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At least 343 records · Page 19
All sourcesNASA NTRSDOE OSTI
DOE OSTI2014

SU-E-J-225: Quantitative Evaluation of Rigid and Non-Rigid Motion of Liver Tumors Using Stereo Imaging During SBRT

Purpose: To quantitatively evaluate rigid and nonrigid motion of liver tumors based on fiducial tracking in 3D by stereo imaging during CyberKnife SBRT. Methods: Twenty-five liver patients previously treated with three-fractions of SBRT were retrospectively recruited in this study. During treatment, the 3D locations of fiducials were reported by the CyberKnife system after two orthogonal kV X-ray images were taken and further validated by geometry derivations. A total of 5004 pairs of X-ray images acquired during the course of treatment for all the patients, were analyzed. For rigid motion, the rotational angles and translational shifts by aligning 3D fiducial groups in different image pairs after least-square fitting were reported. For nonrigid motion, the relative interfractional tumor shape variations were reported and correlated to the sum of inter-fiducial distances. The individual fiducial displacements were also reported after rigid corrections and without angle corrections. Results: The relative tumor volume variation indicated by the inter-fiducial distances demonstrated an increasing trend in the second (101.6±3.4%) and third fraction (101.2±5.6%) among most patients. The cause could be possibly due to radiation-induced edema. For all the patients, the translational shift was 8.1±5.7 mm, with shifts in LR, AP and SI were 2.1±2.4 mm, 2.8±2.9 mm and 6.7±5.1 mm, respectively. The greatest translation shift occurred in SI, mainly due the breathing motion of diaphragm The rotational angles were 1.1±1.7°, 1.9±2.6° and 1.6±2.2°, in roll, pitch, and yaw, respectively. The 3D fiducial displacement with rigid corrections were 0.2±0.2 mm and increased to 0.6±0.3 mm without rotational corrections. Conclusion: The fiducial locations in 3D can be precisely reconstructed from CyberKnife stereo imaging system during treatment. The fiducials provide close estimation of both rigid and nonrigid motion of .liver tumors. The reported data could be further utilized for tumor margin design and motion management in in conventional linac-based treatments.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

SU-E-T-163: Evaluation of Dose Distributions Recalculated with Per-Field Measurement Data Under the Condition of Respiratory Motion During IMRT for Liver Cancer

Purpose: The dose distributions within the real volumes of tumor targets and critical organs during internal target volume-based intensity-modulated radiation therapy (ITV-IMRT) for liver cancer were recalculated by applying the effects of actual respiratory organ motion, and the dosimetric features were analyzed through comparison with gating IMRT (Gate-IMRT) plan results. Methods: The 4DCT data for 10 patients who had been treated with Gate-IMRT for liver cancer were selected to create ITV-IMRT plans. The ITV was created using MIM software, and a moving phantom was used to simulate respiratory motion. The period and range of respiratory motion were recorded in all patients from 4DCT-generated movie data, and the same period and range were applied when operating the dynamic phantom to realize coincident respiratory conditions in each patient. The doses were recalculated with a 3 dose-volume histogram (3DVH) program based on the per-field data measured with a MapCHECK2 2-dimensional diode detector array and compared with the DVHs calculated for the Gate-IMRT plan. Results: Although a sufficient prescription dose covered the PTV during ITV-IMRT delivery, the dose homogeneity in the PTV was inferior to that with the Gate-IMRT plan. We confirmed that there were higher doses to the organs-at-risk (OARs) with ITV-IMRT, as expected when using an enlarged field, but the increased dose to the spinal cord was not significant and the increased doses to the liver and kidney could be considered as minor when the reinforced constraints were applied during IMRT plan optimization. Conclusion: Because Gate-IMRT cannot always be considered an ideal method with which to correct the respiratory motional effect, given the dosimetric variations in the gating system application and the increased treatment time, a prior analysis for optimal IMRT method selection should be performed while considering the patient's respiratory condition and IMRT plan results.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

SU-E-T-187: Feasibility Study of Stereotactic Liver Radiation Therapy Using Multiple Divided Partial Arcs in Volumetric Modulated Arc Therapy

