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Introduction: We investigated the clinical outcomes of stereotactic body radiation therapy (SBRT) alone versus SBRT after incomplete transarterial chemoembolization (TACE) for a single recurrent hepatocellular carcinoma (HCC) smaller than 5 cm., Methods: We retrospectively reviewed the medical records of patients who underwent SBRT for a single recurrent HCC ≤5 cm, without vascular invasion or extrahepatic metastasis. Patients were divided into the SBRT-alone group and the TACE-SBRT group. The primary outcome was the local control (LC) rate, and secondary outcomes were survivals and treatment-related toxicities. We additionally conducted a propensity score matching (PSM) analysis., Results: A total of 477 patients were available for analysis. Among them, 54 patients received SBRT without prior treatment to the target lesion (SBRT-alone group), whereas 423 patients received SBRT for viable HCC after TACE (TACE-SBRT group). The 3-year LC rates did not differ between the two groups (SBRT-alone group, 88.6% vs. TACE-SBRT group, 89.6%, P = 0.918). The 3-year rates of overall survival, out-of-field intrahepatic recurrence-free survival and recurrence-free survival were also not significantly different (P = 0.479, 0.290 and 0.273, respectively). Even after PSM, LC and survival rates at 3 years were not significantly different., Conclusion: SBRT alone demonstrated comparable local control and survival outcomes to SBRT following incomplete TACE. SBRT alone may be considered an alternative treatment option for a single recurrent HCC smaller than 5 cm when curative treatments or TACE are not feasible., (© 2024 Royal Australian and New Zealand College of Radiologists.)

Objective: Differentiating hepatic epithelioid hemangioendothelioma (EHE) and angiosarcoma (AS), the two most common vascular tumors in the liver, is important due to disparities in their prognosis and treatment. We aimed to compare clinical and MRI features of the two tumors., Methods: This retrospective study included patients with pathologically-confirmed AS or EHE who underwent MRI using gadoxetate disodium between 2008 and 2023. Two radiologists independently reviewed MR images. Wilcoxon rank sum and Fisher's exact tests were used to compare clinical and imaging features. Overall survival was compared using restricted mean survival time at 3 years., Results: 32 patients with AS (18 women [56.3%]; median age, 68 years) and 38 with EHE (24 women [63.2%]; 51 years) were included. Patients with AS were generally older (81.3% ≥ 60 years; P < 0.001), had more frequent laboratory abnormalities (P ≤ 0.018), and poorer overall survival (11.2 vs. 31.8 months; P < 0.001) than those with EHE. On MRI, a large dominant mass accompanied by smaller nodules (14/32, 43.8%), often with ill-defined margins (15/32, 46.9%) was prevalent in AS; compared with nodules of similar sizes (24/38, 63.2%; P = 0.015) with well-defined margin (30/38, 78.9%; P = 0.002) in EHE. Cirrhotic appearance of the liver was more frequent in AS (62.5%, P < 0.001), along with decreased parenchymal enhancement on hepatobiliary phase (31.3%, P < 0.001) and ascites (37.5%, P = 0.010). AS frequently presented with avid enhancement of bizarrely-shaped foci, with a centrifugal enhancement pattern. In comparison, targetoid appearance was characteristic of EHE (78.9% on T2-weighted, 54.1% on diffusion-weighted, 65.8% on multiphase images) (P ≤ 0.002), with enhancement degree typically lower than that of the aorta. On hepatobiliary phase, all the AS exhibited hypointensity, while 39.5% of EHE showed targetoid appearance (P < 0.001)., Conclusion: Patients aged ≥ 60 years presenting with laboratory abnormalities, typically with a large dominant mass accompanied by smaller nodules, exhibiting avid, bizarre, and centrifugal enhancement-particularly in the cirrhotic-appearing liver-suggests the likelihood of AS over EHE., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: This single-center retrospective study was approved by the Institutional Review Board. The requirement for obtaining informed consent was waived owing to the retrospective nature of the data analysis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: To compare the efficacy of transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) for patients with single small (≤ 3 cm) hepatocellular carcinoma (HCC) and preserved liver function (Child-Pugh class A)., Materials and Methods: The clinical features of treatment-naïve patients who underwent TACE and RFA as first-line treatment were balanced through propensity score matching (PSM). The primary endpoint was overall survival (OS), and the secondary endpoints were local tumor recurrence (LTR) and recurrence-free survival (RFS)., Results: The analysis included 440 patients who received TACE, and 430 patients who received RFA. After PSM adjustment (323 pairs), the 5- and 10-year OS rates were 81% and 61%, respectively, in patients who underwent RFA, and 77% and 51%, respectively, for patients who underwent TACE (p = 0.021). Subgroup analyses showed that OS, LTR, and RFS were homogeneously better in the RFA group., Conclusion: RFA was associated with better survival outcomes than TACE in patients with single small HCC and preserved liver function., Clinical Relevance Statement: This large-scale comparative study provides evidence that radiofrequency ablation has a better overall survival rate than chemoembolization for small (≤ 3 cm) hepatocellular carcinomas., Key Points: • The relative effectiveness of transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) for early HCC is unclear. • Overall survival rate was significantly higher in the RFA group. • The effects of RFA on overall survival, local tumor recurrence, and recurrence-free survival were homogeneously better in all subgroups., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Background: LI-RADS version 2018 (v2018) is used for non-invasive diagnosis of hepatocellular carcinoma (HCC). A recently proposed modification (known as mLI-RADS) demonstrated improved sensitivity while maintaining specificity and positive predictive value (PPV) of LI-RADS category 5 (definite HCC) for HCC. However, mLI-RADS requires multicenter validation., Purpose: To evaluate the performance of v2018 and mLI-RADS for liver lesions in a large, heterogeneous, multi-national cohort of patients at risk for HCC., Study Type: Systematic review and meta-analysis using individual participant data (IPD) [Study Protocol: https://osf.io/duys4]., Population: 2223 observations from 1817 patients (includes all LI-RADS categories; females = 448, males = 1361, not reported = 8) at elevated risk for developing HCC (based on LI-RADS population criteria) from 12 retrospective studies., Field Strength/sequence: 1.5T and 3T; complete liver MRI with gadoxetate disodium, including axial T2w images and dynamic axial fat-suppressed T1w images precontrast and in the arterial, portal venous, transitional, and hepatobiliary phases. Diffusion-weighted imaging was used when available., Assessment: Liver observations were categorized using v2018 and mLI-RADS. The diagnostic performance of each system's category 5 (LR-5 and mLR-5) for HCC were compared., Statistical Tests: The Quality Assessment of Diagnostic Accuracy Studies version 2 (QUADAS-2 was applied to determine risk of bias and applicability. Diagnostic performances were assessed using the likelihood ratio test for sensitivity and specificity and the Wald test for PPV. The significance level was P < 0.05., Results: 17% (2/12) of the studies were considered low risk of bias (244 liver observations; 164 patients). When compared to v2018, mLR-5 demonstrated higher sensitivity (61.3% vs. 46.5%, P < 0.001), similar PPV (85.3% vs. 86.3%, P = 0.89), and similar specificity (85.8% vs. 90.8%, P = 0.16) for HCC., Data Conclusion: This study confirms mLR-5 has higher sensitivity than LR-5 for HCC identification, while maintaining similar PPV and specificity, validating the mLI-RADS proposal in a heterogeneous, international cohort., Level of Evidence: 3 TECHNICAL EFFICACY: Stage 2., (© 2023 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Objectives: We aimed to compare Liver Imaging Reporting and Data System (LI-RADS) category 4/5 and category M (LR-M) of proliferative hepatocellular carcinomas (HCCs) in cirrhotic patients and evaluate their impacts on prognosis., Methods: This retrospective multi-reader study included cirrhotic patients with single treatment-naïve HCC ≤ 5.0 cm who underwent contrast-enhanced CT, MRI, and subsequent hepatic resection within 2 months. The percentages of CT/MRI LR-4/5 and LR-M in proliferative and non-proliferative HCCs were compared. Univariable and multivariable Cox proportional hazards regression analyses were performed to assess the association of LI-RADS categories (LR-4/5 vs. LR-M) and pathologic classification (proliferative vs. non-proliferative) with overall survival (OS) and recurrence-free survival (RFS). Subgroups of patients with proliferative and non-proliferative HCCs were analyzed to compare OS and RFS between LR-4/5 and LR-M., Results: Of the 204 included patients, 38 were classified as having proliferative HCC. The percentages of LR-M were higher in proliferative than non-proliferative HCC on both CT (15.8% vs. 3.0%, p = 0.007) and MRI (26.3% vs. 9.6%, p = 0.016). Independent of pathologic classification, CT and MRI LR-M were significantly associated with poorer OS (hazard ratio (HR) = 4.58, p = 0.013, and HR = 6.45, p < 0.001) and RFS (HR = 3.66, p = 0.005, and HR = 6.44, p < 0.001) than LR-4/5. MRI LR-M was associated with significantly poorer OS (p ≤ 0.003) and RFS (p < 0.001) than MRI LR-4/5 in both proliferative and non-proliferative HCCs., Conclusions: This multi-reader study showed that the percentages of LR-M were significantly higher in proliferative than non-proliferative HCCs. CT/MRI LR-M was significantly associated with poor OS and RFS, independent of the pathologic classification of proliferative versus non-proliferative HCCs., Clinical Relevance Statement: CT and MRI LI-RADS category M can be clinically useful in predicting poor outcomes in patients with proliferative and non-proliferative hepatocellular carcinomas., Key Points: • The percentages of LR-M tumors on both CT and MRI were significantly higher in proliferative than non-proliferative hepatocellular carcinomas. • Independent of pathologic classification, CT/MRI LR-M categories were correlated with poor overall survival and recurrence-free survival. • Patients with both proliferative and non-proliferative hepatocellular carcinomas categorized as MRI LR-M had significantly poorer overall survival and recurrence-free survival than those categorized as MRI LR-4/5., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Background & Aims: Lymphocyte-rich hepatocellular carcinoma (LR-HCC) is largely unknown and a rare subtype of HCC with immune-rich stroma. Tertiary lymphoid structures (TLS), frequently observed in LR-HCC, are known to be prognostically significant in various malignancies; however, their significance in HCC remains unevaluated., Methods: Clinicopathologic data of 191 cases of surgically resected conventional HCC (C-HCC, n = 160) and LR-HCC (n = 31) were retrieved. Immunohistochemistry, multiplex immunofluorescence staining, RNA sequencing and proteomic analysis were conducted. Differences between the subtypes were statistically evaluated., Results: LR-HCC was significantly correlated to larger tumour size, higher Edmondson-Steiner grade, presence of TLS and higher CD3-, CD8- and FOXP3-positive T cell, high PD-1 and PD-L1 expression (p < .001 for all) compared to C-HCC. Patients with LR-HCC exhibited significantly better overall survival (OS) (p = .044) and recurrence-free survival (RFS) (p = .025) than C-HCC. LR-HCC demonstrated TLS signatures with significantly higher proteomic-based immune scores in 14 of 17 types of tumour-infiltrating immune cells. Furthermore, C-HCC with secondary follicles, the most mature form of TLS, exhibited significantly better OS (p = .031) and RFS (p = .033) than those without. Across the global proteome, LR-HCC was well-differentiated from C-HCC and a map of protein-protein interactions between tumour-infiltrating lymphocytes and HCC in tumour microenvironment was completed., Conclusion: LR-HCC is clinicopathologically and molecularly distinct and shows better prognosis compared to C-HCC. Also, the presence of secondary follicle can be an important prognostic marker for better prognosis in both LR-HCC and C-HCC., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

