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Ultrasound Sonoporation in Pancreatic Adenocarcinoma
S94
Ultrasound in Medicine and Biology
Acoustic Angiography: High-Resolution ContrastEnhanced Ultrasound Imaging of the Microvasculature Paul Dayton Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States Presenting Author: Paul A. Dayton1 Co-authors: Coauthors: Sarah Shelton1, Brooks Lindsey1, Ryan Gessner1, Yueh Z. Lee4, Stephen Aylward2, Mike Lee3, Emmanuel Cherin3, F. Stuart Foster3 Joint Graduate Department of Biomedical Engineering, University of North Carolina and North Carolina State University, NC, USA Kitware Medical Imaging, 101 East Weaver Street, Carrboro, NC Department of Medical Biophysics, Sunnybrook Health Sciences Centre,Toronto, ON, Canada Department of Neuroradiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 Contrast enhanced ultrasound is FDA approved in the US for cardiology applications, and has demonstrated substantial utility off-label and in preclinical research studies. However, to date, contrast enhanced ultrasound in patients is largely performed at low frequencies and does not provide sufficient resolution or tissue suppression to visualize structural details of microvasculature blood flow. Through the use of new dual-frequency ultrasound transducer technology, contrast enhanced ultrasound can be performed with unprecedented resolution and contrast-to-tissue ratio, albeit at shallow penetration depths. This imaging technique enables the visualization of microvascular architecture without signal from background tissues, and can simultaneously provide anatomical information for registration. The resulting images are similar to x-ray angiography, and provide a new means to assess microvascular density and structure. Initial results indicate this new imaging modality can provide non-invasive insight into angiogenic processes involved in tumor growth and progression. We demonstrate the application of this imaging technique in evaluation of cancer angiogenesis in pre-clinical models, and provide a report of first in-human use. Ultrasound Sonoporation in Pancreatic Adenocarcinoma Odd Helge Gilja Medicine, NCUG, Bergen, NORWAY Spiros Kotopoulis,1,2 Georg Dimcevski,1,3 4 1,2 Dag Hoem, Michiel Postema, Odd Helge Gilja1,3 1 National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway; 2 Department of Physics and Technology, University of Bergen, Bergen, Norway; 3Department of Clinical Medicine, University of Bergen, Bergen, Norway; 4Department of Surgery, Haukeland University Hospital, Bergen, Norway Objectives: The objectives of this Phase I study were to investigate the safety and the ability of inducing sonoporation in a clinical setting, using commercially available technology, to increase the patients’ quality of life and to possibly increase the overall survival in patients with pancreatic adenocarcinoma. Methods: 10 Patients were treated using a customized configuration of a commercial clinical ultrasound scanner (GE LOGIQ 9) over a time period of 31.5 min following standard chemotherapy treatment with gemcitabine. SonoVue was injected intravenously during the treatment with the aim of inducing sonoporation. To ensure microbubbles were present throughout the whole treatment, 0.5 ml of contrast agent followed by 5 ml saline were injected every 3.5 min, i.e., at T 5
Volume 41, Number 4S, 2015
30.0, 33.5, 37.0, 40.5, 44.0, 47.5, 51.0, 54.5, and 58.0min. A single vial (4.5 ml) was used throughout each treatment. Treatment was stopped at T561.5 min. The total cumulated ultrasound treatment time was only 18.9 s. Gemcitabine was administered by intravenous infusion at a dose of 1000 mg/m2 over 30 min. Results: Using the authors’ custom acoustic settings, the 10 patients were able to undergo an increased number of treatment cycles; from an average of 8 cycles, to an average of 14 cycles when comparing to a historical control group of 80 patients. In the first two out of five patients treated (published data, ref below), the maximum tumor diameter was temporally decreased to 80 6 5% and permanently to 70 6 5% of their original size, while the other patients showed reduced growth. Compared to historical data, there was increased survival with 60% of patients surviving 12 months (versus 10% in literature). Conclusions: It is possible to combine ultrasound, microbubbles, and chemotherapy in a clinical setting using commercially available clinical ultrasound scanners to increase