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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 Methods and Materials Figures S1: Schematic representation of LIPU generator set up. Supp Table 1: Summary of histological evaluation of CNS after one course of US-PTX Supp. Table 2: STR results of PDX cell lines. Figures S2: Cell viability in response to PTX and ABX

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.

Purpose:Paclitaxel shows little benefit in the treatment of glioma due to poor penetration across the blood–brain barrier (BBB). Low-intensity pulsed ultrasound (LIPU) with microbubble injection transiently disrupts the BBB allowing for improved drug delivery to the brain. We investigated the distribution, toxicity, and efficacy of LIPU delivery of two different formulations of paclitaxel, albumin-bound paclitaxel (ABX) and paclitaxel dissolved in cremophor (CrEL-PTX), in preclinical glioma models.Experimental Design:The efficacy and biodistribution of ABX and CrEL-PTX were compared with and without LIPU delivery. Antiglioma activity was evaluated in nude mice bearing intracranial patient-derived glioma xenografts (PDX). Paclitaxel biodistribution was determined in sonicated and nonsonicated nude mice. Sonications were performed using a 1 MHz LIPU device (SonoCloud), and fluorescein was used to confirm and map BBB disruption. Toxicity of LIPU-delivered paclitaxel was assessed through clinical and histologic examination of treated mice.Results:Despite similar antiglioma activity in vitro, ABX extended survival over CrEL-PTX and untreated control mice with orthotropic PDX. Ultrasound-mediated BBB disruption enhanced paclitaxel brain concentration by 3- to 5-fold for both formulations and further augmented the therapeutic benefit of ABX. Repeated courses of LIPU-delivered CrEL-PTX and CrEL alone were lethal in 42% and 37.5% of mice, respectively, whereas similar delivery of ABX at an equivalent dose was well tolerated.Conclusions:Ultrasound delivery of paclitaxel across the BBB is a feasible and effective treatment for glioma. ABX is the preferred formulation for further investigation in the clinical setting due to its superior brain penetration and tolerability compared with CrEL-PTX.

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 10µl/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 open the BBB. BBB opening was confirmed visually and microscopically using Evans’s blue dye and magnetic resonance imaging. UMBO plus anti-PDL-1 was associated with a significant improvement of the 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 to increase the efficacy of anti-PD-L1 in GBM and supports clinical trials combining UMBO and in GBM patients.

Purpose: The blood–brain barrier (BBB) inhibits adequate dosing/penetration of therapeutic agents to malignancies in the brain. Low-intensity pulsed ultrasound (LIPU) is a safe therapeutic method of temporary BBB disruption (BBBD) to enhance chemotherapeutic delivery to the tumor and surrounding brain parenchyma for treatment of glioblastoma. Experimental Design: We investigated if LIPU could enhance therapeutic efficacy of anti–PD-1 in C57BL/6 mice bearing intracranial GL261 gliomas, epidermal growth factor receptor variant III (EGFRvIII) chimeric antigen receptor (CAR) T cells in NSG mice with EGFRvIII-U87 gliomas, and a genetically engineered antigen-presenting cell (APC)-based therapy producing the T-cell attracting chemokine CXCL10 in the GL261-bearing mice. Results: Mice treated with anti–PD-1 and LIPU-induced BBBD had a median survival duration of 58 days compared with 39 days for mice treated with anti–PD-1, and long-term survivors all remained alive after contralateral hemisphere rechallenge. CAR T-cell administration with LIPU-induced BBBD resulted in significant increases in CAR T-cell delivery to the CNS after 24 (P < 0.005) and 72 (P < 0.001) hours and increased median survival by greater than 129%, in comparison with CAR T cells alone. Local deposition of CXCL10-secreting APCs in the glioma microenvironment with LIPU enhanced T-cell glioma infiltration during the therapeutic window (P = 0.004) and markedly enhanced survival (P < 0.05). Conclusions: LIPU increases immune therapeutic delivery to the tumor microenvironment with an associated increase in survival and is an emerging technique for enhancing novel therapies in the brain.

BACKGROUND The blood-brain barrier (BBB) is a major impediment to pharmacological treatment of gliomas. Low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU/MB), temporarily opens the BBB. Here we investigate the pharmacokinetics and safety of this approach of repeated delivery of albumin-bound paclitaxel (Abraxane®, ABX) to the peri-tumoral brain. To perform LIPU/MB-based BBB opening prior to ABX infusions, we used a novel 6 x 6 cm device with 9 ultrasound emitters (SC9) that is implanted in a skull window after tumor resection. METHODS A Phase 1 dose-escalation trial using Bayesian adaptive design was conducted (NCT04528680). Patients with recurrent operable glioblastoma, a WHO PS ≤ 2 and adequate bone marrow and organ function were eligible. After tumor resection and implantation of SC9, repeated cycles of BBB opening by LIPU/MB immediately followed by ABX, was performed every 3 weeks. Intraoperative LIPU/MB and low dose ABX was given prior to tumor resection allowed for investigation tissue concentrations and pharmacokinetics. RESULTS Seventeen patients have been treated at six escalating ABX dose levels (40-260 mg/m2). At dose of 260 mg/m2, a grade 3 reversible taxane-associated dose limiting encephalopathy was observed in one patient. The patient continued treatment at a lower dose in subsequent cycles. A second patient exhibited encephalopathy on cycle 2. One patient developed grade 2 cumulative peripheral neuropathy. Intraoperative pharmacokinetic studies showed that ABX tissue concentrations in non-enhancing peri-tumoral brain were increased 3.7-fold after LIPU/MB. sc-RNA-sequencing showed transcriptional dysregulation of membrane transporters, pathways related to trans-cytosis as well as cell-cell and cell-matrix adhesion. CONCLUSIONS The LIPU/MB using skull-implantable ultrasound enhances the penetration of ABX in large regions of the brain. The procedure can be performed repeatedly and safely. LIPU-based BBB opening leads to transcriptional alterations in brain endothelium. Funding: NIH/NCI 1R01CA245969-01A1, CarThera (SC9 devices), BMS/Celgene (Abraxane®).

