Biology of Bone Sarcomas and New Therapeutic Developments

Hannah K Brown, Kristina Schiavone, François Gouin, Marie-Françoise Heymann, Dominique Heymann, Hannah K Brown, Kristina Schiavone, François Gouin, Marie-Françoise Heymann, Dominique Heymann

Abstract

Bone sarcomas are tumours belonging to the family of mesenchymal tumours and constitute a highly heterogeneous tumour group. The three main bone sarcomas are osteosarcoma, Ewing sarcoma and chondrosarcoma each subdivided in diverse histological entities. They are clinically characterised by a relatively high morbidity and mortality, especially in children and adolescents. Although these tumours are histologically, molecularly and genetically heterogeneous, they share a common involvement of the local microenvironment in their pathogenesis. This review gives a brief overview of their specificities and summarises the main therapeutic advances in the field of bone sarcoma.

Keywords: Chondrosarcoma; Clinical trials; Ewing sarcoma; Giant cell tumour of bone; Immunotherapy; Osteosarcoma; Tumour microenvironment.

Figures

Fig. 1
Fig. 1
Origin of bone sarcomas. Based on the current knowledge, osteosarcoma, Ewing sarcoma and chondrosarcoma share a common mesenchymal origin. According to their differentiation level and in association with oncogenic events and an adapted microenvironment their common precursor, a “mesenchymal stem cell” could be transformed into an osteosarcoma, chondrosarcoma or an Ewing sarcoma. Sox9 Sry-related high-mobility group box (Sox) transcription factor 9 related to chondrogenic differentiation, Runx2 runt-related transcription factor 2 related to osteoblastogenesis, ALP alkaline phosphatase, OC osteocalcin, BSP bone sialoprotein
Fig. 2
Fig. 2
The tumour microenvironment contributes to the control of bone sarcoma formation, their recurrence and associated metastatic process. The bone sarcoma microenvironment is composed of highly diversified cell populations forming specific local niches: vascular niche, immune niche, bone niche, muscular and pulmonary niches (e.g. metastatic niches), neuronal control and activity of neurotrophic factors. These various cell types establish a mutual dialogue with sarcoma cells through physical contact, the release of soluble factors or the formation of extracellular vesicles. All these communications will lead to strong alterations of the microenvironment (e.g. qualitative modifications of the extracellular matrix) and the behaviour of cancer cells, which increase their proliferation, and/or invasion/migration properties
Fig. 3
Fig. 3
Recent on-going clinical trials in osteosarcoma. Numerous therapeutic approaches are in clinical development and are based on specific and direct targeting of cancer cells (e.g. DNA repair, cell cycle or glycoprotein targeting), or indirect targeting of cancer cells by modulation of their microenvironment (e.g. immunotherapies). After integration in extracellular tumour bone matrix, alpha radiotherapeutic agents can indirectly kill the cancer cells. NCT: National Clinical Trial NuClinicalTrials.gov registry Number
Fig. 4
Fig. 4
Giant cell tumours of bone: a benign entity with malignant features. Giant cell tumours of bone are composed of three main cell populations: stromal cells, macrophages and multinucleated osteoclast-like cells. These tumours are responsible for a marked local bone resorption leading to the formation of large osteolytic foci easily detectable by X-ray radiography. RANKL/M-CSF and/or RANKL/IL-34 released by stromal cell could induce the differentiation of macrophages considered as osteoclast precursors towards immature and mature osteoclasts resorbing bone. Soluble OPG and membrane LGR4 are two receptors that negatively control osteoclastogenesis. OPG acts as a decoy receptor to RANK resulting in blocked RANKL–RANK interactions. LGR4 is expressed by osteoclasts and binds to RANKL leading to Gαq/GS3K-β signalling and repression of the NFATc1 molecular pathway. IL-34 Interleukin-34, LGR-4 G-protein-coupled receptor 4, M-CSF Macrophage Colony-Stimulating Factor, OPG osteoprotegerin, RANKL Receptor of Nuclear factor kappaB Ligand

References

    1. Stiller CA, Craft AW, Corazziari I. Survival of children with bone sarcoma in Europe since 1978: results from the EUROCARE study. Eur J Cancer. 2001;37:760–766. doi: 10.1016/S0959-8049(01)00004-1.
    1. The ESMO/European Sarcoma Network Working Group Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23:vii100–vii109.
    1. Heymann D. Bone cancer: primary bone cancer an bone metastases. 2. San Diego: Elsevier; 2014.
    1. Heymann D, Redini F. Bone sarcomas: pathogenesis and new therapeutic approaches. IBMS BoneKEy. 2011;8:402–414. doi: 10.1138/20110531.
    1. Deschaseaux F, Sensébé L, Heymann D. Mechanisms of bone repair and regeneration. Trends Mol Med. 2009;15:417–429. doi: 10.1016/j.molmed.2009.07.002.
    1. Panaroni C, Tzeng YS, Saeed H, Wu JY. Mesenchymal progenitors and the osteoblast lineage in bone marrow hematopoietic niches. Curr Osteoporos Rep. 2014;12:22–32. doi: 10.1007/s11914-014-0190-7.
    1. Garg P, Mazur MM, Buck AC, Wandtke ME, Liu J, Ebraheim NA. Prospective review of mesenchymal stem cells differentiation into osteoblasts. Orthop Surg. 2017;9:13–19. doi: 10.1111/os.12304.
    1. Mohseny AB, Hogendoorn PC. Concise review: mesenchymal tumors: when stem cells go mad. Stem Cells. 2011;29:397–403. doi: 10.1002/stem.596.
    1. Wagner ER, Luther G, Zhu G, Luo Q, Shi Q, Kim SH, Gao JL, Huang E, Gao Y, Yang K, Wang L, Teven C, Luo X, Liu X, Li M, Hu N, Su Y, Bi Y, He BC, Tang N, Luo J, Chen L, Zuo G, Rames R, Haydon RC, Luu HH, He TC. Defective osteogenic differentiation in the development of osteosarcoma. Sarcoma. 2011;2011:325238.
