Whoopi Goldberg is a prolific artist, producer, and entrepreneur. She has achieved the EGOT, meaning she is one of just 17 people to have won the Emmy, the Grammy, the Academy Award – or Oscar, and the Tony.
Key Points In a preclinical study, researchers sought to determine the optimal method to use focused ultrasound and microbubbles to open a larger volume of the blood-brain barrier.The research team also attempted to deliver an immune checkpoint inhibitor to the brainstem.Ultimately, the group is working to develop the technology for treating brainstem tumors. Comparison of Sonication Patterns and Microbubble Administration Strategies for Focused Ultrasound–Mediated Large-Volume Drug Delivery The research team at Washington University in St. Louis led by Hong Chen, PhD, sought to determine the optimal method to use focused ultrasound and microbubbles to open a larger volume of the blood-brain barrier (BBB) than what has typically been opened. The reason for increasing the volume of the BBB opening is to develop the technology for treating diffuse intrinsic pontine gliomas (DIPGs). DIPGs are fatal brainstem tumors that occur in children. Increasing the volume of focused ultrasound—based BBB opening for the brainstem could allow new cancer therapies like immune checkpoint inhibitors (ICIs) reach DIPG and other difficult cancers. Opening the BBB near a DIPG tumor is challenging because DIPGs are tough to penetrate, they have a complicated microenvironment, and they spread and migrate quite rapidly. In the preclinical study, which was conducted in wild-type mice (not a DIPG model), the research team tested and compared two sonication patterns and two methods of microbubble administration. After conducting the experiments, the team determined that an interleaved sonication pattern combined with a bolus injection of microbubbles (Definity, Lantheus Medical Imaging, N. Billerica, MA, USA) led to the most efficient and homogenous results. To assess safety during the process, the researchers used passive cavitation imaging and physiological monitoring. They noted that the base of the skull reflected acoustic energy at higher pressures (0.45 MPa), which can cause microhemorrhages near the bottom of the brainstem (as little as 2 mm above the base of the skull). The group then used interleaved sonication and bolus injection of microbubbles to deliver an ICI to 15 mice. They measured the amount that reached the brainstem at three different sonication pressures. A correlation was found between the cavitation dose and the amount of the ICI at each of the pressures (0.15, 0.30, and 0.45 MPa). See IEEE Transactions on Biomedical Engineering >
Key Points For the past 13 years, Dr. Meaghan O’Reilly has been an integral part of Sunnybrook Research Institute’s dynamic Focused Ultrasound Research group.She has gained national attention for her research developing focused ultrasound–based therapies for brain and spinal cord disorders.Her goal is to use the technology to treat conditions that affect the entire central nervous system. As the Canada Research Chair in Biomedical Ultrasound, Meaghan O’Reilly, PhD, has been gaining national attention for her research developing focused ultrasound–based therapies for brain and spinal cord disorders. In fact, her overall goal is to use the technology to treat conditions that affect the entire central nervous system. For the past 13 years, Dr. O’Reilly has been an integral part of Sunnybrook Research Institute’s large and dynamic Focused Ultrasound Research group. We interviewed her to learn more about her groundbreaking research. Focused Ultrasound Work When and how did you get interested in focused ultrasound?I first heard about focused ultrasound when I was a master’s student at the University of Oxford in the (now defunct) Master of Science in Biomedical Engineering program. It was a year-long, course-based program with a mini thesis, and Professor Constantin Coussios, PhD, taught two modules in biomedical acoustics. I really enjoyed the acoustics classes, and at the end of all our rotations and modules and eight months of coursework, we had to pick a project for the mini thesis. Everyone wanted to work with Constantin because they thought this focused ultrasound technology was so cool. He had two projects and about eight students lining up to try and get a spot with him. I thought, “Well, that was interesting, but, you know, not that interesting,” because I didn’t want to compete for those spots, and I had planned to go into biomechanics. I thought I would end up working in a gait lab or designing assistive devices, so my mini thesis was on finite element modeling of flatfoot in children. I defended my mini thesis in September of 2008 and applied for jobs everywhere, including Sunnybrook Research Institute (SRI), because I had previously worked there in the orthopedics laboratory. I knew they had many different research programs, so I looked at all the opportunities. There was a posting for a research assistant or