Meeting report: 2017 Winter School on Therapeutic Ultrasound

Meeting report: 2017 Winter School on Therapeutic Ultrasound The Winter School on Therapeutic Ultrasound held its biennial meeting at the Ecole de Physique des Houches in Les Houches, France from March 26-31, 2017. The program brought together a globally and scientifically diverse group of faculty, clinicians, and trainees with interest in elements of therapeutic ultrasound. The meeting agenda was composed of daily lectures on various topics of relevance, supplemented with evening seminars, excursions, and networking opportunities. In anticipation of the next edition of the Winter School expected in 2019, we are nearly reaching the half way point between offerings of this unique and specialized meeting. Thus, this meeting report offers a reflection on the 2017 Winter School with the intention of setting the stage for 2019. Reviewed within this report are the lectures, student presentation series, and evening seminars encompassed within meeting agenda. It is my hope that this resource will be utilized by investigators within the therapeutic ultrasound community considering attending the Winter School in 2019. Keywords: Therapeutic ultrasound, Focused ultrasound, Image guidance, Meeting Introduction and student presentations, all of which will be discussed The Winter School on Therapeutic Ultrasound is a in greater detail herein. unique workshop opportunity offered once every 2 years for students, postdocs, faculty, clinicians, and industrial Lectures partners to explore the rapidly expanding field of thera- Each lecture was delivered by a world authority peutic ultrasound. This year’s workshop brought well-positioned to discuss a topic pertaining to therapeutic together individuals from multiple countries spanning ultrasound within the context of his/her own research. North America, Europe, and the Middle East. Partici- The content of each lecture is summarized below. pants convened at the Ecole de Physique des Houches to engage in advanced multidisciplinary lectures provided Acoustic propagation – Soft tissue by a globally renowned panel of invited speakers. Robin Cleveland (University of Oxford) delivered a lec- A typical day of the workshop consisted of 6-7 lec- ture on ultrasound propagation through soft tissue on tures, intermingled with opportunities to explore Les behalf of Vera Khokhlova (University of Washington; Houches and engage in activities such as skiing, hiking, Moscow State University). The core concepts of acous- walking, and networking with fellow attendees. The tics were overviewed in this lecture, including reflection, unique environment, located amid the breathtaking refraction, and impedance in the context of beam propa- landscape of the French Alps, provided for a reserved gation, attenuation and power, sound speed and imped- and refreshing retreat wherein a diverse group of ance. The content additionally advanced into topics such students and experts could engage about research in a as nonlinearity, shock theory, KZK equation, Pennes relaxed, amicable, and approachable manner. Beyond Bioheat Transfer Equation, and heat deposition. daily lectures, additional learning opportunities included two special evening seminars, a documentary screening, Focusing ultrasound Jean Francois-Aubry (CNRS; Institut Langevin) discussed Correspondence: nds3sa@virginia.edu the concept of wave focusing, techniques for numerical Department of Biomedical Engineering, Health System, University of Virginia, Box 800759, Charlottesville, VA 22908, USA modeling of multi-transducer arrays, implications of © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sheybani Journal of Therapeutic Ultrasound (2018) 6:3 Page 2 of 7 sparse array spatial distribution for therapy, and the chal- Basics of ultrasound imaging lenges of skull attenuation. Strategies for focusing and Thomas Deffieux (Institut Langevin, INSERM, ESPCI) non-invasive target verification were elucidated, such as provided an introduction to the principles of ultrasound CT co-registry for skull characterization, single cavitation imaging and how these concepts underlie the various mo- bubble induction at the focus to verify the target, radiation dalities of ultrasound. Ultrasound is a versatile imaging pressure detection by MRI, and exploitation of natural modality that operates on the basis of sound wave trans- acoustic reflectors (e.g. kidney stones, microcalcifications) mission and reception. The defining principles of ultra- or systemically introduced acoustic amplifiers (e.g. tar- sound imaging were discussed in the context of geted ultrasound contrast agents). Amid the progression impedance, reflection, and transmission/reception of pulse towards non-invasive strategies for delivering therapeutic echoes. The acoustic window and imaging applications for ultrasound to the brain, one of the major challenges for various transducer geometries - including linear array, non-invasive transcranial therapy has been overcoming convex (curved) array, and phased array – were intro- skull attenuation. Currently, the predominating algorithms duced as a segue into subsets of ultrasound imaging, in- for performing transcranial aberration correction are (1) cluding B-mode, Doppler, ultrafast, and 3D imaging. reversal/phase shift correction, which optimizes energy deposition at the focus and (2) amplitude compensation, Basics of Magnetic Resonance Imaging (MRI) which optimizes pressure distribution within the focal Florian Steinmeyer (Technische Hochschule Neurnberg) plane. These techniques hold appeal for transcranial ther- introduced the basic physics underlying nuclear mag- mal and non-thermal therapies, respectively. netic resonance (NMR), including spin, magnetic mo- ments, T1 and T2 relaxation, and induction decay. The Biophysics – Heating & thermometry translation from NMR to MRI was explicated in terms Gail ter Haar (Institute of Cancer Research, London) de- of pulse sequences, slice selection, phase encoding, and livered a lecture on heating by ultrasound. The bio- image reconstruction from complex magnetization. MRI logical consequences of heating tissue are tunable based is a powerful tool for imaging that, while slower than on temperature rise and duration. Induction of ultrasound with respect to scan time, holds particular temperature rises ranging from 3 to 5 °C is generally appeal for high intensity focused ultrasound (HIFU) ap- classified as hyperthermia, while induction of plications due to the capability for near real-time temperature rises between 20 and 60 °C is categorized as temperature mapping. thermal ablation. Monitoring of these temperatures via thermometry can occur in a variety of ways; strategies Ultrasound transducers for thermometry include thermocouples, fiber-optic hy- Remi Berriet (Imasonic) delivered a lecture on medical drophones (temperature and pressure feedback), MR ultrasound transducers, beginning with the main com- thermometry, and ultrasound temperature mapping. ponents of a transducer and the role of piezoelectric ma- This final strategy is an emerging technique whereby terial in converting between electrical and mechanical displacement serves as a proxy for heat induction within energy. Essential characteristics of transducers include the tissue being imaged. Despite compelling advantages frequency, bandwidth/pulse length, and sensitivity. in the way of cost, availability, sensitivity, and precision, These characteristics extend to therapeutic transducers, ultrasound thermometry faces limitations including lack but additional specifications that are of particular im- of feedback regarding absolute temperature, poor sensi- portance include focusing, mean power, and peak pres- tivity in the presence of fat, and motion artifacts. sure. Ultrasound fulfills a variety of clinical needs, but design of the transducer can vary vastly depending on Cavitation – Applications access requirements. An