    1. Mohseny AB, Szuhai K, Romeo S, Buddingh EP, Briaire-de Bruijn I, de Jong D, van Pel M, Cleton-Jansen AM, Hogendoorn PC. Osteosarcoma originates from mesenchymal stem cells in consequence of aneuploidization and genomic loss of Cdkn2. J Pathol. 2009;219:294–305. doi: 10.1002/path.2603.
    1. Tang X, Lu X, Guo W, Ren T, Zhao H, Zhao F, Tang G. Different expression of Sox9 and Runx2 between chondrosarcoma and dedifferentiated chondrosarcoma cell line. Eur J Cancer Prev. 2010;19:466–471. doi: 10.1097/CEJ.0b013e32833d942f.
    1. de Andrea CE, Reijnders CM, Kroon HM, de Jong D, Hogendoorn PC, Szuhai K, Bovée JV. Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT. Oncogene. 2012;31:1095–1104. doi: 10.1038/onc.2011.311.
    1. Zuntini M, Pedrini E, Parra A, Sgariglia F, Gentile FV, Pandolfi M, Alberghini M, Sangiorgi L. Genetic models of osteochondroma onset and neoplastic progression: evidence for mechanisms alternative to EXT genes inactivation. Oncogene. 2010;29:3827–3834. doi: 10.1038/onc.2010.135.
    1. Musso N, Caronia FP, Castorina S, Lo Monte AI, Barresi V, Condorelli DF. Somatic loss of an EXT2 gene mutation during malignant progression in a patient with hereditary multiple osteochondromas. Cancer Genet. 2015;208:62–67. doi: 10.1016/j.cancergen.2015.01.002.
    1. The Delattre O, Zucman J, Melot T, Garau XS, Zucker JM, Lenoir GM, Ambros PF, Sheer D, Turc-Carel C, Triche TJ, Aurias A, Thomas G. Ewing family of tumors—a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 331:294–299. 10.1056/NEJM199408043310503
    1. Tirode F, Laud-Duval K, Prieur A, Delorme B, Charbord P, Delattre O. Mesenchymal stem cell features of Ewing tumors. Cancer Cell. 2007;11:421–429. doi: 10.1016/j.ccr.2007.02.027.
    1. von Levetzow C, Jiang X, Gwye Y, von Levetzow G, Hung L, Cooper A, Hsu JH, Lawlor ER. Modeling initiation of Ewing sarcoma in human neural crest cells. PLoS ONE. 2011;6:e19305. doi: 10.1371/journal.pone.0019305.
    1. Tanaka M, Yamazaki Y, Kanno Y, Igarashi K, Aisaki K, Kanno J, Nakamura T. Ewing’s sarcoma precursors are highly enriched in embryonic osteochondrogenic progenitors. J Clin Investig. 2014;124:3061–3074. doi: 10.1172/JCI72399.
    1. Riggi N, Cironi L, Provero P, Suva ML, Kaloulis K, Garcia-Echeverria C, Hoffmann F, Trumpp A, Stamenkovic I. Development of Ewing’s sarcoma from primary bone marrow-derived mesenchymal progenitor cells. Cancer Res. 2005;65:11459–11468. doi: 10.1158/0008-5472.CAN-05-1696.
    1. Uluçkan Ö, Segaliny A, Botter S, Santiago JM, Mutsaers AJ. Preclinical mouse models of osteosarcoma. BoneKEy Rep. 2015;4:670. doi: 10.1038/bonekey.2015.37.
    1. Botter SM, Arlt MJE, Fuchs B. Mammalian models of bone sarcomas. In: Heymann D, editor. Bone cancer, second edition, chapter 30. San Diego: Elsevier; 2015. pp. 349–364.
    1. Cleton-Jansen AM. Zebrafish models for studying bone cancers: mutants, transgenic fish and embryos. In: Heymann D, editor. Bone cancer, second edition, chapter 31. San Diego: Elsevier; 2015. pp. 365–370.
    1. Walkley CR. Modeling osteosarcoma: in vitro and in vivo approaches. In: Heymann D, editor. Bone cancer, second edition, chapter 17. San Diego: Elsevier; 2015. pp. 195–204.
    1. Hoffman RM. Patient-derived orthotopic xenografts: better mimic of metastasis than subcutaneous xenografts. Nat Rev Cancer. 2015;15:451–452. doi: 10.1038/nrc3972.
    1. Sampson VB, Kamara DF, Kolb EA. Xenograft and genetically engineered mouse model systems of osteosarcoma and Ewing’s sarcoma: tumor models for cancer drug discovery. Expert Opin Drug Discov. 2013;8:1181–1189. doi: 10.1517/17460441.2013.817988.
    1. Swarm RL, Correa JN, Andrews JR, Miller E. Morphologic demonstration of recurrent tumor following X irradiation. Histologic study of irradiated murine chondrosarcoma transplants. J Natl Cancer Inst. 1964;33:657–672.
    1. van Oosterwijk JG, Plass JR, Meijer D, Que I, Karperien M, Bovée JV. An orthotopic mouse model for chondrosarcoma of bone provides an in vivo tool for drug testing. Virchows Arch. 2015;466:101–109. doi: 10.1007/s00428-014-1670-y.
    1. Monderer D, Luseau A, Bellec A, David E, Ponsolle S, Saiagh S, Bercegeay S, Piloquet P, Denis MG, Lodé L, Rédini F, Biger M, Heymann D, Heymann MF, Le Bot R, Gouin F, Blanchard F. New chondrosarcoma cell lines and mouse models to study the link between chondrogenesis and chemoresistance. Lab Invest. 2013;93:1100–1114. doi: 10.1038/labinvest.2013.101.
    1. Brown HK, Tellez-Gabriel M, Heymann D. Cancer stem cells in osteosarcoma. Cancer Lett. 2017;386:189–195. doi: 10.1016/j.canlet.2016.11.019.
    1. Bousquet M, Noirot C, Accadbled F, Sales de Gauzy J, Castex MP, Brousset P, Gomez-Brouchet A. Whole-exome sequencing in osteosarcoma reveals important heterogeneity of genetic alterations. Ann Oncol. 2016;27:738–744. doi: 10.1093/annonc/mdw009.
