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Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of death from cancer by 2030. Despite intensive research in the field of therapeutics, the 5-year overall survival is approximately 8%, with only 20% of patients eligible for surgery at the time of diagnosis. The tumoral microenvironment (TME) of the PDAC is one of the main causes for resistance to antitumoral treatments due to the presence of tumor vasculature, stroma, and a modified immune response. The TME of PDAC is characterized by high stiffness due to fibrosis, with hypo microvascular perfusion, along with an immunosuppressive environment that constitutes a barrier to effective antitumoral treatment. While systemic therapies often produce severe side effects that can alter patients' quality of life, locoregional therapies have gained attention since their action is localized to the pancreas and can thus alleviate some of the barriers to effective antitumoral treatment due to their physical effects. Local hyperthermia using radiofrequency ablation and radiation therapy - most commonly using a local high single dose - are the two main modalities holding promise for clinical efficacy. Recently, irreversible electroporation and focused ultrasound-derived cavitation have gained increasing attention. To date, most of the data are limited to preclinical studies, but ongoing clinical trials may help better define the role of these locoregional therapies in the management of PDAC patients.

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.

Liposome encapsulation of drugs is an interesting approach in cancer therapy to specifically release the encapsulated drug at the desired treatment site. In addition to thermo-, pH-, light-, enzyme- or redox-responsive liposomes, which have had promising results in (pre-) clinical studies, ultrasound-triggered sonosensitive liposomes represent an exciting alternative to locally trigger the release from these cargos. Localized drug release requires precise tumor visualization to produce a targeted and ultrasound stimulus. We used ultrasound molecular imaging (USMI) with BR55, a vascular endothelial growth factor receptor 2 (VEGFR2)-targeted ultrasound contrast agent, to guide ultrasound-triggered release of sonosensitive liposomes encapsulating doxorubicin (L-DXR) in an orthotopic prostatic rodent tumor model. Forty-eight hours after L-DXR injection, local release of doxorubicin was triggered with a confocal ultrasound device with two focused transducers, 1.1-MHz center frequency, and peak positive and negative pressures of 20.5 and 13 MPa at focus. Tumor size decreased by 20% in 2 wk with L-DXR alone (n = 9) and by 70% after treatment with L-DXR and confocal ultrasound (n = 7) (p0.01). The effect of doxorubicin on perfusion/vascularity and VEGFR2 expression was evaluated by USMI and immunohistochemistry of CD31 and VEGFR2 and did not reveal differences in perfusion or VEGFR2 expression in the absence or after the triggered release of liposomes. USMI can provide precise guidance for ultrasound-triggered release of liposomal doxorubicin mediated by a confocal ultrasound device; moreover, the combination of B-mode imaging and USMI can help to follow the response of the tumor to the therapy.

Chemotherapeutic agents such as doxorubicin induce cell cytotoxicity through induction of DNA double-strand breaks. Recent studies have reported the occurrence of DNA double-strand breaks in different cell lines exposed to cavitational ultrasound. As ultrasound stable cavitation can potentiate the therapeutic effects of cytotoxic drugs, we hypothesized that combined treatment with unseeded stable cavitation and doxorubicin would lead to increased DNA damage and would reduce cell viability and proliferation in vitro. In this study, we describe how we determined, using 4T1 murine mammary carcinoma as a model cell line, that unseeded stable cavitation combined with doxorubicin leads to additive DNA double-strand break induction. Combined treatment with doxorubicin and unseeded stable cavitation significantly reduced cell viability and proliferation at 72 h. A mechanistic study of the potential mechanisms of action of the combined treatment identified the presence of cavitation necessary to increase early DNA double-strand break induction, likely mediated by a bystander effect with release of extracellular calcium.

Purpose:We sought to report the preliminary results of salvage high-intensity focused ultrasound for locally recurrent prostate cancer in the prostatic bed after radical prostatectomy and adjuvant ...

