Radiopaque Microspheres Research Articles

Fusible and Radiopaque Microspheres for Embolization.

In this work, fusible microspheres loaded with radiopaque agents as an embolic agent for transcatheter arterial embolization (TAE) are developed. A poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) multi-block copolymer basing polyurethane (PCEU) is synthesized and fabricated into blank microspheres (BMs). The microspheres are elastic in compression test. A clinical contrast agent lipiodol is encapsulated in the microspheres to receive fusible radiopaque microspheres (FRMs). The sizes of FRMs are uniform and range from 142.2 to 343.1µm. The encapsulated lipiodol acts as the plasticizer to reduce the melting temperature point (Tm) of PECU microspheres, thus, leading to the fusion of microspheres to exhibit efficient embolization in vivo. The performance of FRMs is carried out on a rabbit ear embolization model. Serious ischemic necrosis is observed and the radiopacity of FRMs sustains much longer time than that of commercial contrast agent Loversol in vivo. The fusible and radiopaque microsphere is promising to be developed as an exciting embolic agent.

Changes in Microwave Ablation Zone Dimensions after Transarterial Embolization in an Ex Vivo Human Kidney Perfusion Model

PurposeTo utilize a novel ex vivo perfused human renal model and quantify microwave ablation (MWA) size differences in renal tissue when combining MWA with transarterial embolization (TAE). Materials and MethodsHuman kidneys (n = 5) declined for transplantation were obtained and connected to a fluoroscopy-compatible ex vivo perfusion system. Two ablations—1 standard MWA and 1 TAE-MWA—were performed in each kidney for 2 minutes at 100 W using a MWA system (Solero Angiodynamics). MWA alone was performed in the upper pole. In the lower pole, MWA was performed after TAE with 40–90 μm radiopaque microspheres to achieve angiographic stasis. Ablation zones of coagulative necrosis were sectioned along the long axis and segmented for maximal short-axis diameter (SAD) and long-axis diameter (LAD) measurements. ResultsA total of 10 ablations (5 MWAs and 5 TAE-MWAs) were performed in 5 human kidneys. TAE-MWA resulted in significantly increased SAD, LAD, volume, and sphericity compared with standard MWA ± SD, with mean measurements as follows (5 standard MWAs ± SD vs 5 TAE-MWAs ± SD, 2-tailed t-test): (a) SAD, 1.8 cm (SD ± 0.1) versus 2.5 cm (SD ± 0.1) (P < .001); (b) LAD, 2.9 cm (SD ± 0.3) versus 3.2 cm (SD ± 0.1) (P = .039); (c) volume, 5.0 mL (SD ± 0.5) versus 11.0 mL (SD ± 0.7) (P < .001); and (d) sphericity, 0.4 (SD ± 0.2) versus 0.6 (SD ± 0.1) (P = .049). Histology demonstrated no differences in TAE-MWA other than concentrated microspheres. ConclusionsThis ex vivo human kidney perfusion model confirmed that combined MWA-TAE significantly increased ablation size and spherical shape compared with MWA alone.

Balancing Safety and Efficacy to Determine the Most Suitable Size of Imaging-Visible Embolic Microspheres for Bariatric Arterial Embolization in a Preclinical Model

ObjectivesTo identify the most suitable size of imaging-visible embolic agents with balanced safety and efficacy for bariatric arterial embolization (BAE) in a preclinical model. Materials and MethodsTwenty-seven pigs were divided into 3 cohorts. In Cohort I, 16 pigs were randomized to receive (n = 4 each) 40–100-μm microspheres in 1 or 2 fundal arteries, 70–340-μm radiopaque microspheres in 2 fundal arteries, or saline. In Cohort II, 3 pigs underwent renal arterial embolization with either custom-made 100–200-μm, 200–250-μm, 200–300-μm, or 300–400-μm radiopaque microspheres or Bead Block 300–500 μm with microsphere distribution assessed histologically. In Cohort III, 8 pigs underwent BAE in 2 fundal arteries with tailored 100–200-μm radiopaque microspheres (n = 5) or saline (n = 3). ResultsIn Cohort I, no significant differences in weight or ghrelin expression were observed between BAE and control animals. Moderate-to-severe gastric ulcerations were noted in all BAE animals. In Cohort II, renal embolization with 100–200-μm microspheres occluded vessels with a mean diameter of 139 μm ± 31, which is within the lower range of actual diameters of Bead Block 300–500 μm. In Cohort III, BAE with 100–200-μm microspheres resulted in significantly lower weight gain (42.3% ± 5.7% vs 51.6% ± 2.9% at 8 weeks; P = .04), fundal ghrelin cell density (16.1 ± 6.7 vs 23.6 ± 12.6; P = .045), and plasma ghrelin levels (1,709 pg/mL ± 172 vs 4,343 pg/mL ± 1,555; P < .01) compared with controls and superficial gastric ulcers (5/5). ConclusionsIn this preclinical model, tailored 100–200-μm microspheres were shown to be most suitable for BAE in terms of safety and efficacy.