Opening of the blood–brain barrier (BBB) by pulsed low intensity ultrasound has been developed during the last decade and is now recognized as a safe technique to transiently and repeatedly open the BBB. This non- or minimally invasive technique allows for a targeted and uniform dispersal of a wide range of therapeutic substances throughout the brain, including immune cells and antibodies. In this review article, we summarize pre-clinical studies that have used BBB-opening by pulsed low intensity ultrasound to enhance the delivery of immune therapeutics and effector cell populations, as well as several recent clinical studies that have been initiated. Based on this analysis, we propose immune therapeutic strategies that are most likely to benefit from this strategy. The literature review and trial data research were performed using Medline/Pubmed databases and clinical trial registry www.clinicaltrials.gov . The reference lists of all included articles were searched for additional studies. A wide range of immune therapeutic agents, including small molecular weight drugs, antibodies or NK cells, have been safely and efficiently delivered to the brain with pulsed low intensity ultrasound in preclinical models, and both tumor control and increased survival have been demonstrated in different types of brain tumor models in rodents. Ultrasound-induced BBB disruption may also stimulate innate and cellular immune responses. Ultrasound BBB opening has just recently entered clinical trials with encouraging results, and the association of this strategy with immune therapeutics creates a new field of brain tumor treatment.

Brain tumors account for over 20% of childhood cancers and are the biggest cancer killer in children and young adults. Several initiatives over the past 40 years have tried to identify more effective drug treatments, but with very limited success. This is largely due to the bloodâ brain barrier, which restricts the entry of many drugs into the brain. In this review, we describe the main techniques that are being developed to enhance brain tumor drug delivery and explore the preclinical brain tumor models that are essential for translational development of these techniques. We also identify existing approved drugs that, if coupled with an efficient delivery method, could have potential as brain tumor treatments. Bringing this information together is part of a funded initiative to highlight drug delivery as a research strategy to overcome the current challenges for children diagnosed with brain tumors., This review was written on behalf of the Children's Brain Tumor Drug Delivery Consortium, which is funded by Children with Cancer UK, grant number 16-244. This review was also supported by Maryland's Cancer Moonshot Initiative in Pediatric Cancer Research, grant number Project 4'.

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

Low intensity pulsed ultrasound in combination with microbubbles can be used to temporarily disrupt the blood-brain barrier (BBB). A phase 1/2 clinical study (NCT03744026) was initiated to demonstrate the safety and efficacy of BBB disruption using an implantable ultrasound system (SonoCloud-9) in patients with recurrent glioblastoma receiving carboplatin chemotherapy. The SonoCloud-9 device, which contains nine, 1-MHz, 10-mm diameter ultrasound emitters (Carthera, Paris, France) was placed at the end of tumor resection and replaced the bone flap. The device was activated 9-14 days after surgery for a duration of 270 seconds every four weeks until progression or treatment completion, concomitantly with IV DEFINITY microbubbles (10 ml/kg, Lantheus, Billerica, US). The Phase 1 cohort consisted of an escalation of BBB disruption volume by activation of 3 (n = 3), 6 (n = 3), then 9 (n = 3) emitters of the device. Dose limiting toxicity (DLT) was assessed during the first two weeks after the 1st sonication. A subsequent expansion cohort consisted of patients treated with nine emitters in which the primary endpoint was assessment of BBB opening on MRI using gadolinium (< 1 hr after sonication). All patients received carboplatin either after (n = 21) or before (n = 12) device activation to disrupt the BBB. In addition, a sub-study was performed to investigate carboplatin concentration enhancement in the peritumoral region with sonication at time of device implantation. Study accrual is complete with 33 patients having been implanted and received at least one sonication. A total of 101 sonications were performed (range = 1-10 sonication sessions/patient). No DLTs were observed. Five serious adverse events (all resolved) were considered as possibly related to the study procedure. BBB disruption was confirmed by gadolinium enhancement after sonication. In three patients who underwent intraoperative sonication and carboplatin administration, a 7.58-fold increase in brain/plasma drug levels was demonstrated. Updated survival results will be presented.

