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At least 253 records · Page 14
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Cumulative dose of radiation therapy of hepatocellular carcinoma patients and its deterministic relation to radiation-induced liver disease

This study aimed to investigate the relationship between dose and radiation-induced liver disease (RILD) in patients with hepatocellular carcinoma (HCC) receiving 3-dimensional conformal radiotherapy (3DCRT). Twenty-three patients with HCC who received conventional fractionated 3DCRT, including 7 who were diagnosed with classic RILD, were enrolled in this retrospective investigation. Cone-beam computed tomography (CBCT) scans were acquired at the time of treatment for each patient. The beams from each patient's treatment plan were applied to each pretreatment CBCT (the modified CBCT or mCBCT) to construct the delivered dose distribution of the day considering inter-treatment anatomy changes. The daily doses were summed together with the help of deformable image registration (DIR) to obtain the adjusted cumulative dose (D{sub adjusted}). The dose changes to the normal liver between the original planned dose (D{sub plan}) and D{sub adjusted} were evaluated by V20, V30, V40, and the mean dose to normal liver (MDTNL). Univariate analysis was performed to identify the significant dose changes. Among the 23 patients, the liver V20, V30, V40, and MDTNL showed significant differences between D{sub plan} and D{sub adjusted}, with average values of these parameters increased by 4.1%, 4.7%, 4.5%, and 3.9 Gy, respectively (p adjusted . Determination of a reconstructed D{sub adjusted} using the mCBCT scans are more accurate in predicting RILD and has the potential to reduce the risk of RILD.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Optimal beam margins in linac-based VMAT stereotactic ablative body radiotherapy: a Pareto front analysis for liver metastases

We explored the Pareto fronts mathematical strategy to determine the optimal block margin and prescription isodose for stereotactic body radiotherapy (SBRT) treatments of liver metastases using the volumetric-modulated arc therapy (VMAT) technique. Three targets (planning target volumes [PTVs] = 20, 55, and 101 cc) were selected. A single fraction dose of 26 Gy was prescribed (prescription dose [PD]). VMAT plans were generated for 3 different beam energies. Pareto fronts based on (1) different multileaf collimator (MLC) block margin around PTV and (2) different prescription isodose lines (IDL) were produced. For each block margin, the greatest IDL fulfilling the criteria (95% of PTV reached 100%) was considered as providing the optimal clinical plan for PTV coverage. Liver D{sub mean}, V7Gy, and V12Gy were used against the PTV coverage to generate the fronts. Gradient indexes (GI and mGI), homogeneity index (HI), and healthy liver irradiation in terms of D{sub mean}, V7Gy, and V12Gy were calculated to compare different plans. In addition, each target was also optimized with a full-inverse planning engine to obtain a direct comparison with anatomy-based treatment planning system (TPS) results. About 900 plans were calculated to generate the fronts. GI and mGI show a U-shaped behavior as a function of beam margin with minimal values obtained with a +1 mm MLC margin. For these plans, the IDL ranges from 74% to 86%. GI and mGI show also a V-shaped behavior with respect to HI index, with minimum values at 1 mm for all metrics, independent of tumor dimensions and beam energy. Full-inversed optimized plans reported worse results with respect to Pareto plans. In conclusion, Pareto fronts provide a rigorous strategy to choose clinical optimal plans in SBRT treatments. We show that a 1-mm MLC block margin provides the best results with regard to healthy liver tissue irradiation and steepness of dose fallout.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2014

Prenatal ethanol exposure programs an increased susceptibility of non-alcoholic fatty liver disease in female adult offspring rats

