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Hepatitis C Virus and Hepatocellular Carcinoma (HCV & HCC)

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Causes, Screening and Diagnosis".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 20214

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Special Issue Editors

Dr. Liliana Chemello

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Guest Editor

Internal Medicine, Department of Medicine, DIMED, University of Padua, 35128 Padua, Italy
Interests: clinical and epidemiological features of chronic hepatitis C and B and its antiviral treatments; cirrhosis and complication of evolutive liver disease; natural history and treatment of hepatocellular carcinoma; transient elastography for staging of chronic liver diseases; cardiac cirrhosis and Fontan associate liver disease
Special Issues, Collections and Topics in MDPI journals

Dr. Luisa Cavalletto

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Internal Medicine, University of Padova, Padova, Italy
Interests: hepatitis C virus
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Erica Villa

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Guest Editor

Gastroenterology, University of Modena and Reggio, Modena, Italy
Interests: HCC; sex hormones; coagulation; chronic liver disease; non-alcoholic fatty liver disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chronic hepatitis C is one of the leading causes of hepatocellular carcinoma (HCC) worldwide. The new antiviral era revolutionized the efficacy and outcomes of chronic HCV infection with the use of direct acting drugs (DAAs), through the maximization of viral eradication and the reduction of cases with cirrhosis and related-complications.

The open issues and debated areas in the literature on HCV and HCC relations are manifold, and this Cancers Special Issue will be focused on the following main topics:

- I: Evidence of HCV infection and development of liver cancer.

In this section are encouraged papers that will provide aspects and biological and/or molecular links between HCV viral infection and the growth and expansion of liver tumors.

- II: Interplay between DAAs and risk of HCC.

Here are considered publications that describe treated cohorts or meta-analysis, reporting the prevalence and risk factors for ongoing hepatic and extrahepatic complications after DAA therapies, but also efficacious outcomes, particularly through life-expectancy restoration in cases with SVR.

- III: Liver cirrhosis and risk factors of HCC: medical and surgical strategies. This section is aimed at focusing on patient characteristics and epidemiological and clinical features suggestive of liver cancer development in chronic hepatitis C, in particular also the description of medical and surgical curative strategies and of radiological and surgical aspects predictive of HCC occurrence and/or recurrence

Dr. Liliana Chemello
Dr. Luisa Cavalletto
Prof. Dr. Erica Villa
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. Cancers 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 2900 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

Hepatitis C virus or HCV
Liver cirrhosis
Direct acting antivirals therapy
Hepatocellular carcinoma or HCC
Biomarkers
miRNAs
Loco-regional therapy
Surgery HCC treatment
MRI
FibroScan

Published Papers (7 papers)

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Research

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14 pages, 1923 KiB

Open AccessArticle

Association between Immunologic Markers and Cirrhosis in Individuals from a Prospective Chronic Hepatitis C Cohort

by Ilona Argirion, Jalen Brown, Sarah Jackson, Ruth M. Pfeiffer, Tram Kim Lam, Thomas R. O’Brien, Kelly J. Yu, Katherine A. McGlynn, Jessica L. Petrick, Ligia A. Pinto, Chien-Jen Chen, Allan Hildesheim, Hwai-I Yang, Mei-Hsuan Lee and Jill Koshiol

Cancers 2022, 14(21), 5280; https://doi.org/10.3390/cancers14215280 - 27 Oct 2022

