A new preclinical ultrasound platform for widefield 3D imaging of rodents.

Noninvasive in vivo imaging technologies enable researchers and clinicians to detect the presence of disease and longitudinally study its progression. By revealing anatomical, functional, or molecular changes, imaging tools can provide a near real-time assessment of important biological events. At the preclinical research level, imaging plays an important role by allowing disease mechanisms and potential therapies to be evaluated noninvasively. Because functional and molecular changes often precede gross anatomical changes, there has been a significant amount of research exploring the ability of different imaging modalities to track these aspects of various diseases. Herein, we present a novel robotic preclinical contrast-enhanced ultrasound system and demonstrate its use in evaluating tumors in a rodent model. By leveraging recent advances in ultrasound, this system favorably compares with other modalities, as it can perform anatomical, functional, and molecular imaging and is cost-effective, portable, and high throughput, without using ionizing radiation. Furthermore, this system circumvents many of the limitations of conventional preclinical ultrasound systems, including a limited field-of-view, low throughput, and large user variability.

[1]  S. Lyons,et al.  Imaging Mouse Models of Cancer. , 2015, Cancer journal.

[2]  Mallika Singh,et al.  Genetically engineered mouse models: closing the gap between preclinical data and trial outcomes. , 2012, Cancer research.

[3]  Dimitre Hristov,et al.  VEGFR2-Targeted Three-Dimensional Ultrasound Imaging Can Predict Responses to Antiangiogenic Therapy in Preclinical Models of Colon Cancer. , 2016, Cancer research.

[4]  D O Cosgrove,et al.  Quantitative contrast-enhanced ultrasound imaging: a review of sources of variability , 2011, Interface Focus.

[5]  Paul A. Dayton,et al.  Ultrasound Molecular Imaging of VEGFR-2 in Clear-Cell Renal Cell Carcinoma Tracks Disease Response to Antiangiogenic and Notch-Inhibition Therapy , 2018, Theranostics.

[6]  Paul A. Dayton,et al.  Early Assessment of Tumor Response to Radiation Therapy using High-Resolution Quantitative Microvascular Ultrasound Imaging , 2018, Theranostics.

[7]  Apurva A Desai,et al.  Sorafenib in advanced clear-cell renal-cell carcinoma. , 2007, The New England journal of medicine.

[8]  Dimitre Hristov,et al.  Early prediction of tumor response to bevacizumab treatment in murine colon cancer models using three-dimensional dynamic contrast-enhanced ultrasound imaging , 2017, Angiogenesis.

[9]  Wolfgang A Weber,et al.  Time course of tumor metabolic activity during chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  F. Stuart Foster,et al.  Microultrasound Molecular Imaging of Vascular Endothelial Growth Factor Receptor 2 in a Mouse Model of Tumor Angiogenesis , 2007, Molecular imaging.

[11]  Paul A Dayton,et al.  Mapping microvasculature with acoustic angiography yields quantifiable differences between healthy and tumor-bearing tissue volumes in a rodent model. , 2012, Radiology.

[12]  Dimitre Hristov,et al.  Three-Dimensional Ultrasound Molecular Imaging of Angiogenesis in Colon Cancer Using a Clinical Matrix Array Ultrasound Transducer , 2015, Investigative radiology.

[13]  Haesun Choi,et al.  We should desist using RECIST, at least in GIST. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  Nathalie Lassau,et al.  Advanced Hepatocellular Carcinoma: early evaluation of response to targeted therapy and prognostic value of Perfusion CT and Dynamic Contrast Enhanced-Ultrasound. Preliminary results. , 2013, European journal of radiology.

[15]  Jonathan R Lindner,et al.  Quantitative assessment of placental perfusion by contrast-enhanced ultrasound in macaques and human subjects. , 2016, American journal of obstetrics and gynecology.

[16]  Paul A Dayton,et al.  Validation of dynamic contrast-enhanced ultrasound in rodent kidneys as an absolute quantitative method for measuring blood perfusion. , 2011, Ultrasound in medicine & biology.

[17]  Sanjiv S Gambhir,et al.  Ultrasound Molecular Imaging With BR55 in Patients With Breast and Ovarian Lesions: First-in-Human Results. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  Andras Lasso,et al.  PLUS: Open-Source Toolkit for Ultrasound-Guided Intervention Systems , 2014, IEEE Transactions on Biomedical Engineering.

[19]  M. van Glabbeke,et al.  New guidelines to evaluate the response to treatment in solid tumors , 2000, Journal of the National Cancer Institute.

[20]  François Tranquart,et al.  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. , 2015, Radiology.

[21]  François Tranquart,et al.  First-in-Human Ultrasound Molecular Imaging With a VEGFR2-Specific Ultrasound Molecular Contrast Agent (BR55) in Prostate Cancer: A Safety and Feasibility Pilot Study , 2017, Investigative radiology.

