Combined treatment of sorafenib and doxorubicin-loaded microbubble-albumin nanoparticle complex for hepatocellular carcinoma: A feasibility study.

PURPOSE: To assess the feasibility of the combined sorafenib (SOR) and doxorubicin-loaded microbubble-albumin nanoparticle complex (DOX-MAC) treatment effect in an orthotopic rat model of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Sixty-two rats with N1-S1 hepatoma were divided into four groups according to the treatment methods, i.e. G1 (SOR and DOX-MAC; n = 12), G2 (SOR; n = 15), G3 (DOX-MAC; n = 12), G4 (DOX; n = 11), and G5 (normal saline; n = 12). We performed the theragnostic, contrast-enhanced ultrasound examination and treatment at the baseline, one-week, and two-weeks. Tumor volume and perfusion parameters were compared at each time point and the differences between all of the groups over time were analyzed using repeated measures ANOVA. We also analyzed the apoptotic index and microvessel density (MVD) per each tumor specimen in all of the groups. RESULTS: The tumors increased from the beginning in all of the groups to the final follow-up, whereas the tumor growth in the G1 group and the G2 group was inhibited during the treatment period compared to the baseline tumor volume (P = 0.016 and P = 0.031). The G1 group resulted in tumor growth inhibition compared to the control group (P = 0.008). The G1 group showed that the peak enhancement and wash-in area under the curve were lower than that of the G4 group (P = 0.010 and 0.022). However, there was no difference in perfusion parameters in the other treated group compared to control group. The MVD of the G1 group tumor was lower than that of the G4 group (P = .016). CONCLUSION: Our results suggest that the combination therapy of SOR and DOX-MAC can cause inhibition of tumor growth after treatment and that this therapy can be adequately monitored using the theragnostic DOX-MAC agent.

Therapeutic response monitoring after targeted therapy in an orthotopic rat model of hepatocellular carcinoma using contrast-enhanced ultrasound: Focusing on inter-scanner, and inter-operator reproducibility.

PURPOSE: To assess therapeutic response monitoring after targeted therapy in an orthotopic rat model of hepatocellular carcinoma (HCC) using CEUS with focusing on inter-scanner and inter-operator reproducibility. MATERIALS AND METHODS: For reproducibility, CEUS was performed using two different US scanners by two operators in sixteen rat models of HCC. Using perfusion analysis software (VueBox ®), eleven parameters were collected, and intra-class correlation coefficient (ICC) was used to analyze reproducibility. Then seventeen rat models of HCC were divided into treatment group (n = 8, 30 mg/kg/day sorafenib for five days) and control group (n = 9). CEUS was performed at baseline and 14 days after first treatment, and changes of perfusion parameters were analyzed. RESULTS: In treatment group, CEUS perfusion parameters showed a significant change. The peak enhancement (PE, 2.50 x103±1.68 x103 vs 5.55x102±4.65x102, p = 0.010) and wash-in and wash out AUC (WiWoAUC, 1.07x105±6.48 x104 vs 2.65x104±2.25x104, p = 0.009) had significantly decreased two weeks after treatment. On the contrary, control group did not show a significant change, including PE (1.15 x103±7.53x102 vs 9.43x102± 7.81 x102, p = 0.632) and WiWoAUC (5.09 x104±3.25x104 vs 5.92 x104±3.20x104, p = 0.646). For reproducibility, the various degrees of inter-scanner reproducibility were from poor to good (ICC: <0.01-0.63). However, inter-operator reproducibility of important perfusion parameters, including WiAUC, WoAUC, and WiWoAUC, ranged from fair to excellent (ICC: 0.59-0.93) in a different scanner. CONCLUSION: Our results suggest that CEUS is useful for assessment of the treatment response after targeted therapy and with fair to excellent inter-operator reproducibility.

Non-invasive monitoring of the therapeutic response in sorafenib-treated hepatocellular carcinoma based on photoacoustic imaging.

