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Diagnostics
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Biomarkers in Hepatocellular Carcinoma
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Biomarkers in Hepatocellular Carcinoma

A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 15608

Special Issue Editors

Prof. Dr. Lory Saveria Croce'

E-Mail Website
Guest Editor
Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
Interests: NAFLD; NASH; HCV; ALD; liver cirrhosis; HCC; portal hypertension; elastography
Dr. Mauro Giuffrè

E-Mail Website
Guest Editor
Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
Interests: liver cirrhosis; HCC; portal hypertension; esophageal varices; liver elastography; spleen elastography
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hepatocellular Carcinoma (HCC) is the sixth most common cancer and the third cancer-related cause of death, with more than 800,000-related deaths each year.  In such a complicated scenario, tools for early diagnosis and prognosis prediction are fundamental for patient stratification.

HCC early diagnosis is currently achieved by ultrasound screening in cirrhotic patients, accompanied by evaluation in alpha-fetoprotein (AFP) fluctuation over time. However, this screening strategy is far from perfect, especially considering that even patients with liver disease and without advanced fibrosis can develop HCC. 

With advances in the understanding of tumor biology, along with the development of cellular and molecular techniques, the use of biomarkers related to early detection, invasiveness, metastasis, and recurrence have attracted a great deal of investigative interest resulting in the identification and utilization of several novel markers in this disease. This Special Issue will address the current advances in biomarkers in HCC.

Prof. Dr. Lory Saveria Croce'
Dr. Mauro Giuffrè
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Diagnostics is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Liver
  • Liver Cirrhosis
  • Hepatocellular Carcinoma
  • HCC
  • Biomarkers
  • Diagnostic Biomarkers
  • Prognostic Biomarkers
  • Early Diagnosis

Published Papers (6 papers)

