Image-Guided Transbronchial Pulmonary Cryoablation with a Flexible Cryoprobe in Swine: Performance and Radiology-Pathology Correlation.

PURPOSE: To evaluate the performance of a prototype flexible transbronchial cryoprobe compared with that of percutaneous transthoracic cryoablation and to define cone-beam computed tomography (CT) imaging and pathology cryolesion features in an in vivo swine model. MATERIALS AND METHODS: Transbronchial cryoablation was performed with a prototype flexible cryoprobe (3 central and 3 peripheral lung ablations in 3 swine) and compared with transthoracic cryoablation performed with a commercially available rigid cryoprobe (2 peripheral lung ablations in 1 swine). Procedural time and cryoablation success rates for endobronchial navigation and cryoneedle deployment were measured. Intraoperative cone-beam CT imaging features of cryolesions were characterized and correlated with gross pathology and hematoxylin and eosin-stained sections of the explanted cryolesions. RESULTS: The flexible cryoprobe was successfully navigated and delivered to each target through a steerable guiding sheath (6/6). At 4 minutes after ablation, 5 of 6 transbronchial and 2 of 2 transthoracic cryolesions were visible on cone-beam CT. The volumes on cone-beam CT images were 55.5 cm3 (SE ± 8.0) for central transbronchial ablations (n = 2), 72.5 cm3 (SE ± 8.1) for peripheral transbronchial ablations (n = 3), and 79.5 cm3 (SE ±11.6) for peripheral transthoracic ablations (n = 2). Pneumothorax developed in 1 animal after transbronchial ablation and during ablation in the transthoracic cryoablation. Images of cryoablation zones on cone-beam CT correlated well with the matched gross pathology and histopathology sections of the cryolesions. CONCLUSIONS: Transbronchial cryoablation with a flexible cryoprobe, delivered through a steerable guiding sheath, is feasible. Transbronchial cryoablation zones are imageable with cone-beam CT, with gross pathology and histopathology similar to those of transthoracic cryoablation.

Woodchuck Hepatic Anatomy and Vascular Alterations Due to Hepatocellular Carcinoma with Angiographic Atlas of the Abdomen and Pelvis.

PURPOSE: To characterize the hepatic and abdominal angiographic anatomy of woodchucks and vascular changes associated with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Twenty-nine woodchucks (23 with viral-associated HCC, 6 without) underwent multiphasic computed tomography (CT). Fourteen woodchucks (8 with HCC) also underwent diagnostic angiography. Hepatic arterial diameters were measured on the CT scans. Woodchucks were divided into 3 groups: non-tumor-bearing, largest tumor supplied by the right hepatic artery (RHA), and largest tumor supplied by the left hepatic artery (LHA). Statistical analysis with a repeated measures model was performed to determine the effects of tumor location (right, left), vessel measured (RHA, LHA), and interaction between the 2 on vessel diameter. Lobar arteries supplying HCC were compared with those that did not. RESULTS: CT anatomy and normal and variant vascular anatomy were defined. In woodchucks with HCC, LHA and RHA supplying tumors had mean diameters of 2.0 mm ± 0.3 and 1.6 mm ± 0.3 versus 1.5 mm ± 0.3 and 1.1 mm ± 0.2 for non-tumor-supplying arteries (P = .0002 and P < .0001), respectively. Lobar arteries supplying tumors were similarly ectatic. The right lateral lobe artery had the most profound increase in the mean diameter when supplying tumors, measuring 1.7 mm ± 0.1 versus 1.0 mm ± 0.1 in the non-tumor-supplying artery (P < .0001). There were no differences in the diameters of the aorta and celiac, common, and proper hepatic arteries between tumor- and non-tumor-bearing woodchucks. An angiographic atlas of the abdominal vessels was generated. CONCLUSIONS: HCC tumoral vasculature in woodchucks was ectatic compared with normal vasculature. This phenomenon recapitulates human HCC and may facilitate investigation of transcatheter and drug delivery therapies in an HCC animal model.

Monopolar Radiofrequency Energy Delivered by a Conductive Endovascular Basket or Guidewire Leads to Thermal Occlusion in a Swine Model.

