Children’s National Hospital is the Foundation’s first focused ultrasound Center of Excellence focused exclusively on pediatrics. Their active clinical trials and translational research program have already begun to make a difference in the way that pediatric solid tumors are treated. With their sights on novel cancer applications of focused ultrasound, this innovative group will be worth watching. We interviewed Dr. Karun Sharma to learn more.
Background Information
The Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Hospital (CNH), was launched in 2009 with a mission to make pediatric surgery more precise, less invasive, and pain free. The development and clinical translation of magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) for pediatric patients is ideally suited to meet this mission.
Based in Washington, DC, CNH celebrates 150 years of pediatric care, research, and commitment to community in 2020. Volunteers opened the hospital in 1870 with 12 beds to care for Civil War orphans. Today, 150 years stronger, it is the nation’s No. 7 children’s hospital. It is ranked No. 1 for newborn care for the fourth straight year and ranked in all specialties evaluated by U.S. News & World Report.
CNH is transforming pediatric medicine for all children. In 2021, it will open the Children’s National Research & Innovation Campus, the first in the nation dedicated to pediatric research. It has been designated twice as a Magnet® hospital, demonstrating the highest standards of nursing and patient care delivery.
Besides the Sheikh Zayed Institute for Pediatric Surgical Innovation (SZI), CNH is home to the Children’s National Research Institute and is the nation’s seventh-highest National Institutes of Health (NIH)–funded children’s hospital. It is recognized for its expertise and innovation in pediatric care and as a strong voice for children through advocacy at the local, regional, and national levels.
When was your focused ultrasound program started, who started it, and why?
In 2015, our Image-guided Non-invasive Therapeutic Energy (IGNITE) team opened the first pediatric clinical trial of MR-HIFU in the US for painful osteoid osteomas in children. Since then, our IGNITE team has built an active clinical trials program and become a leader in translation of MR-HIFU for the treatment of pediatric solid tumors.
What is the program’s vision and mission?
The mission of the COE aligns nicely with the mission of our SZI, to make pediatric surgery more precise, less invasive, and pain free. Our vision is to develop and clinically translate focused ultrasound for improved care of pediatric patients with cancer.
What types of facilities, space, and equipment does the site have?
Our Center of Excellence is located on CNH’s main campus, the Sheikh Zayed Campus for Advanced Pediatric Medicine, and within the SZI. Being located within hospital affords our Center and team convenient access to all of the resources that accompany one of the top children’s hospitals in the country.
In addition to our desirable location within CNH, our location in Washington, DC, is also a significant benefit. Such close physical proximity to policymakers on Capitol Hill, as well as medical leaders at the NIH and the FDA, among other government agencies, allows us to more easily connect with, educate, and influence those in a position to make decisions about the focused ultrasound field as a whole.
The Institute has a 22,000 square foot laboratory and office space that facilitates current and future research collaborations. Award-winning design of the Institute features glass walls and white board–lined corridors. Our location has fostered productive collaborations with researchers and staff who work next door in the Centers for Neuroscience and Neurobehavior, Genetic Medicine, and Clinical and Community Research. In this uplifting and productive environment, clinicians work side-by-side with scientists and engineers, identifying challenges and exploring solutions.
The institute has a state-of-the-art Supersonic Aixplorer diagnostic ultrasound (Aix-En Provence, France) system to perform pre-clinical in vivo imaging in real-time. This ultrasound system can provide real-time 3D images of tumor anatomy, elastic properties, and vasculature. Additionally, this system can produce high-quality hemodynamics of tumor vasculature.
Our team also uses a state-of-the-art diagnostic ultrasound system, a Philips iU22 ultrasound system (Philips Healthcare, Andover, MA) equipped with 3D/4D volumetric transducer (X6-1), with a 1-6 MHz bandwidth. This system can provide real-time 3D reconstructed images of tumor anatomy and vasculature hemodynamics.
For preclinical HIFU studies, our institute is equipped with several pre-clinical transducers (ranging from 6mm to 20 cm in diameter) that can be used in a wide range of frequencies (250 kHz – 4 MHz) to produce both mechanical and thermal tissue damage. Several powerful commercially available RF amplifiers from E&I (A150, 1140LA and 1240L) are used to power these pre-clinical transducers. A fully MR-compatible RK100 MR-HIFU system (FUS Instruments) is also available for pre-clinical studies in rodents. For clinical MR-HIFU studies, the team at the institute relies on clinical equipment in the Division of Radiology.
