CurrentCurrent andand FutureFuture ApplicationsApplications of Focused UltrasoundUltrasound 20142014 4th4th InternationalInternational SymposiumSymposium

ProgramProgram && AbstractAbstract Book OctoberOctober 12-16,12–16, 20142014

BethesdaBethesda North Marriott Hotel & ConferenceConference Center FFocusedocused Ultrasound Ultrasound Foundation Foundation www.fusfoundation.orgwww.fusfoundation.org | Charlottesville, | Charlottesville, VA | TVA 434.220.4993 | T 434.220.4993 Washington,Washington, DC MetroMetro Area, USA FUSF Symposium Ad - Final.pdf 1 9/12/2014 10:36:49 AM

Sponsor Acknowledgements Your partner in advancing the field

Platinum Sponsors The Focused Ultrasound Foundation was created to improve the lives of millions of patients by accelerating the development and adoption of focused ultrasound. We leverage our independent status to drive progress by:

Funding Research A key priority for the Foundation is funding translational studies, applying the growing body of knowledge to complex problems. We organize and conduct research internally and through an C External Awards Program, which funds investigator-initiated

M clinical and technical research projects through a competitive peer-reviewed process. Y

CM

MY

CY

Bronze Sponsors CMY Fostering K Collaboration We act as a global connector, hosting a variety of workshops and biennial symposia to stimulate innovation and increase awareness. International Society for Thearapeutic Ultrasound

Overcoming Barriers Media Partner We partner with industry to help usher this technology through the regulatory and reimbursement processes and move the technology closer to patients.

www.fusfoundation.org

FUSF_Symposium_2014_Program_Cover_Inside.indd 1 9/29/2014 4:37:28 PM Welcome Messages

From the Honorary President

It is an exciting time for the fi eld to come together. Great strides have been made in the two years since the last Symposium. From my perspective into Europe and Asia, there has been clear progress in treating neurological disorders, pain management and cancers. Patients with prostate cancer, breast cancer, soft tissue tumors and liver cancer are increasingly offered this non-invasive option, and there is a promising study being discussed this week on treating pancreatic cancer. After more than 25 years in this fi eld, I have personally seen focused ultrasound evolve from a concept to a global treatment reality.

Having been involved in technical development and treating tumor patients in China and the UK, I know it requires countless stakeholders working in tandem to make real progress. To continue on this trajectory, I believe we must broaden our scope past our own organizations and fi elds of study to seek out new partnerships and applications for this promising technology.

The symposium is an opportunity for both clinicians and scientists in the fi eld to learn from each other and understand how their work reinforces one another. My hope is that with our great efforts, we will work towards establishing international standards or guidelines for devices and clinical applications in the future. With this groundwork laid, I believe we will see the fi eld grow immensely.

I look forward to spending time with you over the next several days.

Sincerely,

Feng Wu, MD, PhD Focused Ultrasound Consultant and Senior Clinical Scientist Oxford University Honorary Symposium President

Focused Ultrasound 2014 4th International Symposium 1 Welcome Messages (continued)

From the Foundation Chairman

Dear Colleagues:

Welcome to the 4th International Symposium on Focused Ultrasound. This week, we will take part in the most extensive program we have hosted to date, featuring more than 200 oral and poster presentations. This year’s program allows for nearly four full days of scientifi c talks and engaging discussions, necessitated by signifi cant advances achieved by you — the focused ultrasound community.

The fi eld’s momentum is tangible. Since we met last, focused ultrasound is emerging as a relevant option for countless patients as the technology is transitioning from research to clinical uses. The treatment of pain from bone metastases was approved by the U.S. Food and Drug Administration in late 2012, while the number of indications in various stages of research, development and commercialization has skyrocketed, including neurological conditions like essential tremor and Parkinson’s disease; cancers of the breast, pancreas, liver, lung and kidney; as well as agonizing musculoskeletal conditions like osteoid osteoma and back pain. Two prostate devices are currently under FDA review, and enrollment is nearly complete on an essential tremor pivotal study, putting the technology on the path for FDA approval for the fi rst of what we hope will be several neurological applications.

The symposium is an important vehicle for disseminating knowledge and sharing ideas, serving as an incubator to foster collaboration and hasten the speed of progress. Please take advantage of the opportunities to establish new partnerships this week.

Several special events are planned during the symposium, including keynote talks by Frederic Moll, MD, serial medical device entrepreneur and founder of Intuitive Surgical, the makers of the Da Vinci Surgical System; Andrew von Eschenbach, MD, former Commissioner of the FDA and Director of the NCI; and Rick Hamilton, IBM’s most prolifi c inventor and innovation evangelist.

The Focused Ultrasound Foundation is proud to serve as the nexus for the global focused ultrasound ecosystem. We are deeply appreciative of your participation in the symposium and of your steadfast commitment to advancing focused ultrasound. I am confi dent that this event will inspire and facilitate your continued contributions to the growing body of focused ultrasound research and knowledge.

In closing, I would like to acknowledge the generosity of our donors and the support of our sponsors. They have made this meeting possible. Thank you.

Sincerely,

Neal F. Kassell, MD Chairman, Focused Ultrasound Foundation

2 Focused Ultrasound 2014 4th International Symposium Symposium Organizer

About the Focused Ultrasound Foundation

The Focused Ultrasound Foundation is a medical technology research, education and advocacy organization dedicated to improving the lives of millions of people with serious medical disorders by accelerating the development and adoption of focused ultrasound.

Positioned at the nexus of a large, diverse group of stakeholders comprising the focused ultrasound community, the Foundation functions as an independent, unbiased third-party, aligning organizations into a cohesive ecosystem with a single goal: To make this technology available to patients in the shortest time possible. It strives to catalyze progress while instilling a patient-centric sense of urgency.

The Foundation works to clear the path to global adoption by organizing and funding research, fostering collaboration, building awareness at our various workshops and symposia, and cultivating the next generation through internships and fellowships.

The Foundation is on the leading edge of the venture philanthropy and social entrepreneurship movements and is a model of how private philanthropy can work in concert with academia, industry and government to bridge the gap between research and commercialization.

To learn more about focused ultrasound and the Focused Ultrasound Foundation, visit the Foundation’s website: www.fusfoundation.org

Organizing Committee

Neal F. Kassell, MD, Chair Chairman, Focused Ultrasound Foundation; Professor of Neurosurgery, University of Virginia

Jessica Foley, PhD, Co-Vice Chair Scientifi c Director Focused Ultrasound Foundation

Arik Hananel, MD, MBA, Co-Vice Chair Medical Director Focused Ultrasound Foundation

Robin Jones, Project Lead Director of Clinical Trials Coordination Focused Ultrasound Foundation

Focused Ultrasound 2014 4th International Symposium 3 Symposium Organizer (continued)

Board of Directors Dorothy N. Batten Edward D. Miller, MD Director, Amazon Conservation Association Former CEO, Johns Hopkins Medicine Former Director, Landmark Communications Frederic H. Moll, MD Lodewijk J.R. de Vink Co-founder, Intuitive Surgical Founding Partner, Blackstone Healthcare Partners, LLC Chairman & CEO, Auris Surgical Robotics, Inc. Former Chairman & CEO, Warner-Lambert Steve H. Rusckowski Eugene V. Fife President and CEO, Quest Diagnostics Inc. Founding Principal, Vawter Capital, LLC Former CEO, Philips Healthcare Former Chairman, Goldman Sachs International Andrew C. von Eschenbach, MD John R. Grisham President, Samaritan Health Initiative Author Former Commissioner, U.S. Food and Drug Administration Former Director, National Cancer Institute Daniel P. Jordan, PhD President Emeritus, Thomas Jefferson Foundation, Inc. Carl P. Zeithaml, PhD Dean and F.S. Cornell Professor of Free Enterprise, Neal F. Kassell, MD McIntire School of Commerce, University of Virginia Chairman, Focused Ultrasound Foundation Professor of Neurosurgery, University of Virginia

Scientifi c Program Committee Jean-François Aubry, PhD Hidemi Furusawa, MD Stephen Monteith, MD Institut Langevin Breastopia Namba Hospital Swedish Medical Center Paris, France Miyazaki, Japan Seattle, Washington, United States Jin Woo Chang, MD, PhD Arik Hananel, MD, MBA Alessandro Napoli, MD YUMC Severance Hospital Focused Ultrasound Foundation University of Rome – La Sapienza Seoul, Republic of Korea Charlottesville, Virginia, United States Rome, Italy Christian Chaussy, MD Mark Hurwitz, MD Franco Orsi, MD University of Munich Thomas Jefferson University European Institute of Oncology Munich, Germany Philadelphia, Pennsylvania, United States Milan, Italy Larry Crum, PhD Joo Ha Hwang, MD, PhD Elizabeth Stewart, MD University of Washington University of Washington Mayo Clinic Seattle, Washington, United States Seattle, Washington, United States Rochester, Minnesota, United States Emad Ebbini, PhD Ferenc Jolesz, MD Gail ter Haar, PhD University of Minnesota Brigham and Women’s Hospital The Institute of Cancer Research Minneapolis, Minnesota, United States Boston, Massachusetts, United States London, United Kingdom Keyvan Farahani, PhD Young-Sun Kim, MD National Cancer Institute Samsung Medical Center Rockville, Maryland, United States Seoul, Republic of Korea Jessica Foley, PhD Nathan McDannold, PhD Focused Ultrasound Foundation Brigham and Women’s Hospital Charlottesville, Virginia, United States Boston, Massachusetts, United States

4 Focused Ultrasound 2014 4th International Symposium Map | Grand Ballroom

Abstract Types BM Bone Metastases

BN Bone Non-metastases P-100-BM P-101-BM P-102-BM P-103-BN P-104-BN P-105-BN BR Brain P-111-BR P-110-BR P-109-BR P-108-BR P-107-BR P-106-BN BT Breast Tumors EA Emerging Applications P-112-BR P-113-BR P-114-BR P-115-BR P-117-BR P-118-BR P-124-BR P-123-BR P-122-BR P-121-BR P-120-BR P-119-BR EI Enhanced Immunotherapy JN Journal P-125-BRP-126-BR P-127-BR P-128-BR P-129-BR P-130-BR LV Liver and Pancreas P-136-BR P-135-BR P-134-BR P-133-BR P-132-BR P-131-BR PR Prostate

UF Uterine Fibroids P-137-BRP-138-BR P-139-BR P-204-BR P-140-BT P-141-BT P-147-LV P-146-LV P-145-LV P-144-LV P-143-BT P-142-BT

P-148-LV P-149-LV P-150-LV P-151-LV P-152-LV P-153-EA

P-159-EA P-158-EA P-157-EA P-156-EA P-155-EA P-154-EA P-197-YI P-198-YI P-199-YI P-200-YI P-201-YI P-202-YI P-203-YI

P-160-EA P-161-EA P-162-EA P-163-EA P-164-EA P-169-EA P-168-EA P-167-EA P-166-EA P-165-EA

P-170-EA P-171-EA P-172-EA P-173-EA P-174-EA P-179-EA P-178-EA P-177-EA P-176-EA P-175-EA

P-180-EA P-181-PR P-182-PR P-205-PR P-183-UF P-188-UF P-187-UF P-186-UF P-185-UF P-184-UF P-192-YI P-193-YI P-194-YI P-195-YI P-196-YI

Salon D

P-189-YI P-190-YI P-191-YI Posters

Image Special Events, Guided Food & Beverage Posters Oral Sessions Therapy Monitor Salon A - C Salon D Salon E - H Philips KAI Research EUFUS EDAP Alpinion ISTU

Sponsors & Exhibitors Monitor

FUS Electronics Sonic Imasonic InSightec & Innovation Concepts Verasonics Registration Instruments Fibroid Relief Found- ation FUS

Focused Ultrasound 2014 4th International Symposium 5 General Information

Registration & Information Hours Meals Sunday 16:00 – 21:00 Included in Symposium Registration Monday 7:00 – 18:00 Tuesday 7:00 – 18:00 Registration includes continental breakfast, Wednesday 7:00 – 18:00 lunch, break refreshments and special events Thursday 7:00 – 13:00 in Salon A – C.

Dinner Options Local Transportation Symposium registration does not include dinner. Information about taxis and other local Meeting participants are welcome to dine at the transportation options is available from the hotel Marriott Bethesda North or at a location of their Concierge Desk located in the lobby. choice. Information about nearby restaurants is available from the hotel Concierge Desk located in the lobby. Internet Access

Wireless internet access is complimentary in the Special Events hotel lobby and in guest rooms that were reserved at the special conference rate. Sunday, 12 October 2014 Please come to the Symposium Registration Desk Welcome Reception for the Conference Center access code. 18:00 – 21:00 | Salon A – C Includes Drinks and hors d’oeuvres Symposium Mobile App Monday, 13 October 2014 sched.fusfoundation.org Focused Ultrasound Showcase Access the symposium schedule, speaker 18:00 – 21:00 | Salon A – D information and more in the mobile application Includes Drinks and hors d’oeuvres at the address above. For quick access, scan the QR code below with a QR reader on your device. Tuesday, 14 October 2014 Need a QR reader? Try the Apple App Store, Google Play or reader.kaywa.com/getit. Poster Session and Young Investigator Spotlight 18:00 – 21:00 | Salon A – D Includes Drinks and hors d’oeuvres

Symposium Feedback Survey To assist the Focused Ultrasound Foundation in evaluating the success of the symposium, attendees will be asked to complete a brief, anonymous online survey each day of the meeting, and at the end of the Symposium. Daily Surveys: Monday bit.do/FUSM #FUSF2014 Tuesday bit.do/FUST Follow the Symposium on Twitter Wednesday bit.do/FUSW and add your own impressions with Thursday bit.do/FUSTH the hash tag above. Overall Survey: bit.do/FUSF2014

6 Focused Ultrasound 2014 4th International Symposium Program

Program at a Glance Keynote Speakers 8 Sunday, 12 October 2014 8 Monday, 13 October 2014 9 Tuesday, 14 October 2014 10 Wednesday, 15 October 2014 11 Thursday, 16 October 2014 12

Detailed Program Sunday, 12 October 2014 13 Monday, 13 October 2014 13 Tuesday, 14 October 2014 15 Wednesday, 15 October 2014 16 Thursday, 16 October 2014 18

Poster Session Overview Topics by Application 19

Session Moderators 24

Focused Ultrasound 2014 4th International Symposium 7 Program at a Glance (continued)

Sunday 16:00 October 12

17:00

18:00 Registration Foyer 16:00 – 21:00

19:00 Welcome Reception Keynote Address: Frederic Moll, MD Salon A – C 18:00 – 21:00 20:00

21:00

Keynote Speakers Special Presenters Frederic Moll, MD

Sunday, October 12 | 18:00 – 21:00 Dr. Moll will deliver a keynote address entitled “Developing a New, Disruptive Therapeutic Modality: From Laboratory Research Tool to Standard of Care.”

Andrew von Eschenbach, MD

Tuesday, October 14 | 8:00 – 8:20 From Clandestine Operations Batten Family Lecture to Non-Invasive Operations: Dr. von Eschenbach will speak to, “The A Discussion with Tony and Virtuous Cycle of Discovery, Development, Jonna Mendez and Delivery: The 21st Century Paradigm for Advancing Bioscience.” Tuesday, October 14 | 11:45 – 12:30 Join the former CIA spymasters as Rick Hamilton they discuss Tony’s experience as the mastermind of the ARGO mission, Wednesday, October 15 | 8:00 – 8:20 their careers in intelligence technical Mr. Hamilton will discuss the rising development and his latest mission importance of innovation in today’s of managing Parkinson’s disease economy by examining the driving factors, and supporting the advancement of how organizations are responding, and focused ultrasound. what it means to us as individuals.

8 Focused Ultrasound 2014 4th International Symposium Program at a Glance (continued)

Monday 7:00 Continental Breakfast October 13 Salon A – D 7:00 – 8:00

8:00 Welcome | Diane and David Heller Lecture by Honorary President Salon E – H 8:00 – 8:25 Brain Essential Tremor | Parkinson’s Disease 9:00 Spontaneous Intracerebral Hemorrhage Cornelia Flagg Keller Lecture: Intractable Obsessive Compulsive Disorders Salon E – H 8:25 – 9:55 10:00 Break Salon A – D 9:55 – 10:25 Registration, Posters and Exhibits Salon D and Foyer 7:00 – 18:00 11:00 Brain Tumors | Blood Brain Barrier Salon E – H 10:25 – 12:10

12:00

Lunch Salon A – D 12:10 – 13:40 13:00

Brain 14:00 Neuropathic Pain | Neuromodulation Salon E – H 13:40 – 14:45

Break 15:00 Salon A – D 14:45 – 15:15

16:00 Brain Epilepsy | Treatment Envelope | Imaging Salon E – H 15:15 – 17:20

17:00

18:00

19:00 Focused Ultrasound Showcase Salon A – D 18:00 – 21:00

20:00

21:00

Focused Ultrasound 2014 4th International Symposium 9 Program at a Glance (continued)

Tuesday 7:00 Continental Breakfast October 14 Salon A – D 7:00 – 8:00 8:00 Keynote Address: Batten Family Lecture: Andrew von Eschenbach, MD Salon E – H 8:00 – 8:20 Panel Discussion: Enhanced Immunotherapy Salon E – H 8:20 – 9:05 9:00 Bone Non-Metastases Salon E – H 9:05 – 10:10 10:00 Break Salon A – D 10:10 – 10:40

11:00 Bone Metastases Salon E – H 10:40 – 11:45

Special Presentation: Tony and Jonna Mendez

12:00 Registration, Posters and Exhibits Salon E – H 11:45 – 12:30 Salon D and Foyer 7:00 – 21:00

13:00 Lunch Salon A – D 12:30 – 14:15

14:00 Panel Discussion: Controversies in Prostate Cancer Treatment Salon E – H 14:15 – 15:00 15:00 Prostate Salon E – H 15:00 – 15:55

16:00 Break Salon A – D 15:55 – 16:25

Prostate (continued) 17:00 Salon E – H 16:25 – 17:45

18:00

19:00 Poster Session and Young Investigator Spotlight Salon A – D 18:00 – 21:00

20:00

21:00

10 Focused Ultrasound 2014 4th International Symposium Program at a Glance (continued)

Wednesday 7:00 Continental Breakfast October 15 Salon A – D 7:00 – 8:00

8:00 Keynote Address: Rick Hamilton Salon E – H 8:00 – 8:20 Journal of Therapeutic Ultrasound Salon E – H 8:20 – 8:25

9:00 Emerging Applications Salon E – H 8:25 – 10:15

10:00 Break Salon A – D 10:15 – 10:45 Registration, Posters and Exhibits

11:00 Panel Discussion: Beyond Thermal Ablation Salon D and Foyer 7:00 – 18:00 Salon E – H 10:45 – 11:30

Breast 12:00 Salon E – H 11:30 – 12:40

13:00 Lunch Salon A – D 12:40 – 14:10

14:00 Panel Discussion: Controversies in Liver Tumor Treatment Salon E – H 14:10 – 14:55

15:00 Liver and Pancreas Salon E – H 14:55 – 16:00

16:00 Break Salon A – D 16:00 – 16:30

17:00 Liver and Pancreas (continued) Salon E – H 16:30 – 17:50

18:00

19:00

20:00

Focused Ultrasound 2014 4th International Symposium 11 Program at a Glance (continued)

Thursday 7:00 Continental Breakfast October 16 Salon A – C 7:00 – 8:00

8:00 Panel Discussion: Disruptive Effects in Medical Practice Salon E – H 8:00 – 8:45 Registration and Exhibits 9:00 Uterine Fibroids Foyer 7:00 – 13:00 Salon E – H 8:45 – 9:50

10:00 Break Salon A – C 9:50– 10:20

11:00 Uterine Fibroids — continued Salon E – H 10:20 – 12:15

12:00 Closing Remarks Salon E – H 12:15 – 12:25 Box Lunches Available 13:00

12 Focused Ultrasound 2014 4th International Symposium Detailed Program (continued)

Sunday Welcome Reception | 18:00 – 21:00 | Salon A – C Welcome ...... N. Kassell October 12 Keynote Address: Developing a New, Disruptive Therapeutic Modality: From Laboratory Research Tool to Standard of Care ...... F. Moll

Monday Welcome; Honorary President’s Address | 8:00 – 8:25 | Salon E – H Welcome and Opening Remarks ...... N. Kassell October 13 Diane and David Heller Lecture: Welcome by Honorary President ...... F. Wu Brain | 8:25 – 9:55 | Salon E – H 1-BR Essential Tremor ...... W.J. Elias Parkinson’s Disease Moderator: F. Wooten 2-BR Parkinson's Tremor ...... R. Dallapiazza 3-BR MR Guided Focused Ultrasound as a Treatment Tool for Essential and Parkinsonian Tremor...... M. Zaaroor 4-BR Bilateral MR Imaging-Guided High Intensity Focused Ultrasound for the Treatment of Tremor-dominant Parkinson’s Disease: First Experience with 9 Months Follow Up ...R. Bauer 5-BR Magnetic Resonance Guided Focused Ultrasound Pallidotomy for Parkinson’s disease ...... J.W. Chang 6-BR Staged Subthalamotomy ...... W.J. Elias Discussion 7-BR MRIgFUS in the Treatment of Spontaneous Intracerebral Hemorrhage ...... L. da Costa 8-BR Cornelia Flagg Keller Lecture: Magnetic Resonance Guided Focused Ultrasound Capsulotomy for Intractable Obsessive Compulsive Disorders ...... J.W. Chang Discussion ...... R. Cosgrove Brain (continued) | 10:25 – 12:10 | Salon E – H Brain Tumors Moderator: E. Oldfi eld 9-BR “Non-thermal” Ablation Using Focused Ultrasound and an Ultrasound Contrast Agent ...... N. McDannold 10-BR Sonodynamic Therapy for Treatment of C6 Glioma in a Rat Model Step 1: Feasibility of Tumor Model ...... P. Schmitt 11-BR First Non-Invasive Thermal Ablation of a Brain Tumor with MR guided Focused Ultrasound ...... J. Fandino 12-BR Clinical Trial Update: Treatment of Metastatic Brain Tumors Using MRgFUS ...... S. Monteith Discussion Blood-Brain Barrier (BBB) Moderator: N. McDannold 13-BR Clinical Glioblastoma ...... T. Mainprize 14-BR Temporary Disruption of the Blood-Brain Barrier Using an Implantable Ultrasound System for Recurrent Glioblastoma Patients Under IV Carboplatin Chemotherapy: Initial Phase 1/2a Clinical Trial Observations ...... M. Canney 15-BR Disruption of Vascular Barriers in Tumors and in the Brain ...... N. McDannold

Focused Ultrasound 2014 4th International Symposium 13 Detailed Program (continued)

16-BR Therapeutic Effects of Focused Ultrasound-mediated Blood-Brain Barrier Opening in a Mouse Model of Alzheimer’s Disease ...... K. Hynynen 17-BR Delivery of Stem Cells to the Brain: Potential for Treatment of Neurodegenerative Disease ...... K. Hynynen 18-BR Neurotrophic Delivery in Alzheimer’s-model Mice ...... E. Konofagou 19-BR Neuroprotection and Neuroregeneration Triggered through the FUS-induced Opening of the Blood-Brain Barrier in a Parkinson’s Mouse Model ...... E. Konofagou 20-BR Ultrasound-Targeted Nanoparticle Delivery Across the Blood-Brain Barrier ...... R. Price 21-BR Microbubble Protein Delivery for Parkinson's ...... J. Keenan Discussion Brain (continued) | 13:40 – 14:45 | Salon E – H 22-BR Neuropathic Pain: Long Term Follow-up ...... E. Martin Neuromodulation Moderator: J. Aubry 23-BR FUS-mediated Functional Neuromodulation for Neurophysiologic Assessment in a Large Animal Model ...... W. Lee 24-BR Ultrasound-induced Suppression of Visually-evoked Potentials: Experience in Nonhuman Primates with a Clinical Transcranial MRI-guided Focused Ultrasound System ...N. McDannold 25-BR Low Intensity Focused Ultrasound Modulates Monkey Visuomotor Behavior ...... J. Aubry 26-BR Image-guided Transcranial Focused Ultrasound Stimulation of Primary Somatosensory Cortex in Humans ...... S.S. Yoo 27-BR Safety and Feasibility of Focused Ultrasound Neuromodulation in Temporal Lobe Epilepsy ...... A. Bystritsky Discussion Brain (continued) | 15:15 – 17:20 | Salon E – H Epilepsy Moderator: R. Gwinn 28-BR Treatment of Mesial Temporal Lobe Epilepsy Using MRgFUS: Laboratory Feasibility Study ...... S. Monteith 29-BR Potential of Focused Ultrasound in Epilepsy Surgery ...... N. Fountain Discussion Treatment Envelope Moderator: E. Zadicario 30-BR Can Ultrasound Contrast Agents Increase the Treatment Envelope? ...... N. McDannold 31-BR Expanding the Treatment Envelope for Brain Therapy: Simulation Models and Head Phantoms ...... J. Aubry 32-BR Visualization of Mechanically Fractionated Lesions Generated by Boiling Histotripsy in Tissue by MRI ...... N. Farr 33-BR ExAblate Neuro Transcranial Treatment Considerations ...... E. Zadicario Discussion Imaging Moderator: K. Butts Pauly 34-BR Magnetic Resonance Acoustic Radiation Force (Impulse) Imaging (MR-ARFI) ...K. Butts Pauly 35-BR Volumetric Thermometry ...... D. Parker

14 Focused Ultrasound 2014 4th International Symposium Detailed Program (continued)

36-BR Improving Signal-to-Noise Ratio in Transcranial Magnetic Resonance Guided Focused Ultrasound ...... R. Hadley 37-BR MR Bone Imaging ...... W. Miller 38-BR Cavitation Detection for Brain Imaging and Therapy ...... M. O'Reilly Discussion Focused Ultrasound Showcase | 18:00 – 21:00 | Salon A – D

Tuesday Keynote Address | 8:00 – 8:20 | Salon E – H Batten Family Lecture: The Virtuous Cycle of Discovery, Development, and Delivery: October 14 The 21st Century Paradigm for Advancing Bioscience ...... A. von Eschenbach Panel Discussion: Enhanced Immunotherapy | 8:20 – 9:05 | Salon E – H Enhanced Immunotherapy K. Ferrara, M. Hurwitz, T. Khokhlova, B. Repasky, F. Wu 39-EI Focused Ultrasound: An Effective Technique for Unleashing the Power of Immunotherapy in the Tumor Microenvironment? ...... B. Repasky 40-EI HIFU Immunotherapy: Lessons from Animal to Clinical Studies ...... F. Wu 41-EI Immune Activation and MRgFUS ...... K. Ferrara 42-EI Focused Ultrasound and Immunotherapy ...... M. Hurwitz 43-EI T-cell Mediated Immune Response to HIFU-induced Liquefaction of Murine B16 Melanoma ...... T. Khokhlova Bone Non-Metastases | 9:05 – 10:10 | Salon E – H Moderators: M. Hurwitz, A. Napoli 44-BN Magnetic Resonance guided Focused Ultrasound Surgery (MRgFUS) Treatment of Osteoid Osteoma: a Prospective Development Study...... A. Napoli 45-BN MRgFUS Treatment of Superfi cial Osteoid Osteomas of the Lower Limbs ...... A. Bazzocchi 46-BN MRgFUS New Applications in Musculoskeletal Pathology: A Miscellaneous Case Review ...... A. Bazzocchi 47-BN Dual Echo Gradient Echo Imaging for Simultaneous Thermal Mapping in Cortical Bone and Soft Tissue...... E. Ramsay 48-BN Magnetic Resonance Guided Focused Ultrasound for Noninvasive Pain Therapy of Osteoid Osteoma in Children ...... A. Waspe Bone Metastases | 10:40 – 11:45 | Salon E – H Moderators: M. Hurwitz, A. Napoli 49-BM International Consensus on Use of MR-guided High-intensity Focused Ultrasound for Bone Metastases: Current Status and Future Directions...... M. Huisman 50-BM MR-guided Focused Ultrasound for Painful Bone Metastases: Safety When Combined with Chemotherapy ...... J. Meyer 51-BM Palliative Treatment of Painful Bone Metastases with MR Imaging–guided Focused Ultrasound Surgery: a Two-centre Study ...... A. Napoli 52-BM Palliation of Painful Bone Metastases: The "Rizzoli" Experience ...... A. Bazzocchi 53-BM Modeling of Temperature in Bone During MR-HIFU ...... S.Y. Yeo Panel Discussion: Prostate Controversies | 13:15– 14:00 | Salon E – H Controversies in Prostate Cancer Treatment C. Chaussy, R. Chopra, A. Gelet, S. Ghai, M. Hurwitz, J. Jurige, S. Scionti

Focused Ultrasound 2014 4th International Symposium 15 Detailed Program (continued)

Prostate | 14:00 – 14:55 | Salon E – H Moderators: H. Soule, C. Chaussy 54-PR Focal Treatment of Prostate Cancer Using Focal One Device: Pilot Study Results ...... A. Gelet 55-PR External Beam Radiation Therapy or High Intensity Focused Ultrasound for Localized Prostate Cancer: A Matched Pair Analysis in the Prostate-Specifi c Antigen Era ...... A. Gelet 56-PR Radical Prostatectomy versus High Intensity Focused Ultrasound for Localized Prostate Cancer: A Matched Pair Comparison ...... A. Gelet 57-PR Transrectal Focal HIFU: The Use of MRI Fusion in Guiding Treatment...... S. Scionti 58-PR Magnetic Resonance Guided Focused Ultrasound for Focal Therapy of Locally Confi ned Low Risk Prostate Cancer: Preliminary Outcomes ...... S. Ghai Prostate (continued) | 15:25 – 16:45 | Salon E – H 59-PR Transurethral MR-HIFU for the Treatment of Localized Prostate Cancer ...... R. Chopra 60-PR MRI-guided Transurethral Ultrasound Prostate Ablation: Midterm Outcomes of a Phase I Clinical Trial ...... M. Burtnyk 61-PR Transurethral Prostate Thermotherapy: Filtering the Bowel Motion During MR-thermometry Processing ...... A. Schmitt 62-PR Implementation of Sonication and Feedback Control Strategies for Targeted Hyperthermia in Prostate with a Commercial MR-guided Endorectal Ultrasound Ablation Array ....V. Salgaonkar 63-PR Immunomodulation of Prostate Cancer Cells after Low Energy Focused Ultrasound ...K. Skalina 64-PR High Intensity Focused Ultrasound-induced Bubbles Stimulate the Release of Nucleic Acid Cancer Biomarkers ...... T. Khokhlova Special Presentation | 17:00 – 17:30 | Salon A – D From Clandestine Operations to Non-Invasive Operations: A Discussion with Tony and Jonna Mendez Poster Session and Young Investigator Spotlight 18:00 – 21:00 | Salon E – H See Poster Overview on pages 19 – 23 and Young Investigators on pages 25 – 30

Wednesday Keynote Address | 8:00 – 8:20 | Salon E – H Innovation ...... R. Hamilton October 15 Journal | 8:20 – 8:25 | Salon E – H 65-JN The Journal of Therapeutic Ultrasound ...... W. Gedroyc Emerging Applications | 8:25 – 10:15 | Salon E – H Moderators: L. Crum, E. Ebbini 66-EA Quality Assurance and Field Characterisation for MRgHIFU Treatments: Their Need, and the Challenges Presented ...... J. Civale 67-EA Direct Nanodroplet and Microbubble Comparison for High Intensity Focused Ultrasound Ablation Enhancement and Safety ...... L. Phillips 68-EA Renal Denervation Using Externally Delivered Focused Ultrasound: Summary of Clinical Experience to Date and Validation of Supporting Computational Simulations ...... M. Gertner 69-EA MR Guided Focused Ultrasound Treatment Of Soft Tissue Tumors Of The Extremities - Preliminary Experience ...... P. Ghanouni 70-EA AAPM MRgFUS Task Group ...... K. Farahani 71-EA Preliminary Results of the Initial Human Clinical Trial of Focused Ultrasound to Reposition Kidney Stones ...... M. Bailey 16 Focused Ultrasound 2014 4th International Symposium Detailed Program (continued)

72-EA Destruction of Atherosclerotic Plaque Using Pulse Ultrasound with a Planar Rectangular Transducer...... C. Damianou 73-EA Mesenchymal Stem Cell (MSC) Homing to Kidneys is Suppressed by Inhibiting Interleukin 1-α, Tumor Necrosis Factor-α, or Cyclooxygenase-2 Signaling ...... S. Burks Panel Discussion: Beyond Thermal Ablation | 10:45 – 11:30 | Salon E – H Beyond Thermal Ablation J. Foley, B. Fowlkes, M. Hurwitz, N. McDannold, B. Wood Breast | 11:26 – 12:36 | Salon E – H Moderators: D. Brenin, M. Douek, C. Moonen 74-BT Results from Clinical Phase I Study on Breast Tumor Ablation with Dedicated Breast MR-HIFU System ...... R. Deckers 75-BT MRgFUS of Small Breast Cancer: What Should be Learned from a Case of Local Recurrence ...... H. Furusawa 76-BT Effi cacy and Safety of US-guided High-intensity Focused Ultrasound for Treatment of Breast Fibroadenoma ...... R. Kovatcheva 77-BT High Intensity Focused Ultrasound (HIFU) in the Treatment of Breast Fibroadenomata: a Feasibility Study...... M. Peek 78-BT Treatment of Breast Fibroadenoma with High Intensity Focused Ultrasound (HIFU): A Feasibility Study ...... D. Brenin Panel Discussion: Liver Controversies | 14:10– 14:55 | Salon E – H Controversies in Liver Tumor Treatment W. Gedroyc, C. Moonen, A. Napoli, G. ter Haar, F. Wu Liver and Pancreas | 14:55 – 16:00 | Salon E – H Moderators: G. ter Haar, F. Wu 79-LV UltraSound Guided High Intensity Focused Ultrasound (USgHIFU) For Malignant Tumors: Survival Advantage in Stage III and IV Pancreatic Cancer ...... J. Vidal-Jove 80-LV Magnetic Resonance guided Focused Ultrasound Surgery (MRgFUS) Treatment of Moving Organs: Non-invasive Treatment for Pain Palliation and Tumor Control of Locally Advanced Pancreatic Cancer and Hepatocellular Carcinoma ...... M. Anzidei 81-LV Harmonic Motion Imaging for Pancreatic Tumor Detection and High-intensity Focused Ultrasound Ablation Monitoring ...... H. Chen 82-LV Intra-operative High Intensity Focused Ultrasound in Patients with Colorectal Liver Metastases: Results of a Phase I-II Study in 21 Patients ...... D. Melodelima 83-LV MRgHIFU – Experimental Perivascular Volumetric Ablation in the Liver ...... U. Carling Liver and Pancreas (continued) | 16:30 – 17:50 | Salon E – H 84-LV Usefulness of 3D Slicer for the Planning and Monitoring of Hepatocellular Carcinoma Treatment Using FUS ...... N. Doba 85-LV TRANS-FUSIMO -- Clinical Translation of Patient Specifi c Planning and Conduction of FUS Treatment in Moving Organs ...... T. Preusser 86-LV Feasibility of Intercostal High Intensity Focused Ultrasound Ablation of Clinically Relevant Volumes Under The Application of Beam Shaping ...... M. de Greef 87-LV Spontaneous Breathing vs. Mechanical Ventilation for Respiratory-gated MR-HIFU Ablation in the Liver ...... J. van Breugel 88-LV Boiling Histotripsy Method to Mechanically Fractionate Tissue Volumes in Ex vivo Bovine Liver Using a Clinical MR-guided HIFU System ...... V. Khokhlova 89-LV Real-Time MRI Feedback of Cavitation Ablation Therapy (Histotripsy) ...... S. Allen

Focused Ultrasound 2014 4th International Symposium 17 Detailed Program (continued)

Thursday Panel Discussion: Medical Practice | 8:00 – 8:45 | Salon E – H October 16 Disruptive effects in medical practice C. Chaussy, P. Ghanouni, Y. Inbar, J. Larner , M. Matzko, F. Wu Uterine Fibroids | 8:45 – 9:50 | Salon E – H Moderators: W. Gedroyc, Y. Kim, E. Stewart 90-UF Portable High-intensity Focused Ultrasound System with 3D Electronic Steering for Treatment of Uterine Fibroid: a Clinical Study ...... J.Y. Lee 91-UF MR Guided Focused US for Treatment of Uterine Fibroids: Symptom Reduction in a Multicenter Trial Using a Novel Treatment Algorithm...... N. Tan 92-UF Volumetric MR-guided High-intensity Focused Ultrasound with Direct Skin Cooling for the Treatment of Symptomatic Uterine Fibroids: Proof of Concept Study ...... J. van Breugel 93-UF The Effect of Reimbursement on MRgFUS Treatment of Uterine Fibroids ...... J. Rabinovici 94-UF RELIEF Registry: Large-scale Evidence on the Safety and Long-term Effi cacy of Focused Ultrasound Treatment or Symptomatic Leiomyoma ...... J. Rabinovici Uterine Fibroids (continued) | 10:20 – 12:15 | Salon E – H 95-UF Effi cacy of MR-guided Focused Ultrasound Ablation for Localized Adenomyosis in Comparison to Leiomyoma ...... H. Coy 96-UF The Relationship of T2WI Signal Intensity of Uterine Fibroids and the Temperature Curve in MR-guided High-Intensity Focused Ultrasound (HIFU) Ablation ...... J. Liu 97-UF Treatment Outcomes of Uterine Fibroids with Different Intraprocedual Thermal Parameters in MR-guided HIFU Ablation ...... Y. Kim 98-UF Screening MRI-based Prediction Model for Therapeutic Response of MR-HIFU Ablation of Uterine Fibroids ...... Y. Kim 99-UF MRI Predictors of Clinical Success in MR-guided Focused Ultrasound (MRgFUS) Treatments of Uterine Fibroids: Results from a Single Center ...... I. Mindjuk 100-UF Screening MRI for Uterine Fibroids, Treatment Selection: MR Guided High Intensity Focused Ultrasound (MRgFUS), Uterine Artery Embolization (UAE) and Surgery: A Per Group Analysis of Outcomes...... A. Napoli 101-UF MRI Characterization of Uterine Fibroids May Predict Success of GnRH Agonist Therapy Prior to Magnetic Resonance Focused Ultrasound (MRgFUS) Treatment ...... K. Bryant 102-UF Treatment Analysis Environment for Review of MRgHIFU Treatments: A Multi-parametric Analysis Tool ...... M. van Stralen 103-UF Quantifying Perfusion-related Energy Losses During Magnetic Resonance-guided Focused Ultrasound ...... C. Dillon Closing Remarks | 12:15 – 12:25 | Salon E – H Closing Remarks ...... N. Kassell

18 Focused Ultrasound 2014 4th International Symposium Poster Overview (continued)

Bone Metastases P-100-BM An Instrumented Bone/Soft Tissue Phantom Designed to Mimic HIFU Treatments of Bone ...... J. Brown P-101-BM Primary Treatment of Painful Bone Metastases using Magnetic Resonance guided Focused Ultrasound – Initial Clinical Experience in Taiwan ...... H. Lee P-102-BM HIFU on Bone Metastases: A Comprehensive Preclinical Study ...... S.Y. Yeo Bone Non-Metastases P-103-BN Use of Focused Ultrasound Guided by Magnetic Ressonance in the Treatment of Osteoid Osteoma: Initial Experience ...... L. Fiore P-104-BN Assessing Temperature Dependence of T1 in Cortical Bone Using Ultrashort Echo-time MRI ...... M. Han P-105-BN Simulating Temperature Distribution of High-intensity Focused Ultrasound during Bone Treatments ...... T. Hudson P-106-BN Pain Alleviation and QOL Improvement of MR-guided Focused Ultrasound Surgery (MRgFUS) Treatment for Painful Medial Compartment of Knee Osteoarthritis ...... M. Kawasaki Brain P-107-BR Quantitative Evaluation of Blood-tumor-barrier Response Following Focused Ultrasound and Microbubble Treatment in Rat Glioma: Can We Improve Drug Delivery to Brain Tumors? ...... H. Ahmed P-108-BR Simulation of Hemispherical Transducers for Transcranial HIFU Treatments Using the Hybrid Angular Spectrum Approach ...... S. Almquist P-109-BR Image Guided Focused Ultrasound: Development of a Comprehensive Treatment Planning, Monitoring and Control, and Assessment ...... C. Arvanitis P-110-BR Multiple Sessions of Liposomal Doxorubicin and Focused Ultrasound Mediated Blood-Brain Barrier Disruption: Safety Study ...... M.. Aryal P-111-BR Ultrashort Echo-Time MRI as a Substitute to CT for Skull Aberration Correction in Transcranial Focused Ultrasound: In Vitro Comparison on Human Calvaria ...... J. Aubry P-112-BR Acoustic Characterization of Low Intensity Focused Ultrasound System through Skull ...... M. Babakhanian P-113-BR Acoustic Characterization of a Neonate Skull using a Clinical MR-guided High Intensity Focused Ultrasound System for Pediatric Neurological Disorder Treatment Planning ...... E. Constanciel Colas P-114-BR Feasibility and Safety of MR-guided Focused Ultrasound Lesioning in the Setting Deep Brain Stimulation ...... R. Dallapiazza P-115-BR Behavioral Effects of Targeted Drug Delivery via Non-invasive Microbubble Enhanced Focused Ultrasound Blood Brain Barrier Opening in Non-human Primates ...... M. Downs P-117-BR Spiral-based 3D MR Thermometry ...... S. Fielden P-118-BR Improved k-Space-Based MR Thermometry by Joint PRF Phase Shift and T1/T2* Attenuation Estimation ...... P. Gaur P-119-BR Mouse Positioning Device for Blood Brain Barrier FUS Exposure ...... S. Gong P-120-BR T1-weighted MRI as a Substitute to CT for Skull Aberration Correction in Transcranial Focused Ultrasound: In Vivo Feasibility and In Vitro Comparison on Human Calvaria ...... A. Iyer P-121-BR Incidence Angle and Gray-to-White-Matter Ratio Dependence of the Focused-Ultrasound Induced Blood-Brain Barrier Opening in Non-human Primates ...... M.E. Karakatsani P-122-BR Different MRI Pattern in Patients with ET or OCD after MRgFUS ...... Y.G. Kim

Focused Ultrasound 2014 4th International Symposium 19 Poster Overview (continued)

P-123-BR Blood-Brain Barrier Opening-based Local Delivery of 80 nm-sized Liposomes in Mice Using Pulsed Focused Ultrasound ...... Z. Kovacs P-124-BR Relation of Cooling Rate with Perfusion and Tissue Ablation ...... D. Lee P-125-BR Thermal Dose and Radiation Dose Comparison Based on Cell Survival ...... M. Lee P-126-BR Reduction of Dielectric Artifacts Within an InSightec ExAblate 4000 Head Transducer ...... S. Leung P-127-BR Targeted Delivery of GABA via Ultrasound-induced Blood-Brain Barrier Disruption Blocks Somatosensory-evoked Potentials ...... N. McDannold P-128-BR Localized Delivery of Non-Viral Gene-Bearing Nanoparticles into the Rat Brain Following Focused Ultrasound-mediated BBB Opening ...... B. Mead P-129-BR Enhancement of Blood-Brain Barrier Permeability by the Combination of Bubble Liposomes and High-intensity Focused Ultrasound ...... Y. Negishi P-130-BR Dynamical Model Parameter Adjustments in Model Predictive Filtering MR Thermometry ...... H. Odéen P-131-BR Design of a Robotic Device for the Delivery of Transcranial, Magnetic Resonance Guided Focused Ultrasound for Intraventricular Hemorrhage of Prematurity ...... K. Price P-132-BR Pharmacodynamic Analysis and Concentration Mapping for Effi cient Delivery through the FUS-induced BBB Opening in Non-human Primates In Vivo ...... G. Samiotaki P-133-BR Ultrasound-mediated Delivery of Brain-penetrating Nanoparticles across the Blood-tumor Barrier ...... K. Timbie P-134-BR Acoustic and Thermal Simulations of tcMRgFUS in Patient Specifi c Models: Validation with Experiments ...... U. Vyas P-135-BR Comparison of 3D UTE- and CT-based Phase Aberration Correction for Transcranial MR- Guided Focused Ultrasound Surgery ...... U. Vyas P-136-BR Focused Ultrasound-facilitated AAV-GDNF Delivery Triggers Neuroprotective Effects in a Parkinson’s-disease Mouse Model ...... S. Wang P-137-BR Effect of Increasing Sonication Duration During Transcranial MRgFUS Treatments ...T. Webb P-138-BR Focused Ultrasound-induced Blood-Brain Barrier Opening in Non-human Primates with Transcranial Cavitation Detection In Vivo ...... S. Wu P-139-BR Accelerated MR Thermometry Using the Kalman Filter ...... L. Zhao P-204-BR In vivo low frequency MR-guided thalamotomy with focused ultrasound: thermal vs. mechanical lesioning in pig brain ...... Z. Xu Breast P-140-BT Preclinical Ultrasound Image-guided High Intensity Focused Ultrasound Robot System for Breast Cancer Therapy ...... T. Azuma P-141-BT Performance Analysis of a Dedicated Breast MR-HIFU System During Ablation of Breast Tumors in Patients ...... R. Deckers P-142-BT Soft-embalmed Human Breast Tissue as a Model for Pre-clinical Trials of HIFU — Preliminary Results ...... A. Melzer P-143-BT Feasible Study of MRgFUS of Early Breast Cancer — Report of Completion of BC006 in Japan ...... K. Namba Liver and Pancreas P-144-LV Towards Multi-Criteria Optimization of Transducer Confi gurations ...... D. Acharya P-145-LV Respiratory Motion Tracking System of Hepatocellular Carcinoma Treatment Using FUS ...... H. Fukuda P-146-LV Novel Drug Delivery System Using Acoustic Control of Intratumoral Drug Distribution ...... K. Kawabata

20 Focused Ultrasound 2014 4th International Symposium Poster Overview (continued)

P-147-LV PRF Thermometry During MR-guided Focused Ultrasound Ablation in a Preclinical Thiel Model ...... S. Mihcin P-148-LV Acoustic Detection Of Attenuating Structures Using Cavitation-Enhanced Back Projection ...... P. Ramaekers P-149-LV Accounting for Sliding Motion in Fast Numerical Simulations of Abdominal HIFU Applications for Targets under Respiratory Motion ...... M. Schwenke P-150-LV Ultrasound Tracked Motion Compensated Focused Ultrasound System Evaluated on Ex Vivo Ovine Livers ...... J. Strehlow P-151-LV Ex vivo Ovine Liver Model Simulating Respiratory Motion and Blood Perfusion for Validating Image-guided HIFU Systems ...... X. Xiao P-152-LV A Framework for Slow Physiological Motion Compensation During HIFU Interventions in the Liver: Proof of Concept ...... C. Zachiu Emerging Applications P-153-EA Inhibition of Melanoma Growth in a Subcutaneous Model using Ultrasound with Low Duty Cycle ...... Y. Ando P-154-EA Ultrasound-microbubble Targeted Delivery of ICAM-1 in Mouse Model of Peripheral Arterial Disease ...... L. Badr P-155-EA The Importance of Phase Drift Correction for Accurate MR Thermometry in Long Duration MR-HIFU Exposures ...... C. Bing P-156-EA Focused Ultrasound Treatment of Methicilin Resistant Staphylococcus Aureus Induced Abscesses: Pre-clinical Study ...... L. Curiel P-157-EA Strategies for Reducing Regulatory Barriers to Focused Ultrasound Technology .....L. Dobrenz P-158-EA The Feasibility of Using Arterial Spin Labeling for Visualization of Non Perfused Volumes after HIFU Treatment in the Kidney ...... F. Eschbach P-159-EA HIFU-induced Antigen Release from Melanoma Cells ...... J. Escoffre P-160-EA Simultaneous T2 Mapping in Near-fi eld Subcutaneous Fat Layer and PRFS Temperature Mapping in Target Region using Fast Interleaved Sequences to Monitor MR-HIFU Sonication ...... E. Heijman P-161-EA Identifi cation of MR-HIFU Ablated Tumor with Multi-parametric MR Analysis at 3T ...... E. Heijman P-162-EA Hyperthermia Mediated Drug Delivery Combined with Ablation Improves Therapeutic Effi cacy of MR-HIFU Thermal Therapy ...... E. Heijman P-163-EA Treatment Planning and Patient Positioning for MR-guided High Intensity Focused Ultrasound Treatment: A Systematic Approach ...... D. Kinnaird P-164-EA Ultrasound-triggered Tumor Therapy with Doxorubicin-liposome-microbubble Complexes in a Subcutaneous Murine Colon Adenocarcinoma Model ...... A. Klibanov P-165-EA US-guided High-intensity Focused Ultrasound is a Promising Non-invasive Method for Treatment of Benign Thyroid Nodules ...... R. Kovatcheva P-166-EA Background-Oriented Schlieren Imaging and Tomography for Rapid Measurement of FUS Pressure Fields: Initial Results ...... M. Kremer P-167-EA Pulsed Focused Ultrasound Enhances Mesenchymal Stem Cell Homing to Skeletal Muscle in a Murine Model of Muscular Dystrophy and Homing was Suppressed by Ibuprofen ...... B. Nguyen P-168-EA Brain Targeted Gene Delivery by Combining Bubble Liposomes and Ultrasound .... D. Omata P-169-EA Investigation of the Stress Response to Mechanical Versus Thermal Non-ablative Focused Ultrasound Therapy in Three In Vivo Murine Cancer Models ...... S. Peters P-170-EA Thermochromic Phantom for Therapeutic Ultrasound Daily Quality Assurance...... F. Qureshi

Focused Ultrasound 2014 4th International Symposium 21 Poster Overview (continued)

P-171-EA Development of Novel Echogenic-imageable Thermosensitive Liposome for Optimizing Tumor Drug Distribution using Ultrasound Guided HIFU ...... A. Ranjan P-172-EA 3D MR Neurography Targeted Peripheral Nerve Ablation with MR-guided High Intensity Focused Ultrasound (MR-HIFU): Initial Results of a Feasibility Study in a Swine Model ...... R. Staruch P-173-EA Image Guided Focused Ultrasound Delivery of Macromolecular Drugs in Tumours ...... M. Thanou P-174-EA Thermal Ablation of a Confl uent Lesion in the Porcine Kidney with Magnetic Resonance Guided High Intensity Focused Ultrasound ...... J. van Breugel P-175-EA The Optimization of Treatment Planning and Ablation Rate Improvements on Feasibility of Pediatric MR-HIFU Applications ...... D. Wackerle P-176-EA Towards FUS Lung Cancer Ablation: The Lung Flooding Process from a Physiological and Physical View Point ...... F. Wolfram P-177-EA Targeted Drug Delivery with Modifi ed Gamma-Cyclodextrin Nanocarriers and MR-guided Focused Ultrasound Triggering ...... D. Xu P-178-EA The Hemodynamic and Hematological Effects of Histotripsy ...... Z. Xu P-179-EA Optical Measurement of Skin Temperature in MR-HIFU ...... D. Yang P-180-EA Holder Design for Robotic Assisted Ultrasound and MRI Imaging Guided Needle Biopsy ...... T. Zhang Prostate P-181-PR Software-supported Analysis of MRgFUS Therapy Outcome ...... D. Corr P-182-PR Non-invasive Focal Therapy of Organ Confi ned Prostate Cancer with Magnetic Resonance guided Focused Ultrasound Surgery ...... A. Napoli P-205-PR United States Experience with Primary HIFU Therapy for Patients with Low-Risk Prostate Cancer: Results of the Enlight Trial ...... C. Robertson Uterine Fibroids P-183-UF Patient Selection Guidelines for Magnetic Resonance Focused Ultrasound (MRgFUS) Treatment: An Updated View ...... K. Bryant P-184-UF MRI Pelvis Screening to Guide Treatment of Pelvic Pathology ...... K. Bryant P-185-UF Volumetric MR-guided High-Intensity Focused Ultrasound Ablation to Treat Uterine Fibroids through the Abdominal Scars ...... B. Keserci P-186-UF Relationship between Temperature and T2 in Subcutaneous Fat and Bone Marrow at 3T ...... E. Ozhinsky P-187-UF Possible Vascular Ablation Effect in the MR-guided HIFU Treatment of Uterine Fibroids: Description of an Unexpected or Desired Effect? ...... F.S. Urakawa P-188-UF The Relationship of Area under Temperature Curve During MR Guided HIFU and Diffusion Coeffi cient in Patient Screening ...... X. Yang Young Investigators P-189-YI Real-Time MRI Feedback of Cavitation Ablation Therapy (Histotripsy) ...... S. Allen P-190-YI Palliation of Painful Bone Metastases: the "Rizzoli" Experience ...... A. Bazzocchi P-191-YI MRI Characterization of Uterine Fibroids May Predict Success of GnRH Agonist Therapy Prior to Magnetic Resonance Focused Ultrasound (MRgFUS) Treatment ...... K. Bryant P-192-YI MRgHIFU – Experimental Perivascular Volumetric Ablation in the Liver ...... U. Carling P-193-YI Harmonic Motion Imaging for Pancreatic Tumor Detection and High-intensity Focused Ultrasound Ablation Monitoring ...... H. Chen P-194-YI Quantifying Perfusion-related Energy Losses During Magnetic Resonance-guided Focused Ultrasound ...... C. Dillon 22 Focused Ultrasound 2014 4th International Symposium Poster Overview (continued)

P-195-YI International Consensus on Use of MR-guided High-intensity Focused Ultrasound for Bone Metastases: Current Status and Future Directions...... M. Huisman P-196-YI Image-Guided Sonoporation in an Ex vivo Machine Perfused Porcine Liver ...... C. Keravnou P-197-YI Unilateral Magnetic Resonance Guided Focused Ultrasound Thalamotomy for Essential Tremor: Practices and Clinicoradiological Outcomes ...... Y.G. Kim P-198-YI FUS-mediated Functional Neuromodulation for Neurophysiologic Assessment in a Large Animal Model ...... W. Lee P-199-YI High Intensity Focused Ultrasound (HIFU) in the Treatment of Breast Fibroadenomata: a Feasibility Study ...... M. Peek P-200-YI A Unifying Framework for Understanding Ultrasonic Neuromodulation Mechanisms ...... M. Plaksin P-201-YI Immunomodulation of Prostate Cancer Cells after Low Energy Focused Ultrasound ...... K. Skalina P-202-YI Reestablishment of Perfusion in Critical Limb Ischemia Model with Pulsed Focused Ultrasound (pFUS) and Mesenchymal Stem Cells in Aged Mice ...... P. Tebebi P-203-YI High Speed, High Sensitivity PRF Shift MR Thermometry ...... Y. Zheng

Poster Map | Salon D

Abstract Types BM Bone Metastases BN Bone Non-metastases BR Brain BT Breast Tumors EA Emerging Applications EI Enhanced Immunotherapy JN Journal LV Liver and Pancreas PR Prostate UF Uterine Fibroids

Focused Ultrasound 2014 4th International Symposium 23 Session Moderators

Jean-François Aubry, PhD Nathan McDannold, PhD Institut Langevin Brigham and Women’s Hospital Paris, France Boston, Massachusetts, United States

David Brenin, MD Chrit Moonen, PhD University of Virginia University Medical Center Utrecht (UMCU) Charlottesville, Virginia, United States Utrecht, the Netherlands

Kim Butts Pauly, PhD Alessandro Napoli, MD Stanford University University of Rome – La Sapienza Stanford, California, United States Rome, Italy

Christian Chaussy, MD Edward Oldfi eld, MD University of Munich University of Virginia Munich, Germany Charlottesville, Virginia, United States

Larry Crum, PhD Howard Soule, MD, PhD University of Washington Milken Institute Seattle, Washington, United States Santa Monica, California, United States

Michael Douek, MD Elizabeth Stewart, MD King’s College London Mayo Clinic Guy’s & St. Thomas’ Hospitals Rochester, Minnesota, United States London, United Kingdom Gail ter Haar, PhD Emad Ebbini, PhD The Institute of Cancer Research University of Minnesota London, United Kingdom Minneapolis, Minnesota, United States G. Frederick Wooten, Jr., MD Wladyslaw Gedroyc, MD University of Virginia St. Mary’s Hospital, Imperial College Charlottesville, Virginia, United States London, United Kingdom Feng Wu, MD, PhD Ryder Gwinn, MD Oxford University Swedish Medical Center Oxford, United Kingdom Seattle, Washington, United States Eyal Zadicario, MSc Mark Hurwitz, MD InSightec Inc. Thomas Jefferson University Tirat Carmel, Israel Philadelphia, Pennsylvania, United States

Young-Sun Kim, MD Samsung Medical Center Seoul, Republic of Korea

24 Focused Ultrasound 2014 4th International Symposium Abstracts

Oral Presentations and Discussions Monday Brain 26 Tuesday Enhanced Immunotherapy 60 Bone Non-Metastases 63 Bone Metastases 68 Prostate 71 Wednesday Journal 82 Emerging Applications 83 Breast 92 Liver and Pancreas 97 Thursday Uterine Fibroids 109

Posters Bone Metastases 123 Bone Non-Metastases 125 Brain 129 Breast 166 Liver and Pancreas 170 Emerging Applications 179 Prostate 212 Uterine Fibroids 215 Young Investigators 223 Poster Map 231

Author Index By Name 233 By Organization 239

In accordance with author requests, the following abstracts are not included in this publication: 32-BR P-102-BM 49-BM P-138-BR 53-BM P-159-EA 90-UF

P-116-BR was withdrawn.

Focused Ultrasound 2014 4th International Symposium 25 1-BR Essential Tremor Monday W.J. Elias 13 October 2014 University of Virginia, Charlottesville, Virginia, United States Topic: Brain Presentation type: Oral Background/Introduction: A randomized controlled trial of unilateral stereotactic MRI- guided focused ultrasound thalamotomy is underway. Methods: Seventy-two patients with severe, medication-refractory essential tremor have been enrolled across seven international centers. Standard assessments of tremor severity and disability will be obtained before and after the procedure. Patients are randomized in a one-to-three fashion to receive either sham procedure or MR-guided focused ultrasound thalamotomy. The Tremor Research Group, neurologist specialists in the management of essential tremor, will rate the clinical outcomes from videotaped assessments. Results and Conclusions: NA

2-BR Parkinson’s Tremor Monday W.J. Elias, R. Dallapiazza 13 October 2014 University of Virginia, Charlottesville, Virginia, United States Topic: Brain Presentation type: Oral Background/Introduction: Tremor associated with Parkinson’s disease can be medication resistant and disabling. A clinical trial of stereotactic focused ultrasound thalamotomy is underway. Methods: This pilot study is being conducted in two centers with a randomized, controlled study design using blinded and validated rater assessments and a sham procedure. The primary outcome variable is hand tremor and the Unifi ed Parkinson’s disease rating scale in the medicated state at three months. Comprehensive cognitive assessments before and after the procedure are being conducted for additional safety. A total of thirty patients will be enrolled. Results and Conclusions: NA

26 Focused Ultrasound 2014 4th International Symposium 3-BR MR Guided Focused Ultrasound as a Treatment Tool for Essential and Monday Parkinsonian Tremor 13 October 2014 Menashe Zaaroor, Alon Sinai, Ayelet Eran, Dorit Goldsher, Ilana Erikh, Maria Nassar, Topic: Brain Ilana Schlesinger Presentation type: Oral Rambam Health Care Campus, Haifa, Israel

Background/Introduction: Combining focused ultrasound (FUS) with real time MRI guidance and monitoring enables a new non-invasive treatment of brain disorders. In this technique multisource ultrasound waves are focused at a single point raising the temperature gradually until ablation occurs. Lesions as small as 2-4 mm can be made, without impact on surrounding tissue or remote brain tissue. Our aim was to assess MR guided focused ultrasound (MRgFUS) as a new non-invasive surgical tool for treating essential and parkinsonian tremor by thalamotomy of the ventral- intermediate nucleus. Methods: Eight patients with severe medically refractory tremor, 4 essential tremor and 4 with Parkinsonian tremor, underwent unilateral ventral-intermediate nucleus thalamotomy using MRgFUS. Following the preoperative planning using 3D CT and 3D 3T MRI, patients lay in the MRI scanner while awake with their head immobilized in a stereotactic frame. The transducers helmet was mechanically positioned and a silicone membrane sealed the space between the patient’s head and the helmet. MRI scans was performed with the helmet and frame in place, the target identifi ed and accuracy verifi ed at low temperatures. Treatment consisted of multiple sonications at gradually increased temperatures. MRI thermal scan provided feedback on the temperature achieved and the target accuracy. Between sonications patients provided information concerning side effects and neurological examinations were performed to verify effect. Results and Conclusions: Tremor stopped in the contralateral upper extremity in all patients immediately following the procedure. In two Parkinson disease patients ipsilateral rigidity was decreased as well. Immediate side effects included during sonications: vomiting (n=1), and transient forehead pain (2),transient vertigo (2) and following the procedure: scalp numbness (transient n=2, for 1day-1 week, permanent- mild n=1), subjective transient gait unsteadiness (n=3, for 1 week) Clinical assessment of the examiner and patient changed from severe disability to no functional disability from tremor immediately following the procedure. Follow-up of up to 10 months show sustained effect. No late side effects were noted. Conclusions — Thalamotomy of the VIM using MRIgFUS is safe and effective in both Parkinson disease tremor and essential tremor with minimal mostly transient side effects. Large randomized studies and longer follow up are needed in order to assess safety and effi cacy.

Focused Ultrasound 2014 4th International Symposium 27 4-BR Bilateral MR Imaging-Guided High Intensity Focused Ultrasound for the Monday Treatment of Tremor-dominant Parkinson’s Disease: First Experience with 9 13 October 2014 Months Follow Up

Topic: Brain 1 2 1 1 1 Presentation type: Oral Ronald Bauer , Beat Werner , Stefan Hägele-Link , Georg Kägi , Florian Brugger , Nikolas Arne Wegener1, Ernst Martin2 1 The Kantonsspital St. Gallen, St. Gallen, Switzerland 2 University Children’s Hospital, Zurich, Switzerland

Background/Introduction: MR imaging-guided high intensity focused ultrasound (MRIgFUS) is a novel, noninvasive technique for the treatment of functional brain disorders through the intact human skull at millimeter precision. The ExAblate 4000 transcranial MRIgFUS system (InSightec, Haifa, Israel) uses a 1024-element phased array transducer, which is attached to the patient’s head via a standard stereotactic frame situated inside a 3T MRI scanner, and is CE certifi ed for interventions in the thalamus, subthalamus and pallidum. Methods: Case Report: We report the case of a 45 years old male patient with medication- resistant tremor dominant Parkinson’s disease (PD). Deep brain stimulation (DBS) was contraindicated due to a bipolar disorder. Intervention: During MRIgFUS treatment the target was visually focused by MR-image guidance. In a fi rst step, the correct location of sonication was verifi ed with low, non-ablative energy, and targeted in the pallido-thalamic tract (fasciculus thalamicus) of the subthalamic area. Repeated sonications each lasting 15 to 25 seconds were delivered with stepwise increased acoustic energy up to 13200 J to create thermocoagulations under real-time MR- thermometry. The sonications resulted in peak temperature of 60°C at the target points producing a thermal lesion of approximately 3x3x4mm in size. Circulating de-gassed water between the helmet shaped transducer and the patient’s head provided acoustic coupling and head cooling. After each sonication the patient was interviewed and neurologically tested. The size of the lesion was closely monitored by MR-imaging during and directly after treatment, and again after 48 hours and at one month. Results and Conclusions: Clinically, MRIgFUS intervention resulted in a prompt and complete suppression of the tremor, improvement of gait, posturing and rigor (9 months follow up) leading to signifi cant improvement of quality of life. The motor part III of the Unifi ed Parkinson’s Disease Rating Scale (UPDRS) after the intervention decreased from 56 to 14 out 108 possible points (higher values meaning more impairment). The patient showed a fortiforcation of bipolar disorder as a transient side effect in relation to dynamic of surrounding oedema. MRIgFUS is a novel, non-invasive technique for the treatment of Parkinson’s disease that does not use ionizing or radioactive radiation. The technique has been proven successful worldwide in the treatment of functional brain disorders, such as neuropathic pain, movement disorders and neuropsychiatric diseases in over 180 patients. Our fi rst experience in treating 4 Parkinson patients and 2 patients with essential tremor suggests that MRIgFUS will become a safe and effective treatment method for patients with movement disorders.

Bilateral pallido-thalamo-tractotomy in Parkinon’s Disease 48 h post intervention

28 Focused Ultrasound 2014 4th International Symposium 5-BR Magnetic Resonance Guided Focused Ultrasound Pallidotomy for Monday Parkinson’s Disease 13 October 2014 Jin Woo Chang Topic: Brain Presentation type: Oral Yonsei University College of Medicine, Seoul, Republic of Korea Background/Introduction: Parkinson’s disease (PD) is one of the most common movement disorders in adults, often cannot be adequately controlled with medical treatment, and therby treated with the neurosurgical procedures. Unilateral pallidotomy, making a lesion in the globus pallidus pars interna (GPi), was the predominant surgical technique until early 1900s. Thereafter, deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become a mainstream surgical technique for managing not only the cardinal dopaminergic features of PD, but also levodopa induced motor fl uctuations and dyskinesia. Recent review studies, however, reported that unilateral pallidotomy also has long-term effect on both cardinal symptoms (contralateral tremor and rigidity) and motor complications (contralateral dyskinesia and motor fl uctuations). Currently, transcranial magnetic resonance guided focused ultrasound (MRgFUS), without necessity of opening the cranium, has been developed as a minimal invasive surgical technique, generating precise and focal thermal lesion in the brain compared to previous radiofrequency thermal lesion. Methods: The authors underwent world fi rst MRgFUS pallidotomy to confi rm its effi cacy as well as potential side effects. We hereby demonstrated the benefi cial effects of MRgFUS pallidotomy in PD patient for improving levodopa induced dyskinesia as well as motor symptoms. Results and Conclusions: Further investigation and follow up are mandatory.

6-BR Staged Subthalamotomy Monday W.J. Elias 13 October 2014 University of Virginia, Charlottesville, Virginia, United States Topic: Brain Presentation type: Oral Background/Introduction: A clinical trial is being planned to investigate the management of medication-refractory motor symptoms associated with Parkinson’s disease using a unilateral, focused ultrasound subthalamotomy performed in a staged fashion. Methods: For this study, ten subjects with medication-refractory symptoms or side effects of advanced Parkinson’s disease will be enrolled. Each patient will be treated with a “sub- therapeutic” (stage 1) focused ultrasound subthalamotomy and observed for thirty days. Those who develop severe and involuntary movements, such as hemiballismus, will be excluded from the second stage procedure. For those who tolerate subthreshold lesioning, a second, full subthalamotomy ablation (stage 2) with focused ultrasound will be performed. Validated Parkinson’s disease rating scales, cognitive assessments, and MRI will be obtained before and after the procedures. Results and Conclusions: NA

Focused Ultrasound 2014 4th International Symposium 29 7-BR MRIgFUS in the Treatment of Spontaneous Intracerebral Hemorrhage Monday Leodante da Costa1, Nir Lipsman2, Allison Bethune2, Todd Mainprize2, Kullervo 13 October 2014 Hynynen1 Topic: Brain 1 Sunnybrook Research Institute, Toronto, Canada Presentation type: Oral 2 Sunnybrook Health Sciences Centre, Toronto, Canada

Background/Introduction: Spontaneous cerebral hemorrhage (ICH) is a major cause of mortality and morbidity worldwide. Although the mechanisms leading to ICH are relatively well known, little improvement in outcomes has occurred over the years, in spite of signifi cant advances in surgical techniques and medical management options. Evidence is available to suggest that liquefying and/or removing the clot after ICH might be benefi cial. The objective of this work is to test the feasibility of use of MRI guided focused ultrasound (MRgFUS) in the treatment of ICH. Our hypotheses are that MRgFUS can be used safely to effectively cause clot lysis and it will provide good radiological resolution of ICH. Methods: At least 6 patients with a recent (< 72h) ICH and hematoma > 2 cm will be recruited. MRgFUS will be used to sonicate the clot leading to lysis. Except for the MRgFUS treatment, ICH patients will receive the same treatment as those not in the trial. Stereotactic aspiration can be added if deemed safe by the treating neurosurgeon. The primary outcome is feasibility (statistical analysis is not proposed); adverse events will be examined and analyzed. Secondary end point is the radiological progression of the clot. Results and Conclusions: We expect that MRgFUS be feasible and safe, and clot size reduction will be seen in most patients. It’s possible that the procedure could have some therapeutic value for subjects with few or no other options for treatment.

8-BR Magnetic Resonance Guided Focused Ultrasound Capsulotomy for Monday Intractable Obsessive Compulsive Disorders 13 October 2014 Jin Woo Chang Topic: Brain Presentation type: Oral Yonsei University College of Medicine, Seoul, Republic of Korea Background/Introduction: Surgery for intractable psychiatric illness has generated considerable controversy for a variety of scientifi c, social and philosophical reasons. However, the surgical treatment of obsessive compulsive disorders (OCD) by lesioning techniques such as cingulotomy, capsulotomy was well accepted in the clinical fi eld throughout the world. However, the lacks of direct neuroanatomical and pathophysiological rationales for how lesions in specifi c limbic areas alleviate specifi c OCD symptoms have been consistent criticisms of lesioning procedures. Recently, because the anatomical and neurochemical substrates of brain function in health controls and disease patients are slowly being elucidated by various functional neuroimaging techniques, these criticisms are becoming less valid. Furthermore, by using new technique such as deep brain stimulation (DBS) and by making more precise targets, it enables to treat the patients without making serious complications. Methods: However, as we recognize, DBS also has many disadvantages along with procedures and etc. Currently, MR-guided focused ultrasound (MRgFUS) has been developed as a non-invasive surgical tool of generating precisely placed focal thermal lesion in the brain. The authors underwent a feasibility study of MRgFUS for the treatment of medically refractory OCD. Patients with OCD were treated by making bilateral thermal lesions in the anterior limb of the internal capsule (capsulotomy) with MRgFUS. Results and Conclusions: In this presentation, I would like to demonstrate the not only therapeutic effects but also technical & practical issues of the current MRgFUS for medically refractory OCD.

30 Focused Ultrasound 2014 4th International Symposium 9-BR “Non-thermal” Ablation Using Focused Ultrasound and an Ultrasound Monday Contrast Agent 13 October 2014 Nathan McDannold Topic: Brain Presentation type: Oral Brigham & Women’s Hospital/Harvard Medical School, Boston, Massachusetts, United States Background/Introduction: The combination of focused ultrasound and an intravenously- injected microbubble ultrasound contrast agent offers the ability to reduce the power needed to ablate tissue, which is particularly important for targets in the brain since it can eliminate skull heating. When applied at a low duty cycle so that bulk tissue heating does not occur, the mechanical effects induced by inertial cavitation result in ablation via the destruction of blood vessels. This alternative method for tissue ablation may have advantages for the treatment of brain tumors. Methods: Primates at our institution that evaluated the bioeffects induced during contrast- enhanced ultrasound ablation of targets in the brain. These studies applied burst sonications slightly above the inertial cavitation threshold at a low ultrasound frequency (220-525 kHz) and a 1% duty cycle over several minutes. Each sonication was applied after a bolus injection of ultrasound contrast agent. Results and Conclusions: Such contrast-enhanced sonications produce vascular damage, which leads to a localized infarct and tissue necrosis. The necrotic tissue is removed quickly compared to thermal ablation. When volumes are ablated, a cavity reminiscent of surgical resection is evident in 2-3 weeks. White matter tracts, which have a low vascular density, appear to be somewhat resistant to this type of ablation. No evidence of thermal damage is evident. The combination of focused ultrasound and a microbubble agent can enable ablation of tumors or other targets in the brain over a wider envelope than is currently possible with thermal ablation. The resulting bioeffects may offer advantages for tumors. The relatively quick removal of tissue may be helpful to reduce adverse effects resulting from tumor bulk effects. The resistance of large white matter tracts to these sonications may enable ablation of tumors directly adjacent to cranial nerves which is a current challenge for tumors located near the skull base. However, signifi cantly more work is needed to establish the viability of this technique in tumors and to understand how the method can be applied safely. Major issues needing resolution will be a topic for discussion. Acknowledgements (Funding): Funding: Focused Ultrasound Foundation; NIH grants P01CA174645, P41EB015898

Focused Ultrasound 2014 4th International Symposium 31 10-BR Sonodynamic Therapy for Treatment of C6 Glioma in a Rat Model Step 1: Monday Feasibility of Tumor Model 13 October 2014 Paul Schmitt1, Jessica Foley2, Neal Kassell2, Jason Sheehan1, Zhiyuan Xu1 Topic: Brain 1 Presentation type: Oral University of Virginia, Charlottesville, Virginia, United States 2 Focused Ultrasound Foundation, Charlottesville, Virginia, United States

Background/Introduction: Gliomas represent the most common and devastating primary CNS tumor. While surgical resection is the mainstay of treatment, treating physicians are seeking a safer and more effective treatment modality that is non-invasive, deep-penetrating, and less prone to infection and damage to surrounding tissues. Photodynamic therapy, utilizing a photosensitizing agent with laser light, while effective in a variety of solid tissue tumors, has not proven to be especially advantageous in the treatment of gliomas, due to the poor penetration of the light. Sonodynamic therapy has been explored as an alternative to PDT. Sensitizers such as 5-aminolevulinic acid (5-ALA) and indocyanine green (IcG) have been shown to be preferentially taken up by glioma cells. Low-intensity ultrasound waves can provide enough energy to activate sensitizing agents and induce apoptosis, without the collateral damage to surrounding tissues seen with laser light in PDT. The aim of this initial study is to determine whether the sonosensitizers 5-ALA and IcG can be effectively delivered to, and detected in, the subcutaneous C6 glioma rat model. Methods: A total of 12 rats were inoculated with the C6 rat glioma cell line for use in this initial study. The rats were then split into three groups: 4 rats were treated with 100 mg/kg of intravenous 5-ALA, 4 rats were treated with 150 mg/mL of intravenous IcG, and 4 rats were used as a control. Rats given 5-ALA were euthanized 2 to 4 hours later. Tumors were then harvested for fl uorescent spectroscopy study. In rats which were given IcG, we used in vivo imaging system to visualize the fl uorescence intensity of the tumor as compared with the adjacent normal tissues. Results and Conclusions: Tumor assays for all 8 of the experimental rats demonstrated uptake of the sensitizing agents. None of the assays for the control rats were positive. Our results confi rm that 5-ALA and IcG were enriched in the subcutaneous C6 glioma in rats via the fl uorescence spectroscopy or in vivo imaging. Future steps will include another proof-of- concept study to assess the ability of low-intensity ultrasound to cause hyperthermia-induced apoptosis in C6 gliomas via activation of 5-ALA and IcG. A larger study would then be needed compare the effectiveness of these sonosensitizers, and further optimize ultrasound parameters. Ultimately we would like to move this work towards a clinical trial.

32 Focused Ultrasound 2014 4th International Symposium 11-BR First Non-Invasive Thermal Ablation of a Brain Tumor with MR guided Monday Focused Ultrasound 13 October 2014 Javier Fandino1, Daniel Coluccia1, Lucia Schwyzer1, Javier Anon1, Luca Remonda1, Topic: Brain Ruth O’Gormann2, Ernst Martin2, Beat Werner2 Presentation type: Oral 1 Kantonsspital Aarau, Aarau, Switzerland 2 University Children’s Hospital, Zurich, Switzerland

Background/Introduction: Introduction: Focused ultrasound (FUS) can penetrate soft tissue noninvasively and induce physiological effects deep within target tissues. MR-image guidance, lesioning precision, sparing of healthy tissue and absence of ionizing radiation make FUS an ideal modality for brain interventions. Based on the encouraging results in treating patients with chronic pain or movement disorders through thermal ablation of thalamic and subthalamic targets, noninvasive transcranial MR guided focused ultrasound (tcMRgFUS) recently received CE marking for functional neurosurgery. Here, we report the world’s fi rst successful application of noninvasive tcMRgFUS for tumor ablation in a patient suffering from a centrally located malignant glioma. Methods: Case Report: A 63 year old patient presented in our clinic with tumor recurrence in the left thalamic and subthalamic region fi ve years after fi rst surgery for a glioblastoma. After giving informed written consent he was included in our ongoing clinical phase-1 study on the feasibility and safety of tcMRgFUS for the treatment of brain tumors. Due to the location of the tumor within eloquent brain areas and considering previous radiotherapy and various cycles of different chemotherapeutics, surgical resection was excluded as a treatment option. The tcMRgFUS procedure was performed using the ExAblate Neuro® system (InSightec Ltd, Haifa, Israel) integrated into a clinical 3T MR system (GE Healthcare, Little Chalfont, UK). The patient received local anesthesia for positioning a stereotactic frame (Integra LifeSciences Corporation, New Jersey, USA), and prophylactic administration of paracetamol and ondansetron for preventing pain or nausea. Post-interventional assessment included follow-up MRI immediately after and on days 1, 5 and 21 after the procedure. The patient was awake and responsive during the whole intervention with stable neurological assessment and without additional medication needed. In the 3 hours lasting procedure, a total of 25 sonications were applied with up to 19’550 Joules of acoustic energy. 17 sonications reached ablative temperatures of over 55°C with a maximum of 65°C, as recorded by intraoperative realtime MR thermometry. MRI scans acquired immediately after the intervention revealed signifi cant lesions to the sonicated tumor tissue that were particularly well visible in DWI and ADC maps. Later on, contrast-enhanced MRI showed well-circumscribed volumes of non-perfused tissue, indicative for ablated tumor tissue. As expected from earlier experience, perifocal edema developed around the thermal lesions, but gradually disappeared during the follow-up period. Neurological examination on day 5 revealed improvement of the preexisting right arm paresis while no additional neurological defi cits were observed. Results and Conclusions: The successful ablation of a brain tumor demonstrates the feasibility of noninvasive tcMRgFUS tumor surgery. Further clinical interventions in the context of our ongoing clinical phase I study will be needed to assess the safety and effi cacy of tcMRgFUS for brain tumor treatment and its relevance for future treatment strategies against brain tumors. Acknowledgements (Funding): No confl icts of interest. This study was supported by the Department of Neurosurgery, Kantonsspital Aarau, and the Center of MR-Research, University Children’s Hospital, Switzerland

Focused Ultrasound 2014 4th International Symposium 33 12-BR Clinical Trial Update: Treatment of Metastatic Brain Tumors Using MRgFUS Monday Stephen Monteith, David Newell, Sandra Vermeulen, Charles Cobbs 13 October 2014 Swedish Neuroscience Institute, Seattle, Washington, United States Topic: Brain Presentation type: Oral Background/Introduction: Metastatic brain tumors are common lesions that are currently treated with multimodal therapy. Surgical resection, focused stereotactic radiosurgery, and whole brain radiation remain traditional therapies. It has been postulated that metastatic brain tumors could be treated effectively with MRgFUS using thermal ablation. Methods: Treatment of metastatic brain tumors using MRgFUS continues as an open clinical trial. As of the current time we have been unable to enroll patients in the current trial. There are several factors which have resulted in challenges in patient recruitment despite a large referral base. Results and Conclusions: Many patients present with greater than 3 metastatic lesions and so are excluded from the clinical trial. Patients with metastatic malignancy to the brain will often have many tiny (in the order of a few mm on high resolution MRI) asymptomatic lesions which results in their exclusion in the current trial based on current criteria. Exclusion based on any prior hemorrhage in a metastatic lesion has also been raised as a concern. Many lesions may have tiny microhemorrhages on gradient echo imaging without clinically occult manifestation or clinical relevance. Metastatic tumors tend to present at the gray-white matter junction and not in the center of the brain which is more favorable for MRgFUS treatment. Exclusion of patients due to unfavorable tumor location based on the limited treatment envelope offered by current treatment systems remains a challenge. Experience with a large volume of screened patients has led to modifi cations suggested to current protocols in order to take in to consideration these fi ndings. Acknowledgements (Funding): Focused Ultrasound Foundation, Swedish Neuroscience Institute, InSightec

13-BR Clinical glioblastoma Monday Todd Mainprize 13 October 2014 University of Toronto, Toronto, Canada Topic: Brain Presentation type: Oral

34 Focused Ultrasound 2014 4th International Symposium 14-BR Temporary Disruption of the Blood-Brain Barrier Using an Implantable Monday Ultrasound System for Recurrent Glioblastoma Patients Under IV 13 October 2014 Carboplatin Chemotherapy: Initial Phase 1/2a Clinical Trial Observations

Topic: Brain 1 2 2 1 Presentation type: Oral Alexandre Carpentier , Michael Canney , Alexandre Vignot , Catherine Horodyckid , Lauriane Goldwirt3, Delphine Leclercq1, Jean-Yves Delattre1, Jean-Yves Chapelon4, Ahmed Idbaih1 1 Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, Paris, France 2 CarThera, Lyon, France 3 Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris, Paris, France 4 Inserm, Lyon, France

Background/Introduction: One of the main limitations to the effi cacy of chemotherapy in the brain is the blood-brain barrier (BBB). Previous pre-clinical studies have demonstrated that disruption of the BBB using pulsed ultrasound in combination with an ultrasound microbubble contrast agent can signifi cantly increase the concentration of chemotherapy agents in the brain. Our group has developed an implantable, MR compatible ultrasound device for temporarily disrupting the BBB. The safety of repeated disruption of the BBB using such a device was previously demonstrated in a long-term safety study in four non- human primates. The purpose of this work was to determine the safety and potential effi cacy of temporarily disrupting the BBB in patients with recurrent glioblastoma before chemotherapy administration in a fi rst-in-man clinical trial. Methods: A Phase 1/2a clinical trial to open the BBB in recurrent glioblastoma patients was approved to start in July 2014 at the Hospital Pitie Salpetriere in Paris, France. Participating patients will be implanted with a 11.5-mm diameter biocompatible 1 MHz ultrasound transducer, which will be fi xed to the skull bone in a standard burr hole, after which the skin will be closed. Once a month, the device will be connected to an external generator system using a transdermal needle connection, and patients will receive a two minute pulsed ultrasound sonication (25,000 cycles/burst, 1 Hz) in combination with systemic administration of an ultrasound contrast agent. BBB disruption will be monitored immediately after sonication using dynamic T1-weighted MR imaging using a gadolinium based MR contrast agent to measure the permeability coeffi cient, Ktrans, to quantify the magnitude of BBB disruption. Systemic intravenous injection of Carboplatin (Area Under the Curve 4-6) will be delivered immediately following MR imaging. Patients will follow a progression of ultrasound dose in which the pressure is increased from 0.5 to 0.8 MPa throughout the course of the study. Results and Conclusions: Pre-clinical results in a non-human primate demonstrated an increase in concentration of carboplatin of 200-600% after ultrasound-induced disruption of the BBB. Note that this clinical trial was approved to begin in July 2014 and thus no results were yet available in patients at the time of abstract submission. The most recent results will be presented at the meeting. These studies will verify that the BBB can be safely disrupted in patients with recurrent glioblastoma and will evaluate the tolerance and potential effi cacy of such an approach in combination with intravenous administration of a chemotherapy regimen of carboplatin. Acknowledgements (Funding): Work supported by CarThera.

Focused Ultrasound 2014 4th International Symposium 35 15-BR Disruption of Vascular Barriers in Tumors and in the Brain Monday Nathan McDannold 13 October 2014 Brigham & Women’s Hospital/Harvard Medical School, Boston, Massachusetts, United States Topic: Brain Presentation Type: Oral Background/Introduction: While most brain tumors do not have an intact blood-brain barrier (BBB), vascular barriers in the tumor and the surrounding intact brain tissue are major challenges for the use of chemotherapy for CNS malignancies. The permeability of brain tumor vessels can be highly heterogeneous, and factors such as high interstitial pressures can prevent agents from reaching an effective concentration in all tumor regions. Furthermore, tumors such as glioma are highly infi ltrative, and these infi ltrating tumor cells in the brain tissue surrounding the vascular portion of the tumor are protected by the BBB. Methods: Numerous studies have demonstrated that when combined with an ultrasound contrast agent, ultrasound can temporarily disrupt the BBB and increase the delivery of agents across the “blood-tumor barrier”. This presentation will review data obtained in rat and mice brain tumor models that evaluated tumor growth rates and survival after ultrasound-enhanced chemotherapy delivery. These studies have evaluated a range of primary and metastatic models and drugs. Results and Conclusions: These studies have all demonstrated that ultrasound-induced permeabilization of the BTB and chemotherapy can improve outcomes in rodent and human tumor models. Drugs including BCNU, doxorubicin (both free and liposomal), temozolimide, and trastuzumab have been tested. While in some cases the response has been modest, with multiple treatments dramatic improvements have been reported. These studies demonstrate the potential for this technology, either alone or in combination with focused ultrasound ablation, to provide more effective treatment options for patients with brain tumors. The next steps needed for clinical translation, including the need for tests in better tumor models, improvements to transcranial focused ultrasound systems to enable sonication of large volumes, and the development of effective methods to monitor and guide the procedure outside the MRI will be discussed. Acknowledgements (Funding): Funding: NIH grants R01EB003268 , P01CA174645, P41EB015898

36 Focused Ultrasound 2014 4th International Symposium 16-BR Therapeutic Effects of Focused Ultrasound-mediated Blood-brain Barrier Monday Opening in a Mouse Model of Alzheimer’s Disease 13 October 2014 Alison Burgess, Sonam Dubey, Tam Nhan, Isabelle Aubert, Kullervo Hynynen Topic: Brain Presentation Type: Oral Sunnybrook Research Institute, Toronto, Canada Background/Introduction: Focused ultrasound (FUS)-mediated opening of the blood- brain barrier (BBB) has been used to promote drug delivery to the brain. However, in a mouse model of Alzheimer’s disease, FUS has proven to be effective for reducing pathology and improving cognition, even in the absence of exogenous drug application. We have explored single and repeated FUS treatments in mice at both early and late stages of plaque pathology using a transgenic (Tg) mouse model of Alzheimer’s disease. Methods: Mice received single or weekly FUS treatments using a 1.68 MHz transducer, (10 ms pulses, 1Hz pulse repetition frequency, 120 second duration). Defi nity microbubble contrast agent was delivered at the onset of sonication. Effective BBB opening was confi rmed using contrast enhanced MR images. Following FUS treatments, mice were evaluated using cognitive tests and histology. Results and Conclusions: In the Y maze with novel arm, untreated Tg mice were found to spend signifi cantly less time in the novel arm compared to their non-Tg littermates. Following FUS treatment, Tg mice performed as well as their non-Tg counterparts. These results indicate that repeated FUS treatments are safe and may improve cognitive behavior, even in a model of late-stage AD. To support these fi ndings, mice treated with FUS also had reduced plaque burden in the brain and increased plasticity in the hippocampus, both of which have been correlated to improved learning and memory. Together this data demonstrates that FUS-mediated BBB opening can improve cognition related even in the absence of exogenous drug delivery and suggests that FUS should be considered part of the overall therapeutic strategy for treatment of Alzheimer’s disease.