PURPOSE: We investigated the changes of tissue oxygen saturation (sO2) in sorafenib-treated HCC (hepatocelluar carcinoma) mouse models using photoacoustic imaging (PI). MATERIALS AND METHODS: Nude mice, implanted with human HCC (HepG2-RFP) cells in the liver, were randomised to the sorafenib-treated group (n = 21) or the control group (n = 20). Tumour volume and sO2 were measured by PI at baseline and then one week later, and radiant efficiency (RE) and therapeutic response were analysed by fluorescence imaging and histologic analysis. RESULTS: Sorafenib was effective in treating HCC by evaluating necrotic fraction, apoptosis index, and microvessel density (MVD). One week after treatment, the sO2 of HCC and residual healthy liver tissue decreased, and the hypoxia inducible factor-1α (HIF-1α) protein expression of HCC increased, correlating with the apoptosis index. The ΔsO2 in HCC showed a significantly positive correlation with the necrotic fraction and the apoptosis index of tumour and a negative correlation with the MVD of tumour. CONCLUSION: Sorafenib treatment results in changes of sO2 in HCC and liver parenchyma and induces the accumulation of HIF-1α by hypoxic environment. sO2 as measured by PI, can be a useful marker for non-invasive monitoring of the therapeutic response in orthotopic HCC mouse models. KEY POINTS: • Hypoxia is a characteristic feature of the tumour microenvironment • It is important to monitor sO 2 in HCC during sorafenib treatment • PI is useful for non-invasive monitoring of sO 2 in HCC. • ΔsO 2 in HCC showed a significantly correlation with tumour response.

Evaluation of Hepatic Steatosis by Using Acoustic Structure Quantification US in a Rat Model: Comparison with Pathologic Examination and MR Spectroscopy.

Purpose To determine factors that significantly affect the focal disturbance (FD) ratio calculated with an acoustic structure quantification (ASQ) technique in a dietary-induced fatty liver disease rat model and to assess the diagnostic performance of the FD ratio in the assessment of hepatic steatosis by using histopathologic examination as a standard of reference. Materials and Methods Twenty-eight male F344 rats were fed a methionine-choline-deficient diet with a variable duration (3.5 days [half week] or 1, 2, 3, 4, 5, or 6 weeks; four rats in each group). A control group of four rats was maintained on a standard diet. At the end of each diet period, ASQ ultrasonography (US) and magnetic resonance (MR) spectroscopy were performed. Then, the rat was sacrificed and histopathologic examination of the liver was performed. Receiver operating characteristic curve analysis was performed to assess the diagnostic performance of the FD ratio in the evaluation of the degree of hepatic steatosis. The Spearman correlation coefficient was calculated to assess the correlation between the ordinal values, and multivariate linear regression analysis was used to identify significant determinant factors for the FD ratio. Results The diagnostic performance of the FD ratio in the assessment of the degree of hepatic steatosis (area under the receiver operating characteristic curve: 1.000 for 5%-33% steatosis, 0.981 for >33% to 66% steatosis, and 0.965 for >66% steatosis) was excellent and was comparable to that of MR spectroscopy. There was a strong negative linear correlation between the FD ratio and the estimated fat fraction at MR spectroscopy (Spearman ρ, -0.903; P < .001). Multivariate linear regression analysis showed that the degree of hepatic steatosis (P < .001) and fibrosis stage (P = .022) were significant factors affecting the FD ratio. Conclusion The FD ratio may potentially provide good diagnostic performance in the assessment of the degree of hepatic steatosis, with a strong negative linear correlation with the estimated fat fraction at MR spectroscopy. The degree of steatosis and stage of fibrosis at histopathologic examination were significant factors that affected the FD ratio. © RSNA, 2017 Online supplemental material is available for this article.

Feasibility of Using Volumetric Contrast-Enhanced Ultrasound with a 3-D Transducer to Evaluate Therapeutic Response after Targeted Therapy in Rabbit Hepatic VX2 Carcinoma.

