Optimal hyperthermia (HT) treatment of advanced extremity sarcomas using combined Dynamic-Enhanced...
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Track 19. Biotransport 6517 Th, 09:00-09:15 (P39) Preliminary examination of a noninvasive technique for the measurement of thermal conductivity and thermal diffusivity of biological materials H. Takamatsu 1, S. Uchida 1, K. Yoshida 1, X. Zhang 2, M. Fujii 2. 1Department of Mechanical Engineering Science, Kyushu University, Fukuoka, Japan, 1Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga, Japan A noninvasive technique was developed to measure the thermophysical prop- erties of biological materials. In this technique temperature response of a target surface is measured by infrared thermometry during heating by CO2 laser irra- diation and compared with the theoretical response. The thermal conductivity and the thermal diffusivity are determined as those which yield the smallest deviation between the measured and analyzed temperature responses. The objective of the present paper is to establish this technique by investigating it both by a simulation and an experiment. An appropriate model of heat transfer is discussed first by taking into account of the effect of the laser absorption within the material and a heat loss from the target to the ambient. Then the accuracy of measurement is examined using simulated experimental data to involve the effect of expected fluctuation of measured temperature during the experiment. The simulated experimental data are generated by adding artificial perturbation to a theoretical temperature response. The accuracy of measurement is estimated as a function of the extent of temperature fluctuation and the irradiation time. The effect of uncertainty in the absorption coefficient of the target material is also examined. Finally, experiments are conducted with agar gels as a sample material. The thermal conductivity and the thermal diffusivity of the agar gel are also measured by the other invasive method, the short hot-wire method, for comparison. Preliminary experiments will be also carried out for in-vitro measurement of several other biological materials. 5283 Th, 09:15-09:30 (P39) Influence of solution on time-series recrystallization of ice crystals in tissues during slow-warming after rapid-freezing H. Ishiguro 1, H. Imai 2, N. Suzuki 2. 1Graduate School efLife Science and Systems Engineering, Kyushu Institute of Technology, Fukuoka, Japan, 2 Graduate School of Engineering Mechanics, University of Tsukuba, Ibaraki, Japan Morphological behavior of ice crystals and cells in the tissues during the slow- warming after rapid-freezing was visualized in time-series using a confocal laser scanning microscope (CLSM) with a fluorescent dye. Recrystallization of intracellular ice crystals was investigated quantitatively. Size and number of ice crystals were measured from the CLSM images and analyzed statistically to obtain frequency, average, and standard deviation of the size of ice crystals, total amount and number density of ice crystals, etc. in time-series during the warming. Influence of aqueous solution on these characteristics was made clear. The muscle tissues (fresh tender meat of chicken) were stained with a fluo- rescent dye, acridine orange, in the aqueous solutions. Two kinds of solutions were used: physiological saline and physiological saline with 2.0M dimethyl sulfoxide (DMSO). Then, the sample was frozen on the cryostage rapidly at a cooling rate of -100°C/min, maintained at -50°C for 15 min, and warmed slowly at a warming rate of 0.1°C/min. Time-series images taken by the CLSM every ten minutes indicated distinctly that with an increase in temperature at each solution, fine ice crystals melted and disappeared and the number of ice crystals decreased monotonously, while relatively large ice crystals grew coarser and rounder, which increased local deformation of muscle fibers. The frequency distribution of equivalent diameters of ice crystals shifted from a distribution of higher frequencies in the range of smaller size to that of higher frequencies in the range of larger size. The mean equivalent-diameter of the coarsening ice crystals (the largest ten ice crystals) increased, took the maximum, and then decreased near the complete-thawing with an increasing temperature. These results indicated that addition of DMSO lowered the temperature of active recrystallization and widened the range of the temperature, and the ice crystals recrystallized more actively in the tissues including DMSO. 19.7. Multiscale Imaging and Visualization in Biotransport $381 19.7. Multiscale Imaging and Visualization in Biotransport 4447 Th, 11:00-11:15 (P42) Optimal hyperthermia (HT) treatment of advanced extremity sarcomas using combined Dynamic-Enhanced Magnetic Resonance Imaging (DE-MRI) and Magnetic Resonance Thermal Imaging (MRTI) O.I. Craciunescu 1, J.R. MacFall 2, T.E. Raidy 1, Z. Vujaskovic 1, E.L. Jones 1, N.A. Larrier 1, O.A. Arabe 1, V. Liotcheva 1, T.Z. Wong 2, T.V. Samulski 1, M.W. Dewhirst 1. 