Ewing Sarcoma: Clinical, Radiological, Pathological Differentiation and Treatment Review

Yıl 2017, Cilt: 9 Sayı: 3, 133 - 157, 01.09.2017

Orhan Balta Recep Kurnaz Murat Aşçı Kürşad Aytekin Utkan Sobay Bora Bostan

Öz

Ewing's sarcoma, also known as peripheral neuroectodermal tumor, is a primary bone tumor usually seen in the second decade. Current management consists of extensive chemotherapy a long with local resection and radiation resection and / or radiation. Survival rate in patients without metastasis is 55-75%. Current research aims to provide a more effective treatment by reviewing combined gene abnormalities and targeted therapies. After being told for the first time by James Ewing 95 years ago, there has been a dramatic increase in the understanding and treatment of Ewing's sarcoma. Systemic chemotherapy, surgery and / or local control with radiation is important for survival. Current research aims to detect the EWS fusion protein in order to develop new treatment modalities to improve survival and to reduce toxicity and morbidity associated with current treatment options. The purpose of this article is to review and compile the literature for Ewing's bone sarcoma.

Anahtar Kelimeler

Ewing Sarcoma, Clinical, Radiological

Ewing Sarkomu: Klinik, Radyolojik, Patolo ik Ayrım ve Tedavi itaratürün G zden Geçirilmesi

Öz

Periferal nöroektodermal tümör olarak
da bilinen Ewing  sarkomu genellikle
ikinci on yılda görülen primer bir kemik tümörüdür. Güncel tedavi  yönetimi, cerrahi rezeksiyon ve radyoterapi
ile  lokal kontrolün yanı sıra kapsamlı
kemoterapiden oluşur. Metastazı olmayan ve tedavi edilen hastalarda hayatta
kalma oranı% 55-75 aralığındadır. Mevcut araştırmalar genlerdeki anormallikler
incelenerek  hedefe yönelik tedaviler
sunmayı amaçlamaktadır. 95 yıl önce James Ewing tarafından
ilk kez tanıtıldıktan sonra Ewing sarkomunun tedavisinde dramatik  gelişmeler olmuştur. Sistemik kemoterapi,
cerrahi ve / veya radyoterapi ile  lokal
kontrol ve  sağkalımda önemli gelişmeler
meydana gelmiştir. Mevcut araştırmalar hayatta kalmayı artıracak yeni tedavi
yöntemleri geliştirmek ve mevcut tedavi seçenekleri ile ilişkili toksisite ve
morbiditeyi azaltmak amacındadır. Bu yazının amacı  Ewing kemik sarkomu tanı ve tedavisindeki
yenilikleri ve prognozu etkileyen parametreleri değerlendirmek için literatürün
gözden geçirilmesi ve derlenmesidir.

Anahtar Kelimeler

Ewing Sarkomu, Klinik, Radyolojik

Kaynakça

• 1. Esiashvili N, Goodman M, Marcus RB, Jr. Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J Pediatr Hematol Oncol. 2008;30(6):425-30.
• 2. Dorfman HD, Czerniak B. Bone cancers. Cancer. 1995;75(1 Suppl):203-10.
• 3. Stiller CA, Desandes E, Danon SE, Izarzugaza I, Ratiu A, Vassileva-Valerianova Z, et al. Cancer incidence and survival in European adolescents (1978-1997). Report from the Automated Childhood Cancer Information System project. Eur J Cancer. 2006;42(13):2006-18.
• 4. Patricio MB, Vilhena M, Neves M, Raposo S, Catita J, De Sousa V, et al. Ewing's sarcoma in children: twenty-five years of experience at the Instituto Portuges de Oncologia de Francisco Gentil (I.P.O.F.G.). J Surg Oncol. 1991;47(1):37-40.
• 5. Widhe B, Widhe T. Initial symptoms and clinical features in osteosarcoma and Ewing sarcoma. J Bone Joint Surg Am. 2000;82(5):667-74.
