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Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide. Patients with NAFLD often suffer steatohepatitis, which can progress to cirrhosis and hepatocellular carcinoma. The presence of visceral obesity or type 2 diabetes mellitus (T2DM) is a major risk factor and potential therapeutic target for NAFLD. The establishment of animal models with these metabolic comorbidities and with the rapid progression of the disease is needed for developing treatments for NAFLD but remains to be archived. In the present study, KK-A

With the evolution of personalized medicine in the field of oncology, which includes optimal treatment selection using next-generation sequencing-based companion diagnostic systems and tumor-agnostic treatments according to common biomarkers, a liver tumor biopsy technique that can obtain a sufficient specimen volume must be established. The current study aimed to evaluate the safety and availability of a liver tumor biopsy technique with multiple puncture sites made using a coaxial introducer needle and embolization with gelatin sponge particles.Patients with primary or metastatic liver cancer who underwent liver tumor biopsies with puncture tract embolization using gelatin sponge (SpongelIn total, 96 patients were enrolled in this analysis. The median total number of puncture times per patient was 3 (range 1-8). The pathological diagnostic rate was 79.2%. Using the FoundationOneLiver biopsy with puncture tract embolization using a gelatin sponge may be safe and effective for collecting specimens with a volume sufficient for modern cancer treatments.

Background and Aim Immune checkpoint inhibitors and their combination with other agents have recently been available in advanced hepatocellular carcinoma (HCC). Hence, a thorough understanding of the tumor microenvironment based on tumor samples is yet to be achieved. This study aimed to explore the tumor microenvironment in advanced HCC in terms of microsatellite instability‐high (MSI‐H) by using tumor samples from advanced HCC patients eligible for systemic therapy. Methods MSI‐H was assessed by polymerase chain reaction, and the expression of mismatch repair proteins, PD‐L1, CD8, VEGF, and HLA‐class1 was evaluated by immunohistochemistry. Whole‐exome sequencing was performed for MSI‐H tumor samples. Results Of 50 patients, one (2.0%) was confirmed with MSI‐H. In the MSI‐H advanced HCC tumor, a high tumor mutation burden, infiltration of CD8+ lymphocytes, and low expression of VEGF were identified. Although PD‐L1 expression was negative, there was shrinkage of tumor following pembrolizumab. However, another tumor nonresponsive to pembrolizumab was present simultaneously. Checking the Cancer Genome Atlas (TCGA) database, we found a similar case to this patient. The TCGA case had unique gene features of miR‐21 and miR‐155 overexpression and hypermethylation of the MSH2 gene. Conclusion We identified a very small number of MSI‐H cases in HCC using one tumor biopsy sample for each patient with advanced HCC. In addition, epigenetic aberrations possibly lead to MSI‐H in HCC patients. Since different HCC clones might coexist in the liver, sampling from multiple tumors should be considered to clarify the true proportion of MSI‐H in HCC and to analyze tumor microenvironments., We confirmed that microsatellite instability‐high (MSI‐H) in hepatocellular carcinoma (HCC) was an extraordinarily rare case by using tumor samples of advanced HCC patients that were eligible for systemic therapies. Since the existence of heterogeneity in tumor microenvironment of advanced HCC was also implied, sampling from multiple tumors should be considered for analyzing tumor microenvironment including MSI‐H in patients with HCC.

Macrovascular invasion (MVI), including portal vein tumor thrombosis (PVTT), is strongly associated with poor prognosis in patients with hepatocellular carcinoma (HCC). While recommended standard treatment for patients with advanced HCC is systemic therapy, various treatment approaches, including resection, transarterial chemoembolization, and radiation, have been empirically suggested to improve prognosis by eliminating or controlling MVI. Herein, we report our experience of a case with advanced HCC where MVI was controlled by carbon-ion radiotherapy (CIRT) while on systemic therapy, resulting in a prolonged survival. A female patient with HCC in her early 60s had multiple intrahepatic lesions (maximum 60 mm in diameter) with PVTT. The PVTT of this patient had reached the main trunk of the portal vein despite the use of lenvatinib. The other intrahepatic lesions of the patient, except PVTT, had been controlled by lenvatinib. Therefore, hoping to control PVTT, we attempted CIRT. The patient resumed lenvatinib therapy after the irradiation. During lenvatinib re-treatment, no evident progression of PVTT was observed in the patient.

