Prognostic markers in osteosarcoma

Expert Review of Anticancer Therapy

Volumn 10, Issue 2, 2010, Pages 271-287

  Bakhshi, Sameer ^a   Radhakrishnan, Venkatraman ^a  

^a INSTITUTE ROTARY CANCER HOSPITAL   (India)

Author keywords

Chemotherapy; Osteosarcoma; Prognostic marker

Indexed keywords

ANTHRACYCLINE DERIVATIVE; ANTINEOPLASTIC METAL COMPLEX; BEVACIZUMAB; BIOLOGICAL MARKER; CASPASE 8; CISPLATIN; CYTOCHROME C; DOXORUBICIN; EPIDERMAL GROWTH FACTOR RECEPTOR 2; ETOPOSIDE; EXCISION REPAIR CROSS COMPLEMENTING PROTEIN 1; FLUORODEOXYGLUCOSE F 18; GLYCOPROTEIN P; HEAT SHOCK PROTEIN; IFOSFAMIDE; LACTATE DEHYDROGENASE; LIVIN; METHOTREXATE; MIGRATION INHIBITION FACTOR; PROTEIN BAX; PROTEIN BCL 2; PROTEIN FOS; PROTEIN MDM2; PROTEIN P27; PROTEIN P53; PROTEIN TYROSINE KINASE; S PHASE KINASE ASSOCIATED PROTEIN 2; SORAFENIB; SUNITINIB; UNINDEXED DRUG;

AMPUTATION; ANGIOGENESIS; APOPTOSIS; CANCER COMBINATION CHEMOTHERAPY; CANCER GROWTH; CANCER RADIOTHERAPY; CANCER RESISTANCE; CANCER STAGING; CELL CYCLE; CELL DIFFERENTIATION; CLINICAL TRIAL; COMPARATIVE GENOMIC HYBRIDIZATION; COMPUTER ASSISTED EMISSION TOMOGRAPHY; CONTRAST ENHANCEMENT; DIFFUSION WEIGHTED IMAGING; DRUG MEGADOSE; DRUG UPTAKE; EVENT FREE SURVIVAL; HISTOLOGY; HUMAN; LACTATE DEHYDROGENASE BLOOD LEVEL; METASTASIS; ONCOGENE C MYC; OSTEOSARCOMA; OVERALL SURVIVAL; POSITRON EMISSION TOMOGRAPHY; PROGNOSIS; PROTEIN EXPRESSION; REVIEW; SENSITIVITY AND SPECIFICITY; SURVIVAL; TREATMENT RESPONSE; TUMOR VOLUME;

BONE NEOPLASMS; HUMANS; OSTEOSARCOMA; POSITRON-EMISSION TOMOGRAPHY; PROGNOSIS; SURVIVAL RATE; TOMOGRAPHY, X-RAY COMPUTED; TUMOR MARKERS, BIOLOGICAL;

EID: 76749088991     PISSN: 14737140     EISSN: 17448328     Source Type: Journal    
DOI: 10.1586/ERA.09.186     Document Type: Review

References (117)

