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Scientific Articles   |    
Telomere-Maintenance Mechanisms in Soft-Tissue Malignant Fibrous Histiocytomas
Toshihiro Matsuo, MD, PhD1; Jerry W. Shay, PhD2; Woodring E. Wright, MD, PhD2; Eiso Hiyama, MD, PhD1; Shoji Shimose, MD, PhD1; Tadahiko Kubo, MD, PhD1; Takashi Sugita, MD, PhD1; Yuji Yasunaga, MD, PhD1; Mitsuo Ochi, MD, PhD1
1 Department of Artificial Joints and Biomaterials (T.M. and Y.Y.), Natural Science Center for Basic Research and Development (E.H.), and Department of Orthopaedic Surgery (S.S., T.K., T.S., and M.O.), Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. E-mail address for T. Matsuo: tomatsuo@hiroshima-u.ac.jp
2 Department of Cell Biology, University of Texas, Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9039
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Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. 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. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.
Investigation performed at Hiroshima University, Hiroshima, Japan, and University of Texas, Southwestern Medical Center, Dallas, Texas

The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2009 Apr 01;91(4):928-937. doi: 10.2106/JBJS.G.01390
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Abstract

Background: Sarcomas are distinct from carcinomas in that a substantial portion of them use the alternative lengthening of telomeres (ALT) mechanism to maintain their telomeres. The present study clarifies the prevalence of the ALT mechanism and examines the prognostic importance of telomere factors in soft-tissue malignant fibrous histiocytomas.

Methods: We investigated a series of forty-three soft-tissue malignant fibrous histiocytoma samples from forty-three patients with regard to telomere length, telomerase activity, and human telomerase reverse transcriptase (hTERT) mRNA expression. Tumor samples were obtained from surgical specimens and were stored at -80°C until use. Univariate analysis of the tumor samples from patients for whom data were available on age, sex, histological grade, tumor size, surgical margin, recurrence, and telomere factors was performed with use of the log-rank test. Multivariate analysis with only significant variables was then performed.

Results: Telomerase activity was detectable in 79.1% of the tumor samples, hTERT expression was demonstrated in 90.7% of the tumor samples, and evidence of engagement of the ALT mechanism of telomere length maintenance was observed in 32.6% of the tumor samples. Among the variables tested, ALT-positive status emerged as the only independent prognostic factor for death of the patient (hazard ratio, 0.275; 95% confidence interval, 0.104 to 0.724; p = 0.0089). There were no significant differences in survival rates between patients with ALT-positive, telomerase-positive tumors and those with ALT-positive, telomerase-negative tumors (p = 0.301) or between patients with ALT-positive tumors that showed above-average telomerase activity and those with ALT-positive tumors that showed below-average telomerase activity (p = 0.900). Therefore, telomerase activity does not affect the prognosis in patients with ALT-positive malignant fibrous histiocytoma. High telomerase expression is associated with a poor prognosis in patients with ALT-negative malignant fibrous histiocytoma (p = 0.0027).

Conclusions: More detailed analysis will be needed to identify the most valuable prognostic factor in patients with malignant fibrous histiocytoma, and a more thorough understanding of telomere biology may give an indication of telomere-targeting therapy in the future.

Level of Evidence: Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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