Macrovascular invasion (MVI), including portal vein tumor thrombosis (PVTT), is strongly associated with poor prognosis in patients with hepatocellular carcinoma (HCC). While recommended standard treatment for patients with advanced HCC is systemic therapy, various treatment approaches, including resection, transarterial chemoembolization, and radiation, have been empirically suggested to improve prognosis by eliminating or controlling MVI. Herein, we report our experience of a case with advanced HCC where MVI was controlled by carbon-ion radiotherapy (CIRT) while on systemic therapy, resulting in a prolonged survival. A female patient with HCC in her early 60s had multiple intrahepatic lesions (maximum 60 mm in diameter) with PVTT. The PVTT of this patient had reached the main trunk of the portal vein despite the use of lenvatinib. The other intrahepatic lesions of the patient, except PVTT, had been controlled by lenvatinib. Therefore, hoping to control PVTT, we attempted CIRT. The patient resumed lenvatinib therapy after the irradiation. During lenvatinib re-treatment, no evident progression of PVTT was observed in the patient.

Purpose Ramucirumab was shown to be effective as a second-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein levels > 400 ng/mL in a worldwide phase 3 trial. Ramucirumab is used in patients pretreated with various systemic therapies in clinical practice. We retrospectively examined the treatment outcomes of ramucirumab administered to advanced HCC patients after diverse systemic therapies. Methods Data were collected from patients with advanced HCC who received ramucirumab at three institutions in Japan. Radiological assessments were determined according to both Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and modified RECIST and the Common Terminology Criteria for Adverse Events version 5.0 was used to assess adverse events. Results A total of 37 patients treated with ramucirumab between June 2019 and March 2021 were included in the study. Ramucirumab was administered as second, third, fourth, and fifth-line treatment in 13 (35.1%), 14 (37.8%), eight (21.6%), and two (5.4%) patients, respectively. Most patients (29.7%) who received ramucirumab as a second-line therapy were pretreated with lenvatinib. We found grade 3 or higher adverse events only in seven patients and no significant changes in the albumin-bilirubin score during ramucirumab treatment in the present cohort. The median progression-free survival of patients treated with ramucirumab was 2.7 months (95% confidence interval, 1.6–7.3). Conclusion Although ramucirumab is used for various lines of treatment other than second-line immediately after sorafenib, its safety and effectiveness were not significantly different from the findings of the REACH-2 trial.

Background and Aim Standardization of the sedation protocol during radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC) is needed. This randomized, single‐blind, investigator‐initiated trial compared clinical outcomes during and after RFA using propofol and midazolam, respectively, in patients with HCC. Methods Few‐ and small‐nodule HCC patients (≤3 nodules and ≤3 cm) were randomly assigned to either propofol or midazolam. Patient satisfaction was assessed using a 100‐mm visual analog scale (VAS) (1 mm = not at all satisfied, 100 mm = completely satisfied). Sedation recovery rates 1, 2, 3, and 4 h after RFA were evaluated based on Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores; full recovery was defined as a MOAA/S score of 5. Results Between July 2013 and September 2017, 143 patients with HCC were enrolled, and 135 patients were randomly assigned to the treatment group. Compared with midazolam, propofol exhibited similar median procedural satisfaction (propofol: 73.1 mm, midazolam: 76.9 mm, P = 0.574). Recovery rates 1 and 2 h after RFA were higher in the propofol group than in the midazolam group. Meanwhile, recovery rates observed 3 and 4 h after RFA were similar in the two groups. The safety profiles during and after RFA were almost identical in the two groups. Conclusion Patient satisfaction was almost identical in patients receiving propofol and midazolam sedation during RFA. Propofol sedation resulted in reduced recovery time compared with midazolam sedation in patients with HCC. The safety profiles of both propofol and midazolam sedation during and after RFA were acceptable., The standardization of sedation protocol during radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC) is needed. This randomized, single‐blind, investigator‐initiated trial compared clinical outcomes during and after RFA using propofol and midazolam, respectively, in patients with HCC.

