Marybeth A Pysz1, Steven B Machtaler, E Scott Seeley, John J Lee, Teresa A Brentnall, Jarrett Rosenberg, François Tranquart, Jürgen K Willmann. 1. From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford School of Medicine, Stanford University, 300 Pasteur Dr, Room H1307, Stanford, CA 94305 (M.A.P., S.B.M., J.R., J.K.W.); Department of Pathology, University of California at San Francisco, San Francisco, Calif (E.S.S.); Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Howard Hughes Medical Institute, Stanford School of Medicine, Stanford University, Stanford, Calif (J.J.L.); Department of Medicine, University of Washington, Seattle, Wash (T.A.B.); and Bracco Suisse SA, Geneva, Switzerland (F.T.).
Abstract
PURPOSE: To test ultrasonographic (US) imaging with vascular endothelial growth factor receptor type 2 (VEGFR2)-targeted microbubble contrast material for the detection of pancreatic ductal adenocarcinoma (PDAC) 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 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-targeted microbubble contrast material. The pancreata in wild-type (WT) 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. The Wilcoxon rank sum test and linear mixed-effects model were used for statistical analysis. RESULTS: VEGFR2-targeted US of PDAC showed significantly higher signal intensities (26.8-fold higher; mean intensity ± standard deviation, 6.7 linear arbitrary units [lau] ± 8.5; P < .001) in transgenic mice compared with normal, control pancreata of WT mice (mean intensity, 0.25 lau ± 0.25). The highest VEGFR2-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 ± 9.3 [P < .001]; and 1.7-fold higher than lesions larger than 3 mm in diameter with mean intensity of 4.6 lau ± 5.8 [P < .024]). Ex vivo quantitative VEGFR2 immunofluorescence demonstrated that VEGFR2 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-targeted microbubbles allows detection of small foci of PDAC in transgenic mice.
PURPOSE: To test ultrasonographic (US) imaging with vascular endothelial growth factor receptor type 2 (VEGFR2)-targeted microbubble contrast material for the detection of pancreatic ductal adenocarcinoma (PDAC) in a transgenicmouse 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 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-targeted microbubble contrast material. The pancreata in wild-type (WT) 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. The Wilcoxon rank sum test and linear mixed-effects model were used for statistical analysis. RESULTS:VEGFR2-targeted US of PDAC showed significantly higher signal intensities (26.8-fold higher; mean intensity ± standard deviation, 6.7 linear arbitrary units [lau] ± 8.5; P < .001) in transgenic mice compared with normal, control pancreata of WT mice (mean intensity, 0.25 lau ± 0.25). The highest VEGFR2-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 ± 9.3 [P < .001]; and 1.7-fold higher than lesions larger than 3 mm in diameter with mean intensity of 4.6 lau ± 5.8 [P < .024]). Ex vivo quantitative VEGFR2 immunofluorescence demonstrated that VEGFR2 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-targeted microbubbles allows detection of small foci of PDAC in transgenic mice.
Authors: Randall E Brand; Markus M Lerch; Wendy S Rubinstein; John P Neoptolemos; David C Whitcomb; Ralph H Hruban; Teresa A Brentnall; Henry T Lynch; Marcia I Canto Journal: Gut Date: 2007-10 Impact factor: 23.059
Authors: Tuomas T Rissanen; Petra Korpisalo; Henna Karvinen; Timo Liimatainen; Svetlana Laidinen; Olli H Gröhn; Seppo Ylä-Herttuala Journal: JACC Cardiovasc Imaging Date: 2008-01
Authors: Marcela Brissova; Alena Shostak; Masakazu Shiota; Peter O Wiebe; Greg Poffenberger; Jeannelle Kantz; Zhongyi Chen; Chad Carr; W Gray Jerome; Jin Chen; H Scott Baldwin; Wendell Nicholson; David M Bader; Thomas Jetton; Maureen Gannon; Alvin C Powers Journal: Diabetes Date: 2006-11 Impact factor: 9.461
Authors: Mark Topazian; Felicity Enders; Michael Kimmey; Randall Brand; Amitabh Chak; Jonathan Clain; John Cunningham; Mohamad Eloubeidi; Hans Gerdes; Frank Gress; Sanjay Jagannath; Sergey Kantsevoy; Julia Kim LeBlanc; Michael Levy; Charles Lightdale; Joseph Romagnuolo; John R Saltzman; Thomas Savides; Maurits Wiersema; Timothy Woodward; Gloria Petersen; Marcia Canto Journal: Gastrointest Endosc Date: 2007-03-23 Impact factor: 9.427
Authors: Emmy Ludwig; Sara H Olson; Sharon Bayuga; Jennifer Simon; Mark A Schattner; Hans Gerdes; Peter J Allen; William R Jarnagin; Robert C Kurtz Journal: Am J Gastroenterol Date: 2011-04-05 Impact factor: 10.864
Authors: Jürgen K Willmann; Ramasamy Paulmurugan; Kai Chen; Olivier Gheysens; Martin Rodriguez-Porcel; Amelie M Lutz; Ian Y Chen; Xiaoyuan Chen; Sanjiv S Gambhir Journal: Radiology Date: 2008-01-07 Impact factor: 11.105
Authors: Kenneth P Olive; Michael A Jacobetz; Christian J Davidson; Aarthi Gopinathan; Dominick McIntyre; Davina Honess; Basetti Madhu; Mae A Goldgraben; Meredith E Caldwell; David Allard; Kristopher K Frese; Gina Denicola; Christine Feig; Chelsea Combs; Stephen P Winter; Heather Ireland-Zecchini; Stefanie Reichelt; William J Howat; Alex Chang; Mousumi Dhara; Lifu Wang; Felix Rückert; Robert Grützmann; Christian Pilarsky; Kamel Izeradjene; Sunil R Hingorani; Pearl Huang; Susan E Davies; William Plunkett; Merrill Egorin; Ralph H Hruban; Nigel Whitebread; Karen McGovern; Julian Adams; Christine Iacobuzio-Donahue; John Griffiths; David A Tuveson Journal: Science Date: 2009-05-21 Impact factor: 47.728
Authors: Kimberly A Kelly; Michael A Hollingsworth; Randall E Brand; Christina H Liu; Vikesh K Singh; Sudhir Srivastava; Ajay D Wasan; Dhiraj Yadav; Dana K Andersen Journal: Pancreas Date: 2015-11 Impact factor: 3.327
Authors: Hua Zhang; Elizabeth S Ingham; M Karen J Gagnon; Lisa M Mahakian; Jingfei Liu; Josquin L Foiret; Juergen K Willmann; Katherine W Ferrara Journal: Biomaterials Date: 2016-11-21 Impact factor: 12.479
Authors: Shiying Wang; Elizabeth B Herbst; F William Mauldin; Galina B Diakova; Alexander L Klibanov; John A Hossack Journal: Invest Radiol Date: 2016-12 Impact factor: 6.016
Authors: Jianhua Zhou; Huaijun Wang; Huiping Zhang; Amelie M Lutz; Lu Tian; Dimitre Hristov; Jürgen K Willmann Journal: Cancer Res Date: 2016-05-20 Impact factor: 12.701