PURPOSE: To assess the feasibility of inducing vascular occlusion by application of radiofrequency (RF) energy via conductive endovascular wires or baskets. MATERIALS AND METHODS: A retrievable nitinol basket and stainless steel guidewire with a platinum tip were evaluated as conductors for endovascular application of RF energy. Tissue-mimicking thermochromic gel phantoms that change color with heating were cast with 2-, 5-, and 7-mm-diameter lumens and filled with 37 oC saline. After ablation, the phantoms were sectioned, and the thermal footprints were evaluated. Six castrated male domestic swine underwent endovascular ablation using the basket in iliac arteries and guidewires in renal arteries. Post-procedural angiography was performed, and postmortem arterial segments were resected for histopathologic analysis. RESULTS: In the phantom, the depth of thermal change in the 5- and 7-mm lumens averaged 6.3 and 6.0 mm along the basket, respectively, and in the 2- and 5-mm lumens, the depth of thermal change averaged 1.9 and 0.5 mm along the wire, respectively. In the swine, RF energy delivery led to angiographic occlusion at 12 of 13 sites. Thermal injury and occlusion were similar at the proximal, middle, and distal basket treatment zone, whereas injury and occlusion decreased from the proximal to the distal end of the 5-cm wire treatment zone. CONCLUSIONS: Endovascular delivery of RF energy via a conductive basket in medium-sized arteries or a guidewire in small arteries led to acute angiographic and histologic occlusion. The potential to induce stasis might be useful in settings where rapid occlusion is desirable.

Endobronchial Navigation Guided by Cone-Beam CT-Based Augmented Fluoroscopy without a Bronchoscope: Feasibility Study in Phantom and Swine.

PURPOSE: To evaluate the accuracy of cone-beam computed tomography (CT)-based augmented fluoroscopy (AF) image guidance for endobronchial navigation to peripheral lung targets. METHODS: Prototypic endobronchial navigation AF software that superimposed segmented airways, targets, and pathways based on cone-beam CT onto fluoroscopy images was evaluated ex vivo in fixed swine lungs and in vivo in healthy swine (n = 4) without a bronchoscope. Ex vivo and in vivo (n = 3) phase 1 experiments used guide catheters and AF software version 1, whereas in vivo phase 2 (n = 1) experiments also used an endovascular steerable guiding sheath, upgraded AF software version 2, and lung-specific low-radiation-dose protocols. First-pass navigation success was defined as catheter delivery into a targeted airway segment solely using AF, with second-pass success defined as reaching the targeted segment by using updated AF image guidance based on confirmatory cone-beam CT. Secondary outcomes were navigation error, navigation time, radiation exposure, and preliminary safety. RESULTS: First-pass success was 100% (10/10) ex vivo and 19/24 (79%) and 11/15 (73%) for in vivo phases 1 and 2, respectively. Phase 2 second-pass success was 4/4 (100%). Navigation errors were 2.2 ± 1.2 mm ex vivo and 4.9 ± 3.2 mm and 4.0 ± 2.6 mm for in vivo phases 1 and 2, respectively. No major device-related complications were observed in the in vivo experiments. CONCLUSIONS: Endobronchial navigation is feasible and accurate with cone-beam CT-based AF image guidance. AF can guide endobronchial navigation with endovascular catheters and steerable guiding sheaths to peripheral lung targets, potentially overcoming limitations associated with bronchoscopy.

Transarterial Chemoembolization in a Woodchuck Model of Hepatocellular Carcinoma.

PURPOSE: To assess the feasibility of transarterial chemoembolization with drug-eluting embolic (DEE) microspheres in a woodchuck model of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Nine woodchucks were studied: 4 normal animals and 5 animals infected with woodchuck hepatitis virus in which HCC had developed. Three animals with HCC underwent multidetector CT. A 3-F sheath was introduced into the femoral artery, and the hepatic arteries were selectively catheterized with 2.0-2.4-F microcatheters. Normal animals underwent diagnostic angiography and bland embolization. Animals with HCC underwent DEE transarterial chemoembolization with 70-150-µm radiopaque microspheres loaded with 37.5 mg doxorubicin per milliliter. Cone-beam CT and multidetector CT were performed. Following euthanasia, explanted livers underwent micro-CT, histopathologic examination, and fluorescence imaging of doxorubicin. RESULTS: The tumors were hypervascular and supplied by large-caliber tortuous vessels, with arteriovenous shunts present in 2 animals. There was heterogeneous enhancement on multidetector CT with areas of necrosis. Six tumors were identified. The most common location was the right medial lobe (n = 3). Mean tumor volume was 30.7 cm3 ± 12.3. DEE chemoembolization of tumors was achieved. Excluding the 2 animals with arteriovenous shunts, the mean volume of DEE microspheres injected was 0.49 mL ± 0.17. Fluorescence imaging showed diffusion of doxorubicin from the DEE microspheres into the tumor. CONCLUSIONS: Woodchuck HCC shares imaging appearances and biologic characteristics with human HCC. Selective catheterization and DEE chemoembolization may similarly be performed. Woodchucks may be used to model interventional therapies and possibly characterize radiologic-pathologic correlations.

