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Focused Ultrasound Treatment Comparable to Radiation Therapy for Patients with Painful Bone Metastases

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Key Points Prof. Alessandro Napoli and his team at Sapienza University of Rome conducted a comparative phase II clinical trial that enrolled 198 participants with painful bone metastases. When compared with external beam radiation therapy (EBRT), focused ultrasound produced a faster and better pain control response that lasted longer than EBRT. An accompanying editorial praised focused ultrasound as a promising new advance in interventional oncology and suggested that future comparative trials follow this study model as a practical approach to adopting innovative new treatments. Focused Ultrasound and External Beam Radiation Therapy for Painful Bone Metastases: A Phase II Clinical Trial Prof. Alessandro Napoli and his team at Sapienza University of Rome conducted a comparative, nonrandomized, phase II clinical trial that enrolled 198 participants with painful bone metastases. The study compared the safety and effectiveness of treating the bone metastases with focused ultrasound or EBRT. Beyond numeric pain rating scales at 1- and 12-months following treatment, the open-label protocol also included assessment of quality-of-life measures and analysis of adverse events. Focused ultrasound had statistically significant higher overall response rates than EBRT at both 1- and 12-months post procedure and statistically significant lower overall adverse event rates. The authors concluded that focused ultrasound was comparable to EBRT for improving pain palliation and quality of life. In an accompanying editorial, “Radiation Therapy Castle Under Siege: Will It Hold or Fold?” Alexis Kelekis, MD, PhD, EBIR, FSIR, FCIRSE, said that focused ultrasound was among several new advances in interventional oncology for providing local energy deposition. He noted some of the current disadvantages of focused ultrasound (e.g., it is a long and tiring single-session treatment that requires anesthesia) but said that the technology’s absence of ionizing radiation and better overall results than EBRT for treating bone metastases make it “a promising alternative for the future.” After describing that the partial response rate in the study favored EBRT, Dr. Kelekis added, “Perhaps the future lies in combined therapies and hybrid techniques trying to bridge and exploit the advantages of each therapeutic approach.” He went on the praise the study design and suggested that the model should be adopted by more researchers to increase the use of innovative and novel therapies that provide real hope to patients. Suzanne LeBlang, MD, the Foundation’s Director of Clinical Relationships, has known Dr. Napoli for nearly 16 years. She says, “Dr. Napoli was one of the early pioneers in the field, and this important paper adds to the mounting body of knowledge about the benefits of focused ultrasound. Moving forward, we are hopeful that others will perform seminal research projects and publish findings for other indications because focused ultrasound is a platform technology that has widespread applicability to other diseases.” See Radiology > See Dr. Kelekis’ Editorial > See Media Coverage of the Study: Medpage Today
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Research Awards Update: Nine Preclinical Projects Initiated in the Fourth Quarter of 2022

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Key Points The Foundation’s Research Awards Program initiated nine preclinical studies from October through December 2022, the fourth quarter of last year. The funded projects address brain, bone, low back pain, and breast cancer applications of focused ultrasound. The Foundation’s Research Awards Program initiated nine new preclinical studies from October through December 2022, the fourth quarter of last year. The funded projects address brain, bone, low back pain, and breast cancer applications of focused ultrasound. “All of the preclinical brain projects are linked to an initiative that came out of the May 2021 glioblastoma workshop,” said Lauren Powlovich, MD, the Foundation’s Associate Chief Medical Officer. “The aim of this group of projects is to identify a method to better quantify the amount of drug delivered to brain tissue after blood-brain barrier opening (BBBO). We are meeting quarterly to discuss progress and new ideas.” Each newly initiated project is listed below. Brain