Focused Ultrasound Surgery Research Articles

WE‐C‐220‐03: Lessons Learned: Creating a Dedicated Focused Ultrasound Surgery Program

MR‐guided focused ultrasound surgery (MRgFUS) is an emerging technology with the potential to disrupt traditional treatment techniques across a wide variety of surgical and medical disciplines. Proposed applications for MRgFUS are multiplying quickly and include indications as diverse as tumor ablation, thrombolysis, hemostasis, reversible blood‐brain barrier disruption, targeted drug delivery, gene therapy, and neuromodulation. Interest in MRgFUS is quickly increasing, however the desire to find new potential treatment indications may be outpacing work on developing “best practices” for designing new centers, organizing clinical teams, and defining standards for treatment quality and reporting. The University of Virginia recently started up one of the first programs in the world designed from the ground up specifically for the purpose of MR‐guided focused ultrasound surgery. The lessons learned during this process, both positive and negative, may be valuable to the ongoing discussion of best practices. This lecture will provide an overview of the UVA experience, including center design, construction, and administrative organization, and funding /revenue, and program startup. A particular focus will be on the clinical startup experience, and how this might be improved with a more formal risk‐based process analysis.Learning objectives:1. To understand the rationale for a stand‐alone FUS center versus a center created out of existing resources in the medical center.2. To understand the design features of the center, as well as the challenges that had to be overcome in the design and construction of the center.3. To understand the multidisciplinary organization of the center and how inter‐department conflicts are managed.4. To understand the expectations vs. reality of the center regarding the distribution of treatment indications, the effort required to start clinical trials, and the ability to collect clinical revenue.5. To understand the centerˈs experience during clinical startup, and the successes and challenges faced by the center when trying to refine clinical processes and develop standards for quality assurance.Funding Support, Disclosures, and Conflict of Interest: The Focused Ultrasound Center at the University of Virginia has received funding for development and research from the following: The Focused Ultrasound Surgery Foundation, the Commonwealth of Virginia, InSightec Ltd., and the General Electric Co.

WE-G-220-06: Using MR-Guided Focused Ultrasound to Study Heating Pattern Variations Due to Reflections from Interfaces in Both Thermal and Tissue Phantoms

Purpose:To investigate the impact of ultrasoundwave reflections from distal surfaces on aimed treatment center shifts and dose distributions during MR‐ guided‐FUS (focused ultrasound) to provide important information for treatment planning. Methods: An integrated Philips Sonalleve system on a 1.5T was used for this study. FUS waves reflected from four different reflectors (air, acrylic (modeling bone), rubber, and a gel pad) after propagation through a thermal phantom and an ex vivo tissue phantom were investigated. FUS was aimed at positions 1 cm, 2 cm and 4 cm below the distal interface surface. Volumetric sonications were 20 seconds, at 50 watts for all cases. Proton resonance frequency shift imaging was used to measuretemperature during and after FUS. Target location shifts toward the distal interface are reported, along with the maximum temperature at both the center of the treatment area and at the interface. Results: Surface heating was greatest at the acrylic‐thermal phantom interface. The greatest shifts from planned treatment position were beneath acrylic and rubber interfaces at an aimed depth of 2cm in the thermal phantom. Shifts in position observed in the tissue phantom were less extreme. Conclusions: In both the thermal and tissue phantoms, the gel pad interface causes the least increase in temperature at the surface, and minimal displacement from the target. For translational research utilizing animal cancer models, this work demonstrates the benefit of placing a gel pad on the distal surface of small volumes to reduce the shift that would occur if that surface was left open to the air. Future work will compare experimental data with simulations and investigate the effect of reflections from distal surfaces using in vivo animal studies. This work was supported by grants from the Focused Ultrasound Surgery Foundation and Philips Healthcare.

