The Key Role of Staging Definitions for Assessment of Downstaging for Hepatocellular Carcinoma

Seminars in Liver Disease ◽

10.1055/s-0040-1716565 ◽

2021 ◽

Author(s):

Francis Y. Yao ◽

Nicholas Fidelman ◽

Neil Mehta

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Staging ◽

Tumor Stage ◽

Successful Outcome ◽

Viability Assessment ◽

Eligibility Criteria ◽

Tumor Viability ◽

Tumor Downstaging ◽

Structured Approach

AbstractThe success of liver transplant (LT) for hepatocellular carcinoma (HCC) is dependent on accurate tumor staging using validated imaging criteria, and adherence to acceptable criteria based on tumor size and number. Other factors including α-fetoprotein (AFP) and response to local regional therapy (LRT) have now played a larger role in candidate selection. Tumor downstaging is defined as reduction in the size of viable tumors using LRT to meet acceptable criteria for LT, and serves as a selection tool for a subgroup of HCC with more favorable biology. The application of tumor downstaging requires a structured approach involving three key components in tumor staging—initial tumor stage and eligibility criteria, tumor viability assessment following LRT, and target tumor stage prior to LT—and incorporation of AFP into staging and treatment response assessments. In this review, we provide in-depth discussions of the key role of these staging definitions in ensuring successful outcome.

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Downregulation of CRABP2 Inhibit the Tumorigenesis of Hepatocellular Carcinoma In Vivo and In Vitro

BioMed Research International ◽

10.1155/2020/3098327 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Qingmin Chen ◽

Ludong Tan ◽

Zhe Jin ◽

Yahui Liu ◽

Ze Zhang

Keyword(s):

Hepatocellular Carcinoma ◽

Retinoic Acid ◽

Cell Lines ◽

Molecular Mechanisms ◽

Tumor Stage ◽

Migration And Invasion ◽

Hcc Cells

Cellular retinoic acid-binding protein 2 (CRABP2) binds retinoic acid (RA) in the cytoplasm and transports it into the nucleus, allowing for the regulation of specific downstream signal pathway. Abnormal expression of CRABP2 has been detected in the development of several tumors. However, the role of CRABP2 in hepatocellular carcinoma (HCC) has never been revealed. The current study aimed to investigate the role of CRABP2 in HCC and illuminate the potential molecular mechanisms. The expression of CRABP2 in HCC tissues and cell lines was detected by western blotting and immunohistochemistry assays. Our results demonstrated that the expression levels of CRABP2 in HCC tissues were elevated with the tumor stage development, and it was also elevated in HCC cell lines. To evaluate the function of CRABP2, shRNA-knockdown strategy was used in HCC cells. Cell proliferation, metastasis, and apoptosis were analyzed by CCK-8, EdU staining, transwell, and flow cytometry assays, respectively. Based on our results, knockdown of CRABP2 by shRNA resulted in the inhibition of tumor proliferation, migration, and invasion in vitro, followed by increased tumor apoptosis-related protein expression and decreased ERK/VEGF pathway-related proteins expression. CRABP2 silencing in HCC cells also resulted in the failure to develop tumors in vivo. These results provide important insights into the role of CRABP2 in the development and development of HCC. Based on our findings, CRABP2 may be used as a novel diagnostic biomarker, and regulation of CRABP2 in HCC may provide a potential molecular target for the therapy of HCC.

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Prognostic Value of Microvessel Density in Hepatocellular Carcinoma Patients: A Meta-Analysis

The International Journal of Biological Markers ◽

10.5301/jbm.5000087 ◽

2014 ◽

Vol 29 (3) ◽

pp. 279-287 ◽

Cited By ~ 11

Author(s):

Yanyan Li ◽

Xuelei Ma ◽

Jing Zhang ◽

Xiaoxiao Liu ◽

Lei Liu

Keyword(s):