The Division of Radiology houses image-guided therapy facilities, including fluoroscopy, ultrasound, CT, MRI, and nuclear medicine. We have two full-time image-guided therapy suites staffed by anesthesiology, radiology nursing, and technical personnel. These image-guided therapy suites are equipped with the state-of-the-art ultrasound equipment for advanced navigation and fusion image-guidance for ablation. One of the two image-guided therapy suites is a hybrid operating room equipped with cone beam CT, fluoroscopy, and ultrasound capabilities and is routinely used for percutaneous thermal ablation.
The clinical intraoperative MR-HIFU unit is located adjacent to this hybrid OR and used to perform all the clinical MR-HIFU treatments. This room is staffed by dedicated anesthesiology staff and a full time MR-HIFU technologist. Our work makes extensive use of the clinical MRI-HIFU suite (Equipped with Profound Medical Sonalleve V2), which is available off-hours for our team’s preclinical research efforts. Imaging facilities in the Division of Radiology also include six diagnostic ultrasound rooms, one 64-slice CT scanner and one PET-CT scanner, a state-of-the-art diagnostic MRI suite with two 1.5T magnets and one 3T magnet. The MRI suite includes dedicated facilities for anesthesia and co-located facilities for pediatric anesthesiologists, who are on-call 24/7 for sedation, as required for most MRI pediatric imaging. The image-guided therapy program at CNH performs approximately 2,500 image-guided procedures per year. One of the largest growing areas in image-guided therapy at CNH over the past few years has been thermal ablation in pediatric oncology. We are currently routinely performing approximately two to three such procedures per month.
Where does the funding come from, and what is your annual budget?
Besides internal and NIH funding, our focused ultrasound research is funded by philanthropic donations and private industry. We have successfully secured grant monies from Hyundai Hope on Wheels, the Joseph E. Robert, Jr., Endowment, the Board of Visitors, and others.
Our annual budget is about $750,000, including direct costs from grants and internal funds.
Investigators
Do you have institutional support for your focused ultrasound program?
CNH leadership, at all levels of the institution, is fully committed to the work supported by the Focused Ultrasound Foundation and is honored to be named a Focused Ultrasound Center of Excellence, especially one dedicated to the pediatric population.
For the past six years, CNH has dedicated significant resources to build and support the infrastructure needed to support the HIFU program by purchasing clinical equipment, hiring faculty, and funding our first clinical trial. Going forward, our leadership has made focused ultrasound a part of CNH’s strategic initiative, which outlines plans to expand the program into neuroscience, immunology, and urology.
How many total staff do you have, and what are their positions?
The Focused Ultrasound Center of Excellence is directed by Dr. Karun Sharma, MD, PhD, and co-directed by Dr. AeRang Kim, MD, PhD. Both have been committed to the CNH focused ultrasound program since its beginning. They have been active in multiple pre-clinical and clinical projects, jointly conducted clinical trials, and obtained NIH grants to support these clinical trials in FUS. Dr. Pavel Yarmolenko, PhD, serves as the technical lead for the Center. He has also been involved in our focused ultrasound program since its inception, and his engineering and technical expertise has been essential to the growth of our program.
Currently, all three closely collaborate on pre-clinical and clinical projects and jointly mentor junior researchers. They have also jointly published several peer-reviewed papers.
Furthermore, Ann Liew, MS, CCRP, is our Clinical Research Coordinator for oncology and developmental therapeutics, and Sarah Cove, RN, BSN, is our Research Nurse Coordinator for Phase I clinical trials in the Center for Cancer and Blood Disorders.
The Center of Excellence’s Steering Committee engages a cross-section of leadership from SZI, various CNH divisions and departments, and the Focused Ultrasound Foundation.
Who are your key Investigators?
Karun Sharma, MD, PhD: Interventional Radiologist
AeRang Kim, MD, PhD: Pediatric Oncologist
Pavel Yarmolenko, PhD: Biomedical Engineer
Who are your internal and external collaborators?