• 6. Bacci G, Balladelli A, Forni C, Ferrari S, Longhi A, Bacchini P, et al. Adjuvant and neoadjuvant chemotherapy for Ewing sarcoma family tumors in patients aged between 40 and 60: report of 35 cases and comparison of results with 586 younger patients treated with the same protocols in the same years. Cancer. 2007;109(4):780-6.
• 7. Ilic I, Manojlovic S, Cepulic M, Orlic D, Seiwerth S. Osteosarcoma and Ewing's sarcoma in children and adolescents: retrospective clinicopathological study. Croat Med J. 2004;45(6):740-5.
• 8. Nakamura T, Grimer RJ, Gaston CL, Watanuki M, Sudo A, Jeys L. The prognostic value of the serum level of C-reactive protein for the survival of patients with a primary sarcoma of bone. Bone Joint J. 2013;95-B(3):411-8.
• 9. Rutkowski P, Kaminska J, Kowalska M, Ruka W, Steffen J. Cytokine and cytokine receptor serum levels in adult bone sarcoma patients: correlations with local tumor extent and prognosis. J Surg Oncol. 2003;84(3):151-9.
• 10. Biermann JS, Adkins DR, Agulnik M, Benjamin RS, Brigman B, Butrynski JE, et al. Bone cancer. J Natl Compr Canc Netw. 2013;11(6):688-723.
• 11. J E. Diffuse endothelioma of bone. Proc NY Pathol Soc.21:17-24. 1921.
• 12. Suh CH, Ordonez NG, Hicks J, Mackay B. Ultrastructure of the Ewing's sarcoma family of tumors. Ultrastruct Pathol. 2002;26(2):67-76.
• 13. Fellinger EJ, Garin-Chesa P, Triche TJ, Huvos AG, Rettig WJ. Immunohistochemical analysis of Ewing's sarcoma cell surface antigen p30/32MIC2. Am J Pathol. 1991;139(2):317-25.
• 14. Folpe AL, Goldblum JR, Rubin BP, Shehata BM, Liu W, Dei Tos AP, et al. Morphologic and immunophenotypic diversity in Ewing family tumors: a study of 66 genetically confirmed cases. Am J Surg Pathol. 2005;29(8):1025-33.
• 15. Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, Peter M, et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature. 1992;359(6391):162-5.
• 16. Delattre O, Zucman J, Melot T, Garau XS, Zucker JM, Lenoir GM, et al. The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med. 1994;331(5):294-9.
• 17. Peter M, Mugneret F, Aurias A, Thomas G, Magdelenat H, Delattre O. An EWS/ERG fusion with a truncated N-terminal domain of EWS in a Ewing's tumor. Int J Cancer. 1996;67(3):339-42.
• 18. Shulman SC, Katzenstein H, Bridge J, Bannister LL, Qayed M, Oskouei S, et al. Ewing sarcoma with 7;22 translocation: three new cases and clinicopathological characterization. Fetal Pediatr Pathol. 2012;31(6):341-8.
• 19. Wang L, Bhargava R, Zheng T, Wexler L, Collins MH, Roulston D, et al. Undifferentiated small round cell sarcomas with rare EWS gene fusions: identification of a novel EWS-SP3 fusion and of additional cases with the EWS-ETV1 and EWS-FEV fusions. J Mol Diagn. 2007;9(4):498-509.
• 20. Dubois SG, Epling CL, Teague J, Matthay KK, Sinclair E. Flow cytometric detection of Ewing sarcoma cells in peripheral blood and bone marrow. Pediatr Blood Cancer. 2010;54(1):13-8.
• 21. Wagner LM, Smolarek TA, Sumegi J, Marmer D. Assessment of minimal residual disease in ewing sarcoma. Sarcoma. 2012;2012:780129.
• 22. Bridge RS, Rajaram V, Dehner LP, Pfeifer JD, Perry A. Molecular diagnosis of Ewing sarcoma/primitive neuroectodermal tumor in routinely processed tissue: a comparison of two FISH strategies and RT-PCR in malignant round cell tumors. Mod Pathol. 2006;19(1):1-8.
