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American Institute of Ultrasound in Medicine <strong>Proceedings</strong> J Ultrasound Med 32(suppl):S1–S134, 2013to use positron emission tomography (PET) to study (1) the biodistributionof an emulsion used in ADV and (2) the extent to which localized hypoxiacan be induced by ADV.Methods—For the biodistribution study, a metabolic tracer,18F-fluorodeoxyglucose (FDG) was injected into Fisher 344 rats (n = 3)bearing vascular endothelial growth factor–positive glioma tumors (9L).The rats were imaged for 60 minutes after injection using dynamic PETimaging. After 24 hours, the same rats were injected with a PFC-FDGemulsion (2 µm mean size) and imaged again. In both cases, standardizeduptake values (SUVs) were calculated using the tissue activity concentration,body weight, and injected dose. To confirm the imaging findings, atraditional ex vivo biodistribution was performed (n = 5 rats). For the hypoxiastudy, similar animal and tumor models were used. A PFC singleemulsion was administered, followed by ADV in the feeder artery of thetumor using focused pulsed ultrasound (3.5 MHz). Dynamic PET imagingwas performed before and after ADV using 18 F-fluoroazomycin arabinoside(FAZA) as a tracer for hypoxia.Results—The area under the curve (AUC) for the SUVs wascalculated for brain, tumor, and lungs as a measure of drug/FDG exposurefor future drug encapsulation. A 39.1% ± 5.3% and 35.7% ± 15.6%AUC decrease was observed when compared to solution for brain andtumor, respectively. No significant difference in AUC was observed forlung. The biodistribution study showed a 67% and 70% decrease in thepercent injected dose per gram for brain and tumor tissue, respectively,when comparing FDG emulsion versus solution. FAZA was retained in thetumor after ADV.Conclusions—The lower AUC values for the emulsion inhighly metabolic tissues (brain and tumor) demonstrate that FDG is retainedwithin the emulsion and is confirmed by alternative biodistribution.FAZA imaging confirms generation of localized hypoxia using ADV.Overall, PET imaging can provide critical feedback in developing stabledrug-loaded PFC emulsions as well as tracking the effects of ADV- inducedhypoxia.1540880 Evaluation and Optimization of Nonfocused SonothrombolysisParameters in an In Vitro Chamber ModelShane Fleshman,* Adelaide de Guillebon, George Lewis JrZetroz, LLC, Ithaca, New York USAObjectives—Sonothrombolysis is emerging as a potential clinicaltool to rapidly emulsify acute and chronic thrombi. The goal of thiswork was to study the effects of different therapeutics, frequency, thrombusdiameter, and type of surrounding medium on the percent mass reductionof a thrombus after 1, 2, and 3 hours of sonothrombolysis treatment.Methods—Silicone tubing of 10 or 15 mm diameter was coatedwith or without 500 U of thrombin, filled with fresh porcine blood, allowedto clot for 1 hour, and stored at 4°C for 8 to 10 days (InstitutionalAnimal Care and Use Committee–approved protocol). Sonothrombolysiswas evaluated in multiple-element custom ultrasonic chambers (75 ×55 × 55 cm) designed at both 85- and 191-kHz resonant frequencies.Blood clots of 2.0 ± 0.1 g were perforated with a guide wire, placed insidea chamber filled with either Dulbecco’s phosphate-buffered saline (DPBS)or freshly thawed human plasma, and injected with 0.5 mL of either 0.5-mg/mL human tissue plasminogen activator (tPA), 1-mg/mL active plasmin,or 1× DPBS with a Uni-Fuse catheter 30 minutes after treatmentcommencement. Blood clot mass was recorded 1, 2, and 3 hours aftertreatment.Results—Thrombus treatment at 85 kHz with a peak pressureof 1.7 MPa was the only treatment that yielded significant results forthrombin and nonthrombin blood clots when compared to the control(P < .01) and was further used in the remaining experiments. Both thrombinand nonthrombin clots treated with ultrasound were statistically differentfrom the control at all time points (P < .01). Comparisons of 15- or10-mm-diameter clots and clots in DPBS or human plasma media treatedwith ultrasound yielded no significant results (P > .05). Comparisons ofultrasound-treated, tPA- or plasmin-injected clots with their respectivecontrols yielded significant results at all time points (P < .0001) and at 1hour (P < .01), respectively.Conclusions—We discovered that diameter, thrombin treatment,and medium do not play significant roles in thrombus dissolution.Using twelve 85-kHz transducers with mean peak pressures of 1.7 MPaand injecting the thrombus with tPA yielded the most significant results,with mean percent mass losses of >90% after 3 hours.1540858 Hydrogel Materials as Ultrasound Coupling MediaMatthew Langer,* Shane Fleshman, George Lewis JrZetroz, LLC, Ithaca, New York USAObjectives—The use of ultrasound in therapeutic medicine topromote healing