Internally, our musculoskeletal and orthopedics team includes Karun Sharma, MD, PhD, Pavel Yarmolenko, PhD, AeRang Kim, MD, PhD, and Matt Oetgen, MD, who is the Division Chief of Orthopaedic Surgery and Sports Medicine.
Our internal oncology and immunology group includes AeRang Kim, MD, PhD, Karun Sharma, MD, PhD, Pavel Yarmolenko, PhD, plus Caitlin Tydings, MD, who is a pediatric oncologist and hematologist; Catherine Bollard, MD, MBChB, a pediatric oncologist and hematologist who is also the Director of both the Center for Cancer and Immunology and the Program for Cell Enhancement and Technologies for Immunotherapy; and Jeffrey Dome, MD, who is a pediatric oncologist and hematologist who serves as the Vice President of the Center for Cancer and Blood Disorders, Division Chief of Oncology, and Associate Director of the Center for Cancer and Immunology Research.
The ongoing collaborations with leaders in neurology and neurosurgery will allow us to soon expand our program for neuroscience applications, and we have plans to obtain a brain system in the near future. We have assembled the following team for neuroscience: Kevin Cleary PhD, Associate Director for Engineering at SZI, has extensive experience in image-guided interventions and MR-compatible robotics. Reza Monfaredi, PhD, is a biomedical engineer with expertise in MR-compatible robotics. Chima Oluigbo, MD, is a pediatric neurosurgeon with experience in deep brain stimulation surgery and interest in focused ultrasound ablation for pediatric epilepsy. Roger Packer, MD, is a pediatric neurologist and Director of the Gilbert Neurofibromatosis Institute and Brain Tumor Institute, who is interested in using focused ultrasound–mediated drug delivery for pediatric tumors. Monica Pearl, MD, is a neurointerventional radiologist with experience in catheter and focused ultrasound–mediated drug delivery for pediatric brain tumors. Karun Sharma, MD, PhD, and Pavel Yarmolenko, PhD, are also on the neuroscience team.
For our planned expansion into pediatric urology applications, our urology team includes Daniel Casella MD, a pediatric urologist with experience in nerve stimulation and urinary bladder conditions, Michael Hsieh, MD, PhD, an adolescent urologist with experience in immunology and chronic urinary bladder inflammation, and Karun Sharma, MD, PhD.
Externally, we have a longstanding collaboration with Dr. Brad Wood’s group at NIH and several other research groups throughout the focused ultrasound community.
Projects
Which focused ultrasound applications and biomechanisms are being investigated?
The applications that we are studying or treating are painful osteoid osteoma, malignant solid tumors, pre-malignant tumors, and neurofibromatosis. The biomechanisms that we use are ablation, hyperthermia, and chemosensitization.
Our group’s clinical experience began with a clinical trial evaluating the safety and feasibility of focused ultrasound ablation for painful osteoid osteoma. Our team will continue this work by completing an NIH-funded pivotal clinical trial of 30 pediatric patients with painful osteoid osteoma. We are also investigating other painful bone conditions in children which may be well suited for this treatment.
Our clinical experience with focused ultrasound applications in pediatric oncology has been gained through two ongoing clinical trials led by Dr. Kim and a third trial scheduled to begin in late 2020 in collaboration with NIH.
Historically, our hospital has been limited to clinical applications for body applications due to limitations of our current clinical system. However, we will expand our program to neuroscience applications with plans to obtain a clinical system for brain applications. We have expanded our team to include appropriate neuroscience expertise in pediatric epilepsy, brain tumors, neurofibromatosis, and intracranial hemorrhage. With this expertise in the COE, we will be poised to evaluate ablation in pediatric epilepsy and enhanced drug delivery to pediatric brain tumors. We are also exploring the utility of MR-HIFU in patients with neurofibromatosis (NF). Specifically, we are designing a treat-and-resect trial for NF patients who have resectable premalignant tumors.
We also envision expansion into pediatric urology applications. Our group has considered, designed, and will conduct preclinical work on pediatric conditions affecting the urinary bladder. This may allow us to expand ultrasound-guided focused ultrasound applications to augment our MR-guided program.
How many different focused ultrasound studies are being conducted at this site?