• 23. Peersman B, Vanhoenacker FM, Heyman S, Van Herendael B, Stam M, Brys P, et al. Ewing's sarcoma: imaging features. JBR-BTR. 2007;90(5):368-76.
• 24. Kuleta-Bosak E, Kluczewska E, Machnik-Broncel J, Madziara W, Ciupinska-Kajor M, Sojka D, et al. Suitability of imaging methods (X-ray, CT, MRI) in the diagnostics of Ewing's sarcoma in children - analysis of own material. Pol J Radiol. 2010;75(1):18-28.
• 25. Eary JF, Mankoff DA. Tumor metabolic rates in sarcoma using FDG PET. J Nucl Med. 1998;39(2):250-4.
• 26. Eary JF, O'Sullivan F, Powitan Y, Chandhury KR, Vernon C, Bruckner JD, et al. Sarcoma tumor FDG uptake measured by PET and patient outcome: a retrospective analysis. Eur J Nucl Med Mol Imaging. 2002;29(9):1149-54.
• 27. Sharma P, Khangembam BC, Suman KC, Singh H, Rastogi S, Khan SA, et al. Diagnostic accuracy of 18F-FDG PET/CT for detecting recurrence in patients with primary skeletal Ewing sarcoma. Eur J Nucl Med Mol Imaging. 2013;40(7):1036-43.
• 28. Kumar J, Seith A, Kumar A, Sharma R, Bakhshi S, Kumar R, et al. Whole-body MR imaging with the use of parallel imaging for detection of skeletal metastases in pediatric patients with small-cell neoplasms: comparison with skeletal scintigraphy and FDG PET/CT. Pediatr Radiol. 2008;38(9):953-62.
• 29. Newman EN, Jones RL, Hawkins DS. An evaluation of [F-18]-fluorodeoxy-D-glucose positron emission tomography, bone scan, and bone marrow aspiration/biopsy as staging investigations in Ewing sarcoma. Pediatr Blood Cancer. 2013;60(7):1113-7.
• 30. Treglia G, Salsano M, Stefanelli A, Mattoli MV, Giordano A, Bonomo L. Diagnostic accuracy of (1)(8)F-FDG-PET and PET/CT in patients with Ewing sarcoma family tumours: a systematic review and a meta-analysis. Skeletal Radiol. 2012;41(3):249-56.
• 31. Franzius C, Sciuk J, Daldrup-Link HE, Jurgens H, Schober O. FDG-PET for detection of osseous metastases from malignant primary bone tumours: comparison with bone scintigraphy. Eur J Nucl Med. 2000;27(9):1305-11.
• 32. Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res. 1980(153):106-20.
• 33. American Joint Committee on Cancer (2010) AJCC cancer staging manual teS, New York.
• 34. Womer RB, West DC, Krailo MD, Dickman PS, Pawel BR, Grier HE, et al. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol. 2012;30(33):4148-54.
• 35. Juergens C, Weston C, Lewis I, Whelan J, Paulussen M, Oberlin O, et al. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer. 2006;47(1):22-9.
• 36. Wang CC, Schulz MD. Ewing's sarcoma; a study of fifty cases treated at the Massachusetts General Hospital, 1930-1952 inclusive. N Engl J Med. 1953;248(14):571-6.
• 37. Donaldson SS, Torrey M, Link MP, Glicksman A, Gilula L, Laurie F, et al. A multidisciplinary study investigating radiotherapy in Ewing's sarcoma: end results of POG #8346. Pediatric Oncology Group. Int J Radiat Oncol Biol Phys. 1998;42(1):125-35.
• 38. Pinkel D. Cyclophosphamide in children with cancer. Cancer. 1962;15:42-9.
• 39. Sutow WW, Sullivan MP. Cyclophosphamide therapy in children with Ewing's sarcoma. Cancer Chemother Rep. 1962;23:55-60.
