Reproducibility study of [F-18]FPP(RGD)(2) uptake in murine models of human tumor xenografts

Molecular Imaging Program at Stanford, Department of Radiology, School of Medicine, Stanford University, 1201 Welch Road, Lucas Center, P020A, Stanford, CA 94305-5484, USA.
European Journal of Nuclear Medicine (Impact Factor: 5.38). 12/2010; 38(4):722-30. DOI: 10.1007/s00259-010-1672-1
Source: PubMed


An (18)F-labeled PEGylated arginine-glycine-aspartic acid (RGD) dimer {[(18)F]FPP(RGD)(2)} has been used to image tumor α(v)β(3) integrin levels in preclinical and clinical studies. Serial positron emission tomography (PET) studies may be useful for monitoring antiangiogenic therapy response or for drug screening; however, the reproducibility of serial scans has not been determined for this PET probe. The purpose of this study was to determine the reproducibility of the integrin α(v)β(3)-targeted PET probe, [(18)F]FPP(RGD)(2,) using small animal PET.
Human HCT116 colon cancer xenografts were implanted into nude mice (n = 12) in the breast and scapular region and grown to mean diameters of 5-15 mm for approximately 2.5 weeks. A 3-min acquisition was performed on a small animal PET scanner approximately 1 h after administration of [(18)F]FPP(RGD)(2) (1.9-3.8 MBq, 50-100 μCi) via the tail vein. A second small animal PET scan was performed approximately 6 h later after reinjection of the probe to assess for reproducibility. Images were analyzed by drawing an ellipsoidal region of interest (ROI) around the tumor xenograft activity. Percentage injected dose per gram (%ID/g) values were calculated from the mean or maximum activity in the ROIs. Coefficients of variation and differences in %ID/g values between studies from the same day were calculated to determine the reproducibility.
The coefficient of variation (mean±SD) for %ID(mean)/g and %ID(max)/g values between [(18)F]FPP(RGD)(2) small animal PET scans performed 6 h apart on the same day were 11.1 ± 7.6% and 10.4 ± 9.3%, respectively. The corresponding differences in %ID(mean)/g and %ID(max)/g values between scans were -0.025 ± 0.067 and -0.039 ± 0.426. Immunofluorescence studies revealed a direct relationship between extent of α(ν)β(3) integrin expression in tumors and tumor vasculature with level of tracer uptake. Mouse body weight, injected dose, and fasting state did not contribute to the variability of the scans; however, consistent scanning parameters were necessary to ensure accurate studies, in particular, noting tumor volume, as well as making uniform: the time of imaging after injection and the ROI size. Reanalysis of ROI placement displayed variability for %ID(mean)/g of 6.6 ± 3.9% and 0.28 ± 0.12% for %ID(max)/g.
[(18)F]FPP(RGD)(2) small animal PET mouse tumor xenograft studies are reproducible with relatively low variability.

