Isolated hepatic perfusion for lapine liver metastases: Impact of hyperthermia on permeability of tumor neovasculature

Michael F X Gnant, Linda A. Noll, Richard E. Terrill, Peter C. Wu, Adam C. Berger, Hung Q. Nguyen, Titia E. Lans, Bernard M. Flynn, Steven K. Libutti, David L. Bartlett, H. Richard Alexander

Research output: Contribution to journalArticle

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Abstract

Background. Hyperthermic isolated hepatic perfusion (IHP) has been shown to cause significant regression of advanced unresectable liver metastases in patients. Although there are different agents and treatment modalities used in IHP, the contribution of perfusion hyperthermia is unknown. Purpose. A large animal model of unresectable liver metastases and a technical standard for IHP in this model were established. This model was used to assess the effects of hyperthermia on vascular permeability of tumors and normal liver tissue during IHP. Methods. Sixty-five New Zealand White rabbits were used in a series of experiments. Disseminated liver tumors were established by direct injection of 1 x 106 VX-2 cells into the portal vein by laparotomy in anesthetized animals. Several surgical perfusion techniques were explored to determine a reliable and reproducible IHP model. Vascular permeability in tumor versus liver was then assessed with Evan's Blue labeled bovine albumin under normothermic (tissue temperature 36.5°C ± 0.5°C), moderate hyperthermic (39°C ± 0.5°C), or severe hyperthermic (41°C ± 0.5°C) conditions. Results. Tumor model and perfusion techniques were successfully established with inflow through the portal vein and outflow through an isolated segment of the inferior vena cava. A gravity driven perfusion circuit with stable perfusion parameters and complete vascular isolation was used. Vascular permeability was higher in tumor than in normal tissues (P = .03) at all time points during IHP. Hyperthermia resulted in a significant (up to 5-fold) increase in permeability of neovasculature; when severe hyperthermia was used, tumor vascular permeability was increased even more than normal liver permeability (P =.01). Conclusions. The VX-2/New Zealand White rabbit system can be used as a reproducible large-animal model for IHP of unresectable liver metastases. It can be used to characterize the contribution and mechanism of action of different treatment parameters used in IHP. Hyperthermia preferentially increases vascular permeability in tumors compared with liver tissue in a dose-dependent fashion, thus providing a mechanism for its presumed benefit during isolated organ perfusion.

Original languageEnglish (US)
Pages (from-to)890-899
Number of pages10
JournalSurgery
Volume126
Issue number5
DOIs
StatePublished - 1999
Externally publishedYes

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Permeability
Fever
Perfusion
Neoplasm Metastasis
Liver
Neoplasms
Capillary Permeability
Portal Vein
Animal Models
Rabbits
Evans Blue
Inferior Vena Cava
Gravitation
Laparotomy
Blood Vessels
Albumins

ASJC Scopus subject areas

  • Surgery

Cite this

Gnant, M. F. X., Noll, L. A., Terrill, R. E., Wu, P. C., Berger, A. C., Nguyen, H. Q., ... Alexander, H. R. (1999). Isolated hepatic perfusion for lapine liver metastases: Impact of hyperthermia on permeability of tumor neovasculature. Surgery, 126(5), 890-899. https://doi.org/10.1016/S0039-6060(99)70030-9

Isolated hepatic perfusion for lapine liver metastases : Impact of hyperthermia on permeability of tumor neovasculature. / Gnant, Michael F X; Noll, Linda A.; Terrill, Richard E.; Wu, Peter C.; Berger, Adam C.; Nguyen, Hung Q.; Lans, Titia E.; Flynn, Bernard M.; Libutti, Steven K.; Bartlett, David L.; Alexander, H. Richard.

In: Surgery, Vol. 126, No. 5, 1999, p. 890-899.

Research output: Contribution to journalArticle

Gnant, MFX, Noll, LA, Terrill, RE, Wu, PC, Berger, AC, Nguyen, HQ, Lans, TE, Flynn, BM, Libutti, SK, Bartlett, DL & Alexander, HR 1999, 'Isolated hepatic perfusion for lapine liver metastases: Impact of hyperthermia on permeability of tumor neovasculature', Surgery, vol. 126, no. 5, pp. 890-899. https://doi.org/10.1016/S0039-6060(99)70030-9
Gnant, Michael F X ; Noll, Linda A. ; Terrill, Richard E. ; Wu, Peter C. ; Berger, Adam C. ; Nguyen, Hung Q. ; Lans, Titia E. ; Flynn, Bernard M. ; Libutti, Steven K. ; Bartlett, David L. ; Alexander, H. Richard. / Isolated hepatic perfusion for lapine liver metastases : Impact of hyperthermia on permeability of tumor neovasculature. In: Surgery. 1999 ; Vol. 126, No. 5. pp. 890-899.
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title = "Isolated hepatic perfusion for lapine liver metastases: Impact of hyperthermia on permeability of tumor neovasculature",
abstract = "Background. Hyperthermic isolated hepatic perfusion (IHP) has been shown to cause significant regression of advanced unresectable liver metastases in patients. Although there are different agents and treatment modalities used in IHP, the contribution of perfusion hyperthermia is unknown. Purpose. A large animal model of unresectable liver metastases and a technical standard for IHP in this model were established. This model was used to assess the effects of hyperthermia on vascular permeability of tumors and normal liver tissue during IHP. Methods. Sixty-five New Zealand White rabbits were used in a series of experiments. Disseminated liver tumors were established by direct injection of 1 x 106 VX-2 cells into the portal vein by laparotomy in anesthetized animals. Several surgical perfusion techniques were explored to determine a reliable and reproducible IHP model. Vascular permeability in tumor versus liver was then assessed with Evan's Blue labeled bovine albumin under normothermic (tissue temperature 36.5°C ± 0.5°C), moderate hyperthermic (39°C ± 0.5°C), or severe hyperthermic (41°C ± 0.5°C) conditions. Results. Tumor model and perfusion techniques were successfully established with inflow through the portal vein and outflow through an isolated segment of the inferior vena cava. A gravity driven perfusion circuit with stable perfusion parameters and complete vascular isolation was used. Vascular permeability was higher in tumor than in normal tissues (P = .03) at all time points during IHP. Hyperthermia resulted in a significant (up to 5-fold) increase in permeability of neovasculature; when severe hyperthermia was used, tumor vascular permeability was increased even more than normal liver permeability (P =.01). Conclusions. The VX-2/New Zealand White rabbit system can be used as a reproducible large-animal model for IHP of unresectable liver metastases. It can be used to characterize the contribution and mechanism of action of different treatment parameters used in IHP. Hyperthermia preferentially increases vascular permeability in tumors compared with liver tissue in a dose-dependent fashion, thus providing a mechanism for its presumed benefit during isolated organ perfusion.",
author = "Gnant, {Michael F X} and Noll, {Linda A.} and Terrill, {Richard E.} and Wu, {Peter C.} and Berger, {Adam C.} and Nguyen, {Hung Q.} and Lans, {Titia E.} and Flynn, {Bernard M.} and Libutti, {Steven K.} and Bartlett, {David L.} and Alexander, {H. Richard}",
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T1 - Isolated hepatic perfusion for lapine liver metastases

