Simple Summary: Giant cell tumor of bone (GCTB) is an intermediate bone neoplasm which consists of several cell populations, including the neoplastic "stromal" cells. These cells harbor a mutation... Show moreSimple Summary: Giant cell tumor of bone (GCTB) is an intermediate bone neoplasm which consists of several cell populations, including the neoplastic "stromal" cells. These cells harbor a mutation in one of the histone H3.3 genes (H3F3A), and are therefore considered as the driving component of GCTB. This mutation causes changes in the epigenetic landscape, leading to aberrant gene expression patterns that may drive tumor growth. Surgery is currently the only curative treatment option because contemporary systemic therapies cannot remove the neoplastic cells from GCTB lesions, leading to re-outgrowth of the tumor when the treatment is discontinued. Therefore, the aim of this study was to explore whether therapeutic targeting of the epigenome can eliminate the neoplastic cells from GCTB lesions. The findings from this study indicate that histone deacetylase (HDAC) inhibitors may represent such a treatment strategy, which could improve the quality of life of GCTB patients who currently require life-long treatment. The neoplastic "stromal" cells in giant cell tumor of bone (GCTB) harbor a mutation in the H3F3A gene, which causes alterations in the epigenome. Current systemic targeted therapies, such as denosumab, do not affect the neoplastic cells, resulting in relapse upon treatment discontinuation. Therefore, this study examined whether targeting the epigenome could eliminate the neoplastic cells from GCTB. We established four novel cell lines of neoplastic "stromal" cells that expressed the H3F3A p.G34W mutation. These cell lines were used to perform an epigenetics compound screen (n = 128), which identified histone deacetylase (HDAC) inhibitors as key epigenetic regulators in the neoplastic cells. Transcriptome analysis revealed that the neoplastic cells expressed all HDAC isoforms, except for HDAC4. Therefore, five HDAC inhibitors targeting different HDAC subtypes were selected for further studies. All GCTB cell lines were very sensitive to HDAC inhibition in both 2D and 3D in vitro models, and inductions in histone acetylation, as well as apoptosis, were observed. Thus, HDAC inhibition may represent a promising therapeutic strategy to eliminate the neoplastic cells from GCTB lesions, which remains the paramount objective for GCTB patients who require life-long treatment with denosumab. Show less
Heijden, L. van der; Lipplaa, A.; Langevelde, K. van; Bovee, J.V.M.G.; Sande, M.A.J. van de; Gelderblom, H. 2022
Purpose of review Giant cell tumors of bone (GCTB) are intermediate, locally aggressive primary bone tumors. For conventional GCTB, surgery remains treatment of choice. For advanced GCTB, a more... Show morePurpose of review Giant cell tumors of bone (GCTB) are intermediate, locally aggressive primary bone tumors. For conventional GCTB, surgery remains treatment of choice. For advanced GCTB, a more important role came into play for systemic therapy including denosumab and bisphosphonates over the last decade. Recent findings In diagnostics, focus has been on H3F3A (G34) driver mutations present in GCTB. The most frequent mutation (G34W) can be detected using immunohistochemistry and is highly specific in differentiating GCTB from other giant cell containing tumors. PD-L1 expression can be used as biological marker to predict higher recurrence risks in GCTB patients. The use of bisphosphonate-loaded bone cement is under investigation in a randomized controlled trial. A new technique consisting of percutaneous microwave ablation and bisphosphonate-loaded polymethylmethacrylate cementoplasty was proposed for unresectable (pelvic) GCTB. Increased experience with use of denosumab raised concern on elevated recurrence rates. However, conclusions of meta-analyses should be interpreted with risk of indication bias in mind. Several small studies are published with short-course denosumab (varying from 3 to 6 doses). One small trial directly compared denosumab and zoledronic acid, with no statistical differences in radiological and clinical outcome, and nonsignificantly higher recurrence rate after denosumab. As bisphosphonates directly target neoplastic stromal cells in GCTB, larger directly comparative trials are still warranted. Neoadjuvant denosumab is highly effective for advanced GCTB, and a short-course is advised to facilitate surgery, whereas increased recurrence rates remain of concern. Randomized controlled trials are conducted on bisphosphonate-loaded bone cement and on optimal dose and duration of neoadjuvant denosumab. PD-L1 could be a potential new therapy target in GCTB. Show less
