Blood-brain barrier opening with neuronavigation-guided focused ultrasound in pediatric patients with diffuse midline glioma

Focused ultrasound (FUS)–mediated blood-brain barrier (BBB) opening with microbubbles is an emerging technology that enables drug delivery for central nervous system diseases. To date, most clinical trials assessing BBB opening in adults were designed to deliver US with a frequency of one treatment over several weeks. Little is known about the feasibility of shorter intervals of US delivery or whether this can be achieved in a pediatric population using a mobile device. Here, FUS and panobinostat were shown to have additive therapeutic effects in a syngeneic orthotopic model of diffuse midline glioma (DMG). We then conducted a single-arm first-in-pediatric trial to investigate the safety and feasibility of delivering neuronavigation-guided FUS treatment in combination with oral panobinostat in children with relapsed DMGs. We included an intrapatient escalation of FUS delivery to assess the feasibility of opening multiple sites in the brain. We demonstrated successful BBB opening using neuronavigation-guided FUS as frequently as every 2 days. Magnetic resonance imaging with contrast was used to identify the region of BBB opening. Three patients were accrued; 22 FUS procedures were delivered for 1 NOTS (number of tumor sites) treated, and four FUS procedures were delivered for 2 NOTS. All three patients received 1 NOTS, without serious adverse events, and two of the patients received 2 NOTS, all without sedation. For 2 NOTS, prolonged BBB opening and one grade 5 event, unlikely related to FUS, were observed. This study demonstrates feasibility of FUS for BBB opening and drug delivery without sedation in pediatric patients.