Preclinical Probing the Abilities of Contrast-Enhanced MRI to Track Microbubble-Enhanced Focused Ultrasound Nano-Medicine Delivery in the Brain and Brain Tumors led by Costas Arvanitis, PhD, at the Georgia Institute of Technology For this project, researchers will determine how to confirm therapeutic delivery of nanoparticles to the brain during microbubble-enhanced focused ultrasound (MB-FUS) procedures. The goal is to improve the delivery of therapeutic nanoparticles to brain tumors by studying optimal nanoparticle properties and methods to confirm nanoparticle delivery in the brain and brain tumors. Mapping Drug Concentrations After Blood-Brain Barrier Disruption Using MALDI Mass Spectrometry Imaging led by Nathan McDannold, PhD, at Brigham and Women’s Hospital For this project, researchers will explore the use of matrix-assisted laser desorption/ionization (MALDI) mass spectrometry to quantify the amount of therapeutic delivered to brain tissue after BBBO, then creating specific calibration curves to compare with the MRI images. The goal is to identify a method to better quantify the amount of drug delivered to the brain tissue following BBBO. PET-Labeling and Testing of Paclitaxel Nanoformulations with Microbubbles and Focused Ultrasound led by Graeme Woodworth, MD, at the University of Maryland School of Medicine For this project, researchers will determine whether PET-labeling of nanoparticle therapeutics could enable quantitative visualization of localized nanoparticle delivery during microbubble-enhanced blood-brain barrier opening with clinical focused ultrasound systems in advanced preclinical models of glioblastoma. Mapping of Antibody and Liposome Permeability into the Brain Following Focused Ultrasound Treatment Through T1/T2w Dynamic Contrast-Enhanced (DCE) Magnetic Resonance Imaging led by Antonios Pouliopoulos, PhD, at King’s College Hospital in London For this project, the research team will confirm focused ultrasound–mediated delivery of antibody- and liposome-based therapies by delivering two MR-labelled model drugs across the blood-brain barrier (BBB) and then conducting DCE MRI scans to determine the extent of drug delivery within the tissue. Evaluation of MRI Visualization of Focused Ultrasound–Induced Blood-Brain Barrier (BBB) Opening in White Matter led by Meghan O’Reilly, PhD, at Sunnybrook Health Sciences Centre For this project, researchers will determine how to improve drug delivery to white matter in the brain. Contrast-enhanced MRI is used to assess changes in BBB permeability following focused ultrasound treatment but the contrast enhancement in white matter is lower than in grey matter, so research is needed to be able to use MRI visualization for both applications. MRI Compatible Optical-Driven Focus Ultrasound for Neuromodulation led by Chen Yang, PhD, at Boston University Ultrasound neural modulation is an emerging noninvasive neuromodulation tool. The goal of this project is to develop a compact, MRI-compatible, optically driven focused ultrasound source for ultrasound neural modulation with a broader accessibility than standard focused ultrasound systems. Its application in noninvasive brain modulation and its efficacy in treating epilepsy in a mouse model will be demonstrated. Body Ultrasound-Triggered Gelation to Treat Discogenic Lower Back Pain led by Constantin Coussios, PhD, at the University of Oxford This one-year collaborative study will combine the materials engineering expertise at Imperial College with the biomedical ultrasound expertise at the University of Oxford to optimize material formulations and focused ultrasound exposure parameters with the objective of translating these techniques for percutaneous nucleus pulposus replacement. Doing so would offer a new minimally invasive day case procedure to treat discogenic lower back pain and restore spinal function. Patterning of Mesenchymal Stem Cell Differentiation for Bone Regeneration Using Focused Ultrasound–Mediated Hydrogel Stiffening led by Mario Fabiilli, PhD, at the University of Michigan For this project, researchers will use focused ultrasound to alter the stiffness of a custom acoustic responsive scaffold (ARS) and stimulate bone regeneration. The ARS contains mesenchymal stem cells encapsulated within hydrogels The hydrogel acts as a surrogate for the native extracellular matrix. The studies seek to demonstrate a proof-of-concept for implanting ARS at the site of bone loss. Preclinical High-Intensity Focused Ultrasound (HIFU) Treatment of Breast Adenocarcinoma Using a Noninvasive Toroidal Transducer led by David Melodelima, PhD, at Inserm LabTAU For this project, researchers will determine whether HIFU ablation of breast adenocarcinoma is feasible and effective with a toroidal transducer. The group will use a clinical device that has previously been effective for liver metastases and pancreatic tumors. Learn How to Apply for a Research Award >
