Honors & Awards

  • Outstanding Self-financed Student Award, Chinese Government (2008)
  • Dean's Fellowship, Stanford University (2011-2012)

Professional Education

  • Doctor of Philosophy, Katholieke Universiteit Leuven (2011)

Stanford Advisors


All Publications

  • Molecular Imaging of Inflammation in Inflammatory Bowel Disease with a Clinically Translatable Dual-Selectin-targeted US Contrast Agent: Comparison with FDG PET/CT in a Mouse Model RADIOLOGY Wang, H., Machtaler, S., Bettinger, T., Lutz, A. M., Luong, R., Bussat, P., Gambhir, S. S., Tranquart, F., Tian, L., Willmann, J. K. 2013; 267 (3): 818-829


    Purpose: To develop and test a molecular imaging approach that uses ultrasonography (US) and a clinically translatable dual-targeted (P- and E-selectin) contrast agent (MBSelectin) in the quantification of inflammation at the molecular level and to quantitatively correlate selectin-targeted US with fluorodeoxyglucose (FDG) combined positron emission tomography (PET) and computed tomography (CT) in terms of visualization and quantification of different levels of inflammation in a murine acute colitis model. Materials and Methods: Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. MBSelectin was developed by covalently binding an analog of the naturally occurring binding ligand P-selectin glycoprotein ligand 1 fused to a human fragment crystallizable(or Fc) domain onto the lipid shell of perfluorobutane and nitrogen-containing MBs. Binding specificity of MBSelectin was assessed in vitro with a flow chamber assay and in vivo with a chemically induced acute colitis murine model. US signal was quantitatively correlated with FDG uptake at PET/CT and histologic grade. Statistical analysis was performed with the Student t test, analysis of variance, and Pearson correlation analysis. Results: MBSelectin showed strong attachment to both human and mouse P- and E-selectin compared with MBControl in vitro (P ? .002). In vivo, US signal was significantly increased (P < .001) in mice with acute colitis (173.8 arbitrary units [au] ± 134.8 [standard deviation]) compared with control mice (5.0 au ± 4.5). US imaging signal strongly correlated with FDG uptake on PET/CT images (? = 0.89, P < .001). Ex vivo analysis enabled confirmation of inflammation in mice with acute colitis and high expression levels of P- and E-selectin in mucosal capillaries (P = .014). Conclusion: US with MBSelectin specifically enables detection and quantification of inflammation in a murine acute colitis model, leveraging the natural pathway of leukocyte recruitment in inflammatory tissue. US imaging with MBSelectin correlates well with FDG uptake at PET/CT imaging. © RSNA, 2013 Supplemental material:

    View details for DOI 10.1148/radiol.13122509

    View details for Web of Science ID 000319445400018

  • Comparison of two vascular-disrupting agents at a clinically relevant dose in rodent liver tumors with multiparametric magnetic resonance imaging biomarkers ANTI-CANCER DRUGS Wang, H., Cona, M. M., Chen, F., Yu, J., Feng, Y., Li, J., De Keyzer, F., Marchal, G., Ni, Y. 2012; 23 (1): 12-21


    We sought to compare the therapeutic efficacy between two vascular-disrupting agents, combretastatin A4 phosphate (CA4P) and ZD6126, at a clinically relevant dose on tumor models with magnetic resonance imaging (MRI). Thirty rats with liver rhabdomyosarcoma were randomized into CA4P (10 mg/kg), ZD6126 (10 mg/kg), and control group (n=10 for each group). Multiparametric MRI biomarkers including tumor volume, enhancement ratio, necrosis ratio, apparent diffusion coefficient (ADC), and K (volume transfer constant) derived from T2-weighted, T1-weighted, contrast-enhanced T1-weighted, and diffusion-weighted imaging, and dynamic contrast-enhanced MRI were compared at pretreatment, 1?h, 6?h, 24?h, 48?h, and 120?h posttreatment; they were validated using ex-vivo techniques. Relative to rapidly growing tumors without necrosis in control rats, tumors grew slower in the CA4P group compared with the ZD6126 group with a higher necrosis ratio at 120 h (P<0.05), as proven by histopathology. In the CA4P group, K decreased from 1 h until 6 h, and partially recovered at 120 h. In the ZD6126 group, the reduced K at 1 h began to rebound from 6 h and exceeded the baseline value at 120 h (P<0.05), parallel to evolving enhancement ratios (P<0.05). ADC revealed more necrotic tumors with CA4P versus ZD6126 at 120 h (P<0.05). The different tumor responses were confirmed by ex-vivo microangiography and histopathology. CA4P was more effective than ZD6126 in impairing blood supply, inducing necrosis, and delaying growth in rat liver tumors at a clinically relevant dose. A single dose of vascular-disrupting agent was insufficient to destroy the tumor. The multiparametric MRI biomarkers enabled in-vivo noninvasive comparison of therapeutic efficacy between CA4P and ZD6126.