Abstract No. 133 Fabrication and Characterization of Highly Radiopaque Microspheres for Prostate Cancer Chemoembolization

The purpose of this study was to develop and characterize embolic microspheres that are highly radiopaque, such that they could be used for prostate cancer chemo-embolization. The goals are that the spheres can be visualized during injection on fluoroscopic imaging without additional contrast media (with reasonable injection force), and that they can be imaged (with C-arm CT or MSCT) within the prostate and other non-target organs, both during and after the procedure. Finally, these spheres should be loadable with long-release chemotherapeutic agents. A process was developed to manufacture polyethylene glycol (PEG) microspheres where one of two radiopaque agents were added during the manufacturing process. The process was based on droplet generation microfluidics using an olive oil base. The first type had 1 um barium sulfate particles added at 40% wbv. The second type had 100 nm zirconium oxide particles added at 50% wbv. After curing, particles were washed to remove the olive oil. Sphere diameter was measured using light microscopy. The spheres' radiopacity were evaluated individually using microCT, and in aggregate, within a 3D printed vascular phantom, using MSCT. Injection force from a syringe was measured. Finally, the spheres were imaged with x-ray fluoroscopy during injection, using a body-sized, water-filled, vascular phantom. The barium and zirconium spheres measured 111 ± 14 um and 73 ± 18 um respectively. MicroCT measurements of individual sphere radiopacity were 6772 ± 501 HU and 13,486 ± 638 HU. MSCT radiopacity values in a 0.5 mm vessel were 264 HU and 226 HU. The measured injection force from a 3-cc syringe was 20 N, compared with 25 N for commercial microspheres with 50% contrast agent. The detectability on the microspheres on fluoroscopy was very similar to that of commercial microspheres with 50% contrast agent, approximately a 30 pixel-value enhancement over the background value. This project demonstrated the ability to produce highly radiopaque microspheres that have reasonable injection force and are visible both during injection using fluoroscopy, without additional contrast agent, and using MSCT. The HU values in MSCT are lower that microCT due to the lower tube voltage in microCT and also due to the limited spatial resolution (partial volume effect) of MSCT, but these small vessels are nevertheless visible within a 0-100 HU prostate gland. Further work is underway to evaluate drug elution characteristics.

Safety, Efficacy and Distribution of Doxorubicin Loaded Radiopaque Beads in Chemoembolization in Intermediate Stage Hepatocellular Carcinoma (HCC) with Correlation with Local Response.

The primary objectives of this study were to evaluate safety, and efficacy of Transarterial Chemoembolization (TACE) using doxorubicin-loaded radiopaque microspheres (DC Bead LUMI™) for the treatment of early and intermediate stage Hepatocellular Carcinoma (HCC) not amenable for curative treatments. Distribution of the microspheres was correlated with results post embolization. This was a prospective, single arm, open label study. The primary outcome measures were distribution of the radiopaque microspheres as showed by computerized tomography (CT) and local response measured by modified Response Evaluation Criteria (mRECIST) after Magnetic Resonance Imaging (MRI). Secondary measures were Time to Progression (TTP) and Overall Survival (OS). Fifty patients were enrolled over 36months. Median age was 69.0years; mean sum of target lesions diameters was 78.6 ± 36.8mm. There were no Grade 4 or 5 adverse events (AEs). At 6months Complete Response (CR) (18%), Partial Response (PR) (62%), Objective Response OR (80%) and Stable Disease (SD) (20%) were recorded. Before embolization, Diffusion Weighted Imaging (DWI) showed high signal (restricted diffusion). Post procedure, patients with dense deposition (< 5mm distance of microsphere aggregations) showed 100% absence of enhancement and no restriction in 30.6%. Median TTP was 8.3months. TTP for patients with CR was 13.3months and 7.2 and 5.6 for PR and SD, respectively. At 6 and 36months, survival was 94% and 34%, respectively. DC Bead LUMI™ is well tolerated and effective in early and intermediate stage HCC with maximal necrosis obtained in dense deposition in the target.

