PROJECT SUMMARY Each year, nearly 2 million Americans receive a cancer diagnosis, with surgical removal being the primary treatment approach for solid tumors. Nowhere are the challenges and benefits of high precision surgery more apparent than in the brain where maximal resection is the primary therapeutic approach and where healthy tissue must be preserved. For glioblastoma multiforme (GBM), one of the deadliest and treatment-resistant malignancies, the extent of surgical resection provides the best indication of overall survival which is why establishing maximum safe boundaries is a fundamental neuro-surgical objective. Despite two decades of relentless improvements in surgical techniques, the median survival for GBM remains at 16 months using best- practice radiosurgery with temozolomide. Advancements in diagnostic and imaging capabilities must be matched by surgical practices to be effective. Consequently, as imaging modalities such as MRI, CT, or ultrasound have improved in resolution, sensitivity, and specificity, so has the precision of surgical tools, such robotic surgery systems or navigation systems, and minimally or non-invasive methods such as laparoscopies, radio-frequency ablation, radiosurgery, and high intensity focused ultrasound. However, these methods struggle to achieve a resolution beyond 2 mm, which is a significant hurdle when precision is crucial for the resection of complex tumors near critical structures. In this application, UNC-Chapel Hill and Caltech will collaborate to develop non-invasive transcranial volumetric super-resolution imaging, targeted contrast agents, and image-guided focused ultrasound surgery. Our proposal focuses on combining these techniques to resolve the persistent challenges of a) identifying tumor boundaries b) targeting them with ultrasound, and c) establishing interaction between imaging and therapy systems to avoid and/or target critical microvasculature. Advancements in imaging resolution (10 µm) will be matched by the co- registered focused ultrasound beams (750 µm diameter, 50 µm positional accuracy). New ultrasound array designs combined with super-harmonic sequences will enable the targeting of GV contrast agents as well as freely circulating microbubble contrast agents that quantitatively image the intra- and extra-tumoral microvascular environment. A programmable ultrasound scanner platform will control both the proposed therapy array and a 3D imaging array which will allow high-precision volumetric targeting and monitoring as well as enabling sophisticated feedback between thermoablation and its effect on tumor microvasculature. If successful, this project will thus enable effective surgical interventions in the highest mortality tumors.

RELEVANCE TO PUBLIC HEALTH The challenges and benefits of high precision surgery are starkly apparent in the brain where maximal resection is the primary therapeutic approach, the primary indicator of overall survival, and where healthy tissue must be preserved. Advancements in diagnostic and imaging capabilities must be matched by surgical practices to be effective. Our proposal focuses on an order of magnitude improvement in surgical precision by resolving the persistent challenges of a) identifying tumor boundaries b) targeting them with ultrasound, and c) establishing interaction between imaging and therapy systems to avoid and/or target critical microvasculature.