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Original Article |
1 Department for General, Visceral, and Vascular Surgery, University of Saarland, D-66421 Homburg/Saar, Germany
2 Department of Radiology, University of Saarland, D-66421, Homburg/Saar, Germany
3 Institute for Clinical & Experimental Surgery, University of Saarland, D-66421, Homburg/Saar, Germany
4 Department of Experimental Surgery, University of Rostock, D-18055, Rostock, Germany
Correspondence: Address correspondence and reprint requests to: Michael D. Menger, MD; E-mail: exmdme{at}uniklinik-saarland.de.
Background: Tissue destruction by cryosurgery not only is mediated by direct cell damage, but also involves secondary mechanisms, such as ischemia due to shutdown of the microcirculation. Clinicians favor repetitive cryoapplication, although there is no proven evidence for a more effective tumor eradication.
Methods: The aims of this study were (1) to establish a rat liver tumor model that allows for intravital microscopic analysis of hepatic tumor microcirculation and (2) to elucidate critical determinants of shutdown of microvascular perfusion after single and repetitive cryotherapy. In WAG-Rji rats (n = 14), syngeneic colon carcinoma cells (CC531) were implanted into the left liver lobe. Hepatic and tumor microcirculation were studied by intravital microscopy.
Results: Two weeks after implantation, the tumors had developed a microvasculature with a capillary density markedly (P < .05) lower compared with the sinusoidal density of normal liver. However, at the tumor margin, venule diameters were significantly enlarged (P < .05), with high red blood cell velocities and arteriolovenular shunts. Both freeze procedures (temperature at the tumor margin: –32.4°C ± 1.6°C and –36.4°C ± 2.0°C) resulted in a complete shutdown of intratumoral and peritumoral capillary and hepatic sinusoidal perfusion. In contrast, some large venules showed maintenance of blood flow initially after freezing (15 minutes); however, this was abolished during the subsequent 2-hour observation period.
Conclusions: Enlarged high-flow venules at the tumor margin, which participate in arteriolovenular shunting, critically determine the shutdown of the microcirculation upon cryotherapy. Repetitive freezing is not more effective than a single-freeze procedure to achieve complete tumor microcirculatory stasis.
Key Words: Cryotherapy • Cryosurgery • Microcirculation • Hepatic carcinoma • Hepatic metastasis • Colon carcinoma
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