Vascular endothelial growth factor blockade: A potential new therapy in the management of cerebral arteriovenous malformations

Abstract OBJECTIVE To compare the angiogenic potentials of embolized, gamma knife–treated or untreated cerebral arteriovenous malformations (AVMs), using a rat cornea angiogenesis model. METHODS Tissue samples from cerebral AVM patients who were either untreated or had previously been treated with embolization or gamma knife radiosurgery and who had undergone operations for hemorrhage at the Neurosurgery Department or the Neurological Sciences Institute of Marmara University were used. For the macroscopic evaluation of angiogenesis, tissue samples were inoculated in a micropocket created on the rat eye, and the level of angiogenic activity was graded macroscopically for 15 days, with glioblastoma multiforme and normal brain artery tissues serving as positive and negative controls, respectively. For the other part of the experiment, eyes of another set of rats were inoculated with the study samples only using the same cornea angiogenesis model, in which microvessel count and vascular endothelial growth factor assessment was done at days 3, 7, 11, and 15. RESULTS Based on our macroscopic findings in the cornea angiogenesis model, embolized AVMs exhibited the highest angiogenic activity, followed by untreated AVMs and gamma knife–treated AVMs. Evaluations of vascular endothelial growth factor expression and microvessel counts showed a similar relation among the 3 tissue groups with regard to the level of angiogenic activity, supporting the results of macroscopic examinations. CONCLUSION This study, for the first time, provides experimental semiquantitative data to compare the angiogenic potentials of embolized and gamma knife–treated AVM tissues. Embolization may increase angiogenic activity, and gamma knife radiosurgery may decrease it when compared with activity in previously untreated AVMs. These data can be useful to understand why recurrence of AVMs after angiographically demonstrated endovascular occlusion is common but after gamma knife occlusion is rare.

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Abstract TP445: Bevacizumab Therapy for Brain Arteriovenous Malformations

Stroke ◽

10.1161/str.48.suppl_1.tp445 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Daniel L Cooke ◽

Helen Kim ◽

Wade Smith ◽

Michael Lawton ◽

Jennifer Clarke ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Arteriovenous Malformations ◽

Vascular Malformations ◽

Vascular Endothelial ◽

Open Label ◽

Beneficial Effects ◽

Brain Arteriovenous Malformations ◽

Bevacizumab Treatment ◽

Endothelial Growth Factor

Introduction: Brain arteriovenous malformations (bAVM) are dynamic vascular malformations and a significant source of intracranial hemorrhage (ICH). Obliteration by interventional therapy is the only proven method to remove this hemorrhagic risk. Partial bAVM volume reduction using combination therapy does not lessen the risk of future ICH, though such adjuvant treatment is routinely practiced to permit definitive microsurgical resection or radiosurgery. High expression of vascular endothelial growth factor (VEGF) has been reported in bAVM and there is evidence for the beneficial effects of bevacizumab on AVMs from studies using the hereditary hemorrhagic telangiectasia (HHT) bAVM model and in liver AVMs in HHT patients. There is, however, no medical therapy approved to treat bAVMs. The goal of this study is to determine the beneficial effects of the anti-vascular endothelial growth factor drug, Bevacizumab, on bAVM. Hypothesis: Our hypothesis is that bAVM volume will decrease after 12 weeks of bevacizumab treatment. Additionally, we expect that bevacizumab treatment for bAVMs will not increase the occurrence of symptomatic ICH beyond that expected for natural history. Methods: The trial is a 10 patient one-armed, open-label study that will administer bevacizumab (5 mg/kg every 2 weeks) by IV infusion over the course of 12 weeks. The study will assess feasibility, safety, and preliminary evidence of efficacy in bAVMs deemed inoperable by current interventional means. For the purpose of estimating our effect size, we assumed that the bevacizumab treatment effect on bAVM volume will be proportional to the reduction of blood flow measured by the cardiac index in the hepatic AVM-bevacizumab trial. With a sample size of 10 paired observations and a one-tailed α =0.05, we have 84% power to detect a change in bAVM volume of 13%. We will compare pre- and post-treatment (26 weeks) volumes using a paired t-test. Significance: This study is the first medical intervention trial for bAVM. The study will meaningfully impact the clinical and research communities managing AVMs, regardless their anatomic location, and in turn those patients who suffer from them.

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