overview was provided of the Larry Crum (University of Washington) introduced the considerations for external, endo-cavitary, and intersti- topic of acoustic cavitation and passive cavitation detec- tial/intraluminal access using therapeutic ultrasound tion, followed by a survey of emerging applications. The probes. Closing remarks were provided on safety criter- lecture delved into a myriad of applications that can ex- ion, safety evaluation, and ongoing developments such tend from the biological consequences of cavitation, in- as improvement of efficiency, safety, and performance, cluding sonothrombolysis, sonoporation and gene reduction of treatment time, and optimization of coup- transfection, blood brain barrier disruption, and kidney ling between imaging and therapy for improved targeting stone comminution. Specific ultrasound techniques that and monitoring of treatment. harness acoustic cavitation to mediate these effects in- clude histotripsy, as in the example of thrombolysis, and Monitoring & guidance – US shock wave lithotripsy, as in the example of kidney stone Mathieu Pernot (INSERM, Institut Langevin, ESPCI) fragmentation. discussed the importance of image guidance and Sheybani Journal of Therapeutic Ultrasound (2018) 6:3 Page 3 of 7 monitoring for safety and efficacy of ultrasound therapy. and aberrant vasculature, both of which are in part dic- Ultrasound enables image guidance for targeting, tated by tumor size. Part of the challenge of heat induc- real-time monitoring, and post-treatment assessment. tion in tumors is the heterogeneity in these Pending exposure conditions, standard B-mode imaging characteristics and the resulting influences on heat de- can be useful for qualitatively detecting changes in tissue position and damage. Pre-clinical studies are underway backscatter following treatment. However, emerging to explore how hyperthermia interfaces with different qualitative methods for detecting changes in tissue com- tumor microenvironments. Meanwhile, hyperthermia position include ultrasonic thermometry and elastogra- has already been demonstrated to be a potent enhancer phy. The former quantifies apparent displacement of of radiotherapy in patients, thereby implicating a role for sound scatterers to measure temperature as a function therapeutic ultrasound in such combination therapies. of strain. Limitations include influence of motion arti- facts, necessity of a priori knowledge of tissue compos- Current applications of HIFU in oncology ition, and the fact that the dependence of the speed of Joo Ha Hwang (University of Washington) provided an sound on temperature is not monotonic for tempera- overview of applications, both approved and emerging, tures exceeding 50 °C. Soft tissues have been demon- of HIFU in oncology. Currently, the oncologic indica- strated to increase in stiffness with heating; thus, tions for HIFU include pain palliation and localized elastography quantifies changes in the stiffness of soft tumor ablation. In the example of pancreatic cancer, tissues as a proxy for temperature change. This modality HIFU is used for pain control through the ablation of is not as robust for heterogeneous/granular tissues, e.g. proximal nerves. A similar approach is used for palli- tumors, as compared with homogenous tissues. ation of painful bone metastases. Alternatively, HIFU has been used to ablate primary tumors as in the cases Monitoring & guidance – MRI of prostate and liver cancers. For these applications, Bruno Quesson (Inserm, Universite de Bordeaux) deliv- acoustic window is and will continue to be a critical fea- ered a lecture on MR monitoring and guidance. Tissue ture of the instrumentation as HIFU becomes more alteration depends on temperature and time of exposure, widely adopted for focal therapy and palliation. which on MRI monitoring, translates to mapping of thermal dose and temperature. Techniques for MR Biophysics – Cavitation temperature mapping include quantitation of correlates Ronald Roy (University of Oxford) delivered a lecture on such as diffusion, longitudinal relaxation, frequency shift bubble acoustics, acoustic cavitation, and bubble dynam- of water resonance, and 1H spectroscopic imaging. ics. Bubbles are potent scatterers of sound. At low inten- MRI-guided ablation can be confounded by factors such sities, single bubbles respond as linear oscillators, as motion of mobile targets, cooling effect conferred by mimicking the behavior of a classic 2nd order system blood flow, and energy absorption by skin and bones. and structure of a forced spring-mass-dashpot oscillator. These factors must be overcome and monitored in order The radius of spherical bubbles influences resonance fre- to ensure delivery of appropriate acoustic intensities at quency and scattering. In ultrasound imaging and ther- the focus. MRI techniques are varied in design and per- apy applications, systemically administered microbubbles mit compensation for motion artifacts, monitoring of serve as contrast agents. At high intensities, single bub- temperature elevation and/or tissue displacement, perfu- bles can respond nonlinearly. In general, the response of sion imaging, and in emerging applications, automatic bubbles to an acoustic pressure field is characterized by feedback control of HIFU energy deposition. two modes of acoustic cavitation: stable and inertial. Stable cavitation refers to repetitive pulsations of the Tumor biology & physiology bubble about its spherical radius and is dominated by Michael Horsman (Aarhus University Hospital) dis- compressibility. Inertial cavitation, however, is mediated cussed biological mechanisms that extend from heat in- by liquid inertia and results in unstable growth that ul- duction in the tumor microenvironment, and timately results to violent collapse. The physical effects physiological considerations for effective application of of these modes of cavitation can include radiation stress, hyperthermia to tumors - with emphasis on the role of cavitation microstreaming, heating, collapse microjets, vascular supply on tissue response. Studies have demon- sonoluminescence, and radiation stress. strated at the cellular level that heat induction influences oxygen consumption, protein inactivation, and cell sur- Calibration & field characterization vival, among other effects. Tumor cell type, cell cycle, Oleg Sapozhnikov (Moscow State University; University of and microenvironmental parameters such as oxygen- Washington) provided insight into techniques for trans- ation, can also play a role in response to heating. Tu- ducer calibration and acoustic field characterization. mors are characterized by hypoxic microenvironments Techniques for observing an ultrasound field include Sheybani Journal of Therapeutic Ultrasound (2018) 6:3 Page 4 of 7 indirect observation of effects such as radiation pressure, The aforementioned applications have been enabled by heating, or cavitation through a propagation medium, op- the Insightec ExAblate MR-guided FUS system and tical shadowgraphy (schlieren), and infrared emission CarThera SonoCloud. from ultrasound-heated layers. Therapeutic ultrasound probes are typically characterized using a combination of Histology for HIFU approaches including acoustic pressure sensing (hydro- Gail ter Haar (Institute of Cancer Research, London) phones), radiation force balance, calorimetry, laser vibro- discussed the basic types of tissue (muscle, nervous, con- metry, and infrared imaging. In order to characterize the nective, and epithelial) and strategies for analyzing them in situ field, however, it is necessary to know information by histology. Histology is an essential technique for char- about the source, medium, and modeling of wave acterizing HIFU lesions at the cellular and tissue levels. propagation. Since HIFU is effectively a strategy for inducing cell death, the mode of histological analysis can be in part The route to commercialization