Therapeutic efficacy of an alpha-particle emitter labeled anti-GD2 humanized antibody against osteosarcoma-a proof of concept study.

PURPOSE: Current treatments for osteosarcoma (OS) have a poor prognosis, particularly for patients with metastasis and recurrence, underscoring an urgent need for new targeted therapies to improve survival. Targeted alpha-particle therapy selectively delivers cytotoxic payloads to tumors with radiolabeled molecules that recognize tumor-associated antigens. We have recently demonstrated the potential of an FDA approved, humanized anti-GD2 antibody, hu3F8, as a targeted delivery vector for radiopharmaceutical imaging of OS. The current study aims to advance this system for alpha-particle therapy of OS. METHODS: The hu3F8 antibody was radiolabeled with actinium-225, and the safety and therapeutic efficacy of the [225Ac]Ac-DOTA-hu3F8 were evaluated in both orthotopic murine xenografts of OS and spontaneously occurring OS in canines. RESULTS: Significant antitumor activity was proven in both cases, leading to improved overall survival. In the murine xenograft's case, tumor growth was delayed by 16-18 days compared to the untreated cohort as demonstrated by bioluminescence imaging. The results were further validated with magnetic resonance imaging at 33 days after treatment, and microcomputed tomography and planar microradiography post-mortem. Histological evaluations revealed radiation-induced renal toxicity, manifested as epithelial cell karyomegaly and suggestive polyploidy in the kidneys, suggesting rapid recovery of renal function after radiation damage. Treatment of the two canine patients delayed the progression of metastatic spread, with an overall survival time of 211 and 437 days and survival beyond documented metastasis of 111 and 84 days, respectively. CONCLUSION: This study highlights the potential of hu3F8-based alpha-particle therapy as a promising treatment strategy for OS.

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

OBJECTIVES: To 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 METHODS: Twenty-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). RESULTS: In 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). CONCLUSIONS: In this preclinical model, tailored 100-200-µm microspheres were shown to be most suitable for BAE in terms of safety and efficacy.

Anti-GD2 antibody for radiopharmaceutical imaging of osteosarcoma.

PURPOSE: Osteosarcoma (OS) is the most frequently diagnosed bone cancer in children with little improvement in overall survival in the past decades. The high surface expression of disialoganglioside GD2 on OS tumors and restricted expression in normal tissues makes it an ideal target for anti-OS radiopharmaceuticals. Since human and canine OS share many biological and molecular features, spontaneously occurring OS in canines has been an ideal model for testing new imaging and treatment modalities for human translation. In this study, we evaluated a humanized anti-GD2 antibody, hu3F8, as a potential delivery vector for targeted radiopharmaceutical imaging of human and canine OS. METHODS: The cross-reactivity of hu3F8 with human and canine OS cells and tumors was examined by immunohistochemistry and flow cytometry. The hu3F8 was radiolabeled with indium-111, and the biodistribution of [111In]In-hu3F8 was assessed in tumor xenograft-bearing mice. The targeting ability of [111In]In-hu3F8 to metastatic OS was tested in spontaneous OS canines. RESULTS: The hu3F8 cross reacts with human and canine OS cells and canine OS tumors with high binding affinity. Biodistribution studies revealed selective uptake of [111In]In-hu3F8 in tumor tissue. SPECT/CT imaging of spontaneous OS canines demonstrated avid uptake of [111In]In-hu3F8 in all metastatic lesions. Immunohistochemistry confirmed the extensive binding of radiolabeled hu3F8 within both osseous and soft lesions. CONCLUSION: This study demonstrates the feasibility of targeting GD2 on OS cells and spontaneous OS canine tumors using hu3F8-based radiopharmaceutical imaging. Its ability to deliver an imaging payload in a targeted manner supports the utility of hu3F8 for precision imaging of OS and potential future use in radiopharmaceutical therapy.

Identifying the Ideal Target Vessel Size for Bariatric Embolization: Histologic Analysis of Swine and Human Gastric Fundi.