1. Mirabello L, Troisi RJ, Savage SA. International osteosarcoma incidence patterns in children and adolescents, middle ages and elderly persons. Int. J. Cancer 125(1), 229-234 (2009).
2. Arndt CA, Crist WM. Common musculoskeletal tumors of childhood and adolescence. N. Engl. J. Med. 341(5), 342-352 (1999).
3. Link MP, Gebhardt MC, Meyers PA. Osteosarcoma. In: Principles and Practices of Pediatric Oncology (5th edition). Pizzo PA, Poplack DG (Eds). Lippincott Williams & Wilkins, PA, USA, 1074-1115 (2006).
4. Wu PK, Chen WM, Chen CF, Lee OK, Haung CK, Chen TH. Primary osteogenic sarcoma with pulmonary metastasis, clinical results and prognostic factors in 91 patients. Jpn J. Clin. Oncol. 39(8), 514-522 (2009).
5. Bramer JA, Van Linge JH, Grimer RJ, Scholten RJ. Prognostic factors in localized extremity osteosarcoma, a systematic review. Eur. J. Surg. Oncol. 35(10), 1030-1036 (2009). •• Study highlights the lack of quality trials on prognostic markers in osteosarcoma.
6. Bacci G, Longhi A, Versari M, Mercuri M, Briccoli A, Picci P. Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy, 15-year experience in 789 patients treated at a single institution. Cancer 106(5), 1154-1161 (2006).
7. Bielack SS, Kempf-Bielack B, Delling G et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk, an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J. Clin. Oncol. 20(3), 776-790 (2002).
8. Pakos EE, Nearchou AD, Grimer RJ et al. Prognostic factors and outcomes for osteosarcoma: an international collaboration. Eur. J. Cancer 45(13), 2367-2375 (2009). •• First international collaboration in osteosarcoma, which has validated previously known prognostic factors.
9. Ozaki T, Flege S, Liljenqvist U et al. Osteosarcoma of the spine, experience of the Cooperative Osteosarcoma Study Group. Cancer 94(4), 1069-1077 (2002).
10. Ozaki T, Flege S, Kevric M et al. Osteosarcoma of the pelvis, experience of the Cooperative Osteosarcoma study group. J. Clin. Oncol. 21(2), 334-341 (2003).
11. Bieling P, Rehan N, Winkler P et al. Tumor size and prognosis in aggressively treated osteosarcoma. J. Clin. Oncol. 14(3), 848-858 (1996).
12. Rehan N, Bieling P, Winkler P et al. The prognostic significance of tumor volume in osteosarcoma with neoadjuvant chemotherapy. Klin. Padiatr. 205(4), 200-209 (1993).
13. Lee JA, Kim MS, Kim DH et al. Relative tumor burden predicts metastasis-free survival in pediatric osteosarcoma. Pediatr. Blood Cancer 50(2), 195-200 (2008).
14. Munajat I, Zulmi W, Norazman MZ, Wan Faisham WI. Tumour volume and lung metastasis in patients with osteosarcoma. J. Orthop. Surg. (Hong Kong) 16(2), 182-185 (2008).
15. Aljubran AH, Griffin A, Pintilie M, Blackstein M. Osteosarcoma in adolescents and adults, survival analysis with and without lung metastases. Ann. Oncol. 20(6), 1136-1141 (2009).
16. Bacci G, Ferrari S, Mercuri M et al. Neoadjuvant chemotherapy for osteosarcoma of the extremities in patients aged 41-60 years, outcome in 34 cases treated with adriamycin, cisplatinum and ifosfamide between 1984 and 1999. Acta Orthop. 78(3), 377-384 (2007).
17. Harting MT, Lally KP, Andrassy RJ et al. Age as a prognostic factor for patients with osteosarcoma, an analysis of 438 patients. J. Cancer Res. Clin. Oncol. DOI: 10.1007/ s00432-009-0690-5 (2009) (Epub ahead of print).
18. Bacci G, Balladelli A, Palmerini E et al. Neoadjuvant chemotherapy for osteosarcoma of the extremities in preadolescent patients, the Rizzoli Institute experience. J. Pediatr. Hematol. Oncol. 30(12), 908-912 (2008).
19. Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin. Orthop. Relat. Res. 153, 106-120 (1980).
20. Greene FL, Page DL, Fleming ID et al. Osteosarcoma. In: AJCC cancer staging manual. Springer, NY, USA 213-220 (2002).