The aim of this study was to assess the feasibility of using dynamic contrast-enhanced ultrasound (DCE-US) with a 3-D transducer to evaluate therapeutic responses to targeted therapy. Rabbits with hepatic VX2 carcinomas, divided into a treatment group (n = 22, 30 mg/kg/d sorafenib) and a control group (n = 13), were evaluated with DCE-US using 2-D and 3-D transducers and computed tomography (CT) perfusion imaging at baseline and 1 d after the first treatment. Perfusion parameters were collected, and correlations between parameters were analyzed. In the treatment group, both volumetric and 2-D DCE-US perfusion parameters, including peak intensity (33.2 ± 19.9 vs. 16.6 ± 10.7, 63.7 ± 20.0 vs. 30.1 ± 19.8), slope (15.3 ± 12.4 vs. 5.7 ± 4.5, 37.3 ± 20.4 vs. 15.7 ± 13.0) and area under the curve (AUC; 1004.1 ± 560.3 vs. 611.4 ± 421.1, 1332.2 ± 708.3 vs. 670.4 ± 388.3), had significantly decreased 1 d after the first treatment (p = 0.00). In the control group, 2-D DCE-US revealed that peak intensity, time to peak and slope had significantly changed (p < 0.05); however, volumetric DCE-US revealed that peak intensity, time-intensity AUC, AUC during wash-in and AUC during wash-out had significantly changed (p = 0.00). CT perfusion imaging parameters, including blood flow, blood volume and permeability of the capillary vessel surface, had significantly decreased in the treatment group (p = 0.00); however, in the control group, peak intensity and blood volume had significantly increased (p = 0.00). It is feasible to use DCE-US with a 3-D transducer to predict early therapeutic response after targeted therapy because perfusion parameters, including peak intensity, slope and AUC, significantly decreased, which is similar to the trend observed for 2-D DCE-US and CT perfusion imaging parameters.

Accuracy of MRI for predicting the circumferential resection margin, mesorectal fascia invasion, and tumor response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer.

PURPOSE: To evaluate the diagnostic accuracy of MRI for predicting the circumferential resection margin (CRM), mesorectal fascia (MRF) invasion, and the tumor response to neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer. MATERIALS AND METHODS: Sixty-five consecutive patients with locally advanced rectal cancer (> or =T3 or lymph node-positive) who underwent neoadjuvant CRT and subsequent surgery were enrolled in this retrospective study. Two blinded radiologists independently reviewed both the pre- and post-CRT rectal MR images and measured the post-CRT CRM; they recorded their confidence level with respect to the MRF invasion and tumor response using a 5-point scale. The diagnostic accuracy of each reviewer was calculated using receiver operating characteristic curve (ROC) analysis. RESULTS: The measured CRM was not significantly different from the reference standard (mean difference, -1.4 mm; 95% limits of agreement, -8.3-5.4 mm; interclass correlation coefficient, 0.82). The diagnostic accuracy (A(z)) for determining MRF invasion was 0.890 for reviewer 1 (95% confidence interval [CI], 0.788-0.954) and 0.829 for reviewer 2 (95% CI, 0.715-0.911). The A(z) for predicting complete or near-complete regression was 0.791 for reviewer 1 (95% CI, 0.672-0.882) and 0.735 for reviewer 2 (95% CI, 0.611-0.837). CONCLUSION: MRI provides accurate information regarding the CRM of locally advanced rectal cancer after neoadjuvant CRT; it also shows relatively high accuracy for predicting MRF invasion and moderate accuracy for assessing tumor response.

Intraarterial gene delivery in rabbit hepatic tumors: transfection with nonviral vector by using iodized oil emulsion.