dictated by the nature of cell death (i.e. apoptosis versus Frederic Sottilini (CarThera) discussed the process of de- necrosis). The sequence for tissue processing generally veloping a product and achieving milestones towards involves fixation, dehydration, infiltration and embed- commercialization in the context of CarThera’s experi- ding, sectioning, mounting, staining, and analysis by mi- ence. CarThera is a Paris-based company that pioneers croscopy. The most common histological stain is ultrasound-based medical devices for the treatment of hematoxylin & eosin (H&E) staining, which stains for brain disorders. Thus far, its two breakthrough medical nucleic acids and other tissue components, respectively; devices (Sonocloud© and Sonoprobe) span four indica- this stain can be used to determine tissue integrity and tions, including Glioblastoma Multiforme, Alzheimer’s identify regions of inflammation. A diverse range of im- disease, brain metastasis of melanoma, and brain tu- munohistochemical stains are available for evaluating mors. The pathway to commercialization involves identi- more specific biological consequences of HIFU such as fication of an unmet clinical need. The compelling need changes in perfusion, hypoxia, vessel patency, stress (e.g. for minimally invasive interventions for the aforemen- heat shock proteins), progressive damage, inflammation, tioned neurological pathologies drives CarThera’s path cell proliferation, etc. towards commercialization. However, once a market op- portunity for this need is confirmed, a multi-year Ultrasound mediated drug delivery process ensues wherein subsequent steps include com- Holger Gruell (University Hospital of Cologne, prehensive pre-clinical establishment, pre-clinical publi- Germany) delivered a lecture on the use of ultrasound cations, regulatory tests, pilot clinical studies to establish for drug delivery. In cancer therapy, standard chemo- safety and efficacy, and pivotal clinical studies. The therapy delivery poses challenges including resistance, achievement of these milestones ultimately predicates poor tumor uptake, off-target effects, stability, etc. Bar- the review and approval of biomedical innovations for riers to delivery include tight junctions between cells lin- FDA designation (U.S.) and/or CE marking (Europe). ing blood vessels that prevent extravasation into the tissue, renal filtration cutoff at which particles exceeding Brain therapies – Delivery a certain size get taken up by liver and spleen, and more. Beat Werner (University Children’s Hospital Zurich) pre- Tumors are characterized by the enhanced permeability sented on the topic of brain applications of therapeutic and retention effect, whereby leaky vasculature can fa- ultrasound. Applications of MR-guided focused ultra- cilitate uptake of nanoparticles, despite the presence of sound (FUS) neurosurgery include thalamotomy against high interstitial fluid pressure. Ultrasound can mediate neuropathic pain, essential tremor, and Parkinson move- drug delivery by way of mechanisms such as sonopora- ment disorders; ablation of the anterior limb of the in- tion, cavitation, and hyperthermia, which can increase ternal capsule for treatment of obsessive compulsive local vascular permeability, widening of junctions, transi- disorder (OCD); and brain tumor ablation. Functional ent pore induction, and even drug release in response to neurosurgery and tumor ablation pose different chal- pressure and/or temperature changes. lenges and criterion when it comes to focused ultra- sound therapy. The acoustic environment, ablation rate, Thermal biology and thermal dose and treatment envelope pose unique challenges for ef- Holger Gruell (University Hospital of Cologne, fective tumor ablation despite its proven safety and Germany) discussed thermal biology, reviewing its his- therapeutic benefit in patients. Blood brain barrier open- tory and overviewing the biology of thermotoxicity as it ing with FUS and microbubbles is another category of pertains to cells, proteins, and membranes. The effects therapy that is currently being explored in Phase I trials that extend from heating of these entities are dictated by for brain tumors and early stage Alzheimer’s disease. thermal dose, a concept which was developed based on Sheybani Journal of Therapeutic Ultrasound (2018) 6:3 Page 5 of 7 studies revealing a breakpoint in rate of cell survival covered in detail. Histotripsy results in mechanical tissue (specifically a doubling in cell death) with every degree fractionation with sharp lesion margins and is detectable temperature increase above 43 °C. In general these ef- by various modalities, such as histology, ultrasound im- fects can include increased metabolism, increased gener- aging, MR imaging, and shear wave imaging. Histotripsy ation of reactive oxygen species, loss of clonogenicity, has been demonstrated to be efficacious in a variety of ap- heat shock response, nuclear damage to proteins and plications spanning urology, cardiology, gastroenterology, DNA repair mechanisms, and ultimately, cell death. cancer therapy, immunomodulation, and more. Below the threshold temperature, thermotolerance is likely to play a role in greater cell survival. However, the Tumor immunology/immunotherapy concept of thermal dose remains poorly characterized in Elizabeth Repasky (Roswell Park Cancer Institute) pro- vivo and in particular for temperatures above the sup- vided an overview of immunology and the implications of posed breakpoint of 43 °C. Meanwhile, thermotoxicity cancer immunotherapy for ultrasound applications. The can have large variations across cell lines, species and two major branches of adaptive immune response are microenvironments; thus, clinical hyperthermia has yet humoral immunity (involving antibody production and B to be adopted as a mainstream technique despite dem- lymphocyte mediated response) and cell-mediated im- onstrated efficacy. Pre-clinical studies are still urgently munity (involving production of a host of cell types, cyto- needed to characterize this variability and to delineate kines, and T lymphocyte mediated response). These differences between normal and tumor cell response to responses are generally driven by the presence of antigens. heating given the emerging role of immune response to In the setting of a tumor, the presence of tumor antigens high intensity therapeutic ultrasound application. drives recognition of, and response to, tumor by antigen-presenting cells and T cells in the tumor and Competing technologies draining lymph node. Tumors are capable of interfering Afshin Gangi (University Hospital Strasbourg France; with this sequence of cancer immunity through check- Kings College London) provided examples of competing point molecules, wherein tumor cells hijack key check- technologies, overviewing the various imaging tech- points on which immune cells typically rely to avoid niques available for image guidance of focal therapies, over-acting on healthy cells. In doing so, tumor cells can including MRI, PET, and ultrasound. Subsequently, clin- evade the immune system. Checkpoint inhibitor mole- ical case studies were shared to highlight the applica- cules can block the interaction between T cells and tumor tions of non-invasive or minimally invasive modalities cells to effectively lift the veil of tumor immunosuppres- beyond HIFU that are available for pain palliation and sion. Anti-PD1 and anti-CTLA4 therapies have already tumor decompression, as in the examples of cryoabla- found success in the clinic. The coupling of these inter- tion and RF ablation. The conclusion from these high- ventions with focal therapies that can induce immuno- lights was that in the emerging era of personalized genic tumor cell death - e.g. chemotherapy, radiation medicine, each intervention is likely to have its own therapy, thermal therapy, HIFU, cryotherapy – holds place in an interventional radiologist’s arsenal