Abstract OBJECTIVES DIPG/DMG is a fatal brain tumor developing in delicate areas of the brain with a median overall survival of 1 year. The dismal outcome is partly due to the blood-brain barrier (BBB) which poses a major challenge to delivering effective therapeutic agents. Over the past 4 years we opened two Phase I clinical trials using Delsona focused ultrasound (FUS) device developed at Columbia University to treat pediatric and AYA patients with relapsed DMG. In the first study, we delivered FUS with concomitant panobinostat and during the second study we gave oral etoposide. Here we present our experience of delivering neuronavigation based FUS for pediatric patients with progressive DMG. METHODS Pediatric and AYA patients with biopsy proven DIPG/DMG at disease progression were enrolled (FUS with oral panobinostat: NCT04804709 and FUS with oral etoposide: NCT05762419). Patients were allowed to have prior therapies, including radiation and reirradiation. FUS was delivered over the course of six or four cycles respectively. MRI was performed to validate BBB-opening and closure. RESULTS During the FUS-panobinostat study, we treated 3 patients. The study was closed prematurely when panobinostat was taken off the US market. In the FUS-etoposide study, we have already treated 2 patients (the study is currently open). For the two trials combined, we delivered over twenty-five FUS treatments. Four of the five patients treated had achieved BBB-opening. Two patients in the FUS and panobinostat study showed improvement in their neurological symptoms. The average time for FUS-delivery was approximately 47 minutes. All treatments were performed in the outpatient settings in the Department of Radiation Oncology. Side effects from FUS was limited to one grade 1 dermatological toxicity. CONCLUSION FUS-mediated BBB-opening delivered as an outpatient procedure is feasible, to date, in children with relapsed DIPG/DMG. Further studies are needed to assess for efficacy.