the number of treatment cycles. Our study also indicates increased survival in patients with inoperable pancreatic adenocarcinoma. Ref: Medical Physics, Vol. 40, No. 7, July 2013. Therapeutic Applicaitons of Contrast–Enhanced Ultrasound Charles Caskey Vanderbilt University, Nashville, Tennessee, United States A multi-disciplinary approach is required to engineer methods for using ultrasound contrast agents for drug delivery and imaging. In this talk, microbubble activity will be examined in a variety of scenarios that mimic those found in vivo to provide intuition about the mechanisms for contrast-enhanced imaging and drug delivery, including ex vivo vessels and in vitro tissue mimics. The bubble concentration and acoustic parameters associated with vascular disruption and vessel displacement will be examined with respect to theoretical predictions, and methods for tracking bubble activity during therapy will be discussed. Finally, we will report on recent extensions of this work to in vivo therapeutic goals, such as delivery of chemotherapeutics beyond the blood brain barrier for treatment of metastatic melanoma. Ultrasound Contrast Agents Accelerate Sonothrombolysis Christy Holland Internal Medicine, Division of Cardiovascular Health and Disease, and Biomedical Engineering, University of Cincinnati, Cincinnati, Ohio, United States Cardiovascular disease is the number one cause of death worldwide and thrombo-occlusive disease is a leading cause of morbidity and mortality. Ultrasound has been developed as a tool to induce the release, delivery and enhanced efficacy of a thrombolytic drug (rt-PA) and bioactive gases from echogenic liposomes. By encapsulating drugs into micron-sized and nano-sized liposomes, the therapeutic can be shielded from degradation within the vasculature until delivery is triggered by ultrasound exposure. Insonification accelerates clot breakdown in combination with a thrombolytic drug (rt-PA) and ultrasound contrast agents, which nucleate sustained bubble activity, or cavitation. Mechanisms for ultrasound enhancement of thrombolysis, with a special emphasis on cavitation and radiation force, will be reviewed. The delivery of bioactive gases from echogenic liposomes to promote vasodilation and cytoprotection will also be discussed.
Ultrasound in Medicine and Biology
Acoustic Angiography: High-Resolution ContrastEnhanced Ultrasound Imaging of the Microvasculature Paul Dayton Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States Presenting Author: Paul A. Dayton1 Co-authors: Coauthors: Sarah Shelton1, Brooks Lindsey1, Ryan Gessner1, Yueh Z. Lee4, Stephen Aylward2, Mike Lee3, Emmanuel Cherin3, F. Stuart Foster3 Joint Graduate Department of Biomedical Engineering, University of North Carolina and North Carolina State University, NC, USA Kitware Medical Imaging, 101 East Weaver Street, Carrboro, NC Department of Medical Biophysics, Sunnybrook Health Sciences Centre,Toronto, ON, Canada Department of Neuroradiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 Contrast enhanced ultrasound is FDA approved in the US for cardiology applications, and has demonstrated substantial utility off-label and in preclinical research studies. However, to date, contrast enhanced ultrasound in patients is largely performed at low frequencies and does not provide sufficient resolution or tissue suppression to visualize structural details of microvasculature blood flow. Through the use of new dual-frequency ultrasound transducer technology, contrast enhanced ultrasound can be performed with unprecedented resolution and contrast-to-tissue ratio, albeit at shallow penetration depths. This imaging technique enables the visualization of microvascular architecture without signal from background tissues, and can simultaneously provide anatomical information for registration. The resulting images are similar to x-ray angiography, and provide a new means to assess microvascular density and structure. Initial results indicate this new imaging modality can provide non-invasive insight into angiogenic processes involved in tumor growth and progression. We demonstrate the application of this imaging technique in evaluation of cancer angiogenesis in pre-clinical models, and provide a report of first in-human use. Ultrasound Sonoporation in Pancreatic Adenocarcinoma Odd Helge Gilja Medicine, NCUG, Bergen, NORWAY Spiros Kotopoulis,1,2 Georg Dimcevski,1,3 4 1,2 Dag Hoem, Michiel Postema, Odd Helge Gilja1,3 1 