Cited by 1 | Viewed by 1501

Abstract

Background: Chronic hepatitis C virus (HCV) infection can affect immune response and inflammatory pathways, leading to severe liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). Methods: In a prospective cohort of chronically HCV-infected individuals, we sampled 68 individuals who developed cirrhosis, 91 controls who did not develop cirrhosis, and 94 individuals who developed HCC. Unconditional odds ratios (ORs) from polytomous logistic regression models and canonical discriminant analyses (CDAs) were used to compare categorical (C) baseline plasma levels for 102 markers in individuals who developed cirrhosis vs. controls and those who developed HCC vs. cirrhosis. Leave-one-out cross validation was used to produce receiver operating characteristic curves to assess predictive ability of markers. Lastly, biological pathways were assessed in association with cirrhotic development compared to controls. Results: After multivariable adjustment, DEFA-1 (OR: C2v.C1 = 7.73; p < 0.0001), ITGAM (OR: C2v.C1 = 4.03; p = 0.0002), SCF (OR: C4v.C1 = 0.19; p-trend = 0.0001), and CCL11 (OR: C4v.C1 = 0.31; p-trend= 0.002) were all associated with development of cirrhosis compared to controls; these markers, together with clinical/demographics variables, improved prediction of cirrhosis from 55.7% (in clinical/demographic-only model) to 74.9% accuracy. A twelve-marker model based on CDA results further increased prediction of cirrhosis to 88.0%. While six biological pathways were found to be associated with cirrhosis, cell adhesion was the only pathway associated with cirrhosis after Bonferroni correction. In contrast to cirrhosis, DEFA-1 and ITGAM levels were inversely associated with HCC risk. Conclusions: Pending validation, these findings highlight the important role of immunological markers in predicting HCV-related cirrhosis even 11 years post-enrollment. Full article

(This article belongs to the Special Issue Hepatitis C Virus and Hepatocellular Carcinoma (HCV & HCC))

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11 pages, 1311 KiB

Open AccessArticle

Risk Factors for Liver Decompensation and HCC in HCV-Cirrhotic Patients after DAAs: A Multicenter Prospective Study

by Filomena Morisco, Alessandro Federico, Massimo Marignani, Mariarita Cannavò, Giuseppina Pontillo, Maria Guarino, Marcello Dallio, Paola Begini, Rosa G. Benigno, Flavia L. Lombardo and Tommaso Stroffolini

Cancers 2021, 13(15), 3810; https://doi.org/10.3390/cancers13153810 - 29 Jul 2021

Cited by 7 | Viewed by 1791

Abstract

Background: Prospective studies on predictors of liver-related events in cirrhotic subjects achieving SVR after DAAs are lacking. Methods: We prospectively enrolled HCV cirrhotic patients in four Italian centers between November 2015 and October 2017. SVR and no-SVR cases were compared according to the presence or absence of liver-related events during a 24-month follow-up. Independent predictors of liver-related events were evaluated by Cox regression analysis. Results: A total of 706 subjects started DAAs therapy. SVR was confirmed in 687 (97.3%). A total of 61 subjects (8.9%) in the SVR group and 5 (26.3%) in the no-SVR group had liver-related events (p < 0.03). The incidence rate x 100 p/y was 1.6 for HCC, 1.7 for any liver decompensation, and 0.5 for hepatic death. Baseline liver stiffness (LSM) ≥ 20 kPa (HR 4.0; 95% CI 1.1–14.1) and genotype different from 1 (HR 7.5; 95% CI 2.1–27.3) were both independent predictors of liver decompensation. Baseline LSM > 20 KPa (HR 7.2; 95% CI 1.9–26.7) was the sole independent predictor of HCC. A decrease in liver stiffness (Delta LSM) by at least 20% at the end of follow-up was not associated with a decreased risk of liver-related events. Conclusion: Baseline LSM ≥ 20 kPa identifies HCV cirrhotic subjects at higher risk of liver-related events after SVR. Full article

(This article belongs to the Special Issue Hepatitis C Virus and Hepatocellular Carcinoma (HCV & HCC))

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12 pages, 1123 KiB

Open AccessArticle

Five-Year Follow-Up of Cured HCV Patients under Real-World Interferon-Free Therapy

by Robert Flisiak, Dorota Zarębska-Michaluk, Ewa Janczewska, Tadeusz Łapiński, Magdalena Rogalska, Ewa Karpińska, Tomasz Mikuła, Beata Bolewska, Jolanta Białkowska, Katarzyna Flejscher-Stępniewska, Krzysztof Tomasiewicz, Kornelia Karwowska, Monika Pazgan-Simon, Anna Piekarska, Hanna Berak, Olga Tronina, Aleksander Garlicki and Jerzy Jaroszewicz

Cancers 2021, 13(15), 3694; https://doi.org/10.3390/cancers13153694 - 22 Jul 2021