Focused Ultrasound 2014 4th International Symposium 37 17-BR Delivery of Stem Cells to the Brain: Potential for Treatment of Monday Neurodegenerative Disease 13 October 2014 Alison Burgess, Isabelle Aubert, Kullervo Hynynen Topic: Brain Presentation Type: Oral Sunnybrook Research Institute, Toronto, Canada Background/Introduction: Stem cell therapy is a promising strategy to treat neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. However, for stem cell therapy to be considered for clinical use, new delivery methods need to be developed. We have used focused ultrasound (FUS) as a method to induce transient opening of the blood-brain barrier (BBB) to promote the passage of therapeutic stem cells into the brain. Methods: As a proof of principle study to demonstrate the application of this therapeutic strategy for Parkinson’s disease, we targeted the striatum using magnetic resonance imaging (MRI) for BBB opening. Defi nity microbubble contrast agent was injected intravenously at the onset of FUS application using a 558 kHz transducer (~0.3 MPa estimated in situ pressure, 10 ms bursts, 1 Hz pulse repetition frequency, 120 s total exposure duration). Results and Conclusions: During FUS application, neural stem cells expressing green- fl uorescent protein (GFP) and labeled with superparamagnetic iron oxide (SPIO) were injected into the carotid artery. Follow up contrast enhanced MR imaging confi rmed the opening of the BBB and at 24 hrs, MRI was used to detect the SPIO labeled stem cells in the region of interest. After sacrifi ce, GFP expressing cells were present in the targeted regions of the brain and expressed a neuronal phenotype indicative of their survival post-delivery through the BBB. Histological analysis showed some red blood cell extravasation but there was no evidence of brain tissue damage due to FUS treatment. Together, these data suggest that FUS is an effi cient method for delivery of stem cells to the brain and may be the key to reducing the risks of cell transplantation helping to move stem cell therapy forward.

38 Focused Ultrasound 2014 4th International Symposium 18-BR Neurotrophic Delivery in Alzheimer’s-model Mice Monday Elisa Konofagou, Hong Chen, Oluyemi Olumolade, Karen Duff 13 October 2014 Columbia University, New York, New York, United States Topic: Brain Presentation Type: Oral Background/Introduction: Alzheimer’s disease (AD), which has emerged as one of the most common brain disorders, begins in the hippocampal formation and gradually spreads to the remaining brain at its most advanced stages, and is characterized partly by deposition of amyloid plaques in the brain tissue but also in the blood vessels themselves. Our studies have dealt with both the delivery of neurotrophic factors through the FUS-induced blood- brain barrier (BBB) opening to the hippocampus in both the presence and absence of disease in AD mouse models. The Brain-Derived Neurotrophic Factor (BDNF) is widely and abundantly expressed in the CNS and is available to some peripheral nervous system neurons that uptake the neurotrophin produced by peripheral tissues. BDNF can modulate neuronal synaptic strength and has been implicated in hippocampal mechanisms of learning and memory. As BDNF has been proven to serve as a neuroprotective agent, delivery of exogenous BDNF is a good candidate for therapeutic treatment of several CNS disorders. Methods: FUS at 1.5 MHz with in-house microbubbles of an average diameter of 4-5 mm was performed in transgenic AD mice. Two transgenic mouse models, the PS/APP and J20, were used, which are characterized by amyloid plaques and cognitive defi cits, respectively. BDNF was injected following BBB opening. The BDNF bioactivity was assessed quantitatively by immunohistochemical detection of the pTrkB receptor and activated pAkt, pMAPK, and pCREB in the hippocampal neurons. Results and Conclusions: BBB opening using FUS and microbubbles was found to have similar characteristics and follows similar timelines in AD mouse models as in wildtype mice. BDNF was found to trigger molecular pathways with the pTrkB, pMAPK and pCREB showing signifi cant enhancement compared to the contralateral hemisphere (no FUS). Current efforts include demonstration of therapeutic effi cacy of BDNF delivery in AD mouse models. Targeting of the hippocampus in non-human primates will also be shown.

Focused Ultrasound 2014 4th International Symposium 39 19-BR Neuroprotection and Neuroregeneration Triggered through the FUS- Monday induced Opening of the Blood-brain Barrier in a Parkinson’s Mouse Model 13 October 2014 Elisa Konofagou, Gesthimani Samiotaki, Shutao Wang, Vernice Jackson-Lewis, Serge Topic: Brain Przedborski Presentation Type: Oral Columbia University, New York, New York, United States

Background/Introduction: Over the past decade, numerous small- and large-molecule products have been developed for treatment of neurodegenerative diseases with mixed success. When administered systemically in vivo, the blood-brain barrier (BBB) inhibits their delivery to the regions affected by those diseases. A successful drug delivery system requires transient, localized, and noninvasive targeting of a specifi c tissue region as provided by Focused Ultrasound (FUS). Neurturin (NTN) is a neurotrophic factor that has demonstrated to have neuroprotective and regenerative effects on dopaminergic neurons in vivo using invasive drug delivery methods. Utilizing recombinant adeno-associated virus (rAAV), therapeutic genes can be delivered to the brain for long-lasting treatments. In this study, we investigate the neuroprotective and neuroregenerative effects of non-invasively delivered rAAV-GDNF vectors and NTN in a PD mouse model, respectively. Methods: FUS at 1.5 MHz with in-house polydisperse microbubbles was performed. In the NTN study, NTN bioavailability and downstream signaling were detected and quantifi ed through immunostaining for NTN, phosphorylated RET, ERK1/2 and CREB. To test for neuroprotection and neuroregeneration, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model was used with FUS before and after MPTP administration, respectively. In the rAAV study, the expression of GDNF after 4 weeks due to AAV transduction was assessed in MPTP mice using FUS-mediated AAV delivery prior to MPTP administration (for neuroprotection only). Results and Conclusions: In the neurotrophic study, within the fi rst hour of NTN administration, triggering of the signaling cascade was detected downstream to the neuronal nuclei. In the adenoviral study, the ratio of ipsilateral (FUS treated for FUS only and AAV+FUS groups) to the contralateral side showed signifi cantly higher live neurons ratio from the AAV+FUS group (ANOVA, p=0.03) when compared to the control, AAV only and FUS only groups. These fi ndings thus indicate the potential of the FUS method to mediate transport of proteins and mediate gene delivery through the blood-brain barrier for reversibility of the PD phenotype.

40 Focused Ultrasound 2014 4th International Symposium 20-BR Ultrasound-Targeted Nanoparticle Delivery Across the Blood-Brain Barrier Monday Richard Price 13 October 2014 University of Virginia, Charlottesville, Virginia, United States Topic: Brain Presentation Type: Oral Background/Introduction: The delivery of systemically administered drugs and genes to the CNS is hindered by both the blood-brain barrier (BBB), which limits transport from the bloodstream to the brain to only a few privileged molecules, and the nanoporous electrostatically charged tissue space, denoted here as the “brain tissue barrier” (BTB). Our group engineers targeted drug and gene delivery approaches, capable of overcoming both of these physical barriers, for the treatment of brain tumors and neurodegenerative diseases. We focus on nanoparticle (NP) delivery systems, as they offer the potential for enhanced transfection effi ciencies and controlled-drug release. Methods: To deliver drug- and gene-bearing NPs across the BBB, we use focused ultrasound (FUS) and contrast agent microbubbles (MBs). FUS may be applied using either MR-guidance or with a simple table-top system. We and others have shown that activating MBs with FUS yields safe and transient BBB opening in the FUS focal zone. Technologies for overcoming the BTB center on coating the drug and gene bearing NPs with an extremely dense brush layer of polyethylene glycol (PEG). NPs are injected at the time of BBB opening to permit their delivery to the CNS. Results and Conclusions: Drug Bearing NP Delivery – PEG-coated polystyrene (PS) tracer NPs (60 nm diameter) and biodegradable polylactide-co-glycolide (PLGA) NPs (75 nm) were engineered to penetrate brain tissue and then delivered across the BBB in rats using 1 MHz FUS. NPs were delivered to endothelium and as “clouds” to brain tissue. PS-NP delivery through the brain continued over 24 hours, yielding enhancements of cloud size and intensity Figure 1 (Figure 1A). FUS at 0.6 MPa delivered a larger fraction of PS-NP to the interstitial space (Figure 1D) and increased PS-NP coverage area (Figure 1B). The percentage of PS-NP+ vessels producing clouds was increased (P<0.05) to 50% at 0.6 MPa (Figure 1C). The higher US pressure produced a signifi cant 4.6-fold increase in large (i.e. >200 μm2) PS-NP clouds. Focal spot intensity on MRI predicted the number of PS-NP clouds (Figure 1E). We also verifi ed that BBB opening with MBs and FUS at 0.6 MPa can be used to substantially increase 60 nm PS-NP delivery to intracranial 9L rat tumors. Gene Bearing NP Delivery — We used a blend of non-PEGylated and highly PEGylated polymers at an optimized ratio to engineer brain- penetrating DNA NPs with a polyethylenemine (PEI) core polymer. Figure 2 We delivered PEI-NPs (~50 nm in diameter) carrying either luciferase or mCherry plasmid DNA (driven by the unmethylated CpG-free β-actin promoter) across the BBB in rats using MR-guided FUS and MBs. Robust luciferase transgene expression, corresponding to a single focal site of FUS exposure, was visible (Figure 2A), and the intensity of gene expression was correlated with PEI-NP concentration (Figure 2B). After delivering mCherry PEI-NPs across the BBB with FUS and MBs, we immunochemically detected mCherry in both glial cells (GFAP, red) and neuronal cell nuclei (NeuN, green) (Figure 2C). mCherry expression was homogeneously distributed throughout the sonicated area (Figure 2C), demonstrating the benefi t of combining FUS-mediated delivery across the BBB with brain-penetrating NPs. We believe these studies represent the fi rst evidence for brain transfection via the delivery of a non-viral gene NP across the BBB with FUS. Going forward, this approach may be used to deliver genes for neurotrophic factors for the treatment of neurodegenerative diseases. Acknowledgements (Funding): Supported by NIH CA164789, NIH EB016784, and the Focused Ultrasound Foundation.

Focused Ultrasound 2014 4th International Symposium 41 21-BR Microbubble Protein Delivery for Parkinson’s Monday James Keenan1, Umar Iqbal2, Maria Moreno2, Jagdeep Sandhu2 13 October 2014 1 Artenga Inc., Ottawa, Canada Topic: Brain 2 National Research Council of Canada, Ottawa, Canada Presentation Type: Oral Background/Introduction: Microbubbles (MBs) are small (1-5 μm diameter), perfl uorcarbon gas fi lled lipid microspheres used for contrast enhancement during ultrasound imaging. MBs (Defi nity®, others) are approved for contrast echocardiography and widely used (6 M patient injections) as ultrasound contrast agents with established pharmacokinetics and clearance data. Recent research has shifted to the therapeutic potential of MBs and the NRC and Artenga Inc. developed a novel strategy (Patent to be fi led) to load biologics onto MBs with high, consistent loading using a novel clinically scalable methodology. Investigators at Sunnybrook Research Institute have pioneered MR guided focused ultrasound (MRgFUS) plus MB techniques to deliver a wide range of therapeutic agents through the blood-brain-barrier (BBB) and developed a state of the art MRgFUS system for animal models. MRgFUS can precisely target the substantia nigra (SN) and striatum (ST) for simultaneous targeting of multiple brain regions. Neurotrophic factors (NTFs) are being developed in the hope of halting or reversing the progression of neuronal loss in chronic neurodegenerative diseases, however, their clinical utility is limited by drug delivery issues. Recently the University of Helsinki discovered a novel NTF, cerebral dopamine neurotrophic factor (CDNF), with a unique structure and mode of action. CDNF has demonstrated improved effi cacy compared to GDNF in various preclinical models of PD. Artenga, Inc., Sunnybrook Research Institute, the National Research Council of Canada (NRC), and the University of Helsinki plan is to use MR guided focused ultrasound (MRgFUS) and neurotrophic drug-loaded microbubbles (NTF-MBs) for targeted, noninvasive, blood brain barrier (BBB) drug delivery of CDNF. Methods: Although CDNF neuroprotection and neurorestoration data are promising, clinical development might be hampered by its inability to cross the BBB and rely on delivery methods that are either highly invasive or non-targeted [15]. Hence, our focus on non- invasive targeted delivery of CDNF into the SN and ST using CDNF-MBs coupled with MRgFUS to open the BBB for the delivery of therapeutic doses of CDNF. Artenga’s goal is to commercialize our technology to treat multiple diseases with different compounds and tumour-targeting agents. The Artenga-NRC MB conjugation technology permits extremely high and consistent drug loading per MB for a wide range of compounds including antibodies, proteins, complex 3D folded antibodies, antibody drug conjugates, and gene therapy. The covalent bond results in reliable in vivo performance. The technology can also be adopted for cancer treatments. A novel therapeutic method of action was developed at Sunnybrook Research Institute to damage tumour vasculature using focused ultrasound and MBs. The technique has shown synergy with chemotherapy to signifi cantly increase tumour reduction compared to the drug alone. Testing is ongoing with tumour targeting MBs. Indications suitable for treatment with drug loaded MBs and focused ultrasound include Parkinson’s disease, other CNS disorders, and different types of cancer. For cancer applications a tumour targeting, drug loaded MB will be used. Results and Conclusions: NA Acknowledgements (Funding): The Michael J Fox Foundation Neurotrophic Factors Challenge program is funding a project: ‘Non-invasive, targeted delivery of Cerebral Dopamine Neurotrophic factor (CDNF) with Microbubbles and MRI-Guided Focused Ultrasound (MRgFUS)’. Hermo Pharma (Helsinki FN) has donated neurotrophic factor drug (CDNF protein) for the project.

42 Focused Ultrasound 2014 4th International Symposium 22-BR Neuropathic Pain: Long Term Follow-up Monday Ernst Martin1, Beat Werner1, Ronald Bauer2 13 October 2014 1 University Children’s Hospital Zurich, Zurich, Switzerland Topic: Brain 2 Kantonsspital St. Gallen, St. Gallen, Switzerland Presentation Type: Oral Background/Introduction: Radio frequency induced thalamotomy has been used in patients with neuropathic pain for many years. Today, transcranial MR imaging-guided focused ultrasound (tcMRIgFUS) offers the opportunity to conduct this treatment non- invasively under closed-loop MR-imaging guidance. Methods: So far we have treated a total of 23 patients suffering from chronic neuropathic pain of various origins using tcMRIgFUS. Targeting the posterior part of the central lateral nucleus of the thalamus (pCL), we applied both unilateral and bilateral lesions, depending on the severity and extent of the clinical symptoms. Also, depending on clinical presentation, the effected lesions were created either by a single ablation cell, or, where the lesion volume of a single ablation cell seemed insuffi cient, by combining two to three adjoining ablation cells that were generated by electronically steering the acoustic focus a few millimetres in order to increase the lesion volume. Using a custom built eight channel phased array coil which snugly fi ts around the ultrasound transducer, high resolution images could be acquired during the whole intervention procedureThe temperature evolution in the target region was continuously monitored by MR-thermometry and therapeutically effective temperatures were considered to lie between 54 and 62°C. Results and Conclusions: Long term effects resulting from pCL thalamotomy with tcMRIgFUS in the 23 patients evaluated here during a follow-up period of 1 to 2 years will be presented. The median pain relief is 56%, with an average reduction of subjectively felt maximal pain intensity of 34% estimated by the patients on a numerical rating scale. Here we will present important physical parameters such as lesion size and its evolution over time, as well as maximal temperature achieved during the FUS intervention. We will demonstrate the relationship between therapeutic effect and lesion size and Tmax, respectively. Apart from the pain relief, changes in quality of life and activity of daily living are at least as important for the patients. The results will also demonstrate the mutual compliment of deep brain stimulation and focused ultrasound. They form the basis for discussing possible improvements in patient management and new methodological approaches in order to allow application of tcMRIgFUS also in diffi cult and desperate patient situations.

Focused Ultrasound 2014 4th International Symposium 43 23-BR FUS-mediated Functional Neuromodulation for Neurophysiologic Monday Assessment in a Large Animal Model 13 October 2014 Wonhye Lee1, Hyungmin Kim2, Stephanie D. Lee1, Michael Y. Park1, Seung-Schik Yoo1 Topic: Brain 1 Presentation Type: Oral Brigham & Women’s Hospital, Boston, Massachusetts, United States 2 Korea Institute of Science and Technology, Seoul, Republic of Korea

Background/Introduction: Focused ultrasound (FUS) is gaining momentum as a new modality of non-invasive neuromodulation of regional brain activity, with both stimulatory and suppressive potentials. The utilization of the method has largely been demonstrated in small animals. Considering the small size of the acoustic focus, having a diameter of only a few millimeters, FUS insonifi cation to a larger animal’s brain is conducive to examining the region-specifi c neuromodulatory effects on discrete anatomical areas, including the white matter (WM) tracts. The study involving large animals would also establish preliminary safety data prior to its translational research in humans. Methods: Sheep (all female, 25–40 kg, n = 8) were chosen for the transcranial application of FUS due to their round cranium and skull thickness (4–5 mm) that was close to that of humans. All procedures were approved by the local Institutional Animal Care and Use Committee, and done under the intravenous Tiletamine anesthesia. To provide the information for positioning of the FUS focus to the individual functional neuroanatomy, sheep’s brain was imaged using a 3T MRI scanner (GE VH, Waukesha, WI) using anatomical (both T1- and T2-weighted) and functional MR protocols (fMRI, T2*-weighted). The somatosensory and visual areas of the sheep brain were mapped while using sensorimotor (i.e. gentle 2 Hz squeeze of the right hind leg muscle) and visual (i.e. 2 Hz strobe lights to both eyes) stimuli. As guided by these neuroimage data, the sonication (250 kHz, single- element FUS transducer with radius-of-curvature of 7 cm) was transcranially delivered to the unilateral sensorimotor cortex, the optic radiation (WM tract) as well as the visual cortex. An acoustic intensity of 1.4–15.5 W/cm2 Isppa, tone-burst-duration of 1 ms, pulse- repetition frequency of 500 Hz (i.e. duty cycle of 50%), sonication duration of 300 ms, were used for the stimulation. A batch of continuous sonication ranging from 50 to 150 ms in duration were also given. Evoked electromyogram responses from the hind legs and electroencephalogram from the Fz and Oz-equivalent sites were measured. The histology of the extracted brain tissue (within one week and 2 months post-sonication) was obtained. Results and Conclusions: The acoustic transmission measured through the extracted skulls (n = 8) was 41.5% of incident intensity. We detected a motor evoked potential (EP) from the hind leg muscle contralateral to the sonicated hemisphere above 6.9 W/cm2 Isppa (i.e. 3.5 W/cm2 Ispta), which served as a threshold intensity. The stimulation was not accompanied by the actual muscle movement. The amplitude of EP was greater than the one obtained using the lower acoustic intensity. Similarly, FUS-mediated visual EP was also detected at a similar threshold level without the presence of external lights. Continuous sonication also elicited stimulatory responses, suggesting that continuous short bursts of the FUS can also stimulate the brain. On the other hand, no response was detected from the sonication of the optic radiation, which indicates that FUS may not stimulate the WM tracts. The sheep’s health status was normal throughout all the sonication experiments. Histological analysis of the extracted brain showed no apparent biological damages. The transcranial FUS may serve as a novel tool to transiently and reversibly modulate regional brain functions, which will enable electrophysiological assessments on the function of an ablative target prior to FUS- mediated neurosurgery. Acknowledgements (Funding): This study was supported by the Focused Ultrasound Foundation.

44 Focused Ultrasound 2014 4th International Symposium 24-BR Ultrasound-induced Suppression of Visually-evoked Potentials: Experience Monday in Nonhuman Primates with a Clinical Transcranial MRI-guided Focused 13 October 2014 Ultrasound System

Topic: Brain 1 1 1 2 Presentation Type: Oral Nathan McDannold , Costas Arvanitis , Natalia Vykhodtseva , Margaret Livingstone 1 Brigham & Women’s Hospital/Harvard Medical School, Boston, Massachusetts, United States 2 Harvard Medical School, Boston, Massachusetts, United States

Background/Introduction: Previous works by Fry et al. and others demonstrated that ultrasound exposures on the optic tract and/or the lateral geniculate nucleus (LGN) can temporarily block visually-evoked potentials in small animals. We attempted to repeat these experiments in a rhesus macaque using the ExAblate Neuro system (InSightec) operating at 650 kHz. Methods: The animal was deeply anesthetized using ketamine and dexdormitor. First we targeted the LGN using MR temperature imaging, and then we relocated the MRI table just outside the MRI. Visually-evoked potentials driven by a strobe light were recorded transcranially using electrodes placed over the visual cortex. Recordings were obtained before, during, and after sonications at different targets over a range of pulse parameters and acoustic power levels. In some cases the focal point was steered electronically to multiple targets during each sonication. In some sessions we tested whether disabling portions of the array to increase the length of the focal region could improve the outcome. We also confi rmed the targeting at the end of the sessions by disrupting the blood-brain barrier using sonications with Optison microbubbles. Results and Conclusions: We were able to reliably obtain strong visually-evoked potentials within the ExAblate system. Over seven sessions, a total of 133 sonications at 57 different targets on and around the LGN were evaluated. In no case were we able to signifi cantly suppress the evoked potentials. In a few cases, large DC shifts that lasted several minutes were induced, perhaps indicative of cortical spreading depolarization. No tissue damage was evident in MRI, and the animal recovered and behaved normally after each session. It is not clear why these experiments failed to suppress the evoked potentials as observed in other studies. We could not tell whether the targeting was bad, the focal exposure level was insuffi cient, incorrect pulsing parameters were used, or if other factors such as anesthesia were responsible. This work highlights the challenge inherent in this type of experiment.

Focused Ultrasound 2014 4th International Symposium 45 25-BR Low Intensity Focused Ultrasound Modulates Monkey Visuomotor Behavior Monday Thomas Deffi eux1, Nicolas Wattiez2, Mickael Tanter1, Pierre Pouget3, Jean-Francois 13 October 2014 Aubry1, Youliana Younan1 Topic: Brain 1 Institut Langevin, Paris, France Presentation Type: Oral 2 Institute of Brain and Spinal Cord, Paris, France 3 Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, Paris, France

Background/Introduction: In vivo feasibility of using low intensity focused ultrasound to transiently modulate the function of regional brain tissue has been recently tested in anesthetized rabbits and rodents. In this work, antisaccade latencies have been modulated with non-invasive low intensity focused ultrasound (FUS) in the brain of two awake Maccaca Mulatta monkeys (Y and L). Methods: Animals were specifi cally trained in an antisaccade (AS) paradigm: after fi xation of a central visual stimulus on a screen, this stimulus disappeared and a peripheral target appeared, right or left. Monkeys were trained not to look at this peripheral target but instead initiate a saccade towards the opposite direction. Eye movements were recorded with an infra-red eye tracker (Eyelink 1k, SR-Research, Ontario, Canada), and eye position was digitized and stored for off-line analyses. In each experiment session, animals performed a total of 3 blocks of AS training per session. First, monkeys performed a 100 trials block of AS (50 for each side) as baseline. Then, a second block of 400 trials was performed: 360 trials without US (180 for each side) and 40 trials with US (20 for each side) were presented. Trials with US were pseudo-randomly interleaved with trials without US. A fi nal block of 100 trials was performed as a post-test. Monkey Y performed 10 sessions and monkey L 12 sessions. Control sessions, using identical procedures, with the transducer positioned over the pre- motor cortex instead of the left FEF were performed (Monkey Y – 8 sessions, Monkey L – 7 sessions). Finally, sham sessions inspired from TMS sham experiments were performed: the ultrasound transducer was moved 4 cm away from the animal’s head so that ultrasound could not reach previous target (Monkey Y – 5 sessions, Monkey L – 2 sessions). FUS consisted in continuous 100ms sonication with a 320KHz transducer (H115, Sonic Concept, Bothell, WA, USA) focused at the Frontal Eye Field (identifi ed according to stereotaxic coordinates). The estimated derated pressure in the brain was 0.35 ± 0.05 MPa. Results and Conclusions: Ipsilateral mean AS latencies with ultrasound stimulation were signifi cantly slowed (monkey Y: p= 0.0018; monkey L: p< 0.001) compared to the non- stimulated condition (monkey Y: noUS= 221 ms US= 235 ms; monkey L: noUS= 239 ms US= 269 ms). For the two animals, contralateral mean AS latencies were not signifi cantly slowed (t-test: monkey Y: p> 0.8; monkey L: p>0.6) compared to the non-stimulated condition. Focused ultrasound stimulation applied within a control pre-motor cortex did not signifi cantly affect ipsilateral anti-saccade latencies (t-test: monkey Y: p> 0.69; monkey L: p> 0.1) or contralateral latencies (monkey Y: p> 0.11; monkey L: p> 0.74). In both monkeys, sham focused ultrasound did not interfere with ipsi- or contralateral saccade latency (p> 0.5). The study demonstrates the feasibility of using focused ultrasound stimulation to causally modulate behavior in the awake non-human primate brain. Acknowledgements (Funding): This work was supported by LABEX WIFI (Laboratory of Excellence within the French Program ‘‘Investments for the Future’’) under references ANR-10-LABX-24 and ANR-10-IDEX-0001-02 PSL and by the Agence Nationale de la Recherche under the program ‘‘Future Investments’’ with the reference ANR-10-EQPX-15.

46 Focused Ultrasound 2014 4th International Symposium 26-BR Image-Guided Transcranial Focused Ultrasound Stimulation of Primary Monday Somatosensory Cortex in Humans 13 October 2014 Yong An Chung1, Wonhye Lee2, Hyungmin Kim3, Yujin Jung1, In-Uk Song1, Seung- Topic: Brain Schik Yoo2 Presentation Type: Oral 1 Incheon St. Mary’s Hospital, Incheon, Republic of Korea 2 Brigham & Women’s Hospital, Boston, Massachusetts, United States 3 Korea Institute of Science and Technology, Seoul, Republic of Korea

Background/Introduction: Development of novel brain stimulation modalities may offer new niche in the creation of functional mapping probes for basic neuroscientifi c research as well as for tools for non-pharmacological neurotherapeutics. The use of focused ultrasound for the modulation of the central nervous system has been suggested as a new mode of brain stimulation. Methods: We transcranially applied low-intensity FUS to the human hand somatosensory cortex of the brain, and examined the presence of elicited sensory responses on the fi ngers and hand, including the type and location of responses. Cortical EEG potential evoked by the FUS was measured to quantitatively examine the effects of FUS stimulation. Due to the individual variations in cranial structures as well as anatomical and functional neuroanatomy, multi-modal image-guidance using computerized tomography (CT) and magnetic resonance imaging (MRI) was employed to guide the sonication focus to the desired cortical somatosensory area. Results and Conclusions: The sonication elicited transient tactile sensations on the hand area contralateral to the sonicated hemisphere, with anatomical specifi city of up to a fi nger, while EEG recording revealed the elicitation of sonication-specifi c evoked potential. Our data provide the fi rst evidence of active creation of stimulatory responses from the brain elicited by FUS in the absence of any external tactile stimulation. The stimulatory effects were transient and reversible and did not cause any discomfort or adverse effects across the participants.

Focused Ultrasound 2014 4th International Symposium 47 27-BR Safety and Feasibility of Focused Ultrasound Neuromodulation in Temporal Monday Lobe Epilepsy 13 October 2014 Alexander Bystritsky, Alexander Korb, John Stern, Mark Cohen Topic: Brain Presentation Type: Oral University of California at Los Angeles, Los Angeles, California, United States Background/Introduction: Temporal lobe epilepsy (TLE) is the most common pharmacologically refractory form of epilepsy. While it can often be effectively treated by temporal lobe surgery, that does not always eliminate seizures, and many patients are not suitable candidates for surgery. A non-invasive method to augment surgical or medical treatment of TLE would be highly useful. Low-intensity focused ultrasound pulsation (LIFUP) offers the potential for non-invasive neuromodulation, and in animal studies has not shown any evidence of tissue damage. However, the technology has not yet been tested in humans. We are currently testing the safety and feasibility of using a LIFUP device on humans to modulate brain activity in the temporal lobe. Methods: Participants will be recruited from patients with temporal lobe epilepsy treated by the UCLA Seizure Disorder Center’s who have elected to undergo temporal lobe surgery. In the week prior to the scheduled surgery participants will undergo simultaneous LIFUP and fMRI using various LIFUP pulsing paradigms to excite or suppress neural tissue. The BOLD signal will be analyzed to determine whether LIFUP can activate or suppress region-specifi c neural activity in the temporal lobe. LIFUP will be administered at 3 different intensities. To help determine safety of LIFUP participants will also undergo pre- and post-EEG and neuropsychological testing. To determine whether or not LIFUP causes tissue damage, post- surgery samples of the resected temporal lobe tissue in both sonicated and un-sonicated areas will undergo histological analysis. Results and Conclusions: We will report preliminary results and also discuss different challenges that came up during the study. Acknowledgements (Funding): We would like to thank the Gerald J. and Dorothy R. Friedman NY Foundation for Medical Research for funding.

48 Focused Ultrasound 2014 4th International Symposium 28-BR Treatment of Mesial Temporal Lobe Epilepsy Using MRgFUS: Laboratory Monday Feasibility Study 13 October 2014 Stephen Monteith1, John Snell2, Matt Eames2, David Newell1, Ryder Gwinn1 Topic: Brain 1 Presentation Type: Oral Swedish Neuroscience Institute, Seattle, Washington, United States 2 Focused Ultrasound Foundation, Charlottesville, Virginia, United States

Background/Introduction: Temporal lobe epilepsy remains a signifi cant cause of disabling morbidity. Patients that are refractory to medical treatment are often considered for invasive surgery to remove the epileptogenic focus originating from the structures of the medial temporal lobe. A range of surgical options now exist with varying degrees of effi cacy. The goal of any surgical intervention is to minimize disruption of adjacent normal cortical tissue while removing the offending structures. MRgFUS provides the opportunity to perform this task in an elegant fashion. We tested the feasibility of this approach in a cadaveric model. Methods: Cadaveric skulls were fi lled with custom fi tted thermo reactive gels and thermocouples placed along anatomical areas of interest along the skull base to assess temperature rises during the sonication process using the InSightec ExAblate Neuro System (650Khz). The volume of temporal lobe structures typically removed by standard surgical excision was mapped on 3D volumetric MRI scans and overlaid onto the thermal gels to provide an appropriate target for ablation. Temperature maps in the treatment volume were created for various sonication parameters and temperature effects at key skull base structures were monitored with thermocouples. Results and Conclusions: By adjusting sonication parameters it was possible to create a lesion of therapeutic signifi cance in the required temporal lobe treatment volume using thermoreactive gels in cadaveric skulls. Temperature rises seen at the periphery of the target volume did decrease compared to more medial structures. Treatment of temporal lobe epilepsy with MRgFUS appears feasible based on this laboratory model. Thoughtful planning using a disconnection strategy or highly focused sonications on key anatomical epileptogenic foci may be required due to the large volume required to ablate an equivalent volume for an anatomic temporal lobectomy. Blocking of distant FUS beams may be required to circumvent temperature rises in the anterolateral temporal fossa. Acknowledgements (Funding): Focused Ultrasound Foundation, Swedish Neuroscience Institute

Focused Ultrasound 2014 4th International Symposium 49 29-BR Potential of Focused Ultrasound in Epilepsy Surgery Monday Nathan Fountain, Phil Tseng, Mark Quigg, Robert Dallapiazza, W. Jeff Elias 13 October 2014 University of Virginia, Charlottesville, Virginia, United States Topic: Brain Presentation Type: Oral Background/Introduction: The minimally invasive nature of FUS makes it an excellent candidate technology for epilepsy surgery. The limitation of currently available FUS systems is that the lesion must be deep in the brain to avoid bone heating. Thus, it is best suited for “subcortical” epilepsies, i.e. epilepsy resulting from lesions below the cortex. It is also desirable that the lesion be relatively small volume to avoid long treatment times and not be in eloquent cortex. Previous reports of seizure freedom after laser ablation of hypothalamic hamartomas and radiofreqency ablation of single subcortical nodules have been reported. Thus, we designed the Focused Ultrasound Subcortical Epilepsy (FUSE) study with these principles in mind. Methods: The FUSE study is an open label safety and feasibility pilot study. It will enroll 15 subjects with subcortical lesions as the cause of medically refractory epilepsy, including hypothalamic hamartomas, periventricular nodular heterotopia, focal “cortical” dysplasia that is suffi ciently far from the skull, and hamartomas of tuberous sclerosis. The main outcome is safety and feasibility of ablating the lesion but secondary outcome includes seizure reduction. Subjects will undergo a single MR guided FUS treatment session. Subjects may be sedated since they are likely to be in the MRI for 2-4 hours. A targeting model will be created before the procedure. Low temperature heating will fi rst insure proper localization of energy at the lesion, and then a high temperature ablation will be performed. If this study is successful, then it could change the standard treatment of hypothalamic hamartoma which now currently is primarily treated by laser ablation or open surgery. If the study is successful in treating periventricular nodules then it could be transformative for these patients because there is currently no common method of surgical treatment. FUS has a high potential to provide effective ablation of subcortical lesions causing epilepsy. Future developments will likely allow a larger treatment envelope and expand its use to other epilepsies. If it is a low risk procedure then it could shift the risk-benefi t ratio towards empiric treatment of lesions and help avoid intracranial monitoring and its attendant risks. Results and Conclusions: NA

50 Focused Ultrasound 2014 4th International Symposium 30-BR Can Ultrasound Contrast Agents Increase the Treatment Envelope? Monday Nathan McDannold1, Natalia Vykhodtseva1, Costas Arvanitis1, 13 October 2014 Margaret Livingstone2, Ferenc Jolesz1 Topic: Brain 1 Brigham & Women’s Hospital, Boston, Massachusetts, United States Presentation Type: Oral 2 Harvard Medical School, Boston, Massachusetts, United States

Background/Introduction: Currently, thermal ablation via transcranial MRI-guided focused ultrasound is restricted to centrally-located regions in the brain. This limitation is the result of skull heating when the focal region is steered to more peripheral regions in the brain, along with other factors such as limitations in beam steering in the currently-available clinical brain focused ultrasound systems. The treatment envelope could be expanded if the time averaged acoustic power needed for ablation could be reduced. Methods: The introduction of ultrasound contrast agents – preformed microbubbles that are injected intravenously – can reduce the power needed to ablate tissue. These commercially-available microbubble agents respond strongly to an acoustic fi eld, even at low intensities, and greatly magnify the resulting bioeffects. Results and Conclusions: This presentation will provide a summary of animal data obtained in small animals and in nonhuman primates at our institution and by others that tested contrast-enhanced ultrasound ablation. Overall, these studies have demonstrated that ablation can be achieved at time-averaged acoustic power levels at least an order of magnitude less than what is needed for thermal ablation. The huge reduction in acoustic power that can be achieved with ablation combined with ultrasound contrast agents may enable a substantial increase in the “treatment envelope” for transcranial focused ultrasound systems. New methods are being developed to control the procedure and to ensure that unwanted tissue effects do not occur outside of the focal region. These developments, along with other unresolved issues with this mode of ablation will be topics for discussion. Acknowledgements (Funding): Funding: Focused Ultrasound Foundation; NIH grants P01CA174645, P41EB015898

Focused Ultrasound 2014 4th International Symposium 51 31-BR Expanding the Treatment Envelope for Brain Therapy: Simulation Models Monday and Head Phantoms 13 October 2014 Matt Eames1, Gianmarco Pinton2, Mohamad Khaled3, W. Jeff Elias3, John Snell1, Topic: Brain Laurent Marsac2, Arik Hananel1, Mickael Tanter2, Wilson Miller3, Neal Kassell1, Presentation Type: Oral Max Wintermark3, Jean-Francois Aubry2,3 1 Focused Ultrasound Foundation, Charlottesville, Virginia, United States 2 Institut Langevin, Paris, France 3 University of Virginia, Charlottesville, Virginia, United States

Background/Introduction: Thermal therapy is currently limited to central areas of the brain in order to maximize the antenna gain between the outer cortex and the target. So far, clinical applications have been limited to thalamotomies for neuropathic pain, essential tremor and parkinsonian tremor. We developed numerical simulations and head phantoms in order to investigate the possibility to target more eccentric targets in the brain in silico and in vitro. Methods: Simulations: The acoustic fi eld was modeled with a 3D fi nite difference fullwave acoustic code developed at Institut Langevin. CT measurements of human heads were converted to acoustical maps. Two types of hemispheric therapeutic transducers were modeled: a low frequency 220 kHz transducer, and a 1 MHz transducer that required aberration correction with a time reversal approach. The therapeutic pulses propagated across multiple skull lengths to establish a stable reverberation pattern. Head phantoms: Three different models of phantoms have been developed: cadavers, gel-fi lled skulls, and a head mold containing a skull and fi lled with gel that mimics the brain and the skin. Each was positioned in a clinical tcMRgFUS system, sonicated at 1100 acoustic watts for 12 seconds at different locations under MR thermometry monitoring. Results and Conclusions: Simulations: For an equivalent energy deposition rate, it is shown that at high frequency the volume of the brain that is above a set of MI thresholds is over 3 orders of magnitude smaller than for the low frequency, and it is entirely confi ned to a compact focal spot. High frequency transducers seem more suited to expand the treatment envelop towards the skull base and the low frequency to expand the treatment envelop towards the skull vault and to target larger volumes. Head phantoms: The cadaveric phantom, gel-fi lled skull, and full head models had heating effi ciencies of 5.3, 4.0, and 3.9 °C/kW/s, respectively, compared to a heating effi ciency of 2.6 °C/kW/s for a sample of essential tremor clinical treatments. Acknowledgements (Funding): Simulation models are most suited to investigate novel strategies, including transducer design and positioning, but experiments are mandatory to fully validate such approaches and test novel MR imaging techniques for a better targeting, a larger temperature monitoring volume, or a shorter treatment time.

52 Focused Ultrasound 2014 4th International Symposium 33-BR ExAblate Neuro Transcranial Treatment Considerations Monday Eyal Zadicario 13 October 2014 InSightec, Tirat Carmel, Israel Topic: Brain Presentation Type: Oral Background/Introduction: ExAblate Neuro is the only technology that enables clinical treatment of transcranial MR guided focused ultrasound. It is CE approved for the treatment of certain neurological disorders and is under evaluation for additional regulatory approval. We will review the existing applications and the limitations of the current technology. Two of the key limitations are the treatment envelope and the effects of different skull on the effectiveness of the transcranial ultrasound delivery. Methods: Expanding the treatment envelope requires to overcome technological barriers. The current clinical experience is limited to anatomical targets that are limited to deep and centralized locations in the brain. This is a signifi cant limitation since there are compelling clinical targets that are located beyond the existing treatment envelope. We will suggest treatment concepts which are being developed to overcome these limitations and enable to extend the treatment envelope. Results and Conclusions: The accumulated clinical experience with transcranial focusing shows as signifi cant variability of the acoustic parameters which are applied during the treatments. It is assumed that the skull is the most signifi cant contributor to this variability due to its non-homogenous and quite variable characteristics. The variability has been studied and found to be correlated with skull density parameters. We will describe how patient selection criteria may be applied to optimize the treatment for different patient selection criteria.

Focused Ultrasound 2014 4th International Symposium 53 34-BR Magnetic Resonance Acoustic Radiation Force (Impulse) Imaging (MR-ARFI) Monday Kim Butts Pauly 13 October 2014 Stanford University, Stanford, California, United States Topic: Brain Presentation Type: Oral Background/Introduction: MR-ARFI adds to the rich toolbox of MR imaging methods for guiding focused ultrasound. MRI has exquisite soft tissue contrast for targeting focused ultrasound and a variety of contrast mechanisms for assessing the effect of focused ultrasound. In addition, MR can provide temperature mapping in near-realtime. MR-ARFI is an imaging method that compliments these other capabilities: MR-ARFI can provide a very low temperature rise method to locate the focal spot, calibrate the beam intensity, and potentially evaluate and improve focusing. MR-ARFI typically uses a relatively long ultrasound pulse (1-20 ms) during the application of a magnetic fi eld gradient to encode the displacement of tissue into the phase of the MR image. MR-ARFI is related to elastography, shear-wave imaging, and harmonic motion imaging methods, which evaluate tissue stiffness by evaluation of the ultrasound shear wave that propagates after the ultrasound pulse. However, MR-ARFI is instead visualizing the quasi-static displacement of tissue during the ultrasound pulse, rather than the shear wave after the pulse. Methods: There is no single method for MR-ARFI in either the encoding gradients or the readout method. For the encoding method, early publications used unipolar gradients, similar to diffusion gradients. [1-4] Inverted bipolar gradients were used to reduce the diffusion weighting, [5-7] and repeated bipolar gradients to additionally reduce eddy current errors and motion sensitivity. [8-16] For gradient echo imaging, single bipolar gradients have been used. [2, 17, 18] Many different readout methods have been used including line scan, [1, 6, 8] spin echo, [3, 5, 10, 12, 15, 16], gradient echo, [2] EPI [2, 4, 6, 7, 13], RS-fl yback-SE-EPI, [9] GRE-EPI, [17] 3D, [13, 18] single shot FSE, [11] and fl uctuating equilibrium MR. [19] Results and Conclusions: Applications For the fi rst two goals, the phase of the MR-ARFI picture has been shown to increase linearly with ultrasound power in phantoms and tissues [1, 8, 10, 20] and in vivo [5] and to reasonably agree with ultrasound ARFI in vivo. [21] In addition, the focal spot spatial location has been shown in vivo to be in good agreement with the location of the subsequent temperature rise. [4, 9] For the third goal of evaluating and improving focusing, there have been several proposed methods. One method for adaptive focusing uses an iterative method that chooses the phase of the elements to maximize the phase of the ARFI image. [6] A second method uses direct inversion of spatially coded emissions. [7, 20, 22] A third method uses simulation to iteratively fi nd the phase aberrations consistent with a single measured MR-ARFI image. [15] While the former two methods require signifi cant time be spent on imaging (with associated ultrasound power deposition), the last method instead spends time on the computation, without the same power deposition. MR-ARFI has also been used to identify calcifi cations, [3, 16] and evaluate tissue stiffness after FUS. [12, 23] Discussion With respect to safety, keeping the amplitude of the ultrasound pulse low reduces heat and possibility of cavitation. Several studies with simultaneous MR-ARFI and temperature imaging have shown that the temperature at the focal spot can rise during an MR-ARFI acquisition, but also that the temperature can remain low with suitable choice of parameters. [5, 6, 14, 18]

54 Focused Ultrasound 2014 4th International Symposium 35-BR Volumetric Thermometry Monday Dennis Parker 13 October 2014 University of Utah, Salt Lake City, Utah, United States Topic: Brain Presentation Type: Oral Background/Introduction: Many applications of thermal therapy would benefi t from temperature distribution measurements with high spatial and temporal resolution that cover a large 3D volume. Although MRI can acquire 3D temperature measurements, it is not possible to obtain fully sampled 3D MRI measurements that cover the insonifi ed fi eld of view with suffi cient spatial and temporal resolution for most thermal therapy procedures. With multiple receiver coils, acquisition speed can be improved with undersampling and parallel image reconstruction methods. Constrained or model-based image reconstruction methods can allow increased undersampling. Depending on the anatomic region of interest, the effects of motion, chemical shift, and susceptibility need to be addressed. Non-Cartesian methods can reduce sensitivity to motion, but are less forgiving to off resonance effects. Applications to the brain and the breast are considered. Methods: Brain: We have investigated several methods of k-space undersampling using temporally constrained reconstruction (TCR) and model-predictive fi ltering (MPF) methods. Volumetric MRTI was performed to test the ability to track heating throughout the volume, including the focus and critical points near the skull. Breast: Although fat does not have frequency temperature dependence, it does have relaxation rates (T1, and T2) that change reproducibly with temperature. We have investigated hybrid MRTI sequences using dual fl ip angles to measure T1 simultaneously with PRF. Results and Conclusions: Important observations include: 1) Volumetric MRTI measurements obtained during transcranial heating of plastic skull demonstrated temperature tracking at critical positions throughout the volume, including the focus and all areas near the skull. 2) Very large undersampling factors (up to R=12) were obtained and reconstructed with both TCR and MPF methods. 3) The TCR method is relatively accurate, but not real time and results in errors at times of rapid temperature transitions. 4) The MPF method yields volumetric MRTI measurements in real time to help guide treatment. Although MPF relies on estimates of tissue thermal properties and ultrasound SAR distribution, it is relatively insensitive to errors in these properties. Because MPF incorporates the transition times (on/off) of ultrasound power, rapid temperature transitions are more accurately represented. 5) With fully 3D measurements, band limited (zero-fi lled) interpolation can be performed in all three directions to decrease spacing between voxels and thereby decrease partial volume effects. 6) Reverse centric k-space trajectories, which can increase effective echo-time and increase temperature SNR, can result in a systematic T1-dependent error (downward bias) of measured temperature in narrowly focused heating patterns. 7) Sequential (non-centric) k-space trajectories can yield fast and accurate temperature measurements. Acknowledgements (Funding): This abstract includes work from Nick Todd, Henrik Odeen, Bryant Svedin, and Allison Payne. The work has been supported by the Focused Ultrasound Foundation, and NIH grants R01 EB013433, R01 CA134599, and R01 CA172787.

Focused Ultrasound 2014 4th International Symposium 55 36-BR Improving Signal-to-Noise Ratio in Transcranial Magnetic Resonance Monday Guided Focused Ultrasound 13 October 2014 Rock Hadley, Dennis Parker, Emilee Minalga Topic: Brain Presentation Type: Oral University of Utah, Salt Lake City, Utah, United States Background/Introduction: Signal-to-Noise Ratio (SNR) can be increased in Magnetic Resonance Imaging (MRI) using Radio Frequency (RF) coils. Of all the options for increasing SNR, coils provide the greatest gains for the dollars spent. Coils for 1.5 and 3 Tesla MRI systems consist of conductive loops that are tuned to resonate at the fundamental frequency associated with the fi eld strength of the MRI scanner. These coils are the transducers between the MR signal and the system electronics and are sensitive to the magnetic fi elds of the MR signal via Faraday’s Law of Maxwell’s equations. Sensitivity of a coil to the signal in the imaging sample depends primarily on the geometry and position of the loop with respect to the sample. To achieve the highest SNR requires the coil to be in close proximity to the sample of interest, small enough that it is not sensitive to regions outside the region of interest and large enough to pick up the signal at the depth of interest. Other factors such as dielectric or conductive material loading of the coils can signifi cantly affect the tuning and function of a coil. Custom coils designed for a specifi c application typically provide much higher SNR than commercial coils that are designed for general purpose imaging of a broad range body habitus. Coils that provide even small gains in SNR provide signifi cant imaging improvement. For example, a specifi c-purpose (SP) coil that can provide a 40% SNR improvement over a general-purpose (GP) coil, can achieve the same image quality as the GP coil in half the imaging time. Similarly, an SP coil that can provide a factor of 2 improvement in SNR over a GP coil can achieve the same image quality 4 times faster than the GP coil. SNR can be used to improve image quality, temporal and spatial resolution, and enable or improve imaging functionality such as temperature measurement accuracy, Diffusion Tensor Imaging (DTI), and MR Acoustic Radiation Force Imaging (MR- ARFI). Methods: TcMRgFUS systems present many obstacles to achieving maximum SNR. Specifi cally, the large US transducer array with its associated housing and cables, the water bath required for US transmission, the membrane that contains the water and it’s position on the head (the head is partly in and partly out of the water), the stereotactic head frame, and the requirement that RF coils cannot interfere with the US beam make RF coil design for this application very diffi cult at best. In addition to signal reception, signal transmission can be diffi cult with the US housing shielding the sample from the transmit coil, resulting in a inhomogeneous or reduced fl ip angle across the volume of the sample. The large water bath can cause standing wave effects in the transmit RF fi eld and moving water can cause motion artifacts in the images. Because of all these imaging obstacles, it’s easiest to implement the use of system body RF coils for signal transmission and reception. Because of their size and distance from the imaging volume, they are inherently more forgiving to variable loads like the TcMRgFUS system. However, they also provide relatively low SNR, and are clearly not suffi cient for high-end imaging applications. Some research groups working on TcMRgFUS are using coils that have been developed specifi cally for that application. Some of the coils currently in use consist of arrays of coils that are wrapped around or integrated into the housing of the TcMRgFUS system. Others use arrays of coils that fi t close to the head. The close fi tting coils can be inside the water bath and outside the water bath. One institution is using coils that use conductors that cross the water bath membrane where part of the loop is in the waster and a part of the same loop is outside the water. Watkins et. al. at Stanford have developed a 2-part birdcage-like Transmit/Receive coil where one half is in the water bath and the other half is outside the water bath. The two halves are inductively coupled to generate a homogenous fi eld throughout the volume of the brain. This coil design also eliminates the need to use the body coil for transmission and therefore avoids the shielding effects that can be associated with use of the body coil transmission through the US transducer. This coil does not, however, enable parallel imaging techniques to be used as the multiple coil element arrays do. Results and Conclusions: In each case where a dedicated RF coil is being used for TcMRgFUS, the SNR provided by the dedicated RF coil is signifi cantly higher than the body coil of the MRI system by factors as much as 5x and more. Results of using the dedicated

56 Focused Ultrasound 2014 4th International Symposium RF coils include improved anatomical imaging and improved temperature accuracy, which is important for patient safety, for improved assessment of thermal dose and effi cacy, and for overall patient treatment planning. It is diffi cult to make an accurate SNR comparison of the TcMRgFUS coils currently in use because the SNR measures are being done in different environments, across different MR platforms and with different transducer designs. As we gain experience with the RF coils that are currently being used and continue to push the MRg limits for FUS requirements in the human brain, coil designs with higher SNR will become more important. Achieving the ultimate SNR coil design will require the development of a TcMRgFUS system with the RF coils integrated into the design. Optimized RF coil design and implementation will prove to be a signifi cant contribution for obtaining precise, accurate, and effi cacious patient treatment planning for FUS treatments of brain disorders and disease.

Focused Ultrasound 2014 4th International Symposium 57 37-BR MR Bone Imaging Monday Wilson Miller 13 October 2014 University of Virginia, Charlottesville, Virginia, United States Topic: Brain Presentation Type: Oral Background/Introduction: Bone is highly relevant to focused ultrasound therapy, both as a potential treatment target and because it interferes with treatment of other organs such as the brain. It is challenging to image cortical bone using MRI, however, due to low water density and fast signal decay in bony tissues. Ultrashort echo time (UTE) imaging is a specialized MR technique that allows the weak, short-lived signal from cortical bone to be imaged despite these limitations. Potential applications of UTE bone imaging in MR-guided focused ultrasound include direct MR thermometry of bone heating, which is not possible using standard proton resonance shift (PRFS) techniques, and in situ skull imaging during brain treatment procedures, which could replace the separate CT scan currently required for transcranial focused ultrasound. Methods: In UTE MRI, imaging data is acquired using a spoke-radial k-space trajectory with gradient ramp sampling. This allows data acquisition to begin immediately after RF excitation, to capture the MR signal from cortical bone before it decays away. The basic UTE imaging technique can be implemented as either a 2D slice-selective or a 3D volumetric acquisition. A volumetric acquisition is ideal for 3D skull imaging. Achieving adequate spatial resolution, however, requires a relatively long scan time (~10 min). Fast UTE imaging of 2D slices can be performed by using specially designed half-RF pulses. Although more challenging to implement, such an acquisition would be much more suitable for monitoring transient temperature changes in bone during FUS treatment. Because bone signal decays too quickly to perform PRFS-based thermometry, however, other temperature-dependent MR properties must be used to generate sensitivity to temperature changes. For instance, the T1 relaxation time generally decreases with increasing temperature, whereas T2 generally increases. Either of these effects might therefore provide a basis for MR thermometry in cortical bone. Results and Conclusions: Figure 1 shows several images of the same 1.25mm-thick slice, reconstructed from a dual-echo 3D UTE head scan. Cortical bone in the skull has weak, but clearly nonzero, signal in the UTE image (a), but appears black in the long-TE image (b). The conspicuity of cortical bone can be enhanced by taking the difference of these images and dividing by their sum (c), which facilitates automatic segmentation of bone pixels (d). Investigations are currently underway to use such UTE bone scans in place of CT scans to compute aberration corrections for transcranial ultrasound. Figure 2 shows T1-weighted UTE images of a beef bone obtained during focused ultrasound heating. The MR signal decreases at the location of focal heating, which is the expected behavior as T1 increases. Calibrating such signal changes to quantitative temperature changes is the focus of ongoing research. In conclusion, MR bone imaging using UTE techniques holds substantial promise for improving MR-guided focused ultrasound treatments of bone and other organs. Although UTE pulse sequences are not standardly available on existing commercial scanners, this situation is likely to change over the next few years. MR images reconstructed from a dual-echo 3D scan of a human head, showing the potential for skull imaging and segmentation using UTE MRI. Imaging resolution is 1.25 mm isotropic.

T1-weighted UTE images of a beef long bone during focused ultrasound application, showing the potential for MR thermometry using UTE MRI. To make the technique quantitative, the size of the T1-dependent signal decrease must be calibrated to temperature. 58 Focused Ultrasound 2014 4th International Symposium 38-BR Cavitation Detection for Brain Imaging and Therapy Monday Meaghan O’Reilly, Ryan Jones, Kullervo Hynynen 13 October 2014 Sunnybrook Research Institute, Toronto, Canada Topic: Brain Presentation Type: Oral Background/Introduction: Cavitation-mediated therapies for the brain, such as ultrasound-induced Blood-Brain barrier opening and sonothrombolysis for the treatment of stroke, are being increasingly investigated. Robust methods for monitoring and controlling cavitation are necessary for safe translation of these techniques into clinical practice. This talk will review our work detecting and mapping cavitation activity in the brain, as well as using the cavitation signals to control treatments. The potential application of these techniques for mapping the vasculature will also be discussed. Methods: NA Results and Conclusions: NA

Focused Ultrasound 2014 4th International Symposium 59 39-EI Focused Ultrasound: An Effective Technique for Unleashing the Power of Tuesday Immunotherapy in the Tumor Microenvironment? 14 October 2014 Elizabeth Repasky Topic: Enhanced Immunotherapy Roswell Park Cancer Institute, Buffalo, New York, United States Presentation Type: Oral Background/Introduction: The tumor microenvironment presents signifi cant barriers to the infi ltration of anti-tumor immune effector cells as well as to the delivery of cancer therapeutics. In part, physical parameters such as high interstitial pressure, defective vascular elements and abnormally dense stromal elements contribute signifi cantly to poor uptake of immune cells. However, growing evidence also shows that tumor-cells can produce infl ammatory cytokines as well as express certain surface receptors that drive both the accumulation of immunosuppressive cells as well as block the activation of antigen-specifi c immune effector cells, such as CD8+ T cells, which are able to traverse the physical barriers to the interior of tumors. Methods: In a brief Introduction to this session, I will highlight some exciting new advances in tumor immunology/immunotherapy as well as outline several properties of focused ultrasound (FUS) that could make it a very attractive immune adjuvant that can non-invasively manipulate the tumor microenvironment for enhanced anti-tumor immunity. I will also highlight several recent publications which strongly support the ability of FUS to stimulate endogenous anti-tumor immunity and support its combination with immunotherapy. Results and Conclusions: NA

40-EI HIFU Immunotherapy: Lessons from Animal to Clinical Studies Tuesday Feng Wu 14 October 2014 University of Oxford, Oxford, United Kingdom Topic: Enhanced Immunotherapy Background/Introduction: The ideal cancer therapy not only induces the death of all Presentation Type: Oral localized tumor cells, but also activates a systemic antitumor immunity. High intensity focused ultrasound (HIFU) has the potential to be such a treatment, as it can non-invasively ablate a targeted tumor below the skin surface, and may subsequently augment host antitumor immunity. Methods: This talk is to introduce increasing animal and clinical evidences linking antitumor immune response to HIFU ablation, review the potential mechanisms, and discuss challenges and opportunities involved in HIFU-enhanced host antitumor immunity. Results and Conclusions: It is concluded that HIFU immunotherapy may play an important role in preventing local recurrence and metastasis of cancer after HIFU treatment.

60 Focused Ultrasound 2014 4th International Symposium 41-EI Immune Activation and MRgFUS Tuesday Katherine Ferrara, Elizabeth Ingham, Andrew Wong, Azadeh Kheirolomoom, Brett 14 October 2014 Fite, Yu Liu, Lisa Mahakian, Sarah Tam Topic: Enhanced University of California Davis, Davis, California, United States Immunotherapy Presentation Type: Oral Background/Introduction: For many years, immune activation following tumor ablation has been evaluated in the treatment of systemic cancer. Ultrasound ablation is thought to promote dendritic cell maturation and T-cell immunity, and is particularly advantageous because it is non-invasive, can be controlled with high spatial precision and uses no harmful ionizing radiation. Methods: Recently, immune adjuvants have been shown to be effective in treating metastatic cancer, with cancer immunotherapy named as the “breakthrough of the year” in 2013. At this time, combining ablation with immune adjuvants is a promising technique for expanding the utility of ultrasound for the treatment of systemic disease. We will briefl y review the status of this combined therapy and opportunities for future studies. Results and Conclusions: NA

42-EI Focused Ultrasound and Immunotherapy Tuesday Mark Hurwitz 14 October 2014 Jefferson University Hospitals, Philadelphia, Pennsylvania, United States Topic: Enhanced Immunotherapy Background/Introduction: Thermal therapy has tremendous potential to augment the Presentation Type: Oral benefi ts of immunotherapy. The ability of heat to stimulate both general and tumor specifi c responses, in part through heat shock protein mediated mechanisms has been known for over two decades. Signifi cant challenges persist however in translating these effects into predictable and meaningful clinical responses. More recently the association of radiation with immune stimulation and in some cases specifi c anti-tumor immune response has been defi ned. Methods: Coupled with the introduction of new immunotherapuetics including check point inhibitors which have demonstrated clinical survival benefi t, the combination of heat, radiation, and immunotherapy to combat cancer is a timely area for investigation. The potential of focused ultrasound to augment immunotherapy including targeted heat and drug delivery will be discussed including the opportunity to enhance immune effects arising from the heated but non-ablated rim present with tumor ablation. Results and Conclusions: NA

Focused Ultrasound 2014 4th International Symposium 61 43-EI T-cell Mediated Immune Response to HIFU-induced Liquefaction of Murine Tuesday B16 Melanoma 14 October 2014 Tatiana Khokhlova Topic: Enhanced Immunotherapy University of Washington, Seattle, Washington, United States Presentation Type: Oral Background/Introduction: Anti-tumor immune response caused by High Intensity Focused Ultrasound (HIFU) therapy has been a subject of controversy. Most agree that the response is more likely to be induced by mechanical, rather than thermal effects of HIFU. The goal of the current work was to study the effect of HIFU-induced liquefaction of a tumor on tumor-specifi c and non-specifi c T-cell mediated immune response in a mouse model. Methods: B16 melanoma was inoculated in a hind limb of B6 wild type mice. When the tumor reached the diameter of 1 cm, it was treated with HIFU optimized for boiling histotripsy (BH) - a technique utilizing millisecond-long pulses to create boiling bubbles via rapid shockwave heating. The interaction of shocks with the ensuing vapor cavity fractionates tissue into subcellular debris with negligible thermal effect. The control group received sham treatment. Groups of animals were sacrifi ced 2 and 7 days post treatment, and the lymphatic organs, blood and tumor tissue were analyzed by fl ow cytometry for T cell and dendritic cell activation status, phenotype, specifi city and reactivity. Results and Conclusions: Although BH delayed the tumor growth compared to the control group, it did not change subsequent growth rate. No statistically signifi cant difference from the control group was found in neither the number, nor the phenotype and activation of cytotoxic, helper and regulatory T cells (neither tumor-specifi c, nor non-specifi c). Activation status of the dendritic cells was also unaltered by the treatment. However, a two-fold difference in the number of non-dendritic cells bearing MHCII receptor was found in the spleen and inguinal lymph nodes suggesting a humoral response. These results indicate that T cell mediated mechanism is unlikely to be triggered by BH alone, but warrant further investigation of the systemic effects of this unique treatment modality. Acknowledgements (Funding): Work supported by NIH DK007742 and NSBRI through NASA NCC 9-58.

62 Focused Ultrasound 2014 4th International Symposium 44-BN Magnetic Resonance guided Focused Ultrasound Surgery (MRgFUS) Tuesday Treatment of Osteoid Osteoma: A Prospective Development Study 14 October 2014 Alessandro Napoli, Fulvio Zaccagna, Gaia Cartocci, Brachetti Giulia, Gianluca Caliolo, Topic: Fabrizio Andrani, Carlo Catalano Bone Non-metastases Presentation Type: Oral University of Rome – Sapienza, Rome, Italy

Background/Introduction: To investigate mid- to long-term effi cacy of MRgFUS in the treatment of symptomatic osteoid osteomas. Methods: This prospective, IRB approved study involved 29 consecutive patients with clinical and imaging diagnosis of Osteoid Osteoma; all patients underwent MRgFUS ablation (ExAblate, InSightec; Discovery 750 MR unit, GE). Lesions located in vertebral body were excluded; prior RFA or surgery was not considered an exclusion criteria. Patients received therapy using MRgFUS, delivered toward the nidus, identifi ed on MRI and/or CT. Primary endpoints were adverse events (serious and otherwise) and pain relief assessed using questionnaires on Visual Analog Pain Score (VAS) and daily intake of Non-steroidal drugs (NSAIDs). Patient’s follow-up, including clinical and imaging examinations, was established at 1, 12 and 24 months. As secondary endpoint, imaging examinations (CT and CE-MRI; Gd-BOPTA, Bracco) were used to evaluate infl ammatory status after treatment and bone remodeling. Results and Conclusions: 29 patients (female 8; male, 21; mean age 23) were recruited for MRgFUS treatment; all safely completed the procedure. The treatment was well tolerated by all patients and no adverse events were recorded after and during 12-24 months follow- up period. A mean number of 4 ± 1.8 sonications with mean energy of 894 ± 209 J was necessary to complete the treatment. Three patients underwent staged treatment (1 post- RFA, 1 post surgery, 1 intrarticular position). Complete clinical response was found in 27/29 (93% CI 6–18) patients in term of pain absence and no intake of NSAIDs. There was a statistically signifi cant difference (p=0,001) between baseline (7,9 ± 1,4) and follow-up values (0,7 ± 0,1) for pain severity, according to VAS. Two patients (0.6%) reported pain recurrence requiring both RFA. Imaging evaluation with CE-MRI demonstrated edema and hyperemia decrease in every lesion associated with complete response. At CT, bone remodeling was evident in all complete responders (27/29); in 15/27 (55%) patients, nidus fading was demonstrated. MRgFUS can be safely and effectively adopted for the treatment of Osteoid Osteoma. This application is totally non-invasive, carried out in a single session and with pain relief attainable since the following day after treatment. Our results also indicated a positive trend to bone restoration.

Focused Ultrasound 2014 4th International Symposium 63 45-BN MRgFUS Treatment of Superfi cial Osteoid Osteomas of the Lower Limbs Tuesday Alberto Bazzocchi1, Alessandro Napoli2, Giacomo Filonzi1, Giancarlo Facchini2, 14 October 2014 Paolo Spinnato1, Maurizio Busacca1, Carlo Catalano2, Ugo Albisinni1 Topic: 1 The “Rizzoli” Orthopaedic Institute, Bologna, Italy Bone Non-metastases 2 University of Rome – Sapienza, Rome, Italy Presentation Type: Oral Background/Introduction: Osteoid osteoma (OO) is a relatively common benign bone tumor (2-3% of all bone tumors, 10% of benign bone tumors) usually developing in children and young adults. It is quite painful and patients typically complain of localized pain that is worse at night and characteristically relieved by non-steroid anti-infl ammatory drugs (NSAIDs). Conventional treatment options include surgery, systemic drugs administration, and imaging guided percutaneous procedures. Minimally invasive procedures are considered of primary importance, and this is even enhanced considering the benign nature of the lesion and the young age of the affected population. CT guided radiofrequency ablation (CTgRFA) is the most popular percutaneous technique with clinical success rate reported between 85% and 98%. However, CTgRFA is still rather invasive, and it requires CT-guidance, with obvious concerns linked to radiosensitivity especially of young patients. MR guided focused ultrasound surgery (MRgFUS) is a minimally invasive procedure that can be performed relatively fast, in a single session and with limited amount of energy deposition and no use of ionizing radiation. Methods: From March 2013 to May 2014, 7 consecutive patients (6M, 1F; mean age 33.5±12.4, range 19-64 years old) with superfi cial osteoid osteomas of the lower limb were treated at our Institute with MRgFUS (ExAblate 2100, InSightec). Six lesions were located at the femur, one at the tibia. The mean time between the onset of symptoms and the diagnosis was 3.75 months (range 1-9 months). One patient had previously undergone CTgRFA (in a different hospital) but experienced a relapse of symptoms 4 months after, and imaging revealed that the lesion was still there. For all other patients MRgFUS was used as fi rst-line treatment (apart from NSAIDs). Patients were examined clinically (visual analogue scale score – VAS; Qol) at baseline and at 1, 3, 6 and 12 months of follow-up. Results and Conclusions: In fi ve patient the 12-month follow-up period has been completed, while two patients are still at 1- and 3-month check points. The mean VAS at the baseline was 7.5. In all patients VAS dropped to 0 after 1 month. In 6 patients (86%) VAS remained 0 during the follow-up, while in 1 patient VAS dropped from 9 to 0 after 1 month but rose to 2 after 3 months (6-month control available, no recurrence documented). No intra-operative complications or short/mid-terms adverse events were observed. These preliminary data showed that MRgFUS can be effectively adopted for the treatment of superfi cial OO and can be performed safely ad with a high rate of success for the noninvasive treatment of this condition.

64 Focused Ultrasound 2014 4th International Symposium 46-BN MRgFUS New Applications in Musculoskeletal Pathology: A Miscellaneous Tuesday Case Review 14 October 2014 Alberto Bazzocchi1, Alessandro Napoli2, Giacomo Filonzi1, Maurizio Busacca1, Topic: Emanuela Palmerini1, Stefano Ferrari1, Carlo Catalano2, Ugo Albisinni1 Bone Non-metastases Presentation Type: Oral 1 The “Rizzoli” Orthopaedic Institute, Bologna, Italy 2 University of Rome – Sapienza, Rome, Italy

Background/Introduction: Magnetic resonance guided focused ultrasound surgery (MRgFUS) of the musculoskeletal system achieved signifi cant results in the treatment of painful bone metastases, and recently showed promise for benign bone lesions (e.g. osteoid osteoma) and osteoarthiritis (e.g. facet joint syndrome and knee osteoarthritis). MRgFUS works on the main basis of pain relief and tumor control / killing. In this case review fi ve patients affected by different diseases not commonly treated by MRgFUS are presented. Methods: (A) A patient (M; 47 years old) suffering from femuroacetabular impingement developed a small focal lesion in the anterosuperior profi le of the femoral neck (herniation pit). The lesion was harshly painful at baseline (visual analogue scale score – VAS 9), with severe mobility impairment. Conservative treatments failed and the patient was in list for arthroplasty. (B and C) In 2 patients (1F, 1M; 64 and 40 years old, respectively), the targeted lesion was a small (about 1 cm) subcortical alteration of the posterosuperior profi le of the femoral neck, diagnosed as a focal degenerative change caused by posterior impingement syndrome. At baseline patients suffered from pain (VAS 9 and 8, respectively) and relevant mobility impairment like in case A; both patients started with symptoms several months before and they were unsuccessfully treated by drugs and surgery (arthroscopic approach – male patient). (D) A young female patient (29 years old) was found with a 1-cm sclerotic alteration of the 8th right rib, dimensionally stable at 6-month imaging follow-up; scintigraphy and FDG positron emission tomography were both negative, with no nidus or other signs detected by CT or perfusion MR. No history of oncological disorders. The lesion was painful (VAS 9), and previous treatments (systemic drugs, local injections) failed in controlling pain. We decided to proceed to MRgFUS without histological diagnosis (fi brous dysplasia, osteoid osteoma or osteitis were the most likely hypotheses). (E) A 40-year-old man with aggressive fi bromatosis presented with a 10-cm mass extended from the left popliteal fossa to the leg; The disease was discovered at the age of 20, and the patient underwent several surgical sessions, radiation therapy and pharmacological treatment throughout two decades, particularly over the site of the presented fi broma (large scars, venous varicosity and incontinence, and arterial bypass). He suffered from relapses and also infective and vascular complications. All patient were examinated clinically and by imaging, before treatment (ExAblate 2100, InSightec) and up to 12 months of follow-up (1-, 3-, 6- and 12-month checks). Results and Conclusions: Patient with focal degenerative diseases (A, B, and C) showed an excellent response to treatment: VAS dropped to 0 after 1 month and persisted to 0 in all the subsequent follow-up controls (12 months), with signifi cant improvement in the mobility of the affected hip. The young lady (D) with rib lesion of unknown origin had only a partial improvement (VAS from 9 to 6 after 1 month, the only check reached). The man affected by fi bromatosis showed VAS fl attening to 0 (1-month check) with improvement of the perceived quality of life. The lesion showed dimensional reduction and no enhancement at contrast media injection from the 3-month control (6 months of follow- up). Several and different applications of MRgFUS in musculoskeletal disorders are coming, to fi nd an effective solution or to minimize invasivity and avoid or postpone any major intervention.

Focused Ultrasound 2014 4th International Symposium 65 47-BN Dual Echo Gradient Echo Imaging for Simultaneous Thermal Mapping in Tuesday Cortical Bone and Soft Tissue 14 October 2014 Elizabeth Ramsay1, Charles Mougenot2, Mohammad Kazem1, Theodore W Laetsch3, Topic: Rajiv Chopra3 Bone Non-metastases Presentation Type: Oral 1 Sunnybrook Research Institute, Toronto, Canada 2 Philips Healthcare Canada, Toronto, Canada 3 University of Texas Southwestern Medical Center, Dallas, Texas, United States

Background/Introduction: MRI-guided high-intensity focused ultrasound (MR-HIFU) therapy can relieve pain associated with metastatic and benign bone tumours in patients who fail to respond to conventional radiation therapy. However, since existing MR-thermometry techniques do not provide temperature information within the bone, HIFU exposures in bone are currently monitored using temperature changes in adjacent soft tissues. In this study, a standard dual echo spoiled gradient echo (SPGR) sequence is proposed to monitor thermal effects in both bone and soft tissue simultaneously. Magnitude signal changes at the shorter TE (~1ms) refl ect thermal changes in cortical bone, while phase changes at the longer TE (~10ms) allow conventional PRF thermometry in surrounding tissues. Methods: As shown in Fig A, ex vivo cortical beef bones were stripped of marrow and connective tissue, embedded in gel, and sonicated using a Sonalleve V2 HIFU system (Philips Healthcare). A proximal region of the bone was exposed to ultrasound for periods of 30 seconds at powers of 20-60 W, while a dual echo SPGR (echo times TE1 = 1 ms, TE2 =~ 10 ms) sequence was run repeatedly using a 3T Achieva MRI system (Philips). Bone temperature was measured as a function of time using fi ber-optic temperature sensors (Neoptix) inserted in pre-drilled holes in the bone, two in the heated region and two distant from the region of heating. The correlation of the temperature with magnitude and phase images at the two echo times was examined. Results and Conclusions: As shown in the Figure, local cortical bone temperature changes were well-correlated temporally (B) and spatially (C) with changes in signal magnitude at short (~1ms) echo times, while temperature in the gel could be measured via changes in the voxel phase at long (10ms) echo times (D). These results demonstrate a simple method for monitoring thermal changes simultaneously in cortical bone and soft tissue using a dual echo gradient echo sequence. The technique can be easily translated onto existing MR imaging systems thus improving the safety of MR HIFU treatments. Acknowledgements (Funding): This research was supported by the NIH.

A. Schematic of HIFU heating experiment. B. The left axis shows the magnitude signal change observed in the ROIs shown in C during heating. The ROIs are centered on the sensor positions. The right axis shows the average temperature of sensors 1 and 2. C. Correlation coeffi cient map of the average temperature of sensors 1 and 2 with signal change derived from TE1 magnitude images. The correlation is positive in the heated area within the bone, negative in the gel outside the bone, and negligible for areas of the bone distant from the treated region. D. PRF temperature change in the gel surrounding the bone, derived from the TE2 phase images.

66 Focused Ultrasound 2014 4th International Symposium 48-BN Magnetic Resonance Guided Focused Ultrasound for Noninvasive Pain Tuesday Therapy of Osteoid Osteoma in Children 14 October 2014 Adam Waspe1, Yuexi Huang2, Ruby Endre2, Joao Amaral1, Joost de Ruiter1, Topic: Fiona Campbell1, Charles Mougenot3, Kullervo Hynynen2, Gregory Czarnota2, Bone Non-metastases James Drake1, Michael Temple1 Presentation Type: Oral 1 Hospital for Sick Children, Toronto, Canada 2 Sunnybrook Health Sciences Centre, Toronto, Canada 3 Philips Healthcare, Toronto, Canada

Background/Introduction: Osteoid osteoma (OO), a small painful benign bone tumor, is the most common bone tumor in children. Pain is managed with nonsteroidal anti- infl ammatory drugs but minimally invasive techniques, such as CT-guided laser ablation, have become a standard intervention. However, the potential for non-target injury is a concern as tissue temperature cannot be measured with CT and the laser induces temperatures >90°C for 10 minutes. It also includes risks from exposure to ionizing radiation, fracture, infection and transmitted thermal damage from the access needle. Magnetic resonance guided high intensity focused ultrasound (MRgHIFU) has been used successfully in small cohorts of adults with OO. The noninvasive nature of the energy means that procedures do not need to be conducted in a sterile environment since there is no mechanical penetration of the bone, reducing the chance of pathologic fracture and infection. Figure 1: Planned treatment cells to cover the volume of Methods: A Philips Sonalleve MRgHIFU device is being used to thermally ablate OO in the osteoid osteoma. A total pediatric patients. MR provides excellent soft tissue contrast, which enhances the interface of seven 4mm treatment between bone and surrounding soft tissues as well as the highly vascularized core of the cells, arranged in a circular OO, known as the nidus. The nidus is the primary target of thermal OO treatments since cluster, covered the extent of the 1cm lesion. destroying it will prevent regrowth of this painful lesion. Ten patients will be recruited and complete age-appropriate and validated surveys (Pediatric Ouch, and PedsQLTM) to determine how lesion/bone pain and medication usage affects health-related quality of life (HRQL) metrics, such as physical, emotional, social, and school functioning. A planning MRI will be used to ensure lesion accessibility/patient eligibility and MR thermometry will measure temperature in the target and surrounding tissue to ensure patient safety. As thermal bone ablation is painful, patients will be under general anesthesia for the treatment. Follow-up on days 2, 7, 14, 30, 90 and 180 following treatment will record pain, HRQL, and drug usage. Clinical visits on days 30, 90 and 180 will comprise a physical examination and a diagnostic MRI of the OO. Contrast enhanced MRI will indicate non-perfused tissues corresponding to the ablated tissue volume, which should be fully resolved by day 180. Results and Conclusions: One patient with a 1cm OO on the left femoral head is currently enrolled in the study and was treated with MRgHIFU using seven 4mm Figure 2: Representative treatment cells (Fig1). Individual treatments were 12s in duration with a power of 40- thermal map from one of the treatment sonications. A 50W 60W. Temperatures >55°C were measured at the bone surface and a thermal dose of exposure produced a maximum 240EM@43°C was achieved (Fig2). A small region of non-perfused tissue was observed in temperature above 55°C at the contrast enhanced MRI corresponding to the thermal dose margins (Fig3). One week after bone surface. A small region treatment the patient is pain free, off medication, and is consistently sleeping throughout (approximately 1 x 4 mm) adjacent to the osteoid osteoma the night. Study assessment of pain, HRQL and medication will follow. It is expected reached suffi cient temperatur that MRgHIFU will be effective for reducing pain and medication usage, leading to an temperatures to achieve a improvement in HRQL. thermal dose of 240EM@43 °C, causing necrosis. Acknowledgements (Funding): We acknowledge project funding from the Focused Ultrasound Foundation and the Hospital for Sick Children Innovation Fund. This clinical study is not industry sponsored but we do receive technical support from Philips Healthcare and collaborate with Philips on preclinical focused ultrasound projects.

Figure 3: Gadolinium enhanced T1-w image of the osteoid osteoma and treatment area following thermal ablation. A small region of non-perfused tissue is visible at the bone surface, adjacent to the osteoid osteoma lesion that is approximately the same extent as the thermal dose contour. Focused Ultrasound 2014 4th International Symposium 67 50-BM MR-guided Focused Ultrasound for Painful Bone Metastases: Safety When Tuesday Combined with Chemotherapy 14 October 2014 Joshua Meyer1, Raphael Pfeffer2, Sergey Kanaev3, Dmitri Iozeffi 4, David Gianfelice5, Topic: Bone Metastases Pejman Ghanouni6, Daniela Militianu7, Mark Hurwitz8 Presentation Type: Oral 1 Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States 2 Assuta Hospital, Tel Aviv, Israel 3 N.N. Petrov Research Institute of Oncology, Saint Petersburg, Russian Federation 4 Rostov Scientifi c Research Institute of Oncology, Rostov-On-Don, Russian Federation 5 Laennec Imagix Imaging Center • Medical Imaging, Ville Mont-Royal, Canada 6 Stanford University, Stanford, California, United States 7 Rambam Health Care Campus, Haifa, Israel 8 Jefferson University Hospitals, Philadelphia, Pennsylvania, United States

Background/Introduction: Magnetic Resonance guided Focused Ultrasound (MRgFUS) is a non-invasive, non-ionizing treatment producing thermal ablation using high intensity focused ultrasound and MR thermometry to denervate pain from bone metastases. A recent phase III study comparing MRgFUS to sham treatment for a painful bone metastasis allowed patients to be treated with concurrent chemotherapy as long as the regimen was stable for at least 4 weeks. We performed a retrospective analysis of the safety of combination MRgFUS with active systemic chemotherapy in patients treated on this study. Methods: Chemotherapy data were available for 104 patients who were treated with MRgFUS in 17 medical centers worldwide as part of a randomized phase III study comparing MRgFUS to sham treatment for a painful bone metastasis previously irradiated or unsuitable for radiation therapy. Patients were followed for 3 months. Response was defi ned as a combination of at least two-point decrease on a standard numerical rating scale and <25% increase from baseline in analgesic medication at 3 months follow-up. Toxicity data was collected as any adverse event possibly related to treatment or its associated procedures. In spite of being an expected part of the procedure, sonication pain was scored as an event. Patients initially randomized to sham treatment who were offered rescue MRgFUS were also included in this analysis, bringing the safety population to 121 patients. All comparisons were performed using a z-score, with a signifi cance level of 0.05. Results and Conclusions: Ninety patients were treated without chemotherapy, and fourteen were treated with chemotherapy. There was no signifi cant difference between the response rates of the chemotherapy group (71%) and the non-chemotherapy group (68%) (p=0.78). The overall event rates were 57% for chemotherapy patients and 45% for non- chemotherapy patients (p=0.38). Sonication pain was not signifi cantly different between the groups, with 50% pain in the chemotherapy group and 28% pain in the non-chemotherapy group (p=0.11). Other events were limited to one patient with numbness of the skin in the chemotherapy group (7%). The non-chemotherapy group reported 18 events that were not sonication pain (17%). These rates were not signifi cantly different (p=0.17). In this retrospective analysis of a prospective study, no difference was found in effi cacy or toxicity of MRgFUS between patients receiving and not receiving active chemotherapy. Further studies are necessary to confi rm the safety of these two modalities in combination. If confi rmed, this may be an important reason to choose MRgFUS in the palliation of pain from bone metastases. Acknowledgements (Funding): The authors wish to thank Insightec for help in collating the data.

68 Focused Ultrasound 2014 4th International Symposium 51-BM Palliative Treatment of Painful Bone Metastases with MR Imaging–guided Tuesday Focused Ultrasound Surgery: A Two-centre Study 14 October 2014 Fulvio Zaccagna1, Brachetti Giulia1, Alberto Bazzocchi2, Paolo Spinnato1, Topic: Bone Metastases Ugo Albisinni2, Alessandro Napoli1, Carlo Catalano1 Presentation Type: Oral 1 University of Rome – Sapienza, Rome, Italy 2 The “Rizzoli” Orthopaedic Institute, Bologna, Italy

Background/Introduction: To evaluate the effi cacy of non-invasive high intensity MR guided focused Ultrasound Surgery (MRgFUS) for pain palliation of bone metastasis in patients who had exhausted EBRT or refused other therapeutic options. Methods: This is a prospective, single arm, multicentre study performed after IRB approval. 72 patients (female: 24, male: 48, mean age: 61.6) with painful bone metastases were enrolled. 87 non-spinal lesions underwent MRgFUS treatment using ExAblate 2100 system (InSightec). European Organization for Research and Treatment of Cancer QLQ- BM22 was used for clinical assessment additionally to Visual Analog Scale (VAS), at baseline and 1,3 and 6 months after treatment. All patients underwent CT and MRI before treatment and 3-6 months afterward. Results and Conclusions: Results: No treatment-related adverse events were recorded. 34/72 (47.2%) patients reported complete response to treatment and discontinued medications. 29/72 (40.3%) experienced a pain score reduction >2 points, consistent with partial response. Remaining 9 (12.5%) patients had recurrence after treatment. Statistically signifi cant differences between baseline (6, 95%CI 5-8) and follow-up (2, 95%CI 0-3) VAS values and medication intake were observed (p<0.05). Similarly a signifi cant difference was found for QLQ- BM22 between baseline and follow-up (p<0.05). Conclusion: MRgFUS can be safely and effectively used as totally noninvasive treatment for pain palliation of bone metastasis in patients who had exhausted EBRT and also in patients not previously treated with EBRT.

Focused Ultrasound 2014 4th International Symposium 69 52-BM Palliation of Painful Bone Metastases: The “Rizzoli” Experience Tuesday Alberto Bazzocchi1, Alessandro Napoli2, G Filonzi1, Paolo Spinnato1, 14 October 2014 Marco Colangeli1, Milva Battaglia1, Eugenio Rimondi1, Carlo Catalano2, Topic: Bone Metastases Davide Donati1, Ugo Albisinni1 Presentation Type: Oral 1 The “Rizzoli” Orthopaedic Institute, Bologna, Italy 2 University of Rome – Sapienza, Rome, Italy

Background/Introduction: Bone is a common site for metastasis. The primary cancers that most frequently metastasize to bone include the most prevalent worldwide (postmortem incidence of bone metastases: breast –73%, prostate –68%, thyroid –42%, lung –36%, renal –35%). The median survival of patients with bone metastasis from lung cancer is only a few months, whereas patients with breast cancer or prostate cancer may live for several years. In patients with aggressive tumor growth at the primary site, bone metastases are relatively uncommon, since tumor cells may not have the time to grow in bone. Bone metastases are the most common cause of cancer-related pain and quality of life impairment. The increasing longevity of the population coupled with the progress of cancer treatments, corresponding to improved survival of patients, is enhancing the incidence and the burden of distant metastasis such as bone metastasis. Hence, the treatment of secondary lesions will become even more important in the near future. Several limitations affect current clinically available treatment options. The aim of this work is to evaluate the clinical outcome of patients affected by painful bone metastases and submitted to magnetic resonance guided focused ultrasound (MRgFUS) at the “Rizzoli” Orthopaedic Institute (Bologna, Italy). Methods: Fifty-seven secondary bone lesions affecting 17 men and 22 women (mean age 61.5± 7.9, ranging 31-84 years old) were treated, with primary cancers including breast (15 – 39.5%), kidney (5), lung (5), colorectal (4), prostate (3), thyroid (3), stomach (1), soft-tissue sarcoma (1), and Ewing sarcoma (1). The lesions were distributed as follows: pelvis (37 – 64.9%); femur (6); ribs (4); humerus (3); sacrum (3); spine (spinous process) (2); scapula (1); calcaneus (1). The treated lesions ranged between 1 and 13 cm. Nine patients (23.7%) were affected by a single bone metastasis, while 5 of them showed no other distant metastasis at all in the staging. All patients were clinically examined (VAS, QoL) at baseline with a follow-up (FU) program including 1-, 3-, 6-, and 12-month check points. Results and Conclusions: Forty-fi ve lesions were evaluated after 1 month, while 31 lesions reached the 3-month (54.4%), 17 the 6-month (29.8%) and 8 the 12-month (14.0%) FU point. Four patients died during the FU (primary cancer related events), and 3 lesions required retreatment. On a lesion-based approach, VAS score at baseline was 5.19 ± 2.53. This decreased to 2.47 ± 2.34 (mean ΔVAS = 2.84 ± 3.15; Δ% = 42.01%) at 1 month, and to 2.0 ± 2.63, 2.14 ± 2.44, and 1.16 ± 1.83 after 3, 6 and 12 months respectively (ΔVAS% vs. baseline: 48.7%, 57.8% and 53.6%). A statistically signifi cant difference between baseline and all follow-up time points was observed for pain severity and pain interference (both p=0.001). In 14\45 lesions (31.1%) the VAS dropped to 0 one month after the treatment; VAS persisted 0 in 8 patients up to 3 months, in 5 up to 6 months, and in 3 up to 12 months. The major determinant of MRgFUS success was the size of the lesion. Treatment-related adverse events: a single case of small skin burns, and a case of prostate infl ammation (patient affected by benign prostate hypertrophy submitted to a MRgFUS of the ischiopubic branch). This single-center experience strengthens the proofs of effi cacy of MRgFUS in palliating painful bone metastases, coming from different primary cancers.