1Dept. of Radiation Oncologyl2 Radiology, University Medical Center, Durham, NC, USA At Duke University Medical Center, elective patients with advanced extremity sarcomas are treated on a protocol using standard radiotherapy and HT with/without chemotherapy in a setting that allows the use of a dedicated 1.5 T GE magnet for imaging. Pre and post treatment DE-MR images of the tumor are acquired and the enhancing patterns are analyzed. The catheter for invasive temperature measurements is placed under MR guidance and aided by the enhancing maps. The catheter spans from normal to highly enhancing, to necrotic tumor areas (if existent). Quasi-real time 2D or 3D temperature maps are obtained using the proton resonance frequency shift. These maps are used during the treatment to steer the power, with the ultimate goal of heating the tumor uniformly, while maintaining surrounding normal tissue at controlled temperatures. The before and after DE-MR images are analyzed with software from CAD Sciences (White Plains, NY) based on a full time point pharmacokinetics analysis that measures tumor's permeability and extracellular volume fraction. The MRT data is analyzed using in-house software. Thermal dose metrics are calculated for each of the HT fractions. Data for five patients included on this protocol will be shown. As expected, tumors that are more vascularized heat less than tumors with high degree of necrosis or fluid pockets. Correlation between the invasive and MRT data will be shown demonstrating the accuracy of the latter within one degree from the former. The correlation between the thermal metrics and pathological response will be discussed, as well as possible correlation with other tumor physiology parameters extracted from DE-MR analysis. In conclusion, DE-MRI coupled with MRTI generates information related to tumor environment that creates the basis for a complex approach to HT treatments. Supported by a grant from the NCI CA4274. 6481 Th, 11 : 15-11:30 (P42) Efficacy and biodistribution of gold nanoparticles R. Visaria 1, R. Griffin 1, S. Hui 1, B. Williams 1, E. Ebbini 1, G. Paciotti 2, C. Song 1, J. Bischof 1. 1University of Minnesota, Minneapolis, MN, USA, 2 Cytlmmune Sciences, Inc., Rockville, MD, USA To enhance in vivo thermal therapy while sparing adjacent normal tissue, 33 nm pegylated colloidal gold nanoparticles (PT-cAu-TNF) coated with TNF was used to actively sequester TNF within solid tumors. To better understand the drug delivery process, the biodistribution of nanoparticles and their drug payload was also studied. FSall fibrosarcoma and SCK mammary carci- noma grown in hind limb of 7+ cases of C3H and A/J mice, respectively, were treated with 50-250~tg/kg PT-cAu-TNF and 4 hr later local water-bath hyperthermia (42.5°C, 60 min). The combination of PT-cAu-TNF with heat significantly improved the anti-tumor response caused by either treatment alone. The combination treatment increased tumor doubling time from 2 to 6 days and in 75% of cases caused complete regression of the tumor. The data correlated with the induction of blood perfusion defects (measured with contrast enhanced ultrasound) that completely blocked blood flow in many regions of the tumors. Tumor blood flow measured using 86Rb uptake was significantly suppressed (20% of control) 4-6 hours after an i.v. injection of free TNF or PT-cAu-TNE These blood perfusion/flow effects were coincident with the specific accumulation of TNF and gold within the tumors. For example, 5 hours after injection, PT-cAu-TNF increased intratumor TNF concentration 3- fold over baseline whereas TNF concentrations in other healthy tissues (liver and blood) were reduced by 86%. We found preferential tumor uptake of gold 4-6 hrs after i.v. injection of PT-cAu-TNF. The gold concentration was quantified using AES that can linearly detect gold in the range of 5-500 ~tg/I (R=0.99) and is direct, quantitative but invasive approach. We are exploring non-invasive modes such as CT which detected intratumoral gold in live animals and was found to be linear in the range of 5-175 ~tg/ml (R = 0.99). Thus pretreatment with PT-cAu-TNF enhances hyperthermic injury due to the localized preferential tumor delivery of TNF by nanoparticles.
