Hypervascular Hepatocellular Carcinoma Research Articles

Multiregional whole-genome sequencing of hepatocellular carcinoma with nodule-in-nodule appearance reveals stepwise cancer evolution.

Recent genetic analyses revealed genetic heterogeneity in hepatocellular carcinoma (HCC), although it remains unclear how genetic alterations contribute to the multistage progression of HCC, especially the early step from hypovascular liver nodules to hypervascular HCC. We conducted multiregional whole-genome sequencing on HCCs with a nodule-in-nodule appearance, consisting of inner hypervascular HCC surrounded by hypovascular HCC arising from a common origin, and identified point mutations, structural variations, and copy-number variations in each specimen. According to the genetic landscape of the inner and outer regions, together with the pathological and radiological findings, we examined the stepwise evolution of cancer cells from slow-growing HCC to rapid-growing HCC. We first demonstrated that most tumor cells consisting of hypovascular well-differentiated HCCs already harbored thousands of point mutations and even several structural variations, including chromosomal translocations and chromothripsis, as the trunk events. Telomerase reverse transcriptase (TERT)-associated aberrations, including promoter mutations, chromosomal translocation, and hepatitis B virus DNA integration, as well as abnormal methylation status, were commonly detected as the trunk aberrations, while various liver cancer-related genes, which differed in each case, had additionally accumulated in the inner dedifferentiated nodules. Further, differences in the trunk and branch mutational signatures suggested a multistep contribution to the mutagenesis in each case. In conclusion, genomic alterations associated with the TERT gene could be the key driver events to form the hypovascular HCC, and additional case-specific driver mutations accumulate during the progression phase, forming intra- and inter-tumoral heterogeneity, confirming the importance of genetic testing before targeting therapy. These data shed light on the process of multistep hepatocarcinogenesis and will be helpful toward investigating new therapeutic strategies for HCC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Gd-EOB-DTPA-enhanced MRI in Hepatocellular Carcinoma : Molecular and Genetic Background

Hepatobiliary specific contrast medium Gd-EOB-DTPA-enhanced MRI (EOB-MRI) is excellent for the detection and characterization of nodular lesions and plays an important role in the diagnosis of hepatocellular carcinoma (HCC). Gd-EOB-DTPA is received by normal hepatocytes, and then, excreted into bile ducts, under mediation by hepatocyte membrane transporters. The expression of uptake transporter organic anion transporting polypeptide 1B3 (OATP1B3) correlates with the enhancement ratio in the hepatobiliary phase of HCC. Consequently, OATP1B3 is the main uptake transporter of Gd-EOB-DTPA in HCC. The hepatobiliary phase of EOB-MRI can sensitively detect pathologically early HCC as a hypointense nodule, because the OATP1B3 expression decreases at an early stage of multistep hepatocarcinogenesis. Hypervascular HCC commonly presents hypointensity in the hepatobiliary phase with the decrease in the OATP1B3 expression ; however, approximately 10% of HCC atypically demonstrates hyperintensity, owing to OATP1B3 overexpression. HCC presenting hyperintensity in the hepatobiliary phase is a unique genetic subtype of HCC with a biologically less aggressive nature and mature hepatocyte-like molecular/genetic features. The interaction between β-catenin signaling and hepatocyte nuclear factor (HNF) 4α may plays an important role in the OATP1B3 expression and less aggressive biological nature of the hyperintense HCC in the hepatobiliary phase. Thus, EOB-MRI is crucial for the detection and characterization of HCC as well as for personalized medicine, such as an imaging biomarker.

Validation study of perfusion parameter in hypervascular hepatocellular carcinoma and focal nodular hyperplasia using dynamic susceptibility magnetic resonance imaging with super-paramagnetic iron oxide: comparison with single level dynamic CT arteriography.