Purpose: To verify volumetric modulated arc therapy (VMAT) using flattening filter free (FFF) mode with jaw tracking (JT) feature for single breath hold as long as 15 s per arc in liver stereotactic body radiation therapy (SBRT) against intensity modulated radiation therapy (IMRT) FFF-JT. Methods: Ten hepatocellular carcinoma (HCC) cases were planned with 10 MV FFF using Pinnacle3 treatment planning system which delivered by TrueBeam to administer 48 Gy/ 4 fractions. Eight non-coplanar beams were assigned to IMRT using step-and-shoot technique. For VMAT, two or three non-coplanar partial arcs (up to 180 degrees) were further divided into subarcs with gantry rotation less than 80 degrees to limit delivery time within 15 s. Dose distributions were verified using OCTAVIUS II system and pass rates were evaluated using gamma analysis with criteria of 3%/3 mm at threshold of 5% to the maximum dose. The actual irradiation time was measured. Results: The VMAT-FFF-JT of partial-arcs with sub-divided arcs was able to produce a highly conformal plan as well as IMRT-FFF-JT. Isodose lines and DVH showed slight improvement in dosimetry when JT was employed for both IMRT and VMAT. Consequently, VMAT-FFF-JT was superior in reducing the dose to liver minus gross tumor volume. VMAT-FFF-JT has shorter total treatment time compared with 3D conformal radiation therapy (3D-CRT) FFF because the gantry was rotated simultaneously with the beam delivery in VMAT. Moreover, due to the small and regular shape of HCC, VMAT-FFF-JT offered less multileaf collimator motion, thus the interplay effect is expected to be reduced. The patient specific QA of IMRT and VMAT acquired the pass rates higher than 90%. Conclusion: VMAT-FFF-JT could be a promising technique for liver SBRT as the sub-divided arcs method was able to accommodate a single breath hold irradiation time of less than 15 s without deterioration of the dose distribution compared with IMRT-FFF-JT.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Evaluation of potential internal target volume of liver tumors using cine-MRI

Purpose: Four-dimensional computed tomography (4DCT) is widely used for evaluating moving tumors, including lung and liver cancers. For patients with unstable respiration, however, the 4DCT may not visualize tumor motion properly. High-speed magnetic resonance imaging (MRI) sequences (cine-MRI) permit direct visualization of respiratory motion of liver tumors without considering radiation dose exposure to patients. Here, the authors demonstrated a technique for evaluating internal target volume (ITV) with consideration of respiratory variation using cine-MRI. Methods: The authors retrospectively evaluated six patients who received stereotactic body radiotherapy (SBRT) to hepatocellular carcinoma. Before acquiring planning CT, sagittal and coronal cine-MRI images were acquired for 30 s with a frame rate of 2 frames/s. The patient immobilization was conducted under the same condition as SBRT. Planning CT images were then acquired within 15 min from cine-MRI image acquisitions, followed by a 4DCT scan. To calculate tumor motion, the motion vectors between two continuous frames of cine-MRI images were calculated for each frame using the pyramidal Lucas–Kanade method. The target contour was delineated on one frame, and each vertex of the contour was shifted and copied onto the following frame using neighboring motion vectors. 3D trajectory data were generated with the centroid of the contours on sagittal and coronal images. To evaluate the accuracy of the tracking method, the motion of clearly visible blood vessel was analyzed with the motion tracking and manual detection techniques. The target volume delineated on the 50% (end-exhale) phase of 4DCT was translated with the trajectory data, and the distribution of the occupancy probability of target volume was calculated as potential ITV (ITV {sub Potential}). The concordance between ITV {sub Potential} and ITV estimated with 4DCT (ITV {sub 4DCT}) was evaluated using the Dice’s similarity coefficient (DSC). Results: The distance between blood vessel positions determined with motion tracking and manual detection was analyzed. The mean and SD of the distance were less than 0.80 and 0.52 mm, respectively. The maximum ranges of tumor motion on cine-MRI were 2.4 ± 1.4 mm (range, 1.0–5.0 mm), 4.4 ± 3.3 mm (range, 0.8–9.4 mm), and 14.7 ± 5.9 mm (range, 7.4–23.4 mm) in lateral, anterior–posterior, and superior–inferior directions, respectively. The ranges in the superior–inferior direction were larger than those estimated with 4DCT images for all patients. The volume of ITV {sub Potential} was 160.3% ± 13.5% (range, 142.0%–179.2%) of the ITV {sub 4DCT}. The maximum DSC values were observed when the cutoff value of 24.7% ± 4.0% (range, 20%–29%) was applied. Conclusions: The authors demonstrated a novel method of calculating 3D motion and ITV {sub Potential} of liver cancer using orthogonal cine-MRI. Their method achieved accurate calculation of the respiratory motion of moving structures. Individual evaluation of the ITV {sub Potential} will aid in improving respiration management and treatment planning.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

