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Background: The Hippo signaling pathway regulates organ size by regulating cell proliferation and apoptosis with terminal effectors including Yes-associated protein-1 (YAP-1). Dysregulation in Hippo pathway has been proposed as one of the therapeutic targets in hepatocarcinogenesis. The levels of reactive oxygen species (ROS) increase during the progression from early to advanced hepatocellular carcinoma (HCC)., Aim: To study the activation of YAP-1 by ROS-induced damage in HCC and the involved signaling pathway., Methods: The expression of YAP-1 in HCC cells (Huh-7, HepG2, and SNU-761) was quantified using real-time polymerase chain reaction and immunoblotting. Human HCC cells were treated with H 2 O 2 , which is a major component of ROS in living organisms, and with either YAP-1 small interfering RNA (siRNA) or control siRNA. To investigate the role of YAP-1 in HCC cells under oxidative stress, MTS assays were performed. Immunoblotting was performed to evaluate the signaling pathway responsible for the activation of YAP-1. Eighty-eight surgically resected frozen HCC tissue samples and 88 nontumor liver tissue samples were used for gene expression analyses., Results: H 2 O 2 treatment increased the mRNA and protein expression of YAP-1 in HCC cells (Huh-7, HepG2, and SNU-761). Suppression of YAP-1 using siRNA transfection resulted in a significant decrease in tumor proliferation during H 2 O 2 treatment both in vitro and in vivo (both P < 0.05). The oncogenic action of YAP-1 occurred via the activation of the c-Myc pathway, leading to the upregulation of components of the unfolded protein response (UPR), including 78-kDa glucose-regulated protein and activating transcription factor-6 (ATF-6). The YAP-1 mRNA levels in human HCC tissues were upregulated by 2.6-fold compared with those in nontumor tissues ( P < 0.05) and were positively correlated with the ATF-6 Levels (Pearson's coefficient = 0.299; P < 0.05)., Conclusion: This study shows a novel connection between YAP-1 and the UPR through the c-Myc pathway during oxidative stress in HCC. The ROS-induced activation of YAP-1 via the c-Myc pathway, which leads to the activation of the UPR pathway, might be a therapeutic target in HCC., Competing Interests: Conflict-of-interest statement: The authors declare that they do not have anything to disclose regarding any funding or conflict of interest with respect to this manuscript., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Crosstalk between tumors and their microenvironment plays a crucial role in the progression of hepatocellular carcinoma (HCC). However, there is little existing information about the key signaling molecule that modulates tumor-stroma crosstalk., Methods: Complementary DNA (cDNA) microarray analysis was performed to identify the key molecule in tumor-stroma crosstalk. Subcutaneous xenograft in vivo murine model, immunoblotting, immunofluorescence, and real-time polymerase chain reaction using HCC cells and tissues were performed., Results: The key molecule, regenerating gene protein-3A (REG3A), was most significantly enhanced when coculturing HCC cells and activated human hepatic stellate cells (HSCs) (+8.2 log) compared with monoculturing HCC cells using cDNA microarray analysis. Downregulation of REG3A using small interfering RNA significantly decreased the proliferation of HSC-cocultured HCC cells in vitro and in vivo, and enhanced deoxycholic acid-induced HCC cell apoptosis. Crosstalk-induced REG3A upregulation was modulated by platelet-derived growth factor ββ (PDGF-ββ) in p42/44-dependent manner. REG3A mRNA levels in human HCC tissues were upregulated 1.8-fold compared with non-tumor tissues and positively correlated with PDGF-ββ levels., Conclusions: REG3A/p42/44 pathway/PDGF-ββ signaling plays a significant role in hepatocarcinogenesis via tumor-stroma crosstalk. Targeting REG3A is a potential novel therapeutic target for the management of HCCs by inhibiting crosstalk between HCC cells and HSCs.

Background US has served as a standard surveillance tool for hepatocellular carcinoma (HCC); however, the detection rate and false referral rate with this modality are suboptimal. Purpose To evaluate the added value of perfluorobutane-enhanced US when combined with conventional B-mode US as an HCC surveillance tool in participants with liver cirrhosis. Materials and Methods This prospective multi-institution diagnostic trial ( https://ClinicalTrials.gov , NCT02188901) used an intraindividual comparison design in a single arm of study participants and was conducted at five referral hospitals. Eligible participants who had liver cirrhosis related to viral hepatitis and were undergoing US for HCC surveillance were enrolled from October 2014 to August 2016. Immediately after completion of B-mode US but before performance of perfluorobutane-enhanced US, operating radiologists entered the results of B-mode US. After completion of subsequent perfluorobutane-enhanced US (Kupffer phase with or without vascular-phase US), the radiologists recorded the results. The presence of HCC was confirmed either with pathologic analysis or radiologically by using dynamic contrast material-enhanced CT or gadoxetic acid-enhanced MRI. The primary end points were the detection rate of early-stage HCC (Barcelona Clinic Liver Cancer staging system stage 0 or A) and false referral rate. The primary end points were compared in a per-participant manner by using the McNemar test. Results A total of 524 participants (mean age, 54 years ± 9 [standard deviation]) were included. Of these, 493 (94.1%) had liver cirrhosis related to the hepatitis B virus. Ten HCCs were confirmed in eight participants. The detection rate of early-stage HCC was not significantly improved by adding perfluorobutane-enhanced US to conventional B-mode US (difference, 0.4% [95% confidence interval: -0.3%, 1.1%]; P = .16). The false referral rate was significantly reduced (difference, -3.2% [95% confidence interval: -5.0%, -1.4%]; P < .001). Conclusion The addition of perfluorobutane-enhanced US to conventional B-mode US reduced the false referral rate without a significant improvement in the detection rate of early-stage hepatocellular carcinoma for surveillance in a population in which the hepatitis B virus predominated. © RSNA, 2019 Online supplemental material is available for this article.