Dynamic susceptibility contrast MR imaging (DSC-MRI) offers direct evaluation of neo-vascularity. Ferucarbotran does not accumulate in the interstitial space, instead remaining in the intravascular space during early phase imaging. We investigate tracer kinetic analysis with DSC-MRI with ferucarbotran and single level CT during hepatic arteriography (SL-CTHA) in assessment of hypervascular hepatocellular lesions and evaluate the usefulness of DSC-MRI with ferucarbotran. Six patients having hypervascular hepatocellular carcinoma (HCC) and 3 patients having focal nodular hyperplasia (FNH) were included in the study. SL-CTHA was performed with the infusion of 3 mL of contrast media at a rate of 1 mL/s and scanned at a rate of 0.8 second per rotation. DSC-MRI was acquired with the echo-planar method at 1.5T system. A total dose of 1.4 mL (0.5 mol Fe/L) of ferucarbotran was used. Ferucarbotran was injected at a rate of 2 mL/s with 40 mL of physiological saline. Imaging was obtained at a temporal resolution of 1.2 or 0.46 seconds in 5 and 4 patients, respectively. For both CT and MRI modalities, a model-free analysis method was used to derive region of interest-based perfusion parameters. Plasma flow, distribution volume (DV) of contrast agent and estimated mean transit time (EMTT) were estimated. A strong correlation was obtained with plasma flow (r=0.8231, P=0.0064) between DSC-MRI and SL-CTHA. No significant correlation was obtained for DV and EMTT between DSC-MRI and SL-CTHA. All perfusion parameters showed no significant difference between SL-CTHA and DSC-MRI in FNH. On the other hand, in HCC, DV and EMTT showed significant differences (P=0.046 and 0.046), and plasma flow showed no significant difference between DSC-MRI and SL-CTHA. This pilot study demonstrates the possibility of quantitative analysis of liver tumor using superparamagnetic iron oxide (SPIO)-based agent and highlights the potential for SPIO-based agent in more precisely assessing the perfusion characteristic of hypervascular liver tumors than by using extracellular contrast media.

Surgical Indications for Hepatocellular Carcinoma with Non-hypervascular Hypointense Nodules Detected by Gd-EOB-DTPA-Enhanced MRI.

The surgical indication for non-hypervascular hypointense nodules (NHVN) detected incidentally on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-MRI) for classical hepatocellular carcinoma (HCC) is unknown. Our aim is to clarify the long-term outcomes in patients with this finding. We reviewed the cases of 290 HCC patients, including 66 patients with NHVN, who underwent Gd-EOB-MRI prior to hepatectomy, between October 2008 and December 2017 at our center. We divided the patients into three groups: a no-NHVN group, a treated NHVN group, and an untreated NHVN group. There was no significant difference in (RFS) or overall survival (OS) between the no-NHVN and untreated NHVN groups (p = 0.103 and 0.103, respectively). There was no significant difference between these two groups after propensity score matching. Multivariate analyses showed that microscopic intrahepatic metastases and the size of the main classical HCC, the target tumor, were independent prognostic factors of overall survival, but the presence of non-hypervascular hypointense nodules was not. There was no significant difference in RFS or OS between the treated NHVN and untreated NHVN groups (p = 0.158 and 0.109, respectively). Non-hypervascular hypointense nodules detected incidentally on Gd-EOB-MRI associated with targeted hypervascular HCC did not reflect prognosis of HCC after hepatectomy. Surgical procedures for classical enhancing HCC may be performed even if non-hypervascular hypointense nodules adjacent to the targeted HCC cannot be removed completely.

Gadoxetic acid-enhanced MR imaging for hepatocellular carcinoma: molecular and genetic background.

Gadoxetic acid-enhanced magnetic resonance imaging (MRI) plays important roles in diagnosis of hepatic lesions because of its superiority in the detectability of small lesions, its differentiation ability, and its utility for the early diagnosis of hepatocellular carcinoma (HCC). In HCC, expression of organic anion transporting polypeptide (OATP) 1B3 correlates with the enhancement ratio in the hepatobiliary phase. Gadoxetic acid-enhanced MRI, an indirect molecular imaging method, reflects OATP1B3 expression in HCC. OATP1B3 expression gradually decreases from the dysplastic nodule stage to advanced HCC. Decreased expression is a sensitive marker of multistep hepatocarcinogenesis, especially in the early stages. Hypervascular HCCs commonly show hypointensity in the hepatobiliary phase corresponding to a decrease in OATP1B3; however, approximately 10% of HCCs show hyperintensity due to OATP1B3 overexpression. This hyperintense HCC shows less aggressive biological features and has a better prognosis than hypointense HCC. Hyperintense HCC can be classified into a genetic subtype of HCC with a mature hepatocyte-like molecular expression. OATP1B3 expression and the less aggressive nature of hyperintense HCC are regulated by the molecular interaction of β-catenin signaling and hepatocyte nuclear factor 4α, a tumor suppressor factor. Gadoxetic acid-enhanced MR imaging has the potential to be an imaging biomarker for HCC. KEY POINTS: • The hepatobiliary phase is a sensitive indirect indicator of organic anion transporting polypeptide1B3 (OATP1B3) expression in hepatocellular carcinoma (HCC). • The OATP1B3 expression, namely, enhancement in the hepatobiliary phase, decreases from the very early stage of hepatocarcinogenesis, contributing to early diagnosis of HCC. • HCC showing hyperintensity on the hepatobiliary phase is a peculiar genetic subtype of HCC with OATP1B3 overexpression, a less aggressive nature, and mature hepatocyte-like molecular/genetic features.