Ovarian teratoma in a woodchuck (Marmota monax) with hepatocellular carcinoma: radiologic and pathologic features.

BACKGROUND: Teratomas are germ cell neoplasms composed of a wide variety of tissues. In the woodchuck, only one testicular teratoma has been described in the literature. The objective of this report was to describe the radiologic and pathologic findings in a female woodchuck (Marmota monax) with an ovarian teratoma consisting of mature tissues originating from all three germ layers. CASE PRESENTATION: A 2-year-old female woodchuck that had been infected at birth with woodchuck hepatitis virus and subsequently developed hepatocellular carcinoma was incidentally discovered to have a mobile 6.6 × 4.8 × 4.7 cm abdominal mass on computed tomography (CT) imaging. The tumor was predominantly solid and heterogenous on CT with soft tissue, fat, and areas of dense calcification. The teratoma did not enhance with intravenous contrast administration. On ultrasound, the tumor was solid with heterogeneous echogenicity, reflecting the fat content and areas of calcification. Sonolucent areas were present that may have represented cysts. There was heterogeneously increased signal on T1-weighted magnetic resonance imaging (MRI) and heterogeneous hyperintensity in T2-weighted imaging. Fat was evident within the tumor. At necropsy, the tumor was attached to the distal end of the right uterine horn. Histopathology showed mature tissue types representing all three germ layers. CONCLUSIONS: Ovarian teratoma should be considered in the differential diagnosis of ovarian or abdominal masses in woodchucks. The tumor displayed mature tissue derived from all three germ layers. CT, ultrasound, and MRI findings were presented in detail and matched the typical imaging appearance of teratomas.

In Vivo Characterization of the Swine Airway Morphometry and Motion Based on Computed Tomographic Imaging During Respiration.

Swine are a commonly used model in translational pulmonary research. However, in vivo airway morphometry during respiration has not been studied in extensive detail using modern imaging tools. Chest computed tomographic was performed in swine (n = 3) at multiple stages of respiration. Morphometric parameters of each airway segment at end-expiration and end-inspiration were compared as well as among matched anatomical regions (proximal and distal; ventral, lateral, and dorsal). Analysis included segment diameter, length, ellipticity, and the bifurcation angle between daughter branches. Deformation of the airway during respiration was qualitatively visualized using a point-to-point deformation map. Comparison of airway generation showed airway diameter and length were larger at end-inspiration in the fourth and seventh generations compared to end-expiration. Bifurcation angle was larger at end-inspiration compared to end-expiration. Analysis by anatomical region showed that length and bifurcation angle were larger at inspiration in the distal airway regions only. Regardless of respiratory phase, the lateral regions had larger diameters and lengths compared to the ventral and dorsal regions at similar generations and proximal regions had larger bifurcation angles. The findings that morphological changes were more prevalent in distal airways during respiration was confirmed by analysis of a deformation map. Compared to human airway models, the relative diameter may be smaller and length may be greater in swine in similar airway generations. This morphometric description of the swine airways during respiration may guide conduct of preclinical translational studies, revealing advantages and limitations of swine models for specific evaluations. Such morphometric parameters may directly determine the suitability of the swine model for the study of lung interventions, in terms of recapitulation of human morphometry dynamics.

Radiofrequency Ablation Duration per Tumor Volume May Correlate with Overall Survival in Solitary Hepatocellular Carcinoma Patients Treated with Radiofrequency Ablation Plus Lyso-Thermosensitive Liposomal Doxorubicin.

