Characterization and influence of ipsilateral scapula fractures among patients who undergo surgical stabilization of sub-scapular rib fractures.

BACKGROUND: Current decision algorithms involving surgical stabilization of rib fractures (SSRF) do not consider either specific fracture locations or other chest wall bony injuries. Our objective was to characterize the impact of scapula fractures on morbidity among patients who underwent fixation of sub-scapular rib fractures. We hypothesized that an ipsilateral scapula fracture was associated with poor acute and long-term outcomes. METHODS: Retrospective review of two institutions' prospectively maintained SSRF databases (October 2010 to January 2019). Patients who underwent repair of ≥ 1 sub-scapular rib fracture were included. Patients were grouped by the presence of an ipsilateral scapula fracture. Outcomes were acute SSRF complications, long-term rib implant removal, and quality of life via phone survey. RESULTS: A total of 144 patients were analyzed; 53 (36.8%) had an ipsilateral scapula fracture. Patients with a scapula fracture had a higher injury severity score (p = 0.02), degree of pulmonary contusion (p < 0.01), and RibScore (p < 0.01). The overall incidence of both acute re-operation (n = 4, 2.8%) and long-term implant removal (n = 5, 3.8%) following SSRF was low and did not vary by the presence of a scapula fracture. Only twenty-one patients completed phone questionnaires a median of 38 months after SSRF; both shoulder and rib outcomes were excellent and did not vary by the presence of a scapula fracture. CONCLUSION: Ipsilateral scapula fractures are common in patients who undergo surgical stabilization of sub-scapular rib fractures. Despite higher injury severity, patients with an ipsilateral scapula fracture did not incur worse outcomes.

The mTOR kinase inhibitors, CC214-1 and CC214-2, preferentially block the growth of EGFRvIII-activated glioblastomas.

PURPOSE: mTOR pathway hyperactivation occurs in approximately 90% of glioblastomas, but the allosteric mTOR inhibitor rapamycin has failed in the clinic. Here, we examine the efficacy of the newly discovered ATP-competitive mTOR kinase inhibitors CC214-1 and CC214-2 in glioblastoma, identifying molecular determinants of response and mechanisms of resistance, and develop a pharmacologic strategy to overcome it. EXPERIMENTAL DESIGN: We conducted in vitro and in vivo studies in glioblastoma cell lines and an intracranial model to: determine the potential efficacy of the recently reported mTOR kinase inhibitors CC214-1 (in vitro use) and CC214-2 (in vivo use) at inhibiting rapamycin-resistant signaling and blocking glioblastoma growth and a novel single-cell technology-DNA Encoded Antibody Libraries-was used to identify mechanisms of resistance. RESULTS: Here, we show that CC214-1 and CC214-2 suppress rapamycin-resistant mTORC1 signaling, block mTORC2 signaling, and significantly inhibit the growth of glioblastomas in vitro and in vivo. EGFRvIII expression and PTEN loss enhance sensitivity to CC214 compounds, consistent with enhanced efficacy in strongly mTOR-activated tumors. Importantly, CC214 compounds potently induce autophagy, preventing tumor cell death. Genetic or pharmacologic inhibition of autophagy greatly sensitizes glioblastoma cells and orthotopic xenografts to CC214-1- and CC214-2-induced cell death. CONCLUSIONS: These results identify CC214-1 and CC214-2 as potentially efficacious mTOR kinase inhibitors in glioblastoma, and suggest a strategy for identifying patients most likely to benefit from mTOR inhibition. In addition, this study also shows a central role for autophagy in preventing mTOR-kinase inhibitor-mediated tumor cell death, and suggests a pharmacologic strategy for overcoming it.

PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies.

Despite their nearly universal activation of mammalian target of rapamycin (mTOR) signaling, glioblastomas (GBMs) are strikingly resistant to mTOR-targeted therapy. We analyzed GBM cell lines, patient-derived tumor cell cultures, and clinical samples from patients in phase 1 clinical trials, and find that the promyelocytic leukemia (PML) gene mediates resistance to mTOR-targeted therapies. Direct mTOR inhibitors and EGF receptor (EGFR) inhibitors that block downstream mTOR signaling promote nuclear PML expression in GBMs, and genetic overexpression and knockdown approaches demonstrate that PML prevents mTOR and EGFR inhibitor-dependent cell death. Low doses of the PML inhibitor, arsenic trioxide, abrogate PML expression and reverse mTOR kinase inhibitor resistance in vivo, thus markedly inhibiting tumor growth and promoting tumor cell death in mice. These results identify a unique role for PML in mTOR and EGFR inhibitor resistance and provide a strong rationale for a combination therapeutic strategy to overcome it.