Risk analysis for hypervascular transformation of precancerous lesion of hepatocellular carcinoma

Objective: To investigate the risk factors for diagnosis of transformation of high-grade dysplastic nodules (HGDN) to hypervascular hepatocellular carcinoma (HCC) in patients with chronic liver disease with gadoxetate disodium-enhanced magnetic resonance imaging (MRI). Methods: 2 037 cases that underwent gadoxetate disodium-enhanced magnetic resonance imaging from January 2012 to December 2014 were retrospectively analyzed. 51 cases of HGDN with a background of chronic liver disease were screened and followed-up for at least 2 times with gadoxetate disodium-enhanced MRI scans and contrast enhanced CT scans was performed within 1 month before and after the first MRI. The endpoint of study was transformation of HGDN to hypervascular hepatocellular carcinoma, with a deadline of April 2019. Transformation was divided into transformed (group A) and untransformed (group B) group according to the presence or absence of hypervascularization. Linear regression was used to analyze the possible risk factors for hypervascular transformation. Results: There were 36 nodules in group A and 79 nodules in group B, and hypervascular transformation rate was 31.3% (36/115). On univariate analysis, the length and diameter of nodule was > 10.2 mm (P = 0.034), with annual growth rate > 2% (P < 0.001), and lipid content (P = 0.007) was related to the occurrence of hypervascularity. On multivariate analysis, the annual growth rate of nodules was an independent risk factor for the occurrence of hypervascularity (P < 0.000 1). Conclusion: The annual growth rate of HGDN in patients with chronic liver disease diagnosed with gadoxetate disodium-enhanced MRI imaging can be used as a potential predictor of hypervascularization.

Cone-Beam Computed Tomography-Hepatic Arteriography as a Diagnostic Tool for Small Hypervascular Hepatocellular Carcinomas: Method and Clinical Implications.

This study proposes a novel reference standard for hypervascular hepatocellular carcinomas (HCCs), established by cone-beam computed tomography-hepatic arteriography (CBCT-HA) and two-year imaging follow-up, and discusses its clinical implication on tumor staging and understanding the intrahepatic distant recurrence (IDR) in relation to dynamic computed tomography (CT). In this retrospective study, 99 patients were enrolled, who underwent CBCT-HA during initial chemoembolization for HCC suspected on CT. All patients underwent chemoembolization and regular clinical and imaging follow-up for two years. If IDR appeared on follow-up imaging, initial CBCT-HA images were reviewed to determine if a hypervascular focus pre-existed at the site of recurrence. Pre-existing hypervascular foci on CBCT-HA were regarded as HCCs in initial presentation. Initial HCCs were classified into three groups according to their mode of detection (Group I, detected on CT and CBCT-HA; Group II, additionally detected on CBCT-HA; Group III, confirmed by interval growth). We assessed the influence of CBCT-HA and two-year follow-up on initial tumor stage and calculated the proportion of IDR that pre-existed in initial CBCT-HA. A total of 405 nodules were confirmed as HCCs, and 297 nodules initially pre-existed. Of the initial 297 HCCs, 149 (50.2%) lesions were in Group I, 74 (24.9%) lesions were in Group II, and the remaining 74 (24.9%) lesions were in Group III. After applying CBCT-HA findings, 11 patients upstaged in T stage, and 4 patients had a change in Milan criteria. Our reference standard for HCC indicated that 120 of 148 (81.1%) one-year IDR and 148 of 256 (57.8%) two-year IDR existed on initial CBCT-HA. The proposed method enabled the confirmation of many sub-centimeter-sized, faintly vascularized HCC nodules that pre-existed initially but clinically manifested as IDR. Our reference standard for HCC helped in understanding the nature of IDR and the early development of HCC as well as the clinical impact of tumor staging and treatment decision.