Prenatal ethanol exposure (PEE) induces dyslipidemia and hyperglycemia in fetus and adult offspring. However, whether PEE increases the susceptibility to non-alcoholic fatty liver disease (NAFLD) in offspring and its underlying mechanism remain unknown. This study aimed to demonstrate an increased susceptibility to high-fat diet (HFD)-induced NAFLD and its intrauterine programming mechanisms in female rat offspring with PEE. Rat model of intrauterine growth retardation (IUGR) was established by PEE, the female fetus and adult offspring that fed normal diet (ND) or HFD were sacrificed. The results showed that, in PEE + ND group, serum corticosterone (CORT) slightly decreased and insulin-like growth factor-1 (IGF-1) and glucose increased with partial catch-up growth; In PEE + HFD group, serum CORT decreased, while serum IGF-1, glucose and triglyceride (TG) increased, with notable catch-up growth, higher metabolic status and NAFLD formation. Enhanced liver expression of the IGF-1 pathway, gluconeogenesis, and lipid synthesis as well as reduced expression of lipid output were accompanied in PEE + HFD group. In PEE fetus, serum CORT increased while IGF-1 decreased, with low body weight, hyperglycemia, and hepatocyte ultrastructural changes. Hepatic IGF-1 expression as well as lipid output was down-regulated, while lipid synthesis significantly increased. Based on these findings, we propose a “two-programming” hypothesis for an increased susceptibility to HFD-induced NAFLD in female offspring of PEE. That is, the intrauterine programming of liver glucose and lipid metabolic function is “the first programming”, and postnatal adaptive catch-up growth triggered by intrauterine programming of GC-IGF1 axis acts as “the second programming”. - Highlights: • Prenatal ethanol exposure increase the susceptibility of NAFLD in female offspring. • Prenatal ethanol exposure reprograms fetal liver’s glucose and lipid metabolism . • Prenatal ethanol exposure cause the adaptive change of glucocorticoid-IGF1 axis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury

Metabolic activation and oxidant stress are key events in the pathophysiology of acetaminophen (APAP) hepatotoxicity. The initial mitochondrial oxidative stress triggered by protein adduct formation is amplified by c-jun-N-terminal kinase (JNK), resulting in mitochondrial dysfunction and ultimately cell necrosis. Apoptosis signal-regulating kinase 1 (ASK1) is considered the link between oxidant stress and JNK activation. The objective of the current study was to assess the efficacy and mechanism of action of the small-molecule ASK1 inhibitor GS-459679 in a murine model of APAP hepatotoxicity. APAP (300 mg/kg) caused extensive glutathione depletion, JNK activation and translocation to the mitochondria, oxidant stress and liver injury as indicated by plasma ALT activities and area of necrosis over a 24 h observation period. Pretreatment with 30 mg/kg of GS-459679 almost completely prevented JNK activation, oxidant stress and injury without affecting the metabolic activation of APAP. To evaluate the therapeutic potential of GS-459679, mice were treated with APAP and then with the inhibitor. Given 1.5 h after APAP, GS-459679 was still protective, which was paralleled by reduced JNK activation and p-JNK translocation to mitochondria. However, GS-459679 treatment was not more effective than N-acetylcysteine, and the combination of GS-459679 and N-acetylcysteine exhibited similar efficacy as N-acetylcysteine monotherapy, suggesting that GS-459769 and N-acetylcysteine affect the same pathway. Importantly, inhibition of ASK1 did not impair liver regeneration as indicated by PCNA staining. In conclusion, the ASK1 inhibitor GS-459679 protected against APAP toxicity by attenuating JNK activation and oxidant stress in mice and may have therapeutic potential for APAP overdose patients. - Highlights: • Two ASK1 inhibitors protected against acetaminophen-induced liver injury. • The ASK1 inhibitors protect when used as pre- or post-treatment. • Protection by ASK1 inhibitor is not due to inhibition of APAP metabolism. • The ASK1 inhibitor prevents JNK activation and translocation to mitochondria. • Treatment with ASK1 inhibitors does not impair liver regeneration after APAP.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Crosstalk between liver antioxidant and the endocannabinoid systems after chronic administration of the FAAH inhibitor, URB597, to hypertensive rats