The aim of this multicenter retrospective study was to evaluate the impact of the eradication of hepatitis C virus (HCV) on the clinical outcomes of patients with hepatocellular carcinoma (HCC) treated with molecular-targeted agents (MTAs).Among 877 patients who received any MTA as first-line systemic therapy for HCC between June 2009 and March 2019, 569 patients with HCV-related HCC were enrolled in this retrospective study. Of these, 109 patients achieved sustained virological response (SVR) before starting MTA. After propensity score matching, the clinical outcomes of 109 patients in the SVR group and 109 patients in the non-SVR group were compared.The median time to progression in the SVR group (7.8 months) was similar to that in the non-SVR group (5.6 months) (p = 0.212). The median time to treatment failure in the SVR group (5.3 months) was longer than that in the non-SVR group (2.8 months) (p = 0.059), and post-progression survival and overall survival in the SVR group were significantly longer than those in the non-SVR group (12.0 months vs 7.2 months; p = 0.039, and 18.1 months vs 11.3 months; p = 0.019). At the end of first-line MTA therapy, the albumin-bilirubin (ALBI) score in the SVR group ( - 2.25) was significantly lower than that in the non-SVR group ( - 2.10) (p = 0.008).The eradication of HCV before MTA therapy maintained liver function and led to a prolonged treatment period and improved overall survival of HCV-related HCC patients. We should not overlook the benefits of HCV eradication in HCC patients.

Previous RNA immunoprecipitation followed by proteomic approaches successfully demonstrated that Embryonic Lethal, Abnormal Vision, Drosophila-Like 1 (ELAVL1) interacts with hepatitis B virus (HBV)-derived RNAs. Although ELAVL family proteins stabilize AU-rich element (ARE)-containing mRNAs, their role in HBV transcription remains unclear. This study conducted loss-of-function assays of ELAVL1 for inducible HBV-replicating HepAD38 cells and HBx-overexpressed HepG2 cells. In addition, clinicopathological analyses in primary hepatocellular carcinoma (HCC) surgical samples have also been conducted. Lentivirus-mediated short hairpin RNA knockdown of ELAVL1 resulted in a decrease in both viral RNA transcription and production of viral proteins, including HBs and HBx. Cell growth in tetracycline-treated replication-stopping HepAD38 cells was more significantly impaired in ELAVL1 knockdown than those in the control group, indicating that ELAVL1 is involved in proliferation not only by the suppression of HBV replication but also by other factors. Immunohistochemical analyses of 77 paired HCC surgical specimens have demonstrated that diffuse ELAVL1 expression was detected more frequently in HCC tissues (61.0%) than in nontumor tissues (27.3%). In addition, the abundant expression of ELAVL1 tended to affect postoperative recurrence in HBV-related HCC patients. In conclusion, ELAVL1 contributes not only to HBV replication but also to HCC cell growth. It may be a potent therapeutic target for HBV-related HCC treatment.

