Therapies for metastatic castration-resistant prostate cancer (mCRPC) include targeting the androgen receptor (AR) with androgen receptor inhibitors (ARIs) and prostate-specific membrane antigen ...(PSMA). Having the ability to detect AR, AR splice variant 7 (AR-V7), or PSMA in circulating tumor cells (CTCs) or circulating exosomal cell-free RNA (cfRNA) could be helpful to guide selection of the appropriate therapy for each individual patient. The Vortex Biosciences VTX-1 system is a label-free CTC isolation system that enables the detection of the expression of multiple genes in both CTCs and exosomal cfRNA from the same blood sample in patients with mCRPC. Detection of both AR-V7 and PSMA gene expression in both CTCs and cfRNA simultaneously has not yet been reported. To characterize the combined VTX-1-AdnaDetect workflow, 22Rv1 cancer cells were spiked into blood from healthy donors and processed with the VTX-1 to mimic patient samples and assess performances (capture efficiency, purity, AR and AR-V7 expression). Then, we collected 19 blood samples from 16 patients with mCRPC and therapeutic resistance to androgen receptor inhibitors (ARIs). Plasma was separated and the plasma-depleted blood was processed further with the VTX-1 to collect CTCs. Both plasma exosomal cfRNA and CTCs were subsequently analyzed for AR, AR-V7, PSMA, and prostate-specific antigen (PSA) mRNA expression using the AdnaTest ProstateCancerPanel AR-V7 assay. AR-V7 expression could be detected in 22Rv1 cells spiked into blood from healthy volunteers as well as in CTCs and plasma-derived exosomal cfRNA from patients with mCRPC by processing blood with the VTX-1 CTC isolation system followed by the AdnaTest ProstateCancerPanel AR-V7 assay. 94.7% of patient blood samples (18/19) had detectable AR expression in either CTCs or exosomal cfRNA (16 in CTCs, 12 in cfRNA). 15.8% of the 19 patient blood samples (3/19) were found to have AR-V7-positive (AR-V7+) CTCs, one of which was also AR-V7+ in the exosomal cfRNA analysis. 42.1% of patient blood samples (8/19) were found to be PSMA positive (PSMA+): 26.3% (5/19) were PSMA+ in the CTC analysis and 31.6% (6/19) were PSMA+ in the exosomal cfRNA analysis. Of those 8 PSMA+ samples, 2 had detectable PSMA only in CTCs, and 3 had detectable PSMA only in exosomal cfRNA. VTX-1 enables isolation of CTCs and plasma exosomes from a single blood draw and can be used for detecting AR-V7 and PSMA mRNA in both CTCs and cfRNA in patients with mCRPC and resistance to ARIs. This technology facilitates combining RNA measurements in CTCs and exosomal cfRNA for future studies to develop potentially clinically relevant cancer biomarker detection in blood.
The primary safety and efficacy endpoints of the randomized FIRE AND ICE trial have recently demonstrated non-inferiority of cryoballoon vs. radiofrequency current (RFC) catheter ablation in patients ...with drug-refractory symptomatic paroxysmal atrial fibrillation (AF). The aim of the current study was to assess outcome parameters that are important for the daily clinical management of patients using key secondary analyses. Specifically, reinterventions, rehospitalizations, and quality-of-life were examined in this randomized trial of cryoballoon vs. RFC catheter ablation.
Patients (374 subjects in the cryoballoon group and 376 subjects in the RFC group) were evaluated in the modified intention-to-treat cohort. After the index ablation, log-rank testing over 1000 days of follow-up demonstrated that there were statistically significant differences in favour of cryoballoon ablation with respect to repeat ablations (11.8% cryoballoon vs. 17.6% RFC; P = 0.03), direct-current cardioversions (3.2% cryoballoon vs. 6.4% RFC; P = 0.04), all-cause rehospitalizations (32.6% cryoballoon vs. 41.5% RFC; P = 0.01), and cardiovascular rehospitalizations (23.8% cryoballoon vs. 35.9% RFC; P < 0.01). There were no statistical differences between groups in the quality-of-life surveys (both mental and physical) as measured by the Short Form-12 health survey and the EuroQol five-dimension questionnaire. There was an improvement in both mental and physical quality-of-life in all patients that began at 6 months after the index ablation and was maintained throughout the 30 months of follow-up.
Patients treated with cryoballoon as opposed to RFC ablation had significantly fewer repeat ablations, direct-current cardioversions, all-cause rehospitalizations, and cardiovascular rehospitalizations during follow-up. Both patient groups improved in quality-of-life scores after AF ablation.