SU-E-J-110: Dosimetric Analysis of Respiratory Motion Based On Four-Dimensional Dose Accumulation in Liver Stereotactic Body Radiotherapy

Purpose: Respiratory motion in thoracic and abdominal region could lead to significant underdosing of target and increased dose to healthy tissues. The aim of this study is to evaluate the dosimetric effect of respiratory motion in conventional 3D dose by comparing 4D deformable dose in liver stereotactic body radiotherapy (SBRT). Methods: Five patients who had previously treated liver SBRT were included in this study. Four-dimensional computed tomography (4DCT) images with 10 phases for all patients were acquired on multi-slice CT scanner (Siemens, Somatom definition). Conventional 3D planning was performed using the average intensity projection (AIP) images. 4D dose accumulation was calculated by summation of dose distribution for all phase images of 4DCT using deformable image registration (DIR) . The target volume and normal organs dose were evaluated with the 4D dose and compared with those from 3D dose. And also, Index of achievement (IOA) which assesses the consistency between planned dose and prescription dose was used to compare target dose distribution between 3D and 4D dose. Results: Although the 3D dose calculation considered the moving target coverage, significant differences of various dosimetric parameters between 4D and 3D dose were observed in normal organs and PTV. The conventional 3D dose overestimated dose to PTV, however, there was no significant difference for GTV. The average difference of IOA which become ‘1’ in an ideal case was 3.2% in PTV. The average difference of liver and duodenum was 5% and 16% respectively. Conclusion: 4D dose accumulation which can provide dosimetric effect of respiratory motion has a possibility to predict the more accurate delivered dose to target and normal organs and improve treatment accuracy. This work was supported by the Radiation Technology R&D program (No. 2013M2A2A7043498) and the Mid-career Researcher Program (2014R1A2A1A10050270) through the National Research Foundation of Korea funded by the Ministry of Science, ICT&Future Planning (MSIP) of Korea.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

MO-DE-210-05: Improved Accuracy of Liver Feature Motion Estimation in B-Mode Ultrasound for Image-Guided Radiation Therapy

Purpose: In similarity-measure based motion estimation incremental tracking (or template update) is challenging due to quantization, bias and accumulation of tracking errors. A method is presented which aims to improve the accuracy of incrementally tracked liver feature motion in long ultrasound sequences. Methods: Liver ultrasound data from five healthy volunteers under free breathing were used (15 to 17 Hz imaging rate, 2.9 to 5.5 minutes in length). A normalised cross-correlation template matching algorithm was implemented to estimate tissue motion. Blood vessel motion was manually annotated for comparison with three tracking code implementations: (i) naive incremental tracking (IT), (ii) IT plus a similarity threshold (ST) template-update method and (iii) ST coupled with a prediction-based state observer, known as the alpha-beta filter (ABST). Results: The ABST method produced substantial improvements in vessel tracking accuracy for two-dimensional vessel motion ranging from 7.9 mm to 40.4 mm (with mean respiratory period: 4.0 ± 1.1 s). The mean and 95% tracking errors were 1.6 mm and 1.4 mm, respectively (compared to 6.2 mm and 9.1 mm, respectively for naive incremental tracking). Conclusions: High confidence in the output motion estimation data is required for ultrasound-based motion estimation for radiation therapy beam tracking and gating. The method presented has potential for monitoring liver vessel translational motion in high frame rate B-mode data with the required accuracy. This work is support by Cancer Research UK Programme Grant C33589/A19727.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