INTRODUCTION Given the limited drug penetration across the blood-brain barrier (BBB), the therapeutic potential of new and existing therapies has not been fully exploited for the benefit of glioblastoma (GBM) patients. METHODS Here we employed a novel drug delivery technology based on low-intensity pulsed ultrasound combined with intravenous microbubbles (LIPU/MB) that temporarily opens the BBB to deliver liposomal doxorubicin (DOX) and anti-PD-1 therapy (aPD-1) in mouse glioma models and 3 recurrent GBM patients. Immunological variables were evaluated in tumor and immune cells as well as efficacy in glioma-bearing mice treated with DOX delivered by LIPU. These included measurement of HLA ABC and HLA DR protein expression by tumor cells, microglia, and macrophages and IFN-g production by glioma-associated microglia and macrophages in mouse and human tumors. We also assessed efficacy of LIPU/MB enhanced combination therapy in glioma-bearing mice. RESULTS Upregulation of HLA ABC and HLA DR was observed in GBM cell lines at low concentrations of DOX. Tumor cells from GBM patients treated with DOX, aPD-1 and LIPU/MB showed increased expression of HLA ABC and HLA DR compared to paired pretreatment samples. In both mice and humans, LIPU/MB liposomal DOX increased absolute brain drug concentrations and elicited a specific IFN-g phenotype and MHC I expression in glioma-associated microglia and macrophages in mice and humans. Furthermore, LIPU/MB-mediated BBB opening increased brain concentrations of aPD-1 in mice and in peritumoral regions of GBM patients. Combined treatment with liposomal DOX and aPD-1 delivered with LIPU/MB resulted in long-term survival of glioma-bearing mice that relied on the activity of CD8+ T cells for its efficacy. CONCLUSIONS Overall, this translational study demonstrates the utility of LIPU/MB to stimulate intracranial immune responses in the context of treatment with DOX and aPD-1 for gliomas.

2016 Background: The blood-brain barrier (BBB) is a major impediment to pharmacological treatment of gliomas, a diffuse tumor infiltrating the peri-tumoral normal brain. Low-intensity pulsed ultrasound directed at the brain with concomitant administration of intravenous microbubbles (LIPU/MB), temporarily opens the BBB. This technique was previously shown with a first generation of the device in combination with carboplatin chemotherapy (Idbaih et al. 2019). Here we investigate the pharmacokinetics and safety of this approach in the context of repeated delivery of albumin-bound paclitaxel (ABX) to the peri-tumoral brain. To perform LIPU/MB-based BBB opening prior to ABX infusions, we used a novel 6 x 6 cm device with 9 ultrasound emitters (SC9) that is implanted in a skull window after tumor resection. Methods: A Phase 1 dose-escalation trial using Bayesian adaptive design was initiated at our institution (NCT04528680). Patients with recurrent operable glioblastoma, a WHO PS ≤ 2 and normal bone marrow and organ function were eligible. After tumor resection and implantation of SC9, repeated cycles of BBB opening by LIPU/MB immediately followed by ABX, was performed every 3 weeks. Intraoperative LIPU/MB and low dose ABX was given prior to tumor resection for investigation of pharmacokinetics. Results: Seventeen patients have been enrolled and six dose levels of ABX were used (40-260 mg/m2). Severe, reversible taxane-associated encephalopathy was observed in one patient at the max. planned dose level (260 mg/m2). The patient continued treatment at a lower dose in subsequent cycles. One patient developed grade 2 cumulative peripheral neuropathy. Other mild to moderate and reversible toxicities for ABX including myelosuppression, fatigue, alopecia were observed as expected. Intraoperative sonication and pharmacokinetic studies showed that ABX tissue concentrations in non-enhancing peri-tumoral brain were increased several-fold after LIPU/MB. On electron microscopy, sonicated tissue showed ultra-structural alterations in brain capillary endothelial cells. Molecular studies showed transcriptional dysregulation of membrane transporters, pathways related to trans-cytosis, cell permeability as well as cell-cell and cell-matrix adhesion. Updated results will be presented. Conclusions: The LIPU/MB using skull-implantable ultrasound enhances the penetration of large chemotherapeutic drugs such as ABX in large regions of the brain, a procedure that can be performed repeatedly and safely. LIPU-based BBB opening leads to ultrastructural and transcriptional alterations in brain endothelial cells. A Phase 2 clinical trial is planned to investigate efficacy of this approach. Funding: NIH/NCI 1R01CA245969-01A1, Carthera (SC9 devices), Celgene/BMS, Malnati Brain Tumor Institute, Moceri Family Foundation. Clinical trial information: NCT04528680.

2049 Background: Low intensity pulsed ultrasound (LIPU) in conjunction with intravenous microbubbles can transiently and reversibly disrupt the blood-brain barrier (BBB), allowing for an increase in the tissue concentration of chemotherapy agents in the brain. Mass spectrometry data from preclinical models (mouse, swine) showed a > 5x enhancement in carboplatin brain concentrations, which correlated well with the spatial distribution of a Gadolinium (Gd) contrast agent used for magnetic resonance imaging (MRI). Methods: The primary objective of this phase I/IIa study (NCT03744026) was to demonstrate the safety of BBB disruption using LIPU in patients with recurrent glioblastoma. This study was a 3+3 design using escalating numbers (3, 6, 9) of activated 1 MHz ultrasound emitters. Nine patients were treated in the escalation phase and another 12 patients were treated with 9 emitters in the expansion phase. Eligibility included recurrent GBM (any recurrence) with a maximum tumor size of < 70 mm. The SonoCloud-9 device (CarThera, Paris, France) was implanted during tumor debulking/resection surgery and replaced the bone flap, with the device targeting the tumor and surrounding peritumoral brain. The device was activated every four weeks for a duration of 270 seconds, concomitantly with IV DEFINITY microbubbles (10 ml/kg), to disrupt the BBB prior to administration of carboplatin (AUC 4-6). MRI was performed to verify safety and evaluate efficacy of BBB disruption with Gd enhancement. Results: No DLTs were observed. The overall tolerance of the SonoCloud-9 implant was good, with two transient, manageable grade 3 wound infections and one grade 1 acquired meningocele event considered as probably related to the overall procedure. The most frequent neurologic adverse events were grade 1 blurred vision (5%) and dizziness (5%). Conclusions: Significant Gd enhancement was observed after more than 90% of sonication sessions, suggesting effective BBB disruption and carboplatin enhancement. Clinical trial information: NCT03744026.