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Research

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12 pages, 594 KiB  
Article
Predictors of Hepatocellular Carcinoma Early Recurrence in Patients Treated with Surgical Resection or Ablation Treatment: A Single-Center Experience
by Mauro Giuffrè, Enrico Zuliani, Alessia Visintin, Paola Tarchi, Paola Martingano, Riccardo Pizzolato, Deborah Bonazza, Flora Masutti, Rita Moretti and Lory Saveria Crocè
Diagnostics 2022, 12(10), 2517; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics12102517 - 17 Oct 2022
Cited by 4 | Viewed by 1263
Abstract
Introduction: Hepatocellular carcinoma (HCC) is the sixth most diagnosed malignancy and the fourth leading cause of cancer-related death worldwide, with poor overall survival despite available curative treatments. One of the most crucial factors influencing survival in HCC is recurrence. The current study aims [...] Read more.
Introduction: Hepatocellular carcinoma (HCC) is the sixth most diagnosed malignancy and the fourth leading cause of cancer-related death worldwide, with poor overall survival despite available curative treatments. One of the most crucial factors influencing survival in HCC is recurrence. The current study aims to determine factors associated with early recurrence of HCC in patients with BCLC Stage 0 or Stage A treated with surgical resection or local ablation. Materials and Methods: We retrospectively enrolled 58 consecutive patients diagnosed with HCC within BCLC Stage 0 or Stage A and treated either by surgical resection or local ablation with maximum nodule diameter < 50 mm. In the first year of follow-up after treatment, imaging was performed regularly one month after treatment and then every three months. Each case was discussed collectively by the Liver Multidisciplinary Group to decide diagnosis, treatment, follow-up, and disease recurrence. Variables resulting in statistically significant difference were then studied by Cox regression analysis; univariately and then multivariately based on forward stepwise Cox regression. Results are represented in hazard ratio (H.R.) with 95% confidence interval (C.I.). Results: There was no statistically significant difference in recurrence rates (34.8 vs. 45.7%, log-rank test, p = 0.274) between patients undergoing surgical resection and local ablation, respectively. Early recurrence was associated with male gender (HR 2.5, 95% C.I. 1.9–3.1), nodule diameter > 20 mm (HR 4.5, 95% C.I. 3.9–5.1), platelet count < 125 × 103 cell/mm3 (HR 1.6, 95% C.I. 1.2–1.9), platelet-lymphocyte ratio < 95 (HR 2.1, 95% C.I. 1.7–2.6), lymphocyte-monocyte ratio < 2.5 (HR 1.9, 95% C.I. 1.4–2.5), and neutrophil-lymphocyte ratio > 2 (HR 2.7, 95% C.I. 2.2–3.3). Discussion and Conclusions: Our results are in line with the current literature. Male gender and tumor nodule dimension are the main risk factors associated with early HCC recurrence. Platelet count and other combined scores can be used as predictive tools for early HCC recurrence, although more studies are needed to define cut-offs. Full article
(This article belongs to the Special Issue Biomarkers in Hepatocellular Carcinoma)
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17 pages, 1933 KiB  
Article
MRI-Based Radiomic Features Help Identify Lesions and Predict Histopathological Grade of Hepatocellular Carcinoma
by Valentina Brancato, Nunzia Garbino, Marco Salvatore and Carlo Cavaliere
Diagnostics 2022, 12(5), 1085; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics12051085 - 26 Apr 2022
Cited by 12 | Viewed by 3992
Abstract
Hepatocellular carcinoma (HCC) is the most common form of liver cancer. Radiomics is a promising tool that may increase the value of magnetic resonance imaging (MRI) in the management of HCC. The purpose of our study is to develop an MRI-based radiomics approach [...] Read more.
Hepatocellular carcinoma (HCC) is the most common form of liver cancer. Radiomics is a promising tool that may increase the value of magnetic resonance imaging (MRI) in the management of HCC. The purpose of our study is to develop an MRI-based radiomics approach to preoperatively detect HCC and predict its histological grade. Thirty-eight HCC patients at staging who underwent axial T2-weighted and dynamic contrast-enhanced MRI (DCE-MRI) were considered. Three-dimensional volumes of interest (VOIs) were manually placed on HCC lesions and normal hepatic tissue (HT) on arterial phase post-contrast images. Radiomic features from T2 images and arterial, portal and tardive post-contrast images from DCE-MRI were extracted by using Pyradiomics. Feature selection was performed using correlation filter, Wilcoxon-rank sum test and mutual information. Predictive models were constructed for HCC differentiation with respect to HT and HCC histopathologic grading used at each step an imbalance-adjusted bootstrap resampling (IABR) on 1000 samples. Promising results were obtained from radiomic prediction models, with best AUCs ranging from 71% to 96%. Radiomics MRI based on T2 and DCE-MRI revealed promising results concerning both HCC detection and grading. It may be a suitable tool for personalized treatment of HCC patients and could also be used to develop new prognostic biomarkers useful for HCC assessment without the need for invasive procedures. Full article
(This article belongs to the Special Issue Biomarkers in Hepatocellular Carcinoma)
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12 pages, 8096 KiB  
Article
The Relevance of SOCS1 Methylation and Epigenetic Therapy in Diverse Cell Populations of Hepatocellular Carcinoma
by Loraine Kay D. Cabral, Peter Andrew C. Reyes, Lory S. Crocè, Claudio Tiribelli and Caecilia H. C. Sukowati
Diagnostics 2021, 11(10), 1825; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11101825 - 02 Oct 2021
Cited by 5 | Viewed by 2430
Abstract
The suppressor of cytokine signaling 1 (SOCS1) is a tumor suppressor gene found to be hypermethylated in cancers. It is involved in the oncogenic transformation of cirrhotic liver tissues. Here, we investigated the clinical relevance of SOCS1 methylation and modulation upon [...] Read more.
The suppressor of cytokine signaling 1 (SOCS1) is a tumor suppressor gene found to be hypermethylated in cancers. It is involved in the oncogenic transformation of cirrhotic liver tissues. Here, we investigated the clinical relevance of SOCS1 methylation and modulation upon epigenetic therapy in diverse cellular populations of hepatocellular carcinoma (HCC). HCC clinical specimens were evaluated for SOCS1 methylation and mRNA expression. The effect of 5-Azacytidine (5-AZA), a demethylation agent, was assessed in different subtypes of HCC cells. We demonstrated that the presence of SOCS1 methylation was significantly higher in HCC compared to peri-HCC and non-tumoral tissues (52% vs. 13% vs. 14%, respectively, p < 0.001). In vitro treatment with a non-toxic concentration of 5-AZA significantly reduced DNMT1 protein expression for stromal subtype lines (83%, 73%, and 79%, for HLE, HLF, and JHH6, respectively, p < 0.01) compared to cancer stem cell (CSC) lines (17% and 10%, for HepG2 and Huh7, respectively), with the strongest reduction in non-tumoral IHH cells (93%, p < 0.001). 5-AZA modulated the SOCS1 expression in different extents among the cells. It was restored in CSC HCC HepG2 and Huh7 more efficiently than sorafenib. This study indicated the relevance of SOCS1 methylation in HCC and how cellular heterogeneity influences the response to epigenetic therapy. Full article
(This article belongs to the Special Issue Biomarkers in Hepatocellular Carcinoma)
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10 pages, 1071 KiB  
Article
Detection of CTNNB1 Hotspot Mutations in Cell-Free DNA from the Urine of Hepatocellular Carcinoma Patients
by Selena Y. Lin, Ting-Tsung Chang, Jamin D. Steffen, Sitong Chen, Surbhi Jain, Wei Song, Yih-Jyh Lin and Ying-Hsiu Su
Diagnostics 2021, 11(8), 1475; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11081475 - 14 Aug 2021
Cited by 7 | Viewed by 2600
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. The beta-catenin gene, CTNNB1, is among the most frequently mutated in HCC tissues. However, mutational analysis of HCC tumors is hampered by the difficulty of obtaining tissue samples using traditional biopsy. Here, [...] Read more.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. The beta-catenin gene, CTNNB1, is among the most frequently mutated in HCC tissues. However, mutational analysis of HCC tumors is hampered by the difficulty of obtaining tissue samples using traditional biopsy. Here, we explored the feasibility of detecting tumor-derived CTNNB1 mutations in cell-free DNA (cfDNA) extracted from the urine of HCC patients. Using a short amplicon qPCR assay targeting HCC mutational hotspot CTNNB1 codons 32–37 (exon 3), we detected CTNNB1 mutations in 25% (18/73) of HCC tissues and 24% (15/62) of pre-operative HCC urine samples in two independent cohorts. Among the CTNNB1-mutation-positive patients with available matched pre- and post-operative urine (n = 13), nine showed apparent elimination (n = 7) or severalfold reduction (n = 2) of the mutation in urine following tumor resection. Four of the seven patients with no detectable mutations in postoperative urine remained recurrence-free within five years after surgery. In contrast, all six patients with mutation-positive in post-operative urine recurred, including the two with reduced mutation levels. This is the first report of association between the presence of CTNNB1 mutations in pre- and post-operative urine cfDNA and HCC recurrence with implications for minimum residual disease detection. Full article
(This article belongs to the Special Issue Biomarkers in Hepatocellular Carcinoma)
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11 pages, 907 KiB  
Article
Chemerin Is a Valuable Biomarker in Patients with HCV Infection and Correlates with Liver Injury
by Georg Peschel, Jonathan Grimm, Karsten Gülow, Martina Müller, Christa Buechler and Kilian Weigand
Diagnostics 2020, 10(11), 974; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics10110974 - 19 Nov 2020
Cited by 18 | Viewed by 2105
Abstract
Hepatitis C virus (HCV)-induced inflammation contributes to progressive liver disease. The chemoattractant protein chemerin is associated with systemic inflammation. We hypothesized that chemerin is a biomarker that predicts the severity of liver disease in HCV patients. Furthermore, we investigated whether serum chemerin levels [...] Read more.
Hepatitis C virus (HCV)-induced inflammation contributes to progressive liver disease. The chemoattractant protein chemerin is associated with systemic inflammation. We hypothesized that chemerin is a biomarker that predicts the severity of liver disease in HCV patients. Furthermore, we investigated whether serum chemerin levels change during the course of HCV treatment using direct-acting antivirals (DAAs). Therefore, we measured serum concentration of chemerin in a cohort of 82 HCV-infected patients undergoing DAA treatment. Serum chemerin was positively associated with leukocyte count and negatively with markers of hepatic function and the model of end-stage liver disease (MELD) score. Low circulating chemerin levels significantly correlated with advanced liver fibrosis and cirrhosis as measured by the fibrosis-4 (FIB-4) score, the aminotransferase/platelet (AST/PLT) ratio index (APRI) score and the non-alcoholic fatty liver disease (NAFLD) score. Chemerin did not correlate with viral load or viral genotype. Treatment with DAAs did not improve MELD score and leukocyte count within the observation period, up to three months after the end of DAA treatment. Accordingly, chemerin levels remained unchanged during the treatment period. We conclude that low circulating chemerin is a noninvasive biomarker for hepatic dysfunction and advanced liver fibrosis and cirrhosis in HCV infection. Full article
(This article belongs to the Special Issue Biomarkers in Hepatocellular Carcinoma)
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Review