Microfluidic Fabrication and Characterization of Radiopaque Barium Sulfate Polyethylene Glycol‐Based Hydrogel Microspheres

The objective of this study was to fabricate and characterize monodisperse polyethylene glycol (PEG)‐based barium sulfate hydrogel microspheres for applications in prostatic hyperplasia and prostate cancer treatments. Currently, catheter embolization procedures used in prostatic hyperplasia treatments employ non‐opaque microspheres with a tracer dye, which can result in off‐target embolization. The goal of this study was to fabricate monodisperse, radiopaque microspheres that can be easily tracked via microcomputed tomography (microCT) during embolization procedures. The hydrogel microspheres were fabricated using 4‐arm PEG‐Acrylate macromer and PEG‐dithiol crosslinker solutions in a custom‐designed microfluidic chip that allowed for on‐chip mixing and gelation of a timed‐gelation system, greatly improving bead fabrication throughput and reproducibility. Microspheres were loaded with 1 μm barium sulfate particles and bovine serum albumin to aid in barium suspension. Microspheres were imaged both before and after washing with buffer using an inverted microscope to measure microsphere diameter and degradation. Settling of barium sulfate solutions was measured qualitatively in microcentrifuge tubes. Monodisperse, barium sulfate loaded‐hydrogel microspheres were produced, the size of which could be controlled by modulating the inlet flow rates of the dispersed and continuous phases. Furthermore, the results show that the opacity of the barium sulfate microspheres increased with increased barium sulfate concentration. In conclusion, the results indicate that this study successfully fabricated monodisperse and opaque barium sulfate PEG‐based hydrogel microspheres. Future experiments will evaluate the radiopacity under microCT, swelling and degradation properties, and injectability of the hydrogel microspheres to help further confirm the application of these microspheres in catheter embolization procedures.

Precision dosimetry in yttrium-90 radioembolization through CT imaging of radiopaque microspheres in a rabbit liver model

PurposeTo perform precision dosimetry in yttrium-90 radioembolization through CT imaging of radiopaque microspheres in a rabbit liver model and to compare extracted dose metrics to those produced from conventional PET-based dosimetry.Materials and methodsA CT calibration phantom was designed containing posts with nominal microsphere concentrations of 0.5 mg/mL, 5.0 mg/mL, and 25.0 mg/mL. The mean Hounsfield unit was extracted from the post volumes to generate a calibration curve to relate Hounsfield units to microsphere concentration. A nominal bolus of 40 mg of microspheres was administered to the livers of eight rabbits, followed by PET/CT imaging. A CT-based activity distribution was calculated through the application of the calibration curve to the CT liver volume. Post-treatment dosimetry was performed through the convolution of yttrium-90 dose-voxel kernels and the PET- and CT-based cumulated activity distributions. The mean dose to the liver in PET- and CT-based dose distributions was compared through linear regression, ANOVA, and Bland–Altman analysis.ResultsA linear least-squares fit to the average Hounsfield unit and microsphere concentration data from the calibration phantom confirmed a strong correlation (r2 > 0.999) with a slope of 14.13 HU/mg/mL. A poor correlation was found between the mean dose derived from CT and PET (r2 = 0.374), while the ANOVA analysis revealed statistically significant differences (p < 10−12) between the MIRD-derived mean dose and the PET- and CT-derived mean dose. Bland–Altman analysis predicted an offset of 15.0 Gy between the mean dose in CT and PET. The dose within the liver was shown to be more heterogeneous in CT than in PET with an average coefficient of variation equal to 1.99 and 1.02, respectively.ConclusionThe benefits of a CT-based approach to post-treatment dosimetry in yttrium-90 radioembolization include improved visualization of the dose distribution, reduced partial volume effects, a better representation of dose heterogeneity, and the mitigation of respiratory motion effects. Post-treatment CT imaging of radiopaque microspheres in yttrium-90 radioembolization provides the means to perform precision dosimetry and extract accurate dose metrics used to refine the understanding of the dose–response relationship, which could ultimately improve future patient outcomes.