Objectives: To compare the safety and efficacy of RFA for single HCCs ≤ 3 cm in subcapsular versus nonsubcapsular locations using a propensity score matched analysis., Materials and Methods: This retrospective study included patients with solitary HCCs ≤ 3 cm in size who underwent percutaneous RFA from 2005 to 2015 as initial treatment at two large-volume liver centers. Patients were divided into two groups, consisting of those with subcapsular and nonsubcapsular tumor locations. Complications, local tumor progression (LTP), and overall survival (OS) were compared in these two groups before and after propensity score matching (PSM)., Results: The study population consisted of 964 patients (712 men [74%]) of mean age 58.3 years. Of these 964 patients, 561 (58%) had nonsubcapsular and 403 (42%) had subcapsular HCCs. PSM generated 402 pairs of patients. Major complication rate was low, but significantly higher in the subcapscular group (p = 0.047). Rates of technical effectiveness in these two groups were 99% and 98%, respectively (p = 0.315). However, during follow-up, cumulative 1-, 3-, 5-, and 10-year LTP and OS rates did significantly differ in both entire and PSM cohorts, resulting in the latter 8%, 15%, 20%, and 26% in the nonsubcapsular group vs. 13%, 24%, 30%, and 31% in the subcapsular group (p = 0.015), and 99%, 91%, 80%, and 59% vs. 98%, 85%, 73%, and 50% in the two groups (p = 0.004), respectively., Conclusion: Rates of major complications, LTP, and OS differed significantly following first-line RFA treatment of single HCCs ≤ 3 cm in favor of the nonsubcapsular locations., Clinical Relevance Statement: This large-scale study provides evidence that radiofrequency ablation for small (≤ 3 cm) hepatocellular carcinomas is safer and more effective in nonsubcapsular location than in subcapsular location., Key Points: • There exist conflicting outcomes on the effectiveness of RFA for early HCC depending on tumor location. • Rate of local tumor progression was significantly higher in the subcapsular hepatocellular carcinomas. • Overall survival rate was significantly poorer in the subcapsular hepatocellular carcinomas., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Background The independent contribution of each Liver Imaging Reporting and Data System (LI-RADS) CT or MRI ancillary feature (AF) has not been established. Purpose To evaluate the association of LI-RADS AFs with hepatocellular carcinoma (HCC) and malignancy while adjusting for LI-RADS major features through an individual participant data (IPD) meta-analysis. Materials and Methods Medline, Embase, Cochrane Central Register of Controlled Trials, and Scopus were searched from January 2014 to January 2022 for studies evaluating the diagnostic accuracy of CT and MRI for HCC using LI-RADS version 2014, 2017, or 2018. Using a one-step approach, IPD across studies were pooled. Adjusted odds ratios (ORs) and 95% CIs were derived from multivariable logistic regression models of each AF combined with major features except threshold growth (excluded because of infrequent reporting). Liver observation clustering was addressed at the study and participant levels through random intercepts. Risk of bias was assessed using a composite reference standard and Quality Assessment of Diagnostic Accuracy Studies 2. Results Twenty studies comprising 3091 observations (2456 adult participants; mean age, 59 years ± 11 [SD]; 1849 [75.3%] men) were included. In total, 89% (eight of nine) of AFs favoring malignancy were associated with malignancy and/or HCC, 80% (four of five) of AFs favoring HCC were associated with HCC, and 57% (four of seven) of AFs favoring benignity were negatively associated with HCC and/or malignancy. Nonenhancing capsule (OR = 3.50 [95% CI: 1.53, 8.01]) had the strongest association with HCC. Diffusion restriction (OR = 14.45 [95% CI: 9.82, 21.27]) and mild-moderate T2 hyperintensity (OR = 10.18 [95% CI: 7.17, 14.44]) had the strongest association with malignancy. The strongest negative associations with HCC were parallels blood pool enhancement (OR = 0.07 [95% CI: 0.01, 0.49]) and marked T2 hyperintensity (OR = 0.18 [95% CI: 0.07, 0.45]). Seventeen studies (85%) had a high risk of bias. Conclusion Most LI-RADS AFs were independently associated with HCC, malignancy, or benignity as intended when adjusting for major features. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Crivellaro in this issue.

Background/aims: Local ablation therapy (LAT) is primarily recommended for solitary inoperable hepatocellular carcinomas (HCCs) of ≤3 cm in diameter. However, only two-thirds of uninodular small HCCs are suitable for LAT, and the second-best treatment option for managing these nodules is unclear. We aimed to compare the therapeutic outcomes of chemoembolization and radiotherapy in small HCCs unsuitable for LAT., Methods: The study included 651 patients from a tertiary referral center who underwent planning sonography for LAT. These patients had 801 solitary HCCs of ≤3 cm in diameter and were treated with LAT, chemoembolization, or radiotherapy. Local tumor progression (LTP)-free survival and overall survival (OS) were measured according to the type of treatment of the index nodule., Results: LAT, chemoembolization, and radiotherapy were used to treat 561, 185, and 55 nodules in 467, 148, and 36 patients, respectively. LTP-free survival was significantly shorter in patients treated with chemoembolization than for those treated with LAT (multivariate hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.61 to 3.47) but not for those treated with radiotherapy (HR, 0.83; 95% CI, 0.38 to 1.83). However, OS was not affected by treatment modality. Matching and weighting analyses confirmed that radiotherapy gave comparable results to chemoembolization in terms of OS despite better LTP-free survival (HR, 2.91; 95% CI, 1.13 to 7.47 and HR, 3.07; 95% CI, 1.11 to 8.48, respectively)., Conclusions: Our data suggest that chemoembolization and radiotherapy are equally effective options for single small HCCs found to be unsuitable for LAT after sonographic planning. Betterfit indications for each procedure should be established by specifically designed studies.

Background A simplification of the Liver Imaging Reporting and Data System (LI-RADS) version 2018 (v2018), revised LI-RADS (rLI-RADS), has been proposed for imaging-based diagnosis of hepatocellular carcinoma (HCC). Single-site data suggest that rLI-RADS category 5 (rLR-5) improves sensitivity while maintaining positive predictive value (PPV) of the LI-RADS v2018 category 5 (LR-5), which indicates definite HCC. Purpose To compare the diagnostic performance of LI-RADS v2018 and rLI-RADS in a multicenter data set of patients at risk for HCC by performing an individual patient data meta-analysis. Materials and Methods Multiple databases were searched for studies published from January 2014 to January 2022 that evaluated the diagnostic performance of any version of LI-RADS at CT or MRI for diagnosing HCC. An individual patient data meta-analysis method was applied to observations from the identified studies. Quality Assessment of Diagnostic Accuracy Studies version 2 was applied to determine study risk of bias. Observations were categorized according to major features and either LI-RADS v2018 or rLI-RADS assignments. Diagnostic accuracies of category 5 for each system were calculated using generalized linear mixed models and compared using the likelihood ratio test for sensitivity and the Wald test for PPV. Results Twenty-four studies, including 3840 patients and 4727 observations, were analyzed. The median observation size was 19 mm (IQR, 11-30 mm). rLR-5 showed higher sensitivity compared with LR-5 (70.6% [95% CI: 60.7, 78.9] vs 61.3% [95% CI: 45.9, 74.7]; P < .001), with similar PPV (90.7% vs 92.3%; P = .55). In studies with low risk of bias ( n = 4; 1031 observations), rLR-5 also achieved a higher sensitivity than LR-5 (72.3% [95% CI: 63.9, 80.1] vs 66.9% [95% CI: 58.2, 74.5]; P = .02), with similar PPV (83.1% vs 88.7%; P = .47). Conclusion rLR-5 achieved a higher sensitivity for identifying HCC than LR-5 while maintaining a comparable PPV at 90% or more, matching the results presented in the original rLI-RADS study. © RSNA, 2023 Supplemental material is available for this article . See also the editorial by Sirlin and Chernyak in this issue.