We have two ongoing trials for which we are currently recruiting patients with malignant refractory solid tumors. These clinical trials investigate treatment with MR-HIFU ablation alone (NCT02076906) and with MR-HIFU ablation combined with heat-sensitive chemotherapy (NCT02536183).
In late 2020, we will add two more trials: one for MR-HIFU hyperthermia combined with heat-sensitive chemotherapy for refractory solid tumors, and a pivotal trial for MR-HIFU ablation for painful osteoid osteoma.
We are also developing a treat-and-resect clinical trial of MR-HIFU ablation for pre-malignant tumors in patients with Neurofibromatosis Type 1.
What are your preclinical projects?
We have a preclinical research program evaluating the use of HIFU to augment immunotherapy for pediatric cancers that we plan to translate to the clinical setting within the next few years. This preclinical work has benefitted greatly from close collaboration with Dr. Brad Wood’s group at NIH.
Although this preclinical work has been aimed at evaluating a rational combination of focused ultrasound and immunotherapy, our long-term goal is to translate our promising preclinical findings into clinical trials at CNH and other pediatric hospitals. We recently expanded our team to include the appropriate expertise to facilitate this goal.
Does your group have a role in device commercialization?
CNH is the home of the National Capital Consortium for Pediatric Device Innovation (NCC-PDI), one of five such FDA-funded consortia in the country (FDA-P50FD006430). NCC-PDI’s mission is to facilitate the development and commercialization of devices that are indicated for use in pediatric patients or that are intended to treat, diagnose, or cure diseases from which pediatric patients suffer. The Consortium has served as an accelerator to medical device innovators that intend to label their device for use, in the United States, in the general pediatric population or as a subpopulation. This Consortium provides a unique opportunity to raise awareness of the importance of development and clinical translation of focused ultrasound technologies for pediatric patients.
What is on your wish list to increase your impact?
Ideally, we would like to go to the US Congress and explain that focused ultrasound is a lesser known technology with a potentially high impact that is currently underappreciated. Although, like many emergency technologies, it is expensive at first, several institutions in the beltway region [e.g., CNH, NIH, Johns Hopkins, Bethesda Naval Hospital, the University of Maryland, and the University of Virginia] have made the investment because of its incredible potential. So, one wish list item is to create a “Beltway Consortium” to increase the power of the group to lobby for funding to pay for treating 100 pediatric patients. Forming this type of consortium would create power through numbers to make it easier and faster to recruit kids for studies. This would accelerate research and reduce the time it takes to prove that the treatments are safe, effective, less invasive, and ultimately less expensive when considering the reduction in surgical complications. It is hard for only one or two institutions to recruit kids with cancer.
Education
What is your role in education?
We plan to leverage the coexistence of the NCC-PDI and COE at CNH to develop a formal program that is designed to educate policymakers on Capitol Hill and at the FDA, as well as stakeholders in industry, on the importance of developing focused ultrasound technology for pediatrics. Specifically, we envision a jointly funded position that will establish a fellow-in-residence dedicated to this goal. In addition, Drs. Sharma, Kim, and Yarmolenko will be available for additional policymaker education opportunities, including on site tours of our focused ultrasound facilities and discussion regarding ongoing research and clinical trials. These could be coordinated with the Capitol Hill fly-ins that are already organized by the Focused Ultrasound Foundation in Washington, DC.
Publications
L.W. Lau, A. Eranki, H. Celik, A. Kim, P.C.W. Kim, K.V. Sharma, P.S. Yarmolenko. Are Current Technical Exclusion Criteria for Clinical Trials of Magnetic Resonance-Guided High-Intensity Focused Ultrasound Too Restrictive? Early Experiences at a Pediatric Hospital. J Ultrasound Med 2020; 39:1849-1855. doi:10.1002/jum.15259.
C. Tydings, A. Kim. Technology and precision therapy delivery in childhood cancers. Curr Opin Pediatr February 2020; 32(1):1–6. PMID 31876621.
A. Eranki, P. Srinivasan, M. Ries, A. Kim, C.A. Lazarski, C.T. Rossi, T.D. Khokhlova, E. Wilson, S.M. Knoblach, K.V. Sharma, B.J. Wood, C. Moonen, A.D. Sandler, P.C.W. Kim. High-Intensity Focused Ultrasound (HIFU) Triggers Immune Sensitization of Refractory Murine Neuroblastoma to Checkpoint Inhibitor Therapy. Clin Cancer Res 2020;26:1152–1161.
