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  • 1
    Online Resource
    Online Resource
    Circulating Cell-Free DNA Profiling Predicts the Therapeutic Outcome in Advanced Hepatocellular Carcinoma Patients Treated with Combination Immunotherapy
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 14 ( 2022-07-11), p. 3367-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 14 ( 2022-07-11), p. 3367-
    Abstract: Combination immunotherapy with anti-programmed cell death1-ligand1 (PD-L1) and anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for patients with unresectable HCC (u-HCC). However, limited patients obtain clinical benefits. Cell-free DNA (cfDNA) in peripheral blood contains circulating tumor DNA (ctDNA) that reflects molecular abnormalities in tumor tissue. We investigated the potential of cfDNA/ctDNA as biomarkers for predicting the therapeutic outcome in u-HCC patients treated with anti-PD-L1/VEGF therapy. We enrolled a multicenter cohort of 85 HCC patients treated with atezolizumab and bevacizumab (Atezo/Bev) between 2020 and 2021. Pretreatment plasma was collected, and cfDNA levels were quantified. Ultradeep sequencing of cfDNA was performed with a custom-made panel for detecting mutations in 25 HCC-related cancer genes. We evaluated the association of cfDNA/ctDNA profiles and clinical outcomes. Patients with high plasma cfDNA levels showed a significantly lower response rate and shorter progression-free survival and overall survival (OS) than those with low cfDNA levels. ctDNA detected in 55% of HCC patients included the telomerase reverse transcriptase (TERT) promoter in 31% of these patients, tumor protein 53 (TP53) in 21%, catenin beta 1 (CTNNB1) in 13% and phosphatase and tensin homolog (PTEN) in 7%. The presence or absence of ctDNA did not predict the efficacy of Atezo/Bev therapy. Twenty-six patients with a TERT mutation had significantly shorter OS than those without. The presence of a TERT mutation and alpha-fetoprotein (AFP) ≥ 400 ng/mL were independent predictors of poor OS according to multivariate Cox proportional hazard analysis and could be used to stratify patients treated with Atezo/Bev therapy based on prognosis. In conclusion, pretreatment cfDNA/ctDNA profiling may be useful for predicting the therapeutic outcome in u-HCC patients treated with anti-PD-L1/VEGF therapy.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14143367
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 2
    Online Resource
    Online Resource
    Thrombospondin-2 as a Predictive Biomarker for Hepatocellular Carcinoma after Hepatitis C Virus Elimination by Direct-Acting Antiviral
    MDPI AG ; 2023
    In:  Cancers Vol. 15, No. 2 ( 2023-01-11), p. 463-
    Details
    In: Cancers, MDPI AG, Vol. 15, No. 2 ( 2023-01-11), p. 463-
    Abstract: We evaluated the value of secreted glycoprotein thrombospondin-2 (TSP-2) to predict hepatocellular carcinoma (HCC) occurrence in chronic hepatitis C (CHC) patients after Hepatitis C virus (HCV) elimination by direct-acting antiviral agents (DAAs). A total of 786 CHC patients without an HCC history who achieved a sustained virological response (SVR) with DAAs were randomly assigned 2:1, with 524 patients as the derivation cohort and 262 patients as the validation cohort. Serum TSP-2 levels at the end of treatment were measured by enzyme-linked immunosorbent assay (ELISA). In the derivation cohort, the cumulative HCC rate was significantly higher in the high TSP-2 group than in the low TSP-2 group. Multivariate Cox proportional hazards analysis revealed that TSP-2, α-fetoprotein (AFP), and the fibrosis-4 (FIB-4) index were independent HCC risk factors. The area under the receiver operating characteristic curve (AUROC) of the score calculated from these three factors (AFT score) for predicting HCC was 0.83, which was significantly higher than that of each factor alone (TSP-2: 0.70, AFP: 0.72, FIB-4: 0.69). The AFT score was used to stratify patients according to the risk of HCC occurrence in the validation cohort. Lastly, in patients with a FIB-4 index 〈 3.25, the serum TSP-2 levels could be used to identify those patients with a high risk of HCC occurrence. Serum TSP-2 levels are a predictive biomarker of HCC occurrence in CHC patients after HCV elimination by DAA treatment. The AFT score using TSP-2, AFP, and the FIB-4 index may identify those who require HCC surveillance.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers15020463
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2527080-1
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  • 3
