Automated Quantitative Imaging Measurements of Disease Severity in Patients with Nonthrombotic Iliac Vein Compression.

PURPOSE: An automated segmentation technique (AST) for computed tomography (CT) venography was developed to quantify measures of disease severity before and after stent placement in patients with left-sided nonthrombotic iliac vein compression. MATERIALS AND METHODS: Twenty-one patients with left-sided nonthrombotic iliac vein compression who underwent venous stent placement were retrospectively identified. Pre- and poststent CT venography studies were quantitatively analyzed using an AST to determine leg volume, skin thickness, and water content of fat. These measures were compared between diseased and nondiseased limbs and between pre- and poststent images, using patients as their own controls. Additionally, patients with and without postthrombotic lesions were compared. RESULTS: The AST detected significantly increased leg volume (12,437 cm3 vs 10,748 cm3, P < .0001), skin thickness (0.531 cm vs 0.508 cm, P < .0001), and water content of fat (8.2% vs 5.0%, P < .0001) in diseased left limbs compared with the contralateral nondiseased limbs, on prestent imaging. After stent placement in the left leg, there was a significant decrease in the water content of fat in the right (4.9% vs 2.7%, P < .0001) and left (8.2% vs 3.2%, P < .0001) legs. There were no significant changes in leg volume or skin thickness in either leg after stent placement. There were no significant differences between patients with or without postthrombotic lesions in their poststent improvement across the 3 measures of disease severity. CONCLUSIONS: ASTs can be used to quantify measures of disease severity and postintervention changes on CT venography for patients with lower extremity venous disease. Further investigation may clarify the clinical benefit of such technologies.

Why Temporary Filters Are Not Removed: Clinical Predictors in 1,000 Consecutive Cases.

BACKGROUND: Compared to permanent inferior vena cava (IVC) filters, higher complication rates occur with long-term use of temporary IVC filters. We aimed to identify patient clinical factors at the time of placement that could predict failure to remove a temporary IVC filter. METHODS: A retrospective review was performed of both vascular surgery and interventional radiology prospective databases between December 2008 and December 2013. We analyzed a total number of 1,024 consecutive, temporary IVC filters stratified by whether retrieval was attempted or made permanent. Univariate, multivariate, and prediction modeling analyses with internal validation were performed on abstracted data, which included risk factors, treatment modalities, and indications for IVC filter placement. RESULTS: Of 1,024 temporary IVC filters, removal was attempted in 60% and no attempt at removal (kept permanent) in 40%. Of the 619 with attempted removal, the overall successful retrieval rate was 95%. The majority of filters were not attempted to be removed because of persistent filter indications (360 cases). Risk factors associated with IVC filter permanence included male sex, older age, history, or indication of venous thromboembolism (VTE) with inability to anticoagulate, malignancy, and neurologic condition. Risk factors most predictive of permanence in the multivariate model were malignancy (odds ratio [OR]: 3.0, P < 0.001) or neurologic disorder (OR: 2.69, P = 0.0005). Validation revealed our model had a sensitivity of 60.4% and specificity of 69.9%. CONCLUSIONS: Our study shows that patients who are more likely to have a temporary IVC filter kept permanent are more likely to be older males with a history of malignancy, neurologic condition, or VTE. These factors are also predictive of permanence and can be used in our predictive model to provide insight into the significant preoperative risk factors that should play into the decision-making process.

Image-guided local delivery strategies enhance therapeutic nanoparticle uptake in solid tumors.

Nanoparticles (NP) have emerged as a novel class of therapeutic agents that overcome many of the limitations of current cancer chemotherapeutics. However, a major challenge to many current NP platforms is unfavorable biodistribution, and limited tumor uptake, upon systemic delivery. Delivery, therefore, remains a critical barrier to widespread clinical adoption of NP therapeutics. To overcome these limitations, we have adapted the techniques of image-guided local drug delivery to develop nanoablation and nanoembolization. Nanoablation is a tumor ablative strategy that employs image-guided placement of electrodes into tumor tissue to electroporate tumor cells, resulting in a rapid influx of NPs that is not dependent on cellular uptake machinery or stage of the cell cycle. Nanoembolization involves the image-guided delivery of NPs and embolic agents directly into the blood supply of tumors. We describe the design and testing of our innovative local delivery strategies using doxorubicin-functionalized superparamagnetic iron oxide nanoparticles (DOX-SPIOs) in cell culture, and the N1S1 hepatoma and VX2 tumor models, imaged by high resolution 7T MRI. We demonstrate that local delivery techniques result in significantly increased intratumoral DOX-SPIO uptake, with limited off-target delivery in tumor-bearing animal models. The techniques described are versatile enough to be extended to any NP platform, targeting any solid organ malignancy that can be accessed via imaging guidance.