Microfluidic fabrication of imageable and resorbable polyethylene glycol microspheres for catheter embolization.

Radiopaque and degradable hydrogel microspheres have a range of potential uses in medicine including proper placement of embolic material during occlusion procedures, acting as inherently embolic materials, and serving as drug carriers that can be located after injection. Current methods for creating radiopaque microspheres are either unable to fully and homogeneously incorporate radiopaque material throughout the microspheres for optimal imaging capabilities, do not result in degradable or fully compressible microspheres, or require elaborate, time-consuming preparation. We used a simple one-step microfluidic method to fabricate imageable, degradable polyethylene glycol (PEG) microspheres of varying sizes with homogenous dispersion of barium sulfate-a biocompatible, high-radiopacity contrast agent. The imageability of the microspheres was characterized using optical microscopy and microcomputed tomography as a function of barium sulfate loading. Microspheres with 20%wt/vol barium sulfate had a mean CT attenuation value of 1,510 HU, similar to that of cortical bone, which should enable visualization with soft tissue. Compared with unloaded microspheres, barium sulfate-loaded ones saw an increase in gelation and degradation times and storage modulus and decrease in swelling. Imageable microspheres retained compressibility and were injectable via catheter. The developed radiopaque, degradable PEG microspheres have various potential uses for interventional radiologists and imaging laboratories.

Abstract No. 49 Bariatric arterial embolization with radiopaque microspheres: the effect of embolic size and embolization coverage on the outcome

To evaluate the embolization effect of calibrated radiopaque microspheres on the safety and efficacy of bariatric arterial embolization (BAE) Twenty-four healthy growing swine were recruited in two cohorts. In the first cohort, 16 animals were randomized to receive either 40-90 μm-sized radiopaque microspheres in the left gastroepiploic artery (LGEA, n = 4), or in the right gastric artery (RGA) and LGEA (n = 4), or 100-300 μm-sized microspheres in the LGEA and RGA (n = 4), or saline (n = 4). In the second cohort, eight animals underwent BAE with tightly calibrated 100-200 μm radiopaque microspheres (n = 5) or saline (n = 3) in the LGEA and RGA. Animal weight and serum hormones were measured at baseline and weekly after BAE for up to 8 weeks. Cone-beam CT (CBCT) images of the stomachs were acquired immediately and at 8 weeks after embolization to assess the embolization coverage of the fundus and the persistence of the microspheres. Endoscopy of the stomach was performed at 1-2 weeks after BAE to examine mucosal integrity. Ghrelin-expressing cell densities were assessed by immunohistochemistry staining and analyzed using the Wilcoxon rank sum test. Plasma ghrelin levels were assessed using a radioimmunoassay. Radiopaque microspheres were visible both on fluoroscopy and CBCT images irrespective of the microsphere sizes. BAE with 40-90 μm and 100-300 μm microspheres resulted in severe gastric ulceration in embolized animals and no significant weight changes compared to controls. In contrast, BAE with 100-200 μm-sized microspheres induced mild gastric ulcerations and a significant reduction of weight gain relative to controls (42.3% ± 5.7 BAE vs 51.6% ± 2.9 controls at 8 weeks, P = 0.04). This weight reduction was correlated to greater fundal embolization coverage. Both fundal ghrelin-expressing cell densities (16.1 ± 6.7 BAE vs 23.6 ± 12.6 control, P = 0.045) and plasma ghrelin levels of (1709 ± 172 BAE vs 4343 ± 1555 controls, P < 0.01) BAE-treated animals were significantly lower than those of controls at 8 weeks. Radiopaque microspheres enable direct visualization of embolic material during and after embolization. The size and fundal embolization coverage of the microspheres affect the outcome of BAE. The calibrated 100-200 μm radiopaque microspheres appear to be safe and effective for weight management via BAE.

