Magnetic resonance imaging biomarkers for pulsed focused ultrasound treatment of pancreatic ductal adenocarcinoma

BACKGROUND: The robust fibroinflammatory stroma characteristic of pancreatic ductal adenocarcinoma (PDA) impedes effective drug delivery. Pulsed focused ultrasound (pFUS) can disrupt this stroma and has improved survival in an early clinical trial. Non-invasive methods to characterize pFUS treatment effects are desirable for advancement of this promising treatment modality in larger clinical trials. AIM: To identify promising, non-invasive pre-clinical imaging methods to characterize acute pFUS treatment effects for in vivo models of PDA. METHODS: We utilized quantitative magnetic resonance imaging methods at 14 tesla in three mouse models of PDA (subcutaneous, orthotopic and transgenic - Kras(LSL-G12D/+), Trp53(LSL-R172H/+), Cre or “KPC”) to assess immediate tumor response to pFUS treatment (VIFU 2000 Alpinion Medical Systems; 475 W peak electric power, 1 ms pulse duration, 1 Hz, duty cycle 0.1%) vs sham therapy, and correlated our results with histochemical data. These pFUS treatment parameters were previously shown to enhance tumor permeability to chemotherapeutics. T1 and T2 relaxation maps, high (126, 180, 234, 340, 549) vs low (7, 47, 81) b-value apparent diffusion coefficient (ADC) maps, magnetization transfer ratio (MTR) maps, and chemical exchange saturation transfer (CEST) maps for the amide proton spectrum (3.5 parts per million or “ppm”) and the glycosaminoglycan spectrum (0.5-1.5 ppm) were generated and analyzed pre-treatment, and immediately post-treatment, using ImageJ. Animals were sacrificed immediately following post-treatment imaging. The whole-tumor was selected as the region of interest for data analysis and subsequent statistical analysis. T-tests and Pearson correlation were used for statistical inference. RESULTS: Mean high-b value ADC measurements increased significantly with pFUS treatment for all models. Mean glycosaminoglycan CEST and T2 measurements decreased significantly post-treatment for the KPC group. Mean MTR and amide CEST values increased significantly for the KPC group. Hyaluronic acid focal intensities in the treated regions were significantly lower following pFUS treatment for all animal models. The magnetic resonance imaging changes observed acutely following pFUS therapy likely reflect: (1) Sequelae of variable degrees of microcapillary hemorrhage (T1, MTR and amide CEST); (2) Lower PDA glycosaminoglycan content and associated water content (glycosaminoglycan CEST, T2 and hyaluronic acid focal intensity); and (3) Improved tumor diffusivity (ADC) post pFUS treatment. CONCLUSION: T2, glycosaminoglycan CEST, and ADC maps may provide reliable quantitation of acute pFUS treatment effects for patients with PDA.