    1. Kovac M, Blattmann C, Ribi S, Smida J, Mueller NS, Engert F, Castro-Giner F, Weischenfeldt J, Kovacova M, Krieg A, Andreou D, Tunn PU, Dürr HR, Rechl H, Schaser KD, Melcher I, Burdach S, Kulozik A, Specht K, Heinimann K, Fulda S, Bielack S, Jundt G, Tomlinson I, Korbel JO, Nathrath M, Baumhoer D. Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. Nat Commun. 2015;6:8940. doi: 10.1038/ncomms9940.
    1. Kresse SH, Rydbeck H, Skårn M, Namløs HM, Barragan-Polania AH, Cleton-Jansen AM, Serra M, Liestøl K, Hogendoorn PC, Hovig E, Myklebost O, Meza-Zepeda LA. Integrative analysis reveals relationships of genetic and epigenetic alterations in osteosarcoma. PLoS ONE. 2012;7:e48262. doi: 10.1371/journal.pone.0048262.
    1. Balamuth NJ, Womer RB. Ewing’s sarcoma. Lancet Oncol. 2010;11:184–192. doi: 10.1016/S1470-2045(09)70286-4.
    1. Burdach S, Jurgens H. High-dose chemoradiotherapy (HDC) in the Ewing family of tumors (EFT) Crit Rev Oncol Hematol. 2002;41:169–189. doi: 10.1016/S1040-8428(01)00154-8.
    1. Iwamoto Y. Diagnosis and treatment of Ewing’s sarcoma. Jpn J Clin Oncol. 2007;37:79–89. doi: 10.1093/jjco/hyl142.
    1. Llombart-Bosch A, Machado I, Navarro S, Bertoni F, Bacchini P, Alberghini M, Karzeladze A, Savelov N, Petrov S, Alvarado-Cabrero I, Mihaila D, Terrier P, Lopez-Guerrero JA, Picci P. Histological heterogeneity of Ewing’s sarcoma/PNET: an immunohistochemical analysis of 415 genetically confirmed cases with clinical support. Virchows Arch. 2009;455:397–411. doi: 10.1007/s00428-009-0842-7.
    1. Zhang N, Liu H, Yue G, Zhang Y, You J, Wang H. Molecular heterogeneity of Ewing sarcoma as detected by ion torrent sequencing. PLoS ONE. 2016;11(4):e0153546. doi: 10.1371/journal.pone.0153546.
    1. Bühnemann C, Li S, Yu H, Branford White H, Schäfer KL, Llombart-Bosch A, Machado I, Picci P, Hogendoorn PC, Athanasou NA, Noble JA, Hassan AB. Quantification of the heterogeneity of prognostic cellular biomarkers in Ewing sarcoma using automated image and random survival forest analysis. PLoS ONE. 2014;9:e107105. doi: 10.1371/journal.pone.0107105.
    1. Sheffield NC, Pierron G, Klughammer J, Datlinger P, Schönegger A, Schuster M, Hadler J, Surdez D, Guillemot D, Lapouble E, Freneaux P, Champigneulle J, Bouvier R, Walder D, Ambros IM, Hutter C, Sorz E, Amaral AT, de Álava E, Schallmoser K, Strunk D, Rinner B, Liegl-Atzwanger B, Huppertz B, Leithner A, de Pinieux G, Terrier P, Laurence V, Michon J, Ladenstein R, Holter W, Windhager R, Dirksen U, Ambros PF, Delattre O, Kovar H, Bock C, Tomazou EM. DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma. Nat Med. 2017;23:386–395. doi: 10.1038/nm.4273.
    1. Franzetti GA, Laud-Duval K, van der Ent W, Brisac A, Irondelle M, Aubert S, Dirksen U, Bouvier C, de Pinieux G, Snaar-Jagalska E, Chavrier P, Delattre O. Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in Ewing sarcoma cells. Oncogene. 2017;36:3505–3514. doi: 10.1038/onc.2016.498.
    1. Brohl AS, Solomon DA, Chang W, Wang J, Song Y, Sindiri S, Patidar R, Hurd L, Chen L, Shern JF, Liao H, Wen X, Gerard J, Kim JS, Lopez Guerrero JA, Machado I, Wai DH, Picci P, Triche T, Horvai AE, Miettinen M, Wei JS, Catchpool D, Llombart-Bosch A, Waldman T, Khan J. The genomic landscape of the Ewing sarcoma family of tumors reveals recurrent STAG2 mutation. PLoS Genet. 2014;10:e1004475. doi: 10.1371/journal.pgen.1004475.
    1. Huang HY, Illei PB, Zhao Z, Mazumdar M, Huvos AG, Healey JH, Wexler LH, Gorlick R, Meyers P, Ladanyi M. Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion: a highly lethal subset associated with poor chemoresponse. J Clin Oncol. 2005;23:548–558. doi: 10.1200/JCO.2005.02.081.
    1. Bovée JV, Cleton-Jansen AM, Taminiau AH, Hogendoorn PC. Emerging pathways in the development of chondrosarcoma of bone and implications for targeted treatment. Lancet Oncol. 2005;6:599–607. doi: 10.1016/S1470-2045(05)70282-5.
    1. Bovée JV, Hogendoorn PC, Wunder JS, Alman BA. Cartilage tumours and bone development: molecular pathology and possible therapeutic targets. Nat Rev Cancer. 2010;10:481–488. doi: 10.1038/nrc2869.
    1. Bovée JV, Hogendoorn PC, Wunder JS, Alman BA. Cartilage tumours and bone development: molecular pathology and possible therapeutic targets. Nat Rev Cancer. 2010;10:481–488. doi: 10.1038/nrc2869.
    1. Fletcher CDM, Bridge JA, Hogendoorn P, Mertens F (2013) Who classification of tumours of soft tissue and bone, fourth edition, IARC Ed. ISBN-13 9789283224341$4
    1. Speetjens FM, de Jong Y, Gelderblom H, Bovée JV. Molecular oncogenesis of chondrosarcoma: impact for targeted treatment. Curr Opin Oncol. 2016;28:314–322. doi: 10.1097/CCO.0000000000000300.
    1. O’Neal LW, Ackerman LV. Chondrosarcoma of bone. Cancer. 1952;5:551–577. doi: 10.1002/1097-0142(195205)5:3<551::AID-CNCR2820050317>;2-Z.