Transcranial high-intensity focused ultrasound is used in clinics for treating essential tremor (ET) and proposed for many other brain disorders. This promising treatment modality requires high energy resulting eventually in undesired cavitation and potential side effects. The goals of the present work were: 1) to evaluate the potential increase of the cavitation threshold using pseudorandom gated sonications and 2) to assess the heating capabilities with such sonications. The experiments were performed with the transcranial magnetic resonance (MR)-compatible ExAblate Neuro system (InSightec, Haifa, Israel) operating at a frequency of 670 kHz, either in continuous wave (CW) or with pseudorandom gated sonications of 50% duty cycle. Cavitation activity with the two types of sonications was compared using chemical dosimetry of hydroxyl radical production at the focus of the transducer, after propagation in water or through a human skull. Heating trials were performed in a hydrogel tissue-mimicking material embedded in a human skull to mimic a clinical situation. The temperature was measured by MR-thermometry when focusing at the geometrical focus and steering off focus up to 15 mm. Compared with CW sonications, the use of gated sonication did not affect the efficiency (60%) nor the steering abilities of the transducer. After propagation through a human skull, gated sonication required a higher pressure level (10 MPa) to initiate cavitation as compared with CW (5.8 MPa). Moreover, at equivalent acoustic power above the cavitation threshold, the level of cavitation activity initiated with gated sonications was much lower with gated sonication than with continuous sonications, almost half after propagation through water and one-third after propagation through a skull. This lowered cavitation activity may be attributed to a breaking of the dynamic of the bubbles moving from monochromatic to more broadband sonications and to the removal of residual cavitation nuclei between pulses with gated sonications. The heating capability was not affected by the gated sonications, and similar temperature increases were reached at focus with both types of sonications when sonicating at equivalent acoustic power, both in water or after propagation through a human skull (+15 °C at 325 W for 10 s). These data, acquired with a clinical system, suggest that gated sonication could be an alternative to continuous sonications when cavitation onset is an issue.

Focused ultrasound is a treatment modality increasingly used for diverse therapeutic applications, and currently approved for several indications, including prostate cancers and uterine fibroids. But what about breast cancer? Breast cancer is the most common and deadliest cancer in women worldwide. While there are different treatment strategies available, there is a need for development of more effective and personalized modalities, with fewer side effects. Therapeutic ultrasound is such an option, and this review summarizes the state of the art in their use for the treatment of breast cancer and evaluate potentials of novel treatment approaches combining therapeutic ultrasound, immuno- and chemo-therapies.

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%.

Pancreatic ductal adenocarcinoma (PDAC) diagnosis accompanies a somber prognosis for the patient, with dismal survival odds: 5% at 5 years. Despite extensive research, PDAC is expected to become the second leading cause of mortality by cancer by 2030. Ultrasound (US) has been used successfully in treating other types of cancer and evidence is flourishing that it could benefit PDAC patients. High-intensity focused US (HIFU) is currently used for pain management in palliative care. In addition, clinical work is being performed to use US to downstage borderline resectable tumors and increase the proportion of patients eligible for surgical ablation. Focused US (FUS) can also induce mechanical effects, which may elicit an anti-tumor response through disruption of the stroma and can be used for targeted drug delivery. More recently, sonodynamic therapy (akin to photodynamic therapy) and immunomodulation have brought new perspectives in treating PDAC. The aim of this review is to summarize the current state of those techniques and share our opinion on their future and challenges.

In the 1980s, HIFU was successfully tested for treating refractory glaucoma (Lizzi et al.). A more recent device from EyeTechCare, made of six cylindrical transducers operating at 21MHz, can perform a conformal, partial, and fast thermal ablation of the ciliary bodies, a technique known as ultrasound cycloplasty (UCP). For the last 10 years, we investigated the safety and efficacy of UCP for reducing the production of aqueous humor and intraocular pressure (IOP). The primary outcomes that were validated (more than 55%) were therapeutic success (IOP reduction from baseline ≥20% and IOP >5 mm Hg without other surgical procedures) and vision-threatening complications. Secondary outcomes included mean IOP change from baseline at each follow-up visit, medication use, complications, and subsequent UCP and/or other postsurgical interventions. This technique was associated with a low complication rate and no cases of phthisis. In this presentation, we also highlight the remaining challenges in increasing the efficacy and reliability of UCP and its future developments. [Disclosure: Dietrich Wolf is CEO at EyeTechCare.]