Hepatocellular Carcinoma ◽

Microvessel Density ◽

Meta Analysis ◽

Tumor Stage ◽

Disease Recurrence ◽

Prognostic Role ◽

Kaplan Meier ◽

Poorly Differentiated ◽

Predictive Role

Introduction The identification of microvessel density (MVD) in patients suffering from different types of cancer has become a hot point as an emerging and promising biomarker. The aim of the present study is to clarify the prognostic relevance of MVD in hepatocellular carcinoma (HCC). Methods Relevant articles were screened in PubMed and EMBASE databases. Patients' clinical characteristics, overall survival (OS), disease/recurrence-free survival (DFS/RFS), and MVD levels were extracted for further analysis. The statistical analysis derived from the Kaplan—Meier survival curves was calculated indirectly with the methods developed by Parmar, Williamson, and Tierney. Multivariate Cox hazard regression analysis was used directly in Stata 11.0. The pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated to evaluate the prognostic role of MVD in HCC. Results Our online literature search identified 12 articles including a total of 1,138 HCC patients. Meta-analysis of all the included studies considering survival outcomes showed a positive correlation between poor prognosis and higher-MVD levels. The pooled HRs (and 95% CIs) for OS and DFS/RFS were respectively 2.08 [1.77-2.45] and 2.64 [2.12-3.29]. Subgroup analyses considering tumor stage (I-II/III-IV), tumor size (<5 cm/≥5 cm), differentiation (well/poor), or cirrhosis status (≥20%/<20%) were also conducted, and all the above analyses supported the prognostic role of MVD in HCC. Conclusion Our meta-analysis showed that the available evidence supports the proposition that MVD has a good predictive role in HCC, especially when the patients have late stage, large size, or poorly differentiated tumors.

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The interplay of UBE2T and Mule in regulating Wnt/β-catenin activation to promote hepatocellular carcinoma progression

Cell Death and Disease ◽

10.1038/s41419-021-03403-6 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Nicole Pui Yu Ho ◽

Carmen Oi Ning Leung ◽

Tin Lok Wong ◽

Eunice Yuen Ting Lau ◽

Martina Mang Leng Lei ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Stage ◽

Attractive Potential ◽

Advanced Tumor Stage ◽

E3 Ligases ◽

Related Data ◽

Protein Levels ◽

Advanced Tumor ◽

Ubiquitin Conjugating Enzyme

AbstractEmerging evidence indicates the role of cancer stem cells (CSCs) in tumor relapse and therapeutic resistance in patients with hepatocellular carcinoma (HCC). To identify novel targets against liver CSCs, an integrative analysis of publicly available datasets involving HCC clinical and stemness-related data was employed to select genes that play crucial roles in HCC via regulation of liver CSCs. We revealed an enrichment of an interstrand cross-link repair pathway, in which ubiquitin-conjugating enzyme E2 T (UBE2T) was the most significantly upregulated. Consistently, our data showed that UBE2T was upregulated in enriched liver CSC populations. Clinically, UBE2T overexpression in HCC was further confirmed at mRNA and protein levels and was correlated with advanced tumor stage and poor patient survival. UBE2T was found to be critically involved in the regulation of liver CSCs, as evidenced by increases in self-renewal, drug resistance, tumorigenicity, and metastasis abilities. Mule, an E3 ubiquitin ligase, was identified to be the direct protein binding partner of UBE2T. Rather than the canonical role of acting as a mediator to transfer ubiquitin to E3 ligases, UBE2T is surprisingly able to physically bind and regulate the protein expression of Mule via ubiquitination. Mule was found to directly degrade β-catenin protein, and UBE2T was found to mediate liver CSC functions through direct regulation of Mule-mediated β-catenin degradation; this effect was abolished when the E2 activity of UBE2T was impaired. In conclusion, we revealed a novel UBE2T/Mule/β-catenin signaling cascade that is involved in the regulation of liver CSCs, which provides an attractive potential therapeutic target for HCC.