21. Kager L, Zoubek A, Kastner U et al. Skip metastases in osteosarcoma, experience of the Cooperative Osteosarcoma Study group. J. Clin. Oncol. 24(10), 1535-1541 (2006).
22. Sajadi KR, Heck RK, Neel MD et al. The incidence and prognosis of osteosarcoma skip metastases. Clin. Orthop. Relat. Res. 426, 92-96 (2004).
23. Ferrari S, Briccoli A, Mercuri M et al. Late relapse in osteosarcoma. J. Pediatr. Hematol. Oncol. 28(7), 418-422 (2006).
24. Bacci G, Bertoni F, Longhi A et al. Neoadjuvant chemotherapy for high-grade central osteosarcoma of the extremity. Histologic response to preoperative chemotherapy correlates with histologic subtype of the tumor. Cancer 97(12), 3068-3075 (2003).
25. Bacci G, Mercuri M, Longhi A et al. Grade of chemotherapy-induced necrosis as a predictor of local and systemic control in 881 patients with non-metastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy in a single institution. Eur. J. Cancer 41(14), 2079-2085 (2005).
26. Grimer RJ, Taminiau AM, Cannon SR; Surgical Subcommittee of the European Osteosarcoma Intergroup. Surgical outcomes in osteosarcoma. J. Bone Joint Surg. Br. 84(3), 395-400 (2002).
27. Barr RD, Wunder JS. Bone and soft tissue sarcomas are often curable - but at what cost? A call to arms (and legs). Cancer 115(18), 4046-4054 (2009).
28. Bramer JA, Abudu AA, Grimer RJ, Carter SR, Tillman RM. Do pathological fractures influence survival and local recurrence rate in bony sarcomas? Eur. J. Cancer 43(13), 1944-1951 (2007).
29. González-Billalabeitia E, Hitt R, Fernández J, Conde E et al. Pre-treatment serum lactate dehydrogenase level is an important prognostic factor in high-grade extremity osteosarcoma. Clin. Transl. Oncol. 11(7), 479-483 (2009).
30. Bacci G, Longhi A, Ferrari S et al. Prognostic significance of serum lactate dehydrogenase in osteosarcoma of the extremity, experience at Rizzoli on 1421 patients treated over the last 30 years. Tumori 90(5), 478-484 (2004).
31. Bacci G, Picci P, Orlandi M et al. Prognostic value of serum alkaline phosphatase in osteosarcoma. Tumori 73(4), 331-336 (1987).
32. Bramer JA, Abudu AA, Tillman RM, Carter SR, Sumathi VP, Grimer RJ. Pre- and post-chemotherapy alkaline phosphatase levels as prognostic indicators in adults with localised osteosarcoma. Eur. J. Cancer 41(18), 2846-2852 (2005).
33. Davis AM, Bell RS, Goodwin PJ. Prognostic factors in osteosarcoma, a critical review. J. Clin. Oncol. 12(2), 423-431(1994).
34. Ferrari S, Briccoli A, Mercuri M et al. Neoadjuvant chemotherapy for osteosarcoma of the extremity, intensification of preoperative treatment does not increase the rate of good histologic response to the primary tumor or improve the final outcome. J. Pediatr. Hematol. Oncol. 25(11), 845-853 (2003).
35. Ferrari S, Palmerini E. Adjuvant and neoadjuvant combination chemotherapy for osteogenic sarcoma. Curr. Opin. Oncol. 19(4), 341-346 (2007).
36. Van Dalen EC, de Camargo B. Methotrexate for high-grade osteosarcoma in children and young adults. Cochrane Database Syst. Rev. 21(1), CD006325 (2009).
37. Serra M, Pasello M, Manara MC et al. May P-glycoprotein status be used to stratify high-grade osteosarcoma patients? Results from the Italian/ Scandinavian Sarcoma Group 1 treatment protocol. Int. J. Oncol. 29(6), 1459-1468 (2006).
38. Baldini N, Scotlandi K, Serra M et al. P-glycoprotein expression in osteosarcoma, a basis for risk-adapted adjuvant chemotherapy. J. Orthop. Res. 17(5), 629-632 (1999).
39. Schwartz CL, Gorlick R, Teot L et al. Multiple drug resistance in osteogenic sarcoma, INT0133 from the Children's Oncology Group. J. Clin. Oncol. 25(15), 2057-2062 (2007).
