Intra-arterial Delivery Research Articles

Feasibility and Safety of Intra-arterial Pericyte Progenitor Cell Delivery Following Mannitol-Induced Transient Blood-Brain Barrier Opening in a Canine Model.

Stem cell therapy is currently being studied with a view to rescuing various neurological diseases. Such studies require not only the discovery of potent candidate cells but also the development of methods that allow optimal delivery of those candidates to the brain tissues. Given that the blood-brain barrier (BBB) precludes cells from entering the brain, the present study was designed to test whether hyperosmolar mannitol securely opens the BBB and enhances intra-arterial cell delivery. A noninjured normal canine model in which the BBB was presumed to be closed was used to evaluate the feasibility and safety of the tested protocol. Autologous adipose tissue-derived pericytes with platelet-derived growth factor receptor β positivity were utilized. Cells were administered 5 min after mannitol pretreatment using one of following techniques: (1) bolus injection of a concentrated suspension, (2) continuous infusion of a diluted suspension, or (3) bolus injection of a concentrated suspension that had been shaken by repeated syringe pumping. Animals administered a concentrated cell suspension without mannitol pretreatment served as a control group. Vital signs, blood parameters, neurologic status, and major artery patency were kept stable throughout the experiment and the 1-month posttreatment period. Although ischemic lesions were noted on magnetic resonance imaging in several mongrel dogs with concentrated cell suspension, the injection technique using repeated syringe shaking could avert this complication. The cells were detected in both ipsilateral and contralateral cortices and were more frequent at the ipsilateral and frontal locations, whereas very few cells were observed anywhere in the brain when mannitol was not preinjected. These data suggest that intra-arterial cell infusion with mannitol pretreatment is a feasible and safe therapeutic approach in stable brain diseases such as chronic stroke.

Hepatic arterial infusional chemotherapy in the management of colorectal cancer liver metastases.

Colorectal liver metastases (CRLM) receive their blood supply predominantly through the hepatic artery. Intra-arterial drug delivery can optimize the dose and time exposure of chemotherapy to tumor cells while limiting systemic toxicity. Chemotherapy is most commonly administered through a catheter surgically placed in the gastroduodenal artery and connected to a subcutaneous pump. Due to its pharmacokinetics features, floxuridine is the most commonly used drug in the USA with hepatic arterial infusional (HAI) chemotherapy. To date, many clinical trials have shown the positive impact of HAI in the management of CRLM. Hence, in unresectable patients, HAI is associated with high response rates and commonly enables subsequent resection in both chemonaive and previously treated patients. Outcomes in patients converted to complete resection are similar to patients who present with initially resectable disease. In the adjuvant setting, HAI with floxuridine improves survival as well as hepatic and overall disease-free survival after complete resection of CRLM, as compared with 5-FU alone, in three of four randomized studies. To date, no trials have compared HAI combined with modern chemotherapy alone to modern chemotherapy alone in the adjuvant setting.

Ethanol for the treatment of cardiac arrhythmias.

Ethanol infusion was an early mode of ablative treatment for cardiac arrhythmias. Its initial descriptions involved coronary intra-arterial delivery, targeting arrhythmogenic substrates in drug-refractory ventricular tachycardia or the atrioventricular node. Largely superseded by radiofrequency ablation (RFA) and other contact-based technologies as a routine ablation strategy, intracoronary arterial ethanol infusion remains as an alternative option in the treatment of ventricular tachycardia when conventional ablation fails. Arrhythmic foci that are deep-seated in the myocardium may not be amenable to catheter ablation from either the endocardium or the epicardium by RFA, but they can be targeted by an ethanol infusion. Recently, we have explored ethanol injection through cardiac venous systems, in order to avoid the risks of complications and limitations of coronary arterial instrumentation. Vein of Marshall ethanol infusion is being studied as an adjunctive procedure in ablation of atrial fibrillation, and coronary venous ethanol infusion for ventricular tachycardia. Ethanol ablation remains useful as a bail-out technique for refractory cases to RFA, or as an adjunctive therapy that may improve the efficacy of catheter ablation procedures.