Background: There is no standard posttreatment for patients with advanced hepatocellular carcinoma (HCC) in whom lenvatinib therapy has failed. This study aimed to investigate rates of migration to posttreatment after lenvatinib and to explore candidates for second-line agents in the patients with failed lenvatinib therapy. Methods: We retrospectively collected data on patients with advanced HCC who received lenvatinib as the first-line agent in 7 institutions. Results: Overall survival and progression-free survival (PFS) of 178 patients who received lenvatinib as the first-line agent were 13.3 months (95% confidence interval [CI], 11.5–15.2) and 6.7 months (95% CI, 5.6–7.8), respectively. Sixty-nine of 151 patients (45.7%) who discontinued lenvatinib moved on to posttreatment. The migration rates from lenvatinib to the second-line agent and from the second-line agent to the third-line agent were 41.7 and 44.4%, respectively. Based on multivariate analysis, response to lenvatinib (complete or partial response according to modified RECIST) and discontinuation of lenvatinib due to radiological progression, as well as male were associated with a significantly higher probability of migration to posttreatment after lenvatinib. On the other hand, alpha-fetoprotein levels of 400 ng/mL or higher was correlated with a significantly lower probability of migration to posttreatment after lenvatinib. Of 63 patients who received second-line systemic therapy, 53 (84.2%) were administered sorafenib. PFS, objective response rate (ORR), and disease control rate (DCR) for sorafenib treatment were 1.8 months (95% CI, 0.6–3.0), 1.8%, and 20.8%, respectively. According to the Cox regression hazard model, Child-Pugh class B significantly contributed to shorter PFS. PFS, ORR, and DCR of 22 patients who received regorafenib after lenvatinib in any lines were 3.2 months (range, 1.5–4.9 months), 13.6%, and 36.3%, respectively. Similarly, PFS, ORR, and DCR of 17 patients who received regorafenib after lenvatinib in the third-line (after sorafenib) were 3.8 months (range, 1.1–6.5 months), 17.6%, and 41.2%, respectively. Conclusion: Sorafenib may not be a candidate for use as a posttreatment agent after lenvatinib, according to the results of the present study. Regorafenib has the potential to become an appropriate posttreatment agent after lenvatinib.

468 Background: Atezolizumab plus bevacizumab (Atezo + Bev) has been the standard treatment for frontline systemic therapy in advanced hepatocellular carcinoma (HCC). Immune check point inhibitors and its combination therapies are completely ineffective in some population of patients based on previous reports in several other malignancies. Regarding the results of a phase III trial (IMbrave 150) and several reports from real world practice, ̃20% of patients were determined to be progression disease (PD) as the best radiological response to Atezo + Bev in patients with advanced HCC. In this study, we analyzed the tumor microenvironment using tumor biopsy samples obtained before starting Atezo + Bev to clarify the mechanism of resistance to Atezo + Bev in patients with advanced HCC. Methods: This study enrolled patients with advanced HCC treated with Atezo + Bev at Chiba University Hospital between October 2020 and April 2021. We defined an ineffective group as patients with PD within 2 months according to RECIST version 1.1. The analysis of the tumor microenvironment in this study was performed using the nCounter PanCancer IO 360TM Panel. Results: Of 56 patients who initiated Atezo + Bev during the study period, biopsy samples with a sufficient amount of tumor tissue for analysis were obtained from 30 patients by percutaneous needle biopsy immediately before administering Atezo + Bev. According to radiological assessments, 7 and 23 patients were classified as ineffective and effective groups, respectively. Comparing baseline characteristics of the two groups, the rate of alpha fetoprotein (AFP) ≥ 400 ng/mL was significantly higher in the ineffective group (ineffective group: 85.7%; effective group: 34.8%; p = 0.031). According to gene expression analyses, 101 of 775 genes were differentially expressed between the two groups. Gene set enrichment analysis showed that antigen presentation, cytokine and chemokine signaling, cytotoxicity, immune cell adhesion and migration, and interferon signaling had a lower expression in the ineffective group. Conversely, a higher expression of cell proliferation signaling was observed in the ineffective group. In this cohort, the expression of Wnt signaling showed no significant difference between the two groups. We calculated the cytolytic activity based on the expression of granzyme A and perforin 1, and it was significantly lower in the ineffective group (6.1 in the effective group and 5.3 in the ineffective group, p = 0.013). Conclusions: Analysis of the tumor microenvironment found differences of several gene expressions and those of signaling between the ineffective and effective groups of Atezo + Bev in patients with advanced HCC. The ineffectiveness of Atezo + Bev is due to the reduced action of T cell infiltration and its immune response to tumor.