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Purpose:The blood–brain barrier (BBB) limits the efficacy of drug therapies for glioblastoma (GBM). Preclinical data indicate that low-intensity pulsed ultrasound (LIPU) can transiently disrupt the BBB and increase intracerebral drug concentrations.Patients and Methods:A first-in-man, single-arm, single-center trial (NCT02253212) was initiated to investigate the transient disruption of the BBB in patients with recurrent GBM. Patients were implanted with a 1-MHz, 11.5-mm diameter cranial ultrasound device (SonoCloud-1, CarThera). The device was activated monthly to transiently disrupt the BBB before intravenous carboplatin chemotherapy.Results:Between 2014 and 2016, 21 patients were registered for the study and implanted with the SonoCloud-1; 19 patients received at least one sonication. In 65 ultrasound sessions, BBB disruption was visible on T1w MRI for 52 sonications. Treatment-related adverse events observed were transient and manageable: a transient edema at H1 and at D15. No carboplatin-related neurotoxicity was observed. Patients with no or poor BBB disruption (n = 8) visible on MRI had a median progression-free survival (PFS) of 2.73 months, and a median overall survival (OS) of 8.64 months. Patients with clear BBB disruption (n = 11) had a median PFS of 4.11 months, and a median OS of 12.94 months.Conclusions:SonoCloud-1 treatments were well tolerated and may increase the effectiveness of systemic drug therapies, such as carboplatin, in the brain without inducing neurotoxicity.See related commentary by Sonabend and Stupp, p. 3750

Supplementary Table 1. The acoustic pressure levels are determined by a calibration of the implants in water prior to implantation in patients. The 95% confidence interval given in the table denotes the measurement uncertainty inherent to this process. Acoustic pressure levels reported previously (19) were re-evaluated using enhanced acoustic calibration methods with reduced uncertainty. The former values are given in the pold column to ease comparison with our previous publication. Supplementary Table 2. BBB disruption grade and acoustic pressure. Data are n (%). Supplementary Table 3. The secondary outcomes of the trial were calculated based on the grading assigned to post-contrast MR images evaluating the level of BBB disruption. Greater amounts of post-sonication BBB disruption resulted in a trend towards longer PFS and OS.

Exposure to ultrasound combined with intravenous injection of microbubbles is a technique that can be used to temporarily disrupt the blood-brain barrier. Transcranial monitoring of cavitation can be done with one or more passive cavitation detectors (PCDs). However, the positioning of the PCDs relative to the cavitation site and the attenuation of these signals by the skull are two sources of error in the quantification of cavitation activity. The aim of this study was to evaluate in vitro the amplitude variation of cavitation signals that can be expected for an excised porcine skull model. The variation caused by the relative positioning of the PCD with respect to the cavitation site was quantified. A position-based correction of the signal amplitude was evaluated. Pig skull samples were used to assess variation in signal amplitude caused by bone. The overall coefficient of variation of the signals owing to these measurement biases was estimated at 30.8%.

Cavitation is a critical parameter in various therapeutic applications involving ultrasound (US) such as histotripsy, lithotripsy, drug delivery, and cavitation-enhanced hyperthermia. A cavitation exposure outside the region of interest may lead to suboptimal treatment efficacy or in a worse case, to safety issues. Current methods of localizing cavitation are based on imaging approaches, such as beamforming the cavitation signals received passively by a US imager. These methods, although efficient, require expensive equipment, which may discourage potential future developments. We propose a three-hydrophone method to localize the cavitation cloud source. First, the delays between the three receptors are measured by detecting the maximum of their intercorrelations. Then, the position of the source is calculated by either minimizing a cost function or solving hyperbolic equations. After a numerical validation, the method was assessed experimentally. This method was able to track a source displacement with accuracy similar to the size of the cavitation cloud (2-4 mm). This light and versatile method provides interesting perspectives since localization can be executed in real time, and the extension to 3-D localization seems straightforward.

