Tumors are thought to be sustained by a reservoir of self-renewing cells, termed tumor initiating cells or cancer stem cells. Osteosarcomas are high-grade sarcomas derived from osteoblast progenitor cells and are the most common pediatric bone malignancy. In this report we show that the stem cell transcription factor Sox2 is highly expressed in human and murine osteosarcoma cell lines as well as in tumor samples. Osteosarcoma cells have increased ability to grow in suspension as osteospheres, that are greatly enriched in expression of Sox2 and the stem cell marker, Sca-1. Depletion of Sox2 by shRNAs in independent murine osteosarcoma-derived cells drastically reduces their transformed properties in vitro and their ability to form tumors. Sox2-depleted osteosarcoma cells can no longer form osteospheres, and differentiate into mature osteoblasts. Concomitantly, they exhibit decreased Sca-1 expression and upregulation of the Wnt signaling pathway. Thus, despite other mutations, these tumor cells maintain a proliferative requirement for Sox2. Our data indicate that Sox2 is required for osteosarcoma cell self-renewal, and that Sox2 antagonizes the pro-differentiation Wnt pathway, that can in turn reduce Sox2 expression. These studies define Sox2 as a survival factor and a novel biomarker of self-renewal in osteosarcomas, and support a tumor suppressive role for the Wnt pathway in tumors of mesenchymal origin. Our findings could provide the basis for novel therapeutic strategies based on inhibiting Sox2 or enhancing Wnt signaling for the treatment of osteosarcomas.
Although further follow-up evaluation is needed, the authors believe on the basis of this review that this treatment protocol may be considered for patients who are poor candidates for surgical fusion.
Background Metastatic bone disease is a substantial burden to patients and the healthcare system as a whole. Metastatic disease can be painful, is associated with decreased survival, and is emotionally traumatic to patients when they discover their disease has progressed. In the United States, more than 250,000 patients have metastatic bone disease, with an estimated annual cost of USD 12 billion. Prior studies suggest that patients who receive prophylactic fixation for impending pathologic fractures, compared with those treated for realized pathologic fractures, have decreased pain levels, faster postoperative rehabilitation, and less in-hospital morbidity. However, to our knowledge, the relative economic utility of these treatment options has not been examined.
The introduction of the hospitalist co-management model represents an opportunity to improve care by changing the system as it applies to a small group of patients. Eighty-six consecutive patients with multiple comorbidities were selectively enrolled in an academic medical center hospitalist-orthopedic surgery co-management patient care program. Patients were stratified by all patient refined diagnosis-related groups, severity of illness, and risk of mortality. Hospital length of stay, cost of care, in-hospital mortality, complications, and intensive care unit admissions were compared with a retrospectively constructed control group of 54 patients undergoing similar surgery during the period immediately preceding initiation of the program. The University Health System Consortium observed-to-expected ratio for hospital length of stay was 0.693 compared to 0.862 for the control group. The severity of illness and risk of mortality scores represented a relatively higher risk stratification in the study group. While the overall observed-to-expected cost of care remained virtually unchanged, the positive impact of the study model revealed an increased positive effect on the more severely affected severity of illness and risk of mortality patients. The results of this study suggest that a proactive, cooperative, co-management model for the perioperative management of high-risk patients undergoing complex surgery can improve the quality and efficiency metrics associated with the delivery of service to patients.
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