Protein induced by vitamin K absence (PIVKA) is measured using various assays and is used to help diagnose hepatocellular carcinoma. The present study evaluated the analytical and clinical performances of the recently released Abbott Architect PIVKA assay. Precision, linearity, and correlation tests were performed in accordance with the Clinical Laboratory Standardization Institute guidelines. Sample type suitability was assessed using serum and plasma samples from the same patients, and the reference interval was established using sera from 204 healthy individuals. The assay had coefficients of variation of 3.2-3.5% and intra-laboratory variation of 3.6-5.5%. Linearity was confirmed across the entire measurable range. The Architect PIVKA assay was comparable to the Lumipulse PIVKA assay, and the plasma and serum samples provided similar results. The lower reference limit was 13.0 mAU/mL and the upper reference limit was 37.4 mAU/mL. The ability of the Architect PIVKA assay to detect hepatocellular carcinoma was comparable to that of the alpha-fetoprotein test and the Lumipulse PIVKA assay. The Architect PIVKA assay provides excellent analytical and clinical performance, is simple for clinical laboratories to adopt, and has improved sample type suitability that could broaden the assay's utility., (© 2018 by the Association of Clinical Scientists, Inc.)

Background: Ultrasonography (US) is widely used as a standard surveillance tool for patients who are at a high risk of having hepatocellular carcinoma (HCC); however, conventional B-mode US appears to be insufficient in order to ensure the early detection of HCC. Perfluorobutane allows very stable Kupffer phase imaging for at least 60 min, which is tolerable for examinations of the entire liver. The purpose of our study is to evaluate the added value of contrast-enhanced US using perfluorobutane to that of conventional B-mode US as an HCC surveillance tool for patients with liver cirrhosis., Methods/design: SCAN (Sonazoid-US for surveillance of hepatoCellulArcarciNoma) is a prospective, multi-institutional, diagnostic trial using an intra-individual comparison design in a single arm of patients. This study was approved by our five institutional review board and informed consent was obtained from all participating. We obtained consent for publication of these data (contrast enhanced US images, CT or MRI images, laboratory findings, age, sex) from all participating patients. All patients will undergo conventional B-mode US immediately followed by contrast-enhanced US. The standardized case report forms will be completed by operating radiologists after B-mode US and contrast-enhanced US, respectively. If any lesion(s) is detected, the likelihood of HCC will be recorded. The primary endpoints are a detection rate of early-stage HCC and a false referral rate of HCC. Intra-individual comparison using Mcnemar's test will be performed between B-mode US and contrast-enhanced US. The study will include 523 patients under HCC surveillance in five medical institutions in Korea., Discussion: SCAN is the first study to investigate the efficacy of contrast-enhanced US in surveillance using two reciprocal endpoints specialized for the evaluation of a surveillance test. SCAN will provide evidence regarding whether patients can truly benefit from contrast-enhanced US in terms of the detection of early stage HCC while avoiding additional unnecessary examinations. In addition to the study protocol, we elaborate on potentially debatable components of SCAN, including the design of an intra-individual comparison study, study endpoints, composite reference standards, and indefinite imaging criteria regarding the likelihood of HCC., Trial Registration: The date of trial registration (ClincalTrials.gov: NCT02188901 ) in this study is July 3, 2014. The last patient enrolled in August 30, 2016 and follow up to see the primary end point is still ongoing. All authors have no other relationships/conditions/circumstances that present a potential conflict of interest of relationships. Our study protocol has undergone peer-review by the funding body (GE Healthcare). No other relationships/conditions/circumstances that present a potential conflict of interest. Also, we clearly stated in the 'competing interests' section of my manuscript.

Purpose: To compare the diagnostic performance of the noncontrast MRI including DWI to the standard MRI for detecting hepatic malignancies in patients with chronic liver disease., Materials and Methods: We included 135 patients with 136 histologically-confirmed hepatocellular carcinomas (HCCs), 12 cholangiocarcinomas, and 34 benign lesions (≤ 2.0 cm), and 22 patients with cirrhosis but no focal liver lesion who underwent 3.0 T liver MRI. Noncontrast MRI set (T1- and T2-weighted images and DWI) and standard MRI set (gadoxetic acid-enhanced and noncontrast MRI) were analyzed independently by three observers to detect liver malignancies using receiver operating characteristic analysis., Results: The Az value of the noncontrast MRI (mean, 0.906) was not inferior to that of the combined MRI (mean, 0.924) for detecting malignancies by all observers (P>0.05). For each observer, no significant difference was found in the sensitivity and specificity between the two MRI sets for detecting liver malignancies and distinguishing them from benign lesions (P>0.05), whereas negative predictive value was higher with the combined MRI than with the noncontrast MRI (P=0.0001). When using pooled data, the sensitivity of the combined MRI (mean 94.8%) was higher than that of the noncontrast MRI (mean, 91.7%) (P =0.001), whereas specificity was equivalent (78.6% vs 77.5%)., Conclusion: Noncontrast MRI including DWI showed reasonable performance compared to the combined gadoxetic acid-enhanced and noncontrast MRI set for detecting HCC and cholangiocarcinoma and differentiating them from benign lesions in patients with chronic liver disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: The purposes of this study were to assess the widths of the intercostal spaces of the right inferior human rib cage through which high-intensity focused ultrasound therapy would be applied for treating liver cancer and to elucidate the demographic factors associated with intercostal space width., Subjects and Methods: From March 2013 to June 2013, the widths of the intercostal spaces and the ribs at six areas of the right inferior rib cage (area 1, lowest intercostal space on anterior axillary line and the adjacent upper rib; area 2, second-lowest intercostal space on anterior axillary line and the adjacent upper rib; areas 3 and 4, lowest and second-lowest spaces on midaxillary line; areas 5 and 6, lowest and second-lowest spaces on posterior axillary line) were sonographically measured in 466 patients (214 men, 252 women; mean age, 53.0 years) after an abdominal sonographic examination. Demographic factors and the presence or absence of chronic liver disease were evaluated by multivariate analysis to investigate which factors influence intercostal width., Results: The width of the intercostal space was 19.7 ± 3.7 mm (range, 9-33 mm) at area 1, 18.3 ± 3.4 mm (range, 9-33 mm) at area 2, 17.4 ± 4.0 mm (range, 7-33 mm) at area 3, 15.4 ± 3.5 mm (range, 5-26 mm) at area 4, 17.2 ± 3.7 mm (range, 7-28 mm) at area 5, and 14.5 ± 3.6 mm (range, 4-26 mm) at area 6. The corresponding widths of the ribs were 15.2 ± 2.3 mm (range, 8-22 mm), 14.5 ± 2.3 mm (range, 9-22 mm), 13.2 ± 2.0 mm (range, 9-20), 14.3 ± 2.2 mm (range, 9-20 mm), 15.0 ± 2.2 mm (range, 10-22 mm), and 15.1 ± 2.3 mm (range, 8-21 mm). Only female sex was significantly associated with the narrower intercostal width at areas 1, 2, 3, and 5 (regression coefficient, 1.124-1.885; p = 0.01-0.04)., Conclusion: There was substantial variation in the widths of the intercostal spaces of the right inferior rib cage such that the anterior and inferior aspects of the intercostal space were relatively wider. Women had significantly narrower intercostal spaces than men.

