Chondrosarcoma and giant cell tumour of bone (GCTB) are bone tumours characterized by recurrent mutations (IDH1/IDH2 and H3F3A, respectively) that induce remodelling of the epigenetic landscape.... Show moreChondrosarcoma and giant cell tumour of bone (GCTB) are bone tumours characterized by recurrent mutations (IDH1/IDH2 and H3F3A, respectively) that induce remodelling of the epigenetic landscape. The standard of care for both of these sarcoma subtypes is surgery and alternative treatment options for patients with inoperable disease are currently lacking (chondrosarcoma) or suboptimal (GCTB). Therefore, the aim of this thesis was to identify novel therapeutic targets for high-grade chondrosarcoma as well as GCTB, with a focus on potential therapies that could counteract the remodelling of the epigenome. PARP and HDAC inhibition, alone or in combination treatment strategies, were identified as promising therapeutic strategies for chondrosarcoma or both of these bone tumours, respectively. Additionally, this thesis describes the development and use of novel 3D cell culture models which can be used to improve the translation of preclinical findings to the clinic. Show less
GCTB is an osteolytic, locally-aggressive, rarely-metastasizing tumour, characterized by abundance of osteoclastlike giant cells, induced by neoplastic mononuclear cells expressing high-levels of... Show moreGCTB is an osteolytic, locally-aggressive, rarely-metastasizing tumour, characterized by abundance of osteoclastlike giant cells, induced by neoplastic mononuclear cells expressing high-levels of the receptor activator of nuclear factor Kappa-B ligand (RANKL), a mediator of osteoclast activation. Although the mainstay of treatment is complete tumour removal with preservation of bone, therapy with denosumab, an inhibitor of RANKL, has been introduced for selected cases. Objectives: Denosumab-treated GCTB (DT-GCTB) was reported to show a wide spectrum of histological changes such as depletion of osteoclast-like giant cells and intralesional bone deposition, which may lead to diagnostic difficulties. We investigated clinicopathologic and molecular features of DT-GCTB, matched with pre-therapy samples. Participants: 21 cases were included (13 females, 8 males), aged 15 to 64 (median, 30 years). Results: DT-GCTB showed development of sclerotic neocortex and varying degrees of osteosclerosis radiographically. Marked depletion of giant cells, different degree of ossification, fibrosis, and proliferation of mononuclear cells was observed. Staining for H3.3G34W was positive in mononuclear cells in 19 cases (90.5%), while one negative case was positive for H3.3G34V. H3F3A G34W mutation was confirmed in 17 of 19 cases (89.5%), corresponding to nuclear staining with H3.3 G34W antibody. G34L mutation was detected in one G34W negative case, in which H3.3 G34V nuclear positive staining was observed, possibly due to cross-reaction. Conclusions: Post-therapy tumours still exhibit a similar mutation profile, while significantly differing from classic GCTB morphologically. Correlation with history of denosumab administration, awareness of features of DT-GCTB, IHC and molecular studies for histone H3 mutations are important in its assessment. Show less
Giant cell tumours of bone (GCTB) are benign giant cell-rich tumours typically occurring in the epi-metaphysis of skeletally mature patients. Despite their benign classification, GCTB may be... Show moreGiant cell tumours of bone (GCTB) are benign giant cell-rich tumours typically occurring in the epi-metaphysis of skeletally mature patients. Despite their benign classification, GCTB may be locally aggressive with local recurrence as a challenging issue. Denosumab is a human monoclonal antibody that inhibits osteolysis via the RANK-RANK ligand pathway. There is currently no consensus on optimal treatment duration or imaging modality for monitoring patients on denosumab therapy. This review illustrates the radiological findings of GCTB on denosumab treatment seen on plain radiographs, CT, MRI, PET-CT and DEXA, with reference to the current literature. Recognizing imaging features indicative of a positive response to denosumab is important for therapeutic decision-making. Imaging findings with respect to duration of denosumab treatment, tumour upregulation during treatment, tumour recurrence and malignant transformation are discussed. The development of a sclerotic neocortex and varying degrees of matrix osteosclerosis are seen on plain radiographs. Reconstitution of subarticular bone and articular surface irregularity are optimally evaluated on CT which can also quantify tumour density. MRI demonstrates heterogeneous low signal matrix and is useful to assess decrease in size of cystic and/or soft tissue components of GCTB. A fat-suppressed fluid-sensitive MR sequence is important to detect tumour reactivation. Reduction in F-18-FDG-PET avidity represents an early sensitive sign of response to denosumab treatment. Regardless of imaging modality, close follow-up in a specialist centre and careful evaluation of nonresponders is necessary as local recurrence after cessation of denosumab treatment and malignant transformation of GCTB have been described. Show less