M.C. Seward, G.B. Daniel, J.D. Ruth, N. Dervisis, A. Partanen, P.S. Yarmolenko. Feasibility of targeting canine soft tissue sarcoma with MR-guided high-intensity focused ultrasound. Int J Hyperthermia 2019;35:205–215.
P.S. Yarmolenko, A. Eranki, A. Partanen, H. Celik, A. Kim, M. Oetgen, V. Beskin, D. Santos, J. Patel, P.C.W. Kim, K. Sharma. Technical aspects of osteoid osteoma ablation in children using MR-guided high intensity focused ultrasound. Int J Hyperthermia 2018;34:49–58.
A. Eranki, N. Farr, A. Partanen, K.V. Sharma, C.T. Rossi, A.Z. Rosenberg, A. Kim, M. Oetgen, H. Celik, D. Woods, P.S. Yarmolenko, P.C.W. Kim, B.J. Wood. Mechanical fractionation of tissues using microsecond-long HIFU pulses on a clinical MR-HIFU system. Int J Hyperthermia 2018; 34:1213–1224.
K.V. Sharma, P.S. Yarmolenko, A. Eranki, A. Partanen, H. Celik, A. Kim, M. Oetgen, P.C.W. Kim. Magnetic Resonance Imaging-guided High-intensity Focused Ultrasound Applications in Pediatrics: Early Experience at Children’s National Medical Center. Top Magn Reson Imaging 2018;27:45–51.
K.V. Sharma, P.S. Yarmolenko, H. Celik, A. Eranki, A. Partanen, A. Smitthimedhin, A. Kim, M. Oetgen, D. Santos, J. Patel, P. Kim. Comparison of Noninvasive High-Intensity Focused Ultrasound with Radiofrequency Ablation of Osteoid Osteoma. J Pediatr 2017;190; 222–228 e221.
A. Eranki, N. Farr, A. Partanen, K.V. Sharma, H. Chen, C.T. Rossi, S.V. Kothapalli, M. Oetgen, A. Kim, A.H. Negussie, D. Woods, B.J. Wood, P.C.W. Kim. P.S. Yarmolenko. Boiling histotripsy lesion characterization on a clinical magnetic resonance imaging-guided high intensity focused ultrasound system. PLoS One 2017;12: e0173867.
C. Tydings, K. Sharma, A. Kim, P.S. Yarmolenko. Emerging Hyperthermia Applications for Pediatric Oncology. Manuscript accepted to Advanced Drug Delivery Reviews.
C. Tydings, P.S. Yarmolenko, M. Bornhorst, E. Dombi, J. Myseros, R. Keating, K. Sharma, A. Kim. Feasibility of Magnetic Resonance Guided High Intensity Focused Ultrasound for the treatment of Distinct Nodular Lesions or Atypical Neurofibromas in Neurofibromatosis Type 1. Manuscript in preparation for Journal of Neurooncology.
Past Coverage
Watch Now: Discussion on Focused Ultrasound’s Potential Role in Neurofibromatosis Treatment August 2020
Patients and Physicians Advocate for Focused Ultrasound in Washington, DC March 2020
Research Roundup November 2019
Meeting Report: Society for Thermal Medicine (STM) Annual Meeting June 2019
Results of Focused Ultrasound Treatment of Osteoid Osteoma Published September 2017
Meeting Report: AAPM 2017 August 2017
2017 Meeting Report: The 34th Annual Meeting of the Society for Thermal Medicine (STM) May 2017
Focused Ultrasound Represented at SIR 2017 March 2017
Children’s National and Celsion Launch Targeted Drug Delivery Clinical Trial for Childhood Tumors December 2016
Celsion Begins Pediatric Solid Tumor Study October 2016
Physicists in Medicine Meeting Report September 2016
Osteoid Osteoma Treatment Guidelines Now Available June 2016
Painful Bone Tumor Trial Begins at Children’s National May 2015
IGNITE Pursues Non-Invasive Pediatric Solutions May 2015