This study aimed to identify the ideal arteriole size to target in bariatric embolization, with the goal of maximizing weight loss efficacy while maintaining patient safety. Although all published clinical trials of bariatric embolization have used embolic microspheres that were at least 300 µm in diameter, optimal weight loss outcomes have been achieved safely in swine using 50-µm embolics. Human fundal remnants from bariatric surgery were compared with swine fundal sections after bariatric embolization with 50-µm embolic microspheres to assess the ideal fundal vessel size for bariatric embolization. In swine, the 50-µm embolic microspheres deposited in the luminal half of the submucosa with a mean arteriole size of 49 µm ± 30. The mean arteriole diameter in the corresponding submucosal layer of the human gastric fundi was 40 µm ± 30. These measurements may inform future clinical trials and direct the development of embolic agents for bariatric embolization.

Angiographic Revascularization after Bariatric Embolization in a Swine Model.

This study evaluated fundal arteriole angiographic revascularization after embolization with embolic microspheres of 3 different diameters in a swine model (16 swine, 31 arterioles). In the 50-µm group, 7 of 11 (64%) arterioles recanalized completely, 3 of 11 (27%) arterioles recanalized partially, and 1 of 11 (9%) arterioles had collateralization (no recanalization). In the 100- to 300-µm group, 7 of 10 (70%) arterioles recanalized completely and 3 of 10 (30%) arterioles) recanalized partially. In the 300- to 500-µm group, 7 of 10 (70%) arterioles recanalized completely, 1 of 10 (10%) arterioles recanalized partially, and 2 of 10 (20%) arterioles had collateralization. No difference was found between the groups in the degree of recanalization (P = .64). All embolized arterioles exhibited some degree of angiographic revascularization, irrespective of the microsphere size.

Interventional Radiology Obesity Therapeutics: Proceedings from the Society of Interventional Radiology Foundation Research Consensus Panel.

The Society of Interventional Radiology Foundation commissioned a Research Consensus Panel to establish a research agenda on "Obesity Therapeutics" in interventional radiology (IR). The meeting convened a multidisciplinary group of physicians and scientists with expertise in obesity therapeutics. The meeting was intended to review current evidence on obesity therapies, familiarize attendees with the regulatory evaluation process, and identify research deficiencies in IR bariatric interventions, with the goal of prioritizing future high-quality research that would move the field forward. The panelists agreed that a weight loss of >8%-10% from baseline at 6-12 months is a desirable therapeutic endpoint for future IR weight loss therapies. The final consensus on the highest priority research was to design a blinded randomized controlled trial of IR weight loss interventions versus sham control arms, with patients receiving behavioral therapy.

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

PURPOSE: To examine safety and efficacy of bariatric arterial embolization (BAE) with x-ray-visible embolic microspheres (XEMs) and an antireflux catheter in swine. MATERIAL AND METHODS: BAE 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. RESULTS: BAE 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). CONCLUSIONS: XEMs enabled direct visualization of embolic material during and after embolization. BAE with XEMs and antireflux microcatheters was safe and effective.

Bariatric Embolization of Arteries for the Treatment of Obesity (BEAT Obesity) Trial: Results at 1 Year.

