Safety and Feasibility of Repeated and Transient Blood-Brain Barrier Disruption by Pulsed Ultrasound in Patients with Recurrent Glioblastoma.

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.

Safe long-term repeated disruption of the blood-brain barrier using an implantable ultrasound device: a multiparametric study in a primate model.

OBJECTIVE The main limitation to the efficacy of chemotherapy for brain tumors is the restricted access to the brain because of the limited permeability of the blood-brain barrier (BBB). Previous animal studies have shown that the application of pulsed ultrasound (US), in combination with the intravenous injection of microbubbles, can temporarily disrupt the BBB to deliver drugs that normally cannot reach brain tissue. Although many previous studies have been performed with external focused US transducers, the device described in the current work emits US energy using an unfocused transducer implanted in the skull thickness. This method avoids distortion of the US energy by the skull bone and allows for simple, repetitive, and broad disruption of the BBB without the need for MRI monitoring. The purpose of the present study was to determine if the BBB can be safely and repeatedly disrupted using such an implantable unfocused US device in a primate model. METHODS An 11.5-mm-diameter, 1-MHz, planar US device was implanted via a bur hole into the skull of 3 primates (2 Papio anubis [olive] baboons and 1 Macaca fascicularis [macaque]) for 4 months. Pulsed US sonications were applied together with the simultaneous intravenous injection of sulfur hexafluoride microbubbles (SonoVue) every 2 weeks to temporarily disrupt the BBB. In each primate, a total of 7 sonications were performed with a 23.2-msec burst length (25,000 cycles) and a 1-Hz pulse repetition frequency at acoustic pressure levels of 0.6-0.8 MPa. Potential toxicity induced by repeated BBB opening was analyzed using MRI, PET, electroencephalography (EEG), somatosensory evoked potential (SSEP) monitoring, behavioral scales, and histopathological analysis. RESULTS The T1-weighted contrast-enhanced MR images acquired after each sonication exhibited a zone of hypersignal underneath the transducer that persisted for more than 4 hours, indicating a broad region of BBB opening in the acoustic field of the implant. Positron emission tomography images with fluorine-18-labeled fluorodeoxyglucose (FDG) did not indicate any changes in the cerebral metabolism of glucose. Neither epileptic signs nor pathological central nerve conduction was observed on EEG and SSEP recordings, respectively. Behavior in all animals remained normal. Histological analysis showed no hemorrhagic processes, no petechia, and extravasation of only a few erythrocytes. CONCLUSIONS The studies performed confirm that an implantable, 1-MHz US device can be used to repeatedly open the BBB broadly in a large-animal model without inducing any acute, subacute, or chronic lesions.

Clinical trial of blood-brain barrier disruption by pulsed ultrasound.

The blood-brain barrier (BBB) limits the delivery of systemically administered drugs to the brain. Methods to circumvent the BBB have been developed, but none are used in standard clinical practice. The lack of adoption of existing methods is due to procedural invasiveness, serious adverse effects, and the complications associated with performing such techniques coincident with repeated drug administration, which is customary in chemotherapeutic protocols. Pulsed ultrasound, a method for disrupting the BBB, was shown to effectively increase drug concentrations and to slow tumor growth in preclinical studies. We now report the interim results of an ultrasound dose-escalating phase 1/2a clinical trial using an implantable ultrasound device system, SonoCloud, before treatment with carboplatin in patients with recurrent glioblastoma (GBM). The BBB of each patient was disrupted monthly using pulsed ultrasound in combination with systemically injected microbubbles. Contrast-enhanced magnetic resonance imaging (MRI) indicated that the BBB was disrupted at acoustic pressure levels up to 1.1 megapascals without detectable adverse effects on radiologic (MRI) or clinical examination. Our preliminary findings indicate that repeated opening of the BBB using our pulsed ultrasound system, in combination with systemic microbubble injection, is safe and well tolerated in patients with recurrent GBM and has the potential to optimize chemotherapy delivery in the brain.

Enhanced brain distribution of carboplatin in a primate model after blood-brain barrier disruption using an implantable ultrasound device.