• 40. Bacci G, Ferrari S, Avella M, Barbieri E, Picci P, Casadei R, et al. Non-metastatic Ewing's sarcoma: results in 98 patients treated with neoadjuvant chemotherapy. Ital J Orthop Traumatol. 1991;17(4):449-65.
• 41. Bacci G, Toni A, Avella M, Manfrini M, Sudanese A, Ciaroni D, et al. Long-term results in 144 localized Ewing's sarcoma patients treated with combined therapy. Cancer. 1989;63(8):1477-86.
• 42. Nesbit ME, Jr., Gehan EA, Burgert EO, Jr., Vietti TJ, Cangir A, Tefft M, et al. Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: a long-term follow-up of the First Intergroup study. J Clin Oncol. 1990;8(10):1664-74.
• 43. Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003;348(8):694-701.
• 44. Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, et al. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol. 2004;22(14):2873-6.
• 45. Kushner BH, Meyers PA. How effective is dose-intensive/myeloablative therapy against Ewing's sarcoma/primitive neuroectodermal tumor metastatic to bone or bone marrow? The Memorial Sloan-Kettering experience and a literature review. J Clin Oncol. 2001;19(3):870-80.
• 46. Laurence V, Pierga JY, Barthier S, Babinet A, Alapetite C, Palangie T, et al. Long-term follow up of high-dose chemotherapy with autologous stem cell rescue in adults with Ewing tumor. Am J Clin Oncol. 2005;28(3):301-9.
• 47. Navid F, Santana VM, Billups CA, Merchant TE, Furman WL, Spunt SL, et al. Concomitant administration of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide for high-risk sarcomas: the St. Jude Children's Research Hospital experience. Cancer. 2006;106(8):1846-56.
• 48. Womer RB, Daller RT, Fenton JG, Miser JS. Granulocyte colony stimulating factor permits dose intensification by interval compression in the treatment of Ewing's sarcomas and soft tissue sarcomas in children. Eur J Cancer. 2000;36(1):87-94.
• 49. Schuck A, Hofmann J, Rube C, Hillmann A, Ahrens S, Paulussen M, et al. Radiotherapy in Ewing's sarcoma and PNET of the chest wall: results of the trials CESS 81, CESS 86 and EICESS 92. Int J Radiat Oncol Biol Phys. 1998;42(5):1001-6.
• 50. Shankar AG, Pinkerton CR, Atra A, Ashley S, Lewis I, Spooner D, et al. Local therapy and other factors influencing site of relapse in patients with localised Ewing's sarcoma. United Kingdom Children's Cancer Study Group (UKCCSG). Eur J Cancer. 1999;35(12):1698-704.
• 51. Rosito P, Mancini AF, Rondelli R, Abate ME, Pession A, Bedei L, et al. Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: a preliminary report of 6 years of experience. Cancer. 1999;86(3):421-8.
• 52. Yaw KM. Pediatric bone tumors. Semin Surg Oncol. 1999;16(2):173-83.
• 53. Dunst J, Jurgens H, Sauer R, Pape H, Paulussen M, Winkelmann W, et al. Radiation therapy in Ewing's sarcoma: an update of the CESS 86 trial. Int J Radiat Oncol Biol Phys. 1995;32(4):919-30.
• 54. Lissat A, Chao MM, Kontny U. Targeted therapy in Ewing sarcoma. ISRN Oncol. 2012;2012:609439.
• 55. Ludwig JA. Ewing sarcoma: historical perspectives, current state-of-the-art, and opportunities for targeted therapy in the future. Curr Opin Oncol. 2008;20(4):412-8.
• 56. Mitsiades N, Poulaki V, Mitsiades C, Tsokos M. Ewing's sarcoma family tumors are sensitive to tumor necrosis factor-related apoptosis-inducing ligand and express death receptor 4 and death receptor 5. Cancer Res. 2001;61(6):2704-12.