MO-F-CAMPUS-J-02: Commissioning of Radiofrequency Tracking for Gated SBRT of the Liver Using Novel Motion System

Purpose: Tracking soft tissue targets has recently been approved as a new application of the Calypso radiofrequency tracking system allowing for gated treatment of the liver based on the motion of the target volume itself. As part of the commissioning process, an end-to-end test was performed using a 3D diode array and 6D motion platform to verify the dosimetric accuracy and establish the workflow of gated SBRT treatment of the liver using Calypso. Methods: A 4DCT scan of the ScandiDos Delta4 phantom was acquired using the HexaMotion motion platform to simulate realistic breathing motion. A VMAT plan was optimized on the end of inspiration phase of the 4DCT scan and delivered to the Delta4 phantom using the Varian TrueBeam. The treatment beam was gated by Calypso to deliver dose at the end of inspiration. The expected dose was compared to the delivered dose using gamma analysis. In addition, gating limits were investigated to determine how large the gating range can be while still maintaining dosimetric accuracy. Results: The 3%/3mm and 2%/2mm gamma pass rate for the gated treatment delivery was 100% and 98.4%, respectively. When increasing the gating limits beyond the known extent of planned motion from the 4DCT, the gamma pass rates decreased as expected. The 3%/3mm gamma pass rate for a 1, 2, and 3mm increase in gating limits were measured to be 96.0%, 92.7%, and 78.8%, respectively. Conclusion: Radiofrequency tracking was shown to be an effective way to provide gated SBRT treatment of the liver. Baseline gating limits should be determined by measuring the extent of target motion during the respiratory phases used for planning. We recommend adding 1mm to the baseline limits to provide the proper balance between treatment efficiency and dosimetric accuracy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Liver 4DMRI: A retrospective image-based sorting method

Purpose: Four-dimensional magnetic resonance imaging (4DMRI) is an emerging technique in radiotherapy treatment planning for organ motion quantification. In this paper, the authors present a novel 4DMRI retrospective image-based sorting method, providing reduced motion artifacts than using a standard monodimensional external respiratory surrogate. Methods: Serial interleaved 2D multislice MRI data were acquired from 24 liver cases (6 volunteers + 18 patients) to test the proposed 4DMRI sorting. Image similarity based on mutual information was applied to automatically identify a stable reference phase and sort the image sequence retrospectively, without the use of additional image or surrogate data to describe breathing motion. Results: The image-based 4DMRI provided a smoother liver profile than that obtained from standard resorting based on an external surrogate. Reduced motion artifacts were observed in image-based 4DMRI datasets with a fitting error of the liver profile measuring 1.2 ± 0.9 mm (median ± interquartile range) vs 2.1 ± 1.7 mm of the standard method. Conclusions: The authors present a novel methodology to derive a patient-specific 4DMRI model to describe organ motion due to breathing, with improved image quality in 4D reconstruction.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-F-T-189: Dosimetric Comparison of Spot-Scanning Proton Therapy Techniques for Liver Tumors Close to the Skin Surface

Purpose: Spot-scanning technique has been utilized to achieve conformal dose distribution to large and complicated tumors. This technique generally does not require patient-specific devices such as aperture and compensator. The commercially available spot-scanning proton therapy (SSPT) systems, however, cannot deliver proton beams to the region shallower than 4 g/cm2. Therefore some range compensation device is required to treat superficial tumors with SSPT. This study shows dosimetric comparison of the following treatment techniques: (i) with a tabletop bolus, (ii) with a nozzle-mounted applicator, and (iii) without any devices and using intensity-modulated proton therapy (IMPT) technique. Methods: The applicator composed of a combination of a mini-ridge filter and a range shifter has been manufactured by Hitachi, Ltd., and the tabletop bolus was made by .decimal, Inc. Both devices have been clinically implemented in our facility. Three patients with liver tumors close to the skin surface were examined in this study. Each treatment plan was optimized so that the prescription dose of 76 Gy(RBE) or 66 Gy(RBE) would be delivered to 99% of the clinical target volume in 20 fractions. Three beams were used for tabletop bolus plan and IMPT plan, whereas two beams were used in the applicator plan because the gantry angle available was limited due to potential collision to patient and couch. The normal liver, colon, and skin were considered as organs at risk (OARs). Results: The target heterogeneity index (HI = D{sub 5}/D{sub 95}) was 1.03 on average in each planning technique. The mean dose to the normal liver was considerably less than 20 Gy(RBE) in all cases. The dose to the skin could be reduced by 20 Gy(RBE) on average in the IMPT plan compared to the applicator plan. Conclusion: It has been confirmed that all treatment techniques met the dosimetric criteria for the OARs and could be implemented clinically.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-F-T-636: Comprehensive Approach to Motion Assessment for Liver and Pancreas SBRT Patients

