Background Long-term survival for all patients with osteosarcoma using current aggressive adjuvant chemotherapy and surgical resection is between 60% and 70%. In patients who present with nonmetastatic, high-grade extremity osteosarcoma of bone, limb salvage surgery is favored, when appropriate, over amputation to preserve the limb, because limb salvage may lead to a superior quality of life compared with amputation.
Background Avascular necrosis (AVN) of the femoral head is a potential complication in patients with slipped capital femoral epiphysis (SCFE), radiographically occurring in 3-60%. This may lead to early hip fusion or hip arthroplasty. Free vascularized fibular grafting (FVFG) may provide a reasonable means to preserve the femoral head. Questions/Purposes We asked: (1) What percentage of patients with AVN after SCFE treated with FVFG underwent subsequent THA or hip fusion and what was the lifespan of the FVFG? (2) Did the graft survival rate of FVFG for AVN after SCFE coincide with historically reported rates of FVFG for idiopathic AVN? And (3) did hip function improve after FVFG? Methods We retrospectively reviewed 52 patients who underwent FVFG for SCFE. We calculated the longevity of the graft and factors associated with graft survival. Harris hip scores (HHS) were recorded pre-and postoperatively. Minimum followup was 1 month (median, 19 months; range, 1-136 months).
Osteosarcoma (OS) patients exhibit poor overall survival, partly due to copy number variations (CNVs) resulting in dysregulated gene expression and therapeutic resistance. To identify actionable prognostic signatures of poor overall survival, we employed a systems biology approach using public databases to integrate CNVs, gene expression, and survival outcomes in pediatric, adolescent, and young adult OS patients. Chromosome 8 was a hotspot for poor prognostic signatures. The MYC-RAD21 copy number gain (8q24) correlated with increased gene expression and poor overall survival in 90% of the patients (n = 85). MYC and RAD21 play a role in replication-stress, which is a therapeutically actionable network. We prioritized replication-stress regulators, bromodomain and extra-terminal proteins (BETs), and CHK1, in order to test the hypothesis that the inhibition of BET + CHK1 in MYC-RAD21+ pediatric OS models would be efficacious and safe. We demonstrate that MYC-RAD21+ pediatric OS cell lines were sensitive to the inhibition of BET (BETi) and CHK1 (CHK1i) at clinically achievable concentrations. While the potentiation of CHK1i-mediated effects by BETi was BET-BRD4-dependent, MYC expression was BET-BRD4-independent. In MYC-RAD21+ pediatric OS xenografts, BETi + CHK1i significantly decreased tumor growth, increased survival, and was well tolerated. Therefore, targeting replication stress is a promising strategy to pursue as a therapeutic option for this devastating disease.
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