Intraarterial drug delivery for glioblastoma mutiforme: Will the phoenix rise again?

Intraarterial (IA) drug delivery is a physiologically appealing strategy as drugs are widely distributed throughout the tumor capillary network and high regional tissue concentrations can be achieved with low total doses. IA treatment of glioblastoma multiforme (GBM) has been attempted since the 1950s but success has been elusive. Although IA treatments have been embraced for the treatment of retinoblastoma and advanced liver cancers, this has not been the case for GBM. The development of IA drug delivery for the treatment of brain cancer over the last several decades reveals a number of critical oversights. For example, very few studies took into consideration the underlying hydrodynamic factors. Therapeutic failures were often blamed on an inability to penetrate the blood brain barrier or on the streaming of drugs. Similarly, there were few methods to investigate the ultra-fast pharmacokinetics of IA drugs. Despite past failures, clinical interest in IA drugs for the treatment of GBM persists. The advent of modern imaging methods along with a better understanding of hydrodynamics factors, better appreciation of the complex morphology of GBM, improved drug selection and formulations, and development of methods to minimize treatment-related neurological injury, promise to considerably advance the application of IA drugs for GBM treatment. There are several clinical trials with IA treatments in the National Trial Registry that are actively recruiting patients. This review of IA drug delivery for GBM treatment is therefore timely and is intended to assess how this method of drug delivery could be better applied to future treatments.

Differential Clearance of Rat and Human Bone Marrow-Derived Mesenchymal Stem Cells from the Brain after Intra-arterial Infusion in Rats

Intra-arterial (IA) delivery of bone marrow-derived mesenchymal stem cells (BM-MSCs) has shown potential as a minimally invasive therapeutic approach for stroke. The aim of the present study was to determine the whole-body biodistribution and clearance of technetium-99m ((99m)Tc)-labeled rat and human BM-MSCs after IA delivery in a rat model of transient middle cerebral artery occlusion (MCAO) using single-photon emission computed tomography (SPECT). Our hypothesis was that xenotransplantation has a major impact on the behavior of cells. Male RccHan:Wistar rats were subjected to sham operation or MCAO. Twenty-four hours after surgery, BM-MSCs (2 × 10(6) cells/animal) labeled with (99m)Tc were infused into the external carotid artery. Whole-body SPECT images were acquired 20 min, 3 h, and 6 h postinjection, after which rats were sacrificed, and organs were collected and weighed for measurement of radioactivity. The results showed that the majority of the cells were located in the brain and especially in the ipsilateral hemisphere immediately after cell infusion both in sham-operated and MCAO rats. This was followed by fast disappearance, particularly in the case of human cells. At the same time, the radioactivity signal increased in the spleen, kidney, and liver, the organs responsible for destroying cells. Further studies are needed to demonstrate whether differential cell behavior has any functional impact.

Abstract No. 415 - Association between leukopenia and neutropenia with infectious complications following transarterial chemoembolization in patients with hepatocellular carcinoma

