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.

Comparison of hypoxia-inducible factor-1alpha expression before and after transcatheter arterial embolization in rabbit VX2 liver tumors.

PURPOSE: To test the hypothesis that transcatheter arterial embolization (TAE) induces expression of hypoxia-inducible factor-1alpha (HIF-1alpha) within the same rabbit VX2 liver tumor. MATERIALS AND METHODS: Seven VX2 tumors were grown in the livers of five New Zealand white rabbits. Ultrasonography-guided biopsy was performed before and 10 minutes after TAE in all tumors. Pre- and post-TAE tumor biopsy specimens along with post-TAE whole liver tumor sections were stained with HIF-1alpha antibody and analyzed for percentage of HIF-1alpha-positive nuclei by using a spectral unmixing system mounted on a high-powered microscope. Statistical data comparisons were performed with the Wilcoxon signed-rank test (alpha = 0.05). RESULTS: TAE of liver tumors resulted in a statistically significant increase in the mean percentage of HIF-1alpha expression. The mean percentage of HIF-1alpha-positive stained nuclei increased from 23% +/- 3.5 in pre-TAE biopsy specimens to 41% +/- 8.7 in post-TAE biopsy specimens (P < .02). The increase was even more significant when the mean percentage of HIF-1alpha-positive stained nuclei from the same pre-TAE biopsy specimens was compared with sections from post-TAE whole tumor specimens (60% +/- 8.9, P < .02). CONCLUSIONS: The results of this study revealed that hypoxia caused by TAE of VX2 liver tumors activates HIF-1alpha, a transcription factor that in turn regulates other pro-angiogenic factors.

MR tracking of iron-labeled glass radioembolization microspheres during transcatheter delivery to rabbit VX2 liver tumors: feasibility study.

PURPOSE: To prospectively test the hypothesis that iron labeling of radioembolization microspheres permits their visualization by using magnetic resonance (MR) imaging for in vivo tracking during transcatheter delivery to liver tumors. MATERIALS AND METHODS: All experiments were approved by the Institutional Animal Care and Use Committee. Phantom studies were performed to quantify microsphere relaxivity and volume susceptibility properties and compare image contrast patterns resulting from aggregate deposition of unlabeled and iron-labeled microspheres. In seven rabbits in which nine VX2 liver tumors were implanted, T2*-weighted gradient-echo (GRE) MR images with negative image contrast (NC), white-marker (WM) GRE images with positive image contrast (PC), and on-resonance water-suppression turbo spin-echo (SE) images with PC were obtained before and after catheter-directed administration of microspheres into the hepatic artery. During each injection, serial GRE acquisitions were performed for real-time visualization of microsphere delivery. Contrast-to-noise ratios (CNRs) were measured between regions of microsphere accumulation and regions of normal liver parenchyma that demonstrated no apparent microsphere accumulation. Pre- and postinjection CNR measurements at identical spatial positions were compared by using paired t test (alpha = .05). RESULTS: Conventional microspheres did not produce detectable image contrast in phantoms. Iron-labeled microspheres produced susceptibility-induced dipole patterns with spatial extent of image contrast increasing with increasing microsphere dose. Real-time image series depicted both preferential delivery to tumor tissues and nontargeted delivery to adjacent organs. T2*-weighted GRE, WM GRE, and on-resonance water-suppression turbo SE each permitted in vivo visualization of the microsphere deposition, with postinjection CNR values (mean, 14.29 +/- 3.98 [standard deviation], 1.87 +/- 0.93, and 19.30 +/- 8.72, respectively) significantly greater than corresponding preinjection CNR values (mean, 2.02 +/- 4.65, 0.02 +/- 0.27, 0.85 +/- 2.65, respectively) (P < .05). CONCLUSION: Microsphere tracking during radioembolization may permit real-time verification of delivery and detection of extrahepatic shunting.

Four-dimensional transcatheter intraarterial perfusion (TRIP)-MRI for monitoring liver tumor embolization in VX2 rabbits.

Transcatheter intraarterial perfusion (TRIP)-MRI is an intraprocedural technique to iteratively monitor liver tumor perfusion changes during transcatheter arterial embolization (TAE) and chemoembolization (TACE). However, previous TRIP-MRI approaches using two-dimensional (2D) T(1)-weighted saturation-recovery gradient-recalled echo (GRE) sequences provided only limited spatial coverage and limited capacity for accurate perfusion quantification. In this preclinical study, a quantitative 4D TRIP-MRI technique (serial iterative 3D volumetric perfusion imaging) with rigorous radiofrequency (RF) B(1) field calibration and dynamic tissue longitudinal relaxation rate R(1) measurement is presented for monitoring intraprocedural liver tumor perfusion during TAE. 4D TRIP-MRI and TAE were performed in five rabbits with eight VX2 liver tumors (N = 8). After B(1) calibrated baseline and dynamic R(1) quantification, subsequent tissue contrast agent concentration time curves were derived. A single-input flow-limited pharmacokinetic model and peak gradient method were applied for perfusion analysis. The perfusion Frho reduced significantly from pre-TAE 0.477 (95% confidence interval [CI]: 0.384-0.570) to post-TAE 0.131 (95% CI: 0.080-0.183 ml/min/ml, P < 0.001).

Gadolinium-conjugated TiO2-DNA oligonucleotide nanoconjugates show prolonged intracellular retention period and T1-weighted contrast enhancement in magnetic resonance images.