Purpose: Our past practice for liver and pancreas SBRT consisted of free breathing (FB) with gated treatment delivery using a 30-70% phase window. We have recently adopted an assessment method leading to individualized motion management to minimize target motion. We present our results from 47 patients treated with this new approach. Methods: We perform an initial patient coaching and assessment session in our conventional simulator suite to observe the motion of the implanted fiducials with FB anterior and lateral 20-second cine acquisitions. The physician decides whether to attempt inhale or exhale breath-hold (BH). The patient is coached while observing with cine to ascertain their ability to achieve the desired BH mode for long periods as needed for treatment delivery. If the patient cannot comply, a FB approach is adopted using gating or simple ITV method (for patients without fiducials). After achieving a patient-specific motion management mode, we perform CT-simulation using the Varian RPM system to reproduce the chosen mode and record a reference session for treatment delivery. For pre-treatment imaging, the fiducials are observed under fluoro while coaching the patient. Results: Of 47 SBRT cases analyzed, 32 were liver and 15 were pancreas. The chosen techniques were: 32 exhale BH (12 with abdominal compression), 7 FB gated, 4 inhale BH, and 4 FB ITV. Maximum fiducial motion amplitude was 5 mm for the FB gated patients, and less than 5 mm for all BH patients with most able to achieve a maximum amplitude of 3 mm. Conclusion: This study showed that an individualized motion management approach can reduce the target volume and, therefore, the volume of irradiated healthy tissue from liver or pancreas SBRT. Effective coaching is essential in achieving consistent BH with 3 mm amplitude. The fluoro/cine session is helpful in establishing the right coaching approach for each patient.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

WE-E-BRB-02: Implementation of Pencil Beam Scanning (PBS) Proton Therapy Treatment for Liver Patient

Strategies for treating thoracic and liver tumors using pencil beam scanning proton therapy Thoracic and liver tumors have not been treated with pencil beam scanning (PBS) proton therapy until recently. This is because of concerns about the significant interplay effects between proton spot scanning and patient’s respiratory motion. However, not all tumors have unacceptable magnitude of motion for PBS proton therapy. Therefore it is important to analyze the motion and understand the significance of the interplay effect for each patient. The factors that affect interplay effect and its washout include magnitude of motion, spot size, spot scanning sequence and speed. Selection of beam angle, scanning direction, repainting and fractionation can all reduce the interplay effect. An overview of respiratory motion management in PBS proton therapy including assessment of tumor motion and WET evaluation will be first presented. As thoracic tumors have very different motion patterns from liver tumors, examples would be provided for both anatomic sites. As thoracic tumors are typically located within highly heterogeneous environments, dose calculation accuracy is a concern for both treatment target and surrounding organs such as spinal cord or esophagus. Strategies for mitigating the interplay effect in PBS will be presented and the pros and cons of various motion mitigation strategies will be discussed. Learning Objectives: Motion analysis for individual patients with respect to interplay effect Interplay effect and mitigation strategies for treating thoracic/liver tumors with PBS Treatment planning margins for PBS The impact of proton dose calculation engines over heterogeneous treatment target and surrounding organs I have a current research funding from Varian Medical System under the master agreement between University of Pennsylvania and Varian; L. Lin, I have a current funding from Varian Medical System under the master agreement between University of Pennsylvania and Varian.; H. Li, Na.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Radiation Effects on Mortality from Solid Cancers Other than Lung, Liver, and Bone Cancer in the Mayak Worker Cohort: 1948–2008