PURPOSE: To determine whether burn time per tumor volume (BPV) (min/mL), where burn time is the total time during which radiofrequency (RF) energy is being applied, is correlated with hepatocellular carcinoma (HCC) treatment outcomes using RF ablation and lyso-thermosensitive liposomal doxorubicin (LTLD). MATERIALS AND METHODS: The HEAT study was a double-blind, randomized controlled phase III trial of RF ablation only versus RF ablation + LTLD in patients with HCCs 3-7 cm in diameter. Effect of BPV on progression-free survival and overall survival (OS) was analyzed. RESULTS: BPV demonstrated statistically significant differences between study groups for OS (P = .038, hazard ratio [HR] = 0.85), but not for progression-free survival (P = .389, HR = 1.059). In a separate analysis, treatment groups were independently analyzed to determine the effect of BPV within each individual group. OS improved as BPV increased for patients receiving RF ablation + LTLD (P = .017, HR = 0.836, confidence interval [0.722, 0.968]). This same association was not observed in patients receiving RF ablation only (P = .57, HR = 0.99). CONCLUSIONS: BPV may be a useful metric for RF ablation + LTLD combination therapy for solitary HCC. The analysis suggested that the burn time for the tumor needs to be adjusted depending on the tumor volume. Because this is a post hoc study, the results are only suggestive and need to be confirmed with prospective studies.

Mapping Drug Dose Distribution on CT Images Following Transarterial Chemoembolization with Radiopaque Drug-Eluting Beads in a Rabbit Tumor Model.

Purpose To correlate bead location and attenuation on CT images with the quantity and distribution of drug delivered to the liver following transarterial chemoembolization (TACE) with radiopaque drug-eluting beads (DEB) in a rabbit tumor model. Materials and Methods All procedures were performed with a protocol approved by the Institutional Animal Care and Use Committee. TACE was performed in rabbits (n = 4) bearing VX2 liver tumors by using radiopaque DEB (70-150 µm) loaded with doxorubicin (DOX). Livers were resected 1 hour after embolization, immediately frozen, and cut by using liver-specific three-dimensional-printed molds for colocalization of liver specimens and CT imaging. DOX penetration into tissue surrounding beads was evaluated with fluorescence microscopy. DOX levels in liver specimens were predicted by using statistical models correlating DOX content measured in tissue with bead volume and attenuation measured on CT images. Model predictions were then compared with actual measured DOX concentrations to assess the models' predictive power. Results Eluted DOX remained in close proximity (<600 µm) to beads in the liver 1 hour after TACE. Bead volume and attenuation measured on CT images demonstrated positive linear correlations (0.950 and 0.965, respectively) with DOX content in liver specimens. DOX content model predictions based on CT images were accurate compared with actual liver DOX levels at 1 hour. Conclusion CT may be used to estimate drug dose delivery and distribution in the liver following transarterial chemoembolization (TACE) with doxorubicin-loaded radiopaque drug-eluting beads (DEB). Although speculative, this informational map might be helpful in planning and understanding the spatial effects of TACE with DEB. © RSNA, 2018.

Distribution and Detection of Radiopaque Beads after Hepatic Transarterial Embolization in Swine: Cone-Beam CT versus MicroCT.

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.

Smart goggles augmented reality CT-US fusion compared to conventional fusion navigation for percutaneous needle insertion.