Presbyopia is a progressive loss of accommodation capacity due to a rigidification of the lens. In order to prove the efficiency of ultrasonic cavitation to soften the lens, curvilinear SWE has been developed. It is a method to measure stiffness based on the tracking of surface waves on the outer layer of lens. Experimental models have been implemented: flat phantoms and beads made of 10% and 15% of porcine gelatin and finally porcine lenses (young: 6 months and old: 1 to 6 years). A mechanical vibrator created vibrations (0.1–3.5kHz) and an ultrafast ultrasound imaging system was used to track the propagating waves. From the curvature of the frequency domain of the cross-correlated displacement field, the wavelength and velocity were computed. Experimental models enable to validated the method with dispersion curves substantially different between both concentrations. Results in lenses are similar: a dispersion curve highly dependent of the frequency, reflecting the complexity of elastic wave propagating in a multilayered medium surrounded by a membrane. To retrieve quantitative elasticity data, advanced numerical models have to be developed. This method will be applied on lenses treated by cavitation to assess its potential for treating presbyopia.

Presbyopia is the age-related stiffening of the crystalline lens, reducing near vision. One of the main mechanisms of this lens stiffening is the formation of disulfide bonds. We propose ultrasonic cavitation to interact with the lens structure, disrupt disulfide bonds and restore flexibility. Here, we present early results on the feasibility of the technique. Cavitation was nucleated inside the porcine lenses using confocal transducers and signals emitted in the focal area were acquired using an imaging array and reconstructed using frequency-domain passive cavitation imaging. Peak negative pressure of 23MPa for 20-μs pulses at 1.1 MHz provided a clear chance of nucleating cavitation with our system. Exposures were performed during 10 seconds of cavitation at a PRF of 250 Hz. Cavitation clouds were clearly visible in B-mode images for both 6-months old and 3-years old porcine eyes. To provide initial safety data, the absence of cataract was confirmed on transparency images. Histology revealed no damage to the lens structure. A gel phantom with a disulfide bond-dependent hardening is proposed to investigate the potential for cavitation to disrupt the disulfide bonds.

This numerical study aims at evaluating quantitative monitoring of elasticity changes induced by ultrasonic cavitation using shear waves elastography (SWE). SWE is a good method to safely evaluate the lens stiffness. Yet, the absence of backscattered signal inside the lens (regardless of the imaging technique) forbids elastography inside. Experimentally, we, thus, tracked surfaces waves on multiple models (gelatin beads, porcine lens) and evaluated dispersion curves of this waves. Finite difference time domain simulations are performed in order to evaluate elasticity with access to a few surface point, starting with a simple homogeneous inclusion towards complex inclusion closer to the lens configuration. In homogeneous inclusion, we noticed Scholte wave behavior on the dispersion. Complexifying the configuration by adding layers induced a gradient in the dispersion curves, the higher the frequency is the less the surface wave depends on the deepest layers. A similar behavior was observed experimentally: low frequencies with mostly resonances then a plateau matching Scholte wave expectation. Numerical studies indicate that the surface waves is sensitive to the shear elasticity inside the inclusion, yet this behavior is highly frequency dependent. This leads the way to investigate the frequency behavior of guided wave in experiments in lens in our team.

Characterizing myocardial activation is of major interest for understanding the underlying mechanism of cardiac arrhythmias. Electromechanical wave imaging (EWI) is an ultrafast ultrasound-based method used to map the propagation of the local contraction triggered by electrical activation of the heart. This study introduces a novel way to characterize cardiac activation based on the time evolution of the instantaneous frequency content of the cardiac tissue displacement curves. The first validation of this method was performed on an ex vivo dataset of 36 acquisitions acquired from two working heart models in paced rhythms. It was shown that the activation mapping described by spectral analysis of interframe displacement is similar to the standard EWI method based on zero-crossing of interframe strain. An average median error of 3.3 ms was found in the ex vivo dataset between the activation maps obtained with the two methods. The feasibility of mapping cardiac activation by EWI was then investigated on two open-chest pigs during sinus and paced rhythms in a pilot trial of cardiac mapping with an intracardiac probe. Seventy-five acquisitions were performed with reasonable stability and analyzed with the novel algorithm to map cardiac contraction propagation in the left ventricle (LV). Sixty-one qualitatively continuous isochrones were successfully computed based on this method. The region of contraction onset was coherently described while pacing in the imaging plane. These findings highlight the potential of implementing EWI acquisition on intracardiac probes and emphasize the benefit of performing short time-frequency analysis of displacement data to characterize cardiac activation in vivo.