and relieve pain has been thoroughly tested. Recent researchhas demonstrated that low-intensity therapeutic ultrasound appliedon a daily basis is highly effective, and miniaturization technology hasbeen developed, which will enable user-operated ultrasound systems. Onesignificant challenge in developing a user-operated device is finding a couplingmedium that is effective, easily used, and desirable for the patient.To facilitate the spread of user-operated ultrasound devices, novel couplingmaterials must be developed. Water is a perfect coupling medium forultrasound, but its low viscosity makes it impractical to contain. Hydrogelsare swollen polymer networks, which can be as much as 99% waterby weight, but due to the size of the polymer, or its structure, they haveproperties of viscoelastic materials. High–water content hydrogels wereevaluated for their ability to mediate transmission of ultrasound.Methods—Polyethylene oxide (PEO) hydrogels were testedand evaluated, along with polyethylene glycol (PEG) hydrogels and PEGbasedcopolymer hydrogels. The gels were tested as coupling media betweena 3-MHz therapeutic 25-mm-diameter transducer and freshlyharvested porcine skin. On the underside of the skin, ultrasound gel wasused to couple the skin to a transducer hydrophone in a custom measurementapparatus. The electrical signal reported by the detector was read offa digital oscilloscope in millivolts. The signal measured with the hydrogelas a coupling medium was compared to that of the ultrasound gel as acoupling medium. The ultrasound transmission hydrogels was normalizedto traditional ultrasound gel–based coupling.Results—The ultrasonic transmission of several hydrogels wasmeasured. The PEG copolymer–based gel had a relative transmission of0.70 ± 0.06. A PEO hydrogel with water content >90% had a relative transmissionof 1.0 ± 0.07.Conclusions—PEO hydrogels with high water content possesssimilar sonic transmission properties to commercial ultrasound gel. Thesefindings open the door to replacing commercial ultrasound gel with high–water content hydrogels.1541006 Low-Intensity Pulsed Ultrasound Enhances Reactive OxygenSpecies Production Following a Blunt Impact Injury inArticular CartilageKee Jang, 1,2 * Prem Ramakrishnan, 1 Tae-Hong Lim, 2 JosephBuckwalter, 3 James Martin 1 1 Orthopedics and Rehabilitation,2 Biomedical Engineering, University of Iowa, Iowa City,Iowa USA; 3 Veterans Affairs Medical Center, Iowa City, IowaUSAObjectives—Elevated levels of reactive oxygen species (ROS)are associated with development of osteoarthritis. Previously we reportedthat mechanotransduction of mitochondrial ROS modulates cell survivaland metabolism in a dose-dependent manner. Here, we hypothesized thatlow-intensity pulsed ultrasound (LIPUS) elicits its mechanotransductive effectsby inducing ROS in cartilage, and we investigated the effect of LIPUSon ROS release in articular cartilage that underwent a blunt impact injury.Methods—Osteochondral explants (2.5 × 2.5 cm 2 ) were preparedfrom mature bovine stifle joints and cultured in conditioned media atS39
American Institute of Ultrasound in Medicine <strong>Proceedings</strong> J Ultrasound Med 32(suppl):S1–S134, 201337°C and 5% O 2. After 48 hours, explants were subjected to a 7-J/cm 2impact with a customized drop tower device, and LIPUS (1 MHz, 54mW/cm 2 , and durations of 30, 60, and 90 minutes) was immediately applied.A sham group was subjected to identical procedures except LIPUSstimulation. After LIPUS stimulation, cell viability (calcein AM/ethidiumhomodimer) and oxidative stress (dihydroethidine) were imaged with confocalmicroscopy and quantified.Results—Sixty-minute LIPUS after the 7-J/cm 2 impact resultedin a significant increase in ROS production (≈2-fold) compared to thesham group. In contrast, no difference in ROS production was apparent inuninjured explants with or without LIPUS stimulation. After injury, theROS response to the LIPUS duration showed a strong linear relationship(R 2 = 0.75) with an increasing duration of stimulation inside the impactedarea, whereas such a relationship was not observed in areas adjacent tothe impact. No difference in post–24-hour chondrocyte viability was observedbetween LIPUS and sham groups.Conclusions—Our findings demonstrate that LIPUS stimulatesROS production in injured articular cartilage in a duration-dependent manner,and enhanced ROS production did not affect cell viability in cartilage.Although the exact role of enhanced ROS in response to LIPUS ininjured cartilage remains unclear, we hypothesize that the increased oxidativestress may have implications in cartilage repair processes by modulatingchondrocyte energy production, metabolism, and matrix synthesis.1543362 Microbubble and Ultrasound Enhancement of Radiation-Induced Tumor Cell Death In Vivo: ASMase DependenceGregory