70 Focused Ultrasound 2014 4th International Symposium 54-PR Focal Treatment of Prostate Cancer Using Focal One Device: Pilot Study Tuesday Results 14 October 2014 Albert Gelet1, Sebastien Crouzet2, Olivier Rouviere2, Flavie Bratan2, Jean-Yves Topic: Prostate Chapelon3 Presentation Type: Oral 1 Edouard Herriot Hospital, Lyon, France 2 Hospices Civils de Lyon, Lyon, France 3 Inserm, Lyon, France

Background/Introduction: Objectives: To evaluated the effi cacy of Focal One device for focal treatment of localized prostate cancer. Methods: Material and method:Focal One® is a device designed for the focal therapy of Prostate Cancer combing the necessary tools to visualize, target, treat and validate the focal treatment. MR volumes are imported through the hospital’s network. The operator defi nes the contours of the prostate and the regions of interests that have been confi rmed as prostate tumors. The same contouring of the prostate is performed on the live ultrasound volume acquired by the transrectal probe. The software proceeds to an “elastic fusion”: the live Ultrasound volume is considered as the reference volume and the MR volume is smoothly deformed so the 3D contour of the prostate on the MR volume matches perfectly the contours of the prostate on the Ultrasound Volume. The same 3D elastic transformation is applied to the ROIs initially indicated on the MR image so they appear at the adequate position on the live Ultrasound Image, guiding the planning process. The Focal•One is equipped with a new generation of HIFU probe able to electronically vary the focal point along the acoustic axis using a HIFU multi-element phase array transducer. During the HIFU energy delivery process, the operator sees a live ultrasound image of what is being treated and, if necessary, can readjust the treatment planning. At the end of the treatment process, a Contrast-enhanced Ultrasound volume is acquired showing the de-vascularized areas. Teen patients with mono focal prostate cancer were treated between march 2013 and January 2014.HIFU treatment process was realized with the Focal One device using a 6 mm safety margin around the tumor. Contrast enhanced MRI is performed at day 2 after HIFU and Control biopsies guided with contrast-enhanced Ultrasound imaging were achieved one month after HIFU inside and in the rime of the treated area. Results and Conclusions: Results: The mean age of patients was 65.8±5.5 years. The Clinical stage was T1 for 9 patients and T2a for 1 patient. The Gleason sum was 6 for 7 patients and 7(3+4) for 3 patients. The PSA value was 4.47± 3.7 ng/ml and the mean Prostate Volume was 50±23 cc. The mean treated volume was 14 cc (7.3-20.4) 28% of prostate gland. The mean nadir PSA value was 3.46±2 ng/ml. In all patients, targeted biopsies inside the treated area performed day 30 after the HIFU session demonstrated a complete destruction of the targeted tumor. No incontinence was observed. A partial loss of potency (IIEF <17) occurred in 2 patients. Conclusions: Focal One device is able to achieved a complete destruction of small prostate cancer using an elastic magnetic resonance-ultrasound (MR-US) registration system for tumor location and HIFU treatment planning. Multicenter trial is in progress (30 patients). Acknowledgements (Funding): Edouard Herriot Hospital* and Inserm unit 1032 (LabTau)**, Lyon, France

Left: MRI registration with elastic fusion Center: Contrast-enhanced Ultrasound showing the de- vascularized areas. Right: Control MRI after focal HIFU Focused Ultrasound 2014 4th International Symposium 71 55-PR External Beam Radiation Therapy or High Intensity Focused Ultrasound for Tuesday Localized Prostate Cancer: A Matched Pair Analysis in the Prostate-Specifi c 14 October 2014 Antigen Era

Topic: Prostate 1 2 2 3 Presentation Type: Oral Albert Gelet , Sebastien Crouzet , Olivier Rouviere , Jean-Yves Chapelon , Murielle Rabilloud2 1 Edouard Herriot Hospital, Lyon, France 2 Hospices Civils de Lyon, Lyon, France 3 Inserm, Lyon, France

Background/Introduction: Background: In the absence of randomised study data institutional series have shown High Intensity Focused Ultrasound (HIFU) to produce excellent overall and cancer specifi c survival rates in patients with localized prostate cancer (LPCa) compared with alternative curative treatments. Objectives: To evaluate the oncologic outcome of patients treated with HIFU versus conformal external beam radiation therapy (C-EBRT) without previous or associated androgen deprivation(AD).This study is designed to overcome limitations of case series studies by using a matched pair design in patients treated contemporaneously with HIFU and C- EBRT ) in two institutions in the same town. Methods: Design, setting and participants: 256 eligible patients with intermediate risk prostate cancer (d’Amico classifi cation) treated between 2000 and 2005 were prospectively followed and matched to a 1:1 basis following know prognostic variables: prostate-specifi c antigen (PSA) level and Gleason score.190 perfect matches of patients (95 in each group) were further analysed. Progression free survival rate were the primary endpoint. Other endpoints were secondary used of salvage therapy, and survival rate without salvage palliative androgen deprivation therapy (S-ADT).The progression free survival rates were calculated with Kaplan-Meier estimate. For progression free calculation, failure was defi ned using the Phoenix defi nition (nadir + 2ng/ml) or at the time of a salvage treatment for local relapse evidenced by control biopsy. Results and Conclusions: Results: The seven years progression free survival rate was not signifi cantly different after HIFU than after C-EBRT (47% versus 52%, p: 0.311) . The palliative androgen deprivation free rate at seven years was signifi cantly different after HIFU than after C-EBRT (85% versus 58%, p: 0.002). Conclusion: The progression free survival rate was not signifi cantly different after HIFU use than after C-EBRT but the rate of patients who need palliative S-ADT was signifi cantly different after HIFU or C-EBRT: Higher rate of S-ADT was associated with C-EBRT use than with HIFU use. Acknowledgements (Funding): 1 Urology and Transplantation Department, Edouard Herriot Hospital, Hospices Civils de Lyon, F-69437 Lyon, France 2 Department of Genitourinary and Vascular Imaging, Edouard Herriot Hospital, Hospices Civils de Lyon, F-69437 Lyon, France 3 Therapeutic Applications of Ultrasound Research Laboratory,Unit 1032(LabTau), INSERM, Lyon University, F-69003, France 4 Hospices Civils de Lyon, Service de Biostatistique, Lyon, F-69003, France ; Université de Lyon, Lyon, F-69000, France

72 Focused Ultrasound 2014 4th International Symposium 56-PR Radical Prostatectomy versus High Intensity Focused Ultrasound for Tuesday Localized Prostate Cancer: A Matched Pair Comparison 14 October 2014 Albert Gelet1, Sebastien Crouzet2, Olivier Rouviere2, Jean-Yves Chapelon3, Murielle Topic: Prostate Rabilloud2 Presentation Type: Oral 1 Edouard Herriot Hospital, Lyon, France 2 Hospices Civils de Lyon, Lyon, France 3 Inserm, Lyon, France

Background/Introduction: Radical prostatectomy is the gold standard treatment for localized prostate cancer. HIFU is a treatment option with promising outcomes. No randomized study is available to compare those techniques. The goal of the study was to evaluate the oncologic outcome of patients treated with HIFU and radical prostatectomy by using a matched pair analysis to compare the 2 groups. Methods: A total of 710 patients treated between 2000 and 2005 were prospectively followed in our institutional database and matched to a 1:1 basis following know prognostic variables: prostate-specifi c antigen (PSA) level, Gleason score, and clinical stage. After matching, 588 patients (294 in each group) were further analysed. The starts of salvage external beam radiotherapy (S-EBRT) or defi nitive palliative androgen deprivation therapy (ADT) were primary endpoints. Other endpoints were overall, cancer specifi c and metastasis free survival rates: The survival rates were calculated with Kaplan-Meier estimate. Results and Conclusions: The seven years S-EBRT free survival rate was signifi cantly lower after HIFU than after RP (62% versus 78%, p=0.001). The palliative androgen deprivation free rate at nine years was not signifi cantly different between HIFU and RP (86% versus 87%, p=0.271). At nine years the overall, cancer specifi c and metastasis free survival rates were similar: 89%, 97%, 94 % and 89%, 97% and 97% for HIFU and RP respectively (p=0.186, 0.312, 0.107). Matched pair comparison of HIFU and RP has shown a higher rate of S-EBRT for HIFU. At 9 years, the rate of patients who need palliative ADT, the overall cancer specifi c and metastasis free survival rates were not signifi cantly different between HIFU and RP. Acknowledgements (Funding): This work was supported by the following: 1. Urology and Transplantation Department, Edouard Herriot Hospital, Hospices Civils de Lyon, F-69437 Lyon, France 2. Department of Genitourinary and Vascular Imaging, Edouard Herriot Hospital, Hospices Civils de Lyon, F-69437 Lyon, France 3. therapeutic Applications of Ultrasound Research Laboratory,Unit 1032(LabTau), INSERM, Lyon University, F-69003, France 4. Hospices Civils de Lyon, Service de Biostatistique, Lyon, F-69003, France ; Université de Lyon, Lyon, F-69000, France

Focused Ultrasound 2014 4th International Symposium 73 57-PR Transrectal Focal HIFU: The Use of MRI Fusion in Guiding Treatment Tuesday Stephen Scionti 14 October 2014 Scionti Prostate Center Topic: Prostate Presentation Type: Oral Background/Introduction: The ability to effectively ablate prostate cancer with transrectal HIFU has been demonstrated by numerous publications to date. Early results from focal HIFU series suggest that side effect profi les such as stricture, erectile dysfunction, and incontinence can be greatly reduced as compared to total gland ablative HIFU treatment. Methods: Multiparametric MRI combined with both systematic and fusion biopsy is being utilized more frequently worldwide to select patients for focal The ability to effectively ablate prostate cancer with transrectal HIFU has been demonstrated by numerous publications to date. Early results from focal HIFU series suggest that side effect profi les such as stricture, erectile dysfunction, and incontinence can be greatly reduced as compared to total gland ablative HIFU treatment. Multiparametric MRI combined with both systematic and fusion biopsy is being utilized more frequently worldwide to select patients for focal therapy. Commercially available, FDA approved MRI to ultrasound fusion platforms are now readily available for use in the urology clinic setting, however, these have not yet been widely used to guide focal HIFU treatment. The multistep workfl ow requires: 1. Creation of a 3D MRI model using MRI images of the prostate that contain a lesion proven by targeted biopsy to be malignant; 2. Creation of a 3D model of the prostate using ultrasound images, rigid and elastic image fusion; and 3. Use of the fused images to guide treatment. This process will be demonstrated using clinical examples and progress on the integration of an MRI to ultrasound fusion system into the Sonablate device (Sonacare Medical) will be described. Results and Conclusions: NA

74 Focused Ultrasound 2014 4th International Symposium 58-PR Magnetic Resonance Guided Focused Ultrasound for Focal Therapy of Tuesday Locally Confi ned Low Risk Prostate Cancer: Preliminary Outcomes 14 October 2014 Sangeet Ghai, Alyssa Louis, Meghan Van Vliet, Uri Lindner, Masoom Haider, Eugen Topic: Prostate Hlasny, Paula Spensieri, Theodorus Van der Kwast, Stuart McCluskey, Walter Presentation Type: Oral Kucharczyk, John Trachtenberg University of Toronto, Toronto, Canada

Background/Introduction: Focal therapy is an emerging approach for the treatment of localized prostate cancer. We report the six-month follow-up oncologic and functional data of the initial Phase 1 trial of patients treated with focal transrectal magnetic resonance guided focused ultrasound in North America. Methods: After receiving informed consent, four patients with prostate specifi c antigen (PSA) ≤10ng/mL, ≤ cT2a and Gleason score 6 (3+3) with NCCN low risk or very low risk disease were prospectively enrolled in our phase 1 IRB approved (REB#10-0841; clinicaltrial. gov identifi er NCT01226576) focal therapy trial of MRI guided focused ultrasound (Insightec Inc, Haifa, Israel) ablation of localized prostate cancer. Each patient underwent multi parametric magnetic resonance imaging (MRI) and trans-rectal ultrasound guided prostate systematic biopsy to both confi rm and localize the cancer. Under MRI guidance and real-time monitoring with MR thermography, focused high frequency ultrasound energy was delivered to heat only the target tissue to a uniform lethal and irreversible state. Incidence and severity of treatment-related adverse events were recorded along with serial validated quality of life and prostate specifi c functional outcome questionnaires (IPSS, IIEF–15, ICIQ–SF, SF-12) for 6-months after treatment. Oncologic outcomes were evaluated with multiparametric MRI and repeat trans-rectal ultrasound guided biopsy at 6-months after treatment. Results and Conclusions: Results: Four patients with a total of six target lesions were treated with Clavien ≤ I complication. Quality of life parameters were similar between baselines and 6-months. All four patients were MRI negative in their treated regions (100%), three patients were clear of disease in their treated regions on biopsy (75%), representing successful complete treatment of fi ve target lesions (83%). The sixth targeted site also showed a decrease in volume of Gleason 6 disease on biopsy. All patients had at least one low volume Gleason 6 positive core outside of the treated zone. Conclusion: MRI guided focused ultrasound is a feasible method of noninvasively ablating low risk prostate cancers with low morbidity. Further investigation and follow-up is warranted in a larger patient series and appropriate statistical analysis of oncologic and functional outcome measures. Acknowledgements (Funding): This trial was funded by Insightec, Inc. Haifa, Israel, the Ontario Research Fund (ORF) and the Canadian Foundation for Innovation (CFI). All observations and analyses were done solely by the authors. The authors declare no confl ict of interest or personal remuneration in the conduct of the study.

Focused Ultrasound 2014 4th International Symposium 75 59-PR Transurethral MR-HIFU for the Treatment of Localized Prostate Cancer Tuesday Rajiv Chopra 14 October 2014 University of Texas Southwestern Medical Center, Dallas, Texas, United States Topic: Prostate Presentation Type: Oral Background/Introduction: Transurethral MR-HIFU involves the delivery of high- intensity ultrasound energy for targeted coagulation of prostate tissue under real-time MRI temperature control. Methods: In contrast to transrectal approaches, transurethral ultrasound applicators are simple in construction and designed for single use. Delivery of ultrasound from within the prostate gland avoids passing energy through sensitive structures, and enables rapid tissue ablation. Tissue is coagulated radially outwards from the urethra, with the depth of treatment controlled based on the temperatures measured with MR thermometry. One of the challenges with transurethral HIFU is generating coagulation to the boundary of the prostate gland where tumors are often located. Results and Conclusions: Transurethral HIFU has been under development for over two decades with a variety of transducer designs. Recently, this technology has been translated into human studies, and is being developed as a commercial treatment for localized prostate cancer. Phase 0 are complete and Phase 1 trials are underway. This talk will provide a review of the technology, its development, clinical translation, and unique characteristics. Current challenges and opportunities for future development will also be discussed.

76 Focused Ultrasound 2014 4th International Symposium 60-PR MRI-guided Transurethral Ultrasound Prostate Ablation: Midterm Tuesday Outcomes of a Phase I Clinical Trial 14 October 2014 Mathieu Burtnyk1, Michele Billia2, Ionel Valentin Popeneciu3, Jason Hafron4, Topic: Prostate Matthias Roethke5, Heinz-Peter Schlemmer5, James Relle4, Sascha Pahernik3, Joseph Presentation Type: Oral Chin2 1 Profound Medical Inc., Toronto, Canada 2 London Health Sciences Center, London, United Kingdom 3 Heidelberg University Hospital, Heidelberg, Germany 4 Beaumont Health System, Royal Oak, Michigan, United States 5 German Cancer Research Center, Heidelberg, Germany

Background/Introduction: MRI-guided transurethral ultrasound ablation (TULSA) is a new minimally-invasive modality for the treatment of prostate cancer, which aims to provide local disease control with low morbidity. A transurethral ultrasound device generates a continuous volume of thermal coagulation that is shaped precisely to the prostate using real- time MR thermometry and active temperature feedback control. The aim of this multi-center, prospective Phase I clinical study is to determine the safety and feasibility of MRI-guided TULSA, and to assess initial effi cacy for treatment of localized prostate cancer. Methods: A total of 30 patients were enrolled with biopsy-proven, low-risk, localized prostate cancer: age ≥ 65 years, clinical stage T1c/T2a, PSA ≤ 10ng/ml, Gleason Score ≤ 3+3 (3+4 max in Canada only). Treatment was completed under general anesthesia and drainage from a suprapubic catheter (SPC) which remains for 2 weeks. Treatment planning was performed under MRI prostate visualization, with therapeutic intent of whole−gland ablation. Treatment was delivered under continuous MR thermometry active feedback control. Primary endpoints are safety and feasibility, with follow-up to 12 months. Complete clinical monitoring is 5 years, including serial PSA, completion of quality-of-life- questionnaires and prostate biopsy at 12 months. Results and Conclusions: Median (range) prostate volume and treatment time were 47 (21-95) cc and 36 (24-61) min, respectively (n=30). MR thermometry measurements depict a continuous region of heating with a high degree of spatial control of the ablation volume, to within 0.1 ± 1.3 mm (n=30). Median PSA reduced by 90% (60 – 99%) to 0.7 ng/ml at 1 month (n=28), remaining stable to 0.6 ng/ml at 6 months (n=20). MRI-guided TULSA was well-tolerated by all patients, with no intraoperative complications, and no reported cases of urinary incontinence, fi stula or rectal injury. All complications to-date were CTCAE v4 Grade 1-3 and included: hematuria (15), urinary tract infection (10), epididymitis (1), and acute urinary retention (4) requiring prolonged or re-catheterization. Normal micturition returned after SPC removal, with return to baseline by 3 months (n=26) and improvement by 6 months (n=21): IPSS median score 9 (baseline) to 6 (6 months), and peak urinary fl ow 14 ml/s (baseline) to 19 ml/s (6 months). MRI-guidance enables accurate planning and real-time dosimetry and control of the thermal ablation volume. Midterm results indicate that MRI- guided TULSA is safe and clinically feasible with a well-tolerated, low side effect profi le. Acknowledgements (Funding): This study is supported by Profound Medical Inc.

Focused Ultrasound 2014 4th International Symposium 77 61-PR Transurethral Prostate Thermotherapy: Filtering the Bowel Motion during Tuesday MR-thermometry Processing 14 October 2014 Alain Schmitt1, Charles Mougenot2, Rajiv Chopra3 Topic: Prostate 1 Presentation Type: Oral Sunnybrook Research Institute, Toronto, Canada 2 Philips Healthcare Canada, Toronto, Canada 3 University of Texas Southwestern Medical Center, Dallas, Texas, United States

Background/Introduction: Magnetic resonance imaging (MRI)-guided transurethral ultrasound therapy is a minimally-invasive image-guided treatment for localized prostate cancer offering precise targeting of tissue within the gland. The accuracy of MR thermometry is critical for precise on-line feedback control as well as for monitoring potential thermal injury of surrounding tissues, especially the rectum wall. The PRFS thermometry method used is sensitive to tissue motion and change in the local magnetic susceptibility which might be related to the motion of air bubbles in the rectum in the particular case of MR controlled prostate cancer therapy. Methods: This method aims to fi lter sudden temperature artifacts. The fi lter is based on the analysis of the temporal standard deviation of the temperature relatively to the measurement noise and ultrasonic heating distribution. Inconsistent temperature variations are detected and cancelled in a fi rst step. As a second step, a spatial averaging using reliable voxels is applied in this artifacted region to keep consistent heating distribution and maintain a low noise level. Results and Conclusions: This fi lter has been evaluated by post-processing data from fi ve human transurethral ultrasound treatments. The two-steps correction of the artifact detected areas reduces the fi nal standard deviation to levels similar to the originally non-artifacted prostate and rectum areas. Evaluation of the fi lter on the patient data showed that most artifacts due to the presence of moving air bubbles in the rectum have been detected and removed. A quantitative estimation of the fi lter capabilities shows a systematic improvement in the standard deviation of the corrected temperature maps, up to 2.2°C improvement on the artifacted rectum zone. Acknowledgements (Funding): The authors wish to acknowledge fi nancial support from the National Institutes of Health (1R21CA159550), and FedDEv Ontario (Technology Development Program). The authors also acknowledge the technical support provided by Philips MR Finland with respect to the processing of MR temperature maps acquired on the Philips MRI.

MR thermal maps without (A) and with fi lter (B), during transurethral ultrasound therapy with moving air bubble in the rectum (Δ) inducing a temperature artifact (+) that interfered with the real heating (*). Average STD over the Rectum zone by patient.

78 Focused Ultrasound 2014 4th International Symposium 62-PR Implementation of Sonication and Feedback Control Strategies for Tuesday Targeted Hyperthermia in Prostate with a Commercial MR-guided 14 October 2014 Endorectal Ultrasound Ablation Array Topic: Prostate Presentation Type: Oral Vasant Salgaonkar, Eugene Ozhinsky, Viola Rieke, Punit Prakash, I-Chow Hsu, John Kurhanewicz, Chris Diederich University of California at San Francisco, San Francisco, California, United States

Background/Introduction: This study presents the implementation of protracted mild hyperthermia (HT) delivery to large contiguous volumes in prostate quadrants or hemi- gland targets by utilizing a commercially available MR-guided endorectal ultrasound (ERUS) phased array designed for thermal ablation (ExAblate 2100, InSightec. Ltd). HT-specifi c beamforming, sonication and control strategies were devised for the hardware/software limitations imposed with this commercial system. Methods: Various array beamforming alternatives and feedback control methods were explored through extensive numerical simulations consisting of patient-specifi c biothermal modeling for heating with the ExAblate prostate array (2.3 MHz, ~1000 channels), consistent with system constraints such as power densities, sonication durations and switching speeds. Finite element method solvers (Comsol Multiphysics) were utilized to compute 3D thermal distributions for representative patient-specifi c geometries rendered from serial MRIs (Mimics, 3-Matic). The beamforming, sonication and control parameters ascertained during the simulation studies were implemented on the ExAblate prostate array through animal tissue and phantom experiments under MR temperature imaging (MRTI) [3T, PRFS] performed in real-time with a custom software developed in Matlab for temperature reconstruction (Fig. 1). Results and Conclusions: The simulation study confi rmed conformable HT delivery to focal cancer volumes in a single prostate quadrant using focused heating patterns (simultaneous multi-focus [example in Fig. 2], or curvilinear) and hemi-gland HT using diffused patterns (planar or diverging). 4 oC temperature rises were calculated in 13–23 cm3 volumes for planar or diverging beam patterns at 0.9–1.2 W/cm2, in 1.5-4 cm3 volumes for simultaneous multi-point focus patterns at 2 – 3.4 W/cm2, and in ~6.0 cm3 for curvilinear patterns at 0.75 W/cm2. HT-specifi c sonications were successfully performed using the ExAblate prostate array and Figure 1. Custom software for real time MR thermometry therapeutically relevant temperature rises (4 – 8 oC) were sustained for long-durations (>15 during hyperthermia min) in large contiguous volumes. Consistent heat shapes were observed between simulations and tissue phantom experiments for various beamforming schema (example in Fig. 3). MRTI feedback was utilized to control temperature within a target volume through binary, proportional and proportional-integral (PI) control schemes employing temperature-based modulation of sonication power (Fig. 4). Feasibility, practicability and capabilities of the ExAblate ERUS array were evaluated for long-duration, large-volume, temperature-controlled HT through real-time MRTI with the purpose to facilitate rapid clinical translation of targeted prostate HT with the ExAblate prostate array as an adjuvant to focal radiotherapy and targeted chemotherapy. Acknowledgements (Funding): This research is supported by the Focused Ultrasound Foundation.

Figure 3. Example of MRTI-based feedback control

Figure 2. Comparison between Patient-specifi c 3D model modeling and experiment

Focused Ultrasound 2014 4th International Symposium 79 63-PR Immunomodulation of Prostate Cancer Cells after Low Energy Focused Tuesday Ultrasound 14 October 2014 Karin Skalina1, Huagang Zhang1, Lisa Scandiuzzi1, Indranil Basu1, Chandan Guha2 Topic: Prostate 1 Presentation Type: Oral Albert Einstein College of Medicine, New York, New York, United States 2 Montefi ore Medical Center, New York, New York, United States

Background/Introduction: High-Intensity Focused Ultrasound (HIFU) is a promising non-invasive treatment for localized solid tumors. While patients treated with HIFU show symptomatic improvement, the majority die from local recurrence and metastases due to incomplete tumor ablation and inability to control spread outside the primary tumor site. Therefore, improved local control and a concomitant systemic therapeutic effect would be valuable for successful tumor control by HIFU. Low intensity focused ultrasound (LOFU) induces sonic stress by raising the temperature without killing the cells. We demonstrated that tumor pre-treatment with LOFU prior to HIFU results in tumor growth retardation (Figure 1A) and induces a Th1 predominant immune response (Figure 1B). To further validate the immunological consequences of LOFU pre-treatment, we investigated the immunomodulation of prostate cancer caused by LOFU. We previously demonstrated that LOFU induced expression of genes related to the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress. We hypothesize that LOFU increases immunomodulatory surface signals, such as heat shock protein 70 (HSP70) and calreticulin. HSP70 is an endogenous “danger” signal, which can activate dendritic cells. Calreticulin is an “eat me” signal, which encourages phagocytosis and thus antigen processing for presentation on cell surface MHC for T cell recognition. Thus, sequential administration of LOFU and HIFU provides a source of tumor antigens and endogenous “danger” signals for dendritic cell (DC) activation, thereby inducing a tumor-specifi c systemic immune response that augments the effi cacy of therapeutic ultrasound to control both local and systemic disease. Methods: LOFU treatment was performed on the Philips Therapy and Imaging Probe System (TIPS, Philips Research Briarcliff, USA) using 3W, 100% duty cycle, 1.5 seconds, 1 mm spacing. For IF analysis, LOFU-treated cells were cytospined and fi xed with 4% Figure 1: paraformaldehyde and stained with rabbit ant-HSP70 overnight, followed by incubation with A. Tumor Growth a secondary goat anti-rabbit PE conjugated and anti-phalloidin antibodies for 1 hour at room Retardation temperature. DAPI was included in the mounting medium and slides were analyzed using an B. LOFU+HIFU induced Inverted Olympus IX81. Flow cytometry staining included a live/dead cell marker to isolate tumor-specifi c T cell only living cells expressing HSP70 on the cell surface. response Results and Conclusions: The immunomodulatory effect of LOFU was analyzed on C. Flow cytometry of HSP70 and calreticulin of LOFU- prostate cancer cell lines, both human and murine, by detecting the surface expression treated prostate cancer cells of HSP70 and calreticulin by fl ow cytometry & immunofl uorescence (IF) six hours D. IF of RM-1 and PC3 cells following LOFU treatment of a cell pellet. LOFU signifi cantly induced cell surface HSP70 stained for HSP70 expression and calreticulin in vitro in human and mouse prostate cancer cell lines, as shown by fl ow cytometry (Figure 1C) and confi rmed by IF (Figure 1D). Surface HSP70 is a danger signal which can activate dendritic cells to induce an anti-tumor immune response. Surface calreticulin acts as a “eat me” signal for phagocytic cells, resulting in increased phagocytosis and antigen processing. Immunomodulation by LOFU can attract DCs to the tumor and induce a Th1 predominant immune response. Acknowledgements (Funding): This research was supported by the MSTP training grant (T32- GM007288).

80 Focused Ultrasound 2014 4th International Symposium 64-PR High Intensity Focused Ultrasound-induced Bubbles Stimulate the Release Tuesday of Nucleic Acid Cancer Biomarkers 14 October 2014 Tatiana Khokhlova1, John Chevillet2, George Schade1, Maria Giraldez3, Yak-Nam Topic: Prostate Wang1, Joo Ha Hwang1, Muneesh Tewari3 Presentation Type: Oral 1 University of Washington, Seattle, Washington, United States 2 Institute for Systems Biology, Seattle, Washington, United States 3 University of Michigan, Ann Arbor, Michigan, United States

Background/Introduction: Prostate biopsy for prostate cancer (PCa) is invasive with associated morbidity and several diagnostic limitations, suggesting the need for a new approach. Recently, several nucleic acid cancer biomarkers (e.g., microRNA and mutant DNA) have been identifi ed and shown promise for improving cancer diagnostics. However, the abundance of these biomarker classes in the circulation is low, impeding reliable detection and adoption into clinical practice. In order to stimulate the release of these intracellular biomarkers, the exposures optimized for mechanical disruption of cells may be desirable. Here, two approaches based on HIFU-induced bubble activity were tested for their ability to stimulate release of cancer-associated microRNAs in a heterotopic syngeneic rat prostate cancer model. In the fi rst approach, tumor tissue was locally liquefi ed with boiling histotripsy (BH) - a HIFU technique utilizing millisecond-long pulses to create boiling bubbles via rapid shockwave heating. The interaction of shocks with the ensuing vapor cavity fractionates tissue with negligible thermal effect. In the second approach HIFU-induced inertial cavitation was used for permeabilization of tumor tissue and vasculature. Methods: Putative miRNA biomarkers were identifi ed using RT-PCR array profi ling of the syngeneic MatLyLu rat PCa cell line. Adult intact male Copenhagen rats were then subcutaneously grafted with the MatLyLu cells. When the tumors were >1cm, the rats were assigned to one of two HIFU treatment groups: HIFU optimized for inertial cavitation activity (focal peak negative pressure 16 MPa, 1 ms pulses, duty factor 0.001, N=6), BH (intensity ~20kW/cm2, 1% duty factor, N=8) or a to a control group (N=6) that received sham treatment. Treatments were performed in a heated water tank using a single-element 1.5 MHz HIFU transducer (45 mm radius of curvature, 64 mm aperture) under ultrasound image guidance. Blood samples were collected immediately prior to treatment and serially over a 24-hour time course. Specimens were immediately processed into plasma and miRNAs extracted. Plasma concentrations of candidate tumor-derived miRNAs were measured via quantitative RT-PCR and compared with ANOVA and the Mann-Whitney test. Results and Conclusions: Following sham procedure, no signifi cant changes were observed in the relative plasma concentrations of any evaluated miRNA. Conversely, following both cavitation-based and BH treatments, the relative plasma concentrations of the putative PCa-associated miRNAs miR-34c and miR-196a increased signifi cantly while the relative concentration of the broadly expressed, non-PCa specifi c miR-16 was not signifi cantly altered. PCa-associated miRNA concentrations peaked at 0.25 hr (10-23-fold) from initiation of HIFU treatment, remained signifi cantly elevated for 3 hours, and then returned to baseline within 24 hours. Histologic examination of excised tumor confi rmed complete fractionation of targeted tumor by BH and localized areas of intraparenchymal hemorrhage and tissue disruption by cavitation-based treatment. These data suggest a clinically useful application of HIFU-induced bubbles for non-invasive molecular biopsy. Acknowledgements (Funding): Work supported by NIH 1K01EB015745, R01CA154451, Figure 1. Experimental setup R01DK085714.

Figure 2. Changes in relative plasma concentration (copies) of broadly expressed miRNA miR-16 and tumor-associated miRNAs miR-34c and miR-196a following boiling-histotripsy (n=8) or sham treatment (n=6) of subcutaneous rat prostate cancer tumors (*p<0.05)

Focused Ultrasound 2014 4th International Symposium 81 65-JN The Journal of Therapeutic Ultrasound Wednesday Wladyslaw Gedroyc1, Robert Muratore2 15 October 2014 1 Imperial College London, London, United Kingdom Topic: Journal 2 Quantum Now LLC, Huntington, New York, United States Presentation Type: Oral Background/Introduction: Publications in therapeutic ultrasound have been growing exponentially for the past four decades, n = 2 exp((t-1970)/6), R² = 0.965, and reached approximately 1440 papers in 2011. Adoption of new International Electrotechnical Commission standards by regulatory agencies such as the United States Food and Drug Administration will enable more rapid approval of devices and therefore more clinical applications. Thus the exponential growth is likely to continue with a predicted output of 3600 papers by 2015. In order to serve this growing demand, the Journal of Therapeutic Ultrasound (JTU) has been launched. JTU is an online, open access journal designed to accelerate the adoption of focused ultrasound. Methods: The journal website (JTUltrasound.com) is currently accepting manuscripts of research articles, case reports, reviews, meeting reports, and study protocols. Appropriate topics include translational and clinical research in all areas of therapeutic ultrasound, including stimulation, inhibition, destruction, or modifi cation of tissue function or structure via focused ultrasound. As an online journal, color images and supplemental materials such as audio and video fi les are readily accepted and publication rapidly follows review. As an open access journal, authors retain full rights to their papers through the Creative Commons license, and papers will be freely available and thus easily accessible to developing countries and the popular press. Results and Conclusions: JTU serves as the offi cial journal of the Focused Ultrasound Foundation and the International Society for Therapeutic Ultrasound. Our distinguished editorial board of twenty-six members represents ten countries. Author fees are waived through 2014. Acknowledgements (Funding): Support is provided by the Focused Ultrasound Foundation.

82 Focused Ultrasound 2014 4th International Symposium 66-EA Quality Assurance and Field Characterisation for MRgHIFU Treatments: Wednesday Their Need and the Challenges Presented 15 October 2014 Gail ter Haar, Ian Rivens, John Civale, Chris Bunton, Richard Symonds-Tayler Topic: Emerging Applications Presentation Type: Oral The Institute of Cancer Research, London, United Kingdom Background/Introduction: In our drive to increase the clinical recognition of HIFU treatments, it is important that we pay attention to other comparable, but more widely accepted, therapeutic techniques, and match their rigorous quality assurance and calibration practices. Well validated Quality Assurance (QA) and fi eld characterisation techniques are important in order that treatments can be planned and simulated, and so they may be compared between patients, between centres and between machines. There is still some discussion as to which the most relevant parameters for such comparisons are. While the pressure distribution and total power can be measured with reasonable accuracy in the laboratory, the presence of the high magnetic fi elds in the vicinity of an MR scanner render many of the current equipment unuseable. It is therefore important to develop techniques appropriate for MRgHIFU systems, that work within the restricted space available. Methods: We are building an MR compatible acoustic power measurement system which is designed to allow measurements to be made in the magnet bore in a similar way to those made in the laboratory. This system consists of a castor oil target immersed in water, and is connected by fi shing wire to a load cell which enables measurement of the weight of the buoy. The load cell has been calibrated and allows measurement of the ultrasonic radiation force and buoyancy force due to thermal expansion of the castor oil. The use of a load cell instead of the dedicated laboratory balance presents problems in terms of oscillations in the measured weight due to the rapid onset/offset of the acoustic radiation force. Comparative measurements have been made in the laboratory, using a non-MR compatible target, a Sartorius balance and the load cell. We have also designed and built a positioning system which uses electric motors that make use of the static magnetic fi eld to operate This system allows positioning of a hydrophone (Onda HGL-0200) as pressure fi eld mapping. Results and Conclusions: Laboratory testing of the load cell vs. the Sartorius balance showed both that oscillations in the measured weight using the load cell could be successfully removed by applying a carefully chosen time averaging window and that there was good agreement between the acoustic power measured with the Sartorius and the load cell. Our next steps are to build an MR compatible target, a water tank that fi ts into the bore of the magnet and provides coupling to a Sonalleve HIFU transducer and then to verify use of the system in the magnet. The MR compatible positioning system allows precise (sub millimetre) location of the focal peak that is not achievable using the MR positioning system. The output from the Onda hydrophone could be read once it had been passed through a coax connector grounded to the scanners RF cage. Currently software is being written for automated beam plotting in the bore of the MR scanner. Results will be presented at the meeting. Pressure distributions using the modifi ed gantry and MR compatible pressure sensors will also be presented. Fields mapped in the magnet bore will be compared with those obtained in the laboratory for our MR compatible transducers. Acknowledgements (Funding): JC is funded on the ICR Focused Ultrasound Foundation Centre of Excellence grant. IR & RS-T are funded by the UK Engineering & Physical Sciences Research Council.

Test sonication with the Sartorius balance (left), and load cell (right). Note the increased oscillations with the load cell, e.g., just before 280 seconds.

Focused Ultrasound 2014 4th International Symposium 83 67-EA Direct Nanodroplet and Microbubble Comparison for High Intensity Wednesday Focused Ultrasound Ablation Enhancement and Safety 15 October 2014 Linsey Moyer1, Kelsie Timbie2, Paul Sheeran3, Richard Price2, Wilson Miller2, Paul Topic: Emerging Applications Dayton1 Presentation Type: Oral 1 University of North Carolina, Chapel Hill, North Carolina, United States 2 University of Virginia, Charlottesville, Virginia, United States 3 Sunnybrook Health Sciences Centre, Toronto, Canada

Background/Introduction: High intensity focused ultrasound (HIFU) surgery often requires hours of ablation in order to treat an entire tumor. Both perfl uorocarbon gaseous microbubbles and vaporized liquid droplets are known enhancers of HIFU thermal ablation. Microbubbles, however, often lead to surface or skin lesions. Furthermore, they have a relatively short half-life in vivo (minutes) rendering them insuffi ciently stable for an entire HIFU surgery, which can last several hours. Many droplet formuations require very high pressures to activate. Our aim was to design an agent that could shorten ablation procedures without sacrifi cing safety. We designed and investigated a perfl uorocarbon nanodroplet composed of a 1:1 ratio of dodecafl uoropentane and decafl uorobutane. These are tuned to change phase and activate at only 2 MPa peak negative pressure with common HIFU pulse lengths, enabling focused and targeted activation. Additionally, they are stable at body temperature. Methods: Two lipid-shelled agents, microbubbles (2.1 +/-0.5 micron diameter) and nanodroplets (240 +/-65 nm diameter), were manufactured in-house. Effective circulation time of the nanodroplets was investigated in vivo. HIFU-induced temperature rises were measured as a function of the time after the injection of the agent occurred and were compared to controls wherein no agent was injected. HIFU (1 MHz, 4.06 MPa, CW, 15 seconds) was applied in vivo to rat livers 5, 15 or 95 minutes after agent injection, and any thermal enhancement was detected simultaneously by MR thermometry. Results and Conclusions: HIFU applied to livers without any agent induced only a 22 +/-3ºC maximal temperature rise over body temperature. The maximum HIFU-induced temperature rise with microbubbles (55 +/-7 ºC) was observed 5 minutes after their injection, whereas nanodroplets consistently enhanced the HIFU thermal ablation at every time point, with a peak temperature change 95 minutes after their injection of 51 +/-12ºC (see Fig. 1). More importantly, the location where this heating occurred was vastly different between the two agents. Microbubbles primarily heated the surface of the animal and resulted in skin burns, whereas no skin burns were present in any of the control HIFU animals or those that received nanodroplet injections with HIFU. Nanodroplets resulted in HIFU heating at the target location with only minimal surface heating that was not signifi cantly different from the baseline heating observed with HIFU alone (grey line in Fig. 1B,C,D). These results suggest that the nanodroplets are suffi ciently stable to enhance HIFU ablation in vivo for at least 1.5 hours, avoid skin burns, and are a better option over microbubbles. These nanodroplets could potentially reduce focused ultrasound surgical procedure times by as much as 5 fold by more quickly ablating a larger region of tissue, without compromising safety. Acknowledgements (Funding): Funding was provided by the Focused Ultrasound Foundation, the NIH-NIGMS SPIRE Fellowship to LCP and NSF DMR #1122483. The authors would like to thank Jeremy Gatesman and Gina Wimer for veterinary assistance.

84 Focused Ultrasound 2014 4th International Symposium 68-EA Renal Denervation Using Externally Delivered Focused Ultrasound: Wednesday Summary of Clinical Experience to Date and Validation of Supporting 15 October 2014 Computational Simulations Topic: Emerging Applications Presentation Type: Oral Michael Gertner, Francesco Crura, Jimin Zhang Kona Medical, Bellevue, Washington, United States

Background/Introduction: The Kona Medical Surround Sound™ System is a fully non- invasive system for renal denervation which employs ultrasound based imaging for targeting and tracking as well as a phased array therapeutic ultrasound transducer. To date, 69 patients have been treated under three different protocols (WAVE I, WAVE II, and WAVE III). Follow up ranges from 3 months to over 2 years. A subset of 18 patients (WAVE II) was chosen for detailed analysis using numerical simulation. Aims: To evaluate safety, feasibility, and a specifi c dose strategy using a computational model in a Virtual Acoustic Patient (VAP) model and validate these simulations with human data. Methods: A 3D human body acoustic and thermal simulation models has been developed. The model utilizes the cross sectional imaging from MRI or CT of the treated patients and translates these images into 3D acoustic models. Subsequently, the key parameters and variables that infl uence the effi cacy and safety of the high intensity therapeutic ultrasound (HITU) treatment were incorporated into the model. Specifi c anatomic regions which relate to safety and effi cacy were highlighted in the model. Results and Conclusions: The simulations in the virtual acoustic patient models demonstrated the following: 1. The therapeutic dose creates a thermal lesion around the renal artery. 2. There are no signifi cant pre-focal or post-focal regions of unwanted thermal or mechanical tissue damage in vital organs including the kidneys, spine, and bowel. 3. The maximum peak temperature used in the clinical trials is below the thermally-induced cavitation using the most extreme clinical conditions and absorption coeffi cients. 4. The contribution of non-linear content in the acoustic waveform is minimal and is highly unlikely to result in any signifi cant unintended mechanical biological effects such as cavitation. 5. There is potential for unwanted heating starting from the fat/muscle interface and inside fat layer using the extremes of absorption coeffi cients and patients depths. Clinical data in 58 patients who have reached 6 mos follow-up show an average blood pressure drop of 24/10 from baseline and an acceptable safety profi le. Conclusions: Computational ultrasound modeling and simulation developed using the virtual acoustic patient models provides a powerful tool for evaluating and validating the mechanical and thermal effects of treatment protocol used in the clinical for renal denervation. Clinical data correlates well with the simulation and provides validating evidence that the simulation can be predictive of clinical results.

Focused Ultrasound 2014 4th International Symposium 85 69-EA MR Guided Focused Ultrasound Treatment of Soft Tissue Tumors of the Wednesday Extremities — Preliminary Experience 15 October 2014 Pejman Ghanouni, Kim Butts Pauly, Rachelle Bitton, Raffi Avedian, Matthew Topic: Emerging Applications Bucknor, Garry Gold Presentation Type: Oral Stanford University, Stanford, California, United States

Background/Introduction: Soft tissue tumors are a heterogeneous group of tumors arising from connective tissues. These tumors may be benign, benign but locally aggressive, or malignant. Surgery either alone or in combination with adjuvant therapies such as radiation or chemotherapy can potentially cure a patient with a soft tissue tumor. The morbidity and complications associated with treatment can have signifi cant and lasting adverse effects on limb function and quality of life. In some situations, patients develop local recurrence of disease and require further surgery, which can result in further treatment-associated morbidity. We have adapted MR guided focused ultrasound (MRgFUS) techniques to the treatment of benign and malignant soft tissue tumors of the extremities with the goal of safely and effectively performing MRgFUS ablation on human subjects. This presentation describes the use of MRgFUS for the treatment of desmoid fi bromatosis, arteriovenous malformations, and malignant sarcomas. Methods: Patients were treated using an MR imaging-guided focused ultrasound system (ExAblate 2100, InSightec, Ltd, Tirat Carmel, Israel). Treatments were performed under general or regional anesthesia. Patients were positioned such that the targeted tumor was overlying the transducer, using a gel mold for positioning and for coupling to the transducer. MR images were obtained to defi ne the tumor volume and surrounding critical structures in preparation for therapy. The treatment planning software was utilized to defi ne the skin surface as well as the contour of the tumor to be treated. Fiducial markers were placed on the images to monitor for patient motion. Sonication planning was managed by the ExAblate software, and modifi ed as needed by the treating physician. MR generated thermal dose maps were used to confi rm heating in the tumor, and to monitor heat accumulation on the skin. Post-contrast imaging was used to assess the extent of ablation within the targeted tumor. Patients were transferred to a recovery area and monitored prior to discharge home. Results and Conclusions: The primary purpose of this protocol is to assess MR guided high intensity focused ultrasound as an intervention for treatment of soft tissue tumors of the extremities. For patients with benign tumors, MR imaging is used to follow the response to treatment. For malignant tumors, all patients proceed to standard-of-care surgical resection, and the surgical specimen serves as the standard for comparison for the predicted ablation volume on post-treatment contrast-enhanced imaging. Ten patients with benign and malignant soft tissue tumors have been treated thus far, as summarized in the table. Examples of tumor treatments are included in the fi gures. The average treatment time is 4h10” ± 1h47”. The average tumor volume was 184 ± 288 cc. Treatments required an average 96 ± 53 sonications, with an average sonication energy of 1512 J reaching an average maximum average temperature of 55 ± 5°C. The average non-perfused volume as a percentage of the total tumor volume (%NPV) was 68 ± 26%. Adverse events include injury to skin, nerves and surrounding organs.

Table: Individual Treatments Patient # # Treatments Tumor type Tumor location Volume (cc) % NPV 1 1 desmoid popliteal fossa 142 63 2 3 desmoid buttock and thigh 98 74 3 2 desmoid posterior ankle 42 80 4 2 desmoid lateral knee 157 48 5 2 desmoid upper abdomen 1010 67 6 1 desmoid lateral shoulder 40 18 7 1 desmoid lateral calf 320 57 8 1 AVM lateral thigh 8 100* 9 1 AVM anterior thigh 61 100* 10 1 sarcoma medial thigh 20 97 *measurement includes surrounding muscle

86 Focused Ultrasound 2014 4th International Symposium For malignant tumors, there may be a role for MRgFUS in the management of local recurrences. For benign but locally aggressive tumors such as desmoid fi bromatosis, where current standard therapies are often ineffective and are associated with signifi cant morbidity, minimally invasive treatment with MRgFUS may be an appropriate fi rst-line therapy. Challenges to the utilization of MRgFUS for these applications include patient positioning on the MRgFUS table, coupling the targeted area to the transducer, reliable intra-operative treatment monitoring, and speed of treatment for large tumors. More technical development and evidence is needed before MRgFUS can be used routinely for the treatment of soft tissue tumors. Acknowledgements (Funding): NIH P01 CA159992

Focused Ultrasound 2014 4th International Symposium 87 70-EA AAPM Task Group 241 – MR-guided Focused Ultrasound Wednesday Keyvan Farahani1, Jason Stafford2, Rajiv Chopra3 15 October 2014 1 National Institutes of Health, Bethesda, Maryland, United States Topic: Emerging Applications 2 MD Anderson Cancer Center, Houston, Texas, United States Presentation Type: Oral 3 University of Texas Southwestern Medical Center, Dallas, Texas, United States

Background/Introduction: Task Group (TG) 241 of the American Association of Physicists in Medicine (AAPM), operating under the Work Group for Technology Assessment in Image-Guided Interventions, was formed in September of 2013 with an international membership of experts from MR-guided focused ultrasound (MRgFUS), focused ultrasound and ultrasound physics, radiation oncology, industry and federal agencies. The charge of TG-241 is to report through peer-reviewed publications on the assessment of state-of-the-art clinical MRgFUS technology, including the intrinsic system characteristics, quantitative metrics, sources of uncertainty, quality assurance measures, data types and nomenclature as well as training issues for medical physicists. Methods: In addition, through related sub-group activities, TG-241 will consider development of an open tool as a public resource for the MRgFUS research community. Results and Conclusions: The goal of this presentation is to introduce TG-241 to the research community and solicit input about its current activities and future directions.

88 Focused Ultrasound 2014 4th International Symposium 71-EA Preliminary Results of the Initial Human Clinical Trial of Focused Ultrasound Wednesday to Reposition Kidney Stones 15 October 2014 Michael Bailey1, Barbrina Dunmire1, Bryan Cunitz1, Jonathan Harper1, Franklin Lee1, Topic: Emerging Applications James Lingeman2, Mathew Sorensen1 Presentation Type: Oral 1 University of Washington, Seattle, Washington, United States 2 Indiana University, Indianapolis, Indiana, United States

Background/Introduction: Ultrasonic propulsion is a new technology we have developed which uses focused ultrasound to transcutaneously reposition kidney stones. Two applications are expelling small stones or fragments and dislodging obstructing stones. We report preliminary, investigative fi ndings from the fi rst use of this technology in humans. Methods: There are three arms of the study: de novo stones, post-lithotripsy fragments, and large stones within the preoperative setting. A pain questionnaire is completed immediately prior to and following propulsion. A maximum of 40 push attempts are administered on either low (50 V) or high (90 V) power settings. Movement is classifi ed as no motion, movement with rollback (2-3 mm), or movement to a new location (> 3 mm) (Table 1). Results and Conclusions: Eight subjects have been enrolled and undergone ultrasonic propulsion to date. None of the subjects reported pain associated with the treatment. Subjects did report a mild warming of the skin with high (90 V) power pushes; no sensation was reported with low (50 V) power pushes. A summary of push movement results is provided in Table 1. Stones were visualized and repositioned in all subjects. One subject in the post-lithotripsy arm passed two small stones immediately following treatment. At least three post-lithotripsy subjects reported passage of multiple small fragments within two weeks of treatment. In fi ve subjects, ultrasonic propulsion identifi ed a collection of stones previously characterized as a single stone on KUB and ultrasound. Pre-operatively, one of two 7 mm stones was move before surgery. In surgery, it appeared one stone was fi rmly attached to Randall’s plaque and the other stone had been detached from Randall’s plaque and a 4 mm piece moved into the ureter. There have been no treatment related adverse events reported with mean follow-up of 3 months. This is the fi rst report of the successful repositioning of kidney stones in humans using ultrasound. Treatment was therapeutic in four subjects and provided diagnostic information in fi ve. Subjects who did not have signifi cant movement were the fi rst patients and in the de novo arm. To date, there have been no reports of pain or adverse events associated with this treatment. Acknowledgements (Funding): Trial supported by NSBRI through NASA NCC 9-58. Research and development supported by NIH DK043881and DK092197.

Focused Ultrasound 2014 4th International Symposium 89 72-EA Destruction of Atherosclerotic Plaque Using Pulse Ultrasound with a Planar Wednesday Rectangular Transducer 15 October 2014 Christakis Damianou1, Christos Christofi 2, Nicos Mylonas3, Margarita Theodoulou4, Topic: Emerging Applications Christos Makarounas4 Presentation Type: Oral 1 MEDSONIC, LTD, Limassol, Cyprus 2 The Cyprus Institute, Limassol, Cyprus 3 Frederick Research Center, Limassol, Cyprus 4 Cyprus University of Technology, Limassol, Cyprus

Background/Introduction: The aim of this paper is to present a feasibility study for using mechanical mode ultrasound for destroying atherosclerotic plaque with MRI monitoring. Methods: An MRI safe fl at rectangular (3x10 mm2) transducer operating at 5 MHz was used. A spatial average temporal average intensity of 10 W/cm2 for 120 s was used, with DF of 10 % and 1 ms pulse repetition period. This optimized protocol was applied in a rabbit model. The plaque in the rabbit was created using a 2 % cholesterol diet. Results and Conclusions: During the course of the diet, the aorta of the rabbit was imaged using high resolution T2 W FSE every one month in order to assess the progress of the growth of the plaque. Selected rabbits were sacrifi ced in one, two, and three months since the initiation of the diet in order to assess the growth of the plaque histologically. Approximately 50 % of the artery was covered by plaque in 3 months since the initiation of the diet. This was confi rmed using MRI and histology. The proposed mechanical protocol has successfully destroyed plaque in the aorta of the rabbit. The size of the rabbit aorta has similar size with the coronary or carotid arteries in humans. The rabbit is a good model for creating atherosclerotic plaque. Acknowledgements (Funding): This work was supported by the Research Promotion Foundation (RPF) of Cyprus (program ΕΠΙΧΕΙΡΗΣΕΙΣ/ΠΡΟΪΟΝ/0311/01, and the European regional development structural funds).

90 Focused Ultrasound 2014 4th International Symposium 73-EA Mesenchymal Stem Cell (MSC) Homing to Kidneys is Suppressed Wednesday by Inhibiting Interleukin 1-α, Tumor Necrosis Factor-α, or 15 October 2014 Cyclooxygenase-2 Signaling Topic: Emerging Applications Presentation Type: Oral Scott Burks, Ben Nguyen, Saejeong Kim, Michele Bresler, Pamela Tebebi, Joseph Frank National Institutes of Health, Bethesda, Maryland, United States

Background/Introduction: Maximal homing of iv-infused MSC may be critical for cell therapies. Molecular responses from the primarily mechanical effects of pulsed focused ultrasound (pFUS) (i.e., mechanotransduction) in healthy or diseased murine kidneys generate a “molecular zip-code” consisting of local increases in chemoattractants (cytokines, chemokines, cell adhesion molecules) to enhance MSC homing. These fi ndings have substantial potential to improve cell therapies for regenerative medicine. Since molecular signaling post-pFUS drives enhanced MSC homing, other drugs also aiming to treat disease could potentially interfere with molecular responses and subsequent cell migration to targeted tissue thus undermining cell therapy approaches. This study characterized temporal molecular changes post-pFUS to identify critical signals that drive larger changes observed in the chemoattractants and investigates whether inhibition of the early signals could suppress MSC homing to kidneys. Methods: C3H mice received unilateral kidney pFUS (1MHz, 5MPa, 10 ms pulses, 5% duty cycle, VIFU 2000) and kidneys were harvested for ELISA from 10min–72hr after. Pretreatment with drugs included: saline; ibuprofen (nonspecifi c cyclooxygenase [COX] inhibitor; 30mg/kg, po) 15min pre-pFUS; etanercept (tumor necrosis factor-α inhibitor; 100μg, ip) 72 and 24hr pre-pFUS; or Anakinra (interleukin-1α [IL-1α] inhibitor; 200μg, ip) 48, 24, and 1hr pre-pFUS. Drug-treated kidneys were harvested from 10min–24hr. MSC homing in normal or drug-treated mice included 106 human MSC iv 3hr after kidney pFUS. Kidneys were harvested 24hr post-injection and MSC were detected by immunofl uorescence. Cell counts from pFUS-treated kidneys were compared to untreated contralateral kidneys and ANOVA was used for statistical analysis (p<0.05). Results and Conclusions: Proteomic analyses of pFUS-treated kidneys revealed early elevations of TNFα and IL-1α (10min), followed by COX2 upregulation shortly thereafter (1–4hr). Thus lead to chemoattractant elevations that induce MSC homing (2–24hr) that returned to baseline by 72hr (Fig 1). Kidneys in mice pretreated with ibuprofen, etanercept, or anakinra, did not generate the molecular zip-code after pFUS. Infused MSC did not home to pFUS-treated kidneys. MSC also failed to home to pFUS-treated kidneys in COX2-knockout mice, demonstrating ibuprofen inhibited COX2 specifi cally. Drug effects on cell homing remain unexplored and Bloxplot representation of uncontrolled for in cell therapy trials. The statistically signifi cant (p<0.05 by molecular zip-code generated by pFUS is ANOVA) elevations in cytokines, driven by early elevations of TNFα and chemokines, growth factors, IL1α and COX2 expression. Inhibiting and cell adhesion molecules following pFUS to normal kidneys. any of these molecules with clinically Responses enhance MSC homing relevant drugs abrogates the pFUS-induced and are inhibited by clinical drugs. molecular response and suppresses MSC homing to kidneys. These fi ndings suggest drug-host interactions could undermine cell-based therapies in regenerative medicine. Furthermore, in-depth study of pFUS molecular responses may help elucidate MSC homing mechanisms and pFUS could be a useful platform to screen drug-homing interactions. Acknowledgements (Funding): This work was funded by the Intramural Research Program at the National Institutes of Health.

Focused Ultrasound 2014 4th International Symposium 91 74-BT Results from Clinical Phase I Study on Breast Tumor Ablation with Wednesday Dedicated Breast MR-HIFU System 15 October 2014 Floor Knuttel1, Roel Deckers1, Laura Merckel1, Gerald Schubert2, Max Kohler2, Willem Topic: Breast Mali1, Chrit Moonen1, Lambertus W. Bartels1, Maurice van den Bosch1 Presentation Type: Oral 1 University Medical Center Utrecht, Utrecht, Netherlands 2 Philips Healthcare, Vantaa, Finland

Background/Introduction: We have recently conducted a clinical phase I study to assess the safety and spatial accuracy and precision of a newly developed dedicated MR-HIFU system for lateral breast tumor ablation.1 Here, we report on patient inclusion, treatment effi cacy and safety. Methods: All treatments were performed on a dedicated breast MR-HIFU system (Philips Healthcare, Vantaa, Finland) integrated with a clinical 1.5-T MRI scanner (Achieva, Philips Healthcare, Best, The Netherlands). Ten female patients with i) pathologically proven invasive breast cancer after large-core needle biopsy and ii) tumor size ≥ 1 cm were included. The patients were under procedural sedation during the complete HIFU procedure. Fat- suppressed segmented Echo Planar Imaging was performed for PRFS-based thermometry. Online correction of the respiration-induced fi eld disturbances was performed by a Look-Up Table (LUT)-based method.2 Partial tumor ablation was performed to allow for histological analysis of viable versus ablated tumor tissue. The number of sonication performed per patient (1-5) and the acoustic power (50-90 W) used for each sonication was variable. Surgery was performed at least 48 h after the MR-HIFU procedure. After surgical resection H&E and cytokeratin 8/18 staining was performed on histological sections. In order to assess the safety of the system i) the skin of the treated breast was carefully evaluated by a physician, ii) patients were asked to report pain scores according to the Numerical Rating Scale, with a score of 0 (no pain) to 10 (worst pain imaginable) and iii) the temperature evolution in the temperature imaging slice positioned on the pectoral muscle was analyzed to evaluate possible unintended heating in the far fi eld during tumor ablation. Results and Conclusions: Seventeen patients were initially enrolled in the study. Seven patients were excluded or withdrew from the study after a pre-treatment MRI scan. Finally, 10 patients (8 patients with invasive ductal carcinoma and 2 patients with invasive lobular carcinoma) underwent MR-HIFU ablation. The procedural sedation protocol was improved in the course of the clinical study. This lead to less sonication related motion and involuntary patient motion. In addition, the respiration became more regular and shallower, which improved the quality of MR thermometry. The maximum temperature in the focal point increased with increasing power in each patient. Sonications performed with the same acoustic power in different patients lead to different maximum temperatures in the focal point. Finally, clear thermal damage was observed in the tumor tissue in 5 patients. The absence of thermal damage in the other patients was due to technical problems that prevented the sonication to reach temperatures inside the tumor leading to tissue damage. In none of the patients, skin redness, skin burns or other signs of skin damage were observed. Nausea and vomiting in the hours after the MR-HIFU procedure were reported as minor adverse events in one patient. Only two patients reported pain (maximum score of 5) after the MR-HIFU treatment. No temperature increases related to the tumor ablation were observed in the pectoral muscle during sonication. In conclusion, breast tumor ablation with the dedicated breast MR-HIFU system is safe and technical feasible. A good sedation protocol during HIFU ablation is essential for the success of the treatment. References: 1. Merckel, 2013, CVIR 2. Vigen, 2003, MRM Acknowledgements (Funding): Acknowledgements: CTMM (VOLTA)

92 Focused Ultrasound 2014 4th International Symposium 75-BT MRgFUS of Small Breast Cancer: What Should be Learned from a Case of Wednesday Local Recurrence 15 October 2014 Hidemi Furusawa, Junichi Shidooka, Masuko Inomata, Emiko Hirabara, Hiroshi Topic: Breast Nakahara, Yukiko Ymaguchi Presentation Type: Oral Breastopia Clinic, Miyazaki, Japan

Background/Introduction: Background: The aim of local treatment of breast cancer is to completely eradicate the cancer cells. The excisionless study which is an alternative local treatment for the breast cancer with MRgFUS is going on at our facility from June 2005. Purpose: To validate the safety and effi cacy of this local treatment. And to probe the cause of local recurrence. Methods: The main inclusion criteria; 1) breast cancer diagnosed by the needle biopsy 2) Receptor status confi rmation 3) tumor size 15mm 4) well demarcated mass in contrast enhanced MRI. The main exclusion criteria; 1) pure type mucinous carcinoma 2) invasive micropapillary carcinoma 3) location of the tumor requires a high sonication angle. The postoperative needle biopsy was performed again within three weeks after ablation and no residual viable cancer cells were identifi ed pathologically. The following radiotherapy should be performed. The patients are followed by three modalities every 3 to 6 months. Results and Conclusions: Eighty-seven patients were enrolled and 72 breast lesions were treated sequentially. The median age was 56 years old (29 - 79). The average tumor size was 11.0mm (5 - 15). The average treatment duration was 126 minutes (41-246).The median follow-up period was 68 months (2- 108). Thirty-eight cases have been followed up for more than 60 months. Although there were no severe adverse events and any distant recurrence cases, the local recurrence developed seven years after the initial treatment in only one invasive breast cancer case. There are two presumptive causes of this local recurrence. The one reason could be the cancer displacement by the preoperative needle biopsy and another one may be the developing residual cancer after MRgFUS, according to the post MRgFUS needle biopsy specimen and the pathological inspection after excision. Conclusions: MRgFUS as a local treatment for small breast cancer has the potential of replacing usual surgery. However the radio therapy obviously can control the local recurrence, the careful follow-up should be needed. Acknowledgements (Funding): No COI. Acknowledgements: Breastopia MRgFUS team and Takashi Yamamoto, Mayumi Funagayama, Kyoko Fujimoto, Mkiko Ogata, Mayumi Ito

Focused Ultrasound 2014 4th International Symposium 93 76-BT Effi cacy and Safety of US-guided High-intensity Focused Ultrasound for Wednesday Treatment of Breast Fibroadenoma 15 October 2014 Roussanka Kovatcheva1, Jordan Vlahov1, Julian Stoinov1, Katja Zaletel2 Topic: Breast 1 Presentation Type: Oral University Hospital of Endocrinology, Sofi a, Bulgaria 2 University Medical Centre Ljubljana, Ljubljana, Slovenia

Background/Introduction: Breast fi broadenomas (FA) account for up to 70% of benign breast lesions and most frequently, they affect females in the reproductive period. Without treatment, a minority of them decrease in size, more than half of them remain unchanged, whereas some of them signifi cantly increase. Some patients prefer elimination due to large size, cosmetic disturbance, discomfort or emotional stress. The only non-surgical and non-invasive procedure, employed until today, is high-intensity focused ultrasound (HIFU). Although feasibility of the magnetic resonance guided procedure was demonstrated in the past, the experience is limited and no reports about ultrasound (US) guided technique are available in the literature. Thus, the purpose of our study was to establish the effi cacy and tolerability of US-guided HIFU in patients with breast FA. Methods: In our prospective study, 20 symptomatic patients (mean age, 29.4 ± 10.8 years) with 26 FA were selected for treatment with US-guided HIFU. Each patient was treated under conscious sedation on an outpatient basis by a skilled physician using a real time US-guided HIFU system (EchoPulse, THERACLION, Paris, France). After the fi rst HIFU, follow-up visits with US assessment of FA were performed at 1, 3, 6, 9 and 12 months. When FA volume reduced for less than 50 % compared to the baseline or the absolute volume value excedeed 1.5 ml at the 6-month follow-up visit, the second HIFU ablation was performed between 6 and 9 months after the fi rst treatment. Adverse events associated with HIFU were evaluated. The study was approved by the institutional ethics committee and written informed consent was obtained. Results and Conclusions: The mean energy per treated FA volume was 11.8 ± 2.4 kJ/ mL at the fi rst session and 12.5 ± 2.9 kJ/mL in at the second session that was additionally performed in 7 patients. The mean FA volume decreased from 3.00 ± 2.81 mL to 1.87 ± 2.06 mL at 3-month follow-up (p = 0.099), 1.36 ± 1.40 mL (p < 0.01) at 6-month follow up and 0.75 ± 0.66 (p < 0.001) at 12-month follow-up. By the 12th month, the FA volume reduction ranged from 47.2 to 92.6% (mean, 73.3 ± 10.9%). At 12-month visit the volume reduction was signifi cantly larger in FA that received 2 treatments (p < 0.05). Mild transient complications such as subcutaneous edema or mild skin redness and irritation were observed in 7 patients. Our data indicate that US-guided HIFU ablation is an effective treatment for breast FA, which is well tolerated by the patients. The repetition of treatment, which was performed in selected cases in our study, may provide even better results. Acknowledgements (Funding): The study was supported by THERACLION, France.

Figure 1 Antiradial US scan of breast Figure 2 Twelve months after HIFU Figure 3 A permanent tendency of FA FA in 18 years old patient before US- treatment 84, 7% of volume reduction volume reduction after one session of US- guided HIFU treatment. was found. guided HIFU ablation.

94 Focused Ultrasound 2014 4th International Symposium 77-BT High Intensity Focused Ultrasound (HIFU) in the Treatment of Breast Wednesday Fibroadenomata: A Feasibility Study 15 October 2014 Mirjam Peek1, Muneer Ahmed1, Julie Scudder2, Arnie Purushotham2, Ashutosh Topic: Breast Kothari2, Hisham Hamed2, Tibor Kovacs2, Sarah McWilliams2, Sarah Pinder2, Presentation Type: Oral Bennie ten Haken3, Michael Douek1 1 King’s College London, London, United Kingdom 2 Guy’s and St. Thomas’ Hospitals, London, United Kingdom 3 University of Twente, Enschede, Netherlands

Background/Introduction: Breast fi broadenomata (FAD) are the most common breast lesions in woman. For palpable lesions, three options are available: reassurance (with or without follow-up), vacuum assisted mammotome (VAM) or surgical excision. High intensity focused ultrasound (HIFU) is a non-invasive ablative technique in which an ultrasound (US) beam propagates through tissue as a high-frequency pressure wave and is focused onto targeted tissue which elevates the temperature of the focused area without causing damage to the adjacent tissues. HIFU is normally applied to the whole lesion. In this trial, we performed circumferential HIFU treatment to isolate the fi broadenoma from its blood supply. Primary end points of this trial included the decrease in treatment time and short-term complication rate. Methods: Patients (age ≥18 years) were recruited with symptomatic fi broadenomata which had to be visible on US (grade U2/U3). In patients older than 25 years, a fi ne needle aspiration cytology (FNAC) or core needle biopsy (CNB) was performed to confi rm the diagnosis of a FAD. Patients were treated using the US guided - TH-one Echopulse device (Theraclion, France) under local anaesthesia (1:1, 1% Lignocaine with adrenaline and 0.25- 0.50% Chirocaine). Results and Conclusions: From December 2013, 13 patients with symptomatic fi broadenomata underwent circumferential HIFU treatment. Seven patients opted for HIFU treatment due to pain or discomfort. Average treatment time for approximately 61 sonications (SD, 17 sonications), was 36 minutes (SD, 12 minutes). Circumferential treatment reduced treatment time by an average of 44% (SD, 21%). A two-sample T-test assuming unequal variances showed a signifi cant reduction in treatment time (P = 0.005, two-tailed). Post-treatment follow-up at 2 weeks showed reduced pain in six out of seven patients with resolution of pain in three of these. An additional patient developed new pain after two weeks. Short-term complications were erythema of the skin (n=4), ecchymosis (n=4), temporarily numbness of the skin (n=1) and a fi rst-degree skin burn (n=1). Circumferential HIFU ablation of fi broadenomata is feasible with a signifi cant reduction in treatment time. Acknowledgements (Funding): Educational grant from Theraclion, Paris, France.

Focused Ultrasound 2014 4th International Symposium 95 78-BT Treatment of Breast Fibroadenoma with High Intensity Focused Ultrasound Wednesday (HIFU): A Feasibility Study 15 October 2014 David Brenin Topic: Breast Presentation Type: Oral University of Virginia, Charlottesville, Virginia, United States Background/Introduction: Fibroadenomas are common, benign lesions of the breast. A minority of fi broadenomas will disappear without treatment, but most increase in size or remain unchanged. Current management of patients with fi broadenomas in the United States varies on a case by case basis and includes observation or surgical excision. Many patients fi nd their fi broadenoma bothersome, and opt for surgical excision. The objectives of this study are to evaluate the safety and feasibility of Ultrasound guided High Intensity Focused Ultrasound (USgHIFU) delivered by the Echopulse device (Theraclion, Paris) for treatment of breast fi broadenomas. General patient safety, cosmetic outcome, tumor response, patient experience, physician/operator experience, and device performance will be assessed. Methods: Twenty female patients diagnosed with palpable, non-calcifi ed breast fi broadenomas 1cm or larger will be enrolled in a single arm clinical trial and undergo treatment of their tumor utilizing a computer-driven, continuously cooled, extra-corporal HIFU probe mounted on an arm moved by motors, and guided in real-time with an integrated ultrasound imaging scanner. The integrated probe is positioned by the operator and the lesion is imaged. Treatment planning is automated and presented for review and approval on an integrated computer screen. Optimal energy per sonication is established for each patient by determining the minimal setting found to produce bubbles within the lesion as observed on real-time B-mode ultrasound. Patients will have tumors meeting the following criteria: Distance from the skin of ≤ 23 mm to the posterior border of the fi broadenoma, ≥ 5 mm from the anterior border of the fi broadenoma, and ≥ 11mm from the focal point of the HIFU treatment. The chest wall must be more than 1cm from the posterior margin of the tumor, and tumor volume must be between 0.3cc and 10cc. Results and Conclusions: Subjects will be evaluated immediately after treatment and at 3, 6, and 12 months. Primary endpoints assessed will include: • Palpability of breast lesion at 12 months following HIFU treatment session • Patient-rated pain of the HIFU treatment assessed after completion of the treatment session • Patient satisfaction at 3, 6 and 12 months following HIFU treatment session • Change in volume of the fi broadenoma compared to baseline at 3, 6 and 12 months after the IFU session as assessed by ultrasound Secondary endpoints assessed will include: • Palpability of breast lesion at 3 and 6 months following HIFU treatment session • Cosmetic evaluation at 3, 6 and 12 months following HIFU treatment session • Investigator-rated evaluation of the device • Incidence of local and/ or general adverse events and other associated symptoms at 3, 6 and 12 months follow-up • Treatment parameters including duration of the treatment session and device energy settings • The IDE application for this study has been approved, and the trial is under accrual.

Minimum Tumor Criteria

96 Focused Ultrasound 2014 4th International Symposium 79-LV UltraSound Guided High Intensity Focused Ultrasound (USgHIFU) For Wednesday Malignant Tumors: Survival Advantage in Stage III and IV Pancreatic 15 October 2014 Cancer. Topic: Liver & Pancreas Presentation Type: Oral Joan Vidal-Jove, Eloi Perich, Angels Jaen, Alvarez del Castillo Manuel Hospital University Mutua Terrassa, Terrassa, Spain

Background/Introduction: We describe the experience of the HIFU Surgical Oncology Unit of Hospital University Mutua Terrassa (Barcelona, Spain) treating malignant tumors. We analyze results in unresectable pancreatic tumors treated with USgHIFU hyperthermic ablation plus adjuvant chemotherapy. Methods: From February 2008 to April 2014 we have treated 148 malignant cases. Of those, 48 cases of non resectable pancreatic tumors were treated from March 2010 to April 2014, and we include the fi rst 43 patients to the analysis (until December 2013). All of them underwent systemic chemotherapy with an standard combination. Clinical responses (thermical ablation achieved) were measured by image techniques. They were 29 Stage III cases and 14 Stage IV cases. Complications were also analyzed. Results and Conclusions: The distribution of the 148 cases treated refl ects a majority of pancreatic and liver tumors. We analyze the 43 pancreatic tumors. Clinical responses (ablation obtained) were 82% in all cases, sustained at 8 weeks of the procedure. We obtained 11 complete responses (25%) at the end of the combined treatment, 9 from stage III patients and 2 from stage IV. Major complications included severe pancreatitis with GI bleeding (1), skin burning grade III that required plastic surgery (2). No deaths due to the procedure were registered. Overall Median Survival is 16 month (6 mo – 3.4 year) Conclusions: HIFU is a potentially effective and safe modality for the treatment of malignant tumors. Compared with published data, HIFU proves survival advantage in non resectable stage III and IV pancreatic cancer.

Focused Ultrasound 2014 4th International Symposium 97 80-LV Magnetic Resonance guided Focused Ultrasound Surgery (MRgFUS) Wednesday Treatment of Moving Organs: Non-invasive Treatment for Pain 15 October 2014 Palliation and Tumor Control of Locally Advanced Pancreatic Cancer and Topic: Liver & Pancreas Hepatocellular Carcinoma Presentation Type: Oral Michele Anzidei, Fulvio Zaccagna, Gianluca Caliolo, Carola Palla, Francesco Sandolo, Alessandro Napoli University of Rome – Sapienza, Rome, Italy

Background/Introduction: Pancreatic cancer and primary hepatic tumors (HCC) represent two of the most challenging abdominal tumors due to their vascular relationship and the poor prognosis. Both these cancers have been successfully treated with focused ultrasound under conventional us-guidance. MRgFUS introduces the advantage of real time monitoring, allowing a more precise lesion’s ablation and a more accurate in-treatment patient management. This technique has been widely used in other application while its use to treat pancreatic cancer and HCC is still in its preliminary phase. Therefore our purpose was to evaluate safety and effectiveness of high intensity MR-guided focused Ultrasound (MRgFUS) treatment in pancreatic cancer and HCC. Methods: 5 patients with pancreatic cancer and 1 with unresectable right lobe HCC underwent MRgFUS treatment (ExAblate2100,InSightec). Treatments were done in a single ambulatory session. To evaluate tumor control, perfusion T1w-images after contrast medium administration (MultiHance®, Bracco) were obtained pre- and post-treatment. Follow-up examinations were scheduled at 1, 3, 6 and 12 months. Results and Conclusions: All patients well tolerated the treatment and no heating-related adverse event was recorded. Immediately after treatment all patients showed coagulative necrosis with a mean non-perfused volume of 65.4±16.6[45 - 90]. All patients with pancreatic cancer showed a signifi cant decrease of pain. At follow-up no local progression was recorded; after MRgFUS, 2 patients with pancreatic cancer underwent RT meanwhile another one required a second MRgFUS treatment. Our preliminary experience indicates that MRgFUS can be a promising noninvasive treatment modality in patients with unresectable pancreatic cancer and HCC. MRgFUS is a safe procedure and could be repeated without increase of adverse event risk.

98 Focused Ultrasound 2014 4th International Symposium 81-LV Harmonic Motion Imaging for Pancreatic Tumor Detection and High- Wednesday intensity Focused Ultrasound Ablation Monitoring 15 October 2014 Hong Chen, Thomas Payen, Yang Han, Carmine Palermo, Kenneth Olive, Elisa Topic: Liver & Pancreas Konofagou Presentation Type: Oral Columbia University, New York, New York, United States

Background/Introduction: Harmonic motion imaging (HMI) is a radiation force-based elasticity imaging technique that estimates tissue harmonic displacements induced by an oscillatory ultrasonic radiation force to assess tissue stiffness. The objective of this study was to evaluate the feasibility of applying HMI on pancreatic tumor detection and high-intensity focused ultrasound (HIFU) treatment monitoring. Methods: A transgenic mouse model of pancreatic cancer (KPC) as well as wild-type mice were used in this study. The HMI system consisted of a focused ultrasound transducer (FUS), which generated oscillatory radiation force that then induced harmonic tissue motion at 50 Hz at the focus, and a diagnostic ultrasound transducer, which detected the axial tissue displacement within the targeted region using 1D cross-correlation of acquired radiofrequency signals. For pancreatic tumor detection, HMI displacement maps were generated for pancreatic tumors in transgenic mice and healthy pancreases of wild-type mice. For pancreatic tumor ablation monitoring, FUS was used to induce thermal ablation and tissue motion at the same time, allowing HMI monitoring without interrupting tumor ablation. HMI images were acquired at 3-s intervals to monitor changes in tissue stiffness during ablation. All pancreases were excised immediately after sonication for histological evaluation, including hematoxylin and eosin (H&E) staining, cleaved caspace-3 antibody staining, and trichrome staining. Results and Conclusions: The obtained HMI displacement maps showed a high contrast between normal and malignant tissues (with an average lesion-to-normal displacement ratio of 2.4). HMI monitoring of the HIFU ablation depicted consistent pancreatic stiffening with a mean HMI displacement reduction rate of 25% after 2 min ablation, and the formation of thermal lesions was confi rmed by the histological analysis. H&E staining confi rmed accurate targeting of the pancreatic tumor. Cleaved caspace-3 antibody staining confi rmed apoptosis (a) Illustration of the induced by HIFU ablation. Trichrome staining revealed the damaging effects of HIFU on experimental setup. (b) Picture the stromal matrix. This study demonstrated thus for the fi rst time the feasibility of HMI in of the 1D HMI transducers. pancreatic tumor detection and HIFU ablation monitoring. It was also the fi rst application of (c) Picture of the 2D HMI transducers. a radiation-force based technique for HIFU ablation monitoring of an abdominal organ. Acknowledgements (Funding): The work was supported by the National Institutes of Health (R01EB014496) and a grant from the Lustgarten Foundation for Pancreatic Cancer Research.

HMI displacement maps of (a) normal pancreas and (b) pancreas tumor. The corresponding Vevo B-mode images obtained at the same scanning plane are shown in (c) and (d), respectively. Pancreas locations were confi rmed with biopsy shown in (e) and (f).

continued, next page

Focused Ultrasound 2014 4th International Symposium 99 HMI displacement image at different HIFU treatment time point (b-f). The corresponding B-mode image obtained before HIFU ablation is shown in (a). (g) Mean and standard deviation of HMI displacements within the focal region (square in (a)) over time.

H&E staining images of the pancreatic tumor after HIFU ablation.

100 Focused Ultrasound 2014 4th International Symposium 82-LV Intra-operative High Intensity Focused Ultrasound in Patients with Wednesday Colorectal Liver Metastases: Results of a Phase I-II Study in 21 Patients 15 October 2014 David Melodelima1, Aurelien Dupre2, Chen Yao2, Jeremy Vincenot1, Jean-Yves Topic: Liver & Pancreas Chapelon1, Michel Rivoire2 Presentation Type: Oral 1 Inserm, Lyon, France 2 Centre Leon Berard, Lyon, France

Background/Introduction: Managing colorectal liver metastases (CLM) is a major clinical challenge, and surgery remains the only potentially curative treatment. Five-year survival rates of up to 51% have been recently reported. However, only 10-20% of patients are eligible for surgery, which is often precluded by the number, size and/or location of metastases, or because the necessary resection will leave insuffi cient volume of functional liver. A toroidal transducer for HIFU ablation has been developed and tested in vivo enabling destruction of large liver volumes. Preliminary in vitro and preclinical work demonstrated the potential, feasibility and safety of such HIFU ablations. These preclinical studies are now translated into clinical practice through controlled trials, and the aim of this study was to assess the feasibility and safety of HIFU ablation in patients undergoing hepatectomy for CLM, as well to collect preliminary effi cacy and accuracy data Methods: The transducer has a toroidal shape 70 mm in diameter and is divided into 32 ultrasound emitters of 0.13 cm2 operating at 3 MHz. The radius of curvature is 70 mm. A 7.5 MHz ultrasound imaging probe was placed in the centre of the device and was used to guide the treatment. The imaging plane was aligned with the HIFU focal zone. The clinical protocol was reviewed and validated by a national ethics committee according to European directives. Since this study was the fi rst use in man of intra-operative hepatic HIFU, ablations were made only in the part of the liver scheduled for resection. This allowed real-time evaluation of HIFU ablation while protecting participating patients from any adverse effects related to this new technique. Only areas included within the planned resection were treated with HIFU. Six patients were included in the Phase I. Two single thermal ablations were created in each patient. Thirteen patients were included in Phase IIa and two HIFU ablations were to be placed precisely in a target previously identifi ed in ultrasound images (step 1) and then at distance (step 2) from a target. Two patients were included in Phase IIb. HIFU ablations were created to ablate metastases (20 mm maximal diameter) with safety margins in all directions. Results and Conclusions: In agreement with preclinical studies, the demarcation between ablated and non-ablated tissue was clearly apparent in ultrasound images and histology. The dimensions measured on ultrasound imaging were correlated (r=0.88, p<0.0001) with dimensions measured during histological analysis. All HIFU ablations were obtained in 40 seconds. The average dimensions obtained from each HIFU ablation were a diameter of 21.0 ± 3.9 mm and a depth of 27.5 ± 6.0 mm. The phase IIa study showed both that the area of ablation could be precisely targeted on a previously implanted metallic mark and that ablations could be created deliberately to avoid such a mark. Ablations were achieved with a precision of 1-2 mm. In Phase IIb, one metastasis of 10 mm in diameter was ablated in 40 seconds with safety margins. Using electronic focusing a second metastasis was ablated with safety margins in 130 seconds. The dimensions of the HIFU ablation were a diameter of 48 mm and a long axis of 51 mm. HIFU was feasible, safe and effective in ablating large areas of liver scheduled for resection. Acknowledgements (Funding): This work was supported by funding from the Cancéropôle Lyon Auvergne Rhône Alpes and the French NCI (under PHRC grant 12007 and Lyric grant INCa-DGOS-4664).

Focused Ultrasound 2014 4th International Symposium 101 83-LV MRgHIFU – Experimental Perivascular Volumetric Ablation in the Liver Wednesday Ulrik Carling, Leonid Barkhatov, Frederic Courivaud, Tryggve Storås, Richard 15 October 2014 Doughty, Eric Dorenberg, Per Kristian Hol, Bjørn Edwin Topic: Liver & Pancreas Oslo University Hospital, Oslo, Norway Presentation Type: Oral Background/Introduction: Thermal ablation techniques using heat conduction (e.g. radiofrequency ablation) are sensitive to the cooling effect of blood fl ow, the heat sink effect. Thermal ablation by high intensity ultrasound guided by magnetic resonance imaging (MRgHIFU), is less dependent on heat conduction, and produces sharply delineated ablated volumes. The aim of this study was to ablate adjacent to large hepatic and portal veins, to study the heat sink effect on the ablation cells, as well as vessel wall patency. A secondary aim was to study features of second sonication cycles. Methods: This acute animal study using Norwegian land swine was approved by The Norwegian Animal Research Authority. The pigs were under total intravenous anaesthesia, including muscle relaxation for optimal breath control. MR compatible equipment included tracheostomy, ECG, gastric tube, arterial and venous accesses, urine catheter, and an oesophageal temperature monitor. After pre-procedural preparations, the pigs were positioned in the prone position on the MR table. T1w sequences were performed, and hepatic and portal veins measuring > 5 mm within the reach of the ultrasound waves were identifi ed. Two clusters of 6-7 ablation cells of 8x8x20 mm, were placed around separate vessels in normal liver parenchyma. In one pig, 4x4x10 mm cells were used. Volumetric ablations were performed during one minute breath-hold in exhale, and the cells were ablated twice. A proton frequency shift sequence was performed for temperature monitoring, and three coronal and one sagittal temperature maps were produced by the HIFU system. Based on these maps, the system registered estimated ablation volume and treatment offset (difference in mm between planned and registered location). Expected volume in an 8 mm cell is 0.74 ml. Further, time to temperature peak was assessed on the temperature maps. Postsonication imaging (Figure 1) was performed including diffusion weighted imaging (DWI), and T1w contrast enhanced imaging. The livers were then extracted and put in formalin for histopathological analyses (Figure 1). Results and Conclusions: A total of 154 ablations, in six pigs, were performed. Of these, 126 ablations were in 8 mm cells, and 28 were in 4 mm cells. In the 126 ablations the median registered ablated volume was 0,3 ml (range 0-2,5), and in 28/154 (25%) no signifi cant volume was registered. Median registered heating offset was 4.2 mm (range 0,3-14,5). Second sonication cycles in 46 cells with a registered ablation volume, had slightly faster heating on central coronal temperature map (0.14ºC/s, p= 0.005). Preliminary histopathology results indicate that liver parenchyma adjacent to vein walls can be ablated, while keeping the vessel wall patent. Further analyses of the sonication data, and the histopathological samples are in progress. Acknowledgements (Funding): Research is funded by the Norwegian Cancer Society (Kreftforeningen).

Figure 1. Post-sonication imaging, and histo- pathology at 400x enlargement

A. Sagittal T1w; ablation cluster adjacent to liver vein

B. Coronal T1w; ablation cluster around portal vein

C. Ablated hepatocytes upper left part, and patent vessel wall in centre.

102 Focused Ultrasound 2014 4th International Symposium 84-LV Usefulness of 3D Slicer for the Planning and Monitoring of Hepatocellular Wednesday Carcinoma Treatment Using FUS 15 October 2014 Nobutaka Doba, Hiroyuki Fukuda, Kazushi Numata, Ayako Takeda, Yoshiharu Hao, Topic: Liver & Pancreas Akito Nozaki, Makoto Chuma, Masaaki Kondo, Shin Maeda, Shigeo Takebayash, Presentation Type: Oral Akira Kobayashi, Juichi Tokuda, Katsuaki Tanaka Yokohama City University, Yokohama, Japan

Background/Introduction: FUS is a noninvasive treatment method, as complete coagulation necrosis is achieved without the insertion of any instruments. However, FUS monitor has the poor visualization because of the presence of the multi-refl ections, rib shadows and the emergence of the hyperecho after the FUS treatment. 3D Slicer imaging is a diagnostic imaging support system that can provide the same cross-sectional MPR images on the same monitor screen using DICOM volume data from MRI which are not infl uenced by those artifacts. The purpose of this study was to utilize an interventional navigation system designed for FUS assisted by 3D Slicer was proposed, and a phantom study was carried out to assess the proposed system. Methods: The FUS system (Mianyang Haifu Tech) was used under ultrasound guidance. In this system, the open-source navigation software is connected together images using an open network communication protocol, OpenIGTLink. A Polaris Vicra optical tracker (Northern Digital, Ontario, Canada) was used. MRI scans (Signa HDX 3.0T system; GE Healthcare) were performed, and 3D Slicer was customized to combine MR images for the navigation. Testing was performed using an abdominal phantom (CIRS Model057, Norfolk, VA). Results and Conclusions: 3D slicer could make the multiplanar reconstruction images of MRI displayed in the same sections of US. The synchronous movements of the same sections of US and MRI were shown in real time. Performance tests of phantom show that the registration error of the system was 2.2 ± 1.8 mm within the liver (n=12). Conclusion: 3D Slicer imaging is useful for FUS treatment for HCC, compensating for the occasionally poor visualization provided by US monitor.

Figure 1a. The tumor therapy system. A 2-5 MHz Figure 2a. The cystic lesion of the phantom imaging probe was positioned in the center of the was depicted in the US monitor of the FUS transducer and was mounted in a reservoir of tumor therapy system. degassed water. Phantom was positioned in contact Figure 2b. 3D slicer image of MRI with with the degassed water. high intensity area was displayed in a Figure 1b. An optical tracker (Northern Digital, manner resembling conventional monitor Ontario, Canada) was attached outside of a reservoir US to assist the FUS treatment. of degassed water and followed by Polaris Vicra.

Focused Ultrasound 2014 4th International Symposium 103 85-LV TRANS-FUSIMO -- Clinical Translation of Patient Specifi c Planning and Wednesday Conduction of FUS Treatment in Moving Organs 15 October 2014 Tobias Preusser1, Mario Bezzi2, Jürgen Jenne3, Thomas Langø4, Yoav Levy5, Topic: Liver & Pancreas Michael Mueller6, Giora Sat7, Christine Tanner8, Stephan Zangos9, Presentation Type: Oral Matthias Guenther10, Andreas Melzer11 1 Fraunhofer MEVIS/Jacobs University Bremen, Bremen, Germany 2 Universita Degli Studi Di Roma La Sapienza, Rome, Italy 3 Mediri GmbH, Heidelberg, Germany 4 Stiftelsen SINTEF, Trondheim, Norway 5 InSightec Ltd, Tirat Carmel, Israel 6 IBSmm Engineering spol. s r. o, Brno, Czech Republic 7 GE Medical Systems Israel Ltd., Tirat Carmel, Israel 8 ETH Zurich, Computer Vision Laboratory, Zurich, Switzerland 9 Johann Wolfgang Goethe-Universität, Frankfurt, Germany 10 Fraunhofer MEVIS, Bremen, Germany 11 University of Dundee, Dundee, United Kingdom

Background/Introduction: The movement of the target challenges the application of high intensive focused ultrasound (HiFU/MRgFUS) for the treatment of malignancies in moving abdominal organs such as liver and kidney. Moreover, the anatomical location of the lesion is often behind the rib cage. The physiology of the organs, the dynamic and complex blood perfusion impairs the energy disposition in the tissue due to the heat transfer within the organ. To explore the full potential of extracorporeal FUS to safely and precisely destroy tissue in the depth of a moving organ requires sophisticated software and advanced hardware. In the EU project FUSIMO (www.fusimo.eu) a software demonstrator for the patient specifi c planning of FUS in the liver has been developed in order to empower the physician to perform safe, effective and effi cient ablation of tumours and to facilitate prediction of the outcome. The new EU project TRANS-FUSIMO (www.trans-fusimo.eu) aims at the translation of this software demonstrator into a fully integrated system for the FUS treatment of the liver. Methods: The FUSIMO software demonstrator based on MeVisLab incorporates a set of dynamic organ models for the physical and biophysical processes involved in MR guided FUS treatment: (i) an organ motion model simulates the patient specifi c deformation of the relevant anatomical structures during breathing; (ii) a patient specifi c tissue model represents the ultrasound propagation, the energy distribution as well as the tissue heating and cooling; (iii) an organ/tumour model captures the patient specifi c tissue’s response to the therapy. These model components are integrated into a software demonstrator, which orchestrates the interplay between the models and feeds them with model parameters that are extracted from patient specifi c MR and/or US imaging data. The system and the model components are being validated in phantom and ex vivo experiments and in Thiel soft embalmed human cadavers. In TRANS-FUSIMO the safety, effi cacy and effi ciency of the software assistant will be evaluated in an in vivo animal study. Moreover, a two-arm study (neoadjuvant TRANS- FUSIMO MRgFUS + resection, TRANS-FUSIMO MRgFUS only) for human patients with metastases or HCC will show the feasibility of the TRANS-FUSIMO system for the clinical setting. Results and Conclusions: The FUSIMO/TRANS-FUSIMO software demonstrator comprises specifi c models for the simulation of FUS application in moving organs based on imaging data derived from volunteers. It supports the assessment of the feasibility of the intervention, predicting and optimizing the outcome, detecting potential risks and avoiding them, as well as monitoring the progress and tracking deviations from the planned procedure. Our ex vivo experiments show that the FUSIMO system is capable of compensating organ motion through real-time motion detection, motion modelling and real-time beam steering. In TRANS-FUSIMO a fully integrated system will be developed for which in vivo animal studies and fi rst patient study shall show that MRgFUS in moving organs can be performed safely, effi caciously and effectively. Acknowledgements (Funding): The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreements no. 270186 (FUSIMO) and no. 611889 (TRANS-FUSIMO).

