A dedicated Focused Ultrasound Center with comprehensive research plans
The Symposium was opened by James M. Larner, MD, chair of the Department of Radiation Oncology at UVA, and director of the new Focused Ultrasound Center. “If this technology is half as successful as many people in this audience today would say, a number of other technologies will be disrupted,” Larner said. “But we have no choice but to recognize and help uncover the truth.”
Dr. Larner pointed out some unique advantages of the MR-guided Focused Ultrasound (MRgFUS) technology: Its dose fall-off is more abrupt than ionizing radiation; focused ultrasound is not ionizing radiation, which can lead to secondary malignancies; and, most fundamental, focused ultrasound is truly ablative, destroying cells by heat, which offers no potential for resistance.
Noting the current use of MRgFUS for uterine fibroids, Dr. Larner then outlined focused ultrasound studies “in the UVA pipeline.” Among these are treatment of bone metastases, breast, prostate, and liver cancers, Parkinson’s disease, essential tremor, epilepsy, and stroke. “We have potentially a highly game-changing technology that will replace many therapies,” he concluded.
Frontier of focused ultrasound technology, with MRI integration
Jacob Vortman, PhD, president and CEO of InSightec, the manufacturers of focused ultrasound equipment, expanded on the technical capabilities of MRgFUS.
Working with “acoustics” (ultrasound) is a great advantage, he said. Acoustic mechanisms are much slower than optical mechanisms, so today’s electronics are fast enough to steer the acoustic beam and focus it within tissue. Dr. Vortman explained that MRI is used “not only for imaging, but also as a machine that can generate tissue-viability data.” In the past 30 years, temperature has been accepted as a surrogate for tissue viability: If you heat human cells to 60o C, in 0.1 second the cells are destroyed, and we can see this happening in real time using MRI.
“The new center at UVA will have every therapy module that InSightec has developed – body system and brain system,” Dr. Vortman said. But InSightec isn’t satisfied with the status quo. Future plans include reducing treatment time and developing an acoustic beam that follows the target to treat moving organs like liver and kidney. “It’s a call to everyone to use this technology to the maximum extent,” Vortman said, “and we will be here to help.”
Current, future applications: Experience at St. Mary’s Hospital, London
The next speaker, Wladislaw Gedroyc, MD, professor of radiology, Imperial College & St. Mary’s Hospital, London, shared his clinical experiences from treating more than 500 cases in Great Britain. “Treating fibroids has allowed us to evolve our techniques in a relatively safe area, and we’ve learned a great amount,” he said. His presentation then looked ahead to a broad spectrum of focused ultrasound applications.
“Neural structures have proteins that begin to denature at 45o C., not 60o C.,” said Dr. Gedroyc. In fact each tissue has unique treatment characteristics. For treating bone metastases, the principle is to heat the periosteum (a membrane tightly surrounding the bone). Heat does not go deeper but destroys periosteal nerves and so provides pain relief.
For liver, “Some of the best results of the ablation are reasonably comparable to surgery,” Dr. Gedroyc reported, although treatment is challenging because ribs get in the way and, as Dr. Vortman had noted earlier, the liver moves with respiration. People come into hospitals all over the world with liver metastases; we can make an immense contribution by treating these patients with focused ultrasound, and more research is needed. In addition, with the increase in hepatitis B and C, hepatic carcinomas will increase in the future. Liver may be “the biggest application of FUS we have yet thought of,” Dr. Gedroyc observed.
Focused ultrasound has been used in Japan to treat breast tumors, which were then removed surgically. And a trans-rectal focused ultrasound unit has been used to achieve discrete areas of cell destruction in the prostate, an image-guided approach that may reduce post-surgical impotence.
Focused ultrasound as a neurosurgical tool: Research at the University of Zurich
Ernst Martin-Fiori, MD, professor of neuroradiology at the University of Zurich, Switzerland, described his group’s clinical research using focused ultrasound to place thalamic lesions: The thalamus and basal ganglia are major therapeutic targets for neurogenic pain, movement disorders, tinnitus, epilepsy, and some neuropsychiatric disorders.
In a recent feasibility study the Zurich group, which also includes neurosurgeon Daniel Jeanmonod MD, and Beat Werner, PhD, ablated the medial thalamic region in 11 patients with chronic neurogenic pain. A stereotactic frame was utilized, and the head surface was water-cooled. The thermal dose led to cell death in the treatment area. “The median precision of lesion placement in the first 10 patients was 0.5 mm dorso-ventral and medio-lateral, and 1.0 mm antero-posterior,” commented Dr Martin. “I think this precision is really remarkable,” he added.
This non-invasive MRgFUS method of placing lesions avoids the possible infection, hemorrhage, and collateral damage to normal brain that is associated with approaches such as RF ablation. After an average pain duration longer than 7 years, nearly 60% of patients experienced immediate pain relief, 44% reported pain relief after 3 months, and none had neurological deficits. Drs. Jeanmonod and Martin plan future clinical studies on Parkinson’s disease and epilepsy.
Non-ablative approaches: Neuromodulation and targeted drug delivery
The next two speakers were US-based although not exactly neighbors. William J. Tyler, PhD, is assistant professor in the School of Life Sciences at Arizona State University, Tempe. He investigates non-destructive applications of FUS, using very low intensity and low frequency ultrasound. Frequencies lower than 1 MHz have relatively reduced spatial resolution but are readily transmitted through the skull. “Do you want to ablate the circuit or stimulate the circuit?” Dr. Tyler asked. His goal is to achieve neuromodulation by FUS stimulation of the intact brain.