Purpose: We aimed to evaluate and compare the diagnostic performance of Liver Imaging Reporting and Data System (LI-RADS) v2018 for hepatocellular carcinoma (HCC) ≤ 3.0 cm on gadoxetic acid-enhanced MRI according to the etiology of cirrhosis., Methods: Thirty-eight patients with alcoholic liver cirrhosis (ALC) and 37 with hepatitis C virus-related cirrhosis (HCV) who underwent preoperative MRI and subsequent surgical resection or transplantation were included. For comparison groups, patients with hepatitis B virus-related cirrhosis (HBV) were included by 1:1 matching with HCV and ALC groups according to age, lesion size, and Child-Pugh classification. The imaging characteristics of background liver and focal lesions were analyzed. The diagnostic performance of LI-RADS was compared between HCV and HBV groups, and between ALC and HBV groups., Results: ALC group showed significantly higher frequency of hepatic steatosis (25.8 % vs. 6.1 %, p =.04) and lower frequency of nonperipheral washout on portal venous-phase in HCC (63.2 % vs. 97.1 %, p <.001) compared with HBV group. ALC group showed significantly lower sensitivity than HBV group (52.6 % vs. 88.6 %, p<.001). No significant differences in diagnostic performance were found between HCV and HBV groups. In ALC group, hepatobiliary-phase hypointensity provided significantly higher sensitivity (76.3 % vs. 52.6 %, p =.008)., Conclusion: The sensitivity of LI-RADS for diagnosing HCC ≤ 3.0 cm was significantly lower in the ALC group than in the HBV group., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The temporal investigation of high-risk areas of cancer incidence and mortality can provide practical implications in cancer control. We aimed to investigate the changes in spatial clusters of incidence and mortality from 1999 through 2013 by major cancer types in South Korea., Methods: We applied flexible scan statistics to identify spatial clusters of cancer incidence and mortality by three 5-year periods and seven major cancer types using the counts of new cases and deaths and population in 244 districts during 1999-2013. Then, we compared the changes across three periods in the locations of primary clusters of incidence and mortality by cancer types. To explore the determinants that possibly affect cancer cluster areas, we compared geographic characteristics between clustered and non-clustered areas., Results: While incidence clusters for lung, stomach, and liver cancer remained in the same areas over 15 years, mortality clusters were relocated to the areas similar to those of incidence clusters. In contrast, colorectal, breast, cervical, and prostate cancer displayed consistently different locations of clusters over time, indicating the disappearance of existing clusters and the appearance of new clusters. Cluster areas tended to show higher portions of older population, unemployment, smoking, and cancer screening compared to non-cluster areas particularly for mortality., Conclusions: Our findings of diverse patterns of changes in cancer incidence and mortality clusters over 15 years can indicate the degree of effectiveness in cancer prevention and treatment depending on the area and suggest the need for area-specific applications of different cancer control programs., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Liver metastasis is a major cause of death in patients with colorectal cancer (CRC). Fatty liver promotes liver metastasis, but the underlying mechanism remains unclear. We demonstrated that hepatocyte-derived extracellular vesicles (EVs) in fatty liver enhanced the progression of CRC liver metastasis by promoting oncogenic Yes-associated protein (YAP) signaling and an immunosuppressive microenvironment. Fatty liver upregulated Rab27a expression, which facilitated EV production from hepatocytes. In the liver, these EVs transferred YAP signaling-regulating microRNAs to cancer cells to augment YAP activity by suppressing LATS2. Increased YAP activity in CRC liver metastasis with fatty liver promoted cancer cell growth and an immunosuppressive microenvironment by M2 macrophage infiltration through CYR61 production. Patients with CRC liver metastasis and fatty liver had elevated nuclear YAP expression, CYR61 expression, and M2 macrophage infiltration. Our data indicate that fatty liver-induced EV-microRNAs, YAP signaling, and an immunosuppressive microenvironment promote the growth of CRC liver metastasis., Competing Interests: Declaration of interests M.N. is a member of the advisory board of Altimmune, BI, BMS, Cytodyn, 89BIO, EchoSens, Gilead, GSK, Madrgial, Merck, Novo Nordisk, OWL, Prespecturm, Pfizer, Roche Diagnostic, and Siemens, Terns and Takeda; received research support from Allergan, Akero, BMS, Gilead, Galectin, Genfit, GSK, Conatus, Corcept, Enanta, Madrigal, Novartis, Novo Nordisk, Shire, Takeda, Terns, Viking, and Zydus; and is a stockholder in Anaetos, Rivus Pharma, CIMA, ChronWell, and Viking., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Sonazoid, a second-generation ultrasound contrast agent, was introduced for the diagnosis of hepatic nodules. To clarify the issues with Sonazoid contrast-enhanced ultrasonography for the diagnosis of hepatocellular carcinoma (HCC), the Korean Society of Radiology and Korean Society of Abdominal Radiology collaborated on the guidelines. The guidelines are de novo, evidence-based, and selected using an electronic voting system for consensus. These include imaging protocols, diagnostic criteria for HCC, diagnostic value for lesions that are inconclusive on other imaging results, differentiation from non-HCC malignancies, surveillance of HCC, and treatment response after locoregional and systemic treatment for HCC., Competing Interests: Min Woo Lee, Jung Hoon Kim, Ijin Joo, So Yeon Kim, Yong Eun Chung, Jeong Min Lee, contributing editors of the Korean Journal of Radiology, were not involved in the editorial evaluation or decision to publish this article. Woo Kyoung Jeong received honorarium from GE Healthcare and Bayer; Hyo-Jin Kang received honorarium from GE Healthcare; Mi-Suk Park received grant from GE Healthcare and Guerbet; Bohyun Kim was a consultant for Samsung Medison; Min Woo Lee received honorarium from Bracco, Starmed, Bonston Scientific, and Medtronic, and was a consultant for Starmed and Medtronic; Jeong Ah Hwang received honorarium from GE Healthcare; Jae Young Lee received grant from Canon Healthcare, Siemens Healthcare, Alpinion Medical System, and GE Healthcare and received honorarium from Philips, Canon Healthcare, GE Healthcare, Alpinion Medical System, and Siemens Healthcare; Jung Hoon Kim received honorarium from GE Healthcare; Ijin Joo received honorarium from Samsung Medison; So Yeon Kim received grant from Bayer Healthcare and Canon Healthcare; Jeong Min Lee received grant from Bayer Healthcare, Canon Healthcare, Siemens Healthcare, GE Healthcare, CMS, Guerbet, Samsung Medison, Starmed, RF medical, Clarify, and Dongkuk Pharma and received honorarium from Samsung Medison, Philips, GE Healthcare, Bayer, Guerbet, and Clarify. The funders had no role in the data analysis, or the decision to publish. All remaining authors have declared no conflicts of interest., (Copyright © 2023 The Korean Society of Radiology.)

Through a comprehensive analysis of the gene expression and dependency in HCC patients and cell lines, LAT1 was identified as the top amino acid transporter candidate supporting HCC tumorigenesis. To assess the suitability of LAT1 as a HCC therapeutic target, we used CRISPR/Cas9 to knockout (KO) LAT1 in the epithelial HCC cell line, Huh7. Knockout of LAT1 diminished its branched chain amino acid (BCAA) transport activity and significantly reduced cell proliferation in Huh7. Consistent with in vitro studies, LAT1 ablation led to suppression of tumor growth in a xenograft model. To elucidate the mechanism underlying the observed inhibition of cell proliferation upon LAT1 KO, we performed RNA-sequencing analysis and investigated the changes in the mTORC1 signaling pathway. LAT1 ablation resulted in a notable reduction in phosphorylation of p70S6K, a downstream target of mTORC1, as well as its substrate S6RP. This reduced cell proliferation and mTORC1 activity were rescued when LAT1 was overexpressed. These findings imply an essential role of LAT1 for maintenance of tumor cell growth and additional therapeutic angles against liver cancer.

Purpose: To investigate added value of late portal venous phase (LPVP) for identification of enhancing capsule (EC) on gadoxetate disodium-enhanced MRI (GD-MRI) for diagnosing hepatocellular carcinoma (HCC) in patients with chronic liver disease (CLD)., Methods: This retrospective study comprised 116 high-risk patients with 128 pathologically proven HCCs who underwent GD-MRI including arterial phase, conventional portal venous phase (CPVP, 60 s), LPVP (mean, 104.4 ± 6.7 s; range, 90-119 s), and transitional phase (TP, 3 min). Two independent radiologists assessed the presence of major HCC features, including EC on CPVP and/or TP (CPVP/TP) and EC on LPVP. The frequency of EC was compared on GD-MRI between with and without inclusion of LPVP. The radiologists assigned Liver Imaging Reporting and Data System (LI-RADS) v2018 categories before and after identifying EC on LPVP., Results: Of the total 128 HCCs, 74 and 73 revealed EC on CPVP/TP for reviewer 1 and 2, respectively. After inclusion of LPVP, each reviewer identified seven more EC [Reviewer 1, 57.8% (74/128) vs. 63.3% (81/128); Reviewer 2, 57.0% (73/128) vs. 62.5% (80/128); P = 0.016, respectively]. Sensitivities of LR-5 assignment for diagnosing HCCs were not significantly different in GD-MRI with or without LPVP for EC identification [Reviewer 1, 71.9% (92/128) vs. 72.7% (93/128); Reviewer 2, 75.0% (96/128) vs. 75.8% (97/128); P = 1.000, respectively]., Conclusion: Including the LPVP in GD-MRI may improve identification of EC of HCC in patients with CLD. However, LI-RADS v2018 using GD-MRI showed comparable sensitivity for diagnosing HCC regardless of applying LPVP for EC., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Aims: Multiple arterial-phase magnetic resonance imaging (MA-MRI) was introduced to overcome the limitations of gadoxetic acid-enhanced MRI, but its clinical impacts on hepatocellular carcinoma (HCC) diagnosis have not been well assessed. We investigated whether MA-MRI with gadoxetic acid could improve the diagnosis of HCC ≤3.0 cm in comparison with single arterial-phase MRI (SA-MRI)., Methods: This retrospective study included 397 patients from two tertiary institutions who underwent gadoxetic acid-enhanced MRI (243 patients with 271 lesions in cohort-1 underwent SA-MRI, and 154 patients with 166 lesions in cohort-2 underwent MA-MRI). The patients had 437 hepatic lesions ≤3.0 cm with pathologic confirmation. The arterial-phase image quality and diagnostic performance of SA-MRI and MA-MRI were analysed and compared. To minimize the effects of selection bias because of potential confounding between the two groups, propensity score-matching was additionally performed., Results: MA-MRI showed a significantly higher percentage of optimal arterial-phase timing (94.2% vs. 74.5%, p < .001) and lower incidence of inadequate examinations (1.3% vs. 5.8%, p = .034) than SA-MRI. MA-MRI had a significantly higher non-rim arterial-phase hyperenhancement (APHE) detection rate (94.9% vs. 85.5%, p = .005) and sensitivity for diagnosing HCC (87.4% vs. 70.0%, p < .001) than SA-MRI, but no significant difference in specificity (92.9% vs. 93.1%, p = .966). In 123 pairs of propensity score-matched patients, MA-MRI had significantly higher sensitivity (89.1% vs. 74.5%, p = .006) than SA-MRI with equal specificity (92.3% vs. 92.3%, p > .999)., Conclusions: Compared with SA-MRI, MA-MRI with gadoxetic acid can detect more non-rim APHE and significantly improve sensitivity for diagnosing HCC ≤3.0 cm, without a significant decrease in specificity., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aberrant adenosine-to-inosine (A-to-I) RNA editing, catalyzed by adenosine deaminase acting on double-stranded RNA (ADAR), has been implicated in various cancers, but the mechanisms by which microRNA (miRNA) editing contributes to cancer development are largely unknown. Our multistage hepatocellular carcinogenesis transcriptome data analyses, together with publicly available data, indicated that ADAR1 was the most profoundly dysregulated gene among RNA-editing enzyme family members in liver cancer. Targeted inactivation of ADAR1 inhibited the in vitro tumorigenesis of liver cancer cells. An integrative computational analyses of RNA-edited hotspots and the known editing frequency of miRNAs suggested that the miRNA miR-3144-3p was edited by ADAR1 during liver cancer progression. Specifically, ADAR1 promoted A-to-I editing of canonical miR-3144-3p to replace the adenosine at Position 3 in the seed region with a guanine (ED&#95;miR-3144-3p(3&#95;A < G)) in liver cancer cells. We then demonstrated that Musashi RNA-binding protein 2 (MSI2) was a specific target of miR-3144-3p and that MSI2 overexpression was due to excessive ADAR1-dependent over-editing of canonical miR-3144-3p in liver cancer. In addition, target prediction analyses and validation experiments identified solute carrier family 38 member 4 (SLC38A4) as a specific gene target of ED&#95;miR-3144-3p(3&#95;A < G). The ectopic expression of both ADAR1 and the ED&#95;miR-3144-3p(3&#95;A < G) mimic enhanced mitotic activities, and ADAR1 suppressed SLC38A4 expression in liver cancer cells. Treatments with mouse-specific ADAR1-, MSI2-siRNA-, or SLC38A4-expressing plasmids suppressed tumorigenesis and tumor growth in a mouse model of spontaneous liver cancer. Our findings suggest that the aberrant regulation of ADAR1 augments oncogenic MSI2 effects by excessively editing canonical miR-3144-3p and that the resultant ED&#95;miR-3144-3p(3&#95;A < G) simultaneously suppresses tumor suppressor SLC38A4 expression, contributing to hepatocellular carcinogenesis., (© 2022. The Author(s).)