104 Focused Ultrasound 2014 4th International Symposium 86-LV Feasibility of Intercostal High Intensity Focused Ultrasound Ablation of Wednesday Clinically Relevant Volumes under the Application of Beam Shaping 15 October 2014 Martij n de Greef1, Gerald Schubert2, Joost Wij lemans1, Julius Koskela2, Lambertus W. Topic: Liver & Pancreas Bartels1, Chrit Moonen1, Mario Ries1 Presentation Type: Oral 1 University Medical Center Utrecht, Utrecht, Netherlands 2 Philips Healthcare, Vantaa, Finland

Background/Introduction: Obstruction by the thoracic cage of the high intensity focused ultrasound (HIFU) beam is one of the major challenges in the ablation of abdominal lesions. Several beam shaping methods have been proposed to reduce exposure of the ribs to acoustic energy and to recover focal point intensity. The feasibility of HIFU ablation of a clinically relevant volume applying beam shaping remains however unaddressed. In this study, feasibility was evaluated based on exposure of both the ribs as well as the near-fi eld to acoustic energy. In addition, the volumetric ablation rate was estimated to evaluate whether clinically relevant ablation speeds can be achieved. Methods: To establish a safety limit for the exposure of the ribs to acoustic energy, rib heating was studied in an in vivo porcine model using MR thermometry (Achieva, Philips Healthcare, Best, The Netherlands). The animals (n = 2) were installed on the Sonalleve V2 HIFU platform (Philips Healthcare, Vantaa, Finland) and sonications (n = 3) were performed for transducer positions where rib obstruction occurred. Ray tracer simulations were used to estimate the corresponding exposure to acoustic energy. Four different sonication geometries were defi ned (sonication at 30 mm and 50 mm behind rib cage at both 15 mm and 20 mm rib spacing) for which single point sonication and volumetric sonications (circular trajectory with 2mm and 4mm diameter) were simulated. Based on the time required to achieve 65 °C in a defi ned ROI according to simulation, acoustic energy density at the ribs and the fat – muscle interface was estimated based on ray tracer and ASPW simulations of the acoustic intensity, respectively. Beam shaping was based on rib – ray collision detection and total acoustic power was kept constant. The volumetric ablation rate was estimated based on the ablated volume according to the defi ned ROI and the inter-sonication waiting time based on a cycle-average energy deposition rate of 100 kJ/h. Results and Conclusions: Based on MR thermometry, rib temperature increases of 20 – 34 °C were observed at simulated acoustic energy densities of 5.4 – 6.6 J/mm2 (minimum of the 10% surface with the highest exposure). With increasing volume ablated in a single sonication, the near-fi eld energy density at the fat – muscle interface increased with peak levels above 5 J/mm2 in case of sonication with a 4mm diameter circular trajectory (safety limit 2.5 J/mm2). The corresponding rib acoustic energy density in the 1cm2 of rib surface with the highest exposure was < 1 J/mm2 for 30 mm and < 2 J/mm2 for 50 mm sonication depth. For the sonication scenarios for which the near-fi eld energy density was within the specifi ed limits, volumetric ablation rates of ≤ 1 ml/h were estimated. In conclusion, beam shaping by means of the collision detection method is an effective means to protect the ribs against excessive heating. However, by conserving the total acoustic power emitted, this mitigated risk is replaced by the risk of excessive near-fi eld heating. As a consequence, for the particular hardware studied, the volume that can be ablated in a single sonication is required to be limited and this limits the volumetric ablation rate. Acknowledgements (Funding): This work was fi nancially supported by the Center for Translational Molecular Medicine (CTMM), project VOLTA (grant 05T-201).

Focused Ultrasound 2014 4th International Symposium 105 87-LV Spontaneous Breathing vs. Mechanical Ventilation for Respiratory-gated Wednesday MR-HIFU Ablation in the Liver 15 October 2014 Joost Wij lemans, Johanna van Breugel, Martij n de Greef, Chrit Moonen, Maurice Topic: Liver & Pancreas van den Bosch, Mario Ries Presentation Type: Oral University Medical Center Utrecht, Utrecht, Netherlands

Background/Introduction: Magnetic resonance-guided High Intensity Focused Ultrasound (MR-HIFU) ablation in the liver is complicated by the continuous motion of the target due to the respiratory cycle. Several motion compensation strategies have been proposed in the past, such as breath-holding, respiratory gating and dynamic beam steering. Respiratory gating for sonication and MR thermometry uses a pencil beam navigator on the diaphragm to limit power output and image acquisition to the resting phase of the diaphragm. Previously, we have used General Anesthesia with mechanical ventilation (GA) to obtain a long and reproducible resting phase of the diaphragm. From a patient’s perspective however, Procedural Sedation and Analgesia (PSA) has several advantages over GA such as a lower risk of complications and shorter recovery. In addition, it has lower associated costs and can be performed by non-anesthesiologists. The purpose of this animal study was to investigate the feasibility of respiratory-gated MR-HIFU ablation in the liver under PSA with spontaneous breathing. Methods: Normal Dalland land pigs (n = 2) were placed in prone position on a clinical Sonalleve MR-HIFU therapy system integrated with a 1.5T Achieva MRI (Philips Healthcare) with minor modifi cations. First, PSA was induced using continuous intravenous (i.v.) infusion of and propofol (4.5 mg/kg/h) and remifentanil (6,6 μg/kg/h). Remifentanil was chosen because of its depressant effect on the respiration combined with a short plasma half-life of <10 min. Volumetric sonications were performed under PSA (4 mm diameter trajectory, 450 W, 20 – 25 sec.). Subsequently the animal was intubated and GA was induced using continuous i.v. infusion of midazolam (1 mg/kg/h), cisatracurium (0.09 mg/kg/h), and sufentanil (11.3 mg/kg/h). Mechanical ventilation was set to 13/min (cycle: 4.5 sec, resting phase: 3 sec). A similar lesion was sonicated using the same sonication protocol. For both the GA and PSA experiments, the non-perfused volumes (NPVs) on contrast-enhanced imaging were expressed in milliliter and the duty cycles of the therapeutic sonications were expressed in median percentages (interquartile range, range) and compared using the Mann-Whitney U test. Results and Conclusions: A total of 38 sonications were performed in two animals. Under GA, a median duty cycle of 65.0% (IQR 62.6 - 66.5, range 46.0 - 68.7) was achieved. Under PSA, a duty cycle of 80.0% (IQR 77.5 - 85.6, range 18.0 - 89.9) was achieved (p < 0.001). The resulting non-perfused volumes from the GA experiments measured 0.70 ml (10 therapeutic sonications) and 0.51 ml (9 therapeutic sonications). The NPVs from the PSA experiments measured 0.70 ml (7 therapeutic sonications) and 1.16 ml (8 therapeutic sonications). The average NPV per sonication was 0.06 for the GA experiments and 0.21 for the PSA experiments. In conclusion, respiratory-gated MR-HIFU in the liver under PSA with spontaneous breathing is feasible and allows for a duty cycle which is at least comparable to GA. Remifentanil seems particularly suited for this purpose because of its strong inhibitory effect on the ventilation, which leads to a long resting phase of the diaphragm. A downside is the risk of apneas, which may require intervention (e.g. short-term ventilation of the patient). Future work will need to compare the frequency of patient movement under GA and PSA before clinical use is warranted. Acknowledgements (Funding): This study was performed within the framework of CTMM, the Center for Translational Molecular Medicine, project VOLTA (grant 05T-201).

106 Focused Ultrasound 2014 4th International Symposium 88-LV Boiling Histotripsy Method to Mechanically Fractionate Tissue Volumes in Wednesday Ex vivo Bovine Liver Using a Clinical MR-guided HIFU System 15 October 2014 Vera Khokhlova1, Ari Partanen2, Adam Maxwell1, Tatiana Khokhlova1, Topic: Liver & Pancreas Wayne Kreider1, Michael Bailey1, Navid Farr1, Yak-Nam Wang1, George Schade1, Presentation Type: Oral Oleg Sapozhnikov3 1 University of Washington, Seattle, Washington, United States 2 Philips Healthcare, Bethesda, Maryland, United States 3 Moscow State University, Moscow, Russian Federation

Background/Introduction: Most current HIFU approaches to treat liver tumors rely on thermal tissue ablation. Challenges still remain that prevent widespread clinical application of this technology including long treatment times, side effects such as skin burns, attenuation and aberration by ribs, heat diffusion and perfusion. Recently, a new method named boiling histotripsy (BH) was developed at the UW/MSU to address these challenges. BH applies a sequence of millisecond-long pulses with high-amplitude shocks that rapidly heat tissue and initiate boiling within each pulse. Interaction of shocks with the resulting vapor cavity leads to tissue fractionation into subcellular debris. Multiple BH lesions can be generated to sonicate clinically relevant tissue volumes. The goal of this study was to evaluate the feasibility of a clinical HIFU system to treat tissue with BH and to develop exposure protocols for such treatments with real-time and post-treatment MR imaging. Methods: Experiments were conducted with a 256-element 1.2 MHz HIFU phased array (Sonalleve, Philips Healthcare, Vantaa, Finland). Sonications were performed in ex vivo bovine liver at a tissue depth of 2 cm with 10 ms-long pulses and pulse repetition frequencies (PRFs) of 1 – 10 Hz. Pulses were delivered at 250 W acoustic power providing a 65 MPa in situ shock amplitude. Using electronic steering transverse to the beam axis, volumetric lesions were generated by treating circles of 2, 4, 6, and 8 mm radii, with 2 mm separation between focal points along each circle and 5 mm separation between the circles along the beam axis. Two treatment protocols were tested: a sequential treatment with a set number of pulses delivered at each target location before proceeding to the next location, and a non-sequential treatment with consecutive HIFU pulses sent to different target locations to diminish heat accumulation and thermal effects. For all treatments, each point received 30 pulses. MR imaging was used to monitor treatments in real-time as well as to characterize lesions post- HIFU. Finally, lesions were also analyzed grossly and histologically. Results and Conclusions: It was shown that the clinical HIFU system was capable of producing mechanically fractionated volumetric lesions in tissue using boiling histotripsy combined with electronic steering of the HIFU beam. The lesions were visible by MR both in real time and post-treatment. Successful sonications performed at 2 cm depth in tissue required less than 25% of the maximum system power, thus permitting implementation of this approach under clinically relevant conditions with greater attenuation. Homogenized lesions of 3 – 5 cm3 were produced with a 1 Hz PRF while increasing thermal effects were observed for sonications at 3 – 10 Hz PRF. With a 2 mm lesion separation, adjacent lesions merged to produce a single volume of fractionated tissue. It was observed that larger vessels could be spared while surrounding liver tissue was effectively fractionated. Acknowledgements (Funding): Work supported by NIH EB7643, K01 EB 015745, T32 DK007779, NSBRI through NASA NCC 9-58, and RSF 14-12-00974.

Photograph of the experimental setup at MR imaging of BH treatment in Post-treatment T2-weighted Mechanically fractionated the patient table of the real time: temperature map in MR image of mechanically volumetric lesions in ex vivo Sonalleve HIFU system for coronal imaging plane within the fractionated lesion in ex-vivo bovine liver with (top) and ex vivo tissue sonications. ex vivo bovine liver. bovine liver. without (bottom) the content. Focused Ultrasound 2014 4th International Symposium 107 89-LV Real-Time MRI Feedback of Cavitation Ablation Therapy (Histotripsy) Wednesday Steven Allen, Timothy Hall 15 October 2014 University of Michigan, Ann Arbor, Michigan, United States Topic: Liver & Pancreas Presentation Type: Oral Background/Introduction: Histotripsy ablation of liver tumors is a non-invasive surgery that uses high-intensity acoustic pulses to control an inertial cavitation cloud. Repeated exposure to the cavitation cloud renders a target tissue into a homogenous slurry which is then gradually absorbed by the body. Like other non-invasive surgeries, histotripsy requires a feedback system that can estimate therapy location and dose in real-time. Because the time-average power output of histotripsy is very small, the treatment region does not express a signifi cant rise in temperature, making MRI thermometry an ineffective method to actively monitor therapy. Previous work has shown that MRI pulse sequences can be made sensitive to the chaotic water fl ow present during inertial cavitation. This is done by synchronizing the timing of the histotripsy pulses with the timing of the sequence’s gradient waveforms. Incoherent water fl ow caused by cavitation attenuates the MR signal through a process similar to that used in diffusion-weighted MRI. It was shown that these sequences can give localized contrast specifi c to histotripsy bubble clouds. However, the MR images could only be acquired in a piecemeal fashion over several minutes such that a single image represented the infl uence of many cavitation events. Here, we introduce a single-shot MR acquisition sequence that is able to rapidly acquire a complete MR image and remain sensitive to histotripsy cavitation. This is done by syncronizing each histotripsy pulse with incoherent motion-weighting gradients placed just before the readout portion of the sequence. When repeated at the same rate as the histotripsy pulses, the resulting MR images can give feedback on the location of every cavitaiton cloud applied to the target tissue. Methods: An MR-compatible transducer was placed in the bore of a 7T MRI scanner and coupled to a water bath and a 2 cm surface RF coil. A cavitation sensitive, single- shot, spiral readout sequence was used to repeatedly image a plane transecting the focus of the transducer. Acoustic pulses from the transducer were triggered to fi re between the incoherent-motion sensitizing gradients of the sequence and the readout gradients. See fi gure (1). Control images were also acquired with the sensitizing gradients disabled. Results and Conclusions: An example control image and an example cavitation weighted image are shown in fi gure 2. In the fi gure, the surface coil is centered about the transducer focus while the tranducer itself and the majority of the water bath lie outside the fi eld of view. The acoustic pulses propagate from bottom to top of the image. The cavitation weighted image displays a small region of signal attenuation at the transducer focus which is not present in the control image. Each image is acquired over the course of 30 ms and repeated every 400 ms, resulting in localization information for every cavitaiton pulse applied to the target. Acknowledgements (Funding): Author Timothy Hall has equity, consulting, and royalty interests in Histosonics Inc. This work is funded in part by NIH grants R01DK087871, R01CA134579.

Figure 1: Cavitation sensitive, single-shot Figure 2: Single shot, cavitation sensitive image of the pulse sequence. A histotripsy pulse (arrow) transducer focus with the weighting gradients turned off is placed in between motion encoding (left). When the weighting gradients are turned on, a gradients and the readout gradients. small region of attenuation appears at the transducer focus RF = radio frequency, SS = slice select, (right). PE = phase encode, RO = readout, US = ultrasound.

108 Focused Ultrasound 2014 4th International Symposium 91-UF MR Guided Focused US for Treatment of Uterine Fibroids: Symptom Thursday Reduction in a Multicenter Trial Using a Novel Treatment Algorithm 16 October 2014 Nelly Tan, David Lu, Steven Raman, Simin Bahrami Topic: Uterine Fibroids University of California at Los Angeles, Los Angeles, California, United States Presentation Type: Oral

Background/Introduction: Enhanced sonication (ES) is a newer technique to ablate symptomatic uterine fi broids. ES uses nearly twice the amount of energy and is able ablate nearly twice the region of interest compared to standard sonications. As a result, more volume of uterine fi broids are able to be treated within the same amount of time. The objective of the multi-center trial was to evaluate the clinical effi cacy of enhanced sonication. Methods: A HIPAA-complaint, IRB-approved prospective single-arm multi-center trial study of women consecutively evaluated at seven tertiary care institutions in the United States of women with symptomatic uterine fi broids was performed. The study was approved by the institutional review board at seven tertiary care centers in the United States between Jan 2010 and Mar-2013. This study was under a post-PMA approval (open label), single-arm, multicenter study using the ExAblate 2000 system. Patients were followed for safety at one week and one month post-treatment. For effectiveness patients had to consent again to be followed for 3 years. Safety was measured by the incidence, severity and duration of adverse events; effectiveness was measured by immediate post-treatment non-perfused ratio, SSS- UFS-QOL score as compared to baseline and retreatment rate. We performed paired t-test to evaluate the difference in UFS-QOL pre and post treatment. Statistics were considered signifi cant at p = 0.05. Results and Conclusions: Out of 245 screened patients 115 patients underwent 164 treatment sessions (54 patients had a second treatment.) Of these, 100 agreed to be followed up. Patients were an average age of 44 and average BMI of 24.9. Of 115, 71 were Caucasian, 13 African American, 8 Asian, and 8 others. 58 patients had a single fi broid, 28 patients had between 2 to 4 fi broids, and 14 patients had 5 or more fi broids. The total fi broids volume per patient was in average 235cc ± 220 (range 10-1300). The average nonperfused ratio measured immediately after the treatment was 65% ±23% (range 6%- 100%). Baseline SSS for the 100 patients was 66.7±15.7 (range 28-100). At 6 months, in 91 patients who followed up, the SSS decreased to 26.8±16.2 (range 0-75). There were signifi cant improvements in the UFS-QOL score overall and the sub-scales including symptom severity score (66.4 vs. 25.5, p<0.01), concern (35.7 v. 74.0, p<0.01), activities (37.61 vs. 77.5, p<0.01), energy (35.7 v 74.4, p<0.01), control (38.2 v. 76.6, p<0.01), self- consciousness (35.5 v 70.6, p<0.01), sexual function (36.5 v. 73.3, p<0.01) and health- related quality of life (36.6 v. 75, p<0.01) between baseline and 12 month post treatment, respectively. The number of patients who underwent alternative treatments at 12 months was 9 (9%). There were no major complications. Minor complications occurred in <5% of the patients. Those that lasted longer than 7 days were one skin burn, patient reported fatigue, one complaint of abdominal cramping, one of perineal pain, and one with leg pain for two months. Conclusion: In this multicenter cohort, sustained symptom relief was possible up to 12 months with the addition of enhanced sonicatons to standard sonication during MR guided HIFU. Acknowledgements (Funding): The study was funded by InSightec.

Focused Ultrasound 2014 4th International Symposium 109 92-UF Volumetric MR-guided High-intensity Focused Ultrasound with Direct Thursday Skin Cooling for the Treatment of Symptomatic Uterine Fibroids: Proof of 16 October 2014 Concept Study

Topic: Uterine Fibroids 1 1 2 1 Presentation Type: Oral Marlij ne Ikink , Johanna van Breugel , Gerald Schubert , Robbert Nij enhuis , Lambertus W. Bartels1, Chrit Moonen1, Maurice van den Bosch1 1 University Medical Center Utrecht, Utrecht, Netherlands 2 Philips Healthcare, Vantaa, Finland

Background/Introduction: To prospectively assess the safety and technical feasibility of volumetric magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) ablation with direct skin cooling (DISC) during treatment of uterine fi broids. Methods: In this proof-of-concept study, eight patients were selected for clinical MR-HIFU ablation of uterine fi broids with use of an additional DISC device to maintain a constant temperature (T≈20°C) at the interface between the HIFU table-top and the patients’ skin (Figure 1). Technical feasibility was determined by verifi cation of successful completion of MR-HIFU ablation. Contrast-enhanced T1-weighted MRI was used to measure the treatment effect (non-perfused volume (NPV) ratio). Safety was evaluated by recording of adverse events (AEs) and their relation to the investigational DISC device within 30 days’ follow-up. Results and Conclusions: Results: All MR-HIFU treatments were successfully completed in an outpatient setting. The median NPV-ratio was 0.56 (IQR[0.27-0.72]). Immediately after treatment, two patients experienced coldness related discomfort which resolved the same day. No serious AEs were reported within 30-days’ follow-up. No skin burns, cold injuries or subcutaneous edema were observed in patients treated with the DISC device. Conclusion: This study showed that it is technically feasible and safe to complete a volumetric MR-HIFU ablation with DISC. This technique may further reduce the risk of thermal injury to the abdominal wall during MR-HIFU ablation of uterine fi broids.

110 Focused Ultrasound 2014 4th International Symposium 93-UF The Effect of Reimbursement on MRgFUS Treatment of Uterine Fibroids Thursday Ronit Machtinger, Yael Inbar, Aviva Alagem-Mizrachi, Jaron Rabinovici 16 October 2014 Sheba Medical Center, Tel Hashomer, Israel Topic: Uterine Fibroids Presentation Type: Oral Background/Introduction: The demand for conservative treatments for uterine fi broids has increased during the last decade, as more women wish to retain their uterus and avoid invasive procedures. MRgFUS is a well established conservative technology for the treatment of uterine fi broids. The procedure is offered as a clinical treatment option (not as a part of clinical trials) at the Sheba Medical Center for many years, and was mostly self-paid by the patients. From November 2013, the procedure has been covered by the HMOs as a part of the Israeli National Health Insurance Law. The aim of the study was to assess how reimbursement affects the number of MRgFUS enrollments and treatments in a single tertiary center. Methods: A retrospective analysis of the number of patients attending MRgFUS clinics before (December 2012 to February 2013, period I) and after reimbursement (December 2013 to February 2014, period II). For statistical analysis Fisher exact test was performed. Results and Conclusions: In period I, 15 women out of 20 (75%) fulfi lled basic MRgFUS criteria and were referred for MRI. Twelve MRI, 7 were found suitable and 3 were ultimately treated. In period I I, 39 women out of 63 (61.9%) fulfi lled basic MRgFUS criteria and were referred for MRI. Thirty performed MRI, 12 were found suitable all underwent MRgFUS treatment. The number of treated patients was signifi cantly higher following the reimbursment (p<0.001). Conclusions: Reimbursement signifi cantly increased the number of patients who attended the MRgFUS clinics and quadrupled the number of treatments.

Focused Ultrasound 2014 4th International Symposium 111 94-UF RELIEF Registry: Large-scale Evidence on the Safety and Long-term Effi cacy Thursday of Focused Ultrasound Treatment of Symptomatic Leiomyoma 16 October 2014 Arik Hananel1, Elizabeth David2, Wladyslaw Gedroyc3, Young-sun Kim4, Topic: Uterine Fibroids Matthias Matzko5, Harsh Rastogi6, Anne Roberts7, Elizabeth Stewart8, Presentation Type: Oral Robert Zurawin9, Jaron Rabinovici10 1 Focused Ultrasound Foundation, Charlottesville, Virginia, United States 2 Sunnybrook Health Sciences Centre, Toronto, Canada 3 Imperial College London, London, United Kingdom 4 Samsung Medical Center, Seoul, Republic of Korea 5 Amper Kliniken AG, Dachau, Germany 6 Indraprastha Apollo Hospital, Delhi, India 7 University of California at San Diego, San Diego, California, United States 8 Mayo Clinic, Rochester, Minnesota, United States 9 Baylor College of Medicine, Houston, Texas, United States 10 Sheba Medical Center, Tel Hashomer, Israel

Background/Introduction: In this work we will present our plan for an (MR)-guided, high- intensity focused ultrasound (FUS) uterine fi broid registry, with the goal of providing large- scale evidence on the safety and long-term effi cacy of FUS for the treatment of symptomatic uterine fi broids. Methods: 1,000 patients will be enrolled to the registry in multiple sites worldwide. Patient would get FUS treatment and be followed for a period of three years. Only FUS qualifi ed patients and sites meeting registry treatment criteria would participate in the study. Results and Conclusions: Treatment outcome and follow-up data will be collected by a contract research organization, (CRO), and analyzed for safety and effi cacy. We will then compare our results to similar results in the literature. Subgroups will be selected and analyzed to address heterogeneity and usage of non-uniform treatment methods.

112 Focused Ultrasound 2014 4th International Symposium 95-UF Effi cacy of MR-guided Focused Ultrasound Ablation for Localized Thursday Adenomyosis in Comparison to Leiomyoma 16 October 2014 Heidi Coy, Nelly Tan, Daniel Margolis, Peiyun Lu, Grace Kim, Matthew Brown, David Topic: Uterine Fibroids Lu, Jonathan Goldin, Steven Raman Presentation Type: Oral University of California at Los Angeles, Los Angeles, California, United States

Background/Introduction: Symptomatic localized adenomyosis is generally treated conservatively, or with more radical treatments such as hysterectomy. An effective non- invasive therapy is needed, especially for those who wish to preserve their fertility. MR- guided Focused Ultrasound ablation (MRgFUS) has been shown as an effective treatment for symptomatic uterine leiomyomas with a large non-perfused volume (NPV) immediately after treatment. Our specifi c aim was to compare the change in NPV in subjects with localized adenomyomas treated with MRgFUS, with the change in NPV in subjects treated with MRgFUS for symptomatic uterine leiomyomas to determine if similar results were achieved in the localized adenomyoma cohort. Methods: With IRB approval, we performed a HIPAA compliant retrospective review of women treated with MRgFUS at our comprehensive treatment center for symptomatic localized adenomyosis. We matched cases with leiomyoma bearing-controls with the following criteria: 1) Similar baseline total lesion volume. 2) Similar number of lesions at baseline. 3) Similar age. Subjects who had imaging performed both prior and immediately post-treatment were included. All lesions were contoured on the T1 post-constrast sagittal series, and volumes were calculated with a validated proprietary software. All contours were confi rmed by two genitourinatry trained radiologists. The software automatically calculated the total lesion volume and it’s perfused volume, from which we derived the NPV by subtracting the perfused lesion volume from the total lesion volume. Results and Conclusions: 10 lesions in 9 subjects were analyzed. Adenomyoma and leiomyoma cohorts were similar in baseline characteristics including age (42 vs. 43) and mean baseline total lesion volume (96cc vs. 97cc), respectively. Post-tx characteristics were also similar between adenomyoma and leiomyoma cohorts in mean total lesion volume (97cc vs. 90 cc), mean post-tx NPV (41cc vs. 52cc) and sonication number (74 vs. 65), respectively. From our results we can conclude that MRgFUS can offer signifi cant reduction in perfused volume of localized adenomyosis similar to leiomyoma, and may offer complete ablation of the adenomyoma. Therefore indicating MRgFUS may be a viable non-invasive treatment for patients with symptomatic adenomyosis, and may offer an alternative to conventional therapies. Acknowledgements (Funding): Center for Computer Vision and Imaging Biomarkers, Department of Radiology, David Geffen School of Medicine, University of California, Los Angeles

Focused Ultrasound 2014 4th International Symposium 113 96-UF The Relationship of T2WI Signal Intensity of Uterine Fibroids and the Thursday Temperature Curve in MR-guided High-Intensity Focused Ultrasound (HIFU) 16 October 2014 Ablation

Topic: Uterine Fibroids 1 2 1 2 1 Presentation Type: Oral Jia Liu , Bilgin Keserci , Rong Rong , Juan Wei , Xiaoying Wang 1 Peking University First Hospital, Beij ing, China 2 Philips Healthcare, Seoul, Republic of Korea

Background/Introduction: MR guided high-intensity focused ultrasound (HIFU) ablation is increasingly being used worldwide to treat symptomatic uterine fi broids because of its excellent therapeutic effi cacy in controlling symptoms and its excellent safety record. High signal intensity on T2WI MR images of fi broids is fi rstly considered a factor that induces poor ablation outcomes. Nevertheless, to our HIFU clinical practice, signal intensity on T2WI MR images is not that accurate for determining whether the fi broids are hyper- perfusion or hypo-perfusion because signal intensity on T2WI is just a relative and subjective parameter, which cannot quantify perfusion. It is demonstrated that the temperature curve (ie.temperature change as a function of time) during HIFU treatments is a relatively accurate manifestation of fi broids’ reaction to sonication. The purpose of this study was to retrospectively study the relationship of T2WI signal intensity of uterine fi broids and the temperature curve in MR guided HIFU. Methods: All 15 female patients (mean age, 44.7±5.4 years) who were given written informed consent underwent MRI screening. In the screening, subjects were positioned prone, feet fi rst, on the 3T MRI scanner (Achieva TX, Philips Medical Systems, Best, the Netherlands) with a 32-channel phased array coil. T2W images were acquired on the sagittal plan across the uterus. The fi broids were classifi ed into 3 types according to the signal intensity on T2WI MRI: Type 1(n=7), with signal intensity lower than the skeletal muscle. Type 2(n=7),with signal intensity lower than the myometrium but higher than the skeletal muscle. Type 3(n=1), with signal intensity higher than the myometrium. Thermometry got during the treatments was used to create temperature curves as shown in Figure 1 and 2. For better interpretation, two points were chosen on the temperature curve: The fi rst point was the time point at the end of the ascending segment before the temperature got stable. The second point was the time point at the beginning of the descending segment before the temperature began to decay. As shown in Figure 3, the Matlab software accompanied with linear regression and defi nite integration methods was used to analyze the temperature curve to generate several parameters as follows: (i) heating slope, the slope between the beginning point of the curve to the fi rstpoint; (ii) decay slope, the slope between the second point to the last point of the curve; (iii) area under heating curve (AUC), the area under the curve between the beginning point of the curve to the second point; (iv) heating time, the time span between the fi rst point to the second point of the curve; (v) max temp, the average of all temperatures between the fi rst to the second point of the curve; and (vi) time to peak, the time span of between the beginning point to the fi rst point of the curve. Results and Conclusions: As shown in Table 1, the temperature curve of type 1 fi broids ascended quickly (heating slope: 1.67±0.73°C/s, time to peak: 12.5±4.2s), descended quickly (decay slope: 0.83±0.29°C/s) and had the longest plateaus(heating time: 38.5±18.2s).It had the most effective therapy(AUC: 2221.7±769.4°C• s). The temperature curve of type 2 fi broids ascended slowly (heating slope: 0.80±0.66°C/s, time to peak 22.5±11.1s), descended slowly (decay slope: 0.47±0.30°C/s) and had a shorter plateaus (heating time: 24.8±7.2s). It had a less effective therapy (AUC: 2036.5±361.5°C• s). The temperature curve of type 3 fi broids ascended slowly (heating slope: 0.52°C/s, time to peak: 20.6s), descended most slowly (decay slope: 0.39°C/s) and had the least effective therapy(AUC: 1597.2°C• s, heating time: 12.9s). The effi cacy of HIFU treatments based on temperature curve correlates well with the T2WI signal intensity of uterine fi broids.

114 Focused Ultrasound 2014 4th International Symposium A graph of temperature change as a function of time obtained during treatment in therapy control graphical user interface

Coronal (left) and sagittal (right) MR thermometry images show temperature overlay during volumetric MR HIFU ablation.

Temperature curve of type 1, 2, 3 fi broids

Parameters of the temperature curves of type1(n=7), 2(n=7), and 3(n=1) fi broids

Focused Ultrasound 2014 4th International Symposium 115 97-UF Correlation of T2 Signal Intensity of Uterine Fibroids with Semiquantitative Thursday Perfusion MR Parameters in Candidates for MR-HIFU Ablation: Analysis 16 October 2014 According to Fibroid Types Topic: Uterine Fibroids Presentation Type: Oral Young-sun Kim, Hyo Keun Lim, Hyunchul Rhim Samsung Medical Center, Seoul, Republic of Korea

Background/Introduction: T2 signal intensity and perfusion MR fi ndings are known to be important infl uencing factors for therapeutic response of uterine fi broids to MR-guided high-intensity focused ultrasound (MR-HIFU) ablation. While T2 signal intensity of fi broids is easy to assess, perfusion MRI is relatively diffi cult to perform. The aim of this study was to evaluate relationships between T2 signal intensity and semiquantitative perfusion MR parameters of uterine fi broids to know whether T2-weighted image can replace a role of perfusion MRI for procedure screening. Methods: A total of 170 most symptom-relevant, non-degenerated uterine fi broids (mean diameter, 7.3cm; range 3.0–17.2cm) in 170 women (mean age, 43.5 years, range 24-56) who underwent screening MRI exams for MR-HIFU ablation were retrospectively analyzed. Signal intensity of uterine fi broid was assessed as a ratio of T2 signal intensity of uterine fi broids to that of skeletal muscle. Parameters of semiquantitative perfusion MRI (100 dynamics, 3s time resolution) which included peak enhancement, relative peak enhancement (%; 0% refers same signal intensity as in precontrast image), time to peak (s), wash-in rate (/s), and wash-out rate (/s) based on analyses of time-signal intensity curve were investigated to know their relationships with T2 signal intensity ratio using multiple linear regression test. The correlations between T2 signal intensity and the independently signifi cant semiquantitative perfusion MR parameter were then evaluated using Spearman’s correlation test according to the fi broid types. Results and Conclusions: Multiple linear regression test revealed that only relative peak enhancement had an independently signifi cant relationship with T2 signal intensity of uterine fi broid (B=0.023, p<0.001). Based on analyses according to fi broid types, submucosal protruding type failed to show signifi cant correlation (n=20, rho=0.275, p=0.240) while signifi cant correlations were noticed in all the other types (submucosal type, n=45, rho=0.629, p<0.001; intramural type, n=25, rho=0.411, p=0.041; transmural type, n=40, rho=0.493, p=0.001; subserosal type, n=40, rho=0.486, p=0.001). Conclusion: In candidates of MR-HIFU ablation therapy for uterine fi broids, T2 signal intensity of non-degenerated uterine fi broid had an independently signifi cant positive correlation with relative peak enhancement of semiquantitative perfusion MRI in most cases, other than in submucosal protruding type.

116 Focused Ultrasound 2014 4th International Symposium 98-UF Screening MRI-based Prediction Model for Therapeutic Response of MR- Thursday HIFU Ablation of Uterine Fibroids 16 October 2014 Young-sun Kim1, Bilgin Keserci2, Hyo Keun Lim1, Hyunchul Rhim1 Topic: Uterine Fibroids 1 Presentation Type: Oral Samsung Medical Center, Seoul, Republic of Korea 2 Philips Healthcare, Seoul, Republic of Korea

Background/Introduction: With regards to MR- HIFU ablation of uterine fi broids, there have been no screening MR criteria that comprehensively consider multiple infl uencing factors. The aims of this study was to generate screening MRI-based prediction model for therapeutic responses of MR-guided high-intensity focused ultrasound (MR-HIFU) ablation of uterine fi broids comprehensively considering multiple infl uencing factors. Methods: A total of 160 symptomatic uterine fi broids (diameter 8.3cm, range 3.1-15.0cm) in 112 women (age 43.3, range 25-55) who were treated with MR-HIFU ablation were retrospectively analyzed. The following three parameters of screening MRI were evaluated. 1) Subcutaneous fat was measured as a thickness of the most compressed point (mm) on prone position. 2) Relative peak enhancement (%) was calculated based on time-signal intensity curve analysis of fi broid in perfusion MRI (100 dynamics, 3s time resolution), in which 0% refers the same signal intensity as in precontrast image. 3) Signal intensity was assessed as a ratio of T2 signal intensity of uterine fi broids to that of skeletal muscle. Those parameters were used to generate prediction models with regards to ablation effi ciency (i.e., non-perfused volume/treatment cell volume) and ablation quality (grade 1~5, from poor to excellent), respectively, using generalized estimating equation (GEE) analysis. Then, cut-off values for successful treatment (ablation effi ciency >1.0; ablation quality grade 4 or 5) were determined based on receiver operating characteristic (ROC) curve analyses. Results and Conclusions: GEE analyses produced the models of “y1=2.2637– 0.0415x1–0.0011x2–0.0772x3” and “y2=6.8148–0.1070x1–0.0050x2–0.2163x3”, where y1=ablation effi ciency, y2=ablation quality, x1=subcutaneous fat thickness, x2=relative peak enhancement, and x3=T2 signal intensity ratio (p-values for x1, 0.0068 and <0.0001; for x2, 0.1952 and 0.0001; for x3, <0.0001 and <0.0001, respectively). Cut-off values for successful treatments based on ROC curve analyses turned out to be 1.312 for of ablation effi ciency (AUC, .7236; sensitivity, .6882; specifi city, .6866) and 4.019 for ablation quality (AUC, .8794; sensitivity, .7156; specifi city, .9020). Conclusion: Simple equation models to predict therapeutic responses of MR- HIFU ablation of uterine fi broids in terms of ablation effi ciency and quality were generated, which are easily applicable to screening MRI.

Focused Ultrasound 2014 4th International Symposium 117 99-UF MRI Predictors of Clinical Success in MR-guided Focused Ultrasound Thursday (MRgFUS) Treatments of Uterine Fibroids: Results from a Single Center 16 October 2014 Irene Mindjuk Topic: Uterine Fibroids Presentation Type: Oral Amper Kliniken AG, Dachau, Germany Background/Introduction: To assess the technical and clinical results of MRgFUS treatment and factors affecting clinical treatment success. Methods: 252 women (mean age, 42.1 ± 6.9 years) with uterine fi broids underwent MRgFUS treatment using an ExAblate 2100 system (Insightec Ltd., Israel). All patients underwent MRI screening before treatment. Results were evaluated with respect to posttreatment non-perfused volume (NPV), symptom severity score (SSS), reintervention rate, pregnancy and safety data. Results and Conclusions: NPV ratio was signifi cantly higher in fi broids characterized by low signal intensity in contrast-enhanced T1-weighted fat saturated MRI images and in fi broids that are distant from spine (>3cm). NPV ratio was lower in fi broids with septations, with subserosal component and in skin-distant fi broids (p< 0.001). NPV ratio was in high correlation with clinical success: NPV of more than 80% resulted clinical success in more than 80% of patients. Reintervention rate was 12.7% (mean follow-up time, 19.4±8 months; range, 3-38). Expulsion of fi broids (22%) signifi cantly correlated with a high clinical success rate. No severe adverse events were reported. Acknowledgements (Funding): Adequate patient selection and correct treatment techniques, based on the learning curve of this technology, combined with technical advances of the system, lead to higher clinical success rates with low complications rate, comparable to other uterine sparing treatment options.

118 Focused Ultrasound 2014 4th International Symposium 100-UF Screening MRI for Uterine Fibroids, Treatment Selection: MR-guided High Thursday Intensity Focused Ultrasound (MRgFUS), Uterine Artery Embolization (UAE) 16 October 2014 and Surgery. A Per Group Analysis of Outcomes Topic: Uterine Fibroids Presentation Type: Oral Fulvio Zaccagna, Federica Ciolina, Francesco Sandolo, Carola Palla, Fabrizio Andrani, Alessandro Napoli, Carlo Catalano University of Rome – Sapienza, Rome, Italy

Background/Introduction: To retrospectively evaluate the outcome of patients affected by uterine leiomyoma and treated using either Magnetic Resonance Focused Ultrasound (MRgFUS), Uterine Artery Embolization (UAE) and Surgery. Methods: 451 women (group A) affected by uterine leiomyoma (mean age 39±5) referred our department for treatment of uterine fi broids with MRgFUS (July 2010-March 2014). Pre- treatment evaluation was done in order to assess symptoms and fi broids MR characteristics for MRgFUS viability. Patients not eligible for MRgFUS were addressed to UAE (group B) or surgery (group C). Primary endpoints were Symptoms Severity Score (SSS) (48.6±13.4), volume shrinkage (Group A and B) and the necessity for further treatment. Satisfaction related to different treatment was evaluated using a 5 point scale. Results and Conclusions: 131/451 patients underwent MRgFUS (29%;Group A), 320 were excluded (70%) and therefore assigned to Group B (123/451, 27%) and Group C (157/451, 35%). Remaining 40% patients (8%) were lost at follow up or refused the proposed treatment. In group A 112/131 patients (86%) showed a decrease in SSS (19.3±6.8), an average NPV of 70±15% (P=0.001), a volume shrinkage of 20±15% and an excellent satisfaction related to treatment. In 7/131 (5%) treatment was stopped at the beginning (bowel loops interposition or absence of compliance). 4 patients had a pregnancy; 3 patients experienced minor adverse events. In 12/131 patients (9%) we obtained NPV< 60% and patients needed surgical treatment. In group B patients showed a decrease in SSS (15.3±5.6), an average NPV of 98% (P=0.001), a volume shrinkage of up to 70% and a good satisfaction related to treatment. The major dissatisfaction was related to post-procedural pain that needed analgesic therapy. No pregnancy was observed. In Group C 80 patients underwent myomectomy,40 hysterectomy while the remaining refused other treatment. 3 pregnancies were observed. MRgFUS treatment of uterine fi broids is a reliable, noninvasive method for treatment symptomatic uterine fi broids; clinical success is directly related to NPV ratio. Eligibility is limited to 30% of screened women with symptomatic fi broids. All patients not suitable for this treatment should necessarily undergo surgery or UAE both with signifi cant lower patient tolerance.

Focused Ultrasound 2014 4th International Symposium 119 101-UF MRI Characterization of Uterine Fibroids May Predict Success of GnRH Thursday Agonist Therapy Prior to Magnetic Resonance Focused Ultrasound 16 October 2014 (MRgFUS) Treatment Topic: Uterine Fibroids Presentation Type: Oral Kelli Bryant, Suzanne LeBlang University MRI, Boca Raton, Florida, United States

Background/Introduction: In managing women with large uterine fi broids, GnRH agonists can be used to reduce fi broid volume and decrease vascularity to enhance treatment outcomes with MRgFUS. GnRH agonists have been shown to reduce fi broid volume by as much as 30-40%. The purpose of this study was to examine the responsiveness of fi broids to pre-treatment with a GnRH agonist in relation to their appearance on T2 weighted images and MRgFUS treatment outcomes. Methods: Fifteen women (ages 34-52) with symptomatic uterine fi broids were pre-treated with a GnRH agonist prior to undergoing MRgFUS treatment using the ExAblate device. 7 patients received treatment for 3 months, 4 received treatment for 4 months, 2 received treatment for 6 months and 2 received treatment for an unknown time before the MRgFUS procedure. Other than the 2 patients with unknown GnRH agonist therapy times, all patients obtained their last GnRH agonist injection 3-4 weeks before MRgFUS treatment. These women were selected to receive a GnRH agonist if they possessed fi broids in excess of 10 cm or had a fi broid volume greater than 300 cc. Fibroids were classifi ed by their intensity on T2 weighted images relative to normal myometrium (hypointense, isointense, or hyperintense as well as tissue homogeneity or heterogeneity). A total of 22 fi broids were treated with MRgFUS: 17 hypointense, 3 heterogeneously hypointense, 1 heterogeneously hyperintense and 1 isointense fi broid. Data regarding fi broid volume reduction following GnRH administration, Joules of energy delivered per cc of fi broid tissue ablated and the fi nal non- perfused volume (NPV) were investigated. Results and Conclusions: The average reduction in size of fi broids following GnRH treatment based on T2 appearance was: hypointense (22%), isointense (44%) heterogeneously hypointense (33%) and heterogeneously hyperintense (40%). The average Joules of energy delivered per sonication was greater for isointense (4550 J) and heterogeneously hyperintense (4200 J) fi broids than for heterogeneously hypointense (3227 J) and hypointense (2654 J) fi broids. Additionally, the volume of tissue ablation per Joule of energy applied was signifi cantly larger for the heterogeneously hypointense (0.066 cm3) and heterogeneously hyperintense (0.057 cm3) than for the hypointense (0.036 cm3) and isointense (0.018 cm3). The NPV per fi broid was greater for heterogeneously hyperintense (85%), heterogeneously hypointense (63%) and hypointense (72%) fi broids than for isointense (32%) fi broids. Fibroid image characteristics may be used to predict the effectiveness of GnRH agonist therapy prior to MRgFUS treatment. While more vascular fi broids require greater energy to treat, they show a more favorable response to pre treatment with a GnRH agonist in terms of fi broid volume reduction and thermoablative treatment effectiveness than hypointense fi broids. Acknowledgements (Funding): We would like to thank Lisa Mckenzie and Gina Boykin for their knowledge and dedication in helping to take care of our MRgFUS patients.

1a. Sagittal T2-weighted image depicting a 471 cc 1b. Sagittal T2-weighted image following 1c. Sagittal post-contrast T1- heterogeneously hyperintense fi broid. 3 months of GnRH agonist therapy, weighted image following MRgFUS showing a 281 cc fi broid representing a treatment demonstrates a non- 40% reduction in volume. perfused volume of 85%.

120 Focused Ultrasound 2014 4th International Symposium 102-UF Treatment Analysis Environment for Review of MRgHIFU Treatments: A Thursday Multi-parametric Analysis Tool 16 October 2014 Marij n van Stralen, Roel Deckers, Wilbert Bartels, Clemens Bos, Chrit Moonen Topic: Uterine Fibroids Presentation Type: Oral University Medical Center Utrecht, Utrecht, Netherlands Background/Introduction: Magnetic resonance imaging (MRI) provides a wide spectrum of imaging contrasts, which have utility for preparation and evaluation of HIFU treatments, as well as for guiding HIFU energy delivery (MRgHIFU). Currently, research into the prospective value of these imaging markers and their ability to predict and probe treatment success is challenged by the lack of an analysis environment that is able to process the spectrum of imaging and treatment data as a whole, and allows assessing correlation between data sets. As an example, we may want to relate the placement and temperature evolution of sonication cells with the resulting non-perfused volume, assessed by MRI perfusion imaging.1 An important factor in this issue is that treatment data is poorly accessible to researchers. E.g. for the Philips Sonalleve platform, treatment data is almost exclusively available in log fi les and thermometry images are exported in a proprietary format (Par/Rec). We propose an analysis environment for clinical and basic imaging research in the context of MRgHIFU treatments. It will be made available to the research community to i) accelerate developments in the fi eld, ii) enable effective use of advanced imaging in MRgHIFU research and iii) stimulate collaboration between centers. Methods: We set up a modular framework for the analysis of MRgHIFU treatments. Tools to access treatment and imaging data were implemented, including DICOM image data and segmentations, treatment data such as treatment cell geometry and parameters, and importantly, intra-operative thermometry data. Next, image registration of these data was implemented and analysis tools were developed that enable correlation of treatment data with imaging parameters based on the targeted treatment geometries. These analysis tools were built, based on the MeVisLab medical imaging development environment (MeVis A screenshot of the modular Medical Solutions, Bremen, Germany), allowing easy distribution among research sites. We development environment that demonstrate its functionality and value in clinical and basic science in the analysis of uterine is easily extendible with new fi broid treatments. modules. Results and Conclusions: After import of the relevant pre-, per- and post treatment HIFU and imaging data, the analysis environment successfully registered the data for combined analysis. Fig.1 shows a screenshot of the modular framework of the analysis tools, which easily allows extension to new imaging methodology or treatment possibilities. Fig. 2 demonstrates the ability to correlate treatment cells to various image-based tissue parameter maps, such as diffusion parameters. The temporal analysis of the thermometry images is shown in Fig. 3. The provided toolset extends functionality that is available on the treatment console and allows further extensions by its modular framework. Also interfaces to popular existing data processing packages, such as Matlab, ITK, VTK and python are included. We intend to make the tools available for research use at the time of the symposium aiming at further development of the analysis tools as a community effort. This could accelerate research into the role of imaging in patient selection, treatment planning, Visualization and regional image analysis for multi-parametric as well as prediction and evaluation of treatment success, as was for example assessed for treatment analysis: relating uterine fi broids.2 treatment cell geometry (white) to an apparent diffusion coeffi cient References: (ADC) map (colored), overlaid on a 1. Voogt et al. European Radiology 2012;22(2);411-417. planning T2w scan. 2. Funaki et al. J Obstet Gynaecol Res. 2007;33(6):834-9. Acknowledgements (Funding): This work was partly funded by the NMP priority of the European 7th Framework Program (Project reference 603028). We would like to thank MeVis Medical Solutions for the use of MeVisLab as a development environment for this tool.

Temporal analysis of thermometry data. The three orthogonal views show cumulative thermal dose maps. The upper left graph displays temperature curves within a treatment cell, for coaxial ellipsoids with varying diameter. Focused Ultrasound 2014 4th International Symposium 121 103-UF Quantifying Perfusion-related Energy Losses during Magnetic Resonance- Thursday guided Focused Ultrasound 16 October 2014 Christopher Dillon, Robert Roemer, Allison Payne Topic: Uterine Fibroids University of Utah, Salt Lake City, Utah, United States Presentation Type: Oral

Background/Introduction: The focused ultrasound power required for successful ablation of uterine fi broid tissue varies substantially between patients and within single treatments.1,2 Fibroids with high signal intensity in pretreatment T2-weighted MR images have been shown to require increased power to achieve adequate temperature elevation for ablation;2-4 thus, T2-weighted signal intensity has been suggested as a predictor of MRgFUS treatment response.2-3 Physiologically, the high intensity of T2-weighted MR images of uterine fi broids may represent vascularization, fl uid-rich tissues, or degeneration.4-6 By quantifying perfusion- related energy losses (Qb) during MRgFUS treatments, this study is the fi rst step in linking perfusion-related energy losses with MR perfusion imaging. This knowledge could be used to improve biothermal modeling of MRgFUS fi broid treatments and as a potential independent predictor of treatment response and outcome. Image 1. Experimental setup for MRgFUS heating Methods: Experiments were performed in ex vivo porcine kidneys perfused with a heparin- of ex vivo perfused porcine H2O solution in variable fl ow (0, 20, 40 mL/min) situations and embedded in a gelatin kidney embedded in a gelatin phantom (Image 1). Heating was achieved by electronically steering a phased-array ultrasound phantom. Solid lines indicate transducer (256 elements, f=1 MHz) in an 8 mm-radius circle for 120 s (Image 2). MR the 3D MR temperature imaging volume and the dashed temperature data (Image 3) were acquired with a 3T Siemens Trio MRI (3D segmented-EPI, line indicates the location of the TR/TE=30/11 ms, FA=15°, EPI factor=9, 2x2x3 mm3, 3.3 s acquisition, ZFI to 0.5-mm coronal magnitude image seen isotropic spacing). Based on conservation of energy principles, deviation of a thermal model in Image 2. that excludes perfusion effects from the experimental temperatures was used to quantify Qb. Estimates of Qb were obtained at the time of each MR acquisition during cooling, transformed into perfusion values via the Pennes bioheat transfer equation,7 and averaged to mitigate the effects of noise. Results and Conclusions: High perfusion values (Image 4) correspond to regions of increased cooling (Image 3) and likely indicate locations of discrete vasculature. Constant, uniform perfusion values ranged from -0.7–0.1, 1.6–3.9, and 3.4–4.4 kg/m3/s for 0, 20, and 40 mL/min fl ow rates, respectively, following anticipated trends with perfusion approximately zero for the no fl ow case and increasing with fl ow rate. Future work will relate MR perfusion imaging to Qb, which should eliminate the need for tissue heating for improved biothermal modeling. This study demonstrates that obtaining perfusion estimates from 3D MR temperature data during MRgFUS is feasible and has the potential to improve biothermal models of MRgFUS fi broid treatments. 6. Oguchi J Obstet Gynaecol 1995 Image 2. Coronal magnitude image 7. Pennes J Appl Physiol 1948 obtained during MRgFUS heating. References: Fiberoptic probes measured the 1. McDannold J Vasc Interv Radiol 2006 Acknowledgements (Funding): background temperature. The This work was funded by Siemens dashed line indicates the circular 2. Lenard J Genitourinary Imag 2008 heating region and the solid line 3. Funaki Am J Obstet Gynecol 2007 Healthcare AG, the FUS Foundation, identifi es the region of interest for 4. Fennessy Curr Radiol Rep 2013 the Ben and Iris Margolis Foundation, data presented in images 3 and 4. 5. Swe Radiat Med 1992 and by NIH grants R01 CA87785 and R01 EB013433.

Image 3 (left). Temperature change resulting from 120 s FUS heating and 30 s cooling with a fl ow rate of 40 mL/min. Areas of increased cooling (blue) are likely locations of discrete vasculature. Image 4 (right). Perfusion values averaged for the fi rst 30 s of cooling. High perfusion values (red) correspond to regions of increased cooling (blue in Image 3) and likely indicate locations of discrete vasculature.

122 Focused Ultrasound 2014 4th International Symposium P-100-BM An Instrumented Bone/Soft Tissue Phantom Designed to Mimic HIFU Tuesday Treatments of Bone 14 October 2014 Jemma Brown, Gail ter Haar Topic: Bone Metastases Presentation Type: Poster Institute of Cancer Research, London, United Kingdom Background/Introduction: Clinically, HIFU exposures of bone are used to palliate pain from primary or secondary bone tumours. Such tumours weaken bone structure and render the patient susceptible to bone fracture. Ultrasound metrology for bone exposures is extremely challenging. The ultrasound beam is strongly refl ected at the bone surface, with rapid surface absorption of sound entering the cortex. Pain relief is obtained when the HIFU induced temperature increase ablates the peri-osteal nerves. Standard PRF based MR thermometry, used for treatment monitoring, is inappropriate for bone. Thus, a method of determining the temperature distribution in a clinical environment is needed. Methods: An instrumented bone phantom which will allow HIFU exposure levels to be quantifi ed, is being developed to address the problems described above. This phantom will initially be characterised in terms of its thermal, acoustic, and MR properties. Probes which allow simultaneous temperature and pressure measurements are being incorporated into the phantom. These will allow real-time mapping of these parameters under clinically realistic conditions. Access to the “research platform” on the ICR’s Sonalleve system will allow control of FUS exposure conditions, in this clinically relevant setting. The phantom composition is determined by subjecting fresh bone, and potential bone mimicking samples (with adjacent ex vivo soft tissue or soft tissue mimics) to varying levels of ultrasound exposures. Measurements of acoustic pressure and temperature at bone surfaces are compared to allow identifi cation of the best bone mimic. The differences between wet and dry bone, in acoustic and thermal terms, are to be determined in order to gauge the viability of using animal bone as the mimic material. Soft tissues alone will be subjected to similar exposures in an effort to understand the effect of bone on the acoustic fi eld in terms of delivered treatment. Simulated acoustic fi eld and temperature distributions will be compared with those determined experimentally. The most appropriate phantom geometry (in terms of the dimensions of bone and overlying tissue paths) is being determined from patient CT scans. If deemed necessary, different geometries, representative of different anatomical sites will be used. Compromises must be made in order to determine the temperature distribution throughout the bone phantom accurately, whilst not changing its structural integrity signifi cantly. Techniques such as infrared imaging and the use of thermochromatic crystals are being employed to provide surface temperature measurements. Optical fi bre probes are being used for more invasive measurements. These are safe in an MR environment, avoid the problems associated with metallic thermocouples and can be used to simultaneously measure temperature and acoustic pressure. The effects of ultrasound exposure of simple fresh ex vivo tissues or 3D cell containing gel matrices, will be compared with samples that contain bone and/or bone phantom, using simulation, pathological and thermometric studies. Results and Conclusions: An instrumented bone phantom will be developed. This will provide a valuable tool for assisting in planning of bone treatments, and it is hoped that this will help to accelerate their increased clinical availability. Acknowledgements (Funding): JB is funded on the Focused Ultrasound Foundation’s global intern scheme. IR and GRtH are partially funded by the FUSF’s ICR Centre of Excellence.

Focused Ultrasound 2014 4th International Symposium 123 P-101-BM Primary Treatment of Painful Bone Metastases using Magnetic Resonance Tuesday guided Focused Ultrasound – Initial Clinical Experience in Taiwan 14 October 2014 Hsin-Lun Lee1, Jeng-Fong Chiou1, Jo-Ting Tsai1, Chia-Chun Kuo1, Shiu-Chen Jeng1, Topic: Bone Metastases Gong-Yau Lan1, Cheng-Yu Chen2 Presentation Type: Poster 1 Taipei Medical University, Taipei, Taiwan 2 Chang Gung Memorial Hospital, Taipei, Taiwan

Background/Introduction: Magnetic Resonance guided Focused Ultrasound (MRgFUS) has been recently proven and was approved by the FDA as an effective method for pain palliation in patients with painful bone metastases from the US, Europe and Russia. This report describes the fi rst clinical experience in Taiwan. Methods: Between May and June 2014, 8 patients suffering from painful bone metastases were identifi ed and recruited by the radiation oncology departments of Taipei Medical University Hospital, Wan Fang Hospital and Shuang Ho Hospital in Taipei, Taiwan. All patients chose to undergo MRgFUS treatment as their fi rst choice of treatment for their painful bone lesions. Treatment was conducted using the ExAblate system (InSightec Ltd.), which integrates a focused ultrasound phased array therapeutic compartment with a magnetic resonance imaging (MRI) scanner (GE 1.5T MRI). Therapeutic ultrasound waves were targeted to the painful lesions while monitoring the accumulated heat using real-time MR images. Effi cacy of MRgFUS treatment was evaluated using the numerical rating scale (NRS), before treatment, and at 1 and 3 days; 1 and 2 weeks and at 1 month after treatment. (3 months follow-up results will be collected and reported when available). Results and Conclusions: The median age of the 8 treated patients (5 male and 3 female) was 58 years old (range, 40 – 76). Each patient underwent treatment of a single lesion. Majority of treatments were aimed at lesions located in the pelvis (5 sacro-iliac joints and one ilium), one at the femur and one at the sterno-clavicular joint. Three of the targeted lesions were osteoblastic, two osteolytic and three were mixed. None of the patients experienced any procedure related adverse events and the treatment was tolerated well by all. At day 1 post-treatment, 100% of patients reported a signifi cant reduction of pain (median 3.5 points reduction in the NRS, P<0.001) from median baseline NRS of 6 (4-8). By the fi rst month after treatment the median NRS decreased to 3 (range, 1-5, P=0.001). 25% of patients experienced complete response (pain score decreased to 0). The median length of the procedure (patient walk-in to walk-out) was 01:45 hours (01:05 to 02:20 hours), of which the median treatment time was 52 minutes (25-80). The results of these 8 primary treatments are similar to those of Hurwitz et al (2014) which were mainly obtained from radiation failures or patients who could not obtain radiation.

124 Focused Ultrasound 2014 4th International Symposium P-103-BN Use of Focused Ultrasound Guided by Magnetic Ressonance in the Tuesday Treatment of Osteoid Osteoma: Initial Experience 14 October 2014 Lucas Fiore, Marcello Rovella, Mauricio Moura, Guilherme Martins, Topic: Felipe Shoiti Urakawa, João Paulo Bernardes, Públio Viana, Bone Non-metastases Marcos Roberto de Menezes Presentation Type: Poster Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil

Background/Introduction: MRI guided High-Intensity Focused Ultrasound (MRGFUS) is a non-invasive and highly precise hyperthermia therapy that applies high-intensity focused sonic energy to locally heat and destroy diseased and damaged tissue through ablation under magnetic ressonance guindance. In this context, thermoablation of osteoid osteomas emerged as a new modality of non-invasive treatment option. The purpose of this study was to evaluate effi cacy, safety, and clinical outcomes of MR-guided HIFU thermoablation of osteoid osteomas. Methods: We selected four patients with osteoid osteoma lesion, confi rmed at CT or MR, and reduced quality of life due to the pain. MRGFUS (ExAblate 2100, InSightec, Haifa, Israel) housed into a 1,5T MR system (GE) was performed. All patients were treated on an outpatient basis, and each of them was planned with multiple sonications (8 up to 12) with power ranging 225J up to 2507J each sonication, to perform complete nidus ablation. Clinical and imaging (MRI) follow-up were performed after treatment. Results and Conclusions: We treated four lesions and after treatment, all patients referred complete disappearance of painful symptoms. There was a self-limited small focal skin burn in one patient (only complication). There were no other treatment-related complications peri and post procedure. The use of analgesics were suspended and all patients returned to their normal activities quickly, but after 1 month, one patient presented pain recurrence. In our experience, MRGFUS seems to be a non-invasive option and a promising technique in the treatment of osteoid osteoma, representing a safe and effective method for the ablation of these tumors. We believe that the sucess of the procedure is related with the nidus ablation.

Focused Ultrasound 2014 4th International Symposium 125 P-104-BN Assessing Temperature Dependence of T1 in Cortical Bone Using Ultrashort Tuesday Echo-time MRI 14 October 2014 Misung Han, Serena Scott, Eugene Ozhinsky, Vasant Salgaonkar, Peter Jones, Peder Topic: Larson, Chris Diederich, Roland Krug, Viola Rieke Bone Non-metastases Presentation Type: Poster University of California at San Francisco, San Francisco, California, United States

Background/Introduction: MR-guided high-intensity focused ultrasound (HIFU) ablation is a promising, noninvasive method for treatment of bone tumors and palliation of pain. During thermal therapy, temperature mapping is necessary to ensure proper heat deposition in targeted tumors as well as to prevent undesired heating in healthy tissues. However, conventional proton resonance frequency-based MR thermometry cannot be applied in cortical bone due to its short T2* relaxation time. Recently, it was shown that ultrashort echo- time MRI can be used to assess T1 change in cortical bone due to temperature change (Han M, ISMRM 2014, P262). This work focused on characterization of temperature dependence of T1 in cortical bone by performing a calibration experiment. Methods: A calibration experiment was conducted using cortical bone samples from diaphysis segments of bovine femurs. Two bone samples were placed in a container fi lled with circulating water controlled by a water bath. To monitor temperature, fi ber optic temperature sensors (Luxtron, LumaSense Technologies, Santa Clara, CA) were placed, with one sensor inside the water bath and one in a bone sample. Imaging was performed at a GE discovery MR750 widebore 3T scanner (GE healthcare, Milwakee, WI) using a 16-channel large fl ex coil (GE healthcare, Cleveland, OH). Cortical bone T1 was measured at temperatures of approximately 25, 35, 45, 55, 65, and 70°C during the heating phase and 55, 35, and 25°C during the cooling phase after the cortical bone samples and the water reached thermal equilibrium. For T1 mapping, 3D UTE imaging was performed by incorporating a nonselective hard pulse with a 200 μs duration followed by 3D radial imaging. The scan parameters included a 75 μs TE, 11 ms TR, and 1.7 mm isotropic resolution. To measure T1 using a variable fl ip angle scheme, UTE imaging was performed at 8° and 44° fl ip angles, resulting in a total 8 min scan time. Results and Conclusions: Our calibration results are shown in Figs 1-2. Figure 1a-b Figure 1. (a-b) Bone T1 maps at temperatures of 25.1°C and shows T1 maps at two different temperatures, 25.1°C and 70.1°C, overlaid on a UTE 70.1°C, respectively, overlaid image. Figure 2a-b shows average T1 values from regions of interest on twelve slices over on a UTE image. Regions of temperature values measured from the fi ber optic sensor. A linear relationship between interest used for analysis are temperature and T1 was observed for both bone samples. For the fi rst bone sample, the depicted. linear coeffi cient was 0.77 ms/°C during heating and 0.73 ms/°C during cooling; for the second bone sample, it was 0.73 ms/°C during heating and 0.84 ms/°C during cooling. Although the linear coeffi cients were not identical for heating and cooling, the T1-temperature plots from the two bone samples indicated reversibility in T1 variation. The variable fl ip angle method is very sensitive to B1 inhomogeneities and fl ip angle calibration errors, and thus can result in signifi cant T1 measurement errors. Still, our experiment demonstrated a linear temperature dependence of T1 in cortical bone for a temperature range of 25°C and 70°C. By improving accuracy in T1 measurement, direct quantifi cation of temperature changes in cortical bone could be possible, and thermal dose might be more accurately monitored during thermal ablation of bone tumors. Acknowledgements (Funding): The authors acknowledge our funding sources, NIH R01AR057336, NIH R00HL097030, GE healthcare, and InSightec. The authors also thank Dr. Prasheel Lillaney for helping with the use of fi ber-optic temperature sensors.

Figure 2. (a-b) T1-temperature plots for two bone samples, respectively. Linear regression lines during heating and cooling are denoted as well.

126 Focused Ultrasound 2014 4th International Symposium P-105-BN Simulating Temperature Distribution of High-intensity Focused Ultrasound Tuesday during Bone Treatments 14 October 2014 Thomas Hudson1, Thomas Looi2, Adam Waspe2, James Drake2, Samuel Pichardo3 Topic: 1 Bone Non-metastases Hospital for Sick Children, Toronto, Canada 2 Presentation Type: Poster Centre for Image Guided Innovation and Therapeutic Intervention, Toronto, Canada 3 Thunder Bay Research Institute/Lakehead University, Toronto, Canada

Background/Introduction: To help improve therapeutic results for treatment of bone tumors, high intensity focused ultrasound (HIFU) is being investigated as a non-invasive alternative to surgery and radiotherapy. HIFU ablative treatments require an imaging modality for guidance, and magnetic resonance (MR) imaging is currently the strongest choice as it is able to provide temperature mapping throughout the treatment process. Unfortunately, the temperature feedback that is critical to ensuring safety and optimal soft tissue ablation is often unobtainable in bone structures. As an alternative to obtaining feedback, this project is focused on developing a simulator that is capable of predicting the temperature distribution in and around bone tissue during HIFU therapy. Having such a simulation would provide a better understanding of the thermal dosages incurred by the bone during HIFU treatment of tumors. Methods: The simulator consists of three primary components: semi-automatic segmentation, acoustic fi eld simulation and the bio-heat transfer model. The segmentation is performed using a mesh-based method, applying Gaussian statistics to conform to the outer surface. The acoustic fi eld uses a modifi ed solution to the Rayleigh integral to track the change in complex ultrasonic velocity potential through solid and soft tissue. The velocity potentials at each voxel are then converted to form a volumetric heat distribution required by the bio-heat model. This model then computes a numerical solution to the heat transfer problem, creating a four dimensional temperature map capable of demonstrating specifi c time intervals throughout a therapeutic ultrasound procedure. The simulation has been implemented using parallel GPU architecture, capable of producing large 4D bone maps in under one minute. Results and Conclusions: Figure 1 demonstrates the fi nal bio-heat model from a 40W sonication of 30s duration. The heat appears to accumulate mostly in the cortical layer, reaching 77.2°C at its peak cortical temperature. Repeated acoustic simulations required between 18 and 22 seconds of computation time and bio-heat between 6 and 9 seconds. Previous MR thermometry data (Figure 2) of an experiment on a porcine femur yielded a maximum temperature of 73.4°C during a 40W, 20s treatment, almost four degrees lower than the simulation. Heat also appeared to spread more freely into the bone during the actual therapy. Differences in material properties are likely to account for a large part of these discrepancies, as many reported porcine properties are highly variable across the literature. The next steps of this project will be to conduct a material property study of both healthy and cancerous tissue, and to collect enough data to characterize the accuracy and validate the functionality of the model. With a fully validated prototype, this software tool will be able to start demonstrating the thermal effects of HIFU in various bone structures, and will help both physicians and scientists in understanding the full effects of this therapy for improved HIFU procedures. Acknowledgements (Funding): We acknowledge that the project is jointly funded through the Collaborative Health Research Program from the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council.

Figure 1. (left) Simulated therapy on segmented bone, 40W applied for 30 seconds. Target is close to center of bone. Figure 2. (right) Porcine experiment with the same bone, target and parameters as in previous fi gure.

Focused Ultrasound 2014 4th International Symposium 127 P-106-BN Pain Alleviation and QOL Improvement of MR-guided Focused Ultrasound Tuesday Surgery (MRgFUS) Treatment for Painful Medial Compartment of Knee 14 October 2014 Osteoarthritis

Topic: 1 1 1 1 1 Bone Non-metastases Motohiro Kawasaki , Syota Oda , Hiroshi Kondo , Masashi Izumi , Tomonari Kato , 1 2 Presentation Type: Poster Masahiko Ikeuchi , Takahiro Ushida 1 Kochi Medical School, Nankoku, Japan 2 Aichi Medical University, Nagakute, Japan

Background/Introduction: A major symptom of knee osteoarthritis (OA) in the elderly is chronic knee pain, which has a signifi cant effect on patients’ quality of life (QOL). Although total knee arthroplasty (TKA) is the validated and reliable treatment for alleviating refractory knee pain, this is often not an option for patients with poor health status or unwillingness to undergo major surgery. Therefore, alternative approaches to alleviate knee pain other than conventional treatments are necessary. Now, we are performing a prospective, non- randomized, single-arm study to evaluate the safety and effi cacy of MRgFUS using the ExAblate 2100 conformal bone system (InSightec Ltd.) in the treatment of pain resulting from medial compartment of knee osteoarthritis. Methods: The study protocol was approved by the institutional review board of Kochi Medical School. Eleven patients (3 males and 8 females with a mean age of 78 years) who had medial knee pain and tenderness resistant to other conservative treatments for more than 6 months were included. All patients had Kellgren-Lawrence grade-III or IV varus knee OA. We performed a single-session treatment for more painful unilateral knee joint in each patient. Prior to MRgFUS, patient underwent local anesthesia with 0.75% ropivacaine to the treated sites. Sonications from a transducer fi xed to the medial side of the knee were applied just around the osteophyte of medial femorotibial joint. They are then monitored at 1 week, 1, 3, 6 months and 1 year for treatment-related complications, levels of the worst knee pain in the past 24 hours using numerical rating scale (NRS) pain score, performance-based functional outcomes using Timed Up and Go (TUG) test and health-related QOL measures using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and EuroQol 5D (EQ-5D) questionnaires. MRI and CT were also evaluated after the treatment. Results and Conclusions: Responders, defi ned as a 50% or greater decrease in NRS score compared with pre-treatment, were 8 patients one month post-treatment. In three non- responders, one patient underwent TKA. NRS pain score of the treated knee signifi cantly decreased from 6.4 +/- 1.4 (mean +/- SD) before the treatment to 3.2 +/- 1.5 (p<0.002) at the fi nal follow-up visit (3.5mos: 1 - 12mos) in 10 patients other than one treated with TKA. Time to perform the TUG test was signifi cantly shorter at the fi nal visit than pre- treatment. We also observed a signifi cant improvement in the WOMAC scores (from 42.8 to 19.0: p<0.02) and EQ-5D scores (from 0.580 to 0.744: p<0.004). There were no obvious complications associated with the treatment. However, changes in MRI intensity signals on the treated sites were observed in all patients. In conclusion, MRgFUS treatment has the possibility to provide an improvement in patients’ quality of life, as well as the noninvasive pain management of osteoarthritic knees. Acknowledgements (Funding): This study was supported by a research grant from the Focused Ultrasound Foundation.

128 Focused Ultrasound 2014 4th International Symposium P-107-BR Quantitative Evaluation of Blood-tumor-barrier Response following Focused Tuesday Ultrasound and Microbubble Treatment in Rat Glioma: Can We Improve 14 October 2014 Drug Delivery to Brain Tumors? Topic: Brain Presentation Type: Poster Hassaan Ahmed Western University, London, United Kingdom

Background/Introduction: The increased interstitial fl uid pressure (IFP) from vasogenic edema, which results from a leaky blood-tumor-barrier (BTB), creates a barrier for transvascular drug delivery, particularly larger molecules that are unable to diffuse across and must resort to bulk fl uid fl ow. We have previously used dynamic contrast enhanced- computed tomography (DCE-CT) to quantitatively evaluate the blood-brain-barrier (BBB) response in normal brain - and have shown that focused ultrasound (FUS) and microbubble (MB) treatment in a rat brain demonstrates a 3-4 times transient increase at our optimized parameters. The purpose of this study was to quantitatively evaluate the BTB response following FUS and MB treatment in rat glioma, in the context of improving drug delivery to brain tumors. Methods: At 10-15 days before treatment, 1 x 106 C6 glioma cells are surgically implanted using a stereotactic frame into a region in the right cerebral hemisphere of a Wistar rat. The rats were broken into 2 groups before treatment: 1) evaluating the acute response out to 4 h post for tumor and normal hemispheres (n=3), and 2) recovery at 2 h post followed by scans at 24 and 72 h post (n=5). The tumor is transcranially sonicated at previously optimized parameters that demonstrate transient opening in the normal BBB without any vascular or tissue damage - 10 ms burst length with 1 Hz repetition frequency for 120s, with an applied power of 0.5 W, using a 0.563-MHz FUS system. 2 ul/kg of Defi nity microbubbles are injected simultaneously with the start of the sonication. Axial CT scans as well as the DCE-CT perfusion maps were used to target the tumor. DCE-CT (80 kVp, 250 mA, axial slice thickness = 1.25 mm) was performed using a two phase protocol: 1st phase consisting of continuous 0.5 s rotations for 30 s, and a 2nd phase of 0.5 s rotations at 14.5 s intervals for 150s. 2.5 ml/ kg of iodinated contrast agent was injected over 5 seconds simultaneous to the start of each DCE-CT scan. Proprietary CT Perfusion software was used to compute permeability surface area product (PS), cerebral blood fl ow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) maps using a standard small molecule contrast agent (Isovue ~ 760 Da) that is able to diffuse across the BTB. The BTB PS was also evaluated using a much larger contrast agent (eXia ~ 65,000 Da) that mimics the delivery of agents such as monoclonal antibodies. Results and Conclusions: Instead of a transient increase in BBB permeability that is seen in the normal brain, FUS and MB demonstrated a gradual decrease in BTB permeability in the hours following treatment (p < 0.05). An acute vascular shutdown, drop in CBF and CBV (p < 0.05), was also observed immediately following treatment, as previously reported in other tumor models. The drop in PS persisted at 24 h post (p < 0.05), returning at 72 h post, whereas the CBF and CBV returned back to baseline levels by 24 h post. A trend of increasing eXia penetration suggests that the decrease in BTB PS alleviates the elevated IFP that results from vasogenic edema and improves the penetration of larger drugs or molecules that are unable to diffuse across the BTB. When plotted against the MTT, which is the inverse of perfusion pressure, BTB PS (isovue) shows a moderate positive correlation (r2 = 0.71), whereas BTB PS (eXia) shows a weak negative correlation (r2 = - 0.50). Our fi ndings indicate that although FUS and MB treatment at our parameters may not necessarily be useful for increasing the delivery

Acute blood-tumor-barrier (BTB) and blood-brain-barrier (BBB) permeability surface-area product (PS) time curves following focused ultrasound (FUS) and microbubble (MB) treatment for the tumor and contralateral hemispheres (n=3) Focused Ultrasound 2014 4th International Symposium 129 of small molecule drugs, it may be more useful for increasing the delivery of larger molecules where the IFP is a barrier. Acknowledgements (Funding): Canadian Institute for Health Research, Canada Foundation for Innovation, Federal Development Canada Agency, Ontario Brain Institute

Blood-tumor-barrier (BTB) permeability surface-area product (PS) maps at baseline,1, 24, and 72 h following focused ultrasound (FUS) and microbubble (MB) treatment

Comparison of isovue (~760 Da), and eXia (~65,000 Da) blood-tumor-barrier (BTB) permeability surface-area product (PS) plotted against the mean-transit-time (MTT) as measured with the standard iodine diffusable iodine contrast (Isovue)

130 Focused Ultrasound 2014 4th International Symposium P-108-BR Simulation of Hemispherical Transducers for Transcranial HIFU Treatments Tuesday Using the Hybrid Angular Spectrum Approach 14 October 2014 Scott Almquist, Dennis Parker, Douglas Christensen Topic: Brain Presentation Type: Poster University of Utah, Salt Lake City, Utah, United States Background/Introduction: Transcranial focused ultrasound is emerging as a promising treatment modality for a variety of disorders including essential tremor and glioblastoma. However, traditional full-wave methods of simulating ultrasound pressure fi elds for these treatments, such as FDTD, are computationally intensive. The situation is exacerbated by the large area insonifi ed by the transcranial transducers, which are typically hemispherical to spread the intensity over a large area of the skull and prevent burns. The Hybrid Angular Spectrum (HAS) approach1 has been used to rapidly model ultrasonic beam propagation. Here we present a method for adapting the HAS technique to hemispherical transducers. Methods: The HAS approach assumes that the pressure pattern incident on the front face of the 3D rectangular model is defi ned on a plane nominally perpendicular to the propagation axis of the transducer. This is problematic for a hemispherical transducer that wraps around the model. To circumvent this limitation, we divide the transducer into seven sections of spatially clustered elements. For each section, the elements, along with the acoustic model, are rotated into a coordinate system with the direction of propagation away from the center of the section. The HAS method is applied using the specifi c elements of the section, then the resulting pressure pattern is rotated and interpolated back to the original coordinate frame. The fully insonifi ed fi eld is the superposition of the resulting pressure patterns from each section. The resulting fi eld can be used in temperature simulations or to verify the usefulness of phase corrections. Simulations of a 1024-element 650-kHz InSightec ExAblate transducer were carried out using this method on a selected set of retrospective clinical data. The acoustic speed of sound, density and attenuation values for the skull were derived from a CT scan with 0.43 x 0.43 x 1.0-mm resolution using a previously published Figure 1a. (top) Transverse slice 2 of simulated pressure pattern method of conversion. The simulated skull/brain model contained 512 x 512 x 195 voxels. through the skull with no phase correction employed. Skull is Results and Conclusions: The average calculation time for each of the sections, including outlined in white rotation of the model, propagation, and backwards rotation and interpolation of the pressure Figure 1b. (bottom) Zoomed-in fi eld, was under 14.5 minutes. Figure 1a shows a transverse slice at the location of peak view of focal spot for pressure pressure for one clinical case; Figure 1b shows a zoomed-in view of the focal point. Figures pattern shown in 1a. 2a-b present the same pressure fi eld using the experimentally obtained phase corrections. There is an increase of approximately 25% in peak intensity when phase correction is employed. References: 1. U. Vyas and D. Christensen, “Ultrasound beam simulations in inhomogeneous tissue geometries using the hybrid angular spectrum method,” Trans. UFFC, vol. 59, no. 6, pp. 1093–1100, 2012. 2. S. Pichardo, V. W. Sin, and K. Hynynen, “Multi-frequency characterization of the speed of sound and attenuation coeffi cient for longitudinal transmission of freshly excised human skulls,” Phys. Med. Biol., vol. 56, no. 1, p. 219, Jan. 2011. Acknowledgements (Funding): The authors thank Eyal Zadicario and Gilat Schiff of InSightec for providing data used in these simulations. This work was funded by NIH grant 5R01EB013433-03 and by the Focused Ultrasound Foundation.

Figure 2a. (left) Transverse slice of simulated pressure pattern through the skull with experimentally employed phase correction. Skull is outlined in white Figure 2b. (right) Zoomed-in view of focal spot for pressure pattern shown in 2a.

Focused Ultrasound 2014 4th International Symposium 131 P-109-BR Image Guided Focused Ultrasound: Development of a Comprehensive Tuesday Treatment Planning, Monitoring and Control, and Assessment 14 October 2014 Costas Arvanitis1, Gregory Clement2, Nathan McDannold1 Topic: Brain 1 Presentation Type: Poster Brigham & Women’s Hospital/Harvard Medical School, Boston, Massachusetts, United States 2 Cleveland Clinic, Cleveland, Ohio, United States

Background/Introduction: MRgFUS offers unambiguous advantages over other current treatment modalities, as it is noninvasive and does not use ionizing radiation. Further, ultrasonically-controlled stable and inertial microbubble oscillations exert forces that can, among others, activate cell’s mechanoreceptors, disrupt cellular and vascular membranes, accelerate the dissolution of blood clots, enhance thermal ablation, and induce localized tissue erosionetc. FUS can also be used transcranially for tumor ablation, blood-brain barrier disruption, neuromodulation, etc. Harnessing and, potentially, combining these abilities holds great promise for therapy and diagnosis of cancer and cardiovascular and central nervous system diseases and disorders. For the wide-spread use of these approaches, development of methods and technology to enable precise planning, monitoring and control, and assessment of their outcome are essential. Methods: We developed a novel noninvasive and clinically relevant framework (Fig. 1) that combines i) multimodality imaging (US/MR/CT), ii) 3D Finite Difference Time Domain (FDTD) numerical simulations, and iii) an integrated MR and US imaging FUS system for guiding FUS therapy. The proposed framework enables accurate treatment planning, via visualization of anatomic structures (MRI), extraction of their acoustic properties (CT) and simulation of US propagation (3D FDTD), which includes realistic microbubble acoustic emissions. The co-registration of CT (skull) with the MR and US datasets allowed us to model and study the microbubble emissions propagation through the skull and refi ne a standard PAM back-projection algorithm to account for spatially varying wave propagation effects, such as refraction and diffraction. The key component of our framework is the MR and US imaging guided FUS system that is used to monitor and control both the thermal and mechanical effects of FUS transcranially, here using manual and simple on-off controllers. Finally, using MR contrast agent as drug surrogate, the proposed framework is used to assess drug uptake after FUS-BBB disruption. Results and Conclusions: The incorporation of a variable speed of sound to the PAM back-projection algorithm corrected the aberrations introduced by the skull (NHP and Human). Further, more than 94% agreement in the FWHM of the axial and transverse line profi les between the simulations incorporating microbubble emissions and experimentally- determined PAMs was observed in NHP. The acoustic emissions monitoring allowed to fi ne- tune the sonication power for effi cacious FUS-BBB disruption in glioma-bearing rat, while, MR temperature imaging based FUS controller allowed to attain constant focal temperature (temperature rise: 7±1.5 0C, for 5 mins) in the brain of a healthy rat. These abilities that have not been previously shown provide a clinically relevant framework for guiding FUS in the brain. We envision that the proposed framework will be essential for developing, optimizing, and translating current and new therapeutic FUS approaches to the clinics. Acknowledgements (Funding): The authors would like to thank Dr Andriy Fedorov for his help with the software 3D Slicer and image registration. This work was supported by the NIH grants R25CA089017, P01CA174645, P41RR019703. InSightec provided the clinical TcMRgFUSsystem.

Figure 1: Image Guided FUS framework

132 Focused Ultrasound 2014 4th International Symposium P-110-BR Multiple Sessions of Liposomal Doxorubicin and Focused Ultrasound Tuesday Mediated Blood-brain Barrier Disruption: Safety Study 14 October 2014 Muna Aryal1, Natalia Vykhodtseva2, Yong-Zhi Zhang3, Nathan McDannold2 Topic: Brain 1 Presentation Type: Poster Boston College/Harvard Medical School, Boston, Massachusetts, United States 2 Brigham & Women’s Hospital/Harvard Medical School, Boston, Massachusetts, United States 3 Harvard Medical School, Boston, Massachusetts, United States

Background/Introduction: Transcranial MRI-guided focused ultrasound is a rapidly advancing fi eld for delivering therapeutic and imaging agents to the brain. It has the ability to facilitate the passage of therapeutics from the vasculature to the brain parenchyma, which is normally protected by the blood-brain barrier (BBB). Its main advantages are that it is targeted, noninvasive, and readily repeatable in nature. Studies have shown that it can deliver liposomal doxorubicin (DOX), a chemotherapy agent with promise for tumors in the central nervous system, into the brain across BBB. However, prior studies have suggested that this agent may be signifi cantly neurotoxic, even at small concentrations. Here, we studied whether multiple sessions of DOX administered after FUS-induced BBB disruption (FUS- BBBD) caused adverse events in the normal brain. First, we used fl uorometry to measure the doxorubicin concentrations in the brain after FUS-BBBD. Next, we performed three weekly sessions with FUS-BBBD ± DOX administration. Methods: FUS-BBBD was produced in one hemisphere in 18 male Sprague-Dawley rats (250-350g); the other hemisphere served as a control. Nine animals were assigned to one of two groups: (1) three weekly treatments with FUS and concurrent chemotherapy (FUS+DOX) (N=5), (2) three weekly treatments with FUS only (N = 4). Sonications (0.69 MHz; 0.55-0.81 MPa; 10 ms bursts; 1 Hz PRF; 60s duration) were performed over three weeks in a grid pattern at 5, 9, and 12 targets, respectively, following a schedule described previously in a survival study in glioma-bearing rats (Aryal et al., Journal of Control Release, 2013). Each sonication was combined with an i.v. injection of Defi nity (10μl/kg). DOX (5.67 mg/kg) was administered in fractions before each sonication. Contrast enhanced T1-weighted imaging and T2*-weighted imaging were used to confi rm BBBD and detect hemorrhage in the targeted areas, respectively. The animals’ health was monitored regularly, and MRI was obtained to evaluate treatment effects. Seven weeks after the last treatment, animals were sacrifi ced, and the brains were sectioned and stained for histological analysis. To confi rm that we were delivering DOX liposomes across the BBB, nine additional animals were sacrifi ced four hours after sonication (0.55 MPa; nine targets in a 3×3 grid) and DOX concentrations were measured in both hemispheres (sonicated and non-sonicated) using fl uorometry. Results and Conclusions: We found that clinically-relevant concentrations of doxorubicin (4.8±0.5 μg/g) were delivered to the brain with the sonications parameters, microbubble concentration (Defi nity, 10 μl/kg), and the administered DOX dose used. We also noted that the resulting concentration was reduced by 38% when the agent was injected 10 minute after the last sonication. In histology, focal planes were unaffected in rats who received FUS- BBBD but not DOX. The brain of one rat who received FUS-BBBD and DOX appeared unaffected at focal plane. Three others had small scars and one had a small infarct. Overall this work demonstrates that ultrasound can deliver clinically-relevant concentrations of DOX across the BBB, particularly when administered before the FUS exposures. The results indicate that while delivery of DOX to the rat brain can result in minor damage, the severe neurotoxicity seen in earlier work does not appear to occur with delivery via FUS-BBB disruption. Acknowledgements (Funding): This work was supported by NIH grants P01CA174645 and R01EB003268.

Focused Ultrasound 2014 4th International Symposium 133 P-111-BR Ultrashort Echo-Time MRI as a Substitute to CT for Skull Aberration Tuesday Correction in Transcranial Focused Ultrasound: In Vitro Comparison on 14 October 2014 Human Calvaria

Topic: Brain 1 2 2 1 Presentation Type: Poster Jean-Francois Aubry , Matt Eames , John Snell , Wilson Miller 1 University of Virginia, Charlottesville, Virginia, United States 2 Focused Ultrasound Foundation, Charlottesville, Virginia, United States

Background/Introduction: Clinical transcranial MR-guided focused ultrasound (TcMRgFUS) brain treatment systems compensate for skull-induced beam aberrations by adjusting the phase and amplitude of individual ultrasound transducer elements. These corrections are currently calculated based on a pre-acquired CT scan of the patient’s head. The purpose of the work presented here is to demonstrate the feasibility of using ultrashort echo-time (UTE) MRI instead of CT to calculate and apply aberration corrections on a clinical TcMRgFUS system. Methods: Phantom experiments were performed in three ex vivo human skulls fi lled with tissue mimicking hydrogel. Each skull phantom was imaged with both CT and UTE MRI. The MR images were then segmented into “skull” and “not-skull” pixels using a computationally effi cient, threshold-based algorithm, and the resulting three-dimensional binary skull map was converted into a series of two-dimensional virtual CT images. Each skull was mounted in the head transducer of a clinical TcMRgFUS system (ExAblate Neuro, Insightec, Israel), and transcranial sonications were performed using a power setting of approximately 750 Acoustic Watts at several different target locations within the electronic steering range of the transducer. Each target location was sonicated three times: once using aberration corrections calculated from the actual CT scan, once using corrections calculated from the MRI-derived virtual CT scan, and once without applying any aberration correction. MR thermometry was performed in conjunction with each 10-second sonication, and the highest single-pixel temperature rise and surrounding-pixel mean were recorded for each sonication. Results and Conclusions: Fig. 1 shows a UTE MR image and segmentation results from one of the skull phantoms. Fig. 2 shows a photograph of another skull phantom along with a 3D surface rendering generated from the binary bone map. The sonication results are summarized in Fig. 3. The measured temperature rises were ~45% larger for aberration- corrected sonications than for non-corrected sonications. This improvement was highly signifi cant (p < 10−4). The difference between the single-pixel peak temperature rise and the surrounding pixel mean, which refl ects the sharpness of the thermal focus, was also signifi cantly larger for aberration-corrected sonications. There was no signifi cant difference between the sonication results achieved using CT-based and MR-based aberration correction. Acknowledgements (Funding): Jean- Francois Aubry is a consultant for the Focused Ultrasound Foundation.

Figure 1. Representative UTE MR image and segmentation results from skull #3. For imaging, the skull was immersed in a bucket of water. The segmentation algorithm assigned each image voxel to one of three classes: (1) air, (2) water/gelatin, (3) bone.

Figure 2. (left) Photograph of one of the skull phantoms (#2), and a 3D surface rendering generated from the MR-derived bone map. Figure 3. (right) Graphical summary of sonication results. Each bar represents the average temperature rise of all sonications performed in all skulls using the same aberration correction method (none, CT- based, or MR-based).