    1. Meijer D, de Jong D, Pansuriya TC, van den Akker BE, Picci P, Szuhai K, Bovée JV. Genetic characterization of mesenchymal, clear cell, and dedifferentiated chondrosarcoma. Genes Chromosoms Cancer. 2012;51(10):899–909. doi: 10.1002/gcc.21974.
    1. Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, Pollock R, O’Donnell P, Grigoriadis A, Diss T, Eskandarpour M, Presneau N, Hogendoorn PC, Futreal A, Tirabosco R, Flanagan AM. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol. 2011;224:334–343. doi: 10.1002/path.2913.
    1. Tarpey PS, Behjati S, Cooke SL, Van Loo P, Wedge DC, Pillay N, Marshall J, O’Meara S, Davies H, Nik-Zainal S, Beare D, Butler A, Gamble J, Hardy C, Hinton J, Jia MM, Jayakumar A, Jones D, Latimer C, Maddison M, Martin S, McLaren S, Menzies A, Mudie L, Raine K, Teague JW, Tubio JM, Halai D, Tirabosco R, Amary F, Campbell PJ, Stratton MR, Flanagan AM, Futreal PA. Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma. Nat Genet. 2013;45:923–926. doi: 10.1038/ng.2668.
    1. Ottaviani G, Jaffe N. The etiology of osteosarcoma. Cancer Treat Res. 2009;152:15–32. doi: 10.1007/978-1-4419-0284-9_2.
    1. Fiorenza F, Abudu A, Grimer RJ, Carter SR, Tillman RM, Ayoub K, Mangham DC, Davies AM. Risk factors for survival and local control in chondrosarcoma of bone. J Bone Joint Surg Br. 2002;84:93–99. doi: 10.1302/0301-620X.84B1.11942.
    1. Wang ZQ, Ovitt C, Grigoriadis AE, Möhle-Steinlein U, Rüther U, Wagner EF. Bone and haematopoietic defects in mice lacking c-fos. Nature. 1992;360(6406):741–745. doi: 10.1038/360741a0.
    1. Wang ZQ, Liang J, Schellander K, Wagner EF, Grigoriadis AE. c-fos-induced osteosarcoma formation in transgenic mice: cooperativity with c-jun and the role of endogenous c-fos. Cancer Res. 1995;55:6244–62451.
    1. Correa H. Li-Fraumeni syndrome. J Pediatr Genet. 2016;5:84–88. doi: 10.1055/s-0036-1579759.
    1. Simon T, Kohlhase J, Wilhelm C, Kochanek M, De Carolis B, Berthold F. Multiple malignant diseases in a patient with Rothmund-Thomson syndrome with RECQL4 mutations: case report and literature review. Am J Med Genet A. 2010;152A:1575–1579.
    1. Murata K, Hatamochi A, Shinkai H, Ishikawa Y, Kawaguchi N, Goto M. A case of Werner’s syndrome associated with osteosarcoma. J Dermatol. 1999;26:682–686. doi: 10.1111/j.1346-8138.1999.tb02072.x.
    1. Lu L, Jin W, Liu H, Wang LL. RECQ helicases and osteosarcoma. Adv Exp Med Biol. 2014;804:129–145. doi: 10.1007/978-3-319-04843-7_7.
    1. Ng AJ, Walia MK, Smeets MF, Mutsaers AJ, Sims NA, Purton LE, Walsh NC, Martin TJ, Walkley CR. The DNA helicase recql4 is required for normal osteoblast expansion and osteosarcoma formation. PLoS Genet. 2015;11(4):e1005160. doi: 10.1371/journal.pgen.1005160.
    1. Ren W, Gu G (2017) Prognostic implications of RB1 tumour suppressor gene alterations in the clinical outcome of human osteosarcoma: a meta-analysis. Eur J Cancer Care 26. 10.1111/ecc.12401
    1. Beltrami G, Ristori G, Scoccianti G, Tamburini A, Capanna R. Hereditary Multiple Exostoses: a review of clinical appearance and metabolic pattern. Clin Cases Miner Bone Metab. 2016;13(2):110–118.
    1. Czajka CM, DiCaprio MR. What is the proportion of patients with multiple hereditary exostoses who undergo malignant degeneration? Clin Orthop Relat Res. 2015;473:2355–2361. doi: 10.1007/s11999-015-4134-z.
    1. Alfranca A, Martinez-Cruzado L, Tornin J, Abarrategi A, Amaral T, de Alava E, Menendez P, Garcia-Castro J, Rodriguez R. Bone microenvironment signals in osteosarcoma development. Cell Mol Life Sci. 2015;72:3097–3113. doi: 10.1007/s00018-015-1918-y.
    1. Simard FA, Richert I, Vandermoeten A, Decouvelaere AV, Michot JP, Caux C, Blay JY, Dutour A. Description of the immune microenvironment of chondrosarcoma and contribution to progression. Oncoimmunology. 2016;6:e1265716. doi: 10.1080/2162402X.2016.1265716.
    1. David E, Blanchard F, Heymann MF, De Pinieux G, Gouin F, Rédini F, Heymann D. The bone niche of chondrosarcoma: a sanctuary for drug resistance, tumour growth and also a source of new therapeutic targets. Sarcoma. 2011;2011:932451. doi: 10.1155/2011/932451.
    1. Bailey KM, Airik M, Krook MA, Pedersen EA, Lawlor ER. Micro-Environmental stress induces Src-dependent activation of invadopodia and cell migration in Ewing sarcoma. Neoplasia. 2016;18:480–488. doi: 10.1016/j.neo.2016.06.008.
    1. Lissat A, Joerschke M, Shinde DA, Braunschweig T, Meier A, Makowska A, Bortnick R, Henneke P, Herget G, Gorr TA, Kontny U. IL6 secreted by Ewing sarcoma tumor microenvironment confers anti-apoptotic and cell-disseminating paracrine responses in Ewing sarcoma cells. BMC Cancer. 2015;15:552. doi: 10.1186/s12885-015-1564-7.