    View details for DOI 10.1097/CAD.0b013e328349dd60

    View details for Web of Science ID 000298135900002

    View details for PubMedID 21857503

  • Comparison between nonspecific and necrosis-avid gadolinium contrast agents in vascular disrupting agent-induced necrosis of rodent tumors at 3.0T. Investigative radiology Wang, H., Miranda Cona, M., Chen, F., Li, J., Yu, J., Feng, Y., Peeters, R., De Keyzer, F., Marchal, G., Ni, Y. 2011; 46 (9): 531-538


    : To compare a commercial contrast agent (CA) Dotarem and a necrosis-avid CA (NACA) for their ability to evaluate the therapeutic necrosis with a vascular disrupting agent (VDA) on magnetic resonance imaging in rodent liver tumors to determine which could better correlate with the histopathologic outcome.: After the VDA treatment, 16 rats with 32 liver rhabdomyosarcomas were randomized into Dotarem and NACA groups (n = 8 per group) for both interindividual and intraindividual comparisons. T2-weighted imaging, T1-weighted imaging (T1WI), contrast-enhanced T1-weighted imaging (CE-T1WI), and diffusion-weighted imaging were performed at baseline, after VDA treatment and CA injections. The enhancing efficacy of CAs at immediate and delayed enhancement on CE-T1WI in viable tumor and necrosis was compared. Tumor necrosis ratios calculated from NACA and Dotarem were compared and correlated with gold-standard histopathology.: On the immediate CE-T1WI, viable tumor was enhanced by either CA. On the delayed CE-T1WI at 30 minutes, both CAs failed to demarcate viable tumor from necrosis. At 24 hours post-NACA, the necrosis was clearly distinguished from viable tumor and thus derived necrosis ratio matched that from histopathology (P = 0.99); necrosis ratio from Dotarem was significantly lower than that from NACA and histopathology (P < 0.05, both), with a higher correlation of NACA than that of Dotarem with histopathology (r = 0.99 vs. r = 0.82).: NACA better evaluated VDA-induced tumor necrosis than nonspecific CA on T1WI in tumor models of rat liver. NACA showed a closer correlation with histopathology than nonspecific CA for the delineation of true necrosis. Delayed enhancement on T1WI with nonspecific CA is not suitable for the assessment of VDA-induced tumor necrosis.

    View details for DOI 10.1097/RLI.0b013e31821a2116

    View details for PubMedID 21577133

  • Multiparametric MRI biomarkers for measuring vascular disrupting effect on cancer. World journal of radiology Wang, H., Marchal, G., Ni, Y. 2011; 3 (1): 1-16


    Solid malignancies have to develop their own blood supply for their aggressive growth and metastasis; a process known as tumor angiogenesis. Angiogenesis is largely involved in tumor survival, progression and spread, which are known to be significantly attributed to treatment failures. Over the past decades, efforts have been made to understand the difference between normal and tumor vessels. It has been demonstrated that tumor vasculature is structurally immature with chaotic and leaky phenotypes, which provides opportunities for developing novel anticancer strategies. Targeting tumor vasculature is not only a unique therapeutic intervention to starve neoplastic cells, but also enhances the efficacy of conventional cancer treatments. Vascular disrupting agents (VDAs) have been developed to disrupt the already existing neovasculature in actively growing tumors, cause catastrophic vascular shutdown within short time, and induce secondary tumor necrosis. VDAs are cytostatic; they can only inhibit tumor growth, but not eradicate the tumor. This novel drug mechanism has urged us to develop multiparametric imaging biomarkers to monitor early hemodynamic alterations, cellular dysfunctions and metabolic impairments before tumor dimensional changes can be detected. In this article, we review the characteristics of tumor vessels, tubulin-destabilizing mechanisms of VDAs, and in vivo effects of the VDAs that have been mostly studied in preclinical studies and clinical trials. We also compare the different tumor models adopted in the preclinical studies on VDAs. Multiparametric imaging biomarkers, mainly diffusion-weighted imaging and dynamic contrast-enhanced imaging from magnetic resonance imaging, are evaluated for their potential as morphological and functional imaging biomarkers for monitoring therapeutic effects of VDAs.

    View details for DOI 10.4329/wjr.v3.i1.1

    View details for PubMedID 21286490

  • Morphological, functional and metabolic imaging biomarkers: assessment of vascular-disrupting effect on rodent liver tumours EUROPEAN RADIOLOGY Wang, H., Li, J., Chen, F., De Keyzer, F., Yu, J., Feng, Y., Nuyts, J., Marchal, G., Ni, Y. 2010; 20 (8): 2013-2026


    To evaluate effects of a vascular-disrupting agent on rodent tumour models.Twenty rats with liver rhabdomyosarcomas received ZD6126 intravenously at 20 mg/kg, and 10 vehicle-treated rats were used as controls. Multiple sequences, including diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE-MRI) with the microvascular permeability constant (K), were acquired at baseline, 1 h, 24 h and 48 h post-treatment by using 1.5-T MRI. [(18)F]fluorodeoxyglucose micro-positron emission tomography ((18)F-FDG microPET) was acquired pre- and post-treatment. The imaging biomarkers including tumour volume, enhancement ratio, necrosis ratio, apparent diffusion coefficient (ADC) and K from MRI, and maximal standardised uptake value (SUV(max)) from FDG microPET were quantified and correlated with postmortem microangiography and histopathology.In the ZD6126-treated group, tumours grew slower with higher necrosis ratio at 48 h (P < 0.05), corresponding well to histopathology; tumour K decreased from 1 h until 24 h, and partially recovered at 48 h (P < 0.05), parallel to the evolving enhancement ratios (P < 0.05); ADCs varied with tumour viability and perfusion; and SUV(max) dropped at 24 h (P < 0.01). Relative K of tumour versus liver at 48 h correlated with relative vascular density on microangiography (r = 0.93, P < 0.05).The imaging biomarkers allowed morphological, functional and metabolic quantifications of vascular shutdown, necrosis formation and tumour relapse shortly after treatment. A single dose of ZD6126 significantly diminished tumour blood supply and growth until 48 h post-treatment.

