Murine liver implantation of radiation-induced fibrosarcoma: characterization with MR imaging, microangiography and histopathology.

Department of Radiology, University Hospitals, Catholic University of Leuven, Herestraat 49, 3000 Leuven, Belgium.
European Radiology (Impact Factor: 4.34). 07/2008; 18(7):1422-30. DOI: 10.1007/s00330-008-0904-2
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Frederik De Keyzer, Jun 30, 2015
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Investigative radiology 12/2008; 44(1):44-53. DOI:10.1097/RLI.0b013e31818e5ace
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Acta Radiologica 01/2009; 50(3):276-87. DOI:10.1080/02841850802647021
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Journal of Magnetic Resonance Imaging 03/2009; 29(3):621-8. DOI:10.1002/jmri.21675