The 9th Annual International Society of Therapeutic Ultrasound (ISTU) met recently in Aix en Provence, France and featured 128 speakers, dozens of technical posters, and brought together hundreds of experts in the field of focused ultrasound research. The meeting, sponsored in part by the FUS Foundation, is the premier yearly conference highlighting the engineering and technical work done to allow focused ultrasound to treat a myriad of medical conditions. Particularly exciting was the number of young and talented investigators that are leading the wave of new advances and applications. Also exciting was the large presence of equipment manufacturers showcasing their latest advancements including Philips, InSightec, Siemens, Haifu, Supersonic Imagine, and Profound Medical.
Featured prominently at the meeting was the more established use of focused ultrasound in heating targeted areas of the body to destroy diseased tissue and the conference included the latest advances in using the technology to treat uterine fibroids, prostate cancer, breast cancer, brain tumors, and other diseases. One of the tumor types receiving particular attention this conference were liver tumors which require special techniques to pass the ultrasound beams through the rib cage and visualize and track the liver while in motion due to the patient’s respiration. In addition to the use of focused ultrasound to ablate diseased tissue non-invasively, there was more emphasis than ever on the non-thermal applications of focused ultrasound in areas such as targeted drug delivery and the disruption of clots found in stroke patients.
Some highlights of the ISTU meeting observed by members of the Foundation staff include the following:
Breast Cancer Research:
Hidemi Furusawa presented a tremendous amount of progress achieved in the past year in the work he’s doing in Breast Cancer at Breastopia Hospital in Miyazaki, Japan. At the 1st International MRgFUS Symposium in Washington, DC last October, they presented their phase III clinical research plans to treat patients with breast cancer where these patients were receiving focused ultrasound to ablate the tumor in a manner comparable to a standard lumpectomy. Less than a year later, Furusawa and his team have accumulated data on 46 treated patients with a mean age of 56-years old and mean tumor size of 10.6 mm. Of these 46 cases, 30 have reached a 2 year follow-up point with no observed recurrence. The aim is to follow these patients for 5 years and prove that focused ultrasound followed by radiation therapy is at least as effective as lumpectomy in treatment of some breast tumors, where the current standard of care is breast conserving surgery followed by radiation therapy. We eagerly await a research update at the 2nd International MRgFUS Symposium in Washington, DC October 2010.
Targeted Drug Delivery:
The group out of Teikyo University in Kanagawa, Japan presented extremely elegant work in HIFU mediated drug delivery whereby they utilized a combination of bubble liposomes, ultrasound, and a novel gene delivery system to stimulate the immune response and cultivate tumor suppression in a mouse model of colon cancer.
Strong antitumor immunity is thought to occur when tumor-antigen-specific dendritic cells are introduced following ultrasound therapy. In addition, collapse, or cavitation, may be induced by ultrasound exposure to bubble lymphocytes, which in this case also include the introduction of the immunostimulatory IL-12 gene via a novel bubble liposome approach developed by Maruyama’s group at Teikyo University. It was only the combination of bubble liposomes, tumor-antigen specific dendritic cells, and high intensity ultrasound therapy that resulted in efficient suppression of tumor growth.
Liver Tumor Applications:
Clearly transcostal liver therapy is currently an area of intense research amongst the academic community. The time-reversal techniques presented at ISTU allow optimal heating of the liver while only minimally heating bone and tissue in the nearfield, thus reducing or eliminating skin burns and patient discomfort. Some groups have adopted an element deactivation technique, which avoids nearfield heating without optimizing ablative therapy. It will be interesting to observe which of these techniques shows more promise next year. Certainly the time-reversal method developed for this application may also be used to correct aberrations originating from the skull in HIFU brain applications.
Topics of discussion in this session range from ultrasound dosimetry to adaptive focusing to thermal and cavitation modeling.
Ultrasound dose is not a clearly defined quantity and likely never will be as straightforward to compute as radiation dose due to ultrasound’s complex interaction with tissue. An alternative to the conventional thermal dose threshold estimation of tissue necrosis was presented by a member of the FDA. This method was based on the use of an intensity-time product to determine a necrosis threshold. It is important that a broadly accepted, clinically-relevant metric be established in order for HIFU to gain further clinical acceptance in the U.S.
Because the aim of HIFU is typically the generation of thermal effects in tissue, researchers have focused on minimizing unwanted heating and maximizing desired or planned heating. This is a concern when the target tissue lies in the acoustic shadow of bone, which is often the case when treating the liver or the brain. Pre-calculated time-reversal techniques were presented as an optimal solution to both minimize unwanted heating and maximize desired therapeutic heating when applying HIFU to ablate liver tissue. Real-time, acoustic radiation force MR-guided adaptive focusing correction due to aberrators was presented as an accurate way to maintain a small focal size in brain tissue.
Modeling the application and effects of HIFU in the body is a necessary tool to further understand the challenges involved in its use. In order to better estimate the resulting cavitation that occurs as a result of high-power application of HIFU, a visco-elastic liver model was presented to illustrate how the inclusion of visco-elastic tissue properties slows bubble collapse, thus prolonging the existence of cavitation bubble clouds in tissue beyond what may be anticipated if these tissue properties are ignored. An inaccurate prediction of cavitation may result in errors in HIFU treatment planning. Another presentation in this session addressed the need to accurately model the steep thermal gradients generated with HIFU in conjunction with blood perfusion in order to better understand the limits of thermal treatment in highly-perfused tissues.
While the invited speaker for this session, Pierre Khuri-Yakub, presented his vision for the future use of CMUTs (capacitive micromachined ultrasonic transducers) for therapeutic applications, the remaining presentations focused on the design and evaluation of conventional piezoelectric ceramic-based devices that either overcome technical challenges associated with HIFU transducer operation or permit improved therapeutic applications.
The presented method for improving HIFU device operation addresses the relatively high electrical impedance of HIFU transducer elements. A novel technique for reducing the impedance by positioning element electrodes across an element’s width dimension, as opposed to its thickness dimension, was presented. Using this method, researchers were able to increase acoustic power output by 50% compared to intracavitary HIFU devices currently in clinical use.
Treating uterine fibroids or other potentially large targets for thermal ablation can be a very time-consuming task. A toroidal transducer was presented that permits a large focus volume. This is achieved by pairing acoustic lens focusing and geometric focusing in a single device in such a way that the foci lie adjacent to one another. By distributing the ultrasound energy this way to increase focus size it is possible to accelerate the thermal ablation of large volumes of tissues and reduce operation time.
Thermal ablation within the brain is currently monitored through MR-thermometry. While methods have been developed to allow ultrasound thermometry or guidance of HIFU ablation of soft tissue, current transcranial HIFU devices are transmit-only and therefore cannot take advantage of these techniques. The last talk in this session presented the development of ultrasonic receivers that may be positioned within individual annular HIFU elements comprising a transcranial transducer array. These receivers were implemented with PVDF (), a polled plastic material commonly used in hydrophones, and incorporated an amplifier to drive the relatively long cable associated with transcranial devices. The evolution of this technology may, in the future, permit USgFUS of the brain.