for cancer promise for bolstering antitumor immune response. therapy. A final highlight of the lecture was the potential role of the abscopal effect in adaptive immunity that can stem from these interventions; this compelling prospect Lithotripsy & Shock Wave Lithotripsy (SWL) has been elucidated by multiple clinical observations Robin Cleveland (University of Oxford) discussed the wherein ablative treatment of a primary tumor site has development of extracorporeal SWL. The lecture began led to shrinkage of distant, untreated lesions. with an introduction to the history of SWL, description of what constitutes a shock wave, and key physics under- Histotripsy lying SWL such as stress wave formation and cavitation Oleg Sapozhnikov (Moscow State University; University of bubble dynamics. SWL has revolutionized the treatment Washington) presented a lecture on histotripsy on behalf of kidney stones as a mainstream therapy since its FDA of Vera Khokhlova (University of Washington; Moscow approval in 1984. However, SWL has also been linked State University). In contrast to thermal ablation, histo- with injury, including hematuria, subcapsular hemato- tripsy is a method of mechanical ablation whereby tissue mas, onset hypertension, and anecdotally, diabetes melli- is disintegrated using high intensity, pulsed energy that tus. Despite the advancement of competing technologies leads to cavitation and shock wave formation. There are such as ureteroscopy and percutaneous nephrolithot- two modes of histotripsy: (1) cavitation cloud (short, omy, SWL still remains a major treatment modality. microsecond-scale pulses) and (2) boiling (long, Emerging applications include chronic soft tissue pain millisecond-scale pulses). In this lecture, the physics and palliation and repair, scar tissue removal and osteogen- instrumentation underlying each of these modes was esis by bone tissue disruption. Sheybani Journal of Therapeutic Ultrasound (2018) 6:3 Page 6 of 7 Matching transducer geometry to clinical targets to know about MRI and did not dare to ask.” In this ses- Cyril Lafon (LabTau, INSERM; University of Virginia; sion, students formulated a list of questions pertaining FUS Foundation) delivered a lecture on design of ultra- to the basics of MRI imaging, MRI applications, types of sonic devices for conformal therapies. The nature of MRI imaging, challenges of imaging in specific applica- clinical targets often dictates the requirements for beam tions, etc. to which the faculty provided detailed shape and desired bioeffects. In order to modulate these answers. parameters extracorporeally, it is necessary to consider Larry Crum delivered the Gluhwein Lecture on “Trials the transducer frequency, transducer diameter, exposure and Tribulations of Translation,” wherein he discussed conditions such as power and duration, and tissue com- his experiences with translating ultrasound technologies position effects leading to attenuation. Examples of from bench to bedside. The lecture provided a candid translational efforts that have led to clinical devices for glimpse into the nuances of commercializing biomedical conformal ultrasound treatment include a disposable innovations – e.g. financial investments, patents, intel- non-image guided device for HIFU-induced lectual property, market identification, etc. – and the cyclo-coagulation in the treatment of refractory glau- ways in which translational efforts can succeed and fail. coma (EyeTechCare) and the SonoCloud implantable The lecture closed with practical advice for students ultrasound device for repeated BBB-opening (CarThera). based on the lessons that Dr. Crum learned from his The remainder of the lecture focused on the preclinical experiences. and clinical efforts that led to the development and im- plementation of these devices. Student presentations Over 40 participants, including graduate students, Experimental design post-doctoral fellows, and members of industry, each Gail ter Haar (Institute of Cancer Research, London) gave a three-minute oral presentation highlighting their provided an overview of methods for properly designing ongoing research followed by a two-minute Q&A ses- experiments to answer scientific questions pertaining to sion. Awards were given for the top three presenters, therapeutic ultrasound. The four classic experimental honorable mentions, best overall presentation, and best models are in vitro (cells), ex vivo (excised tissue), in questions. vivo (animals), and in silico (computational model). The Winter School on Therapeutic Ultrasound 2017 Guidance was provided on how to select an appropriate was directed by Gail ter Harr (Sutton), Vera Khokhlova model from among these options, the importance of (Moscow) and Jean-Francois Aubry (Paris), and orga- ultrasound field calibration, and criterion for reporting nized by Thomas Deffieux (Paris), Cyril Lafon (Lyon) exposure conditions. and David Melodelima (Lyon). The next Winter School Jean Francois-Aubry (CNRS; Institut Langevin) closed on Therapeutic Ultrasound will be held in Spring 2019 the winter school lecture series with an overview of FDA in Les Houches, France. and CE approved devices for therapeutic ultrasound. Abbreviations FUS: Focused ultrasound; H&E: Hematoxylin & eosin; HIFU: High intensity Special events focused ultrasound; MRI: Magnetic resonance imaging; NMR: Nuclear magnetic resonance;; OCD: Obsessive compulsive disoreder; SWL: Shock Documentary screening wave lithotripsy Filmmaker Martin Freeth showcased a short film follow- ing a young patient who underwent treatment for essen- Acknowledgements The author of this work is supported by the National Science Foundation tial tremor with MRI-guided FUS. Afterwards a longer Graduate Research Fellowship and UVA Robert R. Wagner Fellowship. A documentary describing The Antikythera Mechanism special thanks is extended to the Winter School 2017 organizers and was aired. This documentary described researchers’ dis- Focused Ultrasound Foundation for generously supporting the costs of travel and registration for this meeting. covery and journey to unlocking the complexities of the first known analogue computer using gamma-ray and Funding high-resolution X-ray tomography. A 5-min trailer for Travel funding for attendance at the Winter School for Therapeutic Ultrasound that led to the generation of this meeting report was provided this documentary, entited “The X-Ray Time Machine” is by the Focused Ultrasound Foundation. Registration funding was provided available here. by the Winter School on Therapeutic Ultrasound organizing committee. Author’s contributions Evening lectures NDS attended the Winter School for Therapeutic Ultrasound and generated Two special evening lectures were offered in order to the manuscript for this meeting report. The author read and approved the provide students with yet another opportunity to engage final manuscript. with the faculty on topics that piqued there curiosities. Author’s information The first in this series was led by Florian Steinmeyer and N.D.S. is currently a Ph.D. Candidate in Biomedical Engineering at the Bruno Quesson and entitled “What you always wanted University of Virginia working under the mentorship of Dr. Richard Price, Sheybani Journal of Therapeutic Ultrasound (2018) 6:3 Page 7 of 7 Professor of Biomedical Engineering and Research Director of the UVA Focused Ultrasound Center. Ethics approval and consent to participate Not applicable Consent for publication The individuals portrayed in Martin Freeth’s videos (to which links are provided) have provided consent to the film-maker previously. All materials, including images and videos, are already published online. Competing interests The author declares that she has no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Received: 8 March 2018 Accepted: 11 May 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Therapeutic Ultrasound Springer Journals

