Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease: The CCTRN PACE Trial (Patients With Intermittent Claudication Injected With ALDH Bright Cells).

BACKGROUND: Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute-sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow-derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms. METHODS: All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by 10 injections into the thigh and calf of the index leg. The coprimary end points were change from baseline to 6 months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging, as well as safety. RESULTS: A total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at 9 sites, of whom 78 had analyzable data (57 male, 21 female patients; mean age, 66±9 years). The mean±SEM differences in the change over 6 months between study groups for PWT (0.9±0.8 minutes; 95% confidence interval [CI] -0.6 to 2.5; P=0.238), collateral count (0.9±0.6 arteries; 95% CI, -0.2 to 2.1; P=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/s; 95% CI, -0.8 to 0.8; P=0.978), and capillary perfusion (-0.2±0.6%; 95% CI, -1.3 to 0.9; P=0.752) were not significant. In addition, there were no significant differences for the secondary end points, including quality-of-life measures. There were no adverse safety outcomes. Correlative relationships between magnetic resonance imaging measures and PWT were not significant. A post hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI, 0.1-2.9; P=0.047) in participants with completely occluded femoral arteries. CONCLUSIONS: ALDHbr cell administration did not improve PWT or magnetic resonance outcomes, and the changes in PWT were not associated with the anatomic or physiological magnetic resonance imaging end points. Future peripheral artery disease cell therapy investigational trial design may be informed by new anatomic and perfusion insights. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01774097.

Reoperative cardiac surgery after long-term ventricular support therapy.

The use of investigational passive support devices continues to be evaluated in the treatment of heart failure. One concern with this technology is the future need for a reoperation such as coronary artery bypass surgery, placement of a left ventricular assist device or cardiac transplantation. In this report, we describe our experience with two patients who required reoperation after long-term use of a passive ventricular support device.

Perspectives on the development of a therapeutic HER-2 cancer vaccine.

With good reason, the majority of cancer vaccines tested, or being tested, have targeted the induction of anti-tumour CTL responses. However, the clinical success of monoclonal antibodies such as Rituximab/CD20, Trastuzumab/HER-2, Cetuximab/EGFR and Bevacisumab/VEGF suggests that their respective targets may also be relevant for cancer vaccines aiming at the induction of an effective humoral anti-tumour response to mimic, or potentially improve upon, the effects of monoclonal therapies. We report here an overview of the development of a protein vaccine targeting HER-2/neu, with an emphasis on the immunologic results obtained from the testing of the vaccine in animal models of disease and in toxicology programs, to its evaluation in three clinical trials in breast cancer patients.

Linked foreign T-cell help activates self-reactive CTL and inhibits tumor growth.

Transgenic mice expressing membrane-bound OVA under the rat insulin promoter, RIP-mOVA, has previously been suggested to display deletional tolerance toward the dominant CTL epitope, SIINFEKL, and provide an elegant model system to test the hypothesis that the lack of T cell help contributes to the tolerance. To understand how the CD8 tolerance is maintained in these mice, a set of neo-self-Ags, OVA, modified to contain a foreign Th peptide, were constructed and tested for their ability to induce CTL responses in RIP-mOVA mice. Immunization with these Th peptide-modified OVA molecules and not with the wild-type OVA induced self-reactive CTLs recognizing dominant CTL peptide, SIINFEKL. Importantly, immunization with the modified OVA constructs also prevented the growth of OVA-expressing tumors in transgenic mice. Since endogenous OVA Th peptides did not contribute toward breaking self CTL tolerance, these results also highlighted a very robust CD4 T cell tolerance toward OVA in RIP-mOVA mice that has not been previously described. These results therefore provide direct evidence that it is the tolerance in the CD4 Th cell compartment that helps maintain the CTL tolerance against self-Ag in these mice. Since the CTL tolerance can be broken or bypassed by foreign Th peptides inserted into a self Ag, potential of using this approach in generating effective therapeutic cancer vaccines is discussed.

HER-2 DNA and protein vaccines containing potent Th cell epitopes induce distinct protective and therapeutic antitumor responses in HER-2 transgenic mice.

Overexpression of the growth factor receptor HER-2 (c-erbB-2, neu) has transforming potential and occurs in approximately 20-30% of breast and ovarian cancers. HER-2 is a self Ag, but Abs and T cells specific for HER-2 have been isolated from cancer patients, suggesting HER-2 may be a good target for active immunotherapy. We constructed rat HER-2 DNA and protein vaccines containing potent Th cell epitopes derived from tetanus toxin and studied their potency in two strains of mice transgenic for the rat HER-2 molecule. Vaccination with HER-2 DNA protected nontransgenic mice from tumor challenge, but induced only moderate protection in one of the tumor models. However, vaccination with the modified HER-2 protein resulted in almost complete protection from tumor challenge in both tumor models. This protection could be mediated by Abs alone. In addition, protein vaccination efficiently eliminated pre-established tumors in both models, even when vaccination occurred 9 days after tumor implantation. These data demonstrate the potential of HER-2-based vaccines as therapeutic agents for the treatment of cancers overexpressing HER-2.

Comparison of dobutamine versus milrinone therapy in hospitalized patients awaiting cardiac transplantation: a prospective, randomized trial.