Objective: This study aimed to evaluate the usefulness of quantitative indices obtained from deep learning analysis of gadoxetic acid-enhanced hepatobiliary phase (HBP) MRI and their longitudinal changes in predicting decompensation and death in patients with advanced chronic liver disease (ACLD)., Materials and Methods: We included patients who underwent baseline and 1-year follow-up MRI from a prospective cohort that underwent gadoxetic acid-enhanced MRI for hepatocellular carcinoma surveillance between November 2011 and August 2012 at a tertiary medical center. Baseline liver condition was categorized as non-ACLD, compensated ACLD, and decompensated ACLD. The liver-to-spleen signal intensity ratio (LS-SIR) and liver-to-spleen volume ratio (LS-VR) were automatically measured on the HBP images using a deep learning algorithm, and their percentage changes at the 1-year follow-up (ΔLS-SIR and ΔLS-VR) were calculated. The associations of the MRI indices with hepatic decompensation and a composite endpoint of liver-related death or transplantation were evaluated using a competing risk analysis with multivariable Fine and Gray regression models, including baseline parameters alone and both baseline and follow-up parameters., Results: Our study included 280 patients (153 male; mean age ± standard deviation, 57 ± 7.95 years) with non-ACLD, compensated ACLD, and decompensated ACLD in 32, 186, and 62 patients, respectively. Patients were followed for 11-117 months (median, 104 months). In patients with compensated ACLD, baseline LS-SIR (sub-distribution hazard ratio [sHR], 0.81; p = 0.034) and LS-VR (sHR, 0.71; p = 0.01) were independently associated with hepatic decompensation. The ΔLS-VR (sHR, 0.54; p = 0.002) was predictive of hepatic decompensation after adjusting for baseline variables. ΔLS-VR was an independent predictor of liver-related death or transplantation in patients with compensated ACLD (sHR, 0.46; p = 0.026) and decompensated ACLD (sHR, 0.61; p = 0.023)., Conclusion: MRI indices automatically derived from the deep learning analysis of gadoxetic acid-enhanced HBP MRI can be used as prognostic markers in patients with ACLD., Competing Interests: Seung Soo Lee and So Yeon Kim who is on the editorial board of the Korean Journal of Radiology was not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Korean Society of Radiology.)

Hepatocellular carcinoma (HCC) is an aggressive and incurable cancer. Although understanding of the molecular pathogenesis of HCC has greatly advanced, therapeutic options for the disease remain limited. In this study, we demonstrated that SETD5 expression is positively associated with poor prognosis of HCC and that SETD5 depletion decreased HCC cell proliferation and invasion while inducing cell death. Transcriptome analysis revealed that SETD5 loss downregulated the interferon-mediated inflammatory response in HCC cells. In addition, SETD5 depletion downregulated the expression of a critical glycolysis gene, PKM (pyruvate kinase M1/2), and decreased glycolysis activity in HCC cells. Finally, SETD5 knockdown inhibited tumor growth in xenograft mouse models. These results collectively suggest that SETD5 is involved in the tumorigenic features of HCC cells and that targeting SETD5 may suppress HCC progression.

Objectives: The multiple arterial-phase (AP) technique was introduced for liver MRI, but it is not really known if multiple AP MRI (MA-MRI) improves image quality and lesion detection rate on gadoxetate disodium-enhanced MRI in comparison with single AP MRI (SA-MRI). We aimed to determine the clinical usefulness of MA-MRI in comparison with SA-MRI., Methods: Original articles reporting the percentage of adequate AP imaging and the lesion detection rate on gadoxetate disodium-enhanced MA-MRI were identified in PubMed, EMBASE, and Cochrane Library databases. The pooled percentage of adequate AP imaging and lesion detection rate were calculated using random-effects meta-analysis of single proportions. Subgroup analysis was performed to explain causes of study heterogeneity, and publication bias was evaluated using Egger's test., Results: Of 772 articles screened, 22 studies in 12 articles were included: 18 studies (ten MA-MRI and eight SA-MRI) suitably defined the percentage of adequate AP imaging and four (three MA-MRI and one SA-MRI) defined the lesion detection rate. MA-MRI had 16.1% higher pooled percentage of adequate AP imaging than SA-MRI (94.8% vs. 78.7%, p < 0.01). MA-MRI additionally detected 33.2% of lesions than SA-MRI (83.2% vs. 50.0%, p = 0.06). Substantial study heterogeneity was found in MA-MRI, and the definition of adequate AP imaging, lesion characteristics, and reference standards were significant factors affecting study heterogeneity (p ≤ 0.02). Significant publication bias was found in MA-MRI (p < 0.01) but not in SA-MRI studies (p = 0.87)., Conclusions: Gadoxetate disodium-enhanced MA-MRI may be more clinically useful than SA-MRI, but further study is necessary to validate this finding because of study heterogeneity and publication bias., Key Points: • Multiple arterial-phase MRI (MA-MRI) had a 16.1% higher pooled percentage of adequate AP imaging than single arterial-phase MRI (SA-MRI) (94.8% vs. 78.7%, p < 0.01). • MA-MRI additionally detected an extra 33.2% of lesions compared with SA-MRI (83.2% vs. 50.0%, p = 0.06). • Substantial study heterogeneity and significant publication bias were found across MA-MRI studies., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Objectives: With the increasing use of gadoxetic acid-enhanced MRI for HCC surveillance, hepatobiliary phase (HBP) hypointense nodules without arterial phase hyperenhancement (APHE) are frequently encountered. We investigated the rate of these nodules with hypervascular transformation, which suggests hepatocarcinogenesis, by using a prospectively collected longitudinal surveillance cohort data., Methods: This study included 382 prospectively enrolled patients at high risk for developing HCC who underwent 1-3 rounds of bi-annual surveillance gadoxetic acid-enhanced MRI. MRI was analyzed to detect HBP hypointense nodules without APHE. Follow-up dynamic CTs and MRIs were evaluated to detect hypervascular transformation of the nodules. Cox proportional hazards regression analyses were used to find predictors for hypervascular transformation., Results: A total of 76 HBP hypointense nodules without APHE were found in 48 patients, giving a prevalence of 12.6% (48/382). The mean nodule size was 10.8 mm, with 43.4% (33/76) being ≥ 10 mm. Over a median follow-up of 78.6 months, 19 nodules (25.0%) showed hypervascular transformation, all of which demonstrated typical imaging features of HCC. On multivariable Cox-regression analysis, size (≥ 10 mm) was the only independent predictor of hypervascular transformation (hazard ratio, 3.31; 95% confidence interval, 1.21-9.05). The cumulative incidence of hypervascular transformation at 12 and 60 months of nodules ≥ 10 mm was 12.3% and 50.4%, respectively, while that of nodules < 10 mm was 2.5% and 13.9%, respectively., Conclusions: About half of the HBP hypointense nodules ≥ 10 mm without APHE transformed to HCC at 5 years of follow-up, indicating the necessity for cautious monitoring with an augmented and extended follow-up schedule for these nodules., Key Points: • The prevalence of HBP hypointense nodules without APHE was 12.6% in a prospectively recruited population at high risk of developing HCC. • Nodule size ≥ 10 mm was significantly associated with hypervascular transformation, and approximately half of the HBP hypointense nodules ≥ 10 mm without APHE transformed to HCC during 5 years of follow-up. • Given the risk of malignant transformation, HBP hypointense nodules ≥ 10 mm without APHE should be closely monitored., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Background & Aims: We aimed to compare the performance of gadoxetic acid-enhanced abbreviated MRI (AMRI)-based surveillance and ultrasound-only surveillance in high-risk patients for hepatocellular carcinoma (HCC)., Methods: Prospectively recruited high-risk patients (>5% annual risk of HCC) who underwent one to three rounds of complete gadoxetic acid-enhanced MRI (CMRI) and ultrasound at 6-months intervals were retrospectively analysed. AMRI consisted of diffusion-weighted, T2-weighted, and hepatobiliary phase imaging. The sensitivity, specificity, and accuracy of CMRI followed by AMRI (CAA), AMRI-only (AAA), and ultrasound-only (US) were compared using generalized estimating equations. Image quality was assessed., Results: In 382 patients, HCC was diagnosed in 43 (11.3%), including 42 with early-stage HCCs. The sensitivities of CAA (90.7%, 39/43) and AAA (86.0%, 37/43) were higher than US (27.9% [12/43]; P < 0.001), whereas the sensitivities of the two MRI approaches did not significantly differ (P = 0.56). The specificity of CAA (97.1%, 983/1012) was higher than AAA (95.6% [967/1012]; P = 0.01) and not significantly different from US (96.3% [975/1012]; P = 0.59). The CAA approach had the best accuracy of 96.9% (1022/1055), higher than the AAA approach (95.2% [1004/1055]; P = 0.01) and the US approach (93.6% [987/1055]; P = 0.01). Image quality was inadequate in 33.7% (356/1055) of US examinations but in only 10.0% (105/1055) of the AAA and 11.1% (117/1055) of the CAA approach., Conclusions: In high-risk patients, AMRI-based surveillance approaches had higher sensitivities than ultrasound-only surveillance for early-stage HCC. A sequential MRI approach of CMRI followed by AMRIs showed superior accuracy than the AMRI-only or ultrasound-only approach., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: We aimed to determine a new strategy for Liver Imaging Reporting and Data System category M (LR-M) criteria to improve the diagnosis of HCC ≤ 3.0 cm on magnetic resonance imaging (MRI)., Methods: A total of 463 pathologically confirmed hepatic observations ≤ 3.0 cm (375 HCCs, 32 other malignancies, 56 benignities) in 384 patients at risk of HCC who underwent gadoxetate-enhanced MRI were retrospectively analyzed. Two radiologists evaluated the presence of major, ancillary, and LR-M features according to LI-RADS v2018. Of the ten LR-M features, those significantly associated with non-HCC malignancy were identified using multivariable logistic regression analysis, and new LR-M criteria for improving the diagnosis of HCC were investigated. Generalized estimating equations were used to compare sensitivity and specificity of LR-5 for diagnosing HCC using the new LR-M criteria with values calculated using the original LR-M criteria. p < 0.05 was considered to indicate a significant difference., Results: Of ten LR-M features, rim arterial-phase hyperenhancement, delayed central enhancement, targetoid restriction, and targetoid transitional-phase/hepatobiliary-phase appearance were independently significantly associated with non-HCC malignancy (adjusted odds ratio ≥ 6.2; p ≤ 0.02). Using the new LR-M criteria (two or more of these significant features), the sensitivity of LR-5 for diagnosing HCC was higher than that with the original LR-M criteria (69% [95% confidence interval 64-73%] vs. 65% [61-70%], p = 0.002), whereas the specificity was similar (90% [82-95%] vs. 92% [83-96%], p = 0.28)., Conclusion: The new LR-M criteria (two or more significant features) can improve the sensitivity of LR-5 for diagnosing HCC ≤ 3.0 cm, without compromising specificity., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: This study aimed to compare the treatment outcomes of radiofrequency ablation (RFA) and stereotactic body radiation therapy (SBRT) for colorectal cancer liver metastases (CRLM) and to determine the favorable treatment modality according to tumor characteristics., Materials and Methods: We retrospectively analyzed the records of 222 colorectal cancer patients with 330 CRLM who underwent RFA (268 tumors in 178 patients) or SBRT (62 tumors in 44 patients) between 2007 and 2014. Kaplan-Meier method and Cox models were used by adjusting with inverse probability of treatment weighting (IPTW)., Results: The median follow-up duration was 30.5 months. The median tumor size was significantly smaller in the RFA group than in the SBRT group (1.5 cm vs 2.3 cm, p<0.001). In IPTW-adjusted analysis, difference in treatment modality was not associated with significant differences in 1-year and 3-year recurrence-free survival (35% vs 43%, 22% vs 23%; p=0.198), overall survival (96% vs 91%, 58% vs 56%; p=0.508), and freedom from local progression (FFLP; 90% vs 72%, 78% vs 60%; p=0.106). Significant interaction effect between the treatment modality and tumor size was observed for FFLP (p=0.001). In IPTW-adjusted subgroup analysis of patients with tumor size >2 cm, the SBRT group had a higher FFLP compared with the RFA group (HR, 0.153; p<0.001)., Conclusion: SBRT and RFA showed similar local control in the treatment of patients with CRLM. Tumor size was an independent prognostic factor for local control and SBRT may be preferred for larger tumors.