    Online Resource
    Online Resource
    Interleukin-6 Is a Circulating Prognostic Biomarker for Hepatocellular Carcinoma Patients Treated with Combined Immunotherapy
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 4 ( 2022-02-10), p. 883-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 4 ( 2022-02-10), p. 883-
    Abstract: Atezolizumab/bevacizumab (Atezo/Bev) combination therapy has become a front-line therapy for advanced hepatocellular carcinoma (HCC), but approximately 20% of patients are nonresponders. We investigated circulating biomarkers to predict therapeutic outcomes. We performed simultaneous measurement of 34 proteins using a multiplex bead-based immunoassay in baseline plasma from 34 patients who underwent Atezo/Bev therapy as first- or second-line treatment. Logistic regression analysis showed that plasma IL-6 and interferon alpha (IFNα) levels were significant predictors of non-responders (odds ratio of 13.33 and FDR p = 0.021 for IL-6 and IFNα). The progression-free survival (PFS) and overall survival (OS) of patients with high IL-6 levels were significantly shorter than those of patients with low IL-6 levels. Next, we measured baseline plasma IL-6 levels in 64 HCC patients who underwent Atezo/Bev therapy by ELISA. The IL-6-high group showed higher female ratio, AST levels, tumor markers, Child–Pugh score, and vascular invasion ratio. The PFS and OS of the IL-6-high group were significantly shorter than those of the IL-6-low group. Multivariate Cox proportional hazards analysis showed that IL-6 level and age were independent risk factors for disease progression (hazard ratio of 2.785 and p = 0.015 for IL-6, and hazard ratio 0.306 and p = 0.03 for age). In conclusion, circulating IL-6 levels are a novel prognostic biomarker for advanced HCC patients who undergo combined immunotherapy.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14040883
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 4
    Online Resource
    Online Resource
    Regnase-1 downregulation promotes pancreatic cancer through myeloid-derived suppressor cell-mediated evasion of anticancer immunity
    Springer Science and Business Media LLC ; 2023
    In:  Journal of Experimental & Clinical Cancer Research Vol. 42, No. 1 ( 2023-10-09)
    Details
    In: Journal of Experimental & Clinical Cancer Research, Springer Science and Business Media LLC, Vol. 42, No. 1 ( 2023-10-09)
    Abstract: Pancreatitis is known to be an important risk factor for pancreatic ductal adenocarcinoma (PDAC). However, the exact molecular mechanisms of how inflammation promotes PDAC are still not fully understood. Regnase-1, an endoribonuclease, regulates immune responses by degrading mRNAs of inflammation-related genes. Herein, we investigated the role of Regnase-1 in PDAC. Methods Clinical significance of intratumor Regnase-1 expression was evaluated by immunohistochemistry in 39 surgically-resected PDAC patients. The functional role of Regnase-1 was investigated by pancreas-specific Regnase-1 knockout mice and Kras-mutant Regnase-1 knockout mice. The mechanistic studies with gene silencing, RNA immunoprecipitation sequencing (RIP-seq) and immune cell reconstitution were performed in human/mouse PDAC cell lines and a syngeneic orthotopic tumor transplantation model of KrasG12D-mutant and Trp53-deficient PDAC cells. Results Regnase-1 expression was negatively correlated with the clinical outcomes and an independent predictor of poor relapse-free and overall survival in PDAC patients. Pancreas-specific Regnase-1 deletion in mice promoteed pancreatic cancer with PMN-MDSC infiltration and shortened their survival. A syngeneic orthotopic PDAC model exhibited that Regnase-1 downregulation accelerated tumor progression via recruitment of intratumor CD11b + MDSCs. Mechanistically, Regnase-1 directly negatively regulated a variety of chemokines/cytokines important for MDSC recruitment and activation, including CXCL1, CXCL2, CSF2, and TGFβ, in pancreatic cancer cells. We subsequently showed that IL-1β-mediated Regnase-1 downregulation recruited MDSCs to tumor sites and promoted pancreatic cancer progression via mitigation of cytotoxic T lympohocytes-mediated antitumor immunity. Conclusions IL-1b-mediated Regnase-1 downregulation induces MDSCs and promotes pancreatic cancer through the evasion of anticancer immunity.
    Type of Medium: Online Resource
    ISSN: 1756-9966
    URL: Article
    DOI: 10.1186/s13046-023-02831-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2430698-8
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