    1. Paget S. The distribution of secondary growths in cancer of the breast. Lancet 133:571–573. 10.1016/S0140-6736(00)49915-0
    1. Wittrant Y, Théoleyre S, Chipoy C, Padrines M, Blanchard F, Heymann D, Rédini F. RANKL/RANK/OPG: new therapeutic targets in bone tumours and associated osteolysis. Biochim Biophys Acta. 2004;1704:49–57.
    1. Odri GA, Dumoucel S, Picarda G, Battaglia S, Lamoureux F, Corradini N, Rousseau J, Tirode F, Laud K, Delattre O, Gouin F, Heymann D, Redini F. Zoledronic acid as a new adjuvant therapeutic strategy for Ewing’s sarcoma patients. Cancer Res. 2010;70:7610–7619. doi: 10.1158/0008-5472.CAN-09-4272.
    1. Moriceau G, Ory B, Mitrofan L, Riganti C, Blanchard F, Brion R, Charrier C, Battaglia S, Pilet P, Denis MG, Shultz LD, Mönkkönen J, Rédini F, Heymann D. Zoledronic acid potentiates mTOR inhibition and abolishes the resistance of osteosarcoma cells to RAD001 (Everolimus): pivotal role of the prenylation process. Cancer Res. 2010;70:10329–10339. doi: 10.1158/0008-5472.CAN-10-0578.
    1. Moriceau G, Ory B, Gobin B, Verrecchia F, Gouin F, Blanchard F, Redini F, Heymann D. Therapeutic approach of primary bone tumours by bisphosphonates. Curr Pharm Des. 2010;16:2981–2987. doi: 10.2174/138161210793563554.
    1. Ohba T, Cole HA, Cates JM, Slosky DA, Haro H, Ando T, Schwartz HS, Schoenecker JG. Bisphosphonates inhibit osteosarcoma-mediated osteolysis via attenuation of tumor expression of MCP-1 and RANKL. J Bone Miner Res. 2014;29:1431–1445. doi: 10.1002/jbmr.2182.
    1. Lamoureux F, Richard P, Wittrant Y, Battaglia S, Pilet P, Trichet V, Blanchard F, Gouin F, Pitard B, Heymann D, Redini F. Therapeutic relevance of osteoprotegerin gene therapy in osteosarcoma: blockade of the vicious cycle between tumor cell proliferation and bone resorption. Cancer Res. 2007;67:7308–7318. doi: 10.1158/0008-5472.CAN-06-4130.
    1. Gouin F, Ory B, Rédini F, Heymann D. Zoledronic acid slows down rat primary chondrosarcoma development, recurrent tumor progression after intralesional curretage and increases overall survival. Int J Cancer. 2006;119:980–984. doi: 10.1002/ijc.21951.
    1. Ory B, Blanchard F, Battaglia S, Gouin F, Rédini F, Heymann D. Zoledronic acid activates the DNA S-phase checkpoint and induces osteosarcoma cell death characterized by apoptosis-inducing factor and endonuclease-G translocation independently of p53 and retinoblastoma status. Mol Pharmacol. 2007;71:333–343. doi: 10.1124/mol.106.028837.
    1. Endo-Munoz L, Cumming A, Rickwood D, Wilson D, Cueva C, Ng C, Strutton G, Cassady AI, Evdokiou A, Sommerville S, Dickinson I, Guminski A, Saunders NA. Loss of osteoclasts contributes to development of osteosarcoma pulmonary metastases. Cancer Res. 2010;70:7063–7072. doi: 10.1158/0008-5472.CAN-09-4291.
    1. Cackowski FC, Anderson JL, Patrene KD, Choksi RJ, Shapiro SD, Windle JJ, Blair HC, Roodman GD. Osteoclasts are important for bone angiogenesis. Blood. 2010;115:140–149. doi: 10.1182/blood-2009-08-237628.
    1. Endo-Munoz L, Evdokiou A, Saunders NA. The role of osteoclasts and tumour-associated macrophages in osteosarcoma metastasis. Biochim Biophys Acta. 2012;1826:434–442.
    1. Perrot P, Rousseau J, Bouffaut AL, Rédini F, Cassagnau E, Deschaseaux F, Heymann MF, Heymann D, Duteille F, Trichet V, Gouin F. Safety concern between autologous fat graft, mesenchymal stem cell and osteosarcoma recurrence. PLoS ONE. 2010;5(6):e10999. doi: 10.1371/journal.pone.0010999.
    1. Cortini M, Massa A, Avnet S, Bonuccelli G, Baldini N. Tumor-Activated Mesenchymal stromal cells promote osteosarcoma stemness and migratory potential via IL-6 secretion. PLoS ONE. 2016;11:e0166500. doi: 10.1371/journal.pone.0166500.
    1. Massa A, Perut F, Chano T, Woloszyk A, Mitsiadis TA, Avnet S, Baldini N. The effect of extracellular acidosis on the behaviour of mesenchymal stem cells in vitro. Eur Cell Mater. 2017;33:252–267. doi: 10.22203/eCM.v033a19.
    1. Avnet S, Di Pompo G, Chano T, Errani C, Ibrahim-Hashim A, Gillies RJ, Donati DM, Baldini N. Cancer-associated mesenchymal stroma fosters the stemness of osteosarcoma cells in response to intratumoral acidosis via NF-κB activation. Int J Cancer. 2017;140(6):1331–1345. doi: 10.1002/ijc.30540.
    1. Tellez-Gabriel M, Charrier C, Brounais-Le Royer B, Mullard M, Brown HK, Verrecchia F, Heymann D. Analysis of gap junctional intercellular communications using a dielectrophoresis-based microchip. Eur J Cell Biol. 2017;96:110–118. doi: 10.1016/j.ejcb.2017.01.003.
    1. Xu H, Gu S, Riquelme MA, Burra S, Callaway D, Cheng H, Guda T, Schmitz J, Fajardo RJ, Werner SL, Zhao H, Shang P, Johnson ML, Bonewald LF, Jiang JX. Connexin 43 channels are essential for normal bone structure and osteocyte viability. J Bone Miner Res. 2015;30:436–448. doi: 10.1002/jbmr.2374.
    1. Talbot J, Verrecchia F. Gap junctions and bone remodeling. Biol Aujourdhui. 2012;206:125–134. doi: 10.1051/jbio/2012016.