PURPOSE: Targeting accuracy determines outcomes for percutaneous needle interventions. Augmented reality (AR) in IR may improve procedural guidance and facilitate access to complex locations. This study aimed to evaluate percutaneous needle placement accuracy using a goggle-based AR system compared to an ultrasound (US)-based fusion navigation system. METHODS: Six interventional radiologists performed 24 independent needle placements in an anthropomorphic phantom (CIRS 057A) in four needle guidance cohorts (n = 6 each): (1) US-based fusion, (2) goggle-based AR with stereoscopically projected anatomy (AR-overlay), (3) goggle AR without the projection (AR-plain), and (4) CT-guided freehand. US-based fusion included US/CT registration with electromagnetic (EM) needle, transducer, and patient tracking. For AR-overlay, US, EM-tracked needle, stereoscopic anatomical structures and targets were superimposed over the phantom. Needle placement accuracy (distance from needle tip to target center), placement time (from skin puncture to final position), and procedure time (time to completion) were measured. RESULTS: Mean needle placement accuracy using US-based fusion, AR-overlay, AR-plain, and freehand was 4.5 ± 1.7 mm, 7.0 ± 4.7 mm, 4.7 ± 1.7 mm, and 9.2 ± 5.8 mm, respectively. AR-plain demonstrated comparable accuracy to US-based fusion (p = 0.7) and AR-overlay (p = 0.06). Excluding two outliers, AR-overlay accuracy became 5.9 ± 2.6 mm. US-based fusion had the highest mean placement time (44.3 ± 27.7 s) compared to all navigation cohorts (p < 0.001). Longest procedure times were recorded with AR-overlay (34 ± 10.2 min) compared to AR-plain (22.7 ± 8.6 min, p = 0.09), US-based fusion (19.5 ± 5.6 min, p = 0.02), and freehand (14.8 ± 1.6 min, p = 0.002). CONCLUSION: Goggle-based AR showed no difference in needle placement accuracy compared to the commercially available US-based fusion navigation platform. Differences in accuracy and procedure times were apparent with different display modes (with/without stereoscopic projections). The AR-based projection of the US and needle trajectory over the body may be a helpful tool to enhance visuospatial orientation. Thus, this study refines the potential role of AR for needle placements, which may serve as a catalyst for informed implementation of AR techniques in IR.

X-ray imageable, drug-loaded hydrogel that forms at body temperature for image-guided, needle- based locoregional drug delivery.

Liver cancer ranks as the fifth leading cause of cancer-related death globally. Direct intratumoral injections of anti-cancer therapeutics may improve therapeutic efficacy and mitigate adverse effects compared to intravenous injections. Some challenges of intratumoral injections are that the liquid drug formulation may not remain localized and have unpredictable volumetric distribution. Thus, drug delivery varies widely, highly-dependent upon technique. An x-ray imageable poloxamer 407 (POL)-based drug delivery gel was developed and characterized, enabling real-time feedback. Utilizing three needle devices, POL or a control iodinated contrast solution were injected into an ex vivo bovine liver. The 3D distribution was assessed with cone beam computed tomography (CBCT). The 3D distribution of POL gels demonstrated localized spherical morphologies regardless of the injection rate. In addition, the gel 3D conformal distribution could be intentionally altered, depending on the injection technique. When doxorubicin (DOX) was loaded into the POL and injected, DOX distribution on optical imaging matched iodine distribution on CBCT suggesting spatial alignment of DOX and iodine localization in tissue. The controllability and localized deposition of this formulation may ultimately reduce the dependence on operator technique, reduce systemic side effects, and facilitate reproducibility across treatments, through more predictable standardized delivery.

X-ray imageable, drug-loaded hydrogel that forms at body temperature for image-guided, needle-based locoregional drug delivery.

Liver cancer ranks as the fifth leading cause of cancer-related death globally. Direct intratumoral injections of anti-cancer therapeutics may improve therapeutic efficacy and mitigate adverse effects compared to intravenous injections. Some challenges of intratumoral injections are that the liquid drug formulation may not remain localized and have unpredictable volumetric distribution. Thus, drug delivery varies widely, highly-dependent upon technique. An X-ray imageable poloxamer 407 (POL)-based drug delivery gel was developed and characterized, enabling real-time feedback. Utilizing three needle devices, POL or a control iodinated contrast solution were injected into an ex vivo bovine liver. The 3D distribution was assessed with cone beam computed tomography (CBCT). The 3D distribution of POL gels demonstrated localized spherical morphologies regardless of the injection rate. In addition, the gel 3D conformal distribution could be intentionally altered, depending on the injection technique. When doxorubicin (DOX) was loaded into the POL and injected, DOX distribution on optical imaging matched iodine distribution on CBCT suggesting spatial alignment of DOX and iodine localization in tissue. The controllability and localized deposition of this formulation may ultimately reduce the dependence on operator technique, reduce systemic side effects, and facilitate reproducibility across treatments, through more predictable standardized delivery.

Ultrasound and x-ray imageable poloxamer-based hydrogel for loco-regional therapy delivery in the liver.