Hypertension is accompanied by perturbations to the endocannabinoid and antioxidant systems. Thus, potential pharmacological treatments for hypertension should be examined as modulators of these two metabolic systems. The aim of this study was to evaluate the effects of chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl)phenyl]N-cyclohexylcarbamate (URB597) on the endocannabinoid system and on the redox balance in the livers of DOCA-salt hypertensive rats. Hypertension caused an increase in the levels of endocannabinoids [anandamide (AEA), 2-arachidonoyl-glycerol (2-AG) and N-arachidonoyl-dopamine (NADA)] and CB{sub 1} receptor and the activities of FAAH and monoacylglycerol lipase (MAGL). These effects were accompanied by an increase in the level of reactive oxygen species (ROS), a decrease in antioxidant activity/level, enhanced expression of transcription factor Nrf2 and changes to Nrf2 activators and inhibitors. Moreover, significant increases in lipid, DNA and protein oxidative modifications, which led to enhanced levels of proapoptotic caspases, were also observed. URB597 administration to the hypertensive rats resulted in additional increases in the levels of AEA, NADA and the CB{sub 1} receptor, as well as decreases in vitamin E and C levels, glutathione peroxidase and glutathione reductase activities and Nrf2 expression. Thus, after URB597 administration, oxidative modifications of cellular components were increased, while the inflammatory response was reduced. This study revealed that chronic treatment of hypertensive rats with URB597 disrupts the endocannabinoid system, which causes an imbalance in redox status. This imbalance increases the levels of electrophilic lipid peroxidation products, which later participate in metabolic disturbances in liver homeostasis. - Highlights: • Chronic administration of URB597 to hypertensive rats reduces liver inflammation. • URB597 enhances the redox imbalance in the liver of hypertensive rats. • URB597 alters lipid metabolism, which results in enhanced lipid peroxidation. • URB597 disrupts crosstalk between antioxidants, including the Nrf2 pathway and endocannabinoid system.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

The role of PTEN in regulation of hepatic macrophages activation and function in progression and reversal of liver fibrosis

Activation of Kupffer cells (KCs) plays a pivotal role in the pathogenesis of liver fibrosis. The progression and reversal of CCl{sub 4}-induced mouse liver fibrosis showed a mixed induction of hepatic classical (M1) and alternative (M2) macrophage markers. Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in modulating myeloid cell activation has recently been identified, its function in macrophage activation during hepatic fibrosis remains to be fully appreciated. In our study, PTEN expression of KCs was remarkably decreased in CCl{sub 4}-induced mice but increased to a near-normal level in reversed mice. Moreover, PTEN was significantly decreased in IL4-induced RAW 264.7 cells in vitro and lower expression of PTEN was observed in M2 macrophages in vivo. In addition, loss- and gain-of-function studies suggested that PTEN regulates M2 macrophages polarization via activation of PI3K/Akt/STAT6 signaling, but had a limited effect on M1 macrophages polarization in vitro. Additionally, Ly294002, a chemical inhibitor of PI3K/Akt, could dramatically down-regulate the hallmarks of M2 macrophages. In conclusion, PTEN mediates macrophages activation by PI3K/Akt/STAT6 signaling pathway, which provides novel compelling evidences on the potential of PTEN in liver injury and opens new cellular target for the pharmacological therapy of liver fibrosis. - Highlights: • CCl{sub 4} treatment triggered a mixed M1/M2 macrophage phenotype in fibrosis. • Lower expression of PTEN in murine M2 macrophages in vivo and vitro. • PTEN modulates M2 macrophages activation via PI3K/Akt/STAT6 signaling. • Provide a new cellular target modulate macrophage mediated hepatic fibrosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Combining transcriptomics and PBPK modeling indicates a primary role of hypoxia and altered circadian signaling in dichloromethane carcinogenicity in mouse lung and liver

Dichloromethane (DCM) is a lung and liver carcinogen in mice at inhalation exposures ≥ 2000 ppm. The modes of action (MOA) of these responses have been attributed to formation of genotoxic, reactive metabolite(s). Here, we examined gene expression in lung and liver from female B6C3F1 mice exposed to 0, 100, 500, 2000, 3000 and 4000 ppm DCM for 90 days. We also simulated dose measures - rates of DCM oxidation to carbon monoxide (CO) in lung and liver and expected blood carboxyhemoglobin (HbCO) time courses with a PBPK model inclusive of both conjugation and oxidation pathways. Expression of large numbers of genes was altered at 100 ppm with maximal changes in the numbers occurring by 500 or 2000 ppm. Most changes in genes common to the two tissues were related to cellular metabolism and circadian clock. At the lower concentrations, the changes in metabolism-related genes were discordant – up in liver and down in lung. These processes included organelle biogenesis, TCA cycle, and respiratory electron transport. Changes in circadian cycle genes – primarily transcription factors - showed strong concentration-related response at higher concentrations (Arntl, Npas2, and Clock were down-regulated; Cry2, Wee1, Bhlhe40, Per3, Nr1d1, Nr1d2 and Dbp) were up-regulated with similar directionality in both tissues. Overall, persistently elevated HbCO from DCM oxidation appears to cause extended periods of hypoxia, leading to altered circadian coupling to cellular metabolism. The dose response for altered circadian processes correlates with the cancer outcome. We found no evidence of changes in genes indicative of responses to cytotoxic, DNA-reactive metabolites.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