International audience

Over the past 5 years, laser interstitial thermal therapy (LITT) has become a well-recognized and viable addition to the armamentarium of neurosurgeons when considering patient options for brain tumors and epilepsy. In addition, patients are actively seeking such alternative minimally invasive techniques when the prospect of open craniotomy is presented to them. As such, it is important that the fundamentals of LITT are well documented for both physicians and patients. This chapter provides a historical perspective of laser interstitial thermal therapy (LITT), including the fundamental science and contributing technologies including laser, laser-tissue interactions, imaging and thermal dosimetry, cellular effects of LITT and their relation to MR image appearance post-LITT, and clinical applications in brain lesions. The second half of the chapter is devoted to a description that compares and contrasts the two existing commercially available LITT systems, namely NeuroBlate® and Visualase®. In addition, included in this unique perspective are detailed approaches to clinical implementation, trajectory guidance, laser energy delivery probes, user interface and software systems, process workflow, integration with MRI systems, and specifics of thermal calculations for clinical monitoring.

Purpose: Paclitaxel shows little benefit in the treatment of glioma due to poor penetration across the blood–brain barrier (BBB). Low-intensity pulsed ultrasound (LIPU) with microbubble injection transiently disrupts the BBB allowing for improved drug delivery to the brain. We investigated the distribution, toxicity, and efficacy of LIPU delivery of two different formulations of paclitaxel, albumin-bound paclitaxel (ABX) and paclitaxel dissolved in cremophor (CrEL-PTX), in preclinical glioma models. Experimental Design: The efficacy and biodistribution of ABX and CrEL-PTX were compared with and without LIPU delivery. Antiglioma activity was evaluated in nude mice bearing intracranial patient-derived glioma xenografts (PDX). Paclitaxel biodistribution was determined in sonicated and nonsonicated nude mice. Sonications were performed using a 1 MHz LIPU device (SonoCloud), and fluorescein was used to confirm and map BBB disruption. Toxicity of LIPU-delivered paclitaxel was assessed through clinical and histologic examination of treated mice. Results: Despite similar antiglioma activity in vitro, ABX extended survival over CrEL-PTX and untreated control mice with orthotropic PDX. Ultrasound-mediated BBB disruption enhanced paclitaxel brain concentration by 3- to 5-fold for both formulations and further augmented the therapeutic benefit of ABX. Repeated courses of LIPU-delivered CrEL-PTX and CrEL alone were lethal in 42% and 37.5% of mice, respectively, whereas similar delivery of ABX at an equivalent dose was well tolerated. Conclusions: Ultrasound delivery of paclitaxel across the BBB is a feasible and effective treatment for glioma. ABX is the preferred formulation for further investigation in the clinical setting due to its superior brain penetration and tolerability compared with CrEL-PTX.

The treatment of primary brain tumors, especially malignant gliomas, remains challenging. The failure of most treatments for this disease is partially explained by the blood-brain barrier (BBB), which prevents circulating molecules from entering the brain parenchyma. Ultrasound-induced BBB disruption (US-BBBD) has recently emerged as a promising strategy to improve the delivery of therapeutic agents to brain tumors. A large body of preclinical studies has demonstrated that the association of low-intensity pulsed ultrasound with intravenous microbubbles can transiently open the BBB in a localized manner. The safety of this technique has been assessed in numerous preclinical studies in both small and large animal models. A large panel of therapeutic agents have been delivered to the brain in preclinical models, demonstrating both tumor control and increased survival. This technique has recently entered clinical trials with encouraging preliminary data. In this review, we describe the mechanisms and histological effects of US-BBBD and summarize the preclinical studies published to date. We furthermore provide an overview of the current clinical development and future potential of this promising technology.

Introduction: In contrast to brain metastases, gliomas have few antigen-presenting cells (APCs) in the tumor microenvironment, which may limit T cell effector responses. We hypothesized that: (1) an APC could be modified to express a T cell attracting chemokine that could enhance localized immune activation, and (2) that ultrasound-based blood-brain barrier (BBB) opening would enhance delivery of these APCs at the site of tumor antigens. Methods: Murine F4/80 and CD11c expressing APCs were isolated from the bone marrow of C57BL/6 mice and modified via lentiviral transduction to encode the cDNA of immune cell chemokines CXCL9 or CXCL10 and methionine-deficient green fluorescent protein (co-expression) for cell tagging. C57BL/6 mice were implanted with GL261 cells and treated with 1 x 106 CXCL9 or CXCL10 over-expressing APCs intracranially (i.c.), or intravenously (i.v.) with or without ultrasound-based BBB opening. To determine how the CXCL10 expressing APCs were altering the tumor microenvironment, immune cells were isolated from the glioma implanted hemisphere of all treatment groups and analyzed by multicolor flow cytometry. Results: Transduced APCs produced 3,392 pg/ml and 2,987 pg/ml of CXCL9 or CXCL10, respectively. Mice tolerated the treatments well without any adverse events, behavioral changes, or neurological toxicity. Survival analysis of mice treated with CXCL9 expressing APCs using i.c., or i.v. with and without BBB opening ultrasound showed no significant survival benefit compared with PBS-treated control mice. Mice treated i.c. with CXCL10-expressing APCs had significantly improved survival relative to the PBS control group (p Conclusions: The delivery of CXCL10-secreting APCs to the glioma microenvironment with ultrasound-based BBB opening was superior to delivery with direct i.c. injection. BBB disruption may have triggered more diffuse dispersal of the APCs throughout the tumor microenvironment or positioned these cells in closer proximity to the T cells emigrating from the vascular space into the localized glioma microenvironment. Citation Format: Aria Sabbagh, Kevin Beccaria, Xiaoyang Ling, Anantha Marisetty, Martina Ott, Ling-Yuan Kong, Dexing Fang, Jun Wei, Carole Desseaux, Guillaume Bouchoux, Michael Canney, Alexandre Carpentier, Amy B. Heimberger. Deposition of genetically engineered T cell attracting antigen presenting cells in the glioma microenvironment with low intensity pulsed ultrasound-based blood-brain barrier opening triggers therapeutic responses in preclinical glioma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1489.