Post-administration dosimetry in yttrium-90 radioembolization through micro-CT imaging of radiopaque microspheres in a porcine renal model

The purpose of this study is to perform post-administration dosimetry in yttrium-90 radioembolization through micro-CT imaging of radiopaque microsphere distributions in a porcine renal model and explore the impact of spatial resolution of an imaging system on the extraction of specific dose metrics. Following the administration of radiopaque microspheres to the kidney of a hybrid farm pig, the kidney was explanted and imaged with micro-CT. To produce an activity distribution, 400 MBq of yttrium-90 activity was distributed throughout segmented voxels of the embolized vasculature based on an established linear relationship between microsphere concentration and CT voxel value. This distribution was down-sampled to coarser isotropic grids ranging in voxel size from 2.5 to 15 mm to emulate nominal resolutions comparable to those found in yttrium-90 PET and Bremsstrahlung SPECT imaging. Dose distributions were calculated through the convolution of activity distributions with dose-voxel kernels generated using the GATE Monte Carlo toolkit. Contours were computed to represent normal tissue and target volumes. Dose-volume histograms, dose metrics, and dose profiles were compared to a ground truth dose distribution computed with GATE. The mean dose to the target for all studied voxel sizes was found to be within 5.7% of the ground truth mean dose. was shown to be strongly correlated with image voxel size of the dose distribution (r 2 = 0.90). is cited in the literature as an important dose metric and its dependence on voxel size suggests higher resolution dose distributions may provide new perspectives on dose-response relationships in yttrium-90 radioembolization. This study demonstrates that dose distributions with large voxels incorrectly homogenize the dose by attributing escalated doses to normal tissues and reduced doses in high-dose target regions. High-resolution micro-CT imaging of radiopaque microsphere distributions can provide increased confidence in characterizing the absorbed dose heterogeneity in yttrium-90 radioembolization.

Characterization of velocity patterns produced by pulsatile and constant flows using 1000 fps high-speed angiography (HSA).

In order to accurately quantify rapidly changing blood flow velocities, as typically seen in the neurovasculature, high temporal resolution is necessary. Current methods to extract velocity data from angiographic image sequences are generally limited to 30 fps or less. High-speed angiography (HSA) with a maximal frame rate of 1000 fps can be used to evaluate time-dependent flow details normally averaged out with lower frame rates. For new HSA image sequences, two different quantitative methods were utilized to extract high-temporal resolution velocity changes: X-Ray Particle Image Velocimetry (X-PIV) and optical flow (OF). A variety of flow conditions were examined in a range of patient-specific 3D-printed phantoms. Both pulsatile and constant flow settings were investigated. X-PIV was performed using radiopaque sub-millimeter microspheres, which were tracked throughout the image sequence to provide accurate, but limited sampling of the velocity field within the 3D-printed models. Also, an open source optical flow algorithm, OpenOpticalFlow, was used to perform velocity estimation based on the spatio-temporal intensity changes of iodinated contrast wavefronts. Periodic changes in velocity within each phantom ROI can be illustrated throughout the pulsatile cycle capture by the high-speed detector. In the constant flow sequences, changes in velocity across the phantom geometry can be seen. The ability to accurately measure detailed velocity distributions and velocity changes throughout various flow conditions at high temporal resolution enables further insight into the evaluation and treatment of neurovascular disease states.

Safety and effectiveness of new embolization microspheres SCBRM for intermediate-stage hepatocellular carcinoma: A feasibility study.

Transarterial chemoembolization (TACE) is, currently, the recommended treatment for hepatocellular carcinoma (HCC). However, long-term chemoembolization triggers the inflammatory response and may lead to postembolization syndrome (PES). Although several types of degradable microspheres have been developed to reduce drug toxicity and PES incidence, the clinical outcomes remain unsatisfactory. Previously, we have developed a new type of spherical, calibrated, biodegradable, radiopaque microspheres (SCBRM) and demonstrated their safety and efficacy in a pig model. Thus, the goal of this feasibility study was to determine the clinical safety and efficacy of the new SCBRM in intermediate-stage HCC patients. In this study, 12 intermediate-stage HCC patients underwent TACE using SCBRM with a calibrated size of 100–250 μm. The disease control rates at 1 month and 3 months after TACE-SCBRM treatment were 100% and 75.0%, respectively. The objective response rates at 1 month and 3 months after treatment were 66.7% and 58.3%, respectively. Very few adverse events were observed with one patient developing nausea. One day after the treatment, alanine aminotransferase, alanine aminotransferase, and total bilirubin levels were slightly elevated in the patients, but all returned to baseline on day 7. The median and mean overall survival times were 33 months (interquartile range, 12.8–42.0) and 29.2 ± 14.3 months, respectively. The 1-year and 2-year survival rates were 91.7% and 58.3%, respectively. In conclusion, TACE with the new SCBRM microspheres is clinically safe and effective, and it represents a promising approach in the management of intermediate-stage HCC.