Radiation effects on mortality from solid cancers other than lung, liver, and bone cancer in the Mayak worker cohort: 1948–2008. The cohort of Mayak Production Association (PA) workers in Russia offers a unique opportunity to study the effects of prolonged low dose rate external gamma exposures and exposure to plutonium in a working age population. We examined radiation effects on the risk of mortality from solid cancers excluding sites of primary plutonium deposition (lung, liver, and bone surface) among 25,757 workers who were first employed in 1948–1982. During the period 1948–2008, there were 1,825 deaths from cancers other than lung, liver and bone. Using colon dose as a representative external dose, a linear dose response model described the data well. The excess relative risk per Gray for external gamma exposure was 0.16 (95% CI: 0.07 – 0.26) when unadjusted for plutonium exposure and 0.12 (95% CI 0.03 – 0.21) when adjusted for plutonium dose and monitoring status. There was no significant effect modification by sex or attained age. Plutonium exposure was not significantly associated with the group of cancers analyzed after adjusting for monitoring status. Site-specific risks were uncertainly estimated but positive for 13 of the 15 sites evaluated with a statistically significant estimate only for esophageal cancer. Comparison with estimates based on the acute exposures in atomic bomb survivors suggests that the excess relative risk per Gray for prolonged external exposure in Mayak workers may be lower than that for acute exposure but, given the uncertainties, the possibility of equal effects cannot be dismissed.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Serum bile acid and unsaturated fatty acid profiles of non-alcoholic fatty liver disease in type 2 diabetic patients

The understanding of bile acid (BA) and unsaturated fatty acid (UFA) profiles, as well as their dysregulation, remains elusive in individuals with type 2 diabetes mellitus (T2DM) coexisting with non-alcoholic fatty liver disease (NAFLD). Investigating these metabolites could offer valuable insights into the pathophy-siology of NAFLD in T2DM. Our aim is to identify potential metabolite biomarkers capable of distinguishing between NAFLD and T2DM. A training model was developed involving 399 participants, comprising 113 healthy controls (HCs), 134 individuals with T2DM without NAFLD, and 152 individuals with T2DM and NAFLD. External validation encompassed 172 participants. NAFLD patients were divided based on liver fibrosis scores. The analytical approach employed univariate testing, orthogonal partial least squares-discriminant analysis, logistic regression, receiver operating characteristic curve analysis, and decision curve analysis to pinpoint and assess the diagnostic value of serum biomarkers. Compared to HCs, both T2DM and NAFLD groups exhibited diminished levels of specific BAs. In UFAs, particular acids exhibited a positive correlation with NAFLD risk in T2DM, while the ω-6:ω-3 UFA ratio demonstrated a negative correlation. Levels of α-linolenic acid and γ-linolenic acid were linked to significant liver fibrosis in NAFLD. The validation cohort substantiated the predictive efficacy of these biomarkers for assessing NAFLD risk in T2DM patients. This study underscores the connection between altered BA and UFA profiles and the presence of NAFLD in individuals with T2DM, proposing their potential as biomarkers in the pathogenesis of NAFLD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Extraction efficiency and implications for absolute quantitation of propranolol in mouse brain, liver and kidney thin tissue sections using droplet-based liquid microjunction surface sampling-HPLC ESI-MS/MS