Background Bariatric embolization is a new endovascular procedure to treat patients with obesity. However, the safety and efficacy of bariatric embolization are unknown. Purpose To evaluate the safety and efficacy of bariatric embolization in severely obese adults at up to 12 months after the procedure. Materials and Methods For this prospective study (NCT0216512 on ClinicalTrials.gov ), 20 participants (16 women) aged 27-68 years (mean ± standard deviation, 44 years ± 11) with mean body mass index of 45 ± 4.1 were enrolled at two institutions from June 2014 to February 2018. Transarterial embolization of the gastric fundus was performed using 300- to 500-µm embolic microspheres. Primary end points were 30-day adverse events and weight loss at up to 12 months. Secondary end points at up to 12 months included technical feasibility, health-related quality of life (Short Form-36 Health Survey ([SF-36]), impact of weight on quality of life (IWQOL-Lite), and hunger or appetite using a visual assessment scale. Analysis of outcomes was performed by using one-sample t tests and other exploratory statistics. Results Bariatric embolization was performed successfully for all participants with no major adverse events. Eight participants had a total of 11 minor adverse events. Mean excess weight loss was 8.2% (95% confidence interval [CI]: 6.3%, 10%; P < .001) at 1 month, 11.5% (95% CI: 8.7%, 14%; P < .001) at 3 months, 12.8% (95% CI: 8.3%, 17%; P < .001) at 6 months, and 11.5% (95% CI: 6.8%, 16%; P < .001) at 12 months. From baseline to 12 months, mean SF-36 scores increased (mental component summary, from 46 ± 11 to 50 ± 10, P = .44; physical component summary, from 46 ± 8.0 to 50 ± 9.3, P = .15) and mean IWQOL-Lite scores increased from 57 ± 18 to 77 ± 18 (P < .001). Hunger or appetite decreased for 4 weeks after embolization and increased thereafter, without reaching pre-embolization levels. Conclusion Bariatric embolization is well tolerated in severely obese adults, inducing appetite suppression and weight loss for up to 12 months. Published under a CC BY-NC-ND 4.0 license. Online supplemental material is available for this article.

Quantitative CT and 19F-MRI tracking of perfluorinated encapsulated mesenchymal stem cells to assess graft immunorejection.

OBJECTIVES: Peripheral artery disease (PAD) affects 12-14% of the world population, and many are not eligible for conventional treatment. For these patients, microencapsulated stem cells (SCs) offer a novel means to transplant mismatched therapeutic SCs to prevent graft immunorejection. Using c-arm CT and 19F-MRI for serial evaluation of dual X-ray/MR-visible SC microcapsules (XMRCaps) in a non-immunosuppressed rabbit PAD model, we explore quantitative evaluation of capsule integrity as a surrogate of transplanted cell fate. MATERIALS AND METHODS: XMRCaps were produced by impregnating 12% perfluorooctylbromine (PFOB) with rabbit or human SCs (AlloSC and XenoSC, respectively). Volume and 19F concentration measurements of XMRCaps were assessed both in phantoms and in vivo, at days 1, 8 and 15 after intramuscular administration in rabbits (n = 10), by 3D segmenting the injection sites and referencing to standards with known concentrations. RESULTS: XMRCap volumes and concentrations showed good agreement between CT and MRI both in vitro and in vivo in XenoSC rabbits. Injected capsules showed small variations over time and were similar between AlloSC and XenoSC rabbits. Histological staining revealed high cell viability and intact capsules 2 weeks after administration. CONCLUSIONS: Quantitative and non-invasive tracking XMRCaps using CT and 19F-MRI may be useful to assess graft immunorejection after SC transplantation.

Bariatric Arterial Embolization: Effect of Microsphere Size on the Suppression of Fundal Ghrelin Expression and Weight Change in a Swine Model.

Purpose To determine whether microsphere size effects ghrelin expression and weight gain after selective bariatric arterial embolization (BAE) in swine. Materials and Methods BAE was performed in 10 swine by using smaller (100-300 µm; n = 5) or larger (300-500 µm; n = 5) calibrated microspheres into gastric arteries. Nine control pigs underwent a sham procedure. Weight and fasting plasma ghrelin levels were measured at baseline and weekly for 16 weeks. Ghrelin-expressing cells (GECs) in the stomach were assessed by using immunohistochemical staining and analyzed by using the Wilcoxon rank-sum test. Results In pigs treated with smaller microspheres, mean weight gain at 16 weeks (106.9% ± 15.0) was less than in control pigs (131.9% ± 11.6) (P < .001). Mean GEC density was lower in the gastric fundus (14.8 ± 6.3 vs 25.0 ± 6.9, P < .001) and body (27.5 ± 12.3 vs 37.9 ± 11.8, P = .004) but was not significantly different in the gastric antrum (28.2 ± 16.3 vs 24.3 ± 11.6, P = .84) and duodenum (9.2 ± 3.8 vs 8.7 ± 2.9, P = .66) versus in control pigs. BAE with larger microspheres failed to suppress weight gain or GECs in any stomach part compared with results in control swine. Plasma ghrelin levels were similar between BAE pigs and control pigs, regardless of microsphere size. Week 1 endoscopic evaluation for gastric ulcers revealed none in control pigs, five ulcers in five pigs embolized by using smaller microspheres, and three ulcers in five pigs embolized by using larger microspheres. Conclusion In bariatric arterial embolization, smaller microspheres rather than larger microspheres showed greater weight gain suppression and fundal ghrelin expression with more gastric ulceration in a swine model. © RSNA, 2018.