Purpose: To determine imaging features of infiltrative hepatocellular carcinoma (HCC) on 3T magnetic resonance imaging (MRI) including gadoxetic acid-enhanced and diffusion-weighted imaging (DWI)., Materials and Methods: Eighteen patients with infiltrative HCC underwent liver MRI that consisted of T1- and T2-weighted image (T2WI), gadoxetic acid-enhanced arterial, portal, 3-min late and 20-min hepatobiliary phase (HBP), and DWI. Two reviewers evaluated in consensus tumor characteristics and lesion conspicuity using a 4-point scale. The tumor-to-liver contrast ratio was also measured., Results: Most of the tumors (n = 16, 88.9%) were seen as irregular permeative masses (4.0-23.0 cm, mean 10.5 cm in diameter) and the remaining two as poorly defined amorphous infiltration among thrombosed portal veins. Internal reticulation within the tumor was characteristic and was most frequently observed on 3-min late phase (n = 18), followed by HBP (n = 15). Tumor conspicuity and tumor-to-liver contrast ratio was highest with b-800 DWI, which was significantly higher than those of other images (P < 0.05)., Conclusion: DWI provides the highest conspicuity for infiltrative HCC compared to unenhanced T1- and T2WI and gadoxetic acid-enhanced MRI. The gadoxetic acid-enhanced 3-min late image is useful in characterizing infiltrative HCC, as it clearly depicts internal reticulation in all tumors., (Copyright © 2013 Wiley Periodicals, Inc.)

Background/aims: To assess the perfusion parameters and angiogenesis of HCC using dynamic contrast enhanced(DCE) MR and to correlate it with histopathologic findings in an experimental rat model., Methodology: Twenty rats were continuously infused with diethylnitrosamine (DEN) for tumor induction. After 32 to 36 weeks of DEN treatment, the rats underwent MRI of the liver with a 3-T MR imaging system. Perfusion parametric maps and perfusion parameters such as, time to peak (TTP) and peak enhancement (PE) were obtained by using a commercially available software package. The nodules were correlated precisely to DCE MR images., Results: A total of 13 nodules were found in 12 rats; 5 dysplastic nodule (DN)s were identified in 5 rats and 8 HCCs (3 Edmonson grade I, 2 Edmonson grade I-II, 3 Edmonson grade II) were found in 7 rats. There were significant differences in mean values of PE and HPH (histogram peak height) of PE between DN and HCC. Mean value and HPH of PE showed statistically significant correlation with tumor grade., Conclusions: There were significant differences in perfusion parameters between DN and HCC. DCE MR imaging can be used in the differential diagnosis and management of liver disease in hepatocarcinogenesis.

Purpose: To evaluate temporal changes in contrast enhancement patterns of non-tumorous hepatic parenchyma with a focus on arterial hypervascularity on multiphase computed tomography (CT) in patients with hepatocellular carcinoma (HCC) treated with stereotactic body radiotherapy (SBRT)., Methods: We retrospectively identified 61 patients who had undergone multiphase contrast-enhanced CT at one, three, and six months after SBRT. Irradiated versus non-irradiated liver parenchyma was delineated by cross-correlation with the dose-volume histogram of SBRT plan. Serial changes in the contrast enhancement patterns of the irradiated versus non-irradiated liver parenchyma were evaluated by two abdominal radiologists in consensus. We compared the frequency of the contrast enhancement patterns according to the follow-up period using the Fisher-Freeman-Halton exact test., Results: The irradiated non-tumorous hepatic parenchyma showed that the prevalence of arterial hypervascularity increased during the follow-up period (P<.01): 11.5% (7/61) in one, 45.9% (28/61) in three, and 54.1% (33/61) in six months. Contrast wash-out on the delayed phase was uncommon: 1.6% (1/61) in one, 3.3% (2/61) in three, and 0% in six months., Conclusion: The incidence of arterial hypervascularity of the irradiated hepatic parenchyma gradually increased until six months after SBRT, which could interfere with the accurate evaluation of treatment response. The lack of wash-out on the delayed phase in the hypervascular area would distinguish SBRT-related change from residual/recurred HCC.

