One of the serious challenges faced in development of technologies for accurate and effective delivery of ablative therapies to solid organ malignancies is the lack of larger animal models which can simulate the size and scale aspects of the physical environment and the clinical workflow characteristics encountered while treating a human patient. Tumor mimics have been the only model available to examine technical aspects of minimally invasive treatment delivery. Thus far, no animal model has been reported that can truly simulate size or scale of tumors comparable to a human patient, which are suitable for device technical evaluation. We propose to assess the treatment efficacy of 3D spatially-registered real-time image-guided needle/catheter based ultrasound (CBUS) thermal therapy in an induced tumor grown in genetically engineered oncogenic pigs, specifically soft tissue sarcomas of the extremity and retroperitoneal regions, both clinically relevant sites closely simulating human disease.
A transgenic ‘oncopig’ line encoding a Cre recombinase inducible transgene encoding KRASG12D and TP53R17H, a commonly mutated oncogene and tumor suppressor, respectively, in human cancers was created. Treatment of cells derived from these oncopigs with adenoviral vector encoding Cre (AdCre) led to KRASG12D and TP53R17H expression, which rendered the cells transformed in culture and tumorigenic when engrafted into immunocompromised mice. Finally, injection of AdCre directly into these oncopigs led to the rapid and reproducible development of soft tissue sarcomas in the muscle. Ultrasound imaging was used to monitor the growth of these tumors. Once the tumor reached approximately 2cm by 3cm, it was treated with catheter based therapeutic ultrasound energy for thermal therapy. Sectored tubular transducers were used to precisely deliver thermal energy to the treatment region. Ultrasound image guidance combined with 3D EM tracking were used to place the applicator in the target region.
The tumors were successfully grown in the muscle within two weeks of injecting the AdCre virus into the oncopigs. Skin incision less than 1cm length was sufficient to provide for insertion of catheter under image-guided ultrasound for ablating the muscle tumors. The tumors were treated for 6-9 minutes at 7 Watts acoustic power. Thermocouples inserted into the tumors showed temperature range of 55-65 C during the treatment. Histopathology analysis showed complete ablation of the tumor using single applicator configuration.
The results suggest catheter-based therapeutic ultrasound can be used to perform fast volumetric ablation of the tumors. The tracked ultrasound image guidance is important to guide and precisely place the catheter at the target region.