Czarnota, 1 * Amr Hashim, 1 Ahmed El Kaffas, 1 RaffiKarshafian, 2 Anoja Giles, 1 Sara Iradji, 1 Azza Al Mahrouki 11Radiation Oncology/Physical Sciences, Sunnybrook HealthSciences Center, Toronto, Ontario, Canada; 2 Physics, RyersonUniversity, Toronto, Ontario, CanadaObjectives—It is now appreciated that radiation not only damagesthe DNA inside tumor cells in vivo but also may act by damaging theendothelial cells of the vasculature. In this study, we tested the hypothesisthat microbubble agents in vivo may be used a priori to cause endothelialcell perturbations, thus causing “radiosensitization” of tumors.Methods—Fibrosarcoma xenograft-bearing mice (n = 200+)were exposed to combinations of ultrasound, activated microbubbles, andradiation (8 animals per group). For ultrasound treatments, animals wereexposed to a 500-kHz center frequency and 570-kPa peak negative pressurefor treatment. For treatments involving bubbles, Definity bubbles(Bristol Myers-Squibb) were administered, and for radiation treatments160-kVp x-rays were used at doses of 2 and 8 Gy. Representative tumorsections were examined using immunohistochemistry. Clonogenic assaysand growth delay studies were also carried out. Experiments were carriedout in ASMase +/+ and –/– mice to investigate endothelial cell apoptosiseffects.Results—Analyses indicated a synergistic increase in tumorcell kill due to vascular disruption that was ASMase dependent, causedby the combined therapies that increased when microbubbles were usedin conjunction with radiation, with increases of cell kill from 5% to >50%with combined single treatments. Immunohistochemistry indicated endothelialcell apoptosis and activation of the ceramide cell death pathwayto be caused by microbubbles. Multiple treatments indicated a better therapeuticoutcome with multiple treatments combining both modalities comparedto single-modality treatments.Conclusions—Radiation effects were synergistically enhancedby using microbubbles to perturb tumor vasculature prior to the administrationof radiotherapy. Analyses indicated activation of ceramide-mediatedapoptotic cell death in endothelial cells leading to vasculardisruption in tumors. This led to profoundly enhanced tumor cell deatheven after 1 combined treatment using a 2-Gy radiation dose. This workforms the basis for ultrasound-induced spatial targeting of radiotherapyenhancement.1540684 On the Acceleration of Ultrasound Thermal Therapy byPatterned Acoustic Droplet VaporizationOliver Kripfgans, 1 * Mario Fabiilli, 1 Scott Swanson, 1 CharlesMougenot, 2 Paul Carson, 1 Man Zhang, 1 J. Brian Fowlkes 11Radiology, University of Michigan, Ann Arbor, Michigan USA;2Philips Healthcare, Toronto, Ontario, CanadaObjectives—High-intensity focused ultrasound (HIFU), an establishedmethod for treating cancer and hyperplasia, often suffers fromuneven heating and requires in general long treatment times for large targetvolumes. In situ gas bubbles have become more accepted as energyconversion agents for HIFU. If carefully controlled, these agents increaselesion sizes dramatically.Methods—Emulsions of perfluorocarbon droplets (lipid coated,C 5F 12, Ø 2.0 ± 0.1 µm, ≈99% < 8 µm Ø) were used to create thermal agentsin polyacrylamide phantoms. The emulsion concentration in the gel was3 × 10 5 droplets/mL. This corresponds to a volume fraction of 1 ppm(vol/vol). The samples were placed in thermal contact with a heating systemto maintain 35°C. Egg white was incorporated to allow for visual inspectionof the phantoms after acoustic exposure from a Philips Sonallevemagnetic resonance–guided focused ultrasound system (1.5 T) using a256-element phased array with a 120-mm focal length. At a transmit centerfrequency of 1.45 MHz, maximum electronic steering of 10 mm wasachieved at a depth of 10 cm. In situ temperature monitoring limited focalheating to 75°C. Lesion sizes were measured as a function of appliedacoustic power. Acoustic trenches were created to accelerate thermal therapy,in which individual lesions were spaced 5.5 mm apart to create 25-mm-diameter spiral patterns.Results—Single HIFU exposures in droplet-laden phantomsresulted in lesions of 2 to 5 mm in diameter. Rapid repetition of electronicallysteered therapy pulses (40 pulses/s) allowed for the generation of homogeneousand contiguous composite lesions at a rate >1 mL/s. Foracoustic power levels ranging from 40 to 300 W (acoustic), lesion volumesincreased by a factor of at least 15 when comparing lesion volumesin phantoms with droplets to without droplets. With the use of acousticdroplet vaporization (ADV) and the resulting trench, a uniform ablationvolume of 15 mL was achieved in 15 seconds; without ADV,
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Page 7 and 8: 2013 AIUM Award WinnersJoseph H. Ho
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