A two-step model of TiO{sub 2} nanoparticle toxicity in human liver tissue

We examine the toxicity of titanium dioxide (TiO{sub 2}) nanoparticles on human liver through a two-step approach, including a physiologically-based pharmacokinetic (PBPK) model and a cell-response model. The PBPK model predicts the bio-distribution of nanoparticles that remain in the human body after exposure, with special attention to their accumulation in liver tissue. The cell-response model predicts liver cell death as a consequence of the accumulated TiO{sub 2} nanoparticles by considering cell fate dynamics through the interplay between cellular uptake of the nanoparticles and their dilution due to cell division. The results suggest that tissue damage from a low nanoparticle dose is negligible due to renewal cell division, but for higher doses larger fractions of cells must participate in the cell cycle to recover the original tissue mass. By combining the two models, it becomes possible to explain the liver cell viability and cell death after TiO{sub 2} nanoparticle exposure. - Highlights: • The cell-response model is proposed to study hepatotoxicity of TiO{sub 2} nanoparticles in the cellular level. • The model explains how the cell population responds to the deposited nanoparticles. • For low nanoparticle doses, tissue damage is negligible due to renewal through cell division. • For larger doses, larger fractions of cells must participate in the cell cycle to recover the original tissue mass.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

WE-D-17A-03: Improvement of Accuracy of Spot-Scanning Proton Beam Delivery for Liver Tumor by Real-Time Tumor-Monitoring and Gating System: A Simulation Study

Purpose: To improve the accuracy of spot-scanning proton beam delivery for target in motion, a real-time tumor-monitoring and gating system using fluoroscopy images was developed. This study investigates the efficacy of this method for treatment of liver tumors using simulation. Methods: Three-dimensional position of a fiducial marker inserted close to the tumor is calculated in real time and proton beam is gated according to the marker's distance from the planned position (Shirato, 2012). The efficient beam delivery is realized even for the irregular and sporadic motion signals, by employing the multiple-gated irradiations per operation cycle (Umezawa, 2012). For each of two breath-hold CTs (CTV=14.6cc, 63.1cc), dose distributions were calculated with internal margins corresponding to freebreathing (FB) and real-time gating (RG) with a 2-mm gating window. We applied 8 trajectories of liver tumor recorded during the treatment of RTRT in X-ray therapy and 6 initial timings. Dmax/Dmin in CTV, mean liver dose (MLD), and irradiation time to administer 3 Gy (RBE) dose were estimated assuming rigid motion of targets by using in-house simulation tools and VQA treatment planning system (Hitachi, Ltd., Tokyo). Results: Dmax/Dmin was degraded by less than 5% compared to the prescribed dose with all motion parameters for smaller CTV and less than 7% for larger CTV with one exception. Irradiation time showed only a modest increase if RG was used instead of FB; the average value over motion parameters was 113 (FB) and 138 s (RG) for smaller CTV and 120 (FB) and 207 s (RG) for larger CTV. In RG, it was within 5 min for all but one trajectory. MLD was markedly decreased by 14% and 5–6% for smaller and larger CTVs respectively, if RG was applied. Conclusions: Spot-scanning proton beam was shown to be delivered successfully to liver tumor without much lengthening of treatment time. This research was supported by the Cabinet Office, Government of Japan and the Japan Society for the Promotion of Science (JSPS) through the Funding Program for World-Leading Innovative R and D on Science and Technology (FIRST Program), initiated by the Council for Science and Technology Policy (CSTP)

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

WE-G-18C-06: Is Diaphragm Motion a Good Surrogate for Liver Tumor Motion?

