Sith Phongkitkarun

Effect of transcatheter hepatic arterial embolization on angiogenesis in an animal model

Objectives:Transcatheter arterial embolization (TAE) is used for the treatment of patients with malignant liver tumors. However, the proangiogenesis effect of TAE-associated hypoxia has not been adequately studied. The goal of this study was to determine angiogenic activity in tumors subjected to TAE by evaluating the tumor microvessel density (MVD). Materials and Methods:Mammary cancer 13762 NF tumor cells were inoculated into the livers of male Sprague-Dawley rats. TAE was performed 12–14 days after tumor inoculation. Rats were divided into 4 groups on the basis of treatment type. Control group animals (n = 16) were subjected to sham TAE without polyvinyl alcohol (PVA) particles. Animals in the other 3 groups were subjected to TAE with 1 (n = 11), 2 (n = 8), or 3 (n = 10) mg of PVA particles. Rats were killed 3–6 hours or 2 or 3 days after embolization, and the liver tumor tissues were dissected and frozen in liquid nitrogen. Tumor tissue slides were prepared, stained with CD-31, and evaluated for MVD. Blood samples collected just before sacrificing the animals were used to measure serum vascular endothelial growth factor (VEGF) levels. Results:Tumors treated with TAE showed varying degrees of central necrosis with residual viable tumor cells in the periphery. Tumor MVD in animals treated with TAE was significantly higher than that in the control group (23.6 versus 17.5; P = 0.001). Although the MVD in animals treated with TAE using 1 mg of PVA was higher than that in the control group, this difference was not statistically significant. TAE using 2 mg of PVA resulted in a significant increase in tumor MVD (25.9 versus 17.5; P = 0.007). Use of 3 mg of PVA did not result in any further increase in MVD. There was a significant increase in tumor MVD in the animals killed 2 or 3 days after TAE compared with the control group (24.5 versus 17.5; P = 0.002). The animals treated with TAE showed a statistically significant increase in VEGF levels compared with the control group. Conclusions:TAE of hepatic tumors results in the stimulation of angiogenesis in the residual viable tumor, which could have an adverse effect on the therapeutic efficacy of TAE.

Quantification of angiogenesis by functional computed tomography in a matrigel model in rats1

RATIONALE AND OBJECTIVES The aim was to evaluate functional computed tomography (fCT) in the quantification of angiogenesis by comparing the tissue perfusion parameters measured by CT perfusion (CTP) software with histologic vascular parameters in a Matrigel model in rats. It was hypothesized that tissue perfusion parameters and histologic vascular parameters are related. MATERIALS AND METHODS In vivo angiogenesis assays were performed using Matrigel supplemented with escalating doses (0 ng [control group], 250 ng, and 1,000 ng) of recombinant rat vascular endothelial growth factor (VEGF164) subcutaneously injected into the backs of Sprague Dawley rats. On day 7, rats with Matrigel plug underwent fCT following a bolus injection of iodinated contrast medium. Using CTP software, fCT parameters were generated (blood flow [BF], blood volume [BV], mean transit time, and permeability-surface area product) and functional maps on the basis of a distributed parameter tracer kinetic model, the adiabatic approximation to the tissue homogeneity model. The animals were then sacrificed. Matrigel plug was sectioned into slices corresponding to the CT scan plane and stained with CD31 immunohistochemical stain. Histologic vascular parameters, including microvascular density (MVD), vessel number (VN), vascular area, and vascular perimeter, were measured. CTP and histologic parameters were correlated. RESULTS The Matrigel plugs with the 1,000-ng VEGF group exhibited a higher MVD than the 250-ng VEGF and control groups (P < .05). VN differed significantly between the control versus the 250-ng VEGF groups and 250-ng versus 1,000-ng VEGF groups (P < .05), with the highest VN in the 250-ng VEGF group. BF, mean transit time, and permeability-surface area product each differed significantly to VEGF levels. Changes in BF and BV did not correspond with increases in MVD or VN; however, in the 250-ng VEGF group, there was a strong positive correlation (r = 0.9) between BV and VN, vascular area, and vascular perimeter, which was not seen in the control or 1,000-ng VEGF group. All fCT parameters significantly correlated with each other (P < .05), with strong correlations between BF and mean transit time (r = -0.7) and between BF and permeability-surface area product (r = 0.7) and a weak correlation between BF and BV (r = 0.3). CONCLUSION These results validate the VEGF-induced endothelial cell in a rat Matrigel model. In addition, histologic vascular parameter MVD does not correlate with fCT parameters measured by CTP software.