Purpose: The blood–brain barrier (BBB) limits the efficacy of drug therapies for glioblastoma (GBM). Preclinical data indicate that low-intensity pulsed ultrasound (LIPU) can transiently disrupt the BBB and increase intracerebral drug concentrations. Patients and Methods: A first-in-man, single-arm, single-center trial (NCT02253212) was initiated to investigate the transient disruption of the BBB in patients with recurrent GBM. Patients were implanted with a 1-MHz, 11.5-mm diameter cranial ultrasound device (SonoCloud-1, CarThera). The device was activated monthly to transiently disrupt the BBB before intravenous carboplatin chemotherapy. Results: Between 2014 and 2016, 21 patients were registered for the study and implanted with the SonoCloud-1; 19 patients received at least one sonication. In 65 ultrasound sessions, BBB disruption was visible on T1w MRI for 52 sonications. Treatment-related adverse events observed were transient and manageable: a transient edema at H1 and at D15. No carboplatin-related neurotoxicity was observed. Patients with no or poor BBB disruption (n = 8) visible on MRI had a median progression-free survival (PFS) of 2.73 months, and a median overall survival (OS) of 8.64 months. Patients with clear BBB disruption (n = 11) had a median PFS of 4.11 months, and a median OS of 12.94 months. Conclusions: SonoCloud-1 treatments were well tolerated and may increase the effectiveness of systemic drug therapies, such as carboplatin, in the brain without inducing neurotoxicity. See related commentary by Sonabend and Stupp, p. 3750

Cavitation is a critical parameter in various therapeutic applications involving ultrasound (US) such as histotrispy, lithothripsy, drug delivery, and cavitation-enhanced hyperthermia. A cavitation exposure outside the region of interest may lead to suboptimal treatment efficacy or in a worse case, to safety issues. Current methods of localizing cavitation are based on imaging approaches, such as beamforming the cavitation signals received passively by a US imager. These methods, although efficient, require expensive equipment, which may discourage potential future developments. We propose a threehydrophone method to localize the cavitation cloud source. Firstly, the delays between the three receptors are measured by detecting the maximum of their inter-correlations. Then, the position of the source is calculated by either minimizing a cost function or solving hyperbolic equations. After a numerical validation, the method was assessed experimentally. This method was able to track a source displacement with accuracy similar to the size of the cavitation cloud (2-4 millimeters). This light and versatile method provides interesting perspectives since localization can be executed in real time and the extension to three-dimensional localization seems straightforward.

OBJECTIVEOne of the goals in this study was to set up a semiautomatic method to estimate blood-brain barrier disruption obtained in patients with glioblastoma by using an implantable, unfocused, ultrasound device. Another goal was to correlate the probability of significant ultrasound-induced signal enhancement (SUISE) with local acoustic pressure in the brain.METHODSGd-enhanced MR images acquired before and after ultrasound treatments were analyzed prospectively. The image sets were segmented, normalized, and coregistered to evaluate contrast enhancement. The volume of SUISE was calculated with voxels labeled as gray or white matter, in a cylindrical region of interest, and with enhancement above a given threshold. To validate the method, the resulting volumes of SUISE were compared to qualitative grades previously assigned by 3 clinicians for 40 ultrasound treatments in 15 patients. A parametric study was performed to optimize the algorithm prediction of the qualitative grades. The 3D acoustic field in the brain was estimated from measurements in water combined with simulations accounting for ultrasound attenuation in brain and overlaid on each MR image to correlate local acoustic pressure with the probability of SUISE (defined as enhancement > 10%).RESULTSThe algorithm predicted grade 2 or 3 and grade 3 openings with areas under the receiver operating characteristic curve of 0.831 and 0.995, respectively. The probability of SUISE was correlated with local acoustic pressure (R2 = 0.98) and was 3.33 times higher for gray matter than for white matter.CONCLUSIONSAn algorithm for evaluating blood-brain barrier disruption was validated and can be used for future clinical trials to further understand and quantify this technique in humans.Clinical trial registration no.: NCT02253212 (clinicaltrials.gov)