    View details for DOI 10.1007/s00330-010-1743-5

    View details for Web of Science ID 000279656400026

    View details for PubMedID 20182730

  • Development, evaluation, and application of reperfused liver infarction in rats as a practical model for studying ischemic diseases and new diagnostic and therapeutic drugs International Journal of Modelling, Identification and Control Wang H, Wu X, Chen F, Jin L, Li J, Feng Y, et al 2010; 9 (3): 247-261
  • Diffusion-Weighted MRI of Hepatic Tumor in Rats: Comparison Between In Vivo and Postmortem Imaging Acquisitions JOURNAL OF MAGNETIC RESONANCE IMAGING Sun, X., Wang, H., Chen, F., De Keyzer, F., Yu, J., Jiang, Y., Feng, Y., Li, J., Marchal, G., Ni, Y. 2009; 29 (3): 621-628


    To determine the feasibility of in vivo diffusion-weighted imaging (DWI) to distinguish between normal liver, viable tumor and necrosis compared to postmortem DWI in a rat model with vascular-targeting treatment.Fifteen rats with liver implantation of 30 rhabdomyosarcomas were treated with combretastatin A-4-phosphate (CA4P) at 10 mg/kg. Two days after treatment, T2-weighted imaging, precontrast T1-weighted imaging, postcontrast T1-weighted imaging, and DWI were performed in vivo and postmortem with a 1.5T scanner. Apparent diffusion coefficients (ADCs) calculated from DWIs with b values of 0, 50, and 100 seconds/mm2 (ADClow), 500, 750, and 1000 seconds/mm2 (ADChigh), 0, 500, and 1000 seconds/mm2 (ADC3b), and 0-1000 seconds/mm2 (ADC10b) for tumor, liver, therapeutic necrosis, and phantoms were compared and validated with ex vivo microangiographic and histopathologic findings.Except ADClow between tumor and necrosis, in vivo ADCs successfully differentiated liver, viable tumor, and necrosis (P<0.05). Compared to in vivo outcomes, postmortem ADCs significantly dropped in tumor and liver (P<0.05) except ADChigh of tumor, but not in necrosis and phantoms. Compared to ADClow, ADChigh was less affected by vital status.Advantageous over postmortem DWI, in vivo DWI provides a noninvasive easy-performing tool for distinguishing between liver, viable tumor, and necrosis. ADClow and ADChigh better reflect tissue perfusion and water diffusion, respectively.

    View details for DOI 10.1002/jmri.21675

    View details for Web of Science ID 000263923000017

    View details for PubMedID 19243058

  • Treatment of Rodent Liver Tumor With Combretastatin A4 Phosphate Noninvasive Therapeutic Evaluation Using Multiparametric Magnetic Resonance Imaging in Correlation With Microangiography and Histology INVESTIGATIVE RADIOLOGY Wang, H., Sun, X., Chen, F., De Keyzer, F., Yu, J., Landuyt, W., Vandecaveye, V., Peeters, R., Bosmans, H., Hermans, R., Marchal, G., Ni, Y. 2009; 44 (1): 44-53


    To document tumoricidal events after intravenous administration of a vascular targeting agent combretastatin A-4-phosphate (CA4P) in rodent liver tumors by using multiparametric magnetic resonance imaging (MRI) in correlation with microangiography and histopathology.Thirty rhabdomyosarcomas of 8 to 14 mm in diameter were obtained 16 days after implantation in liver lobes of 15 rats. Using a 1.5T magnet and a 4-channel wrist coil, T2-weighted imaging (T2WI), pre- and postcontrast T1-weighted imaging (T1WI), diffusion-weighted imaging (DWI), and dynamic susceptibility imaging (DSI) with relative blood volume (rBV) and flow (rBF) maps were acquired at baseline, 1 hour, 6 hours, and 48 hours after iv injection of CA4P at 10 mg/kg and vehicle in 9 treated and 6 control rats, respectively. In vivo data including signal intensity (SI), tumor volume, apparent diffusion coefficient (ADC), rBV, and rBF were correlated with ex vivo microangiographic and histopathologic findings.CA4P-treated tumors (n = 18) grew slower than those (n = 12) of controls (P < 0.05), with vascular shutdown evident on CE-T1WI at 1 hour but more prominent at 6 hours. However, enhanced rim occurred in the periphery 48 hours after treatment, indicating neovascularization. ADC map enabled distinction between necrotic and viable tumors. DSI-derived tumoral rBV and rBF decreased significantly at 1 hour through 6 hours and partly recovered at 48 hours. SI-time curve reflected diverse therapeutic responses between tumor and liver. MRI findings were verified by ex vivo techniques.Clinical MRI allowed monitoring of CA4P-related vascular shutdown, necrosis, and neovascularization of liver tumors in rats. Single dose of CA4P seemed insufficient for tumor eradication because of evident peripheral residue and recurrence.