BACKGROUND: The use of dobutamine or milrinone for inotropic support in patients with heart failure awaiting cardiac transplantation is largely arbitrary and based on institutional preference. The costs and effectiveness of these drugs have yet to be compared in a prospective, randomized study. METHODS: We compared clinical outcomes and costs associated with the use of dobutamine or milrinone in 36 hospitalized patients awaiting cardiac transplantation. Patients were randomly assigned to receive either dobutamine or milrinone at the time of initial hospitalization and were followed until death, transplantation, or placement of mechanical cardiac support (intra-aortic balloon pump or left ventricular assist device). RESULTS: Seventeen patients were randomly assigned to receive dobutamine (mean dose 4.1 +/- 1.4 microg/kg/min) and 19 patients received milrinone (mean dose 0.39 +/- 1.0 microg/kg/min). Therapy lasted 50 +/- 46 days for those in the dobutamine group and 63 +/- 45 days in the milrinone group. We did not detect differences between the 2 groups in right heart hemodynamics, death, need for additional vasodilator/inotropic therapy, or need for mechanical cardiac support before transplantation. Ventricular arrhythmias requiring increased antiarrhythmic therapy occurred frequently in both groups. Total acquisition cost of milrinone was significantly higher than that of dobutamine (16,270 dollars +/- 1334 vs 380 dollars +/- 533 P <.00001). CONCLUSIONS: Both dobutamine and milrinone can be used successfully as pharmacologic therapy for a bridge to heart transplantation. Despite similar clinical outcomes, treatment with milrinone incurs greater cost.

Ventricular dyssynchrony in dilated cardiomyopathy: the role of biventricular pacing in the treatment of congestive heart failure.

Despite advances in pharmacologic therapy, the prognosis of patients with advanced congestive heart failure (CHF) remains poor. Many of these patients have cardiac conduction abnormalities, such as left bundle-branch block or interventricular conduction delays, that can lead to ventricular dyssynchrony (abnormal ventricular activation that results in decreased ventricular filling and abnormal ventricular wall motion). Biventricular pacing is an alternative, nonpharmacologic therapy under active investigation for the treatment of CHF. Resynchronization devices with transvenous leads in the right atrium, right ventricle, and left ventricle (via the coronary sinus) have been implanted in patients to provide atrial triggered biventricular pacing. The use of such devices has been associated with improvement in ejection fraction, dP/dt, stroke work, and functional class. The proposed mechanisms involved in improving ventricular function with biventricular pacing include improved septal contribution to ventricular ejection, increased diastolic filling times, and reduced mitral regurgitation. This article reviews the pathophysiology of ventricular dyssynchrony and examine insights from clinical trials that are evaluating cardiac resynchronization therapy for CHF.

Percutaneous coronary intervention versus medical therapy for coronary allograft vasculopathy. One center's experience.

BACKGROUND: Coronary allograft vasculopathy, a rapidly progressive form of atherosclerosis, remains the limiting factor in the long-term survival of heart transplant recipients. Some centers have attempted percutaneous coronary intervention to slow the disease process and thereby reduce mortality in these patients, but long-term follow-up data are scarce. We compared clinical outcomes in heart transplant recipients with coronary allograft vasculopathy who were treated either with percutaneous coronary intervention or with aggressive medical therapy alone. METHODS: A retrospective analysis of all heart transplant recipients at our institution who underwent surveillance coronary angiography for coronary allograft vasculopathy between 1995 and 2000 was performed. Patients with coronary allograft vasculopathy were stratified according to whether they received medical therapy or percutaneous coronary intervention. Baseline demographics, results of re-vascularization procedures and outcomes were analyzed. RESULTS: From 1995 to 2000, 301 patients underwent 602 coronary angiograms. Of the 79 patients who had angiographic evidence of coronary allograft vasculopathy, 53 were treated with aggressive medical therapy, while 26 underwent percutaneous coronary intervention in addition to aggressive medical therapy. At baseline, patients treated with aggressive medical therapy tended to be younger (54.6 +/- 13.8 years) than patients treated with percutaneous coronary intervention (62.6 +/- 7.6 years; p = 0.0079). Ejection fraction at time of diagnosis of coronary allograft vasculopathy was similar for both groups (medical therapy group, 44.4 +/- 13.4% vs percutaneous coronary intervention group, 47.2 +/- 12.7%; p = 0.38). In our cohort, heart transplant recipients with coronary allograft vasculopathy demonstrated greater mortality than heart transplant recipients without coronary allograft vasculopathy (p = 0.016). Patients who underwent percutaneous coronary intervention had a 60% re-stenosis rate at 6 months if they were treated with coronary angioplasty and an 18% re-stenosis rate if they received a coronary stent. Kaplan-Meier analysis showed no significant difference in survival in either treatment group at 1 year (80% for medical therapy group vs 95% for percutaneous coronary intervention group) or 3 years (68% for medical therapy group vs 79% for percutaneous coronary intervention group) after the angiographic diagnosis of coronary allograft vasculopathy. CONCLUSION: In this non-randomized trial, heart transplant recipients with coronary allograft vasculopathy were less likely to survive than patients without it. In addition, we found no statistical difference in mortality in heart transplant recipients with coronary allograft vasculopathy, regardless of whether they received percutaneous coronary intervention or aggressive medical therapy alone.