Capacitive micromachined ultrasound transducers (CMUTs) exhibit several potential advantages over conventional piezo technologies for use in therapeutic ultrasound (US) devices, including ease of miniaturization and integration with electronics, broad bandwidth (>several megahertz), and compatibility with magnetic resonance imaging (MRI). In this paper, the electroacoustic performance of CMUTs designed for interstitial high-intensity contact US (HICU) applications was evaluated and the feasibility of generating US-induced heating and thermal destruction of biological tissues was studied. One-dimensional CMUT linear arrays as well as a prism-shaped 2-D array composed of multiple 1-D linear arrays mounted on a cylindrical catheter were fabricated. The electromechanical and acoustic characteristics of the CMUTs were first studied at low intensity. Then, the acoustic output during continuous wave (CW) driving was studied while varying the bias voltage ( $V_{DC}$ ) and driving voltage ( $V_{AC}$ ). US heating was performed in tissue-mimicking gel phantoms under infrared (IR) or MR-thermometry monitoring. Acoustic intensities compatible with thermal ablation were obtained by driving the CMUTs in the collapse-snapback operation mode ( $I_{ac} = 10 - 30\text {W}\cdot \text {cm}^{-2}$ ). Hysteresis in the acoustic output was observed with varying $V_{DC}$ . IR- and MR-thermometry monitoring showed directional US-induced heating patterns in tissue-mimicking phantoms (frequency: 6–8 MHz and exposure time: 60–240 s) extending over 1.5-cm depth from the CMUT surface. Irreversible thermal damage was produced in turkey breast tissue samples ( $\Delta T_{\mathrm {max}} > 40^{\circ }\text{C}$ ). Multidirectional US-induced heating was also achieved in 3-D with the CMUT catheter. These studies demonstrate that CMUTs can be integrated into HICU devices and be used for heating and destruction of tissue under MR guidance.

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.

International audience; The blood-spinal cord barrier (BSCB) considerably limits the delivery and efficacy of treatments for spinal cord diseases. The blood-brain barrier can be safely opened with low-intensity pulsed ultrasound when microbubbles are simultaneously administered intravenously. This technique was tested on the BSCB in a rabbit model in this work. Twenty-three segments of spinal cord were sonicated with a 1-MHz unfocused pulsed ultrasound device and compared with non-sonicated segments. BSCB disruption was assessed using Evan's blue dye (EBD) extravasation. Tolerance was assessed by histologic analysis. An increased EBD concentration indicating BSCB disruption was clearly observed in sonicated segments compared with controls (p = 0.004). On one animal, which received 10 sonications, repetitive BSCB disruptions revealed no evidence of cumulative toxicity. BSCB can be disrupted using an unfocused pulsed ultrasound device in combination with microbubbles without neurotoxicity even in case of repeated sonications.

BACKGROUND The blood-brain barrier (BBB) limits penetration of drug therapies to the brain and may account for the limited effectiveness of chemotherapies in patients with primary brain cancer. An implantable ultrasound (US) device, SonoCloud, was developed to temporarily disrupt the BBB in patients with recurrent glioblastoma (rGBM) prior to carboplatin chemotherapy administration to enhance brain drug concentrations. BBB disruption was investigated with a single emitter device, SonoCloud-1 (SC1) and a three-emitter device, SonoCloud-3 (SC3) in a safety and feasibility study in rGBM patients at the Hôpitaux Universitaires La Pitié Salpêtrière in Paris, France (NCT02253212). MATERIAL AND METHODS The SC1 implant consisted of a 1 MHz, 10-mm diameter ultrasound transducer encapsulated in a biocompatible housing while the SC3 consisted of (3) separate SC1 emitters implanted in a triangular pattern to disrupt the BBB over a 3x larger volume. Patients were implanted with the SonoCloud device during tumor debulking or in a dedicated surgical procedure. The devices were activated monthly by connecting the device to an external generator via a transdermal needle. Intravenous injection of SonoVue® microbubbles was performed with device activation to temporarily disrupt the BBB. Magnetic resonance imaging (MRI) was performed after sonications with gadolinium contrast to verify BBB disruption followed by carboplatin infusion at AUC4-6. Patients received treatments until disease progression. RESULTS Between 2014 and 2016, 21 patients were registered for the study and implanted with the SC1; 19 patients received at least one sonication. Six additional patients were implanted and received sonications with the SC3. A total of 89 US sessions were performed to disrupt the BBB - 65 with the SC1 and 24 with the SC3. Treatment-related adverse events observed were transient and manageable. No carboplatin-related neurotoxicity was observed. SC1 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. SC1 patients with clear BBB disruption (n=11) had a median PFS of 4.11 months, and a median OS of 12.94 months. The SC3 device was as well-tolerated as the SC1 device, with SC3 patients receiving between 1–12 monthly sonications. CONCLUSION These results provide the first safety data on the effects of disrupting the BBB in rGBM patients prior to carboplatin chemotherapy using an implantable low intensity pulsed ultrasound device on enlarged areas of brain. This study has now been completed. A new safety study with a larger device, SonoCloud-9, that covers the tumor and surrounding infiltrative regions, has started in France in early 2019 (NCT03744026). Work supported by CarThera and APHP.