Safety and Tolerability of Topotecan-Eluting Radiopaque Microspheres for Hepatic Chemoembolization in a Rabbit Preclinical Model.

Topotecan is a camptothecin analogue with potential advantages over irinotecan for transarterial chemoembolization (TACE) of hepatic colorectal metastases including greater anti-neoplastic activity without enzymatic activation. The purpose of this study was to assess safety and tolerability of topotecan-loaded radiopaque microspheres (ROMTOP) administered by TACE in a rabbit model and to compare the in vitro elution of topotecan from microspheres to irinotecan. Topotecan was loaded into radiopaque microspheres (70-150µm, DC Bead LUMI™, Biocompatibles UK Ltd-Boston Scientific Corporation) to the maximum capacity of 80mg/mL of microspheres. Six healthy New Zealand White rabbits underwent hepatic TACE with ROMTOP under fluoroscopic guidance until angiographic stasis. Assessment of toxicities included regular liver function tests and complete blood counts until euthanasia 28days post-TACE. In vitro topotecan elution from the microspheres was assessed using an open-loop flow-through system and compared to irinotecan. The mean bead volume and topotecan dose delivered were 0.086mL (0.076-0.105mL) and 1.99mg/kg (1.51-2.55mg/kg), respectively. Aspartate aminotransferase and alanine aminotransferase were elevated post-embolization but resolved within 2 weeks. One rabbit died two days after TACE with pyloric duodenal perforation observed at necropsy, potentially due to non-target embolization. In vitro elution of topotecan from ROMTOP was complete in 10h compared to 3h for irinotecan-loaded microspheres. Selective embolization with ROMTOP was tolerated at a dose of 2mg/kg (24mg/m2) in rabbits. In vitro topotecan elution from microspheres was more prolonged compared to irinotecan.

Bariatric Arterial Embolization with Calibrated Radiopaque Microspheres and an Antireflux Catheter Suppresses Weight Gain and Appetite-Stimulating Hormones in Swine

PurposeTo examine safety and efficacy of bariatric arterial embolization (BAE) with x-ray–visible embolic microspheres (XEMs) and an antireflux catheter in swine. Material and MethodsBAE with selective infusion of XEMs (n = 6) or saline (n = 4, control) into gastric fundal arteries was performed under x-ray guidance. Weight and plasma hormone levels were measured at baseline and weekly for 4 weeks after embolization. Cone-beam CT images were acquired immediately after embolization and weekly for 4 weeks. Hormone-expressing cells in the stomach were assessed by immunohistochemical staining. ResultsBAE pigs lost weight 1 week after embolization followed by significantly impaired weight gain relative to control animals (14.3% vs 20.9% at 4 weeks, P = .03). Plasma ghrelin levels were significantly lower in BAE pigs than in control animals (1,221.6 pg/mL vs 1,706.2 pg/mL at 4 weeks, P < .01). XEMs were visible on x-ray and cone-beam CT during embolization, and radiopacity persisted over 4 weeks (165.5 HU at week 1 vs 158.5 HU at week 4, P = .9). Superficial mucosal ulcerations were noted in 1 of 6 BAE animals. Ghrelin-expressing cell counts were significantly lower in the gastric fundus (17.7 vs 36.8, P < .00001) and antrum (24.2 vs 46.3, P < .0001) of BAE pigs compared with control animals. Gastrin-expressing cell counts were markedly reduced in BAE pigs relative to control animals (98.5 vs 127.0, P < .02). Trichrome staining demonstrated significantly more fibrosis in BAE animals compared with control animals (13.8% vs 8.7%, P < .0001). ConclusionsXEMs enabled direct visualization of embolic material during and after embolization. BAE with XEMs and antireflux microcatheters was safe and effective.

Use of 70- to 150-μm Radiopaque Spherical Embolics for Prostatic Artery Embolization

This retrospective report describes treatment of 21 patients who underwent prostatic artery embolization using 70- to 150-μm radiopaque microspheres for lower urinary tract symptoms secondary to benign prostatic hyperplasia. Seventeen patients (81%) received successful bilateral prostatic artery embolization. At a mean follow-up of 42 days (range, 25–59 days), patients showed improvement in International Prostate Symptom Score (n = 11; mean = 10.6; P = .001), quality of life score (n = 17; mean = 2.0; P = .02), and International Index of Erectile Function (n = 17; mean = 9.3; P = .01). The mean prostate volume reduction was 28 mL (16.2%; P = .003). Nontarget embolization occurred twice, resulting in 1 minor adverse event of hematospermia.