• 57. Zhou Z, Jia SF, Hung MC, Kleinerman ES. E1A sensitizes HER2/neu-overexpressing Ewing's sarcoma cells to topoisomerase II-targeting anticancer drugs. Cancer Res. 2001;61(8):3394-8.
• 58. Gonzalez I, Andreu EJ, Panizo A, Inoges S, Fontalba A, Fernandez-Luna JL, et al. Imatinib inhibits proliferation of Ewing tumor cells mediated by the stem cell factor/KIT receptor pathway, and sensitizes cells to vincristine and doxorubicin-induced apoptosis. Clin Cancer Res. 2004;10(2):751-61.
• 59. Juergens H, Daw NC, Geoerger B, Ferrari S, Villarroel M, Aerts I, et al. Preliminary efficacy of the anti-insulin-like growth factor type 1 receptor antibody figitumumab in patients with refractory Ewing sarcoma. J Clin Oncol. 2011;29(34):4534-40.
• 60. Malempati S, Weigel B, Ingle AM, Ahern CH, Carroll JM, Roberts CT, et al. Phase I/II trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol. 2012;30(3):256-62.
• 61. Pappo AS, Patel SR, Crowley J, Reinke DK, Kuenkele KP, Chawla SP, et al. R1507, a monoclonal antibody to the insulin-like growth factor 1 receptor, in patients with recurrent or refractory Ewing sarcoma family of tumors: results of a phase II Sarcoma Alliance for Research through Collaboration study. J Clin Oncol. 2011;29(34):4541-7.
• 62. Tap WD, Demetri G, Barnette P, Desai J, Kavan P, Tozer R, et al. Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors. J Clin Oncol. 2012;30(15):1849-56.
• 63. Naing A, LoRusso P, Fu S, Hong DS, Anderson P, Benjamin RS, et al. Insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with refractory Ewing's sarcoma family tumors. Clin Cancer Res. 2012;18(9):2625-31.
• 64. Bond M, Bernstein ML, Pappo A, Schultz KR, Krailo M, Blaney SM, et al. A phase II study of imatinib mesylate in children with refractory or relapsed solid tumors: a Children's Oncology Group study. Pediatr Blood Cancer. 2008;50(2):254-8.
• 65. Ginsberg JP WS, Johnson ME, Hicks MJ, Horowitz ME. Ewing’s sarcoma family of
• 66. tumors: Ewing’s sarcoma of bone and soft tissue and peripheral primitive neuroectodermal
• 67. tumors. In: Pizzo P, Poplack D, editors. Principles and practice of pediatric oncology. 4th ed.
• 68. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 973–1016.
• 69. .
• 70. Wagner TD, Kobayashi W, Dean S, Goldberg SI, Kirsch DG, Suit HD, et al. Combination short-course preoperative irradiation, surgical resection, and reduced-field high-dose postoperative irradiation in the treatment of tumors involving the bone. Int J Radiat Oncol Biol Phys. 2009;73(1):259-66.
• 71. Cotterill SJ, Ahrens S, Paulussen M, Jurgens HF, Voute PA, Gadner H, et al. Prognostic factors in Ewing's tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing's Sarcoma Study Group. J Clin Oncol. 2000;18(17):3108-14.
• 72. Dalinka MK, Edeiken J, Finkelstein JB. Complications of radiation therapy: adult bone. Semin Roentgenol. 1974;9(1):29-40.
• 73. Donaldson SS. Ewing sarcoma: radiation dose and target volume. Pediatr Blood Cancer. 2004;42(5):471-6.
• 74. Krasin MJ, Rodriguez-Galindo C, Davidoff AM, Billups CA, Fuller CE, Neel MD, et al. Efficacy of combined surgery and irradiation for localized Ewings sarcoma family of tumors. Pediatr Blood Cancer. 2004;43(3):229-36.
• 75. Bacci G, Longhi A, Briccoli A, Bertoni F, Versari M, Picci P. The role of surgical margins in treatment of Ewing's sarcoma family tumors: experience of a single institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys. 2006;65(3):766-72.