Meeting report: 2017 Winter School on Therapeutic Ultrasound

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Abstract

The Winter School on Therapeutic Ultrasound held its biennial meeting at the Ecole de Physique des Houches in Les Houches, France from March 26-31, 2017. The program brought together a globally and scientifically diverse group of faculty, clinicians, and trainees with interest in elements of therapeutic ultrasound. The meeting agenda was composed of daily lectures on various topics of relevance, supplemented with evening seminars, excursions, and networking opportunities. In anticipation of the next edition of the Winter School expected in 2019, we are nearly reaching the half way point between offerings of this unique and specialized meeting. Thus, this meeting report offers a reflection on the 2017 Winter School with the intention of setting the stage for 2019. Reviewed within this report are the lectures, student presentation series, and evening seminars encompassed within meeting agenda. It is my hope that this resource will be utilized by investigators within the therapeutic ultrasound community considering attending the Winter School in 2019. Keywords: Therapeutic ultrasound, Focused ultrasound, Image guidance, Meeting Introduction and student presentations, all of which will be discussed The Winter School on Therapeutic Ultrasound is a in greater detail herein. unique workshop opportunity offered once every 2 years for students, postdocs, faculty, clinicians, and industrial Lectures partners to explore the rapidly expanding field of thera- Each lecture was delivered by a world authority peutic ultrasound. This year’s workshop brought well-positioned to discuss a topic pertaining to therapeutic together individuals from multiple countries spanning ultrasound within the context of his/her own research. North America, Europe, and the Middle East. Partici- The content of each lecture is summarized below. pants convened at the Ecole de Physique des Houches to engage in advanced multidisciplinary lectures provided Acoustic propagation – Soft tissue by a globally renowned panel of invited speakers. Robin Cleveland (University of Oxford) delivered a lec- A typical day of the workshop consisted of 6-7 lec- ture on ultrasound propagation through soft tissue on tures, intermingled with opportunities to explore Les behalf of Vera Khokhlova (University of Washington; Houches and engage in activities such as skiing, hiking, Moscow State University). The core concepts of acous- walking, and networking with fellow attendees. The tics were overviewed in this lecture, including reflection, unique environment, located amid the breathtaking refraction, and impedance in the context of beam propa- landscape of the French Alps, provided for a reserved gation, attenuation and power, sound speed and imped- and refreshing retreat wherein a diverse group of ance. The content additionally advanced into topics such students and experts could engage about research in a as nonlinearity, shock theory, KZK equation, Pennes relaxed, amicable, and approachable manner. Beyond Bioheat Transfer Equation, and heat deposition. daily lectures, additional learning opportunities included two special evening seminars, a documentary screening, Focusing ultrasound Jean Francois-Aubry (CNRS; Institut Langevin) discussed Correspondence: nds3sa@virginia.edu the concept of wave focusing, techniques for numerical Department of Biomedical Engineering, Health System, University of Virginia, Box 800759, Charlottesville, VA 22908, USA modeling of multi-transducer arrays, implications of © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sheybani Journal of Therapeutic Ultrasound (2018) 6:3 Page 2 of 7 sparse array spatial distribution for therapy, and the chal- Basics of ultrasound imaging lenges of skull attenuation. Strategies for focusing and Thomas Deffieux (Institut Langevin, INSERM, ESPCI) non-invasive target verification were elucidated, such as provided an introduction to the principles of ultrasound CT co-registry for skull characterization, single cavitation imaging and how these concepts underlie the various mo- bubble induction at the focus to verify the target, radiation dalities of ultrasound. Ultrasound is a versatile imaging pressure detection by MRI, and exploitation of natural modality that operates on the basis of sound wave trans- acoustic reflectors (e.g. kidney stones, microcalcifications) mission and reception. The defining principles of ultra- or systemically introduced acoustic amplifiers (e.g. tar- sound imaging were discussed in the context of geted ultrasound contrast agents). Amid the progression impedance, reflection, and transmission/reception of pulse towards non-invasive strategies for delivering therapeutic echoes. The acoustic window and imaging applications for ultrasound to the brain, one of the major challenges for various transducer geometries - including linear array, non-invasive transcranial therapy has been overcoming convex (curved) array, and phased array – were intro- skull attenuation. Currently, the predominating algorithms duced as a segue into subsets of ultrasound imaging, in- for performing transcranial aberration correction are (1) cluding B-mode, Doppler, ultrafast, and 3D imaging. reversal/phase shift correction, which optimizes energy deposition at the focus and (2) amplitude compensation, Basics of Magnetic Resonance Imaging (MRI) which optimizes pressure distribution within the focal Florian Steinmeyer (Technische Hochschule Neurnberg) plane. These techniques hold appeal for transcranial ther- introduced the basic physics underlying nuclear mag- mal and non-thermal therapies, respectively. netic resonance (NMR), including spin, magnetic mo- ments, T1 and T2 relaxation, and induction decay. The Biophysics – Heating & thermometry translation from NMR to MRI was explicated in terms Gail ter Haar (Institute of Cancer Research, London) de- of pulse sequences, slice selection, phase encoding, and livered a lecture on heating by ultrasound. The bio- image reconstruction from complex magnetization. MRI logical consequences of heating tissue are tunable based is a powerful tool for imaging that, while slower than on temperature rise and duration. Induction of ultrasound with respect to scan time, holds particular temperature rises ranging from 3 to 5 °C is generally appeal for high intensity focused ultrasound (HIFU) ap- classified as hyperthermia, while induction of plications due to the capability for near real-time temperature rises between 20 and 60 °C is categorized as temperature mapping. thermal ablation. Monitoring of these temperatures via thermometry can occur in a variety of ways; strategies Ultrasound transducers for thermometry include thermocouples, fiber-optic hy- Remi Berriet (Imasonic) delivered a lecture on medical drophones (temperature and pressure feedback), MR ultrasound transducers, beginning with the main com- thermometry, and ultrasound temperature mapping. ponents of a transducer and the role of piezoelectric ma- This final strategy is an emerging technique whereby terial in converting between electrical and mechanical displacement serves as a proxy for heat induction within energy. Essential characteristics of transducers include the tissue being imaged. Despite compelling advantages frequency, bandwidth/pulse length, and sensitivity. in the way of cost, availability, sensitivity, and precision, These characteristics extend to therapeutic transducers, ultrasound thermometry faces limitations including lack but additional specifications that are of particular im- of feedback regarding absolute temperature, poor sensi- portance include focusing, mean power, and peak pres- tivity in the presence of fat, and motion artifacts. sure. Ultrasound fulfills a variety of clinical needs, but design of the transducer can vary vastly depending on Cavitation – Applications access requirements. An overview was