134 Focused Ultrasound 2014 4th International Symposium P-112-BR Acoustic Characterization of Low Intensity Focused Ultrasound System Tuesday through Skull 14 October 2014 Meghedi Babakhanian, Bryan Nowroozi, George Saddik, Ashkan Maccabi, Topic: Brain Neha Bajwa, Warren Grundfest Presentation Type: Poster University of California at Los Angeles, Los Angeles, California, United States

Background/Introduction: Low Intensity Focused Ultrasound (LIFU) continues to gain traction in the fi eld of non-invasive neuromodulation. Recent in vivo rat studies suggest that LIFU can be used to modulate region-specifi c brain activity in the motor cortex, leading investigators to conclude that LIFU may be a better alternative to more prominent, and more invasive, mechanisms of neuromodulation for conditions such as Parkinson’s disease, Epilepsy, and applications such as drug delivery applications. Despite these recent successes, a comprehensive understanding of beam patterns within the skull remains elusive. Methods: LIFU neuromodulation requires precise targeting within the brain. The skull deforms the beam and makes the localization and precise energy deposition diffi cult to determine in both animal models and humans. We hypothesize that a better understanding of beam deformation will improve our ability to compensate for the effects of the skull, thereby enhancing targeting during focused ultrasound mediated neuromodulation. Results and Conclusions: In preparation for in vivo LIFU effi cacy studies, we examined beam deformation in rat skulls, 2.8mm inferior from the bregma. We obtained beam patterns using a precision acoustic measurement tank (AIMS, Sonora/Unisyn), Olympus focused V301-SU transducer, and a precision hydrophone, targeting different regions of the brain. Specifi cally, we investigated intensity attenuation, beam shape modulation, focal accuracy, and reverberation within the skull. Preliminary data from ten rat skulls reveal that beam intensity, beam shape, and targeting are all signifi cantly affected during transcranial sonication, and that changes in these parameters must be taken into account to accurately target specifi c neuronal structures. This suite of studies will enhance our understanding of beam targeting, accuracy and precession in vivo. In addition, insights gleaned from this approach are expected to promote new avenues of clinical applications for the treatment of drug delivery, gene therapy and neurological illnesses.

Focused Ultrasound 2014 4th International Symposium 135 P-113-BR Acoustic Characterization of a Neonate Skull using a Clinical MR-guided Tuesday High Intensity Focused Ultrasound System for Pediatric Neurological 14 October 2014 Disorder Treatment Planning

Topic: Brain 1 1 2 1 Presentation Type: Poster Elodie Constanciel Colas , Adam Waspe , Charles Mougenot , Thomas Looi , Samuel Pichardo3, James Drake1 1 Centre for Image Guided Innovation and Therapeutic Intervention, Toronto, Canada 2 Philips Healthcare Canada, Toronto, Canada 3 Thunder Bay Regional Research Institute, Thunder Bay, Canada

Background/Introduction: Transcranial MR-guided Focused Ultrasound (TcMRgFUS) treatments are now clinically performed on adult patients for brain tumor or essential tremor therapies. However, no application has been proposed for children despite their thinner skull being less of an acoustic barrier and the presence of a fontanelle on neonates, which could constitute a natural acoustic window for the transmission of ultrasound waves. As there is minimal literature data on the attenuation and speed-of-sound of the skull in neonatal patients, the aim of this study was to perform the acoustic characterization of a neonate skull. Methods: A 0.2 mm needle acoustic hydrophone was placed in a tank of degassed water and aligned to the geometric focus of a clinical HIFU transducer (Philips Sonalleve). The signals of the 256 elements of the phased array transducer were acquired as a baseline measurement using this hydrophone. A degased cadaveric neonate skull was then placed inside the tank between the hydrophone and the transducer. Acquisitions were performed for different angular orientations of the skull according to the sagittal and coronal axes in the range of ± 15°. Insertion losses (IL) and time-of-fl ight (TOF) delays due to the skull and the fontanelle were deducted from these measurements performed at 1 MHz and 1.2 MHz. Results and Conclusions: When the acoustic axis of the transducer was normal to the fontanelle, the average IL and TOF delay due to the fontanelle were respectively 0.9 ± 0.8 dB and -0.09 ± 0.02 μs at 1 MHz. At 1.2 MHz, the IL decreased at 0.5 ± 0.5 dB and the TOF delay remained the same. Rotations of the skull around the coronal axis giving access to the parietal and frontal bones, their average IL were respectively 1.6 ± 0.7 dB and 2.9 ± 1.1 dB at 1MHz and 1.2 ± 0.5 dB and 2.0 ± 0.7 dB at 1.2 MHz. Rotations of the skull around the sagittal axis allowed the measurements of the properties of the bones on the left and the right sides of the skull. The average IL of the bones on the left side was 2.0 ± 0.8 dB at 1MHz and 1.2 MHz. The average IL of the bones on the right side was 2.1 ± 0.7 dB at 1MHz and at 1.7 ± 0.4 dB at 1.2 MHz. The average TOF delay due to the skull bones was globally the same and was -0.17 ± 0.02 μs at 1 MHz and 1.2 MHz. For the two studied frequencies, low IL and TOF delay values were obtained for the fontanelle and to a lesser extent for the skull bones. Slightly higher IL were obtained at 1 MHz compared to 1.2 MHz. These results confi rm that the fontanelle can act as an acoustic window for future TcMRgFUS applications. They also emphasise the potential of this technology for neurological disorder treatments on neonate patients. Acknowledgements (Funding): We acknowledge funding provided by the Brain Canada Multi-investigator Research Initiative, and the Focused Ultrasound Foundation. In-kind technical support provided by Philips Healthcare.

Computer rendering showing the skull and hydrophone positioning relative to the HIFU transducer beam

136 Focused Ultrasound 2014 4th International Symposium P-114-BR Feasibility and Safety of MR-guided Focused Ultrasound Lesioning in the Tuesday Setting Deep Brain Stimulation 14 October 2014 Robert Dallapiazza1, Mohamad Khaled1, Matt Eames2, John Snell2, M. Beatriz Topic: Brain Lopes1, Max Wintermark1, W. Jeff Elias1 Presentation Type: Poster 1 University of Virginia, Charlottesville, Virginia, United States 2 Focused Ultrasound Foundation, Charlottesville, Virginia, United States

Background/Introduction: Patients treated with DBS often develop symptom progression. If safe, focused ultrasound lesioning could be used for patients unable to undergo further DBS surgery. The objective of these experiments is to test the feasibility and safety of MR- guided FUS surgery in the setting of previously implanted DBS system. Methods: Three preclinical experiments were designed to test feasibility and safety. Hydrogels were implanted with an electrode, and FUS lesions were targeted adjacently. Cadavers were implanted with a thalamic electrode, and FUS lesions were targeted in the contralateral thalamus. Finally, DBS systems were implanted in swine, and FUS lesioning was targeted to the contralateral thalamus, MRI was used to assess the treatments, and histological analyses were performed at 2 days and at 1 month. Results and Conclusions: In gel experiments and cadavers, FUS resulted in target heating to 29-32 °C without any heating at the electrode. In animal experiments, there were no MRI signal changes near the electrode in 3 of 4 animals. Histological analysis showed no evidence of damage surrounding the electrode tracts in 3 of 4 animals. FUS is feasible in the setting of a pre-implanted DBS device. In these experiments, there was minimal heating of the device during the procedure. Acknowledgements (Funding): Focused Ultrasound Foundation

Focused Ultrasound 2014 4th International Symposium 137 P-115-BR Behavioral Effects of Targeted Drug Delivery via Non-invasive Microbubble Tuesday Enhanced Focused Ultrasound Blood Brain Barrier Opening in Non-human 14 October 2014 Primates Topic: Brain Presentation Type: Poster Matthew Downs, Amanda Marie Buch, Maria Eleni (Marilena) Karakatsani, Carlos Sierra Sanchez, Shangshang Chen, Vincent Ferrera, Elisa Konofagou Columbia University, New York, New York, United States

Background/Introduction: The Blood Brain Barrier (BBB) in Non-Human Primates (NHP) can be non-invasively opened through the use of Focused Ultrasound (FUS) in conjunction with microbubbles. This procedure allows for a targeted, transient opening in the BBB of the NHP which can be utilized to facilitate drug delivery. While FUS has been used to deliver various pharmacological compounds to promote neurogenesis or treat cancer, no group has investigated if drug delivery can affect behavioral responses. In this study, we show the effects of targeted ME-FUS drug delivery on the responses of NHP to a decision making task. Methods: The ME-FUS procedure was conducted on three (n = 3) NHP under general anesthesia (isofl urane) and in stereotactical positioning to ensure accurate targeting. Microbubbles (4-5 um, in-house prepared) were administered IV at the onset of applying the FUS (Single element transducer, 500 kHz, 0.3-0.4 Mpa, 10 ms pulse length, 120 second duration). The putamen region of the basal ganglia was targeted for all behavioral experiments. After the ME-FUS procedure there was a three hour recovery period allowing the NHP to fully recover normal motor functions impaired from the general anesthesia. IM injections of haloperidol (D2 antagonist, 0.01mg/kg) in the awake monkey were administered fi ve minutes prior to the start of behavioral testing. The NHPs were trained to complete a reward magnitude bias and dot direction coherence task for water reward. One day after the ME-FUS procedure BBB opening and safety of the procedure was verifi ed with contrast enhanced T1-weighted and T2- weighted MRI scans respectively. Results and Conclusions: The BBB was successfully opened in the putamen region of each NHP for all ME-FUS procedures. No damage from the ME-FUS procedure was detected with the T2-weighted MRI scans. Delivery of haloperidol after BBB opening was shown to nullify a signifi cant difference of reaction time between the contralateral and ipsilateral hands to the ME-FUS procedure observed with the saline controls. This signifi cant difference in reaction time between hands was observed when haloperidol was administered without BBB opening. Delivery of haloperidol after BBB opening also negated a signifi cant difference in reaction time between the high and low reward cues observed with the saline controls. Overall preliminary results show that FUS-induced BBB opening in NHP can be used to facilitate delivery of D2 antagonists to the putamen region causing signifi cant effects on motivation and reaction time. Acknowledgements (Funding): This study was funded in part by the Focused Ultrasound Foundation, NIH R01AG038961, NIH R01EB009041, the Coulter Foundation, the Kavli Foundation, and the Alfonso Martin Escudero Foundation (CSS).

138 Focused Ultrasound 2014 4th International Symposium P-117-BR Spiral-based 3D MR Thermometry Tuesday Samuel Fielden1, Li Zhao1, Wilson Miller1, Xue Feng1, Max Wintermark1, Kim Butts 14 October 2014 Pauly2, Craig Meyer1 Topic: Brain 1 University of Virginia, Charlottesville, Virginia, United States Presentation Type: Poster 2 Stanford University, Stanford, California, United States

Background/Introduction: Real time MR thermometry, usually based on the proton- resonance frequency shift, is a key aspect of MR-guided focused ultrasound procedures. The desire to monitor the entire sonicated volume has led the fi eld towards the development of rapid, 3D methods; however, acquiring fully sampled 3D volumetric data to monitor heating is time consuming, and so fast methods must be developed in order to meet the spatial and temporal requirements for adequate monitoring of thermal therapy. The data acquisition effi ciency of spiral trajectories is higher than that of Cartesian scanning. Therefore, spiral trajectories are an attractive way to improve temporal resolution while maintaining spatial resolution in MR thermometry. We have recently reported that a variation on the traditional spiral-out trajectory, called the redundant spiral-in/out trajectory, has certain advantages in terms of off-resonance performance. We hypothesize this trajectory to also be advantageous for PRF thermometry. Here, we have implemented this –in/out trajectory, compared its performance in terms of the focal spot size and position shift versus a Cartesian and spiral-out acquisition, and have generated rapid 3D temperature maps using the method. Methods: All experiments were performed in a gel phantom, using an MR-compatible FUS system (RK-100, FUS Instruments Inc., Toronto) in a 3T whole-body scanner (Siemens Trio). 2D temperature maps were acquired with a GRE sequence with TR/TE = 15/6 ms, FA = 25-degrees, FOV = 64 mm2, matrix size 64 x 64. Spiral readout length was 1 ms. Spatial/temporal resolution for Cartesian imaging was 1x1x3 mm3/960 ms vs. 1x1x3 Figure 1. (top) Focal spot mm3/720 ms for spiral imaging. The size and relative shift of the ultrasound hot spot was shift measured between measured for all acquisitions. For spiral 3D acquisitions, rapid imaging was achieved by a scans with switched readout 3D interleaved stack-of-spirals spoiled GRE sequence. All 3D phase encoding partitions per / phase encoding directions. Low bandwidths are used volume were collected, for a total acquisition time per volume of 4.1 seconds. The redundant to improve SNR in Cartesian –in/out method requires 2X averaging, yielding a temporal footprint of 8.2 seconds per imaging and in fast EPI volume, reconstructed in a sliding window fashion. Sixteen 3D slices were acquired; all other methods, but result in greater MRI parameters were identical to the 2D experiments. shifts. Figure 2. (bottom) Full width Results and Conclusions: Figure 1 shows that, using spiral readouts, temperature-induced at half maximum (FWHM) phase does not cause a position shift of the ultrasound focal spot. In Figure 2, we show measurements of focal spot size that the hot spot is better resolved when using the redundant in/out method, compared to at maximum temperature time spiral-out. Figure 3 shows time-temperature plots of the hot spot, indicating the measured point. Spiral-in/out recovers the slight blurring observed in temperature using the spiral methods is accurate. Figure 4 shows 3D temperature maps the spiral-out images. obtained using the spiral-based methods. In conclusion, the effi ciency of spiral readouts supports rapid generation of 3D temperature maps, with no shift of the focal spot. The reconstruction can easily be performed in real-time, with little concern for computational burden that exists for constrained methods. Acknowledgements (Funding): Focused Ultrasound Foundation; Siemens Medical Solutions.

Figure 4. 3D temperature map of phantom calculated from spiral-out data (top) and spiral- Figure 3. Measured temperature in/out data (bottom). The FUS focal spot is an at ultrasound focal position for ellipsoid with Cartesian, spiral-out, and spiral-in/ the long-axis out acquisitions. oriented in the through-plane direction.

Focused Ultrasound 2014 4th International Symposium 139 P-118-BR Improved k-Space-Based MR Thermometry by Joint PRF Phase Shift and T1/ Tuesday T2* Attenuation Estimation 14 October 2014 Pooja Gaur, William Grissom Topic: Brain Presentation Type: Poster Vanderbilt University, Nashville, Tennessee, United States Background/Introduction: MR temperature mapping based on the proton resonance frequency (PRF) shift is used in MR-guided focused ultrasound procedures for dosimetry and safety monitoring. While conventional PRF-shift thermometry is based on calculating a phase difference between two reconstructed MR images, Gaur et al1,2 have recently described two algorithms that estimate temperature-induced phase shifts directly from MR k-space data, prior to image reconstruction. The approach enables large dynamic scan acceleration factors1 and the correction of chemical-shift (CS) effects that geometrically distort the temperature maps.2 However, that work neglected image attenuation that accompanies the PRF phase shift and is primarily caused by increasing T1 with temperature.3 Here it is shown that attenuation degrades the accuracy of k-space-based reconstructions, but that it can be accounted for in the reconstructions. Methods: Simulations and experiments were performed using gradient-recalled echo scans at 3 Tesla (Philips Achieva with Sonalleve HIFU) with 16 ms echo time and 44 Hz bandwidth. A phantom was simulated with Gaussian-shaped hot spots ranging from 0 to pi and exponential attenuation factors ranging from 0 to 0.8. A tissue-mimicking gel phantom was imaged and sonicated for 41 s with a 4 mm diameter treatment cell at 110 W and 1.2 MHz. Temperature maps were reconstructed using image-domain hybrid,4 CS-compensated,2 and proposed joint Figure 1. Simulation results. attenuation- and CS-compensated approaches. The latter reconstructions were implemented (a) Magnitude images with attenuation factors as a refi nement stage after a hybrid reconstruction. Gradient descent was used to iteratively (alpha) and phase image. update the temperature phase shift and exponential attenuation maps to minimize the error (b) Comparison of true and between the measured k-space data and the treatment k-space signal model. reconstructed temperature maps using the three Results and Conclusions: Figure 1 shows the simulation results, which demonstrate that algorithms. (c) Root-mean- temperature reconstructions that do not account for image magnitude attenuation only square-error (RMSE) over partially correct chemical shift-induced geometric distortions. Figure 2 shows the phantom the hot spot at 3 attenuation factors. experiment results, in which chemical shift distortions are more completely corrected when image magnitude attenuation is accounted for, and that the small reduction of error in the temperature map for each dynamic translates into a large difference in cumulative thermal dose. These results demonstrate that accounting for image magnitude attenuations improves k-space-based temperature map reconstructions, and that it is possible to jointly estimate PRF-shift temperature maps and accompanying image magnitude attenuations using an extended k-space-based temperature reconstruction algorithm. References: 1. P. Gaur et al. Magn Reson Med, 2014, In Press. 2. P. Gaur et al. Proc 22nd ISMRM, p. 2362, 2014. 3. V. Rieke et al. J Magn Reson Imag, 27(2):376–390, 2008. 4. W. Grissom et al. Med Phys, 37(9):5014–5026, 2010. Acknowledgements (Funding): This work was supported by the Focused Ultrasound Foundation, the HHMI/VUMC Certifi cate Program in Molecular Medicine, NIH R25CA136440, and DoD W81XWH-12-BCRP-IDEA

Figure 2. Phantom experiment results. (a) Magnitude image shows signal attenuation caused by heating. (b) Temperature reconstructions, and estimate of attenuation component. (c) Temperature profi les across the hot spot. (d) Thermal dose estimates.

140 Focused Ultrasound 2014 4th International Symposium P-119-BR Mouse Positioning Device for Blood Brain Barrier FUS Exposure Tuesday Shawn Gong, Bruno Adamczyk, Cleiton Dos Santos, Thiabault Estrade, Laura Curiel 14 October 2014 Thunder Bay Regional Research Institute, Thunder Bay, Canada Topic: Brain Presentation Type: Poster Background/Introduction: Gaucher’s disease is an inherited metabolic disorder that results in a defi ciency of the enzyme glucocerebrosidase, which acts on the glycolipid glucocerebroside. This causes a rapid accumulation of glucocerebroside in affected persons, which manifests in organ malfunctions and disfi guration, swelling, and severe neurologic complications, among other symptoms. Enzyme replacement therapy can manage the symptoms but when the brain is affected, the treatment is not effective since the enzymes cannot cross the blood brain barrier (BBB). Imaging of enzyme replacement therapy has shown that only insignifi cant amounts reach the brain.1 In this work, we intend to evaluate brain uptake of enzyme replacement after BBB opening mediated by focused ultrasound (FUS) to validate this delivery technique for the treatment of neurologic complications caused by Gaucher’s disease. Our goal is to develop a system for Blood Brain Barrier delivery that can be followed up using positron emission tomography (PET) imaging. It will then be used to create and validate the delivery after intravenous injection of radiolabelled enzymes. Methods: A stereotactic animal setting for mice was designed using SolidWorks to allow for repetitive FUS exposures of the brain, and was formed with ABS plastic using a MakerBot Replicator 3-D printer. The device was designed for dual MRI and PET imaging after exposures. A waterproof RF coil was attached and formed into the positioner to provide MR images. The device can deliver gas anesthesia and allows for the animal to receive FUS exposures in a repetitive manner. The device has an integrated simple immobilizing system for test mice that allows for experiments to be done at the same location (Figure 1). The system was tested by placing multiple mice one at a time, as well as repositioning the same animal by different operators, and comparing the images produced by the MRI. Images were performed and the deviation of anatomical markers between different experiments was measured. The ability of the positioning system to target the FUS transducer at the same location by the use of the device was measured as well on MR images. Results and Conclusions: The device was able to hold the test subject in the desired position (Figure 2), and was able to ensure that the water level of the positioning table did Figure 1. The physical not rise above the head of the test subjects thanks to markers in the device. MR images of appearance of the stereotactic system holding the device with a test mouse are shown in Figure 3. These images were performed using the a test mouse coil embedded into the device and allowed for precise targeting by localizing both the FUS transducer and the brain in a repetitive and reproducible fashion. The results indicate that the system is able to hold a mouse in a repetitive position, regardless of the operator. Thus, allowing for much faster focused ultrasound tests that can be seaminglessly followed by PET scans. The ultimate goal will be to perform FUS exposures at a fi xed target location, without using the MRI for guidance. We will be then able to perform a PET scan immediately after FUS exposure and validate the delivery of enzymes through the BBB. 1. Phenix, Christopher P., et al. “Imaging of enzyme replacement therapy using PET.” Proceedings of the National Academy of Sciences 107.24 (2010): 10842-10847. Acknowledgements (Funding): Our group would like to thank the Focused Ultrasound Foundation and the Thunder Bay Regional Research Institute for providing funding for our research.

Figure 4. MR images showing the transducer used during Figure 2. The animal setting Figure 3. MR images of the brains of two trials that holds the test mouse in separate mice held using the stereotactic system. the desired position As shown the brains are at the same locations

Focused Ultrasound 2014 4th International Symposium 141 P-120-BR T1-weighted MRI as a Substitute to CT for Skull Aberration Correction Tuesday in Transcranial Focused Ultrasound: In Vivo Feasibility and In Vitro 14 October 2014 Comparison on Human Calvaria

Topic: Brain 1 1 2 2 2 Presentation Type: Poster Apoorva Iyer , Olivia Hatch , Nicholas Tustison , James Patrie , Wenjun Xin , Matt Eames1, Suna Sumer2, Benison Lau2, Alan Cupino2, John Snell1, Arik Hananel1, Neal Kassell1, Jean-Francois Aubry1, Max Wintermark2 1 Focused Ultrasound Foundation, Charlottesville, Virginia, United States 2 University of Virginia, Charlottesville, Virginia, United States

Background/Introduction: CT scans have been used to refocus ultrasound for clinical transcranial MRI-guided focused ultrasound (TcMRgFUS). The refocusing of the ultrasound arrays is a crucial step in TcMRgFUS therapy because skulls distort sound beams due to the ununiformed shape and composition of the bone. CT scan based algorithms have been developed to estimate the phase shifts induced by the bone. The corresponding phase conjugated signals are then emitted by ultrasound arrays to be refocused on brain targets through the skull. However, CT scans elongate the TcMRgFUS treatment process and expose patients to ionizing radiation. This study tested three different MRI pulse sequences (T1, T2, and proton density) against CT to determine if MRI data could be a viable alternative to CT for planning ultrasound refocusing in TcMRgFUS. Methods: Ten adult patients who had CT scans showing an intact skull and were scheduled for an MRI of the brain were enrolled in this study and had three MR scans: 3DT weighted 3D volume interpolated breath hold examination (VIBE), proton density weighted 3D Sampling Perfection with Application Optimized Contrast using different fl ip angle Evolutions (SPACE), and 3D true Fast Imaging with Steady State Precession T2-weighted imaging (FISP). Template masks were created from the MRI data and Bayesian segmentation was then applied to calculate total skull thickness and individual thicknesses of the three skull layers (inner table, diploe and outer table). The virtual average CT density was derived from the average MRI intensity. A fi rst training-dataset was compiled to create regression predictions which were then applied to a second validation-dataset. The discrepancy in measurements of total skull thickness between the MRI modalities and the CT modalities was examined and the optimal MRI sequence was identifi ed. Phase shifts were calculated by importing standard and virtual CT data into the ExAblate© Neuro system operated at 720kHz and formatting the virtual CT data header to mimic real CT data. As further validation, a phantom study was performed, in which a degassed human skull was embedded in a mannequin head and fi lled with tissue-like hydrogel. The standard and virtual CT data were imported into the software and phase correction was used to sonicate and induce a thermal rise at the desired focal point in the phantom. Results and Conclusions: The T1 sequence gave values closest to those of the CT reference for total skull thickness (mean discrepancy = 0.025 + 0.112, p = 0.825). T1 MRI sequence was found to systematically overestimate CT skull thickness for thicker skulls and underestimate for thinner skulls. The accuracy of the predictions of CT inner, middle, and outer skull layers ranged from 0.42 to 0.57 mm. For the phantom data set, the mean absolute difference between the standard CT and MRI derived CT was 0.8 + 0.6 rad with mean 7 + 4% drop in temperature elevation. These results indicate that MRI based phase correction in TcMRgFUS is a viable alternative to CT based refocusing. Acknowledgements (Funding): This clinical study was funded through a grant from Focused Ultrasound Foundation.

142 Focused Ultrasound 2014 4th International Symposium P-121-BR Incidence Angle and Gray-to-White-Matter Ratio Dependence of the Tuesday Focused-Ultrasound Induced Blood-Brain Barrier Opening in Non-human 14 October 2014 Primates Topic: Brain Presentation Type: Poster Maria Eleni (Marilena) Karakatsani, Gesthimani Samiotaki, Matthew Downs, Elisa Konofagou Columbia University, New York, New York, United States

Background/Introduction: FUS coupled with the systemic administration of microbubbles has been proved to open the Blood-Brain Barrier (BBB) locally, transiently and non-invasively in non-human primates (NHP). However, the complexity of the NHP brain constitutes an obstacle in relating the volume size of the induced opening (VBBB) to the geometric aspects of the method as well as the physiologic characteristics of the targeted areas. The objective of the current study is to quantify the correlation between the VBBB, the FUS pressure and the incidence angle. Additionally, the dependence of the opening shift on the gray-to-white-matter ratio at the targeted area is studied. Methods: Five (n=5) NHP, i.e., four macaques of the mulatta and one fascicularis, were sonicated in two brain structures, the caudate (Cau) and putamen (Pu) using FUS (F0: 500kHz; PRF: 2Hz; duration 120s; PNP 300-600 kPa) while being intravenously administered with monodisperse (4-5 micron in diameter) microbubbles. The NHPs were scanned in a 3T MR scanner (Philips, USA) acquiring 3D T1 weighted (T1w) pre- and post-contrast images approximately 24 hours after BBB opening to allow for behavioral assessment in a separate study. The estimation of the incidence angle and the center of the targeted area was were by projecting the ultrasound beam propagation and the focal region onto the BBB opening site detected on post-contrast T1w images. To estimate the shift, an automated intensity-based algorithm was designed that identifi ed the centroid of the actual opening and the VBBB. Finally, the opening was overlayed onto the brain region on a thresholded T1w image (fi gure) to quantify the percentage of gray matter (GM) and white matter (WM) affected from FUS. Results and Conclusions: VBBB increased from 106.79±50 mm3 to 305.7±50 mm3 at an incidence angle range of 73.67 ± 0.19° to 89.83 ± 0.19° at 300kPa, respectively. Similar increase was obtained at other pressures suggesting a linear correlation between the three aforementioned components. The squared correlation coeffi cient (R2) varied from 0.71 to 0.97 when studying each NHP separately. The opening in the GM accounted for an average of 88.5±8.9% of the opening cases when targeting the Pu, while 78.3±6.6% occurred in the GM when focusing on the Cau. In conclusion, the VBBB was found to strongly depend on both the incidence angle and the pressure applied. It was also concluded that the shift in the BBB opening region from the targeted one depends on the gray-to-white-matter ratio present in the focal region. Acknowledgements (Funding): The authors would like to thank Shih Ying Wu, Carlos Sierra Sanchez and Amanda Marie Buch for their contribution. This study was supported by the National Institutes of Health (AG038961 and EB009041), the Focused Ultrasound Foundation and the W.H. Coulter Foundation.

Overlay of the BBB opening onto a thresholded T1w image.

Focused Ultrasound 2014 4th International Symposium 143 P-122-BR Different MRI Pattern in Patients with ET or OCD after MRgFUS Tuesday Young Goo Kim 14 October 2014 Yonsei University Health System, Seoul, Republic of Korea Topic: Brain Presentation Type: Poster Background/Introduction: We report different magnetic resonance imaging (MRI) patterns in patients with essential tremor (ET) or obsessive-compulsive disorder (OCD) after transcranial MR-guided focused ultrasound (MRgFUS) and discuss possible causes of occasional MRgFUS failure. Methods: Between March 2012 and August 2013, MRgFUS was used to perform unilateral thalamotomy or bilateral anterior limb capsulotomy for 11 ET and 6 OCD patients who were drug refractory. Sequential MR images were obtained from patients across a six-month follow-up period. Results and Conclusions: Results. For OCD patients, lesion size slowly increased and reached a peak one week after treatment, after which lesion size gradually decreased. For ET patients, lesions were visible immediately after treatment and markedly reduced in size as time passed. In three ET and one OCD patient, there was no or little (i.e., less than 52°C) temperature rise during MRgFUS. Successful and failed patient groups showed differences in their ratio of cortical-to-bone marrow thickness (i.e., skull density). Conclusions: We found different MRI evolution after MRgFUS for white matter and gray matter. Our results suggest that skull characteristics, such as low skull density, should be evaluated prior to MRgFUS to successfully achieve thermal rise. Acknowledgements (Funding): This study was supported by a research grant from InSightec, Ltd. (Haifa, Israel) for clinical trial using the transcranial MRgFUS. InSightec was the regulatory sponsor of this study, and provided technical assistance. This research received no specifi c grant from any funding agency in the public, commercial or not-for-profi t sectors.

144 Focused Ultrasound 2014 4th International Symposium P-123-BR Blood-brain Barrier Opening-based Local Delivery of 80 nm-sized Tuesday Liposomes in Mice Using Pulsed Focused Ultrasound 14 October 2014 Zsofi a Kovacs1, Paola Luciani2, Patrick Roth3, Jean-Christophe Leroux2, Ernst Martin4, Topic: Brain Beat Werner4 Presentation Type: Poster 1 National Institutes of Health, Bethesda, Maryland, United States 2 ETH Zurich, Zurich, Switzerland 3 University Hospital Zurich, Zurich, Switzerland 4 University Children’s Hospital, Zurich, Switzerland

Background/Introduction: Continuous focused ultrasound (FUS) has been mostly used to generate high temperatures necessary for tissue ablation. Pulsed FUS in combination with intravenously injected microbubbles has been shown to open the blood-brain barrier (BBB) to increase plasma-to-tissue permeability, thus presenting a new opportunity for local drug delivery to the targeted part of the brain. We have previously demonstrated a local delivery of doxorubicin to mouse brain tumor tissues by transient BBB opening.1 However, the next generation of therapeutics is associated with a broader range of clinically meaningful applications. Liposomes are particularly interesting since drug and contrast agent can be combined in a single safe and biodegradable system with a sustained release of content. Therefore, we investigated the brain delivery of fl uorescently labeled liposomes by FUS- mediated BBB opening in healthy mice. Methods: The 80 nm-sized vesicles were either labeled with cholesteryl 4,4-difl uoro-5,7- dimethyl-4-bora-3a,4a-diaza-s-indacene-3-dodecanoate (chol-BODIPY®) incorporated into the lipid bilayer or both with BODIPY® and an additional dye, whose crosstalking with BODIPY® was ruled out (IRDye® 680LT and ROX™) and was conjugated to the liposome surface. The systemically injected liposomes (100 μL) were washed out of the bloodstream 2 h after sonication. FUS was created by a single-element, spherical FUS transducer (center frequency: 612.5 kHz; focal depth: 50 mm; active diameter: 64 mm; model: H-107_MR, Sonic Concepts, Bothell, WA). All FUS sonications started 30 s after the injection of 60 μL lipid-coated gas microbubbles via the tail vein in B6 (Cg)-Tyrc-2J/J mice (n=8). Results and Conclusions: Selective and effi cient delivery of long-circulating fl uorescent liposomes could be achieved by optimal acoustic parameters: 612.5 kHz, 0.4 MPa for a 4 min duration in bursts of 10 ms length at 1 Hz repetition time. In the case of dually- labeled liposomes the IRDye® 680LT and ROX™ showed co-localized extravasation pattern with BODIPY® on the mouse brain sections (Figure 1), which indicates intact liposomes at the sonication site. This demonstration of liposome delivery across the BBB via FUS has opened new scenarios to deliver relevant therapeutics up to 80 nm in size to the brain. Furthermore, it may represent the basis for other therapeutic directions involving pulsed or continuous FUS sonications. Reference: 1. Kovacs, Z., B. Werner, A. Rassi, J. O. Sass, E. Martin-Fiori and M. Bernasconi (2014). “Prolonged survival upon ultrasound-enhanced doxorubicin delivery in two syngenic glioblastoma mouse models.” J Control Release 187: 74-82. Acknowledgements (Funding): Funded by CoMe and Sinergia.

Figure 1. Stereomicroscopy images of horizontal mouse brain section showing identical extravasation of BODIPY® and IRDye® 680LT as well as BODIPY® and ROX™ at the sonication site. Focused Ultrasound 2014 4th International Symposium 145 P-124-BR Relation of Cooling Rate with Perfusion and Tissue Ablation Tuesday Daniela Lee1, Taylor Webb2, Patrick Peiyong Ye, Pejman Ghanouni2, Kim Butts Pauly2 14 October 2014 1 The Harker School, San Jose, California, United States Topic: Brain 2 Stanford University, Stanford, California, United States Presentation Type: Poster Background/Introduction: One of the greatest strengths of MR guided focused ultrasound is the ability to monitor the temperature in real time during a treatment. Though this temperature data can be used over time to compute a thermal dose [1], the intra- procedural thermal dose map does not always match the non-perfused volume visualized on post-contrast scans at the end of the treatment. Because tissue perfusion changes after ablation, measuring a change in perfusion would provide an extra method for determining ablated tissue volumes. By comparing changes in the cooling rate before and after tissue reaches a suffi cient temperature threshold to result in tissue ablation, this study assesses whether changes in the cooling rate can be used to monitor changes in tissue perfusion and hence tissue ablation. Methods: Temperature images from MR scans of four patients undergoing transcranial FUS were used. The temperature at the focal spot of the single highest voxel after the end of the sonication was recorded over time and fi t to an exponential of the form a*e-bt. Only the fi rst fi ve timepoints post sonication were used in order to reduce the effects of noise. The cooling coeffi cients, b, for each sonication were collected and grouped into two groups: sonications before a critical temperature of 55°C was reached and sonications after that temperature was reached. Results and Conclusions: Results: Figure 1 shows the resulting cooling coeffi cients for each group. The sonications before the focus reaches the threshold temperature had cooling coeffi cients that were signifi cantly greater than those of the later sonications. This can be understood to be the result of a decrease in perfusion after tissue ablation. The results are made more signifi cant by considering that the later sonications achieved higher temperatures and therefore, assuming the thermal properties of the tissue did not change, we would expect these later sonications to cool at a faster not a slower rate. The decrease in cooling coeffi cient therefore strongly implies a change in the thermal properties of the tissue. Because tissue ablation leads to a decrease of blood fl ow to the diseased tissue, a decrease in perfusion is a likely explanation for this change. Conclusion: These fi ndings suggest that cooling rate coeffi cients can be used as an additional metric during treatments to help determine that the tissue has received suffi cient thermal dose for ablation. Moreover, this information can be used to determine how long to wait between sonications. If the wait is too long for the sonications before the threshold, then the time could be reduced to speed up the process since the tissue cools faster. If the wait is not long enough for the sonications after the threshold, then the cooling time should be extended to increase patient safety. Future work includes using a larger patient sample and understanding interpatient variation to provide more information about the robustness of the current results. Acknowledgements (Funding): P01 CA159992, General Electric, Focused Ultrasound Foundation

Figure 1: Averages of the cooling rates for sonications before and after the achieving a temperature of 55°C. p-value = 0.035.

146 Focused Ultrasound 2014 4th International Symposium P-125-BR Thermal Dose and Radiation Dose Comparison Based on Cell Survival Tuesday Meredith Lee1, David Schlesinger2, Gail ter Haar3, Benjamin Sela1, Matt Eames1, 14 October 2014 John Snell1, Arik Hananel1, Neal Kassell1, Jason Sheehan2, James Larner2, Topic: Brain Jean-Francois Aubry2 Presentation Type: Poster 1 Focused Ultrasound Foundation, Charlottesville, Virginia, United States 2 University of Virginia, Charlottesville, Virginia, United States 3 The Institute of Cancer Research, London, United Kingdom

Background/Introduction: The biologic dose response curves of thermal dose and absorbed radiation dose have not been compared to each other even though they have both been extensively investigated separately and combined. Although heat and radiation produce cell kill by different biological mechanisms (Thermal dose denatures proteins and the radiation dose causes DNA damage) a comparison of dose response curves is possible using the endpoint of cell survival. Methods: Survival curves for both thermal and radiation doses were extracted for three different types of cells from previously published data. Using models based on the beam shapes of the current clinical systems for the dose profi le, the survival curves were generated and the survival profi les were compared for both modalities, Focused Ultrasound (FUS) and Gamma Knife (GK), for a thalamotomy. The thermal dose profi le was calculated according to Dewey (1994), from temperature maps simulated with a 3D fi nite differences time domain code solving the bio-heat equation with a heat deposition term dependent on the pressure fi eld. Radiosurgery dose distributions were exported from the Gamma Knife treatment planning software (Leksell GammaPlan versions 8.0 - 10.1, Elekta AB, Stockholm) with the smallest target as an input. Results and Conclusions: The comparison showed that focused ultrasound exhibits a steeper dose and survival profi le than gamma knife. As shown in Figure 1, a smaller percentage of cells are dead a short distance away from the FUS target compared with GK. Also, cell death drops more gradually for GK than FUS. Our results establish that the penumbra is steeper for FUS than GK and have implications for making treatment decisions as well as for rationally combing the two modalities. Acknowledgements (Funding): Focused Ultrasound Foundation Dewey, W. (1994). “Arrhenius relationships from the molecule and cell to the clinic.” International journal of hyperthermia 10(4): 457-483

Fraction of cell death radially from the focus of the gamma beams and focused ultrasound beams.

Focused Ultrasound 2014 4th International Symposium 147 P-126-BR Reduction of Dielectric Artifacts Within an InSightec ExAblate 4000 Head Tuesday Transducer 14 October 2014 Steve Leung, Pejman Ghanouni, Kim Butts Pauly Topic: Brain Presentation Type: Poster Stanford University, Stanford, California, United States Background/Introduction: High intensity focused ultrasound (HIFU) ablation of the brain has been increasingly used as a non-invasive treatment for essential tremor and neuropathic pain. However, artifacts arise in magnetic resonance (MR) images as a result of dielectric properties of the water bath coupler and of the tissues being investigated. As radio frequency (RF) waves enter a dielectric medium, their wavelengths decrease by a factor equal to the square root of the medium’s relative permittivity (Webb 2011). The shortened wavelength can cause a standing wave pattern within the sample, with regions of constructive and destructive interference. This RF inhomogeneity results in dielectric artifacts that appear as shaded regions in the intensity image. Modifying the RF coil can be used to bypass this issue, but is non-trivial. We present a simpler solution by decreasing the permittivity of the water bath, thereby reducing the standing wave effect that creates dielectric artifacts. Methods: To decrease the permittivity of the water bath, sodium chloride (NaCl) was dissolved at concentrations of 12.5 to 62.5 mM at 12.5 mM increments. Higher concentrations correlated with lower permittivity. A fast gradient echo (FGRE) T1W sequence (TR 250, TE 13.2, FOV 40 cm x 40 cm, slice thickness 5 mm, 256 x 128 matrix) was performed on a 3T GE scanner. A region of interest (ROI) was drawn at the center of the head transducer along the superior/inferior direction. Signal to noise ratio (SNR) was calculated, in which signal was the mean intensity across the ROI and noise was the standard deviation of background. Results and Conclusions: Varying the concentration of NaCl had a noticeable effect on the dielectric artifact (Figure 1). Qualitatively, the artifact was signifi cantly reduced at a concentration of 37.5 mM. At higher concentrations, the images look relatively homogenous. The SNR profi les along the rectangular ROI are given in Figure 2. Due to dielectric artifacts, images at concentrations of 0, 12.5, and 25.0 mM displayed SNR inhomogeneity. In comparison, images at concentrations of 37.5 mM and above were much more homogenous. Higher concentrations showed a gradual loss of signal due to reduction of the dielectric effect. Salts such as NaCl act as corrosive agents, therefore it is best to limit its use with electrical equipment. The optimal concentration appears to be 37.5 mM, due to the fact Figure 2. SNR profi le along the length of the ROI. The distance on the x-axis is the distance from the geometric focus. No signal was measured from 0 to 5 mm due to the Plexiglas protrusion into the water bath. Salts such as NaCl act as corrosive agents, therefore it is best to limit its use with electrical equipment. The optimal concentration appears to be 37.5 mM, due to the fact that it best balances the tradeoffs between signal homogeneity, SNR, and salt concentration. This study presents a simple and inexpensive solution to reduce dielectric artifacts seen in MR images when using an InSightec ExAblate 4000 head transducer for non-invasive treatment. The reduction of dielectric artifacts will allow for ease of image diagnosis and analysis. Acknowledgements (Funding): Stanford Bio-X Bioengineering Fellowship, NIH P01 CA159992, Grant, InSightec, General Electric

Figure 1. Side-by-side comparison of intensity images at different Figure 2. SNR profi le along the length of the ROI. concentrations. Images show a sagittal view of an InSightec ExAblate The distance on the x-axis is the distance from the 4000 head transducer with a water bath and head phantom. geometric focus. No signal was measured from 0 to 5 mm due to the Plexiglas protrusion into the water bath. 148 Focused Ultrasound 2014 4th International Symposium P-127-BR Targeted Delivery of GABA via Ultrasound-induced Blood-brain Barrier Tuesday Disruption Blocks Somatosensory-evoked Potentials 14 October 2014 Nathan McDannold1, Yong-Zhi Zhang2, Chanikarn Power1, Costas Arvanitis1, Natalia Topic: Brain Vykhodtseva1, Margaret Livingstone2 Presentation Type: Poster 1 Brigham & Women’s Hospital/Harvard Medical School, Boston, Massachusetts, United States 2 Harvard Medical School, Boston, Massachusetts, United States

Background/Introduction: This study investigated whether targeted delivery of the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA), a small molecule (103 Da) that normally does not reach the brain with systemic administration, can temporarily block brain activity after ultrasound-induced blood-brain barrier (BBB) disruption. Methods: Focused ultrasound exposures (10 ms bursts applied at 1 Hz for 60 s; pressure amplitude in water: 0.64-0.71 MPa) were delivered immediately after the administration of Defi nity microbubbles (20 or 40 μl/kg) to disrupt the BBB. The focal point was targeted to 10 overlapping targets on and around the somatosensory motor cortex (2 mm lateral, 2 mm posterior to bregma) under MRI guidance in 5 rats. BBB disruption was confi rmed using Gd- DTPA MRI contrast agent (Magnevist, 0.25 ml/kg). After the sonications, electrodes were implanted into the thigh muscle to electrically stimulate the sciatic nerve (stimulation voltage: 9-20 V). Somatosensory evoked potentials (SSEP) were recorded transcranially before and after intravenous GABA at doses ranging from 0.8 to 519 mg/kg. The SSEP recordings were repeated in two animals at 24h after sonication and one animal at 5 days. SSEP measurements were obtained in two control animals who received GABA but not ultrasound-induced BBB disruption. Results and Conclusions: The amplitude of the SSEP recordings in the animals who received GABA and ultrasound-induced BBB disruption were reduced by 6-94%. There was a good correlation (R²: 0.79) between the percent suppression in SSEP magnitude and GABA dose. This suppression also correlated with the degree of BBB disruption – for similar GABA doses, animals that had less suppression also had weaker enhancement in MRI after Gd-DTPA administration. For relatively small doses of GABA (0.8-64 mg/kg), the duration of the suppression lasted between 2-20 min, with higher doses resulting in longer durations. At high doses (422 mg/kg and above) the suppression lasted the length of the recordings (up to 100 min). No suppression was observed after GABA administration in control animals or in recordings performed 24h or 5d after the sonications. This work demonstrates an alternative ultrasound-based method to block neuronal function. It has some advantages over other ultrasound “neuromodulation” techniques: the ability to use contrast MRI to defi nitively confi rm where the suppression is targeted, the ability to titrate the GABA dose to control the level of suppression, and the ability to recover the animal from anesthesia and transiently block function in a freely behaving animal. Since the effects of GABA and other neurotransmitters have been studied for decades, the mechanisms of the suppression are well understood. We anticipate that the use of GABA and other neurotransmitters in this way can be useful for noninvasively mapping brain function and potentially for surgical planning or novel therapies. Acknowledgements (Funding): NIH grants P01CA174645, P41EB015898, P41RR019703,

Focused Ultrasound 2014 4th International Symposium 149 P-128-BR Localized Delivery of Non-Viral Gene-Bearing Nanoparticles into the Rat Tuesday Brain following Focused Ultrasound-mediated BBB Opening 14 October 2014 Brian Mead1, Panagiotis Mastorakos2, Jung Soo Suk2, Ji Song1, Justin Hanes2, Richard Topic: Brain Price1 Presentation Type: Poster 1 University of Virginia, Charlottesville, Virginia, United States 2 Johns Hopkins University, Baltimore, Maryland, United States

Background/Introduction: By preventing more than 98% of currently used pharamaceutical agents from entering the brain, the blood-brain barrier critically reduces the ability of therapeutics to treat a variety of central nervous system (CNS) disorders including glioblastoma and neurodegenerative diseases. Focused ultrasound (FUS) mediated microbubble oscillation and subsequent blood brain barrier (BBB) permeabilization has been explored as a powerful non-invasive strategy for the delivery of circulating therapeutic agents into the CNS. FUS in conjunction with microbubbles has been shown to facilitate non- damaging, reversible and localized disruption of the BBB, leading to substantial increases in nanoparticle (NP) concentrations in ultrasound-treated tissue. Once beyond the BBB, the extracellular matrix acts as a steric and adhesive barrier and limits NP distribution. Coating sub-100 nm nanoparticles with a dense brush layer of polyethylene glycol (PEG) to limit the interactions with the ECM leads to a signifi cant improvement of their diffusivity in brain tissue. The current study investigates the ability of FUS to deliver densely PEGylated brain penetrating cationic polymer-based gene vectors across the BBB to mediate robust and long- term transgene expression. Methods: Anesthetized 200g Sprague-Dawley rats were secured in a stereotaxic frame and their heads were depilated. A 1.5-inch single element 1MHz focused ultrasound transducer was ultrasonically coupled. The tail vein was cannulated, and a coinjection of microbubbles (105/g) and 50 nm PEGylated polyethylenimine (PEG-PEI) nanoparticles (50 ug, 100 ug, 200 ug or 350 ug doses) immediately preceded ultrasound treatment. We delivered luciferase and mCherry transgenes under control of a beta-actin promoter. All sonications were performed with a 0.5% duty cycle, a total time of two minutes, and a peak negative pressure of 0.6 MPa. Luciferase expression was assessed through bioluminescent imaging following a 150 mg/kg injection of luciferin in an In Vivo Imaging System. Following euthanasia, animals were perfused with saline, and brains were dehydrated and cryosectioned. Mounted sections were stained with mCherry, Draq5 or H&E. Results and Conclusions: Delivery of luciferase-bearing PEG-PEI NP resulted in robust bioluminescence through day 28, the last day tested. Bioluminescence was dose-dependent (Figure 1). Under H&E, no signs of histological defect were found at the lowest two doses administered, while the 200 ug dose had only a single site of minor damage. In order to assess transfection effi ciency rat brains treated with FUS and 200 ug of mCherry-expressing PEG-PEI seven days prior were sectioned and stained with a marker for cell nuclei. 41% of cells in the FUS-treated region were found to express the mCherry reporter gene compared to only 6% on the contralateral non-treated region. FUS mediated BBB disruption presents a novel platform for drug and gene delivery technologies to the brain. Our results indicate that robust gene expression can be achieved by systemically delivering densely PEGylated cationic polymer gene vectors and that transgene expression can be maintained for at least 28 days. Currently, we are analyzing the therapeutic effi cacy of FUS-mediated gene therapy in a rat model of neurodegenerative disease. Acknowledgements (Funding): This work was funded through grant support from the National Institutes of Health (R01 CA164789). B.P.M. was funded by NHLBI- sponsored Basic Cardiovascular Research Training Grant (5 T32 HL007284).

Figure 1. FUS mediated delivery of luciferase-bearing PEG-PEI NP mediates targeted, dose-dependent bioluminescence in a rat. 150 Focused Ultrasound 2014 4th International Symposium P-129-BR Enhancement of Blood-Brain Barrier Permeability by the Combination of Tuesday Bubble Liposomes and High-intensity Focused Ultrasound 14 October 2014 Yoichi Negishi1, Masaya Yamane1, Naho Kurihara1, Yoko Endo-Takahashi1, Norio Topic: Brain Takagi1, Ryo Suzuki2, Kazuo Maruyama2, Yukihiko Aramaki1 Presentation Type: Poster 1 Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan 2 Teikyo University, Itabashi-ku, Japan

Background/Introduction: The blood-brain barrier is a major obstacle that prevents therapeutic drugs or genes being delivered into the central nervous systems. Therefore, it is important to develop enabling enhance the permeability of blood-brain barrier (BBB). So far, we have developed echo-contrast gas (C3F8) entrapping liposomes (Bubble liposomes, BLs) which can be work as a gene delivery tool in the combination of ultrasound (US) exposure. Here, we investigated whether the delivery effi ciency of intravenously injected large molecular agents can be induced by the combination of BLs and high-intensity focused ultrasound (HIFU). Methods: In this study, we prepared BLs of submicron size (~ 500 nm). Male ICR mice were injected intravenously with Evans blue dye (EB) which binds with albumin in blood stably. Subsequently, BLs were also injected and then right hemispheres were exposed with a 1.0 MHz pulsed HIFU (10% duty, 10-60 sec) with different intensities (0.1-1.5 kW/ cm2). After 3 hours, their treated mice were infused intravenously with PBS as a perfusion medium by a syringe pump at a constant speed. The mice were perfused with PBS via the left ventricle. After perfusion and brain removal, the brains were then divided into right and left hemispheres before measuring the amount of EB extravasated. Non-focused left hemispheres of the treated mice were used as the control. Samples were weighed, soaked in formamide solution, and the incubated for 24 hours at 55 degrees. After that, the extracted dye was fi nally determined using a spectrophotometer at 620 nm. Similarly, FITC-dextrans (molecular weight 70-2000 kDa) were also delivered intravenously into right hemispheres by the combination of BLs and HIFU. Then, sections of the treated brains were examined by fl uorescence microscopy. Results and Conclusions: The accumulations of EB in the focused on brain were increased in dependent on the intensity and the duration of HIFU. In contrast, non-focused left hemispheres of the treated mice were almost background level. Furthermore, it was also shown that delivery in the effi cient brain of a compound (molecular weight 70-2000 kDa) becomes possible by the combination method of Bubble liposome and HIFU. These results suggest that BBB permeability after the treatment of BLs and HIFU can be enhanced. It was thought that the method of combining Bubble liposome and HIFU together served as a useful means as the technique of accelerating the permeability of BBB. Therefore, it may be expected as a future low invasive drugs or genes delivery system within a brain. Acknowledgements (Funding): This work was supported by JSPS KAKENHI Grant Number 25560240.

Focused Ultrasound 2014 4th International Symposium 151 P-130-BR Dynamical Model Parameter Adjustments in Model Predictive Filtering MR Tuesday Thermometry 14 October 2014 Henrik Odéen, Dennis Parker Topic: Brain Presentation Type: Poster University of Utah, Salt Lake City, Utah, United States Background/Introduction: In magnetic resonance guided focused ultrasound (MRgFUS) brain applications the fully insonifi ed fi eld-of-view (FOV) is ideally monitored. This can be achieved by k-space subsampling and using a dedicated reconstruction method, such as the previously described model predictive fi ltering (MPF) method.1 MPF utilizes the Pennes Bioheat transfer equation (PBTE) and tissue thermal and acoustic properties determined from a low-power pre-treatment heating (which ideally does not deliver any thermal dose, i.e. ΔT<2°C). The accuracy of the determined tissue parameters, and hence of the MPF reconstruction, depends on the low power heating. In this work we investigate dynamical adjustment of model parameters during heating for improved MPF temperature measurement accuracy. Methods: All imaging used a 3D segmented EPI pulse sequence (table 1) with variable density k-space subsampling (R=7)2 on a 3T MR scanner (Tim Trio, Siemens Healthcare). FUS heating was performed in a gelatin phantom with a 1MHz 256 elements phased array transducer (Imasonic/IGT). In MPF a temperature forward prediction (based on PBTE) is used in conjunction with sub-sampled k-space data to estimate the current temperatures. In this work the tissue acoustic (power density, Q) and thermal (conductivity, k) properties were determined with recently published methods3,4 from an average of 5 low power heatings, and the MPF reconstructions were compared to fully sampled “truths.” Temperature maps were calculated with the PRF shift method. The subsampled data was reconstructed with three implementations of the MPF algorithm: 1. No adjustment The original implementation, using fi xed values of k and Q3,4 for all time- frames. 2. Best current estimate Implementation where Q from 1) is iteratively adjusted in each time- frame when the US is on, and k from 1) is iteratively adjusted when the US is off, so that the difference between the forward predicted model-only temperatures and the MPF estimates are minimized in each dynamic time-frame, fi gure 1a. 3. Final adjustment Here the average values of Q and k achieved from all time-frames in 2) are used in the reconstruction. Since the average values of Q/k are used, the data cannot be reconstructed until all data is acquired, hindering real-time reconstruction. Temperature measurement accuracy was evaluated by investigating a local (hottest voxel) and a global (all voxels with ΔT>20°C) root-mean-square-error (RMSE).

Table 1. MR and US parameters used for the 5 Low Power heatings (to estimate Q and k), for the fully sampled “truth,” and for the subsampled MPF heatings. TR/TE Resolution FOV EPI BW FA Tacq US [ms] [mm] [mm] [Hz/px] [deg] [s]

Low Power 22/11 1.15x1.15x2.50 147x96x45 7 752 15 4.8 3W Heating 28.18s Fully Sampled 22/11 1.15x1.15x2.50 147x96x45 7 752 15 4.8 40W “Truth” 28.18s MPF 22/11 1.15x1.15x2.50 147x110x135 7 752 15 2.4 40W 28.18s

Iteratively updating MPF temperatures by adjusting Q/k. Blue dots are iterations for each dynamic time - larger adjustments are needed when US is turned on/off (black arrows). Red line indicates temperatures as obtained with the optimized parameters.

152 Focused Ultrasound 2014 4th International Symposium Results and Conclusions: The mean and STD of the 5 low power heatings were 2.10±0.10°C, resulting in a negligible thermal dose (0.002 for hottest voxel). Figure 1b shows the hottest voxel vs. time for fully sampled “truth” and the three MPF implementations, and table 2 shows the RMSEs. A 31-50% reduction in RMSE can in the present study be achieved by dynamically adjusting Q and k during the heating. Achieving accurate estimates of tissue acoustic and thermal properties can be challenging from very low power heatings resulting in only a few degrees temperature rise. In this work we have shown that increased temperature measurement accuracy can be achieved by dynamically adjusting the model parameters as the heating progresses. Future work will aim at adjusting both Q and k during the heating by incorporating estimates of the focal spot FWHM.

Table 2. Mean and standard deviation (STD) of the RMSE for three repeated 40W heatings, for the three implementations of the MPF algorithm. RMSE RMSE Hottest voxel ΔT>20°C 1) No adjustment 1.37±0.03 1.89±0.25 2) Best current estimate 0.69±0.03 1.26±0.31 3) Final adjustment 0.94±0.04 1.24±0.25 Temperature rise vs. time for fully sampled “truth” compared to the three implementations of the MPF References: algorithm. Mean and STD of three separate heatings are shown. 1. Todd MRM 63:1269-79 Increased accuracy is achieved 2. Odéen ISMRM 2013 p1802 when Q/k are dynamically adjusted 3.Dillon Phys. Med. Biol. 57:4527–44 throughout the heating. 4. Dillon ISMRM 2013 p1824 Acknowledgements (Funding): This work was supported by The Focused Ultrasound Foundation, The Ben B. and Iris M. Margolis Foundation, Siemens Healthcare, and NIH grants R01s EB013433, CA134599, and CA172787.

Focused Ultrasound 2014 4th International Symposium 153 P-131-BR Design of a Robotic Device for the Delivery of Transcranial, Magnetic Tuesday Resonance Guided Focused Ultrasound for Intraventricular Hemorrhage of 14 October 2014 Prematurity

Topic: Brain 1 1 2 1 3 Presentation Type: Poster Karl Price , Vivian Sin , Charles Mougenot , Thomas Looi , Samuel Pichardo , Adam Waspe1, James Drake1 1 Centre for Image Guided Innovation and Therapeutic Intervention, Toronto, Canada 2 Philips Healthcare Canada, Toronto, Canada 3 Thunder Bay Research Institute/Lakehead University, Toronto, Canada

Background/Introduction: Premature birth affects 12.5% of pregnancies, and as a result, intraventricular hemorrhage (IVH) of the brain with subsequent development of hydrocephalus is a major cause of morbidity, mortality, and poor intellectual outcomes. Prospective clinical trials to dissolve IVH clots with intraventricular infusion of tissue plasminogen activator through surgically implanted catheters demonstrated improved intellectual outcome in the survivors but at an increased risk of hemorrhage. A non-invasive method to lyse the clots may result in a reduced risk of subsequent hydrocephalus, and better intellectual outcome for these patients. Magnetic resonance guided focused ultrasound (MRgFUS) delivered through the open fontanel is such a therapy, but requires a versatile transducer positioning system that adapts to the MRI compatible transport and imaging incubator used to manage these fragile neonates. Methods: A fi ve degree of freedom MRI compatible robotic device has been designed to precisely position an MRgFUS transducer (Philips Sonalleve brand) for transcranial therapies within the constraints of the neonatal incubator system. Pulsed focused ultrasound (FUS) energy is used to lyse IVH blood clots in the brain of the patient. The robot is used to position the transducer above the head of the patient while the patient is inside the MRI machine. Five ultrasonic, non-magnetic motors are used to actuate the robot. Specially selected, non-magnetic materials are used to construct the robot. A workspace analysis for delivery of the FUS to the intraventricular system of the brain in typical premature neonates was carried out, as were predicted load and speed requirements. A mock-up of the treatment system, with a 3D printed neonatal skull inside the incubator was constructed. The fi rst prototype of the robot was tested for MRI compatibility while the motors were in operation. A master-slave control system, integrated with the MRI imaging system was also designed. Results and Conclusions: Tests of individual components of the robot show that it has the potential for highly accurate targeting with the FUS transducer through the anterior fontanel of a neonatal head within the incubator transport system in the MRI environment. The design meets workspace, load and speed requirements. The activated components do not create signifi cant imaging artifacts or degradation of signal to noise ratio (SNR). Geometric distortions due to large metal objects (such as the drive motors) are negligible at distances longer than half the focal length of the transducer. We conclude from these experiments that the design of the robot is appropriate for transcranial MRgFUS thrombolysis and could signifi cantly improve treatment of IVH in premature infants. Acknowledgements (Funding): We would like to acknowledge funding provided by the Brain Canada Multi-investigator Research Initiative, and the Focused Ultrasound Foundation. In-kind technical support provided by Phillips Healthcare.

154 Focused Ultrasound 2014 4th International Symposium P-132-BR Pharmacodynamic Analysis and Concentration Mapping for Effi cient Tuesday Delivery through the FUS-induced BBB Opening in Non-human Primates 14 October 2014 In Vivo Topic: Brain Presentation Type: Poster Gesthimani Samiotaki, Maria Eleni (Marilena) Karakatsani, Shih-Ying Wu, Amanda Marie Buch, Elisa Konofagou Columbia University, New York, New York, United States

Background/Introduction: FUS in conjunction with systemically administered microbubbles has been previously shown to open the Blood-Brain Barrier (BBB) locally, non- invasively and reversibly in non-human primates. However, a trans-BBB pharmacodynamic analysis has not been performed as of yet. The objective of this study was to perform such an analysis, i.e. permeability, relaxivity and gadolinium concentration mapping, of the NHP brain in vivo in order to further investigate the effect of FUS, and its dependence on the acoustic parameters used for safe and effi cient drug-delivery as well as the gray vs. white matter occurrence. Methods: Two brain structures, the caudate and the putamen, were targeted in three rhesus macaques using FUS (center frequency: 500 kHz; pulse length: 5,000 cycles; PRF: 2 Hz; sonication duration: 120 s; peak negative pressure: 300-500 kPa) immediately after the IV administration of monodisperse bubbles (diameter: 4-5 μm, 2.5*108#/kg). Following sonication, the macaques were placed in a 3T MR scanner (Philips Medical System, Andover, MA, USA). Five pre-contrast 3D Spoiled Gradient Echo (SPGR) images (TR/TE: 10/4ms, FA: 5o-35o, NEX: 3, matrix: 256x256, resolution: 1x1x1 mm3) were acquired and used for variable fl ip angle *VFA) based T1 relaxivity mapping. Subsequently, Dynamic Contrast Enhanced (DCE) imaging was performed, with the acquisition of 90 dynamic T1-weighted 3D repetitions (TR/TE: 4.2/1.7 ms; matrix: 256x256, resolution 1x1x2 mm3). The data of the DCE were processed off-line using a customized Matlab-based algorithm and fi tted to the General Kinetic Model using the Patlak method to generate permeability maps. Quantitative permeability changes (Ktrans)and the volume of BBB opening after excluding the vasculature were obtained based on the T1 relaxivity maps. The areas of gray and white matter where BBB opening was induced were also determined, since they have distinctive characteristic relaxivity times. Gadolinium concentration [Gd] maps were then calculated from the T1,pre map before MR-CA injection and the T1,post maps after MR-CA injection using the following equation: [Gd] =1/r_Gd (1/T_(1,post) -1/T_(1,pre) ). Vasculature and CSF were excluded from the opening volume based on their T1 relaxivity which was measured to be above 1400 ms. Results and Conclusions: The volume of opening increased from 92±10 mm3 to 262±34 mm3 with a pressure increase from 300 kPa to 500 kPa increased. The average permeability was increased from 1.0531 ± 0.0761*10-4 s-1 to 1.863 ± 0.132*10-4 s-1 with the same pressure increase. When targeting the putamen, an average of 95% of the BBB opening regions was contained in the grey matter (T1 relaxivity range: 1001-1400 ms), while when targeting the caudate 87% of the BBB-opened regions were in the gray matter and the rest in the white (T1 relaxivity range: 600-1000 ms). No edema or hemorrhage was detected in any of the cases studied. FUS-induced drug delivery effi ciency was measured in vivo for the fi rst time and increased with the acoustic pressure used; the amount of gadolinium in the opened BBB area increased from 10 μg to 20 μg on average when pressure increased from 300 to 600 kPa. This type of analysis as performed in this study may prove critical for clinical applications. Acknowledgements (Funding): The authors wish to acknolwedge Matthew Downs and Carlos Sierra Sanchez for their input and help. Funding: National Institutes of Health (R01 EB009041 & R01AG038961), Wallas H. Coulter Foundation, Focused Ultrasound Foundation

T1 map overlaid with permeability map in a coronal view

Focused Ultrasound 2014 4th International Symposium 155 P-133-BR Ultrasound-mediated Delivery of Brain-penetrating Nanoparticles across Tuesday the Blood-tumor Barrier 14 October 2014 Kelsie Timbie1, Clark Zhang2, Elizabeth Nance2, Ji Song1, Wilson Miller1, Topic: Brain Justin Hanes2, Richard Price1 Presentation Type: Poster 1 University of Virginia, Charlottesville, Virginia, United States 2 Johns Hopkins University, Baltimore, Maryland, United States

Background/Introduction: The intact blood-brain barrier (BBB) presents a major obstacle for drug delivery to the brain. In addition, both high interstitial pressure and a nanoporous electrostatically charged tissue composition, produce a “blood-tumor barrier” (BTB), further complicating the treatment of diseases like glioblastoma. Focused ultrasound (FUS) in conjunction with microbubbles (MB) has been shown to cause reversible, localized disruption of the BBB. Incorporating MR guidance with FUS offers the ability to exquisitely target the BBB disruption to specifi c regions of the brain, thereby permitting drug delivery in a highly localized manner. This work examines the ability of MR guided FUS to deliver highly specialized brain-penetrating nanoparticles (NP) across both the BBB and the BTB in tumor-bearing rats. NPs were 60 nm in diameter and covered with an exceptionally dense brush layer of PEG to permit excellent diffusion through brain tissue. Initial studies utilized fl uorescent polystyrene tracer particles to measure NP delivery and inform dosing of cisplatin-loaded biodegradable NPs. Methods: One to two weeks prior to FUS treatment, 160-170 g rats were inoculated intracranially with luciferase- transfected 9L cells. On the day of treatment, the heads of the anesthetized rats were depilated and positioned in a degassed water bath coupled to the FUS system. Rats received an intravenous co-injection of NPs and MBs 30 seconds before sonication. All sonications were performed using a 1.14 MHz single element focused transducer operating at a 0.5% duty cycle for 2 minutes. Peak negative pressure was 0.6 MPa. High resolution contrast-enhanced MR images were utilized to visualize the tumor region and place sonication focal points with high accuracy. Targets were chosen to cover the entire tumor region as well as the immediate tumor periphery, thereby disrupting both the BTB and the intact BBB. Immediately following sonication, MRI contrast agent was delivered intravenously and T1-weighted contrast enhanced MRI images were captured to verify BBB disruption. Animals were recovered and monitored for 1hr-2 weeks post treatment. In animals receiving fl uorescent tracer NPs, brains were perfused with 2% heparinized saline, dessicated and cryosectioned. Mounted sections were stained with BS-I lectin to reveal endothelial cells (ECs) and imaged with fl uorescent microscopy. In animals receiving drug- loaded NPs, tumor growth post treatment was measured using IVIS. Results and Conclusions: Initial studies with fl uorescent tracer particles indicate that FUS and MBs are capable of disrupting the BTB and enhancing the delivery of 60 nm NPs in the tumor region. In Figure 1, fl uorescent microscopy shows signifi cant NP delivery in a FUS+ tumor, equating to a 30-fold increase when compared to a FUS- tumor. Although the BBB is compromised in the tumor region, as indicated by pre-sonication MR imaging, additional treatment with FUS and MBs was required to overcome the BTB and permit signifi cant NP delivery. Combined with prior work demonstrating the ability of FUS to deliver these large NPs to healthy brain tissue, our results provide promising evidence that delivery of a therapeutic drug dose to both the tumor core and periphery is possible, and work continues in this area. Acknowledgements (Funding): Supported by the UVa Cardiovascular Research Center Training Grant, the Focused Ultrasound Foundation and NIH R01 CA164789.

Figure 1: FUS and MBs are able to deliver 60 nm NPs across the BTB. Contrast-enhanced MR images demonstrate FUS-mediated BBB opening in the tumor periphery, compared to US- images. Fluorescent images show clear enhancement of NP delivery in FUS+ tumors.

156 Focused Ultrasound 2014 4th International Symposium P-134-BR Acoustic and Thermal Simulations of tcMRgFUS in Patient Specifi c Models: Tuesday Validation with Experiments 14 October 2014 Urvi Vyas, Taylor Webb, Rachelle Bitton, Kim Butts Pauly, Pejman Ghanouni Topic: Brain Presentation Type: Poster Stanford University, Stanford, California, United States Background/Introduction: In tcMRgFUS, acoustic and spatial heterogeneities of the skull cause refl ection, attenuation, and phase aberrations of the acoustic beams, which may cause patient-specifi c thermal responses to the same transducer power. In this work, we use acoustic and thermal simulations based on patient-specifi c 3D heterogeneous tissue models to predict heating at the center of the brain. We validate the model through comparison of the simulated temperature rises to experimentally derived energies for fi ve patients treated using tcMRgFUS. Further, we separate the components of energy loss in the acoustic simulations into refl ection-only, attenuation-only, phase aberration-only, and refl ection and attenuation both to understand the cause of potential inter-patient variability in these treatments. Methods: In fi ve cases, human CT scans were used to create acoustic and thermal tissue models. The hybrid angular spectrum technique1 was used to model the acoustic beam propagation of the InSightec ExAbalate brain system, for each patient’s skull geometry, yielding maps of the specifi c absorption rate (SAR). Finite Difference Time Domain simulation of Penne’s Bioheat Transfer Equation were used to model the temperature. Tissue properties used in the simulations are given in Table 1. Simulated skull effi ciency was calculated for each case using the following equation, Simulated Skull Effi ciency=Power23°C temp rise/Powermin. Figure 1: The correlation where Power23C temp rise is the power required in the simulation to reach a 23°C between the experimental energy effi ciency and the temperature rise in the center of the brain for a 10 second sonication and the Powermin is simulated skull effi ciency is the minimum power required in the simulation to reach a 23°C temperature rise in the fi ve plotted, with a correlation data sets. Additionally, acoustic simulations for each skull used the tissue property groupings coeffi cient of 0.90. The specifi ed in Table 1B-1E to quantify effects of beam propagation. Simulated skull effi ciency treatment case number (correlating with Figure 2) is was compared to experimental energy effi ciency calculated for each case using the following given in the data labels. equation, Experimental Energy Effi ciency = Energy/Energymin where Energy was the energy used in the fi nal sonication to reach a temperature of 53-60°C and Energymin was the minimum energy of the fi nal sonication in the group of 5 datasets. These data were derived from fi ve patients who underwent tcMRgFUS treatment conducted using the InSightec ExAbalate 4000 650 kHz brain system. Results and Conclusions: Figure 1 plots the experimental energy effi ciency vs. the simulated skull effi ciency for the fi ve patient’s skulls, showing a correlation of 0.90. Figure 2 decomposes (using simulations) the overall effect of heterogeneity into the individual components - attenuation, refl ection, phase aberration and attenuation and refl ection - for each skull. The simulated skull effi ciency using individual-specifi c heterogeneous models predicts well (R=0.9) the experimental energy effi ciency, while being computationally feasible. Sources of noise in the data include differences in the simulated and the experimental focal location, simulated temperature rise of 60°C vs. experimental temperature rise over a range from 53°C-60°C and accuracy of phase correction. The decomposed pressure simulations quantify the role of individual acoustic effects and demonstrates that both refl ection and attenuation vary between subjects.

Figure 2: The overall effect of skull heterogeneity is decomposed into the individual components - attenuation, refl ection, phase aberration and attenuation and refl ection - for each individual skull. The Y-axis plots the loss in focal pressure due to the the component considered, normalized to a homogeneous-only case. Focused Ultrasound 2014 4th International Symposium 157 References: 1. U. Vyas and D. Christensen, IEEE,TUFFC vol. 59, no. 6, pp. 1093 –1100, Jun. 2012. 2. J.-F. Aubry, M. Tanter, M. Pernot, J.-L. Thomas, and M. Fink, JASA vol. 113, p. 84, 2003. 3. A. Fairchild, JASA., vol. 105, no. 2, pp. 1324–1324, 1999. Acknowledgements (Funding): Funding P01 CA159992

158 Focused Ultrasound 2014 4th International Symposium P-135-BR Comparison of 3D UTE- and CT-based Phase Aberration Correction for Tuesday Transcranial MR-Guided Focused Ultrasound Surgery 14 October 2014 Urvi Vyas, Ethan Johnson, Kim Butts Pauly Topic: Brain Presentation Type: Poster Stanford University, Stanford, California, United States Background/Introduction: In tcMRgFUS treatments, a high intensity ultrasound transducer is used to create a region of necrosis at a location in the brain, through an intact skull. Variations in the shape and density of the calvarium can cause aberrations in the location and shape of the beam’s focus. CT imaging is currently used clinically to correct for these skull-caused aberrations. In this work, we assess the current clinical utility of ultra- short TE (UTE) imaging for phase aberration correction for three in vivo human skulls for tcMRgFUS with the aim of utilizing MRI images for both treatment planning and guidance and reducing ionizing radiation. Methods: Three subjects underwent a CT scan (0.485mm×0.485mm×0.625mm) and a UTE scan (1mm isotropic) on separate days. A 3D UTE pulse sequence acquired four echoes at 0.042ms, 1.442ms, 2.242ms, and 3.642ms with the imaging parameters given in Table 1a. An R2* map using a least square fi t to the equation (xn = intensity, tn = acquisition time) was calculated using the four echoes of the UTE image. A bone contour model was calculated from the R2* map using region growing, clustering and thresholding, with the voxels with an R2* > .5ms-1 assumed as cortical bone and rest assumed as water. Three types of CT models for each subject skull were calculated with the calculation parameters and acoustic properties of each given in Table 1b-1d. For the fi rst model the CT image resolution was downgraded to equal the nominal resolution of the UTE and thresholded to two tissue types- bone and water. The second model used the downgraded resolution CT without thresholding, using the full range of CT Hounsfi eld (HU) units. The third model used the full-resolution CT and the full range of CT HU units as would be done clinically. Time reversal simulation using the hybrid angular spectrum method was used to calculate the correction phases for the InSightec Exablate Hemispherical Head system for all four models specifi ed in Table 1a-1d. The phases calculated using the high resolution all-HU CT model were considered as true aberrations and were applied numerically to all elements of the transducer in the simulation resulting in an aberrated focus. The simulated intensity at focus was compared when applying corrections calculated using each model (with the high-resolution all-HU CT model resulting in perfect corrections by defi nition). Results and Conclusions: Fig. 1 displays the high density bone contours from the corresponding slices of the CT and the UTE images, both with 1 mm resolution. Fig. 2 plots the axial profi le of the simulated focal intensities for corrections using all four models for one subject skull. Fig. 3 compares the percentage of the focal intensity (without attenuation) that was recovered using aberration correction calculated using four models for the three subject skulls. Intensity improvements from all aberration estimates were compared to a model that used the entire CT information. On average for the three subjects considered aberration corrections calculated using UTE images resulted in recovering 55 % of the focal intensity compared to a high resolution CT using the full range of HU. When compared to a CT with the same resolution and thresholding the UTE based correction recovered 75% of the total focal intensity (neglecting losses due to attenuation). Future work will include evaluating tradeoffs in SNR, voxel size and scan time for the UTE images, calculating acoustic properties from R2* values. Acknowledgements (Funding): Focused Ultrasound Foundation, P01 CA159992

Focused Ultrasound 2014 4th International Symposium 159 Figure 3.

160 Focused Ultrasound 2014 4th International Symposium P-136-BR Focused Ultrasound-facilitated AAV-GDNF Delivery Triggers Tuesday Neuroprotective Effects in a Parkinson’s-disease Mouse Model 14 October 2014 Shutao Wang, Oluyemi Olumolade, Vernice Jackson-Lewis, Javier Blesa, Tao Sun, Topic: Brain Gesthimani Samiotaki, Serge Przedborski, Elisa Konofagou Presentation Type: Poster Columbia University, New York, New York, United States

Background/Introduction: Parkinson’s Disease (PD), one of the most prevalent neurodegenerative diseases, is characterized by the relatively selective death of nigro-striatal dopaminergic neurons. Utilizing recombinant adeno-associated virus (rAAV), therapeutic genes can be delivered to the brain for long-lasting expression. However, the existence of the blood-brain barrier (BBB) prevents effi cient delivery of the systemically administered viral vectors. Transcranial focused Ultrasound (FUS) in combination with microbubbles (MB) has been shown capable of inducing reversible blood-brain barrier (BBB) opening. In this study, we investigate the neuroprotective effects of non-invasively delivered rAAV-GDNF vectors after transcranial FUS induced BBB opening in a PD mouse model. Methods: Animals were divided into four groups (n = 4-6 per group): control, FUS only, rAAV injection only, and rAAV+FUS. For the FUS only and AAV+FUS groups, both striatum (Str) and substantia nigra (SN) were sonicated unilaterally at 1.5 MHz with a peak rarefactional pressure of 0.45 MPa. For the rAAV+FUS group, immediately before sonication, a 100 ml mixture of rAAV1-CAG-hGDNF-GFP vectors (8.5×1011 GC/animal) and in-house polydispersed microbubbles (~2.5×107 #/animal) were administered IV. After 4-week survival, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was administered at 30 mg/kg IP over fi ve consecutive days. Twenty-seven days after the last MPTP injection, the mice were sacrifi ced and their brains were prepared for tyrosine hydroxylase (TH) staining for subsequent TH-positive neuronal counting in SN. The optical density (OD) and the integrated OD (IOD) were quantifi ed in MATLAB (Mathworks). Results and Conclusions: The ratio of ipsilateral (FUS treated side) to contralateral side with TH-positive neurons in the AAV+FUS group was found to be signifi cantly higher (p=0.03) compared to all other groups. The OD and IOD of TH levels in the caudate- putamen was only statistical signifi cant in the AAV+FUS group (p=0.0059 and p=0.0063, respectively) compared to all other groups. The IOD of the TH level in the caudate-putamen further confi rmed the neuroprotective effects of the non-invasively delivered rAAV-GDNF vectors. FUS in combination with MB provide a non-invasive and targeted approach for gene delivery to specifi c brain targets. This study, for the fi rst time, demonstrated neuroprotective effects of non-invasively delivered rAAV1-GDNF through the FUS-opened BBB in a PD animal model. Acknowledgements (Funding): This study was supported in part by NIH R01EB009041, NIH R01AG038961, and the Kinetics Foundation.

TH staining of substantia nigra revealed neuroprotective effects of non-invasively delivered of AAV1-GDNF through FUS- induced BBB opening.

Focused Ultrasound 2014 4th International Symposium 161 P-137-BR Effect of Increasing Sonication Duration During Transcranial MRgFUS Tuesday Treatments 14 October 2014 Taylor Webb, Urvi Vyas, Pejman Ghanouni, Kim Butts Pauly Topic: Brain Presentation Type: Poster Stanford University, Stanford, California, United States Background/Introduction: Patient-specifi c variations in skull thickness, density, and structure result in variations in the energy required to achieve ablative temperatures at the focal spot during transcranial MRgFUS treatments. Energy delivered to the focal spot can be increased by increasing either the duration or power of a sonication. The purpose of this research is to use simulations and measurements to consider the effect of varying these two parameters on focal spot size. Methods: Data from two patient treatments with a variety of sonication durations were retrospectively selected. CT data from the treatments were used to derive acoustic parameters that were used in the hybrid angular spectrum method to simulate the deposition of acoustic power. A fi nite difference time domain solver of the Pennes’ bioheat equation was then used to model the temperature. Thermal parameters were assigned based on the ICRU report. Two sets of simulated sonications were performed for each patient. In each set the power for the fi rst sonication was selected to achieve a temperature rise of 13°C at the focal spot. In the fi rst set the power was held constant while the duration was varied from 10 to 30 seconds and in the second set the duration was held constant at 10 seconds and the power was tripled. The resulting simulated temperature maps were used to measure the focal zone area in the axial plane immediately following the sonication. Focal zone area was also analyzed using temperature images from the actual treatment. Only axial images were used and images where the noise resulted in a focal spot that was not easily visible were removed. In order to limit the affect of noise, only sonications with a temperature rise of at least 5°C were analyzed. For both the simulated and experimental results we measured the area within the contour line at 75% of the maximum temperature. To compare results across patients the data was normalized to the area of a focal spot resulting from a sonication with both equal duration and power. Results and Conclusions: Figures 1 and 2 show the simulated affect of duration and power respectively on the focal zone area. The fi gures show a nearly linear dependence Figure 1. on sonication duration and no dependence on power. This is intuitive because a longer sonication time allows time for more thermal conduction to take place, resulting in a spreading of the focal spot. Figures 3 and 4 show the results from the patient treatment. These fi gures support the simulation results, showing a much stronger trend with respect to duration than with respect to power. They also show a much larger variation in the focal spot area than simulations predict. This discrepancy can be explained by inaccuracies in the thermal properties assumed by the model as well as added sources of blurring in patient treatments such as movement of the focal spot or imperfect phase corrections. The actual focal spot spread directly traceable to changes in sonication duration is likely somewhere between the simulated values and those shown in fi gures 3 and 4. Acknowledgements (Funding): P01 CA159992

Figure 2. Figure 3. Figure 4.

162 Focused Ultrasound 2014 4th International Symposium P-139-BR Accelerated MR Thermometry Using the Kalman Filter Tuesday Li Zhao1, Samuel Fielden1, Wilson Miller1, Xue Feng1, Max Wintermark1, Kim Butts 14 October 2014 Pauly2, Craig Meyer1 Topic: Brain 1 University of Virginia, Charlottesville, Virginia, United States Presentation Type: Poster 2 Stanford University, Stanford, California, United States

Background/Introduction: Magnetic resonance (MR) imaging plays an important role in monitoring thermal treatment. It can quantify thermal dose with temperature maps based on the proton-resonance frequency shift. Volumetric coverage is desirable, but acquiring multiple slices imaging is time consuming. Therefore, accelerated methods are needed to improve the spatial and temporal resolution in MR thermometry. Multi-channel coils are not widely available for MR-guided FUS systems, so conventional parallel imaging methods cannot be used for acceleration. Compressed sensing methods show promise, but the computation is currently too slow to provide real-time feedback. The Kalman fi lter is an optimal estimation method that has been widely used for real-time tracking in other fi elds. It has been studied for fi ltering of temperature for FUS. Here we apply it to accelerate image acquisition for thermometry. Methods: The Kalman fi lter (KF) uses prior state information to predict the current state with a dynamic system model: x(k) = x(k-1) + w(k-1) z(k) = U(k) F x(k) + v(k) x(k) is the target image at the kth frame and the fi rst function describes the state transition. z(k) is the corresponding acquired data. F is a Fourier transform operator and U(k) is an undersampling pattern. w and v are the system and measurement noise, assumed to have white Gaussian distributions with covariance matrices estimated by the KF. w models state changes resulting from heating. A numerical phantom was used to validate the proposed method. One normalized slice was sampled with a 128x128 matrix. The focal spot followed a 2D Gaussian distribution spatially. The temperature evolves with exponential increase and decay, with 15-degree peak. 100 image frames were simulated with complex Gaussian noise (std = 0.01). A gel phantom was tested with a HIFU system (RK-100, FUS Instruments Inc., Toronto) in a 3T Siemens Trio. Fully sampled data were acquired by a gradient echo sequence with 64x64 matrix, FOV 64mm×64mm and resolution 1mm×1mmx5mm. TR/TE = 15/6 ms and bandwidth 500 Hz provided temporal resolution 0.96s per frame. The sequence acquired data continuously during three consecutive 30-second intervals corresponding to baseline, continuous sonication, and cooling. Data were undersampled by a factor of 2 along the phase encoding direction (y) and reconstructed by zero fi lling, view sharing, KF, and KF with fi rst frame initialized by view sharing. Temperature maps were calculated by the PSF method. The temperature map of fully sampled k-space was chosen as the standard to evaluate the performance of the above methods. Results and Conclusions: Figs. 1 and 2 show the simulated spatial and temporal temperature maps. The KF method produced negligible aliasing artifacts in the temperature map (top) and resulted in better approximation of the standard temperature with less error (bottom). With the fi rst image initialized by view sharing, KF further reduced the error in the fi rst few frames. Fig. 3 shows the experimental temporal temperature maps. Fig. 4 shows the temporal profi le of the focal spot (3x3 pixels). The KF method approximated the fully sampled image accurately and provided a temperature map with less error. In conclusion, the KF method can estimate temperature accurately with a speed-up of at least 2X, enabling real- time thermometry with greater spatial coverage.

Figure 1. Simulated accelerated Acknowledgements spatial temperature maps. (Funding): Focused The fully sampled noiseless Ultrasound Foundation, temperature map is shown as standard. Absolute error maps Siemens Medical show the KF method reduced Solutions undersampling artifacts and estimation error in the temperature map.

Focused Ultrasound 2014 4th International Symposium 163 Figure 2. Simulated accelerated temporal temperature maps. The fully sampled noiseless temperature map is shown as standard. The KF method reduced aliasing and error. Initialized by view sharing, KF further reduced the error in the fi rst few frames.

Figure 3. Experimental accelerated temporal temperature maps. The fully sampled temperature map is shown as reference. The KF method reduced aliasing and error. Initialized by view sharing, KF further reduced the error in the fi rst few frames.

Figure 4. Temporal plot of focal spot in gel phantom. ROIs (3x3 pixels) were selected around the highest temperature. The average temperature shows the KF method approximated the temperature more accurately than other methods with 2X acceleration.

164 Focused Ultrasound 2014 4th International Symposium P-204-BR In Vivo Low Frequency MR-guided Thalamotomy with Focused Ultrasound: Tuesday Thermal vs Mechanical Lesioning in Pig Brain 14 October 2014 Zhiyuan Xu1, Carissa Carlson2, John Snell2, Matt Eames2, Arik Hananel2, Topic: Brain M. Beatriz Lopes1, Prashant Raghavan1, Cheng-Chia Lee1, Chun-Po Yen1, Presentation Type: Poster David Schlesinger1, Neal Kassell2, Jean-Francois Aubry1,3, Jason Sheehan1 1 University of Virginia, Charlottesville, Virginia, United States 2 Focused Ultrasound Foundation, Charlottesville, Virginia, United States 3 Institut Langevin, Paris, France

Background/Introduction: The purpose of this study was to investigate the thresholds for inducing two possible means of tissue destruction with low frequency Magnetic Resonance guided Focused Ultrasound (MRgFUS): either mechanical lesioning in presence of ultrasonic cavitation or pure thermal lesioning (without cavitation). Methods: Ten craniectomized pigs where sonicated with an ExAblate4000 Neuro (InSightec, Haifa, Israel) operated with a 220Hz array made of 1024 transducers. For each animal, a thermal lesion was aimed on the right thalamus, while a cavitation (mechanical) lesion was aimed on the contralateral side. For thermal lesioning, 40s duration sonications were performed and the acoustical energy ranged between 5600J and 12000J. For mechanical lesioning, 20s duration sonications were performed and similar total acoustic energy was used: energy ranged between 6000J and 14000J (power was increased to compensate for the short sonication time). Signals collected by two passive cavitation detectors (custom made by Insightec) were stored in memory during each sonication and cavitation activity was integrated within the bandwidth of the detectors, from 50kHz to 182kHz. 2D MR thermometry was performed during treatment. T1-weighted pre- and post-Gadolinium contrast-enhanced, T2-weighted, T2*-weighted, gradient echo and FLAIR were acquired after treatment. Pigs were euthanized immediately after the last series of MR imaging. Pig brains were harvested and fi xed in formalin solution. Histology was performed to identify lesions. Results and Conclusions: For thermal lesioning, the peak temperature at focus ranged between 49°C and 59°C. All thermal lesions were induced for peak temperature higher than 53°C. For mechanical lesioning, the peak temperature at focus ranged between 50°C and 57°C. Passive cavitation signals exhibited three main types of signal interpreted as follows: no cavitation, stable cavitation and inertial cavitation. Pure thermal lesions, as assessed by histology, could be generated with low frequency ultrasound. Such lesions showed up on T2 MR post treatment images as a hypointense core surrounded by a hyperintense ring. Mechanical lesions where associated with hemorrhages. The size of the hemorrhages measured on gross histology correlated with cavitation activity (R2=0.74) and a threshold for cavitation activity of 0.09V.Hz (given the sensitivity of the Insightec cavitation detector or the frequency range) was found to divide the experiments into two separate groups: with and without hemorrhage. This work demonstrates that low frequency ultrasound can induce thermal lesions in the brain of living swines without hemorrhage. This work paves the way towards passive-cavitation-based automatic shutdown of low frequency ultrasound for safe ablation. Acknowledgements (Funding): This work was funded by a grant from the Focused Ultrasound Foundation.