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Screening hypoxia-related genes as prognostic biomarkers and modeling the individualized prognostic predictor in hepatocellular carcinoma

10.21203/rs.2.19456/v1 ◽

2019 ◽

Author(s):

Hao Guo ◽

Jun Yan Zhang ◽

Shu Jing Lv ◽

Zhi Wang ◽

Wei Wei Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Risk Score ◽

Cox Regression ◽

Risk Groups ◽

Tumor Stage ◽

Clinical Prognosis ◽

Prognostic Predictor ◽

Univariate Analyse ◽

Auc Value

Abstract Background Hypoxia closely relates to malignant progression and appears to be prognostic for outcome in hepatocellular carcinoma (HCC). Our research aims to mine the Hypoxic related genes (HRGs) on the role of clinical prognosis in HCC. Moreover, we construct and define a model of prognostic predictor (PP) to estimate and improve prognosis of HCC patients.Results 37 differentially expressed HRGs were obtained. It contained 28 up-regulated and 9 down-regulated genes. After the univariate Cox regression model analysis, we obtained 27 prognosis-related HRGs. Of these, 25 genes were risk factors for cancer and 2 genes were protective factors. The PP was composed of the 10 key genes (HDLBP, SAP30, PFKP, DPYSL4, SLC2A1, PGK1, ERO1A, LDHA, ENO2, TPI1), and significantly divided patients of HCC into high- and low-risk groups according to overall survival (OS) ( P <0.001). We got the Area Under Curve(AUC) value of risk score calculated by PP was 0.777, which much bigger than other clinical parameters. Besides, PP was verified as an independent prognosis-related parameter (in univariate analyse, HR=1.484, 95% CI=1.342–1.642, P<0.001; in multivariate analyse, HR=1.414, 95% CI=1.258–1.588, P <0.001). Finally, the application of PP in clinic was concluded that the higher the patient's risk score, the higher the corresponding tumor stage and T stage, and the patient's prognosis was poor.Conclusions This study provides hypoxic related molecular targets for the therapeutic intervention. In addition, an individualized prognostic predictor was constructed to predict prognosis for HCC patients .

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Effect of prior cancer on survival of hepatocellular carcinoma: implications for clinical trial eligibility criteria

BMC Cancer ◽

10.1186/s12885-021-07870-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xuqi Sun ◽

Lingling Li ◽

Li Xu ◽

Zhongguo Zhou ◽

Jinbin Chen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trials ◽

Cox Regression ◽

Tumor Stage ◽

Eligibility Criteria ◽

Cancer History ◽

Cox Regression Analysis ◽

Patients With Cancer ◽

Kaplan Meier ◽

Tumor Stages

Abstract Background Patients with cancer history are usually excluded from hepatocellular carcinoma (HCC) clinical trials. However, whether previous malignancy affects the oncological outcomes of HCC patients has not been fully assessed. This study aimed to evaluate whether prior cancer compromised the survival of HCC patients. Methods Patients with HCC were extracted from the Surveillance, Epidemiology, and End Results database between 2004 and 2015, and then they were classified into groups with and without prior cancer. The Kaplan-Meier and multivariate Cox regression analysis were adopted to evaluate whether prior cancer impacted clinical outcomes after propensity score matching (PSM) adjusting baseline differences. Validation was performed in the cohort from our institution. Results We identified 2642 HCC patients with prior cancer. After PSM, the median overall survival (OS) time were 14.5 and 12.0 months respectively for groups with and without prior cancer. Prior cancer did not compromise prognosis in patients with HCC (p = 0.49). The same tendency was found in subgroups stratified by tumor stages and cancer interval period: OS was similar between groups with and without prior cancer (both p values> 0.1). In the multivariate Cox regression model, prior cancer did not adversely impact patients’ survival (HR: 1.024; 95% CI: 0.961–1.092). In the validation cohort from our institution, prior cancer had no significant association with worse outcomes (p = 0.48). Conclusion For HCC patients, prior cancer did not compromise their survival, regardless of tumor stage and cancer interval period. Exclusion criteria for HCC clinical trials could be reconsidered.

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