Background and Aims: We assessed the imaging outcomes of Liver Imaging Reporting and Data System (LI-RADS) v2018 categories in prospective hepatocellular carcinoma (HCC) surveillance cohort and determined imaging features significantly predictive of progression to a malignant LI-RADS category., Methods: The imaging outcomes of 120 patients (162 observations) prospectively enrolled between November 2011 and August 2012 were analysed according to LI-RADS v2018. Cumulative incidences for progression to a malignant category (LR-5 or LR-M) and LR-4 or higher were calculated for each baseline category and compared using log-rank tests. Clinical variables and imaging features significantly predictive of progression to a malignant category were evaluated using Cox proportional hazards modelling., Results: The 162 observations were initially categorized into 60 LR-2, 75 LR-3 and 27 LR-4. For LR-4 observations, the 1-year, 3-year and 5-year cumulative incidences of progression to a malignant category were 18.5% (95% confidence interval, 6.6-35.2%), 43.0% (23.1-61.5%) and 52.5% (25.9-73.5%), which were significantly higher than those of LR-2 and LR-3 (p  < .001). For LR-3, the 1-year, 3-year and 5-year cumulative incidences of progression to LR-4 or higher were 4.1% (1.1-10.4%), 13.9% (6.7-23.6%) and 23.1% (12.7-35.4%), which were significantly higher than that of LR-2 (p  = .009). In multivariable analysis, size ≥1.0 cm (hazard ratio [HR] = 2.58, 1.04-6.40) and nonrim arterial-phase hyperenhancement (HR = 2.45, 1.11-5.42) were significantly independently associated with progression to a malignant category., Conclusion: Long-term imaging outcomes differed significantly according to LI-RADS category. Size ≥1.0 cm and nonrim arterial-phase hyperenhancement were imaging features significantly predictive of progression to a malignant category., (© 2022 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

While ultrasound (US) is considered an important tool for hepatocellular carcinoma (HCC) surveillance, it has limited sensitivity for detecting early-stage HCC. Abbreviated MRI (AMRI) has recently gained popularity owing to better sensitivity in its detection of early-stage HCC than US, while also minimizing the time and cost in comparison to complete contrast-enhanced MRI, as AMRI includes only a few essential sequences tailored for detecting HCC. Currently, three AMRI protocols exist, namely gadoxetic acid-enhanced hepatobiliary-phase AMRI, dynamic contrast-enhanced AMRI, and non-enhanced AMRI. In this study, we discussed the rationale and technical details of AMRI techniques for achieving optimal surveillance performance. The strengths, weaknesses, and current issues of each AMRI protocol were also elucidated. Moreover, we scrutinized previously performed AMRI studies regarding clinical and technical factors. Reporting and recall strategies were discussed while considering the differences in AMRI protocols. A risk-stratified approach for the target population should be taken to maximize the benefits of AMRI and the cost-effectiveness should be considered. In the era of multiple HCC surveillance tools, patients need to be fully informed about their choices for better adherence to a surveillance program., Competing Interests: So Yeon Kim who is on the editorial board of the Korean Journal of Radiology was not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Korean Society of Radiology.)

Background: Current major guidelines for diagnosis of hepatocellular carcinoma (HCC) based on imaging findings are different from each other and do not include clinical risk factors as a diagnostic criteria., Purpose: To developed and validated a new diagnostic score system using MRI and clinical features as applied in chronic hepatitis B patients., Study Type: Retrospective observational study., Subject: A total of 418 treatment-naïve patients (out of 902 patients) with chronic hepatitis B having 556 lesions suspected for HCC which were eligible for curative treatment., Field Strength/sequence: T1W GRE in- and opposed-phase, T2W FSE, DWI, and T1W 3D-GRE dynamic contrast-enhanced sequences at 1.5  T and 3  T., Assessment: Six radiologists with 7-22 years of experience independently evaluated MR images based on Liver Imaging Reporting and Data System (LI-RADS) version 2018., Statistical Tests: Based on logistic regression analysis of MRI features and clinical factors, a risk score system was devised in derivation cohorts (268 patients, 352 lesions) and externally validated (150 patients, 204 lesions). The performance of the new score system was assessed by Harell's c-index. Using cutoff value of 12, maintaining positive predictive value ≥95%, the diagnostic performances of the score system were compared with those of LR-5., Results: The 15-point diagnostic scoring system used MRI features (lesion size, nonrim arterial phase hyperenhancement, portal venous phase hypointensity, hepatobiliary phase hypointensity, and diffusion restriction) and clinical factors (alpha-fetoprotein and platelet). It showed good discrimination in the derivation (c-index, 0.946) and validation cohorts (c-index, 0.907). Using a risk score of 12 as a cut-off, this system yielded higher sensitivity than LR-5 (derivation cohort, 76.8% vs. 52.1%; validation cohort, 73.4% vs. 49.5%) without significant decrease in specificity (derivation cohort, 93.1% vs. 97.2%, P = 0.074; validation cohort, 91.7% vs. 96.1%, P = 0.299)., Data Conclusion: A new score system showed improved sensitivity in chronic hepatitis B patients compared to LI-RADS without significant compromise in specificity. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2., (© 2021 International Society for Magnetic Resonance in Medicine.)

Purpose: This work aimed to explore in depth the genomic and molecular underpinnings of hepatocellular carcinoma (HCC) with increased 2[18F]fluoro-2-deoxy-d-glucose (FDG) uptake in PET and to identify therapeutic targets based on this imaging-genomic surrogate., Experimental Design: We used RNA sequencing and whole-exome sequencing data obtained from 117 patients with HCC who underwent hepatic resection with preoperative FDG-PET/CT imaging as a discovery cohort. The primary radiogenomic results were validated with transcriptomes from a second cohort of 81 patients with more advanced tumors. All patients were allocated to an FDG-avid or FDG-non-avid group according to the PET findings. We also screened potential drug candidates targeting FDG-avid HCCs in vitro and in vivo., Results: High FDG avidity conferred worse recurrence-free survival after HCC resection. Whole transcriptome analysis revealed upregulation of mTOR pathway signals in the FDG-avid tumors, together with higher abundance of associated mutations. These clinical and genomic findings were replicated in the validation set. A molecular signature of FDG-avid HCCs identified in the discovery set consistently predicted poor prognoses in the public-access datasets of two cohorts. Treatment with an mTOR inhibitor resulted in decreased FDG uptake followed by effective tumor control in both the hyperglycolytic HCC cell lines and xenograft mouse models., Conclusions: Our PET-based radiogenomic analysis indicates that mTOR pathway genes are markedly activated and altered in HCCs with high FDG retention. This nuclear imaging biomarker may stimulate umbrella trials and tailored treatments in precision care of patients with HCC., (©2022 American Association for Cancer Research.)

Objective: Since its introduction in 2011, the CT/MRI diagnostic Liver Imaging Reporting and Data System (LI-RADS) has been updated in 2014, 2017, and 2018. We evaluated the impact of CT/MRI diagnostic LI-RADS on liver MRI research methodology for the diagnosis of hepatocellular carcinoma (HCC)., Materials and Methods: The MEDLINE, EMBASE, and Cochrane databases were searched for original articles reporting the diagnostic performance of liver MRI for HCC between 2011 and 2019. The MRI techniques, image analysis methods, and diagnostic criteria for HCC used in each study were investigated. The studies were classified into three groups according to the year of publication (2011-2013, 2014-2016, and 2017-2019). We compared the percentage of studies adopting MRI techniques recommended by LI-RADS, image analysis methods in accordance with the lexicon defined in LI-RADS, and diagnostic criteria endorsed by LI-RADS. We compared the pooled sensitivity and specificity between studies that used the LI-RADS and those that did not., Results: This systematic review included 179 studies. The percentages of studies using imaging techniques recommended by LI-RADS were 77.8% for 2011-2013, 85.7% for 2014-2016, and 84.2% for 2017-2019, with no significant difference ( p = 0.951). After the introduction of LI-RADS, the percentages of studies following the LI-RADS lexicon were 0.0%, 18.4%, and 56.6% in the respective periods ( p < 0.001), while the percentages of studies using the LI-RADS diagnostic imaging criteria were 0.0%, 22.9%, and 60.7%, respectively ( p < 0.001). Studies that did not use the LI-RADS and those that used the LI-RADS version 2018 showed no significant difference in sensitivity and specificity (86.3% vs. 77.7%, p = 0.102 and 91.4% vs. 89.9%, p = 0.770, respectively), with some difference in heterogeneity (I² = 94.3% vs. 86.7% in sensitivity and I² = 86.6% vs. 53.2% in specificity)., Conclusion: LI-RADS imparted significant changes in the image analysis methods and diagnostic criteria used in liver MRI research for the diagnosis of HCC., Competing Interests: So Yeon Kim and Seung Soo Lee who is on the editorial board of the Korean Journal of Radiology was not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Korean Society of Radiology.)

