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.
Authors
- Elisa E. Konofagou (ORCID: https://orcid.org/0000-0002-9636-7936)
- Neil A. Feldstein (ORCID: https://orcid.org/0009-0001-2352-1031)
- Zachary Englander (ORCID: https://orcid.org/0000-0001-8544-7490)
- Angela Lignelli (ORCID: https://orcid.org/0000-0003-2908-9179)
- Sua Bae (ORCID: https://orcid.org/0000-0003-1276-8677)
- Alexis Maddocks (ORCID: https://orcid.org/0000-0001-5858-1790)
- Masih Tazhibi
- Danae Kokossis (ORCID: https://orcid.org/0000-0001-6285-3728)
- Nicholas McQuillan (ORCID: https://orcid.org/0000-0002-6589-3204)
- Xander Berg (ORCID: https://orcid.org/0009-0003-1365-6877)
- Robyn D. Gartrell (ORCID: https://orcid.org/0000-0003-3287-4223)
- Cheng–Chia Wu (ORCID: https://orcid.org/0000-0002-5908-0143)
- Omid Yousefian (ORCID: https://orcid.org/0000-0002-5990-3744)
- Luca Szalontay (ORCID: https://orcid.org/0000-0002-7341-0014)
- Stergios Zacharoulis
- Jovana Pavisic (ORCID: https://orcid.org/0000-0002-6968-600X)
- Peter Canoll (ORCID: https://orcid.org/0000-0002-7001-0226)
- Nina Yoh (ORCID: https://orcid.org/0000-0002-3058-9122)
- Zhezhen Jin (ORCID: https://orcid.org/0000-0002-3801-0680)
- Matthew Gallitto (ORCID: https://orcid.org/0000-0002-5210-742X)
- Hong-Jian Wei (ORCID: https://orcid.org/0000-0002-5962-7831)
- Antonios N. Pouliopoulos (ORCID: https://orcid.org/0000-0002-8891-1495)
- Robin Ji (ORCID: https://orcid.org/0000-0003-1361-141X)
- Andrea Webster Carrion (ORCID: https://orcid.org/0000-0001-5405-5072)
- Chankrit Sethi
- James H. Garvin (ORCID: https://orcid.org/0000-0003-4709-1088)
- Jennifer Lipina
- Keyu Liu (ORCID: https://orcid.org/0000-0001-8194-4692)
- Jessica Fino (ORCID: https://orcid.org/0009-0004-6527-2696)
- Genesis De Los Santos
- Halina Shatravka (ORCID: https://orcid.org/0009-0008-5437-6966)
Institutions
- Children's Hospital of Philadelphia (US)
- Johns Hopkins University (US)
- Washington University in St. Louis (US)
- Columbia University Irving Medical Center (US)
- Johns Hopkins Medicine (US)
- Neurological Surgery (US)
- Columbia University (US)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2025-11-12
- DOI
- https://doi.org/10.1126/scitranslmed.adq6645
- Citations
- 5
- Primary Topic
- Ultrasound and Hyperthermia Applications
- Type
- article
- Field-Weighted Citation Impact
- 3.37
Funders
- Musella Foundation For Brain Tumor Research and Information
- Rally Foundation
- Focused Ultrasound Foundation
- Memorial Sloan-Kettering Cancer Center
- George Washington University
- Virginia Polytechnic Institute and State University
- Strong
- Swim Across America
- Children's National Hospital
- King's College London
- Sogang University
- National Institutes of Health
- Hyundai Hope On Wheels