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Meeting Report: European Society for Hyperthermic Oncology (ESHO) 2022

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The 34th Annual Meeting of the European Society for Hyperthermic Oncology (ESHO) was held September 14–17, 2022, in Gothenburg, Sweden. Topics discussed included: Measuring temperature during exposure to high-intensity focused ultrasound (HIFU)Developing a HIFU transducer-based system for hyperthermiaCombining hyperthermia and radiotherapy on a preclinical glioblastoma modelDelivering liposomal cisplatin using MR-HIFU hyperthermiaOptimizing combined thermal ablation and high dose radiotherapy for dose reduction and tumor controlUsing Fractionated MR-HIFU hyperthermia in the pancreas of a large animal modelUsing an in vitro system with spheroids for focused ultrasound hyperthermia (and radiotherapy) studiesStudying the impact of sequence-dependent drift characteristics on PRFS thermometryUsing hyperthermia-activated intravenous liposomal-vitamin C plus microbubbles for sonoporation in bulky tumors Nine abstracts and posters that may be of interest to the focused ultrasound community are listed below. L12Intercomparison of temperature measurements during ultrasound exposure by R. Baêsso, A. Ivory, G. Dündar, D. Bingöl, N. Hossain, S. Pozzi, B. Karaböce, B. Caccia, V. Wilkens, and P. Miloro from National Physical Laboratory, Teddington, United Kingdom; İstanbul University, Physics Department, Istanbul, Turkey; Physikalisch-Technische Bundesanstalt, Braunschweig, Germany; Istituto Superiore di Sanità, Rome, Italy; and TUBITAK Ulusal Metroloji Enstitüsü (UME), Gebze, Turkey. Ultrasound-based therapies continue to develop and show promise as noninvasive tools for cancer treatments. High-intensity focused ultrasound (HIFU) can be used for both thermal ablation and hyperthermia. However, measuring the temperature during HIFU exposure can be quite challenging if the final aim is to measure it accurately. L15Development and implementation of a HIFU transducer–based system for a closed-loop controlled focused hyperthermia treatment by A. Ivory, R. Baêsso, F. Saba, A. Spinelli, P. Miloro, and G. Durando from National Physical Laboratory, Teddington, United Kingdom; INRIM, Torino, Italy; and OSR, Milan, Italy. The ability to maintain a specific temperature in a target region is key to any hyperthermia delivery system, to achieve the desired effects, ensure necrosis is not induced (due to increased temperatures consistent with thermal ablation) or healthy tissue treated (requiring sufficient treatment localization to avoid sensitizing healthy tissue). L16Combination of ultrasounds, hyperthermia, and radiotherapy on a preclinical glioblastoma model by G. Durando, F. Vurro, F. Saba, P. Miloro, A. Ivory, R. Baêsso, and A. Spinelli from the Italian Metrological Institute, Turin, Italy; San Raffaele Scientific Institute, Experimental Imaging Centre, Milan, Italy; and the National Physical Laboratory, Teddington, United Kingdom. Glioblastoma (GBM) is one of the most malignant brain tumours, with a short life expectancy and an elevated mortality because of the lack of effective therapies and, thus, innovative treatments need to be developed. In this work a combined ultrasounds (US) hyperthermia (HT) with radiotherapy (RT) using a preclinical GMB model has been investigated. L54Liposomal drug delivery of cisplatin using MR-HIFU hyperthermia in a large animal model by L. Sebeke, J. D. Castillo Gomez, E. Heijman, P. Rademann, A. Simon, S. Ekdawi, S. Vlachakis, D. Toker, B. Mink, C. Schubert-Quecke, S. Y. Yeo, P. Schmidt, M. Hossann, L. Lindner, and H. Grüll from the