Background: Glypican-3 (GPC3), a membrane-bound heparan sulfate proteoglycan, is a biomarker of hepatocellular carcinoma (HCC) progression. Aptamers specifically binding to target biomolecules have recently emerged as clinical disease diagnosis targets. Here, we describe 3D structure-based aptaprobe platforms for detecting GPC3, such as aptablotting, aptaprobe-based sandwich assay (ALISA), and aptaprobe-based imaging analysis., Results: For preparing the aptaprobe-GPC3 platforms, we obtained 12 high affinity aptamer candidates (GPC3&#95;1 to GPC3&#95;12) that specifically bind to target GPC3 molecules. Structure-based molecular interactions identified distinct aptatopic residues responsible for binding to the paratopic nucleotide sequences (nt-paratope) of GPC3 aptaprobes. Sandwichable and overlapped aptaprobes were selected through structural analysis. The aptaprobe specificity for using in HCC diagnostics were verified through Aptablotting and ALISA. Moreover, aptaprobe-based imaging showed that the binding property of GPC3&#95;3 and their GPC3 specificity were maintained in HCC xenograft models, which may indicate a new HCC imaging diagnosis., Conclusion: Aptaprobe has the potential to be used as an affinity reagent to detect the target in vivo and in vitro diagnosing system., (© 2022. The Author(s).)

Purpose: We aimed to determine the optimal image sequence for measurement of hepatic observations on gadoxetate disodium-enhanced MRI in comparison with pathologic measurement, and to evaluate its clinical impact on the Liver Imaging Reporting and Data System (LI-RADS) v2018 classification., Methods: Two hundred and fifty-three patients (279 hepatic observations) who underwent gadoxetate disodium-enhanced MRI and subsequent hepatectomy were retrospectively included. Two radiologists independently evaluated the visualization score (five-point scale) and size of each observation on six MRI sequences (T1-weighted, T2-weighted, arterial-phase, portal venous-phase, transitional-phase [TP], and hepatobiliary-phase [HBP] images) and assigned a LI-RADS category. Correlations between MRI and pathologic measurements were evaluated using Pearson correlation coefficients. A repeated measures analysis of variance with Bonferroni post hoc comparison tests was used to compare the visualization scores and absolute differences between MRI sequences and pathologic measurements. The LI-RADS classification according the size measurement of each MRI sequence was compared using Cochran's Q test with a post hoc McNemar's test., Results: Of the MRI sequences, HBP had the highest visualization score (4.1 ± 0.6) and correlation coefficient (r = 0.965). The absolute difference between MRI and pathologic measurement was lowest on TP (2.3 mm ± 2.2), followed by HBP (2.4 mm ± 2.1). In the LI-RADS classifications, HBP did not have any non-visible observations. Regarding LR-3, LR-4, and LR-5, there was no significantly different LI-RADS classification among the six MRI sequences (p ≥ 0.122)., Conclusion: Hepatobiliary-phase images are clinically useful for measuring hepatic observations on gadoxetate disodium-enhanced MRI, especially regarding visibility and correlation with pathologic findings., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: To evaluate the clinical outcomes of patients who received stereotactic body radiation therapy (SBRT) for single viable hepatocellular carcinoma (HCC) at the site of incomplete transarterial chemoembolization (TACE)., Methods: Patients treated with SBRT for single viable HCC after incomplete TACE between 2012 and 2017 at Asan Medical Center (Seoul, South Korea) were included. Incomplete TACE was defined as (1) evidence of viable HCC at the site of TACE on follow-up dynamic computed tomography (CT) or magnetic resonance imaging following one or more consecutive TACEs, (2) no definite tumor staining on superselective hepatic angiogram, or (3) no definite iodized oil uptake on post-embolization angiogram or CT. Doses of 10-15 Gy per fraction were given over 3-4 consecutive days. The primary outcome was local control rate at 3 years and secondary outcome included tumor response, overall survival rate, out-of-field intrahepatic recurrence-free survival, distant metastasis-free survival and treatment-related toxicities. Treatment-related adverse events were evaluated according to the common terminology criteria for adverse events, version 4.03., Results: A total of 302 patients were analyzed. The median follow-up duration was 32.9 months (interquartile range [IQR], 23.6-41.7) and the median tumor size was 2.0 cm (range, 0.7-6.9). The local control (LC) and overall survival rates at 3 years were 91.2 and 72.7%, respectively. 95.4% of the tumors reached complete response (CR) during the entire follow-up period (anyCR). The median interval from SBRT to anyCR was 3.4 months (IQR, 1.9-4.7), and 39.9 and 83.3% of the lesions reached CR at 3- and 6-months after SBRT, respectively. Radiation-induced liver disease was observed in 8 (2.6%) patients. No patients experienced gastroduodenal bleeding within the radiation field., Conclusion: SBRT could be considered a feasible salvage treatment option for HCC after incomplete TACE., (© 2022. The Author(s).)

Background The Liver Imaging Reporting and Data System (LI-RADS) assigns a risk category for hepatocellular carcinoma (HCC) to imaging observations. Establishing the contributions of major features can inform the diagnostic algorithm. Purpose To perform a systematic review and individual patient data meta-analysis to establish the probability of HCC for each LI-RADS major feature using CT/MRI and contrast-enhanced US (CEUS) LI-RADS in patients at high risk for HCC. Materials and Methods Multiple databases (MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Scopus) were searched for studies from January 2014 to September 2019 that evaluated the accuracy of CT, MRI, and CEUS for HCC detection using LI-RADS (CT/MRI LI-RADS, versions 2014, 2017, and 2018; CEUS LI-RADS, versions 2016 and 2017). Data were centralized. Clustering was addressed at the study and patient levels using mixed models. Adjusted odds ratios (ORs) with 95% CIs were determined for each major feature using multivariable stepwise logistic regression. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) (PROSPERO protocol: CRD42020164486). Results A total of 32 studies were included, with 1170 CT observations, 3341 MRI observations, and 853 CEUS observations. At multivariable analysis of CT/MRI LI-RADS, all major features were associated with HCC, except threshold growth (OR, 1.6; 95% CI: 0.7, 3.6; P = .07). Nonperipheral washout (OR, 13.2; 95% CI: 9.0, 19.2; P = .01) and nonrim arterial phase hyperenhancement (APHE) (OR, 10.3; 95% CI: 6.7, 15.6; P = .01) had stronger associations with HCC than enhancing capsule (OR, 2.4; 95% CI: 1.7, 3.5; P = .03). On CEUS images, APHE (OR, 7.3; 95% CI: 4.6, 11.5; P = .01), late and mild washout (OR, 4.1; 95% CI: 2.6, 6.6; P = .01), and size of at least 20 mm (OR, 1.6; 95% CI: 1.04, 2.5; P = .04) were associated with HCC. Twenty-five studies (78%) had high risk of bias due to reporting ambiguity or study design flaws. Conclusion Most Liver Imaging Reporting and Data System major features had different independent associations with hepatocellular carcinoma; for CT/MRI, arterial phase hyperenhancement and washout had the strongest associations, whereas threshold growth had no association. © RSNA, 2021 Online supplemental material is available for this article.

Background: Because of the heterogeneity of metastatic colorectal cancer (mCRC), a genome-wide analysis was performed to characterize the tumor immune microenvironment (TIME)., Methods: RNA-seq analysis of 62 primary CRCs without and 63 with systemic metastasis (SM- and SM+ groups) was conducted, and the data were used in a training set after adjustment by propensity score matching. Samples were further subdivided into those with hepatic metastasis (CHM subgroup), pulmonary metastasis (CPM subgroup), or concurrent CHM and CPM (concurrent group). Validation was done by quantitative reverse-transcription polymerase chain reaction using another 40 primary CRC samples., Results: Compared with the CHM or CPM subgroups, the concurrent group showed upregulated in inflammatory or immune processes, cytokine secretion, and myeloid leukocyte migration. Nine candidate genes were selected: SM-specific IDO1, JAM3, and PDE2A; CHM- or CPM-specific BIRC7; CPM-specific HISI1H2BK, and both SM-specific and CHM- or CPM-specific EPHB6, LPL, THBD, and PPBP. In a validation set of primary CRCs, JAM3 and IDO1 (p = 0.044 and p = 0.036, respectively) were confirmed to show significant upregulation and downregulation, respectively, in the SM+ group, whereas HIST1H2BK (p = 0.017) was significantly upregulated in the CPM subgroup., Conclusions: Our findings indicate that a host-suppressive TIME is established in the primary tumor of mCRC and identify immune-related site-specific markers of mCRC., (© 2021 Wiley Periodicals LLC.)

Background: Repeated transarterial chemoembolization (TACE) can be associated with loss of its efficacy and subsequent tumor progression., Purpose: To identify features of gadoxetic acid-enhanced magnetic resonance imaging (MRI) associated with TACE refractoriness and to develop a prediction model for estimating the risk of TACE refractoriness., Material and Methods: Among 1025 patients with intermediate-stage hepatocellular carcinoma (HCC) who underwent TACE as a first-line treatment during 2010-2017, 427 patients who underwent preoperative gadoxetic acid-enhanced MRI were analyzed. According to the date of initial TACE, patients were divided into the development cohort (n = 211) and the test cohort (n = 216). TACE refractoriness was determined according to the Japan Society of Hepatology guidelines. Univariable and multivariable analyses were performed to investigate the association between clinical/MRI features and TACE refractoriness. The performance of the prediction model was internally and externally assessed using the C-index of discrimination and a Hosmer-Lemeshow goodness-of-fit test for calibration., Results: By analyzing 427 patients, we constructed a prediction model with the following independent features associated with TACE refractoriness: maximum tumor size; tumor number; peritumoral hypointensity on hepatobiliary phase (HBP); and the presence of non-hypervascular hypointense nodule on HBP. This system enabled the prediction of TACE refractoriness in the development cohort (C-index, 0.796) and the test cohort (C-index, 0.738) with good discrimination and calibration abilities., Conclusion: The prediction model based on gadoxetic acid-enhanced MRI features in addition to the known predictors including tumor size and number can be used to estimate the risk of TACE refractoriness in patients with intermediate-stage HCC.