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14 pages, 10982 KiB  
Review
MicroRNAs Related to TACE Treatment Response: A Review of the Literature from a Radiological Point of View
by Alessandro Marco Bozzato, Paola Martingano, Roberta Antea Pozzi Mucelli, Marco Francesco Maria Cavallaro, Matteo Cesarotto, Cristina Marcello, Claudio Tiribelli, Devis Pascut, Riccardo Pizzolato, Fabio Pozzi Mucelli, Mauro Giuffrè, Lory Saveria Crocè and Maria Assunta Cova
Diagnostics 2022, 12(2), 374; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics12020374 - 01 Feb 2022
Cited by 8 | Viewed by 2053
Abstract
Hepatocellular Carcinoma (HCC) is the sixth most common cancer in the world. Patients with intermediate stage (Barcelona Clinic Liver Cancer, B stage) hepatocellular carcinoma (HCC) have been able to benefit from TACE (transarterial chemoembolization) as a treatment option. MicroRNAs (miRNAs), i.e., a subclass [...] Read more.
Hepatocellular Carcinoma (HCC) is the sixth most common cancer in the world. Patients with intermediate stage (Barcelona Clinic Liver Cancer, B stage) hepatocellular carcinoma (HCC) have been able to benefit from TACE (transarterial chemoembolization) as a treatment option. MicroRNAs (miRNAs), i.e., a subclass of non-coding RNAs (ncRNAs), participate in post-transcriptional gene regulation processes and miRNA dysfunction has been associated with apoptosis resistance, cellular proliferation, tumor genesis, and progression. Only a few studies have investigated the role of miRNAs as biomarkers predicting TACE treatment response in HCC. Here, we review the studies’ characteristics from a radiological point of view, also correlating data with radiological images chosen from the cases of our institution. Full article
(This article belongs to the Special Issue Biomarkers in Hepatocellular Carcinoma)
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