Transcript of Optimal hyperthermia (HT) treatment of advanced extremity sarcomas using combined Dynamic-Enhanced...
Track 19. Biotransport
6517 Th, 09:00-09:15 (P39) Preliminary examination of a noninvasive technique for the measurement of thermal conductivity and thermal diffusivity of biological materials H. Takamatsu 1 , S. Uchida 1 , K. Yoshida 1 , X. Zhang 2, M. Fujii 2. 1Department of Mechanical Engineering Science, Kyushu University, Fukuoka, Japan, 1Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga, Japan
A noninvasive technique was developed to measure the thermophysical prop- erties of biological materials. In this technique temperature response of a target surface is measured by infrared thermometry during heating by CO2 laser irra- diation and compared with the theoretical response. The thermal conductivity and the thermal diffusivity are determined as those which yield the smallest deviation between the measured and analyzed temperature responses. The objective of the present paper is to establish this technique by investigating it both by a simulation and an experiment. An appropriate model of heat transfer is discussed first by taking into account of the effect of the laser absorption within the material and a heat loss from the target to the ambient. Then the accuracy of measurement is examined using simulated experimental data to involve the effect of expected fluctuation of measured temperature during the experiment. The simulated experimental data are generated by adding artificial perturbation to a theoretical temperature response. The accuracy of measurement is estimated as a function of the extent of temperature fluctuation and the irradiation time. The effect of uncertainty in the absorption coefficient of the target material is also examined. Finally, experiments are conducted with agar gels as a sample material. The thermal conductivity and the thermal diffusivity of the agar gel are also measured by the other invasive method, the short hot-wire method, for comparison. Preliminary experiments will be also carried out for in-vitro measurement of several other biological materials.
5283 Th, 09:15-09:30 (P39) Influence of solution on time-series recrystallization of ice crystals in tissues during slow-warming after rapid-freezing H. Ishiguro 1, H. Imai 2, N. Suzuki 2. 1Graduate School efLife Science and Systems Engineering, Kyushu Institute of Technology, Fukuoka, Japan, 2 Graduate School of Engineering Mechanics, University of Tsukuba, Ibaraki, Japan
Morphological behavior of ice crystals and cells in the tissues during the slow- warming after rapid-freezing was visualized in time-series using a confocal laser scanning microscope (CLSM) with a fluorescent dye. Recrystallization of intracellular ice crystals was investigated quantitatively. Size and number of ice crystals were measured from the CLSM images and analyzed statistically to obtain frequency, average, and standard deviation of the size of ice crystals, total amount and number density of ice crystals, etc. in time-series during the warming. Influence of aqueous solution on these characteristics was made clear. The muscle tissues (fresh tender meat of chicken) were stained with a fluo- rescent dye, acridine orange, in the aqueous solutions. Two kinds of solutions were used: physiological saline and physiological saline with 2.0M dimethyl sulfoxide (DMSO). Then, the sample was frozen on the cryostage rapidly at a cooling rate of -100°C/min, maintained at -50°C for 15 min, and warmed slowly at a warming rate of 0.1°C/min. Time-series images taken by the CLSM every ten minutes indicated distinctly that with an increase in temperature at each solution, fine ice crystals melted and disappeared and the number of ice crystals decreased monotonously, while relatively large ice crystals grew coarser and rounder, which increased local deformation of muscle fibers. The frequency distribution of equivalent diameters of ice crystals shifted from a distribution of higher frequencies in the range of smaller size to that of higher frequencies in the range of larger size. The mean equivalent-diameter of the coarsening ice crystals (the largest ten ice crystals) increased, took the maximum, and then decreased near the complete-thawing with an increasing temperature. These results indicated that addition of DMSO lowered the temperature of active recrystallization and widened the range of the temperature, and the ice crystals recrystallized more actively in the tissues including DMSO.