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Focused Ultrasound for Pediatric Brain Tumors: Clinical Trial Begins in Toronto

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Key Points Researchers at Sunnybrook Health Sciences Centre and The Hospital for Sick Children are collaborating on a clinical trial using focused ultrasound in patients with diffuse intrinsic pontine glioma (DIPG). DIPGs are highly aggressive and devastating brain tumors that affect young children. In this trial, physicians are exploring focused ultrasound-induced blood-brain barrier opening to enhance delivery of chemotherapy to the tumor. Researchers at Sunnybrook Health Sciences Centre and The Hospital for Sick Children (SickKids) have begun a collaborative clinical trial using focused ultrasound to open the blood-brain barrier (BBB) and deliver chemotherapy in patients with diffuse intrinsic pontine glioma (DIPG). DIPGs are highly aggressive and devastating brain tumors that affect young children, typically aged 5–9. They affect a region of the brainstem that regulates the body’s involuntary activities such as breathing, heart rate, and swallowing. Only 10 percent of children survive past the two-year mark after diagnosis because current therapies are highly ineffective. One reason that brain tumors – including DIPG – are challenging to treat is the BBB. This protective layer of tightly joined cells that lines the blood vessels in the brain prevents harmful substances, such as toxins and infectious agents, from diffusing into the surrounding brain tissue. However, it can also prevent therapeutic agents – like chemotherapy – from getting into the brain. Focused ultrasound has been shown to temporarily disrupt the BBB in a noninvasive, safe, and targeted manner. The ultrasound waves interact with microbubbles in the vessels, causing them to vibrate rapidly and create openings that can enable therapies to pass through. In this trial, researchers are investigating the safety and feasibility of using Insightec’s Exablate Neuro device to open the BBB in 10 participants between the ages of 5 and 18. Participants will undergo focused ultrasound therapy in conjunction with chemotherapy during three treatment cycles, about four to six weeks apart. The first patient underwent the initial procedure earlier this month. The trial is being led by Nir Lipsman, MD, PhD, neurosurgeon and director of Sunnybrook’s Harquail Centre for Neuromodulation, and James Rutka, MD, PhD, director of the Arthur and Sonia Labatt Brain Tumour Research Centre at SickKids.  “DIPG is a devastating pediatric brain tumor which is inoperable due to its location in the brainstem,” says Dr. Lipsman. “Focused ultrasound is an innovative and noninvasive approach to more effectively delivering chemotherapy directly to the tumor. Our hope is that this continued research will bring us closer to enhancing treatments to help change the course of the disease.” Sunnybrook Health Sciences Centre is a Focused Ultrasound Foundation Center of Excellence, and the Foundation is funding a portion of this clinical trial. For PatientsIf you are interested in learning more about this clinical trial, please contact James Rutka, MD, (416-813-6425, james.rutka@sickkids.ca) or Maheleth Llinas (416-480-6100 ext 2476, maheleth.llinas@sunnybrook.ca). Read Sunnybrook’s Announcement >See Coverage by CTV > Additional DIPG Trials in the USFocused ultrasound is being investigated to address DIPG at other sites in the US. At Children’s National Hospital (CNH) in Washington, DC, a team of researchers is conducting two clinical trials. One approach is similar to the Sunnybrook trial, where focused ultrasound will be used to open the BBB in an effort to deliver chemotherapy to the tumor. The other trial at CNH is testing sonodynamic therapy as a way to destroy the tumor. Both clinical trials are currently recruiting patients. CNH became the Foundation’s first pediatric Center of Excellence in 2020. Another DIPG clinical trial investigating focused ultrasound-induced BBB opening to deliver chemotherapy began in July 2021 at Columbia University.