• 76. Kuttesch JF, Jr., Wexler LH, Marcus RB, Fairclough D, Weaver-McClure L, White M, et al. Second malignancies after Ewing's sarcoma: radiation dose-dependency of secondary sarcomas. J Clin Oncol. 1996;14(10):2818-25.
• 77. Givens SS, Woo SY, Huang LY, Rich TA, Maor MH, Cangir A, et al. Non-metastatic Ewing's sarcoma: twenty years of experience suggests that surgery is a prime factor for successful multimodality therapy. Int J Oncol. 1999;14(6):1039-43.
• 78. Donati D, Yin J, Di Bella C, Colangeli M, Bacci G, Ferrari S, et al. Local and distant control in non-metastatic pelvic Ewing's sarcoma patients. J Surg Oncol. 2007;96(1):19-25.
• 79. Frassica FJ, Frassica DA, Pritchard DJ, Schomberg PJ, Wold LE, Sim FH. Ewing sarcoma of the pelvis. Clinicopathological features and treatment. J Bone Joint Surg Am. 1993;75(10):1457-65.
• 80. Puri A, Gulia A, Jambhekar NA, Laskar S. Results of surgical resection in pelvic Ewing's sarcoma. J Surg Oncol. 2012;106(4):417-22.
• 81. Sucato DJ, Rougraff B, McGrath BE, Sizinski J, Davis M, Papandonatos G, et al. Ewing's sarcoma of the pelvis. Long-term survival and functional outcome. Clin Orthop Relat Res. 2000(373):193-201.
• 82. Thorpe SW WK, Goodman MA, Heyl AE, McGough RL. Should aggressive
• 83. surgical local control be attempted in all patients with metastatic or pelvic Ewing’s sarcoma?
• 84. Sarcoma 2012:953602. doi:10.1155/2012/953602
• 85. . 2012.
• 86. Yang RS, Eckardt JJ, Eilber FR, Rosen G, Forscher CA, Dorey FJ, et al. Surgical indications for Ewing's sarcoma of the pelvis. Cancer. 1995;76(8):1388-97.
• 87. Bacci G, Ferrari S, Longhi A, Donati D, Barbieri E, Forni C, et al. Role of surgery in local treatment of Ewing's sarcoma of the extremities in patients undergoing adjuvant and neoadjuvant chemotherapy. Oncol Rep. 2004;11(1):111-20.
• 88. Sluga M, Windhager R, Lang S, Heinzl H, Krepler P, Mittermayer F, et al. The role of surgery and resection margins in the treatment of Ewing's sarcoma. Clin Orthop Relat Res. 2001(392):394-9.
• 89. Henderson ER, Groundland JS, Pala E, Dennis JA, Wooten R, Cheong D, et al. Failure mode classification for tumor endoprostheses: retrospective review of five institutions and a literature review. J Bone Joint Surg Am. 2011;93(5):418-29.
• 90. Horowitz SM, Glasser DB, Lane JM, Healey JH. Prosthetic and extremity survivorship after limb salvage for sarcoma. How long do the reconstructions last? Clin Orthop Relat Res. 1993(293):280-6.
• 91. Malawer MM, Chou LB. Prosthetic survival and clinical results with use of large-segment replacements in the treatment of high-grade bone sarcomas. J Bone Joint Surg Am. 1995;77(8):1154-65.
• 92. Benedetti MG, Bonatti E, Malfitano C, Donati D. Comparison of allograft-prosthetic composite reconstruction and modular prosthetic replacement in proximal femur bone tumors: functional assessment by gait analysis in 20 patients. Acta Orthop. 2013;84(2):218-23.
• 93. Donati D, Di Bella C, Frisoni T, Cevolani L, DeGroot H. Alloprosthetic composite is a suitable reconstruction after periacetabular tumor resection. Clin Orthop Relat Res. 2011;469(5):1450-8.