PURPOSE: To evaluate the feasibility of an iodized oil emulsion that is used for the chemoembolization of hepatocellular carcinoma as a modifier of a nonviral gene transfer system for intraarterial gene delivery in experimentally induced hepatic tumors. MATERIALS AND METHODS: Experiments were performed in accordance with National Institutes of Health guidelines for the care and use of laboratory animals and were approved by the animal research committee at Seoul National University Hospital. VX2 carcinoma was implanted into the liver of 26 rabbits. Four nonviral gene transfer systems were prepared by using pCMV-luc+ as a reporter gene. The first system consisted of a DNA and polyethylenimine (PEI) complex (n = 7); the second, of a DNA and PEI complex mixed with iopamidol and iodized oil (n = 7); the third, of a DNA and PEI complex mixed with iopamidol (n = 7); and the fourth, of a DNA and PEI complex mixed with iodized oil (n = 5). For the DNA and PEI complex that was mixed with iopamidol and iodized oil, iopamidol was used to stabilize the emulsion. Twenty days after tumor implantation, intraarterial gene delivery was performed by selective catheterization of the hepatic artery. Rabbits were euthanized 24 hours after gene delivery. Luciferase activity was assayed in the tumor, left hepatic lobe, right hepatic lobe, and other organs and was statistically analyzed for comparison between complexes by using the Kruskal-Wallis test. RESULTS: Luciferase activity in the tumor was significantly higher for the group that received DNA, PEI, iopamidol, and iodized oil than for any other group (Kruskal-Wallis test, P < .05). Luciferase activity in the left hepatic lobe, right hepatic lobe, and other organs was not significantly different between complexes. Selective gene expression in tumor cells was confirmed by means of immunohistochemical analysis for luciferase. CONCLUSION: It is feasible to use an iodized oil emulsion system for the intratumoral transfection of nonviral vectors in experimentally induced hypervascular hepatic tumors.

Postbiopsy splenic bleeding in a dog model: comparison of cauterization, embolization, and plugging of the needle tract.

OBJECTIVE: The purpose of our study was to compare radiofrequency cauterization, embolization using an absorbable gelatin sponge, and a Histoacryl-Lipiodol mixture plugging as postbiopsy bleeding reduction methods after splenic core needle biopsy in a dog model. MATERIALS AND METHODS: Eleven mongrel dogs were randomly separated into nonheparinized (n = 5) and heparinized (n = 6) groups. Eight splenic biopsies per animal were performed using an 18-gauge automated core biopsy needle: two as controls, two ablated by radiofrequency, two embolized using an absorbable gelatin sponge, and two plugged using a Histoacryl-Lipiodol mixture. Procedure times and postbiopsy bleeding amounts were assessed. Statistically significant differences were determined by repeated measures analysis of variance; the Tukey-Kramer test for multiple comparisons was used for post hoc comparisons. Three-day follow-up CT scans were obtained to check for procedure-related complications or delayed bleeding. RESULTS: The postbiopsy bleeding reduction groups showed significantly less blood loss than the control group for both the nonheparinized (p < 0.0001) and heparinized groups (p < 0.0001). In the heparinized group, both radiofrequency cauterization (p < 0.01) and gelatin sponge embolization (p < 0.05) significantly reduced bleeding compared with Histoacryl-Lipiodol mixture plugging. Gelatin sponge embolization was the longest procedure (p < 0.001). On follow-up CT, no delayed bleeding was observed. However, multiple Histoacryl-Lipiodol emboli were observed in the splenic and portal veins in all the dogs we treated. CONCLUSION: Radiofrequency cauterization was found to be the most useful postbiopsy bleeding reduction method in terms of the amount of bleeding and the procedure time.

In vitro CT evaluation of intrahepatic stones: correlation with chemical composition.