[22]  W. Pao,et al.  How genetically engineered mouse tumor models provide insights into human cancers. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  Paul A Dayton,et al.  A Pilot Clinical Study in Characterization of Malignant Renal-cell Carcinoma Subtype with Contrast-enhanced Ultrasound , 2017, Ultrasonic imaging.

[24]  J. Yeh,et al.  A Comparative Evaluation of Ultrasound Molecular Imaging, Perfusion Imaging, and Volume Measurements in Evaluating Response to Therapy in Patient-Derived Xenografts , 2013, Technology in cancer research & treatment.

[25]  B. Ariff,et al.  The role of early 18F-FDG PET/CT in prediction of progression-free survival after 90Y radioembolization: comparison with RECIST and tumour density criteria , 2012, European Journal of Nuclear Medicine and Molecular Imaging.

[26]  Molly L Flexman,et al.  Contrast ultrasound imaging for identification of early responder tumor models to anti-angiogenic therapy. , 2012, Ultrasound in medicine & biology.

[27]  F. Stuart Foster,et al.  Acoustic Angiography: A New Imaging Modality for Assessing Microvasculature Architecture , 2013, Int. J. Biomed. Imaging.

[28]  L. Bolondi,et al.  Use of VEGFR-2 Targeted Ultrasound Contrast Agent for the Early Evaluation of Response to Sorafenib in a Mouse Model of Hepatocellular Carcinoma , 2015, Molecular Imaging and Biology.

[29]  P. Dayton,et al.  Vascular channels formed by subpopulations of PECAM1+ melanoma cells , 2014, Nature Communications.

[30]  Paul A Dayton,et al.  Improving Sensitivity in Ultrasound Molecular Imaging by Tailoring Contrast Agent Size Distribution: In Vivo Studies , 2010, Molecular imaging.

[31]  Ingrid Leguerney,et al.  Molecular ultrasound imaging using contrast agents targeting endoglin, vascular endothelial growth factor receptor 2 and integrin. , 2015, Ultrasound in medicine & biology.

[32]  Fabian Kiessling,et al.  Squamous Cell Carcinoma Xenografts: Use of VEGFR2-targeted Microbubbles for Combined Functional and Molecular US to Monitor Antiangiogenic Therapy Effects. , 2016, Radiology.

[33]  Jimmy Espinoza,et al.  Applications of 2‐Dimensional Matrix Array for 3‐ and 4‐Dimensional Examination of the Fetus , 2006, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[34]  Vicky Goh,et al.  CT response assessment combining reduction in both size and arterial phase density correlates with time to progression in metastatic renal cancer patients treated with targeted therapies , 2010, Cancer biology & therapy.

[35]  Fabian Kiessling,et al.  Molecular and functional ultrasound imaging in differently aggressive breast cancer xenografts using two novel ultrasound contrast agents (BR55 and BR38) , 2011, European Radiology.

[36]  Fabio Cominelli,et al.  Targeting mucosal addressin cellular adhesion molecule (MAdCAM)-1 to noninvasively image experimental Crohn's disease. , 2006, Gastroenterology.

[37]  Linda Chami,et al.  To predict progression-free survival and overall survival in metastatic renal cancer treated with sorafenib: pilot study using dynamic contrast-enhanced Doppler ultrasound. , 2006, European journal of cancer.

[38]  Michael B Lawrence,et al.  Ultrasound-based molecular imaging and specific gene delivery to mesenteric vasculature by endothelial adhesion molecule targeted microbubbles in a mouse model of Crohn's disease. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[39]  Maximilian Reiser,et al.  Contrast-Enhanced Ultrasound with VEGFR2-Targeted Microbubbles for Monitoring Regorafenib Therapy Effects in Experimental Colorectal Adenocarcinomas in Rats with DCE-MRI and Immunohistochemical Validation , 2017, PloS one.

[40]  J Nuyts,et al.  18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). , 2003, European journal of cancer.

[41]  K. Cox,et al.  Contrast-Enhanced Ultrasound Biopsy of Sentinel Lymph Nodes in Patients with Breast Cancer: Implications for Axillary Metastases and Conservation , 2015, Annals of Surgical Oncology.

[42]  Paul A Dayton,et al.  Quantification of Microvascular Tortuosity during Tumor Evolution Using Acoustic Angiography. , 2015, Ultrasound in medicine & biology.

[43]  Seth M Steinberg,et al.  A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. , 2003, The New England journal of medicine.

[44]  Alexandra Branzan Albu,et al.  A Morphology-Based Approach for Interslice Interpolation of Anatomical Slices From Volumetric Images , 2008, IEEE Transactions on Biomedical Engineering.

[45]  Paul A Dayton,et al.  Quantitative Volumetric Perfusion Mapping of the Microvasculature Using Contrast Ultrasound , 2010, Investigative radiology.

[46]  Dimitre Hristov,et al.  Intra-Animal Comparison between Three-dimensional Molecularly Targeted US and Three-dimensional Dynamic Contrast-enhanced US for Early Antiangiogenic Treatment Assessment in Colon Cancer. , 2017, Radiology.

[47]  Haesun Choi,et al.  Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.