Purpose: To investigate whether diaphragm motion is a good surrogate for liver tumor motion by comparing their motion trajectories obtained from cine-MRI. Methods: Fourteen patients with hepatocellular carcinoma (10/14) or liver metastases (4/14) undergoing radiation therapy were included in this study. All patients underwent single-slice 2D cine-MRI simulations across the center of the tumor in three orthogonal planes. Tumor and diaphragm motion trajectories in the superior-inferior (SI), anteriorposterior (AP), and medial-lateral (ML) directions were obtained using the normalized cross-correlation based tracking technique. Agreement between tumor and diaphragm motions was assessed by calculating the phase difference percentage (PDP), intra-class correlation coefficient (ICC), Bland-Altman analysis (Diffs) and paired t-test. The distance (D) between tumor and tracked diaphragm area was analyzed to understand its impact on the correlation between tumor and diaphragm motions. Results: Of all patients, the means (±standard deviations) of PDP were 7.1 (±1.1)%, 4.5 (±0.5)% and 17.5 (±4.5)% in the SI, AP and ML directions, respectively. The means of ICC were 0.98 (±0.02), 0.97 (±0.02), and 0.08 (±0.06) in the SI, AP and ML directions, respectively. The Diffs were 2.8 (±1.4) mm, 2.4 (±1.1) mm, and 2.2 (±0.5) mm in the SI, AP and ML directions, respectively. The p-values derived from the paired t-test were < 0.02 in SI and AP directions, whereas were > 0.58 in ML direction primarily due to the small motion in ML direction. Tumor and diaphragmatic motion had high concordance when the distance between the tumor and tracked diaphragm areas was small. Conclusion: Preliminary results showed that liver tumor motion had good correlations with diaphragm motion in the SI and AP directions, indicating diaphragm motion in the SI and AP directions could potentially be a reliable surrogate for liver tumor motion. NIH (1R21CA165384-01A1), Golfers Against Cancer (GAC) Foundation, The China Scholarship Council (CSC)

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

TH-A-BRF-10: Quantification of Subject-Specific Susceptibility-Related Geometric Distortion in Clinical Liver MRI for Radiation Therapy

Purpose: Subject-specific susceptibility-induced B0 inhomogeneity affects the geometric accuracy of MRI images, with potential impact on the accuracy of treatment planning and image guidance. This study quantifies individual distortions for patients with intrahepatic tumors. Methods: Liver MRI scans of 13 patients who were enrolled in an IRB approved study were acquired on a 3T scanner (Skyra, Siemens). Clinical contrast-enhanced images were acquired by a 3D Volume Interpolated Breath-Hold Examination (VIBE) sequence with TE/TR =1.65/4.3ms, voxel size = 2.5×2.5×3mm (axial sets) or 3.5×3.5×5mm (coronal sets), and frequency-encoding (FE) bandwidth of 440Hz/pixel. B0 inhomogeneity was evaluated by acquisition of dual gradient echoes (GRE) with TE1/TE2/TR =4.92/7.38/106ms, a voxel size of 3.5×3.5×3.75mm, a FE bandwidth of 290Hz/pixel and breath-hold. The phase difference maps from the two echoes were unwrapped using a quantitative MRI analysis software package (FSL, FMRIB, Oxford, UK). The resulting calculated B0 inhomogeneity maps (ΔB0 in Hz) were converted to voxel distortion maps in the FE direction (ΔX in mm) corresponding to the VIBE images. Results: Maximum susceptibility-induced distortions were observed in the liver dome near the diaphragm. Using results from coronal VIBE images in this study as examples, we observed clusters of voxels displaced close to or greater than ΔX=3.5mm (440 Hz in ΔB0) in the VIBE images of the liver in 3 patients, and greater than 2 mm but less than 3.5 mm in 12 patients. On average, approximately 14% of imaged liver voxels had distortions ΔX>±1mm (ΔB0>±125Hz) and 1% of the voxels had ΔX>±2mm (ΔB0>±250Hz). Conclusion: Although advanced MRI techniques, like VIBE, permit faster acquisitions allowing for breath-held examinations with limited motion-induced artifacts, this study suggests that localized distortions due to subject-specific susceptibility variations can occur and require additional advanced corrections based on measuring patient-specific B0 inhomogeneity maps. The authors would like to acknowledge funding support from NIH R01EB016079 and NIH/NCI RO1 CA132834.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Motion tracking in the liver: Validation of a method based on 4D ultrasound using a nonrigid registration technique