Purpose: To determine whether the diagnostic performance of combined gadoxetic acid-enhanced dynamic phases and diffusion-weighted imaging (DWI) is comparable to the standard protocol with hepatobiliary phase (HBP) and DWI for detection and characterization of focal liver lesions in chronic liver disease., Materials and Methods: A total of 176 patients with 181 HCCs, 15 cholangiocarcinomas, and 32 benign lesions were included. Three combined gadoxetic acid-enhanced and DWI sets (dynamic phases [arterial, portal, and 3-min delay {3-min set} and dynamic phases with 10-min HBP [10-min set] or 20-min HBP [20-min set]) were analyzed by two observers to determine the diagnostic accuracy and sensitivity in detection of malignancy, and ability for lesion characterization., Results: There was a trend, although not statistically significant, toward highest diagnostic accuracy and sensitivity for detecting malignancies in the 20-min set (mean, 0.945, 96.2), followed by the 10-min set (0.937, 95.9), and the 3-min set (0.923, 94.1) (P > 0.05). For lesion characterization, three image sets were equivalent (P > 0.05)., Conclusion: For lesion detection and characterization in chronic liver diseases, 3-min set with DWI showed comparable efficacy to 10-min or 20-min set. However, the best diagnostic performance could be achieved by combination of all image sets., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Even with early stage hepatocellular carcinoma (HCC), patients are often ineligible for surgical resection, transplantation, or local ablation due to advanced cirrhosis, donor shortage, or difficult location. Stereotactic body radiation therapy (SBRT) has been established as a standard treatment option for patients with stage I lung cancer, who are not eligible for surgery, and may be a promising alternative treatment for patients with small HCC who are not eligible for curative treatment., Materials and Methods: A registry database of 93 patients who were treated with SBRT for HCC between 2007 and 2009 was analyzed. A dose of 10-20 Gy per fraction was given over 3-4 consecutive days, resulting in a total dose of 30-60 Gy. The tumor response was determined using dynamic computed tomography or magnetic resonance imaging, which was performed 3 months after completion of SBRT., Results: The median follow-up period was 25.6 months. Median size of tumors was 2 cm (range: 1-6 cm). Overall patients' survival rates at 1 and 3 years were 86.0% and 53.8%, respectively. Complete and partial tumor response were achieved in 15.5% and 45.7% of patients, respectively. Local recurrence-free survival rate was 92.1% at 3 years. Most local failures were found in patients with HCCs > 3 cm, and local control rate at 3 years was 76.3% in patients with HCC > 3 cm, 93.3% in patients with tumors between 2.1-3 cm, and 100% in patients with tumors ≤ 2 cm, respectively. Out-of-field intrahepatic recurrence-free survival rates at 1 and 3 years were 51.9% and 32.4%, respectively. Grade ≥ 3 hepatic toxicity was observed in 6 (6.5%)., Conclusions: SBRT was effective in local control of small HCC. SBRT may be a promising alternative treatment for patients with small HCC which is unsuitable for other curative therapy.

Objective: The objective of this study was to determine the features of scirrhous hepatocellular carcinoma (sHCC) on gadoxetic acid-enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) with an emphasis on the differentiation from intrahepatic cholangiocarcinoma (ICC)., Materials and Methods: A total of 41 patients with sHCCs and 41 patients with ICCs underwent gadoxetic acid-enhanced MRI and DWI. Images were analyzed for shape of lesions, surface retraction, enhancement pattern, proportion of arterial hyperenhancement, target appearance on the hepatobiliary phase and DWI, and presence of necrosis., Results: Lobulating shape, rim enhancement, and target appearance on the hepatobiliary phase and DWI were the main features in both tumors. The proportion of arterial hyperenhancement of 20% of tumor diameter or more was the only significant MRI feature for differentiating sHCC from ICC (P ≤ 0.006 in the multivariate analysis)., Conclusions: Although the features of sHCC on gadoxetic acid-enhanced MRI and DWI are similar to those of ICC, the proportion of hyperenhancement of 20% or more on the arterial phase is a helpful feature in distinguishing sHCC from ICC.

Objective: The objective of this study was to determine whether unenhanced magnetic resonance (MR) angiography using repetitive arterial or vein labeling (RAVEL) is feasible to visualize effectively the intrahepatic portal vein (PV) at 3.0 T., Methods: Forty patients underwent liver MR imaging (MRI) with unenhanced MR portography using RAVEL. Two radiologists performed a consensus review of unenhanced MR portography and portal-phase MRI with regard to anatomic type of PV, vessel conspicuity, and image quality., Results: For determination of the anatomic type of PV, the 2 techniques were equivalent. There were tendencies toward increased conspicuity for right segmental PV and its branches with unenhanced MR portography and for left PV with conventional MRI, although significant differences were not found between MRIs (P > 0.05). Image quality for unenhanced MR portography was poor in 1, moderate in 8, and good in 31 patients., Conclusions: Unenhanced MR portography using RAVEL at 3.0 T is feasible and provides effective visualization of intrahepatic PV.

Purpose: To compare the image quality between T1 high-resolution isotropic volume examination using the multi-echo Dixon technique (mDixon-eTHRIVE) and that using spectrally adiabatic inversion recovery (SPAIR-eTHRIVE) in gadoxetic acid-enhanced liver MRI, and to evaluate the detectability of hepatocellular carcinoma (HCC) on mDixon-eTHRIVE., Materials and Methods: Seventy patients with 117 HCCs underwent gadoxetic acid-enhanced liver MRI using mDixon-eTHRIVE. All patients also underwent gadoxetic acid-enhanced MRI using SPAIR-eTHRIVE (mean interval of 96 days). Two radiologists performed a consensus review of MRIs for image quality, homogeneity of fat suppression, artifact, and anatomic sharpness using a four-point scale. The detectability for HCC with mDixon-eTHRIVE was assessed using alternative-free response receiver operating characteristic., Results: All mDixon-eTHRIVE images received higher scores for homogeneity of fat suppression and image quality (P < 0.05) compared with those for SPAIR-eTHRIVE. With respect to artifact and anatomic sharpness, there was no significant difference between two MRIs (P > 0.05). Diagnostic accuracy (Az) and sensitivity for detecting HCCs with mDixon-eTHRIVE images were mean 0.954 and 93.2%, respectively., Conclusion: For gadoxetic acid-enhanced liver MRI, mDixon-eTHRIVE showed improved homogeneity of fat suppression and overall image quality compared with SPAIR-eTHRIVE., (Copyright © 2013 Wiley Periodicals, Inc.)