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    • "As opposed to clinical PET images that can be interpreted both visually and semi-quantitatively, SA-PET images, when used for therapy monitoring, are interpreted only by means of changes in semi-quantitative values like SUVs or percentage injected dose per gram of tissue (%ID/g). The overestimation of quantitative values due to contrast media, which never exceeded 10% in our study, could be a source of inter-animal variability, previously demonstrated to be 15% on average in mice-bearing tumors imaged twice on the same day, after injection and reinjection of 18F-FDG [28], 18F-FLT [29], or 18F-labeled RGD [30]. Another implication of the use of contrast media is the possible interaction between intraperitoneal contrast media and chemotherapy, molecularly targeted therapies, or vehicle administered intraperitoneally the day of the PET examination. "
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    ABSTRACT: Background The use of iodinated contrast media in small-animal positron emission tomography (PET)/computed tomography (CT) could improve anatomic referencing and tumor delineation but may introduce inaccuracies in the attenuation correction of the PET images. This study evaluated the diagnostic performance and accuracy of quantitative values in contrast-enhanced small-animal PET/CT (CEPET/CT) as compared to unenhanced small animal PET/CT (UEPET/CT). Methods Firstly, a NEMA NU 4–2008 phantom (filled with 18F-FDG or 18F-FDG plus contrast media) and a homemade phantom, mimicking an abdominal tumor surrounded by water or contrast media, were used to evaluate the impact of iodinated contrast media on the image quality parameters and accuracy of quantitative values for a pertinent-sized target. Secondly, two studies in 22 abdominal tumor-bearing mice and rats were performed. The first animal experiment studied the impact of a dual-contrast media protocol, comprising the intravenous injection of a long-lasting contrast agent mixed with 18F-FDG and the intraperitoneal injection of contrast media, on tumor delineation and the accuracy of quantitative values. The second animal experiment compared the diagnostic performance and quantitative values of CEPET/CT versus UEPET/CT by sacrificing the animals after the tracer uptake period and imaging them before and after intraperitoneal injection of contrast media. Results There was minimal impact on IQ parameters (%SDunif and spillover ratios in air and water) when the NEMA NU 4–2008 phantom was filled with 18F-FDG plus contrast media. In the homemade phantom, measured activity was similar to true activity (−0.02%) and overestimated by 10.30% when vials were surrounded by water or by an iodine solution, respectively. The first animal experiment showed excellent tumor delineation and a good correlation between small-animal (SA)-PET and ex vivo quantification (r2 = 0.87, P < 0.0001). The second animal experiment showed a good correlation between CEPET/CT and UEPET/CT quantitative values (r2 = 0.99, P < 0.0001). Receiver operating characteristic analysis demonstrated better diagnostic accuracy of CEPET/CT versus UEPET/CT (senior researcher, area under the curve (AUC) 0.96 versus 0.77, P = 0.004; junior researcher, AUC 0.78 versus 0.58, P = 0.004). Conclusions The use of iodinated contrast media for small-animal PET imaging significantly improves tumor delineation and diagnostic performance, without significant alteration of SA-PET quantitative accuracy and NEMA NU 4–2008 IQ parameters.
    Full-text · Article · Jan 2013 · EJNMMI Research
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    • "The coefficient of variation (CV) for tracer uptake was set at 15 % based on the results of studies by researchers at Stanford University who imaged tumour-bearing mice twice on the same day after injection and reinjection of 18F-FDG [9], 18F-FLT [10] or 18F-labelled RGD [11] and determined the CV for standardized uptake value and/or percent injected dose per gram (%ID/g) as the ratio between standard deviation of the two measurements and their mean. The mean CVs were 15.4 %, 14 % and 10.5 % for 18F-FDG [9], 18F-FLT [10] and 18F-labelled RGD, respectively [11]. These authors showed that the observed CVs were likely to have been due to the sizes of the volumes of interest (VOI). "
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    ABSTRACT: Over the last decade, small-animal PET imaging has become a vital platform technology in cancer research. With the development of molecularly targeted therapies and drug combinations requiring evaluation of different schedules, the number of animals to be imaged within a PET experiment has increased. This paper describes experimental design requirements to reach statistical significance, based on the expected change in tracer uptake in treated animals as compared to the control group, the number of groups that will be imaged, and the expected intra-animal variability for a given tracer. We also review how high-throughput studies can be performed in dedicated small-animal PET, high-resolution clinical PET systems and planar positron imaging systems by imaging more than one animal simultaneously. Customized beds designed to image more than one animal in large-bore small-animal PET scanners are described. Physics issues related to the presence of several rodents within the field of view (i.e. deterioration of spatial resolution and sensitivity as the radial and the axial offsets increase, respectively, as well as a larger effect of attenuation and the number of scatter events), which can be assessed by using the NEMA NU 4 image quality phantom, are detailed.
    Full-text · Article · Jul 2012 · European Journal of Nuclear Medicine
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    ABSTRACT: We evaluated noninvasive positron emission tomography (PET) imaging for monitoring tumor response to the VEGFR-2 tyrosine kinase (TK) inhibitor ZD4190 during cancer therapy. Orthotopic MDA-MB-435 tumor-bearing mice were treated with ZD4190 (100 mg/kg orally per day for three consecutive days). Tumor growth was monitored by caliper measurement. During the therapeutic period, longitudinal PET scans were acquired using (18)F-FDG, (18)F-FLT and (18)F-FPPRGD2 as imaging tracers to evaluate tumor glucose metabolism, tumor cell proliferation, and angiogenesis, respectively. Imaging metrics were validated by immunohistochemical analysis of Ki67, GLUT-1, F4/80, CD31, murine integrin β3, and human integrin αvβ3. Three consecutive daily oral administrations of 100 mg/kg of ZD4190 were effective in delaying MDA-MB-435 tumor growth. A significant difference in tumor volume was observed on day 7 between the treatment group and the control group (p < 0.01). After the final treatment, tumor growth resumed after a short delay. In the control tumors, (18)F-FPPRGD2 uptake was stable between days 0 and 7. In ZD4190-treated tumors, (18)F-FPPRGD2 uptake had decreased significantly relative to baseline by 26.74 ± 8.12% (p < 0.05) on day 1 and by 41.19 ± 6.63% (p < 0.01) on day 3, then had returned to baseline on day 7. Tumor uptake of (18)F-FLT had also decreased on both day 1 and day 3 after initiation of ZD4190 treatment. No significant change in (18)F-FDG uptake in ZD4190-treated tumors was observed, however, compared with the control group. All of the imaging findings were supported by ex vivo analysis of related biomarkers. The longitudinal imaging results demonstrated the usefulness of quantitative (18)F-FLT and (18)F-FPPRGD2 PET imaging in evaluating the early antiproliferative and antiangiogenic effects of ZD4190. The quantification data from the PET imaging were consistent with the pattern of initial growth inhibition with treatment, followed by tumor relapse after treatment cessation.
    Full-text · Article · Mar 2011 · European Journal of Nuclear Medicine
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