Intratumoral injections have the potential for enhanced cancer treatment efficacy while reducing costs and systemic exposure. However, intratumoral drug injections can result in substantial off-target leakage and are invisible under standard imaging modalities like ultrasound (US) and x-ray. A thermosensitive poloxamer-based gel for drug delivery was developed that is visible using x-ray imaging (computed tomography (CT), cone beam CT, fluoroscopy), as well as using US by means of integrating perfluorobutane-filled microbubbles (MBs). MBs content was optimized using tissue mimicking phantoms and ex vivo bovine livers. Gel formulations less than 1% MBs provided gel depositions that were clearly identifiable on US and distinguishable from tissue background and with minimal acoustic artifacts. The cross-sectional areas of gel depositions obtained with US and CT imaging were similar in studies using ex vivo bovine liver and postmortem in situ swine liver. The gel formulation enhanced multimodal image-guided navigation, enabling fusion of ultrasound and x-ray/CT imaging, which may enhance targeting, definition of spatial delivery, and overlap of tumor and gel. Although speculative, such a paradigm for intratumoral drug delivery might streamline clinical workflows, reduce radiation exposure by reliance on US, and boost the precision and accuracy of drug delivery targeting during procedures. Imageable gels may also provide enhanced temporal and spatial control of intratumoral conformal drug delivery.

Patient-specific needle guidance templates drilled intraprocedurally for image guided intervention: feasibility study in swine.

PURPOSE: Thermal ablation of large tumors may benefit from simultaneous placement of multiple needles, but accurate placement becomes challenging as the number of needles increases. The aim of this work was to evaluate use of personalized needle guidance grid templates based on intraprocedural CT and fabricated at the point of care to implement ablation treatment plans with multiple needles in vivo. METHODS: A plastic frame was designed to hold two parallel plastic guide plates in a rigid relationship, fixed over the abdomen by a mounting arm. Steel ball targets (1.5 mm) were implanted under ultrasound in the livers of two domestic swine under general anesthesia. Following breath-hold CT of the subject and frame, the targets and frame were identified using customized 3D Slicer-based planning software. Multiple needle trajectories targeting the balls were planned, including complex off-plane trajectories. A machining program for drilling the hole pattern corresponding to the planned needle trajectories was generated. The pattern was drilled in the two plates with a numerical-controlled milling machine in the suite. The plates were attached to the frame and needles passed through the paired holes to the calculated depth. Placement accuracy was defined as needle tip-to-target distance on post-placement CT. RESULTS: The planning process and manufacturing required approximately 6 and 15 min, respectively. Needles were rapidly inserted (n = 11) to the target points without complications or traversing nontarget anatomy. The mean needle tip-to-target distance error was 3.4 ± 2.2, range 0-7 mm. CONCLUSION: Rapid and accurate needle placement was feasible using a subject-specific, custom-drilled, needle guidance grid template fabricated intraprocedurally. Targeting accuracy and performance were similar to more complex and expensive tracking systems which may enable accurate intraprocedural implementation of treatment plans in the liver or other organs. This may be of value in complex ablation cases or in areas where more advanced guidance systems are not available.

Morphometric characterization and temporal temperature measurements during hepatic microwave ablation in swine.

PURPOSE: Heat-induced destruction of cancer cells via microwave ablation (MWA) is emerging as a viable treatment of primary and metastatic liver cancer. Prediction of the impacted zone where cell death occurs, especially in the presence of vasculature, is challenging but may be achieved via biophysical modeling. To advance and characterize thermal MWA for focal cancer treatment, an in vivo method and experimental dataset were created for assessment of biophysical models designed to dynamically predict ablation zone parameters, given the delivery device, power, location, and proximity to vessels. MATERIALS AND METHODS: MWA zone size, shape, and temperature were characterized and monitored in the absence of perfusion in ex vivo liver and a tissue-mimicking thermochromic phantom (TMTCP) at two power settings. Temperature was monitored over time using implanted thermocouples with their locations defined by CT. TMTCPs were used to identify the location of the ablation zone relative to the probe. In 6 swine, contrast-enhanced CTs were additionally acquired to visualize vasculature and absence of perfusion along with corresponding post-mortem gross pathology. RESULTS: Bench studies demonstrated average ablation zone sizes of 4.13±1.56cm2 and 8.51±3.92cm2, solidity of 0.96±0.06 and 0.99±0.01, ablations centered 3.75cm and 3.5cm proximal to the probe tip, and temperatures of 50 ºC at 14.5±13.4s and 2.5±2.1s for 40W and 90W ablations, respectively. In vivo imaging showed average volumes of 9.8±4.8cm3 and 33.2±28.4cm3 and 3D solidity of 0.87±0.02 and 0.75±0.15, and gross pathology showed a hemorrhagic halo area of 3.1±1.2cm2 and 9.1±3.0cm2 for 40W and 90W ablations, respectfully. Temperatures reached 50ºC at 19.5±9.2s and 13.0±8.3s for 40W and 90W ablations, respectively. CONCLUSION: MWA results are challenging to predict and are more variable than manufacturer-provided and bench predictions due to vascular stasis, heat-induced tissue changes, and probe operating conditions. Accurate prediction of MWA zones and temperature in vivo requires comprehensive thermal validation sets.