University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Diagnostic and Interventional Radiology, Cologne, Germany; University of Cologne, Faculty of Mathematics and Natural Sciences, Department of Chemistry, Cologne, Germany; Philips Research Eindhoven, Eindhoven, Netherlands; University of Cologne, Faculty of Medicine and University Hospital Cologne, Experimental Medicine, Cologne, Germany; Profound Medical GmbH, Hamburg, Germany; Thermosome GmbH, Planegg, Germany; and LMU Klinikum München, Munich, Germany. Hyperthermia-induced local release of cytotoxic drugs from thermosensitive liposomes (TSLs) is an effective way to increase their therapeutic window. For clinical translation of this concept, we performed a series of swine studies using a novel formulation of cisplatin (CisPt) in phosphatidyldiglycerol (DPPG2)-TSLs in combination with magnetic resonance guided high intensity focused ultrasound (MR-HIFU)-mediated hyperthermia. L64Combined thermal ablation and high dose radiotherapy: Optimizing for dose reduction and tumor control by R. Griffin from the University of Arkansas for Medical Sciences, Radiation Oncology, Little Rock, AR, United States. The field of radiation oncology continues to advance in the application of high dose, low fraction number regimens, with many noted improvements in response rates. At the same time, the field of thermal medicine has advanced with the advent of image-guided (MRI or Ultrasound) thermal ablation (HIFU, RF, etc.) as well as various interventional oncology approaches. As technologies advance, the use of MRI or ultrasound to assist in radiotherapy or thermal therapy treatment planning suggests that a single treatment room may be possible for image guided high dose radiation and thermal ablation. L65Fractionated MR-HIFU hyperthermia in the pancreas of a large animal model by S. Berger, L. Sebeke, E. Heijman, J. Lindemeyer, P. Rademann, A. Simon, and H. Grüll from the University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Diagnostic and Interventional Radiology, Cologne, Germany; University of Cologne, Faculty of Mathematics and Natural Sciences, Department of Chemistry, Cologne, Germany; Philips Research Eindhoven, Eindhoven, Netherlands; and University Hospital of Cologne, Experimental Medicine, Cologne, Germany. Several clinical studies using ultrasound-guided high-intensity focused ultrasound (HIFU) for thermal ablation of pancreatic cancer have shown to improve local control and alleviate pain. Preclinical studies showed that hyperthermia-mediated drug delivery with temperature sensitive liposomes prior to ablation allows treatment of the tumor rim adding additional therapeutic efficacy. As a step towards this combination therapy, we investigate the application of hyperthermia in the pancreas of landrace pigs using MR-guided HIFU. L69An in vitro system for focused ultrasound hyperthermia (and radiotherapy) studies using spheroids by I. Rivens, P. Mouratidis, D. Andres Bautista, R. Symonds-Taylor, N. Jiménez, F. Camarena, and G. Ter Haar from the Institute of Cancer Research, Centre for Cancer Imaging, Sutton, United Kingdom; and Universitat Politècnica de València, Instituto de Instrumentación para Imagen Molecular – CSIC, Valencia, Spain. Ultrasound can be used for clinical hyperthermia. In vitro studies are challenging as acoustic interactions in 2D cell suspensions are not representative of those in vivo. The lack of absorption in culture medium means acoustically induced thermal effects are absent. A system for ultrasound (US) hyperthermia studies (+/- radiotherapy (RT)) of 3D in vitro models with thermal dosimetric control has been built with the aim of improving prediction of in vivo outcomes. L76The ...