The Warburg effect is important for cancer cell proliferation. This phenomenon can be flexible by interaction between glycolysis and mitochondrial oxidation for energy production. We aimed to investigate the anticancer effects of the pyruvate dehydrogenase kinase inhibitor, dichloroacetate (DCA) and the mitochondrial respiratory complex I inhibitor metformin in liver cancer cells. The anticancer effect of DCA and/or metformin on HepG2, PLC/PRF5 human liver cancer cell lines, MH-134 murine hepatoma cell lines, and primary normal hepatocytes using MTT assay. Inhibition of lactate/ATP production and intracellular reactive oxygen species generation by DCA and metformin was investigated. Inhibition of PI3K/Akt/mTOR complex I was evaluated to see whether it occurred through AMPK signaling. Anticancer effects of a combination treatment of DCA and metformin were evaluated in HCC murine model. The results showed that metformin and DCA effectively induced apoptosis in liver cancer cells. A combination treatment of metformin and DCA did not affect viability of primary normal hepatocytes. Metformin upregulated glycolysis in liver cancer cells, thereby increasing sensitivity to the DCA treatment. Metformin and DCA inhibited mTOR complex I signaling through upregulated AMPK-independent REDD1. In addition, metformin and DCA increased reactive oxygen species levels in liver cancer cells, which induced apoptosis. A combination treatment of metformin and DCA significantly suppressed the tumor growth of liver cancer cells using in vivo xenograft model. Taken together, the combined treatment of metformin and DCA suppressed the growth of liver cancer cells. This strategy may be effective for patients with advanced liver cancer.

Objectives: To establish inter-reader reliability of CT Liver Imaging Reporting and Data System (LI-RADS) and explore factors that affect it., Methods: MEDLINE and EMBASE databases were searched from January 2014 to March 2020 to identify original articles reporting the inter-reader reliability of CT LI-RADS. The imaging analysis methodology of each study was identified, and pooled intraclass correlation coefficient (ICC) or kappa values (κ) were calculated for lesion size, major features (arterial-phase hyperenhancement [APHE], nonperipheral washout [WO], and enhancing capsule [EC]), and LI-RADS categorization (LR) using random-effects models. Subgroup analyses of pooled κ were performed for the number of readers, average reader experience, differences in reader experience, and LI-RADS version., Results: In the 12 included studies, the pooled ICC or κ of lesion size, APHE, WO, EC, and LR were 0.99 (0.96-1.00), 0.69 (0.58-0.81), 0.67 (0.53-0.82), 0.65 (0.54-0.76), and 0.70 (0.59-0.82), respectively. The experience and number of readers varied: studies using readers with ≥ 10 years of experience showed significantly higher κ for LR (0.82 vs. 0.45, p = 0.01) than those with < 10 years of reader experience. Studies with multiple readers including inexperienced readers showed significantly lower κ for APHE (0.55 vs. 0.76, p = 0.04) and LR (0.45 vs. 0.79, p = 0.02) than those with all experienced readers., Conclusions: CT LI-RADS showed substantial inter-reader reliability for major features and LR. Inter-reader reliability differed significantly according to average reader experience and differences in reader experience. Reported results for inter-reader reliability of CT LI-RADS should be understood with consideration of the imaging analysis methodology., Key Points: • The CT Liver Imaging Reporting and Data System (LI-RADS) provides substantial inter-reader reliability for three major features and category assignment. • The imaging analysis methodology varied across studies. • The inter-reader reliability of CT LI-RADS differed significantly according to the average reader experience and the difference in reader experience., (© 2021. European Society of Radiology.)

Objectives: To develop and evaluate a deep learning-based model capable of detecting primary hepatic malignancies in multiphase CT images of patients at high risk for hepatocellular carcinoma (HCC)., Methods: A total of 1350 multiphase CT scans of 1280 hepatic malignancies (1202 HCCs and 78 non-HCCs) in 1320 patients at high risk for HCC were retrospectively analyzed. Following the delineation of the focal hepatic lesions according to reference standards, the CT scans were categorized randomly into the training (568 scans), tuning (193 scans), and test (589 scans) sets. Multiphase CT information was subjected to multichannel integration, and livers were automatically segmented before model development. A deep learning-based model capable of detecting malignancies was developed using a mask region-based convolutional neural network. The thresholds of the prediction score and the intersection over union were determined on the tuning set corresponding to the highest sensitivity with < 5 false-positive cases per CT scan. The sensitivity and the number of false-positives of the proposed model on the test set were calculated. Potential causes of false-negatives and false-positives on the test set were analyzed., Results: This model exhibited a sensitivity of 84.8% with 4.80 false-positives per CT scan on the test set. The most frequent potential causes of false-negatives and false-positives were determined to be atypical enhancement patterns for HCC (71.7%) and registration/segmentation errors (42.7%), respectively., Conclusions: The proposed deep learning-based model developed to automatically detect primary hepatic malignancies exhibited an 84.8% of sensitivity with 4.80 false-positives per CT scan in the test set., Key Points: • Image processing, including multichannel integration of multiphase CT and automatic liver segmentation, enabled the application of a deep learning-based model to detect primary hepatic malignancy. • Our model exhibited a sensitivity of 84.8% with a false-positive rate of 4.80 per CT scan., (© 2021. European Society of Radiology.)

SWItch/Sucrose Non-Fermentable (SWI/SNF) is a multiprotein complex essential for the regulation of eukaryotic gene expression. SWI/SNF complex genes are genetically altered in over 20% of human malignancies, but the aberrant regulation of the SWI/SNF subunit genes and subsequent dysfunction caused by abnormal expression of subunit gene in cancer, remain poorly understood. Among the SWI/SNF subunit genes, SMARCA4, SMARCC1, and SMARCA2 were identified to be overexpressed in human hepatocellular carcinoma (HCC). Modulation of SMARCA4, SMARCC1, and SMARCA2 inhibited in vitro tumorigenesis of HCC cells. However, SMARCA4-targeting elicited remarkable inhibition in an in vivo Ras-transgenic mouse HCC model (Ras-Tg), and high expression levels of SMARCA4 significantly associated with poor prognosis in HCC patients. Furthermore, most HCC patients (72-86%) showed SMARCA4 overexpression compared to healthy controls. To identify SMARCA4-specific active enhancers, mapping, and analysis of chromatin state in liver cancer cells were performed. Integrative analysis of SMARCA4-regulated genes and active chromatin enhancers suggested 37 genes that are strongly activated by SMARCA4 in HCC. Through chromatin immunoprecipitation-qPCR and luciferase assays, we demonstrated that SMARCA4 activates Interleukin-1 receptor-associated kinase 1 (IRAK1) expression through IRAK1 active enhancer in HCC. We then showed that transcriptional activation of IRAK1 induces oncoprotein Gankyrin and aldo-keto reductase family 1 member B10 (AKR1B10) in HCC. The regulatory mechanism of the SMARCA4-IRAK1-Gankyrin, AKR1B10 axis was further demonstrated in HCC cells and in vivo Ras-Tg mice. Our results suggest that aberrant overexpression of SMARCA4 causes SWI/SNF to promote IRAK1 enhancer to activate oncoprotein Gankyrin and AKR1B10, thereby contributing to hepatocarcinogenesis., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Aim: We compared the clinical outcomes of radiofrequency ablation (RFA) and stereotactic body radiation therapy (SBRT) in small (≤ 3 cm) hepatocellular carcinoma., Methods: A total of 266 patients treated with RFA (n = 179) or SBRT (n = 87) were reviewed. Local control rates (LCRs), intrahepatic recurrence-free survival (IHRFS) rates, and overall survival (OS) rates were compared. Inverse probability of treatment weighting (IPTW) was used to adjust for imbalances in baseline characteristics between the two groups., Results: The median follow-up period was 50.3 months, and treatment method (RFA vs SBRT) was not a significant prognostic factor for LCR, OS, and IHRFS in both multivariate and IPTW-adjusted analyses. The 4-year LCRs after RFA and SBRT were 92.7% and 95.0%, respectively. Perivascular location was a significant prognostic factor for LCR in the entire patients and in the RFA group, but not in the SBRT group. The 4-year OS rates in the RFA and SBRT groups were 78.1% and 64.1%, respectively (P = 0.012). After IPTW adjustment, the 4-year LCRs (90.6% vs 96.3%) and OS rates (71.8% vs 70.2%) were not significantly different between the two groups. The rate of grade ≥ 3 adverse events was 0.6% (n = 1) in the RFA group and 1.1% (n = 1) in the SBRT group., Conclusions: The two treatment methods showed comparable outcomes in terms of LCR, OS rate, and IHRFS rate after IPTW adjustment. SBRT seems to be a viable alternative method for small hepatocellular carcinomas that are not suitable for RFA due to tumor location., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objective: To evaluate and compare the diagnostic performance of the updated HCC guidelines using gadoxetic acid-enhanced MRI., Methods: In this study, patients at risk of HCC who underwent gadoxetic acid-enhanced MRI following US/CT surveillance were retrospectively recruited from 3 centers. Three radiologists independently evaluated hepatic nodule imaging features relevant to the diagnostic criteria outlined in each guideline. Per-lesion sensitivity, specificity, and accuracy were compared between guidelines using logistic regression with a generalized estimating equation. Inter-observer agreements on imaging features were determined using Fless κ statistics., Results: Altogether, 447 nodules (310 HCCs, 20 combined hepatocellular-cholangiocarcinomas, 2 cholangiocarcinomas, and 115 benign entities) measuring 1-3 cm from 386 patients were assessed. The KLCA-NCC and APASL guidelines showed the highest sensitivity (82.3-90.6%, p < .001) and accuracy (83.9-88.6%) among the five guidelines. The OPTN/UNOS guideline showed the highest specificity (94.9-97.1%), followed by the AASLD/LI-RADS, EASL, KLCA-NCC, and APASL guidelines, with significant difference only with the APASL guideline. The diagnostic performance of the updated AASLD/LI-RADS and EASL guidelines and of the KLCA-NCC and APASL guidelines was comparable (p > .05). Inter-observer agreement was substantial to almost perfect (κ = 0.73-0.87)., Conclusions: For the diagnosis of HCC using gadoxetic acid-enhanced MRI, the KLCA-NCC and APASL guidelines showed the highest sensitivity and accuracy. The OPTN/UNOS guideline showed the highest specificity. Acknowledging their relative strengths and weaknesses could help adapt the diagnostic criteria according to the clinical context., Key Points: • APASL and KLCA-NCC provided significantly the highest sensitivity and accuracy, followed by AASLD/LI-RADS and EASL in an endemic area for hepatitis B. • OPTN/UNOS showed the highest specificity, followed by AASLD/LI-RADS, EASL, KLCA-NCC, and APASL guidelines, with significant difference only with APASL. • Broadened definition of arterial hyperenhancement, washout, and the size of the lesion eligible to apply diagnostic criteria may improve the diagnostic performance for HCC in an endemic area for hepatitis B.