provided of the Larry Crum (University of Washington) introduced the considerations for external, endo-cavitary, and intersti- topic of acoustic cavitation and passive cavitation detec- tial/intraluminal access using therapeutic ultrasound tion, followed by a survey of emerging applications. The probes. Closing remarks were provided on safety criter- lecture delved into a myriad of applications that can ex- ion, safety evaluation, and ongoing developments such tend from the biological consequences of cavitation, in- as improvement of efficiency, safety, and performance, cluding sonothrombolysis, sonoporation and gene reduction of treatment time, and optimization of coup- transfection, blood brain barrier disruption, and kidney ling between imaging and therapy for improved targeting stone comminution. Specific ultrasound techniques that and monitoring of treatment. harness acoustic cavitation to mediate these effects in- clude histotripsy, as in the example of thrombolysis, and Monitoring & guidance – US shock wave lithotripsy, as in the example of kidney stone Mathieu Pernot (INSERM, Institut Langevin, ESPCI) fragmentation. discussed the importance of image guidance and Sheybani Journal of Therapeutic Ultrasound (2018) 6:3 Page 3 of 7 monitoring for safety and efficacy of ultrasound therapy. and aberrant vasculature, both of which are in part dic- Ultrasound enables image guidance for targeting, tated by tumor size. Part of the challenge of heat induc- real-time monitoring, and post-treatment assessment. tion in tumors is the heterogeneity in these Pending exposure conditions, standard B-mode imaging characteristics and the resulting influences on heat de- can be useful for qualitatively detecting changes in tissue position and damage. Pre-clinical studies are underway backscatter following treatment. However, emerging to explore how hyperthermia interfaces with different qualitative methods for detecting changes in tissue com- tumor microenvironments. Meanwhile, hyperthermia position include ultrasonic thermometry and elastogra- has already been demonstrated to be a potent enhancer phy. The former quantifies apparent displacement of of radiotherapy in patients, thereby implicating a role for sound scatterers to measure temperature as a function therapeutic ultrasound in such combination therapies. of strain. Limitations include influence of motion arti- facts, necessity of a priori knowledge of tissue compos- Current applications of HIFU in oncology ition, and the fact that the dependence of the speed of Joo Ha Hwang (University of Washington) provided an sound on temperature is not monotonic for tempera- overview of applications, both approved and emerging, tures exceeding 50 °C. Soft tissues have been demon- of HIFU in oncology. Currently, the oncologic indica- strated to increase in stiffness with heating; thus, tions for HIFU include pain palliation and localized elastography quantifies changes in the stiffness of soft tumor ablation. In the example of pancreatic cancer, tissues as a proxy for temperature change. This modality HIFU is used for pain control through the ablation of is not as robust for heterogeneous/granular tissues, e.g. proximal nerves. A similar approach is used for palli- tumors, as compared with homogenous tissues. ation of painful bone metastases. Alternatively, HIFU has been used to ablate primary tumors as in the cases Monitoring & guidance – MRI of prostate and liver cancers. For these applications, Bruno Quesson (Inserm, Universite de Bordeaux) deliv- acoustic window is and will continue to be a critical fea- ered a lecture on MR monitoring and guidance. Tissue ture of the instrumentation as HIFU becomes more alteration depends on temperature and time of exposure, widely adopted for focal therapy and palliation. which on MRI monitoring, translates to mapping of thermal dose and temperature. Techniques for MR Biophysics – Cavitation temperature mapping include quantitation of correlates Ronald Roy (University of Oxford) delivered a lecture on such as diffusion, longitudinal relaxation, frequency shift bubble acoustics, acoustic cavitation, and bubble dynam- of water resonance, and 1H spectroscopic imaging. ics. Bubbles are potent scatterers of sound. At low inten- MRI-guided ablation can be confounded by factors such sities, single bubbles respond as linear oscillators, as motion of mobile targets, cooling effect conferred by mimicking the behavior of a classic 2nd order system blood flow, and energy absorption by skin and bones. and structure of a forced spring-mass-dashpot oscillator. These factors must be overcome and monitored in order The radius of spherical bubbles influences resonance fre- to ensure delivery of appropriate acoustic intensities at quency and scattering. In ultrasound imaging and ther- the focus. MRI techniques are varied in design and per- apy applications, systemically administered microbubbles mit compensation for motion artifacts, monitoring of serve as contrast agents. At high intensities, single bub- temperature elevation and/or tissue displacement, perfu- bles can respond nonlinearly. In general, the response of sion imaging, and in emerging applications, automatic bubbles to an acoustic pressure field is characterized by feedback control of HIFU energy deposition. two modes of acoustic cavitation: stable and inertial. Stable cavitation refers to repetitive pulsations of the Tumor biology & physiology bubble about its spherical radius and is dominated by Michael Horsman (Aarhus University Hospital) dis- compressibility. Inertial cavitation, however, is mediated cussed biological mechanisms that extend from heat in- by liquid inertia and results in unstable growth that ul- duction in the tumor microenvironment, and timately results to violent collapse. The physical effects physiological considerations for effective application of of these modes of cavitation can include radiation stress, hyperthermia to tumors - with emphasis on the role of cavitation microstreaming, heating, collapse microjets, vascular supply on tissue response. Studies have demon- sonoluminescence, and radiation stress. strated at the cellular level that heat induction influences oxygen consumption, protein inactivation, and cell sur- Calibration & field characterization vival, among other effects. Tumor cell type, cell cycle, Oleg Sapozhnikov (Moscow State University; University of and microenvironmental parameters such as oxygen- Washington) provided insight into techniques for trans- ation, can also play a role in response to heating. Tu- ducer calibration and acoustic field characterization. mors are characterized by hypoxic microenvironments Techniques for observing an ultrasound field include Sheybani Journal of Therapeutic Ultrasound (2018) 6:3 Page 4 of 7 indirect observation of effects such as radiation pressure, The aforementioned applications have been enabled by heating, or cavitation through a propagation medium, op- the Insightec ExAblate MR-guided FUS system and tical shadowgraphy (schlieren), and infrared emission CarThera SonoCloud. from ultrasound-heated layers. Therapeutic ultrasound probes are typically characterized using a combination of Histology for HIFU approaches including acoustic pressure sensing (hydro- Gail ter Haar (Institute of Cancer Research, London) phones), radiation force balance, calorimetry, laser vibro- discussed the basic types of tissue (muscle, nervous, con- metry, and infrared imaging. In order to characterize the nective, and epithelial) and strategies for analyzing them in situ field, however, it is necessary to know information by histology. Histology is an essential technique for char- about the source, medium, and modeling of wave acterizing HIFU lesions at the cellular and tissue levels. propagation. Since HIFU is effectively a strategy for inducing cell death, the mode of histological analysis can be in part The route to commercialization dictated by the nature