WE‐E‐220‐05: On‐Thermal Pulsed Focused Ultrasound for Cancer Therapy

Purpose: MR guided focused ultrasound (MRgFUS) has been investigated for ablative therapy and drug enhancement for gene therapy and chemotherapy in our institution. The aim of this work is to explore the feasibility of pulsed focused ultrasound (pFUS) for non‐thermal cancer therapy using an in vivo animal model. Methods: An InSightec ExAblate 2000 with a 1.5T GE MR scanner was used in this study. Suitable ultrasound parameters were investigated to perform non‐thermal sonications, keeping the temperature below 42C as measured in real time by MR thermometry. LNCaP cells (106) were injected into the prostates of male mice (n=20). When tumors reached the volume of 100±50mm3 on MRI, the tumor‐bearing mice (n=8) were treated with pFUS (US frequency 1MHz; 25W acoustic power; pulse frequency 1Hz; 0.1 duty cycle) for 60sec. A total of 4–6 sonications were used to cover the entire tumor volume under MR image guidance. The animals were allowed to survive for 4 weeks after the treatment. The tumor growth was monitored on MRI and compared with the control group (n=12). Results: Significant tumor growth delay was observed in the tumor‐bearing mice treated with pFUS. The mean tumor volume for the pFUS treated mice remained the same 1 week after the pFUS treatment while the mean tumor volume of the control mice grew 42% over the same time. Two weeks after the pFUS treatment the cont Conclusions: Our results demonstrated that non‐thermal pFUS has a great potential for cancer therapy. Further experiments are needed to derive optimal ultrasound parameters and fractionation schemes to maximize the therapeutic effect. This work is supported by Focused Ultrasound Surgery Foundation, Varian Medical Systems, DOD PC073127 and DOD BC102806. Technical support from InSightec is acknowledged.

WE‐G‐220‐04: Enhanced Uptake of Doxorubicin in Prostate Tumor Using Pulsed Focused Ultrasound — An in Vivo Study

Purpose: To investigate the effect of pulsed focused ultrasound (pFUS) on the uptake of doxorubicin (DOX) in prostate tumor in vivo. Methods: A mouse prostate tumor model was used in this study by implanting and growing LNCaP tumor cells in male nude mice prostate. An InSightec ExAblate 2000 system with a 1.5T GE MR scanner was used for MRI‐ guided pFUS treatment. Non‐thermal sonications were delivered by keeping the local body temperature below 42°C as measured in real‐time by MR thermometry. Tumor‐bearing mice were exposed to pFUS (1MHz; 25W acoustic power; 10% duty cycle with 0.1 sec on and 0.9 sec off) for 60 sec in each sonication. A total of 4–8 sonication spots, depending on the tumor size, were used to cover the whole tumor. Immediately after pFUS exposure, DOX (10mg/kg) was injected via tail vein. Mice were euthanized after two hours and the DOX concentration in tumor (microgram of DOX per gram of tumor weight) was measured using the fluorescence technique. Mice were randomly assigned to two groups (n=8 for each group). One group received DOX injection only (group: DOX). The other received both pFUS exposure and DOX injection (group: FUS+DOX). Results: The DOX concentration in the FUS+DOX group was 14.9+/−2.5 ug/g compared to 9.5+/−1.6 ug/g of the DOX group (p=0.051). There was an about 60% increase of the DOX uptake in the prostate tumor exposed to pFUS. Conclusion: Results show that pFUS exposures significantly enhanced the uptake of DOX in prostate tumors. This result is consistent with our previous study of enhanced [3H]‐docetaxel uptake in prostate tumors. Further studies are being conducted to investigate the optimal pFUS parameters to maximize the uptake enhancement and its clinical benefits for cancer therapy (Study supported by a grant from Focused Ultrasound Surgery Foundation and partially by DOD PC073127).

WE-G-220-07: Treatment Assessment for Pulsed Focused Ultrasound Therapy of Prostate Tumor Using a Clinical 1.5T MRI