Imaging and Pathologic Evaluation of Cryoablation of Woodchuck (Marmota monax) Hepatocellular Carcinoma.

We characterized cryoablation as a mode of clinical intervention in adult woodchucks with hepatocellular carcinoma (HCC). Woodchucks (n = 4) were infected with woodchuck hepatitis virus at birth and developed LI-RADS-5 hypervascular HCC. At 21 mo of age, they underwent ultrasound (US), contrast-enhanced CT (CECT) imaging, and US-guided subtotal cryoablation (IcePearl 2.1 CX, Galil, BTG) of their largest tumor (Mean HCC volume of 49 ± 9 cm³). Cryoablation was performed using two 10-min freeze cycles, each followed by an 8-min thaw cycle. The first woodchuck developed significant hemorrhage after the procedure and was euthanized. In the other 3 woodchucks, the probe track was cauterized and all 3 completed the study. Fourteen days after ablation, CECT was performed, and woodchucks were euthanized. Explanted tumors were sectioned using subject-specific, 3D-printed cutting molds. Initial tumor volume, the size of the cryoablation ice ball, gross pathology and hematoxylin and eosin-stained tissue sections were evaluated. On US, the edges of the solid ice balls were echogenic with dense acoustic shadowing and average dimensions of 3.1 ± 0.5 × 2.1 ± 0.4 cm and cross-sectional area of 4.7 ± 1.0 cm². On day 14 after cryoablation, CECT of the 3 woodchucks showed devascularized hypo-attenuating cryolesions with dimensions of 2.8 ± 0.3 × 2.6 ± 0.4 × 2.93 ± 0.7 cm and a cross sectional area of 5.8 ± 1.2 cm². Histopathologic evaluation showed hemorrhagic necrosis with a central amorphous region of coagulative necrosis surrounded by a rim of karyorrhectic debris. A rim of approximately 2.5 mm of coagulative necrosis and fibrous connective tissue clearly demarcated the cryolesion from adjacent HCC. Partial cryoablation of tumors produced coagulative necrosis with well-defined ablation margins at 14 d. Cauterization appeared to prevent hemorrhage after cryoablation of hypervascular tumors. Our findings indicate that woodchucks with HCC may provide a predictive preclinical model for investigating ablative modalities and developing new combination therapies.

Immune Effects of Cryoablation in Woodchuck Hepatocellular Carcinoma.

Objectives: Local and systemic immune responses evoked by locoregional therapies such as cryoablation are incompletely understood. The aim of this study was to characterize cryoablation-related immune response and the capacity of immune drugs to augment immunity upon cryoablation for the treatment of hepatocellular carcinoma (HCC) using a woodchuck hepatocellular carcinoma model. Materials and Methods: Twelve woodchucks chronically infected with woodchuck hepatitis virus and with hepatocellular carcinoma underwent imaging with contrast-enhanced CT. Partial cryoablation of tumors in three woodchucks was performed. Fourteen days after cryoablation, liver tissues were harvested and stained with H&E and TUNEL, and immune infiltrates were quantified. Peripheral blood mononuclear cells (PBMC) were collected from ablated and nonablated woodchucks, labeled with carboxyfluorescein succinimidyl ester (CFSE) and cultured with immune-modulating drugs, including a small PD-L1 antagonist molecule (BMS-202) and three TLR7/8 agonists (DSR 6434, GS-9620, gardiquimod). After incubation, cell replication and immune cell populations were analyzed by flow cytometry. Results: Local immune response in tumors was characterized by an increased number of CD3+ T lymphocytes and natural killer cells in the cryolesion margin compared to other tumor regions. T regulatory cells were found in higher numbers in distant tumors within the liver compared to untreated or control tumors. Cryoablation also augmented the systemic immune response as demonstrated by higher numbers of PBMC responses upon immune drug stimulation in the cryoablation group. Conclusions: Partial cryoablation augmented immune effects in both treated and remote untreated tumor microenvironments, as well as systemically, in woodchucks with HCC. Characterization of these mechanisms may enhance development of novel drug-device combinations for treatment of HCC.

