摘要
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-KrasLSLG12D/+,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.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.
BACKGROUND The robust fibroinflammatory stroma characteristic of pancreatic ductal adenocarcinoma(PDA) impedes effective drug delivery. Pulsed focused ultrasound(p FUS) can disrupt this stroma and has improved survival in an early clinical trial. Non-invasive methods to characterize p FUS 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 p FUS 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 LSLG12 D/+, Trp53 LSL-R172 H/+, Cre or "KPC") to assess immediate tumor response to p FUS 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 p FUS 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 Image J. 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 p FUS 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 p FUS treatment for all animal models. The magnetic resonance imaging changes observed acutely following p FUS 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 p FUS treatment.CONCLUSION T2, glycosaminoglycan CEST, and ADC maps may provide reliable quantitation of acute p FUS treatment effects for patients with PDA.
基金
Supported by National Institutes of Health,National Cancer Institute,No.R01 CA188654 and No.R01CA154451