    1. Plotkin LI, Davis HM, Cisterna BA, Sáez JC. Connexins and pannexins in bone and skeletal muscle. Curr Osteoporos Rep. 2017;15:326–334. doi: 10.1007/s11914-017-0374-z.
    1. Talbot J, Brion R, Picarda G, Amiaud J, Chesneau J, Bougras G, Stresing V, Tirode F, Heymann D, Redini F, Verrecchia F. Loss of connexin43 expression in Ewing’s sarcoma cells favors the development of the primary tumor and the associated bone osteolysis. Biochim Biophys Acta. 2013;1832:553–564. doi: 10.1016/j.bbadis.2013.01.001.
    1. Torreggiani E, Roncuzzi L, Perut F, Zini N, Baldini N. Multimodal transfer of MDR by exosomes in human osteosarcoma. Int J Oncol. 2016;49:189–196. doi: 10.3892/ijo.2016.3509.
    1. Baglio SR, Lagerweij T, Pérez-Lanzón M, Ho XD, Léveillé N, Melo SA, Cleton-Jansen AM, Jordanova ES, Roncuzzi L, Greco M, van Eijndhoven MAJ, Grisendi G, Dominici M, Bonafede R, Lougheed SM, de Gruijl TD, Zini N, Cervo S, Steffan A, Canzonieri V, Martson A, Maasalu K, Köks S, Wurdinger T, Baldini N, Pegtel DM. Blocking tumor-educated MSC paracrine activity halts osteosarcoma progression. Clin Cancer Res. 2017
    1. Heymann D, Ory B, Blanchard F, Heymann MF, Coipeau P, Charrier C, Couillaud S, Thiery JP, Gouin F, Redini F. Enhanced tumor regression and tissue repair when zoledronic acid is combined with ifosfamide in rat osteosarcoma. Bone. 2005;37:74–86. doi: 10.1016/j.bone.2005.02.020.
    1. Karsenty G, Oury F. The central regulation of bone mass, the first link between bone remodeling and energy metabolism. J Clin Endocrinol Metab. 2010;95:4795–4801. doi: 10.1210/jc.2010-1030.
    1. Corr A, Smith J, Baldock P. Neuronal control of bone remodeling. Toxicol Pathol. 2017
    1. Dimitri P, Rosen C. The central nervous system and bone metabolism: an evolving story. Calcif Tissue Int. 2017;100:476–485. doi: 10.1007/s00223-016-0179-6.
    1. Kondo A, Mogi M, Koshihara Y, Togari A. Signal transduction system for interleukin-6 and interleukin-11 synthesis stimulated by epinephrine in human osteoblasts and human osteogenic sarcoma cells. Biochem Pharmacol. 2001;61:319–326. doi: 10.1016/S0006-2952(00)00544-X.
    1. Broadhead ML, Choong PF, Dass CR. Efficacy of continuously administered PEDF-derived synthetic peptides against osteosarcoma growth and metastasis. J Biomed Biotechnol. 2012;2012:230298. doi: 10.1155/2012/230298.
    1. Punzo F, Tortora C, Di Pinto D, Manzo I, Bellini G, Casale F, Rossi F. Anti-proliferative, pro-apoptotic and anti-invasive effect of EC/EV system in human osteosarcoma. Oncotarget. 2017;8:54459–54471. doi: 10.18632/oncotarget.17089.
    1. Otero JE, Stevens JW, Malandra AE, Fredericks DC, Odgren PR, Buckwalter JA, Morcuende J. Osteoclast inhibition impairs chondrosarcoma growth and bone destruction. J Orthop Res. 2014;32:1562–1571. doi: 10.1002/jor.22714.
    1. Piperno-Neumann S, Le Deley MC, Rédini F, Pacquement H, Marec-Bérard P, Petit P, Brisse H, Lervat C, Gentet JC, Entz-Werlé N, Italiano A, Corradini N, Bompas E, Penel N, Tabone MD, Gomez-Brouchet A, Guinebretière JM, Mascard E, Gouin F, Chevance A, Bonnet N, Blay JY, Brugières L, Sarcoma Group of UNICANCER. French Society of Pediatric Oncology (SFCE) French Sarcoma Group (GSF-GETO) Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016;17:1070–1080. doi: 10.1016/S1470-2045(16)30096-1.
    1. Lézot F, Chesneau J, Navet B, Gobin B, Amiaud J, Choi Y, Yagita H, Castaneda B, Berdal A, Mueller CG, Rédini F, Heymann D. Skeletal consequences of RANKL-blocking antibody (IK22–5) injections during growth: mouse strain disparities and synergic effect with zoledronic acid. Bone. 2015;73:51–59. doi: 10.1016/j.bone.2014.12.011.
    1. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51. doi: 10.1016/j.cell.2010.03.014.
    1. Sousa S, Auriola S, Mönkkönen J, Määttä J. Liposome encapsulated zoledronate favours M1-like behaviour in murine macrophages cultured with soluble factors from breast cancer cells. BMC Cancer. 2015;15:4. doi: 10.1186/s12885-015-1005-7.
    1. Veltman JD, Lambers ME, van Nimwegen M, Hendriks RW, Hoogsteden HC, Hegmans JP, Aerts JG. Zoledronic acid impairs myeloid differentiation to tumour-associated macrophages in mesothelioma. Br J Cancer. 2010;103:629–641. doi: 10.1038/sj.bjc.6605814.
    1. Buddingh EP, Kuijjer ML, Duim RA, Bürger H, Agelopoulos K, Myklebost O, Serra M, Mertens F, Hogendoorn PC, Lankester AC, Cleton-Jansen AM. Tumor-infiltrating macrophages are associated with metastasis suppression in high-grade osteosarcoma: a rationale for treatment with macrophage activating agents. Clin Cancer Res. 2011;17:2110–2119. doi: 10.1158/1078-0432.CCR-10-2047.
    1. Dumars C, Ngyuen JM, Gaultier A, Lanel R, Corradini N, Gouin F, Heymann D, Heymann MF. Dysregulation of macrophage polarization is associated with the metastatic process in osteosarcoma. Oncotarget. 2016;7:78343–78354. doi: 10.18632/oncotarget.13055.
