Cerebral arteriovenous malformations: radiosurgery-enhanced molecular targeting therapy

Object: Cerebral arteriovenous malformations (AVMs) are a major cause of stroke in children andyoung adults. Surgery and stereotactic radiosurgery are treatment options for selected AVMspatients. However surgery is not suitable for larger deeply located AVMs. Radiosurgery has a long latency period and has a relatively low efficacy. Molecular targeting therapy to promote intravascular thrombosis is a new treatment strategy for high grade AVMs. This proposed treatment might improve the efficacy of radiosurgery in treating AVMs that not treatable with the current therapies. Non-ligand molecular therapy using lipopolysaccharides and tissue factor has been shown effectiveness in treating AVMs in an animal model. However, nonligand therapy might be not safe in humans. Ligand-based therapies may overcome safety concerns of non-ligand therapy. Ligand based vascular targeting therapy for brain AVMs requires a specific endothelial cell surface molecule that distinguishes AVMs from the normal vessels. Unlike in tumours, endothelial cells of AVMs do not have specific markers that differentiate them from normal endothelial cells. Radiosurgery may have the ability to induce molecular endothelial changes sufficient to allow targeting. Materials and methods: A Gamma Knife irradiated animal model of AVM was developed in this study. A specific animal frame was designed for this purpose. Identification of the created AVMs using 3D reconstructed CT images was achieved and the radiation treatment for each animal was planned using the Gamma Knife software. Responses of the AVM model to Gamma Knife radiation were studied using haemodynamic, morphological and histological techniques. Immunohistochemistry was used to investigate specific endothelial cell molecules in the animal model and their response to radiosurgery. Results: Gamma Knife irradiation produced angiographic changes at 6 and 12 weeks, with statistically significant differences in the proximal and distal left external jugular vein diameters between the treatment group and the control group (P < 0.05).Compared to the controls, the treated group had lower blood flow when assessed across all time points using ANOVA (P < 0.001). At 12 weeks, there was a significantly lower flow rate in the left common carotid artery and left external jugular vein in the treated group compared with the control group (P < 0.001) and (P < 0.05) respectively. Histologically, Gamma Knife radiosurgery induced concentric sub-endothelial cell growth. Intercellular adhesion molecule-1 (ICAM-1) expression significantly increased in the Gamma Knife treated group compared to the non-irradiated group (P < 0.05). Confocal analysis indicated that ICAM-1 expression was primarily confined to the endothelial cell surface. An increase in the expression of tissue factor in irradiated AVMs was identified at 1, 3, 6 and 12 weeks after radiation, however, this was not significant (P>0.05). Conclusions:In the animal model of AVM, Gamma Knife irradiation induces angiographic, histological and haemodynamic responses may resemble that of human AVMs. This thesis shows that the Gamma Knife radiated animal model is suitable for studying methods to enhance radiation responses in AVMs. The study improves our understanding of the mechanism of radiosurgery for treating AVM. Moreover, radio surgery appears to induce specific molecular changes that discriminate AVM endothelium from normal endothelium, thus paving the way for targeted molecular therapy.