Clinical Safety of Bariatric Arterial Embolization: Preliminary Results of the BEAT Obesity Trial.

Purpose To conduct a pilot prospective clinical trial to evaluate the feasibility, safety, and short-term efficacy of bariatric embolization, a recently developed endovascular procedure for the treatment of obesity, in patients with severe obesity. Materials and Methods This is an institutional review board- and U.S. Food and Drug Administration-approved prospective physician-initiated investigational device exemption study. This phase of the study ran from June 2, 2014, to August 4, 2015. Five severely obese patients (four women, one man) who were 31-49 years of age and who had a mean body mass index of 43.8 kg/m2 ± 2.9 with no clinically important comorbidities were enrolled in this study. Transarterial embolization of the gastric fundus with fluoroscopic guidance was performed with 300-500-µm Embosphere microspheres. The primary end point was 30-day adverse events (AEs). The secondary end points included short-term weight loss, serum obesity-related hormone levels, hunger and satiety assessments, and quality of life (QOL) surveys, reported up to 3 months. Simple statistics of central tendencies and variability were calculated. No hypothesis testing was performed. Results The left gastric artery, with or without the gastroepiploic artery, was embolized in five patients, with a technical success rate of 100%. There were no major AEs. There were two minor AEs-subclinical pancreatitis and a mucosal ulcer that had healed by the time of 3-month endoscopy. A hospital stay of less than 48 hours for routine supportive care was provided for three patients. Mean excess weight loss of 5.9% ± 2.4 and 9.0% ± 4.1 was noted at 1 month and at 3 months, respectively. Mean change in serum ghrelin was 8.7% ± 34.7 and -17.5% ± 29 at 1 month and 3 months, respectively. Mean changes in serum glucagon-like peptide 1 and peptide YY were 106.6% ± 208.5 and 17.8% ± 54.8 at 1 month. There was a trend toward improvement in QOL parameters. Hunger/appetite scores decreased in the first 2 weeks after the procedure and then rose without reaching preprocedure levels. Conclusion Bariatric embolization is feasible and appears to be well tolerated in severely obese patients. In this small patient cohort, it appears to induce appetite suppression and may induce weight loss. Further expansion of this study will provide more insight into the long-term safety and efficacy of bariatric embolization. © RSNA, 2017 Online supplemental material is available for this article.

Bariatric embolization of the gastric arteries for the treatment of obesity.

Obesity is a public health epidemic in the United States that results in significant morbidity, mortality, and cost to the health care system. Despite advancements in therapeutic options for patients receiving bariatric procedures, the number of overweight and obese individuals continues to increase. Therefore, complementary or alternative treatments to lifestyle changes and surgery are urgently needed. Embolization of the left gastric artery, or bariatric arterial embolization (BAE), has been shown to modulate body weight in animal models and early clinical studies. If successful, BAE represents a potential minimally invasive approach offered by interventional radiologists to treat obesity. The purpose of the present review is to introduce the interventional radiologist to BAE by presenting its physiologic and anatomic bases, reviewing the preclinical and clinical data, and discussing current and future investigations.

Fused X-ray and MR imaging guidance of intrapericardial delivery of microencapsulated human mesenchymal stem cells in immunocompetent swine.