T2 - Impact of hyperthermia on permeability of tumor neovasculature

AU - Gnant, Michael F X

AU - Noll, Linda A.

AU - Terrill, Richard E.

AU - Wu, Peter C.

AU - Berger, Adam C.

AU - Nguyen, Hung Q.

AU - Lans, Titia E.

AU - Flynn, Bernard M.

AU - Libutti, Steven K.

AU - Bartlett, David L.

AU - Alexander, H. Richard

PY - 1999

Y1 - 1999

N2 - Background. Hyperthermic isolated hepatic perfusion (IHP) has been shown to cause significant regression of advanced unresectable liver metastases in patients. Although there are different agents and treatment modalities used in IHP, the contribution of perfusion hyperthermia is unknown. Purpose. A large animal model of unresectable liver metastases and a technical standard for IHP in this model were established. This model was used to assess the effects of hyperthermia on vascular permeability of tumors and normal liver tissue during IHP. Methods. Sixty-five New Zealand White rabbits were used in a series of experiments. Disseminated liver tumors were established by direct injection of 1 x 106 VX-2 cells into the portal vein by laparotomy in anesthetized animals. Several surgical perfusion techniques were explored to determine a reliable and reproducible IHP model. Vascular permeability in tumor versus liver was then assessed with Evan's Blue labeled bovine albumin under normothermic (tissue temperature 36.5°C ± 0.5°C), moderate hyperthermic (39°C ± 0.5°C), or severe hyperthermic (41°C ± 0.5°C) conditions. Results. Tumor model and perfusion techniques were successfully established with inflow through the portal vein and outflow through an isolated segment of the inferior vena cava. A gravity driven perfusion circuit with stable perfusion parameters and complete vascular isolation was used. Vascular permeability was higher in tumor than in normal tissues (P = .03) at all time points during IHP. Hyperthermia resulted in a significant (up to 5-fold) increase in permeability of neovasculature; when severe hyperthermia was used, tumor vascular permeability was increased even more than normal liver permeability (P =.01). Conclusions. The VX-2/New Zealand White rabbit system can be used as a reproducible large-animal model for IHP of unresectable liver metastases. It can be used to characterize the contribution and mechanism of action of different treatment parameters used in IHP. Hyperthermia preferentially increases vascular permeability in tumors compared with liver tissue in a dose-dependent fashion, thus providing a mechanism for its presumed benefit during isolated organ perfusion.

AB - Background. Hyperthermic isolated hepatic perfusion (IHP) has been shown to cause significant regression of advanced unresectable liver metastases in patients. Although there are different agents and treatment modalities used in IHP, the contribution of perfusion hyperthermia is unknown. Purpose. A large animal model of unresectable liver metastases and a technical standard for IHP in this model were established. This model was used to assess the effects of hyperthermia on vascular permeability of tumors and normal liver tissue during IHP. Methods. Sixty-five New Zealand White rabbits were used in a series of experiments. Disseminated liver tumors were established by direct injection of 1 x 106 VX-2 cells into the portal vein by laparotomy in anesthetized animals. Several surgical perfusion techniques were explored to determine a reliable and reproducible IHP model. Vascular permeability in tumor versus liver was then assessed with Evan's Blue labeled bovine albumin under normothermic (tissue temperature 36.5°C ± 0.5°C), moderate hyperthermic (39°C ± 0.5°C), or severe hyperthermic (41°C ± 0.5°C) conditions. Results. Tumor model and perfusion techniques were successfully established with inflow through the portal vein and outflow through an isolated segment of the inferior vena cava. A gravity driven perfusion circuit with stable perfusion parameters and complete vascular isolation was used. Vascular permeability was higher in tumor than in normal tissues (P = .03) at all time points during IHP. Hyperthermia resulted in a significant (up to 5-fold) increase in permeability of neovasculature; when severe hyperthermia was used, tumor vascular permeability was increased even more than normal liver permeability (P =.01). Conclusions. The VX-2/New Zealand White rabbit system can be used as a reproducible large-animal model for IHP of unresectable liver metastases. It can be used to characterize the contribution and mechanism of action of different treatment parameters used in IHP. Hyperthermia preferentially increases vascular permeability in tumors compared with liver tissue in a dose-dependent fashion, thus providing a mechanism for its presumed benefit during isolated organ perfusion.

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