Tumor Hyperthermia and Ablation in Rats using a Clinical MR-HIFU System Equipped with a Dedicated Small Animal Setup
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Purpose: Treatment of malignant tumors by either hyperthermia induced drug delivery or thermal ablation requires complete coverage of the treatment area and precise control of the thermal dose.Both can be achieved by volumetric ultrasonic heating in combination with simultaneous MR-based temperature mapping. The translation ofthese techniques to the clinic requires thorough preclinical testing in large cohorts. Mouse and rat studies are preferred over largeranimals for ethical reasons as well as the larger variety of available tumor models. Our work aims to develop temperature induced drug delivery and ablation protocols in rats and to subsequently evaluatetreatment outcome using small animal imaging methods. To this end, we adapted a clinical MR-HIFU system for the treatment of rats by utilizing a dedicated small animal setup. Methods: All animals were positioned in a HIFU dedicated small animal 4-channel MR volume coil that was used as add-on to a clinical 3T Philips Sonalleve MR-HIFU system. Hyperthermia was performed for 15 min using binary temperaturecontrol on lateral gastrocnemius muscle (n = 5) and on subcutaneousinoculated tumors on the hind limb of rats (9L rat glioma; n = 5).For thermal ablation, tumors were partly heated to T = 65 °C with continuous wave ultrasound (1.44 MHz) under MR temperature monitoring(n = 5). The treatment effect was assessed with T2-weighted imagingand dynamic contrast enhanced (DCE-) MRI using Gd-DTPA as contrast agent. Excised muscle and tumors were further evaluated with histology. Results: The target temperatures were readily achieved in hyperthermia and ablation treatments while changes in body temperature remained below 1 °C. For hyperthermia treatments, no indication of tissue damage was found on MR images. Analysis of the Gd-DTPA uptake kinetics post ablation indicated a difference in non-perfused volume inthe tumor of 371 ± 123 mm3 (Δ tissue volume with ktrans ≥ 0.04 min-1). NADH-diaphorase staining of ablated tumors showed a sharp demarcation between viable and non-viable cells. Conclusion: These results demonstrate that both controlled hyperthermia and thermal ablation treatment of malignant tumors in small animals can be performed on a clinical MR-HIFU system. This approach provides all theadvantages of clinical MR-HIFU, such as volumetric heating, temperature feedback control and a clinical software interface, while also having many of the advantages of a dedicated small animal system. Theuse of a clinical system facilitates a rapid translation of these protocols into the clinic.