40. Pakos EE, Ioannidis JP. The association of P-glycoprotein with response to chemotherapy and clinical outcome in patients with osteosarcoma. A metaanalysis. Cancer 98(3), 581-589 (2003). • Reported no correlation between Pgp expression and histological necrosis. There was a trend towards inferior survival with P-glycoprotein expression.
41. Tang N, Song WX, Luo J, Haydon RC, He TC. Osteosarcoma development and stem cell differentiation. Clin. Orthop. Relat. Res. 466(9), 2114-2130 (2008).
42. Wang L, Park P, Lin CY. Characterization of stem cell attributes in human osteosarcoma cell lines. Cancer Biol. Ther. 8(6), 543-552 (2009).
43. Fujii H, Honoki K, Tsujiuchi T, Kido A, Yoshitani K, Takakura Y. Sphere-forming stem-like cell populations with drug resistance in human sarcoma cell lines. Int. J. Oncol. 34(5), 1381-1386 (2009).
44. Oda Y, Sakamoto A, Shinohara N et al. Nuclear expression of YB-1 protein correlates with P-glycoprotein expression in human osteosarcoma. Clin. Cancer Res. 4(9), 2273-2277 (1998).
45. Caronia D, Patiño-García A, Milne RL et al. Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients. Pharmacogenomics J. 9(5), 347-353 (2009). • ERCC gene polymorphism is responsible for cisplatinum resistance; it can be used to tailor therapy according to patients' polymorphism profile.
46. Mintz MB, Sowers R, Brown KM et al. An expression signature classifies chemotherapy-resistant pediatric osteosarcoma. Cancer Res. 65(5), 1748-1754 (2005). • DNA microarray technology provides us with real-time data regarding expression of thousands of genes; this can be used to generate specific signature profiles for prognostication.
47. Fellenberg J, Bernd L, Delling G, Witte D, Zahlten-Hinguranage A. Prognostic significance of drug-regulated genes in high-grade osteosarcoma. Mod. Pathol. 20(10), 1085-1094 (2007).
48. Huang Y, Lin Z, Zhuang J, Chen Y, Lin J. Prognostic significance of a V integrin and VEGF in osteosarcoma after chemotherapy. Onkologie 31(10), 535-540 (2008).
49. Mikulic D, Ilic I, Cepulic M et al. Tumor angiogenesis and outcome in osteosarcoma. Pediatr. Hematol. Oncol. 21(7), 611-619 (2004).
50. Wang D, Chen L, Gao F. Correlation of tumor microvessel density with prognosis in osteogenic sarcoma. Zhonghua Bing Li Xue Za Zhi 26(5), 266-269 (1997).
51. Charity RM, Foukas AF, Deshmukh NS, Grimer RJ. Vascular endothelial growth factor expression in osteosarcoma. Clin. Orthop. Relat. Res. 448, 193-198 (2006).
52. Ek ET, Ojaimi J, Kitagawa Y, Choong PF. Does the degree of intratumoural microvessel density and VEGF expression have prognostic significance in osteosarcoma? Oncol. Rep. 16(1), 17-23 (2006).
53. Sznurkowska K, Lenckowski R, Popadiuk S, Szumera M, Renke J, Korzon M. Assessment of angiogenesis in children's osteosarcoma. Med. Wieku Rozwoj. 10(3 Pt 1), 737-744 (2006).
54. Bajpai J, Sharma M, Sreenivas V et al. VEGF expression as a prognostic marker in osteosarcoma. Pediatr. Blood Cancer 53(6), 1035-1039 (2009).
55. Kaya M, Wada T, Nagoya S, Sasaki M, Matsumura T, Yamashita T. The level of vascular endothelial growth factor as a predictor of a poor prognosis in osteosarcoma. J. Bone Joint Surg. Br. 91(6), 784-788 (2009).
56. Han I, Lee MR, Nam KW, Oh JH, Moon KC, Kim HS. Expression of macrophage migration inhibitory factor relates to survival in high-grade osteosarcoma. Clin. Orthop. Relat. Res. 466(9), 2107-2113 (2008).
57. Pakos EE, Kyzas PA, Ioannidis JP. Prognostic significance of TP53 tumor suppressor gene expression and mutations in human osteosarcoma, a meta-analysis. Clin. Cancer Res. 10(18 Pt 1), 6208-6214 (2004). • Reports a trend towards inferior survival with P53 expression. Studies that used PCR and were blinded showed statistically significant inferior outcome.
58. Wunder JS, Gokgoz N, Parkes R et al. TP53 mutations and outcome in osteosarcoma, a prospective, multicenter study. J. Clin. Oncol. 23(7), 1483-1490 (2005).