Purpose: Recent in vivo experiments have showed non‐thermal effects of pulsed focused ultrasound (pFUS) on tumor growth delay. This study investigates the application of a clinical 1.5T MR scanner for treatment assessment of prostate tumors after pFUS treatment, which provides a non‐ invasive and accurate way to measure tumor volume for treatment efficacy evaluation, and also an alternative way for small animaltumor model study that generally requires high‐magnetic‐field MRI facility (e.g., the Bruker NMR system). Methods: A mouse tumor model was developed by implanting LNCaP tumor cells in nude mice prostates. When tumor volume reached ∼130 mm3 on MRI, mice were randomly assigned into two groups (n=8): (1) pFUS treatment; (2) control. MRI‐guided pFUS treatment was performed using InSightec ExAblate 2000 with a 1.5T GE MR scanner. Non‐thermal pFUS was delivered for 60 sec per sonication (1MHz; 25W acoustic power; 10% duty cycle, on/off=0.1/0.9 sec). The body temperature was kept 40% reduction in tumor volume was shown in mice treated with pFUS compared to that for the control mice Conclusion: Clinical 1.5T MRI is able to assess the tumor volume change after pFUS treatment for a small animal model (tumor size: 3–10mm). It may provide an alternative way for treatment assessment for small animal studies. This work is supported by Focused Ultrasound Surgery Foundation, Varian Medical Systems, DOD PC073127 and DOD BC102806.

Magnetic resonance-guided focused ultrasound surgery for leiomyoma-associated infertility

ObjectiveTo describe magnetic resonance-guided focused ultrasound surgery (FUS) as a treatment for a case of leiomyoma-associated infertility.DesignCase report from a randomized clinical trial.SettingAcademic medical center.Patient(s)A 37-year-old woman with known leiomyomas and a history of 18 months of home-inseminations from a known donor.Intervention(s)Magnetic resonance-guided FUS treatment of uterine fibroids, where the dominant fibroid distorted the uterine cavity.Main Outcome Measure(s)Pregnancy.Result(s)A viable intrauterine pregnancy, with a full-term vaginal delivery, was conceived after a single clomiphene citrate and intrauterine insemination cycle.Conclusion(s)The role of FUS for enhancement of fertility in women with nonhysteroscopically resectable uterine fibroids distorting the uterine cavity should be investigated further.

Focused Ultrasound Surgery in Oncology: Overview and Principles

Focused ultrasound surgery (FUS) is a noninvasive image-guided therapy and an alternative to surgical interventions. It presents an opportunity to revolutionize cancer therapy and to affect or change drug delivery of therapeutic agents in new focally targeted ways. In this article the background, principles, technical devices, and clinical cancer applications of image-guided FUS are reviewed.

Focus Shift and Phase Correction in Soft Tissues During Focused Ultrasound Surgery

During the treatment of soft tissue tumors using focused ultrasound surgery (FUS), the focus can shift away from the desired point due to tissue inhomogeneity. In this paper, a numerical method to calculate the focus shift in multiple-layered tissues and a faster phase-correction method to restore the focus were developed. Data from the simulations showed that the focus shifted about 2 mm along the transducer axis in multiple-layered soft tissues. After phase correction, the focus was restored at the desired point. The ex vivo experiments were conducted to verify the simulations, and the results agreed well with those of the simulations. An empirical formula was obtained to estimate the focus shift in a two-layered water-tissue model and was verified by numerical calculations. Moreover, the focus shift in multiple-layered tissues can be summed by the shifts in the component of each layer of tissues. The factors affecting the focus shift were studied. The focus shift varied linearly with the tissue acoustic speed and tissue thickness, whereas it slightly changed with transducer F number (radius of curvature/diameter). Overall, the findings of this study can help in the development of a better treatment plan for FUS in soft tissues.

OP07.10: Focused ultrasound surgery for conservative fibroids treatment

OP07.10: Focused ultrasound surgery for conservative fibroids treatment

ExAblate® magnetic resonance-guided focused ultrasound system in multiple body applications

Focused ultrasound surgery (FUS) is a completely noninvasive method of thermally destroying a target tissue while sparing adjacent tissues and organs. Treatment is relatively painless and can be carried out under conscious sedation on an out-patient basis. The combination of magnetic resonance guidance with FUS (MRgFUS) provides the ability to plan and monitor treatments in near real-time, further increasing the safety profile of MRgFUS. This technology provides a very personalized treatment, adjusted to the individual patient anatomy, pathology and treatment response, hence it meets the needs of patients, as well as of physicians. MRgFUS has been used extensively in the successful treatment of uterine fibroids, and has been shown to be an effective treatment in the breast and in bone metastases in smaller scale studies. It shows great potential in the treatment of prostate and liver tumors, as well as in the brain and facet joints.