    1. Fujiwara T, Fukushi J, Yamamoto S, Matsumoto Y, Setsu N, Oda Y, Yamada H, Okada S, Watari K, Ono M, Kuwano M, Kamura S, Iida K, Okada Y, Koga M, Iwamoto Y. Macrophage infiltration predicts a poor prognosis for human Ewing sarcoma. Am J Pathol. 2011;179:1157–1170. doi: 10.1016/j.ajpath.2011.05.034.
    1. Inagaki Y, Hookway E, Williams KA, Hassan AB, Oppermann U, Tanaka Y, Soilleux E, Athanasou NA. Dendritic and mast cell involvement in the inflammatory response to primary malignant bone tumours. Clin Sarcoma Res. 2016;6:13. doi: 10.1186/s13569-016-0053-3.
    1. Heymann MF, Lezot F, Heymann D. The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma. Cellular Immunol. 10.1016/j.cellimm.2017.10.011 (in press)
    1. Théoleyre S, Mori K, Cherrier B, Passuti N, Gouin F, Rédini F, Heymann D. Phenotypic and functional analysis of lymphocytes infiltrating osteolytic tumors: use as a possible therapeutic approach of osteosarcoma. BMC Cancer. 2005;5:123. doi: 10.1186/1471-2407-5-123.
    1. Meftah M, Schult P, Henshaw RM. Long-term results of intralesional curettage and cryosurgery for treatment of low-grade chondrosarcoma. J Bone Joint Surg Am. 2013;95:1358–1364. doi: 10.2106/JBJS.L.00442.
    1. Riedel RF, Larrier N, Dodd L, Kirsch D, Martinez S, Brigman BE. The clinical management of chondrosarcoma. Curr Treat Options Oncol. 2009;10:94–106. doi: 10.1007/s11864-009-0088-2.
    1. Heymann MF, Brown HK, Heymann D. Drugs in early clinical development for the treatment of osteosarcoma. Expert Opin Investig Drugs. 2016;25:1265–1280. doi: 10.1080/13543784.2016.1237503.
    1. Meyers PA, Schwartz CL, Krailo MD, Healey JH, Bernstein ML, Betcher D, Ferguson WS, Gebhardt MC, Goorin AM, Harris M, Kleinerman E, Link MP, Nadel H, Nieder M, Siegal GP, Weiner MA, Wells RJ, Womer RB, Grier HE, Children. ’. s Oncology Group Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival–a report from the Children’s Oncology Group. J Clin Oncol. 2008;26:633–638. doi: 10.1200/JCO.2008.14.0095.
    1. Redini F, Odri GA, Picarda G, Gaspar N, Heymann MF, Corradini N, Heymann D. Drugs targeting the bone microenvironment: new therapeutic tools in Ewing’s sarcoma? Expert Opin Emerg Drugs. 2013;18:339–352. doi: 10.1517/14728214.2013.823948.
    1. Gaspar N, Hawkins DS, Dirksen U, Lewis IJ, Ferrari S, Le Deley MC, Kovar H, Grimer R, Whelan J, Claude L, Delattre O, Paulussen M, Picci P, Sundby Hall K, van den Berg H, Ladenstein R, Michon J, Hjorth L, Judson I, Luksch R, Bernstein ML, Marec-Bérard P, Brennan B, Craft AW, Womer RB, Juergens H, Oberlin O. Ewing sarcoma: current management and future approaches through collaboration. J Clin Oncol. 2015;33:3036–3046. doi: 10.1200/JCO.2014.59.5256.
    1. Xing M, Yan F, Yu S, Shen P. Efficacy and cardiotoxicity of liposomal doxorubicin-based chemotherapy in advanced breast cancer: a meta-analysis of ten randomized trials. PLoS ONE. 2015;10:e0133569. doi: 10.1371/journal.pone.0133569.
    1. Kang MH, Wang J, Makena MR, Lee JS, Paz N, Hall CP, Song MM, Calderon RI, Cruz RE, Hindle A, Ko W, Fitzgerald JB, Drummond DC, Triche TJ, Reynolds CP. Activity of MM-398, nanoliposomal irinotecan (nal-IRI), in Ewing’s family tumor xenografts is associated with high exposure of tumor to drug and high SLFN11 expression. Clin Cancer Res. 2015;21:1139–1150. doi: 10.1158/1078-0432.CCR-14-1882.
    1. Mitchison TJ. The proliferation rate paradox in antimitotic chemotherapy. Mol Biol Cell. 2012;23:1–6. doi: 10.1091/mbc.E10-04-0335.
    1. Ségaliny AI, Tellez-Gabriel M, Heymann MF, Heymann D. Receptor tyrosine kinases: characterisation, mechanism of action and therapeutic interests for bone cancers. J Bone Oncol. 2015;4:1–12. doi: 10.1016/j.jbo.2015.01.001.
    1. Heymann D, Rédini F. Targeted therapies for bone sarcomas. BoneKEy Rep. 2013;2:378. doi: 10.1038/bonekey.2013.112.
    1. Safwat A, Boysen A, Lücke A, Rossen P. Pazopanib in metastatic osteosarcoma: significant clinical response in three consecutive patients. Acta Oncol. 2014;53:1451–1454. doi: 10.3109/0284186X.2014.948062.
    1. Attia S, Okuno SH, Robinson SI, Webber NP, Indelicato DJ, Jones RL, Bagaria SP, Jones RL, Sherman C, Kozak KR, Cortese CM, McFarland T, Trent JC, Maki RG. Clinical activity of pazopanib in metastatic extraosseous Ewing sarcoma. Rare Tumors. 2015;7:5992. doi: 10.4081/rt.2015.5992.
    1. Mross K, Frost A, Steinbild S, Hedbom S, Büchert M, Fasol U, Unger C, Krätzschmar J, Heinig R, Boix O, Christensen O. A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res. 2012;18:2658–2667. doi: 10.1158/1078-0432.CCR-11-1900.
    1. Subbiah V, Anderson P, Rohren E. Alpha emitter radium 223 in high-risk osteosarcoma: first clinical evidence of response and blood-brain barrier penetration. JAMA Oncol. 2015;1:253–255. doi: 10.1001/jamaoncol.2014.289.