59. Bakhshi S, Gupta A, Sharma MC, Khan SA, Rastogi S. Her-2/neu, p-53, and their coexpression in osteosarcoma. J. Pediatr. Hematol. Oncol. 31(4), 245-251 (2009).
60. Kaseta MK, Gomatos IP, Khaldi L et al. Prognostic value of bax, cytochrome C, and caspase-8 protein expression in primary osteosarcoma. Hybridoma (Larchmt) 26(6), 355-362 (2007).
61. Nedelcu T, Kubista B, Koller A et al. Livin and Bcl-2 expression in high-grade osteosarcoma. J. Cancer Res. Clin. Oncol. 134(2), 237-244 (2008).
62. Osaka E, Suzuki T, Osaka S et al. Survivin as a prognostic factor for osteosarcoma patients. Acta Histochem. Cytochem. 39(3), 95-100 (2006).
63. Trieb K, Lehner R, Stulnig T, Sulzbacher I, Shroyer KR. Survivin expression in human osteosarcoma is a marker for survival. Eur. J. Surg. Oncol. 29(4), 379-382 (2003).
64. Trieb K, Gerth R, Holzer G, Grohs JG, Berger P, Kotz R. Antibodies to heat shock protein 90 in osteosarcoma patients correlate with response to neoadjuvant chemotherapy. Br. J. Cancer 82(1), 85-87 (2000).
65. Huang J, Zhu B, Lu L et al. The expression of novel gene URG4 in osteosarcoma, correlation with patients' prognosis. Pathology 41(2), 149-154 (2009).
66. Liao QD, Zhong D, Chen Q. Protein expression of Skp2 in osteosarcoma and its relation with prognosis. Zhong Nan Da Xue Xue Bao Yi Xue Ban 33(7), 606-611 (2008).
67. Lee WI, Bacchni P, Bertoni F, Maeng YH, Park YK. Quantitative assessment of HER2/neu expression by real-time PCR and fluorescent in situ hybridization analysis in low-grade osteosarcoma. Oncol. Rep. 12(1), 125-128 (2004).
68. Anninga JK, van de Vijver MJ, Cleton-Jansen AM et al. Overexpression of the HER-2 oncogene does not play a role in high-grade osteosarcomas. Eur. J. Cancer 40(7), 963-970 (2004).
69. Tsai JY, Aviv H, Benevenia J et al. HER-2/neu and p53 in osteosarcoma, an immunohistochemical and fluorescence in situ hybridization analysis. Cancer Invest. 22(1), 16-24 (2004).
70. Somers GR, Ho M, Zielenska M, Squire JA, Thorner PS. HER2 amplification and overexpression is not present in pediatric osteosarcoma, a tissue microarray study. Pediatr. Dev. Pathol. 8(5), 525-532 (2005).
71. Rakesh Kumar V, Gupta N, Kakkar N, Sharma SC. Prognostic and predictive value of c-erbB2 overexpression in osteogenic sarcoma. J. Cancer Res. Ther. 2(1), 20-23 (2006).
72. Thomas DG, Giordano TJ, Sanders D, Biermann JS, Baker L. Absence of HER2/ neu gene expression in osteosarcoma and skeletal Ewing's sarcoma. Clin. Cancer Res. 8(3), 788-793 (2002).
73. Yalçin B, Gedikoglu G, Kutluk T, Varan A, Akyüz C, Büyükpamukçu M. C-erbB-2 expression and prognostic significance in osteosarcoma. Pediatr. Blood Cancer 51(2), 222-227 (2008).
74. Fellenberg J, Krauthoff A, Pollandt K, Delling G, Parsch D. Evaluation of the predictive value of Her-2/neu gene expression on osteosarcoma therapy in laser-microdissected paraffin-embedded tissue. Lab. Invest. 84(1), 113-121 (2004).
75. Morris CD, Gorlick R, Huvos G, Heller G, Meyers PA, Healey JH. Human epidermal growth factor receptor 2 as a prognostic indicator in osteogenic sarcoma. Clin. Orthop. Relat. Res. 382, 59-65 (2001).
76. Gorlick R, Huvos AG, Heller G et al. Expression of HER2/erbB-2 correlates with survival in osteosarcoma. J. Clin. Oncol. 17(9), 2781-2788 (1999).
77. Onda M, Matsuda S, Higaki S et al. ErbB-2 expression is correlated with poor prognosis for patients with osteosarcoma. Cancer 77(1), 71-78 (1996).
78. Zhou H, Randall RL, Brothman AR, Maxwell T, Coffin CM, Goldsby RE. Her-2/neu expression in osteosarcoma increases risk of lung metastasis and can be associated with gene amplification. J. Pediatr. Hematol. Oncol. 25(1), 27-32 (2003).
79. Li YG, Geng X. A meta-analysis on the association of HER-2 overexpression with prognosis in human osteosarcoma. Eur. J. Cancer Care (Engl). (2009) (Epub ahead of print).