TH‐C‐204B‐06: MR Guided High‐Intensity Focused Ultrasound for Cancer Therapy: A Feasibility Study Using an Animal Model

Purpose: Ultrasound is a non‐invasive agent that has high precision and deep penetration in tissues enabling increased doses to the tumor while sparing nearby normal tissues. MR guided focused ultrasound (MRgFUS) thermal ablation has been applied for cancer surgery and bone palliation clinically. The aim of this work is to explore the feasibility of MRgFUS for prostate cancer therapy. Method and Materials: An InSightec ExAblate 2000 with a 1.5T GE MR scanner was used in this study. Suitable ultrasound parameters were investigated to perform non‐thermal sonications keeping the temperature below 42°C as measured in real time by MR thermometry. LNCaP cells (106) were injected into the prostate of male mice (n=8). When tumors reached the volume of 49±3mm3 on MRI the tumor‐bearing mice were treated with MRgFUS once a week for two consecutive weeks. Animals were treated with pulsed ultrasound (1MHz; 5W acoustic power; 5Hz frequency; 0.5duty cycle: 0.1sec power on 0.1sec power off) for 60sec in each sonication. A total of 4–6 sonications were used to cover the entire tumor volume. The animals were allowed to survive for 4 weeks after the last treatment. The tumor growth was monitored on MRI and compared with the control group. Results: Significant tumor growth delay was observed in the mice treated with MRgFUS. The mean tumor volume for the MRgFUS treated mice was about 30% smaller than that of the control mice 1 week after the MRgFUS treatment and it was about 50% smaller 4 weeks after the MRgFUS treatment. Conclusions: Our results demonstrated that non‐thermal MRgFUS has a great potential for cancer therapy. Further experiments are needed to derive optimal ultrasound parameters and fractionation schemes to maximize the therapeutic effect. This work is supported by Focused Ultrasound Surgery Foundation DOD PC073127 and Varian Medical Systems. Technical support from InSightec is acknowledged.

SU‐GG‐J‐134: Non‐Thermal Cell Damage and Therapeutic Potential of MR Guided High‐Intensity Focused Ultrasound

Purpose: High‐intensity focused ultrasound (HIFU) has garnered increasing interest in therapeutic applications for occlusion of blood flow, sealing of bleeding vessels, sonothrombolysis, myocardium revascularization channel creation, opening of the blood brain barrier and transdermal drug delivery. In this work, we investigate the non‐thermal cell damage and therapeutic potential of HIFU for treating non‐operable, radiation‐ and chemo‐resistant cancers. Method and Materials: An InSightec ExAblate 2000 with a 1.5T GE MR scanner was used in this study. MR thermometry was used to monitor the temperature elevation in real time to ensure non‐thermal (below 42°C) sonication. LNCaP and PC3 cells were placed in thin plastic vessels and inserted in an ultrasound gel phantom with the ultrasound beam focused on the tumor cells. Cells were exposed to pulsed ultrasound (1MHz; 6W and 10W acoustic power; 5Hz frequency; 0.5duty cycle: 0.1s power on, 0.1s power off) for 60sec. Cell viability was assessed by trypan blue dye exclusion and clonogenic assay. Results: Non‐thermal cell damage by HIFU exposure was observed for both LNCaP and PC3 cells. At 6W acoustic power, the cell‐death rate was 23.3+1.7% and at 10W it was 46.3+1.9% for the LNCaP cells (see table below). The control group has a 12.7+0.3% death rate. For PC3 cells, the cell‐death rate was 18.7+0.7% for the treated group and 9.0+0.6% for the control cells at 6W. The clonogenic assay results were consistent with the trypan blue dye analysis. Conclusions: Our in vitro experiments confirmed the non‐thermal effect of HIFU on prostate tumor cells. The exact mechanism for non‐thermal cell damage needs to be investigated. Further in vivo experiments are warranted to derive optimal ultrasound parameters for HIFU cancer therapy and to provide preclinical toxicity data. This work is supported by Focused Ultrasound Surgery Foundation, DOD PC073127 and Varian Medical Systems. Technical support from InSightec is acknowledged.

