Dataset Information

Neuronavigation-guided focused ultrasound (NaviFUS) for transcranial blood-brain barrier opening in recurrent glioblastoma patients: clinical trial protocol.

ABSTRACT:

Background

Blood-brain barrier (BBB) limits over 95% of drugs' penetration into brain, which has been a major obstacle in treating patients with glioblastoma. Transient BBB opening in glioblastoma (GBM) is feasible by combining focused ultrasound (FUS) with systemic infusion of microbubbles (MB). NaviFUS, a novel device that integrates neuronavigation and FUS-MB system, is able to intraoperatively direct the ultrasound energy precisely and repeatedly at targeted CNS areas. This clinical trial evaluates the safety and feasibility of NaviFUS in recurrent glioblastoma patients.

Methods

The study is a first-in-human, prospective, open-label, single-center, single-arm, dose escalation phase 1 clinical trial. A total of 6 patients will be enrolled. Patients will be enrolled into three groups, each group receiving an escalating dose of FUS energy (acoustic power is 4, 8, and 12 W) with concomitant systemic microbubbles (0.1 mL/kg) applied 1 week before surgical resection.

Results

Dynamic contrast-enhanced MRI will be obtained immediately and 24 hours after FUS procedures, while heavily T2-weighted sequence will be obtained to evaluate for any micro-hemorrhages. We anticipate that there will be minimal side effects associated with NaviFUS-mediated transient BBB opening.

Conclusions

Obtained results will support a planned phase 2 trial to evaluate whether NaviFUS can effectively enhance the delivery of chemotherapeutic agents and improve tumor control.

SUBMITTER: Chen KT

PROVIDER: S-EPMC7327352 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

Neuronavigation-guided focused ultrasound (NaviFUS) for transcranial blood-brain barrier opening in recurrent glioblastoma patients: clinical trial protocol.

Chen Ko-Ting KT Lin Ya-Jui YJ Chai Wen-Yen WY Lin Chia-Jung CJ Chen Pin-Yuan PY Huang Chiung-Yin CY Kuo John S JS Liu Hao-Li HL Wei Kuo-Chen KC

Annals of translational medicine 20200601 11

<h4>Background</h4>Blood-brain barrier (BBB) limits over 95% of drugs' penetration into brain, which has been a major obstacle in treating patients with glioblastoma. Transient BBB opening in glioblastoma (GBM) is feasible by combining focused ultrasound (FUS) with systemic infusion of microbubbles (MB). NaviFUS, a novel device that integrates neuronavigation and FUS-MB system, is able to intraoperatively direct the ultrasound energy precisely and repeatedly at targeted CNS areas. This clinical ...[more]

PMID: 32617293

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Project description:An emerging approach with potential in improving the treatment of neurodegenerative diseases and brain tumors is the use of focused ultrasound (FUS) to bypass the blood-brain barrier (BBB) in a non-invasive and localized manner. A large body of pre-clinical work has paved the way for the gradual clinical implementation of FUS-induced BBB opening. Even though the safety profile of FUS treatments in rodents has been extensively studied, the histological and behavioral effects of clinically relevant BBB opening in large animals are relatively understudied. Here, we examine the histological and behavioral safety profile following localized BBB opening in non-human primates (NHPs), using a neuronavigation-guided clinical system prototype. We show that FUS treatment triggers a short-lived immune response within the targeted region without exacerbating the touch accuracy or reaction time in visual-motor cognitive tasks. Our experiments were designed using a multiple-case-study approach, in order to maximize the acquired data and support translation of the FUS system into human studies. Four NHPs underwent a single session of FUS-mediated BBB opening in the prefrontal cortex. Two NHPs were treated bilaterally at different pressures, sacrificed on day 2 and 18 post-FUS, respectively, and their brains were histologically processed. In separate experiments, two NHPs that were earlier trained in a behavioral task were exposed to FUS unilaterally, and their performance was tracked for at least 3 weeks after BBB opening. An increased microglia density around blood vessels was detected on day 2, but was resolved by day 18. We also detected signs of enhanced immature neuron presence within areas that underwent BBB opening, compared to regions with an intact BBB, confirming previous rodent studies. Logistic regression analysis showed that the NHP cognitive performance did not deteriorate following BBB opening. These preliminary results demonstrate that neuronavigation-guided FUS with a single-element transducer is a non-invasive method capable of reversibly opening the BBB, without substantial histological or behavioral impact in an animal model closely resembling humans. Future work should confirm the observations of this multiple-case-study work across animals, species and tasks.

Dataset Information

Neuronavigation-guided focused ultrasound (NaviFUS) for transcranial blood-brain barrier opening in recurrent glioblastoma patients: clinical trial protocol.

Background

Methods

Results

Conclusions

Publications

Neuronavigation-guided focused ultrasound (NaviFUS) for transcranial blood-brain barrier opening in recurrent glioblastoma patients: clinical trial protocol.

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