IL-6 and CXCL8 mediate osteosarcoma-lung interactions critical to metastasis.

Osteosarcoma (OS), a malignant tumor of bone, kills through aggressive metastatic spread almost exclusively to the lung. Mechanisms driving this tropism for lung tissue remain unknown, though likely invoke specific interactions between tumor cells and other cells within the lung metastatic niche. Aberrant overexpression of ΔNp63 in OS cells directly drives production of IL-6 and CXCL8. All these factors were expressed at higher levels in OS lung metastases than in matched primary tumors from the same patients. Expression in cell lines correlated strongly with lung colonization efficiency in murine xenograft models. Lentivirus-mediated expression endowed poorly metastatic OS cells with increased metastatic capacity. Disruption of IL-6 and CXCL8 signaling using genetic or pharmaceutical inhibitors had minimal effects on tumor cell proliferation in vitro or in vivo, but combination treatment inhibited metastasis across multiple models of metastatic OS. Strong interactions occurred between OS cells and both primary bronchial epithelial cells and bronchial smooth muscle cells that drove feed-forward amplification of IL-6 and CXCL8 production. These results identify IL-6 and CXCL8 as primary mediators of OS lung tropism and suggest pleiotropic, redundant mechanisms by which they might effect metastasis. Combination therapy studies demonstrate proof of concept for targeting these tumor-lung interactions to affect metastatic disease.

Using simulation to identify and resolve threats to patient safety.

BACKGROUND: The simulation-based team training used in commercial aviation can provide healthcare professionals with guidance on improving patient safety. OBJECTIVE: To show how in situ simulation can identify latent environmental threats to patient safety. STUDY DESIGN: Case study. METHODS: This in situ simulation took place at a large Midwestern hospital in January 2007. It involved a patient with chest pain and hypotension that required cardiac catheterization. The simulation had 2 phases: emergency department and catheterization laboratory. Materials included a patient manikin, a high-definition camcorder, and software for annotating the video in real time. Props (eg, simulated electrocardiogram results, chest x-rays) were used. A Master Scenario Event List was used to orchestrate the entire simulation event. RESULTS: Three latent environmental threats to patient safety were identified: procedures for transporting patients between the 2 units, for managing the handoff process, and for organizing the cardiac catheterization process. These were not training issues, but were due to poorly developed or nonexistent procedures that affected the performance of all healthcare teams on those units every working day. The threats were identified by the simulation participants (along with their supervisors) during the post-simulation debriefing as being sufficiently common and dangerous to warrant further review and remedy. CONCLUSION: By conducting our simulations in the actual environment of care, using intact teams of healthcare professionals who practiced their actual technologies and work processes during the simulation, we could identify latent environmental threats to patient safety that could never be explored in an artificial laboratory environment.