Purpose: Treatments like radiotherapy and focused ultrasound in the abdomen require accurate motion tracking, in order to optimize dosage delivery to the target and minimize damage to critical structures and healthy tissues around the target. 4D ultrasound is a promising modality for motion tracking during such treatments. In this study, the authors evaluate the accuracy of motion tracking in the liver based on deformable registration of 4D ultrasound images. Methods: The offline analysis was performed using a nonrigid registration algorithm that was specifically designed for motion estimation from dynamic imaging data. The method registers the entire 4D image data sequence in a groupwise optimization fashion, thus avoiding a bias toward a specifically chosen reference time point. Three healthy volunteers were scanned over several breathing cycles (12 s) from three different positions and angles on the abdomen; a total of nine 4D scans for the three volunteers. Well-defined anatomic landmarks were manually annotated in all 96 time frames for assessment of the automatic algorithm. The error of the automatic motion estimation method was compared with interobserver variability. The authors also performed experiments to investigate the influence of parameters defining the deformation field flexibility and evaluated how well the method performed with a lower temporal resolution in order to establish the minimum frame rate required for accurate motion estimation. Results: The registration method estimated liver motion with an error of 1 mm (75% percentile over all datasets), which was lower than the interobserver variability of 1.4 mm. The results were only slightly dependent on the degrees of freedom of the deformation model. The registration error increased to 2.8 mm with an eight times lower temporal resolution. Conclusions: The authors conclude that the methodology was able to accurately track the motion of the liver in the 4D ultrasound data. The authors believe that the method has potential in interventions on moving abdominal organs such as MR or ultrasound guided focused ultrasound therapy and radiotherapy, pending the method is enabled to run in real-time. The data and the annotations used for this study are made publicly available for those who would like to test other methods on 4D liver ultrasound data.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Sci—Sat AM: Stereo — 09: Accuracy of Liver Cancer Treatment on Cyberknife® with Synchrony™ Optical Tracking Throughout the Respiratory Cycle

The Cyberknife® robotic stereotactic body radiation therapy system is well-suited for treating liver lesions over the respiratory cycle as it includes room-mounted orthogonal x-ray tracking of internal fiducial markers and optical tracking of external markers. The Synchrony™ software generates a model of internal target positions during patient respiration and correlates it to the external optical tracking system for real-time optical-based position corrections of the linear accelerator during beam delivery. Although clinical studies have provided preliminary outcomes for liver lesions treated with the Cyberknife system, to date, there is little data demonstrating the ability of the Synchrony software to track targets in the liver, which deforms throughout the respiratory cycle. In this study, we investigated the respiratory motion model performance for predicting tumour motion. We conducted a retrospective analysis of fifteen liver cancer patients treated on the Cyberknife using the Synchrony optical tracking system. We analyzed Cyberknife tracking information stored in the log files to extract the left-right (LR), anterior-posterior (AP) and superior-inferior (SI) correlation errors between the model-predicted position and the internal fiducial centroid position determined by x-ray imaging. Only translational tracking and corrections were applied during treatment. Overall, the correlation errors were greatest in the SI direction. We calculated radial correlation errors, and determined that the 95{sup th}, 98{sup th} and 99{sup th} percentile errors were 3.4 mm, 4.4 mm and 5.1 mm, respectively. Based on translational correlation tracking errors we expect the clinical target volume will be within 3.4 mm of the planning target volume for 95 % of beam delivery time.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

SU-E-I-64: Transverse Relaxation Time in Methylene Protons of Non-Alcoholic Fatty Liver Disease Rats