Purpose: To identify the value of discrepancies in the central scar (CS)-like structure between dynamic CT and gadoxetate disodium-enhanced MRI for differentiating FNH from HCA., Methods: This retrospective study included 113 patients with pathologically-diagnosed FNH (n = 80) or HCA (n = 37). CS-like structures were evaluated on arterial phase (AP) CT and hepatobiliary phase (HBP) MRI. Presence of the CS-like structure, its discrepancy in visibility or size between AP CT and HBP MRI and between AP and HBP MRI, and features of non-scarred tumor portion were evaluated by two radiologists. Inter-observer agreement was evaluated by intraclass correlation coefficients (ICCs) and weighted kappa. Univariable and multivariable logistic regression and ROC analysis were performed to explore features differentiating FNH from HCA., Results: Inter-observer agreement was moderate-to-excellent (ICCs≥0.74, kappa≥0.65). On univariable analysis, presence of CS-like structures (P < 0.001), discrepancy of the CS-like structures between AP CT and HBP MRI (73.8 % in FNH; 16.2 % in HCA, P < 0.001) and between AP and HBP MRI (70.0 % in FNH; 16.2 % in HCA, P < 0.001), and the features of non-scarred tumor portion (P ≤ 0.011) were significantly different between FNH and HCA. On multivariable analysis, the discrepancy of CS-like structures between AP CT and HBP MRI, and the absence of low SI of the non-scarred tumor portion on HBP MRI, were suggestive of FNH (P = 0.036 and P < 0.001, respectively; area under the ROC curve, 0.96 [95 % CI, 0.93-0.99])., Conclusion: Evaluation of discrepancy in the visibility or size of CS-like structures between dynamic CT and gadoxetate disodium-enhanced MRI may facilitate the differentiation of FNH from HCA., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) can develop in patients with and without risk factors for hepatocellular carcinoma (HCC)., Purpose: To compare the clinical and magnetic resonance imaging (MRI) characteristics of cHCC-CCA in patients with and without risk factors for HCC, and to assess the influence of risk factors on patient prognosis., Study Type: Retrospective., Population: A total of 152 patients with surgically confirmed cHCC-CCA., Field Strength/sequence: 1.5-T and 3-T/T1-weighted dual gradient-echo in- and opposed-phase, T2-weighted turbo-spin-echo, diffusion-weighted single-shot spin-echo echo-planar, and T1-weighted three-dimensional gradient-echo contrast-enhanced sequences., Assessment: MRI features according to the Liver Imaging Reporting and Data System (LI-RADS) and pathologic findings based on revised classification were compared between patients with and without risk factors for HCC. Overall survival (OS) and recurrence-free survival (RFS) were also compared between the two groups, and factors associated with survival were evaluated., Statistical Tests: The clinico-pathologic and MRI features of the two groups were compared using Student's t-tests, Mann-Whitney U-tests, and chi-square tests. OS and RFS were evaluated by the Kaplan-Meier method, and factors associated with survival were evaluated by Cox proportional hazard model., Results: cHCC-CCA in patients with risk factors were more frequently classified as LI-RADS category 4 or 5 (LR-4/5; probably or definitely HCC) (48.7%), whereas those without risk factors were more frequently classified as category M (LR-M; probably malignant, not specific for HCC) (63.6%). RFS and OS did not differ significantly according to risk factors (P = 0.63 and 0.83). Multivariable analysis showed that pathologic tumor type (hazard ratio 2.02; P < 0.05) and LI-RADS category (hazard ratio 2.19; P < 0.05) were significantly associated with RFS and OS, respectively., Data Conclusion: Although MRI features of cHCC-CCA differed significantly between patients with and without risk factors for HCC, postsurgical prognosis did not. LI-RADS category and pathologic tumor type were independently correlated with postsurgical prognosis in patients with cHCC-CCA., Level of Evidence: 3 TECHNICAL EFFICACY STAGE: 2., (© 2021 International Society for Magnetic Resonance in Medicine.)

Background/purpose: Imaging diagnosis of hepatocellular carcinoma (HCC) is important, but the diagnostic performance of combined computed tomography (CT) and magnetic resonance imaging (MRI) using the Liver Imaging Reporting and Data System (LI-RADS) v2018 is not fully understood. We evaluated the clinical usefulness of combined CT and MRI for diagnosing HCC ≤ 3.0 cm using LI-RADS., Methods: In 222 patients at risk of HCC who underwent both contrast-enhanced dynamic CT and gadoxetate disodium-enhanced MRI in 2017, 291 hepatic nodules ≤ 3.0 cm were retrospectively analyzed. Two radiologists performed image analysis and assigned a LI-RADS category to each nodule. The diagnostic performance for HCC was evaluated for CT, ordinary-MRI (washout confined to portal venous-phase), and modified-MRI (washout extended to hepatobiliary phase), and sensitivity and specificity were calculated for each modality. Generalized estimating equations were used to compare the diagnostic performance for HCC between combined CT and ordinary-MRI, combined CT and modified-MRI, and CT or MRI alone. p < 0.0062 (0.05/8) was considered statistically significant following Bonferroni correction for multiple comparisons., Results: In 291 nodules, the sensitivity and specificity of CT, ordinary-MRI, and modified-MRI were 70.2% and 92.8%, 72.6% and 96.4%, and 84.6% and 88.0%, respectively. Compared with CT or MRI alone, both combined CT and ordinary-MRI (sensitivity, 83.7%; specificity, 95.2%) and combined CT and modified-MRI (sensitivity, 88.9%; specificity, 89.2%) showed significantly higher sensitivity (p ≤ 0.006), without a significant decrease in specificity (p ≥ 0.314)., Conclusions: Compared with CT or MRI alone, combined CT and MRI can increase sensitivity for diagnosing HCC ≤ 3.0 cm, without a significant decrease in specificity., (© 2021. Asian Pacific Association for the Study of the Liver.)

Purpose: To differentiate the computed tomography (CT) and magnetic resonance imaging (MRI) features of porto-sinusoidal vascular disease (PSVD) and liver cirrhosis (LC)., Methods: In this retrospective case-control study of patients with PSVD matched in a 1:3 ratio with LC patients according to liver function, initial diagnosis and time to final diagnosis were analyzed. Imaging features on CT and the parenchymal enhancement on hepatobiliary phase of hepatobiliary agent-enhanced MRI (HBA-MRI) were compared using a generalized linear mixed model. Focal hepatic lesions in the PSVD group were analyzed., Results: In total, 43 PSVD patients and 129 LC patients were included. Among PSVD patients, 72.1% were initially misdiagnosed with LC. PSVD patients had a longer diagnostic delay than LC patients (32 months vs. 4 months; p < 0.001). Liver surface nodularity was less common in the PSVD group than in the LC group (16.3% vs. 89.2%, p < 0.001). Increased caudate-to-right lobe ratio, heterogeneous parenchymal enhancement, and portal vein abnormalities were more frequently noted in the PSVD group than in the LC group (all p < 0.001). The grade of portal hypertension was significantly higher in the PSVD group than in the LC group (p < 0.001), and they also had brighter parenchymal enhancement during the hepatobiliary phase of HBA-MRI (p < 0.001). In the PSVD group, 14% patients had at least one focal hepatic lesion, primarily a focal nodular hyperplasia (FNH)-like nodule., Conclusions: Some imaging features on CT and HBA-MRI can distinguish PSVD from LC. Benign focal lesions, most commonly FNH-like nodules, can develop in PSVD.

Goal: The goal of this study was to determine disparities in liver cancer surveillance among people with disabilities is the goal of this study., Background: Using the linked administrative database in Korea, we sought to investigate (1) whether there are disparities in liver cancer surveillance according to degree and type of disability and (2) temporal trends in liver cancer surveillance among people with disabilities., Materials and Methods: We linked national disability registration data with national cancer surveillance data. We analyzed age-standardized participation rates for each year during the 2006-2015 period according to presence, type, and severity of the disability. We also examined factors associated with liver cancer surveillance by multivariate logistic regression using the most current data (2014-2015)., Results: The age-adjusted and sex-adjusted surveillance rate for liver cancer in people with disabilities increased from 25.7% in 2006 to 49.6% in 2015; however, during the same period, surveillance rate among people without disabilities increased from 24.9% to 54.5%. As a result, disparities in surveillance for liver cancer increased over time. The surveillance participation rate among people with disabilities was 12% lower than among people without disabilities. Surveillance rates were markedly lower among people with severe disabilities [adjusted odds ratio (aOR)=0.71] and people with renal disease (aOR=0.43), brain injuries (aOR=0.60), ostomy problems (aOR=0.60), and intellectual disabilities (aOR=0.69)., Conclusions: Despite the availability of a national liver cancer surveillance program, a marked disparity was found in liver cancer surveillance participation, especially among people with severe disabilities, renal disease, or brain-related or mental disabilities., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Coptidis Rhizoma is the dried rhizome from the Coptis chinensis Franch. that has been shown to have a number of beneficial pharmacological properties including antioxidant, anti-inflammatory, and anti-cancer effects. However, the anti-cancer effects of Coptidis Rhizoma on hepatocellular carcinoma (HCC) remain unclear. In this study, we investigated the anti-cancer properties of Coptidis Rhizoma ethanol extract (CR) in HCC Hep3B cells and in a xenograft mouse model. Our results showed that the CR significantly inhibited cell growth and induced apoptosis in Hep3B cells through increased expression of Bcl-2 associated x-protein (Bax) and cleavage of poly-ADP ribose polymerase (PARP), reduced expression of Bcl-2, and activated caspases. CR also increased the generation of intracellular reactive oxygen species (ROS), which caused a loss of mitochondrial membrane potential (MMP, ΔΨm) and activation of the mitochondria-mediated intrinsic apoptosis pathway. Moreover, N -acetylcysteine (NAC), a ROS inhibitor, markedly blocked the effects of CR on apoptotic pathways. CR also induced the expression of light chain 3 (LC3)-I/II, a key autophagy regulator, whereas CR-mediated autophagy was significantly suppressed by NAC. In addition, pre-treatment with NAC perfectly attenuated the inhibition of cell invasion and migration of CR-stimulated Hep3B cells. Furthermore, oral administration of CR suppressed Hep3B tumor growth in xenograft mice without toxicity, alterations to body weight, or changes in hematological and biochemical profiles. Taken together, our findings suggest that CR has anti-tumor effects that result from ROS generation, and may be a potential pharmacological intervention for HCC.