International audience; High-intensity focused ultrasound (HIFU) is a promising method used to treat cardiac arrhythmias, as it can induce lesions at a distance throughout myocardium thickness. Numerical modeling is commonly used for ultrasound probe development and optimization of HIFU treatment strategies. This study was aimed at describing a numerical method to simulate HIFU thermal ablation in elastic and mobile heart models. The ultrasound pressure field is computed on a 3-D orthonormal grid using the Rayleigh integral method, and the attenuation is calculated step by step between cells. The temperature distribution is obtained by resolution of the bioheat transfer equation on a 3-D non-orthogonally structured curvilinear grid using the finite-volume method. The simulation method is applied on two regions of the heart (atrioventricular node and ventricular apex) to compare the thermal effects of HIFU ablation depending on deformation, motion type and amplitude. The atrioventricular node requires longer sonication than the ventricular apex to reach the same lesion volume. Motion considerably influences treatment duration, lesion shape and distribution in cardiac HIFU treatment. These results emphasize the importance of considering local motion and deformation in numerical studies to define efficient and accurate treatment strategies.

OBJECTIVES To evaluate the oncological and functional outcomes of salvage high-intensity focused ultrasound (S-HIFU) for locally recurrent prostate cancer after low-dose-rate (LDR) brachytherapy. PATIENTS AND METHODS Clinical phase II studies (2003-2015) included 50 consecutive patients with post-brachytherapy local recurrence treated by S-HIFU. S-HIFU was performed with post-external beam radiotherapy (EBRT) parameters and, since 2008, with specific post-brachytherapy parameters. Treatments were whole-gland ablation and, since 2009, hemi-ablation in cases of unilateral prostate cancer. The primary objective was to assess oncological outcomes: treatment failure-free survival, progression-free survival (PFS), overall survival (OS), cancer-specific survival (CSS), and metastasis-free survival (MFS) rates. The secondary objective was to evaluate adverse events, continence, and erectile function. Kaplan-Meier analysis estimated oncological outcomes. RESULTS In all, 13 patients were treated with post-EBRT parameters, 37 with post-brachytherapy parameters, 35 with whole-gland treatment, and 15 with hemi-ablation. The median follow-up was 4.6 years. After S-HIFU, the median prostate-specific antigen level was 0.3 ng/mL. At 6 years, treatment failure-free survival, PFS, OS, CSS, and MFS rates were 41%, 45%, 93%, 98%, and 80%, respectively. Post-brachytherapy compared with post-EBRT parameters reduced Grade 2-3 incontinence (34% vs 62%, P = 0.015). Incontinence, bladder outlet obstruction and Grade ≥III complications were significantly reduced with hemi-ablation compared with whole-gland treatment (14% vs 54%, P

Presbyopia is the age-related stiffening of the crystalline lens, reducing near vision. We propose ultrasonic cavitation to interact with the lens structure and restore its flexibility. Here, we present early results on the feasibility of the technique. First, the cavitation threshold was determined: the focus of a 4-elements transducer was placed in the lens nucleus in a porcine eye, and signals emitted in the focal area were acquired using an imaging array and reconstructed using frequency-domain passive cavitation imaging (PCI) with Richardson-Lucy deconvolution. Inharmonic emissions inside the lens were calculated, and we evidenced two distinct populations: low and high amount of signal inside the lens, when cavitation was absent or present, respectively. Peak negative pressure of 23 MPa for 20 μs pulses at 1.1 MHz provided a clear chance of nucleating cavitation with our system. Exposures were performed after 10 s of cavitation using a PRF of 250 Hz. Cavitation clouds were clearly visible in B-mode images for both 6-months old and 3-years old porcine eyes. The absence of cataract was confirmed on transparency images, and histology revealed no damages to the lens structure. These preliminary results are encouraging towards the application of cavitation in the crystalline lens.