Purpose: The aim of this study was to evaluate transverse relaxation time of methylene resonance compared to other lipid resonances. Methods: The examinations were performed using a 3.0 T scanner with a point — resolved spectroscopy (PRESS) sequence. Lipid relaxation time in a lipid phantom filled with canola oil was estimated considering repetition time (TR) as 6000 msec and echo time (TE) as 40 — 550 msec. For in vivo proton magnetic resonance spectroscopy ({sup 1}H — MRS), eight male Sprague — Dawley rats were given free access to a normal - chow (NC) and eight other male Sprague-Dawley rats were given free access to a high — fat (HF) diet. Both groups drank water ad libitum. T{sub 2} measurements in the rats’ livers were conducted at a fixed TR of 6000 msec and TE of 40 – 220 msec. Exponential curve fitting quality was calculated through the coefficients of determination (R{sup 2}). Results: A chemical analysis of phantom and liver was not performed but a T{sub 2} decay curve was acquired. The T{sub 2} relaxation time of methylene resonance was estimated as follows: NC rats, 37.07 ± 4.32 msec; HF rats, 31.43 ± 1.81 msec (p < 0.05). The extrapolated M0 values were higher in HF rats than in NC rats (p < 0.005). Conclusion: This study of {sup 1}H-MRS led to sufficient spectral resolution and signal — to — noise ratio differences to characterize all observable resonances for yielding T{sub 2} relaxation times of methylene resonance. {sup 1}H — MRS relaxation times may be useful for quantitative characterization of various liver diseases, including fatty liver disease. This study was supported by grant (2012-007883 and 2014R1A2A1A10050270) from the Mid-career Researcher Program through the NRF funded by Ministry of Science. In addition, this study was supported by the Industrial R&D of MOTIE/KEIT (10048997, Development of the core technology for integrated therapy devices based on real-time MRI-guided tumor tracking)

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

SU-E-T-103: An Evaluation of Multiple Irradiations of the IROC Houston QA Center Anthropomorphic Liver Phantom

Purpose: Analyze the results from irradiations of an anthropomorphic liver phantom based on irradiation technique and number of isocenters used for the SBRT delivery. Methods: The phantom consists of a water-fillable plastic shell that has a polystyrene insert, representing the liver which includes two Solid WaterTM targets (PTV1 and PTV2) mimicking liver metastases. The two targets, PTV1 and PTV2 are non-coplanar and are an ovoid 2 cm in diameter and 2.5 cm long and a 3 cm diameter sphere, respectively. Each PTV houses one TLD and 2 planes of radiochromic film. The phantom and a motion table to simulate respiratory motion is sent to institutions sthat are instructed to design and deliver a stereotactic treatment plan that delivers 6 Gy to ≥ 95% of each PTV. The maximum motion of the phantom on the motion table was 1 cm in the superior-inferior direction. Results: Irradiations from 93 institutions have been analyzed. The acceptance criteria are ±7% for the TLD and 85% of the pixels in a region surrounding each PTV passing a ±7%/4 mm global gamma analysis. Sixty-seven (71%) irradiations meet this criteria. The majority, 74 (80%), of the irradiations were performed with IMRT. 73% of the IMRT deliveries were within criteria and 68% of the 3D CRT delivery were within criteria. 32 of the irradiations had a single isocenter plan, 50 were performed with two isocenters and 11 irradiations were performed with CyberKnife and TomoTherapy units where the concept of isocenter is not applicable. The pass rate for the single, dual and no isocenter irradiations were 69%, 74% and 73%, respectively and are not statistically different. Conclusion: The pass rate for the anthropomorphic liver phantom is approximately 70%. There does not seem to be any correlation with number of isocenters used or irradiation technique used for the delivery. This work was supported by PHS CA180803 awarded by NCI, DHHS.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

MO-DE-210-07: Investigation of Treatment Interferences of a Novel Robotic Ultrasound Radiotherapy Guidance System with Clinical VMAT Plans for Liver SBRT Patients

Purpose: To evaluate the proportion of liver SBRT cases in which robotic ultrasound image guidance concurrent with beam delivery can be deployed without interfering with clinically used VMAT beam configurations. Methods: A simulation environment incorporating LINAC, couch, planning CT, and robotic ultrasound guidance hardware was developed. Virtual placement of the robotic ultrasound hardware was guided by a target visibility map rendered on the CT surface. The map was computed on GPU by using the planning CT to simulate ultrasound propagation and attenuation along rays connecting skin surface points to a rasterized imaging target. The visibility map was validated in a prostate phantom experiment by capturing live ultrasound images of the prostate from different phantom locations. In 20 liver SBRT patients treated with VMAT, the simulation environment was used to place the robotic hardware and ultrasound probe at imaging locations indicated on the visibility map. Imaging targets were either entire PTV (range 5.9–679.5 ml) or entire GTV (range 0.9–343.4 ml). Presence or absence of mechanical collisions with LINAC, couch, and patient body as well as interferences with treated beams were recorded. Results: For PTV targets, robotic ultrasound guidance without mechanical collision was possible in 80% of the cases and guidance without beam interference was possible in 60% of the cases. For the smaller GTV targets, these proportions were 95% and 85% correspondingly. GTV size (1/20), elongated shape (1/20), and depth (1/20) were the main factors limiting the availability of non-interfering imaging positions. Conclusion: This study indicates that for VMAT liver SBRT, robotic ultrasound tracking of a relevant internal target would be possible in 85% of cases while using treatment plans currently deployed in the clinic. With beam re-planning in accordance with the presence of robotic ultrasound guidance, intra-fractional ultrasound guidance may be an option for 95% of the liver SBRT cases. This project was funded by NIH Grant R41CA174089.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

