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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 4_suppl ( 2022-02-01), p. 468-468
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 2
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 19 ( 2022-10-10), p. 12015-
    Abstract: A functional cure of hepatitis B virus (HBV) infection or HB antigen loss is rarely achieved by nucleos(t)ide analogs which target viral polymerase. HBx protein is a regulatory protein associated with HBV replication. We thought to identify antiviral compounds targeting HBx protein by analyzing HBx binding activity. Recombinant GST-tagged HBx protein was applied on an FDA-approved drug library chip including 1018 compounds to determine binding affinity by surface plasmon resonance imaging (SPRi) using a PlexArray HT system. GST protein alone was used for control experiments. Candidate compounds were tested for anti-HBV activity as well as cell viability using HepG2.2.15.7 cells and HBV-infected human hepatocytes. Of the 1018 compounds screened, 24 compounds showed binding to HBx protein. Of the top 6 compounds with high affinity to HBx protein, tranilast was found to inhibit HBV replication without affecting cell viability using HepG2.2.15.7 cells. Tranilast also inhibited HBV infection using cultured human hepatocytes. Tranilast reduced HB antigen level dose-dependently. Overall, theSPRi screening assay identified novel drug candidates targeting HBx protein. Tranilast and its related compounds warrant further investigation for the treatment of HBV infection.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 3
    In: Liver Cancer, S. Karger AG, Vol. 10, No. 5 ( 2021), p. 473-484
    Abstract: 〈 b 〉 〈 i 〉 Background: 〈 /i 〉 〈 /b 〉 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. 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 We retrospectively collected data on patients with advanced HCC who received lenvatinib as the first-line agent in 7 institutions. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 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. 〈 b 〉 〈 i 〉 Conclusion: 〈 /i 〉 〈 /b 〉 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.
    Type of Medium: Online Resource
    ISSN: 2235-1795 , 1664-5553
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2021
    detail.hit.zdb_id: 2666925-0
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  • 4
    In: Journal of Cancer, Ivyspring International Publisher, Vol. 12, No. 9 ( 2021), p. 2694-2701
    Type of Medium: Online Resource
    ISSN: 1837-9664
    Language: English
    Publisher: Ivyspring International Publisher
    Publication Date: 2021
    detail.hit.zdb_id: 2573318-7
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  • 5
    In: Liver International, Wiley, Vol. 42, No. 9 ( 2022-08), p. 2055-2066
    Abstract: The incidence rate of hepatocellular carcinoma (HCC) is expected to increase, with most cases occurring in Asia. In some parts of Asia, the occurrence of HCC developing from metabolic‐related liver disease has markedly increased in recent years, whereas the occurrence of HCC developing from viral‐hepatitis–related liver disease has decreased. Advancements in the treatment of HCC over the past few decades has been remarkable, with most treatment strategies to remove or control liver tumours (hepatic resection, local ablation, radiation therapy, transarterial chemoembolisation, hepatic arterial infusion chemotherapy) primarily developing in Asia. In addition, recent progress in systemic therapies has prolonged the prognosis of advanced HCC. Nowadays, six regimens of systemic therapies have become available in most countries, according to phase III trials (atezolizumab plus bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab). In a global randomised phase III trial (IMbrave 150 trial), the most effective of the latest drug designs was newly emerged combination immunotherapy (atezolizumab plus bevacizumab), which has shown significantly prolonged overall survival compared with sorafenib, which was the first‐line systemic therapy for more than a decade. Now, the treatment dynamics for HCC are undergoing a major transition as a result of two important changes: the replacement of viral‐related HCC by metabolic‐related HCC and the emergence of combination immune therapy.
    Type of Medium: Online Resource
    ISSN: 1478-3223 , 1478-3231
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2124684-1
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  • 6
    In: BMC Gastroenterology, Springer Science and Business Media LLC, Vol. 23, No. 1 ( 2023-03-11)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1471-230X
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2041351-8
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  • 7
    In: BMC Gastroenterology, Springer Science and Business Media LLC, Vol. 23, No. 1 ( 2023-03-31)
    Abstract: Hyperprogressive disease (HPD) is a phenomenon with greatly accelerated tumor growth and clinical deterioration rates compared to pre-therapy, in patients treated with immune checkpoint inhibitors (ICI). The aim of this study is to clarify the reality of HPD in patients with advanced hepatocellular carcinoma (HCC) who were treated with atezolizumab plus bevacizumab (Atez/Bev) using tumor dynamics. Methods Medical records of consecutive patients with advanced HCC who were treated with Atez/Bev were retrospectively reviewed. HPD was defined as a more than two- or fourfold increase in tumor growth rate (TGR) or tumor growth kinetics rate (TGK R ) before and after treatment. Overall survival (OS) and baseline characteristics with or without HPD were analyzed. Results A total of 85 patients were included in the analysis. When HPD was defined as a twofold of TGR or TGK R , 8 patients (8/85, 9.4%) had HPD and 11 had PD without HPD. A total of 5 patients (5/85, 5.9%) were diagnosed with HPD and 14 with PD without HPD when HPD was defined as a fourfold of TGR or TGK R . No significant difference was observed in the baseline characteristics between HPD and non-HPD. Conclusion The prevalence of HPD in patients with advanced HCC treated with Atez/Bev was lower than those treated with nivolumab monotherapy. The HPD mechanism in ICI combined with antibodies targeting vascular endothelial growth factor (VEGF) remains to be elucidated.
