The role of out-of-hospital cardiac arrest in predicting hospital mortality for percutaneous coronary interventions in the Clinical Outcomes Assessment Program.

Published mortality models for percutaneous coronary intervention (PCI), including the Clinical Outcomes Assessment Program (COAP) model, have not considered the effect of out-ofhospital cardiac arrest. The primary objective of this study was to determine if the inclusion of out-of-hospital cardiac arrest altered the COAP mortality model for PCI. The COAP PCI database contains extensive demographic, clinical, procedural and outcome information, including out-of-hospital cardiac arrest, which was added to the data collection form in 2006. This study included 15,586 consecutive PCIs performed in 31 Washington State hospitals in 2006. Using development and test sets, the existing COAP PCI logistic regression mortality model was examined to assess the effect of out-of-hospital arrest on in-hospital mortality. Overall, 2% of individuals undergoing PCI had cardiac arrest prior to hospital arrival. Among 8 hospitals with PCI volumes < 120 cases per year, 4 had cardiac arrest volumes that exceeded 10% of total volume, whereas none of the centers with > 120 cases per year did. In-hospital mortality was 19% in the arrest group and was 1.0% in remaining procedures (p < 0.0001). In the new multivariate model, out-of-hospital cardiac arrest was highly associated with mortality (odds ratio = 5.50; 95% confidence interval [CI] = 3.28-9.25). When evaluated in the test set, the new model had excellent discrimination (c-statistic = 0.89; 95% CI = 0.85-0.93). Out-of-hospital cardiac arrest is an important determinant of risk-adjusted in-hospital mortality for PCI, particularly for hospitals with low volumes and relatively high volumes of cardiac arrest cases.

Familial eosinophilia: a benign disorder?

Familial eosinophilia (FE) is an autosomal dominant disorder characterized by marked eosinophilia and progression to end organ damage in some, but not all, affected family members. To better define the pathogenesis of FE, 13 affected and 11 unaffected family members (NLs) underwent a detailed clinical evaluation at the National Institutes of Health (NIH). No clinical abnormalities were more frequent in the family members with FE compared with the NLs. There was, however, a decreased prevalence of asthma in family members with FE compared with unaffected family members. Eosinophil morphology as assessed by either light or transmission electron microscopy was normal in family members with and without FE. Although levels of eosinophil-derived neurotoxin (EDN) and major basic protein (MBP) were elevated in patients with FE compared with NL, levels of both granule proteins were lower than in nonfamilial hypereosinophilic syndrome (HES). Similarly, increased surface expression of the activation markers CD69, CD25, and HLA-DR was detected by flow cytometry on eosinophils from patients with FE compared with NL, albeit less than that seen in HES. These data suggest that, despite prolonged marked eosinophilia, FE can be distinguished from HES by a more benign clinical course that may be related to a relative lack of eosinophil activation.

Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms.

PURPOSE: The primary objectives of this trial were to define the maximum tolerated dose (MTD) and to characterize the toxicities and pharmacokinetics of depsipeptide (FR901228) given on a day-1 and day-5 schedule every 21 days. A secondary objective of the trial was to seek evidence of antineoplastic activity. PATIENTS AND METHODS: Patients with advanced or refractory neoplasms received depsipeptide by a 4-h i.v. infusion on days 1 and 5 of a 21-day cycle. On the basis of preclinical data suggesting that depsipeptide may have significant cardiac toxicity, patients were treated while receiving continuous cardiac monitoring and were followed with serial cardiac enzyme determinations, electrocardiograms (ECGs), and nuclear ventriculograms (MUGA scans). The starting dose of the trial was 1 mg/m(2), and dose escalations proceeded through a total of eight dose levels to a maximum of 24.9 mg/m(2). Toxicities were graded using the National Cancer Institute common toxicity criteria, and pharmacokinetics were determined using a liquid chromatography/tandem mass spectrometry method. RESULTS: Patients (37) received a total of 88 cycles of treatment on study (range: one to eight cycles). Dose-limiting toxicity (DLT) was observed, and the MTD exceeded at a dose of 24.9 mg/m(2). The DLTs included grade-3 fatigue (3 patients), grade-3 nausea and vomiting (1 patient), grade-4 thrombocytopenia (2 patients), and grade-4 cardiac arrhythmia (1 patient, atrial fibrillation). The MTD was defined at the seventh dose level (17.8 mg/m(2)). Reversible ST/T changes and mild reversible dysrhythmias were observed on the post-treatment ECG. There were no clinically significant changes in left ventricular ejection fraction. One patient achieved a partial response. The plasma disposition of depsipeptide was well described by a first-order, two-compartment model. The mean volume of distribution, clearance, t(1/2alpha) and t(1/2beta) at a dose of 17.8 mg/m(2) was: 8.6 liters/m(2), 11.6 liters/h/m(2), 0.42 h, and 8.1 h, respectively. The mean maximum plasma concentration at the MTD was 472.6 ng/ml (range: 249-577.8 ng/ml). Biological assays showed that the serum levels achieved could cause the characteristic cell cycle effects of this agent when serum was added to PC3 cells in culture, as well as increased histone acetylation in patient-derived peripheral blood mononuclear cells. CONCLUSION: The MTD of depsipeptide given on a day-1 and -5 schedule every 21 days is 17.8 mg/m(2). The DLTs are fatigue, nausea, vomiting, and transient thrombocytopenia and neutropenia. Whereas cardiac toxicity was anticipated based on preclinical data, there was no evidence of myocardial damage. However, reversible ECG changes with ST/T wave flattening were regularly observed. Biologically active serum concentrations were achieved, and 1 patient obtained a partial response. The recommended Phase II dose is 17.8 mg/m(2) administered on day 1 and 5 of a 21-day cycle.