Focused Ultrasound Blood-Brain Barrier Opening in Pontine Diffuse Midline Glioma to Enhance Temozolomide Therapy: Pilot Feasibility Study (FIDES)

Inclusion Criteria: * Age ≥ 4 years. * Histologically/molecularly verified de novo pontine H3K27-altered diffuse midline glioma. * Main localization ('center of mass') in the brainstem. NB: some degree of extension beyond the brainstem, e.g. cerebellar peduncles, is allowed. * Karnofsky Performance Score (KPS) or Lansky Performance Score (LPS) of ≥ 70/ KPS or LPS 60 and WHO/ECOG performance status ≤ 2. * ASA-score of I-III. * Intention to treat with (TMZ chemo-) radiation and maintenance TMZ as per consensus of the local multidisciplinary tumor board. * Feasible to schedule the first Exablate BBBO procedure preferably within 4-6 weeks, acceptably within 12 weeks, after successful completion of radiotherapy/ concomitant TMZ-chemoradiation, defined as completed treatment as planned without reported CTCAEv6.0 grade 3-4 toxicities or, in case of reported CTCAEv6.0 grade 3-4 toxicities, the toxicities must be resolved to grade 2 prior to inclusion. * If on steroids, stable or decreasing dose for at least 7 days prior to inclusion. * Able to attend all study visits. * Able and willing to give informed consent or have a legal guardian who is able and willing to do so. Exclusion Criteria: * Previous or ongoing participation in other clinical trials with other than standard-of-care tumor-directed treatment(s) for H3K27-altered DMG. * Multifocal or leptomeningeal metastasized disease. Multifocal disease is defined as multiple FLAIR-hyperintense lesions, separated by normal-appearing brain tissue, with or without gadolinium enhancement. Multiple enhancing regions within one continuous FLAIR lesion can be considered as unifocal disease. * Signs/symptoms of elevated intracranial pressure (ICP) (e.g. headache, vomiting, impaired vision/papilledema, impaired consciousness), with corresponding radiographic findings on MRI at time of screening. * Severe dysphagia with feeding tube dependency. * Evidence of acute clinically significant intracranial hemorrhage. NB: minimal hemorrhagic foci without obvious related clinical symptoms will not serve as grounds for exclusion. * Tumor not visible on any pre-therapy or post-radiation imaging. * Presence of extracranial / intracranial structures (e.g. metal prostheses, implants, calcifications) on pre-treatment CT-scan/ MRI-scan, significantly interfering with acoustic impedance as per judgement of the researchers. * Known co-occurring other malignancy that is progressing or has required active treatment within the past 3 years, with exception of: carcinomas in situ (CIS) and non-melanoma skin cancers. * Patients with right-to-left, bi-directional or transient right-to-left cardiac shunts. * Known LVEF \< 40 or unstable hemodynamics. * Severe hypertension, not adequately controlled with study compatible medication (Adults: RR systolic \>180 and/ or RR diastolic \>100; Children: \>p95 + 12mmHg). * History of bleeding disorder and/or coagulopathy. * Treatment with anti-coagulant therapy. * Severely impaired renal function; creatinine clearance \<30 mL/ min. * Subjects with significant liver dysfunction; Child Pugh classification C. * Known diagnosis of active or untreated hepatitis B, hepatitis C, tuberculosis. * Any other illness or medical condition that in the investigator's opinion precludes participation in this study. * Pregnant or lactating women. * Expected uncontrollable therapy non-compliance/ non-cooperation that is likely to interfere with the study procedure, as per judgement of the investigators. * Head circumference ≤ 49 cm. * Weight ≥ 135 kg. * Patient ≥ 18 years old, who requires general anesthesia to undergo the Exablate BBBO procedure. * Contra-indication for MRI procedures. * Known sensitivity to gadolinium-based contrast agents. * Known sensitivity to the resonator agent (perflutren; Luminity®).