PURPOSE: Glioblastoma is both the most common and aggressive primary brain tumor in adults. Carboplatin chemotherapy has shown only modest efficacy in progressive high-grade gliomas. The limited clinical efficacy of carboplatin may be due to its low concentration in tissue when the drug is delivered intravenously. The aim of this study was to assess whether the tissue concentration of intravenously administered carboplatin could be enhanced by ultrasound-induced blood-brain disruption in a primate model. METHODS: Carboplatin was administered intravenously for 60 min to a single primate following blood-brain barrier opening induced by an implantable ultrasound device. Blood and brain samples were collected after animal killing, which occurred 60 min after the end of carboplatin administration. Platinum quantification in ultrafiltrate plasma and brain samples was performed using inductively coupled plasma mass spectrometry. RESULTS: The brain concentration of platinum was highly enhanced (5.2×) in the 3.9 cm(3) region sonicated by the US beam, with a higher concentration in more vascularized anatomical structures. At 5 and 10 mm from the US beam axis, platinum concentrations were slightly enhanced (2.2× and 1.3× respectively). CONCLUSIONS: This study demonstrates that BBB opening using an implantable ultrasound transducer enhances the brain distribution of carboplatin in a loco-regional manner. Such a treatment approach is of significant interest for the treatment of primary brain tumors and is under current evaluation in a phase 1 clinical trial (NCT02253212).

Electronic beam steering used with a toroidal HIFU transducer substantially increases the coagulated volume.

Treatment with high-intensity focused ultrasound is well established but requires extended treatment time. A device composed of 256 elements arranged on a toroidal transducer was developed to increase the coagulated volume. When all the elements are working in phase for 40 s, a volume of 6-8 cm(3) can be ablated. However, the mechanical juxtaposition of single lesions is still necessary for treating one tumor with a diameter of 2 cm. The objective of this study was to combine this toroidal transducer geometry with electronic beam steering to ablate tumors with adequate normal tissue margins and without any mechanical displacement of the high-intensity focused ultrasound device. In vitro tests demonstrated that the coagulated volume obtained from 130 s of total exposure has an average diameter of 41.4 ± 4.0 mm and an average length of 53.3 ± 6.1 mm. This single lesion can be used to treat various size of metastasis, located at depths in the liver ranging 5-45 mm.

Design and evaluation of a transesophageal HIFU probe for ultrasound-guided cardiac ablation: simulation of a HIFU mini-maze procedure and preliminary ex vivo trials.

Atrial fibrillation (AF) is the most frequent cardiac arrhythmia. Left atrial catheter ablation is currently performed to treat this disease. Several energy sources are used, such as radio-frequency or cryotherapy. The main target of this procedure is to isolate the pulmonary veins. However, significant complications caused by the invasive procedure are described, such as stroke, tamponade, and atrioesophageal fistula, and a second intervention is often needed to avoid atrial fibrillation recurrence. For these reasons, a minimally-invasive device allowing performance of more complex treatments is still needed. High-intensity focused ultrasound (HIFU) can cause deep tissue lesions without damaging intervening tissues. Left atrial ultrasound-guided transesophageal HIFU ablation could have the potential to become a new ablation technique. The goal of this study was to design and test a minimally-invasive ultrasound-guided transesophageal HIFU probe under realistic treatment conditions. First, numerical simulations were conducted to determine the probe geometry, and to validate the feasibility of performing an AF treatment using a HIFU mini-maze (HIFUMM) procedure. Then, a prototype was manufactured and characterized. The 18-mm-diameter probe head housing contained a 3-MHz spherical truncated HIFU transducer divided into 8 rings, with a 5-MHz commercial transesophageal echocardiography (TEE) transducer integrated in the center. Finally, ex vivo experiments were performed to test the impact of the esophagus layer between the probe and the tissue to treat, and also the influence of the lungs and the vascularization on lesion formation. First results show that this prototype successfully created ex vivo transmural myocardial lesions under ultrasound guidance, while preserving intervening tissues (such as the esophagus). Ultrasound-guided transesophageal HIFU can be a good candidate for treatment of AF in the future.

"RecognizeCane" : The new concept of a cane which recognizes the most common objects and safety clues.

This paper introduces the new concept of an electronic cane for blind people. While some systems inform the subject only of the presence of the object and its relative distance, RecognizeCane is also able to recognize most common objects and environment clues to increase the safety and confidence of the navigation process. The originality of RecognizeCane is the use of simple sensors, such as infrared, brilliance or water sensors to inform the subject of the presence, for example, of a stairway, a water puddle, a zebra crossing or a trash can. This cane does not use an embedded vision system. RecognizeCane is equipped with several sensors and microprocessors to collect sensor data and extract the desired information about the close environment by means of a dynamic analysis of output signals.