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Simple Summary: Recently, favorable outcomes have been reported for hepatocellular carcinoma treated with transarterial chemoembolization (TACE) combined with lenvatinib (LEN-TACE). However, the optimal treatment protocol remains unclear. In this study, we performed a 4-day lenvatinib administration followed by TACE without an interval (short-term LEN-TACE). The objective was to assess changes in tumor hemodynamics following the 4-day lenvatinib administration and to evaluate the outcomes of this combined therapy. A significant decrease in intra-tumor flow after lenvatinib was observed, with a 100% technical success rate and no severe adverse events. Complete response rates (CR) at 1 month were 75%, and the 12-month progression-free survival (PFS) rate was 75.0%. The lipiodol-washout ratio between 1 week and 4 months after cTACE correlated with the arterial flow reduction radio by lenvatinib prior to TACE (r = −0.55). The short-term LEN-TACE is feasible and safe, demonstrating promising results, including a high CR rate and prolonged PFS. Aim: Transarterial chemoembolization (TACE) combined with lenvatinib, employing a 4-day lenvatinib administration followed by TACE without an interval (short-term LEN-TACE), was performed for hepatocellular carcinoma (HCC). The aim was to assess tumor hemodynamics following the 4-day lenvatinib and to evaluate the treatment outcomes after the short-term LEN-TACE. Methods: 25 unresectable HCC patients received this combined therapy. Lenvatinib (4–12 mg) was administrated for 4 days prior to TACE. Perfusion CT scans were obtained before and after the lenvatinib administration. Either cTACE (76%) or DEB-TACE (24%) were performed. Results: intra-tumor blood flow significantly decreased after the 4-day lenvatinib (p < 0.05). The TACE procedure was successful with no severe adverse events in all patients. The overall complete response (CR) rate was 75% (cTACE 84%, DEB-TACE 40%). The lipiodol-washout ratio between 1 week and 4 months after cTACE correlated with the arterial flow reduction ratio by lenvatinib prior to TACE (r = −0.55). The 12-month progression-free survival (PFS) rate was 75.0%. Conclusions: The short-term LEN-TACE is feasible and safe, demonstrating promising outcomes with a high CR ratio, contributing to lipiodol retention in the tumor after cTACE, and extended PFS. To confirm the advantages of this treatment protocol, a prospective clinical trial is mandatory. [ABSTRACT FROM AUTHOR]

Simple Summary: To date, the indication for transarterial chemoembolization (TACE) of intermediate stage hepatocellular carcinoma (HCC) with a high tumor burden remains controversial. TACE has the advantage of a high possibility of achieving complete response (CR). This study aimed to clarify prognosis and identify predictors of CR by TACE in intermediate stage HCC beyond up-to-7 criteria. Overall, 56.9% of patients obtained CR, which contributed to prolonging survival. On multivariate analysis, the predictor of CR was HCC within up-to-11 criteria. In this study, the treatment strategy for intermediate stage HCC based on the 7–11 criteria is suggested. Aim: To clarify the prognosis and identify predictors for obtaining a complete response (CR) by transarterial chemoembolization (TACE) in intermediate stage HCC beyond up-to-7 criteria. Methods: Of the 120 patients with intermediate stage HCC who were treated by TACE as the initial treatment from February 2007 to January 2016, 72 finally matched the following inclusion criteria: beyond up-to-7 criteria; Child–Pugh score under 7; and no combined therapy within 4 weeks after the initial TACE. The CR rate and overall survival (OS) were evaluated. Logistic regression analysis was performed to identify predictors of CR. The deterioration of liver function after TACE was also evaluated. Results: The CR rate was 56.9%, and the overall median survival time (MST) was 37.7 months. The MST was 38.7 months in the CR group and 28.0 months in the non-CR group (p = 0.018). HCC within up-to-11 criteria was the only predictor of CR. The