ABSTRACT Angiogenesis is recognized as a biomarker of cancer malignancy. Ultrasonic (US) imaging, super-resolution ultrasound, micro Doppler and acoustic angiography enable the imaging of vessel networks, but the information provided by these images is not quantitative. We propose real-time quantitative assessment of angiogenesis based on Ultrasound Multiple Scattering (USMS) analysis from raw ultrasound data. The proposed USMS parameters will enable the development of biomarkers of cancer aggressiveness. We will validate our methods for cancer applications, but this novel biomedical imaging technology will find applications beyond cancer (to atherosclerosis for example). For breast cancer diagnosis, X-Ray mammography can be ineffective in some populations and MRI present some challenges of cost, accessibility, and some contra-indications related to the use of Gadolinium contrast. Conventional US is highly sensitive but lacks specificity. A more specific US tool would improve our ability to discriminate indeterminate non-lethal disease from lethal cancers, and make a clinical impact on a notable percentage of the at-risk population. Studies assessing the prognostic value of tumor angiogenesis have found a positive association between increasing microvessel densities and worsening prognosis. There is a relationship between multiple scattering parameters and vascular density when vessels are populated by contrast agents. We hypothesize that measuring USMS parameters will enable assessing vascular density and therefore increase the specificity of ultrasound for cancer diagnosis. To verify this hypothesis, we propose to develop, optimize and validate novel ultrasound methods utilizing multiple scattering approaches. These methods will enable the quantitative characterization of the micro- architecture of angiogenesis, leading to improvements in ultrasound specificity. In this project, we will: i) Develop and optimize a quantitative ultrasound method to assess microvascular density and anisotropy non-invasively. ii) Establish the proof of concept that multiple scattering can be used to characterize angiogenesis and assess tumor malignancy in two rodent studies. ii) Validate our new technology in a preliminary study on human patients, and compare the diagnostic power of the developed methods to the currently available standard point of care ultrasound. This research will dramatically increase the specificity of US imaging of angiogenesis, and enable Contrast- Enhanced Ultrasound (CEUS) to become a reliable and widely used clinical tool for the diagnosis of cancer, or the evaluation of likelihood of plaque rupture. Ultimately, the methods developed will be used for diagnosis and monitoring of cancer, and could find other applications such as the prediction of plaque rupture in atherosclerosis.

NARRATIVE There is a positive association between increasing cancer-related angiogenesis and worsening prognosis. We will develop a novel technique for the assessment of the architectural properties of angiogenic microvasculature using multiple scattering of ultrasound. Ultimately, the methods developed will be used for diagnosis and monitoring of cancer.