No. 414 Image based biodistribution analysis after intraarterial delivery of Technetium-99m labeled SPIO using SPECT/CT and MRI I. Lee, J. Park, Y. Kim, Y. Lee, J. Chung, J. Jeong, Y. Kim, S. Jeong, H. Kim; Radiology, National Cancer Center, Goyang-si, Korea (the Republic of); Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea (the Republic of); Department of Radiology, Seoul National University Hospital, Seoul, Korea (the Republic of) Purpose: Dextran coated superparamagnetic iron oxide (SPIO) nanoparticle can be used as drug releasing nano-carrier. The aim of this study is to evaluate the biodistribution of SPIO after intraarterial (IA) delivery of Tc-labeled SPIO (Tc-SPIO) using SPECT/CT and MRI in rabbit liver tumor model to confirm the improvement of the selective IA delivery to liver tumor Materials and Methods: Dextran coated SPIO was reacted with sodium periodate and then reacted with cysteamine and sodium borohydride. The modified SPIO was labeled with Tc. Rabbits with hepatic VX2 carcinomas were treated with three different methods; intra-venous delivery of Tc-SPIO (group A, n1⁄43), IA delivery of Tc-SPIO (group B, n1⁄44), and IA delivery of Tc-SPIO and iodized oil mixture (group C, n1⁄44). Sequential acquisition of Tc-SPIO scintigraphy and SPECT/CT was immediately performed to 180 min after the delivery. After that, MRI and pathological specimens were acquired to confirm the deposit of SPIO in the tumor. Results: The uptake ratio of the tumor to normal liver parenchyma was ranged from the highest to lowest values according to the order group C, B, and A, which was well correlated with the trend of signal decrease on liver MRI. Other major uptake organs were liver, kidney, and bladder in all groups. On the CT images, the high attenuated lesions in tumor representing iodized oil deposition were easily detected only in all animals of groups C. Conclusion: Using Tc-SPIO, the biodistribution after intra-arterial delivery could be successfully demonstrated on SPECT/CT and MRI. Intra-arterial delivery of SPIO and iodized oil mixture was confirmed as a good drug delivery system targeting to liver tumors by the biodistribution analysis.

Abstract 168: Intra-arterial Stem Cell Treatment Reduces Ischemic Brain Injury In Reproductively Senescent Female Rats

Background: Cell therapy is emerging as a promising treatment for stroke. We recently we demonstrated the efficacy of intra-arterial delivery of MSCs (IA MSCs) at 24h after a reversible middle cerebral artery occlusion (MCAo). Our study also identified a maximum tolerated dose of MSCs that could be delivered IA without compromising middle cerebral artery flow. The IA approach avoids first-pass trapping of MSCs in the lungs and liver as seen with intravenous delivery. Intra-arterial treatment is also minimally invasive and widely available in clinical practice and thus appealing for clinical translation. Since majority of ischemic strokes in women occur after onset of menopause it is crucial that we test the efficacy of IA MSCs in reproductively senescent females consistent with STAIR recommendations. We aimed to validate the efficacy of IA MSCs in reproductively senescent female rats. Methods: Retired breeder female (9-11 months; 280-350 g) Sprague-Dawley rats showing estrous acyclicity were exposed to MCAo (90 min). A day later, rats were treated with IA MSCs (1x10^5 cells) or phosphate-buffered saline (PBS). MSCs or PBS treated rats were sacrificed at 28-30 days for infarct volume measurement using histology. To test motor function, the rotarod test was performed. Rats were trained for 3 consecutive days for the rotarod test before undergoing the MCAo procedure. The mean duration (in seconds) on the device was recorded from 3 rotarod measurements 1 day before surgery. The rats were tested at 1, 7, 15 and 28-30 days after MCAo. Results: We observed significantly lower mean infarct volume in the MSC-treated group (12 ± 3 mm3; n=6) compared to the PBS-treated group (29 ± 7 mm3; Mean ± SEM; n=4, p<0.05). Treatment at 1 day after MCAO with MSCs significantly improved functional recovery, as evidenced by improved rotarod test results and neurological scores at 7, 15 and 30 days (P<0.05) compared with the PBS-treated group. Conclusions: Intra-arterial stem cell treatment reduces ischemic brain injury and improves functional outcomes in reproductively senescent female rats. Validating the efficacy of IA MSC treatment using a reproductively senescent animal stroke model suggests high potential for future clinical translation in a population at high risk for stroke.