OBJECTIVE: To describe in vitro CT features of intrahepatic stones and to correlate CT attenuation with chemical composition. MATERIALS AND METHODS: Of the patients who underwent choledochoscopic intrahepatic stone removal between 1998 and 2001, 54 patients with stones larger than 3 mm were enrolled in this study. In each case, a chemical compositional analysis was performed to determine calcium, cholesterol, total bilirubin, and inorganic phosphorus compositions. The three largest stones obtained from each patient were imaged by CT. CT attenuation numbers were measured in the center images of each stone by drawing free-hand region of interest (ROI). The measured CT attenuation numbers were correlated with their chemical composition. Also, CT attenuation numbers of stones were compared with that of the liver on non-contrast CT (50-70 HU). RESULTS: Stone size ranged from 3.1 to 10.5 mm (mean +/- S.D.: 6.0 +/- 1.4). The CT attenuation numbers (HU) of stones ranged from 36.4 to 410.19 (mean +/- S.D.: 94.6 +/- 49.9). CT numbers of stones were below 70 HU in 11 patients (20.4%), and below 90 HU in 33 patients (59.3%). The chemical analysis data of the stones were as follows: calcium (0.5-6.5 wt.%; mean +/- S.D., 2.6 +/- 1.4), total bilirubin (0.45-24.4 wt.%; 13.1 +/- 6.2), cholesterol (5.4-73.9 wt.%; 29.3 +/- 17.4), phosphorus (0.1-1.2 wt.%; 0.6 +/- 0.3), and non-soluble residue (17.6-85.4 wt.%; 57.0 +/- 22.6). There was a weak but significant correlation between calcium composition and CT attenuation (r = 0.38, P < 0.01) and no significant correlation between other chemical compositions and the CT attenuation (cholesterol, r = 0.01, P > 0.01; total bilirubin, r = 0.05, P > 0.01; phosphorus, r = 0.01, P > 0.01). CONCLUSION: On non-contrast CT, intrahepatic stones would not be hyperattenuating with respect to liver parenchyma in about one fifth of patients. The CT attenuation of stones correlates with calcium and does not correlate with any other chemical composition.

Computed tomography gastrography with volume-rendering technique: correlation with double-contrast barium study and conventional gastroscopy.

The volume-rendering technique uses computed tomography data to produce simulated images of conventional barium and endoscopic studies of the stomach. Various gastric lesions are detected on volume-rendered images, and submucosal tumors are easily differentiated from mucosal lesions by means of the overlying bridging fold. Lesions that are only manifested by a change of mucosal color (early gastric cancer type 2b) or a loss of mucosal detail (gastritis) are difficult to detect from volume-rendered images, however. In cases of gastric neoplasm and varix, both the extraluminal pathologies of the lesion and the relation between the intraluminal and extraluminal components can be evaluated simultaneously.

Primary colorectal lymphoma: spectrum of imaging findings with pathologic correlation.

Primary colorectal lymphoma is a very uncommon disease; therefore, it has received little attention in the radiology literature. Moreover, imaging features of newly described pathologic subtypes have not been reported such as low-grade B-cell lymphoma arising from mucosa-associated lymphoid tissue and peripheral T-cell lymphoma that involves colorectal area. We retrospectively reviewed double-contrast barium enema and CT scans in the patients with primary colorectal lymphoma. In this article the radiologic appearances of primary colorectal lymphoma are categorized into focal lesion and diffuse lesion. Focal lesion includes polypoid mass, circumferential infiltration with smooth mucosal surface, circumferential infiltration with extensive ulceration, cavitary mass, mucosal nodularity, and mucosal fold thickening. Diffuse lesion includes diffuse ulcerative lesion and diffuse nodular lesion. Peripheral T-cell lymphomas that involve the colon manifested as either a diffuse or focal segmental lesion and showed extensive mucosal ulceration. These findings are similar to those of Crohn's disease or tuberculous colitis and are different from those of previously reported colorectal lymphoma. Low-grade B-cell lymphoma arising from mucosa-associated lymphoid tissue manifest as multiple mucosal nodularity. The imaging features of primary colorectal lymphoma are quite variable and overlap with other colonic pathology; however, it is important for radiologists to know the imaging features of primary colorectal lymphoma with their pathologic correlation.