Title: Transcranial Magnetic Resonance (MR) and ultrasound (US) guided Histotripsy (tcMR-USgHt) Project Summary The goal of this R01 is to develop a transcranial magnetic resonance (MR) and ultrasound (US) guided histotripsy (tcMR-USgHt) system for non-invasive treatment of brain tumors. There are one million brain cancer patients in the U.S. with primary brain tumors, and significantly more patients with brain metastases. The first-line treatment is craniotomy-based, highly invasive surgery associated with high morbidities. Radiation therapy and drug-based chemotherapeutics both have significant limitations for brain tumor treatment. There is an urgent, unmet clinical need for a noninvasive, safe, and effective treatment for brain tumors. Transcranial histotripsy uses microsecond US pulses to generate mechanical ablation in the brain via cavitation. Using a very low duty cycle (<0.1%) to minimize skull heating, transcranial histotripsy has the potential to noninvasively ablate a wide range of locations and volumes in the brain without damaging off-target, normal brain tissue. We have developed a 700kHz, 360- element hemispherical transcranial histotripsy array, and its feasibility for brain treatment was successfully demonstrated in the in vivo porcine brain through an excised human skull and in the brain of human cadavers. MRI can be used for precise pre-treatment targeting with MR-ARFI (acoustic radiation force impulse) or MR thermometry at low heating generated by the focused US, and histotripsy brain ablation can be clearly visualized by MRI. However, the treatment location profile of the current transcranial histotripsy array is limited for skulls with significant density variation and large thicknesses. MRI cannot be used to image cavitation near or on the skull surface or provide real-time monitoring at the frame rate (≥50Hz) histotripsy is delivered. This grant is built upon these promising data and will focus on solving the two challenges critical for clinical translation via two main innovations: 1) a new transcranial histotripsy array to expand the treatment location profile in a diverse set of patients, and 2) simultaneous, co-registered transcranial MRI and US guided histotripsy system with treatment monitoring at high-frame rate capable of skull-surface cavitation detection. Four Specific Aims are as follows. Aim 1 – Design and construct a new MR-compatible, transmit-receive capable transcranial histotripsy phased array that can treat a wide range of brain locations in diverse (>70%) patients. Aim 2 – Develop simultaneous, co-registered MRI and US guided histotripsy with enhanced MRI guidance and high frame rate (≥50Hz) US treatment monitoring capable of skull-surface cavitation detection. Aim 3 – Investigate the treatment location envelope, volume, accuracy, and speed using the tcMR-USgHt system in human head phantoms and head of human cadavers. Aim 4 – Investigate the in vivo safety and feasibility of the tcMR-USgHt system in the porcine normal brain and canine patients with spontaneously occurring brain tumors. The tcMR-USgHt system developed from this grant represents significant technical advancements and will provide an essential platform to enable future research and clinical translation of transcranial histotripsy treatment of brain tumors and other neurological disorders.

Project Narrative The goal of this project is to develop an image-guided noninvasive interventional tool to treat brain tumors. The brain tumors referred here include both primary and metastatic tumors in the brain.