Differentiation between epicardial and endocardial ventricular activation remains a challenge despite the latest technologies available. The aim of the present study was to develop a new tool method, based on electromechanical wave imaging (EWI), to improve arrhythmogenic substrate activation analysis. Experiments were conducted on left ventricles (LVs) of four isolated working mode swine hearts. The protocol aimed at demonstrating that different patterns of mechanical activation could be observed whether the ventricle was in sinus rhythm, paced from the epicardium or from the endocardium. A total of 72 EWI acquisitions were recorded on the anterior, lateral and posterior segments of the LV. A total of 54 loop records were blindly assigned to two readers. EWI sequences interpretations were correct in 89% of cases. The overall agreement rate between the two readers was 83%. When in a paced ventricle, the origin of the wave front was focal and originated from the endocardium or the epicardium. In sinus rhythm, wave front was global and activated within the entire endocardium toward the epicardium at a speed of 1.7 ± 0.28 m·s−1. Wave front speeds were respectively measured when the endocardium or the epicardium were paced at a speed of 1.1 ± 0.35 m·s−1 versus 1.3 ± 0.34 m·s−1 (p = NS). EWI activation mapping allows activation localization within the LV wall and calculation of the wave front propagation speed through the muscle. In the future, this technology could help localize activation within the LV thickness during complex ablation procedures.

This work describes the use of therapeutic ultrasound as a treatment of cardiovascular disease including recent, state of the art approaches. Therapeutic ultrasound researchers have made recent advances in the highly dynamic and changing world of interventional cardiology where they are confronted with several challenges, such as of the complexity of ultrasound propagation in the highly heterogeneous environment of the thorax or the complexity of the heart (in term of motion and physiology). It is believed that with these recent innovations, therapeutic ultrasound for cardiac applications will soon have a place in the toolkit of cardiologists.

Electrical impedance of a medium helps to predict the behavior of electrical currents in a medium. Electrical impedance refers indeed to the “difficulty”, for an electrical current, to spread through the medium. While the first impedance measurements were focused on cardiovascular parameters, techniques are now being applied to the whole body, as electrical impedance present important variations through the human body and could then offer a new source of contrast. Combining electrical current, magnetic fields, and acoustics in various ways have led to interesting techniques to image this parameter: Electrical Impedance Tomography, Magnetic Resonance Electrical Impedance Tomography, Acousto-Electric Imaging, Lorentz Force Electrical Impedance Tomography and Magneto-Acoustic Tomography. These techniques are detailed in this review.

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.

Study Objective Demonstrate the feasibility of Trans Rectal High intensity focused ultrasound (HIFU) treatment in patients presenting rectosigmoid endometriosis Design Phase I, non-controlled, prospective monocentric clinical study Setting Patients filled questionnaires on gynecologic and intestinal symptoms, and on quality of life (MOS-SF36 score, EHP-5) before and at one, three and six months after treatment. Patients or Participants patients older than 25 years, who presented a symptomatic single rectosigmoid location and after failure of hormonal therapy. All lesions were assessed using transvaginal sonography and MRI. Interventions Trans Rectal HIFU treatment Using the FocalOne Probe. Measurements and Main Results Twenty-three patients were included between September 2015 and October 2018. All the lesions were visualized. Twenty lesions were treated (“feasibility rate”: 87.0%): thirteen entirely and seven partially. The mean duration of the procedure was 55.6 minutes. We observed a significant improvement in visual analogic scales at six month for dysmenorrhea (-3.6, p=0.004), dyspareunia (-2.4, p=0.006), diarrhea (-3.0, p=0.006), constipation (-3, p=0.002), dyschezia (-3.2, p=0.003), false urges to defecate (-3.3, p=0.007), posterior pelvic pain (-3.8, p=0.002), and asthenia (-4.3, p=0.002).There was also a significant improvement of the MOS-SF36 with an increase of both Physical Composite Score (+9.3%, p=0.002) and Mental Composite Score (+10.9%, p=0.017) at six months. No major complications occurred during and after the procedure. Conclusion HIFU therapy for rectosigmoid location is feasible. It could be an interesting minimally invasive alternative to surgery for the treatment of rectosigmoid endometriosis. A prospective multicentric study is presently performed in France to confirm these preliminary results.

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.

Acoustic cavitation has found a wide range of applications in the last few decades. For potential applications involving cavitation, the acoustic characteristics of a confocal ultrasonic setup are studied: two high-intensity focused ultrasound transducers are mounted so that their focal points overlap. A mathematical simulator is developed that takes into account nonlinear propagation, absorption, and diffraction. Each one of these physical effects is solved in the frequency domain for successive planes. Comparing the confocal setup with equivalent single transducer setups, it is shown that, with the confocal configuration, nonlinear distortion of the waveform is reduced, resulting in a greater peak rarefactional pressure and a lower peak positive pressure. Furthermore, additional features are investigated for confocal configurations such as a greater spatial stability for the focal point, which can be maintained while increasing the pressure level, and a focal region consisting of interference acting as an acoustic trap.

