Vandetanib in locally advanced or metastatic differentiated thyroid cancer refractory to radioiodine therapy.

The VERIFY study aimed to determine the efficacy of vandetanib in patients with differentiated thyroid cancer (DTC) that is either locally advanced or metastatic and refractory to radioiodine (RAI) therapy. Specifically, VERIFY is a randomized, double-blind, multicenter phase III trial aimed to determine the efficacy and safety of vandetanib in tyrosine kinase inhibitor-naive patients with locally advanced or metastatic RAI-refractory DTC with documented progression (NCT01876784). Patients were randomized 1:1 to vandetanib or placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included best objective response rate, overall survival (OS), safety, and tolerability. Patients continued to receive randomized treatment until disease progression or for as long as they were receiving clinical benefit unless criteria for treatment discontinuation were met. Following randomization, 117 patients received vandetanib, and 118 patients received a placebo. Median PFS was 10.0 months in the vandetanib group and 5.7 months in the placebo group (hazard ratio: 0.75; 95% CI: 0.55-1.03; P = 0.080). OS was not significantly different between treatment arms. Common Terminology Criteria for Adverse Events (CTCAE) of grade ≥3 were reported in 55.6% of patients in the vandetanib arm and 25.4% in the placebo arm. Thirty-three deaths (28.2%; one related to study treatment) occurred in the vandetanib arm compared with 16 deaths (13.6%; two related to treatment) in the placebo arm. No statistically significant improvement was observed in PFS in treatment versus placebo in patients with locally advanced or metastatic, RAI-refractory DTC. Moreover, active treatment was associated with more adverse events and more deaths than placebo, though the difference in OS was not statistically significant.

Endothelial Dysfunction and Heart Failure with Preserved Ejection Fraction-An Updated Review of the Literature.

Heart failure (HF) is a clinical syndrome consisting of typical symptoms and signs due to structural and/or functional abnormalities of the heart, resulting in elevated intracardiac pressures and/or inadequate cardiac output. The vascular system plays a crucial role in the development and progression of HF regardless of ejection fraction, with endothelial dysfunction (ED) as one of the principal features of HF. The main ED manifestations (i.e., impaired endothelium-dependent vasodilation, increased oxidative stress, chronic inflammation, leukocyte adhesion, and endothelial cell senescence) affect the systemic and pulmonary haemodynamic and the renal and coronary circulation. The present review is aimed to discuss the contribution of ED to HF pathophysiology-in particular, HF with preserved ejection fraction-ED role in HF patients, and the possible effects of pharmacological and non-pharmacological approaches. For this purpose, relevant data from a literature search (PubMed, Scopus, EMBASE, and Medline) were reviewed. As a result, ED, assessed via venous occlusion plethysmography or flow-mediated dilation, was shown to be independently associated with poor outcomes in HF patients (e.g., mortality, cardiovascular events, and hospitalization due to worsening HF). In addition, SGLT2 inhibitors, endothelin antagonists, endothelial nitric oxide synthase cofactors, antioxidants, and exercise training were shown to positively modulate ED in HF. Despite the need for future research to better clarify the role of the vascular endothelium in HF, ED represents an interesting and promising potential therapeutic target.