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Purpose. Recently, the association between ATRX and a more aggressive sarcoma phenotype has been shown. We performed a retrospective study of sarcomas from an individual institution to evaluate ATRX as a prognosticator in soft tissue sarcoma. Experimental Design. 128 sarcomas were collected from a single institution and stained for ATRX. The prognostic significance of these markers was evaluated in a smaller cohort of primary soft tissue sarcomas (n = 68). Kaplan–Meier curves were created for univariate analysis, and Cox regression was utilized for multivariate analysis. Results. High expression of ATRX was found to be a positive prognostic indicator for overall survival and metastasis-free survival in our group of soft tissue sarcomas both in univariate analysis and multivariate analysis (HR: 0.38 (0.17–0.85), P = 0.02 and HR: 0.49 (0.24–0.99), P = 0.05 , respectively). Conclusions. High expression of ATRX is a positive prognostic indicator of overall survival and metastasis-free survival in patients with STS. This is consistent with studies in osteosarcoma, which indicate possible mechanisms through which loss of ATRX leads to more aggressive phenotypes. Future prospective clinical studies are required to validate the prognostic significance of these findings. [ABSTRACT FROM AUTHOR]

Metastasis is a multistep process in which cells must detach, migrate/invade local structures, intravasate, circulate, extravasate, and colonize. A full understanding of the complexity of this process has been limited by the lack of ability to study these steps in isolation with detailed molecular analyses. Leveraging a comparative oncology approach, we injected canine osteosarcoma cells into the circulation of transgenic zebrafish with fluorescent blood vessels in a biologically dynamic metastasis extravasation model. Circulating tumor cell clusters that successfully extravasated the vasculature as multicellular units were isolated under intravital imaging (n = 6). These extravasation-positive tumor cell clusters sublines were then molecularly profiled by RNA-Seq. Using a systems-level analysis, we pinpointed the downregulation of KRAS signaling, immune pathways, and extracellular matrix (ECM) organization as enriched in extravasated cells (p < 0.05). Within the extracellular matrix remodeling pathway, we identified versican (VCAN) as consistently upregulated and central to the ECM gene regulatory network (p < 0.05). Versican expression is prognostic for a poorer metastasis-free and overall survival in patients with osteosarcoma. Together, our results provide a novel experimental framework to study discrete steps in the metastatic process. Using this system, we identify the versican/ECM network dysregulation as a potential contributor to osteosarcoma circulating tumor cell metastasis. [ABSTRACT FROM AUTHOR]

Gaze-tracking techniques have advanced our understanding of visual attention and decision making during walking and athletic events, but little is known about how vision influences behavior during running over common, natural obstacles. This study tested hypotheses about whether runners regularly collect visual information and pre-plan obstacle clearance (feedforward control), make improvisational adjustments (online control), or some combination of both. In this study, the gaze profiles of 5 male and 5 female runners, fitted with a telemetric gaze-tracking device, were used to identify the frequency of fixations on an obstacle during a run. Overall, participants fixated on the obstacle 2.4 times during the run, with the last fixation occurring on average between 40% and 80% of the run, suggesting runners potentially shifted from a feedforward planning strategy to an online control strategy during the late portions of the running trial. A negative association was observed between runner velocity and average number of fixations. Consistent with previous studies on visual strategies used during walking, our results indicate that visual attentiveness is part of an important feedforward strategy for runners allowing them to safely approach an obstacle. Thus, visual obstacle attention is a key factor in the navigation of complex, natural landscapes while running. [ABSTRACT FROM AUTHOR]

Simple Summary: Osteosarcoma is a rare bone cancer that occurs primarily in children. The discovery of new treatments for osteosarcoma and other rare cancer types has been severely limited by access to patient samples to study these often-complex diseases. Here we capitalize on naturally-occurring cancers in pet dogs to study the biology of these rare cancers. Using living cells from canine and human patients to test thousands of drugs simultaneously, we identify a unique combination of drugs that disrupts protein degradation and protein trafficking in cancer cells. This drug combination represents a promising new treatment to treat both dogs and people with osteosarcoma. Background: Osteosarcoma is a rare but aggressive bone cancer that occurs primarily in children. Like other rare cancers, treatment advances for osteosarcoma have stagnated, with little improvement in survival for the past several decades. Developing new treatments has been hampered by extensive genomic heterogeneity and limited access to patient samples to study the biology of this complex disease. Methods: To overcome these barriers, we combined the power of comparative oncology with patient-derived models of cancer and high-throughput chemical screens in a cross-species drug discovery pipeline. Results: Coupling in vitro high-throughput drug screens on low-passage and established cell lines with in vivo validation in patient-derived xenografts we identify the proteasome and CRM1 nuclear export pathways as therapeutic sensitivities in osteosarcoma, with dual inhibition of these pathways inducing synergistic cytotoxicity. Conclusions: These collective efforts provide an experimental framework and set of new tools for osteosarcoma and other rare cancers to identify and study new therapeutic vulnerabilities. [ABSTRACT FROM AUTHOR]

Case: A 72-year-old man underwent intramedullary nailing of a humeral diaphysis fracture with passage through an unrecognized pathologic fracture. Four months later, a biopsy of a soft-tissue mass in the arm revealed pleomorphic undifferentiated sarcoma. Only after local recurrence and forequarter amputation was the story of a pathologic fracture through undifferentiated pleomorphic sarcomas of bone clear. The patient developed metastatic disease and died after 2 years postoperatively., Discussion: Orthopaedic surgeons should consider sarcoma when assessing patients with fractures of unknown etiology and an inappropriate mechanism because the placement of an intramedullary device through a sarcoma of bone has consequences., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)