Mesenchymal stromal cells (MSCs) are an attractive choice for regenerative medicine. We previously showed that MSCs enhance wound healing in animals after radiotherapy. The effect of MSCs on tumor growth is not well understood. The potential use of MSCs to enhance wound healing after radiotherapy (RT) and resection of soft tissue sarcoma (STS) is dependent on a satisfactory safety profile to ensure that tumor proliferation does not occur and recurrence is not increased. Primary cell lines (human myxofibrosarcoma and undifferentiated sarcoma) derived from sarcoma bearing patients and a commercialized human fibrosarcoma cell line (HT1080) were used. Cell line proliferation assay after co-culture with MSCs was done using flow cytometry (CFSE) and bioluminescence emission (BLI) (using eGFP/Fluc transduced cell lines). Five xenograft models were developed with NOD/SCID gc-null mice (n=164) harbouring primary tissue lines obtained from patients biopsies (myxofibrosarcoma and three pleomorphic undifferentiated sarcoma [PUS A, B and C]) and a a fibrosarcoma cell line previously transduced with eGFP/Fluc. Tumors were passaged to three mouse generations before a tissue line was established and the model was then used. For the fibrosarcoma model, eGFP/Fluc HT1080 were injected under the dorsal skin. When tumors reached 1cm in diameter, they received localized RT and 48hr later were resected. MSCs (n=82) or medium alone (n=82) was injected subcutaneously adjacent to the wound after tumor resection. Histological and in vivo BLI analysis were performed 3 and 12 weeks after surgery.Purpose
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The focus of current management of soft tissue sarcoma on limb preservation often necessitates that patients undergo multimodal treatment, including both surgery and external beam radiotherapy. Pathologic fracture is a serious, late complication of radiotherapy. In patients who have also undergone wide excision of soft tissue sarcoma, nonunion rates of 80–90% persist despite optimal internal fixationMany sequelae of the treatments for soft tissue sarcoma exhibit the potential to perpetuate failure of bony union. Limb salvage surgery is associated with extensive periosteal excision, disruption of vascular supply and eradication of local osteoprogenitor cells. External beam radiotherapy leads to obliterative endarteritis, decreased osteoblast proliferation and reduction in bone matrix production. We hypothesize that the combination of radiotherapy and surgical periosteal stripping leads to greater impairment in the fracture repair process than either intervention alone will produce. We developed a method for creating a reproducible, low energy, simple femoral fracture in an animal model designed to proceed to nonunion. Female Wistar, retired breeder rats were separated into four treatment groups of 18 animals each: control, radiotherapy, surgery and combination radiotherapy and surgery. Animals were then further randomized to temporal end-points of 21, 28 and 35 days post-fracture. Designated animals first underwent external beam radiotherapy, followed by surgical stripping of the periosteum three weeks later and femoral fracture with fixation after another three weeks. Animals were sacrificed at their randomly assigned end-points.Purpose
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