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Cleveland Clinic’s Comprehensive Review of Focused Ultrasound Brain Treatments

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Key Points Researchers at the Cleveland Clinic conducted a comprehensive review of approved and emerging applications of focused ultrasound for treating brain diseases.The article discusses three mechanisms of action and eleven diseases and conditions.Focused ultrasound can deliver acoustic energy through the skull to eliminate defective neurons, introduce drug and biological therapies, and modulate neurons. Clinical Intervention Using Focused Ultrasound (FUS) Stimulation of the Brain in Diverse Neurological Disorders Researchers at the Cleveland Clinic have conducted a comprehensive review of both emerging and US Food and Drug Administration (FDA)–approved applications of focused ultrasound for treating brain diseases. The article discusses three mechanisms of action and eleven diseases. Thermal ablation is being used to treat essential tremor, Parkinson’s disease, obsessive-compulsive disorder, major depressive disorder, epilepsy, and neuropathic pain.Focused ultrasound–induced blood-brain barrier (BBB) opening is being investigated for brain tumors, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS).Neuromodulation is under investigation for psychiatric disorders related to perception, emotion, and cognition and for impaired consciousness. The authors effectively lay out the publication trail that demonstrates how focused ultrasound has been developed to deliver acoustic energy through the skull to eliminate defective neurons, introduce drug and biological therapies to specific regions, and modulate neurons via excitement or inhibition. The article contains an extensive list of references and clinical trial publications. See Frontiers in Neurology >
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Meeting Report: European Association of Neuro-Oncology (EANO) 2022

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Key Points EANO held its 17th Annual Meeting from September 15–18 in Vienna.Carthera had a prominent presence at the meeting, hosting a lunch symposium and sharing data from its glioblastoma clinical trial.The liquid biopsy consortium meeting included an overview of the ongoing work with focused ultrasound. The European Association of Neuro-Oncology (EANO) held its 17th Annual Meeting from September 15–18, 2022, in Vienna. In the setting of the Hofburg Imperial Palace, approximately 850 neuro-oncologists, neurologists, neurosurgeons, nurses, and scientists shared and discussed recent findings in basic, translational, and clinical science from all fields of neuro-oncology (brain tumors). French ultrasound manufacturer Carthera sponsored the meeting lanyards and presented a well-attended (350 attendees) corporate lunch symposium with presentations and a panel discussion featuring: Michael Canney, PhDAlexandre Carpentier, MD, PhDAhmed Idbaih, MD, PhDRiccardo Soffietti, MDAdam Sonabend, MDRoger Stupp, MD In the highlights from clinical abstracts session, Dr. Idbaih shared new data from Carthera’s Phase 1/2 clinical trial of blood-brain barrier (BBB) opening with the SonoCloud-9 implantable ultrasound device in participants with recurrent glioblastoma (GBM) receiving IV carboplatin. He summarized the results from the trial, which enrolled 33 participants who received 90 sonications. The procedure was easy to perform in less than 10 minutes, well tolerated, and repeatedly feasible over a large volume. Sonication was shown to improve drug delivery (i.e., a 5.9x increase in carboplatin concentration in a select group of patients) and improve radiological and clinical outcomes when performed at peak concentration of carboplatin. A pivotal randomized trial for recurrent GBM is planned. “Beyond the Carthera presentation, focused ultrasound was mentioned in several of the talks, especially for drug delivery,” said Suzanne LeBlang, MD, the Foundation’s Director of Clinical Relationships, who attended the meeting. “Even researchers who do not currently use focused ultrasound were describing how it could impact the field by delivering different substances to the brain.” Hideho Okada, MD, PhD, and Nino Chiocca, MD, PhD, presented information on immunotherapy approaches and suggested that innovative strategies, such as convection–enhanced delivery and ultrasound with microbubbles, can help deliver high molecular weight agents that cannot cross the BBB alone. A dedicated session on “Liquid Biomarkers for Diagnosis/Disease Tracking in CNS Tumors” presented many new advances for the field. “I was appreciative for the invitation to also participate in a separate liquid biopsy (LB) consortium meeting led by Susan Short, MD, PhD, where I presented an overview of focused ultrasound–enhanced LB,” Dr. LeBlang added. The LB consortium will