Focused Ultrasound 2014 4th International Symposium 165 P-140-BT Preclinical Ultrasound Image-guided High Intensity Focused Ultrasound Tuesday Robot System for Breast Cancer Therapy 14 October 2014 Takashi Azuma1, Ryusuke Sugiyama1, Kazuhiro Matsui1, Keisuke Fujiwara2, Topic: Breast Hideki Takeuchi, Kazunori Itani2, Kiyoshi Yoshinaka3, Akira Sasaki1, Shu Takagi1, Presentation Type: Poster Ichiro Sakuma1, Yoichiro Matsumoto1, Toshihide Iwahashi1 1 The University of Tokyo, Tokyo, Japan 2 Hitachi Aloka Medical, Kokubunnji, Japan 3 National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan

Background/Introduction: Ultrasound imaging provides real-time feedback for highly accurate positioning and dosing control. In addition, spatial restriction of high-intensity focused ultrasound (HIFU) transducer position in the ultrasound image-guided system is less than that in the case of MRI-guided system. Therefore, wider beam approaching path can be used in the ultrasound image-guided system. To shorten the total treatment time, reducing the cooling time between sonication intervals is essential. Using a wide approach path promotes a reduction in both the cooling time and the risk of heat deposition to the body surface. The array in our preclinical HIFU system is supported by a 5-axis robotic system that enables motion with a pivot fi xed at the focal point. In this report, we describe a HIFU beam imaging system that provides highly accurate pivoting motion and coagulation monitoring in real-time for dose control during HIFU treatment. Methods: A 256-element concave array HIFU operating at 2 MHz was supported by a parallel link robot in a water tank. A 5-MHz linear imaging array was fi xed in a hole in the center of the HIFU array. The HIFU beam was affected by acoustic inhomogeneous media. Beam refraction during pivoting motions can cause focal shift and reductions in average focal intensity. We thus developed an HIFU beam imaging method capable of adjusting the focal point in varying approach paths. In the HIFU beam imaging process, backscattered echoes of ultrasound pulses transmitted from the HIFU transducer were received by the imaging array, and an HIFU beam profi le was visualized. The imaging array was connected to an ultrasound imaging scanner with a radio frequency (RF) data acquisition system and a ring buffer memory. The ring buffer memory made it possible for the signal processing operations to access the RF data during the acquiring and recording process. Thermal coagulation was able to be detected based on changes in stiffness of the focal tissue. In this prototype system, stiffness change could be monitored based on observation of focal tissue oscillation caused by the modulated HIFU radiation force. Results and Conclusions: The accuracy of the pivoting motion in our prototype system was evaluated by measuring the precessional radius of the focal point. The motion error was suffi ciently-smaller than the width of the HIFU beam. To increase the positioning accuracy of the focal point estimated by the visualized HIFU beam, extraction method of HIFU beam from the distribution of scatter points was tested. For this purpose, the HIFU focal point was scanned and the fi xed pattern noise refl ecting scatters was strongly suppressed. In coagulation monitoring, the maximum and mean computation times for stiffness estimations from tissue oscillation caused by the acoustic radiation force were 0.85 s and 0.6 s, respectively. To measure tissue oscillation, 26 frames of data were obtained within 0.1 s; therefore, tissue coagulation monitoring with a sampling rate of 1 s was achieved in our prototype system. This sampling speed is considered adequate for enabling feedback control of the coagulation area. Acknowledgements (Funding): This work was supported by grants from TSBMI (Translational Systems Biology and Medicine Initiative, Japan).

166 Focused Ultrasound 2014 4th International Symposium P-141-BT Performance Analysis of a Dedicated Breast MR-HIFU System During Tuesday Ablation of Breast Tumors in Patients 14 October 2014 Roel Deckers1, Baudouin Denis de Senneville1, Laura Merckel1, Gerald Schubert2, Topic: Breast Floor Knuttel1, Max Kohler2, Willem Mali1, Chrit Moonen1, Maurice van den Bosch1, Presentation Type: Poster Lambertus W. Bartels1 1 University Medical Center Utrecht, Utrecht, Netherlands 2 Philips Healthcare, Vantaa, Finland

Background/Introduction: We have recently conducted a clinical phase I study to assess the safety and spatial accuracy and precision of a newly developed dedicated MR-HIFU system for breast tumor ablation. In this system the breast is placed in a water fi lled cup, which is surrounded by an arc of ultrasound transducers.1 This lateral sonication approach signifi cantly reduces the risks of heating tissues in the near fi eld (i.e. skin) and in the far fi eld (i.e. ribs, heart and lungs), which in turn allows the usage of higher powers and/or longer sonication durations in a larger treatment area. Here, we report on the performance of real- time MR thermometry and on the accuracy and precision of the dedicated system. Methods: All treatments were performed on a dedicated breast MR-HIFU system (Philips Healthcare, Vantaa, Finland) integrated with a clinical 1.5-T MRI scanner (Achieva, Philips Healthcare, Best, The Netherlands). Ten female patients with pathologically proven invasive breast cancer after large-core needle biopsy were included. The patients were under procedural sedation during the complete HIFU procedure. The tumor tissue was deliberately partially ablated, to be able to use the remaining tumor tissue for histopathological characterization and staging and to allow for histological analysis of viable versus ablated tumor tissue. At least 48 hours after MR-HIFU treatment the tumor was removed surgically. The total number of sonications per patient (1-5, excluding test sonications) varied. Fat- suppressed segmented Echo Planar Imaging was performed for PRFS-based thermometry. A Look-Up-Table (LUT)-based correction method was used to correct on-line for respiration- induced magnetic fi eld fl uctuations.2 The performance of the correction method was assessed in absence of HIFU heating. The temporal standard deviation (SD) in temperature maps calculated before and after applying the correction method and the number of dynamics needed before switching to the intervention phase were used as a measure of performance. The targeting accuracy and precision of the system was assessed using MR thermometry data. For each sonication the trajectory of the center of mass of the heating pattern in the focal area over time was calculated. The standard deviation of the distribution of the distances between the center of mass in time and the mean center of mass was defi ned as precision. The distance between the mean center of mass and the planned treatment position was defi ned as accuracy. Results and Conclusions: The LUT-based correction method signifi cantly improved the precision of MR thermometry, the mean temperature SD decreased from 8.0 °C to 2.9 °C for the coronal slice and from 8.3 °C to 2.9 °C for the sagittal slice. On average, 67 images were required to complete the learning phase for the LUT-based correction method, which corresponds to 150 seconds. The mean accuracy was equal to 2.4 mm in the coronal as well as the sagittal image. The mean precision was equal to 1.4 mm and 1.9 mm in the coronal and sagittal image, respectively. Furthermore, the necrotic areas observed on histology corresponded to the number and location of the sonications performed. In conclusion, the precision of the MRT after respiration-induced temperature error correction is high enough for image guidance during tumor ablation. The dedicated breast MR-HIFU system allows for the ablation of breast cancer with a high spatial accuracy and precision. References: 1. Merckel, 2013, CVIR 2. Vigen, 2003, MRM Acknowledgements (Funding): CTMM (VOLTA)

Focused Ultrasound 2014 4th International Symposium 167 P-142-BT Soft-embalmed Human Breast Tissue as a Model for Pre-clinical Trials of Tuesday HIFU - Preliminary Results 14 October 2014 Joyce Joy, Yang Yang, Ioannis Karakitsios, Roos Eisma, Colin Purdie, Andreas Melzer, Topic: Breast Sandy Cochran, Sarah Vinnicombe Presentation Type: Poster University of Dundee, Dundee, United Kingdom

Background/Introduction: Around 52,000 people are diagnosed with breast cancer each year in the UK. With the controversy around over diagnosis arising from the breast screening programme there is intense interest in the possibility of safe effective non-invasive treatment of cancers. As a non-invasive method of lumpectomy, focused ultrasound surgery (FUS) may offers reduced risk of infection, fewer complications and a shorter recovery time. It also allows more precise treatment as a result of real-time guidance by magnetic resonance (MR) or ultrasound. Even though specially designed FUS transducers for breast cancer treatment are now becoming available, transducer effi cacy needs to be tested with a suitable preclinical model. A specifi c issue is the accuracy of temperature monitoring of FUS with MRI in the breast, since the presence of large amounts of surrounding fat can impair temperature measurement with the proton resonant frequency.. An appropriate anatomical model that enforces comparable physical constraints to the breast and that responds to FUS in the same way would be extremely advantageous. The aim of this feasibility study is to explore the use of soft embalmed cadaveric breast tissue for these purposes. We report here the early results of MRI-guided FUS experiments sonicating dissected breast samples from a soft-embalmed human cadaver with a high body mass index (BMI). Methods: A specially developed MRI compatible chamber and sample holder was developed to secure the sample and ensure reproducible sonications at the transducer focus. A HIFU transducer of frequency of 1.09 MHz and focal length of 69mm was used for sonications. An MRI compatible thermocouple was used to measure the temperature rise induced in the chosen tissues by sonications. The effi cacy of sonication was fi rst studied with chicken breast and porcine tissue. The experiments were then repeated with the dissected fatty breast tissue samples from soft-embalmed human cadavers. Results and Conclusions: After successful testing of the HIFU chamber with fresh animal tissue sonications, the experiments were repeated using cadaveric breast tissue. The thermocouple was placed at the focal zone of the FUS transducer and the position was confi rmed using MR imaging (Fig 1). Lower temperature peaks & the absence of a visible lesion in the soft-embalmed breast tissue were investigated further with sonications of embalmed porcine and chicken breast tissue.. Histopathological analysis of all the sonicated embalmed samples confi rmed the absence of any discrete lesion. As with the embalmed chicken and porcine samples, observed temperature rises were lower in the embalmed human breast samples. Melting of fat during sonications resulted in movement of the thermocouple, resulting in irregular temperature measurements.The preliminary results of sonicating soft- embalmed human breast tissue are discouraging, with diffi culty in creating visible lesions and irregular temperature rises due to the melting of fat. The latter reduces the tissue volume thus moving the tissue along with the thermocouple away from the ultrasound focus. The design of the chamber has now been modifi ed to prevent the movement of the tissue during sonications. The new chamber will be tested in the near future and the results will be compared with the fresh human breast samples from mastectomy specimens. Results to date have confi rmed the inability to produce a discrete lesion in soft embalmed tissue samples suggesting the need for fresh breast tissue samples for pre-clinical HIFU trails. However, more experiments are needed for fi rm conclusions. Reference: Breast Cancer Care, March 2014, BCC32 Edition 3, p 5. Acknowledgements (Funding): Fig 1. MRI Image of the The authors chamber with the tissue would like to thanks Dundee Cancer Centre showing the thermocouple (DCC) for funding this work. tip at the ultrasound focus

168 Focused Ultrasound 2014 4th International Symposium P-143-BT Feasible Study of MRgFUS of Early Breast Cancer - Report of Completion of Tuesday BC006 in Japan 14 October 2014 Kiyoshi Namba, Hiroyuki Kawami, Megumi Nakajima, Kenji Moriyama Topic: Breast Presentation Type: Poster Hokuto Hospital, Obihiro, Japan

Background/Introduction: Among applications of MRgFUS such as uterine fi broid, breast cancer (BC), metastatice bone tumor, prostate, and the brain, the breast is prsently the only organ where complete local control of breast cancer is aimed. Immediately after completion of excision study (BC003, 2002 -2003), one-arm prospective follow-up study to evaluate MRgFUS followed by adjunct radiation therapy (BC004) has been running wiht no local and systemic recurrences among 67 cases at Breastopia Namba Hospital in Japan. We report completion of excision study (BC006) , the goal of which is, similar to BC003, prospective, non-randomized, single-arm, multiinternational study, and is to develop data to evaluate the safety and effectiveness of the Exablate 2000™ (InSightec,Israel) in the ablation of breast cancer by histopathological evaluation of MRI-guidance and the effect of FUS. A prospective randomized 2-arm study of MRgFUS+radiation therapy (RT) and breast conserving surgery + RT will start September, 2014. Methods: Total of 5 eligible patients agreed to join this study after IC, May, 2012 - Feb, 2014 at Hokuto Hospital,Obihiro, Japan, after IRB’s approval. All lesions were diagnosed as discrete invasive ductal carcinoma wiht a maximal size of 2cm by ultrasound-guided vacuum biopsy (Vacora™ 10 gauge, BARD, USA) and 3T MRI (Signa HDxt, 3T, 8 channel Breast Coil, GE, USA). All the patients underwent ablation with MRgFUS. The goal of MRgFUS ablation of breast cancer is to plan and ablate the entire tumor volume in a treatable and device accessible location (lesion planned for ablation that is a minimum distance from unintended structures: dermal under surface, nipple complex and/or ribs shouls be 1.0 cm as defi ned by procedure day MR contrast-enhanced imaging, and with margins of 5-10mm by MRgFUS. MR imaging with and without MR contrast was performed at 10-21 days post ablation in order to assess the effectiveness of MRI in identifying residual disease. Pathological analyses will be performed on all excised samples to assess the endpoints of this study. Results and Conclusions: Median age was 64 ± 13 (51 - 81). All were invasive ductal carcinoma and luminal A. MRgFUS was all tolerated with a minimum of adverse effects. On pathological examination, Median necrosis of the targeted breast tumors was 97.5% ± 2.5(95 - 100%) of tumor volume. The Median % area of carcinoma within the treatment fi eld was 98 ± 2% (96% - 100%) . Retrospective analysis in two patients with residual tumor showed treatment was not delivered to the full recommended area, reaffi rming the need for precise localization and the value of contrast-enhanced images for treatment planning. Adverse effect were mild except one patient who complained of moderately uncomfortable feeling in the ablated area of the breast in one patient only during the treatment. MRgFUS of early breast cancer was suggested to be effective and safe treatment. Acknowledgements (Funding): We sincerely appreciate all six patients and their families in the local area who sincerely volunteered to cooperate this study with profound understanding of the goal of this study despite in their anxious state immediately after diagnosis of breast cancer. We are grateful with Sharon Thomsen, MD for meticulous pathological work, Mr. Jair Bauer in supporting the entire treatment. This study was funded by InSightec, Inc, Israel.

Focused Ultrasound 2014 4th International Symposium 169 P-144-LV Towards Multi-Criteria Optimization of Transducer Confi gurations Tuesday Dinesh Acharya1, Tobias Preusser2, Joachim Georgii1 14 October 2014 1 Fraunhofer MEVIS, Bremen, Germany Topic: Liver & Pancreas 2 Fraunhofer MEVIS/Jacobs University Bremen, Bremen, Germany Presentation Type: Poster Background/Introduction: One of the key challenges of using Focused Ultrasound for killing cancerous cells in the liver or pancreas is to fully destroy the tumor while at the same time widely sparing healthy tissue such as the ribs, colon, stomach, nerves, etc. This requires optimizing transducer parameters such as phase values and pressure amplitude for each single transducer elements to deliver the required energy to the target area in a feasible manner. In particular, it has to be ensured that heating of risk structures like ribs, nerves, gall bladder, intestine etc. is not too high while still delivering enough power to the focal spot. These requirements fi nally lead to a constrained multi-criteria optimization problem. Methods: To solve the constrained multi-criteria optimization problem, the requirements to kill the tumor area and save risk structures have been formulated as objective functions. For example, the destruction of the target tissue can be estimated by the integral of squared pressure amplitude (which is proportional to the heat source) inside the target area. Furthermore, to regularize the problem and to account for the limited power available for the transducer, a penalization term of squared amplitudes is subtracted from the objective function. The Rayleigh-Sommerfeld method is used to compute the pressure fi eld based on the parameters for each transducer element. Finally, the minimization of the objective function leads to an iterative optimization of the transducer parameters such as phase values and amplitudes. The MeVisLab application framework was used to implement the optimization approach. Results and Conclusions: Initially, the constrained optimization was evaluated on artifi cial geometric target structures. Gradually, additional artifi cial risk structures were introduced and fi nally real data has been used to evaluate the multi-criteria optimization technique. Positive results have been obtained during those simulations. We believe that it will be promising to use our approach for planning of Focused Ultrasound treatments in the future. Additionally, we hope that the multi-criteria optimization technique will help to perform Focused Ultrasound treatments more effectively and effi ciently as well as to make such treatments safer for the patients. Acknowledgements (Funding): This work was supported by the FUS Foundation’s Global Internship Program.

170 Focused Ultrasound 2014 4th International Symposium P-145-LV Respiratory Motion Tracking System of Hepatocellular Carcinoma Tuesday Treatment Using FUS 14 October 2014 Hiroyuki Fukuda1, Nobutaka Doba1, Kazushi Numata1, Ayako Takeda1, Topic: Liver & Pancreas Yoshiharu Hao1, Akito Nozaki1, Masaaki Kondo1, Makoto Chuma1, Shin Maeda1, Presentation Type: Poster Tatsuya Fujii2, Dongjuin Lee2, Norihiro Koizumi2, Hiroyuki Tsukihara2, Mamoru Mitsuishi2, Yoichiro Matsumoto2, Kiyoshi Yoshinaka3, Katsuaki Tanaka1 1 Yokohama City University, Yokohama, Japan 2 The University of Tokyo, Tokyo, Japan 3 National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan

Background/Introduction: One of the reasons for the long treatment time of FUS for HCC compared with RFA is that we have to adjust the target lesion which has a respiratory movement. In this study, we evaluated the usefulness of respiratory tracking system for the FUS monitoring images of hepatocellular carcinoma (HCC). Methods: The respiratory motion trackings for the focal lesions were performed in 6 patients with HCC. The maximum diameter of the tumors measured on sonography ranged from 10 to 50 mm (mean, 25 mm; SD, 5.5 mm). The FUS system (Mianyong Haifu Tech) was used under ultrasound guidance. By using the video images during the FUS treatment, we evaluated the respiratory motion tracking system retrospectively. Template matching method was applied to this respiratory motion tracking software. Results and Conclusions: In 6 cases of HCC, we evaluated the tracking system according to the tumor size, and the tracking of the tumor larger 3cm in diameter were successfully performed in all cases (n=2). On the other hand, the tracking of the tumor smaller than 3cm were performed successfully in 3 out of 4 cases. The reason for motion trackings were not performed well was thought to be that the tumor contour became unclear because the maximal cross section of the tumor go out of the plane by the respiratory movement. By using the video images during the FUS treatment (Fig.1), we evaluated the respiratory tracking, and the tumor was successfully tracked. And the tumor after FUS treatment was also tracked well even after the presence of the hyperecho around the tumor (Fig.2). In conclusion, the respiratory motion tracking using template matching method was successfully performed and have a possibility to shorten the FUS treatment time.

Figure 1a. Tumor of the monitor Figure 1b. Tumor of the monitor ultrasonography was tracked in the small ultrasonography in breath in position. square, and it was tracked successfully in breath out position.

Figure 2a Tumor surrounded with hyperecho Figure 2b Tumor surrounded with after the FUS treatment was also tracked hyperecho after the FUS treatment in both successfully in both breath out position. breath in position. Focused Ultrasound 2014 4th International Symposium 171 P-146-LV Novel Drug Delivery System Using Acoustic Control of Intratumoral Drug Tuesday Distribution 14 October 2014 Ken-ichi Kawabata1, Takashi Maruoka1, Rei Asami1, Reiko Ashida2 Topic: Liver & Pancreas 1 Presentation Type: Poster Hitachi, Ltd., Kokubunji, Japan 2 Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan

Background/Introduction: An approach of drug delivery to hypovascular tumor tissues is proposed. For such tumor tissues, it is diffi cult to deliver anti-tumor agents at enough concentration and duration by either systemic or local administration. If we could manipulate the distribution of locally injected drugs by ultrasound, an effi cient drug therapy would be possible. We have found that locally injected perfl uorocarbon droplets (PCNDs) induce mechanical effects when exposed to pulsed HIFU at intensity of several kW/cm2 and further that controllable tissue destruction is possible with the effects. In this paper, preliminary results on a new drug delivery system (DDS) by utilizing such effects will be presented. Methods: All ultrasound exposures were performed using a focused ultrasound transducer with a diameter of 78 mm and F number of 1.0 at 1.1 MHz. Typically, ultrasound pulses with an intensity of 3 kW/cm2 (pulse duration: 300 cycles, PRF: 1 kHz, total exposure time: 60 s) was applied to samples or animals in a water tank fi lled with degassed water kept at 37 degree Celsius. Samples for in vitro experiments were polyacrylamide gels having closed liquid regions. In the regions, PCNDs and sham drug particles (black ink) were incorporated. Samples for ex vivo experiments were freshly excised chicken breast tissues. Before ultrasound application, PCNDs were injected. In vivo experiments were performed with CDF1 mice subcutaneously inoculated with Colon 26 tumor tissues. Before ultrasound application, PCNDs and/or an anti-tumor drug (Adriamycin) were injected into the tumor. Results and Conclusions: 1. In vitro experiments: It was found that the pulsed HIFU application induced the drug transportation toward the transducer. After a drug transportation, the drug-distributed region could be enlarged by shifting the ultrasound focus position. 2. Ex vivo experiments: When pulsed HIFU was applied to tissues samples in the absence of PCND, no damages were observed, while white opaque lesions were created when pulsed HIFU were applied to the PCND-injected regions. With microscopic observation, it was found that the tissue structures in the opaque regions were completely destroyed. By using a spatula, those regions were easily removed. 3. In vivo experiments: When pulsed HIFU were applied to tumor tissues without PCND injection, only short- term (2-3 days) delay in tumor growth was observed. At the same ultrasound conditions, the injection of PCND prior to the pulsed HIFU resulted in a signifi cant brightness increase during application in diagnostic ultrasound scanner and further resulted in an enhanced tumor growth delay for about a week. When PCND and Adriamycin instead of PCND alone were injected to the tumor and the pulsed HIFU was then applied, a drastic tumor growth inhibition was observed. The tumor growth was completely prohibited for two weeks. In two of four cases, regrowth was observed after the two week observation but in the rest two tumor tissues did not regrowth in 30 days observation. No signifi cant anti-tumor effects were observed when Adriamycin was injected and pulsed HIFU was not applied. Our results demonstrated that the combination of a pulsed ultrasound and PCND can destroy tissue structures and further control the distribution of anti-tumor drugs. Such effect can suppress the growth of tumor tissues which cannot be achieved by the combination of ultrasound and PCND or anti-tumor drug alone. Acknowledgements (Funding): This work was supported in part by the Japan Society of Ultrasound in Medicine and Biology, and also by the Japan Society for the Promotion of Science (JSPS) through the “Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program),” initiated by the Council for Science and Technology Policy (CSTP).

172 Focused Ultrasound 2014 4th International Symposium P-147-LV PRF Thermometry During MR-guided Focused Ultrasound Ablation in a Tuesday Preclinical Thiel Model 14 October 2014 Ioannis Karakitsios, Martin Rube, Osnat Dogadkin, Senay Mihcin, Timur Saliev, Topic: Liver & Pancreas Andreas Melzer Presentation Type: Poster University of Dundee, Dundee, United Kingdom

Background/Introduction: Proton Resonance Frequency (PRF) MR Thermometry is a useful method for treatment planning with MR-guided Focused Ultrasound (MRgFUS), as it provides accurate, real-time temperature maps. Thiel is an embalming medium that retains physical properties and life-like characteristics of human and animal tissue. The aim of the present study was to determine the accuracy of PRF Thermometry during MRgFUS and to estimate the value of PRF coeffi cient of pre-clinical Thiel embalmed human and animal tissue, and compare to fresh tissue and gel phantom. Methods: PRF Thermometry was conducted on Thiel embalmed human and animal liver during MRgFUS treatment on a FUS system (ExAblate 2000, InSightec, Tirat Carmel, Israel) embedded on a 1.5T scanner (Signa HDx, GE Medical Systems, Milwaukee, USA). The temperature rise based on PRF Thermometry during treatment was compared to the actual temperature increase measured by fi bre optic thermocouples. To calculate the PRF shift coeffi cient, we applied phase-referenced PRF thermometry during cooling of the tissue, to obtain a series of phase difference, ΔΦ maps (Figure 1). The temperature difference, ΔΤ, was measured by thermocouples. The PRF shift coeffi cient was calculated from the measured ΔΦ,ΔΤ (Figure 2). Results and Conclusions: We found that the temperature differences and the PRF coeffi cient were higher for the Thiel organs than for fresh organs. This leads to the assumption that embalming a tissue with Thiel fl uid can affect PRF Thermometry. The chemical composition of the Thiel fl uid and the electrical conductivity might be some possible reasons for that. For the Thiel embalmed organs, we found temperature difference varying from 1.17C to 3.13C for ovine liver, and from 1.3C to 3.1C for human liver. For fresh tissue and phantom they were less than 0.4C. In the case of bulk heating, average values of PRF coeffi cient (±SD) were 0.016(4×10-4) ppm/C, 0.011(5×10-4) ppm/C for Thiel embalmed ovine liver and human liver, respectively (Figure 3). Acknowledgements (Funding): The authors are thankful for fi nancial assistance provided by the project FUSIMO (“Patient specifi c modelling and simulation of focused ultrasound in moving organs”) funded under the EU’s Seventh Framework Programme for Research and Technological Development. We would also like to thank Dr. Roos Eisma from CAHID project and Mrs. Helen McLeod for providing us with Thiel embalmed human tissue.

Figure 1. Reconstructed temperature maps of fresh ovine Figure 3. Graph of PRF shift liver, heated in bulk, showing the tissue temperature during coeffi cients of Thiel embalmed cooling. ovine and human liver heated with FUS or in bulk. The values of PRF coeffi cient in Thiel were plotted alongside with those for Figure 2. Example of graphs of the phase difference plotted as a fresh tissue found in literature function of temperature difference for: (a) bulk heating and (b) FUS-induced heating of Thiel embalmed human liver.

Focused Ultrasound 2014 4th International Symposium 173 P-148-LV Acoustic Detection of Attenuating Structures Using Cavitation-Enhanced Tuesday Back Projection 14 October 2014 Pascal Ramaekers, Martij n de Greef, Chrit Moonen, Mario Ries Topic: Liver & Pancreas Presentation Type: Poster University Medical Center Utrecht, Utrecht, Netherlands Background/Introduction: One of the major complications in abdominal HIFU interventions is the presence of the thoracic cage, as it obstructs the HIFU beam path. This obstruction can lead to complications during treatment such as skin burns and necrosis of intercostal muscle. Such complications can be prevented by applying an apodization law to the therapeutic transducer. To this end, one has to fi nd out which transducer elements are obstructed by attenuating structures. Current methods for the detection of attenuating structures in abdominal HIFU therapy require elaborate and lengthy image analysis, which is undesired in a clinical setting. Therefore, a method to determine transducer apodizations on-the-fl y is desired. Methods: The proposed method for the detection of attenuating structures makes use of the principle of pulse inversion imaging. In pulse inversion imaging, two pulses of opposite polarity are transmitted into the target volume. The recorded signals from both transmissions are then added in order to suppress refl ections from static scatterers. Contributions from dynamic scatterers and other non-linear contributions are preserved. This principle was applied using a high-power phased array therapeutic transducer with both transmit and receive capabilities. First, a single pulse is used to create cavitation in the target volume at the focal point of the transducer. Subsequently, a second pulse of opposite polarity is transmitted into the target volume. This pulse will be subject to scattering by the induced cavitation bubble cloud. Since the diameter of the bubbles is much smaller than the acoustic wavelength, refl ections are scattered omnidirectionally and incoherently from the focal area. As the refl ections propagate from the focal area back towards the transducer, they are subject to attenuation, projecting any attenuating structure back onto the transducer. As pulse inversion imaging suppresses refl ections from static scatterers in the beam path, the recorded signals contain predominantly refl ections from the bubble cloud in the focal area. These signals were then used to determine which transducer elements were obstructed by attenuating structures. In order to validate the proposed method, a transducer shot position was selected during an in vivo pig experiment. The shot position was placed in the porcine liver in such a way that it was partially obstructed by the thoracic cage. For this shot position, two binary transducer apodizations were obtained: one using the proposed method and one using a collision detection algorithm based on MR image analysis. Results and Conclusions: The proposed method provided a binary transducer apodization which was highly similar to the apodization obtained using a collision detection algorithm based on raytracing and MR image analysis. Advantages of the proposed method are that it is very fast, it doesnt require interactive image analysis and it detects any attenuating structures in the beam path. Disadvantages are that a high-power phased array with both transmit and receive capabilities is required, and that one has to make sure that non-inertial cavitation is induced in the focal area. Acknowledgements (Funding): European Research Council (ERC), project # ERC-2010- AdG 268906-Sound Pharma VOLTA project, Center for Translational Molecular Medicine (CTMM), project # 05T-201 iPaCT project, Seventh Framework Programme (FP7), Grant # 603028

174 Focused Ultrasound 2014 4th International Symposium P-149-LV Accounting for Sliding Motion in Fast Numerical Simulations of Abdominal Tuesday HIFU Applications for Targets under Respiratory Motion 14 October 2014 Michael Schwenke1, Jan Strehlow1, Sabrina Haase1, Christine Tanner2, Yoav Levy3, Topic: Liver & Pancreas Tobias Preusser4 Presentation Type: Poster 1 Fraunhofer MEVIS, Bremen, Germany 2 ETH Zurich, Zurich, Switzerland 3 InSightec Ltd, Tirat Carmel, Israel 4 Fraunhofer MEVIS/Jacobs University Bremen, Bremen, Germany

Background/Introduction: Non-invasive ablation and hyperthermia treatments of abdominal organs using High Intensity Focused Ultrasound (HIFU) still impose severe challenges. Especially for liver and kidney treatments, the target motion and accessibility over the entire respiratory cycle make the application of HIFU diffi cult. To allow for a safe, effective, and effi cient treatment, detailed planning and monitoring of the intervention is needed. Current general-purpose physics simulation software cannot fulfi ll the real-time requirements of the therapy-monitoring application. Our goal is to improve this by numerical simulation to allow for fast and accurate treatment planning and real-time detection of motion-induced risks during HIFU-therapy. Methods: We developed a method to numerically simulate HIFU using patient-specifi c motion information in real time. The bio-heat equation describing the temperature distribution in the patient is mathematically transformed to a static reference anatomy. The numerical solution can then be performed in the reference anatomy on a static computational domain. Patient-specifi c respiratory motion information is provided by an abdominal motion model that can be fed with sparse tracking data in the clinical setting. The respiratory motion is modelled allowing sliding motion of the inner organs along the abdominal wall. Motion information is fed into the simulation by an unstructured moving point cloud. On top of this point cloud a tetrahedral mesh is build to interpolate the motion information. The mesh is split at the abdominal wall into individually moving parts to allow the sliding motion of the liver along the abdominal wall. The numerical simulation thereby resolves the sliding boundary and allows the prediction of the temperature rise also in the beam path between transducer and target. Fast US beam steering is simulated using ultrasound pressure fi eld pre-computations for key states over the respiratory cycle. Any remaining location mismatch between closest pre-computation and actual target location is compensated using an additional transformation. The numerical simulation method is integrated into a HIFU- therapy planning tool. Based on image data the target volume, anatomical and risk structures are defi ned. Treatment planning is then performed guided by direct feedback from the numerical simulation including respiratory motion of the domain. Using the feedback from the simulation, the user can manually optimize transducer and target location and HIFU parameters. Results and Conclusions: The method accounts for patient-specifi c anatomy and motion information in real time. Sliding motion of the inner organs along the abdominal wall is accounted for by the simulation. The transformation to the static reference frame results in an accurate scheme for long simulation durations. The developed method can be a possible important building block for HIFU-therapy planning and conduction in moving organs. Acknowledgements (Funding): The research leading to these results has received funding from the European Community’s Seventh Framework Programme FP7/2007-2013 under grant agreement n° 611889.

Focused Ultrasound 2014 4th International Symposium 175 P-150-LV Ultrasound Tracked Motion Compensated Focused Ultrasound System Tuesday Evaluated on Ex Vivo Ovine Livers 14 October 2014 Jan Strehlow1, Xu Xiao2, Michael Schwenke1, Ioannis Karakitsios3, Markus Topic: Liver & Pancreas Domschke3, Senay Mihcin3, Yoav Levy4, Tobias Preusser5, Andreas Melzer3 Presentation Type: Poster 1 Fraunhofer MEVIS, Bremen, Germany 2 Institute for Medical Science and Technology, Dundee, United Kingdom 3 University of Dundee, Dundee, United Kingdom 4 InSightec Ltd, Tirat Carmel, Israel 5 Fraunhofer MEVIS/Jacobs University Bremen, Bremen, Germany

Background/Introduction: The application of FUS in abdominal organs such as the liver or the kidneys is impeded by a number of complications. One of the most challenging is organ motion due to breathing. To achieve ablation in a target within a moving organ the FUS system has to be steered to focus on the same anatomical position. We present a prototypical system that tracks the motion of an ex vivo ovine liver via diagnostic ultrasound (US) and adjusts the focal spot to a fi xed anatomical position. Methods: Our setup consists of four systems: An organ in breathing-like motion is modeled by a robotic arm periodically moving a fresh ovine liver in water tank. The liver motion is assumed to be unknown, its movement range is 20 mm, and one cycle takes approximately 8 seconds. A diagnostic US system is used to track vessels in the liver (Figure 1). Real time tracking positions are send to a therapy control system that calculates the position of a target using a linear motion model. The therapy control adjusts the focal spot of a steerable FUS system to match the computed target position. Since an active FUS will render our US-tracking images unusable the FUS is pulsed, leaving short imaging windows for tracking. Temperature is assessed by a thermocouple inserted into the liver. The target area is defi ned in vicinity of the thermocouple. Temperature curves of a moving and a static organ are acquired for different update rates and different output powers of the FUS system. The temperature curves of static and moving scenarios are compared to assess the ability of the system to compensate motion. Results and Conclusions: The US-tracking of the organ works reliably when FUS was switched off for at least 80 ms with 2-4 hz. The output power of the FUS system does not infl uence the reliability of the system. Temperature curves for the static and moving scenarios show only minor differences. Figure 2 shows the temperature curves acquired by sonication with a) 15 w, b) 30 w, and c) 45 w for 20 seconds with a sonication update rate of 9 hz and 3 hz US-tracking. The average temperature differences are a) 0.33 °C b) 0.56 °C, and c) 1.0 °C. The area under the curve differs by a) 14.09%, b) 1.17%, and c) 0.99% (static scenario as reference). Our US-tracked steered FUS system can compensates unknown motion that is similar to the one induced by respiration. In our phantom a linear motion model was suffi cient to compute the target position. For in vivo experiments this motion model has to be changed to a deformable one. The system, however, demonstrates the feasibility of US tracked steered FUS. Acknowledgements (Funding): The research leading to these results has received funding from the European Community’s Seventh Framework Programme FP7/2007- 2013 under grant agreement n° 611889. Parts of the Liver vessels used as tracking research were supported by the the University of Dundee, features to assess organ motion a registered Scottish Charity, No: SC015096 Comparison of temperature curves measured during sonications of static and moving organ. Focal spot position was updated with 9 hz and tracking images were acquired every 3 hz. Output power was a) 15 w, b) 30 w, and c) 45 w

176 Focused Ultrasound 2014 4th International Symposium P-151-LV Ex vivo Ovine Liver Model Simulating Respiratory Motion and Blood Tuesday Perfusion for Validating Image-guided HIFU Systems 14 October 2014 Xu Xiao, Markus Domschke, Benjamin Cox, Helen McLeod, Ioannis Karakitsios, Topic: Liver & Pancreas Andreas Melzer Presentation Type: Poster University of Dundee, Dundee, United Kingdom

Background/Introduction: The effect of moving organs and blood perfusion on image guided procedures such as focused ultrasound is challenging therefore we have developed ex vivo ovine liver phantoms to simulate respiratory motion and blood perfusion. The simulator was used to validate ultrasound image-guided HIFU treatment when the target tissue was moving. Methods: The respiratory liver motion simulator consists of a physical ovine liver, agar- gelatine block surrounding the liver, a medical air balloon which is connected to a lung ventilator, and two water balloons which are used to move the phantom back to its original position. The whole setup was MR compatible, including the ventilator which is used to provide simulation of respiratory motion. The movement generated by the simulator was analysed via an MR compatible ultrasound system, and this real-time motion information was used to guide a dynamic high intensity focused ultrasound system (Exablate 2100 system, 0.55MHz) to steer its focus to follow this motion (Figure 1). The liver model is perfused via an extracorporeal circuit driven by a heart lung bypass machine (HL30 Maquet, Germany). Continuous non pulsatile input into the portal vein of 220 ml/min saline, with output free draining into the venous system, forming a perfusion circuit. (Figure 2). Digital Subtraction Angiography contrast images of the vasculature (OEC 9900, GE USA: Ultravist 370, Bayer HealthCare) to scanning with the MR and ultrasound doppler. The perfused vessel was then scanned in the 1.5 T Signa HDxGE (GE, USA) and ultrasound wireless scanner (Accuson SIEMENS, GERMANY). Results and Conclusions: Mean displacement between expiration and inspiration was up to 30 mm along superior-inferior direction. The setup also allowed motion in left-right direction by reducing the width of the phantom block. After establishing the saline water perfusion, the vessels of the ovine liver provides a large contract from the background in x-ray and MR scan (FRFSE-XL, TE=8.7, TR=400). And a clear pulse was observed in the ultrasound colour Doppler (Figure 3). The ovine liver movement generated by the respiratory simulator is comparable to that of a human liver in vivo. This model could be used to test the infl uence of motion on image guided focused ultrasound therapy. The successful re-creation of physiological fl ow in the peripheral arteries of ovine liver has provided a model for testing the infl uence of blood fl ow rate on the image guided focused ultrasound sonication. Therefore the phantom provides a low-cost option for validating ultrasound and MR image- guided focused ultrasound treatment. Acknowledgements (Funding): The research leading to these results has received funding from the European Community’s Seventh Framework Programme FP7 under grant agreement n° 611963.

Figure 1. Illustration and photo of respiratory liver motion simulator, ovine liver is embedded into 3% agar-gelatine phantom

Figure 2. Setup of perfusion of ovine liver

Figure 3. X-ray scan, and MR scan and ultrasound scan results of the ovine liver phantom Focused Ultrasound 2014 4th International Symposium 177 P-152-LV A Framework for Slow Physiological Motion Compensation During HIFU Tuesday Interventions in the Liver: Proof of Concept 14 October 2014 Cornel Zachiu, Baudouin Denis de Senneville, Sjoerd Crij ns, Bas Raaymakers, Chrit Topic: Liver & Pancreas Moonen, Mario Ries Presentation Type: Poster University Medical Center Utrecht, Utrecht, Netherlands

Background/Introduction: While respiratory motion compensation for HIFU interventions for liver cancer therapy has been extensively studied, the infl uence of slow physiological motion, such as peristalsis, has so far been largely neglected. During the lengthy intervention, the magnitude of the latter can exceed acceptable therapeutic margins and lead to a substantial mismatch between planned ablation volume, thermal dose estimates and the measured non-perfused volume (NPV). Given the episodic nature of a HIFU intervention, this study proposes the integration of a 3D motion compensation procedure based on MR- images for slow physiological motion and validates the approach on in vivo ablations on a porcine liver. Methods: Overall strategy: A volumetric HIFU ablation was completed over a time span of 2h using a Phillips Sonalleve system with a respiratory gating strategy for both energy delivery and all MR-imaging. A 3D image was acquired before the fi rst sonication, as well as after each sonication (Δt=5min) to track slow physiological motion. The estimated motion fi elds were used to: 1) Estimate on the planning image the position of the true ablated anatomy; 2) Register the temperature maps into the initial reference position in order to compute a correct thermal dose estimate, and 3) Register the NPV to the initial position. Assessment of 3D liver displacements: Liver displacements were estimated using an optical fl ow algorithm applied on 3D MR images. MR imaging protocol: 3D T1-weighted images were acquired on a 1.5T Philips Achieva MR scanner (Philips Healthcare, Best, The Netherlands) using the following protocol: TE=2ms, TR= 4.3ms, matrix size=192x192x75, FA=10°, voxel size=2x2x2mm3. Results and Conclusions: Motion tracking revealed an initial shift of up to 4mm during the fi rst 10min, which is most likely caused by the muscle relaxant effect of anesthesia and a subsequent continuous shift due to bowel gas development of ~2mm until the end of the intervention. This leads to a continuously increasing mismatch of the initial shot planning, the thermal dose measurements and the true underlying anatomy as shown in Fig.1a,b. The estimated displacements allowed correcting the planned sonication cell cluster positions to the true target position (Fig.1a), as well as the thermal dose estimates (Fig.1c) and the NPV- measurement (data not shown). A spatial coherence of all three is particularly important to assure a confl uent ablation volume and to prevent remaining islets of viable malignant tissue. The in vivo experiment also demonstrates that the proposed framework is compatible with the work-fl ow of a HIFU intervention under clinical conditions. Acknowledgements (Funding): This work was supported by the STW OnTrack grant.

Figure 1. Planned (yellow) and motion corrected (red) sonication cluster overlaid on the corresponding anatomy in the planning image. The hyper-intense regions represent the (b) non-corrected (c) corrected location of the anatomy that receives a lethal thermal dose

178 Focused Ultrasound 2014 4th International Symposium P-153-EA Inhibition of Melanoma Growth in a Subcutaneous Model using Ultrasound Tuesday with Low Duty Cycle 14 October 2014 Yuta Ando, Kelsie Timbie, Ji Song, James Larner, Richard Price, Kumari Andarawewa Topic: Emerging Applications University of Virginia, Charlottesville, Virginia, United States Presentation Type: Poster Background/Introduction: Melanoma has a 5-year survival rate of <10%, primarily due to therapeutic resistance and immune tolerance. Durable responses to therapy of metastatic melanoma are enhanced when the anti tumor immune response is activated. FUS is an emerging non-invasive treatment modality for localized treatment of cancers. Traditionally FUS has been used exclusively for thermal ablation of the target sites; biological responses associated with both thermal and mechanical damage have not been investigated. Damaged tumor cells have release endogenous danger signals, which stimulate an immune response, suggesting that the patient’s dying cancer cells may serve as a therapeutic vaccine which stimulates an antitumor immune response. Specifi cally, we hypothesize that FUS will augment tumor antigen release and danger signals to mediate rejection of both FUS treated and untreated tumors. Methods: Studies using C57BL6 mice inoculated subcutaneously with B16 melanoma cells were approved by the institutional animal care and use committee. When tumors became palpable, 100 cycles of 1MHz ultrasound was applied to the tumor every 5 seconds for 5, 10 or 20 minutes. Following treatment, tumor growth, survival, necrosis, and apoptosis were measured. Tumor volume was evaluated by taking daily measurements with digital calibers. Standard H & E staining was performed to evaluate histological changes that may have occurred as a result of the ultrasound exposures. The detection of apoptotic cells was performed using staining for Caspase 3. Results and Conclusions: Tumors harvested 3 days after treatment were analyzed using H & E and caspase 3 staining. Staining with H & E indicated that signifi cantly more necrotic tissue was present in all tumors treated with ultrasound. Staining for Caspase 3 exhibited more extensive apoptosis in all treatment groups when compared to untreated tumors. Furthermore we found that ultrasound treatment dramatically decreased tumor size. 1MHz ultrasound with low duty cycle can inhibits melanoma tumor. We will use this platform to characterize the immune response in treated tumors. We also plan to combine microbubbles with ultrasound to see if there is a synergistic effect on inhibition of tumor growth. Acknowledgements (Funding): This work is supported by funds from University of Virginia, Department of Radiation Oncology, Focused Ultrasound Center funds.

Focused Ultrasound 2014 4th International Symposium 179 P-154-EA Ultrasound-microbubble Targeted Delivery of ICAM-1 in Mouse Model of Tuesday Peripheral Arterial Disease 14 October 2014 Lena Badr Topic: Emerging Applications University of Virginia, Charlottesville, Virginia, United States Presentation Type: Poster Background/Introduction: Peripheral arterial disease (PAD) affects 12 million people in the United States. Unfortunately, current treatments are highly invasive and have limited effi cacy. Ultrasound (US) in conjunction with microbubbles (MB) has recently been explored as a non-invasive strategy for the delivery of intravascularly circulating therapeutic agents. US mediated MB oscillation can lead to non-damaging, reversible and localized vascular permeabilization resulting in substantial increases of nanoparticle (NP) concentrations in US- treated tissue. Furthermore, by coating NPs with a brush layer of polyethylene glycol (PEG), NPs have long circulating half-lives and limited toxicity. This study investigates the ability of US to deliver ICAM-1-bearing PEG/polyethylenimine (PEG/PEI) NPs to the vascular endothelium in a mouse model of PAD. ICAM-1, an adhesion molecule, expressed post- occlusion by the endothelium of collateral arteries has previously been shown to aid in blood fl ow restoration. Overexpression of ICAM-1 in this model aims to re-establish pre-occlusion blood fl ow non-invasively. Methods: C57BL/6 mice were secured supine and their hind limbs were depilated. A 0.75’’ diameter 1 MHz unfocused US transducer was ultrasonically coupled. The tail vein was cannulated and a coinjection of MBs and 40 μg of ICAM-1 and luciferase bearing NPs was coincident with US treatment. MBs were injected at a dosage of 105/g. Luciferase and ICAM-1 transgenes were under control of the beta-actin promoter. Sonications were performed with a 0.015% duty cycle, a sonication time of 12 minutes, and a peak negative pressure of 0.6 MPa. Three days post US treatment, mice underwent femoral artery ligation (FAL) surgery to simulate an occlusion. Luciferase expression was assessed through bioluminescent imaging following a 150 mg/kg injection of luciferin in an In Vivo Imaging System at 3, 5, 7, 10, and 14 days after US treatment. Following euthanasia, the animal was perfused transcardially with paraformaldehyde and microfi l and whole-mounted or sectioned. Sections were immunostained for smooth muscle alpha actin and ICAM-1 to further investigate ICAM-1 expression in collateral arterial endothelial cells. Results and Conclusions: Delivery of luciferase-bearing PEG/PEI NPs resulted in robust, localized bioluminescence through day 14, the last day tested. Bioluminescence was not detected on the contralateral non-treated limb. Bioluminescence peaked 7 days after US treatment. US mediated vascular permeabilization presents a novel platform for drug and gene delivery technologies. Our results indicate that robust, localized transgene expression can be achieved in a mouse model of PAD. Currently, we are investigating the potential for enhanced US-mediated ICAM-1 gene therapy. Acknowledgements (Funding): This work was funded through grant support from the National Institutes of Health (R01 CA164789). LB was funded as part of the Focused Ultrasound Foundation Global Internship Program.

Localized bioluminescence shown in sonicated left hind limb. Bioluminescence was measured on day 7 after US treatment. No bioluminescence was detected on contralateral non-sonicated limb.

180 Focused Ultrasound 2014 4th International Symposium P-155-EA The Importance of Phase Drift Correction for Accurate MR Thermometry in Tuesday Long Duration MR-HIFU Exposures 14 October 2014 Chenchen Bing1, Charles Mougenot2, Robert Staruch3, Elizabeth Ramsay4, Alain Topic: Emerging Schmitt5, Juha Kortelainen6, Julius Koskela7, Rajiv Chopra1 Applications Presentation Type: Poster 1 University of Texas Southwestern Medical Center, Dallas, Texas, United States 2 Philips Healthcare Canada, Toronto, Canada 3 Philips Research, Dallas, Texas, United States 4 Sunnybrook Health Sciences Centre, Toronto, Canada 5 Sunnybrook Research Institute, Toronto, Canada 6 VTT Technical Research Centre of Finland, Tampere, Finland 7 Philips Healthcare, Vantaa, Finland

Background/Introduction: In MRI-guided high-intensity focused ultrasound (MR- HIFU) therapy, temperature-dependent proton resonance frequency (PRF) shift is a key factor to quantify and visualize the spatial heating pattern in treated and surrounding tissue. However, during treatment, multiple scanner-related changes can impact the accuracy of the temperature measurements obtained with the PRF shift method and cause an over/ under estimation of temperature, which can be a major safety issue for treatments involving real-time temperature control. Hence, it is necessary to apply corrections to ensure accurate temperature measurements during heating. Prior to image acquisition, the central MR

frequency F0 can be measured to adjust the F0 of next image acquisition. After acquisition, corrections can be applied to the acquired images to remove scanner-related infl uences, most importantly phase drift. Different phase drift correction algorithms such as conventional and polynomial adaptive drift correction estimate the background phase by fi tting a linear or polynomial to the image phase outside the treatment area and perform the correction accordingly. The goal of this study was to understand the performance of these algorithms for long heating durations as would be experienced during hyperthermia or transurethral HIFU (>20 minutes). Methods: Data was collected in phantom, animal and human studies ongoing within our research program using both Philips Achieva 3.0T and Ingenia 3.0T MR scanner (Philips Healthcare, Netherlands). Data-sets included heating and no heating, as well as non-invasive and minimally-invasive HIFU devices. MR thermometry with echo-planar imaging (EPI) and conventional gradient echo (FFE) pulse sequences were investigated, with varying repetition time (TR) and EPI factor. Several drift correction algorithms were evaluated, including conventional correction, zero and higher order polynomial adaptive correction, dynamic F0 stabilization by the scanner, and the default drift correction of the clinical MR-HIFU system. Raw data with no correction was analyzed as well. Data acquisition ranged from 5 to 30 minutes, representing the type of acquisition that would be used during hyperthermia or transurethral HIFU. Results and Conclusions: The average temperature change measured due to drift was approximately 2.6°C per min without drift correction for an EPI sequence while close to 0°C per min for an FFE sequence. The temperature change decreased to 0.1°C per min under conventional drift correction and even further

using adaptive drift correction and dynamic F0 stabilization. With longer TR (50ms vs. 33ms) and larger EPI factor (15 vs. 11), the temperature change decreased to 1.7°C per min and 1°C per min separately. In vivo data (rabbit) indicated an average change of 3°C per min (range from 3°C to 3.5°C per min) and was signifi cantly reduced under all four algorithms. During the clinical prostate HIFU treatments a drive of 3°C per min was observed. Image-shifts in the phase encode direction of approximately 1 pixel (1mm) every 10 minutes were measured in the absence of dynamic stabilization. In conclusion, drift corrections is necessary for accurate thermometry during long duration HIFU exposures. Acknowledgements (Funding): CPRIT R1308, Evelyn and M.R. Hudson Foundation, research contract with Philips Healthcare, NIH 1R21CA159550

Focused Ultrasound 2014 4th International Symposium 181 P-156-EA Focused Ultrasound Treatment of Methicilin Resistant Staphylococcus Tuesday Aureus Induced Abscesses: Pre-clinical Study 14 October 2014 Laura Curiel1, Charles Mougenot2, Birgit Rieck1, Kunyan Zhang3, David Bates1, Topic: Emerging Samuel Pichardo1 Applications Presentation Type: Poster 1 Thunder Bay Regional Research Institute, Thunder Bay, Canada 2 Philips Healthcare Canada, Toronto, Canada 3 University of Calgary, Calgary, Canada

Background/Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen that particularly threatens immunocompromised patients who are prone to develop infections that are less and less responsive to regular treatments. Moreover, MRSA can cause abscesses that are diffi cult to treat. Because of its capability to induce a rise of temperature at a very precise location and the known sensitivity to heat of bacteria, FUS can allow for a localized treatment for MRSA-induced abscesses. Methods: MRSA abscesses (strain USA400) were induced after injecting a bacteria suspension at a concentration of 1.32±0.5x105 colony forming units (cfu)/mL subcutaneously in the left fl ank of BALB/c mice. An abscess of 6±2 mm in diameter formed after 48hrs. A small animal focused ultrasound system was then used to perform exposures on the abscess using a transducer operating at 3 MHz with a focal length of 50mm and diameter of 32mm. The focal point was positioned 2mm under the skin at the abscess center and four ultrasound exposures of 9s each were applied to each abscess under Magnetic Resonance Imaging guidance. Real-time estimation of change of temperature was done using water-proton resonance frequency (PRF) and a communication toolbox (matMRI) developed in-house. Three experimental groups of animals were tested: control, moderate temperature (52°C) and high temperature (64°C). The response to the treatment was assessed by culture and count of bacteria after treatment at two different time points: 1 and 4 days after treatment. Immune response after the treatment was evaluated by a Myeloperoxidase (MPO) assay that determined neutrophil recruitment as well as white blood cell count to evaluate the systemic infl ammatory response. Results and Conclusions: Treated abscess diminished on external size 1d after treatment and there were no open wounds. A signifi cant reduction on bacterial count was obtained for the high temperature treatment and it was observed 4 days after the treatment. The median (lower to upper quartile) bacterial count 1 day after treatment was 6.18x103 (0.76x103 to 11.18x103), 2.86x103 (1.22x103 to 7.07x103) and 3.52x103 (1.18 x103 to 6.72 x103) cfu/100mL for control, moderate and high temperature groups, respectively; for the 4-day end point, the count was 1.37x103 (0.67x103 to 2.89x103), 1.35x103 (0.09x103 to 2.96 x103) and 0.07x103 (0.03x103 to 0.36x103) cfu/100mL for control, moderate and high temperature. The MPO amount and the white cell count remained unchanged between groups and days, indicating no change on local neutrophil recruitment and no systemic infl ammatory response caused by the treatment. Focused ultrasound can induce a therapeutic effect in abscesses induced by MRSA. This effect is observed as a reduction of the number bacteria without signifi cantly altering the amount of MPO at the site of an MRSA-induced abscess. These initial results suggest that focused ultrasound is a viable option for the treatment of localized MRSA-related infections. Acknowledgements (Funding): Our group would like to thank the Natural Sciences and Engineering Research Council of Canada for funding this research.

Bacterial count after exposure as a function of temperature and time point

Monitoring of FUS exposure on MRSA abscess in mice

182 Focused Ultrasound 2014 4th International Symposium P-157-EA Strategies for Reducing Regulatory Barriers to Focused Ultrasound Tuesday Technology 14 October 2014 Liz Dobrenz Topic: Emerging Applications Focused Ultrasound Foundation, Charlottesville, Virginia, United States Presentation Type: Poster Background/Introduction: The U.S. Food and Drug Administration (FDA) has automatically classifi ed focused ultrasound (FUS) devices Class III, which requires sponsors to demonstrate the safety and effectiveness of a device through clinical trials. This requirement adds signifi cant time and cost to the device development process; reclassifi cation to Class II would be highly benefi cial for the future of FUS. Methods: Statute outlines two strategies for reclassifying FUS to a class with lower regulatory standards: fi ling a petition for reclassifi cation based on new information and fi ling a de novo application to request a risk-based review of a novel technology. Results and Conclusions: There are three additional options for Focused Ultrasound Foundation action with less direct effects on reclassifi cation: creating grants for regulatory science, educating stakeholders about FDA, and increasing direct-to-FDA advocacy. In this paper, each of these options and alternatives is assessed based on its likelihood of achieving success, time to success, and cost. Ultimately, this analysis recommends that the Focused Ultrasound Foundation take no statutory action to reclassify FUS at this time, and initiate efforts to increase Foundation stakeholder understanding of FDA regulations and their impact on the future of FUS.

Focused Ultrasound 2014 4th International Symposium 183 P-158-EA The Feasibility of Using Arterial Spin Labeling for Visualization of Non Tuesday Perfused Volumes after HIFU Treatment in the Kidney 14 October 2014 Frank Eschbach, Martij n de Greef, Joost Wij lemans, Chrit Moonen, Mario Ries Topic: Emerging Applications University Medical Center Utrecht, Utrecht, Netherlands Presentation Type: Poster Background/Introduction: MR guidance of High Intensity Focused Ultrasound (MFgHIFU) ablation offers the possibility to determine if complete tumor ablation has been established based on imaging the non-perfused volume (NPV). For thermal therapy, contrast enhanced (CE) imaging with a gadolinium-based contrast agent is currently the golden standard to quantify the NPV. A drawback of this method is that gadolinium based intra- vascular contrast agents interfere with HIFU therapy in two ways. First, ablation can release toxic free gadolinium, by long-term decomposition of the encapsulating chelate. Second, it degrades the quality of MR-thermometry. Therefore, even if residual viable tumor tissue is observed with CE-MRI, the treatment cannot be continued. To address this problem for HIFU interventions on the kidney, this study explores other means of perfusion imaging, such as Arterial Spin Labeling (ASL). Martirosian et al. used Flow-sensitive Alternating Inversion Recovery (FAIR) to image perfusion in the kidneys without the use of contrast agents. This in vivo study on a porcine model investigates if ASL potentially allows to perform NPV measurements during therapy and to continue the intervention if incomplete ablation of the target volume is observed. Methods: Image acquisition: An ablation in the renal cortex was performed in an in vivo porcine model. The animal was positioned decubitus right on a Sonalleve HIFU platform (Philips Healthcare, Vantaa, Finland), was under general anesthesia and mechanically ventilated. All scans were performed on a clinical 1.5T MR scanner (Achieva, Philips Healthcare, Best, The Netherlands). 7 treatment cells of 4 mm in diameter each were ablated in a honeycomb-like pattern. To image the NPV without the use of contrast agents, single shot gradient recalled echo-planar imaging of a coronal slice centered at the ablated region was preceded by slice selective inversion and global inversion (in an alternating fashion). Imaging parameters: in-plane resolution: 3x3 mm2, slice thickness: 5mm, TE/TR: 44/4500 ms, inversion time: 1200 ms, matrix size: 128 x 128, number of dynamics: 20, slice selective inversion slice thickness: 10mm, non-selective inversion slice thickness: 300 mm. For the CE scan, a 3D FFE THRIVE sequence was used with an isotropic resolution of 1.5mm, a TR of 5.4 ms, a TE of 2.6 ms, a fl ip angle of 10, 2 averages and a reconstruction matrix of 512x512. Data analysis: Matlab (R2013b, The MathWorks, Inc., Natick, MA, USA) was used to realign the individual images, after which a subtraction per dynamic was performed. The subtractions were subsequently summed. Mevislab 2.4 (MeVis Medical Solutions AG, Bremen, Germany) was used to draw contours of NPV. Results and Conclusions: Figure 1 shows the resulting FAIR images before and after ablation. After ablation, the NVP is visible as a dark area at the left of the kidney. Figure 2 shows the corresponding CE image (golden standard). The yellow contour delineates the NPV as seen in the FAIR image. There is a clear correspondence in terms of location and shape in the NPVs as observed in both images. The NPV in the FAIR image is smaller than Figure 1. FAIR EPI image to the NPV in the CE image, which is, considering the difference in resolution, most likely of the kidney, coronal orientation, before ablation due to a partial volume effect. The preliminary results show good correspondence between (a) and after ablation (b). NPVs in the FAIR and CE images and therefore indicate FAIR to be a promising method After ablation, the NPV is to monitor the NPV progression in between the sonications. Future work is focused on an seen as a black volume on improved spatial resolution and a reduction of the required acquisition of the FAIR scans. the left side of the kidney. Acknowledgements (Funding): This work was fi nancially supported by the Center for Translational Molecular Medicine (CTMM), project VOLTA (grant 05T-201). Figure 2. CE image, coronal orientation, The NPV is clearly visible as a black volume. The contour of the FAIR NPV is shown in yellow. Both the location and shape are comparable, unlike the size, which is smaller. 184 Focused Ultrasound 2014 4th International Symposium P-160-EA Simultaneous T2 Mapping in Near-fi eld Subcutaneous Fat Layer and PRFS Tuesday Temperature Mapping in Target Region using Fast Interleaved Sequences 14 October 2014 to Monitor MR-HIFU Sonication Topic: Emerging Edwin Heij man1, Steffen Weiss2, Jaakko Tolo3, Holger Grüll1, Jochen Keupp1 Applications Presentation Type: Poster 1 Philips Research, Eindhoven, Netherlands 2 Philips, Hamburg, Germany 3 Philips Healthcare, Vantaa, Finland

Background/Introduction: MR guided high-intensity focused ultrasound (MR-HIFU) is establishing as a new treatment option for various diseases that elegantly combines two non-invasive technologies. Treatment options include HIFU ablation as well as adjuvant HIFU hyperthermia – precisely controlled by MR temperature mapping to adjust the applied HIFU acoustic power and focal spot position in real-time. Near-fi eld ultrasound heating of the skin and heat accumulation in the subcutaneous fat layer can become problematic due to the low thermal conductivity of fat. Currently, temperature mapping based on the proton resonance frequency shift (PRFS) is applied during clinical MR-HIFU treatment. However, reliable PRFS temperature maps can only be acquired in non-adipose tissue, while T2-based temperature mapping would be preferable for adipose tissue.1,2 However, for many HIFU applications, simultaneous temperature monitoring would be desirable in separate FOVs, like the adipose far fi eld and non-adipose tumor regions. We here propose a new technology which quickly interleaves a PRFS (gradient-echo) and a T2 (dual spin-echo) sequence on the level of individual repetitions with microsecond latency. Mutual infl uences of interleaved PRFS and T2 mapping were analyzed and feasibility was demonstrated in a model setup using ablation conditions on a clinical MR-HIFU system. Methods: A dynamic interleaved scan protocol was developed containing a PRFS sequence (TR/TE=41/19.5 ms; fl ip angle = 19.5°; FOV=250x250 mm2; resolution = 1.42x1.42 mm2; slice thickness = 4 mm; EPI factor = 7; 3 slices; NSA = 2; fat suppression; dyn. acq. time = 4 s) and a dual-echo single slice fast spin-echo (FSE) sequence for T2 mapping2 (TR/TE1/ TE2= 581/40/180 ms; FOV=250x250 mm2; resolution = 1.42x1.42 mm2; slice thickness = 5 mm; FSE factor = 40 ; water suppression; temporal resolution = 1.7 min). Real-time switching (~10 micro-seconds3 between PRFS (package acquisition) and dual-echo FSE acquisitions (single k-space line acquisition for both echoes) is performed by defi ning parallel threads with individually stored runtime variables in the modifi ed MR spectrometer software. Phantom (TO5, Diagnostic Sonar, United Kingdom) and ex vivo (pork steak with 1 cm thick subcutaneous fat layer) experiments were performed on a 3.0T MR-HIFU system (Sonalleve, Philips Healthcare, Finland) to evaluate potential interference due to none equilibrium magnetization and accuracy of PRFS and T2 mapping in the interleaved mode during ablation. The MatMRI and MatHIFU toolbox4 were used to retrieve the PRFS images and T2 maps during the ablation of pork meat (single spot; 2x2x7 mm3; 20 W of acoustic power; 1.2 MHz frequency). Results and Conclusions: As a result of the phantom tests on T2 quantifi cation and interference between the sequences a delay of 200ms was added between the end of a full package PRFS acquisition and the water suppressed dual-echo FSE acquisition to avoid ghosting image artifacts in the T2 maps. A good correlation was found between the calibrated T2 values of the TO5 phantom and the values measured with the interleaved dual-echo FSE (Figure 1). Figure 2 shows a snapshot 3D view of the pork meat overlaid with the PRFS temperature map oriented along the HIFU transducer beam axis and the T2 map (temporal resolution 1.7 min) within the subcutaneous fat layer during and a sonication, monitored over a total period of 24 minutes. The T2 maps acquired during sonication (Figure 3A, B and C) and 17min post sonication (Figure 3D) show the T2 changes over time in great detail. Heat accumulation in a ring shape region in the far fi eld during sonication as well as diffusive spread of the heat and slow temperature decay after switch-off was observed. Dynamic interleaved sequences can provide detailed temperature information in the near-fi eld and the target region using a fast fi eld echo sequence in adipose tissue and gradient echo sequence in none-

Focused Ultrasound 2014 4th International Symposium 185 adipose tissue, respectively, with different orientation and/or FOV during a MR-HIFU sonication. References: 1. Heijman et al., Proc. FUSF Symposium 2012, P-132-EA 2. Baron et al., MRM 20 (2013) 3. Gdaniec N et al., Proc. ISMRM 21:3714(2013) 4. Zaporzan et al., Journal of Therapeutic Ultrasound 1:7(2013) Acknowledgements (Funding): This research was performed within the framework of the Center for Translational Molecular Medicine (www.ctmm.nl), project VOLTA (grant 05T-201) and within the framework of the European Commission project iPact.

186 Focused Ultrasound 2014 4th International Symposium P-161-EA Identifi cation of MR-HIFU Ablated Tumor with Multi-parametric MR Tuesday Analysis at 3T 14 October 2014 Stefanie Hectors1, Igor Jacobs1, Jochen Keupp2, Monique Berben2, Holger Grüll2, Topic: Emerging Gustav Strij kers1, Klaas Nicolay1, Edwin Heij man2 Applications Presentation Type: Poster 1 Eindhoven University of Technology, Eindhoven, Netherlands 2 Philips Research, Eindhoven, Netherlands

Background/Introduction: To advance the clinical applicability of HIFU-treatment for malignant tumors accurate treatment evaluation is of key importance. In a previous study we have developed a multi-parametric (mp) MRI analysis at 6.3 T to identify HIFU-treated tumor (1). In the present study, a clinical 3T MR-HIFU system was used to facilitate clinical translation of the developed methods. In addition, the more advanced MR methods amide proton transfer (APT) imaging (2) and T1ρ imaging were included in the mp MR protocol (3). Cluster analysis was performed on the mp MRI data and the optimal set of MR parameters to identify successfully treated tumor was assessed by quantitative comparison with histology. Methods: 9L glioma tumor-bearing (hind limb) Fischer 344 rats were subjected to MRI before (n=12), directly after (n=12) and 72 h after (n=6) HIFU. A non-treated control group was included (Figure 1). All animals were positioned in a dedicated rat MR-HIFU setup (4), placed on the tabletop of a clinical Philips 3T Sonalleve MR-HIFU system (Philips Healthcare, Helsinki, Finland). Partial tumor ablation (4 mm diameter treatment cell) was performed with an acoustic power of 35 W and duration of 90 s. During ablation, temperature maps were acquired from which thermal dose maps were calculated in the center slice of all MR acquisitions. The mp MRI protocol consisted of quantitative assessment of: T1, T2, apparent diffusion coeffi cient (ADC), APT-weighted signal and T1ρ. DCE-MRI (0.2 mmol/kg Gd-DOTA) was only performed after ablation for the treated rats. After the fi nal measurements, tumors were marked, excised and sliced according to the central MR slice for histology. NADH diaphorase-staining was performed to assess tumor viability. The DCE- MRI derived transfer constant Ktrans and extravascular extracellular volume fraction ve were determined using the Standard Tofts model. In addition, non-perfused tumor fractions were determined based on the level of signal enhancement. K-means clustering with 4 clusters and all possible feature vectors (i.e. all different combinations of MR parameters) was performed on the MR parameter values in the tumor (excluding the DCE-MRI results). Clusters in which the fraction of pixels signifi cantly increased after HIFU were classifi ed as non-viable. Subsequently, the optimal feature vector for identifi cation of ablated tumor was determined by correlation analysis between clustering-derived and histology-derived non-viable tumor fractions. Results and Conclusions: The whole tumor averaged ADC was signifi cantly different directly after HIFU compared to before HIFU (p=0.036). At 72 h after HIFU, the average T1 (p=0.041) and ADC (p=0.001) were signifi cantly changed. The average Ktrans was signifi cantly lower at both time points after HIFU (p=0.013 and p=0.048 directly after and 72 h after HIFU, respectively) compared to the control rats, whereas ve¬ was only signifi cantly lower directly after HIFU (p=0.000). No signifi cant differences between the experimental time points were observed in the control rats. Figure 2 shows correlation analyses between 240 EM fractions, non-perfused tumor fractions and histology-derived non-viable tumor fractions. A strong, yet non-signifi cant, correlation was observed between the 240 EM fractions and the histology-derived non-viable fractions post HIFU (Figure 2A), while the non-perfused tumor fraction was consistently larger than the 240 EM fraction (Figure 2B). The non-

Focused Ultrasound 2014 4th International Symposium 187 perfused tumor fraction overestimated the extent of non-viable tumor tissue directly after HIFU (Figure 2C), while an underestimation was observed at 72 h after HIFU (Figure 2D). k-means clustering with feature vector {ADC, APTw signal} resulted in the best agreement between clustering-derived and histology-derived non-viable tumor fractions (R2y=x = 0.92 for all groups together (Figure 3A)). The strongest agreement between these fractions was observed at 72 h post MR-HIFU ablation (R2y=x = 0.97, Figure 3C). We demonstrated that a mp MRI approach is able to accurately identify non-viable ablated tumor and expect that the proposed method can be incorporated in the current clinical workfl ow of MR-HIFU therapies. References: 1. Wijlemans et al., Invest Radiol 48:6 (2013) 2. Rouviere et al., Nat Rev Clin Oncol. 9:12 (2012) 3. Hectors et al., PloS One 13:6 (2014) 4. Hijnen et al., Int J Hyperthermia 28:2 (2012) 5. Hijnen et al., Invest Radiol 48:7 (2013) Acknowledgements (Funding): This research was performed within the framework of the Center for Translational Molecular Medicine (www.ctmm.nl), project VOLTA (grant 05T- 201).

188 Focused Ultrasound 2014 4th International Symposium P-162-EA Hyperthermia Mediated Drug Delivery Combined with Ablation Improves Tuesday Therapeutic Effi cacy of MR-HIFU Thermal Therapy 14 October 2014 Edwin Heij man1, Nicole Hij nen2, Mariska de Smet2, Holger Grüll1 Topic: Emerging 1 Applications Philips Research, Eindhoven, Netherlands 2 Presentation Type: Poster Eindhoven University of Technology, Eindhoven, Netherlands Background/Introduction: The objective of this therapy study is to investigate MR guided High Intensity Focused Ultrasound (MR-HIFU) thermal therapy strategies comprised of intravascular local drug delivery and ablation for enhancement of the therapeutic effi cacy. Previously, we showed that intravascular drug release using MR-HIFU hyperthermia with temperature sensitive liposomes (TSL) increased the tumor drug uptake and intratumoral distribution.1,2 In the search for improving the therapeutic effi cacy we hypothesize that MR-HIFU hyperthermia mediated drug delivery combined with MR-HIFU ablation has a synergistic effect. Methods: Syngeneic R1 rhabdomyosarcoma tumors were transplanted from donors into the hind leg of female Wag/Rij rats (n =61). When the tumor reached a size of > 500 mm3 they were treated. An overview of the different therapy groups, number of animals per group, average tumor size and body weight, both during therapy, is listed in Table 1. The abbreviations of the different therapy groups are explained in the caption. All animals were positioned in a dedicated rat MR-HIFU setup3 which was placed on the tabletop of a clinical Philips 3T Sonalleve MR-HIFU system (Philips Healthcare, Helsinki, Finland). For the hyperthermia treated therapy groups a 4 mm hyperthermia treatment cell was placed in the core of the tumor in such way that the whole cell fi tted within the tumor. Ablation was performed by a 4 mm feedback treatment cell equally placed as the hyperthermia treatment cell. The protocol and timelines of the 4 different investigated MR-HIFU thermal therapy options are drawn in Figure 1. The dose of doxorubicin was set to 2.5 mg dox/kg body weight for all animals receiving dox, Caelyx or TSL. For the MR- HIFU treated groups, the hyperthermia or the ablation was started upon the end of the agent injection. A time delay was always available between two consecutive heating sessions to cool the tissue down to baseline. MR-HIFU induced hyperthemia was applied two times 15 minutes with 8W of acoustic power. The acoustic power for ablation was set to 30W. For both therapies the acoustic frequency was set to 1.4 MHz. The ablation was stopped when the tumor reached a maximum temperature of 65 degrees Celsius or that boundaries of the 240EM volume reached the borders of the tumor. The animals of the non-heated therapy groups were also positioned in the dedicated rat MR-HIFU setup for a comparable duration as the tumor heated therapy groups. Every second day the animals were weighted and tumor volume was measured with a caliper. Results and Conclusions: Body weight and the tumor size upon therapy did not differ signifi cant between the therapy groups. Also no signifi cant body weight losses were found during the whole study which was expected since the dose of doxorubicin was half of the normal therapy dose of 5 mg dox/kg body weight.4 From the growth curves Kaplan-Meier survival curves were made by defi ning the endpoint as the time at which the tumor volume was tripled relative to treatment day (Figure 2). Log-rank tests were performed to test signifi cant improvement of survival. Three different groups can be identifi ed in the Kaplan-Meier graph. Highest survival were found for the Hyp+TSL+Ab therapy group. No signifi cant differences in survivorship were found between the Ab, Hyp+TSl and TSL+Ab therapy groups. All other therapy groups showed no improved survival compared to the control group. For all therapy groups the tumor growth was investigated by determine the time to onset of regrowth and the regrowth rate both after treatment. No differences were found in regrowth rate. Survival was dominantly determined by increase in time to onset of regrowth (Figure 3). The synergetic effect of combining hyperthermia mediated drug delivery followed by ablation is shown in time to onset of regrowth of the tumors. The ability of the MR-HIFU technology to perform combinations of thermal therapies creates new opportunities for treating malignant tumors in a more optimal way.

Focused Ultrasound 2014 4th International Symposium 189 References 1. De Smet et al., J Control Release 28;1 (2011) 2. De Smet et al., Invest Radiol.48:6 (2013) 3. Hijnen et al., Int J Hyperthermia 28:2 (2012) 4. Morita et al., Oncol Rep. 20:2 (2008) Acknowledgements (Funding): This research was performed within the framework of the Center for Translational Molecular Medicine (www.ctmm.nl), project VOLTA (grant 05T- 201) and within the framework of the European Commission project Sonodrugs (NMP4- LA-2008-213706).

190 Focused Ultrasound 2014 4th International Symposium P-163-EA Treatment Planning and Patient Positioning for MR-guided High Intensity Tuesday Focused Ultrasound Treatment: A Systematic Approach 14 October 2014 David Kinnaird1, Doug Wackerle2, Daniel Yang3, Matthew Oetgen1, Avinash Eranki1, Topic: Emerging AeRang Kim1, Karun Sharma1, Harry Kim4, Peter Kim1, Pavel Yarmolenko1, Applications Haydar Celik1 Presentation Type: Poster 1 Children’s National Health System, Washington, D.C., United States 2 The George Washington University School of Medicine, Washington, D.C., United States 3 Princeton University, Princeton, New Jersey, United States 4 Texas Scottish Rite Hospital for Children, Dallas, Texas, United States

Background/Introduction: Treatment duration as well as time spent on patient positioning imposes limitations on therapeutic use of MR-guided High Intensity Focused Ultrasound (MR-HIFU). Reduction of overall treatment time is especially important in potential pediatric applications and in other cases where general anesthesia must be used, due to the risks associated with prolonged anesthesia. Typically, up to 4 hours are allotted for the procedure, with patient positioning and treatment planning requiring an hour or more. If re-positioning is required during treatment, acquisition of needed images and re-planning of treatment may require 30 minutes or longer before ablation can resume. These delays limit the total time allowed for treatment, limiting the size of tumors that can be treated and increasing the risks as well as the cost of the procedure. The aim of this study is to evaluate the information needed to accurately plan MR-HIFU ablation of solid extremity tumors and to rationally design a practical approach to patient positioning for such treatments. Methods: Correct positioning of a tumor-bearing limb was accomplished via three methods that rely on three-dimensional segmentation of pre-procedural MR images: 1) a printed, concise, patient-specifi c guide that shows all steps necessary for optimal patient positioning, 2) a printed or projected grid that is spatially referenced to the printed guide, and 3) a patient- specifi c ultrasound stand-off gel pad that accurately orients the targeted extremity relative to the center of the MR-HIFU tabletop membrane. Especially complex cases from a set of 41 patients were examined in development of these methods. Performance characteristics of one of the MR-HIFU devices currently in clinical trials, the Philips Sonalleve V2 (Philips Healthcare, Vantaa, Finland) were used. Results and Conclusions: The methods proposed in this study present practical and time saving approaches to MR-HIFU treatment planning. Patient specifi c stand-off gel allows the determination of the angle and distance of the target extremity to be made prior to treatment. The patient-specifi c measurements can be used to set the height and angle of the target limb relative to the HIFU tabletop membrane, allowing for pre-treatment preparation of an ultrasound stand-off gel pad that optimally positions the limb for treatment. The coordinate algorithm and the grid further lock in the limb position and may allow for more thorough treatment pre-planning in future studies. These methods take a systematic approach to reducing total treatment time for MR-HIFU ablations and they may allow for treatment of a wider variety of lesions. Analysis of especially challenging solid tumors of the extremity from our institution demonstrate that the approach is promising and warrants further study. Acknowledgements (Funding): Funding was provided by the Sheikh Zayed Institute at Children’s National Medical Center in Washington, D.C.

Focused Ultrasound 2014 4th International Symposium 191 P-164-EA Ultrasound-triggered Tumor Therapy with Doxorubicin-liposome- Tuesday microbubble Complexes in a Subcutaneous Murine Colon Adenocarcinoma 14 October 2014 Model Topic: Emerging Applications Alexander Klibanov, Zhongmin Du, Galina Diakova Presentation Type: Poster University of Virginia, Charlottesville, Virginia, United States

Background/Introduction: Triggered release of drugs from carrier systems in vivo is widely investigated for targeted tumor therapy. During the past several years, an ultrasound-sensitive liposome-microbubble pendant carrier has been developed: microbubbles, decorated with liposomes that carry e.g., doxorubicin, release the drug in response to ultrasound pulse. However, due to low drug load, those particles were not successful for tumor therapy in vivo. In this study, we are able to prepare particles with high doxorubicin load, and achieve successful inhibition of tumor growth in a subcutaneous murine tumor model. Methods: Decafl uorobutane microbubbles were stabilized with a shell consisting of DSPC, PEG stearate and biotin-PEG-DSPE (20:20:1 mass ratio). Liposomes carrying sodium citrate were prepared from DOPC, cholesterol and biotin-amidocaproyl-DSPE, Remote loading was used to entrap doxorubicin in liposomes. Streptavidin linker bridged biotinylated microbubbles and liposomes, with pendant complex formation. C57BL/6 mice were injected subcutaneously with MC38 colon carcinoma cells (J. Schlom, NIH); therapy has been initiated as tumors reached 4-5 mm. Doxorubicin-liposome-microbubble complexes were injected intravenously (6 mg/kg doxorubicin). Contrast ultrasound imaging with Sequoia 512 (nondestructive CPS imaging, 7 MHz, MI 0.2) was used to monitor the particles in the tumor vasculature. Therapeutic ultrasound treatment with Birtcher Megason apparatus transducer pointed at the tumor was initiated immediately after complex injection (0.6 W/cm2, 1 MHz continuous sine wave applied for 3 s with 10 s interval between ultrasound pulses to ensure replenishment of drug complexes in the vasculature). Results and Conclusions: Doxorubicin-liposome-microbubble complexes have been prepared. These pendant particles demonstrated excellent drug load (>1 pg doxorubicin per complex, an order of magnitude higher than what was demonstrated earlier with doxil-like liposomes). Thus, administering 6 mg/kg doxorubicin became feasible, and was performed repeatedly, twice a week for the fi rst two weeks, and then repeated once a week; ultrasound imaging confi rmed tumor perfusion with drug carrier. Mice did not lose body mass due to treatment. In response to doxorubicin particle administration combined with insonation, signifi cant suppression of tumor growth was achieved, as compared with control untreated animals (p<0.05); some of treated tumors have reduced size, while untreated controls demonstrated accelerating tumor size increase. Fluorescence microscopy of frozen tumor tissue sections confi rmed doxorubicin deposition. In conclusion, repeated administration of doxorubicin-liposome-microbubble particles combined with ultrasound treatment of the tumor under ultrasound imaging guidance achieved signifi cant suppression of tumor growth in a subcutaneous murine tumor model. Acknowledgements (Funding): This study was supported in part via NIH R21/33 CA102880 and R21 EB016752.

192 Focused Ultrasound 2014 4th International Symposium P-165-EA US-guided High-intensity Focused Ultrasound is a Promising Non-invasive Tuesday Method for Treatment of Benign Thyroid Nodules 14 October 2014 Roussanka Kovatcheva1, Jordan Vlahov1, Julian Stoinov1, Katja Zaletel2 Topic: Emerging 1 Applications University Hospital of Endocrinology, Sofi a, Bulgaria 2 Presentation Type: Poster University Medical Centre Ljubljana, Ljubljana, Slovenia Background/Introduction: Benign thyroid nodules are highly prevalent and by ultrasound (US), they can be detected in 20-30% of unselected populations. Some of them need treatment because of compression symptoms or cosmetic complaints. Beside surgery, various non-surgical techniques have been developed to reduce thyroid nodule size. A feasibility of high intensity focused ultrasound (HIFU) ablation of thyroid nodules has been shown recently, but no follow-up after HIFU has been carried out. Therefore, our aim was to assess the effi cacy and safety of US-guided HIFU ablation for treatment of benign solid thyroid nodules. Methods: In our prospective study, 20 (mean age, 44.5 ± 11.7 years) out of 37 screened patients with benign thyroid nodule were eligible for HIFU treatment. HIFU was performed by a skilled physician with a real time US-guided HIFU system (EchoPulse, THERACLION, Paris, France) in one session and under conscious sedation. Thyroid nodule volume and volume reduction were established at baseline, 1 month, 3 months and 6 months after treatment. Adverse events associated with HIFU were evaluated and pain associated with the treatment was subjectively rated on 1-10 cm visual analogue scale (VAS). The study was approved by the institutional ethics committee and written informed consent was acquired. Results and Conclusions: Energy per nodule volume ranged between 2.1 and 7.2 kJ/ mL (mean, 3.8 ± 1.5 kJ/mL) and there was a signifi cant positive correlation of the applied energy per volume tissue with nodule depth (r = 0.447, p = .048). The mean nodule volume decreased from 4.96 ± 2.79 mL to 3.58 ± 1.99 mL at 1-month follow-up (p = .080) and 3.05 ± 1.96 mL at 3-month follow-up (P < 0.05), reaching 2.91 ± 2.43 mL (p < 0.05) by the 6th month. The mean nodule reduction was 26.3 ± 16.9 % at 1 month (p < 0.001) and 38.5 ± 21.6% (p < 0.001) at 3 months. By the 6th month, the mean nodule volume reduction was 48.7 ± 24.3 % (p < .001) with the maximum reduction of 92.9 %. Minor transient complications such as subcutaneous edema or mild skin redness were observed in 2 patients. VAS score was 2.8 ± 2.0 and correlated signifi cantly with body mass index (r = 0.659, p = 0.002). HIFU is an effective non-invasive treatment for benign thyroid nodules, without serious adverse events. Our results indicate that in the future US-guided HIFU might become an alternative to surgery and other minimally invasive treatment techniques. Figure 1. Longitudinal US scan of Figure 2. One month after the Acknowledgements isoechogenic solid thyroid nodule treatment 45, 2% of volume before US-guided HIFU treatment. reduction was found. (Funding): The study was supported by THERACLION, France.

Figure 3. Three months of follow-up Figure 4. Six months of follow-up with 67, 4% of volume reduction. with 85, 8% of volume reduction. Focused Ultrasound 2014 4th International Symposium 193 P-166-EA Background-Oriented Schlieren Imaging and Tomography for Rapid Tuesday Measurement of FUS Pressure Fields: Initial Results 14 October 2014 Michael Kremer, Charles Caskey, William Grissom Topic: Emerging Applications Vanderbilt University, Nashville, Tennessee, United States Presentation Type: Poster Background/Introduction: FUS pressure fi eld mapping is important for dosimetry, quality assurance, and other uses. Hydrophone measurements are the current standard, and are accurate but costly and slow. As a simple low-cost alternative, background-oriented schlieren (BOS) imaging of ultrasound fi elds has been proposed.1 In that technique, a predetermined image (usually a grid of lines or a random dot pattern) is placed on one side of a water tank and viewed from the other side, through the water and FUS pressure fi eld. When the FUS is on, spatial variations in the water’s index of refraction are created that blur the image. Subtracting images with and without the FUS fi eld provides a rapid visualization of it. The method has also been used to tomographically reconstruct air fl ow density.2 The overall goal of the present work is to develop a low-cost BOS hardware system and BOS tomography acquisitions and reconstructions to enable rapid and cheap volumetric measurements of continuous-wave FUS fi elds. Here we present our current progress towards that goal. Methods: Hardware Setup Figure 1 illustrates our current experimental setup, comprising a water tank, a FUS transducer (Sonic Concepts HB 101, Bothell, WA), an Android tablet (Google Nexus 7) to display the background images, and a webcam (Logitech C920) to record the images. MATLAB (Mathworks) runs on a control PC to automate the acquisitions. In the next stage of the project the tablet and webcam will be mounted on a motorized gantry that rotates around the tank to acquire BOS images at multiple projection angles. Acquisitions During acquisitions, the transducer was continuously pulsed at 1.1 MHz to generate a sound fi eld with a peak negative pressure of 5.7 MPa at the focus. BOS acquisitions used background images comprising alternating white and black lines with varying positions, thicknesses and orientation angles. BOS Tomography Simulation A 2D simulation was performed in MATLAB to validate the principles underlying BOS tomography, by implementing the forward model relating a spatially-varying index of refraction pattern to acquired BOS projection images, and a conjugate gradient reconstruction to invert that model. A parallel beam geometry was assumed. Results and Conclusions: Figure 2 shows how BOS images depend on line widths and orientation. Figure 3 compares BOS images generated by summing across line positions and angles to eliminate stripe artifacts. Figure 4 illustrates the forward model and demonstrates that an accurate reconstruction can be achieved from data acquired under that model. Next we will translate our reconstruction to the true fan beam geometry and construct a motorized gantry to enable projections at multiple angles. References: 1. Butterworth et al. Proc 39th Ultrason Indust Assoc Symp, 2010. 2. L. Venkatakrishnan et al. Exp Fluids, 37:237–247, 2004. Acknowledgements (Funding): This work was supported by the Focused Ultrasound Foundation Global Internship Program and DoD W81XWH-12-BCRP-IDEA.

Hardware setup for BOS acquisitions.

194 Focused Ultrasound 2014 4th International Symposium (a) Varying line widths, 0° angle. Thick widths can leave large gaps in the pattern, and thin widths can wash it out (arrows). (b) Varying angle of rotation, 1.8 mm line width. Different parts of the fi eld pattern are emphasized at different angles.

Comparison of BOS images summed across rotation angles, grid translations, and rotations+translations.

2D Simulation of BOS tomography. (a) The model relating the water index of refraction n to BOS projections. Elements of the displacement equation are embodied in the fl ow graph. (b) An accurate estimate of n can be reconstructed from the projections.

Focused Ultrasound 2014 4th International Symposium 195 P-167-EA Pulsed Focused Ultrasound Enhances Mesenchymal Stem Cell Homing to Tuesday Skeletal Muscle in a Murine Model of Muscular Dystrophy and Homing was 14 October 2014 Suppressed by Ibuprofen Topic: Emerging Ben Nguyen, Scott Burks, Saejeong Kim, Michele Bresler, Pamela Tebebi, Joseph Applications Presentation Type: Poster Frank National Institutes of Health, Bethesda, Maryland, United States

Background/Introduction: Homing of iv-infused stem cells to diseased tissues may be critical for cell therapies and is frequently an obstacle to successful cell therapy. We have previously shown that molecular responses from the mechanotransduction effects of pulsed focused ultrasound (pFUS) in normal murine skeletal muscle generate a “molecular zip-code” consisting of local increases in chemoattractants (cytokines, chemokines, cell adhesion molecules) that induced MSC homing, potentially improving cellular therapies for regenerative medicine. This study investigated whether pFUS could also enhance MSC homing to dystrophic skeletal muscle in a muscular dystrophy (MD) mouse model. Stem cell therapies for MD are promising, but have been hampered by poor cell homing and the need for direct injections that are invasive and ultimately, impractical clinically. Since molecular signals drive cell homing following iv injection, drugs used to treat MD could potentially interfere with pFUS-enhanced homing and undermine cell therapies for MD. Methods: MDX mice (9 weeks) received unilateral pFUS (1MHz, 5MPa, 10 ms pulses, 5% duty cycle, VIFU 2000) to hamstrings. Some mice were pretreated with ibuprofen (nonspecifi c cyclooxygenase [COX] inhibitor; 30mg/kg, po) or saline 15min pre-pFUS. Mice were iv injected with 106 human MSC 3hr post-pFUS. Hamstrings were harvested 24hr post-injection, MSC were detected by immunofl uorescence and compared to untreated contralateral hamstrings (Fig 1a). Results and Conclusions: Minimal MSC homing was observed to skeletal muscle in MDX mice, but pFUS treatment enhanced MSC homing by ~15 fold (p<0.001) (Fig 1b). Numerous MSCs were observed in interstitial spaces between myofi bers (Fig 1c). Furthermore, pFUS failed to increase MSC homing when mice were pretreated with ibuprofen (i.e., MSC homing to pFUS-treated hamstrings was not signifi cantly different (p>0.05) than control contralateral hamstrings). This suggests that COX2 signaling is critical for pFUS-enhanced MSC homing to dystrophic muscle. pFUS-enhanced MSC homing to dystrophic skeletal muscle may represent an ideal platform to deliver MSC and other therapeutic cells (e.g. myogenic stem cells) to tissues that are perpetually in a sub-acute or chronic infl ammatory states not conducive to homing of therapeutic cells. Furthermore, anti-infl ammatory drugs, including ibuprofen, are currently a standard-of- care for treating the progression of MD. Ibuprofen suppression of pFUS-enhanced MSC homing in MD reveals potentially negative drug/host interactions that are currently uncontrolled for in clinical cell trials and will need to be accounted for when developing future MD cell therapies. Acknowledgements (Funding): This research was funded by the Intramural Research Program at the National Institute of Health.