ClinicalTrials.gov identifier: NCT01490814.
Current guidelines recommend pulmonary-vein isolation by means of catheter ablation as treatment for drug-refractory paroxysmal atrial fibrillation. Radiofrequency ablation is the most common method, ...and cryoballoon ablation is the second most frequently used technology.
We conducted a multicenter, randomized trial to determine whether cryoballoon ablation was noninferior to radiofrequency ablation in symptomatic patients with drug-refractory paroxysmal atrial fibrillation. The primary efficacy end point in a time-to-event analysis was the first documented clinical failure (recurrence of atrial fibrillation, occurrence of atrial flutter or atrial tachycardia, use of antiarrhythmic drugs, or repeat ablation) following a 90-day period after the index ablation. The noninferiority margin was prespecified as a hazard ratio of 1.43. The primary safety end point was a composite of death, cerebrovascular events, or serious treatment-related adverse events.
A total of 762 patients underwent randomization (378 assigned to cryoballoon ablation and 384 assigned to radiofrequency ablation). The mean duration of follow-up was 1.5 years. The primary efficacy end point occurred in 138 patients in the cryoballoon group and in 143 in the radiofrequency group (1-year Kaplan-Meier event rate estimates, 34.6% and 35.9%, respectively; hazard ratio, 0.96; 95% confidence interval CI, 0.76 to 1.22; P<0.001 for noninferiority). The primary safety end point occurred in 40 patients in the cryoballoon group and in 51 patients in the radiofrequency group (1-year Kaplan-Meier event rate estimates, 10.2% and 12.8%, respectively; hazard ratio, 0.78; 95% CI, 0.52 to 1.18; P=0.24).
In this randomized trial, cryoballoon ablation was noninferior to radiofrequency ablation with respect to efficacy for the treatment of patients with drug-refractory paroxysmal atrial fibrillation, and there was no significant difference between the two methods with regard to overall safety. (Funded by Medtronic; FIRE AND ICE ClinicalTrials.gov number, NCT01490814.).
Haemophilia B is a X-chromosome linked disease characterised by a deficiency of functionally active coagulation Factor IX (FIX). Patients with severe haemophilia B at risk of recurrent bleeding are ...treated approximately twice a week in a prophylactic setting by application of FIX concentrates. To increase convenience and compliance of the therapy it is desirable to reduce the dosing frequency by improving the pharmacokinetic properties of FIX. Here a concept of rFIX (recombinant factor IX) albumin fusion proteins (rIX-FPs) with cleavable linker peptides derived from the FIX activation sequence is presented. Constructs of the genetic fusion of FIX to albumin via cleavable linkers were expressed in mammalian cells and characterised after purification. In vitro activation studies with FXIa demonstrated that cleavage of the linker and the activation peptide proceeded comparably well. In a clotting assay the rIX-FPs with cleavable linker showed a 10- to 30-fold increase in the molar specific clotting activity compared to fusion proteins with non-cleavable linkers. Furthermore, in-vivo recovery, terminal half-life and the AUC of rIX-FPs in rats and rabbits as determined by FIX antigen measurements were significantly increased compared to rFIX (BeneFIX). In FIX deficient (FIX(-/-)) mice the in-vivo recovery and the AUC were also significantly increased. The efficacy in reducing bleeding time was shown in FIX(-/-) mice by a tail tip bleeding model. The results suggest that rIX-FPs with a cleavable linker between FIX and albumin are a promising concept that may support the use of the albumin fusion technology to extend the half-life of FIX.
The HIV-1 reservoir is the major hurdle to a cure. We here evaluate viral and host characteristics associated with reservoir size and long-term dynamics in 1,057 individuals on suppressive ...antiretroviral therapy for a median of 5.4 years. At the population level, the reservoir decreases with diminishing differences over time, but increases in 26.6% of individuals. Viral blips and low-level viremia are significantly associated with slower reservoir decay. Initiation of ART within the first year of infection, pretreatment viral load, and ethnicity affect reservoir size, but less so long-term dynamics. Viral blips and low-level viremia are thus relevant for reservoir and cure studies.