of cell death (i.e. apoptosis versus Frederic Sottilini (CarThera) discussed the process of de- necrosis). The sequence for tissue processing generally veloping a product and achieving milestones towards involves fixation, dehydration, infiltration and embed- commercialization in the context of CarThera’s experi- ding, sectioning, mounting, staining, and analysis by mi- ence. CarThera is a Paris-based company that pioneers croscopy. The most common histological stain is ultrasound-based medical devices for the treatment of hematoxylin & eosin (H&E) staining, which stains for brain disorders. Thus far, its two breakthrough medical nucleic acids and other tissue components, respectively; devices (Sonocloud© and Sonoprobe) span four indica- this stain can be used to determine tissue integrity and tions, including Glioblastoma Multiforme, Alzheimer’s identify regions of inflammation. A diverse range of im- disease, brain metastasis of melanoma, and brain tu- munohistochemical stains are available for evaluating mors. The pathway to commercialization involves identi- more specific biological consequences of HIFU such as fication of an unmet clinical need. The compelling need changes in perfusion, hypoxia, vessel patency, stress (e.g. for minimally invasive interventions for the aforemen- heat shock proteins), progressive damage, inflammation, tioned neurological pathologies drives CarThera’s path cell proliferation, etc. towards commercialization. However, once a market op- portunity for this need is confirmed, a multi-year Ultrasound mediated drug delivery process ensues wherein subsequent steps include com- Holger Gruell (University Hospital of Cologne, prehensive pre-clinical establishment, pre-clinical publi- Germany) delivered a lecture on the use of ultrasound cations, regulatory tests, pilot clinical studies to establish for drug delivery. In cancer therapy, standard chemo- safety and efficacy, and pivotal clinical studies. The therapy delivery poses challenges including resistance, achievement of these milestones ultimately predicates poor tumor uptake, off-target effects, stability, etc. Bar- the review and approval of biomedical innovations for riers to delivery include tight junctions between cells lin- FDA designation (U.S.) and/or CE marking (Europe). ing blood vessels that prevent extravasation into the tissue, renal filtration cutoff at which particles exceeding Brain therapies – Delivery a certain size get taken up by liver and spleen, and more. Beat Werner (University Children’s Hospital Zurich) pre- Tumors are characterized by the enhanced permeability sented on the topic of brain applications of therapeutic and retention effect, whereby leaky vasculature can fa- ultrasound. Applications of MR-guided focused ultra- cilitate uptake of nanoparticles, despite the presence of sound (FUS) neurosurgery include thalamotomy against high interstitial fluid pressure. Ultrasound can mediate neuropathic pain, essential tremor, and Parkinson move- drug delivery by way of mechanisms such as sonopora- ment disorders; ablation of the anterior limb of the in- tion, cavitation, and hyperthermia, which can increase ternal capsule for treatment of obsessive compulsive local vascular permeability, widening of junctions, transi- disorder (OCD); and brain tumor ablation. Functional ent pore induction, and even drug release in response to neurosurgery and tumor ablation pose different chal- pressure and/or temperature changes. lenges and criterion when it comes to focused ultra- sound therapy. The acoustic environment, ablation rate, Thermal biology and thermal dose and treatment envelope pose unique challenges for ef- Holger Gruell (University Hospital of Cologne, fective tumor ablation despite its proven safety and Germany) discussed thermal biology, reviewing its his- therapeutic benefit in patients. Blood brain barrier open- tory and overviewing the biology of thermotoxicity as it ing with FUS and microbubbles is another category of pertains to cells, proteins, and membranes. The effects therapy that is currently being explored in Phase I trials that extend from heating of these entities are dictated by for brain tumors and early stage Alzheimer’s disease. thermal dose, a concept which was developed based on Sheybani Journal of Therapeutic Ultrasound (2018) 6:3 Page 5 of 7 studies revealing a breakpoint in rate of cell survival covered in detail. Histotripsy results in mechanical tissue (specifically a doubling in cell death) with every degree fractionation with sharp lesion margins and is detectable temperature increase above 43 °C. In general these ef- by various modalities, such as histology, ultrasound im- fects can include increased metabolism, increased gener- aging, MR imaging, and shear wave imaging. Histotripsy ation of reactive oxygen species, loss of clonogenicity, has been demonstrated to be efficacious in a variety of ap- heat shock response, nuclear damage to proteins and plications spanning urology, cardiology, gastroenterology, DNA repair mechanisms, and ultimately, cell death. cancer therapy, immunomodulation, and more. Below the threshold temperature, thermotolerance is likely to play a role in greater cell survival. However, the Tumor immunology/immunotherapy concept of thermal dose remains poorly characterized in Elizabeth Repasky (Roswell Park Cancer Institute) pro- vivo and in particular for temperatures above the sup- vided an overview of immunology and the implications of posed breakpoint of 43 °C. Meanwhile, thermotoxicity cancer immunotherapy for ultrasound applications. The can have large variations across cell lines, species and two major branches of adaptive immune response are microenvironments; thus, clinical hyperthermia has yet humoral immunity (involving antibody production and B to be adopted as a mainstream technique despite dem- lymphocyte mediated response) and cell-mediated im- onstrated efficacy. Pre-clinical studies are still urgently munity (involving production of a host of cell types, cyto- needed to characterize this variability and to delineate kines, and T lymphocyte mediated response). These differences between normal and tumor cell response to responses are generally driven by the presence of antigens. heating given the emerging role of immune response to In the setting of a tumor, the presence of tumor antigens high intensity therapeutic ultrasound application. drives recognition of, and response to, tumor by antigen-presenting cells and T cells in the tumor and Competing technologies draining lymph node. Tumors are capable of interfering Afshin Gangi (University Hospital Strasbourg France; with this sequence of cancer immunity through check- Kings College London) provided examples of competing point molecules, wherein tumor cells hijack key check- technologies, overviewing the various imaging tech- points on which immune cells typically rely to avoid niques available for image guidance of focal therapies, over-acting on healthy cells. In doing so, tumor cells can including MRI, PET, and ultrasound. Subsequently, clin- evade the immune system. Checkpoint inhibitor mole- ical case studies were shared to highlight the applica- cules can block the interaction between T cells and tumor tions of non-invasive or minimally invasive modalities cells to effectively lift the veil of tumor immunosuppres- beyond HIFU that are available for pain palliation and sion. Anti-PD1 and anti-CTLA4 therapies have already tumor decompression, as in the examples of cryoabla- found success in the clinic. The coupling of these inter- tion and RF ablation. The conclusion from these high- ventions with focal therapies that can induce immuno- lights was that in the emerging era of personalized genic tumor cell death - e.g. chemotherapy, radiation medicine, each intervention is likely to have its own therapy, thermal therapy, HIFU, cryotherapy – holds place in an interventional radiologist’s arsenal for cancer promise