Contrast-enhanced ultrasound-guided feeding artery ablation as add-on to percutaneous radiofrequency ablation for hypervascular hepatocellular carcinoma with a modified ablative technique and tumor perfusion evaluation

Objectives To establish a modified strategy of the feeding artery ablation (FAA) procedure as an add-on to percutaneous radiofrequency ablation (RFA) for patients with hypervascular hepatocellular carcinoma (HCC), and to evaluate the outcomes. Materials and methods For this prospective, single-arm study, from June 2014 to August 2016, twenty-five patients with hypervascular HCC, 2–5 cm in diameter were treated by contrast-enhanced ultrasound (CEUS)-guided FAA before conventional RFA. Technical success of FAA and subsequent perfusion change of the tumor were evaluated by CEUS. Technical efficacy and ablation sizes were evaluated by CT/MRI at 1 month. Therapeutic outcomes, including local tumor progression (LTP), overall survival (OS), and recurrence-free survival (RFS) were evaluated using the Kaplan–Meier method. Results One or two target feeding arteries were visible on CEUS for 52.6% (61/116) of the hypervascular HCCs 2–5 cm in diameter. The technical success rate of the FAA was 100%; 13/25 (52.0%) target tumors were evaluated as complete perfusion response, while 12/25 (48.0%) were evaluated as partial perfusion response. The ablation volume was 41.9 ± 17.5 cm3 (14.9–78.2 cm3) and the ablative safety margin was 8.2 ± 1.9 mm (4–12 mm) at the 1-month evaluation. These parameters did not differ significantly between the complete and partial subgroups. The cumulative rates of LTP at 1-, 2-, and 3-year follow-ups were 0.0%, 4.2% and 4.2%, respectively. The 3-year OS and RFS were 70.3% vs. 59.8%, respectively. There were no treatment-related deaths. Major complications occurred in one patient (4.0%). Conclusion As an add-on to conventional percutaneous RFA, tailored CEUS-guided FAA can reduce tumor perfusion and provide good local control of HCC.

Direct-Acting Antiviral Agents Reduce the Risk of Malignant Transformation of Hepatobiliary Phase-Hypointense Nodule without Arterial Phase Hyperenhancement to Hepatocellular Carcinoma on Gd-EOB-DPTA-Enhanced Imaging in the Hepatitis C Virus-Infected Liver

Background and Aims: Hepatobiliary phase-hypointense nodules without arterial phase hyperenhancement (HHNs without APHE) on gadolinium-ethoxybenzyl-diethylenetriamine-enhanced magnetic resonance imaging (Gd-EOB-DTPA-enhanced MRI) are considered to be dysplastic nodules or early hepatocellular carcinoma (HCC) and have high risk of undergoing malignant transformation and progression to hypervascular HCC. The aim of this study was to evaluate the clinical outcome of HHNs without APHE diagnosed by Gd-EOB-DTPA-enhanced MRI before the eradication of HCV by direct-acting antiviral agents (DAAs). Methods: We retrospectively investigated 221 consecutive patients with HCV infection who were treated with DAAs. Thirty patients with 65 HHNs without APHE were enrolled in a sustained virologic response (SVR) cohort and 22 with 43 HHNs without APHE who did not receive DAAs or had failed HCV eradication therapy were enrolled in a non-SVR cohort. Fifty-seven percent of patients in the SVR group and 64% of those in the non-SVR group had a history of HCC. The primary endpoint of this study was the development of hypervascular HCC from HHNs without APHE detected on imaging. The cumulative incidence and relative risk of progression to hypervascular HCC in relation to clinical characteristics were compared between the two cohorts. Results: The 2-year cumulative incidence of progression to hypervascular HCC was 8.5 and 21.9% in the SVR and non-SVR cohorts, respectively. There was a significant reduction in progression of HHNs without APHE to HCC after the eradication of HCV (p = 0.022, log-rank test). Multivariate Cox regression analysis identified hyperintensity on T2-weighted images (relative risk 14.699, p < 0.001) and achieving SVR (relative risk 0.290, p = 0.043) as independent factors associated with the risk of HCC. During follow-up, 6 (9.2%) of the HHNs without APHE in the SVR cohort became undetectable on hepatocyte-phase images. Conclusions: Eradication of HCV by DAAs could reduce the hypervascularization rate of HHNs without APHE, and some of these nodules disappeared.

Fusion imaging with contrast-enhanced ultrasonography for evaluating the early therapeutic efficacy of radiofrequency ablation for small hypervascular hepatocellular carcinomas with iso-echoic or unclear margins on conventional ultrasonography

Fusion imaging with contrast-enhanced ultrasonography for evaluating the early therapeutic efficacy of radiofrequency ablation for small hypervascular hepatocellular carcinomas with iso-echoic or unclear margins on conventional ultrasonography

The emergence of non-hypervascular hypointense nodules on Gd-EOB-DTPA-enhanced MRI in patients with chronic hepatitis C.