reconvene for another progress update during the Society of Neuro-Oncology meeting in November. In another session, Sabine Mueller, MD, PhD, MAS, delivered the presentation “Clinical Trials – A Transatlantic Perspective,” in which she discussed the Focused DMG Consortium to assess the use of focused ultrasound in diffuse intrinsic pontine gliomas. Participating institutions include Children’s National Hospital in Washington DC, Prinses Maxima Centrum, University Kinderspital Zurch, Virginia Tech, and UCSF. EANO showcased more than 370 oral and poster presentations. The following abstracts, which address the treatment of GBM, are of interest to the focused ultrasound community: KS05.6.A Oral DNA vaccination targeting VEGFR2 combined with the anti-PD-L1 antibody avelumab in patients with progressive glioblastoma – final results. NCT03750071 Dr. LeBlang reports: In this presentation, Professor Michael Platten, MD, described how focused ultrasound could be used to activate T cells and make the tumor microenvironment “hot.” The resulting discussion focused on the tumor microenvironment and the role of cytokines. OS07.3.A Phase 1/2 clinical trial of blood-brain barrier opening with the SonoCloud-9 implantable ultrasound device in recurrent glioblastoma patients receiving IV carboplatin. Dr. LeBlang reports: In this clinical trial, 33 participants were implanted with the SonoCloud-9 device and received sonications with IV carboplatin for a total of 90 sonications. Adverse events included two wound infections and two cerebrospinal fluid leaks. The study showed that chemotherapy uptake was 5.9 times higher in the treated area of BBB opening. In a cohort that received IV carboplatin just prior to sonication (n=12 patients) a 1-yr OS of 58% was reported. P14.05.B Plasma-EV based liquid biopsy for precision medicine in the treatment of glioblastoma Dr. LeBlang reports: In this study, the group isolated EV from 2 mL of blood plasma and found the RNA and DNA to mirror the genomic profile of the parental tumor. The group concluded that “Plasma-EV based liquid biopsy could implement the personalization of GBM care for every timepoint of the disease course.” The Foundation sponsored a booth at the meeting where many attendees stopped by to learn more about the technology, manufacturers, our organization, and the larger research community. Dr. LeBlang encourages more focused ultrasound manufacturers to attend future EANO meetings! See the Meeting Abstracts >
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Standardization of Focused Ultrasound–Induced Blood-Brain Barrier (BBB) Opening: A Systematic Review of Protocols, Efficacy, and Safety Outcomes

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Key Points Researchers conducted a systematic review of focused ultrasound parameters used to disrupt the blood-brain barrier (BBB) for drug delivery.The team gathered and collated 107 preclinical and clinical studies, summarized the efficacy and safety findings, and identified gaps and limitations for further study.The group concluded that clinical translation will not become robust until protocols and parameters for BBB disruption have been standardized. Ultrasound–Mediated Blood-Brain Barrier Disruption for Drug Delivery: A Systematic Review of Protocols, Efficacy, and Safety Outcomes from Preclinical and Clinical Studies Source: Gandhi K, Barzegar-Fallah A, Banstola A, Rizwan SB, Reynolds JNJ. Ultrasound-Mediated Blood-Brain Barrier Disruption for Drug Delivery: A Systematic Review of Protocols, Efficacy, and Safety Outcomes from Preclinical and Clinical Studies. Pharmaceutics. 2022 Apr 11;14(4):833. doi: 10.3390/pharmaceutics14040833. A research team based at the University of Otago’s Brain Health Research Centre in New Zealand conducted a systematic review of focused ultrasound parameters used to disrupt the blood-brain barrier (BBB) to deliver drugs or biologicals to the brain. The team gathered and collated protocols and parameters from preclinical and clinical studies, summarized the efficacy and safety findings, and identified gaps and limitations for further study. After cataloguing 107 articles, the factors they identified that affected safety and efficacy were the following: Type of microbubbles usedTransducer frequencyPeak negative pressurePulse characteristicsUltrasound dosing The group concluded that clinical translation will not become robust until protocols and parameters for BBB disruption have been standardized. See Pharmaceutics > Related Stories Bubble Activity in Therapeutic Ultrasound Workshop Series | White Paper and Recordings Available
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Interim Report: Focused Ultrasound for Twin-Twin Transfusion Syndrome

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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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