Timeliness of splenic time-to-peak affects liver tumor CT perfusion measurements

Aim In liver CT perfusion, the dual-input maximum slope (DI-MS) method is commonly used to estimate perfusion to aid diagnosis of tumors. The DI-MS method relies on a model that assumes the splenic time-to-peak (TTP) separates arterial and portal venous perfusion, and occurs prior to venous perfusion. In this preclinical study, we examined how the timeliness of splenic TTP affects DI-MS perfusion calculations of liver tumors. Materials and Methods We analyzed imaging data obtained from 11 New Zealand White rabbits bearing a single implanted VX2 tumor in liver. A liver 320-slice CT perfusion protocol (5,400 images per study) was used to generate images. Times for arterial and portal slopes were recorded, and hepatic arterial perfusion (HAP), portal perfusion (HPP) and perfusion index (HPI) for liver and tumor were separately calculated using manual and automated methods. T-test comparisons and Bland-Altman plot analyses were performed. Results Mean tumor TTP occurred at 9.79 s (SD=3.41) and splenic TTP at 9.75 s (SD=4.47, p=0.98). In 3/11 (27.27%) cases, tumor SP occurred prior to spleen (mean difference=1.33 s, SD=1.15 s). In these cases, mean automated HPP values were 43.8% (SD=52.48) higher compared to manually computed ones. There were statistically significant differences between automated and manual methods for normal liver and tumor HPI and HPP (p<0.01 and p<0.0001, respectively), but not HAP values (p=0.125 and p=0.78, respectively). There was also a statistically significant variation between methods for tumor HPP and HPI (p=0.001, respectively). Conclusion In 320-slice CT perfusion of liver in this preclinical model, we observed that tumor TTP occurred prior to splenic TTP in 27.27% of tumors in liver. This temporal relationship affects tumor perfusion calculations and should be identified to address potential deviations of model assumptions.

Treatment Effect of a Vascular-Disrupting Agent Dynamically Monitored by DWI: An Animal Experimental Study

Objective. To investigate the treatment effect of a vascular-disrupting agent, M410, using diffusion-weighted imaging in a rabbit model of hepatic VX2 tumor. Methods. 28 New Zealand white rabbit models with VX2 liver tumors were established and were randomly divided into M410 (intravenous injection of M410 at a dose of 25 mg/kg every three days) and control (intravenous injection of saline every three days) groups. Conventional and diffusion-weighted imaging (DWI) were acquired on a 3.0 T MR unit at baseline, 4 h, d 1, d 4, d 7, and d 14 posttreatment. B-value with 700 (s/mm2) was chosen during DWI examinations. Tumor volume and apparent diffusion coefficient (ADC) values of the entire tumor and solid component of the tumor at every time point were measured. Two randomly chosen rabbits from each group were sacrificed for H&E staining and CD34 immunohistochemical assessments at each time point. An independent sample t-test was used to assess differences in tumor sizes and ADC values of the entire tumor and solid component of tumors between two groups, with P < 0.05 considered statistically significant. Result. There was no significant difference in tumor volume between the two groups at baseline, 4 h, and d 1. With time, the tumors in the control group grew significantly faster than those in the M410 group, and the average ADC values of the M410 group were lower than those of the control group at d 1 and higher than those of the control group at d 4; as such, there were statistical differences between the two groups at these two time points but not at the other four time points. The following pathological results reflected the underlying morphological changes and vascular alterations. Conclusions. M410 performed well in inhibiting the growth of the hepatic VX2 tumor which could be noninvasively monitored by DWI metrics.