Intrahepatic non-hypervascular hypointense nodules (NHHNs) detected during the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) have the potential to transition into typical hypervascular hepatocellular carcinoma (HCC). However, the incidence and risk factors for the emergence of these nodules in patients with chronic hepatitis C virus (HCV) infection are unknown. To investigate the incidence and risk factors for NHHNs in patients with chronic HCV infection in a longitudinal follow-up study METHODS: EOB-MRI was performed in 608 patients with chronic HCV infection and no history of HCC. The characteristics of patients with and without NHHNs were compared. In patients without NHHNs at baseline, the incidence of NHHN emergence and associated risk factors were analysed. NHHNs were detected at baseline in 93 of 608 patients (15.3%). Among 515 patients without NHHNs at baseline, the 1-year, 3-year and 5-year incidence of NHHN emergence was 1.8%, 9.8% and 16.4%, respectively. Only FIB-4 index was independently associated with the emergence of NHHNs in multivariate analyses. Whereas NHHNs emerged in 24.1% of patients with FIB-4 index≥3.25 at 5years, none emerged in patients with FIB-4 index<1.45. In patients with chronic HCV infection, advanced liver fibrosis is an important risk factor for the presence or emergence of NHHNs.

Performance of gadoxetic acid MRI and diffusion-weighted imaging for the diagnosis of early recurrence of hepatocellular carcinoma.

To determine the diagnostic accuracy and predictive value of gadoxetic acid liver MRI (Gd-EOB-DTPA MRI) alone or in combination with diffusion-weighted imaging (DWI) as a second-line tool for detecting early hepatocellular carcinoma (HCC) recurrence in cirrhotic patients with previous HCC treated with resection or ablation. Between 2014 and 2017, we prospectively included 34 cirrhotic patients with complete response to resection and/or ablation of early HCC in whom a new focal lesion enhancing in the arterial phase without washout was detected during follow-up with EC-MRI. After signing the informed consent, all patients underwent DWI and Gd-EOB-DTPA MRI; two readers analyzed signal intensities on each phase of dynamic study and on DWI. The final diagnosis was established by histology or follow-up EC-MRI. We used cross-tabulation to calculate indices of diagnostic accuracy. We evaluated 34 patients (7 women; 73.5% with hepatitis C virus) with a total of 53 new arterial-phase-enhancing foci (median size, 10 [IQR 9-14] mm). The final diagnosis, reached by histopathology in 15 (35.7%) lesions and EC-MR follow-up in 27 (64.3%), was HCC in 42 (79.2%) and benign conditions in 11 (21.8%). Hepatobiliary-phase hypointensity on Gd-EOB-DTPA MRI plus hyperintensity on DWI yielded 54.8% sensitivity, 90.9% specificity, 95.8% positive predictive value, and 34.5% negative predictive value for diagnosing HCC recurrence. Among potential indices, combining hypointensity on hepatobiliary-phase Gd-EOB-DTPA MRI and hyperintensity on DWI has the highest specificity and positive predictive value to optimally detect HCC recurrence prior to confident diagnosis by conventional imaging criteria on EC-MRI in cirrhotic liver. • In patients at risk of HCC recurrence, the use of gadoxetic acid liver MRI and DWI may improve the differentiation of unspecific new arterial-enhancing foci from early hypervascular HCC recurrence in patients with non-conclusive findings on extracellular liver MRI. • Combined findings on hepatobiliary-phase gadoxetic acid-enhanced liver MRI and DWI had high specificity (90.9%) and positive predictive value (95.8%) for detecting early hypervascular HCC recurrence, but limited sensitivity. • Combining hepatobiliary-phase hypointensity on gadoxetic acid MRI and hyperintensity on diffusion-weighted imaging allows early diagnosis of hypervascular hepatocellular carcinoma and may help select patients for salvage therapy.

MRI-based risk factors of hepatocellular carcinoma in patients with chronic liver disease: A prospective observational study.

