Treatment of Idiopathic Scoliosis With Vertebral Body Stapling.

STUDY DESIGN: Retrospective cohort. OBJECTIVES: Identify the effectiveness of vertebral body stapling (VBS) in children with idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: VBS has been proposed as an alternative to bracing moderate curves in patients with adolescent idiopathic scoliosis (AIS) although a clear picture of comparative efficacy and safety remains to be established. METHODS: Ten skeletally immature patients with AIS and curves between 25° and 35° underwent anterior VBS by a single surgeon from 2008 to 2018. Indications included strong family history, high ScoliScore, curve progression despite bracing, or as an alternative for patients/families refusing bracing. Patients with thoracic kyphosis greater than 40°, curvature with a level above T4 or below L4, and double major curves were contraindicated. Patients with hybrid surgical plans or those who failed to reach skeletal maturity were excluded. Age, gender, levels stapled, pre- and postoperative radiographs, and incidence of secondary surgical intervention were evaluated. Outcomes were also compared with untreated and braced subjects from the BrAIST study. RESULTS: Ten patients met the inclusion criteria. Average age at VBS was 11.8 (9.7-13.5) with an average major Cobb angle of 30.9° (26°-35°). Average duration of follow-up was 6.4 years. All patients demonstrated curve correction at their first postoperative visit. At final follow-up, 50% of patients experienced curve progression greater than 5°, whereas the remaining 50% either remained stable or corrected over time. The five patients whose curves progressed underwent VBS at a significantly younger age (10.8 vs. 12.8; p value .003). Four of these patients required additional surgical intervention for worsening scoliosis. CONCLUSIONS: Although early outcomes after VBS appear to parallel the results of bracing, stapling does not affect the percentage of patients ultimately requiring PSIF. Initial curve correction degraded over time in younger patients with significant growth remaining, and high rates of progression in this group, even with bracing, merits investigation into more efficacious treatment strategies. LEVEL OF EVIDENCE: Level III.

Proteomic identification of 14-3-3ϵ as a linker protein between pERK1/2 inhibition and BIM upregulation in human osteosarcoma cells.

Despite advancements in multimodality chemotherapy, conventional cytotoxic treatments still remain ineffective for a subset of patients with aggressive metastatic or multifocal osteosarcoma. It has been shown that pERK1/2 inhibition enhances chemosensitivity to doxorubicin and promotes osteosarcoma cell death in vivo and in vitro. One of the pro-apoptotic mechanisms is upregulation of Bim by pERK1/2 inhibitors. To this end, we examined proteomic changes of 143B human osteosarcoma cells with and without treatment of PD98059, pERK1/2 inhibitor. Specifically, we identified 14-3-3ϵ protein as a potential mediator of Bim expression in response to inhibition of pERK1/2. We hypothesized that 14-3-3ϵ mediates upregulation of Bim expression after pERK1/2 inhibition. We examined the expression of Bim after silencing 14-3-3ϵ using siRNA. The 14-3-3ϵ gene silencing resulted in downregulation of Bim expression after PD98059 treatment. These data indicate that 14-3-3ϵ is required for Bim expression and that it has an anti-cancer effect under pERK1/2 inhibition in 143B cells. By playing an essential role upstream of Bim, 14-3-3ϵ may potentially be a coadjuvant factor synergizing the effect of pERK1/2 inhibitors in addition to conventional cytotoxic agents for more effective osteosarcoma treatments.

Actin and ERK1/2-CEBPß signaling mediates phagocytosis-induced innate immune response of osteoprogenitor cells.

Wear particles at the host bone-implant interface are a major challenge for successful bone implant arthoplasties. Current understanding of aseptic loosening consists of macrophage-mediated inflammatory responses and increasing osteoclastogenesis, which lead to an imbalance between bone formation and resorption. Despite its significant role in bone regeneration and implant osteointegration, the osteoprogenitor response to wear particles has been examined recent years. More specifically, the intracellular mechanism of osteoprogenitor mediated inflammation has not been fully elucidated. In this study, we examined the role of osteoprogenitors and the cellular mechanism by which metal wear particles elicit an inflammatory cascade. Through both in vivo and in vitro experiments, we have demonstrated that osteoprogenitor cells are capable of initiating inflammatory responses by phagocytosing wear particles, which lead to subsequent accumulation of macrophages and osteoclastogenesis, and the ERK_CEBP/ß intracellular signaling is a key inflammatory pathway that links phagocytosis of wear particles to inflammatory gene expression in osteoprogenitors. AZD6244 treatment, a potent inhibitor of the ERK pathway, attenuated particle mediated inflammatory osteolysis both in vivo and in vitro. This study advances our understanding of the mechanisms of osteoprogenitor-mediated inflammation, and provides further evidence that the ERK_CEBP/ß pathway may be a suitable therapeutic target in the treatment of inflammatory osteolysis.