research engineer in focused ultrasound. It didn’t say who it was working with, it just said, “Research assistant needed.” I applied, and the position was working with Professor Kullervo Hynynen, PhD. I got the position and ended up completing my PhD with Kullervo. What are your areas of interest in focused ultrasound?I study the use of focused ultrasound to treat diseases of the central nervous system (brain and spinal cord). More specifically, I am interested in detecting, monitoring, mapping, and controlling cavitation in bubble-based therapies in complex environments. Providing treatment through the skull or through intact vertebral bone creates a complex acoustic environment with a lot of potential reverberations and distortion for the sound waves. We are now primarily working on the spine, and it is incredibly interesting because of the first challenge of sonicating through the bone and the next challenge of addressing reverberation of the sound in the canal. These challenges create issues with transmission, monitoring, and mapping cavitation activity. What mechanisms and clinical indications do you study?We study blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) opening, mostly for drug delivery. I have some other projects that are getting off the ground, including one comparing bioeffects when the barrier doesn’t open and some orthopedic collaborations that are in the works. What is the goal of your work?Our overall goal is to advance BBB and BSCB opening technologies toward widespread clinical adoption. For this to happen, we need robust control, monitoring, and feedback so that the devices can be safely operated with the push of a button. There are still many challenges to solve for appropriately controlling for the correct and desired bioeffect and the level of that bioeffect. We are seeking to reach the same level of development with the spine as in the brain so we can begin treating diseases that are either spinal cord–specific or that impact the entire CNS. What are your funding sources?Our work has been funded by the Canadian Institutes of Health Research, both through the Project Grant program and the Canada Research Chair Program, the Natural Sciences and Engineering Research Council of Canada, and a new funding mechanism in Canada called the New Frontiers in Research Fund, which was created to support world-leading interdisciplinary, international, high-risk/high-reward, transformative, and rapid-response Canadian-led research. We have received funding from private foundations, too, such as the Focused Ultrasound Foundation and the Terry Fox Research Institute. We have also previously received operating support from the National Institutes of Health and infrastructure funding from the Canadian Foundation for Innovation John Evans Leaders Fund. Research Details Who are your team members?I currently have five PhD students, one master’s student, a research associate, a research engineer, and two technical staff members who I share with the other investigators in the SRI Focused Ultrasound Laboratory. Our team was also joined by three undergraduate and four high school students over the summer. How does your summer internship program work?SRI has a paid, eight-week-long Focused Ultrasound High School Summer Research Program started by Kullervo that began about 15 years ago. Our fantastic lab manager, Kristina Mikloska, coordinates the program, which now receives about 300 applications each summer! It is an amazing program. My lab gets four of the 25 to 30 students accepted each summer. (Last year, we only had 12 students because of pandemic restrictions, and the year before we were shut down.) The high volume of applications is a testament to the program’s outreach efforts. We have worked to broadly advertise the program and in recent years have started doing science outreach in some of the more socioeconomically and culturally diverse areas of the city to engage with the students and make them aware of our program early so that they complete the courses that are prerequisite ...
Key Points Chuck’s Parkinson’s disease symptoms – including tremors and rigidity – disrupted his personal and professional life.Although Chuck was excited to take part in a focused ultrasound clinical trial, his wife Maureen, a physician, was hesitant.Now, three months after the procedure, Chuck has resumed his work and hobbies and is preparing for his second focused ultrasound treatment. Chuck Walker and his wife Maureen Whelihan, MD, are avid adventure seekers, and exercise is part of their daily lives. They enjoy hiking, running, boating, riding motorcycles, and simply being outdoors. But while on a routine run in 2013, Chuck noted a problem with his gait – he was landing flatfooted on his right side. The symptoms steadily progressed to more obvious right-sided rigidity and tremors. He saw a neurologist at the urging of his partner Maureen, who is an obstetrician-gynecologist. “The doctor diagnosed me with Parkinson’s disease right away,” Chuck