Abstract No. 414 - Image based biodistribution analysis after intra-arterial delivery of Technetium-99m labeled SPIO using SPECT/CT and MRI

Abstract No. 414 - Image based biodistribution analysis after intra-arterial delivery of Technetium-99m labeled SPIO using SPECT/CT and MRI

The cerebral embolism evoked by intra-arterial delivery of allogeneic bone marrow mesenchymal stem cells in rats is related to cell dose and infusion velocity.

IntroductionIntra-arterial cell infusion is an efficient delivery route with which to target organs such as the ischemic brain. However, adverse events including microembolisms and decreased cerebral blood flow were recently reported after intra-arterial cell delivery in rodent models, raising safety concerns. We tested the hypothesis that cell dose, infusion volume, and velocity would be related to the severity of complications after intra-arterial cell delivery.MethodsIn this study, 38 rats were subjected to a sham middle cerebral artery occlusion (sham-MCAO) procedure before being infused with allogeneic bone-marrow mesenchymal stem cells at different cell doses (0 to 1.0 × 106), infusion volumes (0.5 to 1.0 ml), and infusion times (3 to 6 minutes). An additional group (n = 4) was infused with 1.0 × 106 cells labeled with iron oxide for in vivo tracking of cells. Cells were infused through the external carotid artery under laser Doppler flowmetry monitoring 48 hours after sham-MCAO. Magnetic resonance imaging (MRI) was performed 24 hours after cell infusion to reveal cerebral embolisms or hemorrhage. Limb placing, cylinder, and open field tests were conducted to assess sensorimotor functions before the rats were perfused for histology.ResultsA cell dose-related reduction in cerebral blood flow was noted, as well as an increase in embolic events and concomitant lesion size, and sensorimotor impairment. In addition, a low infusion velocity (0.5 ml/6 minutes) was associated with high rate of complications. Lesions on MRI were confirmed with histology and corresponded to necrotic cell loss and blood-brain barrier leakage.ConclusionsParticularly cell dose but also infusion velocity contribute to complications encountered after intra-arterial cell transplantation. This should be considered before planning efficacy studies in rats and, potentially, in patients with stroke.

Magnetic nanosphere-guided site-specific delivery of vascular endothelial growth factor gene attenuates restenosis in rabbit balloon-injured artery

New and efficient strategies to protect endothelium or to enhance endothelial regrowth are important for treatment of restenosis after percutaneous transluminal angioplasty. Magnetic DNA microspheres are used to accelerate vascular endothelial growth factor (VEGF) re-endothelialization and to attenuate intimal hyperplasia in balloon-injured artery. This study aimed to assess DNA-gelatin magnetic nanospheres containing VEGF expression plasmids in vascular restenosis attenuation. Ninety-six rabbits underwent balloon injury and were randomly divided for gene transfer with naked VEGF plasmids (NAK group), magnetic VEGF microspheres (MIC group), and LacZ (CON group: naked LacZ plasmid and LacZ nanosphere subgroups). Serum and tissue VEGF levels were measured. Also, the ratios of intima area to media area were determined to assess neointima formation. Microsphere gene delivery through the artery by a magnet resulted in VEGF overexpression in transfected arterial segments. Tissue VEGF integral optical densities were significantly increased in MIC rabbits compared with NAK animals. Serum VEGF was below detection in all animals. X-Gal staining showed higher transfection efficiency in the CON group. The impact of neointimal thickening was evaluated by light microscopy as the ratio of intima area to media area in cross sections. Significant differences in the ratio of intima area to media area were obtained between the NAK group (0.12 ± 0.02, 0.41 ± 0.03, 0.61 ± 0.05, and 0.72 ± 0.04 at 1, 2, 3, and 4 weeks, respectively) and the MIC group (0.06 ± 0.03, 0.20 ± 0.05, 0.25 ± 0.04, and 0.26 ± 0.03 at 1, 2, 3, and 4 weeks, respectively) at 2, 3, and 4 weeks (P < .05). Intra-arterial VEGF gene delivery by magnetic microspheres significantly increased DNA stability, transfection efficiency, and targeting specificity, resulting in exogenous VEGF overexpression and attenuated intimal hyperplasia in balloon-injured artery.