PURPOSE: To assess intrapericardial delivery of microencapsulated, xenogeneic human mesenchymal stem cells (hMSCs) by using x-ray fused with magnetic resonance (MR) imaging (x-ray/MR imaging) guidance as a potential treatment for ischemic cardiovascular disease in an immunocompetent swine model. MATERIALS AND METHODS: All animal experiments were approved by the institutional animal care and use committee. Stem cell microencapsulation was performed by using a modified alginate-poly-l-lysine-alginate encapsulation method to include 10% (wt/vol) barium sulfate to create barium-alginate microcapsules (BaCaps) that contained hMSCs. With x-ray/MR imaging guidance, eight female pigs (approximately 25 kg) were randomized to receive either BaCaps with hMSCs, empty BaCaps, naked hMSCs, or saline by using a percutaneous subxiphoid approach and were compared with animals that received empty BaCaps (n = 1) or BaCaps with hMSCs (n = 2) by using standard fluoroscopic delivery only. MR images and C-arm computed tomographic (CT) images were acquired before injection and 1 week after delivery. Animals were sacrificed immediately or at 1 week for histopathologic validation. Cardiac function between baseline and 1 week after delivery was evaluated by using a paired Student t test. RESULTS: hMSCs remained highly viable (94.8% ± 6) 2 days after encapsulation in vitro. With x-ray/MR imaging, successful intrapericardial access and delivery were achieved in all animals. BaCaps were visible fluoroscopically and at C-arm CT immediately and 1 week after delivery. Whereas BaCaps were free floating immediately after delivery, they consolidated into a pseudoepicardial tissue patch at 1 week, with hMSCs remaining highly viable within BaCaps; naked hMSCs were poorly retained. Follow-up imaging 1 week after x-ray/MR imaging-guided intrapericardial delivery showed no evidence of pericardial adhesion and/or effusion or adverse effect on cardiac function. In contradistinction, BaCaps delivery with x-ray fluoroscopy without x-ray/MR imaging (n = 3) resulted in pericardial adhesions and poor hMSC viability after 1 week. CONCLUSION: Intrapericardial delivery of BaCaps with hMSCs leads to high cell retention and survival. With x-ray/MR imaging guidance, intrapericardial delivery can be performed safely in the absence of preexisting pericardial effusion to provide a novel route for cardiac cellular regenerative therapy.

Histopathologic and immunohistochemical sequelae of bariatric embolization in a porcine model.

PURPOSE: To evaluate the histopathologic sequelae of bariatric embolization on the gastric mucosa and to correlate with immunohistochemical evaluation of the gastric fundus, antrum, and duodenum. MATERIALS AND METHODS: This study was performed on 12 swine stomach and duodenum specimens after necropsy. Of the 12 swine, 6 had previously undergone bariatric embolization of the gastric fundus, and the 6 control swine had undergone a sham procedure with saline. Gross pathologic, histopathologic, and immunohistochemical examinations of the stomach and duodenum were performed. Specifically, mucosal integrity, fibrosis, ghrelin-expressing cells, and gastrin-expressing cells were assessed. RESULTS: Gross and histopathologic evaluation of treatment animals showed healing or healed mucosal ulcers in 50% of animals, with gastritis in 100% of treatment animals and in five of six control animals. The ghrelin-immunoreactive mean cell density was significantly lower in the gastric fundus in the treated animals compared with control animals (15.3 vs 22.0, P < .01) but similar in the gastric antrum (9.3 vs 14.3, P = .08) and duodenum (8.5 vs 8.6, P = .89). The gastrin-expressing cell density was significantly lower in the antrum of treated animals compared with control animals (82.2 vs 126.4, P = .03). A trend toward increased fibrosis was suggested in the gastric fundus of treated animals compared with controls (P = .07). CONCLUSIONS: Bariatric embolization resulted in a significant reduction in ghrelin-expressing cells in the gastric fundus without evidence of upregulation of ghrelin-expressing cells in the duodenum. Healing ulcerations in half of treated animals underscores the need for additional refinement of this procedure.

Tracking of stem cells in vivo for cardiovascular applications.

In the past ten years, the concept of injecting stem and progenitor cells to assist with rebuilding damaged blood vessels and myocardial tissue after injury in the heart and peripheral vasculature has moved from bench to bedside. Non-invasive imaging can not only provide a means to assess cardiac repair and, thereby, cellular therapy efficacy but also a means to confirm cell delivery and engraftment after administration. In this first of a two-part review, we will review the different types of cellular labeling techniques and the application of these techniques in cardiovascular magnetic resonance and ultrasound. In addition, we provide a synopsis of the cardiac cellular clinical trials that have been performed to-date.

