Antiangiogenic and Radiation Therapy Early Effects on In Vivo Computed Tomography Perfusion Parameters in Human Colon Cancer Xenografts in Mice
ABSTRACT To assess early treatment effects on computed tomography (CT) perfusion parameters after antiangiogenic and radiation therapy in subcutaneously implanted, human colon cancer xenografts in mice and to correlate in vivo CT perfusion parameters with ex vivo assays of tumor vascularity and hypoxia.
Dynamic contrast-enhanced CT (perfusion CT, 129 mAs, 80 kV, 12 slices × 2.4 mm; 150 μL iodinated contrast agent injected at a rate of 1 mL/min intravenously) was performed in 100 subcutaneous human colon cancer xenografts on baseline day 0. Mice in group 1 (n=32) received a single dose of the antiangiogenic agent bevacizumab (10 mg/kg body weight), mice in group 2 (n=32) underwent a single radiation treatment (12 Gy), and mice in group 3 (n=32) remained untreated. On days 1, 3, 5, and 7 after treatment, 8 mice from each group underwent a second CT perfusion scan, respectively, after which tumors were excised for ex vivo analysis. Four mice were killed after baseline scanning on day 0 for ex vivo analysis. Blood flow (BF), blood volume (BV), and flow extraction product were calculated using the left ventricle as an arterial input function. Correlation of in vivo CT perfusion parameters with ex vivo microvessel density and extent of tumor hypoxia were assessed by immunofluorescence. Reproducibility of CT perfusion parameter measurements was calculated in an additional 8 tumor-bearing mice scanned twice within 5 hours with the same CT perfusion imaging protocol.
The intraclass correlation coefficients for BF, BV, and flow extraction product from repeated CT perfusion scans were 0.93 (95% confidence interval: 0.78, 0.97), 0.88 (0.66, 0.95), and 0.88 (0.56, 0.95), respectively. Changes in perfusion parameters and tumor volumes over time were different between treatments. After bevacizumab treatment, all 3 perfusion parameters significantly decreased from day 1 (P ≤ 0.006) and remained significantly decreased until day 7 (P ≤ 0.008); tumor volume increased significantly only on day 7 (P=0.04). After radiation treatment, all 3 perfusion parameters decreased significantly on day 1 (P < 0.001); BF and flow extraction product increased again on day 3 and 5, although without reaching statistically significant difference; and tumor volumes did not change significantly at all time points (P ≥ 0.3). In the control group, all 3 perfusion parameters did not change significantly, whereas tumor volume increased significantly at all the time points, compared with baseline (P ≤ 0.04). Ex vivo immunofluorescent staining showed good correlation between all 3 perfusion parameters and microvessel density (ρ=0.71, 0.66, and 0.69 for BF, BV, and flow extraction product, respectively; P < 0.001). There was a trend toward negative correlation between extent of hypoxia and all 3 perfusion parameters (ρ=-0.53, -0.47, and -0.40 for BF, BV, and flow extraction product, respectively; P ≥ 0.05).
CT perfusion allows a reproducible, noninvasive assessment of tumor vascularity in human colon cancer xenografts in mice. After antiangiogenic and radiation therapy, BF, BV, and flow extraction product significantly decrease and change faster than the tumor volume.
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ABSTRACT: Background: To investigate the correlation of computed tomography (CT) perfusion parameters and lymphatic involvement in patients with stage T1b non-small cell lung cancer (NSCLC). Methods: Forty-six patients (30 men and 16 women; age range, 36–73 years; mean age, 57 years), with stage T1b non-small cell lung cancer, underwent perfusion CT before surgery. The correlations between CT perfusion parameters (blood flow, blood volume, peak enhancement intensity), tumor angiogenesis (microvessel density and maturity of microvessels of surgical specimens) and lymphatic involvement were retrospectively investigated. Receiver operator curve (ROC) analysis was used to identify the parameter threshold at which tumors had or did not have lymph node metastasis, and the corresponding sensitivity and specificity were calculated. Results: A significant tendency for tumors with low blood flow and high density of immature microvessels to show lymphatic involvement was found (all P < 0.001). High correlation (r =−0.769, P < 0.001) was observed between tumor blood flow and immature microvessels. The area under ROC curves (AUC) for blood flow to detect lymph node metastasis was 0.866 (95% confidence interval, 0.766–0.966). For blood flow, the sensitivity, specificity, and accuracy of predicting lymph node metastasis were 88.9, 64.3, and 73.9% respectively, if the cutoff point was set at 43.05 mL/100 g/minute. Conclusions: Blood flow may be useful to predict lymphatic involvement before surgery in stage T1b NSCLC.05/2013; 4(2). DOI:10.1111/j.1759-7714.2012.00142.x
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ABSTRACT: Neovascularization was reported to arise early in the adenoma-carcinoma sequence in colorectal cancer (CRC), and the importance of angiogenesis in cancer progression has been established. Computed tomography (CT) perfusion (CTP) based on high temporal resolution CT images enables evaluation of hemodynamics of tissue in vivo by modeling tracer kinetics. CTP has been reported to characterize tumor angiogenesis, and to be a sensitive marker for predicting recurrence or survival in CRC. In this review, we will discuss the biomarker value of CTP in the management of CRC patients.World Journal of Gastroenterology 12/2014; 20(46):17345-17351. DOI:10.3748/wjg.v20.i46.17345 · 2.43 Impact Factor
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ABSTRACT: To utilize phosphorescence to monitor hypoxic microenvironment in solid-tumors and investigate cancer chemotherapeutic effects in vivo. A hypoxia-sensitive probe named BTP was used to monitor hypoxic microenvironment in solid-tumors. The low-dose metronomic treatment with cisplatin was used in anti-angiogenetic chemotherapeutic programs. The phosphorescence properties of BTP were detected by a spectrofluorometer. BTP cytotoxicity utilized cell necrosis and apoptosis, which were evaluated by trypan blue dye exclusion and Hoechst33342 plus propidium iodide assays. Tumor-bearing mouse models of colon adenocarcinoma were used for tumor imaging in vivo. Monitoring of the hypoxic microenvironment in tumors was performed with a Maestro 2 fluorescence imaging system. Tumor tissues in each group were harvested regularly and treated with pathological hematoxylin and eosin and immunohistochemical staining to confirm imaging results. BTP did not feature obvious cytotoxicity for cells, and tumor growth in low-dose metronomic cisplatin treated mice was significantly inhibited by chemotherapy. Hypoxic levels significantly increased due to cisplatin, as proven by the expression level of related proteins. Phosphorescence intensity in the tumors of mice in the cisplatin group was stronger and showed higher contrast than that in tumors of saline treated mice. Conclusions We develop a useful phosphorescence method to evaluate the chemotherapeutic effects of cisplatin. The proposed method shows potential as a phosphorescence imaging approach for evaluating chemotherapeutic effects in vivo, especially anti-angiogenesis.PLoS ONE 01/2015; 10(3):e0121293. DOI:10.1371/journal.pone.0121293 · 3.53 Impact Factor