MRI visible drug eluting magnetic microspheres for transcatheter intra-arterial delivery to liver tumors.

Magnetic resonance imaging (MRI)-visible amonafide-eluting alginate microspheres were developed for targeted arterial-infusion chemotherapy. These alginate microspheres were synthesized using a highly efficient microfluidic gelation process. The microspheres included magnetic clusters formed by USPIO nanoparticles to permit MRI and a sustained drug-release profile. The biocompatibility, MR imaging properties and amonafide release kinetics of these microspheres were investigated during in vitro studies. A xenograft rodent model was used to demonstrate the feasibility to deliver these microspheres to liver tumors using hepatic transcatheter intra-arterial infusions and potential to visualize the intra-hepatic delivery of these microspheres to both liver tumor and normal tissues with MRI immediately after infusion. This approach offer the potential for catheter-directed drug delivery to liver tumors for reduced systemic toxicity and superior therapeutic outcomes.

Intra-arterial transplantation of low-dose stem cells provides functional recovery without adverse effects after stroke.

Cell transplantation therapy for cerebral infarction has emerged as a promising treatment to reduce brain damage and enhance functional recovery. We previously reported that intra-arterial delivery of bone marrow mesenchymal stem cells (MSCs) enables superselective cell administration to the infarct area and results in significant functional recovery after ischemic stroke in a rat model. However, to reduce the risk of embolism caused by the transplanted cells, an optimal cell number should be determined. At 24h after middle cerebral artery occlusion and reperfusion, we administered human MSCs (low dose: 1×10(4) cells; high dose: 1×10(6) cells) and then assessed functional recovery, inflammatory responses, cell distribution, and mortality. Rats treated with high- or low-dose MSCs showed behavioral recovery. At day 8 post-stroke, microglial activation was suppressed significantly, and interleukin (IL)-1β and IL-12p70 were reduced in both groups. Although high-dose MSCs were more widely distributed in the cortex and striatum of rats, the degree of intravascular cell aggregation and mortality was significantly higher in the high-dose group. In conclusion, selective intra-arterial transplantation of low-dose MSCs has anti-inflammatory effects and reduces the adverse effects of embolic complication, resulting in sufficient functional recovery of the affected brain.

Notch signaling regulates myogenic regenerative capacity of murine and human mesoangioblasts.

Somatic stem cells hold attractive potential for the treatment of muscular dystrophies (MDs). Mesoangioblasts (MABs) constitute a myogenic subset of muscle pericytes and have been shown to efficiently regenerate dystrophic muscles in mice and dogs. In addition, HLA-matched MABs are currently being tested in a phase 1 clinical study on Duchenne MD patients (EudraCT #2011-000176-33). Many reports indicate that the Notch pathway regulates muscle regeneration and satellite cell commitment. However, little is known about Notch-mediated effects on other resident myogenic cells. To possibly potentiate MAB-driven regeneration in vivo, we asked whether Notch signaling played a pivotal role in regulating MAB myogenic capacity. Through different approaches of loss- and gain-of-function in murine and human MABs, we determined that the interplay between Delta-like ligand 1 (Dll1)-activated Notch1 and Mef2C supports MAB commitment in vitro and ameliorates engraftment and functional outcome after intra-arterial delivery in dystrophic mice. Furthermore, using a transgenic mouse model of conditional Dll1 deletion, we demonstrated that Dll1 ablation, either on the injected cells, or on the receiving muscle fibers, impairs MAB regenerative potential. Our data corroborate the perspective of advanced combinations of cell therapy and signaling tuning to enhance therapeutic efficaciousness of somatic stem cells.