19.7. Multiscale Imaging and Visualization in Biotransport $381
19.7. Multiscale Imaging and Visualization in Biotransport 4447 Th, 11:00-11:15 (P42) Optimal hyperthermia (HT) treatment of advanced extremity sarcomas using combined Dynamic-Enhanced Magnetic Resonance Imaging (DE-MRI) and Magnetic Resonance Thermal Imaging (MRTI)
O.I. Craciunescu 1 , J.R. MacFall 2, T.E. Raidy 1 , Z. Vujaskovic 1 , E.L. Jones 1 , N.A. Larrier 1 , O.A. Arabe 1 , V. Liotcheva 1 , T.Z. Wong 2, T.V. Samulski 1 , M.W. Dewhirst 1 . 1Dept. of Radiation Oncologyl2 Radiology, University Medical Center, Durham, NC, USA
At Duke University Medical Center, elective patients with advanced extremity sarcomas are treated on a protocol using standard radiotherapy and HT with/without chemotherapy in a setting that allows the use of a dedicated 1.5 T GE magnet for imaging. Pre and post treatment DE-MR images of the tumor are acquired and the enhancing patterns are analyzed. The catheter for invasive temperature measurements is placed under MR guidance and aided by the enhancing maps. The catheter spans from normal to highly enhancing, to necrotic tumor areas (if existent). Quasi-real time 2D or 3D temperature maps are obtained using the proton resonance frequency shift. These maps are used during the treatment to steer the power, with the ultimate goal of heating the tumor uniformly, while maintaining surrounding normal tissue at controlled temperatures. The before and after DE-MR images are analyzed with software from CAD Sciences (White Plains, NY) based on a full time point pharmacokinetics analysis that measures tumor's permeability and extracellular volume fraction. The MRT data is analyzed using in-house software. Thermal dose metrics are calculated for each of the HT fractions. Data for five patients included on this protocol will be shown. As expected, tumors that are more vascularized heat less than tumors with high degree of necrosis or fluid pockets. Correlation between the invasive and MRT data will be shown demonstrating the accuracy of the latter within one degree from the former. The correlation between the thermal metrics and pathological response will be discussed, as well as possible correlation with other tumor physiology parameters extracted from DE-MR analysis. In conclusion, DE-MRI coupled with MRTI generates information related to tumor environment that creates the basis for a complex approach to HT treatments. Supported by a grant from the NCI CA4274.
6481 Th, 11 : 15-11:30 (P42) Efficacy and biodistribution of gold nanoparticles R. Visaria 1 , R. Griffin 1 , S. Hui 1, B. Williams 1 , E. Ebbini 1 , G. Paciotti 2, C. Song 1 , J. Bischof 1 . 1University of Minnesota, Minneapolis, MN, USA, 2 Cytlmmune Sciences, Inc., Rockville, MD, USA
To enhance in vivo thermal therapy while sparing adjacent normal tissue, 33 nm pegylated colloidal gold nanoparticles (PT-cAu-TNF) coated with TNF was used to actively sequester TNF within solid tumors. To better understand the drug delivery process, the biodistribution of nanoparticles and their drug payload was also studied. FSall fibrosarcoma and SCK mammary carci- noma grown in hind limb of 7+ cases of C3H and A/J mice, respectively, were treated with 50-250~tg/kg PT-cAu-TNF and 4 hr later local water-bath hyperthermia (42.5°C, 60 min). The combination of PT-cAu-TNF with heat significantly improved the anti-tumor response caused by either treatment alone. The combination treatment increased tumor doubling time from 2 to 6 days and in 75% of cases caused complete regression of the tumor. The data correlated with the induction of blood perfusion defects (measured with contrast enhanced ultrasound) that completely blocked blood flow in many regions of the tumors. Tumor blood flow measured using 86Rb uptake was significantly suppressed (20% of control) 4 -6 hours after an i.v. injection of free TNF or PT-cAu-TNE These blood perfusion/flow effects were coincident with the specific accumulation of TNF and gold within the tumors. For example, 5 hours after injection, PT-cAu-TNF increased intratumor TNF concentration 3- fold over baseline whereas TNF concentrations in other healthy tissues (liver and blood) were reduced by 86%. We found preferential tumor uptake of gold 4 -6 hrs after i.v. injection of PT-cAu-TNF. The gold concentration was quantified using AES that can linearly detect gold in the range of 5-500 ~tg/I (R=0.99) and is direct, quantitative but invasive approach. We are exploring non-invasive modes such as CT which detected intratumoral gold in live animals and was found to be linear in the range of 5-175 ~tg/ml (R = 0.99). Thus pretreatment with PT-cAu-TNF enhances hyperthermic injury due to the localized preferential tumor delivery of TNF by nanoparticles.