Pulsed focused ultrasound enhances homing of mesenchymal stem cells to dystrophic muscle. a) experimental design. b) quantifi cation of MSC homing. c) representative immunohistochemistry (MSCs indicated by arrows). 196 Focused Ultrasound 2014 4th International Symposium P-168-EA Brain Targeted Gene Delivery by Combining Bubble Liposomes and Tuesday Ultrasound 14 October 2014 Daiki Omata1, Ryo Suzuki1, Yusuke Oda1, Johan Unga1, Mutsumi Seki1, Hitoshi Topic: Emerging Uruga1, Yoichi Negishi2, Kazuo Maruyama1 Applications 1 Presentation Type: Poster Teikyo University, Itabashi-ku, Japan 2 Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan

Background/Introduction: Gene therapy is a promising technology for treatment of central nervous system diseases such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. In gene delivery to brain, the blood brain barrier (BBB) is a major obstacle. To enhance the permeability of the BBB, it has been reported that high intensity focused ultrasound (HIFU) was useful and could deliver genes into brain through the BBB. Recently, we have developed echo-contrast gas entrapping liposomes (Bubble liposomes, BLs). We previously reported that BLs and non-focused ultrasound (US) exposure could deliver genes into cells or tissues via cavitation. In this study, we examined whether BLs and US could selectively deliver genes into the brain. Methods: Mixture of BLs and pcDNA3-Luc plasmid which is an expression vector encoding the fi refl y luciferase gene under the control of a cytomegalovirus promoter was injected into tail vain of ddY mice (6 weeks age, male). Immediately, brain was exposed to transcranial non-focused US (Frequency: 1 MHz, Intensity: 1.2 W/cm2, Duty: 10%, Time: 1 min). After 1 day, brain and several organs were collected and then luciferase activities were measured. To evaluate the damage to brain, the brain treated with BLs and US was collected and cryosection was prepared. The sections were observed by microscopy after staining with hematoxylin and eosin. Results and Conclusions: To assess the brain selective gene delivery, we examined the gene expression in several tissues after treatment of BLs and US. As a result, brain exposed to transcranial US showed higher luciferase activity compared to other tissues such as heart, lung and liver (Fig. 1). This suggested that BLs and US could selectively deliver genes into brain. To assess the damage to brain, we observed the appearance of brain treated with BLs and US exposure. Neither hemorrhage nor degeneration of brain was observed after treatment. We also prepared cryosection of brain at 1 day after treatment followed by hematoxylin-eosin staining. As a result, there were not notable differences in brain after treatment with BLs and US. These results suggest that BLs and US did not induce signifi cant damage to brain. Thus, it is expected that the combination of BLs and US would be a useful tool to establish minimally invasive and brain selective gene delivery system. However, with BLs and non-focused US it is diffi cult to restrict gene delivery to a certain part of the brain. In further studies, we will attempt to combine HIFU and BLs to achieve site specifi c gene delivery. Acknowledgements (Funding): We are grateful to Mr. Toshiya Onuma (Teikyo University) for technical assistance.

Figure 1. Selective gene delivery for brain by BLs and US. BLs and pcDNA3-Luc were injected into tail vain of mice. Then, brain was exposed to transcranial US. After 1 day, luciferase activities in brain and other tissues were measured.

Focused Ultrasound 2014 4th International Symposium 197 P-169-EA Investigation of the Stress Response to Mechanical Versus Thermal Non- Tuesday ablative Focused Ultrasound Therapy in Three In Vivo Murine Cancer 14 October 2014 Models

Topic: Emerging 1 2 2 3 1 Applications Steffi e Peters , Karin Skalina , Lisa Scandiuzzi , Ari Partanen , Holger Grüll , 4 Presentation Type: Poster Chandan Guha 1 Eindhoven University of Technology, Eindhoven, Netherlands 2 Albert Einstein College of Medicine, New York, New York, United States 3 Philips Healthcare, Bethesda, Maryland, United States 4 Montefi ore Medical Center, New York, New York, United States

Background/Introduction: Within the focal point of focused ultrasound (FUS), high pressure fl uctuations cause shear stress on cells and tissues with energy dissipation leading to heating of the targeted tissue. The extent of the mechanical and thermal effects strongly depends on the ultrasound parameters and also potentially the acoustic properties of the tumor. High temperatures lead to coagulative necrosis with little immunogenic response as tumor antigens most likely denature during the ablation. As antigen presentation by activated dendritic cells (DCs) is necessary to activate T cells during an anti-tumor immune response, we hypothesize that non-ablative FUS treatment can be used to increase tumor immunogenicity by activating molecules that enhance intratumor dendritic cell (DC) infi ltration and T cell activation. One of the fi rst steps in this process is an activated stress response, including surface calreticulin (CRT), high mobility group protein B1 (HMGB1) release, ATP secretion and heat shock protein 70 (HSP70) surface expression and release. Using non-ablative FUS, antigen release can be stimulated by mechanical stress, thermal stress, or both. Here, we examine the stress response following non-ablative FUS treatment in three murine tumor models with varying consistencies and determine the causative agent (mechanical or thermal energy) of the stress. Methods: We tested a range of non-ablative FUS treatment protocols in vivo in three subcutaneous tumor models in C57BL/6 mice, varying the mechanical and thermal energies to determine which protocol results in the greatest anti-tumor immunity. We investigated CRT surface expression, ATP release and both intra and extracellular expression/release of HMGB1 and HSP70. Since the effect of FUS treatment may vary depending on the cancer cell type, we investigated three different mouse cancer cell lines varying in consistency from solid to fl uid [TPSA23 (prostate), 3LL (Lewis lung), B16F10 (melanoma)]. Animals were sacrifi ced 24 hours post-treatment and tumors were excised for stress response analysis by fl ow cytometry. Plasma was also obtained for analysis of soluble proteins by ELISA. Stress response was compared to non-treated tumors (control) as well as to in vitro treatment of a cell pellet with the same FUS parameters. For all FUS treatment a Philips Therapy and Imaging Probe System (TIPS, Philips Research Briarcliff, USA) was used. Results and Conclusions: While experiments are still ongoing, we have observed a signifi cant increase (One-way ANOVA p < 0.01) in surface expression of HSP70 in an in vivo model of 3LL 24 hours following FUS treatment that delivers high thermal energy when compared to other treatment settings and no treatment (Figure 1). Future experiments will determine whether there are increased soluble HSP70, HMGB1, and ATP levels with mechanical or thermal stress. Acknowledgements (Funding): This research was supported by Philips Research Eindhoven and MSTP training grant (T32-GM007288).

Figure 1. Mean Fluorescence Intensity for surface HSP70 in 3LL for different FUS settings. High thermal settings show signifi cant increase compared to control as well as other FUS settings

198 Focused Ultrasound 2014 4th International Symposium P-170-EA Thermochromic Phantom for Therapeutic Ultrasound Daily Quality Assurance Tuesday Farhan Qureshi1, Zachary Larrabee1, Chris Roth1, Arik Hananel1, Matt Eames1, 14 October 2014 David Moore1, John Snell1, Neal Kassell1, Jean-Francois Aubry2 Topic: Emerging 1 Focused Ultrasound Foundation, Charlottesville, Virginia, United States Applications 2 Institut Langevin, Paris, France Presentation Type: Poster Background/Introduction: Errors in power output ranging from −100% to +210% have been reported in a multitude of physiotherapy transducers.1 Differences in power output can arise even after careful calibration on an annual or bi-annual schedule, which can either result in harm to the patient or non-effective treatment. Therefore, easy implementation of daily quality assurance is of great importance. We propose a simple, easy to use DQA phantom which allows the user to assess the power output of the focused ultrasound transducer, and determine if it has changed signifi cantly after calibration. The basis of this phantom is the use of a highly attenuating ultrasound absorber with a surface layer of thermochromic liquid crystals (TLC). The use of thermochromic materials as a technique for use in ultrasound phantoms has been an ongoing area of interest. Many of these techniques require complicated set-ups, with large water tanks and imaging systems to produce very accurate data.2,3 Simpler phantoms have been developed for use in benchtop settings, but still with a large emphasis on complicated image analysis.4 Our proposed phantom will be a product where the end-user can visually assess the size of the lesion formed as a function of power output, without resorting to complicated image analysis. Methods: In the phantom, differences in lesion size due to differences in ambient temperature are revealed by visual inspection. A simple temperature scale will correspond to concentric circles of varying radii printed on the phantom. The generated lesion size matches the radius of the corresponding circle at each ambient temperature, giving a visual check as to whether or not the transducer’s power output has changed. A Matlab code has been developed to numerically solve the bio-heat equation in fi nite differences time domain with a generation term dependent on the induced pressure fi eld. The code generates plots with a color map corresponding to the thermochromic material’s color changing properties, and the acoustic absorber’s acoustic attenuation and thermal diffusivity properties. The attenuation coeffi cient of the material, provided by Precision Acoustics Ltd, was 28.8 ±2.6 dB∙cm-1∙MHz-1. The thermal diffusivity was tested by Decagon Devices, Inc. using the transient line heat source method, and was determined to be 0.09 ±0.01 mm2/s. The peak positive pressure is adjusted in the simulation so that the lesion size generated by the simulation corresponds to the actual lesion size measured after sonication, giving an estimate of the pressure at focus. Top: Phantom after Sonication Results and Conclusions: A method for creating a simple DQA phantom has been devised. with HIFU Transducer The main goal of the phantom is to verify that the output power of the transducer does not Bottom: Simulated change compared to initial calibration. The end user places the phantom in their transducer Temperature Elevation system, and sonicates for a set power and time. The power output of the transducer is then checked visually using a system of concentric circles printed on the phantom. This system is a cheap and effective way to produce DQA phantoms, both because of the ease of use, and because the use of TLC makes visual changes in the phantom reversible and reproducible over a long period of time. References: 1. Schabrun, S., H. Walker, et al. (2008). “How Accurate are Therapeutic Ultrasound Machines?” Hong Kong Physiotherapy Journal 26: 39-44. 2. Martin, K. and R. Fernandez (1997). “A thermal beam-shape phantom for ultrasound physiotherapy transducers.” Ultrasound Med Biol 23(8): 1267-1274. 3. Gerardo A. Lopez Munoz and Gerardo. A. Valentino Orozco (2009). Three Dimensional Temperature Distribution Analysis of Ultrasound Therapy Equipments Using Thermochromic Liquid Crystal Films, New Developments in Liquid Crystals, Georgiy V Tkachenko (Ed.), ISBN: 978-953-307-015-5, InTech, Available from: http://www. intechopen.com/books/new-developments-in-liquid-crystals/three-dimensional- temperaturedistribution-analysis-of-ultrasound-therapy-equipments-using-thermochr 4. Butterworth, I., J. Barrie, et al. (2012). “Exploiting thermochromic materials for the rapid quality assurance of physiotherapy ultrasound treatment heads.” Ultrasound Med Biol 38(5): 767-776. Acknowledgements (Funding): This work was funded by the Focused Ultrasound Foundation.

Focused Ultrasound 2014 4th International Symposium 199 P-171-EA Development of Novel Echogenic-imageable Thermosensitive Liposome for Tuesday Optimizing Tumor Drug Distribution using Ultrasound Guided HIFU 14 October 2014 Ashish Ranjan, Danny Maples, Ryan Newhardt, Venkatesan Perumal Topic: Emerging Applications Oklahoma State University, Stillwater, Oklahoma, United States Presentation Type: Poster Background/Introduction: A major challenge in HIFU mediated Image Guided Drug Delivery (IGDD) is developing accurate means to implement real-time drug delivery control, and to optimize intratumoral drug distribution. To facilitate clinical translation, objectives of this study were to: 1) develop echogenic E-LTSL, a low temperature sensitive liposome co-loaded with an US contrast agent (Perfl uoropentane, PFP) and doxorubicin, 2) determine stability of contrast agent encapsulation and characterize doxorubicin release from E-LTSL and 3) investigate the ability of E-LTSL to report on real-time doxorubicin distribution with Ultrasound (US)-guided hyperthermia. Methods: E-LTSL was loaded passively with PFP using an innovative 1-step sonoporation method and actively loaded with doxorubicin. Doxorubicin release and PFP imageability from E-LTSL in phantoms was quantifi ed by fl uorescence spectroscopy, ultrasound imaging and transmission electron microscopy (TEM) in combination with mild hyperthermia (40- 42°C). Ultrasound imageability of E-LTSL was determined in vivo in a mouse xenograft model of human prostate cancer. Results and Conclusions: TEM images confi rmed that the PFP emulsion formation is contained within LTSL. Phantom study clearly showed that only E-LTSLs are echogenic. Temperature vs. size increase and drug release kinetics of E-LTSL demonstrated no difference with control. Doxorubicin release in physiological buffer was <5% in 1 hr at baseline (25°C) and body temperatures (37°C), vs. >99% release with hyperthermia (~41°C). Intensity of observed ultrasound image with respect to temperature in the range of 31- 40°C correlated strongly to the formation of gas bubbles in E-LTSL, and stabilized to a fi xed intensity at the transition temperature. After the transition temperature of E-LTSL reached, the US intensity increased again similar to Dox release. Synthesized E-LTSLs were imageable in vivo and were stable in aqueous environment, with no visual evidence of particle aggregation after 48 hr storage at 4 °C. In conclusion, an US imageable heat sensitive liposome formulation co-loaded with doxorubicin and an US contrast agent was developed. Stability, imageability, and US monitoring of contrast agent and Dox release suggest that US-guided drug delivery from E-LTSL may assist physicians in real-time tumor drug delivery mapping. In vivo US-guided HIFU in combination with E-LTSL to demonstrate enhanced tumor drug distribution in C26 colon cancer model is currently in progress. This technology has potential for clinical translation. Acknowledgements (Funding): Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R15CA179369, and Oklahoma Center for the Advancement of Science and Technology (OCAST) HR13-217. The content is solely the responsibility of the authors and does not necessarily represent the offi cial views of the National Institutes of Health.

200 Focused Ultrasound 2014 4th International Symposium P-172-EA 3D MR Neurography Targeted Peripheral Nerve Ablation with MR-guided Tuesday High Intensity Focused Ultrasound (MR-HIFU): Initial Results of a Feasibility 14 October 2014 Study in a Swine Model

Topic: Emerging 1 2 3 3 Applications Robert Staruch , Merel Huisman , Michelle Ladouceur-Wodzak , Avneesh Chhabra , 3 Presentation Type: Poster Rajiv Chopra 1 Philips Research, Dallas, Texas, United States 2 University Medical Center Utrecht, Utrecht, Netherlands 3 University of Texas Southwestern Medical Center, Dallas, Texas, United States

Background/Introduction: MR-guided HIFU is an effective treatment for metastatic bone pain through periosteal nerve ablation,1 and is being investigated for treating back pain through facet joint denervation.2 For peripheral neuropathy, ultrasound-guided HIFU has been investigated preclinically as a means of achieving either an irreversible conduction block to treat severe spasticity,3 or a reversible partial conduction block to alleviate chronic pain.4 However, ultrasound offers limited visualization of deeply situated pelvic nerves5 and lacks the ability to measure thermal dose, which predicts the extent of changes in peripheral nerve histology and function.6 Recently developed diffusion-prepared 3D MR neurography imaging techniques with fat suppression and nerve-selective T2-weighting7 could improve targeting accuracy over ultrasound guidance. We present initial investigations into the use of MRI to guide HIFU ablation of peripheral nerves in a swine model. The objectives were 1) to evaluate the feasibility of identifying peripheral nerves using MR neurography on the clinical MR-HIFU system, 2) to monitor HIFU ablation of peripheral nerves using MR thermometry, and 3) to evaluate the ability to measure thermal lesions in peripheral nerves using contrast-enhanced T1-weighted images and thermal dose maps calculated from MR thermometry. Methods: Experiments were approved by the local Institutional Animal Care and Use Committee. Volumetric MR-HIFU was used to induce seven thermal lesions in the sciatic nerves of three pigs. 3D MR neurography and T1-weighted images at 3T were used for target identifi cation and treatment planning. A single 8 or 12 mm treatment cell was used to cover the full width of each targeted nerve. Ultrasound exposures were performed under MR thermometry guidance in fi ve image planes across the HIFU beam, and one plane along the beam axis. Sonications were performed at 1.2 MHz with acoustic power ranging from 160 to 300 W over fi xed durations of 20 or 36 seconds (energy 3.2 to 10.8 kJ). Ablation dimensions were measured and compared using thermal dose maps, contrast-enhanced T1-weighted images, and gross pathology. Results and Conclusions: All targeted sciatic nerves were identifi able on MR neurography and T1-weighted images (Fig 1). For sonications at 160 to 300 W, MR thermometry measured peak temperatures of 60.3 to 85.7°C, with 240 equivalent minute thermal dose diameters of 8.5 to 15.9 mm (Fig 2). Thermal lesions were visible on late phase contrast-enhanced T1 (Fig 3), with dimensions matching the coagulated region observed at necropsy (Fig 4). Our preliminary results indicate that targeted peripheral nerve ablation is feasible with MR-HIFU. Diffusion-prep 3D MR neurography has potential for guiding therapy procedures where either nerve targeting or avoidance is desired. References: 1. Hurwitz et al, JNCI 2014. 2. Weeks et al, Eur Radiol 2012. 3. Foley et al, Ann Biomed Eng 2007. 4. Foley et al, Muscle Nerve 2008. 5. Fritz et al, Neuroimag Clin N Am 2014. 6. Vujaskovic et al, Int J Hyperthermia 1994. 7. Yoneyama et al, Magn Reson Med Sci 2013.

MRI targeting of peripheral nerve. Pig sciatic nerve is hyperintense on oblique 3D MR neurography (top), and isointense on T1 where dual-bundle fascicular structures are seen against surrounding fat (bottom). HIFU beam overlay (white) indicates target.

Focused Ultrasound 2014 4th International Symposium 201 Acknowledgements (Funding): Funded provided by the Cancer Prevention and Research Institute of Texas and the M.R. and Evelyn Hudson Foundation. Robert Staruch is a paid employee of Philips Research. The authors thank Dave Hitt of Philips Healthcare for technical support in customizing the MR neurography protocol for the swine model.

MR thermometry guidance of HIFU thermal ablation of peripheral nerves. Temperature maps (top) indicate peak temperature of 82.5°C. Thermal dose maps (bottom) predict lesion size of 12.2 x 29.2 mm for a 12 mm diameter treatment cell.

Evaluation of thermal lesions in peripheral nerve. Non-enhancing region visible on post- contrast T1 images. HIFU beam path overlay (white) indicates target location.

Photograph of HIFU-induced thermal lesion in pig sciatic nerve. Coagulated region appears blanched with a hyperemic rim (arrows).

202 Focused Ultrasound 2014 4th International Symposium P-173-EA Image Guided Focused Ultrasound Delivery of Macromolecular Drugs in Tuesday Tumours 14 October 2014 Maya Thanou1, Mike Wright1, Miguell Centelles1, Wladyslaw Gedroyc2 Topic: Emerging 1 Applications King’s College London, London, United Kingdom 2 Presentation Type: Poster Imperial College London, London, United Kingdom Background/Introduction: Drug delivery using focused ultrasound (focal drug delivery) has attracted signifi cant interest during the last few years. Focused Ultrasound (FUS) can induce local tissue hyperthermia, increasing blood fl ow and vascular permeability, which then enhances the uptake of therapeutics by target tissues. Although a number of studies have focused on nanoparticles (e.g. thermosensitive liposomes) little work has been done on the effects of FUS on the uptake of macromolecular drugs into tumours. In this study we aim to understand the effect of FUS-induced hyperthermia on tumour vascular permeability, as measured by the increased uptake of labelled macromolecules in the tumour. Using optical imaging we monitor the labelled macromolecules tumour localisation in real time in both short (minutes to hours) and long (weeks) term. Methods: Albumin (Murine Serum MSA), IgG, and Trastuzumab were labelled using a NIRF (Near Infrared Fluorescent probe; XL750) and a coupling protocol developed in house. The NIRF labelled macromolecules were purifi ed using a PD-10 column and were characterised by HPLC and SDS-PAGE (both unheated and after heating to 42°C for 7 min). SCID mice were used to form tumours using IGROV-1 (ovarian cancer cells) injected s.c. to both fl anks. When tumours reached suitable size (~6 mm diameter) animals were injected (i.v. tail vein) with the labelled antibodies. FUS applications were performed post injection, on the right tumour using an Ultrasound Therapy Imaging Probe System (TIPS, Phillips). FUS insonations induced a localised temperature increase which was monitored using fi ne- wire thermocouples inserted above and below the tumour body. Temperature was kept at 42±0.3°C for 2-5 min. Multispectral optical imaging was used to assess the accumulation of labelled macromolecules in tumours over time with or without FUS-induced hyperthermia. Results and Conclusions: For all three macromolecules tested in vivo, FUS induced hyperthermia enhanced signifi cantly their uptake by the tumours. Figure shows the effect of FUS induced hyperthermia on murine serum albumin tumour uptake. FUS treatments induced immediate increase on macromolecular drug uptake by tumours. The macromolecules remained in the tumour for several days (with an enhanced signal for about a week). Trastuzumab appeared to persist in the tumours for a longer period probably due to its specifi city for Her-2 receptors. The effect of this rapid and tumour localised macromolecular drug concentration can lead to an improvement of the therapeutic effect, this still needs to be investigated. Image guided antibody drug delivery using FUS can become a useful imaging and therapeutic tool. Acknowledgements (Funding): EPSRC Engineering Physical Sciences Research Council EP/I001700/1

Figure: Optical imaging of NIRF –labelled albumin at 5 h post injection. Right tumour was treated with FUS to induce hyperthermia (post injection).

Focused Ultrasound 2014 4th International Symposium 203 P-174-EA Thermal Ablation of a Confl uent Lesion in the Porcine Kidney with Tuesday Magnetic Resonance Guided High Intensity Focused Ultrasound 14 October 2014 Johanna van Breugel1, Joost Wij lemans1, Martij n de Greef1, Gerald Schubert2, Topic: Emerging Maurice van den Bosch1, Chrit Moonen1, Mario Ries1 Applications 1 Presentation Type: Poster University Medical Center Utrecht, Utrecht, Netherlands 2 Philips Healthcare, Vantaa, Finland

Background/Introduction: Since approximately 1.6 percent of men and women will be diagnosed with kidney and renal pelvis cancer during their lifetime, there is a growing interest in non-invasive kidney sparing therapy for renal cancer. As a consequence, several patient studies investigated the feasibility of high intensity focused ultrasound (HIFU) for the thermal ablation of renal masses.The majority of these studies used either a hand-held extracorporeal ultrasound transducer with ultrasound imaging for guidance or a laparoscopic approach. Drawbacks of these techniques are the lack of respiratory motion compensation, no means to observe the energy deposition in real time, the complexity of the probe positioning, and the risks of bleeding and tumor spillage. Alternatively, recent preclinical studies have demonstrated the feasibility of magnetic resonance guided high intensity focused ultrasound (MR-HIFU) interventions on the kidney with respect to motion compensated real-time thermometry and acoustic energy delivery. Here, we extend this prior work to investigate in an animal study if MR-HIFU can deliver a reliable confl uent volumetric lesion in the renal cortex in a clinically relevant time-frame. Methods: An anesthetized Dalland land pig was placed on its right side on a clinical Sonalleve MR-HIFU therapy system, which is integrated with a 1.5T Achieva MRI (Philips Healthcare) with minor modifi cations. Both acoustic energy delivery and MR-thermometry were respiratory gated (3mm gating window, ~70% duty cycle) and active surface cooling was employed to prevent undesired near-fi eld damage. A honeycomb pattern of seven ablation cells (12-17s, 450W acoustic power, 4x4x10 mm3) was positioned in the cortex of the kidney as shown in fi gure 1. The therapeutic endpoint was evaluated non-invasively at the end of the intervention. Hereto, lethal thermal dose estimates based on MR-thermometry and a non-perfused volume (NPV) measurement using dynamic contrast enhanced T1-weighted MRI (DCE-MRI) were performed. Subsequently, the animal was euthanized and the extend of the induced necrosis examined using a cellular viability staining (nicotinamide adenine dinucleotide, NADH). Results and Conclusions: All ablation cells reached peak temperatures > 80°C during the sonications, resulting in a lethal thermal dose over the entire delineated target area. DCE-MRI displayed a confl uent non-perfused volume within the cortex and partly within the medulla with a volume of ±2 ml as shown in fi gure 2. NADH staining reconfi rmed a confl uent non-viable volume of approximately (12 x 16 x 10 mm3) (Figure 3). No undesired tissue damage in adjacent areas has been observed. These fi rst results indicate that current MR-guided clinical HIFU equipment might be suitable for non invasive therapy of renal masses. Future work will need to demonstrate the reproducibility of the fi ndings and investigate potential adverse effects (cutaneous and subcutaneous damage) as a preparation for a clinical study. Acknowledgements (Funding): This study was performed within the framework of CTMM, the Center for Translational Molecular Medicine, project VOLTA (grant 05T-201).

Figure 1. (left): Planning of 7 treatment cells in the cortex of the kidney Figure 2. (center): Contrast enhanced MR scan shows a non- perfused volume in the kidney Figure 3. (right): NADH staining shows a non- viable area (yellowish) within viable kidney tissue (blue)

204 Focused Ultrasound 2014 4th International Symposium P-175-EA The Optimization of Treatment Planning and Ablation Rate Improvements Tuesday on Feasibility of Pediatric MR-HIFU Applications 14 October 2014 Doug Wackerle1, Haydar Celik2, David Kinnaird2, Daniel Yang3, Avinash Eranki2, Topic: Emerging Matthew Oetgen2, AeRang Kim2, Karun Sharma2, Harry Kim4, Peter Kim2, Applications Pavel Yarmolenko2 Presentation Type: Poster 1 The George Washington University School of Medicine, Washington, D.C., United States 2 Children’s National Health System, Washington, D.C., United States 3 Princeton University, Princeton, New Jersey, United States 4 Texas Scottish Rite Hospital for Children, Dallas, Texas, United States

Background/Introduction: Magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) ablation provides a precise, non-invasive treatment for lesions in adults. In children, MR-HIFU’s potential remains largely unexplored, though its non-invasive and non- ionizing nature holds promise. Yet, pediatric patients pose challenges affecting treatment: young children require general anesthesia, exhibit wide ranges of anatomy, and have varying lesion sizes and locations. These demonstrate a need for standardized treatment approaches and physical aids to optimize patient position, reduce time-intensive repositioning, and thus reduce overall treatment time. Further improvement of ablation rate and reduction of risk are also possible via improved monitoring of skin temperature during ablation and mild hyperthermia. Improvements in treatment planning and volumetric rate may save time and allow for treatment of larger lesions, increase patient throughput, and possibly increase effi cacy and lower cost. This study aims to quantify and examine how such improvements could increase the time allocated for direct ablation and produce better outcomes. Methods: Forty-one pediatric patients with various limb tumors at Children’s National Medical Center from November 2005 to October 2013 were examined retrospectively as potential candidates for MR-HIFU ablation therapy. After identifying the tumor location, software (Avizo Standard Edition 8.0.0, Visualization Sciences Group, SAS, Berlin, Germany) was used to defi ne its area through axial slices and create a 3D segmented model to measure its volume. As a reference, treatment time was estimated at a maximum (180 cc/hour) rate used in ablation of uterine fi broids (obtained from Phillips Healthcare, Vantaa, Finland). Four hours maximum anesthesia time was selected due to risks to children and restraints on surgeon time and focus, room and machine time, and cost. Tumor volume and ablation rate data was graphically combined to show effects of theoretical improvements. Results and Conclusions: Increasing the time available for ablation can substantially increase treatable tumor volume. In the examined 41 patients, utilizing only 1 hour for ablation (at 180 cc/hour) leaves 13 patients (32%) untreated. With more time, all but 2 patients (5%) are treatable with 3 or 4 hours of ablation. Conversely, complete treatment of a lesion is directly related to ablation rate. At the current rate of (180 cc/hour), 2 (5%) are untreatable, yet with double the current rate (360 cc/hour), all 41 lesions can be treated. Improvements in planning guidelines and treatment rates could have substantial impacts on the effectiveness of MR-HIFU ablation and the size of treatable tumors and number of patients treated with this technique. Acknowledgements (Funding): This study was conducted at The Sheikh Zayed Institute at Children’s National Medical Center and funded by the W.T. Gill, Jr. Summer Research Fellowship through The George Washington University School of Medicine.

Focused Ultrasound 2014 4th International Symposium 205 P-176-EA Towards FUS Lung Cancer Ablation: The Lung Flooding Process from a Tuesday Physiological and Physical View Point 14 October 2014 Frank Wolfram, Thomas G. Lesser Topic: Emerging Applications SRH Waldklinikum Gera, Gera, Germany Presentation Type: Poster Background/Introduction: Unilateral lung fl ooding replaces air with saline in lung parenchyma. It has been shown, that in fl ooded condition ultrasound guidance and HIFU ablation of central lung cancer tissue is feasible. The fl ooding process generates a saline-lung compound which is different than known parenchymal tissue. Complete understanding of the fl ooding process is essential for its implementation in a HIFU cancer ablation scheme. Therefore a detailed excurse of the fl ooding mechanism and its infl uences in acoustic and physiological conditions will be discussed. However, before initiating the fi rst human pilot, several issues remain. So far the usability of MR guiding and aspects of HIFU effects on fl ooded lung parenchyma are unknown. Methods: Human lung lobes, containing Non Small Cell Lung Cancer (NSCLC), are resected after complete intra-surgical atelectasis. The lobes are fl ooded in vitro with degased saline under static pressure of 30 cm water column. Images based on T1w, T2w sequences were acquired by MRI (Achieva 1.5T, Phillips, The Netherlands). A broadband acoustic immersion technique is used to determine the attenuation properties of fl ooded lung parenchyma. In vivo lung fl ooding was performed in a porcine large animal model “deutsches Landschwein” ca. 30kg. For ventilation a model specifi c double lumen catheter was trans- bronchially inserted. After 30min FIO 1.0 oxygen ventilation, the left lung wing was fl ooded

with saline under static pressure of 30cm H2O column. Flooding was maintained for 90 min under continuous monitoring of vital parameters (SO2, pCO2, pAp, HR). Results and Conclusions: Flooding was performed successful and all animals (4/4) survived the procedure. Confi rmed by Ultrasound B Mode, Lung parenchyma showed no residual gas content. The fl ooding procedure was stable over 90min, which is a suffi cient treatment window for FUS interventions. Lung cancer tissue (NSCLC) could be well demarked from fl ooded lung in T1 and T2 weighted images. These preliminary results indicate that MR guidance in fl ooded lung is feasible. The attenuation of fl ooded lung parenchyma was estimated to be 0,12 dB/cm/MHz, which serves as a superior acoustic path. A review of published lung fl ooding procedures (perfl uorcarbone, saline) will be discussed regarding its safety and usability for FUS lung cancer treatment. Further capabilities of lung- fl ooding will be demonstrated based on the animal model. Acknowledgements (Funding): The study was supported by the the SRH Waldklinikum Gera (Germany) and the Focused Ultrasound Foundation. Animal experiments were performed with permission of the Veterinary Department of the Thuringian State Authority (TLLV) in compliance with the National Animal Protection Act.

Top: Flooded lung lobe containing NSCLC in T1w MR image Bottom: Flooded lung lobe containing NSCLC in T2w MR image

206 Focused Ultrasound 2014 4th International Symposium P-177-EA Targeted Drug Delivery with Modifi ed Gamma-Cyclodextrin Nanocarriers Tuesday and MR-guided Focused Ultrasound Triggering 14 October 2014 Doudou Xu1, Lij un Wang2, Sandy Cochran2, Andreas Melzer1 Topic: Emerging 1 Applications University of Dundee, Dundee, United Kingdom 2 Presentation Type: Poster Institute for Medical Science and Technology, Dundee, United Kingdom Background/Introduction: NANOPORATION project sets out to explore specifi c solutions to overcome the current challenges of targeted drug delivery (TDD) to tumours using magnetic resonance imaging guided focused ultrasound (MRgFUS) to cavitate microbubbles (MBs) for increasing cell permeability and to open ‘drug nano-capsules’ for releasing proven active anticancer drugs directly to the tumour site with reduction of drug dosage needed for the desired therapeutic effect. Methods: A novel gamma-Cyclodextrin (gamma-CD) based carrier for encapsulation of doxorubicin (DOX) was synthesized and fully characterized. The encapsulation effi ciency was assessed by chemical analysis, in vitro and in vivo. A high-throughput in vitro micro-scale FUS device (sonicator) was designed and applied to cells exposure to carrier-DOX inclusion, in combination with SonoVue® MBs to investigate TDD in monolayer cellular level. Ex vivo and in vivo trials were carried out by clinical ExAblate MRgFUS system (InSightec, Israel) to establish a safe and effi cient clinical TDD protocol on small rodents. Results and Conclusions: The desired gamma-CD based carrier greatly reduced DOX’s toxicity in vitro: up to 95% toxicity reduction in KB human enpidermal carcinoma; up to 92% toxicity reduction in HCT116 colorectal carcinomar. Cellular DOX uptake was reduced 73% in muscle, 69% in kidney, 66% in liver, 65% in heart, 62% in brain, 53% in lungs as 25% in plasma in vivo. The carrier-DOX inclusion is highly stable under physiological temperature and pH as well as under a wide range of acidic conditions (pH 1.0~7.0); the encapsulated DOX is slowly released under hyperthermic conditions (up to 50°C). In the presence of MBs (0.1%, 1%, 2.5% and 5%) application of FUS with low mechanical indexes (0.24, 0.31 and 0.53), under which no thermal effect was observed, enhanced up to 3.89-fold of cellular drug uptake for encapsulated DOX in vitro. Optimal setup of MR parameters: TR/TE = 3180/96.3msec; bandwidth: 10.4kHz; Field of View = 20×20cm; matrix: 384×384, NEX: 2; slice thickness: 2.0mm/1.0sp; number of slices: 8; frequency direction: SI and the spatial resolution: 0.52mm; FUS parameters: 4W, 10sec continued sonication and 45sec pulsed sonication with 2.5sec OFF and 0.5sec ON; temperature increase of 7-10 °C; as well as treatment time frame of 35min were identifi ed ex vivo and in vivo, which allowed application of MRgFUS treatments to live mice bearing tumors under anesthesia with full recovery. Unfortunately, the lack of detectable DOX signal was obtained from the very fi rst pre-clinical trial. However, the study demonstrated the possibility of translation of the constructed gamma-CD derivative to potential clinical use as a delivery vehicle of DOX for combined thermal and mechanical mechanism by clinically applicable MRgFUS, -triggered TDD for cancer therapy. Acknowledgements (Funding): The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n°230674 (NANOPORATION) and n°270186 (FUSIMO). Top left: AFM cell surface morphology comparison of KB cells before (A) and after (B) f=0.4868MHz sonication with 2.5% MBs Top right: Animal positioning on ExAblate 2000 table inside rodent chamber (A); mouse was protected by gloves fi lled with water (B); on top of coupling gel- pad with a small cut-out (C)

Bottom left: MRgFUS system: ExAblate 2000 (A); ExAblate Example of Thermal Monitoring during sonication: 2100 with MR (B); a MR image Coronal MR image showing planned sonication of a sheep liver on top of ExAblate location (A); temperature graph during sonication (B); 2000 FUS transducer (C) the anatomical image acquired during sonication (C)

Focused Ultrasound 2014 4th International Symposium 207 P-178-EA The Hemodynamic and Hematological Effects of Histotripsy Tuesday Rajiv Devanagondi1, Gabe Owens2, Hitinder Gurm2, Albert Levin3, Zhen Xu2 14 October 2014 1 Cleveland Clinic, Cleveland, Ohio, United States Topic: Emerging 2 University of Michigan, Ann Arbor, Michigan, United States Applications 3 Henry Ford Health System, Detroit, Michigan, United States Presentation Type: Poster Background/Introduction: This study is aimed to investigate the extent and consequences of hemolysis caused by histotripsy in vivo. Histotripsy, a novel, non-invasive therapeutic technique, employs controlled pulsed cavitational ultrasound for tissue ablation and is currently being evaluated for thrombolysis and palliation of congenital heart disease. Some forms of therapeutic ultrasound cause intravascular hemolysis. Hemolysis due to histotripsy has not been previously evaluated. Methods: Free fl owing blood in the porcine femoral vein was treated with histotripsy therapy in 11 animals with systemic heparinization and 11 animals without heparin. Serum and hemodynamic measurements were obtained at baseline (0), 2, 5, 10, 15, and 30min, as well as 48-72h post-procedure. Results and Conclusions: Results: Of the 11 non-heparin treated animals, 5 died during or immediately following histotripsy (non-heparin group mortality 45% vs. heparin group mortality 0%, p<0.05). Among all animals, serum hematocrit decreased slightly following histotripsy (32.5 ± 3.6 to 29.4 ± 4.2%, p<0.01). There was a signifi cant increase in free hemoglobin (6.2 ± 4.6 to 348 ± 100 mg/dL, p<0.01) and LDH (365 ± 67.8 ± to 722 ± 84.7 U/L, p<0.01). Right ventricle systolic pressure (RVSP) also increased following therapy (23.2 ± 7.2 to 39.7 ± 12.3 mmHg, p<0.001). After 48 to 72 hours, hematocrit remained slightly decreased, and LDH remained slightly increased, when compared to baseline in surviving animals, though free hemoglobin returned to baseline. Conclusions: Histotripsy applied to the circulating blood volume is associated with high mortality in non –heparinized animals but is generally safe with systemic heparinization. A transient increase in free hemoglobin was observed with no clinically signifi cant reduction in total hematocrit. There is also a transient increase in RVSP. Additional studies evaluating the mechanism conferring heparin mediated protection and strategies to ameliorate hemodynamic aberrations caused by histotripsy are under way as this innovative technology advances towards clinical application. Acknowledgements (Funding): This work was funded by Focused Ultrasound Foundation and the National Institute of Biomedical Imaging And Bioengineering (NIBIB) of the National Institutes of Health under Award Number R01EB008998. Disclosure: Drs. Charles A. Cain and Zhen Xu have fi nancial interest and/or other relationship with HistoSonics Inc.

208 Focused Ultrasound 2014 4th International Symposium P-179-EA Optical Measurement of Skin Temperature in MR-HIFU Tuesday Daniel Yang1, Haydar Celik2, Doug Wackerle3, David Kinnaird2, Avinash Eranki2, 14 October 2014 Matthew Oetgen2, AeRang Kim2, Karun Sharma2, Harry Kim4, Peter Kim2, Topic: Emerging Pavel Yarmolenko2 Applications 1 Princeton University, Princeton, New Jersey, United States Presentation Type: Poster 2 Children’s National Health System, Washington, D.C., United States 3 The George Washington University School of Medicine, Washington, D.C., United States 4 Texas Scottish Rite Hospital for Children, Dallas, Texas, United States

Background/Introduction: MR-guided high-intensity focused ultrasound (MR-HIFU) treatments may cause skin heating in the vicinity of the treatment site. Current MR thermometry methods do not provide reliable measurements of skin temperature either during the sonication or during the cool-down periods between sonications. These technical challenges require additional pauses to decrease the likelihood of skin burns, thus impacting treatment duration. Therefore, quantitative, accurate, and rapid techniques are needed to measure surface skin temperature during HIFU treatment. This study aims to develop an optical method that detects temperature changes at the skin surface to maintain a safe skin temperature during treatment and to reduce pauses between sonications. Methods: Chiral nematic liquid crystal slurry (LCR Hallcrest, LLC, Glenview, IL, #09- NSL33), which displays a change in refl ected light color between 25-30°C was mixed with 0.4% w/v agarose gel at 80-85°C to create a 4 mL mixture of 10% liquid crystal slurry. The mixture was poured onto a black-painted glass microscope slide and then covered with another glass slide (gel thickness = 0.5mm). Nickel-plated steel wire (220μm-thick) was used to heat the slide. Electrical current through the wire was adjusted to ensure a steady-state gradient across the glass slide that spanned from below 25°C to above 30°C. Color change of the liquid crystal gel layer was imaged using a DSLR camera and a stable light source placed at a 57° angle. A 0.2-mm diameter thermocouple (Omega Engineering, Inc., Stamford, CT, USA) sampled temperature at different distances from the heating wire to measure the temperature gradient. Local pixel color intensities around the thermocouple tip were isolated and spatially matched with measured temperatures using a custom MATLAB routine (Mathworks, Inc., Naticks, MA, USA). Multivariate polynomial regression was performed on the data to determine temperature as a function of red, green, and blue intensities (3rd order polynomials used for each). Results and Conclusions: Color of the refl ected light from the thermochromic liquid crystals varied with temperature in the agarose gel. As the temperature increased within the gel, red, green, and blue color intensities increase and level off at different rates. A multivariate polynomial regression showed RMS error of 0.74°C for the fi t. Our data show that thermochromic liquid crystals provide an accurate, dynamic, and absolute method to monitor skin temperature during MR-HIFU treatment and ensure patient safety. While the liquid crystals used herein displayed a change of color in the 25-30°C range, crystals with other color-temperature ranges are commercially available and will be evaluated in further studies. Acknowledgements (Funding): Funding was provided by the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Medical Center and the Princeton Internships in Civic Service program.

Focused Ultrasound 2014 4th International Symposium 209 P-180-EA Holder Design for Robotic Assisted Ultrasound and MRI Imaging Guided Tuesday Needle Biopsy 14 October 2014 Ting Zhang Topic: Emerging Applications University of Dundee, Dundee, United Kingdom Presentation Type: Poster Background/Introduction: Ultrasound and MRI imaging guiding system for Robotic assisted interventional procedures such as needle biopsy and FUS ablation have to be improved to allow a one stop shop multimodality image guidance. A specifi c holder which has the capability for connecting the application module of the interventional robotic system “INNOMOTION” (IBSmm, CZ) with SIEMENS wireless ultrasound probe (Acuson Freestyle) was designed and manufactured in order to achieve the desired function. The work is a subproject in FUTURA an EU FP7 funded project for the development of robotic assisted Ultrasound guided focused ultrasound. Methods: The software SOLIDWORKS is mainly employed for the design and simulation. At the fi rst step, details of the dimensions of the application module of the robot arm should be obtained. Moreover, the motion range should be considered as well as was tested in a mock up situation. Ultrasound positioning, organ tracking and focused ultrasound application have been developed on ex vivo animal organ models and Thiel soft embalmed human cadavers. Cadaver work has been approved by the local IRB TAC according to rules of the Scottish anatomy act. The holder was designed to meet the requirements listed below: 1. As the application module of coaxial probes provides two degrees of freedom and is attached to a robotic arm with fi ve degrees of freedom, which assures stable positioning of the instrument within a tool center point that keeps the ‘‘invariant point of insertion’’ at the skin entry point, the design should not change the default attached position of the needle. 2. The position of the probe should be adjustable according to the actual operating environment, which mainly includes the horizontal, vertical and axial translation and angle rotation. 3. As the skin level will supply a pushing force to the probe, certain spring should be operated to provide the reacting force in order to keep the working position of the probe. 4. The holder should allow easy exchange of probes for both diagnostic and focused ultrasound Furthermore, as the holder should be employed in the MRI working area, ABS plastic is picked for the fabrication material and 3D printing technology has been employed. Results and Conclusions: Results: The holder can be separated into seven parts: hangers, main frame, horizontal slide, connector of horizontal and rotational block, rotational block, axial slide and the probe connector. Moreover, the dimension is approximately 200mm long, 75mm wide and 140mm high,and the sketch diagram is in the imgage attached. The practical effect drawings are displayed in the image attached as well. The robotic arm is roughly simulated by the cylinder bar as that part is not so relative to the holder while the application module at the top of the arm is precise. Basically, when it comes to the actual operation, the motion of the application module is combined by movements forward and backward and rotation right and left. The full function can be achieved when the manual translation and rotation of the cannulae is added. Conclusion: The fi nal holder is currently being manufactured in the 3D printer and has met all the requirements needed for the desired function considering the limited assembly space. For instance, the needle or probe is located in the default spot for the reason that the skin entry point can be confi rmed by the existing program; the relative location between the probe and the needle as well as the angle of the probe can be adjusted for the best imaging view; the axial location of the probe can be regulative for better effect with the specifi c spring. Therefore this design does have the capability to improve robotic positioning of ultrasound during MRI imaging guided robotic assisted needle biopsy procedures and provides a fundamental concept for the advanced precise instruments in this area. Acknowledgements (Funding): I would like to thank my supervisor Pro. Andreas Melzer for all the excellent guidance and supports. I would like to give my deepest gratitude to my 210 Focused Ultrasound 2014 4th International Symposium mentor Xu Xiao for all the invaluable effort and help during the whole project. I would like to thank Mr. Duncan Martin and Mr. Stewart Addison for all the advice in manufacturing. I also would like to give my appreciation to the technicians of Imsat workshop and all the staffs in Imsat for their selfl ess help. Finally, I would like to thank my family and friends for their continuous support and encouragement.

Sketch diagram

Effect drawing 1

Effect drawing 2

Effect drawing 3

Focused Ultrasound 2014 4th International Symposium 211 P-181-PR Software-supported Analysis of MRgFUS Therapy Outcome Tuesday Doerte Corr1, Florian Weiler2, Martij n Hoogenboom3, Martinus J. van Amerongen3, 14 October 2014 Jurgen Fütterer3, Tetiana Dadakova4, Michael Bock4, Matthias Günther2, Jürgen Topic: Prostate Jenne1 Presentation Type: Poster 1 mediri GmbH, Heidelberg, Germany 2 Fraunhofer MEVIS, Bremen, Germany 3 Radboud University Medical Center, Nij megen, Netherlands 4 University Medical Center Freiburg, Freiburg, Germany

Background/Introduction: Recently, fi rst studies on MRgFUS for therapy of localized prostate cancer have been presented. However, MRI is not only useful to monitor and guide FUS prostate cancer therapy but might add valuable morphologic and functional information for therapy stratifi cation and outcome. Since multi-parametric MR protocols are time- consuming to generate and evaluate, they are not performed during an MRgFUS session. Rather these data are acquired before MRgFUS for therapy planning and after therapy for outcome assessment. This approach leads to a plethora of MR images (before, during and after therapy) that can be diffi cult to analyze and correlate. To support the radiologist, a software prototype was therefore developed to analyze MRgFUS therapy outcome based on image registration and synchronization. Methods: Initially, the workfl ow of MRgFUS in combination with multi-parametric MR examinations before and after therapy was analyzed. Based on the analysis, a software prototype addressing the specifi c workfl ow was built with the development environment MeVisLab. The software comprises the following functionalities: 2D viewers with basic interaction functionality (zoom, window/level modifi cation, overlays), display of FUS temperature maps (Fig 1), image ordering and classifi cation, automatic image registration, interactive registration refi nement, synchronization cursor, contouring tool for segmentation and annotations, and ROI statistics. To analyze therapy outcome all available MR data of the patient are imported. Data are automatically ordered and classifi ed for automatic post- processing and visualization. Next, images from different examinations are automatically co-registered. The linear registration focusses on T2w MR images which are available in every examination. If results are insuffi cient, registration can be manually refi ned. The user then selects images for correlated display which are synchronized with crosshairs. Additionally, ROIs can be placed and tracked on follow-up images or across modalities to better discriminate between tumor recurrence and scar formation in suspicious areas. MR thermometry temperature maps can be imported as well to correlate the applied thermal T1w MR image of a meat sample dose with post-therapeutic image changes. Furthermore, with temperature map overlay. contrast-enhanced images acquired at the end of a therapy session can be compared with diagnostic or follow-up images to check if all affected areas were covered. Results and Conclusions: A stable version of the software was released for clinical testing. First tests were performed on anonymized data of prostate cancer patients who had extensive MR imaging prior to and past cryo therapy (Fig 2), as well as on meat data treated with FUS. The software implements all necessary features for analyzing the therapy Screenshot of the software outcome and correlation with called Local Therapy Control previous diagnostic and therapeutic showing pre-therapeutic (top data. In addition it could be used for row) and post-therapeutic therapy planning. Further evaluation (bottom row) prostate T2w and ADC images and a tracked ROI. of the software, including a Images are synchronized at the registration accuracy evaluation, is cross-hair position based on a currently in preparation. registration. Acknowledgements (Funding): This work was supported by the BMBF, Eurostars Project E!6620 PROFUS.

212 Focused Ultrasound 2014 4th International Symposium P-182-PR Non-invasive Focal Therapy of Organ Confi ned Prostate Cancer with Tuesday Magnetic Resonance guided Focused Ultrasound Surgery 14 October 2014 Alessandro Napoli, Fulvio Zaccagna, Pier Luigi Di Paolo, Francesco Sandolo, Carola Topic: Prostate Palla, Fabrizio Andrani, Carlo Catalano Presentation Type: Poster University of Rome – Sapienza, Rome, Italy

Background/Introduction: To assess safety and effectiveness of non-invasive high intensity 3T MR guided Focused Ultrasound Surgery (MRgFUS) treatment of localized prostate cancer as salvage therapy and as an alternative to active surveillance. Methods: 4 patients with biopsy proven focal T2 prostate cancer (low-to-intermediate risk: PSA max 12 and Gleason max 3+4), confi rmed on a previous multiparametric MR exam (Discovery 750, GE) including dynamic contrast enhanced (DCE) imaging (Gd-BOPTA, Bracco), underwent MRgFUS ablation (ExAblate, InSightec). 1 patient had already performed radiotherapy without clinical success, 1 patient underwent US-guided Focused Ultrasound treatment with residual tumour tissue inside the gland needing a second treatment; the last 2 enrolled patients were part of an active surveillance regimen. All patients refused radical laparoscopic prostatectomy. MRgFUS treatment was carried out on the MR identifi able lesion (max 2) using a patient specifi c energy (3000-8500 J) and real time MR thermometry monitor for correct treatment location. Non-perfused volume (NPV) in the post-ablative MRI was used for necrosis assessment. Results and Conclusions: Results: No signifi cant complications were observed in all subjects during or immediately after the procedure. Post-treatment MRI demonstrated extensive coagulative necrosis at the site of sonication. At follow-up examinations 3 patients were free of residual viable tumor within the treated area; in the remaining patient, 10% of residual tumor was observed within the NPV. There was a variable amount of isolated cancer tissue (Gleason max 7, 3+4) within the non-treated parenchyma that was neither identifi able at MRI nor at biopsy. Conclusion: Our results suggest that MR guided Focused Ultrasound Surgery is a safe and effective modality to determine >90% necrosis of identifi able prostate cancer; other prospective studies are needed to extend success rate in larger cohort.

Focused Ultrasound 2014 4th International Symposium 213 P-205-PR United States Experience with Primary HIFU Therapy for Patients with Low- Tuesday Risk Prostate Cancer: Results of the Enlight Trial 14 October 2014 Cary Robertson1, Anthony Sliwinski2, Eric Wallen3, William Orovan4, Inderbir Gill5, Topic: Prostate John Ward6 Presentation Type: Poster 1 Duke University Medical Center, Durham, North Carolina, United States 2 Virginia Urology, Richmond, Virginia, United States 3 University of North Carolina, Chapel Hill, North Carolina, United States 4 McMaster University, Hamilton, Canada 5 University of Southern California, Los Angeles, California, United States 6 MD Anderson Cancer Center, Houston, Texas, United States

Background/Introduction: High Intensity Focused Ultrasound (HIFU) is a non-invasive treatment for localized prostate cancer. The purpose of this study was to investigate the safety and effectiveness of HIFU as a monotherapy for the initial treatment of low-risk prostate cancer (PCa) in the United States. Methods: An Investigational Device Exemption trial received local IRB approval at thirteen sites in the United States and Canada. Subjects with untreated low-risk localized PCa were recruited and treated with single session monotherapy HIFU without adjuvant TURP or hormone ablation. Repeat HIFU procedures were not permitted. Subjects were followed at 1 and 3 months and every three months thereafter. The primary endpoint was 24 month biochemical freedom from failure (the “Phoenix” defi nition). Subjects underwent biopsy for cause (rising PSA) or at the end of study (24 months). Adverse events were assessed at each postoperative visit and reported as mild, moderate or severe and related to the device or procedure at 24 months. Results and Conclusions: A total of 135 subjects were prospectively enrolled. Mean age and PSA at treatment (± SD) was 64.1 ± 6.7 years and 4.6 ± 2.4 ng/ml, respectively. The Gleason grade and stage were 6 and T1c for 97% and 81% of subjects, respectively. A PSA nadir < 0.5 ng/ml was achieved in 74.1% of subjects. The primary biochemical endpoint was achieved by 90.5% (95% CI: 85.2% - 95.8%) of subjects. Freedom from positive biopsy was 97/135 (72%) at two years. The erectile dysfunction rate was 38%, urinary incontinence: 3%, urinary retention: 3% and stricture: 1%. No fi stulae were observed. Both the local (biopsy) control and the biochemical survival rates are promising following HIFU which was utilized as a single session monotherapy without any adjuvants. The adverse event profi le demonstrates promising erectile function preservation and low rates of long term morbidity. These results complement published long term outcomes from Europe, where HIFU is utilized in combination therapy, in repeat treatments, and as salvage treatment. Results from this study show that HIFU appears to be a safe and effi cacious primary therapy for localized prostate cancer. Acknowledgements (Funding): This work was supported by EDAP-TMS.

214 Focused Ultrasound 2014 4th International Symposium P-183-UF Patient Selection Guidelines for Magnetic Resonance Focused Ultrasound Tuesday (MRgFUS) Treatment: An Updated View 14 October 2014 Kelli Bryant, Suzanne LeBlang Topic: Uterine Fibroids Presentation Type: Poster University MRI, Boca Raton, Florida, United States Background/Introduction: The purpose of this retrospective study was to evaluate the selection criteria used to determine patient eligibility for MRgFUS for the treatment of symptomatic uterine fi broids. Methods: 373 women with symptomatic uterine fi broids were screened with MRI exams with and without contrast utilizing T2 coronal and axial, T2 fat suppressed sagittal, T1 axial precontrast images, and post contrast fat saturated images in 3 planes. Patients were initially considered clinically eligible if they met the standard published screening criteria/ Food and Drug Administration-based treatment guidelines. These selection criteria were expanded on a case-by-case basis if it was felt that a NPV of at least 50% could be obtained or if the patient refused other treatment approaches (myomectomy, hysterectomy, uterine artery embolization). Results and Conclusions: Results: Of the 373 patients (ages 26-61) that underwent pelvic screening, 188 (51%) were considered eligible and 135 (36%) were excluded for the MRgFUS procedure based on the published selection criteria. An additional 50 patients (13%) would have been excluded from treatment based on the published criteria, but were given the opportunity for MRgFUS treatment. Of those 50 patients, 35 patients were treated, with 33 having fi broids >10 cm, 1 having prior liposuction and 1 having multiple small fi broids. Of the 33 patients with fi broids in excess of 10 cm, 11 agreed to have pre treatment with a GnRH agonist while the other 22 patients refused all other interventions besides MRgFUS. 135 patients (36%) were excluded from treatment. The reasons for exclusion are listed in Table 1 below. Using the FDA-based treatment guidelines, 188 fi broids were treated with MRgFUS with an average NPV/fi broid of 66%. Using expanded selection criteria, an additional 60 fi broids were treated with an average NPV/fi broid of 56%. Conclusions: Using the published selection criteria, 51% of patients who underwent MRI screening were considered candidates for MRgFUS. An additional 13% of patients were brought into the treatment arm of the study after pre-treatment with a GnRH agonist or after considering patient preference. This individualized approach to determining patient eligibility resulted in only a slightly smaller average NPV/fi broid of 56% vs. 66% under the published selection criteria. As physicians acquire more clinical experience with MRgFUS, an expanded selection criterion may allow more women to benefi t from this more conservative approach to treating uterine fi broids. Acknowledgements (Funding): We would like to thank Lisa Mckenzie and Gina Boykin for their knowledge and dedication in helping to take care of our MRgFUS patients.

Table 1. Patients excluded from MRgFUS treatment following MRI screening

Focused Ultrasound 2014 4th International Symposium 215 P-184-UF MRI Pelvis Screening to Guide Treatment of Pelvic Pathology Tuesday Kelli Bryant, Suzanne LeBlang 14 October 2014 University MRI, Boca Raton, Florida, United States Topic: Uterine Fibroids Presentation Type: Poster Background/Introduction: The purpose of this retrospective study is to examine the incidence and imaging appearance of pelvic malignancies in a symptomatic patient population being screened for MRgFUS treatment. Methods: 373 women with symptomatic uterine fi broids were screened with MRI exams with and without contrast utilizing T2 coronal and axial, T2 fat suppressed sagittal, T1 axial precontrast images, and post contrast fat saturated images in 3 planes. Uterine masses were classifi ed by their intensity on T2 weighted images relative to normal myometrium (hypointense, isointense, or hyperintense as well as tissue homogeneity or heterogeneity). The enhancement pattern was also categorized as homogenous or inhomogeneous. Any extra- uterine masses were also noted as well as any other incidental pelvic fi ndings. Results and Conclusions: Results: Of the 373 patients (ages 26-61) that underwent pelvic screening for MRgFUS treatment, 19 presented with fi ndings suspicious for cancer and after further evaluation, 7 of these patients (1.9 %) were confi rmed to have a pelvic malignancy. 5 patients had a uterine sarcoma, 1 had endometrial carcinoma and 1 had ovarian carcinoma. Three out of the fi ve sarcomas appeared markedly heterogeneous on T2 weighted images with ill-defi ned dark areas and bright fl uid components and demonstrated heterogeneous, poorly defi ned areas of enhancement throughout. The remaining 2 sarcomas appeared more fl uid in nature with eccentric, enhancing soft tissue components and multiple septations. The endometrial carcinoma appeared as an intra-cavitary mass with ill-defi ned margins with a blood clot in the endometrium. This fi nding is highly unusual, as a large endometrial clot is not typically seen in cases where irregular bleeding was noted for fi broids. The ovarian carcinoma appeared as an extra-uterine mass with metastatic spread to the pelvic lymph nodes. Malignancy was considered in the remaining 12 patients due to the MRI imaging characteristics listed in Table 1 below. Three of these patients were excluded from MRgFUS treatment, but in retrospect had non-suspicious fi ndings. Contact information was not available to obtain a defi nitive diagnosis for the other 9 patients. Conclusions: 1.9% of patients with suspected fi broid disease were found to harbor a pelvic malignancy following MRI screening exams for MRgFUS. These fi ndings suggest that before any treatment for pelvic pathology, MRI screening should be used to guide physicians to the appropriate treatment modality (surgical vs. minimally invasive procedures). It is equally important to avoid delayed diagnosis and unintended treatment of malignant diseases with non- excisional approaches at this time. MRI pelvis exams may also help direct patients with more typical benign uterine fi broids to both non-invasive treatments (MRgFUS or uterine artery embolization (UAE)) or surgery (laparoscopy or open surgical procedures). The more liberal use of MRI pelvis exams to screen and characterize pelvic pathology in symptomatic women can help avoid recent deleterious outcomes with morcellation procedures of unsuspected Figure 1a. Sagittal T2-fat malignancies. With increasing familiarity with the MR appearance suppressed image depicting a of uterine pathology and attentive evaluation of screening studies, markedly heterogeneous uterine early diagnosis of pelvic malignancy may be achieved. sarcoma. Acknowledgements (Funding): We would like to thank Lisa Mckenzie and Gina Boykin for their knowledge and dedication in helping to take care of our Table 1. Patients excluded MRgFUS patients. from MRgFUS treatment due to the possibility of underlying malignancy.

Table 1. Patients excluded from MRgFUS treatment due to the possibility of underlying malignancy.

216 Focused Ultrasound 2014 4th International Symposium P-185-UF Volumetric MR-guided High-Intensity Focused Ultrasound Ablation to Treat Tuesday Uterine Fibroids through the Abdominal Scars 14 October 2014 Zhu Ying1, Bilgin Keserci2, Xuedong Yang1, Xiaoying Wang1 Topic: Uterine Fibroids 1 Presentation Type: Poster Peking University First Hospital, Beij ing, China 2 Philips Healthcare, Seoul, Republic of Korea

Background/Introduction: Magnetic resonance (MR)-guided high intensity focused ultrasound (HIFU) is an emerging therapy technique using focused ultrasound to heat and coagulate tissue deep within the body, without damaging intervening tissue. However, massive abdominal scar tissues were considered as relative contraindications as the higher energy absorption of the scar tissue might result in skin heating at the site of the scar.1 Obstruction in the near-fi eld of the focused ultrasound beam, such as indeed extensive abdominal wall scar tissue could lead to increased absorption of acoustic energy and skin burns.2 In some conditions, it is possible avoid the ultrasound beam passing through the scar tissue by tilting the transducer or fi lling the bladder.3 Yoon et al. started to use the scar patch to blocking the beam, which would reduce the risk of skin burn and enlarge indications with point by point technique.4 In our preliminary study, we used the scar patch in three patients, one with transverse incision, and the other two with longitudinal incision using volumetric technique.5 Methods: MR-HIFU treatment was performed by stepping through several treatment cell ablations with cooling times between each sonication using a Philips Healthcare clinical HIFU platform integrated into a 3 T Philips Achieva MR scanner. The scar patch used in this study was made of isolation polyethylene foam (1.5-mm-thick Cell-Aire; Sealed Air, Elmwood Park, New Jersey) covered with a double-coated medical tape (9889; 3M, St. Paul, Minnesota). FFE was performed for the scar and scar patch with the following imaging parameters: coronal, TR/TE 3.4/1.74ms, FOV 200mm, slices 29 thickness 1.0mm, Voxel size 1.5×1.5×1.0mm3, TA 1min 18sec. 3D T2WI was performed for treatment planning: sagittal, FOV 241mm, TR/TE 1550/150ms, thickness 1.6mm, slice 150. Voxel size 1.0×1.0×1.6mm3, TA 5min56sec. The MR sequence used for temperature mapping is an RF-spoiled segmented Echo Planar Imaging sequence (EPI-factor = 11, repetition time TR = 37ms, echo time TE = 19.5ms, 121-binomial water selective excitation). Immediately following the treatment, Fat- saturated T1- weighted THRIVE sequence used to for evaluate the volume of the fi broids ((turbo fi eld echo (TFE), 17 axial slices; TR/TE: 500 / 10 ms; slice thickness: 5 mm with 1 mm gap; FOV, 240 X 240 mm; matrix, 320 X 250; fl ip angle: 90 degree). Results and Conclusions: In the fi rst case, a 41-year-old woman with transverse incision had a single intramural type 1 fi broid. The volume of the fi broid was 111.98ml. The treatment time was 165min 17sec. Following delivery of multiple sonications to the treatment area, The NPV immediately after treatment was 52.35%. No abnormal areas of enhancement within the subcutaneous tissue or the regions of the scar were identifi ed. In the second case, a 49-year-old woman with a longitudinal incision had multiple type 1 fi broids. The target fi broid was located in the anterior wall. The scar patch was in the middle sagittal plane while the fi broid was located left of the uterus. The volume of the fi broid was 71.17ml. The treatment time was 112min 1sec. The NPV immediately after treatment was 50.32%. Skin heating was mild, and no severe advent event occurred. In the last case, a 43-year-old woman with a longitudinal incision also had multiple type 1 fi broids. The volume of the fi broid was 100.90ml. The fi broid was in the left of the uterus, almost beyond the scar. The treatment time was 100 min 44 sec. The NPV immediately after treatment was 73.21%. Mild skin heating was complained, without severe advent events. The scar patch could effectively avoid heating around the scar tissue(both horizontal and longitudinal), and expand the indication of MR-HIFU treatment of uterine fi broids with volumetric technique. References: 1. Yoon S.W., et al. Eur Radiolo, 2008. 18(12): 2997-3006. 2. Leon-Villapalos, et al. Burns, 2005. 31(8): p. 1054-5. 3. Zaher, S., et al., Eur J Radiol 2010. 76(2): p. 269-73. 4. Yoon, S.W., et al., J Vasc Interv Radiol, 2011. 22(12): p. 1747-50. 5. Kohler MO, et al. Med Phys 2009;36(8):3521–3535.

Focused Ultrasound 2014 4th International Symposium 217 P-186-UF Relationship between Temperature and T2 in Subcutaneous Fat and Bone Tuesday Marrow at 3T 14 October 2014 Eugene Ozhinsky, Misung Han, Serena Scott, Chris Diederich, Viola Rieke Topic: Uterine Fibroids Presentation Type: Poster University of California at San Francisco, San Francisco, California, United States

Background/Introduction: MR-guided high-intensity focused ultrasound (HIFU) for treatment of uterine fi broids and painful bone metastases uses the proton resonant frequency shift (PRF) for temperature monitoring in water-based tissues. However, PRF fails to detect temperature changes in tissues with high lipid content, such as fat and bone marrow. Previous studies have shown a change in T2 of subcutaneous fat, red and yellow bone marrow during treatments with focused ultrasound. The lack of calibration data for 3T acquisitions, however, makes it diffi cult to convert T2 values into maps of tissue temperature. In this study we investigated the dependence of T2 temperature on temperature in porcine adipose tissue and bovine yellow bone marrow at thermal equilibrium at 3T. Methods: Two petri dishes were fi lled with porcine adipose tissue and bovine yellow bone marrow (fi g.1 a,b) and placed in a custom-built thermally insulated water bath that was held at a constant temperature by circulating water between scans. Temperature in the water was monitored with a fi ber optic sensor. The time necessary for temperature equilibration between the T2 measurements was measured using fi ber optic sensors, embedded in the samples. T2 was quantifi ed in a 3T MRI scanner with a double-echo fast spin-echo sequence with and without water suppression (TE = 35/181 ms and 30/150 ms, TR = 1500 ms, ETL = 40, FOV = 12 cm, 128 x 128 matrix size, 8 mm slice thickness). Images were acquired during heating (25°, 35°, 45°, 55°, 65° and 70° C) and subsequent cooling (55°, 35° and 25° C) after reaching thermal equilibrium. Results and Conclusions: Figure 1 (c-f) shows examples of T2 maps of fat and marrow at 25° and 70°C. The T2 values within a 10x10 pixel ROI (black square on fi g. 1) versus the temperature of the water bath at equilibrium are plotted in Figure 2. The T2 values in the fat sample (fi g. 2a) increased linearly with heating, but followed a different curve during cooling due to irreversible tissue changes around 45°C. The bone marrow sample exhibited a non-linear relationship between T2 and temperature during heating below 45°C (fi g. 2b). As in the fat sample, the T2 values were higher and followed a more linear curve during cooling. Table 1 shows the linear regression coeffi cients of T2 versus temperature for the different acquisition parameters. There was approximately a 25% difference between the measurements with and without water Figure 1. FSE images of petri suppression. This could be due to the dishes (no water suppression), containing porcine adipose contribution of water spins to the tissue (a) and bovine yellow measured T2 in the non water-suppressed bone marrow (b); T2 maps of acquisitions and due to suppression of the tissues at 25°C (c,d); and a portion of the fat spins in the water- at 70°C (e, f), acquired with water suppression. suppressed acquisition. The difference in the T2/temperature coeffi cients between the two sets of echo-times was smaller. These results suggest that calibration of T2-based thermometry techniques should be done with the same parameters as those used for temperature monitoring during the treatment of patients. In conclusion, we have calibrated the temperature dependence of T2 in porcine subcutaneous fat and yellow bone marrow for temperatures between 25° and 70°C at 3T. This will allow for reliable and accurate monitoring of temperature in adipose tissues and yellow bone marrow during treatment of patients with MR- guided HIFU. continued, next page

218 Focused Ultrasound 2014 4th International Symposium Table 1. Relationship between T2 and temperature (ms/°C) for porcine adipose tissue (fat) and bovine yellow bone marrow (marrow). Fat Marrow Heating Cooling Heating Cooling Water Suppr. TE = 30/150 6.41 5.74 7.05 5.39 Water Suppr. TE = 38/182 6.16 5.37 7.00 5.39 No Water Suppr. TE = 38/182 4.64 4.10 5.48 4.47

Acknowledgements (Funding): This work was supported by NIH Grants R00HL097030, and research support by GE and InSightec.

Focused Ultrasound 2014 4th International Symposium 219 P-187-UF Possible Vascular Ablation Effect in the MR-guided HIFU Treatment of Tuesday Uterine Fibroids: Description of an Unexpected or Desired Effect? 14 October 2014 Felipe Shoiti Urakawa, Marcos Roberto de Menezes, Mauricio Moura, Stephanie Topic: Uterine Fibroids Castro Presentation Type: Poster Institute of Cancer of São Paulo, São Paulo, Brazil

Background/Introduction: Ablation by MR guided high intensity focused ultrasound has become one of the main non-invasive methods for the treatment of symptomatic uterine fi broids, since 2004, when it was approved by the FDA. Much of this growing preference, due to its effectiveness in relieving symptoms, low complication rates, lack of ionizing radiation and prompt recovery after the procedure. Despite all these advantages, the procedure time has become a major constraint in greater diffusion of this technique, especially in the treatment of large fi broids. Another major challenge coming up in the treatment of lesional margins, more susceptible to risks of injuries to surrounding structures, increasing the chances of under-treatment. Given the direct relationship between the non- perfused volume of post-therapy target lesion - which corresponds to the area not contrasted on MRI T1-weighted - and the relief of symptoms, the search for higher ablation zone as possible should always be the ultimate goal. At this time of search for solutions through multicentric experience, a particular vascular effect has been described in the treatment of fi broids for MR-guided HIFU. Melo et al reported a case of shrinking fi broid treated with MR-guided HIFU estimated at 98% in which only the periphery of the lesion had been treated. In this case, the reduced perfusion in the all fi broid was attributed to the tissue ischemia and necrosis caused by the ablation of major peripheral vessels. In 2011, Voogt et al proposed a new method of treatment of uterine fi broids based on vascular mapping by MR angiography and arterial ablation spot, getting good results in the two patients described. Given this phenomenon observed in sporadic cases in the literature, our proposal is to describe fi ndings that corroborate the vascular ablation effect in a retrospective observational study of 6 cases of treatment of uterine fi broids with MR-guided HIFU. Methods: Between February 2011 and March 2014, 36 patients in reproductive age with symptomatic uterine fi broids were subjected to treatment with MRI-HIFU. Six of these patients had in common, besides excellent results in improving symptoms, a peculiar behavior in contimages post-treatment, denoting a particular vascular ablation effect. This effect is characterized by greater non-perfused volume (NPV) than the area effectively treated fi broid, whose regular and well-defi ned margins coincide with the boundaries of the target lesion. Adds to this concept the simultaneous achievement of adjacent satellites not perfused fi broids, non-target lesions, however indirectly affected. This group was gathered through retrospective observation of this peculiar behavior of therapeutic response, identifying all patients underwent coincidentally the same planning sonication. This pattern consisted of transverse division of the fi broid into two equal parts, starting the sonications for the lateral aspects of the periphery of the caudal half, focusing consecutive sessions in the same region. Thus concentrated energy has already been deposited in the region to start the next sonication, avoiding random sonications. Immediately after treatment, post-contrast T1-weighted sequences for evaluation of treatment outcome were performed. Such images were used to calculate the volume of fi broid and not perfused volume (NPV). The volumes of fi broids and NPVs were calculated by a method sectional sum. Regions of interest were outlined in each sectional image through a MR workstation and the volume of each segment was calculated and summed. The NPV is also calculated as a percentage of the volume of the fi broid to indicate the percentage ablated. Patients were followed 6-12 months after treatment with a questionnaire to assess symptoms and quality of life (Uterine Fibroid Symptom and Quality of Life) and magnetic resonance imaging to quantify shrinkage of fi broid volumes. Results and Conclusions: In 6 patients, 9 fi broids were treated with the same pattern of sonication, focusing initially on the periphery of the inferior aspect of the fi broid. MR- HIFU. The treatment resulted in almost total fi broids desvascularization with nonperfused volume greater than 90%. In all cases was observed a peculiar behavior in control images post-treatment, characterized by greater non-perfused volume (NPV) than the area effectively treated fi broid, whose regular and well-defi ned margins coincide with the boundaries of the target lesion, and simultaneous adjacent satellites not perfused fi broids (non-target lesions). These fi ndings contained in the largest series of cases already described in the literature,

220 Focused Ultrasound 2014 4th International Symposium reinforce a pattern of therapeutic response, pointing to a possible vascular ablation effect, idea raised sporadically in the literature. Obtaining this pattern of response, with adequate pre-treatment planning, has shown excellent results in control images post-ablation and major impact on improving the quality of life of patients.

Focused Ultrasound 2014 4th International Symposium 221 P-188-UF The Relationship of Area under Temperature Curve During MR Guided HIFU Tuesday and Diffusion Coeffi cient in Patient Screening 14 October 2014 Xuedong Yang1, Rong Rong1, Jia Liu1, Juan Wei2, Bilgin Keserci2, Xiaoying Wang1 Topic: Uterine Fibroids 1 Presentation Type: Poster Peking University First Hospital, Beij ing, China 2 Philips Healthcare, Seoul, Republic of Korea

Background/Introduction: Different type of fi broid shows different response to MR guided HIFU, which is believed to refl ect different blood suplly.ADC value derived from low b multiple b value DWI may refl ect perfusion information. Our study is to assess the relationship of AUC (area under curve) calculated from the temperature curve during sonication in MR guided HIFU therapy for fi broid and the diffusion coeffi cient derived from multiple b-values DW-MRI in patient screening. Methods: A total of 50 uterine fi broids (diameter: mean, 5.6 cm; range, 3.5–8 cm) in 45 female patients (mean age, 44.8 years) who were given written informed consent underwent MRI screening. In the screening, subjects were positioned prone, feet fi rst, on the 3T MRI scanner (Achieva TX, Philips Medical Systems, Best, the Netherlands) using a 32-channel phased array coil. IVIM MR images were acquired on the axial plan across the uterus. We set different b-values as follows: 0, 25, 50, 75, 100, 150, 200, 500, 800, 1000 (s/mm2). Freehand ROIs circumscribing the fi broids were drawn and data was analyzed by using DWI post- processing software performed in a proprietary programming environment (PRIDE; Philips Medical Systems). For low b-value (<100 s/mm2), monoexp model was used to calculate diffusion coeffi cient which mainly represented blood perfusion. Thermometry got during the treatments was used to create temperature curves. For better interpretation, two points were chosen on the temperature curve: The fi rst point was the time point at the end of the ascending segment before the temperature got stable. The second point was the time point at the beginning of the descending segment before the temperature began to decay. The Matlab software accompanied with defi nite integration method was used to analyze the temperature curve to generate area under heating curve (AUC), which was the area under the curve between the beginning point of the curve to the second point. All fi broids were divided into 3 groups according to their AUC: 1) Fibroids with AUC less than 2000°C•s (n=16). 2) Fibroids with AUC between 2000°C•s to 2400°C•s (n=19). 3) Fibroids with AUC more than 2400°C•s (n=15). Independent sample t test was used to test the difference of diffusion coeffi cient derived from multiple b-values combined with DW-MRI among the 3 group. Results and Conclusions: Group 1 fi broids with the least AUC(1710.74±189.3°C•s) had the least diffusion coeffi cient (2.32±0.34μm2/ms). Group 3 fi broids with the most AUC (2798.15±393.7°C•s) had the most diffusion coeffi cient (2.52±0.19μm2/ms). Group 2 fi broids were with an intermediate AUC and diffusion coeffi cient (2202.29±135.06°C•s; 2.44±0.22μm2/ms). Fibroids with relatively high AUC which represented more energy during sonication had large diffusion coeffi cient representative of hyper blood perfusion. However, there was no statistically signifi cant difference of diffusion coeffi cient among the 3 group (p=0.121). Conclusion: AUC of the temperature curve was related with diffusion coeffi cient derived from multiple b-values combined with DW-MRI which correlated very well with the biological features of fi broids such as vascularity. Fibroids with high diffusion coeffi cient representative of hyper blood perfusion need more sonication energy during MR guided HIFU which ensures good therapeutic effects.

222 Focused Ultrasound 2014 4th International Symposium P-189-YI Real-Time MRI Feedback of Cavitation Ablation Therapy (Histotripsy) Tuesday Steven Allen 14 October 2014 University of Michigan, Ann Arbor, Michigan, United States Topic: Young Investigator Presentation type: Poster This poster is based on oral presentation 89-LV.

P-190-YI Palliation of Painful Bone Metastases: The “Rizzoli” Experience Tuesday Alberto Bazzocchi 14 October 2014 The “Rizzoli” Orthopaedic Institute, Bologna, Italy Topic: Young Investigator Presentation type: Poster This poster is based on oral presentation 52-BM.

P-191-YI MRI Characterization of Uterine Fibroids May Predict Success of GnRH Tuesday Agonist Therapy Prior to Magnetic Resonance Focused Ultrasound 14 October 2014 (MRgFUS) Treatment Topic: Young Investigator Presentation type: Poster Kelli Bryant Florida Atlantic University, Boca Raton, Florida, United States

This poster is based on oral presentation 101-UF.

P-192-YI MRgHIFU – Experimental Perivascular Volumetric Ablation in the Liver Tuesday Ulrik Carling 14 October 2014 Oslo University Hospital, Oslo, Norway Topic: Young Investigator Presentation type: Poster This poster is based on oral presentation 83-LV.

Focused Ultrasound 2014 4th International Symposium 223 P-193-YI Harmonic Motion Imaging for Pancreatic Tumor Detection and High- Tuesday intensity Focused Ultrasound Ablation Monitoring 14 October 2014 Hong Chen Topic: Young Investigator Presentation type: Poster Columbia University, New York, New York, United States This poster is based on oral presentation 81-LV.

P-194-YI Quantifying Perfusion-related Energy Losses During Magnetic Resonance- Tuesday guided Focused Ultrasound 14 October 2014 Christopher Dillon Topic: Young Investigator Presentation type: Poster University of Utah, Salt Lake City, Utah, United States This poster is based on oral presentation 103-UF.

P-195-YI International Consensus on Use of MR-guided High-Intensity Focused Tuesday Ultrasound for Bone Metastases: Current Status and Future Directions 14 October 2014 Merel Huisman Topic: Young Investigator Presentation type: Poster University of Utrecht, Utrecht, Netherlands This poster is based on oral presentation 49-BM.

224 Focused Ultrasound 2014 4th International Symposium P-196-YI Image-Guided Sonoporation in an Ex vivo Machine Perfused Porcine Liver Tuesday Christina Keravnou, Christophoros Mannaris, Maria-Louisa Izamis, Michalakis 14 October 2014 Averkiou Topic: Young Investigator University of Cyprus, Nicosia, Cyprus Presentation Type: Poster Background/Introduction: Sonoporation is the transient and reversible cell membrane permeability change induced with ultrasound and microbubbles. It allows for the uptake of normally impermeable macromolecules and has been suggested for improving drug delivery. The exact sonoporation mechanism and the optimal ultrasound parameters are still under investigation. Ex vivo machine perfused porcine livers are an excellent platform for investigating the sonoporation parameters and specifi cally the interaction of ultrasound driven microbubbles with the capillaries. Our objective was to identify the ultrasound parameters that are capable of causing detectable perfusion changes in the sonoporation area. Three types of perfusion changes were considered: large mechanical damage void of perfusion, reduced perfusion due to capillary destruction, and unaltered perfusion. Methods: Porcine livers were collected from a local slaughterhouse and connected to a machine perfusion system [Fig. 1(a)]. Injections of experimental contrast microbubbles (BR38, Bracco Suisse SA) in either the portal vein or the hepatic artery were followed with ultrasound treatment of a specifi c area. Ultrasound pulses at 1 MHz and varying durations, pressures, and duty cycle (<10% to avoid heating), were fi red by single element transducers (focused and unfocused). The process was monitored with diagnostic ultrasound (C5-1 probe, Philips iU22). The therapy transducer spatial extend was accurately overlaid in the ultrasound images by a novel technique where the RF noise of the power amplifi er was transmitted through the therapy transducer and detected by the diagnostic ultrasound probe [Fig. 1(b)]. The perfusion of the treated area was evaluated with Dynamic Contrast Enhanced Ultrasound (DCEUS) quantifi cation methods. Results and Conclusions: Perfusion change caused by image-guided sonoporation [Fig. 1(c) baseline, (d) after sonoporation] was demonstrated in an ex vivo machine perfused liver with a combined therapy-imaging system. The use of unfocused therapy transducers led to a much larger treatment area and was easier to identify and measure perfusion changes with DCEUS. Focused therapy transducers produced higher acoustic pressures but at smaller areas that were diffi cult to identify with DCEUS unless the focused transducer was mechanically scanned to treat a larger area. Sonoporated areas with ultrasound pressure above 1 MPa showed a detectable perfusion change. Complete mechanical damage was present at much larger acoustic pressures (~10 MPa). Shorter acoustic pulses (50 cycles) produced less perfusion changes than longer pulses (500 cycles) for the same duty cycle. Acknowledgements (Funding): This work was supported by the Didaktor/0311/78 Fellowship under the Framework Program for Research, Technological Development and Innovation 2009-2010; DESMI 2009-2010 is co-funded by the Republic of Cyprus and the European Regional Development Fund. We gratefully acknowledge Bracco Suisse SA for the BR38 contrast microbubbles used in this study.

(a) Ex vivo pig liver machine perfusion system; (b) Therapy transducer RF interference signal picked by the imaging probe; (c) Perfusion image before sonoporation; (d) Perfusion image after sonoporation showing a perfusion defect. Focused Ultrasound 2014 4th International Symposium 225 P-197-YI Unilateral Magnetic Resonance Guided Focused Ultrasound Thalamotomy Tuesday for Essential Tremor: Practices and Clinicoradiological Outcomes 14 October 2014 Young Goo Kim Topic: Young Investigator Presentation Type: Poster Yonsei University Health System, Seoul, Republic of Korea Background/Introduction: Several options exist for surgical management of essential tremor, including radiofrequency lesioning, deep brain stimulation, and gamma knife radiosurgery of the ventralis intermedius nucleus of the thalamus. Recently, magnetic resonance-guided focused ultrasound (MRgFUS) has been developed as a less-invasive surgical tool aimed to precisely generate focal thermal lesions in the brain Methods: Patients underwent tremor evaluation and neuroimaging study at baseline and up to 6 months after MRgFUS. Tremor severity and functional impairment were assessed at baseline and then at 1 week, 1 month, 3 months, and 6 months after treatment. Adverse effects were also sought and ascertained by directed questions, neuroimaging results and neurological examination. Results and Conclusions: The current feasibility study attempted MRgFUS thalamotomy in 11 patients with medication-resistant essential tremor. Among them, eight patients completed treatment with MRgFUS, whereas three patients could not complete the treatment because of insuffi cient temperature. All patients who completed treatment with MRgFUS showed immediate and sustained improvements in tremors lasting for the 6-month follow-up period. Skull volume and maximum temperature rise were linearly correlated (linear regression, p = 0.003). Other than one patient who had mild and delayed postoperative balance, no patient developed signifi cant post-surgical complications; about half of the patients had bouts of dizziness during the MRgFUS. Our results demonstrate that MRgFUS thalamotomy is a safe, effective, and less-invasive surgical method for treating medication-refractory essential tremor. However,several issues must be resolved before clinical application of MRgFUS, including optimal patient selection and management of patients during treatment. Acknowledgements (Funding): This study was supported by a research grant from InSightec, Ltd. (Haifa, Israel) for clinical trial using the transcranial MRgFUS. InSightec was the regulatory sponsor of this study, and provided technical assistance. This research received no specifi c grant from any funding agency in the public, commercial or not-for-profi t sectors.

226 Focused Ultrasound 2014 4th International Symposium P-198-YI FUS-mediated Functional Neuromodulation for Neurophysiologic Tuesday Assessment in a Large Animal Model 14 October 2014 Wonhye Lee Topic: Young Investigator Presentation type: Poster Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States This poster is based on oral presentation 23-BR.

P-199-YI High Intensity Focused Ultrasound (HIFU) in the Treatment of Breast Tuesday Fibroadenomata: a Feasibility Study 14 October 2014 Mirjam Peek Topic: Young Investigator Presentation type: Poster King’s College London, Guy’s and St. Thomas’ Hospitals, London, United Kingdom This poster is based on oral presentation 77-BT.

Focused Ultrasound 2014 4th International Symposium 227 P-200-YI A Unifying Framework for Understanding Ultrasonic Neuromodulation Tuesday Mechanisms 14 October 2014 Michael Plaksin, Eitan Kimmel, Shy Shoham Topic: Young Investigator Presentation Type: Poster Israel Institute of Technology, Haifa, Israel Background/Introduction: Both recent and classical studies have demonstrated the ability of low intensity ultrasound (US) to noninvasively suppress or excite central nervous system (CNS) activity using different combinations of stimulation parameters. Although multiple applications relating to these effects are already emerging, the underlying biophysics remains unclear and the relevant literature is somewhat empirical and speculative, generally lacking explanations for these differences. Recently, we suggested that US-induced intramembrane cavitation within the bilayer membrane could underlie a range of acoustic bioeffects. Here, we use detailed predictive modeling to examine whether this effect could underlie ultrasonic neuromodulation. Methods: To address the problem of the mechanisms underlying ultrasonic neuromodulation, we coupled the modifi ed Rayleigh–Plesset intramembrane cavitation biomechanics with three Hodgkin-Huxley type biophysical models: i) Regular Spiking (RS) cortical pyramidal neuron, ii) Fast Spiking (FS) cortical interneuron and iii) Low Threshold Spiking (LTS) cortical interneuron. These three Neuronal Bilayer Sonophore (NBLS) models can capture the biophysical effect of US on differential excitatory and inhibitory brain neural tissue response, respectively. Results and Conclusions: The three models show that action potentials were generated indirectly from US-induced pulsating nano-bubbles inside the bilayer plasma membrane: the leafl ets’ periodic vibrations induce US-frequency membrane capacitance and potential oscillations, leading to slow charge accumulation across the membrane (on a time scale of tens of milliseconds), until action potentials are generated. The LTS neurons show a much higher relative sensitivity to sparse ultrasonic stimulation compared to the other neurons, resulting from their T-type voltage gated calcium channels. Interestingly, this biophysical/ biomechanical model behavior provides a detailed predictive explanation for waveform- based differential neuromodulation that have been observed in an array of cortical and thalamic studies. These results support our hypothesis that intramembrane piezoelectricity is responsible for ultrasonic neuromodulation and highlight the potential of advanced waveform design for obtaining cell-type selective control. They could thus pave the way towards new CNS therapeutic protocols, using the only method that currently allows targeted noninvasive neuromodulation with millimeter spatial resolution essentially anywhere in the brain. Acknowledgements (Funding): Russell Berrie Nanotechnology Institute, Zeff Scholarship, Johnson & Johnson Grant No. 1010051 and European Research Council Starting Grant No. 211055.

P-201-YI Immunomodulation of Prostate Cancer Cells after Low Energy Focused Tuesday Ultrasound 14 October 2014 Karin Skalina Topic: Young Investigator Presentation type: Poster Albert Einstein College of Medicine, Bronx, New York, United States This poster is based on oral presentation 63-PR.