    View details for Web of Science ID 000262021800007

    View details for PubMedID 19034028

  • Murine liver implantation of radiation-induced fibrosarcoma: characterization with MR imaging, microangiography and histopathology EUROPEAN RADIOLOGY Wang, H., Van de Putte, M., Chen, F., De Keyzer, F., Jin, L., Yu, J., Marchal, G., de Witte, P., Ni, Y. 2008; 18 (7): 1422-1430


    We sought to establish and characterize a mouse liver tumor model as a platform for preclinical assessment of new diagnostics and therapeutics. Radiation-induced fibrosarcoma (RIF-1) was intrahepatically implanted in 27 C3H/Km mice. Serial in vivo magnetic resonance imaging (MRI) with a clinical 1.5-T-magnet was performed using T1- (T1WI), T2- (T2WI), and diffusion-weighted sequences (DWI), dynamic contrast-enhanced MRI (DCE-MRI), and contrast-enhanced T1WI, and validated with postmortem microangiography and histopathology. Implantation procedure succeeded in 25 mice with 2 deaths from overdosed anesthesia or hypothermia. RIF-1 grew in 21 mice with volume doubling time of 2.55+/-0.88 days and final size of 216.2+/-150.4 mm(3) at day 14. Three mice were found without tumor growth and one only with abdominal seeding. The intrahepatic RIF-1 was hypervascularized with negligible necrosis as shown on MRI, microangiography and histology. On DCE-MRI, maximal initial slope of contrast-time curve and volume transfer constant per unit volume of tissue, K, differed between the tumor and liver with only the former significantly lower in the tumor than in the liver (P<0.05). Liver implantation of RIF-1 in mice proves a feasible and reproducible model and appears promising for use to screen new diagnostics and therapeutics under noninvasive monitoring even with a clinical MRI system.

    View details for DOI 10.1007/s00330-008-0904-2

    View details for Web of Science ID 000256823300014

    View details for PubMedID 18343928

  • Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proceedings of the National Academy of Sciences of the United States of America Lee, J. J., Perera, R. M., Wang, H., Wu, D., Liu, X. S., Han, S., Fitamant, J., Jones, P. D., Ghanta, K. S., Kawano, S., Nagle, J. M., Deshpande, V., Boucher, Y., Kato, T., Chen, J. K., Willmann, J. K., Bardeesy, N., Beachy, P. A. 2014; 111 (30): E3091-100


    Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention.

    View details for DOI 10.1073/pnas.1411679111

    View details for PubMedID 25024225

  • Detection of pancreatic ductal adenocarcinoma in mice by ultrasound imaging of thymocyte differentiation antigen 1. Gastroenterology Foygel, K., Wang, H., Machtaler, S., Lutz, A. M., Chen, R., Pysz, M., Lowe, A. W., Tian, L., Carrigan, T., Brentnall, T. A., Willmann, J. K. 2013; 145 (4): 885-894 e3


    Early detection of pancreatic ductal adenocarcinoma (PDAC) allows for surgical resection and increases patient survival times. Imaging agents that bind and amplify the signal of neovascular proteins in neoplasms can be detected by ultrasound, enabling accurate detection of small lesions. We searched for new markers of neovasculature in PDAC and assessed their potential for tumor detection by ultrasound molecular imaging.Thymocyte Differentiation Antigen 1 (Thy1) was identified as a specific biomarker of PDAC neovasculature by proteomic analysis. Upregulation in PDAC was validated by immunohistochemical analysis of pancreatic tissue samples from 28 healthy individuals, 15 with primary chronic pancreatitis tissues, and 196 with PDAC. Binding of Thy1-targeted contrast microbubbles was assessed in cultured cells, in mice with orthotopic PDAC xenograft tumors expressing human Thy1 on the neovasculature, and on the neovasculature of a genetic mouse model of PDAC.Based on immunohistochemical analyses, levels of Thy1 were significantly higher in the vascular of human PDAC than chronic pancreatitis (P=.007) or normal tissue samples (P<.0001). In mice, ultrasound imaging accurately detected human Thy1-positive PDAC xenografts, as well as PDACs that express endogenous Thy1 in genetic mouse models of PDAC.We have identified and validated Thy1 as a marker of PDAC that can be detected by ultrasound molecular imaging in mice. The development of a specific imaging agent and identification of Thy1 as a new biomarker could aid in the diagnosis of this cancer and management of patients.

    View details for DOI 10.1053/j.gastro.2013.06.011

    View details for PubMedID 23791701

  • Detection of Pancreatic Ductal Adenocarcinoma in Mice by Ultrasound Imaging of Thymocyte Differentiation Antigen 1 GASTROENTEROLOGY Foygel, K., Wang, H., Machtaler, S., Lutz, A. M., Chen, R., Pysz, M., Lowe, A. W., Tian, L., Carrigan, T., Brentnall, T. A., Willmann, J. K. 2013; 145 (4): 885-?
  • Enhanced antitumor efficacy of a vascular disrupting agent combined with an antiangiogenic in a rat liver tumor model evaluated by multiparametric MRI. PLoS One Chen F, Feng Y, Zheng K, De Keyzer F, Li J, Feng Y, Cona MM, Wang H, et al. 2012; 7 (7): e41140. doi: 10.1371
  • Study on the microbial safety of an infusion set for contrast-enhanced imaging. Invest Radiol Cona MM, Bauwens M, Zheng Y, Coudyzer W, Li J, Feng Y, Wang H, et al. 2012; 47 (4): 247-251
  • Continuing pursuit for ideal systemic anticancer radiotherapeutics. Invest New Drugs Cona MM, Wang H, Li J, Feng Y, Chen F, de Witte P, Verbruggen A, Ni Y. 2012; 30 (5): 2050-2065
  • Preclinical Imaging of Therapy Response Using Metabolic and Apoptosis Molecular Imaging MOLECULAR IMAGING AND BIOLOGY De Saint-Hubert, M., Wang, H., Devos, E., Vunckx, K., Zhou, L., Reutelingsperger, C., Verbruggen, A., Mortelmans, L., Ni, Y., Mottaghy, F. M. 2011; 13 (5): 995-1002


