Focused Ultrasound Surgery Foundation Research Articles

WE‐H‐209‐00: Carson/Zagzebski Distinguished Lectureship: Image Guided Ultrasound Therapy

Focused ultrasound has been shown to be the only method that allows noninvasive thermal coagulation of tissues and recently this potential has been explored for image‐guided drug delivery. In this presentation, the advances in ultrasound phased array technology for energy delivery, exposure monitoring and control will be discussed. Experimental results from novel multi‐frequency transmit/receive arrays will be presented. In addition, the feasibility of fully electronically focused and steered high power arrays with many thousands of transducer elements will be discussed. Finally, some of the recent clinical and preclinical results for the treatment of brain disease will be reviewed. Learning Objectives: Introduce FUS therapy principles and modern techniques Discuss use of FUS for drug delivery Cover the technology required to deliver FUS and monitor therapy Present clinical examples of the uses of these techniquesThis research was supported by funding from The Canada Research Chair Program, Grants from CIHR and NIH (no. EB003268).; K. Hynynen, Canada Foundation for Innovation; Canadian Institutes of Health Research; Focused Ultrasound Surgery Foundation; Canada Research Chair Program; Natural Sciences and Engineering Research Council of Canada; Ontario Research Fund; National Institutes of Health; Canadian Cancer Society Research Institute; The Weston Brain Institute; Harmonic Medical; Focused Ultrasound Instruments

WE‐H‐209‐01: Advances in Ultrasound Therapy

Focused ultrasound has been shown to be the only method that allows noninvasive thermal coagulation of tissues and recently this potential has been explored for image‐guided drug delivery. In this presentation, the advances in ultrasound phased array technology for energy delivery, exposure monitoring and control will be discussed. Experimental results from novel multi‐frequency transmit/receive arrays will be presented. In addition, the feasibility of fully electronically focused and steered high power arrays with many thousands of transducer elements will be discussed. Finally, some of the recent clinical and preclinical results for the treatment of brain disease will be reviewed. Learning Objectives: Introduce FUS therapy principles and modern techniques Discuss use of FUS for drug delivery Cover the technology required to deliver FUS and monitor therapy Present clinical examples of the uses of these techniquesThis research was supported by funding from The Canada Research Chair Program, Grants from CIHR and NIH (no. EB003268).; K. Hynynen, Canada Foundation for Innovation; Canadian Institutes of Health Research; Focused Ultrasound Surgery Foundation; Canada Research Chair Program; Natural Sciences and Engineering Research Council of Canada; Ontario Research Fund; National Institutes of Health; Canadian Cancer Society Research Institute; The Weston Brain Institute; Harmonic Medical; Focused Ultrasound Instruments

A Pilot Study of Focused Ultrasound Thalamotomy for Essential Tremor

BackgroundRecent advances have enabled delivery of high-intensity focused ultrasound through the intact human cranium with magnetic resonance imaging (MRI) guidance. This preliminary study investigates the use of transcranial MRI-guided focused ultrasound thalamotomy for the treatment of essential tremor.MethodsFrom February 2011 through December 2011, in an open-label, uncontrolled study, we used transcranial MRI-guided focused ultrasound to target the unilateral ventral intermediate nucleus of the thalamus in 15 patients with severe, medication-refractory essential tremor. We recorded all safety data and measured the effectiveness of tremor suppression using the Clinical Rating Scale for Tremor to calculate the total score (ranging from 0 to 160), hand subscore (primary outcome, ranging from 0 to 32), and disability subscore (ranging from 0 to 32), with higher scores indicating worse tremor. We assessed the patients' perceptions of treatment efficacy with the Quality of Life in Essential Tremor Questionnaire (ranging from 0 to 100%, with higher scores indicating greater perceived disability).ResultsThermal ablation of the thalamic target occurred in all patients. Adverse effects of the procedure included transient sensory, cerebellar, motor, and speech abnormalities, with persistent paresthesias in four patients. Scores for hand tremor improved from 20.4 at baseline to 5.2 at 12 months (P=0.001). Total tremor scores improved from 54.9 to 24.3 (P=0.001). Disability scores improved from 18.2 to 2.8 (P=0.001). Quality-of-life scores improved from 37% to 11% (P=0.001).ConclusionsIn this pilot study, essential tremor improved in 15 patients treated with MRI-guided focused ultrasound thalamotomy. Large, randomized, controlled trials will be required to assess the procedure's efficacy and safety. (Funded by the Focused Ultrasound Surgery Foundation; ClinicalTrials.gov number, NCT01304758.)