Heijden, L. van der; Bindt, S.; Scorianz, M.; Ng, C.; Gibbons, M.C.L.H.; Sande, M.J. van de; Campanacci, D.A. 2022
AimsGiant cell tumour of bone (GCTB) treatment changed since the introduction of denosumab from purely surgical towards a multidisciplinary approach, with recent concerns of higher recurrence rates... Show moreAimsGiant cell tumour of bone (GCTB) treatment changed since the introduction of denosumab from purely surgical towards a multidisciplinary approach, with recent concerns of higher recurrence rates after denosumab. We evaluated oncological, surgical, and functional outcomes for distal radius GCTB, with a critically appraised systematic literature review.MethodsWe included 76 patients with distal radius GCTB in three sarcoma centres (1990 to 2019). Median follow-up was 8.8 years (2 to 23). Seven patients underwent curettage, 38 curettage with adjuvants, and 31 resection; 20 had denosumab.ResultsRecurrence rate was 71% (5/7) after curettage, 32% (12/38) after curettage with adjuvants, and 6% (2/31) after resection. Median time to recurrence was 17 months (4 to 77). Recurrences were treated with curettage with adjuvants (11), resection (six), or curettage (two). Overall, 84% (38/45) was cured after one to thee intralesional procedures. Seven patients had 12 months neoadjuvant denosumab (5 to 15) and sixmonths adjuvant denosumab; two recurred (29%). Twelve patients had six months neoadjuvant denosumab (4 to 10); five recurred (42%). Two had pulmonary metastases (2.6%), both stable after denosumab. Complication rate was 18% (14/76, with 11 requiring surgery). At follow-up, median Musculo-Skeletal Tumour Society score was 28 (18 to 30), median Short Form-36 Health Survey was 86 (41 to 95), and median Disability of Arm, Shoulder, and Hand was 7.8 (0 to 58).ConclusionDistal radius GCTB treatment might deviate from general GCTB treatment because of complexity of wrist anatomy and function. Novel insights on surgical treatment are presented in this multicentre study and systematic review. Intralesional surgery resulted in high recurrence-rate for distal radius GCTB, also with additional denosumab. The large majority of patients however, were cured after repeated curettage. Show less
Purpose of review Giant cell tumor of bone (GCTB) is an uncommon benign primary bone tumor, consisting of receptor activator of nuclear factor kappa-B (RANK) expressing reactive osteoclast-like... Show morePurpose of review Giant cell tumor of bone (GCTB) is an uncommon benign primary bone tumor, consisting of receptor activator of nuclear factor kappa-B (RANK) expressing reactive osteoclast-like giant cells and neoplastic spindle-shaped cells. Denosumab was approved by FDA in 2013 and by EMA in 2014 to treat adults and skeletally mature adolescents with unresectable GCTB or when resection is likely to result in severe morbidity. However, there is much discussion regarding the optimal applied treatment strategy.Recent findingsNeoadjuvant treatment of GCTB with denosumab can effectively downstage tumors to facilitate less morbid surgery or completely avoid the need for resection, but there is concern about local recurrence postsurgery. Definitive treatment of unresectable GTCB improves symptoms and halts tumor progression. The optimal treatment duration is unclear and long-term treatment is associated with adverse events like osteonecrosis of the jaw (ONJ) and atypical femoral fractures. Denosumab maintenance dose interval is currently being investigated.SummaryFor the related but heterogenous group of giant cell rich tumors of bone, like aneurysmal bone cysts (ABC) and central giant cell granuloma (CGCG), denosumab is a new treatment modality under investigation. Given the effectiveness in GCTB, this could be a promising treatment option for selected patients with advanced disease. Show less
