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Item ELEVATED LEVELS OF PLATELETS AND MDM2 EXPRESSION ARE CONTRIB-UTING FACTORS TO FACILITATING THE METASTASIS OF OSTEOSARCOMA(Office of the Vice Chancellor for Research, 2012-04-13) Lipking, Kelsey; Kacena, Melissa A.; Konopka, Jeff A.; Mayo, Lindsey D.; Sandusky, George E.Osteosarcoma (OS) is the most common form of primary bone cancer and the 6th leading cause of cancer in pediatric patients. A chart review of OS patients treated at this institution suggests that a high platelet count at di-agnosis is significantly (p=0.023) and inversely associated with the first year of survival. As the effects of platelet interaction with OS have been exten-sively researched and suggest that platelets may facilitate tumor metastasis, and the most important prognostic factor for OS patient survival is metasta-sis to the lungs, we hypothesized that platelets increase metastasis to the lungs and reduce survival. Therefore, we sought to determine whether in-creasing platelet numbers in a well characterized OS mouse model would de-crease survival and/or increase metastasis to the lungs. We found that thrombopoietin (TPO) treated mice, had increased platelet numbers, died earlier than placebo treated controls, and that lungs from TPO treated mice contained a small number of large tumor cells (most metastatic lesions were 2-4 cells), whereas lungs from placebo treated controls showed no signs of metastases. Next, an OS tissue microarray (TMA) was built from OS patients seen at our institution over the past 10 years. Mdm2, p53, TPO, and c-mpl expression were evaluated by immunohistochemical (IHC) staining followed by quantitation using the Aperio Imaging system and analysis software. C-mpl (TPO receptor) expression was higher in the metastatic than the primary tumors, suggesting that platelets may contribute to the metastasis of OS. Elevated levels of Mdm2 correlated with metastasis and lower levels of p53, as detected by IHC. In conclusion, both the mouse model and the human OS data were similar, suggesting that both platelets and Mdm2 promote metas-tases in OS.Item The New Treatment of Osteosarcoma by Biologic Response Modifiers(Office of the Vice Chancellor for Research, 2016-04-08) Chen, Xiaoping; Zhao, Huadong; Cheng, LiangOsteosarcoma is a kind of bone cancer mainly affecting children and young adults and is lethal in about a third of cases. The treatment of osteosarcoma has evolved greatly during the last 40 years, however, the great progress that was seen in the 1970s and early 1980s has since stalled. The main challenge now is that advanced combination treatment can’t continue prolong the survival. Based on the micro-metastatic disease related to shorter survival, biologic response modifiers become a new treatment which can stimulate the immune system to eradicate minimal residual disease post-surgery, chemotherapy and radiotherapy. This kind immune treatment may improve the disease-free and long-term survival rates of patients. Mifamurtide is a novel biologic response modifier which is indicated for the treatment of highgrade, non-metastasizing, resectable osteosarcoma following complete surgical removal in children, adolescents, and young adults. In our study, we searched for non-phase l Mifamurtide clinical studies on osteosarcoma through Medline, Google Scholar, and Clinical Trial Government Database. Among six clinical studies we found, two phase ll trials, one phase lll trial, one patient-access study, one decision study, and one cohort study. We systematically analyzed these studies and further evaluated the efficacy, side effects and safety of Mifamurtide on osteosarcoma.Item Tumour-induced osteomalacia(Nature, 2017-07) Minisola, Salvatore; Peacock, Munro; Fukumoto, Seijii; Cipriani, Cristiana; Pepe, Jessica; Tella, Sri Harsha; Collins, Michael T.; Medicine, School of MedicineTumour-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic disorder caused by tumours that secrete fibroblast growth factor 23 (FGF23). Owing to the role of FGF23 in renal phosphate handling and vitamin D synthesis, TIO is characterized by decreased renal tubular reabsorption of phosphate, by hypophosphataemia and by low levels of active vitamin D. Chronic hypophosphataemia ultimately results in osteomalacia (that is, inadequate bone mineralization). The diagnosis of TIO is usually suspected when serum phosphate levels are chronically low in the setting of bone pain, fragility fractures and muscle weakness. Locating the offending tumour can be very difficult, as the tumour is often very small and can be anywhere in the body. Surgical removal of the tumour is the only definitive treatment. When the tumour cannot be located or when complete resection is not possible, medical treatment with phosphate salts or active vitamin D is necessary. One of the most promising emerging treatments for unresectable tumours that cause TIO is the anti-FGF23 monoclonal antibody KRN23. The recent identification of a fusion of fibronectin and fibroblast growth factor receptor 1 (FGFR1) as a molecular driver in some tumours not only sheds light on the pathophysiology of TIO but also opens the door to a better understanding of the transcription, translocation, post-translational modification and secretion of FGF23, as well as suggesting approaches to targeted therapy. Further study will reveal if the FGFR1 pathway is also involved in tumours that do not harbour the translocation.