recalled. “That was pretty devastating.” His symptoms impeded many of the hobbies that he and Maureen enjoyed. “When I would ride behind him on my motorcycle, I noticed that his brake light would flicker constantly,” she said. “I assumed it was a faulty bulb until I realized that the hand that was most affected by the tremors also controlled the brake. It was his tremors lightly hitting the brake, and soon it became dangerous for him to ride.” Beyond his hobbies, the Parkinson’s symptoms also began to hinder his professional life. “I own my own indoor air quality business and was often on the speaker circuit, but I became uncomfortable with the travel and public speaking,” Chuck said. “The added nerves made my tremors worse, and I didn’t want the shaking to detract from my message on stage.” Following his diagnosis, Chuck’s doctor prescribed medications to control the disease. After much trial and error with various drugs, he found a regimen that worked but didn’t like how the medications made him feel. He was also hesitant about surgical interventions. “I didn’t want deep brain stimulation,” recalled Chuck. “I didn’t want the wires, and the surgery, and the battery pack.” In 2018, Chuck attended a Parkinson’s disease symposium in South Florida and learned about focused ultrasound. He immediately told Maureen about the new treatment. “I was actually quite familiar with focused ultrasound because it has been used to treat uterine fibroids for some time, but I wasn’t aware that it was being used in the brain,” she said. That’s when Maureen reached out to a colleague of more than 15 years, who is also the Foundation’s Director of Clinical Relationships, Suzanne LeBlang, MD. “Susie met us for dinner and told us about the clinical trials for Parkinson’s,” Chuck recalled. “Unfortunately, when I brought it up to my neurologist, he wasn’t initially receptive to the idea because he was an expert in deep brain stimulation.” Maureen was also wholeheartedly against the idea of a phase II safety trial. “As a medical professional, I know enough about the anatomy of the brain that I was uncomfortable with the idea of my loved one taking part in a neurological clinical trial,” she said. “I didn’t doubt the technology, because I knew the level of precision that focused ultrasound is capable of – but I didn’t want to have it tested on Chuck. I honestly thought his disease had not progressed enough to try experimental procedures. I really put the doctors though the ringer asking questions and making sure that Chuck knew the pros and cons.” However, Chuck was not taking no for an answer. “As soon as I learned about the trial, I knew I would participate if I was a good candidate,” he said. “I was going to have this procedure. And once we decided to go for it, Maureen and I approached the physician as a patient-doctor team.” Ultimately, the neurologist referred Chuck to a neurosurgeon who was treating patients as part of a Parkinson’s disease clinical trial using focused ultrasound to target a system of nerve fibers in the middle of the brain called the pallidothalamic tract. He scheduled treatment for July 2022. On the morning of treatment, Chuck remembers that the most daunting part was when doctors placed the stereotactic frame on his head to ensure it remained still during treatment. “I was ready; I wasn’t nervous,” he recalled. “In all, they did six sonications on the side of my brain that affects the right side of my body. The first three sonications were low power to make sure they were targeting the right place, and then they started treating with higher power. By the fourth sonication, my tremor was gone, but they really wanted to relieve my rigidity. After six sonications, the doctors were confident they had achieved their goal.” He returned home later that day, and Maureen remained vigilant for any side effects. “Those first few days, I was watching very closely for any complications,” she said. “The only thing I noticed was that he began to say aloud anything he was reading or writing. I thought that was odd, but it was all coherent; nothing was jumbled. Ultimately, that symptom was transient and resolved quickly.” Thankfully, Maureen also noticed positive effects from the focused ultrasound. “After a few days, he was cleared for light exercise, and we went for a walk. I noticed immediately that his right arm was swinging like normal without any effort. After a week, his shoulders relaxed, and he was standing up straighter.” It has now been nearly three months since his treatment. Chuck has started running again, gotten back in the gym, and is comfortable making presentations at work. He is also looking forward to another treatment. The clinical trial that Chuck took part in is a bilateral trial, meaning patients have the option to have the other side of their brain treated later. He is planning to schedule the second focused ultrasound procedure for later this year. “Focused ultrasound has really changed my life,” he said. “Maureen and I are thrilled that ...