CR rate and MST were 70.7% and 37.7 months, respectively, in patients with HCC within up-to-11 criteria and 38.7% and 32.7 months, respectively, in the patients beyond up-to-11 criteria. Deterioration of the Child–Pugh score after the initial TACE and the 2nd TACE occurred in 24.2% and 12.0%, respectively, and deterioration of the modified albumin-bilirubin (mALBI) grade occurred in 17.6% and 7.4%, respectively. Conclusion: TACE can achieve high CR rates with prolonged overall survival for intermediate stage HCC beyond up-to-7 criteria. The predictor of CR was within up-to-11 criteria. Deterioration of liver function was not severe, but requires caution. Multidisciplinary approach as additional treatment after TACE is important. [ABSTRACT FROM AUTHOR]

We describe the clinical effects of short-term lenvatinib administration prior to conventional transarterial chemoembolization (cTACE) on tumor vasculature. Two patients with unresectable hepatocellular carcinoma underwent high-resolution digital subtraction angiography (DSA) and perfusion four-dimensional computed tomography during hepatic arteriography (4D-CTHA) before and after administration of lenvatinib treatment. The doses and periods of lenvatinib administration were, respectively, 12 mg/day for 7 days and 8 mg/day for 4 days. In both cases, high-resolution DSA revealed a decrease in dilatation and tortuosity of the tumor vessels. Furthermore, the tumor staining became more refined, and newly formed tiny tumor vessels were observed. Perfusion 4D-CTHA revealed a decrease in arterial blood flow to the tumor by 28.6% (from 487.9 to 139.5 mL/min/100 mg) and 42.5% (from 288.2 to 122.6 mL/min/100 mg) in the two cases, respectively. The cTACE procedure resulted in good lipiodol accumulation and complete response. Patients have remained recurrence-free for 12 and 11 months after the cTACE procedure, respectively. The administration of short-term lenvatinib in these two cases resulted in the normalization of tumor vessels, which likely led to improved lipiodol accumulation and a favorable antitumor effect. [ABSTRACT FROM AUTHOR]

Simple Summary: Transarterial chemoembolization (TACE) is the recommended treatment for intermediate-stage hepatocellular carcinoma (HCC), and its role as a curative treatment is now greater than previously due to the introduction of targeted molecular and immunotherapies. An important current concern is patient selection in TACE for intermediate-stage HCC, which includes an extremely heterogeneous population. The hepatobiliary phase (HEB) in gadoxetic acid disodium-enhanced MRI (EOB-MRI) is related to β-catenin, so EOB-MRI could be a molecular imaging biomarker reflecting tumor biology. Although HCC with signal heterogeneity in the HBP of EOB-MRI showed malignant behavior, no previous study has evaluated prognosis after TACE based on signal heterogeneity quantified in the HBP of EOB-MRI. In this study, we showed a quantitative analysis of tumor signal heterogeneity in HBP on EOB-MRI was valuable in predicting the prognosis after TACE and suggested a treatment strategy for patients with intermediate-stage HCC based on this quantitative evaluation. Background: In the era of local and systemic therapies for intermediate-stage hepatocellular carcinoma (HCC), personalized therapy has become available. The aim of our study was to evaluate the usefulness of quantitative analysis of pretreatment gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) to predict prognosis following transarterial chemoembolization (TACE). Methods: This retrospective study included patients with treatment-naïve intermediate-stage HCC who underwent EOB-MRI before the initial TACE and were treated by initial TACE between February 2007 and January 2016. Signal heterogeneity in the hepatobiliary phase (HBP) of EOB-MRI was quantitatively evaluated by the coefficient of variation (CV). The cutoff CV value was determined using the Classification and Regression Tree algorithm. Results: A total of 64 patients were enrolled. In multivariate analysis, High CV (≥0.16) was significantly associated with poor prognosis (p = 0.038). In a subgroup analysis of patients within up-to-7 criteria, MST was significantly shorter in the High CV group than in the Low CV group (37.7 vs. 82.9 months, p = 0.024). In patients beyond up-to-7 criteria, MST was 18.0 and 38.3 months in the High CV and Low CV groups, respectively (p = 0.182). In both groups scanned at 1.5 T or 3.0 T, High CV was significantly associated with poor prognosis (p = 0.001 and 0.003, respectively). Conclusion: CV of the tumor in the HBP of EOB-MRI is a valuable prognostic factor of TACE. [ABSTRACT FROM AUTHOR]