Pediatric brain tumors are the most common solid tumor and the first cause of cancer death in childhood, adolescence, and young adulthood. Current treatments are far from optimal in most of these tumors and the prognosis remains dismal for many of them. One of the main causes of the failure of current medical treatments is in part due to the existence of the blood-brain barrier (BBB), which limits drug delivery to tumors. Opening of the BBB with low-intensity pulsed ultrasound (LIPU) has emerged during the last 2 decades as a promising technique for enhancing drug delivery to the brain. In preclinical models, enhanced delivery of a wide range of therapeutic agents, from low-molecular-weight drugs, to antibodies and immune cells, has been observed as well as tumor control and increased survival. This technique has recently entered clinical trials with extracranial and intracranial devices. The safety and feasibility of this technique has furthermore been shown in patients treated monthly for recurrent glioblastoma receiving carboplatin chemotherapy. In this review, the characteristics of the BBB in the most common pediatric brain tumors are reviewed. Then, principles and mechanisms of BBB disruption with ultrasound (US) are summarized and described at the histological and biological levels. Lastly, preclinical studies that have used US-induced BBB opening in tumor models, recent clinical trials, and the potential use of this technology in pediatrics are provided.

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

Low intensity pulsed ultrasound (LIPU), in combination with systemic injection of microbubbles, can be used to transiently disrupt the blood-brain barrier (BBB) and increase brain-drug concentrations. In pre-clinical models, carboplatin can be enhanced by a factor of 5x in the brain using LIPU and increase the survival of GBM-bearing mice. In clinical studies, a single emitter, implantable ultrasound device (SonoCloud-1) was used to disrupt the BBB in 19 rGBM patients prior to carboplatin chemotherapy (NCT02253212). The feasibility of this approach was demonstrated, and safe acoustic parameters were determined. The primary objective of this subsequent Phase 1/2a study (NCT03744026) was to demonstrate the safety of BBB disruption over a larger volume, including the tumor and surrounding peritumoral region using a nine-emitter version of the device (SonoCloud-9). This study was a 3 + 3 design using escalating numbers of activated 1-cm diameter emitters (3, 6, 9). GBM patients at any recurrence, with a maximum tumor size of < 70 mm were included. The SonoCloud-9 device was implanted during tumor debulking/resection surgery and replaced the bone flap. The device was activated every four weeks for 270 seconds, concomitantly with DEFINITY® microbubbles to disrupt the BBB prior to administration of carboplatin. Magnetic resonance imaging was performed to verify safety and the extent of BBB disruption. As of June 2020, the escalation phase of the study (9 patients) was complete, with a median of four monthly cycles of sonication and carboplatin chemotherapy per patient. No DLTs were observed. The overall tolerance of the SonoCloud-9 implant was good, with only a few, transient, and manageable related adverse events. The safety of administration of multiple repeat treatments of BBB opening using nine emitters of the device at an acoustic pressure of 1.03 MPa will be confirmed in an additional 12 patients to be included in the ongoing expansion phase.

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)

The blood-brain barrier (BBB) limits penetration of systemically administered therapies to brain tumors and peritumoral tissue and may be responsible for the failure of numerous drugs in recent clinical trials for glioblastoma (GBM). Low intensity pulsed ultrasound (LIPU), with concomitant intravenous microbubble injection (DEFINITY®), can temporarily disrupt the BBB for 6–24 hours and allow for enhanced delivery of drugs to the brain. In previous clinical studies, a 1-cm ultrasound (US) device, SonoCloud-1, was implanted in a burr hole of recurrent GBM patients (n=27) and used to disrupt the BBB prior to carboplatin infusion at AUC5. This ongoing pilot phase 1/2 study (NCT03744026) aims to evaluate the safety and efficacy of transient opening of the BBB by LIPU in rGBM with the SonoCloud-9, a larger nine-emitter implantable device, designed to cover the tumor and surrounding infiltrative regions. The ultrasound device is implanted in a 6 cm x 6 cm bone flap window after tumor debulking surgery. Patients receive a 270-second sonication every month with concomitant microbubble injection to disrupt the BBB followed by carboplatin infusion at AUC4-6. Magnetic resonance imaging (MRI) is performed to verify safety and extent of BBB disruption. This study began enrollment in early 2019 and is an international, open-label, single arm, multi-site, dose-escalation and expansion trial to evaluate the safety of escalating sonication volume (“dose”) with concurrent carboplatin. The number of activated emitters in the implant (3, 6, 9) is increased using a 3 + 3 dose escalation design. Safety data of the escalation phase of the study will be presented.