    1. Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, Greninger P, Thompson IR, Luo X, Soares J, Liu Q, Iorio F, Surdez D, Chen L, Milano RJ, Bignell GR, Tam AT, Davies H, Stevenson JA, Barthorpe S, Lutz SR, Kogera F, Lawrence K, McLaren-Douglas A, Mitropoulos X, Mironenko T, Thi H, Richardson L, Zhou W, Jewitt F, Zhang T, O’Brien P, Boisvert JL, Price S, Hur W, Yang W, Deng X, Butler A, Choi HG, Chang JW, Baselga J, Stamenkovic I, Engelman JA, Sharma SV, Delattre O, Saez-Rodriguez J, Gray NS, Settleman J, Futreal PA, Haber DA, Stratton MR, Ramaswamy S, McDermott U, Benes CH. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012;483:570–575. doi: 10.1038/nature11005.
    1. Choy E, Butrynski JE, Harmon DC, Morgan JA, George S, Wagner AJ, D’Adamo D, Cote GM, Flamand Y, Benes CH, Haber DA, Baselga JM, Demetri GD. Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy. BMC Cancer. 2014;4:813. doi: 10.1186/1471-2407-14-813.
    1. van Maldegem AM, Bovée JV, Peterse EF, Hogendoorn PC, Gelderblom H. Ewing sarcoma: the clinical relevance of the insulin-like growth factor 1 and the poly-ADP-ribose-polymerase pathway. Eur J Cancer. 2016;53:171–180. doi: 10.1016/j.ejca.2015.09.009.
    1. Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK, Iyer AK. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol. 2017;8:561. doi: 10.3389/fphar.2017.00561.
    1. Pinto N, Park JR, Murphy E, Yearley J, McClanahan T, Annamalai L, Hawkins DS, Rudzinski ER. Patterns of PD-1, PD-L1, and PD-L2 expression in pediatric solid tumors. Pediatr Blood Cancer. 2017
    1. Paydas S, Bagir EK, Deveci MA, Gonlusen G. Clinical and prognostic significance of PD-1 and PD-L1 expression in sarcomas. Med Oncol. 2016;33:93. doi: 10.1007/s12032-016-0807-z.
    1. Shen JK, Cote GM, Choy E, Yang P, Harmon D, Schwab J, Nielsen GP, Chebib I, Ferrone S, Wang X, Wang Y, Mankin H, Hornicek FJ, Duan Z. Programmed cell death ligand 1 expression in osteosarcoma. Cancer Immunol Res. 2014;2:690–698. doi: 10.1158/2326-6066.CIR-13-0224.
    1. Sundara YT, Kostine M, Cleven AH, Bovée JV, Schilham MW, Cleton-Jansen AM. Increased PD-L1 and T-cell infiltration in the presence of HLA class I expression in metastatic high-grade osteosarcoma: a rationale for T-cell-based immunotherapy. Cancer Immunol Immunother. 2017;66:119–128. doi: 10.1007/s00262-016-1925-3.
    1. Paoluzzi L, Cacavio A, Ghesani M, Karambelkar A, Rapkiewicz A, Weber J, Rosen G. Response to anti-PD1 therapy with nivolumab in metastatic sarcomas. Clin Sarcoma Res. 2016;6:24. doi: 10.1186/s13569-016-0064-0.
    1. Dobrenkov K, Ostrovnaya I, Gu J, Cheung IY, Cheung NK. Oncotargets GD2 and GD3 are highly expressed in sarcomas of children, adolescents, and young adults. Pediatr Blood Cancer. 2016;63:1780–1785. doi: 10.1002/pbc.26097.
    1. Bernstein-Molho R, Kollender Y, Issakov J, Bickels J, Dadia S, Flusser G, Meller I, Sagi-Eisenberg R, Merimsky O. Clinical activity of mTOR inhibition in combination with cyclophosphamide in the treatment of recurrent unresectable chondrosarcomas. Cancer Chemother Pharmacol. 2012;70:855–860. doi: 10.1007/s00280-012-1968-x.
    1. Perez J, Decouvelaere AV, Pointecouteau T, Pissaloux D, Michot JP, Besse A, Blay JY, Dutour A. Inhibition of chondrosarcoma growth by mTOR inhibitor in an in vivo syngeneic rat model. PLoS ONE. 2012;7:e32458. doi: 10.1371/journal.pone.0032458.
    1. Kostine M, Cleven AH, de Miranda NF, Italiano A, Cleton-Jansen AM, Bovée JV. Analysis of PD-L1, T-cell infiltrate and HLA expression in chondrosarcoma indicates potential for response to immunotherapy specifically in the dedifferentiated subtype. Mod Pathol. 2016;29:1028–1037. doi: 10.1038/modpathol.2016.108.
    1. Amelio JM, Rockberg J, Hernandez RK, et al. Population-based study of giant cell tumor of bone in Sweden (1983–2011) Cancer Epidemiol. 2016;42:82–89. doi: 10.1016/j.canep.2016.03.014.
    1. Dahlin DC, Cupps RE, Johnson EW., Jr Giant-cell tumor: a study of 195 cases. Cancer. 1970;25:1061–1070. doi: 10.1002/1097-0142(197005)25:5<1061::AID-CNCR2820250509>;2-E.
    1. Rosario M, Kim HS, Yun JY, Han I. Surveillance for lung metastasis from giant cell tumor of bone. J Surg Oncol. 2017
    1. Renema N, Navet B, Heymann MF, Lezot F, Heymann D. RANK-RANKL signalling in cancer. Biosci Rep. 2016;36(4):e00366. doi: 10.1042/BSR20160150.
    1. Gouin F, Rochwerger AR, Di Marco A, Rosset P, Bonnevialle P, Fiorenza F, Anract P. Adjuvant treatment with zoledronic acid after extensive curettage for giant cell tumours of bone. Eur J Cancer. 2014;50:2425–2431. doi: 10.1016/j.ejca.2014.06.003.
    1. Chawla S, Henshaw R, Seeger L, Choy E, Blay JY, Ferrari S, Kroep J, Grimer R, Reichardt P, Rutkowski P, Schuetze S, Skubitz K, Staddon A, Thomas D, Qian Y, Jacobs Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol. 2013;14:901–908. doi: 10.1016/S1470-2045(13)70277-8.

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