Laboratory Investigation
Direct Quantification and Comparison of Intratumoral Hypoxia following Transcatheter Arterial Embolization of VX2 Liver Tumors with Different Diameter Microspheres

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Abstract

Purpose

To evaluate the effect of embolic diameter on achievement of hypoxia after embolization in an animal model of liver tumors.

Materials and Methods

Inoculation of VX2 tumors in the left liver lobe was performed successfully in 12 New Zealand white rabbits weighing 3.7 kg ± 0.5 (mean ± SD). Tumors were deemed eligible for oxygen measurements when the maximum transverse diameter measured 15 mm or more by ultrasound examination. Direct monitoring of oxygenation of implanted rabbit hepatic VX2 tumors was performed with a fiberoptic electrode during and after transarterial embolization of the proper hepatic artery to angiographic flow stasis with microspheres measuring 70–150 μm, 100–300 μm, or 300–500 μm in diameter.

Results

Failure to achieve tumor hypoxia as defined despite angiographic flow stasis was observed in 10 of 11 animals. Embolization microsphere size effect failed to demonstrate a significant trend on hypoxia outcome among the diameters tested, and pair-wise comparisons of different embolic diameter treatment groups showed no difference in hypoxia outcome. All microsphere diameters tested resulted in similar absolute reduction (24.3 mm Hg ± 18.3, 29.1 mm Hg ± 1.8, and 19.9 mm Hg ± 9.3, P = .66) and percentage decrease in oxygen (56.0 mm Hg ± 23.9, 56.0 mm Hg ± 6.4, and 35.8 mm Hg ± 20.6, P = .65). Pair-wise comparisons for percent tumor area occupied by embolic agents showed a significantly reduced fraction for 300–500 μm diameters compared with 70–150 μm diameters (P < .05).

Conclusions

In the rabbit VX2 liver tumor model, three tested microsphere diameters failed to cause tumor hypoxia as measured by a fiberoptic probe sensor according to the adopted hypoxia definitions.

Section snippets

Materials and Methods

Animal care and experimental design were approved by a National Institutes of Health Institutional Animal Care and Use Committee. VX2 tumors were propagated as described by Lee et al (9) and Geschwind et al (10) and modified by Ranjan et al (11). Briefly, VX2 was propagated in a donor rabbit and inoculated into subsequent donor (hindlimb) rabbits as a single cell suspension under ultrasound guidance. VX2 intrahepatic tumors were established by percutaneous injection of tumor fragments into the

Results

All inclusion criteria for liver tumor size and oxygen measurements were met by 11 animals (n = 3–4 per group). The overall mean VX2 tumor size treated was 2.05 cm ± 0.4, and individual cohort means as determined sonographically (maximum dimension) were 2.47 cm ± 0.51 (70–150 µm), 2.00 cm ± 0.22 (100–300 µm), and 1.78 cm ± 0.21 (300–500 µm), with no statistical difference between groups (P = .19). The distribution of hypovascular tumors was similar, and there was no difference in baseline tumor

Discussion

There is considerable variation in the reported critical thresholds for Po2 in tissue below which vital cellular functions cease (1, 14, 15, 16). In vitro studies have shown that oxidative phosphorylation for adenosine triphosphate can still occur despite cellular Po2 of 0.5–10 mm Hg (14, 15, 16). Hockel and Vaupel reported critical Po2 thresholds for solid tumors and concluded that detrimental changes in metabolic functions resulted below a Po2 of 8–10 mm Hg (1). Vaupel et al (17) identified

Acknowledgment

This research was supported by the Center for Interventional Oncology in the Intramural Research Program (Grant No. ZID BC 011242-06) of the National Institutes of Health. The National Institutes of Health and Biocompatibles BTG are parties to a Cooperative Research and Development Agreement. We thank the Division of Veterinary Resources staff for their expertise and assistance with the animal studies, Dr. Mariam Anver and the National Cancer Institute Pathology/Histotechnology Laboratory Staff

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    • Cited by (0)

    This research was performed while M.R.D was at the Center for Interventional Oncology at the National Institutes of Health, but M.R.D. is now a paid employee of Biocompatibles Inc. A.L.L. is a paid employee of Biocompatibles UK Ltd. B.J.W.’s research is funded wholly or in part by Biocompatibles Inc. None of the other authors have identified a conflict of interest.

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