TU-G-210-02: TRANS-FUSIMO - An Integrative Approach to Model-Based Treatment Planning of Liver FUS

Modeling can play a vital role in predicting, optimizing and analyzing the results of therapeutic ultrasound treatments. Simulating the propagating acoustic beam in various targeted regions of the body allows for the prediction of the resulting power deposition and temperature profiles. In this session we will apply various modeling approaches to breast, abdominal organ and brain treatments. Of particular interest is the effectiveness of procedures for correcting for phase aberrations caused by intervening irregular tissues, such as the skull in transcranial applications or inhomogeneous breast tissues. Also described are methods to compensate for motion in targeted abdominal organs such as the liver or kidney. Douglas Christensen – Modeling for Breast and Brain HIFU Treatment Planning Tobias Preusser – TRANS-FUSIMO – An Integrative Approach to Model-Based Treatment Planning of Liver FUS Tobias Preusser – TRANS-FUSIMO – An Integrative Approach to Model-Based Treatment Planning of Liver FUS Learning Objectives: Understand the role of acoustic beam modeling for predicting the effectiveness of therapeutic ultrasound treatments. Apply acoustic modeling to specific breast, liver, kidney and transcranial anatomies. Determine how to obtain appropriate acoustic modeling parameters from clinical images. Understand the separate role of absorption and scattering in energy delivery to tissues. See how organ motion can be compensated for in ultrasound therapies. Compare simulated data with clinical temperature measurements in transcranial applications. Supported by NIH R01 HL172787 and R01 EB013433 (DC); EU Seventh Framework Programme (FP7/2007-2013) under 270186 (FUSIMO) and 611889 (TRANS-FUSIMO)(TP); and P01 CA159992, GE, FUSF and InSightec (UV)

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

WE-EF-303-02: BEST IN PHYSICS (JOINT IMAGING- THERAPY): A Comprehensive Simulation of Image Guided Beam Gating for Liver Tumor Treatments Using Scanned Proton Therapy

Purpose: To evaluate the effectiveness of image guided beam gating for PBS liver treatments under realistic breathing conditions. Methods: We have previously proposed a Beams’ Eye View (BEV) X-ray image system as an online motion monitoring device for deriving a gating signal for PBS proton therapy. Using dedicated 4D dose calculations (4DDC), in this work we have simulated gated liver treatments using three amplitude-based gating windows (10/5/3mm) based on motion extracted from BEV imaging of fiducial markers or the diaphragm. In order to improve motion mitigation, BEV guided gating has also been combined with either volumetric (VS) or layered (LS) rescanning. Nine 4DCT(MRI) liver data-sets have been used for the investigation, which not only consider realistic patient geometries but also motion variations between different breathing cycles. All 4D plans have been quantified in terms of plan homogeneity in the PTV (D5-D95), the total estimated treatment time and the beam-on duty cycle. Results: Neither gating nor rescanning can fully retrieve a comparable plan homogeneity to the static case, and considerable reductions of the duty cycle (<10%) were observed as a Result motion variations when small gating windows are used. However, once combined with rescanning, dose homogeneity within 1% of the static plan could be achieved with reasonable prolongation of the treatment time for all 9 subjects. No differences were observed between the efficacy of layered or volumetric re-scanning, or of gating signals extracted from fiducial or diaphragm motions. However, layered rescanning may be preferred over volumetric rescanning when performed in combination with gating as it is generally more time-efficient and dosimetrically robust to patient and motion variations Conclusion Combining BEV beam gating with rescanning is an efficient and effective approach to treating mobile liver tumours, and is equally effective if either the diaphragm or fiducial markers are used as motion surrogates.

60 APPLIED LIFE SCIENCES↗