MR-based metrics, including hepatobiliary phase (HBP) hypointense nodules without arterial phase hyperenhancement (APHE), and liver stiffness as measured by MR elastography are useful markers to stratify the risk of hepatocellular carcinoma (HCC) development in chronic liver disease patients. However, prospective studies are needed to clarify their utility. To perform a risk analysis of HCC development in chronic liver disease patients, with a focus on MR-based biomarkers. Prospective. Consecutive 110 cirrhotic patients (61 males, 49 females) without a history of HCC who matched the inclusion criteria. 3T/3D gradient-echo T1 -weighted images and MR elastography. Patients underwent MRI for HCC screening and attended follow-up appointments every 3 months. The primary endpoint was the development of hypervascular HCC. Patients were classified according to the presence of an HBP hypointense nodule without APHE (if present in the liver, the patient was classified in nonclean liver group; if absent, clean liver group), and stiffness value on MR elastography (soft liver, <4.0 kPa; stiff liver, ≥4.0 kPa) at the initial examination. Risk factors were identified in univariate and multivariate Cox regression models. Incidence rates of HCC development were evaluated using the Kaplan-Meier method. Patients were classified into clean-liver (n = 76) and nonclean-liver groups (n = 34), and into soft-liver (n = 53) and stiff-liver groups (n = 45). During the follow-up period (median, 21.0 months), 16 patients developed hypervascular HCC. Patients in the nonclean-liver group showed a higher incidence of hypervascular HCC than those in the clean-liver group (3-year HCC incidence rates: 50.4% and 5.7%, respectively; P < 0.05). A nonclean liver was independently associated with hypervascular HCC development (hazard ratio, 18.75; 95% confidence interval, 4.83-128.63; P < 0.0001), but stiff liver was not (1.91; 0.66-6.23; P = 0.23). An HBP hypointense nodule without APHE observed on a gadoxetic acid-enhanced MR image is a strong indicator of subsequent development of hypervascular HCC in patients with chronic liver disease. 2 Technical Efficacy Stage: 5 J. Magn. Reson. Imaging 2020;51:389-396.

Value of gadoxetic acid-enhanced MRI and diffusion-weighted imaging in the differentiation of hypervascular hyperplastic nodule from small (

Hypervascular hyperplastic nodules (HHNs) occasionally develop in patients with alcoholic liver cirrhosis (ALC) and show arterial enhancement, thus mimicking hepatocellular carcinoma (HCC). Importantly, HHN as a benign lesion should be distinguished from HCC. To evaluate the value of gadoxetic acid-enhanced MRI (Gd-EOB-MRI) and diffusion-weighted imaging (DWI) in distinguishing HHN from small (<3 cm) hypervascular HCC (hHCC) in patients with ALC. Retrospective case-control study. 3.0T/in- and out-of-phase, T1 -weighted, T2 -weighted, diffusion-weighted, apparent diffusion coefficient, and dynamic gadoxetic acid-enhanced images. Among 560 patients with ALC who underwent Gd-EOB-MRI and DWI, 12 patients with 28 HHNs and 22 patients with 29 hHCCs smaller than 3 cm were included. The following MRI features were evaluated by three independent radiologists: signal intensity (SI) on T1 -weighted, T2 -weighted, diffusion-weighted, and hepatobiliary phase (HBP) images; shape, homogeneity, and margin on HBP; diffusion restriction; intralesional fat; necrosis; hemorrhage; washout on portal venous phase (PVP) and/or transitional phase (TP); and capsular enhancement. Quantitative analysis was also conducted. Univariate and multivariate analyses were performed to determine the significant MRI findings, and their diagnostic performance for the prediction of HHN was analyzed. Lesion size of ≤16 mm (odds ratio [OR], 24.41; P = 0.007), low-to-iso SI on DWI (OR, 26.92; P = 0.007), and absence of washout on PVP and/or TP (OR, 31.84; P = 0.009) were significant independent factors for predicting HHN. When all three criteria were satisfied, the specificity was 100%. Compared with hHCCs, HHNs showed significantly smaller size (mean, 13.8 mm vs. 19.9 mm; P < 0.001) and higher mean SI value (994.0 vs. 669.5) and lesion-to-liver SI ratio (1.045 vs. 0.806) on HBP (P < 0.001, respectively). Gd-EOB-MRI and DWI may be helpful in differentiating HHN from small hHCC in patients with ALC. 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:70-80.

Antitumor and Antiangiogenic Activities of Lenvatinib in Mouse Xenograft Models of Vascular Endothelial Growth Factor-Induced Hypervascular Human Hepatocellular Carcinoma

High expression of vascular endothelial growth factor (VEGF) in patients with hepatocellular carcinoma (HCC) is associated with poor prognosis. Here, we investigated the antitumor activity of lenvatinib, a multiple receptor tyrosine kinase inhibitor, in VEGF-overexpressing HCC models. In human umbilical vein endothelial cells, lenvatinib showed potent inhibitory activities against VEGF-induced proliferation and VEGF/basic fibroblast growth factor-induced tube formation. In VEGF-overexpressing HCC xenograft models, characterized by aggressive tumor growth and hypervascularity, lenvatinib had significant antitumor and antiangiogenic activities. These results suggest that potent activity of lenvatinib against VEGF signaling underlies its antitumor and antiangiogenic activities in the hypervascular HCC models.

Second shot arterial phase to overcome degraded hepatic arterial phase in liver MR imaging.