Purpose: To determine the differential MRI features of small mass-forming intrahepatic cholangiocarcinoma (ICC) from hepatocellular carcinoma (HCC)., Methods: Sixty-four patients with pathologically proven small ICCs (n = 32) and HCCs (n = 32) (≤ 3.0 cm in diameter) who had undergone preoperative gadoxetic acid-enhanced MRI and DWI were enrolled in this study. Images were analyzed for the shape of the lesions, the presence of biliary dilatation, hyperenhancement (>50 % of the tumor volume) or rim enhancement on the arterial phase, capsular enhancement, and the presence of target appearance (a central enhancement with hypointense rim) on the hepatobiliary phase and on DWI (a central hypointense area with a peripheral hyperintense rim). Statistical significance of these findings was determined by the χ(2) or Fisher's exact test. Multivariate analysis was performed to identify independent imaging findings that allow differentiation of the two diseases., Results: Univariate analysis revealed that the following significant parameters favor ICC over HCC: lobulating shape, rim enhancement on arterial phase, target appearance on the hepatobiliary phase, and DWI (P < 0.05). Multivariate logistic regression analysis revealed that only target appearance on the DWI was a significant and independent variable predictive of ICC, as 24 ICCs (75.0 %) and one HCC (3.1 %) showed this feature (P = 0.0003)., Conclusion: A target appearance on the DWI was the most reliable imaging feature for distinguishing small mass-forming ICC from small HCC.

Background: Gadoxetic acid and diffusion-weighted imaging (DWI) is increasingly used for the diagnosis of hepatocellular carcinoma (HCC). It is relevant to refine the diagnostic parameters for HCC, using state-of-the-art imaging techniques., Purpose: To validate usefulness of magnetic resonance imaging (MRI) criteria with gadoxetic acid-enhanced MRI and DWI for diagnosis of small HCC by differentiation from dysplastic nodule (DN) or regenerative nodule (RN) in cirrhotic patients with strongly suspected small HCC., Material and Methods: One hundred and eight patients with 102 HCCs and 29 benign nodules including 21 DNs and two large RNs (≤ 2.0 cm), and 40 patients with no HCC underwent gadoxetic acid-enhanced MRI and DWI. All patients also underwent MDCT. Index MR criteria for HCC were: (i) arterial hyperenhancement and hypointensity on hepatobiliary phase (HBP) with hyperintensity on DWI; (ii) hypovascular nodule with hyperintensity on DWI; (iii) arterial hyperenhancement and hypointensity on HBP without hyperintensity on DWI; (iv) arterial hyperenhancement and either iso- or hyperintensity on HBP, with hyperintensity on DWI; and (v) hyperintensity only on DWI. According to these criteria, MRI findings for HCCs and benign nodules were independently classified by two reviewers., Results: On multidetector-row computed tomography, 64 HCCs (62.7%) showed typical features for HCC while 13 (12.8%) were not identified. On MRI, 84 HCCs (82.4%) showed arterial hyperenhancement and hypointensity on HBP, and hyperintensity on DWI. Eight HCCs were regarded as hypovascular HCCs with hyperintensity DWI (category 2). One HCC (0.6 cm in diameter) was demonstrated only by DWI. For each observer, 101 (99.0%) and 100 HCCs (98.0%) were discernible when applying all MRI criteria for HCC, respectively. Three DNs also fit the HCC criteria, thus the specificity was 90.9% for both observers., Conclusion: With the HCC criteria based on combined gadoxetic acid-enhanced MRI and DWI, it is possible to reliably diagnose small HCC including hypovascular HCCs.

Objective: Our objective was to evaluate whether the enhancement pattern, measured by changes in the signal- (SNRs) and contrast-to-noise ratios (CNRs), of hepatocellular carcinomas (HCCs) on gadoxetic acid-enhanced MRI reflects tumor differentiation., Subjects and Methods: Two hundred eighty-five patients with 286 surgically-confirmed HCCs who underwent gadoxetic acid-enhanced MRI were included (11 grade I, 267 grade II, 7 grade III, and 1 grade IV tumor). Unenhanced and dynamic images with a T1-weighted 3D turbo-field-echo sequence were obtained. Relative signal intensities of the tumors with respect to surrounding liver were evaluated and the SNRs and CNRs were calculated., Results: SNR measurements demonstrated a fluctuating pattern (an increase in the SNR, followed by a decrease and a subsequent increase [or a decrease in the SNR followed by an increase and a subsequent decrease]) in 282 of 286 (98.6%) tumors. The SNR measurements also showed a single-peak SNR in the arterial phase (1.0% [3/286]) and 3min delayed images (0.3% [1/286]) followed by a decrease in 4 (1.4% [4/286]) grade II tumors. Nearly all tumors (88.1% [252/286]), 9 (81.8% [9/11]) grade I, 236 (88.4% [236/267]) grade II, 6 (85.7% [6/7]) grade III, and 1 (100% [1/1]) grade IV tumor showed maximum absolute CNRs with negative values, which were most commonly found in 20min delayed images (67.5% [170/252]). The remaining 34 of 286 (11.9%) tumors showed maximum absolute CNRs with positive values., Conclusion: Regardless of the tumor grades, the most common manifestation was a SNR with a fluctuating pattern with time and maximum absolute CNRs with negative values, which were most commonly noted in the hepatobiliary phase., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the risk factors affecting early diffuse recurrence within 1 year of percutaneous ultrasound-guided radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC)., Methods: Out of 146 patients who received transcatheter arterial chemoembolisation (TACE) for treatment of recurrent HCC after percutaneous ultrasound-guided RFA, we selected 23 patients with early diffuse recurrence. Early diffuse recurrence was defined as three or more new recurrent HCCs within 1 year of initial RFA. As a control group, we selected 23 patients, matched exactly for age and sex, in which there was no local tumour progression or new recurrence after RFA. To analyse the risk factors, we examined patient factors and tumour factors., Results: Recurrent tumours occurred from 30 to 365 days after RFA (median time, 203 days). Univariate analysis indicated that larger tumour size and poorly defined margin were significant risk factors (P < 0.05). Multivariate analysis indicated that poorly defined margin was a significant risk factor (P < 0.05)., Conclusion: Larger tumour size and poorly defined margin may be risk factors for early diffuse recurrence of HCC within 1 year of RFA. Tumours with such risk factors should be treated with a combination of TACE to minimise the potential for therapeutic failure.