International audience; Doxorubicin, alone or in combination with other anticancer agents, is one of the most widely used chemotherapeutic agents and is administered in a wide range of cancers. However, the use of doxorubicin is limited due to its potential serious adverse reactions. Previous studies have established the ability of high intensity focused ultrasound (HIFU) in combination with various contrast agents to increase intracellular doxorubicin delivery in a targeted and noninvasive manner. In this study, we developed a new sonoporation device generating and monitoring acoustic cavitation bubbles without any addition of contrast agents. The device was used to potentiate the delivery of active doxorubicin into both adherent and suspended cell lines. Combining doxorubicin with ultrasound resulted in a significant enhancement of doxorubicin intracellular delivery and a decrease in cell viability at 48 and 72 h, in comparison to doxorubicin alone. More importantly and unlike previous investigations, our procedure does not require the addition of contrast agents to generate acoustic cavitation and to achieve high levels of doxorubicin delivery. The successful translation of this approach for an in vivo application may allow a significant reduction in the dosage and the adverse effects of doxorubicin therapy in patients.

Objectifs Evaluer les resultats preliminaires du traitement par HIFU de sauvetage chez les patients presentant une recidive locale d’un cancer de prostate (CaP) dans la loge de prostatectomie apres chirurgie puis radiotherapie adjuvante ou de rattrapage. Methodes De juillet 2009 a novembre 2018, tous les patients traites par HIFU pour une recidive locale apres chirurgie puis radiotherapie adjuvante/rattrapage ont ete evalues, etude retrospective monocentrique. La recidive locale etait confirmee par Pet-TDM a la choline, IRM et biopsies transrectales. La survie sans echec (SSE) etait definie comme l’absence de CaP dans la loge de prostatectomie et/ou de metastases et/ou d’introduction de traitement systemique ; la survie sans progression (SSP) comme l’absence de metastases et/ou d’introduction de traitement systemique ; la survie sans recidive biochimique (SSRB) comme l’absence de deux augmentations du PSA ≥ 0,2 ng/mL au-dessus du nadir post-HIFU. Les complications et la continence etaient evaluees. Resultats Vingt-deux patients ont ete inclus avec un suivi moyen de 3,83 ans. Les caracteristiques de la population lors de la prostatectomie radicale, lors de la radiotherapie et lors de l’HIFU sont presentes dans le Tableau 1 . A 3 ans, la SSE etait de 49,7 %, la SSP de 60,4 % ( Fig. 1 ) et la SSRB de 35,3 %. Vingt patients (90,9 %) avaient une decroissance du PSA et 11 patients (50 %) avaient un nadir de PSA ≤ 0,2 ng/mL. La SSE et la SSP etaient significativement ameliorees chez les patients avec un nadir de PSA ≤ 0,2 par rapport a ceux avec un nadir > 0,2 ng/mL (p = 0,037, p = 0,003, respectivement). Les complications grade IIIb sont survenues chez 6 patients (27,3 %) ; la survenue d’une incontinence grade II/III etait significativement differente selon la localisation de la recidive (peri-anastomotique : 36,4 %, retrovesicale : 0 %, p = 0,027) ( Tableau 2 ). Conclusion L’HIFU de sauvetage chez les patients presentant une recidive locale dans la loge de prostatectomie apres chirurgie puis radiotherapie adjuvante ou de rattrapage prolonge l’histoire naturelle du CaP, retarde la survenue de metastases, l’introduction de traitement systemique et pourrait meme guerir certains patients aux depens d’une morbidite acceptable. La localisation de la recidive par rapport au sphincter influence la continence.