for bolstering antitumor immune response. therapy. A final highlight of the lecture was the potential role of the abscopal effect in adaptive immunity that can stem from these interventions; this compelling prospect Lithotripsy & Shock Wave Lithotripsy (SWL) has been elucidated by multiple clinical observations Robin Cleveland (University of Oxford) discussed the wherein ablative treatment of a primary tumor site has development of extracorporeal SWL. The lecture began led to shrinkage of distant, untreated lesions. with an introduction to the history of SWL, description of what constitutes a shock wave, and key physics under- Histotripsy lying SWL such as stress wave formation and cavitation Oleg Sapozhnikov (Moscow State University; University of bubble dynamics. SWL has revolutionized the treatment Washington) presented a lecture on histotripsy on behalf of kidney stones as a mainstream therapy since its FDA of Vera Khokhlova (University of Washington; Moscow approval in 1984. However, SWL has also been linked State University). In contrast to thermal ablation, histo- with injury, including hematuria, subcapsular hemato- tripsy is a method of mechanical ablation whereby tissue mas, onset hypertension, and anecdotally, diabetes melli- is disintegrated using high intensity, pulsed energy that tus. Despite the advancement of competing technologies leads to cavitation and shock wave formation. There are such as ureteroscopy and percutaneous nephrolithot- two modes of histotripsy: (1) cavitation cloud (short, omy, SWL still remains a major treatment modality. microsecond-scale pulses) and (2) boiling (long, Emerging applications include chronic soft tissue pain millisecond-scale pulses). In this lecture, the physics and palliation and repair, scar tissue removal and osteogen- instrumentation underlying each of these modes was esis by bone tissue disruption. Sheybani Journal of Therapeutic Ultrasound (2018) 6:3 Page 6 of 7 Matching transducer geometry to clinical targets to know about MRI and did not dare to ask.” In this ses- Cyril Lafon (LabTau, INSERM; University of Virginia; sion, students formulated a list of questions pertaining FUS Foundation) delivered a lecture on design of ultra- to the basics of MRI imaging, MRI applications, types of sonic devices for conformal therapies. The nature of MRI imaging, challenges of imaging in specific applica- clinical targets often dictates the requirements for beam tions, etc. to which the faculty provided detailed shape and desired bioeffects. In order to modulate these answers. parameters extracorporeally, it is necessary to consider Larry Crum delivered the Gluhwein Lecture on “Trials the transducer frequency, transducer diameter, exposure and Tribulations of Translation,” wherein he discussed conditions such as power and duration, and tissue com- his experiences with translating ultrasound technologies position effects leading to attenuation. Examples of from bench to bedside. The lecture provided a candid translational efforts that have led to clinical devices for glimpse into the nuances of commercializing biomedical conformal ultrasound treatment include a disposable innovations – e.g. financial investments, patents, intel- non-image guided device for HIFU-induced lectual property, market identification, etc. – and the cyclo-coagulation in the treatment of refractory glau- ways in which translational efforts can succeed and fail. coma (EyeTechCare) and the SonoCloud implantable The lecture closed with practical advice for students ultrasound device for repeated BBB-opening (CarThera). based on the lessons that Dr. Crum learned from his The remainder of the lecture focused on the preclinical experiences. and clinical efforts that led to the development and im- plementation of these devices. Student presentations Over 40 participants, including graduate students, Experimental design post-doctoral fellows, and members of industry, each Gail ter Haar (Institute of Cancer Research, London) gave a three-minute oral presentation highlighting their provided an overview of methods for properly designing ongoing research followed by a two-minute Q&A ses- experiments to answer scientific questions pertaining to sion. Awards were given for the top three presenters, therapeutic ultrasound. The four classic experimental honorable mentions, best overall presentation, and best models are in vitro (cells), ex vivo (excised tissue), in questions. vivo (animals), and in silico (computational model). The Winter School on Therapeutic Ultrasound 2017 Guidance was provided on how to select an appropriate was directed by Gail ter Harr (Sutton), Vera Khokhlova model from among these options, the importance of (Moscow) and Jean-Francois Aubry (Paris), and orga- ultrasound field calibration, and criterion for reporting nized by Thomas Deffieux (Paris), Cyril Lafon (Lyon) exposure conditions. and David Melodelima (Lyon). The next Winter School Jean Francois-Aubry (CNRS; Institut Langevin) closed on Therapeutic Ultrasound will be held in Spring 2019 the winter school lecture series with an overview of FDA in Les Houches, France. and CE approved devices for therapeutic ultrasound. Abbreviations FUS: Focused ultrasound; H&E: Hematoxylin & eosin; HIFU: High intensity Special events focused ultrasound; MRI: Magnetic resonance imaging; NMR: Nuclear magnetic resonance;; OCD: Obsessive compulsive disoreder; SWL: Shock Documentary screening wave lithotripsy Filmmaker Martin Freeth showcased a short film follow- ing a young patient who underwent treatment for essen- Acknowledgements The author of this work is supported by the National Science Foundation tial tremor with MRI-guided FUS. Afterwards a longer Graduate Research Fellowship and UVA Robert R. Wagner Fellowship. A documentary describing The Antikythera Mechanism special thanks is extended to the Winter School 2017 organizers and was aired. This documentary described researchers’ dis- Focused Ultrasound Foundation for generously supporting the costs of travel and registration for this meeting. covery and journey to unlocking the complexities of the first known analogue computer using gamma-ray and Funding high-resolution X-ray tomography. A 5-min trailer for Travel funding for attendance at the Winter School for Therapeutic Ultrasound that led to the generation of this meeting report was provided this documentary, entited “The X-Ray Time Machine” is by the Focused Ultrasound Foundation. Registration funding was provided available here. by the Winter School on Therapeutic Ultrasound organizing committee. Author’s contributions Evening lectures NDS attended the Winter School for Therapeutic Ultrasound and generated Two special evening lectures were offered in order to the manuscript for this meeting report. The author read and approved the provide students with yet another opportunity to engage final manuscript. with the faculty on topics that piqued there curiosities. Author’s information The first in this series was led by Florian Steinmeyer and N.D.S. is currently a Ph.D. Candidate in Biomedical Engineering at the Bruno Quesson and entitled “What you always wanted University of Virginia working under the mentorship of Dr. Richard Price, Sheybani Journal of Therapeutic Ultrasound (2018) 6:3 Page 7 of 7 Professor of Biomedical Engineering and Research Director of the UVA Focused Ultrasound Center. Ethics approval and consent to participate Not applicable Consent for publication The individuals portrayed in Martin Freeth’s videos (to which links are provided) have provided consent to the film-maker previously. All materials, including images and videos, are already published online. Competing interests The author declares that she has no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Received: 8 March 2018 Accepted: 11 May 2018

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Published: Jun 6, 2018

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