malignancies. The potential of CTCs to be used as a "liquid biopsy" to monitor a patient's condition and predict drug response and resistance is currently under investigation. Using a negative depletion, enrichment methodology, CTCs isolated from the peripheral blood of breast cancer patients with stage IV breast cancer undergoing DNA damaging therapy with platinum-based therapy were enriched. The enriched cell suspensions were stained with an optimized labeling protocol targeting: nuclei, cytokeratins 8, 18, and 19, the surface marker CD45, and the presence of the protein γ-H2AX. As a direct or indirect result of platinum therapy, double-strand break of DNA initiates phosphorylation of the histone H2AX, at serine 139; this phosphorylated form is referred to as γ-H2AX. In addition to γ-H2AX staining in specific locations with the cell nuclei, consistent with previous reports and referred to as foci, more general staining in the cell cytoplasm was also observed in some cells suggesting the potential of cell apoptosis. Our study underscores the utility and the complexity of investigating CTCs as predictive markers of response to various therapies. Additional studies are ongoing to evaluate the diverse γ-H2AX staining patterns we report here which needs to be further correlated with patient outcomes.

A MagDot-Nanoconveyor Assay Detects and Isolates Molecular Biomarkers.

The ability to quickly analyze, separate, and manipulate multiple types of biomarkers from small sample volumes is a significant step toward personalized medicine.

Craniofacial injuries due to golf cart trauma.

OBJECTIVE: To characterize craniofacial injuries due to golf cart trauma. STUDY DESIGN: Case series with chart review. SETTING: Level 1 trauma center. SUBJECTS AND METHODS: A tertiary academic medical center's trauma database was queried for golf cart-related trauma from 2000 to 2009 and returned 68 patients. Data were obtained from the trauma database and by individually reviewing patient charts. RESULTS: Of the 68 patients identified, 55% were male, with a median age of 13.4 years. Sixty-nine percent had head injuries, with 32% sustaining skull or facial fracture and 20.6% intracranial hemorrhage. The highest Abbreviated Injury Scale (AIS) by region was the head and neck. The average Glasgow Coma Scale score was 14.2, Injury Severity Score (ISS) 9.0, hospital stay 4.5 days, and intensive care unit (ICU) stay 2.8 days; 36.8% were admitted to the ICU. Ejection and rollover were the most common mechanisms of injury, with ejection having a significantly higher head and neck AIS compared with rollover and hitting a stationary object (P = .0055). Alcohol was detected in 59.2% of patients older than 16 years; the average blood alcohol concentration was 182.6 mg/dL. Children were involved 60.3% of the time, with an average age of 9.2 years, and children were passengers in the golf cart 69.2% of the time. CONCLUSIONS: Golf cart trauma can cause significant craniofacial injuries, particularly in the pediatric population and in adults who consume alcohol.