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Title: A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

Abstract

Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resourcemore » for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.« less

Authors:
 [1];  [2];  [3];  [2];  [1]; ;  [2];  [2];  [4];  [5];  [2]; ;  [6];  [7];  [4]; ;  [7];  [5];  [4];
  1. Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States)
  2. Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States)
  3. (China)
  4. (United States)
  5. Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States)
  6. Department of Radiation Oncology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States)
  7. Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States)
Publication Date:
OSTI Identifier:
22283357
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 88; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0360-3016
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ALKALINE PHOSPHATASE; FIBROSIS; LIVER; MONKEYS; NEOPLASMS; RADIATION DOSES; RADIATION INJURIES; RADIOTHERAPY; RODENTS

Citation Formats

Yannam, Govardhana Rao, Han, Bing, Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, Setoyama, Kentaro, Yamamoto, Toshiyuki, Ito, Ryotaro, Brooks, Jenna M., Guzman-Lepe, Jorge, Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, Galambos, Csaba, Fong, Jason V., Deutsch, Melvin, Quader, Mubina A., Yamanouchi, Kosho, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, Kabarriti, Rafi, Mehta, Keyur, Soto-Gutierrez, Alejandro, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, and and others. A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury. United States: N. p., 2014. Web. doi:10.1016/J.IJROBP.2013.10.037.
Yannam, Govardhana Rao, Han, Bing, Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, Setoyama, Kentaro, Yamamoto, Toshiyuki, Ito, Ryotaro, Brooks, Jenna M., Guzman-Lepe, Jorge, Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, Galambos, Csaba, Fong, Jason V., Deutsch, Melvin, Quader, Mubina A., Yamanouchi, Kosho, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, Kabarriti, Rafi, Mehta, Keyur, Soto-Gutierrez, Alejandro, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, & and others. A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury. United States. doi:10.1016/J.IJROBP.2013.10.037.
Yannam, Govardhana Rao, Han, Bing, Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, Setoyama, Kentaro, Yamamoto, Toshiyuki, Ito, Ryotaro, Brooks, Jenna M., Guzman-Lepe, Jorge, Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, Galambos, Csaba, Fong, Jason V., Deutsch, Melvin, Quader, Mubina A., Yamanouchi, Kosho, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, Kabarriti, Rafi, Mehta, Keyur, Soto-Gutierrez, Alejandro, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, and and others. Sat . "A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury". United States. doi:10.1016/J.IJROBP.2013.10.037.
@article{osti_22283357,
title = {A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury},
author = {Yannam, Govardhana Rao and Han, Bing and Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi and Setoyama, Kentaro and Yamamoto, Toshiyuki and Ito, Ryotaro and Brooks, Jenna M. and Guzman-Lepe, Jorge and Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania and Galambos, Csaba and Fong, Jason V. and Deutsch, Melvin and Quader, Mubina A. and Yamanouchi, Kosho and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York and Kabarriti, Rafi and Mehta, Keyur and Soto-Gutierrez, Alejandro and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania and and others},
abstractNote = {Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.},
doi = {10.1016/J.IJROBP.2013.10.037},
journal = {International Journal of Radiation Oncology, Biology and Physics},
issn = {0360-3016},
number = 2,
volume = 88,
place = {United States},
year = {2014},
month = {2}
}