Summary Targeted and triggered release of liposomal drug using ultrasound (US) induced cavitation represents a promising treatment modality to increase the therapeutic-toxicity ratio of encapsulated chemotherapy. Objectives To study the feasibility and efficacy of a combination of focused US and liposomal doxorubicin (US-L-DOX) release in orthotopic murine models of pancreatic cancer. Material and methods A confocal US setup was developed to generate US inertial cavitation delivery in a controlled and reproducible manner and designed for two distinct murine orthotopic pancreatic cancer models. Controlled cavitation at 1 MHz was applied within the tumors after L-DOX injection according to a preliminary pharmacokinetic study. Results In vitro studies confirmed that L-DOX was cytostatic. In vivo pharmacokinetic study showed L-DOX peak tumor accumulation at 48h. Feasibility of L-DOX injection and US delivery was demonstrated in both murine models. In a nude mouse model, at W9 after implantation (W5 after treatment), US-L-DOX group (median [IQR] 51.43 mm3 [35.1–871.95]) exhibited significantly lower tumor volumes than the sham group (216.28 [96.12–1202.92]), the US group (359.44 [131.48–1649.25]), and the L-DOX group (255.94 [84.09–943.72]), and a trend, although not statistically significant, to a lower volume than Gemcitabine group (90.48 [42.14–367.78]). Conclusion This study demonstrates that inertial cavitation can be generated to increase the therapeutic effect of drug-carrying liposomes accumulated in the tumor. This approach is potentially an important step towards a therapeutic application of cavitation-induced drug delivery in pancreatic cancer.

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.

To evaluate the oncological and functional outcomes of salvage high-intensity focused ultrasound (S-HIFU) for locally recurrent prostate cancer after low-dose-rate (LDR) brachytherapy.Clinical phase II studies (2003-2015) included 50 consecutive patients with post-brachytherapy local recurrence treated by S-HIFU. S-HIFU was performed with post-external beam radiotherapy (EBRT) parameters and, since 2008, with specific post-brachytherapy parameters. Treatments were whole-gland ablation and, since 2009, hemi-ablation in cases of unilateral prostate cancer. The primary objective was to assess oncological outcomes: treatment failure-free survival, progression-free survival (PFS), overall survival (OS), cancer-specific survival (CSS), and metastasis-free survival (MFS) rates. The secondary objective was to evaluate adverse events, continence, and erectile function. Kaplan-Meier analysis estimated oncological outcomes.In all, 13 patients were treated with post-EBRT parameters, 37 with post-brachytherapy parameters, 35 with whole-gland treatment, and 15 with hemi-ablation. The median follow-up was 4.6 years. After S-HIFU, the median prostate-specific antigen level was 0.3 ng/mL. At 6 years, treatment failure-free survival, PFS, OS, CSS, and MFS rates were 41%, 45%, 93%, 98%, and 80%, respectively. Post-brachytherapy compared with post-EBRT parameters reduced Grade 2-3 incontinence (34% vs 62%, P = 0.015). Incontinence, bladder outlet obstruction and Grade ≥III complications were significantly reduced with hemi-ablation compared with whole-gland treatment (14% vs 54%, P 0.001; 13% vs 46%, P = 0.03; 13% vs 63%, P = 0.001; respectively). Before S-HIFU, 25 patients had a five-item version of the International Index of Erectile Function score of ≥17, which was maintained in 48% at 12 months.S-HIFU for locally recurrent prostate cancer after LDR brachytherapy is associated with favourable survival rates at a price of significant morbidity. Dedicated post-brachytherapy parameters and hemi-ablation improve the safety of the treatment.

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

Catheter ablation for the treatment of arrhythmia is associated with significant complications and often-repeated procedures. Consequently, a less invasive and more efficient technique is required. Because high-intensity focused ultrasound (HIFU) enables the generation of precise thermal ablations in deep-seated tissues without harming the tissues in the propagation path, it has the potential to be used as a new ablation technique. A system capable of delivering HIFU into the heart by a transesophageal route using ultrasound (US) imaging guidance was developed and tested in vivo in six male pigs. HIFU exposures were performed on atria and ventricles. At the time of autopsy, visual inspection identified thermal lesions in the targeted areas in three of the animals. These lesions were confirmed by histologic analysis (mean size: 5.5 mm(2) × 11 mm(2)). No esophageal thermal injury was observed. One animal presented with bradycardia due to an atrio-ventricular block, which provides real-time confirmation of an interaction between HIFU and the electrical circuits of the heart. Thus, US-guided HIFU has the potential to minimally invasively create myocardial lesions without an intra-cardiac device.