Errol Stewart

Hepatic perfusion in a tumor model using DCE-CT: an accuracy and precision study

In the current study we investigate the accuracy and precision of hepatic perfusion measurements based on the Johnson and Wilson model with the adiabatic approximation. VX2 carcinoma cells were implanted into the livers of New Zealand white rabbits. Simultaneous dynamic contrast-enhanced computed tomography (DCE-CT) and radiolabeled microsphere studies were performed under steady-state normo-, hyper- and hypo-capnia. The hepatic arterial blood flows (H(A)BF) obtained using both techniques were compared with ANOVA. The precision was assessed by the coefficient of variation (CV). Under normo-capnia the microsphere H(A)BF were 51.9 +/- 4.2, 40.7 +/- 4.9 and 99.7 +/- 6.0 ml min(-1) (100 g)(-1) while DCE-CT H(A)BF were 50.0 +/- 5.7, 37.1 +/- 4.5 and 99.8 +/- 6.8 ml min(-1) (100 g)(-1) in normal tissue, tumor core and rim, respectively. There were no significant differences between H(A)BF measurements obtained with both techniques (P > 0.05). Furthermore, a strong correlation was observed between H(A)BF values from both techniques: slope of 0.92 +/- 0.05, intercept of 4.62 +/- 2.69 ml min(-1) (100 g)(-1) and R(2) = 0.81 +/- 0.05 (P < 0.05). The Bland-Altman plot comparing DCE-CT and microsphere H(A)BF measurements gives a mean difference of -0.13 ml min(-1) (100 g)(-1), which is not significantly different from zero. DCE-CT H(A)BF is precise, with CV of 5.7, 24.9 and 1.4% in the normal tissue, tumor core and rim, respectively. Non-invasive measurement of H(A)BF with DCE-CT is accurate and precise. DCE-CT can be an important extension of CT to assess hepatic function besides morphology in liver diseases.

Effect of an Angiogenesis Inhibitor on Hepatic Tumor Perfusion and the Implications for Adjuvant Cytotoxic Therapy

PURPOSE To determine whether dynamic contrast material-enhanced (DCE) computed tomography (CT) can help identify hepatic tumor perfusion response to vascular remodeling induced by antiangiogenesis treatment in a rabbit model. MATERIALS AND METHODS The study was approved by the Animal Use Subcommittee of the University Council on Animal Care. DCE CT hepatic perfusion measurements were performed in the livers of 20 rabbits implanted with VX2 carcinoma. Vascular remodeling was induced with thalidomide dissolved in dimethyl sulfoxide and sterile water, starting at a tumor diameter of 0.7 cm±0.1 and continuing until metastatic lung nodules were observed. The control group (n=8) was given an equivalent volume of the vehicle. The therapy group was subdivided into animals that survived for more than 24 days without lung metastasis (responder group, n=5) or those that survived for less than 24 days (nonresponder group, n=7). Data were analyzed with the Kruskal-Wallis or Friedman rank test and reported as medians and interquartile ranges. RESULTS DCE CT depicted differential perfusion change within the therapy group after treatment. By day 4, hepatic blood volume (HBV) in the responder group decreased by 29.2% (-32.5% to -11.8%) relative to that before treatment and was significantly different from that in the nonresponder (P=.048) and control (P=.011) groups, where HBV remained stable. By day 8, hepatic artery blood flow decreased by 50.0% (-59.08% to -21.05%) relative to that before treatment in the responder group and was significantly different from that in the nonresponder and control groups (P=.030 for both), which remained stable at -3.5% (-8.5% to 28.7%, P=.50) and -10.0% (-33.8% to 10.4%, P=.48), respectively. CONCLUSION DCE CT can help differentiate responders from nonresponders by their early differential perfusion response to antiangiogenesis therapy.

Perfusion CT estimates photosensitizer uptake and biodistribution in a rabbit orthotopic pancreatic cancer model: a pilot study.

RATIONALE AND OBJECTIVES It was hypothesized that perfusion computed tomography (CT), blood flow (BF), blood volume (BV), and vascular permeability surface area (PS) product parameters would be predictive of therapeutic anticancer agent uptake in pancreatic cancer, facilitating image-guided interpretation of human treatments. The hypothesis was tested in an orthotopic rabbit model of pancreatic cancer, by establishing the model, imaging with endoscopic ultrasound (EUS) and contrast CT, and spatially comparing the perfusion maps to the ex vivo uptake values of the injected photosensitizer, verteporfin. MATERIALS AND METHODS Nine New Zealand white rabbits underwent direct pancreas implantation of VX2 tumors, and CT perfusion or EUS was performed 10 days postimplantation. Verteporfin was injected during CT imaging, and the tissue was removed 1 hour postinjection for frozen tissue fluorescence scanning. Region-of-interest comparisons of CT data with ex vivo fluorescence and histopathologic staining were performed. RESULTS Dynamic contrast-enhanced CT showed enhanced BF, BV, and PS in the tumor rim and decreased BF, BV, and PS in the tumor core. Significant correlations were found between ex vivo verteporfin concentration and each of BF, BV, and PS. CONCLUSIONS The efficacy of verteporfin delivery in tumors is estimated by perfusion CT, providing a noninvasive method of mapping photosensitizer dose.

Pancreas tumor model in rabbit imaged by perfusion CT scans

The goal of this work was to develop and validate a pancreas tumor animal model to investigate the relationship between photodynamic therapy (PDT) effectiveness and photosensitizer drug delivery. More specifically, this work lays the foundation for investigating the utility of dynamic contrast enhanced blood perfusion imaging to be used to inform subsequent PDT. A VX2 carcinoma rabbit cell line was grown in the tail of the pancreas of three New Zealand White rabbits and approximately 3-4 weeks after implantation the rabbits were imaged on a CT scanner using a contrast enhanced perfusion protocol, providing parametric maps of blood flow, blood volume, mean transit time, and vascular permeability surface area product.

Assessment of intratumor hypoxia by integrated 18F-FDG PET / perfusion CT in a liver tumor model

Objectives Hypoxia in solid tumors occurs when metabolic demands in tumor cells surpass the delivery of oxygenated blood. We hypothesize that the 18F-fluorodeoxyglucose (18F-FDG) metabolism and tumor blood flow mismatch would correlate with tumor hypoxia. Methods Liver perfusion computed tomography (CT) and 18F-FDG positron emission tomography (PET) imaging were performed in twelve rabbit livers implanted with VX2 carcinoma. Under CT guidance, a fiber optic probe was inserted into the tumor to measure the partial pressure of oxygen (pO2). Tumor blood flow (BF) and standardized uptake value (SUV) were measured to calculate flow-metabolism ratio (FMR). Tumor hypoxia was further identified using pimonidazole immunohistochemical staining. Pearson correlation analysis was performed to determine the correlation between the imaging parameters and pO2 and pimonidazole staining. Results Weak correlations were found between blood volume (BV) and pO2 level (r = 0.425, P = 0.004), SUV and pO2 (r = -0.394, P = 0.007), FMR and pimonidazole staining score (r = -0.388, P = 0.031). However, there was stronger correlation between tumor FMR and pO2 level (r = 0.557, P < 0.001). Conclusions FMR correlated with tumor oxygenation and pimonidazole staining suggesting it may be a potential hypoxic imaging marker in liver tumor.

Monitoring the growth of tumors in the liver using dynamic CT

Conventional CT imaging methods lack the accuracy that is necessary for detailed assessment of liver metastasis. However, quantitative measurement of hepatic perfusion has the potential to provide important information necessary for both the evaluation and treatment of liver metastasis. VX2 carcinoma cells were injected into the liver of healthy male rabbits. A two-phase scan protocol was used to acquire CT images for the determination of liver perfusion prior to and post implantation. Contrast enhancement curves from the aorta, portal vein and liver parenchyma were obtained from the reconstructed images. The weighted summation of the aortic and portal venous curve were de-convolved against the liver parenchymal curve to derive functional parameters such as total hepatic blood flow (HBF) and hepatic arterial fraction (HAF). Results show that the HAF of the implanted tumor increased throughout the period of the study. Twelve days after tumors were implanted the HAF in the liver significantly increased (P < 0.05) from the normal tissue value of 35 ± 1 to 57 ± 9 %. Functional maps of the HAF have the potential to improve treatment outcome of patients owing to the earlier diagnosis of liver cancer. We are able to detect VX2 tumors in the liver as early as 8 days after they were implanted.