Using brain slices for the initial experiments, Dr. Tyler examined sodium movement, voltage-gated calcium channels, and synaptic transmission in slices exposed to ultrasound, and found evidence that neural activity was stimulated. The studies were extended to mice exposed to as much as 8–10 hours of trans-cranial pulsed ultrasound. Follow-up with a battery detected no behavioral problems; the mouse brains are being examined for changes in synaptic structure and evidence of cell death.
“Ultrasonic neuromodulation seems safe for non-primates,” said Dr. Tyler, who recently began his first primate study. He reports that ultrasound affects the lipid bilayer and brain fluids and can affect membranes and sodium channels. He feels the work holds promise for treating depression, OCD [obsessive compulsive disorder], Parkinson’s, and traumatic brain injury, and may also be useful in brain-computer interfaces and entertainment.
Further non-ablative uses of FUS were described by King Li, MD, the M.D. Anderson Foundation distinguished chair, Department of Radiology, Methodist Hospital, Houston, Texas. Dr. Li described targeted drug and gene delivery with focused ultrasound. “This is clearly a game-changer, and this is clearly a disruptive technology,” he said. “It is changing the way we look at drug therapy in the future.”
Dr. Li noted that 99% of the drugs used today belong to the category of “free drugs” – going everywhere in the body. MRgFUS can localize drug targets and deposit energy in a focused manner. Investigators have coupled drugs with microbubbles that expand or collapse when heated with ultrasound, releasing drugs into tissues such as the brain. Studies show that sub-damaging levels of ultrasound can open the blood-brain barrier and allow drugs to cross. The same approach might open tissue barriers in tumors – enabling thermosensitive nanoparticles to deliver drugs into tumor parenchyma.
In fact, heat-sensitive liposomes are currently in clinical trials. The liposomes are stable until reaching 43o C., at which point they release their contents. Once liposomes are carried to the desired area, focused ultrasound -generated heat will cause them to release their contents. “If you can control the drug remotely,” said Dr. Li, “that fundamentally changes how medical therapy will be given in the future and what our vision is.”
Recent focused ultrasound research at UVA
The final Symposium speakers were UVA faculty with research or clinical practices involving focused ultrasound:
John A. Hossack, PhD, professor of biomedical engineering at UVA, described research on intravascular ultrasound (IVUS) guidance of drug and gene delivery. The procedure permits the use of highly potent drugs that would be risky systemically – specifically, delivery of drugs to prevent intravascular smooth muscle cell (SMC) proliferation. An intravascular ultrasound catheter is combined with a bubble channel/port for local delivery of microbubbles; the bubbles are coupled with a drug/gene that prevents SMC proliferation. Ultrasound affects the microbubbles, allowing the drug/gene to be delivered locally to the vessel wall. Studies in swine have shown gene uptake and expression in coronary arteries.
Richard Price, PhD, associate professor of biomedical engineering at UVA, reported work on targeted drug delivery and ablation of brain tumors with focused ultrasound and microbubbles. As in the previous studies, anti-tumor drugs were attached to the microbubbles, which were injected into an implanted glioma. FUS was used to expand and collapse the bubbles, leading to drug delivery. The study explored different pulsing sequences of 1 MHz ultrasound. Some tumor areas were ablated by the treatment, possibly because ultrasound caused tissue ischemia, leading to apoptosis. A greater necrotic effect was obtained using a “5-burst” pulsing sequence but tumor growth was not inhibited.
UVA – early adopters of radiosurgery, and now Focused Ultrasound
Jason Sheehan, MD, PhD, associate professor of neurological surgery, neuroscience, and radiation oncology at UVA, and co-director of the Focused Ultrasound Center, outlined plans for the UVA FUS Center. “This is a differentiating technology for the University of Virginia,” said Dr. Sheehan. “We can be on the cutting edge of the curve – with the tremendous outpouring of support at UVA and collaborative efforts with some of the speakers.”
Dr. Sheehan recalled the 1989 adoption of the gamma knife, making UVA the second facility in the country with that technology, and portrayed the FUS Center as a place that will combine the expertise of radiation oncologists, neurosurgeons, radiologists, nurses, and medical physicists in a multidisciplinary approach similar to that of stereotactic radiosurgery.
Closing the symposium, Alan Matsumoto, MD, professor of radiology at UVA, and co-director of the Focused Ultrasound Center, presented an extensive review of the uses of MRgFUS in treating uterine fibroids, and pointed to ongoing clinical trials involving bone metastases, uterine fibroids (including fertility), brain tumors, neuropathic pain, and breast tumors. Clinical trials are planned for prostate tumors, liver tumors, Parkinson’s disease, and essential tremor, and even broader areas are being considered for pre-clinical research.
Among funding opportunities for focused ultrasound research, such as NCI and the Coulter Foundation, is the Focused Ultrasound Surgery Foundation (FUSF)– “not the same as the Focused Ultrasound Center,” Dr. Matsumoto clarified. Established in 2006, FUSF supports research and fellowships (6 fellowships and 8 research projects funded to date); holds conferences, symposia, and workshops; and serves as a patient-support organization through its advocacy group, educational efforts, and web site: www.fibroidrelief.org.