University of California.

This study examined the feasibility, efficacy (abscopal effect), and immune effects of TGFβ blockade during radiotherapy in metastatic breast cancer patients. Prospective randomized trial comparing two doses of TGFβ blocking antibody fresolimumab. Metastatic breast cancer patients with at least three distinct metastatic sites whose tumor had progressed after at least one line of therapy were randomized to receive 1 or 10 mg/kg of fresolimumab, every 3 weeks for five cycles, with focal radiotherapy to a metastatic site at week 1 (three doses of 7.5 Gy), that could be repeated to a second lesion at week 7. Research bloods were drawn at baseline, week 2, 5, and 15 to isolate PBMCs, plasma, and serum. Twenty-three patients were randomized, median age 57 (range 35-77). Seven grade 3/4 adverse events occurred in 5 of 11 patients in the 1 mg/kg arm and in 2 of 12 patients in the 10 mg/kg arm, respectively. Response was limited to three stable disease. At a median follow up of 12 months, 20 of 23 patients are deceased. Patients receiving the 10 mg/kg had a significantly higher median overall survival than those receiving 1 mg/kg fresolimumab dose [hazard ratio: 2.73 with 95% confidence interval (CI), 1.02-7.30; = 0.039]. The higher dose correlated with improved peripheral blood mononuclear cell counts and a striking boost in the CD8 central memory pool. TGFβ blockade during radiotherapy was feasible and well tolerated. Patients receiving the higher fresolimumab dose had a favorable systemic immune response and experienced longer median overall survival than the lower dose group. .

BACKGROUND: Percutaneous mitral valve repair (MVR) using the MitraClip system has become a valid alternative for patients with severe mitral regurgitation (MR) and high operative risk. OBJECTIVE: To identify clinical and periprocedural factors that may have an impact on clinical outcome. DESIGN: Multi-centre longitudinal cohort study. SETTING: Tertiary referral centres. PATIENTS: Here we report on the first 100 consecutive patients treated with percutaneous MVR in Switzerland between March 2009 and April 2011. All of them had moderate-severe (3+) or severe (4+) MR, and 62% had functional MR. 82% of the patients were in New York Heart Association (NYHA) class III/IV, mean left ventricular ejection fraction was 48% and the median European System for Cardiac Operative Risk Evaluation was 16.9%. INTERVENTIONS: MitraClip implantation performed under echocardiographic and fluoroscopic guidance in general anaesthesia. MAIN OUTCOME MEASURES: Clinical, echocardiographic and procedural data were prospectively collected. RESULTS: Acute procedural success (APS, defined as successful clip implantation with residual MR grade 2+) was achieved in 85% of patients. Overall survival at 6 and 12 months was 89.9% (95% CI 81.8 to 94.6) and 84.6% (95% CI 74.7 to 91.0), respectively. Univariate Cox regression analysis identified APS (p=0.0069) and discharge MR grade (p=0.03) as significant predictors of survival. CONCLUSIONS: In our consecutive cohort of patients, APS was achieved in 85%. APS and residual discharge MR grade are important predictors of mid-term survival after percutaneous MVR.

Background— Percutaneous mitral valve repair with the MitraClip device has emerged as an alternative to surgery for treating severe mitral regurgitation. However, its effects on left ventricular loading conditions and contractility have not been investigated yet. Methods and Results— Pressure-volume loops were recorded throughout the MitraClip procedure using conductance catheter in 33 patients (mean age, 78±10 years) with functional (45%), degenerative (48%), or mixed (6%) mitral regurgitation. Percutaneous mitral valve repair increased end-systolic wall stress (WS ES ; from [median] 184 mm Hg [interquartile range (IQR), 140–200 mm Hg] to 209 mm Hg [IQR, 176–232 mm Hg]; P =0.001) and decreased end-diastolic WS (WS ED ; from 48 mm Hg [IQR, 28–58 mm Hg] to 34 mm Hg [IQR, 21–46 mm Hg]; P =0.005), whereas the end-systolic pressure-volume relationship was not significantly affected. Conversely, cardiac index increased (from 2.6 L·min −1 ·m −2 [IQR, 2.2–3.0 L·min −1 ·m −2 ] to 3.2 L·min −1 ·m −2 [IQR, 2.6–3.8 L·min −1 ·m −2 ]; P <0.001) and mean pulmonary capillary wedge pressure decreased (from 15 mm Hg [IQR, 12–20 mm Hg] to 12 mm Hg [IQR, 10–13 mm Hg]; P <0.001). Although changes in WS ES were not correlated with changes in cardiac index, changes in WS ED correlated significantly with changes in mean pulmonary capillary wedge pressure ( r =0.63, P <0.001). Total mechanical energy assessed by the pressure-volume area remained unchanged, resulting in a more favorable index of forward output (cardiac index) to mechanical energy (pressure-volume area) after mitral valve repair. On follow-up (153±94 days), New York Heart Association functional class was reduced from 2.9±0.6 to 1.9±0.5 ( P <0.001) at 3 months, and echocardiographic follow-up documented a stepwise reduction in end-diastolic volume (from 147 mL [IQR, 95–191 mL] to 127 mL [IQR, 82–202 mL]; P =0.036). Conclusions— Percutaneous mitral valve repair improves hemodynamic profiles and induces reverse left ventricular remodeling by reducing left ventricular preload while preserving contractility. In nonsurgical candidates with compromised left ventricular function, MitraClip therapy could be considered an alternative to surgical mitral valve repair.

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