Magnetic resonance-guided, real-time targeted delivery and imaging of magnetocapsules immunoprotecting pancreatic islet cells.

In type I diabetes mellitus, islet transplantation provides a moment-to-moment fine regulation of insulin. Success rates vary widely, however, necessitating suitable methods to monitor islet delivery, engraftment and survival. Here magnetic resonance-trackable magnetocapsules have been used simultaneously to immunoprotect pancreatic beta-cells and to monitor, non-invasively in real-time, hepatic delivery and engraftment by magnetic resonance imaging (MRI). Magnetocapsules were detected as single capsules with an altered magnetic resonance appearance on capsule rupture. Magnetocapsules were functional in vivo because mouse beta-cells restored normal glycemia in streptozotocin-induced diabetic mice and human islets induced sustained C-peptide levels in swine. In this large-animal model, magnetocapsules could be precisely targeted for infusion by using magnetic resonance fluoroscopy, whereas MRI facilitated monitoring of liver engraftment over time. These findings are directly applicable to ongoing improvements in islet cell transplantation for human diabetes, particularly because our magnetocapsules comprise clinically applicable materials.

Thermal Characterization and Preclinical Feasibility Verification of an Accessible, Carbon Dioxide-Based Cryotherapy System.

To investigate the potential of an affordable cryotherapy device for the accessible treatment of breast cancer, the performance of a novel carbon dioxide-based device was evaluated through both benchtop testing and an in vivo canine model. This novel device was quantitatively compared to a commercial device that utilizes argon gas as the cryogen. The thermal behavior of each device was characterized through calorimetry and by measuring the temperature profiles of iceballs generated in tissue phantoms. A 45 min treatment in a tissue phantom from the carbon dioxide device produced a 1.67 ± 0.06 cm diameter lethal isotherm that was equivalent to a 7 min treatment from the commercial argon-based device, which produced a 1.53 ± 0.15 cm diameter lethal isotherm. An in vivo treatment was performed with the carbon dioxide-based device in one spontaneously occurring canine mammary mass with two standard 10 min freezes. Following cryotherapy, this mass was surgically resected and analyzed for necrosis margins via histopathology. The histopathology margin of necrosis from the in vivo treatment with the carbon dioxide device at 14 days post-cryoablation was 1.57 cm. While carbon dioxide gas has historically been considered an impractical cryogen due to its low working pressure and high boiling point, this study shows that carbon dioxide-based cryotherapy may be equivalent to conventional argon-based cryotherapy in size of the ablation zone in a standard treatment time. The feasibility of the carbon dioxide device demonstrated in this study is an important step towards bringing accessible breast cancer treatment to women in low-resource settings.

Percutaneous punctures with MR imaging guidance: comparison between MR imaging-enhanced fluoroscopic guidance and real-time MR Imaging guidance.