    Type of Medium: Online Resource
    ISSN: 1471-230X
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2041351-8
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  • 8
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 4_suppl ( 2022-02-01), p. 467-467
    Abstract: 467 Background: The combination of atezolizumab and bevacizumab has become a standard treatment for advanced hepatocellular carcinoma (HCC). The indications for combination immunotherapy, including adjuvant therapy and combination with local therapy, are expected to expand in the future. Although exploring the tumor microenvironment has essential clinical implications in the era of combination immunotherapy, most studies on the tumor microenvironment in HCC are based on the analysis of archival samples at the time of HCC diagnosis. Considering the lengthy clinical course and characteristics of multicentric carcinogenesis, the tumor microenvironment may not be constant, but may differ from that at the time of advanced HCC. The present study aimed to assess the changes in the tumor microenvironment during the evolution to advanced HCC using archival samples and samples obtained prior to systemic therapy from the same patients. Methods: The tumor microenvironment was compared in 20 cases by immunohistochemical analyses of CD8, PD-L1, and VEGF expression. Levels of CD8-positive lymphocytes were defined as the mean number of CD8-positive lymphocytes in the tumor per 1 mm 2 and classified as low or high infiltration using the median value. PD-L1 expression was classified as negative ( 〈 1%) or positive (≥1%). VEGF expression was classified as low ( 〈 50%) or high (≥50%). Of the 20 cases, gene expression analysis was performed by the PanCancer IO360 Panel in 14 cases. Results: Approximately 40% of the archived samples were obtained at the early stage. Comparison of the tumor microenvironment between the two time points showed that 35% of the patients changed to CD8-positive lymphocyte high infiltration, 20% to positive PD-L1 expression, and 29% to high VEGF expression. The result of comparing gene profile was different between the archival samples and those prior to systemic therapy in 64% of the patients on the expression heat map. Gene set enrichment analysis showed significant changes in T cell cytotoxicity between the two time points. Conclusions: The tumor microenvironment might not be constant, but may change during the evolution to advanced HCC. In the present study, based on the results of the gene mutation analysis using whole-exome sequencing, we also reported the analyses by carcinogenic patterns such as multicentric occurrence and intrahepatic metastasis.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 9
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 4_suppl ( 2022-02-01), p. TPS495-TPS495
    Abstract: TPS495 Background: Advanced hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) has the worst prognosis among all HCC cases, due to its uniqueness of disease condition. Development of revolutionary therapeutic approaches to improve prognosis in these patients is an essential medical issue. A phase I/II trial demonstrated that treatment with durvalumab, an anti-programmed death-ligand 1 antibody, alone or in combination with tremelimumab, an anti-cytotoxic T-lymphocyte antigen 4 antibody, exhibited potential efficacy in patients with advanced HCC. Conversely, particle radiotherapy, including carbon-ion radiotherapy, has been shown to achieve unique dose distribution by delivering high-dose radiation to the target tumor while reducing the radiation dose to normal tissues due to its physical characteristics. Studies demonstrated that particle radiotherapy could achieve good local control in patients with HCC, including those with MVI. Additionally, particle radiotherapy as well as photon irradiation not only mediate localized tumor killing but also modify the tumor microenvironment, thereby potentiating the efficacy of immune checkpoint inhibitors. The DEPARTURE trial aims to evaluate whether treatment with durvalumab, alone or in combination with tremelimumab, plus particle radiotherapy is a safe and synergistically effective treatment in patients with advanced HCC and MVI. Methods: This is a phase Ib, multi-center, open-label, single-arm, investigator-initiated clinical trial to assess the safety of durvalumab monotherapy in combination with particle radiotherapy (Cohort A) and that of durvalumab plus tremelimumab in combination with particle radiotherapy (Cohort B) in advanced HCC patients with MVI who are ineligible for standard systemic therapy and Child–Pugh A liver disease. Cohort A will receive 1500 mg durvalumab every four weeks in principle. Cohort B will receive 1500 mg durvalumab every four weeks in principle and 300 mg tremelimumab only on day 1 of the first cycle. Carbon-ion radiotherapy will be administered after day 8 of the first cycle, following the first dose of either durvalumab or durvalumab plus tremelimumab on day 1. Dose prescription and fractionations are 60 Gy (RBE) in four fractions/1 week. Intrahepatic nodule with MVI is the target lesion for carbon-ion radiotherapy. Primary study endpoints are rates of all and severe adverse events including DLTs. Secondary endpoints include rates of overall survival, 6-month survival, objective response, and 6-month progression-free survival as well as time to progression. Clinical trial information: jRCT2031210046.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 10
    In: JGH Open, Wiley, Vol. 5, No. 11 ( 2021-11), p. 1266-1274
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 2397-9070 , 2397-9070
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2919809-4
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