80. Kubo T, Piperdi S, Rosenblum J et al. Platelet-derived growth factor receptor as a prognostic marker and a therapeutic target for imatinib mesylate therapy in osteosarcoma. Cancer 112(10), 2119-2129 (2008).
81. Wei H, Zhao MQ, Dong W, Yang Y, Li JS. Expression of c-kit protein and mutational status of the c-kit gene in osteosarcoma and their clinicopathological significance. J. Int. Med. Res. 36(5), 1008-1014 (2008).
82. Khanna C, Khan J, Nguyen P et al. Metastasis-associated differences in gene expression in a murine model of osteosarcoma. Cancer Res. 61(9), 3750-3759 (2001).
83. Wan X, Mendoza A, Khanna C, Helman LJ. Rapamycin inhibits ezrin-mediated metastatic behavior in a murine model of osteosarcoma. Cancer Res. 65(6), 2406-2411 (2005).
84. Xu-Dong S, Zan S, Shui-er Z et al. Expression of Ezrin correlates with lung metastasis in Chinese patients with osteosarcoma. Clin. Invest. Med. 32(2), E180-E188 (2009).
85. Ferrari S, Zanella L, Alberghini M, Palmerini E, Staals E, Bacchini P. Prognostic significance of immunohistochemical expression of ezrin in non-metastatic high-grade osteosarcoma. Pediatr. Blood Cancer 50(4), 752-756 (2008).
86. Salas S, Bartoli C, Deville JL et al. Ezrin and a-smooth muscle actin are immunohistochemical prognostic markers in conventional osteosarcomas. Virchows Arch. 451(6), 999-1007 (2007).
87. Kubista B, Erovic BM, Klinger H, Sulzbacher I, Trieb K. CD9 expression is not a prognostic factor in human osteosarcoma. Cancer Lett. 209(1), 105-110 (2004).
88. Kim HS, Park YB, Oh JH, Jeong J, Kim CJ, Lee SH. Expression of CD44 isoforms correlates with the metastatic potential of osteosarcoma. Clin. Orthop. Relat. Res. 396, 184-190 (2002).
89. Kuryu M, Ozaki T, Nishida K, Shibahara M, Kawai A, Inoue H. Expression of CD44 variants in osteosarcoma. J. Cancer Res. Clin. Oncol. 125(11), 646-652 (1999).
90. Nakajima G, Patino-Garcia A, Bruheim S et al. CDH11 expression is associated with survival in patients with osteosarcoma. Cancer Genomics Proteomics 5(1), 37-42 (2008).
91. Bjornland K, Flatmark K, Pettersen S, Aaasen AO, Fodstad O, Maelandsmo GM. Matrix metalloproteinases participate in osteosarcoma invasion. J. Surg. Res. 127(2), 151-156 (2005).
92. Uchibori M, Nishida Y, Nagasaka T, Yamada Y, Nakanishi K, Ishiguro N. Increased expression of membrane-type matrix metalloproteinase-1 is correlated with poor prognosis in patients with osteosarcoma. Int. J. Oncol. 28(1), 33-42 (2006).
93. Sato J, Yanagawa T, Dobashi Y, Yamaji T, Takagishi K, Watanabe H. Prognostic significance of 18F-FDG uptake in primary osteosarcoma after but not before chemotherapy, a possible association with autocrine motility factor/ phosphoglucose isomerase expression. Clin. Exp. Metastasis 25(4), 427-435 (2008).
94. Hawkins DS, Conrad EU 3rd, Butrynski JE, Schuetze SM, Eary JF. [F-18]-fluorodeoxy-d-glucose-positron emission tomography response is associated with outcome for extremity osteosarcoma in children and young adults. Cancer 115(15), 3519-3525 (2009).
95. Ye Z, Zhu J, Tian M et al. Response of osteogenic sarcoma to neoadjuvant therapy, evaluated by 18F-FDG-PET. Ann. Nucl. Med. 22(6), 475-480 (2008).
96. Bajpai J, Kumar R, Vishnubhatla S, Sharma MC, Bakhshi S. PET-CT in osteosarcoma for chemotherapy response evaluation: correlation with histological necrosis. J. Nucl. Med. 50(Suppl. 2), 582 (2009).
97. Cheon GJ, Kim MS, Lee JA, Lee SY, Cho WH, Song WS et al. Prediction model of chemotherapy response in osteosarcoma by 18F-FDG PET and MRI. J. Nucl. Med. 50(9), 1435-1440 (2009).
98. Bajpai J, Gamnagatti S, Sreenivas V et al. Role of MRI in osteosarcoma for chemotherapy response evaluation and prediction: correlation with histological necrosis. J. Clin. Oncol. 27, 15s (2009).