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Meeting Report: American Epilepsy Society (AES) 2022

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Key Points The 2022 Annual Meeting of the AES was held December 2–6 in Nashville, Tennessee. Harvard neurologist Ellen Bubrick, MD, led a special session on “Focused Ultrasound: A Rapidly Growing, New Approach to Epilepsy Treatment.” The workshop described how various mechanisms of action of focused ultrasound can be used in the treatment of many types of epilepsy. The 2022 Annual Meeting of the AES was held December 2–6 in Nashville, Tennessee. As one of the oldest neurological professional organizations in the United States, AES holds the largest worldwide meeting and exhibition for scientific and clinical research on epilepsy and clinical neurophysiology. On Sunday, December 4, Ellen Bubrick, MD, assistant professor of neurology at Harvard Medical School and associate neurologist in the Department of Neurology at Brigham and Women’s Hospital, led a special session on focused ultrasound at the meeting. The session was an Investigators Workshop titled “Focused Ultrasound: A Rapidly Growing, New Approach to Epilepsy Treatment.” Along with Dr. Bubrick, the expert panel included Raag Airan, MD, PhD (Stanford University), Charles Caskey, PhD (Vanderbilt University), and Vibhor Krishna, MBBS, MS (the University of North Carolina). The workshop described how focused ultrasound can be used for ablative (high intensity) or neuro-modulatory (low intensity) effects in the treatment of many types of epilepsy. It also covered current clinical trials for ablation and neuromodulation in epilepsy and promising preclinical studies that are using focused ultrasound to open the blood-brain barrier (BBB) for targeted drug delivery. More than 7,600 physicians, scientists, advanced practice providers, nurses, psychiatrists, psychologists, engineers, pharmacists, advocates, and other professionals from 70 countries attend the conference to share data and learn about the diagnosis, study, prevention, treatment, and cure of epilepsy. The meeting also offered a virtual attendance option, ES 2022 Digital Select, to provide recordings of approximately 120 hours of selected programming and access to ePosters from December 13, 2022, through March 13, 2023 (90 days). See the Meeting Website >
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Meeting Report: 183rd Meeting of Acoustical Society of America (ASA) 2022

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Key Points The 183rd meeting of the Acoustical Society of America took place in Nashville, Tennessee, from December 5–9, 2022. All abstracts are searchable on the meeting planning tool or in the PDF of the open access program. The Foundation thanks Kevin J. Haworth, PhD, Schott Schoen, Jr., PhD, Adam Maxwell, PhD, and Eli Vlaisavljevich, PhD, for assistance in writing this meeting report. The 183rd meeting of the Acoustical Society of America (ASA) took place in Nashville, Tennessee, from December 5–9, 2022. Dozens of abstracts were presented in the field of biomedical acoustics (BA) during the meeting, and joint sessions were held with the physical acoustics (PA), computational acoustics (CA), and signal processing acoustics (PA) technical committees. A broad range of topics were covered, and the material extended from fundamental science investigation to translational bench studies, preclinical studies, and in-human investigations in both imaging and therapeutic ultrasound. The sessions relevant to focused ultrasound are listed below. All abstracts are available in a searchable PDF of the open access program or by using the searchable online meeting planning tool. During the open BA Technical Committee meeting on Wednesday evening, several senior researchers, including Larry Crum, Christy Holland, and Mark Schafer, noted that the content of the meeting was excellent in its scope and depth. The range of invited speakers included great talks from both well-established members of the field and early-career speakers (such as Harriet Lea-Banks of Sunnybrook Research Institute and Dongwoon Hyun from Stanford). The early-career speakers introduced some fascinating new topic areas in ultrasound and provided a refreshing influx of new ideas and concepts. It was a reminder of how bright the future is for this research community and an inspiration for further research. The following presentations were particularly notable: 2aBAb6. “Volatile nanodroplets for neurological applications” (Lea-Banks, Sunnybrook Research Institute) discussed delivery of pentobarbital to specific regions of the brain without disruption of the blood-brain barrier and having specific anesthetic effects to those limited regions. 2pBAb3. “Fibrin-targeted phase shift microbubbles outperform fibrin-targeted microbubbles for the treatment of microvascular obstruction” (Pacella, University of Pittsburgh) discussed results from a series of investigations into the use of nanodroplets plus ultrasound to increase perfusion after acute myocardial infarction. Bench, small animal, and large animal model studies were used with an excellent interplay in how each informed the observations of the others. 