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Nitric Oxide Synthases, Cyclooxygenase-2, Nitrotyrosine, and Angiogenesis in Chondrosarcoma and Their Relation to Prognosis
Suely Akiko Nakagawa, MD1; Ademar Lopes, PhD, MD1; André Lopes de Carvalho, PhD, MD2; Benedito Mauro Rossi, PhD, MD1; Isabela Werneck da Cunha, MD1; Fernando Augusto Soares, PhD, MD1; Wu Tu Chung, PhD, MD1; Lucíola Assunção Alves, MD1
1 Departamentos de Cirurgia Pélvica—Ortopedia (S.A.N., A.L., B.M.R., W.T.C., and L.A.A.) e Anatomia Patológica (I.W.C. and F.A.S.), Hospital A.C. Camargo, Rua Prof. Antonio Prudente, 211, São Paulo – S. P., CEP 01509-010, Brazil. E-mail address for S.A. Nakagawa: su@uol.com.br
2 Departamento de Cabeça e Pescoço, Hospital Pio XII–Hospital de Câncer de Barretos, Avenida Antenor Duarte Villela, 1331, Barretos – S. P., CEP 14784-400, Brazil
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Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.

Investigation performed at Departamentos de Cirurgia Pélvica—Ortopedia e Anatomia Patológica, Hospital A.C. Camargo, São Paulo, Brazil

Copyright ©2010 American Society for Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2010 Jul 21;92(8):1738-1746. doi: 10.2106/JBJS.H.00717
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The localization in tumor tissue of various markers by immunohistochemistry can help to establish a diagnosis or predict prognosis. Nitric oxide is associated with tumors and has been studied indirectly by nitrotyrosine analysis and with use of the enzymes nitric oxide synthase (NOS)1, NOS2, and NOS3. Nitric oxide reacts with superoxide anions to yield peroxynitrite, which has toxic effects on genes. Peroxynitrite adds a nitro group to the benzene ring of tyrosine to form nitrotyrosine. The accumulation of nitrotyrosine, a stable product in cells, indicates the formation of peroxynitrite. Nitric oxide stimulates the production of cyclooxygenase-2 (COX-2), which has been associated with angiogenesis in tumors. Neovascularization influences tumor prognosis, as demonstrated by microvessel studies with use of CD34, an immunohistochemical endothelial cell marker. This study examines the expression of these markers in chondrosarcomas and their relation to histological grade and prognosis.


Tissue microarrays composed of formalin-fixed tissue samples from 101 patients with chondrosarcoma were immunohistochemically stained to localize NOS1, NOS2, NOS3, COX-2, nitrotyrosine, and CD34. Five samples of normal cartilage were used as controls. Patient demographics, selected surgical variables, and tumor grade were tabulated, and the associations were analyzed. Analyses of local and overall survival rates were performed with use of the Kaplan-Meier method, and multivariable analyses were performed.


There was a significant association of nitrotyrosine, COX-2, and CD34 with histological grades (p = 0.022, p = 0.014, and p = 0.028, respectively), but not with overall prognosis (p = 0.064, p = 0.143, and p = 0.581, respectively). The presence of NOS2 was associated with a lower rate of local disease-free survival (p = 0.038), and positive expressions of NOS1 and NOS2 were associated with decreased overall survival rates (p = 0.007 and p < 0.001, respectively). On multivariable analysis, NOS2 expression demonstrated an independent prognostic impact on local disease-free survival; NOS1 and NOS2 expression was a dependent variable, and their isolated or combined expression was related to lower overall survival rates (p = 0.046 and p = 0.004) (hazard ratio, 3.17 [95% confidence interval, 1.0 to 9.8] and 5.58 [95% confidence interval, 1.7 to 18.0], respectively).


Immunohistochemical markers may have an independent value in predicting the prognosis for patients with chondrosarcoma.

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