228 Focused Ultrasound 2014 4th International Symposium P-202-YI Reestablishment of Perfusion in Critical Limb Ischemia Model with Pulsed Tuesday Focused Ultrasound (pFUS) and Mesenchymal Stem Cells in Aged Mice 14 October 2014 Pamela Tebebi1, Victor Frenkel2, Rashida Williams1, Scott Burks1, Joseph Frank1, Ben Topic: Young Investigator Nguyen1, Saejeong Kim1 Presentation type: Poster 1 National Institutes of Health, Bethesda, Maryland, United States 2 University of Maryland School of Medicine, Baltimore, Maryland, United States

Background/Introduction: Severe chronic peripheral arterial disease (PAD) manifests as critical limb ischemia (CLI) with a 5-year mortality rate >70%. Mesenchymal stem cells (MSC) show promise to minimize CLI progression and restore perfusion in experimental models, but approaches suffer from minimal homing to ischemic tissue and require clinically impractical direct injections of cells. We show that pulsed focused ultrasound (pFUS) noninvasively establishes a “molecular zip-code” of locally upregulated chemoattractants (i.e. cytokines, chemokines, cell adhesion molecules) that lead to enhanced homing permeability and retention of IV-infused MSC to pFUS-treated muscle. This study investigated if pFUS could enhance MSC homing in a CLI model in aged mice and whether they could ultimately improve limb perfusion. Methods: CLI was induced by ligating the external iliac artery in C3H mice (9-12 months old). At 14 days post-CLI, mice were grouped as followed: saline controls (n=8); pFUS alone (n=7), MSC alone (n=8), or MSC+pFUS (n=17). Mice were treated, according to their group, daily for 3 days (i.e, 3×pFUS, 3×MSC, 3×MSC+pFUS). pFUS was applied to ischemic hamstrings at 40W (5% duty cycle, 5Hz PRF, 100 pulses). For mice receiving MSC, 106 MSC were IV injected via the lateral tail vein. Mice receiving pFUS+MSC had MSC injected ~1hr pre-pFUS. To assess MSC homing, mice were euthanized at 15 days post-CLI (24 hr after last treatment). Fe-labeled MSC were counted by microscopy after Prussian Blue staining. Laser Doppler perfusion imaging (LDPI) was performed weekly for 7-8 weeks post-treatment. Results and Conclusions: Results: Signifi cantly more MSC homed to pFUS-treated ischemic hamstrings than ischemic hamstrings without pFUS (p<0.01) or normal hamstrings (Fig 1). LDPI revealed that restoration of limb perfusion was signifi cantly greater in the pFUS+MSC mice beginning 2 weeks post-treatment (4 weeks post-ischemia) (Fig 2). Limb perfusion in the pFUS+MSC group continued to improve for the remainder of the study (7 weeks post-ischemia), while groups treated with MSC alone, pFUS alone, or saline remained near baseline perfusions levels. Conclusion: pFUS-enhanced MSC homing is a clinically relevant modality with potential to treat PAD. Previous experimental CLI studies have shown promise, but they inadequately model clinical PAD. They utilize direct cell injections into ischemic muscle, administer cells immediately after injury, and use young animals with robust healing capabilities. We show that when treatment is delayed (14 days post-CLI, during sub-acute infl ammation) in aged mice, iv-injected MSC largely fail to home to ischemic muscle and have limited therapeutic potential. However, pFUS can noninvasively establish a molecular zip-code of upregulated chemoattractants to enhance MSC homing where therapeutic MSC can help restore perfusion to ischemic limbs. As direct injections are impractical clinically, systemic MSC delivery is necessary and pFUS guidance of MSC may be critical to develop effective cell therapies in PAD. Acknowledgements (Funding): Funding is sponsered by the Intramural Research Program at the NIH.

Figure 1. (top): 14 days post-CLI, mice were given either MSC alone or pFUS+MSC and hamstrings were harvested 24 hrs. MSC failed to home to ischemic limbs without pFUS, but signifi cantly more (p<0.05) MSC homed to ischemic limbs when they were treated with pFUS. Figure 2. (bottom): 14 days after CLI induction mice received 3 consecutive days of pFUS, MSC, or MSC+pFUS. At 2 weeks post treatment signifi cant increase (p<0.05) in laser Doppler blood fl ow compared to 3XpFUS, 3XMSC, and saline group. Focused Ultrasound 2014 4th International Symposium 229 P-203-YI High Speed, High Sensitivity PRF Shift MR Thermometry Tuesday Yuan Zheng, Wilson Miller 14 October 2014 University of Virginia, Charlottesville, Virginia, United States Topic: Young Investigator Presentation Type: Poster Background/Introduction: MR thermometry of FUS treatments is usually performed by using a gradient-echo (GRE) pulse sequence to measure the proton resonance frequency shift (PRFS) in water-based tissues. This frequency shift causes a phase shift in the GRE image proportional to the temperature change. However, the sensitivity of this approach deteriorates as the imaging speed increases, which makes it less than ideal for measuring small, transient temperature changes. We have developed an alternative pulse sequence strategy for PRFS-based MR thermometry that uses a balanced steady-state free precession (bSSFP) pulse sequence to collect temperature-sensitive phase images. A bSSFP image experiences a sharp phase transition over a narrow frequency range near resonance (Fig. 1), which can be used for high-speed, high-sensitivity thermometry of very small temperature changes. Quantitative accuracy can be achieved, despite the non-linear temperature dependence, by incorporating a brief frequency scan into the procedure. Here we demonstrate the use of this method to precisely measure transient temperature rises generated by low-energy ultrasound sonications. Methods: Experiments were performed in a gel phantom using an MR-compatible 1 MHz FUS system and 3T MR scanner. To demonstrate that bSSFP thermometry can deliver quantitative accuracy similar to the conventional GRE method, we used both pulse sequences to monitor focal heating during a 4W, 10s sonication. The GRE pulse sequence parameters (TR/TE = 17/9ms) provided a temporal resolution of 1s, whereas the bSSFP pulse sequence parameters (TR/TE = 4/2ms) provided a temporal resolution of 0.24s. To demonstrate the advantage of bSSFP over GRE for precisely measuring transient temperature rises, we used both pulse sequences to monitor focal heating due to ultrasound pulses lasting only 1s, using a frame rate of 4 images per second. Results and Conclusions: Fig. 2 shows the measured temperature evolution at the focal spot for the 10s sonications. The GRE and bSSFP measurements agree well, demonstrating the potential for accurate thermometry using the bSSFP technique. Fig. 3 shows results from the 1s sonications. The graph shows the measured temperature change at the center of the focal spot at several different acoustic powers, and the temperature maps show the evolution of the focal spot during the 10W sonication. The bSSFP measurements clearly depict the transient focal heating at all powers, while the GRE measurements were dominated by noise even at the highest power. The bSSFP method demonstrated here could be ideal for locating or characterizing the focal spot using brief, low-energy sonications, or for monitoring mild temperature rises associated with thermotherapy. Because the readout bandwidth is inherently high and the resonant frequency is carefully calibrated as part of the procedure, this technique should be much less sensitive to position shifts that plague spot-localization methods on current clinical systems. Acknowledgements (Funding): Supported in part by a research grant from the Focused Ultrasound Foundation.

Figure 1. (top, left): Phase of bSSFP and GRE images versus temperature at 3T. The GRE phase slope is constant and proportional to TE, while the phase transition curve for bSSFP is independent of both TE and TR. Figure 2. (bottom, left): Temperature evolution at the center of the FUS focal spot due to 10 s of 4W sonication. The temporal resolution of the SSFP pulse sequence is 0.24 s, while that of the GRE sequence is 1s. Figure 3. (bottom, right): Temperature measurements of 1s sonication pulses. The graph shows the temperature evolution at the central pixel. The images show the measured temperature maps for the 10W sonications. The spatial resolution is interpolated from 1mm to 0.25mm for display.

230 Focused Ultrasound 2014 4th International Symposium Poster Map

P-100-BM P-101-BM P-102-BM P-103-BN P-104-BN P-105-BN P-111-BR P-110-BR P-109-BR P-108-BR P-107-BR P-106-BN

P-112-BR P-113-BR P-114-BR P-115-BR P-117-BR P-118-BR P-124-BR P-123-BR P-122-BR P-121-BR P-120-BR P-119-BR

P-125-BRP-126-BR P-127-BR P-128-BR P-129-BR P-130-BR P-136-BR P-135-BR P-134-BR P-133-BR P-132-BR P-131-BR

P-137-BRP-138-BR P-139-BR P-204-BR P-140-BT P-141-BT P-147-LV P-146-LV P-145-LV P-144-LV P-143-BT P-142-BT

P-148-LV P-149-LV P-150-LV P-151-LV P-152-LV P-153-EA

P-159-EA P-158-EA P-157-EA P-156-EA P-155-EA P-154-EA P-197-YI P-198-YI P-199-YI P-200-YI P-201-YI P-202-YI P-203-YI

P-160-EA P-161-EA P-162-EA P-163-EA P-164-EA P-169-EA P-168-EA P-167-EA P-166-EA P-165-EA

P-170-EA P-171-EA P-172-EA P-173-EA P-174-EA P-179-EA P-178-EA P-177-EA P-176-EA P-175-EA

P-180-EA P-181-PR P-182-PR P-205-PR P-183-UF P-188-UF P-187-UF P-186-UF P-185-UF P-184-UF P-192-YI P-193-YI P-194-YI P-195-YI P-196-YI

Salon D

P-189-YI P-190-YI P-191-YI Posters

Focused Ultrasound 2014 4th International Symposium 231 Notes

232 Focused Ultrasound 2014 4th International Symposium Author Index by Name (continued) In accordance with author requests; the following abstracts are not included in this publication: 32-BR; 49-BM; 53-BM; 90-UF; P-102-BM; P-138-BR; P-159-EA. P-116-BR was withdrawn.

A Bock, Michael 212 Ciolina, Federica 119 Acharya, Dinesh 170 Bos, Clemens 121 Civale, John 83 Adamczyk, Bruno 141 Bratan, Flavie 71 Clement, Gregory 132 Ahmed, Hassaan 129 Brenin, David 96 Cobbs, Charles 34 Ahmed, Muneer 95 Bresler, Michele 91, 196 Cochran, Sandy 168, 207 Alagem-Mizrachi, Aviva 111 Brown, Jemma 123 Cohen, Mark 48 Albisinni, Ugo 64, 65, 69, 70 Brown, Matthew 113 Coluccia, Daniel 33 Allen, Steven 108 Brugger, Florian 28 Constanciel Colas, Elodie 136 Almquist, Scott 131 Bryant, Kelli 120, 215, 216 Corr, Doerte 212 Amaral, Joao 67 Buch, Amanda Marie 138, 155 Courivaud, Frederic 102 Andarawewa, Kumari 179 Bucknor, Matthew 86 Cox, Benjamin 177 Ando,Yuta 179 Bunton, Chris 83 Coy, Heidi 113 Andrani, Fabrizio 63, 119, 213 Burgess, Alison 37, 38 Crijns, Sjoerd 178 Anon, Javier 33 Burks, Scott 91, 196, 229 Crouzet, Sebastien 71, 72, 73 Anzidei, Michele 98 Burtnyk, Mathieu 77 Crura, Francesco 85 Aramaki, Yukihiko 151 Busacca, Maurizio 64, 65 Cunitz, Bryan 89 Arvanitis, Costas 45, 51, 132, 149 Butts Pauly, Kim Cupino, Alan 142 Aryal, Muna 133 54, 86, 139, 146, 148, 157, 159, 162, 163 Curiel, Laura 141, 182 Asami, Rei 172 Bystritsky, Alexander 48 Czarnota, Gregory 67 Ashida, Reiko 172 Aubert, Isabelle 37, 38 C D Aubry, Jean-Francois Caliolo, Gianluca 63, 98 da Costa, Leodante 30 46, 52, 134, 142, 147, 165, 199 Campbell, Fiona 67 Dadakova, Tetiana 212 Avedian, Raffi 86 Canney, Michael 35 Dallapiazza, Robert 26, 50, 137 Averkiou, Michalakis 225 Carling, Ulrik 102 Damianou, Christakis 90 Azuma, Takashi 166 Carlson, Carissa 165 David, Elizabeth 112 Carpentier, Alexandre 35 Dayton, Paul 84 B Cartocci, Gaia 63 de Greef, Martijn Babakhanian, Meghedi 135 Caskey, Charles 194 105, 106, 174, 184, 204 Badr, Lena 180 Castro, Stephanie 220 de Menezes, Marcos Roberto 125, 220 Bahrami, Simin 109 Catalano, Carlo de Ruiter, Joost 67 Bailey, Michael 89, 107 63, 64, 65, 69, 70, 119, 213 de Smet, Mariska 189 Bajwa, Neha 135 Celik, Haydar 191, 205, 209 Deckers, Roel 92, 121, 167 Barkhatov, Leonid 102 Centelles, Miguell 203 Deffi eux, Thomas 46 Bartels, Lambertus W. 92, 105, 110, 167 Chang, Jin Woo 29, 30 Delattre, Jean-Yves 35 Bartels, Wilbert 121 Chapelon, Jean-Yves Denis de Senneville, Baudouin Basu, Indranil 80 35, 71, 72, 73, 101 167, 178 Bates, David 182 Chen, Cheng-Yu 124 Devanagondi, Rajiv 208 Battaglia, Milva 70 Chen, Hong 39, 99 Di Paolo, Pier Luigi 213 Bauer, Ronald 28, 43 Chen, Shangshang 138 Diakova, Galina 192 Bazzocchi, Alberto 64, 65, 69, 70 Chevillet, John 81 Diederich, Chris 79, 126, 218 Berben, Monique 187 Chhabra, Avneesh 201 Dillon, Christopher 122 Bernardes, João Paulo 125 Chin, Joseph 77 Doba, Nobutaka 103, 171 Bethune, Allison 30 Chiou, Jeng-Fong 124 Dobrenz, Liz 183 Bezzi, Mario 104 Chopra, Rajiv 66, 76, 78, 88, 181, 201 Dogadkin, Osnat 173 Billia, Michele 77 Christensen, Douglas 131 Domschke, Markus 176, 177 Bing, Chenchen 181 Christofi , Christos 90 Donati, Davide 70 Bitton, Rachelle 86, 157 Chuma, Makoto 103, 171 Dorenberg, Eric 102 Blesa, Javier 161 Chung, Yong An 47 Dos Santos, Cleiton 141

Focused Ultrasound 2014 4th International Symposium 233 Author Index by Name (continued)

Douek, Michael 95 Gelet, Albert 71, 72, 73 Hudson, Thomas 127 Doughty, Richard 102 Georgii, Joachim 170 Huisman, Merel 201 Downs, Matthew 138, 143 Gertner, Michael 85 Hurwitz, Mark 61, 68 Drake, James 67, 127, 136, 154 Ghai, Sangeet 75 Hwang, Joo Ha 81 Du, Zhongmin 192Dubey, Sonam Ghanouni, Pejman Hynynen, Kullervo 30, 37, 38, 59, 67 37 68, 86, 146, 148, 157, 162 Duff, Karen 39 Gianfelice, David 68 I Dunmire, Barbrina 89 Gill, Inderbir 214 Idbaih, Ahmed 35 Dupre, Aurelien 101 Giraldez, Maria 81 Ikeuchi, Masahiko 128 Giulia, Brachetti 63, 69 Ikink, Marlijne 110 E Gold, Garry 86 Inbar, Yael 111 Eames, Matt Goldin, Jonathan 113 Ingham, Elizabeth 61 49, 52, 134, 137, 142, 147, 165, 199 Goldsher, Dorit 27 Inomata, Masuko 93 Edwin, Bjørn 102 Goldwirt, Lauriane 35 Iozeffi , Dmitri 68 Eisma, Roos 168 Gong, Shawn 141 Iqbal, Umar 42 Elias, W. Jeff 26, 29, 50, 52, 137 Grissom, William 140, 194 Itani, Kazunori 166 Endo-Takahashi, Yoko 151 Grüll, Holger 185, 187, 189, 198 Iwahashi, Toshihide 166 Endre, Ruby 67 Grundfest, Warren 135 Iyer, Apoorva 142 Eran, Ayelet 27 Guenther, Matthias 104 Izamis, Maria-Louisa 225 Eranki, Avinash 191, 205, 209 Günther, Matthias 212 Izumi, Masashi 128 Erikh, Ilana 27 Guha, Chandan 80, 198 Eschbach, Frank 184 Gurm, Hitinder 208 J Estrade, Thiabault 141 Gwinn, Ryder 49 Jackson-Lewis, Vernice 40, 161 Jacob, Igor 187 F H Jaen, Angels 97 Facchini, Giancarlo 64 Haase, Sabrina 175 Jeng, Shiu-Chen 124 Fandino, Javier 33 Hadley, Rock 56 Jenne, Jürgen 104, 212 Farahani, Keyvan 88 Hafron, Jason 77 Johnson, Ethan 159 Farr, Navid 107 Hägele-Link, Stefan 28 Jolesz, Ferenc 51 Feng, Xue 139, 163 Haider, Masoom 75 Jones, Peter 126 Ferrara, Katherine 61 Hall, Timothy 108 Jones, Ryan 59 Ferrari, Stefano 65 Hamed, Hisham 95 Joy, Joyce 168 Ferrera, Vincent 138 Han, Misung 126, 218 Jung, Yujin 47 Fielden, Samuel 139, 163 Han, Yang 99 Filonzi, Giacomo 64, 65, 70 Hananel, Arik K Fiore, Lucas 125 52, 112, 142, 147, 165, 199 Kägi, Georg 28 Fite, Brett 61 Hanes, Justin 150, 156 Kanaev, Sergey 68 Foley, Jessica 32 Hao, Yoshiharu 103, 171 Karakatsani, Maria Eleni (Marilena) Fountain, Nathan 50 Harper, Jonathan 89 138, 143, 155Karakitsios, Ioannis Frank, Joseph 91, 196, 229 Hatch, Olivia 142 168, 173, 176, 177 Frenkel, Victor 229 Hectors, Stefanie 187 Kassell, Neal 32, 52, 142, 147, 165, 199 Fujii, Tatsuya 171 Heijman, Edwin 185, 187, 189 Kato, Tomonari 128 Fujiwara, Keisuke 166 Hijnen, Nicole 189 Kawabata, Ken-ichi 172 Fukuda, Hiroyuki 103, 171 Hirabara, Emiko 93 Kawami, Hiroyuki 169 Furusawa, Hidemi 93 Hlasny, Eugen 75 Kawasaki, Motohiro 128 Fütterer, Jurgen 212 Hol, Per Kristian 102 Kazem, Mohammad 66 Hoogenboom, Martijn 212 Keenan, James 42 G Horodyckid, Catherine 35 Keravnou, Christina 225 Gaur, Pooja 140 Hsu, I-Chow 79 Keserci, Bilgin 114, 117, 217, 222 Gedroyc, Wladyslaw 82, 112, 203 Huang, Yuexi 67 Keupp, Jochen 185, 187

234 Focused Ultrasound 2014 4th International Symposium Author Index by Name (continued)

Khaled, Mohamad 52, 137 Lee, Daniela 146 McLeod, Helen 177 Kheirolomoom, Azadeh 61 Lee, Dongjuin 171 McWilliam, Sarah 95 Khokhlova, Tatiana 62, 81, 107 Lee, Franklin 89 Marco Colangeli 70 Khokhlova, Vera 107 Lee, Hsin-Lun 124 Mead, Brian 150 Kim, AeRang 191, 205, 209 Lee, Meredith 147 Melodelima, David 101 Kim, Grace 113 Lee, Stephanie D. 44 Melzer, Andreas Kim, Harry 191, 205, 209 Lee, Wonhye 44, 47 104, 168, 173, 176, 177, 207 Kim, Hyungmin 44, 47 Leroux, Jean-Christoph 145 Merckel, Laura 92, 167 Kim, Peter 191, 205, 209 Lesser, Thomas G. 206 Meyer, Craig 139, 163 Kim, Saejeong 91, 196, 229 Leung, Steve 148 Meyer, Joshua 68 Kim, Young Goo 144, 226 Levin, Albert 208 Mihcin, Senay 173, 176 Kim, Young-sun 112, 116, 117 Levy, Yoav 104, 175, 176 Militianu, Daniela 68 Kimmel, Eitan 228 Lim, Hyo Keun 116, 117 Miller, Wilson Kinnaird, David 191, 205, 209 Lindner, Uri 75 52, 58, 84, 134, 139, 156, 163, 230 Klibanov, Alexander 192 Lingeman, James 89 Minalga, Emilee 56 Knuttel, Floor 92, 167 Lipsman, Nir 30 Mindjuk, Irene 118 Kobayashi, Akira 103 Liu, Jia 114, 222 Mitsuishi, Mamoru 171 Kohler, Max 92, 167 Liu, Yu 61 Monteith, Stephen 34, 49 Koizumi, Norihiro 171 Livingstone, Margaret 45, 51, 149 Moonen, Chrit Kondo, Hiroshi 128Kondo, Masaaki Looi, Thomas 127, 136, 154, 156 92, 105, 106, 110, 121, 167, 174, 178, 184, 204 103, 171 Lopes, M. Beatriz 165 Moore, David 199 Konofagou, Elisa Louis, Alyssa 75 Moreno, Maria 42 39, 40, 99, 138, 143, 155, 161 Lu, David 109, 113 Moriyama, Kenji 169 Korb, Alexander 48 Lu, Peiyun 113 Mougenot, Charles Kortelainen, Juha 181 Luciani, Paola 145 66, 67, 78, 136, 154, 181, 182 Koskela, Julius 105, 181 Moura, Mauricio 125, 220 Kothari, Ashutosh 95 M Moyer, Linsey 84 Kovacs, Tibor 95 Maccabi, Ashkan 135 Mueller, Michael 104 Kovacs, Zsofi a 145 Machtinger, Ronit 111 Muratore, Robert 82 Kovatcheva, Roussanka 94, 193 Maeda, Shin 103, 171 Mylonas, Nicos 90 Kreider, Wayne 107 Mahakian, Lisa 61 Kremer, Michael 194 Mainprize, Todd 30 N Krug, Roland 126 Makarounas, Christos 90 Nakahara, Hiroshi 93 Kucharczyk, Walter 75 Mali, Willem 92, 167 Nakajima, Megumi 169 Kuo, Chia-Chun 124 Mannaris, Christophoros 225Manuel, Namba, Kiyoshi 169 Kurhanewicz, John 79 Alvarez del Castillo 97 Nance, Elizabeth 156 Kurihara, Naho 151 Maples, Danny 200 Napoli, Alessandro Margolis, Daniel 113 63, 64, 65, 69, 70, 98, 119, 213 L Marsac, Laurent 52 Nassar, Maria 27 Ladouceur-Wodzak, Michelle 201 Martin, Ernst 28, 33, 43, 145 Negishi, Yoichi 151, 197 Laetsch, Theodore W 66 Martins, Guilherme 125 Newell, David 34, 49 La, Gong-Yau 124 Maruoka, Takashi 172 Newhardt, Ryan 200 Langø, Thomas 104 Maruyama, Kazuo 151, 197 Nguyen, Ben 91, 196, 229 Larner, James 147, 179 Mastorakos, Panagiotis 150 Nhan, Tam 37 Larrabee, Zachary 199 Matsui, Kazuhiro 166 Nicolay, Klaas 187 Larson, Peder 126 Matsumoto, Yoichiro 166, 171 Nijenhuis, Robbert 110 Lau, Benison 142 Matzko, Matthias 112 Nowroozi, Bryan 135 LeBlang, Suzanne 120, 215, 216 Maxwell, Adam 107 Nozaki, Akito 103, 171 Leclercq, Delphine 35 McCluskey, Stuart 75 Numata, Kazushi 103, 171 Lee, Cheng-Chia 165 McDannold, Nathan 31, 36, 45, 51, 132, 133, 149 Focused Ultrasound 2014 4th International Symposium 235 Author Index by Name (continued)

O R Schubert, Gerald 92, 105, 110, 167, 204 Oda, Syota 128 Raaymakers, Bas 178 Schwenke, Michael 175, 176 Oda, Yusuke 197 Rabilloud, Murielle 72, 73 Schwyzer, Lucia 33 Odéen, Henrik 152 Rabinovichi, Jaron 111, 112 Scionti, Stephen 74 Oetgen, Matthew 191, 205, 209 Raghavan, Prashant 165 Scott, Serena 126, 218 O’Gormann, Ruth 33 Ramaekers, Pascal 174 Scudder, Julie 95 Olive, Kenneth 99 Raman, Steven 109, 113 Seki, Mutsumi 197 Olumolade, Oluyemi 39, 161 Ramsay, Elizabeth 66, 181 Sela, Benjamin 147 Omata, Daiki 197 Ranjan, Ashish 200 Sharma, Karun 191, 205, 209 O’Reilly, Meaghan 59 Rastogi, Harsh 112 Sheehan, Jason 32, 147, 165 Orovan, William 214 Relle, James 77 Sheeran, Paul 84 Owens, Gabe 208 Remonda, Luca 33 Shidooka, Junichi 93 Ozhinsky, Eugene 79, 126, 218 Repasky, Elizabeth 60 Shoham, Shy 228 Rhim, Hyunchul 116, 117 Sierra Sanchez, Carlos 138 P Rieck, Birgit 182 Sin, Vivian 154 Pahernik, Sascha 77 Rieke,Viola 79, 126, 218 Sinai, Alon 27 Palermo, Carmine 99 Ries, Mario 105, 106, 174, 178, 184, 204 Skalina, Karin 80, 198 Palla, Carola 98, 119, 213 Rimondi, Eugenio 70 Sliwinski, Anthony 214 Palmerini, Emanuela 65 Rivens, Ian 83 Snell, John Park, Michael Y. 44 Rivoire, Michel 101 49, 52, 134, 137, 142, 147, 165, 187, 199 Parker, Dennis 55, 56, 131, 152 Roberts, Anne 112 Song, In-Uk 47 Partanen, Ari 107, 198 Robertson, Cary 214 Song, Ji 150, 156, 179 Patrie, James 142 Roemer, Robert 122 Sorensen, Mathew 89 Payen, Thomas 99 Roethke, Matthias 77 Spensieri, Paula 75 Payne, Allison 122 Rong, Rong 114, 222 Spinnato, Paolo 64, 69, 70 Peek, Mirjam 95 Roth, Chris 199 Stafford, Jason 88 Perich, Eloi 97 Roth, Patrick 145 Staruch, Robert 181, 201 Perumal, Venkatesan 200 Rouviere, Olivier 71, 72, 73 Stern, John 48 Peters, Steffi e 198 Rovella, Marcello 125 Stewart, Elizabeth 112 Pfeffer, Raphael 68 Rube, Martin 173 Stoinov, Julian 94, 193 Pichardo, Samuel 127, 136, 154, 182 Storås, Tryggve 102 Pinder, Sarah 95 S Strehlow, Jan 175, 176 Pinton, Gianmarco 52 Saddik, George 135 Strijkers, Gustav 187 Plaksin, Michael 228 Sakuma, Ichiro 166 Sugiyama, Ryusuke 166 Popeneciu, Ionel Valentin 77 Salgaonkar, Vasant 79, 126 Suk, Jung Soo 150 Pouget, Pierre 46 Saliev, Timur 173 Sumer, Suna 142 Power, Chanikarn 149 Samiotaki, Gesthimani Sun, Tao 161 Prakash, Punit 79 40, 143, 155, 161 Suzuki, Ryo 151, 197 Preusser, Tobias 104, 170, 175, 176 Sandhu, Jagdeep 42 Symonds-Tayler, Richard 83 Price, Karl 154 Sandolo, Francesco 98, 119, 213 Price, Richard 41, 84, 150, 156, 179 Sapozhnikov, Oleg 107 T Przedborski, Serge 40, 161 Sasaki, Akira 166 Takagi, Norio 151 Purdie, Colin 168 Sat, Giora 104 Takagi, Shu 166 Purushotham, Arnie 95 Scandiuzzi, Lisa 80, 198 Takebayash, Shigeo 103 Schade, George 81, 107 Takeda, Ayako 103, 171 Q Schlemmer, Heinz-Peter 77 Takeuchi, Hideki 166 Quigg, Mark 50 Schlesinger, David 147, 165 Tam, Sarah 61 Qureshi, Farhan 199 Schlesinger, Ilana 27 Tan, Nelly 109, 113 Schmitt, Alain 78, 181 Tanaka, Katsuaki 103, 171 Schmitt, Paul 32 Tanner, Christine 104, 175

236 Focused Ultrasound 2014 4th International Symposium Author Index by Name (continued)

Tanter, Mickael 46, 52 Wattiez, Nicolas 46 Zhang, Ting 210 Tebebi, Pamela 91, 196, 229 Webb, Taylor 146, 157, 162 Zhang, Yong-Zhi 133, 149 Temple, Michael 67 Wegener, Nikolas Arne 28 Zhao, Li 139, 163 ten Haken, Bennie 95 Wei, Juan 114, 222 Zheng, Yuan 230 ter Haar, Gail 83, 123, 147 Weiler, Florian 212 Zurawin, Robert 112 Tewar, Muneesh 81 Weiss, Steffen 185 Thanou, Maya 203 Werner, Beat 28, 33, 43, 145 Theodoulou, Margarita 90 Wijlemans, Joost 105, 106, 184, 204 Timbie, Kelsie 84, 156, 179 Williams, Rashida 229 Tokuda, Juichi 103 Wintermark, Max Tolo, Jaakko 185 52, 137, 139, 142, 163 Trachtenberg, John 75 Wolfram, Frank 206 Tsai, Jo-Ting 124 Wong, Andrew 61 Tseng, Phil 50 Wright, Mike 203 Tsukihara, Hiroyuki 171 Wu, Feng 60 Tustison, Nicholas 142 Wu, Shih-Ying 155

U X Unga, Johan 197 Xiao, Xu 176, 177 Urakawa, Felipe Shoiti 125, 220 Xin, Wenjun 142 Uruga, Hitoshi 197 Xu, Doudou 207 Ushida, Takahiro 128 Xu, Zhen 208 Xu, Zhiyuan 32, 165 V van Amerongen, Martinus J. 212 Y van Breugel, Johanna 106, 110, 204 Yamane, Masaya 151 van den Bosch, Maurice Yang, Daniel 191, 205, 209 92, 106, 110, 167, 204 Yang, Xuedong 217, 222 Van der Kwast, Theodorus 75 Yang, Yang 168 van Stralen, Marijn 121 Yao, Chen 101 Van Vliet, Meghan 75 Yarmolenko, Pavel 191, 205, 209 Vermeulen, Sandra 34 Ye, Patrick Peiyong 146 Viana, Públio 125 Yen, Chun-Po 165 Vidal-Jove, Joan 97 Ying, Zhu 217 Vignot, Alexandre 35 Ymaguchi, Yukiko 93 Vincenot, Jeremy 101 Yoo, Seung-Schik 44, 47 Vinnicombe, Sarah 168 Yoshinaka, Kiyoshi 166, 171 Vlahov, Jordan 94, 193 Younan, Youliana 46 Vyas, Urvi 157, 159, 162 Vykhodtseva, Natalia 45, 51, 133, 149 Z Zaaroor, Menashe 27 W Zaccagna, Fulvio 63, 69, 98, 119, 213 Wackerle, Doug 191, 205, 209 Zachiu, Cornel 178 Wallen, Eric 214 Zadicario, Eyal 53 Wang, Lijun 207 Zaletel, Katja 94, 193 Wang, Shutao 40, 161 Zangos, Stephan 104 Wang, Xiaoying 114, 217, 222 Zhang, Clark 156 Wang, Yak-Nam 81, 107 Zhang, Huagang 80 Ward, John 214 Zhang, Jimin 85 Waspe, Adam 67, 127, 136, 154 Zhang, Kunyan 182

Focused Ultrasound 2014 4th International Symposium 237 Notes

238 Focused Ultrasound 2014 4th International Symposium Author Index by Organization (continued) In accordance with author requests; the following abstracts are not included in this publication: 32-BR; 49-BM; 53-BM; 90-UF; P-102-BM; P-138-BR; P-159-EA. P-116-BR was withdrawn.

Aichi Medical University McDannold, Nathan Chen, Hong 39, 99 Ushida, Takahiro 128 31, 36, 45, 51, 132, 133, 149 Chen, Shangshang 138 Albert Einstein College of Park, Michael 44 Downs, Matthew 138, 143 Medicine Power, Chanikarn 149 Duff, Karen 39 Basu, Indranil 80 Vykhodtseva, Natalia 45, 51, 133, 149 Ferrera, Vincent 138 Scandiuzzi, Lisa 80, 198 Yoo, Seung-Schik 44, 47 Han, Yang 99 Skalina, Karin 80, 198 Cancer Institute of the State of Jackson-Lewis, Vernice 40, 161 Zhang, Huagang 80 Sao Paulo Karakatsani, Maria Eleni (Marilena) 138, 143, 155 Amper Kliniken AG Bernardes, João Paulo 125 Martins, Guilherme 125 Konofagou, Elisa Matzko, Matthias 112 39, 40, 99, 138, 143, 155, 161 Mindjuk, Irene 118 Rovella, Marcello 125 Urakawa, Felipe Shoiti 125, 220 Olive, Kenneth 99 Artenga Inc. Viana, Públio 125 Olumolade, Oluyemi 39, 161 Keenan, James 42 Palermo, Carmine 99 CarThera Payen, Thomas 99 Assistance Publique - Hôpitaux Canney, Michael 35 Przedborski, Serge 40, 161 de Paris, Hôpital de la Pitié- Vignot, Alexandre 35 Samiotaki, Gesthimani Salpêtrière Centre for Image Guided 40, 143, 155, 161 Carpentier, Alexandre 35 Innovation and Therapeutic Sierra Sanchez, Carlos 138 Delattre, Jean-Yves 35 Sun, Tao 161 Horodyckid, Catherine 35 Intervention Constanciel Colas, Elodie 136 Wang, Shutao 40, 161 Idbaih, Ahmed 35 Wu, Shih-Ying 155 Leclercq, Delphine 35 Drake, James 127, 136, 154 Pouget, Pierre 46 Looi, Thomas 127, 136, 154 Cyprus Institute Price, Karl 154 Christofi , Christos 90 Assistance Publique - Hôpitaux Sin, Vivian 154 Cyprus University of Technology de Paris, Hôpital Saint-Louis Waspe, Adam 127, 136, 154 Goldwirt, Lauriane 35 Makarounas, Christos 90 Centre Leon Berard Theodoulou, Margarita 90 Assuta Hospital Dupre, Aurelien 101 Duke University Medical Center Pfeffer, Raphael 68 Rivoire, Michel 101 Robertson, Cary 214 Baylor College of Medicine Yao, Chen 101 Edouard Herriot Hospital Zurawin, Robert 112 Chang Gung Memorial Hospital Gelet, Albert 71, 72, 73 Beaumont Health System Chen, Cheng-Yu 124 Eindhoven University of Hafron, Jason 77 Children’s National Health System Technology Relle, James 77 Celik, Haydar 191, 205, 209 de Smet, Mariska 189 Eranki, Avinash 191, 205, 209 Breastopia Clinic Grüll, Holger 187, 198 Kim, AeRang 191, 205, 209 Furusawa, Hidemi 93 Hectors, Stefanie 187 Kim, Peter 191, 205, 209 Hirabara, Emiko 93 Hijnen, Nicole 189 Kinnaird, David 191, 205, 209 Inomata, Masuko 93 Jacobs, Igor 187 Oetgen, Matthew 191, 205, 209 Nakahara, Hiroshi 93 Nicolay, Klaas 187 Sharma, Karun 191, 205, 209 Shidooka, Junichi 93 Peters, Steffi e 198 Yarmolenko, Pavel 191, 205, 209 Ymaguchi, Yukiko 93 Strijkers, Gustav 187 Cleveland Clinic Brigham & Women’s Hospital, ETH Zurich Clement, Gregory 132 Harvard Medical School Leroux, Jean-Christophe 145 Devanagondi, Rajiv 208 Arvanitis, Costas 45, 51, 132, 149 Luciani, Paola 145 Jolesz, Ferenc 51 Columbia University Tanner, Christine 104, 175 Lee, Stephanie 44 Blesa, Javier 161 Lee, Wonhye 44, 47 Buch, Amanda Marie 138, 155 Focused Ultrasound 2014 4th International Symposium 239 Author Index by Organization (continued)

Focused Ultrasound Foundation Purushotham, Arnie 95 IBSmm Engineering spol. s r. o Dobrenz, Liz 183 Scudder, Julie 95 Mueller, Michael 104 Carlson, Carissa 165 Harker School ICESP Eames, Matt Lee, Daniela 146 Fiore, Lucas 125 49, 52, 134, 137, 142, 147, 165, 199 Foley, Jessica 32 Harvard Medical School Imperial College London Hananel, Arik Livingstone, Margaret 45, 51, 149 Gedroyc, Wladyslaw 82, 112, 203 52, 112, 142, 147, 165, 199 Zhang, Yong-Zhi 133, 149 Incheon St. Mary’s Hospital, The Hatch, Olivia 142 Harvard Medical School/Boston Catholic University of Korea Iyer, Apoorva 142 College Chung, Yong An 47 Kassell, Neal 32, 52, 142, 147, 165, 199 Aryal, Muna 133 Jung, Yujin 47 Larrabee, Zachary 199 Song, In-Uk 47 Lee, Meredith 147 Heidelberg University Hospital Moore, David 199 Pahernik, Sascha 77 Indiana University Qureshi, Farhan 199 Popeneciu, Ionel Valentin 77 Lingeman, James 89 Roth, Chris 199 Henry Ford Health System Indraprastha Apollo Hospital Sela, Benjamin 147 Levin, Albert 208 Rastogi, Harsh 112 Snell, John Hitachi Aloka Medical Inserm 49, 52, 134, 137, 142, 147, 165, 199 Fujiwara, Keisuke 166 Chapelon, Jean-Yves 35, 71, 72, 73, 101 Fox Chase Cancer Center Itani, Kazunori 166 Melodelima, David 101 Meyer, Joshua 68 Hitachi, Ltd Vincenot, Jeremy 101 Fraunhofer MEVIS Asami, Rei 172 InSightec Ltd Acharya, Dinesh 170 Maruoka, Takashi 172 Levy, Yoav 104, 175, 176 Georgii, Joachim 170 Kawabata, Ken-ichi 172 Zadicario, Eyal 53 Guenther, Matthias 104 Hokuto Hospital Institut Langevin Haase, Sabrina 175 Kawami, Hiroyuki 169 Aubry, Jean-Francois 46, 52, 165, Preusser, Tobias 104, 170, 175, 176 Moriyama, Kenji 169 Deffi eux, Thomas 46 Schwenke, Michael 175, 176 Nakajima, Megumi 169 Marsac, Laurent 52 Strehlow, Jan 175, 176 Namba, Kiyoshi 169 Pinton, Gianmarco 52 Weiler, Florian 212 Hospices Civils de Lyon Tanter, Mickael 46, 52 Frederick Research Center Bratan, Flavie 71 Younan, Youliana 46 Mylonas, Nicos 90 Crouzet, Sebastien 71, 72, 73 Institute for Medical Science and GE Medical Systems Israel Ltd. Rabilloud, Murielle 72, 73 Technology Sat, Giora 104 Rouviere, Olivier 71, 72, 73 Cochran, Sandy 168, 207 George Washington University Hospital for Sick Children Wang, Lijun 207 School of Medicine Amaral, Joao 67 Xiao, Xu 176, 177 Wackerle, Doug 191, 205, 209 Campbell, Fiona 67 Institute for Systems Biology de Ruiter, Joost 67 German Cancer Research Center Chevillet, John 81 Drake, James 67 (DKFZ) Institute of Brain and Spinal Cord Hudson, Thomas 127 Roethke, Matthias 77 Wattiez, Nicolas 46 Temple, Michael 67 Schlemmer, Heinz-Peter 77 Waspe, Adam 67 Instituto do Câncer do Estado de Guy’s and St. Thomas’ Hospitals São Paulo Hospital Universititari Mutua Hamed, Hisham 95 Bernardes, João Paulo 125 Terrassa Kothari, Ashutosh 95 Castro, Stephanie 220 Alvarez del Castillo, Manuel 97 Kovacs, Tibor 95 de Menezes, Marcos Roberto 125, 220 Jaen, Angels 97 McWilliams, Sarah 95 Fiore, Lucas 125 Perich, Eloi 97 Pinder, Sarah 95 Martins, Guilherme 125 Vidal-Jove, Joan 97 240 Focused Ultrasound 2014 4th International Symposium Author Index by Organization (continued)

Instituto do Câncer do Estado de King’s College London N.N. Petrov Research Institute of São Paulo (continued) Ahmed, Muneer 95 Oncology Moura, Mauricio 125, 220 Centelles, Miguell 203 Kanaev, Sergey 68 Rovella, Marcello 125 Douek, Michael 95 National Institute of Advanced Peek, Mirjam 95 Urakawa, Felipe Shoiti 125, 220 Industrial Science and Viana, Públio 125 Thanou, Maya 203 Technology Wright, Mike 203 Institute of Cancer Research Yoshinaka, Kiyoshi 166, 171 Brown, Jemma 123 Kochi Medical School National Institutes of Health Bunton, Chris 83 Ikeuchi, Masahiko 128 Bresler, Michele 91, 196 Civale, John 83 Izumi, Masahi 128 Burks, Scott 91, 196, 229 Rivens, Ian 83 Kato, Tomonari 128 Farahani, Keyvan 88 Symonds-Taylor, Richard 83 Kawasaki, Motohiro 128 Frank, Joseph 91, 196, 229 ter Harr, Gail 83, 123, 147 Kondo, Hiroshi 128 Kim, Saejeong 91, 196, 229 Oda, Syota 128 Israel Institute of Technology Kovacs, Zsofi a 145 Kimmel, Eitan 228 Kona Medical Nguyen, Ben 91, 196, 229 Plaksin, Michael 228 Crura, Francesco 85 Tebebi, Pamela 91, 196, 229 Shoham, Shy 228 Gertner, Michael 85 Williams, Rashida 229 Zhang, Jimin 85 Jacobs University Bremen National Research Council of Preusser, Tobias 104, 170, 175, 176 Korea Institute of Science and Canada Jefferson University Hospitals Technology Iqbal, Umar 42 Hurwitz, Mark 61, 68 Kim, Hyungmin 44, 47 Moreno, Maria 42 Sandhu, Jagdeep 42 Johann Wolfgang Goethe- Laennec Imagix Imaging Center • Universität Medical Imaging Oklahoma State University Zangos, Stephan 104 Gianfelice, David 68 Maples, Danny 200 Newhardt, Ryan 200 Johns Hopkins University London Health Sciences Center Billia, Michele 77 Perumal, Venkatesan 200 Hanes, Justin 150, 156 Ranjan, Ashish 200 Mastorakos, Panagiotis 150 Chin, Joseph 77 Nance, Elizabeth 156 Mayo Clinic College of Medicine Osaka Medical Center for Cancer Suk, Jung Soo 150 Stewart, Elizabeth 112 and Cardiovascular Diseases Ashida, Reiko 172 Zhang, Clark 156 McMaster University Kansas State University Orovan, William 214 Oslo University Hospital Prakash, Punit 79 Barkhatov, Leonid 102 MD Anderson Cancer Center Carling, Ulrik 102 Kantonsspital Aarau Stafford, Jason 88 Courivaud, Frederic 102 Anon, Javier 33 Ward, John 214 Dorenberg, Eric 102 Coluccia, Daniel 33 Mediri GmbH Doughty, Richard 102 Fandino, Javier 33 Corr, Doerte 212 Edwin, Bjørn 102 Remonda, Luca 33 Jenne, Jürgen 104, 212 Hol, Per Kristian 102 Schwyzer, Lucia 33 Storås, Tryggve 102 MEDSONIC Kantonsspital St. Gallen Damianou, Christakis 90 Peking University First Hospital Bauer, Ronald 28, 43 Liu, Jia 114, 222 Montefi ore Medical Center Brugger, Florian 28 Rong, Rong 114, 222 Guha, Chandan 80, 198 Hägele-Link, Stefan 28 Wang, Xiaoying 114, 217, 222 Kägi, Georg 28 Moscow State University Yang, Xuedong 217, 222 Wegener, Nikolas Arne 28 Sapozhnikov, Oleg 107 Ying, Zhu 217

Focused Ultrasound 2014 4th International Symposium 241 Author Index by Organization (continued)

Philips Healthcare Samsung Medical Center Nhan, Tam 37 Berben, Monique 187 Kim, Young-sun 112, 116, 117 O’Reilly, Meaghan 59 Grüll, Holger 185, 187, 189 Lim, Hyo Keun 116, 117 Ramsay, Elizabeth 66, 181 Heijman, Edwin 185, 187, 189 Rhim, Hyunchul 116, 117 Schmitt, Alain 78, 181 Keserci, Bilgin 114, 117, 217, 222 Scionti Prostate Center Sheeran, Paul 84 Keupp, Jochen 185, 187 Scionti, Stephen 74 Swedish Neuroscience Institute Kohler, Max 92, 167 Cobbs, Charles 34 Koskela, Julius 105, 181 Sheba Medical Center Alagem-Mizrachi, Aviva 111 Gwinn, Ryder 49 Mougenot, Charles Monteith, Stephen 34, 49 66, 67, 78, 136, 154, 181, 182 Inbar, Yael 111 Machtinger, Ronit 111 Newell, David 34, 49 Partanen, Ari 107, 198 Vermeulen, Sandra 34 Schubert, Gerald Rabinovichi, Jaron 111, 112 92, 105, 110, 167, 204 SRH Waldklinikum Gera Taipei Medical University Staruch, Robert 181, 201 Lesser, Thomas G. 206 Chiou, Jeng-Fong 124 Tolo, Jaakko 185 Wolfram, Frank 206 Jeng, Shiu-Chen 124 Wei, Juan 114, 222 Kuo, Chia-Chun 124 Stanford University Weiss, Steffen 185 Lan, Gong-Yau 124 Avedian, Raffi 86 Lee, Hsin-Lun 124 Philips Research Bitton, Rachelle 86, 157 Tsai, Jo-Ting 124 Grüll, Holger 185, 189 Bucknor, Matthew 86 Butts Pauly, Kim Teikyo University Princeton University Maruyama, Kazuo 151, 197 Yang, Daniel 191, 205, 209 54,86,139,146,148,157,159,162,163 Ghanouni, Pejman Oda, Yusuke 197 Profound Medical Inc. 68, 86, 146, 148, 157, 162 Omata, Daiki 197 Burtnyk, Mathieu 77 Gold, Garry 86 Seki, Mutsumi 197 Quantum Now LLC Johnson, Ethan 159 Suzuki, Ryo 151, 197 Muratore, Robert 82 Leung, Steve 148 Unga, Johan 197 Uruga, Hitoshi 197 Radboud University Medical Vyas, Urvi 157, 159, 162 Center Webb, Taylor 146, 157, 162 Texas Scottish Rite Hospital for Fütterer, Jurgen 212 Ye, Patrick Peiyong 146 Children Hoogenboom, Martijn 212 Stiftelsen SINTEF Kim, Harry 191, 205, 209 van Amerongen, Martinus 212 Langø, Thomas 104 The George Washington Rambam Health Care Campus Sunnybrook Health Sciences University School of Medicine Eran, Ayelet 27 Center/ Sunnybrook Research Wackerle, Doug 191, 205, 209 Erikh, Ilana 27 Institute The Institute of Cancer Research Goldsher, Dorit 27 Aubert, Isabelle 37, 38 ter Haar, Gail 83, 123, 147 Militianu, Daniela 68 Bethune, Allison 30 The “Rizzoli” Orthopaedic Nassar, Maria 27 Burgess, Alison 37, 38 Institute Schlesinger, Ilana 27 Czarnota, Gregory 67 Albisinni, Ugo 64, 65, 69, 70 Sinai, Alon 27 da Costa, Leodante 30 Battaglia, Milva 70 Zaaroor, Menashe 27 David, Elizabeth 112 Bazzocchi, Alberto 64, 65, 69, 70 Rostov Scientifi c Research Dubey, Sonam 37 Busacca, Maurizio 64, 65 Institute of Oncology Endre, Ruby 67 Colangeli, Marco 70 Iozeffi , Dmitri 68 Huang, Yuexi 67 Donati, Davide 70 Hynynen, Kullervo 30, 37, 38, 59, 67 Ferrari, Stefano 65 Roswell Park Cancer Institute Jones, Ryan 59 Repasky, Elizabeth 60 Filonzi, Giacomo 64, 65, 70 Kazem, Mohammad 66 Palmerini, Emanuela 65 Lipsman, Nir 30 Rimondi, Eugenio 70 Mainprize, Todd 30 Spinnato, Paolo 64, 69

242 Focused Ultrasound 2014 4th International Symposium Author Index by Organization (continued)

Thunder Bay Regional Research Huisman, Merel 201 University of California Davis Institute Ikink, Marlijne 110 Ferrara, Katherine 61 Adamczyk, Bruno 141 Knuttel, Floor 92, 167 Fite, Brett 61 Bates, David 182 Mali, Willem 92, 167 Ingham, Elizabeth 61 Curiel, Laura 141, 182 Merckel, Laura 92, 167 Kheirolomoom, Azadeh 61 Dos Santos, Cleiton 141 Moonen, Chrit Liu, Yu 61 Estrade, Thiabault 141 92, 105, 106, 110, 121, 167, 174, 178, 184, 204 Mahakian, Lisa 61 Gong, Shawn 141 Nijenhuis, Robbert 110 Tam, Sarah 61 Pichardo, Samuel 127, 136, 154, 182 Raaymakers, Bas 178 Wong, Andrew 61 Rieck, Birgit 182 Ramaekers, Pascal 174 University of California San Tokyo University of Pharmacy Ries, Mario Diego 105, 106, 174, 178, 184, 204 and Life Sciences Roberts, Anne 112 van Breugel, Johanna 106, 110, 204 Aramaki, Yukihiko 151 van den Bosch, Maurice University of California San Endo-Takahashi, Yoko 151 92, 106, 110, 167, 204 Francisco Kurihara, Naho 151 van Stralen, Marijn 121 Diederich, Chris 79, 126, 218 Negishi, Yoichi 151, 197 Wijlemans, Joost 105, 106, 184, 204 Han, Misung 126, 218 Takagi, Norio 151 Zachiu, Cornel 178 Hsu, I-Chow 79 Yamane, Masaya 151 Jones, Peter 126 University Medical Centre Universita Degli Studi Di Roma Krug, Roland 126 Ljubljana La Sapienza Kurhanewicz, John 79 Zaletel, Katja 94, 193 Bezzi, Mario 104 Larson, Peder 126 University MRI University Children’s Hospital Ozhinsky, Eugene 79, 126, 218 Bryant, Kelli 120, 215, 216 Martin, Ernst 28, 33, 43, 145 Prakash, Punit 79 LeBlang, Suzanne 120, 215, 216 O’Gormann, Ruth 33 Rieke, Viola 79, 126, 218 Werner, Beat 33, 43, 145 University of Calgary Salgaonkar, Vasant 79, 126 Zhang, Kunyan 182 Scott, Serena 126, 218 University Hospital of University of Cyprus Endocrinology University of California at Los Averkiou, Michalakis 225 Kovatcheva, Roussanka 94, 193 Angeles Izamis, Maria-Louisa 225 Stoinov, Julian 94, 193 Babakhanian, Meghedi 135 Keravnou, Christina 225 Vlahov, Jordan 94, 193 Bahrami, Simin 109 Bajwa, Neha 135 Mannaris, Christophoros 225 University Hospital Zurich Brown, Matthew 113 University of Dundee Roth, Patrick 145 Bystritsky, Alexander 48 Cox, Benjamin 177 University Medical Center Cohen, Mark 48 Cochran, Sandy 168, 207 Freiburg Coy, Heidi 113 Dogadkin, Osnat 173 Bock, Michael 212 Goldin, Jonathan 113 Domschke, Markus 176, 177 Dadakova, Tetiana 212 Grundfest, Warren 135 Eisma, Roos 168 University Medical Center Utrecht Kim, Grace 113 Joy, Joyce 168 Bartels, Lambertus 92, 105, 110, 167 Korb, Alexander 48 Karakitsios, Ioannis 168, 173, 176, 177 Bartels, Wilbert 121 Lu, David 109, 113 McLeod, Helen 177 Bos, Clemens 121 Lu, Peiyun 113 Melzer, Andreas 104, 168, 173, 176, 177, 207 Crijns, Sjoerd 178 Maccabi, Ashkan 135 Mihcin, Senay 173, 176 de Greef, Martijn Margolis, Daniel 113 Purdie, Colin 168 105, 106, 174, 184, 204 Tan, Nelly 109, 113 Rube, Martin 173 Deckers, Roel 92, 121, 167 Nowroozi, Bryan 135 Saliev, Timur 173 Denis de Senneville, Baudouin Raman, Steven 109, 113 Vinnicombe, Sarah 168 167, 178 Saddik, George 135 Wang, Lijun 207 Eschbach, Frank 184 Stern, John 48 Xiao, Xu 177 Focused Ultrasound 2014 4th International Symposium 243 Author Index by Organization (continued)

University of Dundee (continued) University of Tokyo Diakova, Galina 192 Xu, Doudou 207 Azuma, Takashi 166 Du, Zhongmin 192 Yang, Yang 168 Lee, Dongjuin 171 Elias, W. Jeff 26, 29, 50, 52, 137 Zhang, Ting 210 Fujii, Tatsuya 171 Feng, Xue 139, 163 University of Maryland School of Iwahashi, Toshihide 166 Fielden, Samuel 139, 163 Medicine Koizumi, Norihiro 171 Fountain, Nathan 50 Frenkel, Victor 229 Matsui, Kazuhiro 166 Khaled, Mohamad 52, 137 Matsumoto, Yoichiro 166, 171 Klibanov, Alexander 192 University of Michigan Mitsuishi, Mamoru 171 Larner, James 147, 179 Allen, Steven 108 Sakuma, Ichiro 166 Lau, Benison 142 Giraldez, Maria 81 Sasaki, Akira 166 Lee, Cheng-Chia 165 Gurm, Hitinder 208 Sugiyama, Ryusuke 166 Lopes, M. Beatriz 137, 165 Hall, Timothy 108 Takagi, Shu 166 Mead, Brian 150 Owens, Gabe 208 Takeuchi, Hideki 166 Meyer, Craig 139, 163 Tewari, Muneesh 81 Tsukihara, Hiroyuki 171 Miller, Wilson Xu, Zhen 208 University of Toronto 52, 58, 84, 134, 139, 156, 163, 230 University of North Carolina Ghai, Sangeet 75 Patrie, James 142 Dayton, Paul 84 Haider, Masoom 75 Price, Richard 41, 84, 150, 156, 179 Moyer, Linsey 84 Hlasny, Eugen 75 Quigg, Mark 50 Wallen, Eric 214 Kucharczyk, Walter 75 Raghavan, Prashant 165 Lindner, Uri 75 Schlesinger, David 147, 165 University of Oxford Schmitt, Paul 32 Wu, Feng 60 Louis, Alyssa 75 McCluskey, Stuart 75 Sheehan, Jason 32, 147, 165 University of Rome Spensieri, Paula 75 Song, Ji 150, 156, 179 Andrani, Fabrizio 63, 119, 213 Trachtenberg, John 75 Sumer, Suna 142 Anzidei, Michele 98 Van der Kwast, Theodorus 75 Timbie, Kelsie 84, 156, 179 Caliolo, Gianluca 63, 98 Van Vliet, Meghan 75 Tseng, Phil 50 Cartocci, Gaia 63 Tustison, Nicholas 142 Catalano, Carlo University of Twente Wintermark, Max 63, 64, 65, 69, 70, 119, 213 ten Haken, Bennie 95 52, 137, 139, 142, 163 Ciolina, Federica 119 University of Utah Xin, Wenjun 142 Di Paolo, Pier Luigi 213 Almquist, Scott 131 Xu, Zhiyuan 32, 165 Facchini, G 64 Christensen, Douglas 131 Yen, Chun-Po 165 Giulia, Brachetti 63, 69 Dillon, Christopher 122 Zhao, Li 139, 163 Napoli, Alessandro Hadley, Rock 56 Zheng, Yuan 230 63, 64, 65, 69, 70, 98, 119, 213 Minalga, Emilee 56 University of Washington Palla, Carola 98, 119, 213 Odéen, Henrik 152 Bailey, Michael 89, 107 Sandolo, Francesco 98, 119, 213 Parker, Dennis 55, 56, 131, 152 Cunitz, Bryan 89 Zaccagna, Fulvio 63, 69, 98, 119, 213 Payne, Allison 122 Dunmire, Barbrina 89 University of Southern California Roemer, Robert 122 Farr, Navid 107 Gill, Inderbir 214 University of Virginia Harper, Jonathan 89 University of Texas Southwestern Andarawewa, Kumari 179 Hwang, Joo Ha 81 Medical Center Ando, Yuta 179 Khokhlova, Tatiana 62, 81, 107 Bing, Chenchen 181 Aubry, Jean-Francois Khokhlova, Vera 107 Chhabra, Avneesh 201 46, 52, 134, 142, 147, 165, 199 Kreider, Wayne 107 Chopra, Rajiv 66, 76, 78, 88, 181, 201 Badr, Lena 180 Lee, Franklin 89 Ladouceur-Wodzak, Michelle 201 Brenin, David 96 Maxwell, Adam 107 Laetsch, Theodore 66 Cupino, Alan 142 Schade, George 81, 107 Dallapiazza, Robert 26, 50, 137 Sorensen, Mathew 89 Wang, Yak-Nam 81, 107 244 Focused Ultrasound 2014 4th International Symposium Author Index by Organization (continued)

Vanderbilt University Caskey, Charles 194 Gaur, Pooja 140 Grissom, William 140, 194 Kremer, Michael 194 Virginia Urology Sliwinski, Anthony 214 VTT Technical Research Centre of Finland Kortelainen, Juha 181 Western University Ahmed, Hassaan 129 Yokohama City University Chuma, Makoto 103, 171 Doba, Nobutaka 103, 171 Fukuda, Hiroyuki 103, 171 Hao, Yoshiharu 103, 171 Kobayashi, Akira 103 Kondo, Masaaki 103, 171 Maeda, Shin 103, 171 Nozaki, Akito 103, 171 Numata, Kazushi 103, 171 Takebayash, Shigeo 103 Takeda, Ayako 103, 171 Tanaka, Katsuaki 103, 171 Tokuda, Juichi 103 Yonsei University College of Medicine Chang, Jin Woo 29, 30 Kim, Young Goo 144, 226

Focused Ultrasound 2014 4th International Symposium 245 Notes

246 Focused Ultrasound 2014 4th International Symposium Young Investigator Awards Program

The Focused Ultrasound Foundation established the Young Investigator Awards Program to encourage quality research by clinicians and scientists-in-training and to support their presentation of meritorious scientifi c papers at major venues such as the 4th International Symposium on Focused Ultrasound. Graduate students, research fellows, clinical fellows and junior faculty members are eligible to apply for the awards, which include complementary event registration and up to an additional $1,500 in reimbursement for travel and lodging expenses. This year’s awards were funded in part by a $5,000 grant from the National Cancer Institute (R13CA171719). The funding came from the National Institutes of Health (NIH) Conference Grant Program which supports high quality conferences that are relevant to the scientifi c mission of the NIH and to public health. Fifteen Young Investigators are participating in the 4th International Symposium on Focused Ultrasound and being acknowledged in several ways. Pre-symposium Publicity: To emphasize the signifi cance of the Young Investigator Awards, the Foundation is announcing this year’s award recipients and highlighting their research in our monthly e-newsletter. Name Badges and Announcement: Award recipients will receive unique name badges that indicate their status as Young Investigators. They will be acknowledged at the Symposium opening session, and senior investigators will be encouraged to interact with them throughout the conference. Evening Reception and Poster Session: Young Investigators will have a designated section of the Poster Hall. On Tuesday, 14 October 2014, during the Poster Session & Reception, they will have an opportunity to showcase and present their work to the larger focused ultrasound community.

Young Investigator Awards Committee Selection of the 2014 Young Investigator Award recipients was based on peer- reviewed scoring of each applicant’s abstract by the Symposium Scientifi c Committee. The fi nal roster of recipients was determined by the Young Investigator Awards Review Committee: Jean-François Aubry, PhD CNRS Research Scientist, Institut Langevin Paris, France Matt Eames, PhD Director of Extramural Research, Focused Ultrasound Foundation Charlottesville, Virginia, United States Jessica Foley, PhD Scientifi c Director, Focused Ultrasound Foundation Charlottesville, Virginia, United States Arik Hananel, MD, MBA Medical Director, Focused Ultrasound Foundation Charlottesville, Virginia, United States

Focused Ultrasound 2014 4th International Symposium 247 2014 Young Investigator Awards (continued)

Steven Allen Awarded for: Real-Time MRI Feedback of Cavitation Ablation Therapy (Histotripsy) [89-LV/P189-YI]

Steven Allen is a PhD candidate in biomedical engineering at the University of Michigan in Ann Arbor, Michigan. His research is focused on MRI feedback of histotripsy therapy.

Alberto Bazzocchi Awarded for: Palliation of Painful Bone Metastases: The “Rizzoli” Experience [52-BM/P-190-YI] Additional Presentations: 45-BN, 46-BN

Dr. Bazzocchi serves as Consultant Radiologist for clinical and research activity at the “Rizzoli” Orthopaedic Institute (Bologna, Italy). He is author of over 170 works (abstracts) presented by him or by fellows of his team at the most important congresses worldwide, and he wrote over 40 full papers for original research and reviews. Among journals publishing his works it is possible to count some of the top references in medicine (e.g., The Lancet, Bone, and RadioGraphics, for general medicine, skeletal diseases, and radiology respectively, but also journals corresponding to many other specialities – CMAJ, Arthritis & Rheumatism, The Journal of Bone and Joint Surgery (Am), Journal of Shoulder and Elbow Surgery, Clinical Nutrition, Clinical Infectious Diseases, Journal of Pediatrics, European Radiology, Skeletal Radiology). Dr. Bazzocchi is principal investigator and main author in the vast majority of publications in curriculum. Principal Investigator and coordinator of the project “Magnetic Resonance guided High Intensity Focused Ultrasound treatment of bone metastases: pain palliation, and local tumor control? (thematic area: Oncology),” winner in the Call for Young Investigator (“Alessandro Liberati”) 2013, Area 1 “Innovative Research,” of the Research Program Regione- Università. He actively participated and participates in numerous research programs, on a regional, national and international basis. Among these, here is also mentioned “Development of a novel technological platform for the treatment of neoplastic and infectious diseases based on focus ultrasounds” NOP-R&C 2007-2013, funded under the European Union and Italian Ministries. Member of the European Working Group on Focused Ultrasound (2011/2012) and of the European Focused Ultrasound Society (EUFUS) since their establishment (2013).

248 Focused Ultrasound 2014 4th International Symposium 2014 Young Investigator Awards (continued)

Kelli Bryant Awarded for: MRI Characterization of Uterine Fibroids May Predict Success of GnRH Agonist Therapy Prior to Magnetic Resonance Focused Ultrasound (MRgFUS) Treatment [101-UF/P-191-YI]

Additional Presentations: P-183-UF, P-184-UF

Kelli Bryant received her bachelor’s degree in biochemistry from the University of North Carolina at Chapel Hill in 2010. After graduating, she continued to work for the UNC Gene Therapy Center investigating the use of viral gene transfer vectors. Kelli went on to earn a master’s degree in biomedical science from Barry University and is currently a second year medical student at the Florida Atlantic University Charles E. Schmidt College of Medicine.

Ulrik Carling Awarded for: MRgHIFU – Experimental Perivascular Volumetric Ablation in the Liver [83-LV/P-192-YI]

Dr. Ulrik Carling is a research fellow at the Department of Radiology and Nuclear Medicine at Oslo University Hospital. His fellowship is in Interventional Radiology, with focus on image guided treatments of liver tumors. Part of the work is in the fi eld of MR guided HIFU, conducted at the Intervention Center at Oslo University Hospital.

Hong Chen Awarded for: Harmonic Motion Imaging for Pancreatic Tumor Detection and High-intensity Focused Ultrasound Ablation Monitoring [81-LV/P-193-YI]

Dr. Hong Chen received her BE and ME degrees in Biomedical Engineering from Xi’an Jiaotong University in 2003 and 2006, respectively. She joined the Center for Industrial and Medical Ultrasound at the University of Washington in 2006 and received her PhD in Bioengineering in 2011. She then spent one year as a senior fellow at the University of Washington School of Medicine. She is now a postdoctoral research scientist at the Department of Biomedical Engineering at Columbia University.

Focused Ultrasound 2014 4th International Symposium 249 2014 Young Investigator Awards (continued)

Christopher Dillon Awarded for: Quantifying Perfusion-related Energy Losses During Magnetic Resonance-guided Focused Ultrasound [103-UF/P-194-YI] Chris Dillon is a postdoctoral research associate in the Department of Radiology at the University of Utah, where he is developing MR perfusion imaging sequences for validation of biothermal models used in MRgFUS. He received his doctoral degree from the Department of Bioengineering at the University of Utah this past August. His dissertation utilized analytical temperature solutions to improve quantitative estimates of MRgFUS parameters in the bioheat transfer equation.

Merel Huisman Awarded for: International Consensus on Use of MR-guided High- Intensity Focused Ultrasound for Bone Metastases: Current Status and Future Directions [49-BM/P-195-YI] Merel Huisman, MD is a clinical researcher from the department of Radiology, University of Utrecht in The Netherlands. Her research focus is MR-guided HIFU.

Christina Keravnou Awarded for: Image-Guided Sonoporation in an Ex vivo Machine Perfused Porcine Liver [P-196-YI] Christina Keravnou earned a BS in Mechanical and Manufacturing Engineering from the University of Cyprus in 2010. She is currently pursuing a PhD degree in Mechanical Engineering at the Biomedical Ultrasound Laboratory of the University of Cyprus. Her main research interests are in the areas of diagnostic and therapeutic applications of ultrasound. Specifi cally during her PhD, she has been working on the optimization of sonoporation parameters, evaluated on ex vivo machine perfused porcine livers under ultrasound imaging guidance.

Young Goo Kim Awarded for: Unilateral Magnetic Resonance Guided Focused Ultrasound Thalamotomy for Essential Tremor: Practices and Clinicaoradiological Outcomes [P-197-YI] Young Goo Kim is Clinical Fellow of Stereotactic and Functional Neurosurgery at Yonsei University College of Medicine.

250 Focused Ultrasound 2014 4th International Symposium 2014 Young Investigator Awards (continued)

Wonhye Lee Awarded for: FUS-mediated Functional Neuromodulation for Neurophysiologic Assessment in a Large Animal Model [23-BR/P-198-YI] Dr. Lee is a research fellow, working with Prof. Seung-Schik Yoo at the Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School. His research background includes the development of 3 dimensional bioprinting technology and its application to tissue engineering and regenerative medicine, as well as utilization of various neurophysiological methods for neuroscience. Since he obtained his PhD degree from Korea Advanced Institute of Science and Technology (KAIST), Dr. Lee has explored various preclinical applications of FUS-mediated neuromodulation techniques. Currently, he is actively engaged in studies furthering and detailing functional neuromodulation applications achieved by FUS.

Mirjam Peek Awarded for: High Intensity Focused Ultrasound (HIFU) in the Treatment of Breast Fibroadenomata: a Feasibility Study [77-BT/P-199-YI] Miss Mirjam Peek is a sixth year Technical Medicine student from the University of Twente in The Netherlands. She is currently working on the High intensity focused ultrasound in the treatment of fi broadenomata (HIFU-F) trial as her graduation project at Guy’s and St. Thomas’ Hospitals in combination with King’s College London.

Michael Plaksin Awarded for: A Unifying Framework for Understanding Ultrasonic Neuromodulation Mechanisms [P-200-YI] Misha is a PhD student in the Israeli Technion Nanoscience and Nanotechnology program. He fi nished his BSc studies in Biomedical Engineering with summa cum laude and continued to direct PhD track studies. His research interests are: 1. Cell membrane biomechanics and biophysics; 2. Ultrasound based neural stimulation and suppression; 3. Infrared based neural stimulation.

Focused Ultrasound 2014 4th International Symposium 251 2014 Young Investigator Awards (continued)

Karin Skalina Awarded for: Immunomodulation of Prostate Cancer Cells after Low Energy Focused Ultrasound [63-PR/P-201-YI] Karin Skalina is a 4th year student in the Medical Scientist Training Program at Albert Einstein College of Medicine in Bronx, NY. She is currently completing her PhD work in the laboratory of Dr. Chandan Guha, Vice Chair of Radiation Oncology at Montefi ore Medical Center, where she is focusing on the immunomodulatory effects of focused ultrasound therapy. She holds a Master of Science in Pathology from Albert Einstein College of Medicine and a Bachelor of Science in Chemical Engineering from Tufts University in Somerville, MA.

Pamela Tebebi Awarded for: Re-establishment of Perfusion in Critical Limb Ischemia Model with Pulsed Focused Ultrasound (pFUS) and Mesenchymal Stem Cells in Aged Mice [P-202-YI] Pamela Tebebi received her bachelor of engineering in biomedical engineering from Vanderbilt University in 2002. She worked in industry for several years and obtained a master of science in biomedical engineering from University of Texas, Arlington. She is currently a biomedical engineering PhD student at The Catholic University of America with Dr. Victor Frenkel in collaboration Dr. Joseph Frank at the NIH.

Yuan Zheng Awarded for: High Speed, High Sensitivity PRF Shift MR Thermometry [P-203-YI] Mr. Yuan Zheng graduated from Peking University in 2007 and is now a physics PhD candidate at the University of Virginia. His research includes low fi eld imaging of hyper-polarized noble gases, introducing radiation detection techniques to enhance conventional MRI, and currently he’s working with Professor Wilson Miller in the Radiology Department on developing high speed, high sensitivity MR thermometry techniques.

252 Focused Ultrasound 2014 4th International Symposium FUS Foundation Internship Programs

Summer Internship Program

The Focused Ultrasound Foundation’s Summer Internship Program was established in 2012 with a goal of giving bright and accomplished high school, undergraduate and graduate students from around the country the opportunity to collaborate with leaders in the fi eld on a variety of projects that address pre-clinical, clinical and business challenges. The program cultivates enthusiasm for focused ultrasound among the interns who then become invaluable ambassadors for the technology within their universities and the scientifi c community at large. This summer, the Foundation welcomed a record 12 student interns, two of whom were returning from last year. With so many hands on deck this year, many of the interns teamed up and were able to tackle larger, more complicated projects. Seven interns submitted abstracts for the Symposium that were accepted. The 2014 program was generously funded in part by the Claude Moore Charitable Foundation (CMCF) and has been named in honor of Dr. Claude Moore, a physician and philanthropist who established the CMCF before his death in 1991. The Claude Moore Focused Ultrasound Internship Program supports Dr. Moore’s passion for developing academic excellence and leadership skills in young people. We thank the CMCF for helping to make this program possible.

Summer Interns (Left to Right) Front row: Benjamin Sela, Apoorva Iyer, Meredith Lee, Olivia Hatch Middle row: Farhan Qureshi, Andrew Kopca, Caroline Dahmen Back row: Ted Kelly, Christopher Roth, Anders Quigg, Zack Larrabee

Focused Ultrasound 2014 4th International Symposium 253 FUS Foundation Internship Programs (continued)

Global Internship Program

The Focused Ultrasound Foundation offers an international internship opportunity for high-school and university undergraduate students interested in the physical and life sciences. Interns supported through this program will work in an established focused ultrasound laboratory under a researcher recognized in the fi eld.

Dinesh Acharya Shawn Gong Fraunhofer MEVIS Thunder Bay Regional Health Sciences Centre Bremen, Germany Thunder Bay, Ontario, Canada Mentor: Tobias Preusser, PhD Mentor: Laura Curiel, PhD Nassim Alikacem Michael Kremer Brigham and Women’s Hospital Vanderbilt University Boston, Massachusetts, United States Nashville, Tennessee, United States Mentor: Nathan McDannold, PhD Mentor: William Grissom, PhD Lena Badr Daniela Lee University of Virginia Stanford University Charlottesville, Virginia, United States Stanford, California, United States Mentor: Richard Price, PhD Mentor: Kim Butts Pauly, PhD Jemma Brown Bernadette Rogez The Institute of Cancer Research Institut National de la Santé et de la Recherche Médicale (INSERM) London, United Kingdom Paris, France Mentor: Gail ter Haar, PhD Mentor: Cyril Lafon, PhD Amanda Buch Margarita Theodoulou Columbia University University of Cyprus New York, New York, United States Nicosia, Republic of Cyprus Mentor: Elisa Konofagou, PhD Mentor: Christakis Damianou, PhD Laure Duran Regina Zambrano University College London University of Utah London, United Kingdom Salt Lake City, Utah, United States Mentor: Nader Saffari, PhD Mentor: Dennis Parker, PhD

Receiving the highest peer-reviewed rating among submissions from the 2014 FUSF Global Interns, Jemma Brown’s abstract, entitled “An Instrumented Bone/Soft Tissue Phantom Designed to Mimic Clinical HIFU Treatments of Bone,” earned her travel support to attend and present her work at the Symposium. Jemma Brown

254 Focused Ultrasound 2014 4th International Symposium Sponsors and Exhibitors

Platinum Sponsors Description Advertisement

Elekta AB 256 261 GE Healthcare 256 262 InSightec 256 263 Philips Healthcare 256 264

Bronze Sponsors

Alpinion Medical Systems 257 265 International Society for Therapeutic Ultrasound (ISTU) 257 265 Verasonics 257 266

Exhibitors

EDAP Technomed 258 Electronics & Innovation, Ltd. 258 EU FUS 258 FUS Instruments 259 Image Guided Therapy 259 IMASONIC 259 KAI Research, Inc. 259 Sonic Concepts, Inc. 259 Theraclion 259

Foundation

Fibroid Relief 259 268 Focused Ultrasound Foundation 259 Back cover FUS Foundation Research Funding 266 Journal of Therapeutic Ultrasound 267

Image Special Events, Guided Food & Beverage Posters Oral Sessions Therapy Monitor Salon A - C Salon D Salon E - H Philips KAI Research EUFUS EDAP Alpinion ISTU

Sponsors & Exhibitors Monitor

FUS Electronics Sonic Imasonic InSightec & Innovation Concepts Verasonics Registration Instruments Fibroid Relief Found- ation FUS

Focused Ultrasound 2014 4th International Symposium 255 Platinum Sponsors

Elekta AB Elekta pioneers signifi cant innovations and clinical solutions www.elekta.com for treating cancer and brain disorders. The company develops sophisticated, state-of-the-art tools and treatment planning systems Advertisement: page 257 for radiation therapy, radiosurgery and brachytherapy, as well as workfl ow enhancing software systems across the spectrum of cancer care. Website: http://www.elekta.com, Twitter: @Elekta.

GE Healthcare GE Healthcare provides transformational medical technologies www.gehealthcare.com and services that are shaping a new age of patient care. Our broad expertise in medical imaging and information technologies, Advertisement: page 258 medical diagnostics, patient monitoring systems, drug discovery, biopharmaceutical manufacturing technologies, performance improvement and performance solutions services help our customers to deliver better care to more people around the world at a lower cost. In addition, we partner with healthcare leaders, striving to leverage the global policy change necessary to implement a successful shift to sustainable healthcare systems.

InSightec InSightec is a world leader in MR-guided Focused Ultrasound www.insightec.com (MRgFUS). The company has developed a non-invasive therapy platform that transforms medicine in an expanding number of Advertisement: page 259 clinical indications. InSightec’s innovative technology is already adopted and used by world recognized physicians in more than 120 leading medical facilities around the world.

Philips Healthcare Our MR-HIFU activities are concentrated in the MR-Therapy www.philips.com/sonalleve Business Unit located in Helsinki, Finland. We support our customers via global Philips Customer Services on a local [email protected] level. Sonalleve MR-HIFU is approved for Uterine Fibroid and Advertisement: page 260 adenomyosis ablation and bone pain palliation in Europe and other countries.

256 Focused Ultrasound 2014 4th International Symposium Bronze Sponsors

Alpinion Medical Systems Alpinion Medical Systems believes that technology is only www.alpinionusa.com meaningful when it delivers value to health care providers. Guided by this philosophy Alpinion focuses on the development Advertisement: page 261 and production of ultrasound including diagnostic ultrasound, therapeutic HIFU (high-intensity focused ultrasound), and advanced piezoelectric crystal and single-crystal transducer technology.

International Society for The International Society for Therapeutic Ultrasound (ISTU) Therapeutic Ultrasound (ISTU) is a non-profi t organization founded in 2001 to increase and diffuse knowledge of therapeutic ultrasound to the scientifi c and www.istu.org medical community, and to facilitate the translation of therapeutic Advertisement: page 261 ultrasound techniques into the clinical arena for the benefi t of patients worldwide.

Verasonics Verasonics has developed revolutionary technology to accelerate www.verasonics.com medical ultrasound research and development in academia and industry. The Vantage systems are real-time, software-based Advertisement: page 262 ultrasound platforms that provide unsurpassed fl exibility and control to create and test novel techniques in the areas of: HIFU, Cavitation, Sonoporation, Histotripsy, Photoacoustics, transducer development, and more.

Focused Ultrasound 2014 4th International Symposium 257 Exhibitors

EDAP TMS Global leader in therapeutic ultrasound and active in the market www.edap-usa.com for more than 30 years, EDAP TMS (NASDAQ: EDAP) develops, manufactures, promotes and distributes minimally-invasive medical devices for urology using ultrasound technology for two distinct therapeutic applications: non-invasive treatment of prostate cancer and urinary stones treatment by extracorporeal electroconductive shock waves.

Electronics & Innovation, Ltd. Electronics & Innovation Ltd., E&I, is a world leader in providing www.eandiltd.com rugged and reliable RF power amplifi ers. E&I designs and manufacturers RF broadband power amplifi ers, phased array systems, impedance matching and variable transformers, and custom RF solutions. In addition to our standard product lines, we are now offering custom modules and pallets – designed specifi cally to fulfi ll your OEM requirements. Operating globally and continuing to expand our technology, E&I is committed to providing RF power solutions of the highest quality, durability and ruggedness.

Fibroid Relief Fibroid Relief is the patient advocacy initiative of the Focused www.fi broidrelief.org Ultrasound Foundation. Since 2008, we have been dedicated to supporting women suffering from uterine fi broids who seek non- Advertisement: page 240 invasive treatment alternatives, like focused ultrasound.

EUFUS

Focused Ultrasound The Focused Ultrasound Foundation is a medical technology Foundation research, education and advocacy organization dedicated to improving the lives of millions of people with serious medical www.fusfoundation.org disorders by accelerating the development and adoption of Research funding: page 262 focused ultrasound. The Foundation works to clear the path to Advertisement: Inside back cover global adoption by organizing and funding research, fostering collaboration, building awareness at our various workshops and symposia, and cultivating the next generation through internships and fellowships.

258 Focused Ultrasound 2014 4th International Symposium Exhibitors (continued)

FUS Instruments FUS Instruments is the preeminent preclinical focused ultrasound www.fusinstruments.com company. We make systems that meet the needs of researchers. The FUS Instruments line of focused ultrasound systems range from turnkey solutions for new entrants into the fi eld of focused ultrasound to fully modifi able systems. Our mission is to lower the technology barrier to focused ultrasound research in order to accelerate advancement in this exciting fi eld of medicine.

Image Guided Therapy www.imageguidedtherapy.com

IMASONIC IMASONIC is an independent, privately-owned company that www.imasonic.com develops and produces ultrasonic transducers and complete probes for health and safety applications. Since its creation in 1989, IMASONIC has been contributing to improving ultrasonic medical applications by designing and manufacturing transducers for therapeutic, diagnosis and monitoring. Located in France, the company has 85 employees (2014).

KAI Research, Inc. KAI Research, Inc., an Altarum Company, is a full-service www.kai-research.com clinical research organization that provides an array of services focused on health research. KAI has the facilities and staffi ng in place to support activities including protocol review, regulatory tracking, site monitoring and management, safety monitoring, pharmacovigilance, data management, and statistical analysis.

Sonic Concepts, Inc. Sonic Concepts, Inc. manufactures high-power, wide-bandwidth www.sonicconcepts.com ultrasound transducers and related equipment. SCI supplies single- or multi-element transducers, as well as annular, linear, and 2D arrays, transmit electronics, passive cavitation detectors, high- intensity hydrophones, radiation force balances, water degassing equipment, and more. SCI supports customer orders from initial prototyping into full-scale production.

Theraclion Theraclion is a French company specialized in cutting-edge medical www.theraclion.com devices for echotherapy. Theraclion develops and markets a medical device (Echopulse®) that combines ultrasound imaging and High Intensity Focused Ultrasound therapy. Theraclion is ISO 13485 certifi ed and has received the CE mark for non-invasive treatment of breast fi broadenomas and thyroid nodules.

Focused Ultrasound 2014 4th International Symposium 259 Notes

260 Focused Ultrasound 2014 4th International Symposium ...advanced technology with the patient in mind

Neuroscience Oncology With Elekta, it’s reality.

Every day, more than 100,000 patients worldwide are diagnosed, treated or receive follow-up with the help of an oncology or neurosurgery solution from Elekta. Through innovation and Treatment Planning & Brachytherapy Information Software collaboration, we are advancing patient care.

Human care makes the future possible More at elekta.com 4513 371 1128 02:13

Focused Ultrasound 2014 4th International Symposium 261 GE Healthcare

BEYOND RADIOLOGY. Being ready for the future means having an MR system that can not only grow beyond its original design, but surpass it. The Discovery* MR750w was designed with the ability to go further than the traditional boundaries of radiology. If you’re looking for a system capable of imaging during surgical procedures, ready for MR-guided focused ultrasound or adept in radiation therapy planning , look no further . Our exclusive , detachable table options are just one example of the many features developed to keep you at the forefront of healthcare.

WANT TO LEARN MORE? Contact your GE sales representative for information on this revolutionary new system.

© 2014 General Electric Company. All rights reserved. GE Healthcare, a division of General Electric Company. GE and GE monogram are trademarks of General Electric Company. * Trademark of General Electric Company

262 Focused Ultrasound 2014 4th International Symposium Focused Ultrasound 2014 4th International Symposium 263 7KHÀUVWHYHUGLJLWDOEURDGEDQG05LVFKDQJLQJH[SHFWDWLRQV DQGOLYHV(YHQLQURXWLQHLPDJLQJ

Thanks to Philips Imaging 2.0, a revolutionary new imaging approach, the Philips Ingenia 1.5T and 3.0T MR systems set a new standard in clarity, speed and expandability. Ingenia captures and digitizes the signal closest to the patient to improve SNR by up to 40%. Easier coil handling and improved patient comfort help increase productivity by up to 30%. And, Ingenia is designed to meet your demands in fast routine imaging. Discover the revolution in MR technology at www.philips.com/Ingenia30T.

264 Focused Ultrasound 2014 4th International Symposium Alpinion presents its pre-clinical VIFU system with the ŶĞǁͲƵďĞϭϮZΎƌĞƐĞĂƌĐŚƉůĂƞŽƌŵĂƚ&h^͊

Combining premium clinical ultrasound technologyology with ĂŶƵůƚƌĂƐŽƵŶĚƌĞƐĞĂƌĐŚƉůĂƞŽƌŵ͘&ĞĂƚƵƌĞƐŝŶĐůƵĚĞ͗ƵĚĞ͗ ŽŵƉĂƟďůĞĨŽƌƵƐĞǁŝƚŚŽƵƌs/&hϮϬϬϬǁŝƚŚ ƌĞĂůͲƟŵĞŐƵŝĚĂŶĐĞ KƉĞŶƐŽŌǁĂƌĞďĂƐĞĚƉůĂƞŽƌŵĂŶĚƐĞƋƵĞŶĐĞĐŽŶƚƌŽůĐŽŶƚƌŽůĐŽŶƚƌŽů /ŶŶŽǀĂƟǀĞďĞĂŵĨŽƌŵŝŶŐƚĞĐŚŶŽůŽŐLJ ĐŽƵƐƟĐZĂĚŝĂƟŽŶ&ŽƌĐĞ/ŵƉƵůƐĞ;Z&/ͿĐŽŶƚƌŽůů ZĞĂůƟŵĞZ&ĐŚĂŶŶĞůĚĂƚĂĂĐĐĞƐƐ

ŽŶƚƌĂƐƚĂŐĞŶƚďƵďďůĞĂŶĂůLJƐŝƐ * FDA 510K in progress &ĂƐƚŐƌĂŵĞƌĂƚĞŝŵĂŐŝŶŐ;ƵƉƚŽϵϬϬϬ&W^Ϳ ZĞĂůͲƟŵĞĚƵĂůĚŝƐƉůĂLJƵĚŝŶŐĚƵĂůdyͬZyƉĂƚŚƐ

ŝŶĨŽΛůƉŝŶŝŽŶh^͘ĐŽŵ ǁǁǁ͘ůƉŝŶŝŽŶh^͘ĐŽŵ 425-949-4900

ISTU 2015 April 15-18

15th International Symposium on Therapeutic Ultrasound

Dom church, Utrecht The Netherlands

Focused Ultrasound 2014 4th International Symposium 265 Funding Available for Focused Ultrasound Research Grants of up to $100,000 for 12-month projects

The FUS Foundation’s External Research Awards Program supports technical, pre-clinical, and pilot clinical research to accelerate the adoption of image-guided focused ultrasound into clinical practice.

For more information visit For Researchers > Research Program at www.fusfoundation.org or contact Matt Eames, Director of Extramural Research, at [email protected].

Research award recipient Nathan McDannold, PhD, presents at the 2012 Symposium.

266 Focused Ultrasound 2014 4th International Symposium Publish your next research article in Journal of Therapeutic Ultrasound

Editors-in-Chief: Robert Muratore (USA) and Wladyslaw M Gedroyc (UK)

"Research has repeatedly shown that articles available freely online are more often cited and have greater impact than those not freely available, and this trend is increasing over time." Harvard University Open Access Policy t Rapid dissemination of your research t Accessible to all t Reach the Focused Ultrasound community t No charge to publish

Journal of Therapeutic Ultrasound's goal t Share and learn about the latest research as soon as it is available. t Engage scientists and clinical practitioners interested in broadening their knowledge of therapeutic ultrasound.

For all enquiries about the journal, please contact: [email protected]

jtultrasound.com biomedcentral.com

Focused Ultrasound 2014 4th International Symposium 267 FUSF Symposium Ad - Final.pdf 1 9/12/2014 10:36:49 AM

Sponsor Acknowledgements Your partner in advancing the field

Platinum Sponsors The Focused Ultrasound Foundation was created to improve the lives of millions of patients by accelerating the development and adoption of focused ultrasound. We leverage our independent status to drive progress by:

Funding Research A key priority for the Foundation is funding translational studies, applying the growing body of knowledge to complex problems. We organize and conduct research internally and through an C External Awards Program, which funds investigator-initiated

M clinical and technical research projects through a competitive peer-reviewed process. Y

CM

MY

CY

Bronze Sponsors CMY Fostering K Collaboration We act as a global connector, hosting a variety of workshops and biennial symposia to stimulate innovation and increase awareness. International Society for Thearapeutic Ultrasound

Overcoming Barriers Media Partner We partner with industry to help usher this technology through the regulatory and reimbursement processes and move the technology closer to patients.

www.fusfoundation.org

FUSF_Symposium_2014_Program_Cover_Inside.indd 1 9/29/2014 4:37:28 PM 2014 sym cover select_Layout 1 2/13/13 3:42 PM Page 2

CurrentCurrent andand FutureFuture ApplicationsApplications of Focused UltrasoundUltrasound 20142014 4th4th InternationalInternational SymposiumSymposium

Program & ProgramAbstract Book OctoberOctober 12-16,12–16, 20142014

BethesdaBethesda North Marriott Hotel & Conference Center FocusedFocused Ultrasound Ultrasound Foundation Foundation www.fusfoundation.orgwww.fusfoundation.org | |Charlottesville, Charlottesville, VA VA | |TT 434.220.4993 434.220.4993 Washington,Washington, DC MetroMetro Area, USA

FUSF_Symposium_2014_Program_THIN_Cover_Outside.indd 1 9/30/2014 11:36:48 AM