National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway; 2 Department of Physics and Technology, University of Bergen, Bergen, Norway; 3Department of Clinical Medicine, University of Bergen, Bergen, Norway; 4Department of Surgery, Haukeland University Hospital, Bergen, Norway Objectives: The objectives of this Phase I study were to investigate the safety and the ability of inducing sonoporation in a clinical setting, using commercially available technology, to increase the patients’ quality of life and to possibly increase the overall survival in patients with pancreatic adenocarcinoma. Methods: 10 Patients were treated using a customized configuration of a commercial clinical ultrasound scanner (GE LOGIQ 9) over a time period of 31.5 min following standard chemotherapy treatment with gemcitabine. SonoVue was injected intravenously during the treatment with the aim of inducing sonoporation. To ensure microbubbles were present throughout the whole treatment, 0.5 ml of contrast agent followed by 5 ml saline were injected every 3.5 min, i.e., at T 5
Volume 41, Number 4S, 2015
30.0, 33.5, 37.0, 40.5, 44.0, 47.5, 51.0, 54.5, and 58.0min. A single vial (4.5 ml) was used throughout each treatment. Treatment was stopped at T561.5 min. The total cumulated ultrasound treatment time was only 18.9 s. Gemcitabine was administered by intravenous infusion at a dose of 1000 mg/m2 over 30 min. Results: Using the authors’ custom acoustic settings, the 10 patients were able to undergo an increased number of treatment cycles; from an average of 8 cycles, to an average of 14 cycles when comparing to a historical control group of 80 patients. In the first two out of five patients treated (published data, ref below), the maximum tumor diameter was temporally decreased to 80 6 5% and permanently to 70 6 5% of their original size, while the other patients showed reduced growth. Compared to historical data, there was increased survival with 60% of patients surviving 12 months (versus 10% in literature). Conclusions: It is possible to combine ultrasound, microbubbles, and chemotherapy in a clinical setting using commercially available clinical ultrasound scanners to increase the number of treatment cycles. Our study also indicates increased survival in patients with inoperable pancreatic adenocarcinoma. Ref: Medical Physics, Vol. 40, No. 7, July 2013. Therapeutic Applicaitons of Contrast–Enhanced Ultrasound Charles Caskey Vanderbilt University, Nashville, Tennessee, United States A multi-disciplinary approach is required to engineer methods for using ultrasound contrast agents for drug delivery and imaging. In this talk, microbubble activity will be examined in a variety of scenarios that mimic those found in vivo to provide intuition about the mechanisms for contrast-enhanced imaging and drug delivery, including ex vivo vessels and in vitro tissue mimics. The bubble concentration and acoustic parameters associated with vascular disruption and vessel displacement will be examined with respect to theoretical predictions, and methods for tracking bubble activity during therapy will be discussed. Finally, we will report on recent extensions of this work to in vivo therapeutic goals, such as delivery of chemotherapeutics beyond the blood brain barrier for treatment of metastatic melanoma. Ultrasound Contrast Agents Accelerate Sonothrombolysis Christy Holland Internal Medicine, Division of Cardiovascular Health and Disease, and Biomedical Engineering, University of Cincinnati, Cincinnati, Ohio, United States Cardiovascular disease is the number one cause of death worldwide and thrombo-occlusive disease is a leading cause of morbidity and mortality. Ultrasound has been developed as a tool to induce the release, delivery and enhanced efficacy of a thrombolytic drug (rt-PA) and bioactive gases from echogenic liposomes. By encapsulating drugs into micron-sized and nano-sized liposomes, the therapeutic can be shielded from degradation within the vasculature until delivery is triggered by ultrasound exposure. Insonification accelerates clot breakdown in combination with a thrombolytic drug (rt-PA) and ultrasound contrast agents, which nucleate sustained bubble activity, or cavitation. Mechanisms for ultrasound enhancement of thrombolysis, with a special emphasis on cavitation and radiation force, will be reviewed. The delivery of bioactive gases from echogenic liposomes to promote vasodilation and cytoprotection will also be discussed.