The purpose of this study was to assess the effect of bevacizumab on vasculature and hypoxia in a colorectal tumor model. Nude mice with subcutaneous LS174T tumors were treated with bevacizumab or saline. To assess tumor properties, separate groups of mice were imaged using (18) F-Fluoromisonidazole (FMISO) and (18) F-Fluorodeoxyglucose (FDG) positron emission tomography or magnetic resonance imaging before and 2, 6 and 10 days after the start of treatment. Tumors were harvested after imaging to determine hypoxia and vascular density immunohistochemically. The T2 * time increased significantly less in the bevacizumab group. FMISO uptake increased more over time in the control group. Vessel density significantly decreased in the bevacizumab-treated group. The Carbonic anhydrase 9 (CAIX) and glucose uptake transporter 1 (GLUT1) fractions were higher in bevacizumab-treated tumors. However, the hypoxic fraction showed no significant difference. Bevacizumab led to shorter T2 * times and higher GLUT1 and CAIX expression, suggesting an increase in hypoxia and a higher glycolytic rate. This could be a mechanism of resistance to bevacizumab. The increase in hypoxia, however, could not be demonstrated by pimonidazole/FMISO, possibly because distribution of these tracers is hampered by bevacizumab-induced effects on vascular permeability and perfusion.
Objective: To assess the early vascular effects of sunitinib in patients with renal cell carcinoma (RCC) with diffusion-weighted magnetic resonance imaging (DWI), dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and T2* perfusion MRI. Patients and methods: In 10 patients with abdominal RCC lesions, DWI, DCE-MRI and T2* perfusion MRI measurements at 3 Tesla were performed at baseline, 3 and 10 days after start of sunitinib. VEGF-A plasma levels were measured on days 0, 3 and 10. Results: DWI showed a significant increase in the apparent diffusion coefficient (×10−6 s/mm2) from baseline (mean 1158, range 814–2003) to day 3 (mean 1306, range 1008–2097, P = 0.015) followed by a decrease to baseline levels at day 10 (mean 1132, range 719–2005, P = 0.001). No significant changes were found in mean DCE-MRI parameters. T2* perfusion MRI showed a significant decrease in relative tumor blood volume (rBV) and relative tumor blood flow (rBF) at day 3 (rBV P = 0.037, rBF P = 0.018) and day 10 (rBV P = 0.006, rBF P = 0.009). VEGF-A plasma levels significantly increased after 10 days, but did not correlate with MRI parameters. Conclusions: Sunitinib induces antiangiogenic effects as measured by DWI and T2*-perfusion MRI, 3 and 10 days after the start of the initial treatment. DCE-MRI did not show significant changes. In the near future, early functional MRI-based evaluation can play an important role in tailoring treatment to the individual patient with RCC. Further investigation is warranted.
Assessment of the effect of prandial state on ADC estimates is critical, in order to determine the appropriate patient preparation for biological validation in clinical trials.
PurposeThe aim of the study was to investigate the potential of diffusion-weighted magnetic resonance imaging (DW-MRI) and 3′-dexoy-3′-[18F]fluorothymidine ([18F]FLT) positron emission tomography (PET) as early biomarkers of treatment response of 5-fluorouracil (5-FU) in a syngeneic rat model of colorectal cancer liver metastases.ProceduresWag/Rij rats with intrahepatic syngeneic CC531 tumors were treated with 5-FU (15, 30, or 60 mg/kg in weekly intervals). Before treatment and at days 1, 3, 7, and 14 after treatment rats underwent DW-MRI and [18F]FLT PET. Tumors were analyzed immunohistochemically for Ki67, TK1, and ENT1 expression.Results5-FU inhibited the growth of CC531 tumors in a dose-dependent manner. Immunohistochemical analysis did not show significant changes in Ki67, TK1, and ENT1 expression. However, [18F]FLT SUVmean and SUVmax were significantly increased at days 4 and 7 after treatment with 5-FU (60 mg/kg) and returned to baseline at day 14 (SUVmax at days −1, 4, 7, and 14 was 1.1 ± 0.1, 2.3 ± 0.5, 2.3 ± 0.6, and 1.5 ± 0.4, respectively). No changes in [18F]FLT uptake were observed in the nontreated animals. Furthermore, the apparent diffusion coefficient (ADCmean) did not change in 5-FU-treated rats compared to untreated rats.ConclusionThis study suggests that 5-FU treatment induces a flare in [18F]FLT uptake of responsive CC531 tumors in the liver, while the ADCmean did not change significantly. Future studies in larger groups are warranted to further investigate whether [18F]FLT PET can discriminate between disease progression and treatment response.Electronic supplementary materialThe online version of this article (doi:10.1007/s11307-016-1021-2) contains supplementary material, which is available to authorized users.
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