Optional or permanent: clinical factors that optimize inferior vena cava filter utilization.

PURPOSE: To test the hypothesis that patient parameters identifiable at the time of inferior vena cava (IVC) filter placement can be used to predict the need for a permanent versus optional filter. MATERIALS AND METHODS: A comprehensive institutional database of details and patient parameters for all optional IVC filters placed at a single institution between December 2008 and July 2011 was reviewed. IVC filters were categorized as removed if removal was attempted or as kept permanent if not. Patient parameters (age, sex, history of venous thromboembolism [VTE], presence of neurologic disease or malignancy, indication for filter placement) were compared between groups by multiple logistic regression analysis, and a prediction model based on these parameters was constructed. RESULTS: A total of 265 optional IVC filters were placed and analyzed; 167 were removed and 98 were kept permanent. In the multivariable model predicting filter disposition, significant factors associated with permanence were age (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.01-1.05), male sex (OR, 3.01; 95% CI, 1.64-5.54), underlying malignancy (OR, 3.27; 95% CI, 1.77-6.03), and an indication of anticoagulation failure (OR, 8.12; 95% CI, 1.83-36.0). Significant factors associated with removal were history of VTE (OR, 0.39; 95% CI, 0.21-0.74), prophylactic filter placement indication (OR, 0.14; 95% CI, 0.04-0.43), and high-risk VTE (OR, 0.37; 95% CI, 0.15-0.94). The c-statistic for the prediction model based on these parameters was 0.80. CONCLUSIONS: Patient parameters can be used to quantitatively predict an optional IVC filter being kept permanent. These findings can aid in optimization of prospective decision-making in IVC filter placement.

Optimizing IVC filter utilization: a prospective study of the impact of interventional radiologist consultation.

PURPOSE: The use of inferior vena cava filters (IVCFs) is under increasing scrutiny because of device safety and economic considerations. The aim of this study was to test the hypothesis that interventional radiologist (IR) consultation results in better utilization of optional and permanent filters. METHODS: Over 6 months, an IVCF decision-making database at a single institution was prospectively studied. After IR consultation, each case was classified as concordant (agreement between the referring physician and the IR over filter choice) or discordant (disagreement over filter choice). The consulting IR estimated the likelihood of retrieval attempt for all optional filters at the time of placement (0%-100%). Chi-square and t tests were used for statistical analyses. The null hypotheses were rejected at P < .05. RESULTS: Sixty-six IVCFs (23 permanent, 43 optional) were placed in 66 patients. Sixteen of 66 decisions were discordant. In 7 of the 16 discordant cases, patients received optional filters; of these, 6 (86%) were declared permanent by the referring physician. For this group, the IR's prospective estimate of subsequent retrieval was 6.4% (0%-15%; P < .001). Fifty of 66 decisions were concordant. Of these, 36 patients received optional filters. Thirty-one of 36 concordant optional filters (86%) were successfully retrieved (P < .001). For this group, the IR's prospective estimate of subsequent retrieval was 88.3% (80%-100%; P < .001). Of the 5 concordant devices not retrieved, 2 patients died, and 3 devices were declared permanent. There were no IVCF placement or retrieval failures. No patients were lost to follow-up. CONCLUSIONS: Interventional radiologists can prospectively predict the likelihood of optional filter retrieval. Significantly higher retrieval rates are achieved as a result of IR consultation. Interventional radiologist consultation positively affects IVCF device choice, patient safety, and effective utilization.

Nanoparticle therapeutics: FDA approval, clinical trials, regulatory pathways, and case study.