PURPOSE: To evaluate and compare the technical accuracy and feasibility of magnetic resonance (MR) imaging-enhanced fluoroscopic guidance and real-time MR imaging guidance for percutaneous puncture procedures in phantoms and animals. MATERIALS AND METHODS: The experimental protocol was approved by the institutional animal care and use committee. Punctures were performed in phantoms, aiming for markers (20 each for MR imaging-enhanced fluoroscopic guidance and real-time MR imaging guidance), and pigs, aiming for anatomic landmarks (10 for MR imaging-enhanced fluoroscopic guidance and five for MR imaging guidance). To guide the punctures, T1-weighted three-dimensional (3D) MR images of the phantom or pig were acquired. Additional axial and coronal T2-weighted images were used to visualize the anatomy in the animals. For MR imaging-enhanced fluoroscopic guidance, phantoms and pigs were transferred to the fluoroscopic system after initial MR imaging and C-arm computed tomography (CT) was performed. C-arm CT and MR imaging data sets were coregistered. Prototype navigation software was used to plan a puncture path with use of MR images and to superimpose it on fluoroscopic images. For real-time MR imaging, an interventional MR imaging prototype for interactive real-time section position navigation was used. Punctures were performed within the magnet bore. After completion, 3D MR imaging was performed to evaluate the accuracy of insertions. Puncture durations were compared by using the log-rank test. The Mann-Whitney U test was applied to compare the spatial errors. RESULTS: In phantoms, the mean total error was 8.6 mm ± 2.8 with MR imaging-enhanced fluoroscopic guidance and 4.0 mm ± 1.2 with real-time MR imaging guidance (P < .001). The mean puncture time was 2 minutes 10 seconds ± 44 seconds with MR imaging-enhanced fluoroscopic guidance and 37 seconds ± 14 with real-time MR imaging guidance (P < .001). In the animal study, a tolerable distance (<1 cm) between target and needle tip was observed for both MR imaging-enhanced fluoroscopic guidance and real-time MR imaging guidance. The mean total error was 7.7 mm ± 2.4 with MR imaging-enhanced fluoroscopic guidance and 7.9 mm ± 4.9 with real-time MR imaging guidance (P = .77). The mean puncture time was 5 minutes 43 seconds ± 2 minutes 7 seconds with MR imaging-enhanced fluoroscopic guidance and 5 minutes 14 seconds ± 2 minutes 25 seconds with real-time MR imaging guidance (P = .68). CONCLUSION: Both MR imaging-enhanced fluoroscopic guidance and real-time MR imaging guidance demonstrated reasonable and similar accuracy in guiding needle placement to selected targets in phantoms and animals.

Microencapsulated cell tracking.

Microencapsulation of therapeutic cells has been widely pursued to achieve cellular immunoprotection following transplantation. Initial clinical studies have shown the potential of microencapsulation using semi-permeable alginate layers, but much needs to be learned about the optimal delivery route, in vivo pattern of engraftment, and microcapsule stability over time. In parallel with noninvasive imaging techniques for 'naked' (i.e. unencapsulated) cell tracking, microcapsules have now been endowed with contrast agents that can be visualized by (1) H MRI, (19) F MRI, X-ray/computed tomography and ultrasound imaging. By placing the contrast agent formulation in the extracellular space of the hydrogel, large amounts of contrast agents can be incorporated with negligible toxicity. This has led to a new generation of imaging biomaterials that can render cells visible with multiple imaging modalities.

X-ray-visible microcapsules containing mesenchymal stem cells improve hind limb perfusion in a rabbit model of peripheral arterial disease.

The therapeutic goal in peripheral arterial disease (PAD) patients is to restore blood flow to ischemic tissue. Stem cell transplantation offers a new avenue to enhance arteriogenesis and angiogenesis. Two major problems with cell therapies are poor cell survival and the lack of visualization of cell delivery and distribution. To address these therapeutic barriers, allogeneic bone marrow-derived mesenchymal stem cells (MSCs) were encapsulated in alginate impregnated with a radiopaque contrast agent (MSC-Xcaps). In vitro MSC-Xcap viability by a fluorometric assay was high (96.9% ± 2.7% at 30 days postencapsulation) and as few as 10 Xcaps were visible on clinical x-ray fluoroscopic systems. Using an endovascular PAD model, rabbits (n = 21) were randomized to receive MSC-Xcaps (n = 6), empty Xcaps (n = 5), unencapsulated MSCs (n = 5), or sham intramuscular injections (n = 5) in the ischemic thigh 24 hours postocclusion. Immediately after MSC transplantation and 14 days later, digital radiographs acquired on a clinical angiographic system demonstrated persistent visualization of the Xcap injection sites with retained contrast-to-noise. Using a modified TIMI frame count, quantitative angiography demonstrated a 65% improvement in hind limb perfusion or arteriogenesis in MSC-Xcap-treated animals versus empty Xcaps. Post-mortem immunohistopathology of vessel density by anti-CD31 staining demonstrated an 87% enhancement in angiogenesis in Xcap-MSC-treated animals versus empty Xcaps. MSC-Xcaps represent the first x-ray-visible cellular therapeutic with enhanced efficacy for PAD treatment.