Background: As gadoxetic acid-enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) have been widely used for the evaluation of hepatocellular carcinoma (HCC), it is clinically relevant to determine the diagnostic efficacy of gadoxetic acid-enhanced MRI and DWI for detection of HCCs with respect to the severity of liver cirrhosis., Purpose: To compare the diagnostic accuracy and sensitivity of gadoxetic acid-enhanced MRI and DWI for detection of HCCs with respect to the severity of liver cirrhosis., Material and Methods: A total of 189 patients with 240 HCCs (≤3.0 cm) (Child-Pugh A, 81 patients with 90 HCCs; Child-Pugh B, 65 patients with 85 HCCs; Child-Pugh C, 43 patients with 65 HCCs) underwent DWI and gadoxetic acid-enhanced MRI at 3.0 T. A gadoxetic acid set (dynamic and hepatobiliary phase plus T2-weighted image) and DWI set (DWI plus unenhanced MRIs) for each Child-Pugh class were analyzed independently by two observers for detecting HCCs using receiver-operating characteristic analysis. The diagnostic accuracy and sensitivity were calculated., Results: There was a trend toward decreased diagnostic accuracy for gadoxetic acid and DWI set with respect to the severity of cirrhosis (Child-Pugh A [mean 0.974, 0.961], B [mean 0.904, 0.863], C [mean 0.779, 0.760]). For both observers, the sensitivities of both image sets were highest in Child-Pugh class A (mean 95.6%, 93.9%), followed by class B (mean 83.0%, 77.1%), and class C (mean 60.6%, 60.0%) (P < 0.05)., Conclusion: In HCC detection, the diagnostic accuracy and sensitivity for gadoxetic acid-enhanced MRI and DWI were highest in Child-Pugh class A, followed by Child-Pugh class B, and Child-Pugh class C, indicating a tendency toward decreased diagnostic capability with the severity of cirrhosis.

Purpose: To examine the differential features of combined hepatocellular and cholangiocarcinoma (HCC-CC) from mass-forming intrahepatic cholangiocarcinoma (ICC) on gadoxetic acid-enhanced MRI., Materials and Methods: Forty patients with pathologically proven combined HCC-CC (n = 20) and ICCs (n = 20) who had undergone gadoxetic acid-enhanced MRI were enrolled in this study. MR images were analyzed for the shape of lesions, hypo- or hyperintense areas on the T2-weighted image (T2WI), rim enhancement during early dynamic phases, and central enhancement with hypointense rim (target appearance) on the 10-min and 20-min hepatobiliary phase (HBP). The significance of these findings was determined by the χ(2) test., Results: Irregular shape and strong rim enhancement during early dynamic phases, and absence of target appearance on HBP favored combined HCC-CCs (P < 0.05). Lobulated shape, weak peripheral rim enhancement, and the presence of complete target appearance on the 10-min and 20-min HBP favored ICCs (P < 0.05). However, 10 CC-predominant type of combined HCC-CC showed complete or partial target appearance on 10-min HBP., Conclusion: The shape of tumors, degree of rim enhancement during early dynamic phases, and target appearance on HBP were valuable for differentiating between combined HCC-CC and mass-forming ICC on gadoxetic acid-enhanced MRI., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose: To investigate the imaging features of hypovascular hypointense nodules on hepatobiliary phase gadoxetic acid-enhanced magnetic resonance (MR) images in patients with cirrhosis that may be associated with progression to hypervascular hepatocellular carcinoma (HCC)., Materials and Methods: The institutional review board approved this retrospective study and waived informed patient consent. This study included 135 patients with a diagnosis of hepatitis B-induced liver cirrhosis and 214 hypovascular hypointense nodules on hepatobiliary phase gadoxetic acid-enhanced MR images. MR images were analyzed with respect to nodule size, degree of hypointensity at hepatobiliary phase (four grades), presence of fat, and signal intensity on T1- and T2-weighted and diffusion-weighted (DW) images. Univariate and multivariate Cox regression analyses were used to identify variables that are associated with developing hypervascular HCC., Results: On follow-up MR images, 139 nodules (65.0%) had no evidence of HCC (mean follow-up, 522 days) (group 1), but 75 (35.0%) became hypervascular HCC (mean follow-up, 388 days) (group 2). Univariable Cox analysis revealed that the degree of hypointensity on hepatobiliary phase images (P=.044 and .001) and hyperintensity on T2-weighted and DW images (P=.001 and .0001) was significantly related to the development of hypervascular HCC. According to the multivariable Cox analysis, no other variable significantly adjusted the model once hyperintensity at initial DW imaging was already included as an associated variable, (hazard ratio, 7.44; 95% confidence interval: 4.28, 12.94; P=.0001)., Conclusion: Hyperintensity on DW images in hypovascular hypointense nodules on hepatobiliary phase gadoxetic acid-enhanced MR images in patients with cirrhosis is strongly associated with progression to hypervascular HCC., (© RSNA, 2012.)