The approval of drugs for human use by the US Food and Drug Administration (FDA) through the Center for Drug Evaluation and Research (CDER) is a time-consuming and expensive process, and approval rates are low (DiMasi et al., J Health Econ 22:151-185, 2003; Marchetti and Schellens, Br J Cancer 97:577-581, 2007). In general, the FDA drug approval process can be separated into preclinical, clinical, and postmarketing phases. At each step from the point of discovery through demonstration of safety and efficacy in humans, drug candidates are closely scrutinized. Advances in nanotechnology are being applied in the development of novel therapeutics that may address a number of shortcomings of conventional small molecule drugs and may facilitate the realization of personalized medicine (Ferrari, Curr Opin Chem Biol 9:343-346, 2005; Ferrari, Nat Rev Cancer 5:161-171, 2005; Ferrari and Downing, BioDrugs 19:203-210, 2005). Appealingly, nanoparticle drug candidates often represent multiplexed formulations (e.g., drug, targeting moiety, and nanoparticle scaffold material). By tailoring the chemistry and identity of variable nanoparticle constituents, it is possible to achieve targeted delivery, reduce side effects, and prepare formulations of unstable (e.g., siRNA) and/or highly toxic drugs (Ferrari, Curr Opin Chem Biol 9:343-346, 2005; Ferrari, Nat Rev Cancer 5:161-171, 2005; Ferrari and Downing, BioDrugs 19:203-210, 2005). With these benefits arise new challenges in all aspects of regulated drug development and testing.This chapter distils the drug development and approval process with an emphasis on special considerations for nanotherapeutics. The chapter concludes with a case study focused on a nanoparticle therapeutic, CALAA-01, currently in human clinical trials, that embodies many of the potential benefits of nanoparticle therapeutics (Davis, Mol Pharm 6:659-668, 2009). By choosing CALAA-01, reference is made to the infancy of the therapeutic nanoparticle field; in 2008, CALAA-01 was the first targeted siRNA nanoparticle therapeutic administered to humans. Certainly, there will be many more that will follow the lead of CALAA-01 and each will have its own unique challenges; however, much can be learned from this drug in the context of nanotherapeutics and the evolving development and approval process as it applies to them.

Functional magnetic resonance imaging in an animal model of pancreatic cancer.

AIM: To test the hypotheses that diffusion weighed (DW)- and transcatheter intraarterial perfusion (TRIP)-magnetic resonance imaging (MRI) can each be used to assess regional differences in tumor function in an animal pancreatic cancer model. METHODS: VX2 tumors were implanted in pancreata of 6 rabbits. MRI and digital subtraction angiography (DSA) were performed 3 wk following implantation. With a 2-French catheter secured in the rabbit's gastroduodenal artery, each rabbit was transferred to an adjacent 1.5T MRI scanner. DW- and TRIP-MRI were performed to determine if necrotic tumor core could be differentiated from viable tumor periphery. For each, we compared mean differences between tumor core/periphery using a 2-tailed paired t-test (alpha = 0.05). Imaging was correlated with histopathology. RESULTS: Tumors were successfully grown in all rabbits, confirmed by necropsy. On DW-MRI, mean apparent diffusion coefficient (ADC) value was higher in necrotic tumor core (2.1 +/- 0.3 mm(2)/s) than in viable tumor periphery (1.4 +/- 0.5 mm(2)/s) (P < 0.05). On TRIP-MRI, mean perfusion values was higher in tumor periphery (110 +/- 47 relative units) than in tumor core (66 +/- 31 relative units) (P < 0.001). CONCLUSION: Functional MRI can be used to differentiate necrotic from viable tumor cells in an animal pancreatic cancer model using ADC (DW-MRI) and perfusion (TRIP-MRI) values.

Development of a VX2 pancreatic cancer model in rabbits: a pilot study.

PURPOSE: An animal model of pancreatic cancer that is large enough to permit imaging and catheterization would be desirable for interventional radiologists to develop novel therapies for pancreatic cancer. The purpose of this study was to test the hypothesis that the VX2 rabbit model of pancreatic cancer could be developed as a suitable platform to test future interventional therapies. MATERIALS AND METHODS: The authors implanted and grew three pancreatic VX2 tumors per rabbit in six rabbits. Magnetic resonance (MR) imaging was performed at 2 weeks to confirm tumor growth. At 3 weeks, the authors selectively catheterized the gastroduodenal artery under guidance of x-ray digital subtraction angiography (DSA). T2-weighted anatomic imaging, diffusion-weighted MR imaging, and transcatheter intraarterial perfusion (TRIP) MR imaging were then performed. After imaging, tumors were confirmed at necropsy and histopathologically. Tumor sizes at 2 and 3 weeks were compared with a paired t test (P = .05). RESULTS: VX2 pancreatic tumors were grown in all six rabbits. The difference between tumor sizes at 2 and 3 weeks (1.29 cm +/- 0.39 vs 1.91 cm +/- 0.50, respectively) was significant (P < .001). All tumors were confirmed to be located within pancreatic tissue via histopathologic analysis. DSA and TRIP MR imaging were successful in five rabbits. Diffusion-weighted and anatomic MR imaging were successful in all six rabbits. CONCLUSIONS: The VX2 rabbit model of pancreatic cancer is feasible, as verified by imaging and pathologic correlation, and may be a suitable platform to test future interventional therapies.