A long arm for ultrasound: A combined robotic focused ultrasound setup for magnetic resonance‐guided focused ultrasound surgery

Focused ultrasound surgery (FUS) is a highly precise noninvasive procedure to ablate pathogenic tissue. FUS therapy is often combined with magnetic resonance (MR) imaging as MR imaging offers excellent target identification and allows for continuous monitoring of FUS induced temperature changes. As the dimensions of the ultrasound (US) focus are typically much smaller than the targeted volume, multiple sonications and focus repositioning are interleaved to scan the focus over the target volume. Focal scanning can be achieved electronically by using phased-array US transducers or mechanically by using dedicated mechanical actuators. In this study, the authors propose and evaluate the precision of a combined robotic FUS setup to overcome some of the limitations of the existing MRgFUS systems. Such systems are typically integrated into the patient table of the MR scanner and thus only provide an application of the US wave within a limited spatial range from below the patient. The fully MR-compatible robotic assistance system InnoMotion (InnoMedic GmbH, Herxheim, Germany) was originally designed for MR-guided interventions with needles. It offers five pneumatically driven degrees of freedom and can be moved over a wide range within the bore of the magnet. In this work, the robotic system was combined with a fixed-focus US transducer (frequency: 1.7 MHz; focal length: 68 mm, and numerical aperture: 0.44) that was integrated into a dedicated, in-house developed treatment unit for FUS application. A series of MR-guided focal scanning procedures was performed in a polyacrylamide-egg white gel phantom to assess the positioning accuracy of the combined FUS setup. In animal experiments with a 3-month-old domestic pig, the system's potential and suitability for MRgFUS was tested. In phantom experiments, a total targeting precision of about 3 mm was found, which is comparable to that of the existing MRgFUS systems. Focus positioning could be performed within a few seconds. During in vivo experiments, a defined pattern of single thermal lesions and a therapeutically relevant confluent thermal lesion could be created. The creation of local tissue necrosis by coagulation was confirmed by post-FUS MR imaging and histological examinations on the treated tissue sample. During all sonications in phantom and in vivo, reliable MR imaging and online MR thermometry could be performed without compromises due to operation of the combined robotic FUS setup. Compared to the existing MRgFUS systems, the combined robotic FUS approach offers a wide range of spatial flexibility so that highly flexible application of the US wave would be possible, for example, to avoid risk structures within the US field. The setup might help to realize new ways of patient access in MRgFUS therapy. The setup is compatible with any closed-bore MR system and does not require an especially designed patient table.

A Study of Heating Duration and Scanning Path in Focused Ultrasound Surgery

A conventional method of avoiding normal tissue overheating during focused ultrasound surgery (FUS) is to apply equal heating duration for each sonication in between cooling intervals. However, this method is time-consuming and expensive. A novel method with unequal heating duration in different scanning paths without cooling intervals was investigated in this paper. This method was compared with the conventional method through the ablation of a 10 × 10 cm(2) target. The simulation results indicated that the new method was able to reduce treatment time by more than 50%, with higher than 95% coverage index, and more uniform thermal dose distribution. The method was further verified through the ablation of a circular lesion. Ex vivo experiments were also performed to confirm the simulation results. Both simulation and experimental results have proven that the new method can increase heating efficiency, and are a promising new approach in FUS.

Monitoring heat-induced changes in soft tissues with 1D transient elastography

In this paper 1D transient elastography was employed in fresh bovine skeletal muscle samples to assess the shear elastic modulus μ while the tissue was locally heated by means of an electrical resistance. The investigation is based on the study of the time shift of the shear wave propagation produced by the local temperature variation. The experiments show that the thermal expansion contribution to the time shift is negligible when compared with the shear wave speed variation. In such a case, the quantification of μ as a function of temperature becomes possible. Repeated experiments in different samples lead to a reproducible behavior of μ as a function of temperature. Irreversible elasticity changes are produced when the temperature exceeds a certain critical value Tc. The proposed method allows estimating this value as well as the spatial extension of the resulting thermal lesion. This point is important when considering applications in monitoring focused ultrasound surgery (FUS) because the surrounding normal tissue should remain unaffected.

