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Multimodality Imaging of Tumor Xenografts and Metastases in Mice with Combined Small-Animal PET, Small-Animal CT, and Bioluminescence Imaging

¹ Molecular Imaging Program at Stanford (MIPS), Departments of Radiology and Bioengineering, Bio-X Program, Stanford University School of Medicine, Stanford University, Stanford, California; and ² Crump Institute for Molecular Imaging, Department of Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California

View larger version (33K): [in this window] [in a new window]   FIGURE 1.  Validation of CT measurements. (A) Nude mouse in imaging position on polystyrene bed. Two fiducial markers are shown before fixation to bed; positions of other markers are marked by asterisks. Scale bar is 1 cm wide. (B) Correlation between tumor volume measured on CT images and caliper-measured tumor volume. Correlation is strong (r2 = 0.92; P < 0.0001), close to identity line (slope = 1.08).

View larger version (52K): [in this window] [in a new window]   FIGURE 2.  Evolution of xenograft growth at days 12 and 17 after inoculation of 0.5 x 106 C6 cells in nude mouse as seen on CT and on 18F-FDG PET/CT fusion images. Tumor ROIs are outlined in orange. White arrows indicate necrotic area at periphery of tumor, visible on 18F-FDG PET image but not discriminable from viable tumor on CT image alone. Fiducial markers are indicated by blue arrows.

View larger version (62K): [in this window] [in a new window]   FIGURE 3.  Detection of pulmonary metastasis with 18F-FDG PET/CT. Transverse (A) and coronal (B) sections of coregistered 18F-FDG PET and CT images of SCID mouse 45 d after tail-vein injection of 0.7 x 106 A375M-Fluc melanoma cells. White arrows indicate hypermetabolic area seen on 18F-FDG PET image. Yellow arrows show water-density nodule in dorsal apex of right lung in CT image. PET/CT fusion image confirms registration of hypermetabolic image on anatomic reference (red arrow). Physiologic tracer uptake in heart (h), kidneys (k), and bladder (b) is marked.

View larger version (29K): [in this window] [in a new window]   FIGURE 4.  Monitoring of metastasis with BLI. (A) Growth of A375M-3F metastasis after intraventricular injection in nude mice as documented by BLI. Evolution of maximum pixel at site of metastasis over 1 mo is shown (n = 6, error bar represents SD). (B) Growth of A375M-3F pulmonary metastasis in 1 mouse.

View larger version (58K): [in this window] [in a new window]   FIGURE 5.  Evolution of metastasis with 18F-FHBG PET/CT. Transverse (A) and coronal (B) sections of coregistered 18F-FHBG PET/CT images of nude mouse that received injection of A375M-3F in left ventricle. Left (yellow arrows) and right (red arrows) basal fields of lung show increase in tracer uptake from 1.8 to 2.5 %ID/g (39% increase) and from 1.4 to 2.1 %ID/g (50% increase), respectively, from week 4 to week 5, indicating progressive growth of pulmonary metastasis. Blue arrows indicate fiducial markers. Physiologic tracer uptake in intestines (i), right kidney (k), and bladder (b) is marked.

View larger version (40K): [in this window] [in a new window]   FIGURE 6.  Additional value of CT in 18F-FHBG PET images of metastasis. (A) Thirty-five days after intraventricular injection of 1.5 x 106 A375M-3F melanoma cells in nude mouse, 18F-FHBG PET/CT allows precise anatomic localization of metastasis in interscapular fat (a), right eye (b), right humeral head (c), and left mandibula (d) as shown by green arrows. Lack of anatomic landmarks on PET alone is illustrated by white arrows. (B) BLI shows same lesions as seen on 18F-FHBG PET/CT but does not provide information on depth of lesion. (C) Ex vivo thymidine kinase and luciferase assays of lesions (+) and contralateral controls (–) validate imaging observations.

View larger version (27K): [in this window] [in a new window]   FIGURE 7.  Comparison of 18F-FDG and 18F-FHBG for detection of A375M-3F metastasis. (A) Uptake of 18F-FDG and 18F-FHBG in metastatic lesions of A375M-3F in 4 mice (6 lesions) that were scanned at days 33 and 31 after injection, respectively (*P < 0.01). (B) 18F-FDG and 18F-FHBG PET scans of nude mouse on days 30 and 28 after injection of 1.5 x 106 A375M-3F cells in left cardiac ventricle. Red crosshairs show metastatic lesion in right mandibula. 18F-FDG uptake is higher than 18F-FHBG uptake, but latter is specific to metastatic cells whereas 18F-FDG uptake is also prominent in heart, brain, and muscles (labeled h, b, and m, respectively). Blue arrows indicate fiducial markers. (C) Tumor-to-background contrast for muscle (T/M), liver (T/L), heart (T/H), brown fat (T/BF), and intestine (T/I) for 18F-FHBG (n = 6; 10 lesions) and 18F-FDG (n = 4; 6 lesions) in metastatic lesions of A375M-3F (mean ± SEM). Contrast is significantly higher for 18F-FHBG than for 18F-FDG (**P < 0.001), except for intestine, where it is significantly lower (#P < 0.0001).