    Early after therapy, 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) imaging is not always reliable due to the influx of inflammatory cells while apoptosis imaging offers a direct and early measurement of therapy effects. This study uses an improved apoptosis probe ((99m)Tc-hAnxA5) in combination with [(18)F]FDG imaging to evaluate therapy response.Daudi tumor tissue was implanted in the spleen of SCID mice. Treatment was performed with adriamycin and cyclophosphamide. Sequential [(18)F]FDG-positron emission tomography (PET) was acquired over 6 days and (99m)Tc-hAnxA5-SPECT was performed before and 1 day after therapy.On day 1, therapy induced apoptosis was visualized with (99m)Tc-hAnxA5 without a measurable change in [(18)F]FDG uptake. [(18)F]FDG uptake decreased significantly on day 3 and was even more pronounced on day 6.In this preclinical model, (99m)Tc-hAnxA5 imaging was able to detect apoptosis before metabolic changes were measured. These results confirm the value of apoptosis imaging for therapy response and give more insight in [(18)F]FDG imaging and its parameters to evaluate response.

    View details for DOI 10.1007/s11307-010-0412-z

    View details for Web of Science ID 000295176200020

    View details for PubMedID 20848227

  • Animal models of ischemic heart disease for in vivo cardiac MR imaging research International Journal of Modelling, Identification and Control Feng Y, Xie Y, Chen F, Wang H, Li J, Jin L, et al 2010; 9 (3): 288-310
  • Tumor models and specific contrast agents for small animal imaging in oncology METHODS Ni, Y., Wang, H., Chen, F., Li, J., Dekeyzer, F., Feng, Y., Yu, J., Bosmans, H., Marchal, G. 2009; 48 (2): 125-138


    Despite the widespread use of various imaging modalities in clinical and experimental oncology without or with combined application of commercially available nonspecific contrast agents (CAs), development of tissue- or organ- or disease-specific CAs has been a continuing effort for pursuing ever-improved sensitivity, specificity, and applicability. This is particularly true with magnetic resonance imaging (MRI) due to its intrinsic superb spatial/temporal/contrast resolutions and adequate detectability for tiny amount of substances. In this context, research using small animal tumor models has played an indispensible role in preclinical exploration of tissue specific CAs. Emphasizing more on methodological and practical aspects, this article aims to share our cumulated experiences on how to create tumor models for evaluation and development of new tissue specific MRI CAs and how to apply such models in imaging-based research studies. With the results that are repeatedly confirmed by later clinical applications in cancer patients, some of our early preclinical studies have contributed to the designs of subsequent clinical trials on the new CAs, some studies have predicted new utilities of these CAs; and other studies have led to the discoveries of new tissue- or disease-specific CAs with novel diagnostic or even therapeutic potentials. Among commonly adopted tumor models, the chemically induced and surgically implanted nodules in the liver prove very useful to simulate primary and metastatic intrahepatic tumors, respectively in clinical patients. The methods to create tumor models have eased procedures and yielded high success rates. The specific properties of the new CAs could be outshined by intraindividual comparison to the commercial CAs as nonspecific controls. Meticulous imaging-microangiography-histology matching techniques guaranteed colocalization of the lesion on in vivo MRI and postmortem tissue specimen, hence correct imaging interpretation and longstanding conclusions. As exemplified in the real study cases, the present experimental set-up proves applicable in small animals for imaging-based oncological investigations, and may provide a platform for the currently booming molecular imaging in a multimodality environment.

    View details for DOI 10.1016/j.ymeth.2009.03.014

    View details for Web of Science ID 000267398800007

    View details for PubMedID 19328231

  • A modified rabbit model of reperfused myocardial infarction for cardiac MR imaging research INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING Feng, Y., Xie, Y., Wang, H., Chen, F., Ye, Y., Jin, L., Marchal, G., Ni, Y. 2009; 25 (3): 289-298


    We sought to obtain a rabbit myocardial infarction (MI) model for research with cardiac magnetic resonance imaging (cMRI) by overcoming a few technical difficulties. A novel endotracheal method was developed for intubation and ventilation. Fourteen rabbits were divided into group-1 (n = 8) with open-chest occlusion of left circumflex coronary artery and closed-chest reperfusion, and group-2 (n = 6) of non-ischemic control; and received ECG-triggered cMRI with delayed contrast enhancement (DE-cMRI) at a 1.5 T clinical scanner. The MI areas in group-1 were morphometrically compared between DE-cMRI and histochemically stained specimens. Left ventricular (LV) functions were compared between two groups.The success rate of intubation and reperfused MI was 8/8 and 6/8, respectively. Global and regional LV functions significantly decreased in group-1 as evidenced by significant hypokinesis of lateral LV-wall and wall thickening (P \ 0.001). Mean MI-area was 19.41 +/- 21.92% on DE-cMRI and 19.10 +/- 22.61% with histochemical staining (r = 0.985). Global MI-volume was 17.92 +/- 7.42% on DE-cMRI and 16.62 +/- 7.16% with histochemistry (r = 0.994). The usefulness of this model was successfully tested for assessing a new contrast agent. The present rabbit MI model may offer a practical platform for more translational research using clinical MRI-facilities.