Superselective Intracerebral Catheterization for Administration of Oncolytic Virotherapy in a Case of Diffuse Intrinsic Pontine Glioma

New therapies are needed to improve current results in diffuse intrinsic pontine glioma. We present here the initial experience of administering Celyvir, autologous mesenchymal stem cells infected with ICOVIR-5, an oncolytic adenovirus that selectively replicates in cancer cells, by means of superselective intra-arterial delivery, in a patient diagnosed of diffuse intrinsic pontine glioma. Feasibility, safety, and morbidity rates of the superselective catheterization technique are comparable with those of diagnostic angiography. The intra-arterial approach warrants a greater contact of the mesenchymal stem cells with the tumor mass, and minimizes hemorrhages or vascular disruption. The tolerance to the 2 administrations was excellent, with no acute or delayed adverse effect, underscoring the feasibility of this technique for the delivery of virotherapies and/or cellular therapies in this location.

The effect of intra-arterial delivery of temozolomide with or without osmotic blood-brain barrier disruption and combined to radiotherapy

The effect of intra-arterial delivery of temozolomide with or without osmotic blood-brain barrier disruption and combined to radiotherapy

Intra-arterial delivery of AAV vectors to the mouse brain after mannitol mediated blood brain barrier disruption

The delivery of therapeutics to neural tissue is greatly hindered by the blood brain barrier (BBB). Direct local delivery via diffusive release from degradable implants or direct intra-cerebral injection can bypass the BBB and obtain high concentrations of the therapeutic in the targeted tissue, however the total volume of tissue that can be treated using these techniques is limited. One treatment modality that can potentially access large volumes of neural tissue in a single treatment is intra-arterial (IA) injection after osmotic blood brain barrier disruption. In this technique, the therapeutic of interest is injected directly into the arteries that feed the target tissue after the blood brain barrier has been disrupted by exposure to a hyperosmolar mannitol solution, permitting the transluminal transport of the therapy. In this work we used contrast enhanced magnetic resonance imaging (MRI) studies of IA injections in mice to establish parameters that allow for extensive and reproducible BBB disruption. We found that the volume but not the flow rate of the mannitol injection has a significant effect on the degree of disruption. To determine whether the degree of disruption that we observed with this method was sufficient for delivery of nanoscale therapeutics, we performed IA injections of an adeno-associated viral vector containing the CLN2 gene (AAVrh.10CLN2), which is mutated in the lysosomal storage disorder Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL). We demonstrated that IA injection of AAVrh.10CLN2 after BBB disruption can achieve widespread transgene production in the mouse brain after a single administration. Further, we showed that there exists a minimum threshold of BBB disruption necessary to permit the AAV.rh10 vector to pass into the brain parenchyma from the vascular system. These results suggest that IA administration may be used to obtain widespread delivery of nanoscale therapeutics throughout the murine brain after a single administration.

Spatial mapping of drug delivery to brain tissue using hyperspectral spatial frequency-domain imaging.

We present an application of spatial frequency-domain imaging (SFDI) to the wide-field imaging of drug delivery to brain tissue. Measurements were compared with values obtained by a previously validated variation of diffuse reflectance spectroscopy, the method of optical pharmacokinetics (OP). We demonstrate a crosscorrelation between the two methods for absorption extraction and drug concentration determination in both experimental tissue phantoms and freshly extracted rodent brain tissue. These methods were first used to assess intra-arterial (IA) delivery of cationic liposomes to brain tissue in Sprague Dawley rats under transient cerebral hypoperfusion. Results were found to be in agreement with previously published experimental data and pharmacokinetic models of IA drug delivery. We then applied the same scheme to evaluate IA mitoxantrone delivery to glioma-bearing rats. Good correlation was seen between OP and SFDI determined concentrations taken from normal and tumor averaged sites. This study shows the feasibility of mapping drug/tracer distributions and encourages the use of SFDI for spatial imaging of tissues for drug/tracer-tagged carrier deposition and pharmacokinetic studies.

Development and Validation of Endovascular Chemotherapy Filter Device for Removing High-Dose Doxorubicin: Preclinical Study.