Image-Guided Radiofrequency Hyperthermia (RFH)-Enhanced Direct Chemotherapy of Hepatic Tumors: The Underlying Biomolecular Mechanisms

PurposeTo evaluate the treatment effect of radiofrequency-induced hyperthermia (RFH) combined with intra-tumoral chemotherapy for rabbit VX2 liver tumors and explore the underlying mechanism that drives local hyperthermia-enhanced chemotherapy.Materials and MethodsVX2 cell lines and rabbits with liver VX2 tumors were randomly allocated to four treatment groups including: (1) combination therapy of Doxorubicin (DOX) plus hyperthermia/RFH (n=6); (2) DOX only; (3) hyperthermia/RFH only (n=6); and (4) phosphate-buffered saline-treated control (n=6). Cell viability and doxorubicin uptake by VX2 tumor cells were assayed using flow cytometry and fluorescence microscopy 24 h after treatments. Western blot was used to evaluate the expression level of heat shock protein 70 (HSP70) in tumor cells and tissues. For the harvested VX2 tumors, fluorescence microscopy was used to evaluate the distribution and penetration of doxorubicin in tumor tissues and HSP70 expression was analyzed by Western blot and immunohistochemistry.ResultsRFH enhanced the chemotherapeutic effect of doxorubicin in VX2 cells and rabbit liver VX2 tumors resulting in higher apoptosis and lower cell viability. Flowcytometry of VX2 cells showed more apoptotic cells in combination therapy of hyperthermia and DOX, compared with other three groups in-vitro experiments (45.80 ± 1.27% vs 20.66 ± 0.71%, vs 15.16 ± 0.81% and 0.62 ± 0.06%, respectively, p&lt;0.01). The quantitative analysis by Western blot and immunohistochemistry showed increased expression of HSP70 in both VX2 tumor cells (1.28 ± 0.13 vs 0.64 ± 0.13 vs 0.83 ± 0.10 vs 0.15 ± 0.03, respectively, p&lt;0.05) and tumors (1.47 ± 0.13 vs 0.51 ± 0.13 vs 0.74 ± 0.11 vs 0.16 ± 0.04, respectively, p &lt;0.01). Fluorescence microscopy showed increased uptake of DOX in tumor cells in the combination therapy group.ConclusionsRFH/hyperthermia enhanced the chemotherapeutic effect of DOX in VX2 tumors by promoting the uptake of DOX and the expression HSP70 in tumors.

A Preliminary Study on the Diagnostic Efficacy of Proton Magnetic Resonance Spectroscopy at 3.0T in Rabbit With VX2 Liver Tumor

Background: To investigate the diagnostic efficacy of choline (Cho) value of magnetic resonance spectroscopy (MRS) in rabbit with VX2 liver tumor via comparative and quantitative analysis with the choline compounds concentration measured by enzyme linked immunosorbent assay (ELISA). Methods: MRS was performed on normal liver and VX2 tumor. The Cho value of VX2 tumor was compared with that of normal liver. Tissues were harvested for ELISA to detect the concentrations of acetylcholine (ACh), glycophorophosphygholine (GPC) and phosphochorine (PC). The diagnostic performance of Cho value and concentrations of choline compounds were assessed by receiver operating characteristic (ROC) curve and area under ROC curve (AUC). The specificity and sensitivity were discussed by the maximum Youden’s index. Results: The concentration of ACh was obviously higher than that of GPC and PC both in VX2 tumor and normal liver ( P < 0.01). Furthermore, the concentration differences among ACh, GPC and PG were the third power of 10. Both the ACh concentration and Cho value of MRS in VX2 tumor were significantly higher than those in normal liver ( P < 0.01). The AUC of ACh in VX2 tumor was 0.883, when the cutoff value was 7259000, the sensitivity and specificity of the diagnosis of liver cancer were 94.4% and 77.8%, respectively. The AUC of Cho in VX2 tumor was 0.807, when the cutoff value was 28.35, the sensitivity and specificity of the diagnosis of liver cancer were 83.3% and 77.8%, respectively. Conclusion: The change of Cho value in MRS between liver cancer and normal liver was consistent with the changes of concentrations of choline compounds measured by ELISA, especially the change of ACh concentration. The diagnostic efficiency of Cho value and that of choline compounds concentration in liver cancer were extremely similar, with the AUC more than 0.8. We conclude that MRS may be applied as an important, non-invasive biomarker for the diagnosis of liver cancer.

NIR absorbing Prussian Blue Nanoparticles for transarterial infusion photothermal therapy of VX2 tumor implanted in rabbit

Nanomaterials-related photothermal therapy has been intensively investigated in treatment for hepatocellular carcinoma (HCC). However, owing to the low specificity to tumor and easy excretion from the systemic circulation, the low...