Published online Mar 7, 2020. doi: 10.3748/wjg.v26.i9.904
Peer-review started: November 17, 2019
First decision: December 23, 2019
Revised: January 12, 2020
Accepted: February 15, 2020
Article in press: February 15, 2020
Published online: March 7, 2020
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.
To identify promising, non-invasive pre-clinical imaging methods to characterize acute pFUS treatment effects for in vivo models of PDA.
We utilized quantitative magnetic resonance imaging methods at 14 tesla in three mouse models of PDA (subcutaneous, orthotopic and transgenic - KrasLSL-G12D/+, Trp53LSL-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.
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.
T2, glycosaminoglycan CEST, and ADC maps may provide reliable quantitation of acute pFUS treatment effects for patients with PDA.
Core tip: In a genetic model of pancreatic ductal adenocarcinoma, clinically translatable, quantitative magnetic resonance imaging methods of T2, glycosaminoglycan chemical exchange saturation transfer, and apparent diffusion coefficient mapping were effective in non-invasively characterizing the treatment effects of pulsed focused ultrasound treatment. Pulsed focused ultrasound treatment has already been shown to improve survival for patients with pancreatic ductal adenocarcinoma in an early clinical trial, and these complimentary magnetic resonance imaging methods could help to advance this promising therapy in larger clinical trials.