To develop a novel endovascular chemotherapy filter (CF) able to remove excess drug from the blood during intra-arterial chemotherapy delivery (IAC), thus preventing systemic toxicities and thereby enabling higher dose IAC. A flow circuit containing 2.5 mL of ion-exchange resin was constructed. Phosphate-buffered saline (PBS) containing 50 mg doxorubicin (Dox) was placed in the flow model with the hypothesis that doxorubicin would bind rapidly to resin. To simulate IAC, 50 mg of doxorubicin was infused over 10 min into the flow model containing resin. Similar testing was repeated with porcine serum. Doxorubicin concentrations were measured over 60 min and compared to controls (without resin). Single-pass experiments were also performed. Based on these experiments, an 18F CF was constructed with resin in its tip. In a pilot porcine study, the device was deployed under fluoroscopy. A control hepatic doxorubicin IAC model (no CF placed) was developed in another animal. A second CF device was created with a resin membrane and tested in the infrarenal inferior vena cava (IVC) of a swine. In the PBS model, resin bound 76% of doxorubicin in 10 min, and 92% in 30 min (P < 0.001). During IAC simulation, 64% of doxorubicin bound in 10 min and 96% in 60 min (P < 0.001). On average, 51% of doxorubicin concentration was reduced during each pass in single pass studies. In porcine serum, 52% of doxorubicin bound in 10 min, and 80% in 30 min (P < 0.05). CF device placement and administration of IAC were successful in three animals. No clot was present on the resin within the CF following the in vivo study. The infrarenal IVC swine study demonstrated promising results with up to 85% reduction in peak concentration by the CF device. An endovascular CF device was developed and shown feasible in vitro. An in vivo model was established with promising results supporting high-capacity rapid doxorubicin filtration from the blood that can be further evaluated in future studies.

Encapsulated cells expressing a chemotherapeutic activating enzyme allow the targeting of subtoxic chemotherapy and are safe and efficacious: data from two clinical trials in pancreatic cancer.

Despite progress in the treatment of pancreatic cancer, there is still a need for improved therapies. In this manuscript, we report clinical experience with a new therapy for the treatment of pancreatic cancer involving the implantation of encapsulated cells over-expressing a cytochrome P450 enzyme followed by subsequent low-dose ifosfamide administrations as a means to target activated ifosfamide to the tumor. The safety and efficacy of the angiographic instillation of encapsulated allogeneic cells overexpressing cytochrome P450 in combination with low-dose systemic ifosfamide administration has now been evaluated in 27 patients in total. These patients were successfully treated in four centers by three different interventional radiologists, arguing strongly that the treatment can be successfully used in different centers. The safety of the intra-arterial delivery of the capsules and the lack of evidence that the patients developed an inflammatory or immune response to the encapsulated cells or encapsulation material was shown in all 27 patients. The ifosfamide dose of 1 g/m2/day used in the first trial was well tolerated by all patients. In contrast, the ifosfamide dose of 2 g/m2/day used in the second trial was poorly tolerated in most patients. Since the median survival in the first trial was 40 weeks and only 33 weeks in the second trial, this strongly suggests that there is no survival benefit to increasing the dose of ifosfamide, and indeed, a lower dose is beneficial for quality of life and the lack of side effects. This is supported by the one-year survival rate in the first trial being 38%, whilst that in the second trial was only 23%. However, taking the data from both trials together, a total of nine of the 27 patients were alive after one year, and two of these nine patients were alive for two years or more.

O-016 Development and Validation of an Endovascular Chemotherapy Filter Device for Removing High-Dose Doxorubicin from the Blood: In Vivo Porcine Study

Purpose A novel disposable endovascular chemotherapy filter (CF) device was developed to remove excess doxorubicin (Dox) from the blood during intra-arterial chemotherapy delivery to prevent systemic toxicities. Previous proof-of-concept established...