Purpose: To determine if the combination of gadoxetic acid-enhanced magnetic resonance (MR) imaging and diffusion-weighted (DW) imaging helps to increase accuracy and sensitivity in the diagnosis of small hepatocellular carcinomas (HCCs) compared with those achieved by using each MR imaging technique alone., Materials and Methods: The institutional review board approved this retrospective study and waived the requirement for informed consent. The study included 130 patients (95 men, 35 women) with 179 surgically confirmed small HCCs (≤2.0 cm) and 130 patients with cirrhosis (90 men, 40 women) without HCC who underwent gadoxetic acid-enhanced MR imaging and DW imaging at 3.0 T between May 2009 and July 2010. Three sets of images were analyzed independently by three observers to detect HCC: a gadoxetic acid set (unenhanced, early dynamic, and hepatobiliary phases), a DW imaging set, and a combined set. Data were analyzed by using alternative-free response receiver operating characteristic analysis. Diagnostic accuracy (area under the receiver operating characteristic curve [A(z)]), sensitivity, specificity, and positive predictive value were calculated., Results: The mean A(z) values for the combined set (0.952) were significantly higher than those for the gadoxetic acid set (A(z) = 0.902) or the DW imaging set alone (A(z) = 0.871) (P ≤ .008). On a per-lesion basis, observers showed higher sensitivity in their analyses of the combined set (range, 91.1%-93.3% [163-167 of 179]) than in those of the gadoxetic acid set (range, 80.5%-82.1% [144-147 of 179]) or the DW imaging set alone (range, 77.7%-79.9% [139-143 of 179]) (P ≤ .003). Positive predictive values and specificity for all observers were equivalent for the three imaging sets., Conclusion: The combination of gadoxetic acid-enhanced MR imaging and DW imaging yielded better diagnostic accuracy and sensitivity in the detection of small HCCs than each MR imaging technique alone., (© RSNA, 2012)

Facial nerve palsy due to temporal bone metastasis of hepatocellular carcinoma (HCC) has rarely been reported. We experienced a rare case of temporal bone metastasis of HCC that initially presented as facial nerve palsy and was diagnosed by surgical biopsy. This patient also discovered for the first time that he had chronic hepatitis B and C infections due to this facial nerve palsy. Radiation therapy greatly relieved the facial pain and facial nerve palsy. This report suggests that hepatologists should consider metastatic HCC as a rare but possible cause of new-onset cranial neuropathy in patients with chronic viral hepatitis.

Objective: The purpose of this article is to evaluate the value of gadoxetic acid-enhanced hepatobiliary phase imaging and high-b-value diffusion-weighted imaging (DWI) for distinguishing well-differentiated hepatocellular carcinomas (HCCs) from benign hepatocellular nodules in patients with chronic liver disease using 3-T MRI., Materials and Methods: Forty-five patients with 46 well-differentiated HCCs (mean, 2.3 cm) and 21 patients with 24 benign hepatocellular nodules (five large regenerative nodules and 19 dysplastic nodules; mean, 1.8 cm) were included in this study. Diagnosis of well-differentiated HCCs and benign hepatocellular nodules was made histopathologically by percutaneous biopsy (n = 12 and n = 11, respectively) or surgical resection (n = 34 and n = 13, respectively). Gadoxetic acid-enhanced MRI was performed for all patients, and DWI (b values of 0 and 800 s/mm(2)) was performed for 31 well-differentiated HCCs and 11 benign hepatocellular nodules. Two radiologists performed a consensus review of the MRI scans for signal intensity compared with that of the surrounding liver parenchyma on hepatobiliary phase images and DWI (b value, 800 s/mm(2)) for qualitative analysis. The contrast-to-noise ratio (CNR) and relative contrast enhancement of lesions on hepatobiliary phase images and the apparent diffusion coefficient (ADC) values were assessed for quantitative analysis., Results: In the qualitative analysis, 39 well-differentiated HCCs (85%) and 14 benign hepatocellular nodules (58%) were hypointense on hepatobiliary phase images, and seven well-differentiated HCCs (15%) and 10 benign hepatocellular nodules (42%) were iso- or hyperintense (p = 0.04). Twenty-five well-differentiated HCCs (81%) and three benign hepatocellular nodules (27%) were hyperintense on DWI, with b value of 800 s/mm(2), and six well-differentiated HCCs (19%) and eight benign hepatocellular nodules (73%) were iso- or hypointense (p = 0.01). When lesion hypointensity on hepatobiliary phase images or hyperintensity on DWI were considered signs of HCC in cirrhotic liver, our results yielded sensitivities of 85% and 81% and specificities of 42% and 73%, respectively. In the quantitative analysis, the mean (± SD) relative contrast enhancement ratio of the well-differentiated HCCs (0.76 ± 2.30) was significantly higher than that of benign hepatocellular nodules (0.25 ± 0.97) (p = 0.02). The lesion-to-liver CNRs and the mean ADC values were not significantly different between the two groups (p > 0.05)., Conclusion: Hypointensity on gadoxetic acid-enhanced hepatobiliary phase images and hyperintensity on high-b-value DWI to surrounding liver parenchyma suggest well-differentiated HCCs rather than benign hepatocellular nodules in chronic liver disease.

Purpose: To compare ablation zone, local therapeutic efficacy, and complications of ultrasound (US)-guided percutaneous radiofrequency (RF) ablation of medium-sized hepatocellular carcinomas (HCCs) with a cluster electrode versus a single electrode with multiple overlapping ablations., Materials and Methods: From February 2005 to January 2009, a total of 79 consecutive patients (57 men, 22 women; mean age, 58.6 y) with 79 HCCs (range, 2.5-4.0 cm) underwent percutaneous RF ablation with a cluster electrode (n = 37) or a single electrode with multiple overlapping ablations (n = 42). These methods were compared in terms of ablation zone size on immediate follow-up computed tomography and the rates of technique effectiveness and cumulative local tumor progression on further follow-up (range, 12.0-46.2 mo; median, 24.3 mo)., Results: Baseline characteristics did not differ between groups. The ablation zone in the cluster group was significantly smaller in the longitudinal dimension (43.7 mm ± 4.8 vs 46.5 mm ± 5.9; P = .03), but greater in the short axial dimension (30.7 mm ± 3.9 vs 27.3 mm ± 5.5; P = .03), compared with that in the overlapping ablation group. Technique effectiveness rates in the cluster and overlap groups were 100% and 92.9% (39 of 42), respectively (P = .24). The cumulative local tumor progression rate was significantly lower in the cluster group than in the overlapping group (1- and 3- year follow-up: 8.1 and 18.8% vs 23.8 and 42.2%, P = .04). Complications were more frequent in the cluster group than in the overlapping group (27.0% vs 7.1%; P = .03)., Conclusions: In US-guided percutaneous RF ablation of medium-sized HCCs, the cluster electrode showed better local therapeutic efficacy than the single electrode with multiple overlapping ablations, probably because of the favorable shape of the ablation zone; however, complications occurred more frequently., (Copyright © 2011 SIR. Published by Elsevier Inc. All rights reserved.)

