title: A Translational Study of the Neoplastic Cells of Giant Cell Tumor of Bone Following Neoadjuvant Denosumab.
abstract: BACKGROUND
  Giant cell tumor of bone is a primary bone tumor that is treated surgically and is associated with high morbidity in many cases. This tumor consists of giant cells expressing RANK (receptor activator of nuclear factor-κB) and mesenchymal spindle-like stromal cells expressing RANKL (RANK ligand); the interaction of these cells leads to bone resorption. Denosumab is a monoclonal antibody that binds RANKL and directly inhibits osteoclastogenesis. Clinical studies have suggested clinical and histological improvement when denosumab was administered to patients with a giant cell tumor. However, no studies have yet examined the viability and functional characteristics of tumor cells following denosumab treatment.
  
  
  METHODS
  Specimens were obtained from six patients with a histologically confirmed giant cell tumor. Two of the patients had been treated with denosumab for six months. Primary cultures of stromal cells from fresh tumor tissue were established. Cell proliferation was measured over a two-day time course. The expression of RANKL and osteoprotegerin was analyzed with use of real-time PCR (polymerase chain reaction).
  
  
  RESULTS
  Histological specimens from both patients who had completed denosumab treatment showed the absence of giant cells but persistence of stromal cells. Cell proliferation studies indicated that proliferation of stromal cells cultured from clinical specimens following denosumab treatment was approximately 50% slower than that of specimens from untreated patients. The expression of RANKL in the specimens from the treated patients was almost completely eliminated.
  
  
  CONCLUSIONS
  Once the giant cell tumor tissue was no longer exposed to denosumab, the stromal cells continued to proliferate in vitro, albeit to a lesser degree. However, they also showed almost complete loss of RANKL expression.
  
  
  CONCLUSIONS
  It is clear that treatment with denosumab only partially addresses the therapeutic need of patients with a giant cell tumor by wiping out the osteoclasts but leaving the neoplastic stromal cells proliferative.
authors.affiliation: Departments of Surgery (I.W.Y.M., N.E., and M.G.), Pathology and Molecular Science (S.P.), and Oncology (R.T.), McMaster University, 711 Concession Street, Hamilton, ON L8V 1C3, Canada. E-mail addresses for I.W.Y. Mak: isamak@gmail.com; maki2@mcmaster.ca. E-mail address for N. Evaniew: nathan.evaniew@medportal.ca. E-mail address for S. Popovic: popovics@hhsc.ca. E-mail address for R. Tozer: richard.tozer@jcc.hhsc.ca. E-mail address for M. Ghert: michelle.ghert@jcc.hhsc.ca.
authors.forename: Isabella W Y
authors.initials: IW
authors.lastname: Mak
authors.affiliation: Departments of Surgery (I.W.Y.M., N.E., and M.G.), Pathology and Molecular Science (S.P.), and Oncology (R.T.), McMaster University, 711 Concession Street, Hamilton, ON L8V 1C3, Canada. E-mail addresses for I.W.Y. Mak: isamak@gmail.com; maki2@mcmaster.ca. E-mail address for N. Evaniew: nathan.evaniew@medportal.ca. E-mail address for S. Popovic: popovics@hhsc.ca. E-mail address for R. Tozer: richard.tozer@jcc.hhsc.ca. E-mail address for M. Ghert: michelle.ghert@jcc.hhsc.ca.
authors.forename: Nathan
authors.initials: N
authors.lastname: Evaniew
authors.affiliation: Departments of Surgery (I.W.Y.M., N.E., and M.G.), Pathology and Molecular Science (S.P.), and Oncology (R.T.), McMaster University, 711 Concession Street, Hamilton, ON L8V 1C3, Canada. E-mail addresses for I.W.Y. Mak: isamak@gmail.com; maki2@mcmaster.ca. E-mail address for N. Evaniew: nathan.evaniew@medportal.ca. E-mail address for S. Popovic: popovics@hhsc.ca. E-mail address for R. Tozer: richard.tozer@jcc.hhsc.ca. E-mail address for M. Ghert: michelle.ghert@jcc.hhsc.ca.
authors.forename: Snezana
authors.initials: S
authors.lastname: Popovic
authors.affiliation: Departments of Surgery (I.W.Y.M., N.E., and M.G.), Pathology and Molecular Science (S.P.), and Oncology (R.T.), McMaster University, 711 Concession Street, Hamilton, ON L8V 1C3, Canada. E-mail addresses for I.W.Y. Mak: isamak@gmail.com; maki2@mcmaster.ca. E-mail address for N. Evaniew: nathan.evaniew@medportal.ca. E-mail address for S. Popovic: popovics@hhsc.ca. E-mail address for R. Tozer: richard.tozer@jcc.hhsc.ca. E-mail address for M. Ghert: michelle.ghert@jcc.hhsc.ca.
authors.forename: Richard
authors.initials: R
authors.lastname: Tozer
authors.affiliation: Departments of Surgery (I.W.Y.M., N.E., and M.G.), Pathology and Molecular Science (S.P.), and Oncology (R.T.), McMaster University, 711 Concession Street, Hamilton, ON L8V 1C3, Canada. E-mail addresses for I.W.Y. Mak: isamak@gmail.com; maki2@mcmaster.ca. E-mail address for N. Evaniew: nathan.evaniew@medportal.ca. E-mail address for S. Popovic: popovics@hhsc.ca. E-mail address for R. Tozer: richard.tozer@jcc.hhsc.ca. E-mail address for M. Ghert: michelle.ghert@jcc.hhsc.ca.
authors.forename: Michelle
authors.initials: M
authors.lastname: Ghert
mesh_terms: D000328:Adult; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D000069448:Denosumab / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D018212:Giant Cell Tumor of Bone / Q000188:drug therapy* / Q000601:surgery; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D057170:Translational Research, Biomedical; D014407:Tumor Cells, Cultured
chemical_list: D050071:Bone Density Conservation Agents; D000069448:Denosumab