Abstract 3981: Characterization of high intensity focused Ultrasound induced vascular damage using histology, MR, and Ultrasound Imaging

Abstract

Abstract Background High intensity focused ultrasound (HIFU) has considerable clinical potential for noninvasive ablation of solid tumors. HIFU is based on tightly focusing high energy ultrasound at a target, causing a lethal temperature rise which induces thermal coagulative necrosis. Studies have shown that HIFU can also be used for induction of vascular occlusion. Selective occlusion of tumor feeder vessels in conjunction with anti-angiogenic drugs may be a way of treating cancer either by de-bulking a tumor prior to surgery or as a palliative growth retardation therapy. The aim of this work was to characterize the vascular disruption caused by HIFU exposure, including the evolution of any changes, using Magnetic Resonance Imaging (MRI), Ultrasound (US) Imaging and histology. Methods An in-vivo rat liver model was used and four HIFU exposures each at one of 3 different free-field spatial peak intensities (1106 ± 91 W/cm2 for 10s; 1751 ± 119 W/cm2 for 6s; or 2753 ± 192 W/cm2 for 4s) were placed in a row at 4-6 mm separation. Livers (n=4 per time point) were harvested for histology (paraffin based) at 0, 1.5, 3, 6, 12, 24, 48 hrs, 3 and 7 days. Stains used included Haematoxylin and Eosin (H&E), Picrosirius Millers (collagen and Elastin), cleaved Caspase 3 (apoptosis), CD68 (macrophages), Hif1 alpha (hypoxia), Ki67 (proliferation), thrombin and Factor XIIIa (clotting). Some animals were injected with Hoechst (perfusion indicator) and Pimanidazole (hypoxia probe) and the liver was frozen for histological assessment. Some of the animals underwent MRI (7 T) and targeted (VEGF) contrast agent imaging with a high resolution US system (Visual Sonics) to obtain quantitative vessel size and perfusion data. Finally additional three-dimensional quantitative information from vascular casting will be described Results and Conclusions Hoechst data acquired immediately after HIFU showed a lack of perfusion within, and downstream of, the exposed regions. This demonstrated that vessels were occluded. Although H&E images obtained immediately after HIFU showed no distinct cellular changes in the non-ablated unperfused regions, from 6 hours onwards changes indicative of ischemic damage were apparent, confirming vascular occlusion. Apoptosis was also evident in these regions. A band of macrophages observed as early as 1.5 hrs after occlusion was found to gradually infiltrate the center of ischemic damage. Two days after exposure, Ki67 (proliferation) stain showed no positive staining within regions of ischemic damage. The results of the ongoing imaging studies will be presented. This study concludes that HIFU can be used for vessel occlusion in order to nutrient deprive a region significantly larger than the ablated volume. The perfusion poor region then undergoes controlled cell death and phagocytic activity, suggesting the potential use of this technique to inhibit tumor growth. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3981.