3aBA1. “Acoustic droplet vaporization for nonthermal ablation of brain tumors” (Porter, University of Texas at Austin) discussed a series of studies performing mechanical ablation in the rat brain and the improved localization and more thorough treatment when nanodroplets were used as contrast nucleation agents. A special session titled “Detection and quantification of bubble activity in therapeutic ultrasound” was held on Thursday. This session opened with Brian Fowlkes from the University of Michigan providing a summary of the outcomes of the Fall 2021 joint AIUM/FUSF workshop on this topic, as well as current efforts through IEC and other bodies to develop standards. This was followed by presentations in specific areas of cavitation detection and characterization by optical imaging, Doppler, MRI, and passive mapping. A brief panel discussion then outlined considerations for standardizing measurements. Panelists generally agreed that measurements should be guided by application. When possible, it may be valuable to use relative measurements rather than absolute measurement values for the sake of simplicity. Panelists indicated that the technologies to perform at least relative measurements have been well-developed, but the processing and quantities derived from instruments that are specific to each application need further consensus. An afternoon session further highlighted new research areas, including optical and acoustic characterization of histotripsy, tissue permeabilization, biofilm removal, drug delivery, and lithotripsy. New techniques for thermal characterization and computational modeling of microbubble clusters were also presented. During Friday’s 5aBA session, there were several presentations that were relevant to the focused ultrasound community, including abstracts that directly considered focused ultrasound transducers and considerations for characterizing transducer with holography. 5aBA2. “In vivo thermal ablation control using three-dimensional echo decorrelation imaging in swine liver” (Ghahramani, University of Cincinnati) examined the correlation between 3D acoustic correlation images and ablated regions in porcine liver toward controlled ablative treatment. 5aBA3. “The impact of the central opening on nonlinear effects in ultrasound fields generated by Sonalleve V1 and V2 MR-HIFU systems” (V. Khokhlova, University of Washington and Moscow State University) compared the focal patterns and capabilities of the Sonalleve MR-HIFU V1 and V2 systems and described the HIFU-Beam simulation software, which allows time domain nonlinear simulation of annular arrays and layered media. 5aBA4. “Palpating particles using the acoustic radiation force: A new approach to magnetic particle imaging” (Zarcone, Vanderbilt University) proposed using acoustic radiation force to induce motion for magnetic particle imaging. 5aBA5. “Characterizing the steering performance of a diagnostic-therapeutic ultrasound array using measured and synthesized holograms” (Williams, University of Washington and Moscow State University) described the use of holography to characterize the surface of a linear ultrasound array with interleaving measurements to conserve time. 5aBA6. “The use of acoustic holography for simultaneous characterization of various focus steering configurations in ultrasound fields generated by multi-element phased arrays” (V. Khokhlova, University of Washington) performed harmonic and time domain holograms for annular therapeutic focused ultrasound transducers. 5aBA7. “A pipeline to enable large-scale generation of diverse 2D cardiac synthetic ultrasound recordings corresponding to healthy and heart failure virtual patients” (Burman, Katholieke Universiteit Leuven) described the use of augmentation tools for the generation of realistic myocardial velocity profiles toward the generation of large ultrasound training sets for machine learning. 5aBA8. “Contrast-enhanced ultrasound to detect active bleeding” (Schoen, Jr., Harvard Medical School and Massachusetts General Hospital) described methods and in vitro models used to establish the feasibility of microbubbles to assist with the detection of hemorrhage. 5aBA9. “Effect of acoustic output on fetal ultrasound color Doppler performance” (Huber, Duke University) described the setting of as low as reasonably achievable (ALRA) for Doppler ultrasound in neonatal imaging. 5aBA10. “Exploring the benefits of spatial and temporal block-wise filtering architectures” (Weeks, Vanderbilt University) which evaluated the use of spatial and temporal block-wise filtering ...
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Meeting Report: Radiological Society of North America (RSNA) 2022 Meeting Report: Society of Neuro-Oncology (SNO) Annual Meeting and Education Day Meeting Report: Congress of Neurological Surgeons (CNS) 2022 Focused Ultrasound for Pancreatic Cancer: Trial Results Prove Safety, Initial Efficacy Visiting Scholars Work to Accelerate the Field of Focused Ultrasound