Interstitial therapeutic ultrasound devices are a promising technology for performing thermal ablation in a wide variety of organs. In this study, the use of Capacitive Micromachined Ultrasound Transducers (CMUTs) for interstitial heating applications was investigated. CMUTs exhibit potential advantages for use in therapeutic ultrasound applications in comparison to standard piezo ultrasound transducer technologies as they have good characteristics in terms of miniaturization (cell size: few dozens of microns), bandwidth (several MHz) and high electro-acoustic efficiency. Two designs of CMUT arrays were studied: (1) a 1D 128-element planar-CMUT array originally dedicated to abdominal ultrasound imaging purposes (5 MHz, element size: 0.3 × 8.0 mm2); (2) a 12-element linear-array, 32.4-mm long and 0.8-mm wide, developed specifically for minimally-invasive interstitial therapeutic applications (6 MHz, element size: 2.7 × 0.8 mm2). Simulations were performed to evaluate the ability to generate thermal lesions...

The blood-brain barrier (BBB) is a significant obstruction to the delivery of treatments for glioblastoma. Previous studies have demonstrated the use of Low Intensity Pulsed Ultrasound (LIPU) in combination with microbubbles as a safe and therapeutic method for temporary BBB disruption to enhance chemotherapeutic delivery to the tumor and surrounding brain parenchyma. Glioblastoma has minimal T cell infiltration. In this work, we investigated if LIPU sonications (1 MHz, 0.3 MPa, 120 s duration) could enhance T cell delivery to the tumor microenvironment and enhance immunotherapy. NSG mice with established EGFRvIII+U87 tumors were treated intravenously with bioluminescent labeled epidermal growth factor receptor variant III (EGFRvIII) expressing chimeric antigen receptor (CAR) T cells with and without ultrasound BBB disruption. Combining systemic CAR T cell administration with ultrasound BBB disruption, resulted in a significant increase in CAR T cell delivery to the mouse CNS after 12 (p

Object The blood-brain barrier (BBB) is a major impediment to the intracerebral diffusion of drugs used in the treatment of gliomas. Previous studies have demonstrated that pulsed focused ultrasound (US) in conjunction with a microbubble contrast agent can be used to open the BBB. To apply the US-induced opening of the BBB in clinical practice, the authors designed an innovative unfocused US device that can be implanted in the skull and used to transiently and repeatedly open the BBB during a standard chemotherapy protocol. The goal of this preliminary work was to study the opening of the BBB induced by the authors' small unfocused US transducer and to evaluate the effects of the sonications on brain parenchyma. Methods Craniectomy was performed in 16 healthy New Zealand White rabbits; epidural application of a single-element planar ultrasonic transducer operating at 1 MHz was then used with a pulse-repetition frequency of 1 Hz, pulse lengths of 10–35 msec, in situ acoustic pressure levels of 0.3–0.8 MPa, and sonication for 60–120 seconds. SonoVue was intravenously injected during the US applications, and opening of the BBB was determined by detecting extravasation of Evans blue dye (EBD) in brain tissues, quantitative measurement of EBD with UV-visible spectrophotometry, and contrast enhancement after Gd injection in 4.7-T MRI. A histological study was performed to determine adverse effects. Results An opening of the BBB was observed over a large extent of the US beam in the brain corresponding to in situ pressures of greater than 0.2 MPa. The BBB opening observed was highly significant for both EBD (p < 0.01) and MRI Gd enhancement (p < 0.0001). The BBB opening was associated with minor adverse effects that included perivascular red blood cell extravasations that were less than 150 μm in size and not visible on MR images. Moderate edema was visible on FLAIR sequences and limited to the extent of the sonication field. Conclusions The results demonstrate that the BBB can be opened in large areas of the brain in rabbits with lowpower, pulsed, and unfocused US with limited damage to healthy tissue.

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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.

International audience; Introduction: Glioblastomas (GBM) are the most common and aggressive primary malignant brain tumors in adults. The blood brain barrier (BBB) is a major limitation reducing efficacy of anti-cancer drugs in the treatment of GBM patients.Areas covered: Virtually all GBM recur after the first-line treatment, at least partly, due to invasive tumor cells protected from chemotherapeutic agents by the intact BBB in the brain adjacent to tumor. The passage through the BBB, taken by antitumor drugs, is poorly and heterogeneously documented in the literature. In this review, we have focused our attention on: (i) the BBB, (ii) the passage of chemotherapeutic agents across the BBB and (iii) the strategies investigated to overcome this barrier.Expert commentary: A better preclinical knowledge of the crossing of the BBB by antitumor drugs will allow optimizing their clinical development, alone or combined with BBB bypassing strategies, towards an increased success rate of clinical trials.

OBJECTIVE: To determine the safety of repeated disruption of the blood-brain barrier (BBB) by low intensity pulsed ultrasound (LIPU) with the Sonocloud(®) device in children with recurrent malignant supra-tentorial brain tumors prior to intra-venous carboplatin chemotherapy. The safety of this procedure is currently being validated in adult patients with recurrent glioblastoma (Carpentier et al. 2016). MATERIAL AND METHODS: This single-center phase I/IIa clinical trial will include 12 to 24 patients aged 5 to 18 years, with recurrent malignant supra-tentorial brain tumors. The Sonocloud(®) device will be implanted into the skull under general anesthesia, during a standard procedure (biopsy or resection). Thanks to a transdermic connexion, sonications will be performed monthly in combination with injection of an ultrasound contrast agent (Sonovue(®)). US parameters will be based on the adult patients study. BBB disruption will be evaluated using multimodal magnetic resonance imaging (MRI). Carboplatin will be injected during the hour following the sonication. Patients will receive a maximum of 6 monthly sonications and will be followed at least for 6 months after the last sonication. EXPECTED RESULTS: The principal criteria will be the absence of grade ≥ 3 neurological toxicity (NCI-CTCAE 4.0 Version, clinical and radiological assessment) linked to the US-induced opening of the BBB after first treatment. Secondary evaluation criterias will include tolerance of repeated sonications, overall survival and progression-free survival, and feasibility of the technique. CONCLUSION: SONOKID is the first clinical trial assessing the feasibility and tolerance of US-induced opening of the BBB in children. SPONSOR Canceropole Ile de France.