CT quantification of effects of thalidomide in patients with metastatic renal cell carcinoma

OBJECTIVE Our objective was to use functional CT to evaluate the effects of thalidomide in patients with metastatic renal cell carcinoma. SUBJECTS AND METHODS Patients with proven metastatic renal cell carcinoma were examined prospectively with functional CT. Functional CT studies (cine mode, 4 x 5 mm) were performed through the tumor after i.v. administration of a bolus of contrast material before and every 12 weeks after treatment with thalidomide. Quantitative values for blood flow, blood volume, mean transit time, and permeability-surface area product were calculated with commercial software. The average difference in percentage change in functional CT parameters from pretreatment to 12 and 24 weeks after treatment and the median difference in percentage change in functional CT parameters between response groups were assessed. We also tested whether percentage changes in functional CT parameters 12 weeks after treatment correlated with time to progression of disease and size of the perfused lesion. RESULTS Sixteen patients with a total of 23 tumors underwent at least one follow-up functional CT examination. Blood flow, blood volume, and permeability-surface area product decreased significantly 12 weeks (-18%, p = 0.0039; -15%, p = 0.0350; -24%, p = 0.0010) and 24 weeks (-28%, p = 0.017; -19%, p = 0.0300; -25%, p = 0.0031) after treatment with thalidomide. Time to progression correlated significantly with percentage change in blood flow (r = -0.34; p = 0.040) and permeability-surface area product (r = -0.36, p = 0.023) at 12 weeks. Responders had a significantly larger decrease in blood flow 12 weeks after treatment than did nonresponders (-29% vs -6%; p = 0.032). We also found a significant correlation between decrease in size of the perfused lesion and percentage decrease in blood flow 12 weeks after treatment (r = 0.50; p = 0.019). CONCLUSION Changes in functional CT parameters 12 weeks after treatment may be useful for monitoring the effects of thalidomide and predicting treatment outcome among patients with metastatic renal cell carcinoma. Further study with a larger clinical trial is needed.

Nephrogenic Systemic Fibrosis Risk After Liver Magnetic Resonance Imaging With Gadoxetate Disodium in Patients With Moderate to Severe Renal Impairment: Results of a Prospective, Open-Label, Multicenter Study

Objective The objective of this study was to assess the risk of gadoxetate disodium in liver imaging for the development of nephrogenic systemic fibrosis (NSF) in patients with moderate to severe renal impairment. Materials and Methods We performed a prospective, multicenter, nonrandomized, open-label phase 4 study in 35 centers from May 2009 to July 2013. The study population consisted of patients with moderate to severe renal impairment scheduled for liver imaging with gadoxetate disodium. All patients received a single intravenous bolus injection of 0.025-mmol/kg body weight of liver-specific gadoxetate disodium. The primary target variable was the number of patients who develop NSF within a 2-year follow-up period. Results A total of 357 patients were included, with 85 patients with severe and 193 patients with moderate renal impairment, which were the clinically most relevant groups. The mean time period from diagnosis of renal disease to liver magnetic resonance imaging (MRI) was 1.53 and 5.46 years in the moderate and severe renal impairment cohort, respectively. Overall, 101 patients (28%) underwent additional contrast-enhanced MRI with other gadolinium-based MRI contrast agents within 12 months before the start of the study or in the follow-up. No patient developed symptoms conclusive of NSF within the 2-year follow-up. Conclusions Gadoxetate disodium in patients with moderate to severe renal impairment did not raise any clinically significant safety concern. No NSF cases were observed.

Added value of hepatobiliary phase gadoxetic acid-enhanced MRI for diagnosing hepatocellular carcinoma in high-risk patients

AIM To determine the added value of hepatobiliary phase (HBP) gadoxetic acid-enhanced magnetic resonance imaging (MRI) in evaluating hepatic nodules in high-risk patients. METHODS The institutional review board approved this retrospective study and waived the requirement for informed consent. This study included 100 patients at high risk for hepatocellular carcinoma (HCC) and 105 hepatic nodules that were larger than 1 cm. A blind review of two MR image sets was performed in a random order: set 1, unenhanced (T1- and T2-weighted) and dynamic images; and set 2, unenhanced, dynamic 20-min and HBP images. The diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were compared for the two image sets. Univariate and multivariate analyses were performed on the MR characteristics utilized to diagnose HCC. RESULTS A total of 105 hepatic nodules were identified in 100 patients. Fifty-nine nodules were confirmed to be HCC. The diameter of the 59 HCCs ranged from 1 to 12 cm (mean: 1.9 cm). The remaining 46 nodules were benign (28 were of hepatocyte origin, nine were hepatic cysts, seven were hemangiomas, one was chronic inflammation, and one was focal fat infiltration). The diagnostic accuracy significantly increased with the addition of HBP images, from 88.7% in set 1 to 95.5% in set 2 (P = 0.002). In set 1 vs set 2, the sensitivity and NPV increased from 79.7% to 93.2% and from 78.9% to 91.8%, respectively, whereas the specificity and PPV were not significantly different. The hypointensity on the HBP images was the most sensitive (93.2%), and typical arterial enhancement followed by washout was the most specific (97.8%). The multivariate analysis revealed that typical arterial enhancement followed by washout, hyperintensity on T2-weighted images, and hypointensity on HBP images were statistically significant MRI findings that could diagnose HCC (P < 0.05). CONCLUSION The addition of HBP gadoxetic acid-enhanced MRI statistically improved the diagnostic accuracy in HCCs larger than 1 cm. Typical arterial enhancement followed by washout and hypointensity on HBP images are useful for diagnosing HCC.