    View details for DOI 10.1007/s10554-008-9393-2

    View details for Web of Science ID 000263418400011

    View details for PubMedID 19043805

  • Rat Model of Reperfused Partial Liver Infarction: Characterization with Multiparametric Magnetic Resonance Imaging, Microangiography, and Histomorphology ACTA RADIOLOGICA Wu, X., Wang, H., Chen, F., Jin, L., Li, J., Feng, Y., DeKeyzer, F., Yu, J., Marchal, G., Ni, Y. 2009; 50 (3): 276-287


    Rat model of reperfused partial liver infarction (RPLI) has been increasingly used in studying new diagnostics and therapeutics.To characterize the RPLI model using magnetic resonance imaging (MRI), microangiography, and histopathology.RPLI was induced in eight rats by occluding hepatic inflow to the right liver lobe for 3 hours. MRI was performed at a 1.5 T clinical scanner 6 hours after reperfusion to obtain T2-weighted (T2WI), T1-weighted (T1WI), contrast-enhanced (CE) T1WI, diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) maps, T1-weighted dynamic contrast-enhanced (T1-DC) perfusion-weighted imaging (PWI), and T2*-weighted dynamic susceptibility contrast-enhanced (T2*-DSC) PWI images. Rats were sacrificed for microangiography and histomorphology. In vivo morphological and functional MRI parameters, including maximum initial slope (MIS), K value, relative blood flow (rBF), relative blood volume (rBV), time to peak (TTP), and mean transit time (MTT), were matched with postmortem findings.The infarcted lobe was conspicuous from normal liver with lower and higher signal intensity on T1WI (P=0.018) and T2WI (P=0.001), respectively. Contrast between infarcted and normal liver reversed on CE-T1WI after gadolinium injection. The infarction averaged 37.5% of total liver volume. DWI and ADC maps were able to detect subtle perfusion-related differences (P<0.05). With T1-DC-PWI, increased extravasation and vascular permeability were reflected by significantly greater MIS (P=0.034) and K value (P=0.014) in infarction. T2*-DSC-PWI showed lower rBF and rBV with shorter TTP and MTT in infarcted liver (P<0.05). In vivo MRI findings corresponded well with postmortem outcomes.RPLI in rats could be characterized by multiparametric MRI and postmortem assessments, with insight into the no-reflow phenomenon, which implies its further application for preclinical assessments of new pharmaceutics.

    View details for DOI 10.1080/02841850802647021

    View details for Web of Science ID 000264220100005

    View details for PubMedID 19160078

  • Hypericin as a marker for determination of tissue viability after radiofrequency ablation in a murine liver tumor model ONCOLOGY REPORTS De Putte, M. V., Wang, H., Chen, F., de Witte, P. A., Ni, Y. 2008; 19 (4): 927-932


    In this proof-of-principle study, the necrosis avid agent hypericin was investigated as a potential indicator for early therapeutic response following radiofrequency ablation (RFA) of murine liver tumors. Eight mice bearing intrahepatic RIF-1 tumors were intravenously injected with hypericin 1 h before or 24 h after RFA treatment. Mice were euthanized 24 h after hypericin injection and excised livers were investigated by means of fluoromacroscopic and fluoromicroscopic examinations in combination with conventional histomorphology. Significant differences in hypericin fluorescence were found in necrosis, viable tumor and normal liver tissue in a decreasing order: in necrosis, mean fluorescence densities were about 5 times higher than in viable tumor and approximately 12 times higher than in normal liver (p<0.05). Mean fluorescence densities were not significantly different when hypericin was injected 24 h after or 1 h before RFA treatment (p>0.05). As a conclusion, hypericin features the property to specifically enhance the imaging contrast between necrotic and viable tissues and to non-specifically distinguish viable tumor from normal liver. The results suggest that hypericin offers significant potential in the early assessment of response following necrosis-inducing antineoplastic treatments such as RFA.

    View details for Web of Science ID 000254496100013

    View details for PubMedID 18357377

  • Comparing two methods for assessment of perfusion-diffusion mismatch in a rodent model of ischaemic stroke: a pilot study BRITISH JOURNAL OF RADIOLOGY Chen, F., Liu, Q., Wang, H., Suzuki, Y., Nagai, N., Yu, J., Marchal, G., Ni, Y. 2008; 81 (963): 192-198


    This stroke experiment was designed to define the mismatch between perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) in MRI by applying early or instantly acquired PWI. Eight rats were induced with stroke through photothrombotic occlusion of the middle cerebral artery and scanned serially between 1 h and day 3 after induction using DWI and PWI with a 1.5 T MR scanner. The relative lesion volumes (rLV) on MRI and triphenyl tetrazolium chloride-stained specimens were defined as the proportion of lesion volume over brain volume. Discrepancies in the rLV between PWI- and DWI-derived apparent diffusion coefficient (ADC) maps were expressed by subtraction of the ADC from PWI, resulting in three possible patterns: (i) (PWI-ADC > 10% of PWI) denoting a mismatch; (ii) (-(10% of PWI)

    View details for DOI 10.1259/bjr/70940134

    View details for Web of Science ID 000254171500005

    View details for PubMedID 18180261

  • Synthesis and preliminary biological evaluation of a Tc-99m-labeled hypericin derivative as a necrosis avid imaging agent JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS Fonge, H., Jin, L., Wang, H., Bormans, G., Ni, Y., Verbruggen, A. 2008; 51 (1-2): 33-40

    View details for DOI 10.1002/jlcr.1468

    View details for Web of Science ID 000254586300007

  • Non-invasive detection and quantification of acute myocardial infarction in rabbits using mono-[I-123]iodohypericin mu SPECT EUROPEAN HEART JOURNAL Fonge, H., Vunckx, K., Wang, H., Feng, Y., Mortelmans, L., Nuyts, J., Bormans, G., Verbruggen, A., Ni, Y. 2008; 29 (2): 260-269


    Mono-[(123)I]iodohypericin ([(123)I]MIH) has been reported to have high avidity for necrosis. In the present study, by using rabbit models of acute myocardial infarction, we explored the suitability of [(123)I]MIH micro single photon emission computed tomography (microSPECT) for non-invasive visualization of myocardial infarcts in comparison with [(13)N]ammonia micro positron emission tomography (microPET) imaging, postmortem histomorphometry, and [(123)I]MIH autoradiography.Fourteen rabbits were divided into four groups. The left circumflex coronary artery was permanently occluded in group A (n = 3), reperfused by releasing the ligature after 15 min in group B (n = 3) or 90 min in group C (n = 6), or not occluded in group D (n = 2). Animals received [(13)N]ammonia microPET perfusion imaging 18 h after infarct induction followed by microSPECT imaging at 2-3.5, 9-11, and 22-24 h post injection (p.i.) of [(123)I]MIH. The cardiac images were assembled into polar maps for assessment of tracer uptake. Animals were sacrificed and the excised heart was sliced for autoradiography, triphenyl tetrazolium chloride, and haematoxylin-eosin staining. Using [(123)I]MIH microSPECT, infarcts were well delineated at 9 h p.i. Mean microSPECT infarct size was 38.8 and 32.7% of left ventricular area for groups A and C, respectively, whereas group B showed low uptake of [(123)I]MIH. Highest mean infarct/viable tissue activity ratio of 61/1 was obtained by autoradiography in group C animals at 24 h p.i.The study indicates the suitability of [(123)I]MIH for in vivo visualization of myocardial infarcts.

    View details for DOI 10.1093/eurheartj/ehm588

    View details for Web of Science ID 000252543400022

    View details for PubMedID 18156139

  • Synthesis and preliminary biological evaluation of a Tc-99m-labeled hypericin derivative as a necrosis avid imaging agent J Labelled Comp Radiopharm Fonge H, Jin L, Wang H, et al 2008; 51 (1): 33-40
  • Hypericin as a marker for determination of tissue viability after intratumoral ethanol injection in a murine liver tumor model ACADEMIC RADIOLOGY Van de Putte, M., Wang, H., Chen, F., de Witte, P. A., Ni, Y. 2008; 15 (1): 107-113


    In this preclinical proof-of-principle study, the necrosis avid agent hypericin was investigated as a potential early indicator for therapeutic response after ethanol-mediated chemical ablation in murine liver tumors.Seven mice bearing intrahepatic radiation-induced fibrosarcoma-1 tumors were intravenously injected with hypericin 1 hour before (n = 3) or 24 hours after (n = 4) intratumoral ethanol injection. Mice were euthanized 24 hours after hypericin injection and, taking advantage of the fluorescent property of the compound, the excised livers were investigated qualitatively and quantitatively by means of fluoromacroscopic and fluoromicroscopic examinations, colocalized with conventional histomorphology.Significant differences in hypericin fluorescence were found in necrosis, viable tumor and normal liver tissue in decreasing order (P < .05) (ie, in necrosis, mean fluorescence densities were about 4.5 times higher than in viable tumor and approximately 14 times higher than in normal liver). When hypericin was injected 1 hour before, maximal blood concentrations were achieved at the time of ethanol treatment, so that on ablation an outstanding extravasation took place in the entire necrotic area in comparison with accumulation of hypericin only at the peripheral zone of necrosis when it was injected 24 hours after ablation.Hypericin specifically enhanced the imaging contrast between necrotic and viable tissues and nonspecifically distinguished viable tumor from normal liver. Injection of hypericin shortly before ablation is more favorable than after ablation, because it circumvents difficulties with no-entry zones for hypericin and requires shorter intervals between ethanol ablation and imaging.

    View details for DOI 10.1016/j.acra.2007.08.008

    View details for Web of Science ID 000251984600013

    View details for PubMedID 18078913

  • Diffusion weighted imaging in small rodents using clinical MRI scanners METHODS Chen, F., De Keyzer, F., Wang, H., Vandecaveye, V., Landuyt, W., Bosmans, H., Hermans, R., Marchal, G., Ni, Y. 2007; 43 (1): 12-20


    Diffusion weighted imaging (DWI) has emerged as a unique and powerful non-invasive magnetic resonance imaging (MRI) technique with a major potential impact on imaging-based diagnosis in a variety of clinical applications including oncology and tissue viability assessment. In light of increasing demand for applying this technique in preclinical investigations using small animals, we have explored the potentials of a clinical magnet for acquiring the DWI in rats and mice with either cerebral ischemia or solid tumors. Through technical adaptation and optimization, we have been able to perform a series of clinically relevant animal studies with conclusions based on DWI quantification. Focusing more on practical aspects and cross-referencing with the current literature, this paper is aimed to summarize our ongoing DWI studies on small rodents with stroke and tumors, and to provide protocols for researchers to replicate similar techniques in their own preclinical and clinical studies.