• 94. Oberlin O, Deley MC, Bui BN, Gentet JC, Philip T, Terrier P, et al. Prognostic factors in localized Ewing's tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer. 2001;85(11):1646-54.
• 95. Paulussen M, Ahrens S, Burdach S, Craft A, Dockhorn-Dworniczak B, Dunst J, et al. Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol. 1998;9(3):275-81.
• 96. Barker LM, Pendergrass TW, Sanders JE, Hawkins DS. Survival after recurrence of Ewing's sarcoma family of tumors. J Clin Oncol. 2005;23(19):4354-62.
• 97. Bacci G, Longhi A, Ferrari S, Mercuri M, Barbieri E, Bertoni F, et al. Pattern of relapse in 290 patients with nonmetastatic Ewing's sarcoma family tumors treated at a single institution with adjuvant and neoadjuvant chemotherapy between 1972 and 1999. Eur J Surg Oncol. 2006;32(9):974-9.
• 98. Bolling T, Schuck A, Paulussen M, Dirksen U, Ranft A, Konemann S, et al. Whole lung irradiation in patients with exclusively pulmonary metastases of Ewing tumors. Toxicity analysis and treatment results of the EICESS-92 trial. Strahlenther Onkol. 2008;184(4):193-7.
• 99. Miser JS, Goldsby RE, Chen Z, Krailo MD, Tarbell NJ, Link MP, et al. Treatment of metastatic Ewing sarcoma/primitive neuroectodermal tumor of bone: evaluation of increasing the dose intensity of chemotherapy--a report from the Children's Oncology Group. Pediatr Blood Cancer. 2007;49(7):894-900.
• 100. Luksch R, Grignani G, Fagioli F, Brach del Prever A, Podda M, Aliberti S, et al. Response to melphalan in up-front investigational window therapy for patients with metastatic Ewing's family tumours. Eur J Cancer. 2007;43(5):885-90.
• 101. Stahl M, Ranft A, Paulussen M, Bolling T, Vieth V, Bielack S, et al. Risk of recurrence and survival after relapse in patients with Ewing sarcoma. Pediatr Blood Cancer. 2011;57(4):549-53.
• 102. Wasilewski-Masker K, Liu Q, Yasui Y, Leisenring W, Meacham LR, Hammond S, et al. Late recurrence in pediatric cancer: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2009;101(24):1709-20.
• 103. Leavey PJ, Mascarenhas L, Marina N, Chen Z, Krailo M, Miser J, et al. Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence following multi-modality therapy: A report from the Children's Oncology Group. Pediatr Blood Cancer. 2008;51(3):334-8.
• 104. Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, et al. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001;19(6):1818-29.
• 105. Scully SP, Temple HT, O'Keefe RJ, Scarborough MT, Mankin HJ, Gebhardt MC. Role of surgical resection in pelvic Ewing's sarcoma. J Clin Oncol. 1995;13(9):2336-41.
• 106. Denecke T, Hundsdorfer P, Misch D, Steffen IG, Schonberger S, Furth C, et al. Assessment of histological response of paediatric bone sarcomas using FDG PET in comparison to morphological volume measurement and standardized MRI parameters. Eur J Nucl Med Mol Imaging. 2010;37(10):1842-53.
• 107. Lin PP, Jaffe N, Herzog CE, Costelloe CM, Deavers MT, Kelly JS, et al. Chemotherapy response is an important predictor of local recurrence in Ewing sarcoma. Cancer. 2007;109(3):603-11.
• 108. Bacci G, Longhi A, Ferrari S, Mercuri M, Versari M, Bertoni F. Prognostic factors in non-metastatic Ewing's sarcoma tumor of bone: an analysis of 579 patients treated at a single institution with adjuvant or neoadjuvant chemotherapy between 1972 and 1998. Acta Oncol. 2006;45(4):469-75.
• 109. Karski EE, McIlvaine E, Segal MR, Krailo M, Grier HE, Granowetter L, et al. Identification of Discrete Prognostic Groups in Ewing Sarcoma. Pediatr Blood Cancer. 2016;63(1):47-53.