Currently, absolute quantitation aspects of droplet-based surface sampling for thin tissue analysis using a fully automated autosampler/HPLC-ESI-MS/MS system are not fully evaluated. Knowledge of extraction efficiency and its reproducibility is required to judge the potential of the method for absolute quantitation of analytes from thin tissue sections. Methods: Adjacent thin tissue sections of propranolol dosed mouse brain (10- μm-thick), kidney (10- μm-thick) and liver (8-, 10-, 16- and 24- μm-thick) were obtained. Absolute concentration of propranolol was determined in tissue punches from serial sections using standard bulk tissue extraction protocols and subsequent HPLC separations and tandem mass spectrometric analysis. These values were used to determine propranolol extraction efficiency from the tissues with the droplet-based surface sampling approach. Results: Extraction efficiency of propranolol using 10- μm-thick brain, kidney and liver thin tissues using droplet-based surface sampling varied between ~45-63%. Extraction efficiency decreased from ~65% to ~36% with liver thickness increasing from 8 μm to 24 μm. Randomly selecting half of the samples as standards, precision and accuracy of propranolol concentrations obtained for the other half of samples as quality control metrics were determined. Resulting precision ( ±15%) and accuracy ( ±3%) values, respectively, were within acceptable limits. In conclusion, comparative quantitation of adjacent mouse thin tissue sections of different organs and of various thicknesses by droplet-based surface sampling and by bulk extraction of tissue punches showed that extraction efficiency was incomplete using the former method, and that it depended on the organ and tissue thickness. However, once extraction efficiency was determined and applied, the droplet-based approach provided the required quantitation accuracy and precision for assay validations. Furthermore, this means that once the extraction efficiency was calibrated for a given tissue type and drug, the droplet-based approach provides a non-labor intensive and high-throughput means to acquire spatially resolved quantitative analysis of multiple samples of the same type.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Unraveling the Hsp70-ROS-autophagy axis in pentachlorophenol-challenged lung and liver epithelial cells

Pentachlorophenol (PCP) was extensively utilized as an organochlorine pesticide and wood preservative in the United States from the 1930s until the Environmental Protection Agency (EPA) imposed restrictions due to concerns about its toxicity and potential carcinogenic properties. Although it is no longer widely used, PCP remains a concern due to its environmental persistence and potential for long-term health effects. Significant occupational and environmental exposures have likely occurred, with the health and economic costs of PCP exposure potentially being substantial given its known toxicity. Notably, PCP exhibits rapid absorption through both the skin and respiratory system and has been shown to cause hepatotoxicity, developmental toxicity, immunotoxicity, irritation, and carcinogenicity in laboratory animal studies. PCP exposure induces oxidative stress, a key mechanism underlying its inflammatory and toxic effects, which can activate cellular stress responses including upregulation of heat shock protein 70 (Hsp70). Previous studies in lung and liver epithelial cells have shown that Hsp70 and oxidative stress play pivotal roles in triggering autophagy. This study establishes the critical role of the Hsp70-reactive oxygen species (ROS)-autophagy axis in regulating cellular responses to PCP exposure in human alveolar (A549) and liver carcinoma (HepG2) epithelial cells. Our research elucidated the molecular mechanisms underlying PCP's cellular effects, demonstrating that its exposure resulted in increased expression of autophagy-related proteins (Beclin-1, LC3B, ATG12, and ATG16), subunits of NADPH oxidase (NCF-1, NCF-2, NOX2, and Rac), and antioxidant proteins (SOD and GPx) in both lung and liver cell types. Notably, PCP augmented the interaction between Hsp70 and the autophagy regulator Beclin-1. Pretreatment with the ROS inhibitor N-acetylcysteine or Hsp70 knockdown markedly reversed PCP-induced responses. Our in-silico protein–protein docking analysis and molecular dynamics simulation studies revealed enhanced interactions and/or stable confirmations maintained throughout the simulations for TLR4-Hsp70 and Hsp70-Beclin-1 complexes in the presence of PCP. These findings provide a strong foundation for future studies, employing in vivo experimental models and human populations to identify promising targets for PCP-induced toxicity and cellular injury. As a result, these findings may have far-reaching implications for public health and environmental policy, ultimately leading to the identification of biomarkers and the development of more effective interventions for environmentally induced toxicity and diseases.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2014

Long-term Outcomes of Percutaneous Venoplasty and Gianturco Stent Placement to Treat Obstruction of the Inferior Vena Cava Complicating Liver Transplantation