Pulsed high-intensity-focused US and tissue plasminogen activator (TPA) versus TPA alone for thrombolysis of occluded bypass graft in swine.

PURPOSE: Prosthetic arteriovenous or arterial-arterial bypass grafts can thrombose and be resistant to revascularization. A thrombosed bypass graft model was created to evaluate the potential therapeutic enhancement and safety profile of pulsed high-intensity-focused ultrasound (pHIFU) on pharmaceutical thrombolysis. MATERIALS AND METHODS: In swine, a right carotid-carotid expanded polytetrafluoroethylene bypass graft was surgically constructed, containing a 40% stenosis at its distal end to induce graft thrombosis. The revascularization procedure was performed 7 days after surgery. After model development and dose response experiments (n = 11), two cohorts were studied: pHIFU with tissue plasminogen activator (TPA; n = 4) and sham pHIFU with TPA (n = 3). The experiments were identical in both groups except no energy was delivered in the sham pHIFU group. Serial angiograms were obtained in all cases. The area of graft opacified by contrast medium on angiograms was quantified with digital image processing software. A blinded reviewer calculated the change in the graft area opacified by contrast medium and expressed it as a percentage, representing percentage of thrombolysis. RESULTS: Combining pHIFU with 0.5 mg of TPA resulted in a 52% ± 4% increase in thrombolysis on angiograms obtained at 30 minutes, compared with a 9% ± 14% increase with sham pHIFU and 0.5 mg TPA (P = .003). Histopathologic examination demonstrated no differences between the groups. CONCLUSIONS: Thrombolysis of occluded bypass grafts was significantly increased when combining pHIFU and TPA versus sham pHIFU and TPA. These results suggest that application of pHIFU may augment thrombolysis with a reduced time and dose.

Radiopaque drug-eluting beads for transcatheter embolotherapy: experimental study of drug penetration and coverage in swine.

PURPOSE: To determine local doxorubicin levels surrounding radiopaque drug-eluting beads (DEBs) in normal swine liver and kidney following transcatheter arterial chemoembolization. The influence of bead size (70-150 µm or 100-300 µm) was compared with regard to tissue penetration and spatial distribution of the bead, as well as eventual drug coverage (ie, amount of tissue exposed to drug). MATERIALS AND METHODS: Radiopaque DEBs were synthesized by suspension polymerization followed by incorporation of iodized oil and doxorubicin. Chemoembolization of swine liver and kidney was performed under fluoroscopic guidance. Three-dimensional tissue penetration of "imageable" DEBs was investigated ex vivo with micro-computed tomography (microCT). Drug penetration from the bead surface and drug coverage was evaluated with epifluorescence microscopy, and cellular localization of doxorubicin was evaluated with confocal microscopy. Necrosis was evaluated with hematoxylin and eosin staining. RESULTS: MicroCT demonstrated that 70-150-µm DEBs were present in more distal arteries and located in a more frequent and homogeneous spatial distribution. Tissue penetration of doxorubicin from the bead appeared similar (∼300 µm) for both DEBs, with a maximum tissue drug concentration at 1 hour coinciding with nuclear localization of doxorubicin. The greater spatial frequency of the 70-150-µm DEBs resulted in approximately twofold improved drug coverage in kidney. Cellular death is predominantly observed around the DEBs beginning at 8 hours, but increased at 24 and 168 hours. CONCLUSIONS: Smaller DEBs penetrated further into targeted tissue (ie, macroscopic) with a higher spatial density, resulting in greater and more uniform drug coverage (ie, microscopic) in swine.