Focused Ultrasound as a Local Therapy for Liver Cancer

Conventional surgical treatments of liver cancer are invasive (including minimally invasive) with a high incidence of new metastasis and poor success, even after multiple resections or ablations. These limitations motivated research into new, less invasive solutions for liver cancer treatment.Focused ultrasound surgery (FUS), or high-intensity focused ultrasound, has been recognized as a noninvasive technology for benign and malignant tumor treatment. Previously, FUS was guided with ultrasound that has limited target definition and monitoring capability of the ablation process. Combining magnetic resonance imaging (MRI) with multiple-element phased-array transducers to create MRI-guided focused ultrasound thermal therapy provides more accurate targeting and real-time temperature monitoring. This treatment is hindered by the ribcage that limits the acoustic windows to the liver and the respiratory motion of the liver. New advances in MRI and transducer design will likely resolve these limitations and make MRI-guided FUS a powerful tool in local liver cancer therapy. This article reviews this technology and advances that can expand its use for cancer treatment in general and liver cancer in particular.

Local Harmonic Motion Monitoring of Focused Ultrasound Surgery—A Simulation Model

In this paper, a computational model for localized harmonic motion (LHM) imaging-based monitoring of high-intensity focused ultrasound surgery (FUS) is presented. The LHM technique is based on a focused, time-varying ultrasound radiation force excitation, which induces local oscillatory motions at the focal region. These vibrations are tracked, using pulse-echo imaging, and then, used to estimate the mechanical properties of the sonication region. LHM is feasible for FUS monitoring because changes in the material properties during the coagulation process affect the measured displacements. The presented model includes separate models to simulate acoustic sonication fields, sonication-induced temperature elevation and mechanical motion, and pulse-echo imaging of the induced motions. These 3-D simulation models are based on Rayleigh-Sommerfield integral, finite element, and spatial impulse response methods. Simulated-tissue temperature elevation and mechanical motion were compared with previously published in vivo measurements. Finally, the simulation model was used to simulate coagulation and LHM monitoring, as would occur with multiple, neighbouring sonication locations covering a large tumor.

Focused ultrasound treatment of VX2 tumors controlled by local harmonic motion

The purpose of this study was to evaluate the feasibility of using localized harmonic motion (LHM) to monitor and control focused ultrasound surgery (FUS) in VX2 tumors in vivo. FUS exposures were performed on 13 VX2 tumors implanted in nine rabbits. The same transducer induced coagulation and generated a localized oscillatory motion by periodically varying the radiation force. A separate diagnostic ultrasound transducer tracked motion by cross-correlating echo signals at different instances. A threshold in motion amplitude was instituted to cease exposure. Coagulation was confirmed by T2-weighted MR images, thermal dose obtained through MR thermometry and histological examinations. For tumor locations achieving coagulation, the LHM amplitude was 9% (p = 0.04) to 57% (p < 0.0001) lower than that before exposure. Control was successful for 74 (69%) out of 108 cases, with 52 (48%) reaching the threshold and achieving coagulation and 22 (21%) never reaching threshold nor coagulating. For the 34 (31%) unsuccessful exposures, 16 (15%) never reached the threshold but coagulation occurred, and 18 (16%) reached threshold without coagulation confirmed. Noise or radio-frequency signal changes explained motion over- or underestimation in 24 (22%) cases; the remaining 10 (9%) had other causes of error. The control was generally successful, but sudden change or noise in the acquired echo signal caused failure. Coagulation after exposure could be validated by comparing amplitudes before and after exposure.

Hybrid Supervisory Control for Biomechatronic Systems for Non-Invasive Surgery

Several factors affect the safe operation of a bio-mechatronic system such as design limitations of the robots to do complex surgical manoeuvres, malfunction of the system’s components, unpredictability of the working envelope to name a few. One measure that can be taken in order to improve the safe performance is to implement a reliable control system. In our research, an optimal control hierarchy and strategy is considered for implementation for non-invasive surgical applications. A control strategy is proposed for supervisory hybrid control using PID and model-based robust control as the parameterized controllers and its implementation for FUSBOTBS (a custom designed robotic system using Focused Ultrasound Surgery for Breast Surgery) is demonstrated. Mechanical feasibility tests and in-vitro experimental trials supported the results with a positioning accuracy within 0.5mm.

Sustained Relief of Leiomyoma Symptoms by Using Focused Ultrasound Surgery

For the MrgFUS Study Group; Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota