Dynamic Evolutionary Changes in Blood Flow Measured by MDCT in a Hepatic VX2 Tumor Implant over an Extended 28-day Growth Period: Time-Density Curve Analysis

Abstract

Rationale and Objectives The enhancement pattern of malignant tumors has been studied in short-term animal models (7–14 days), but the reported results have been variable and inconsistent. The purpose of this study was to investigate the changing blood flow characteristics of VX2 tumors implanted in rabbit livers with contrast-enhanced multidetector computed tomography (MDCT) to establish a predictable pattern of vascular evolution over an extended 28-day growth period. Materials and Methods VX2 carcinoma was implanted in livers of 10 male New Zealand White rabbits. Dynamic CT (2/seconds × 60 seconds) was conducted on days 7, 14, 21, and 28 after tumor implantation. Enhancement parameters of time-density curve (TDC), time to start (T0), time to peak (TP), maximum enhancement (ΔH), slope of enhancement (SLe), and washout (SLw) in tumor center, tumor rim, and normal liver were analyzed. Tumor samples corresponding to CT images of one tumor on days 14 and 21 and seven tumors on day 28 were stained with hematoxylin and eosin and anti-CD31 monoclonal antibody. The relationship between enhancement parameters and histology parameters (thickness of tumor border, extent of blood stasis, and luminar vessel density) was analyzed. Results Consistent growth, appearance, and vascular changes occurred in 7 of 10 animals over the 4-week observation period. Peripheral rim-like enhancement was noted in CT images. TDC analysis showed that tumor rim enhancement was pronounced and more rapid than normal liver initially but this difference diminished with tumor progression. The SLe, SLw, and ΔH decreased from 10.03 ± 3.25 Hu/second, 0.42 ± 0.25 Hu/sec, and 58.00 ± 25.27 Hu on day 7 to 5.86 ± 2.73 Hu/second, 0.10 ± 0.13 Hu/second, and 37.78 ± 8.89 Hu/second on day 28, respectively. TP increased from 12.71 ± 4.85 seconds on day 7 to 25.57 ± 7.75 seconds on day 28. No significant changes were noted on the TDC parameters in normal liver. The maximum density difference between tumor rim and normal liver (Drim-liver) appeared 10.5 ± 2.1 seconds after contrast injection. The maximum Drim-liver decreased from 54.33 ± 37.86 Hu on day 7 to 11.16 ± 13.03 Hu on day 28. On histological analysis, viable tumor cells were found in tumor rim with few luminar vessels. The tumor border showed desmoplastic reaction, vascular dilation and proliferation, inflammatory cell infiltration, and blood stasis. These findings were more obvious on day 28 than those on day 14. TP showed significant positive correlations with the extent of blood stasis in tumor border and adjacent liver and the maximum thickness of the tumor border (r = 0.945 and 0.893 respectively, P < .05). Conclusion The rabbit VX2 liver tumor is a hypovascular tumor with perilesional enhancement over its lifespan as imaged by MDCT. Consistent changes in the measured vascular parameters correlated with the size/age of the tumor implants. These findings suggest that the accuracy of CT enhancement imaging for VX2 liver tumor detection might be decreased with tumor development.

CT spectral imaging for monitoring the therapeutic efficacy of VEGF receptor kinase inhibitor AG-013736 in rabbit VX2 liver tumours

“…2 The tumour longest diameter showed as mean ± standard deviation at different time points, and five to six tumours were included per group. The tumours in the control and treated groups (three different doses of AG-013736: 1 mg/kg bid in group 2, 6 mg/kg bid in group 3, and 12 mg/kg bid in group 4) all grew gradually as a function of days following initiation of treatment, but grew more slowly in the treated group since D7(P < 0.05) which would have relatively high vascularity and not be too small for imaging [24].…”

Percutaneous Tumor Ablation

“…Contrast-enhanced CT scans on days 7 and 10 confirm the limited effectiveness of the injection alone with an integral peritumoral enhancing rim, known to be hypervascular. 17,42 This region exhibits viable cancer cells and cell clusters at microscopic examination. Conversely, a localized marginal kill (delayed coagulation necrosis) is observed at bottom of cryoablated and injected tumors, which matches with the contrast gap on serial E-CT appearing on day 3 and enlarging until day 10 ( Table 1).…”

“…49 The VX2 tumor model has been extensively used for CA and chemical ablation as well. It is a fast-growing, highly aggressive tumor, 17 with no capsule that could have somehow retained the injected mixture. The intraoperative demonstration of the ice margin localization and tumor margin persistence of the injectate for a few hours (IO) and days (MB) raises much hope, with the potential use of our combinatorial cryo-assisted drug deposition therapy for ill-delineated lesions or metastases that usually lack any peripheral capsular barrier.…”

“…At 3 weeks, E-CT revealed the tumor as a regular round or ovoid-shaped mass, with volume ranging from 3.6 to 4.5 cm 3 (mean 4 + 0.5 cm 3 ), marginal ring enhancement (tumor-enhanced rim [Trm]), and clear boundary. 17 Metastatic-free animals that presented with a well-delineated tumor were entered into the protocol.…”

Evaluation of neovascularization with spectral computed tomography in a rabbit VX2 liver model: a comparison with real-time contrast-enhanced ultrasound and molecular biological findings

“…6,15 In this study, the contrast medium was injected through the auricular vein into the right atrium and then circulated to the abdominal aorta. Thus, in the early stage of circulation, a small amount of contrast media already existed in the vessels, even if portal venous return had reached its peak value.…”