Objectives: The purposes of this study were to evaluate the causes of mistargeting during percutaneous sonographically guided radio frequency ablation in patients with hepatocellular carcinoma and to determine factors affecting the feasibility of a second ablation session., Methods: This study received Institutional Review Board approval, and informed consent was waived. Among 2213 percutaneous sonographically guided radio frequency ablations performed in our hospital, we searched for mistargeting cases and analyzed the causes of mistargeting. To determine which factors affected the feasibility of a second ablation session, univariate and multivariate analyses were performed., Results: Forty-one cases of mistargeting occurred during the first ablation session, and 4 cases occurred during the second session. Of the 41 patients with mistargeted hepatocellular carcinomas during the first session, 39 who underwent replanning sonography were able to be analyzed for causes of mistargeting. The most common cause of mistargeting was confusion with cirrhotic nodules (87.2% [34 of 39]), followed by poor conspicuity of the hepatocellular carcinoma (69.2% [27 of 39]), a poor sonic window (28.2% [11 of 39]), a poor electrode path (7.7% [3 of 39]), and inaccurate electrode placement (2.6% [1 of 39]). Artificial ascites (P = .035) and the presence of more than 3 mistargeting causes (P = .017) were independent factors affecting feasibility., Conclusions: The most common cause of mistargeting was confusion with cirrhotic nodules, followed by poor conspicuity of the hepatocellular carcinoma, a poor sonic window, a poor electrode path, and inaccurate electrode placement. The use of artificial ascites and the presence of more than 3 mistargeting causes were factors affecting the feasibility of a second radio frequency ablation session.

Objective: To evaluate the outcomes of small (5-10 mm), arterially enhancing nodules (SAENs) shown exclusively at the hepatic arterial phase of CT in a hepatocellular carcinoma (HCC) surveillance population and to determine risk factors for developing HCC., Methods: The study population included 112 patients (male:female = 100:12; aged 36-92 years) with 175 SAENs who were at risk of HCC. We evaluated serial changes during follow-up (1.4-41.8 months, mean 35.7 months) and analysed the initial CT findings of SAENs and the accompanying lesions to elucidate the risk factors for HCC development., Results: Of 175 SAENs, 101(57.7%) disappeared and 34(19.4%) persisted. Forty SAENs (22.9%) became HCC in 33 patients (29.5%). Presence of HCC treatment history (p = 0.005, risk ratio = 7.429), a larger size of SAEN (p = 0.003, risk ratio = 1.630), presence of coexistent HCC (p = 0.021, risk ratio = 3.777) and absence of coexistent typical arterioportal shunts (p = 0.003, risk ratio = 4.459) turned out to be independently significant risk factors for future development of HCC., Conclusion: SAENs were frequently seen in an HCC surveillance population and have a 22.9% probability of becoming HCC on a per-lesion basis. Risk increased particularly when the lesion was associated with a previous or concurrent HCC, a large size or found without a coexistent typical arterioportal shunt.

Radiotherapy is not commonly used for the treatment of human hepatocellular carcinoma, due to its poor response rate and poor tolerance of normal liver to ionizing radiation. Recently developed microarray technology makes it possible to verify genes responsive to anticancer therapy of human cancers by simultaneous analysis of gene expression profiles. In the present study, the expression profile of radiation-responsive genes in human hepatocellular carcinoma was evaluated through time-dependent cDNA microarray analysis of expressional variation, following exposure to ionizing radiation. Upon exposure to radiation, more than 13% of genes in both radiation-resistant and -sensitive cells responded to radiation. Time-dependent analysis of radiation-responsive genes revealed that, irrespective of radiation sensitivity, greatly different subsets of genes sequentially participated in cellular response to radiation at their specific activation or deactivation time points. The majority of radiation-responsive genes were differentially but not commonly expressed between radiation-resistant and -sensitive cells. When these differentially regulated genes were classified according to their physiological and functional characteristics and radiation sensitivity, it was prominently obvious that DNA repair-promoting genes were up-regulated in radio-resistant cells and down-regulated or unchanged in radiation-sensitive cells. The present findings indicate that different subsets of genes are sequentially working and DNA repair capacity may control the radiation sensitivity of human hepatocellular carcinoma cells more than any other physiological factor.

Background/aims: Several risk factors, such as size and location, are related to local recurrence after radiofrequency ablation (RFA) in the treatment of hepatocellular carcinoma (HCC). The objectives of this study were to clarify factors related to prognosis., Methods: From October 1999 to December 2002, we performed RFA for 107 consecutive patients with solitary HCC. We evaluated spiral computed tomography and serum alpha-fetoprotein level every 3 months after RFA. Seven possible factors for prognosis were analyzed using the Cox proportional hazards regression model: tumor size, tumor location, age, sex, etiology, platelet count, and Child-Pugh classification. Overall survival and disease free survival rate were estimated using the Kaplan-Meier method, and differences between two groups were compared using the log rank test., Results: The Kaplan-Meier estimates of overall survival after radiofrequency ablation were 90.5% at 12 months, 67.4% at 24 months and 46.4% at 36 months and disease free survival were 71.4%, 46.7% and 20.9%, respectively. Using the Cox proportional hazards regression model, it was shown that with regard to overall survival and disease free survival, Child-Pugh classification (P=0.001, P=0.026) and platelet count (P<0.001, P=0.002) were statistically significant factors. The other factors did not have a statistically significant relationship to overall survival and disease free survival., Conclusions: The size and location known as local recurrence factors were not statistically significant with regard to survival and disease free survival. The Child-Pugh classification and platelet count, that reflect the liver function at the time of RFA, were significant factors for prognosis.