    View details for DOI 10.1016/j.ymeth.2007.03.007

    View details for Web of Science ID 000249886100003

    View details for PubMedID 17720559

  • Microplasmin and tissue plasminogen activator: Comparison of therapeutic effects in rat stroke model at multiparametric MR imaging RADIOLOGY Chen, F., Suzuki, Y., Nagai, N., Sun, X., Wang, H., Yu, J., Marchal, G., Ni, Y. 2007; 244 (2): 429-438


    To prospectively compare therapeutic and hemorrhagic effects of microplasmin and tissue plasminogen activator (tPA) in stroke therapy by using multiparametric magnetic resonance (MR) imaging in a photothrombotic rat stroke model.The animal experiment complied with institutional regulations for laboratory animals. Stroke was induced in rats with photothrombotic occlusion of middle cerebral artery (MCA). T2-weighted, perfusion-weighted (PW), and diffusion-weighted (DW) MR imaging was performed 1 hour and 24 hours after occlusion. On the basis of PW and DW images at 1 hour, 49 rats with cortex and subcortex involvement and with perfusion-diffusion mismatch were randomly assigned into one of four groups: control group, group treated with 7.5 mg microplasmin, group treated with 10 mg/kg microplasmin, or group treated with 10 mg/kg tPA. Agents were intravenously injected 1.5 hours after occlusion. Infarct size and hemorrhagic transformation were assessed with MR imaging and histomorphologic findings. Neurologic deficit was scored. Measurements were statistically analyzed.There were 13 rats in the control group, 13 in the 7.5 mg/kg microplasmin group, nine in the 10 mg/kg microplasmin group, and 14 in the 10 mg/kg tPA group. Despite similar baseline perfusion-diffusion mismatch, histochemically defined total infarct volume was reduced from 25% +/- 5 (standard deviation) in control group to 21% +/- 2, 20% +/- 4, and 20% +/- 5 in 7.5 mg/kg microplasmin, 10 mg/kg microplasmin, and tPA groups, respectively, as similarly shown on T2-weighted, DW, and PW images at 24 hours (P < .05). Cerebral hemorrhage rate at 24 hours was higher in tPA group than in the other three groups. Bederson score of neurologic deficits was significantly reduced in treated groups compared with that in control group.Perfusion-diffusion mismatch appeared useful in selecting candidates for thrombolytic therapy. Multiparametric MR imaging allowed noninvasive assessment of effects of microplasmin and tPA in rats; microplasmin had a significantly lower hemorrhagic rate.

    View details for DOI 10.1148/radiol.2442061316

    View details for Web of Science ID 000248821400012

    View details for PubMedID 17581889

  • Synthesis and preliminary evaluation of mono-[I-123]iodohypericin monocarboxylic acid as a necrosis avid imaging agent BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Fonge, H., Jin, L., Wang, H., Ni, Y., Bormans, G., Verbruggen, A. 2007; 17 (14): 4001-4005


    Hypericin monocarboxylic acid was synthesized in an overall yield of 25% in four steps and radiolabelled with iodine-123 in good yield (>75%). The resulting mono-[(123)I]iodohypericin monocarboxylic acid was evaluated in normal mice and in rats with ethanol induced liver necrosis. In this model, tracer concentration in necrotic liver tissue was 14 times higher than in the viable liver tissue as quantified by autoradiography at 24h post injection. The results indicate the feasibility of visualization of necrotic tissue with the novel tracer.

    View details for DOI 10.1016/j.bmcl.2007.04.083

    View details for Web of Science ID 000248074600039

    View details for PubMedID 17507220

  • Rodent stroke induced by photochemical occlusion of proximal middle cerebral artery: Evolution monitored with MR imaging and histopathology EUROPEAN JOURNAL OF RADIOLOGY Chen, F., Suzuki, Y., Nagai, N., Jin, L., Yu, J., Wang, H., Marchal, G., Ni, Y. 2007; 63 (1): 68-75


    To longitudinally investigate stroke in rats after photothrombotic occlusion of proximal middle cerebral artery (MCA) with magnetic resonance imaging (MRI) in correlation with histopathology.Forty-two rats were subjected to photochemical MCA occlusion and MRI at 1.5T, and sacrificed in seven groups (n=6 each) at the following time points: 1, 3, 6 and 12h, and at day 1, 3 and 9. T2-weighted (T2WI) and diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) map was performed in all rats. Contrast-enhanced T1-weighted imaging (CE-T1WI) was compared to intravital staining with Evans blue in one group for assessing blood-brain barrier (BBB) integrity. The brain was stained histochemically with triphenyl tetrazolium chloride (TTC) and processed for pathological assessment. The evolutional changes of relative lesion volume, signal intensity (SI), and the BBB integrity on MRI with corresponding histopathology were evaluated.The ischemic lesion volume reached a maximum around 12h to day 1 as visualized successively by DWI, ADC map and T2WI, implicating the evolving pathology from cytotoxic edema through vasogenic edema to tissue death. The ADC of brain infarction underwent a significant reversion after 12h, reflecting the colliquative necrosis. On CE-T1WI, BBB leakage peaked at 6h and at day 3 with a transitional partial recovery around 24h. The infarct volume on T2WI, DWI and ADC map matched well with that on TTC staining at 12h and at day 1 (p>0.05).The evolution of the present photothrombotic stroke model in rats could be characterized by MRI. The obtained information may help longitudinal studies of cerebral ischemia and anti-stroke agents using the same model.

    View details for DOI 10.1016/j.ejrad.2007.01.005

    View details for Web of Science ID 000248058800010

    View details for PubMedID 17337149

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