Second shot arterial phase (SSAP) imaging is an additional arterial phase image obtained by re-injecting a small amount of contrast medium after routine dynamic imaging in gadoxetic acid-enhanced liver MRI. We aimed to evaluate the feasibility and additional value of a SSAP image in gadoxetic acid-enhanced liver MRI. One hundred seventy-two patients who underwent SSAP imaging after re-injection of 4mL of contrast material after routine dynamic imaging (original) in gadoxetic acid-enhanced liver MRIs were included. Motion artifacts on arterial phase (AP) images were rated using a 5-point scale and were compared between the original AP images and SSAP images. We evaluated visual detection rates of arterial hypervascularity on the original AP and SSAP images and their subtraction images in patients with hypervascular hepatocellular carcinoma (HCC). The motion artifact of the SSAP images was significantly lower than that of the original AP images (mean score, 1.76 vs 2.06; p < 0.001). In particular, motion artifacts reduced significantly in the SSAP images of patients with substantial motion artifacts in their original AP images (2.28 vs 3.28; p < 0.001). Among the 30 HCC lesions showing hypervascularity on original AP images, only four (4/30, 13.3%) appeared hyperintense on SSAP images. However, subtraction images of SSAP clearly demonstrated arterial hypervascularity in all HCCs. SSAP images showed significantly fewer motion artifacts than the original AP images. Subtraction images of SSAP maintained the detectability of arterial hypervascularity, although SSAP images showed poor visual detection of arterial hypervascularity of HCC. • Arterial phase images obtained after a second injection of a small amount of contrast medium (second shot arterial phase [SSAP]) improved motion artifacts compared to the original AP images. • The motion artifacts improved significantly in the SSAP images of patients with substantial motion artifacts in their original AP images. • Subtraction images of SSAP demonstrated the arterial hypervascularity characteristic of HCC at a level comparable to that of the original AP image.

Modified Rat Hepatocellular Carcinoma Models Overexpressing Vascular Endothelial Growth Factor

PurposeTo compare tumor vascularity in 4 types of rat hepatocellular carcinoma (HCC) models: N1S1, vascular endothelial growth factor (VEGF)-transfected N1S1 (VEGF-N1S1), McA-RH7777, and VEGF-transfected McA-RH7777 (VEGF-McA-RH777) tumors. Materials and MethodsThe N1S1 and McA-RH7777 cell lines were transfected with expression vectors containing cDNA for rat VEGF. Eighty-eight male Sprague–Dawley rats (weight range, 400–450 g) were randomly divided into 4 groups (ie, 22 rats per model), and 4 types of tumor models were created by using the N1S1, VEGF-N1S1, McA-RH7777, and VEGF-McA-RH777 cell lines. Tumor vascularity was evaluated by perfusion computed tomography (CT), enzyme-linked immunosorbent assay of VEGF, CD34 staining, angiography, and Lipiodol transarterial embolization. Intergroup discrepancies were evaluated by Kruskal–Wallis test. ResultsArterial perfusion (P < .001), portal perfusion (P = .015), total perfusion (P < .001), tumor VEGF level (P = .002), and microvessel density (MVD; P = .007) were significantly different among groups. VEGF-McA-RH7777 tumors showed the greatest arterial perfusion (46.7 mL/min/100 mL ± 15.5), total perfusion (60.7 mL/min/100 mL ± 21.8), tumor VEGF level (3,376.7 pg/mL ± 145.8), and MVD (34.5‰ ± 7.5). Whereas most tumors in the N1S1, VEGF-N1S1, and McA-RH7777 groups showed hypovascular staining on angiography and minimal Lipiodol uptake after embolization, 5 of 6 VEGF-McA-RH7777 tumors (83.3%) presented hypervascular tumor staining and moderate to compact Lipiodol uptake. ConclusionsMcA-RH7777 tumors were more hypervascular than N1S1 tumors, and tumor vascularity was enhanced further by VEGF transfection. Therefore, the VEGF-McA-RH7777 tumor is recommended to mimic hypervascular human HCC in rats.

Diagnostic accuracy of contrast-enhanced dynamic CT for small hypervascular hepatocellular carcinoma and assessment of dynamic enhancement patterns: Results of two-year follow-up using cone-beam CT hepatic arteriography.

