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Therapeutic antibodies targeting immune checkpoints have shown limited efficacy in clinical trials in glioblastoma (GBM) patients. Ultrasound-mediated blood–brain barrier opening (UMBO) using low-intensity pulsed ultrasound improved drug delivery to the brain. We explored the safety and the efficacy of UMBO plus immune checkpoint inhibitors in preclinical models of GBM. A blood–brain barrier (BBB) opening was performed using a 1 MHz preclinical ultrasound system in combination with 10 µL/g microbubbles. Brain penetration of immune checkpoint inhibitors was determined, and immune cell populations were evaluated using flow cytometry. The impact of repeated treatments on survival was determined. In syngeneic GL261-bearing immunocompetent mice, we showed that UMBO safely and repeatedly opened the BBB. BBB opening was confirmed visually and microscopically using Evans blue dye and magnetic resonance imaging. UMBO plus anti-PDL-1 was associated with a significant improvement of overall survival compared to anti-PD-L1 alone. Using mass spectroscopy, we showed that the penetration of therapeutic antibodies can be increased when delivered intravenously compared to non-sonicated brains. Furthermore, we observed an enhancement of activated microglia percentage when combined with anti-PD-L1. Here, we report that the combination of UMBO and anti-PD-L1 dramatically increases GL261-bearing mice's survival compared to their counterparts treated with anti-PD-L1 alone. Our study highlights the BBB as a limitation to overcome in order to increase the efficacy of anti-PD-L1 in GBM and supports clinical trials combining UMBO and in GBM patients. [ABSTRACT FROM AUTHOR]

Background: Temporary disruption of the blood-brain barrier (BBB) using pulsed ultrasound leads to the clearance of both amyloid and tau from the brain, increased neurogenesis, and mitigation of cognitive decline in pre-clinical models of Alzheimer's disease (AD) while also increasing BBB penetration of therapeutic antibodies. The goal of this pilot clinical trial was to investigate the safety and efficacy of this approach in patients with mild AD using an implantable ultrasound device. Methods: An implantable, 1-MHz ultrasound device (SonoCloud-1) was implanted under local anesthesia in the skull (extradural) of 10 mild AD patients to target the left supra-marginal gyrus. Over 3.5 months, seven ultrasound sessions in combination with intravenous infusion of microbubbles were performed twice per month to temporarily disrupt the BBB. 18F-florbetapir and 18F-fluorodeoxyglucose positron emission tomography (PET) imaging were performed on a combined PET/MRI scanner at inclusion and at 4 and 8 months after the initiation of sonications to monitor the brain metabolism and amyloid levels along with cognitive evaluations. The evolution of cognitive and neuroimaging features was compared to that of a matched sample of control participants taken from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Results: A total of 63 BBB opening procedures were performed in nine subjects. The procedure was well-tolerated. A non-significant decrease in amyloid accumulation at 4 months of − 6.6% (SD = 7.2%) on 18F-florbetapir PET imaging in the sonicated gray matter targeted by the ultrasound transducer was observed compared to baseline in six subjects that completed treatments and who had evaluable imaging scans. No differences in the longitudinal change in the glucose metabolism were observed compared to the neighboring or contralateral regions or to the change observed in the same region in ADNI participants. No significant effect on cognition evolution was observed in comparison with the ADNI participants as expected due to the small sample size and duration of the trial. Conclusions: These results demonstrate the safety of ultrasound-based BBB disruption and the potential of this technology to be used as a therapy for AD patients. Research of this technique in a larger clinical trial with a device designed to sonicate larger volumes of tissue and in combination with disease-modifying drugs may further enhance the effects observed. Trial registration: ClinicalTrials.gov, NCT03119961 [ABSTRACT FROM AUTHOR]

Magnetic Resonance Imaging (MRI) in patients with severe head injury allows comprehensive assessment of the primary insult thus providing an indicator of possible long term prognosis. Morphological images can now be coupled to metabolic analysis, thus providing a more precise assessment of brain lesions and opening a new exciting field of research. [ABSTRACT FROM AUTHOR]

Previous studies reported interest in intraoperative shear-wave elastography (SWE) guidance for brain-tumor and epilepsy surgeries. Focal cortical dysplasia (FCD) surgery is one of the most appropriate indications for using SWE guidance. The aim of this study was to evaluate the efficacy of ultrasound SWE techniques for the intraoperative detection of FCDs. We retrospectively analyzed data from 18 adult patients with drug-resistant epilepsy associated with FCD who had undergone SWE-guided surgery. Conventional B-mode images detected FCD in 2 patients (11.1%), while SWE detected FCD in 14 patients (77.8%). The stiffness ratios between MRI-positive and -negative cases were significantly different (3.6 ± 0.4 vs. 2.2 ± 0.6, respectively; p < 0.001). FCDs were significantly more frequently detected by interoperative SWE in women (OR 4.7, 95% CI (1.7–12.7); p = 0.004) and in patients in whom FCD was visible on magnetic resonance imaging (MRI; OR 2.3, 95% CI (1.3–4.3); p = 0.04). At 1 year after surgery and at last follow-up (mean = 21 months), seizure outcome was good (International League Against Epilepsy (ILAE) Class 1 or 2) in 72.2% and 55.6% of patients, respectively. Despite some limitations, our study highlighted the potential of SWE as an intraoperative tool to detect FCD. Future technical developments should allow for optimizing intraoperative surgical-cavity evaluation from the perspective of complete FCD resection. Interobserver reliability of SWE measurements should also be assessed by further studies. [ABSTRACT FROM AUTHOR]

Life expectancy of patients treated for brain tumors has lengthened due to the therapeutic improvements. Cognitive impairment has been described following brain radiotherapy, but the mechanisms leading to this adverse event remain mostly unknown. Technical evolutions aim at enhancing the therapeutic ratio. Sparing of the healthy tissues has been improved using various approaches; however, few dose constraints have been established regarding brain structures associated with cognitive functions. The aims of this literature review are to report the main brain areas involved in cognitive adverse effects induced by radiotherapy as described in literature, to better understand brain radiosensitivity and to describe potential future improvements. [ABSTRACT FROM AUTHOR]