• 110. Rodriguez-Galindo C, Liu T, Krasin MJ, Wu J, Billups CA, Daw NC, et al. Analysis of prognostic factors in ewing sarcoma family of tumors: review of St. Jude Children's Research Hospital studies. Cancer. 2007;110(2):375-84.
• 111. Abudu A, Mangham DC, Reynolds GM, Pynsent PB, Tillman RM, Carter SR, et al. Overexpression of p53 protein in primary Ewing's sarcoma of bone: relationship to tumour stage, response and prognosis. Br J Cancer. 1999;79(7-8):1185-9.
• 112. Lopez-Guerrero JA, Machado I, Scotlandi K, Noguera R, Pellin A, Navarro S, et al. Clinicopathological significance of cell cycle regulation markers in a large series of genetically confirmed Ewing's sarcoma family of tumors. Int J Cancer. 2011;128(5):1139-50.
• 113. Ozaki T, Paulussen M, Poremba C, Brinkschmidt C, Rerin J, Ahrens S, et al. Genetic imbalances revealed by comparative genomic hybridization in Ewing tumors. Genes Chromosomes Cancer. 2001;32(2):164-71.
• 114. Schleiermacher G, Peter M, Oberlin O, Philip T, Rubie H, Mechinaud F, et al. Increased risk of systemic relapses associated with bone marrow micrometastasis and circulating tumor cells in localized ewing tumor. J Clin Oncol. 2003;21(1):85-91.
• 115. Roberts P, Burchill SA, Brownhill S, Cullinane CJ, Johnston C, Griffiths MJ, et al. Ploidy and karyotype complexity are powerful prognostic indicators in the Ewing's sarcoma family of tumors: a study by the United Kingdom Cancer Cytogenetics and the Children's Cancer and Leukaemia Group. Genes Chromosomes Cancer. 2008;47(3):207-20.
• 116. Scotlandi K, Remondini D, Castellani G, Manara MC, Nardi F, Cantiani L, et al. Overcoming resistance to conventional drugs in Ewing sarcoma and identification of molecular predictors of outcome. J Clin Oncol. 2009;27(13):2209-16.
• 117. de Alava E, Kawai A, Healey JH, Fligman I, Meyers PA, Huvos AG, et al. EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing's sarcoma. J Clin Oncol. 1998;16(4):1248-55.
• 118. Le Deley MC, Delattre O, Schaefer KL, Burchill SA, Koehler G, Hogendoorn PC, et al. Impact of EWS-ETS fusion type on disease progression in Ewing's sarcoma/peripheral primitive neuroectodermal tumor: prospective results from the cooperative Euro-E.W.I.N.G. 99 trial. J Clin Oncol. 2010;28(12):1982-8.
• 119. van Doorninck JA, Ji L, Schaub B, Shimada H, Wing MR, Krailo MD, et al. Current treatment protocols have eliminated the prognostic advantage of type 1 fusions in Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol. 2010;28(12):1989-94.
• 120. Cash T, McIlvaine E, Krailo MD, Lessnick SL, Lawlor ER, Laack N, et al. Comparison of clinical features and outcomes in patients with extraskeletal versus skeletal localized Ewing sarcoma: A report from the Children's Oncology Group. Pediatr Blood Cancer. 2016;63(10):1771-9.
• 121. Ahrens S, Hoffmann C, Jabar S, Braun-Munzinger G, Paulussen M, Dunst J, et al. Evaluation of prognostic factors in a tumor volume-adapted treatment strategy for localized Ewing sarcoma of bone: the CESS 86 experience. Cooperative Ewing Sarcoma Study. Med Pediatr Oncol. 1999;32(3):186-95.
• 122. 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. 2007;43(13):1944-51.
• 123. Tepper J, Glaubiger D, Lichter A, Wackenhut J, Glatstein E. Local control of Ewing's sarcoma of bone with radiotherapy and combination chemotherapy. Cancer. 1980;46(9):1969-73.