Targeting active angiogenesis, which is a major hallmark of malignant gliomas, is a potential therapeutic approach. For effective inhibition of tumor-induced neovascularization, antiangiogenic compounds have to be delivered in sufficient quantities over a sustained period of time. The short biological half-life of many antiangiogenic inhibitors and the impaired intratumoral blood flow create logistical difficulties that make it necessary to optimize drug delivery for the treatment of malignant gliomas. In this study, we compared the effects of endostatin delivered by daily systemic administration or local intracerebral microinfusion on established intracranial U87 human glioblastoma xenografts in nude mice. Noninvasive magnetic resonance imaging methods were used to assess treatment effects and additional histopathological analysis of tumor volume, microvessel density, proliferation, and apoptosis rate were performed. Three weeks of local intracerebral microinfusion of endostatin (2 mg/kg/day) led to 74% (P < 0.05) reduction of tumor volumes with decreased microvessel densities (33.5%, P < 0.005) and a 3-fold increased tumor cell apoptosis (P < 0.002). Systemic administration of a 10-fold higher amount of endostatin (20 mg/kg/day) did not result in a reduction of tumor volume nor in an increase of tumor cell apoptosis despite a significant decrease of microvessel densities (26.9%, P < 0.005). Magnetic resonance imaging was used to successfully demonstrate treatment effects. The local microinfusion of human endostatin significantly increased survival when administered at 2 mg/kg/day and was prolonged further when the dose was increased to 12 mg/kg/day. Our results indicate that the local intracerebral microinfusion of antiangiogenic compounds is an effective way to overcome the logistical problems of inhibiting glioma-induced angiogenesis.

Despite clear benefits of cardiac resynchronization therapy (CRT) on mortality and morbidity in randomized controlled trials among select patients with systolic dysfunction and severe congestive heart failure (CHF), 1,2 there have been numerous case reports over the past 5 years describing significant ventricular proarrhythmia, which manifests primarily as ventricular tachycardia (VT) storm, encountered usually within hours to days after initiation of biventricular pacing. 3-10 At first, the association appeared to be most significant for polymorphic VT, 3,5 but, subsequently, a predominance of monomorphic VT among patients with ischemic cardiomyopathy has been reported. 4,6,7,9 In almost all cases, cessation of biventricular pacing completely suppressed VT and attempts to resume left ventricular pacing resulted in VT recurrence.The report by Nayak et al. 11 in this issue of the Journal represents the largest reported series of VT storm occurring after initiation of CRT and advances our understanding regarding the clinical characteristics and management of this rare but serious adverse outcome. Within this single referral center, 8 out of 191 patients (4%) developed recurrent episodes of sustained monomorphic VT in temporal proximity to initiation of biventricular pacing. A similar percentage of patients developed this complication in a smaller series from another center as well (5 of 145 patients; 3.4%). 6 In contrast to prior reports, half of the patients in the present series developed VT storm more than a week after initiating CRT. This delayed time course raises the possibility that additional intervening precipitants, such as worsening myocardial dysfunction and CHF, may account for at least part of the observed temporal association. Four of these patients experienced cessation of VT when left ventricular (LV) pacing was turned off, suggesting that LV pacing was indeed playing a role in the initiation of VT in these patients. For the other cases where LV pacing was continued throughout, the evidence that LV pacing was the trigger for the VT storm is less clear.There are several reported mechanisms by which epicardial LV pacing may alter the myocardial substrate and promote ventricular arrhythmias. First, epicardial LV pac-