Although surgical resection is the gold standard for management of small renal masses (SRM), many patients are not surgical candidates due to extensive co-morbidities. Percutaneous cryoablation (PCA) has emerged as an alternative to resection, with low morbidity and oncologic efficacy. We present a retrospective review of efficacy of this therapy with median follow-up of 3 years. After Institutional Review Board approval, we retrospectively reviewed all cases between February 2008 and June 2013. Patient demographics, clinical characteristics, tumor features, and postprocedural outcomes were recorded. Tumors were characterized by R.E.N.A.L. Nephrometry score, a reproducible standardized classification system that grades the salient anatomic characteristics of the lesion. Technical success was defined as ice-ball extension beyond the outer margin of the lesion, and post-contrast images within 3 months demonstrating no contrast enhancement. Local progression was defined as new enhancement within the ablated tumor, or interval tumor growth. Complications were defined using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. Multivariate analysis was performed to evaluate predictors of treatment failure and mortality, with a p<0.05 considered statistically significant. From February 2008 to June 2013, 75 patients underwent 80 PCA procedures. Mean patient age was 70.9 years, with a median follow-up of 36 months. Mean tumor size was 2.2 cm (range: 0.8-5.8), with a mean nephrometry score of 6.2 (range: 4-10). A single major complication was observed (1%). Technical success was achieved in all treatments (100%). Local progression was observed in five patients (7%). Three year overall survival was 94%, with a 5 year overall survival of 73%. Overall treatment success rate was 95%. On multivariate analysis, nephrometry score was the only significant predictor of treatment failure (hazard ratio, 1.5, p=0.04). PCA is safe and effective therapy for management of SRMs in patients not amenable to surgical resection. Lesions with higher nephrometry scores, denoting increased tumor complexity, are associated with higher risk of treatment failure.

Purpose The rationale for this study was to develop and validate methods to non-invasively quantify drug delivery to tumors. The ideal animal model of hepatocellular carcinoma (HCC) would have histological similarity to human HCC yet permit intraarterial (IA) delivery of therapies. The hypervascular McA-RH7777 tumor in the diminutive Buffalo rat resembles HCC histologically, while the N1S1 tumor in the larger Sprague-Dawley rat is hypovascular. We tested the hypotheses that: a) hypervascular McA tumors can be grown in Sprague-Dawley rats; and b) 7T magnetic resonance imaging (MRI) can quantify intra-tumoral uptake of doxorubicin-loaded superparamagnetic iron oxide nanoparticles (DOX-SPIOs) in this model. Materials and Methods We implanted McA cells into multiple sites in the livers of 18 Sprague-Dawley rats. In successfully inoculated animals, we delivered DOX-SPIOs to tumors via the intravenous (IV) (n=9) or IA (n=11) route. Three identical sets of nanoparticle phantoms were used to validate image analysis methods. We obtained pre- and post-treatment T2*-weighted images using 7T MRI, and obtained ΔR2* from mean signal intensities of tumors in these images. We measured tumor iron concentration ([Fe]), an indicator of DOX-SPIO uptake, using mass spectroscopy. The primary outcome variable was the Pearson coefficient (r) to assess linear correlation between ΔR2* and [Fe]. Results Tumors grew successfully in 13/18 animals (72%). Mean maximum tumor diameter (Dmax) was 0.83 ± 0.25 cm (range: 0.31-1.42 cm). Phantom studies revealed a strong positive correlation between ΔR2* and [Fe], with r=0.99 (p Conclusion McA tumors can successfully be grown in Sprague-Dawley rats. MRI quantification of intra-tumoral uptake strongly correlated with iron concentrations in pathological specimens, suggesting that MRI may be used to quantify uptake of iron-oxide nanotherapeutics. In the future, these imaging methods could potentially be used by interventional oncologists as a tool to quantify drug delivery in patients.