The prophylactic treatment of haemophilia B and the management of haemophilia A or B with inhibitors demand frequent administrations of coagulation factors due to the suboptimal half-lives of the ...products commercially available and currently in use, e.g. recombinant factor IX (rFIX) and recombinant factor VIIa (rFVIIa), respectively. The extension of the half-lives of rFIX and rFVIIa could allow for longer intervals between infusions and could thereby improve adherence and clinical outcomes and may improve quality of life. Albumin fusion is one of a number of different techniques currently being examined to prolong the half-life of rFIX and rFVIIa. Results from a phase I clinical trial demonstrated that the recombinant fusion protein linking FIX to albumin (rIX-FP) has a five-times longer half-life than rFIX, and preclinical studies with the recombinant fusion protein linking FVIIa to albumin (rVIIa-FP) suggest that rVIIa-FP possesses a significantly extended half-life versus rFVIIa. In this review, we describe albumin fusion technology and examine the recent progress in the development of rIX-FP and rVIIa-FP.
The FIRE AND ICE trial assessed efficacy and safety of pulmonary vein (PV) isolation using cryoballoon versus radiofrequency current (RFC) ablation in patients with drug refractory, symptomatic, ...paroxysmal atrial fibrillation (AF). The purpose of the current study was to assess index lesion durability as well as reablation strategy and outcomes in trial patients undergoing a reablation procedure.
Patients with reablation procedures during FIRE AND ICEwere retrospectively consented and enrolled at 13 trial centers. The first reablation for each patient was included in the analysis. Documented arrhythmias before reablation, number and location of reconnected PVs, lesions created during reablations, procedural characteristics, and acute as well as long-term outcomes were assessed.
Eighty-nine (36 cryoballoon and 53 RFC) patients were included in this study. Paroxysmal atrial fibrillation was the predominant recurrent arrhythmia (69%) before reablation. Reablations occurred at a median of 173 and 182 days (P=0.54) in the cryoballoon and RFC cohorts, respectively. The number of reconnected PVs was significantly higher in the RFC than the cryoballoon group (2.1±1.4 versus 1.4±1.1; P=0.010), which was driven by significantly more reconnected left superior PVs and markedly more reconnected right superior PVs. The number of (predominantly RFC) lesions applied during reablation was significantly greater in patients originally treated with RFC (3.3±1.3 versus 2.5±1.5; P=0.015) with no difference in overall acute success (P=0.70). After reablation, no differences in procedure-related rehospitalization or antiarrhythmic drug utilization were observed between cohorts.
At reablation, patients originally treated with the cryoballoon had significantly fewer reconnected PVs, which may reflect RFC catheter instability in certain left atrial regions, and thus required fewer lesions for reablation success. Repeat ablations were predominantly performed with RFC and resulted in similar acute success, duration of hospitalization, and antiarrhythmic drug prescription between the study cohorts.
Data on predictors of long-term clinical outcomes after catheter ablation of atrial fibrillation (AF) are limited. We sought to assess the association of baseline covariates with clinical outcomes in ...the 750 patients with drug-refractory paroxysmal AF enrolled in FIRE AND ICE.
In a 2-part analysis, univariate and multivariable Cox regression models were first used to identify baseline patient characteristics predictive of catheter ablation efficacy determined by the clinical end points of (1) atrial arrhythmia recurrence (primary efficacy failure), (2) cardiovascular rehospitalization, and (3) repeat ablation. Propensity score stratification methods were then used to account for differences in baseline characteristics between sexes.
Female sex (hazard ratio HR, 1.37; 95% confidence interval CI, 1.08-1.73;
=0.010) and prior direct current cardioversion (HR, 1.40; 95% CI, 1.07-1.82;
=0.013) were independently associated with atrial arrhythmia recurrence. Female sex (HR, 1.36; 95% CI, 1.02-1.80;
=0.035) and hypertension (HR, 1.48; 95% CI, 1.09-2.00;
=0.013) independently predicted cardiovascular rehospitalization. A longer history of AF (HR, 1.03; 95% CI, 1.00-1.06;
=0.039) increased the rate of repeat ablation. Women continued to have higher rates of primary efficacy failure and cardiovascular rehospitalization after propensity score adjustment, with adjusted HRs of 1.51 (95% CI, 1.16-2.18;
<0.05) and 1.40 (95% CI, 1.15-2.17;
<0.05), respectively.
After catheter ablation of paroxysmal AF, female sex was associated with an almost 40% increase in the risks of primary efficacy failure and cardiovascular rehospitalization. Primary efficacy failure was also adversely impacted by a history of direct current cardioversion, whereas hypertension had a negative impact on cardiovascular rehospitalization. History of AF was the only predictor of repeat ablation.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01490814.
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