ObjectiveTo evaluate the accuracy of CT for small, hypervascular hepatocellular carcinomas (HCCs) and assess the enhancement patterns on CT.Materials and methodsNinety-nine patients who underwent cone-beam CT hepatic arteriography (CBCT-HA) during initial chemoembolization for HCC suspected on CT were enrolled in this study. A total of 297 hypervascular HCCs (142 ≥ 1 cm, 155 < 1 cm) were confirmed as HCCs based on two-year follow-up CT and CBCT-HA images. During the two-year follow-up, pre-existing hypervascular foci on CBCT-HA were regarded as HCCs at the initial presentation. Two radiologists categorized HCCs according to the following enhancement patterns on CT: type I, arterial enhancement and washout; type II, arterial enhancement without washout; and type III, no arterial enhancement. Two blinded reviewers rated the possibility of HCC.ResultsFor the 297 HCCs, the enhancement patterns according to size were as follows: type I ≥1 cm in 114 HCCs; type I <1 cm in 40 HCCs; type II ≥1 cm in 16 HCCs; type II <1 cm in 37 HCCs; type III ≥1 cm in 12 HCCs; and type III <1 cm in 10 HCCs. The remaining 68 HCCs (22.9%) were not detected on CT. The detection rates of HCCs ≥ 1 cm were 83.1%, 76.8%, and 83.1% in the formal report for reviewer 1 and reviewer 2. In comparison, the detection rates of HCCs < 1 cm were 20.6%, 17.4%, and 17.4% in the formal report for reviewer 1 and reviewer 2.ConclusionMany subcentimeter sized hypervascular HCCs were frequently missed or not evident on CT at the initial diagnostic workup. CT has limitations for diagnosing HCCs that are <1 cm in size or have atypical enhancement patterns.

Impact of previously cured hepatocellular carcinoma (HCC) on new development of HCC after eradication of hepatitis C infection with non-interferon-based treatments.

The incidence of hepatocellular carcinoma (HCC) in patients with a history of curatively-treated HCC is higher than in patients with no history of HCC even after sustained virologic response (SVR). To investigate differences in the patterns of HCC development after SVR in patients with a history of curatively-treated HCC and those with no history of HCC, based on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) findings. EOB-MRI was performed in 164 patients with HCV cirrhosis who achieved SVR by interferon-free direct-acting antiviral (DAA) therapy just before the start of therapy. Changes in EOB-MRI findings after SVR were compared prospectively between patients with (n = 62) and without (n = 102) a history of HCC. The incidence of HCC after SVR was higher in patients with a history of HCC (P < 0.0001). The prevalence of nonhypervascular hypointense nodules (NHHNs) by EOB-MRI was significantly higher in patients with a history of HCC at baseline (P = 0.05). Although there was no difference in the incidence of the hypervascularisation of baseline NHHNs to typical hypervascular HCC between patients with and without a history of HCC, the incidence of direct emergence of hypervascular HCC despite the absence of NHHNs at baseline was significantly higher in patients with a history of HCC (P < 0.0001). Direct emergence of hypervascular HCC and a higher prevalence of NHHNs before DD therapy contributed to the higher incidence of HCC after SVR. (UMIN000017020).

Percutaneous ablation of the tumor feeding artery for hypervascular hepatocellular carcinoma before tumor ablation

Objective: To evaluate the efficiency and safety of percutaneous ablation of the tumor feeding artery (PAA) before radiofrequency ablation (RFA) for hypervascular hepatocellular carcinoma (HCC) under ultrasound guidance.Patients and methods: In total, 94 patients with hypervascular HCC and tumor feeding artery visible by contrast-enhanced ultrasound were prospectively randomized to receive either PAA combined with RFA (RFA + PAA) or RFA alone. This study was registered at the clinical trials registry website (No. NCT03143140). The mean tumor size was 3.2 ± 0.9 cm (2.0–5.0 cm). The mean follow-up was 23.7 ± 9.7 months (4–44 months). The technical success, local tumor progression and intrahepatic distant recurrence rates were compared. Survival analysis was performed using the Kaplan–Meier method and compared with the log-rank test.Results: The local tumor progression rate was lower for the PAA + RFA group than for the RFA group (8.5% vs 21.3%, p = .082). No significant differences in the technical success and intrahepatic distant recurrence rates were observed between the two groups (97.9% vs 91.5%, p = .203 and 40.4% vs 42.6%, p = .834). The 1- and 3-year local tumor progression-free survival rates were 91.5% and 69.9% vs 68.1% and 52.1% for the PAA + RFA vs RFA groups, respectively (p = .052). The 1- and 3-year overall survival rates were 95.7% and 69.1% vs 89.4% and 66.6% in the PAA + RFA vs RFA groups, respectively (p = .744). The major complication rate was 4.3% in both groups.Conclusions: PAA appears to be an effective and safe technique for the treatment of hypervascular HCC, with a lower local tumor progression rate than that of conventional RFA.