Preoperative Image-guided Transcranial Histotripsy for Brain Cancer Treatment

Abstract

Malignant brain tumors remain deadly with a 36% five-year survival rate and 5% for glioblastoma (GBM), the most aggressive and prevalent form of malignant brain tumor. The current standard of care includes invasive surgery guided by preoperative images. This invasive surgery can lead to further morbid complications such as bleeding or healthy brain tissue damage. Less invasive surgical options under investigation include laser interstitial thermal therapy (LITT) and magnetic resonance-guided focused ultrasound (MRgFUS). They both require real-time MR guidance for intraoperative monitoring and this requirement leads to limited availability and expensive cost. Histotripsy is a noninvasive cavitational ultrasound surgical method that has shown great promise as a neurosurgical technology. This dissertation presents the first preoperative image-guided transcranial histotripsy targeting platform for brain tumor treatment, the first radiological follow-up study after transcranial histotripsy, and the first study on the state of the blood-brain barrier (BBB) after histotripsy. The first chapter introduces the motivation for this dissertation. The second chapter discusses the development of a focused ultrasound stereotactic platform for transcranial histotripsy of murine brains. The stereotactic procedure was guided by preoperative MRI, and the platform was analyzed for sources of error contributing to the targeting uncertainty. The entire system was calibrated, and the calibrated system showed significantly reduced targeting error of 0.20 ± 0.21, 0.34 ± 0.24, and 0.28 ± 0.21 mm in axial, lateral, and elevational axes, respectively, in the in vivo GBM tumor-bearing mice (N = 10). The third chapter investigates the transcranial histotripsy MRI and histological findings in both normal mice with and without brain tumors and evaluates the changes over time. T2, T2*, T1, and T1-gadolinium (Gd) MR images and H&E histology were acquired on days 0, 2, and 7 for tumor-bearing mice and days 0, 2, 7, 14, 21, and 28 for normal mice. T2 best showed anatomical feature changes due to the treatment, T2* the histotripsy ablation, T1 the blood product evolution from oxygenated blood to hemosiderin, and T1-Gd the BBB opening (BBBO) that arises from a tumor or histotripsy ablation. The fourth chapter investigates the BBBO induced by transcranial histotripsy for the first time and studies how BBB at the periphery of the histotripsy ablation zone changes over time post-histotripsy with MRI and tight junction protein (TJP) staining. Analysis of T1-Gd MRI showed that the hyperintense BBBO area was increased for the first 7 days and subsided gradually over time. The area in the center of the histotripsy ablation, showed complete loss of the TJP immunostaining immediately post histotripsy, while at the border of the ablation, partial recovery of TJP complex was observed on day 7 post-histotripsy, and near-complete recovery of TJP complex was observed on day 21. The fifth chapter discusses the development of the first neuronavigation-guided transcranial histotripsy (NaviTH). The workflow for treatment delivery using NaviTH was developed. The feasibility and targeting accuracy of the system were evaluated using two excised human skulls and two, <96 hours post-mortem whole-body human cadavers. The NaviTH system was calibrated to improve targeting errors. The post-calibration system targeting accuracy was evaluated by RBC phantoms and the resulting accuracy was 2.5 mm. The final chapter summarizes the findings of this dissertation and discusses future work needed to bring transcranial histotripsy closer to the clinic.