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Michal Mauda-Havakuk,1 Andrew S Mikhail,1 Matthew F Starost,2 Elizabeth C Jones,3 Baktiar Karim,4 David E Kleiner,5 Ari Partanen,1 Juan A Esparza-Trujillo,1 Ivane Bakhutashvili,1 Paul G Wakim,6 Michael T Kassin,1 Andrew L Lewis,7 John W Karanian,1 Bradford J Wood,8 William F Pritchard1 1Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA; 2Division of Veterinary Resources, National Institutes of Health, Bethesda, MD, USA; 3Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA; 4National Cancer Institute, National Institutes of Health, Frederick, MD, USA; 5Center for Cancer Research, Clinical Center, National Cancer Institute, Bethesda, MD, USA; 6Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Bethesda, MD, USA; 7Biocompatibles UK Ltd (a BTG International Group Company), Camberley, UK; 8Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institute of Biomedical Imaging and Bioengineering and National Cancer Institute Center for Cancer Research, National Institutes of Health, Bethesda, MD, USACorrespondence: William F PritchardCenter for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 10 Center Drive, Room 3N320B, MSC 1182, Bethesda, MD, 20892, USATel +1 240-760-0153Fax +1 301-496-9933Email william.pritchard@nih.govBackground: Woodchucks chronically infected with woodchuck hepatitis virus (WHV), which resembles human hepatitis B virus, develop spontaneous hepatic tumors and may be an important biological and immunological model for human HCC. Nonetheless, this model requires further validation to fully realize its translational potential.Methods: Woodchucks infected at birth with WHV that had developed HCC (n=12) were studied. Computed tomography, ultrasound, and magnetic resonance imaging were performed under anesthesia. LI-RADS scoring and correlative histologic analysis of sectioned tissues were performed. For immune characterization of tumors, CD3 (T cells), CD4 (T helpers), NCAM (Natural killers), FOXP3 (T-regulatory), PDL-1 (inhibitory checkpoint protein), and the human hepatocellular carcinoma (HCC) biomarker alpha-fetoprotein (AFP) immunohistochemical stains were performed.Results: Forty tumors were identified on imaging of which 29 were confirmed to be HCC with 26 categorized as LR-4 or 5. The remainder of the tumors had benign histology including basophilic foci, adenoma, and lipidosis as well as pre-malignant dysplastic foci. LR-4 and LR-5 lesions showed high sensitivity (90%) and specificity (100%) for malignant and pre-malignant tumors. Natural killers count was found to be 2– 5 times lower in tumors relative to normal parenchyma while other immune cells were located in the periphery of tumors. Tumors expressed AFP and did not express PD-L1.Conclusion: Woodchucks chronically infected with WHV developed diverse hepatic tumor types with diagnostic imaging, pathology, and immune patterns comparable to that in humans. This unique animal model may provide a valuable tool for translation and validation of novel image-guided and immune-therapeutic investigations.Keywords: carcinoma, hepatocellular, radiology, interventional oncology, immunotherapy, models, animal, tumor microenvironment

Purpose: To determine the true distribution of radiopaque beads (ROBs) after hepatic embolization in swine as imaged by micro-computed tomography (microCT) compared with in vivo cone-beam computerized tomography (CT) imaged at different kVp settings., Materials and Methods: Swine (n = 3) underwent hepatic transarterial embolization (n = 6) with the use of 70-150-μm ROBs under fluoroscopic guidance. After stasis, in vivo cone-beam CT was performed at 120, 100, and 80 kVp. The animal was euthanized, the liver resected, and microCT with 17 μm resolution performed on embolized tissue samples. The resulting cone-beam CT and microCT data were segmented and registered. Total vessel length, minimum volume-enclosing ellipsoid (MVEE), and number of independent volumes were measured. Maximum-intensity projections (MIPs) were generated for each cone-beam CT., Results: Metrics for all cone-beam CT segmentations differed significantly from microCT segmentations. Segmentations at 80 kVp presented significantly greater vessel length, MVEE, and number of independent volumes compared with 100 kVp and 120 kVp. In addition, 100 kVp segmentations presented significantly greater vessel length than 120 kVp. MIPs presented greater visualization than cone-beam CT segmentations and improved as kVp decreased., Conclusions: The full ROB distribution was more extensive than was apparent on cone-beam CT. Quantitative measures of embolic distribution demonstrated significantly better correlation with microCT with decreasing kVp. Similarly, qualitative analysis of MIPs showed improved visualization of beads with decreasing kVp. These findings demonstrate the clinical value of 80 kVp and 100 kVp protocols in the imaging of radiopaque embolizations compared with 120 kVp. However, considerations on X-ray penetration and dose may favor use of 100 kVp imaging over 80 kVp., (Published by Elsevier Inc.)

Purpose: To evaluate lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox ® ) in combination with loco-regional mild hyperthermia (HT) for targeted drug delivery to the bladder wall and potential treatment of bladder cancer., Material and Methods: Porcine in vivo studies were performed with the following groups: (i) intravenous (IV) LTLD with hyperthermia (LTLD + HT); (ii) IV doxorubicin (DOX) with hyperthermia (IV DOX + HT) and (iii) IV LTLD without hyperthermia (LTLD - HT). Drug formulations were delivered via 30 min IV infusion coinciding with 1-h bladder irrigation (45 °C water for HT groups, 37 °C for non-HT group), followed by immediate bladder resection. DOX concentrations were measured in consecutive sections parallel to the bladder lumen by liquid chromatography following drug extraction. Computer models were developed to simulate tissue heating and drug release from LTLD., Results: Comparing mean DOX concentrations at increasing depths from the lumen to outer surface of the bladder wall, the ranges for LTLD + HT, IV DOX + HT and LTLD - HT, respectively, were 20.32-3.52 μg/g, 2.34-0.61 μg/g and 2.18-0.51 μg/g. The average DOX concentrations in the urothelium/lamina and muscularis, respectively, were 9.7 ± 0.67 and 4.09 ± 0.81 μg/g for IV LTLD + HT, 1.2 ± 0.39 and 0.86 ± 0.24 μg/g for IV DOX + HT, and 1.15 ± 0.38 and 0.62 ± 0.15 μg/g for LTLD - HT. Computational model results were similar to measured DOX levels and suggest adequate temperatures were reached within the bladder wall for drug release from LTLD., Conclusions: Doxorubicin accumulation and distribution within the bladder wall was achieved at concentrations higher than with free IV doxorubicin by mild bladder hyperthermia combined with systemic delivery of LTLD.