Purpose: Evaluation of long-term outcomes of venoplasty and Gianturco stents to treat inferior vena cava (IVC) obstruction after liver transplantation. Methods: We retrospectively analyzed records from 33 consecutive adult patients referred with the intent to treat suspected IVC obstruction after liver transplantation. Treatment was performed for occlusion or stenosis with a gradient exceeding 3 mmHg. The primary treatment was venoplasty and, if refractory, Gianturco stent placement. Recurrence prompted repeat venoplasty or stent placement. Results: Of the 33 patients, 25 (aged 46.9 ± 12.2 years) required treatment at a mean of 2.3 years (14 days to 20.3 years) after transplantation. For technically successful cases, primary treatment was venoplasty alone (14) or with stent placement (10). Technical success was 96 % (24 of 25) reflecting failure to cross one occlusion. Clinical success was 88 % (22 of 25) reflecting the technical failure and two that died of unrelated complications within 5 weeks. Cumulative primary patencies were 57.1 % at 6 months (n = 21) and 51.4 % at 1 (n = 10), 3 (n = 7), 5 (n = 6), and 7 (n = 5) years. Cumulative primary assisted patency was 95.2 % at 6 months (n = 21) and at 1 (n = 15), 3 (n = 9), 5 (n = 8), and 7 (n = 8) years. The 17 patients stented for refractory (n = 10) or recurrent (n = 7) stenosis had cumulative primary and primary assisted patencies of 86.0 and 100 %, respectively, from 6 months (n = 14) to 7 years (n = 3). No major complications occurred; one fractured stent was observed after 11.6 years. Conclusion: For IVC obstruction following liver transplantation, excellent long-term outcomes can be achieved by venoplasty and Gianturco stent placement.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Impaired vagus function in rats suppresses bile acid synthesis in the liver by disrupting tight junctions and activating Fxr-Fgf15 signaling in the intestine

Highlights: • Unconjugated and glycine-conjugated bile acids were increased in vagotomized rats. • The bile acid synthetic enzyme Cyp7a1 was suppressed in vagotomized rats. • Intestinal Fxr-Fgf15 signaling was activated in vagotomized rats. • Tight junction of the intestine was impaired in vagotomized rats. Bile acids (BAs) circulate between the liver and intestine, and regulate the homeostasis of glucose, lipid, and energy. Recent studies demonstrated an essential role of BAs in neurological diseases, suggesting an interaction between BAs and the nervous system. In the present study, we showed that impaired vagus function in rats induced by vagotomy resulted in an increase in bile flow without causing liver injury. The concentrations of unconjugated and glycine-conjugated BAs were increased in both serum and bile of rats after vagotomy, which was due to impaired tight junctions and thus increased passive absorption of BAs in the intestine. Vagotomy markedly suppressed the expression of the rate-limiting BA synthetic enzyme Cyp7a1, which was not due to activation of Fxr-Shp signaling in the liver, but due to activation of Fxr-Fgf15 signaling in the intestine. Furthermore, vagotomy produced a BA profile in the bile favorable for Fxr activation by decreasing tauro-β-muricholic acid, a natural Fxr antagonist, and increasing glyco-chenodeoxycholic acid, a natural Fxr agonist. In summary, the present study provides the first comprehensive analysis of the critical role of the vagus nerve in regulating BA metabolism and signaling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Albumin in patients with liver disease shows an altered conformation

Abstract Human serum albumin (HSA) constitutes the primary transporter of fatty acids, bilirubin, and other plasma compounds. The binding, transport, and release of its cargos strongly depend on albumin conformation, which is affected by bound ligands induced by physiological and pathological conditions. HSA is both highly oxidized and heavily loaded with fatty acids and bilirubin in chronic liver disease. By employing small-angle X-ray scattering we show that HSA from the plasma of chronic liver disease patients undergoes a distinct opening compared to healthy donors. The extent of HSA opening correlates with clinically relevant variables, such as the model of end-stage liver disease score, bilirubin, and fatty acid levels. Although the mild oxidation of HSA in vitro does not alter overall structure, the alteration of patients’ HSA correlates with its redox state. This study connects clinical data with structural visualization of albumin dynamicity in solution and underlines the functional importance of albumin’s inherent flexibility.

59 BASIC BIOLOGICAL SCIENCES↗