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Vascular Endothelial Growth Factor Receptor Type 2-targeted Contrast-enhanced US of Pancreatic Cancer Neovasculature in a Genetically Engineered Mouse Model: Potential for Earlier Detection. Radiology Pysz, M. A., Machtaler, S. B., Seeley, E. S., Lee, J. J., Brentnall, T. A., Rosenberg, J., Tranquart, F., Willmann, J. K. 2015; 274 (3): 790-799

Abstract

Purpose To test ultrasonographic (US) imaging with vascular endothelial growth factor receptor type 2 ( VEGFR2 vascular endothelial growth factor receptor type 2 )-targeted microbubble contrast material for the detection of pancreatic ductal adenocarcinoma ( PDAC pancreatic ductal adenocarcinoma ) in a transgenic mouse model of pancreatic cancer development. Materials and Methods Experiments involving animals were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. Transgenic mice (n = 44; Pdx1-Cre, KRas(G12D), Ink4a(-/-)) that spontaneously develop PDAC pancreatic ductal adenocarcinoma starting at 4 weeks of age were imaged by using a dedicated small-animal US system after intravenous injection of 5 × 10(7) clinical-grade VEGFR2 vascular endothelial growth factor receptor type 2 -targeted microbubble contrast material. The pancreata in wild-type ( WT wild type ) mice (n = 64) were scanned as controls. Pancreatic tissue was analyzed ex vivo by means of histologic examination (with hematoxylin-eosin staining) and immunostaining of vascular endothelial cell marker CD31 and VEGFR2 vascular endothelial growth factor receptor type 2 . The Wilcoxon rank sum test and linear mixed-effects model were used for statistical analysis. Results VEGFR2 vascular endothelial growth factor receptor type 2 -targeted US of PDAC pancreatic ductal adenocarcinoma showed significantly higher signal intensities (26.8-fold higher; mean intensity ± standard deviation, 6.7 linear arbitrary units [ lau linear arbitrary units ] ± 8.5; P < .001) in transgenic mice compared with normal, control pancreata of WT wild type mice (mean intensity, 0.25 lau linear arbitrary units ± 0.25). The highest VEGFR2 vascular endothelial growth factor receptor type 2 -targeted US signal intensities were observed in smaller tumors, less than 3 mm in diameter (30.8-fold higher than control tissue with mean intensity of 7.7 lau linear arbitrary units ± 9.3 [P < .001]; and 1.7-fold higher than lesions larger than 3 mm in diameter with mean intensity of 4.6 lau linear arbitrary units ± 5.8 [P < .024]). Ex vivo quantitative VEGFR2 vascular endothelial growth factor receptor type 2 immunofluorescence demonstrated that VEGFR2 vascular endothelial growth factor receptor type 2 expression was significantly higher in pancreatic tumors (P < .001; mean fluorescent intensity, 499.4 arbitrary units [au] ± 179.1) compared with normal pancreas (mean fluorescent intensity, 232.9 au ± 83.7). Conclusion US with clinical-grade VEGFR2 vascular endothelial growth factor receptor type 2 -targeted microbubbles allows detection of small foci of PDAC pancreatic ductal adenocarcinoma in transgenic mice. © RSNA, 2014 Online supplemental material is available for this article.

View details for DOI 10.1148/radiol.14140568

View details for PubMedID 25322341