Background: To evaluate the feasibility of a novel approach for predicting hepatocellular carcinoma (HCC) response to drug-eluting beads transarterial chemoembolization (DEB-TACE) using computed tomography hepatic arteriography enhancement mapping (CTHA-EM) method. Methods: This three-institution retrospective study included 29 patients with 46 HCCs treated with DEB-TACE between 2017 and 2020. Pre- and posttreatment CTHA-EM images were generated using a prototype deformable registration and subtraction software. Relative tumor enhancement (TPost/pre-RE) defined as the ratio of tumor enhancement to normal liver tissue was calculated to categorize tumor response as residual (TPost-RE > 1) versus non-residual (TPost-RE ≤ 1) enhancement, which was blinded compared to the response assessment on first follow-up imaging using modified RECIST criteria. Additionally, for tumors with residual enhancement, CTHA-EM was evaluated to identify its potential feeding arteries. Results: CTHA-EM showed residual enhancement in 18/46 (39.1%) and non-residual enhancement in 28/46 (60.9%) HCCs, with significant differences on TPost-RE (3.05 ± 2.4 versus 0.48 ± 0.23, respectively; p < 0.001). The first follow-up imaging showed non-complete response (partial response or stable disease) in 19/46 (41.3%) and complete response in 27/46 (58.7%) HCCs. CTHA-EM had a response prediction sensitivity of 94.7% (95% CI, 74.0–99.9) and specificity of 100% (95% CI, 87.2–100). Feeding arteries to the residual enhancement areas were demonstrated in all 18 HCCs (20 arteries where DEB-TACE was delivered, 2 newly developed collaterals following DEB-TACE). Conclusion: CTHA-EM method was highly accurate in predicting initial HCC response to DEB-TACE and identifying feeding arteries to the areas of residual arterial enhancement. [ABSTRACT FROM AUTHOR]

Introduction: With the advent of effective systemic therapy, transarterial chemoembolization (TACE) is established as a highly effective locoregional treatment modality for carefully selected patients with hepatocellular carcinoma (HCC). This randomized controlled trial was conducted to clarify whether selective TACE with drug-eluting beads (DEB-TACE) loaded with epirubicin or selective conventional TACE (cTACE) with epirubicin-ethiodized oil might be more effective for obtaining complete response(CR) in patients with HCC. Methods: Between March 2016 and May 2019, Child-Pugh class A or B patients with unresectable HCC who were scheduled to receive selective TACE were randomly assigned at a 1:1 ratio to the DEB-TACE arm or the cTACE arm. The primary endpoint was the CR rate at 3 months, as evaluated according to the modified Response Evaluation Criteria in Solid Tumors by an independent review committee, and the secondary endpoints were the CR rate at 1 month and incidences of adverse events. Results: A total of 200 patients (DEB-TACE, 99 patients; cTACE, 101 patients) were enrolled in the study. The CR rates at 3 months and 1 month were significantly higher in the cTACE arm (75.2%, 84.2%) as compared with the DEB-TACE arm (27.6%, 35.7%). However, the frequencies of adverse events of any grade, including pyrexia (DEB-TACE vs. cTACE, 19.4% vs. 45.5%, p = 0.0001), fatigue (5.1% vs. 15.8%, p = 0.0194), malaise (11.1% vs. 25.7%, p = 0.0103), appetite loss (12.1% vs. 28.7%, p = 0.0048), abdominal pain (12.1% vs. 23.8%, p = 0.0423), increased serum bilirubin (22.2% vs. 48.5%, p = 0.0002), hypoalbuminemia (43.4% vs. 60.3%, p = 0.0154), increased serum aspartate aminotransferase (35.7% vs. 81.2%, p < 0.0001), and increased serum alanine aminotransferase (35.7% vs. 77.2%, p < 0.0001), were also significantly higher in the cTACE arm than in the DEB-TACE arm. Conclusions: Selective cTACE appeared to have higher CR rates for local tumor control as compared to selective DEB-TACE for HCC. However, the frequency of postembolization syndrome was also significantly higher in the cTACE group than in the DEB-TACE group. Thus, to achieve CR, cTACE may be selected over DEB-TACE in patients who can be expected to tolerate postembolization syndrome. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma is one of the leading causes of cancer-related death both in Japan and globally. In the advanced stage, hepatic arterial infusion chemotherapy (HAIC) is one of the most commonly used treatment options for liver cancer in Japan, and implantation of a catheter system (called a port system) in the body is a treatment method that has evolved mainly in Japan. The Guideline Committee of the Japanese Society of Interventional Radiology and the Japanese Society of Implantable Port Assisted Treatment jointly published clinical practice guidelines for HAIC with a port system to ensure its appropriate and safe performance in Japanese in 2018. We have written an updated English version of the guidelines with the aim of making this treatment widely known to experts globally. In this article, the evidence, method, indication, treatment regimen, and maintenance of the system are summarized. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to investigate the technical success rate of obtaining 3D-safety margin in superselective conventional transarterial chemoembolization (cTACE) using 3D images for small hepatocellular carcinoma (HCC). Methods: Consecutive 48 HCC nodules (diameter, 1–3 cm) in 44 patients were intentionally treated by superselective cTACE in an attempt to achieve 3D-safety margin. Superselective CT during hepatic arteriography (CTHA) was obtained before cTACE. When negative 3D-safety margin was found, branches supplied into the margin area were detected by using a 3D workstation. The technical success rate to obtain 3D-safety margin was investigated by intend-to-treat analysis. Local tumor recurrence rate and adverse events were also evaluated. Result: Nine of 48 tumors (18.8%) had 3D-safety margin in the initial superselective CTHA. After pulling back of the catheter and/or selection of another branch based on 3D images, 3D-safety margin was finally achieved in 45 (93.8%). There were 8 of 46 tumors (17.4%) with local recurrence after 5-year follow-up. Grade 3–4 of aspartate aminotransferase, alanine aminotransferase, and total bilirubin were found in 38.6, 36.4, and 2.3%, respectively. One portal vein thrombus and 3 biliary dilation or biloma were developed. Conclusion: Superselective cTACE obtaining 3D-safety margin in small HCC was feasible with a high success rate by using 3D images, which could be tolerable and prevent local tumor recurrence. [ABSTRACT FROM AUTHOR]

Activation of the Wnt-signaling pathway is known to play a crucial role in carcinogenesis of various human organs including the colon, liver, prostate, and endometrium. To investigate the mechanisms underlying hepatocellular carcinogenesis, we attempted to identify genes regulated by β-catenin/Tcf complex in a human hepatoma cell line, HepG2, in which an activated form of β-catenin is expressed. By means of cDNA microarray, we isolated a novel human gene, termed MARKL1 (MAP/microtubule affinity-regulating kinase-like 1), whose expression was downregulated in response to decreased Tcf/LEF1 activity. The transcript expressed in liver consisted of 3529 nucleotides that contained an open reading frame of 2256 nucleotides, encoding 752 amino acids homologous to human MARK3 (MAP/microtubule affinity-regulating kinase 3). Expression levels of MARKL1 were markedly elevated in eight of nine HCCs in which nuclear accumulation of β-catenin were observed, which may suggest that MARKL1 plays some role in hepatocellular carcinogenesis. Neoplasia (2001) 3, 4–9. [ABSTRACT FROM AUTHOR]