Introduction to the special issue on therapeutic ultrasound

In the 1950s, the brothers William and Francis Fry treated a number of patients for Parkinson's disease by focusing high intensity ultrasound on the brains of patients after some part their skull was removed. Local thermal ablations were created in targeted areas of brain and these treatments were shown to be beneficial to the patients. At the same time, in the former USSR, the team of A.K. Burov used high intensity unfocused ultrasound to treat aggressive melanoma cancerous tumors and obtained very promising positive response in a number of patients; similar exposure protocols were used to induce specific immune response in an animal model. However, in those days, imaging systems were in their infancy, no MRI or CT systems were available, and ultrasound technology was not ready to extensively explore the ability of ultrasound to non-invasively induce changes in biological tissue. The advancements in tissue imaging, engineering, and the rapid development of computers that occurred during the last decade have now permitted a new cycle of development of therapeutic ultrasound. Successful medical technologies are already in clinical practice, ranging from tumor treatments to cosmetic applications; clinical studies are under way in ultrasound enhanced drug delivery, sonothrombolysis, and hyperthermia. Recently, a pilot study of the use of focused ultrasound for the treatment of dyskinesia in Parkinson's disease was funded by the Michael J. Fox Foundation bringing back Fry's efforts at a new technological level. Every large acoustics professional meeting, and in particular ASA meetings, include special sessions on therapeutic ultrasound. The annual International Symposium for Therapeutic Ultrasound and the biannual Focused Ultrasound Surgery Foundation Symposium bring world experts together to exchange ideas and accelerate development of this field. Even though therapeutic ultrasound technology is rapidly evolving into clinical practice, basic acoustics still remains an important foundation and a critical component in its successful implementation. This issue represents only a snapshot of the scientific and clinical applications at this moment of time. Many questions are not yet answered. Further progress of the field requires merging new interesting acoustic phenomena with biophysics, engineering solutions, and other exciting interdisciplinary studies. We hope that some of the examples of recent studies presented in this issue will be of general interest to the acoustical community helping to bring a younger generation of acousticians into the field. We also anticipate that some of the results reported in this issue will soon be transitioned into the clinic, resulting in the improvement of health care for our society.

TU‐A‐BRA‐11: Targeted Drug Delivery Technique Employing Pulsed Focused Ultrasound for Treatment of Prostate

Purpose: The purpose of this study is to investigate an innovative approach to prostate cancer therapy using nanodroplet‐encapsulated drugs combined with pFUS (pulsed high intensity focused ultrasound) treatment. Pulsed FUS treatment provides a localized drug release from the carrier and enhanced intracellular uptake, which ensures temporal and spatial control of local drug delivery while lowering the systemic toxicity. Methods: LNCaP cells were implanted into the prostates of nude mice. Tumor growth was monitored using MRI. The tumor‐bearing mice were randomly divided into 5 groups (n=3). Group 1, animals were treated with an IV injection of paclitaxel (PTX)‐encapsulated nanodroplets (ND‐PTX) + pFUS. Animals in Group 2 were treated with pFUS alone. Animals in Group 3 were injected (IV) with PTX‐encapsulated nanodroplets alone, Group 4 received pFUS+empty nanodroplets and Group 5 was used as a control group. After treatment, animals were allowed to survive for 4 weeks. Tumor growth delay was monitored by MRI. The formulation of the PTX‐encapsulated nanodroplets is as follows: PTX dose 20 mg/kg, Nanoemulsion composition 0.5% PTX, 1% perfluorocarbon and 2% stabilizing block copolymer. Ultrasound treatment parameters were 1MHz, 25W acoustic power, 10% duty cycle and 60 sec for each sonication. Results: Compared with the control group, significant tumor growth delay was observed in Group 1 with p=0.004, 3 weeks after treatment. There was no significant tumor growth delay observed for Group 2 (p=0.285), Group 3 (p=0.452) and Group 4 (p=0.158). Conclusions: Our preliminary results showed a great potential for prostate cancer therapy using targeted PTX+ nanodroplets, which could be activated by pFUS. More animal studies are warranted to confirm the results. The enhancement effect of pFUS on targeted drug delivery needs to be investigated quantitatively. This work is supported by Focused Ultrasound Surgery Foundation, DOD PC073127 and DOD BC102806. Technical support from InSightec is graciously acknowledged. funding supported partially by Focused Ultrasound Surgery Foundation, DOD PC073127 and DODBC102806

TU-C-BRB-05: BEST IN PHYSICS (THERAPY) - Combined Effects of Pulsed Non-Thermal Focused Ultrasound and Radiotherapy for Prostate Cancer Treatment

Purpose: Recent studies have shown non-thermal effects of pulsed focused ultrasound (pFUS) on tumor growth control. This study is to investigate the combined effects of non-thermal pFUS and radiotherapy (RT) for prostate cancer treatment. Methods: Animal prostate tumor model was developed by implanting LNCaP cells in mice prostates. Tumor-bearing mice were randomly assigned to 3 groups (n=8): (1) pFUS; (2) pFUS+RT; (3) control. MR-guided pFUS treatment was performed using InSightec ExAblate 2000 system with a 1.5T GE MR scanner. Non-thermal sonications were delivered by keeping the body temperature <42°C as measured real-time by MR thermometry. Prostate tumors in groups 1 and 2 were exposed to pFUS (1MHz, 25W focused ultrasound; 1Hz pulse rate with a 10% duty cycle) for 60 sec for each sonication. Each tumor was covered entirely using 4–8 sonication spots. Prostate tumors in group 2 also received 2 Gy radiation dose within 30 minutes after pFUS treatment using Siemens Artiste (6MV photon energy, 300MU/min dose rate). Following the treatment, mice were scanned weekly using MRI for tumor volume measurement. Results: Tumor volumes in the control group showed exponential increase from 121±5 mm3 on treatment day to 172±9, 247±15, 344±28, and 500±42 mm3 at 1, 2, 3, and 4 weeks post treatment, respectively. In contrast, tumor volumes in the pFUS group were 33% (p<0.05), 29% (p<0.05), 14%, and 15% smaller, and the pFUS+RT group were 31%, 31%, 26%, 33% smaller (p<0.05) at week 1, 2, 3, and 4 post treatment, respectively. Both pFUS and pFUS+RT groups showed significant tumor growth delay in the first two weeks. Conclusions: Our study showed that pFUS combined with radiotherapy can significantly delay the tumor growth. Radiation after pFUS treatment provided an additional benefit for tumor control (sponsored by Focused Ultrasound Surgery Foundation, Varian Medical Systems, DOD PC073127, DOD BC102806).

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&amp;#61616;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-220-06: 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‐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.

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.

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.