Transarterial Chemoembolization of HCC with Radiopaque Microspheres: Evaluation with Computed Tomography and the Complementary Role of Contrast-Enhanced Ultrasonography

To assess the diagnostic performance of computed tomography (CT), and of the combination of CT with contrast-enhanced ultrasonography (CT + CEUS), for the early evaluation of local response of hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) with radiopaque drug-eluting microspheres (RO-DEMs). 30 HCC patients (55 target tumors) were treated with TACE with RO-DEMs (diameter: 70-150μm) preloaded with 75mg doxorubicin/2ml of microspheres. Unenhanced and contrast-enhanced CT, followed by CEUS, were performed 1-3days post-RO-DEMs-TACE. Contrast-enhanced magnetic resonance (MR) performed 1month later served as the reference standard. Local tumor response was evaluated with modified Response Evaluation Criteria in Solid Tumors (mRECIST). MR diagnosed 9 tumors with complete response and 46 with residual disease. Compared to MR, CT had 9 false negative and 1 false positive diagnosis for residual tumor. Potential causes for these misdiagnoses were the hyperdensities and associated artifacts (caused by the accumulation of RO-DEMs in the target tumors) and the small size of residual tumor. CT + CEUS had 3 false negative and no false positive diagnosis for residual tumor. The sensitivity, specificity and diagnostic accuracy of CT for detection of residual tumor were, respectively: 80.4%, 88.9% and 81.8%, and for CT + CEUS: 93.5%, 100% and 94.5%, respectively. Agreement (kappa coefficient) in application of mRECIST between MR and CT was lower than between MR and CT + CEUS (0.508 vs. 0.757). CT evaluation of TACE with RO-DEMs is associated with limitations which can be partially overcome by combining CT with CEUS.

Transarterial Chemoembolization in a Woodchuck Model of Hepatocellular Carcinoma

PurposeTo assess the feasibility of transarterial chemoembolization with drug-eluting embolic (DEE) microspheres in a woodchuck model of hepatocellular carcinoma (HCC). Materials and MethodsNine 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. ResultsThe 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. ConclusionsWoodchuck 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.

Abstract No. 688 Bariatric arterial embolization with radiopaque microspheres suppresses ghrelin expression and weight gain in swine

To evaluate the embolization effect of calibrated radiopaque microspheres on ghrelin production and weight change in a swine model. Eight healthy growing swine (∼23 kg) were randomized to receive either bariatric artery embolization (BAE) with 100-200 μm radiopaque microspheres (Boston Scientific) (n = 5) or saline (n = 3) in the left gastroepiploic artery and right gastric artery under x-ray guidance. Weight and fasting blood samples were obtained at baseline and weekly for 8 weeks. Cone beam CT (CBCT) images of the stomachs were acquired immediately after embolization, at 8 weeks prior to sacrifice and postmortem to examine the imaging visibility and persistence of the embolic microspheres. Biopsies of the fundus were taken during endoscopic examination at ∼1 week after embolization. Ulcers were scored from 0 to 3. Plasma ghrelin levels were assessed using a radioimmunoassay. The ghrelin-expressing cell densities in the stomach were assessed by immunohistochemical staining and analyzed using the Wilcoxon rank sum test. Radiopaque microspheres were visible on x-ray and CBCT during the procedure and the radiopacity persisted for 8 weeks after BAE. BAE pigs showed a significant reduction of the percentage of weight gain relative to controls (42.3% ± 5.7 vs. 51.6% ± 2.9, P = 0.04). The ghrelin-expressing cell densities of fundal biopsies were similar between embolized animals and controls. Yet, both fundal ghrelin-expressing cell densities (16.1 ± 6.7 vs. 23.6 ± 12.6, P = 0.04) and plasma ghrelin levels (1709 ± 172 vs. 4343 ± 1555, P <0.01) of embolized animals were significantly lower than those of controls at week 8. All BAE animals developed superficial ulcers (score 1: n = 4, score 2: n = 2) that healed by week 8 after embolization. Radiopaque microspheres enabled direct visualization of embolics delivery and deposition during and post embolization procedure. The suppression of fundal and systemic plasma ghrelin levels as well as the percentage of weight gain in combination with mild mucosal damage suggests that the calibrated 100-200 μm radiopaque microspheres may be the optimal embolics for effective weight management via BAE.

