Publications

PURPOSE

This dedicated QTc phase I study, conducted in advanced-stage cancer patients, assessed the effect of a single supratherapeutic dose (800 mg) of vorinostat on the QTc interval.

EXPERIMENTAL DESIGN

A randomized, partially blind, placebo-controlled, two-period, crossover study was conducted. Patients (n = 25) received single doses of 800 mg vorinostat and placebo in the fasted state. Holter electrocardiogram monitoring was done before each treatment and for 24 h postdose. Blood samples for vorinostat concentration were collected through 24 h postdose following vorinostat treatment only. Prescribed electrocardiogram and blood sampling times were designed to capture the expected C(max) of vorinostat.

RESULTS

Twenty-four of the 25 patients enrolled in the study were included in the QTc analysis. The upper bound of the two-sided 90% confidence interval for the QTcF interval for the placebo-adjusted mean change from baseline of vorinostat was <10 ms at every time point. No patient had a QTcF change from baseline value >30 ms. One patient had QTcF values >450 ms (seen after both vorinostat and placebo administration) and none had values >480 ms. Mean AUC(0-infinity) and C(max) values attained were on the order of approximately 1.93- and approximately 1.41-fold higher, respectively, compared with the 400 mg clinical dose. Based on assessment of clinical and laboratory adverse experiences, single doses of 800 mg vorinostat were generally well tolerated.

CONCLUSIONS

Administration of a single supratherapeutic dose of the histone deacetylase inhibitor vorinostat is not associated with prolongation of the QTc interval. A dedicated QTc study in advanced cancer patients is a robust means for assessing risk for ventricular repolarization prolongation.

Milk fat globule epidermal growth factor 8 (Mfge8) is a soluble glycoprotein known to regulate inflammation and immunity by mediating apoptotic cell clearance. Since fibrosis can occur as a result of exaggerated apoptosis and inflammation, we set out to investigate the hypothesis that Mfge8 might negatively regulate tissue fibrosis. We report here that Mfge8 does decrease the severity of tissue fibrosis in a mouse model of pulmonary fibrosis; however, it does so not through effects on inflammation and apoptotic cell clearance, but by binding and targeting collagen for cellular uptake through its discoidin domains. Initial analysis revealed that Mfge8-/- mice exhibited enhanced pulmonary fibrosis after bleomycin-induced lung injury. However, they did not have increased inflammation or impaired apoptotic cell clearance after lung injury compared with Mfge8+/+ mice; rather, they had a defect in collagen turnover. Further experiments indicated that Mfge8 directly bound collagen and that Mfge8-/- macrophages exhibited defective collagen uptake that could be rescued by recombinant Mfge8 containing at least one discoidin domain. These data demonstrate a critical role for Mfge8 in decreasing the severity of murine tissue fibrosis by facilitating the removal of accumulated collagen.

BACKGROUND: Cardiac magnetic resonance (CMR) imaging has emerged as an important cardiac imaging technique for the evaluation of multiple cardiac pathologies. OBJECTIVE/METHOD: The goal of this review is to describe recent advances in techniques which have extended the potential applications of CMR. The focus will be on the clinical applications of CMR for the evaluation of coronary artery disease and heart failure/cardiomyopathies which are major causes of morbidity and mortality worldwide. CONCLUSION: CMR provides unique tissue characterization which is not available from other imaging modalities and has demonstrated important diagnostic and prognostic information in many forms of heart disease.

Women who have survived cancer may need guidance in choosing a method of contraception. This paper reviews the evidence supporting the safety and efficacy of available methods of contraception for cancer survivors and concludes that the Copper T380A intrauterine device (IUD), a highly effective, reversible, long-acting, hormone-free method should be considered a first-line contraceptive option for women with a history of a hormonally mediated cancer. However, the levonorgestrel-containing IUD may be preferable for women being treated with tamoxifen and women who have survived non-hormonally mediated cancers. Women with IUDs can undergo all forms of imaging, including computed tomography and magnetic resonance imaging.