99. Uhl M, Saueressig U, Koehler G et al. Evaluation of tumour necrosis during chemotherapy with diffusion-weighted MR imaging, preliminary results in osteosarcomas. Pediatr. Radiol. 36(12), 1306-1311 (2006). • MRI can also serve as a noninvasive technique to assess angiogenesis and chemotherapy response.
100. Hoang BH, Dyke JP, Koutcher JA et al. VEGF expression in osteosarcoma correlates with vascular permeability by dynamic MRI. Clin. Orthop. Relat. Res. 426, 32-38 (2004).
101. Selvarajah S, Yoshimoto M, Ludkovski O et al. Genomic signatures of chromosomal instability and osteosarcoma progression detected by high resolution array CGH and interphase FISH. Cytogenet. Genome Res. 122(1), 5-15 (2008).
102. Tarkkanen M, Elomaa I, Blomqvist C et al. DNA sequence copy number increase at 8q, a potential new prognostic marker in high-grade osteosarcoma. Int. J. Cancer 84(2), 114-121 (1999).
103. Hou P, Ji M, Yang B, Chen Z, Qiu J, Shi X, Lu Z. Quantitative analysis of promoter hypermethylation in multiple genes in osteosarcoma. Cancer 106(7), 1602-1609 (2006). • Epigenetic changes are reversible unlike a genetic changes and hence can serve as potential target for drugs such as demethylating agents and histone deacylase inhibitors.
104. Lopez-Guerrero JA, Lopez-Gines C, Pellin A, Carda C, Llombart-Bosch A. Deregulation of the G1 to S-phase cell cycle checkpoint is involved in the pathogenesis of human osteosarcoma. Diagn. Mol. Pathol. 13(2), 81-91 (2004).
105. Benassi MS, Molendini L, Gamberi G, Ragazzini P, Sollazzo MR, Merli M et al. Alteration of pRb/p16/cdk4 regulation in human osteosarcoma. Int. J. Cancer 84(5), 489-493 (1999).
106. Maitra A, Roberts H, Weinberg AG, Geradts J. Loss of p16(INK4a) expression correlates with decreased survival in pediatric osteosarcomas. Int. J. Cancer 95(1), 34-38 (2001).
107. Jung ST, Moon ES, Seo HY, Kim JS, Kim GJ, Kim YK. Expression and significance of TGF-b isoform and VEGF in osteosarcoma. Orthopedics 28(8), 755-760 (2005).
108. Gamberi G, Benassi MS, Bohling T et al. C-myc and c-fos in human osteosarcoma: prognostic value of mRNA and protein expression. Oncology 55(6), 556-563 (1998).
109. Franchi A, Calzolari A, Zampi G. Immunohistochemical detection of c-fos and c-jun expression in osseous and cartilaginous tumours of the skeleton. Virchows Arch. 432(6), 515-519 (1998).
110. Ladanyi M, Cha C, Lewis R, Jhanwar SC, Huvos AG, Healey JH. MDM2 gene amplification in metastatic osteosarcoma. Cancer Res. 53(1), 16-18 (1993).
111. Kanoe H, Nakayama T, Murakami H et al. Amplification of the CDK4 gene in sarcomas: tumor specificity and relationship with the RB gene mutation. Anticancer Res. 18(4A), 2317-2321 (1998).
112. Maelandsmo GM, Berner JM, Florenes VA et al. Homozygous deletion frequency and expression levels of the CDKN2 gene in human sarcomas - relationship to amplification and mRNA levels of CDK4 and CCND1. Br. J. Cancer 72(2), 393-398 (1995).
113. Haydon RC, Deyrup A, Ishikawa A et al. Cytoplasmic and/or nuclear accumulation of the b-catenin protein is a frequent event in human osteosarcoma. Int. J. Cancer 102(4), 338-342 (2002).
114. Sangiorgi L, Gobbi GA, Lucarelli E et al. Presence of telomerase activity in different musculoskeletal tumor histotypes and correlation with aggressiveness. Int. J. Cancer 95(3), 156-161 (2001).
115. Prognostic factor definition. National Cancer Institute www.cancer.gov/ dictionary/?CdrID=44246
116. The European and American Osteosarcoma Study Group. Euramos 1 trial www.ctu.mrc.ac.uk/euramos/e-i-objectives.asp>
117. Daw NC. A study of bevacizumab in combination with chemotherapy for treatment of osteosarcoma. NIH http://clinicaltrials.gov/ct2/show/ NCT00667342