Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: randomized phase II study.

Background: Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase inhibitors, which interfere with DNA damage repair. Veliparib, a potent poly(ADP-ribose) polymerase inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer. Patients and methods: Eligible patients ≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1 : 1 : 1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and overall response rate (ORR). Results: Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively [hazard ratio (HR) 0.789; 95% CI 0.536-1.162; P = 0.227], interim median OS 28.3 and 25.9 months (HR 0.750; 95% CI 0.503-1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR 1.858; 95% CI 1.278-2.702; P = 0.001), interim median OS 19.1 months (HR 1.483; 95% CI 1.032-2.131; P = 0.032), and ORR 28.6% (P < 0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP. Conclusion: Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared with PCP. The addition of veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with veliparib/placebo if chemotherapy is discontinued without progression, in this patient population. Clinical trial information: NCT01506609.

Improved preservation of coronary endothelial function with Celsior compared with blood and crystalloid solutions in heart transplantation.

BACKGROUND: Endothelial injury from preservation solutions has been implicated in acute coronary vasospasm and pathologic activation of the endothelium, which can contribute to the development of graft coronary vasculopathy after heart transplantation. Preservation solutions with a powerful antioxidant capacity may decrease the occurrence of these complications. MATERIALS AND METHODS: This study was designed to evaluate the effect of Celsior (an anti-oxidant solution specifically designed for cardiac preservation) in a model of heart preservation (4 hours at 4 degrees C to reproduce the situation encountered in clinical heart transplantation) compared two commonly used cardioplegic and preservation strategies on coronary endothelial function. Endothelium-dependent relaxation of normal porcine epicardial coronary arteries to serotonin (5-HT, an agonist that activates 5-HT(1d) receptors coupled to Gi proteins) and bradykinin (BK, which activates B2 receptors coupled to Gq proteins) was studied in standard organ chamber experiments in the following groups: a control group was submitted to immediate excision without cardioplegia and preserved in saline solution (0.9% NaCl) for 4 hours (Group 1); two groups had cardioplegia induced with a crystalloid solution and were stored for 4 hours in saline (Group 2) or 4 hours in Celsior solution (Group 3); and two groups had cardioplegia induced with normothermic blood cardioplegia and were stored for 4 hours in the saline (Group 4), or 4 hours in Celsior solution (Group 5). Finally, two groups underwent cardioplegia with Celsior and were stored for 4 hours in saline (Group 6), or 4 hours in the Celsior solution (Group 7). All cardioplegia solutions were at 4 degrees C (except blood cardioplegia at 37 degrees C) and all preservations solutions were at 4 degrees C. RESULTS: Endothelium-dependent relaxations to serotonin were significantly decreased in all groups except the Celsior + Celsior group compared with the control group. There were no significant differences in relaxation to bradykinin except in one group. Use of the Celsior solution for induction of cardioplegia and storage better preserved endothelium-dependent G-protein-mediated relaxation compared with the other arrest and preservation strategies. CONCLUSIONS: The observed effect may be associated with an improvement in both short- and long-term outcome in heart transplantation, especially because these alterations may be further compounded by reperfusion.

Effects on coronary endothelial function of the Cohn stabilizer for beating heart bypass operations.

BACKGROUND: The effects of different stabilizing methods for minimally invasive beating heart coronary artery bypass grafts (CABG) on coronary endothelial function are unknown. METHODS: We compared the effects on endothelial function of the Cohn stabilizer (used with proximal snaring by Retract-o-tape silicone air cushion) and a coronary shunt (CTS flow coil shunt) on an in vivo model of beating heart CABG. The two techniques were applied for 15 minutes on porcine epicardial coronary arteries. Control rings were taken from the same coronary artery. Endothelial function of control and instrumented arterial rings was studied in organ chamber experiments. Evaluation of endothelial coverage was performed with silver nitrate staining. RESULTS: Endothelium-dependent relaxation to serotonin and bradykinin was significantly decreased in the shunt group compared to control, Cohn stabilizer, and snare groups. There were no significant differences in the endothelium-independent relaxation to sodium nitroprusside between groups. CONCLUSIONS: Greater endothelium-dependent relaxation with the Cohn stabilizer suggests better preservation of endothelial coverage at the site of application and reduced propensity for coronary spasm and later development of intimal hyperplasia.

Effects of occlusion devices for minimally invasive coronary artery bypass surgery on coronary endothelial function of atherosclerotic arteries.

BACKGROUND: During minimally invasive coronary artery bypass grafting surgery, technical devices are required to obtain an optimal operative field. However, these devices can cause lesions to the endothelium. Previous studies of the effect of devices on coronary endothelial function have been performed on normal coronary arteries. Balloon denudation is followed by regeneration of the endothelium, which is dysfunctional and by intimal hyperplasia resembling atherosclerosis. The Anastaflo (Baxter, Mississauga, Ontario, Canada) shunt is a surgical device used during the performance of coronary anastomoses that allows a continuous flow inside the artery during the surgery. METHODS: We compared the effects of three commonly used techniques on endothelial function: 1) using the Anastaflo shunt, 2) using Retract-o-tape (Genzyme, Cambridge, MA) silicone air cushion snaring, and 3) using a bulldog clamp on arteries submitted to balloon denudation 30 days prior to the surgical experiment on an in vivo model of beating heart off-pump coronary artery bypass (OPCAB). Balloon denudation was performed on the left anterior descending artery and on the right coronary artery. The devices were applied for 15 minutes on porcine epicardial coronary arteries, on the beating heart, after median sternotomy. Denuded control rings were taken at the site of denudation on which no devices were applied while non-denuded control rings were taken from the left circumflex artery. The endothelial function of control and instrumented arterial rings was studied in organ chambers filled with a modified Krebs-Ringer bicarbonate solution. After contraction to prostaglandin F(2)alpha, endothelium-dependent relaxation to serotonin (an agonist coupled to Gi-proteins) and bradykinin (a non-Gi-protein coupled agonist) were compared in the shunting group, the snaring group, the clamping group, and in controls. RESULTS: There was a significant decrease in the relaxations to serotonin and bradykinin in the denuded control group compared with the non-denuded control group, confirming that balloon denudation caused an endothelial dysfunction. However, there was no significant difference between the denuded control group and the hemostatic device groups (shunting, snaring and clamping) in the relaxation to serotonin. CONCLUSION: These results suggest that hemostatic devices used for OPCAB do not cause any greater injury in atherosclerotic coronary arteries already harbouring an endothelial dysfunction. The effects on platelet aggregation, intimal dissection, and plaque rupture remain to be determined.