3:36 PM Abstract No. 231 Dose escalation study of topotecan-eluting radiopaque microspheres for hepatic chemoembolization in a rabbit preclinical model

To evaluate the loading and elution of topotecan from radiopaque microspheres (ROMTOP) and determine the maximum dose that could be safely administered by transarterial chemoembolization in a rabbit preclinical model. All animal procedures were approved by the Animal Care and Use Committee. Topotecan elution from radiopaque microspheres (70-150 μm) was assessed in vitro using an open-loop flow-through system and compared to irinotecan. Rabbits underwent hepatic transarterial chemoembolization with topotecan-loaded radiopaque microspheres under fluoroscopic guidance until angiographic stasis. A 3+3 dose escalation study design was adopted to determine the maximum tolerated dose (MTD). Physical examination and behavioral assessment for adverse events were performed daily and liver function tests and complete blood counts were performed at regular intervals until euthanasia 28 days post chemoembolization. The maximum topotecan loading capacity in ROMTOP was 80 mg/mL. Complete drug elution of topotecan and irinotecan from microspheres took 10 and 3 hours in vitro, respectively, providing a direct comparison of topotecan to the better-characterized irinotecan. All rabbits survived for 28 days in the bland bead (dose: 0 mg/kg, N = 3) and low-dose (mean dose, 0.54 mg/kg, N = 3) cohorts. In the high-dose cohort (mean dose, 1.99 mg/kg, N = 6), one of six rabbits treated died two days after chemoembolization from pyloric duodenal perforation. All other rabbits survived for 28 days without dose limiting toxicity. An additional 5 rabbits were excluded from the study due to technical / procedural complications. No further dose escalation was possible as the maximum topotecan loading in the microspheres had been reached. Toxicity related to liver embolization with ROMTOP included alanine aminotransferase and aspartate transaminase elevations lasting 7-14 days. Embolization with ROMTOP was well tolerated up to a dose of 2 mg/kg, the maximum loading capacity of the microspheres. Topotecan may be an attractive candidate for local delivery via TACE with radiopaque drug-eluting microspheres due to its high potency and sustained drug release kinetics relative to irinotecan.

In Vitro Characterization of a Novel Type of Radiopaque Doxorubicin-Loaded Microsphere.

To evaluate and compare the material characteristics of a novel type of radiopaque doxorubicin-loaded microsphere (V-100) with radiopaque and non-radiopaque doxorubicin-loaded microspheres. The prototype V-100 featuring inherent radiopacity and three available commercial controls (DC-Bead-LUMI™-70-150, Embozene-Tandem™-100 and DC-Bead™-M1) were analyzed before and after doxorubicin loading (37.5mg doxorubicin/1ml microspheres) in suspension with aqua and/or aqua/iodixanol-320. Study goals included inherent radiopacity [e.g., using conventional computed tomography (CT)], doxorubicin loading efficacy, morphology using light and fluorescence microscopy, size distribution using laser diffraction/light scattering, time-in-suspension, rheological properties using rheometer analysis, and microsphere stability observed over a period of 5days after doxorubicin loading. V-100 showed good inherent radiopacity without adverse imaging artifacts. Under conventional CT, the quantitative radiopacity was as follows: 480.4 ± 2.9HU for V-100, 2432.7 ± 3.2HU for DC-Bead-LUMI™-70-150, 118.1 ± 3.0HU for Embozene-Tandem™-100, and 19.8 ± 1.5HU for DC-Bead™-M1. All of the types of microspheres showed a similar loading efficiency (> 98%) after 24h; however, there were slower doxorubicin loading velocities for the radiopaque microspheres. The doxorubicin-loaded V-100 and Embozene-Tandem™-100 showed typical narrow-sized distributions. In aqua/iodixanol-320 suspension, doxorubicin-loaded V-100 showed the best suspension features and ideal deformability and elasticity characteristics. Similar to other microspheres, doxorubicin-loaded V-100 was very stable and storable for at least 5days. V-100 is a promising novel type of radiopaque doxorubicin-loaded microsphere. Compared with the controls, V-100 shows good inherent radiopacity without adverse imaging artifacts and with comparable doxorubicin loading efficacy. Further advantages of V-100 include narrow-sized distribution and excellent suspension, rheology, and stability features.