Key Points Twin-twin transfusion syndrome (TTTS) is a rare condition where placental blood vessels are abnormally distributed, leading to an imbalance in the blood exchange between twins.Current interventions are high-risk, invasive, and can lead to complications, including miscarriage and very preterm delivery.This interim report, by Professor Christoph Lees, MD, FRCOG, describes an ongoing clinical trial in the UK that is investigating focused ultrasound as a noninvasive solution for this condition. Figure 1: The team (left to right) that undertook the first TTTS treatment in November 2021 are Nma Ofili (lead midwife, Imperial College Healthcare NHS Trust), Richard Symonds-Tayler (Institute for Cancer Research), Professor Christoph Lees & Dr. Caroline Shaw (Imperial College London), Dr. Ian Rivens (Institute for Cancer Research) and Dr. Sana Usman (Imperial College Healthcare NHS Trust) Twin-twin transfusion syndrome (TTTS) is a rare, serious, prenatal condition that can affect identical twins and multiples. In this syndrome, blood vessels are distributed abnormally within the placenta, leading to an imbalance in the blood exchange between twins. One twin, called the donor twin, gives away more blood than it receives and can suffer organ failure and even death. The other twin, the recipient twin, receives too much blood and is susceptible to overworking of the heart, heart failure, and death. The diagnosis of TTTS is usually made upon routine prenatal ultrasound scans. Once identified, more advanced ultrasound techniques can be used to grade the severity of TTTS. Depending on the severity of the disease, physicians will decide the proper treatment path, which might include early delivery of the twins, if they are of appropriate gestational age, or surgical intervention for the most severe cases if birth is not an option. It is estimated that approximately 15% of cases require invasive intervention. Current interventions include amnioreduction and laser fetal surgery. Both procedures are high-risk, invasive, and can lead to complications including miscarriage, premature rupture of the membranes, and very preterm delivery. Ultrasound-guided high intensity focused ultrasound (HIFU) has been proposed as a noninvasive method of treatment for TTTS, potentially providing a safer therapeutic option. HIFU for TTTS The early research for HIFU and TTTS was pioneered by Prof. Gail ter Haar from the Institute of Cancer Research, Prof. Dino Giussani from the University of Cambridge, and Prof. Christoph Lees from Imperial College London. Preclinical Research By 2017, Caroline Shaw, PhD, of the Physiology Department at the University of Cambridge had established that it was possible to noninvasively occlude placental vessels using HIFU in a preclinical model. This work was performed under the supervision of Prof. Giussani. Prof. ter Haar and colleagues also performed preclinical laboratory studies, where they established feasibility, safety, and proof of principle of this technique. Researchers overcame a technical challenge by using a special Doppler setting with state-of-the-art Canon ultrasound equipment. This produced high sensitivity, low flow vascular imaging; for the first time, it was possible to see with precision the tiny vessels that crossed between the two placental circulations. The next step was establishing the clinical need, which was accomplished by conducting surveys and holding focus groups with individuals from two leading patient support groups, Twins trust and The Multiple Births Foundation. First-in-Human Clinical Trial Figure 2: Ultrasound (US) evidence of the technical efficacy of the US-guided HIFU procedure. (A) Before US-guided HIFU, there was bidirectional blood flow within the placental vessel. (B) After US-guided HIFU, no flow was detected. In 2017, having established the feasibility, unmet clinical need, and safety of the technique in preclinical studies, the research group led by Prof. Lees was awarded just under £2M in funding from the Medical Research Council for a phase 1 clinical trial. The Focused Ultrasound Foundation is also funding a portion of this study. The funding enabled the team to build and test the equipment and recruit women with early TTTS throughout the UK to the study. Unfortunately, due to the COVID-19 pandemic, the start of the study was delayed until October 2021. Since that time, the group has enrolled and treated five women with early onset TTTS (Figure 1). In all cases, there has been successful and safe ablation of the targeted placental vessels. The TTTS was severe at the time of treatment, so it is too early to speculate on clinical efficacy. However, some women have reached close to term with healthy twins; in others, the underlying disease has led to very preterm delivery. This trial is not assessing efficacy, but the researchers have seen signs of clinical efficacy in some of the women treated. Technical efficacy has been demonstrated by Doppler imaging of the ablated portion of the blood vessel targeted (Figure 2). The goal is to complete study enrollment by the end of 2022, which would mean recruiting another four to eight participants within that timeframe. Significance This clinical trial is ground-breaking, because it could lead to the first noninvasive treatment option for TTTS. HIFU could substantially decrease the treatment risk for this condition, as no entry into the intrauterine space is needed. The Focused Ultrasound Foundation would like to thank Prof. Lees and Dr. Shaw for providing this interim report on the clinical trial. Prof. Lees wishes to thank Dr. Ian Rivens and Dr. Richard Symonds-Tayler for being available at short notice for treatments and Prof. ter Haar for her continued contributions to the field of focused ultrasound.
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