Impact of bone-targeted therapies in chemotherapy-naïve metastatic castration-resistant prostate cancer patients treated with abiraterone acetate: post hoc analysis of study COU-AA-302.

Background Metastatic castration-resistant prostate cancer (mCRPC) often involves bone, and bone-targeted therapy (BTT) has become part of the overall treatment strategy.Objective Investigation of outcomes for concomitant BTT in a post hoc analysis of the COU-AA-302 trial, which demonstrated an overall clinical benefit of abiraterone acetate (AA) plus prednisone over placebo plus prednisone in asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients.Design, setting, and participants This report describes the third interim analysis (prespecified at 55% overall survival [OS] events) for the COU-AA-302 trial.Intervention Patients were grouped by concomitant BTT use or no BTT use.Outcome measurements and statistical analysis Radiographic progression-free survival and OS were coprimary end points. This report describes the third interim analysis (prespecified at 55% OS events) and involves patients treated with or without concomitant BTT during the COU-AA-302 study. Median follow-up for OS was 27.1 mo. Median time-to-event variables with 95% confidence intervals (CIs) were estimated using the Kaplan-Meier method. Adjusted hazard ratios (HRs), 95% CIs, and p values for concomitant BTT versus no BTT were obtained via Cox models.Results and limitations While the post hoc nature of the analysis is a limitation, superiority of AA and prednisone versus prednisone alone was demonstrated for clinical outcomes with or without BTT use. Compared with no BTT use, concomitant BTT significantly improved OS (HR 0.75; p=0.01) and increased the time to ECOG deterioration (HR 0.75; p<0.001) and time to opiate use for cancer-related pain (HR 0.80; p=0.036). The safety profile of concomitant BTT with AA was similar to that reported for AA in the overall intent-to-treat population. Osteonecrosis of the jaw (all grade 1/2) with concomitant BTT use was reported in <3% of patients.Conclusions AA with concomitant BTT was safe and well tolerated in men with chemotherapy-naïve mCRPC. The benefits of AA on clinical outcomes were increased with concomitant BTT.Patient summary Treatment of advanced prostate cancer often includes bone-targeted therapy. This post hoc analysis showed that in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone in combination with bone-targeted therapy, there was a continued trend in prolongation of life when compared with patients treated with prednisone alone.Trial registration ClinicalTrials.gov NCT00887198

Bacterial load and defective monocyte-derived macrophage bacterial phagocytosis in biomass-smoke COPD

Lower airway colonisation with potentially pathogenic bacterial species (PPBs) is associated with defective bacterial phagocytosis, in monocyte-derived macrophages (MDMs) and alveolar macrophages, from tobacco-smoke associated COPD (S-COPD) subjects. In developing world, COPD among non-smokers is largely due to biomass-smoke (BMS) exposure. Yet, little is known about PPBs colonisation and its association with impaired innate immunity in these subjects.We investigated the PPBs load (Streptococcus pneumoniae, SP; Haemophilus influenzae, HI; Moraxella catarrhalis, MC; and Pseudomonas aeruginosa, PA) in BMS-exposed COPD (BMS-COPD) compared with S-COPD and spirometrically normal subjects. We also examined the association between load of PPBs with phagocytic activity of MDMs and lung function.Induced sputum and peripheral venous blood samples were collected from 18 healthy non-smokers, 15 smokers without COPD, 16 BMS-exposed healthy, 19 S-COPD and 23 BMS-COPD subjects. PPBs load in induced sputum and MDMs phagocytic activity were determined using qPCR and fluorimetry respectively.Higher bacterial load of SP, HI, and PA were observed in BMS-COPD. Increased PPBs load in BMS-exposed subjects was significantly negatively associated with defective phagocytosis in MDMs, and spirometric lung function indices (p<0.05).Increased load of PPBs in airways of BMS-COPD subjects is inversely associated with defective bacterial phagocytosis and lung function

Reliable and Accurate Calcium Volume Measurement in Coronary Artery Using Intravascular Ultrasound Videos

Quantitative assessment of calcified atherosclerotic volume within the coronary artery wall is vital for cardiac interventional procedures. The goal of this study is to automatically measure the calcium volume, given the borders of coronary vessel wall for all the frames of the intravascular ultrasound (IVUS) video. Three soft computing fuzzy classification techniques were adapted namely Fuzzy c-Means (FCM), K-means, and Hidden Markov Random Field (HMRF) for automated segmentation of calcium regions and volume computation. These methods were benchmarked against previously developed threshold-based method. IVUS image data sets (around 30,600 IVUS frames) from 15 patients were collected using 40 MHz IVUS catheter (Atlantis® SR Pro, Boston Scientific®, pullback speed of 0.5 mm/s). Calcium mean volume for FCM, K-means, HMRF and threshold-based method were 37.84 ± 17.38 mm3, 27.79 ± 10.94 mm3, 46.44 ± 19.13 mm3 and 35.92 ± 16.44 mm3 respectively. Cross-correlation, Jaccard Index and Dice Similarity were highest between FCM and threshold-based method: 0.99, 0.92 ± 0.02 and 0.95 + 0.02 respectively. Student’s t-test, z-test and Wilcoxon-test are also performed to demonstrate consistency, reliability and accuracy of the results. Given the vessel wall region, the system reliably and automatically measures the calcium volume in IVUS videos. Further, we validated our system against a trained expert using scoring: K-means showed the best performance with an accuracy of 92.80 %. Out procedure and protocol is along the line with method previously published clinically

Effect of IL-1β, TNF-α and IGF-1 on trans-endothelial passage of synthetic vectors through an in vitro vascular endothelial barrier of striated muscle

International audienceWhen administrated in the blood circulation, plasmid DNA (pDNA) complexed with synthetic vectors must pass through a vascular endothelium to transfect underlying tissues. Under inflammatory condition, cytokines can modify the endothelium integrity. Here, the trans-endothelial passage (TEP) of DNA complexes including polyplexes, lipoplexes and lipopolyplexes was investigated in the presence of tumor necrosis factor-a (TNF-alpha), interleukin-1 beta (IL-1 beta) or insulin-like growth factor-1 (IGF-1). The experiments were performed by using an in vitro model comprising a monolayer of mouse cardiac endothelial cells (MCEC) seeded on a trans-well insert and the transfection of C2C12 myoblasts cultured on the lower chamber as read out of TEP. We report that polyplexes made with a histidinylated derivative of lPEI (His-lPEI) exhibit the highest capacity (10.5 mu g cm(-2) h versus 0.324 mu g cm(-2) h) to cross TNF-alpha-induced inflamed endothelium model, but this positive effect is counterbalanced by the presence of IL-1 beta. His-lPEI polyplex TEP is also increased in the presence of IGF-1 (2.58 mu g cm(-2) h). TEP of lipid-based DNA complexes including lipoplexes and lipopolyplexes was lowest compared with polymer-based DNA complexes. Overall, the results indicate that under inflammation, His-lPEI polyplexes have a good profile to cross a vascular endothelium of striated muscle with low cytotoxicity and high transfection efficiency of C2C12 myoblasts. These data provide insights concerning the endothelial passage of vectors in inflammatory conditions and can serve as a basis towards in vivo studies