Soft-tissue sarcomas (STS) are aggressive, often lethal mesenchymal tumors that represent roughly 1% of adult cancers. The 5-year survival rate of STS has remained unchanged for decades at 50%, highlighting the need for more effective therapies. We are developing protocols and assessing the treatment efficacy of 3D spatially-registered real-time image-guided needle/catheter based ultrasound (CBUS) ablative thermal therapy in STS induced in the transgenic Oncopig cancer model (OCM). The transgenic Oncopig carries a Cre recombinase inducible transgene encoding KRASG12D and TP53R167H; both mutations commonly in human cancers. Cre recombinase induces expression of the transgenes and transformation of cells in culture and rapid and reproducible development of leiomyosarcomas when introduced into the muscle of oncopigs. The flexibility of the model allowed induction of sarcomas in two clinically relevant intramuscular (IM) sites in both the hind limb and retroperitoneal (RP) regions, to closely simulate human disease. We have previously shown that these Oncopig tumors present the same transcriptional hallmarks as human STS including altered TP53 signaling, Wnt signaling activation and evidence of epigenetic reprogramming. Initial acute studies revealed that the tumors could be successfully grown in the muscle reaching mean tumor volume of 19.76cm3 (RP, n= 8) and 25.12cm3 (IM, n=14) cm3 within two weeks following AdCre (5.0x108 to 1.0x109 PFU) injections. Tumors were then treated utilizing ultrasound image guidance combined with 3D EM tracking to place the applicator in the target region. Sectored tubular transducers were introduced through a small skin incision and used to precisely deliver thermal energy to the treatment region. Tumors were treated for 6-9 minutes at 7 watts acoustic power (10.2W/cm2). Thermocouples were inserted into the tumors monitored temperature throughout the treatment. Post-treatment analysis revealed that the mean induced lesion volume exceeded the actual tumor volume for both IM (43.41 cm3) and RP (22.87 cm3) tumors with mean peak temperatures reaching 64.56 ͦ C (IM) and 58.75 ͦ C (RP). The mean peak thermal dose (thermal equivalent minutes at 43 ͦ C - TEM43) accumulated for IM tumors was 3.70E+08, and 1.46E+06 for RP tumors. Histopathology analysis verified that treatment areas reached past tumor margins using single applicator configuration. This study clearly demonstrates that the Oncopig is a suitable model in size and clinically relevant tumor type for evaluation of ultrasound ablation instrumentation. In addition, these STS treatment protocols can reliably and accurately target and treat tumor volumes plus surrounding margins. Future work will include monitoring of treatment lesions for up to 3 months post ablation. Funded by NIH 5R21CA195433