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Annals of Oncology Advance Access originally published online on December 6, 2007
Annals of Oncology 2008 19(4):793-800; doi:10.1093/annonc/mdm559
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© The Author 2007. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

sarcomas

p53 status correlates with histopathological response in patients with soft tissue sarcomas treated using isolated limb perfusion with TNF-{alpha} and melphalan

J. Muret1,8,*, M. Yacoub2,8, P. Terrier2, F. Drusch7, A. Laplanche3, C. Gaudin8, C. Richon8, C. Le Péchoux4, A. Le Cesne5, F. J. Lejeune9, T. Tursz5, P. Fouret2,8,{dagger}, S. Bonvalot6,{dagger} and S. Chouaib8

1 Department of Anesthesia
2 Department of Pathology
3 Department of Public Health
4 Department of Radiotherapy
5 Department of Medical Oncology
6 Department of Surgery
7 Laboratoire de Recherche Translationnelle, Module d'Histocytopathologie
8 Institut National de la Santé et de la Recherche Médicale U753 Unit, Immunologie des Tumeurs Humaines: Interaction Effecteurs Cytotoxiques-système Tumoral, Institut Gustave-Roussy, Villejuif Cedex, France
9 Multidisciplinary Oncology Centre, Centre Pluridisciplinaire d'Oncologie, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

* Correspondence to: Dr J. Muret, Service d'Anesthésie, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France. Tel: +33 1 42 11 40 18; Fax: +33 1 42 11 52 09; E-mail: muret{at}igr.fr

Background: Recombinant tumor necrosis factor-{alpha} (TNF-{alpha}) combined to melphalan is clinically administered through isolated limb perfusion (ILP) for regionally advanced soft tissue sarcomas of the limbs. In preclinical studies, wild-type p53 gene is involved in the regulation of cytotoxic action of TNF-{alpha} and loss of p53 function contributes to the resistance of tumour cells to TNF-{alpha}. The relationship between p53 status and response to TNF-{alpha} and melphalan in patients undergoing ILP is unknown.

Patients and methods: We studied 110 cases of unresectable limbs sarcomas treated by ILP. Immunohistochemistry was carried out using DO7mAb, which reacts with an antigenic determinant from the N-terminal region of both the wild-type and mutant forms of the p53 protein, and PAb1620mAb, which reacts with the 1620 epitope characteristic of the wild-type native conformation of the p53 protein. The immunohistochemistry data were then correlated with various clinical parameters.

Results: P53DO7 was found expressed at high levels in 28 patients, whereas PAb1620 was negative in 20. The tumours with poor histological response to ILP with TNF-{alpha} and melphalan showed significantly higher levels of p53-mutated protein.

Conclusions: Our results might be a clue to a role of p53 protein status in TNF-{alpha} and melphalan response in clinical use.

Key words: isolated limb perfusion, limb sarcoma, melphalan, p53 status, tumour necrosis factor-alpha

{dagger} Both these authors contributed to this article on a par.

Received for publication May 11, 2007. Revision received November 8, 2007. Accepted for publication November 8, 2007.


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