Purpose: A prototype ultrasound-based probe for use in ureteroscopy was used for in vitro measurements of stone fragments in a porcine kidney. Methods: Fifteen human stones consisting of three different compositions were placed deep in the collecting system of a porcine kidney. A 2 MHz, 1.2 mm (3.6F) needle hydrophone was used to send and receive ultrasound pulses for stone sizing. Calculated stone thicknesses were compared with caliper measurements. Results: Correlation between ultrasound-determined thickness and caliper measurements was excellent in all three stone types (r2 = 0.90, p

2016Background: The BBB limits the efficacy of many chemotherapies in GBM patients by blocking the passage of drugs to the brain. Two to four minutes of LIPU in combination with injection of micron...

Nonlinear propagation causes high-intensity ultrasound waves to distort and generate higher harmonics, which are more readily absorbed and converted to heat than the fundamental frequency. Although such nonlinear effects have been investigated previously and found to not significantly alter high-intensity focused ultrasound (HIFU) treatments, two results reported here change this paradigm. One is that at clinically relevant intensity levels, HIFU waves not only become distorted but form shock waves in tissue. The other is that the generated shock waves heat the tissue to boiling in much less time than predicted for undistorted or weakly distorted waves. In this study, a 2-MHz HIFU source operating at peak intensities up to 25,000 W/cm(2) was used to heat transparent tissue-mimicking phantoms and ex vivo bovine liver samples. Initiation of boiling was detected using high-speed photography, a 20-MHz passive cavitation detector and fluctuation of the drive voltage at the HIFU source. The time to boil obtained experimentally was used to quantify heating rates and was compared with calculations using weak shock theory and the shock amplitudes obtained from nonlinear modeling and measurements with a fiber optic hydrophone. As observed experimentally and predicted by calculations, shocked focal waveforms produced boiling in as little as 3 ms and the time to initiate boiling was sensitive to small changes in HIFU output. Nonlinear heating as a result of shock waves is therefore important to HIFU, and clinicians should be aware of the potential for very rapid boiling because it alters treatments.

In this work, the influence of nonlinear and diffraction effects on amplification factors of focused ultrasound systems is investigated. The limiting values of acoustic field parameters obtained by focusing of high power ultrasound are studied. The Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation was used for the numerical modeling. Solutions for the nonlinear acoustic field were obtained at output levels corresponding to both pre- and post- shock formation conditions in the focal area of the beam in a weakly dissipative medium. Numerical solutions were compared with experimental data as well as with known analytic predictions.

Both mechanically induced acoustic cavitation and thermally induced boiling can occur during high intensity focused ultrasound (HIFU) medical therapy. The goal was to monitor the temperature as boiling was approached using magnetic resonance imaging (MRI). Tissue phantoms were heated for 20 s in a 4.7-T magnet using a 2-MHz HIFU source with an aperture and radius of curvature of 44 mm. The peak focal pressure was 27.5 MPa with corresponding beam width of 0.5 mm. The temperature measured in a single MRI voxel by water proton resonance frequency shift attained a maximum value of only 73 degrees C after 7 s of continuous HIFU exposure when boiling started. Boiling was detected by visual observation, by appearance on the MR images, and by a marked change in the HIFU source power. Nonlinear modeling of the acoustic field combined with a heat transfer equation predicted 100 degrees C after 7 s of exposure. Averaging of the calculated temperature field over the volume of the MRI voxel (0.3 x 0.5 x 2 mm(3)) yielded a maximum of 73 degrees C that agreed with the MR thermometry measurement. These results have implications for the use of MRI-determined temperature values to guide treatments with clinical HIFU systems.

Acoustic characterization of high intensity focused ultrasound (HIFU) fields is important both for the accurate prediction of ultrasound induced bioeffects in tissues and for the development of regulatory standards for clinical HIFU devices. In this paper, a method to determine HIFU field parameters at and around the focus is proposed. Nonlinear pressure waveforms were measured and modeled in water and in a tissue-mimicking gel phantom for a 2 MHz transducer with an aperture and focal length of 4.4 cm. Measurements were performed with a fiber optic probe hydrophone at intensity levels up to 24,000 W/cm(2). The inputs to a Khokhlov-Zabolotskaya-Kuznetsov-type numerical model were determined based on experimental low amplitude beam plots. Strongly asymmetric waveforms with peak positive pressures up to 80 MPa and peak negative pressures up to 15 MPa were obtained both numerically and experimentally. Numerical simulations and experimental measurements agreed well; however, when steep shocks were present in the waveform at focal intensity levels higher than 6000 W/cm(2), lower values of the peak positive pressure were observed in the measured waveforms. This underrepresentation was attributed mainly to the limited hydrophone bandwidth of 100 MHz. It is shown that a combination of measurements and modeling is necessary to enable accurate characterization of HIFU fields.