Nanoconjugates composed of titanium dioxide (TiO2) nanoparticles, DNA oligonucleotides, and a gadolinium (Gd) contrast agent were synthesized for use in magnetic resonance imaging. Transfection of cultured cancer cells with these nanoconjugates showed them to be superior to the free contrast agent of the same formulation with regard to intracellular accumulation, retention, and subcellular localization. Our results have shown that 48 hours after treatment, the concentration of Gd in nanoconjugate-treated cells was 1000-fold higher than in cells treated with contrast agent alone. Consequently, T1-weighted contrast enhancements were observed in cells treated with nanoconjugates but not in cells treated by the contrast agent alone. This type of nanoconjugate with increased retention time, Gd accumulation, and intracellular delivery may find its use in Gd neutron-capture cancer therapy.

Comparison of two different methods for inoculating VX2 tumors in rabbit livers and hind limbs.

PURPOSE: To compare two methods to (a) propagate VX2 cell strain in rabbit hind limbs and (b) inoculate liver parenchymal tumors in rabbits. MATERIALS AND METHODS: One hundred forty-two New Zealand white rabbits were used for this study (60 with hind limb tumor [donors] and 82 with liver tumors [recipients]). In the donor group, nine rabbits received frozen VX2 cell suspension and 51 were injected with freshly prepared VX2 cell suspension. In the recipient group, 32 rabbits were injected with VX2 tumor cells and 50 were implanted with a small tumor fragment in the liver parenchyma. Success rates in terms of tumor growth were compared by using chi(2) or Fisher exact tests, with alpha = .05. RESULTS: Hind limb and liver tumors were successfully grown in 48 of the 60 rabbits in the donor group (80%) and 57 of the 82 rabbits in the recipient group (70%). The success rate of growing hind limb tumors increased from 33% (three of nine rabbits) to 88% (45 of 51 rabbits) when fresh VX2 cells instead of frozen were injected percutaneously (P < .0011). Similarly, the success rate for VX2 liver tumors almost doubled from 47% (15 of 32 rabbits) to 84% (42 of 50 rabbits) when a tumor fragment instead of VX2 cell suspension was used (P < .00036). This also significantly reduced the frequency of metastasis (P < .005). CONCLUSIONS: The authors recommend (a) the use of fresh VX2 cell suspension for percutaneous injection in the hind limbs of rabbits to maintain the VX2 cell strain and (b) the surgical implantation of freshly harvested VX2 tumor fragment into the liver parenchyma to establish liver tumors.

Comparison of transcatheter intraarterial perfusion MR imaging and fluorescent microsphere perfusion measurements during transcatheter arterial embolization of rabbit liver tumors.

PURPOSE: Transcatheter intraarterial perfusion (TRIP) magnetic resonance (MR) imaging is clinically used in the interventional MR imaging setting to verify distribution of injected embolic or chemoembolic material during liver-directed transcatheter therapies and to monitor reductions in perfusion. The accuracy of this technique remains unknown. In the present study, rabbit VX2 liver tumors were used to test the hypothesis that TRIP MR imaging accurately measures changes in tumor perfusion during transcatheter arterial embolization (TAE), with injection of fluorescent microspheres used as the gold-standard technique. MATERIALS AND METHODS: Five New Zealand White rabbits were used for this study (two donor rabbits and three with VX2 liver tumors). In three rabbits with implanted VX2 liver tumors, catheters were superselectively placed under digital subtraction angiographic guidance into the left hepatic artery supplying the targeted tumor. Fluorescent microspheres were injected into each rabbit's left ventricle before and after TAE. TRIP MR images were obtained at baseline and after embolizations for all rabbits with intraarterial injections of 2.5% gadopentetate dimeglumine solution. Linear regression was used to compare relative reductions in tumor perfusion between TRIP MR imaging and fluorescent microspheres. Results were considered statistically significant at a P value less than .05. RESULTS: There was good correlation between TRIP MR imaging and fluorescent microsphere measurements of reduction in tumor perfusion (r = 0.722, P < .012). CONCLUSIONS: TRIP MR imaging provides accurate semiquantitative measurement of perfusion reduction during TAE in rabbit liver tumors.

Rabbit VX2 tumors as an animal model of uterine fibroids and for uterine artery embolization.

PURPOSE: To determine the suitability of the rabbit VX2 tumor animal model for uterine fibroids and uterine artery embolization (UAE). MATERIALS AND METHODS: The authors implanted and grew one uterine VX2 tumor per rabbit in six rabbits. UAE was performed by using 100-300 microm embolic particles and confirmed with x-ray digital subtraction angiography, magnetic resonance (MR) imaging, and necropsy. Unenhanced and contrast medium-enhanced MR images of VX2 tumors were obtained before and after UAE. Relative MR signal-to noise-ratio (SNR) was measured in the uterine VX2 tumor and in normal uterine tissue before and after UAE and compared by using a paired t-test (P = .05). RESULTS: VX2 uterine tumors were successfully grown, and both VX2 tumor presence in the uterus and UAE were seen angiographically and confirmed with necropsy in all six rabbits. Statistically significant reductions in relative SNRs were measured in tumors (SNR before UAE, 15.3 +/- 5.15; SNR after UAE, 3.84 +/- 3.94; P < .0001). No statistically significant decrease in SNR was measured in normal uterine tissue before and after UAE (P = .63 for the right uterine horn and P = .93 for the left uterine horn). CONCLUSION: Rabbit VX2 uterine tumors may be a suitable animal model of uterine fibroids and UAE.