Nanoparticles functionalized with chemotherapeutic drugs and MRI contrast agents can serve dual therapeutic and diagnostic applications. Nano-ablation (NA) employs reversible electroporation to temporarily increase cell membrane permeability, offering interventional oncologists a method to enhance drug delivery to tumors. However, it remains unknown if MRI can be combined with NA to predict intratumoral uptake of superparamagnetic iron oxide nanoparticles (SPIOs) injected intravenously. We aimed to test the hypothesis that T2*-w MRI can be used to quantitatively predict intratumoral uptake of SPIOs. Using the N1S1 model of hepatoma, we induced 11 liver tumors in Sprague-Dawley rats. T2*-w MRI was performed using a Bruker 7T ClinScan to determine baseline tumor T2* signal intensity. Two minutes after SPIO injection into the femoral vein, NA was applied to the liver tumor at 1300 V/cm (8 pulses, 100 μs pulse duration) using bipolar electrodes. Animals were euthanized 10 minutes after NA and MRI determined post-procedural tumor T2* signal intensity. We measured the iron concentration of the harvested tissue from treated subjects as a proxy for SPIO uptake using inductively-coupled plasma mass spectroscopy (ICP-MS). Mean tumor iron concentration was correlated with the mean change in tumor T2* (measured in ms) using linear regression, with p<0.05 considered significant. Change in T2*-w MRI signal intensity significantly correlated with tumor SPIO uptake after NA (p=0.014, r=0.71). On average, for each unit of T2* signal intensity change (one millisecond) there was 7.33 μg of iron uptake per mg of tumor tissue. Intratumoral uptake of SPIOs after NA can be successfully quantified with 7T MRI and this uptake correlates with gold standard pathology. Thus, MRI may be used as a non-invasive method to measure the dose of therapeutic nanoparticles taken up by target liver tumors. Before clinical translation, future studies should attempt to replicate these findings using a larger animal model of liver cancer at clinically relevant 1.5T or 3T MRI field strengths.

There is a critical unmet need to monitor intratumoral drug uptake non-invasively. Superparamagnetic iron oxide nanoparticles (SPIOs) are agents with dual diagnostic and therapeutic properties that may meet this need. However, systemic (IV) administration results in unfavorable biodistribution with minimal tumor delivery. To overcome this limitation we propose nano-embolization (NE) as the image-guided delivery of SPIOs and embolic agents directly into the blood supply of tumors. It remains unknown if MRI can quantify the amount of NPs delivered to tumors during NE. Using VX2 liver tumors, we tested the hypotheses that a) NE increases uptake of therapeutic SPIOs over IV administration and b) 7T MRI can quantify intratumoral drug delivery. We induced VX2 liver tumors in 20 rabbits, evenly dividing them into NE and control (IV) groups. Both groups received doxorubicin-loaded therapeutic SPIOs at 0.56 mg/kg body weight. For the NE group, SPIOs and ethiodol were delivered into the hepatic artery under fluoroscopy. T2*-weighted gradient echo imaging (Bruker 7T ClinScan MRI) was performed on both groups pre and post-treatment to quantify SPIO delivery and uptake using T2*W mapping. After necropsy, we used ICP-MS as the gold standard to measure SPIO concentrations in normal liver and tumor pathological specimens. We compared SPIO uptake between the groups using ANOVA with post-hoc Tukey analysis, with p<0.05 considered significant. NE significantly increased tumor SPIO uptake 240% over IV delivery alone (340 vs. 140 μg Fe/mg, p<0.05). This correlated with T2*W MRI, which showed a significant T2 signal drop in NE tumors over controls (ΔT2: 47.4 ms vs. 18.9 ms, p<0.05). Furthermore, NE resulted in 75% less off target delivery to healthy liver tissue than IV delivery (p<0.05). NE improves tumor uptake of therapeutic SPIOs over conventional IV administration, with significantly less off-target delivery. 7T MRI can also quantify SPIO uptake non-invasively. To determine the optimal dose of therapeutic nanoparticles to inject, future studies should correlate SPIO delivery with tumor response.