Cited by 18 | Viewed by 2153

Abstract

(1) Background: Treatment of hepatitis C virus (HCV) infections with direct-acting antivirals (DAA) has demonstrated high efficacy and an excellent safety profile. The cured patients showed a sustained virological response and improved liver function, but also a continued risk of hepatocellular carcinoma (HCC) during the 2–3 years of follow-up after treatment; (2) Methods: A total of 192 patients out of 209 of the primary AMBER study were analyzed five years after treatment with ombitasvir/paritaprevir/ritonavir with or without dasabuvir and with or without ribavirin. Results: We confirmed that HCV clearance after DAA treatment is stable regardless of baseline liver fibrosis. We found that sustained virologic response is associated with a gradual but significant reduction in liver stiffness over 5 years. Liver function improved during the first 2 years of follow-up and remained stable thereafter. The risk of death due to HCC as well as death due to HCV persists through 5 years of follow-up after successful DAA treatment. However, in non-cirrhotic patients, it appears to clear up 3 years after treatment; (3) Conclusions: Monitoring for more than 5 years after curing HCV infection is necessary to assess the long-term risk of possible development of HCC, especially in patients with cirrhosis of the liver. Full article

(This article belongs to the Special Issue Hepatitis C Virus and Hepatocellular Carcinoma (HCV & HCC))

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13 pages, 1292 KiB

Open AccessArticle

HCC in the Era of Direct-Acting Antiviral Agents (DAAs): Surgical and Other Curative or Palliative Strategies in the Elderly

by Stefania Brozzetti, Marsia Tancredi, Simone Bini, Chiara De Lucia, Jessica Antimi, Chiara D’Alterio, Giuseppe Maria De Sanctis, Caterina Furlan, Vittoria Carolina Malpassuti, Pierleone Lucatelli, Michele Di Martino, Mario Bezzi, Antonio Ciardi and Rosa Maria Pascale

Cancers 2021, 13(12), 3025; https://doi.org/10.3390/cancers13123025 - 17 Jun 2021

Cited by 5 | Viewed by 2297

Abstract

Hepatocellular carcinoma (HCC) accounts for 75–85% of primary liver malignancies, and elderlies have the highest incidence rates. Direct-acting antiviral agents (DAAs) have shown satisfying results in terms of HCV sustained viral response (SVR). However, data regarding HCC risk post-DAA-SVR is still conflicting. This study aims to consider HCC onset in moderate underlying liver disease. We conducted a retrospective study on 227 chronically infected patients (cHCV), treated with DAAs. Patients were divided into three groups: “de novo occurrent HCC”, “recurrent HCC”, and “without HCC”. Fifty-six patients aged <65 years (yDAA) were studied separately. HCC patients aged ≥65 years (DAA-HCC) were compared to a historical group of 100 elderly HCC patients, treated with peginterferon (Peg-IFN) ± ribavirin antiviral agents, non-SVR (hHCC). The HCC prevalence in DAA patients was 32.75%: “de novo occurrent’’ 18.13% and “recurrent’’ 14.62%, despite 42.85% of them having no fibrosis to mild or moderate fibrosis (F0-F1-F2). yDAA showed 5.36% “de novo occurrent” HCC. Curative procedure rates were compared between DAA-HCC and hHCC at the first and at recurrent presentation (22 (39.29%) vs. 72 (72%); 17 (30.36%) vs. 70 (70%), respectively (p < 0.001)). No significant difference was found in 3-year OS (p = 0.6). However, in cause-specific mortality analysis, HCC-related death was higher in the DAA-treated group, whereas cirrhosis-related death was more common in the historical group (p = 0.0288), considering together the two causes of death. A more accurate patient stratification according to multifactorial and new diagnostic investigations identifying HCC risk might allow an improvement in management and access to curative therapies. Full article

(This article belongs to the Special Issue Hepatitis C Virus and Hepatocellular Carcinoma (HCV & HCC))

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7 pages, 823 KiB

Open AccessCommunication

Circulating IL-13 Is Associated with De Novo Development of HCC in HCV-Infected Patients Responding to Direct-Acting Antivirals

by Zuzana Macek Jílková, Arnaud Seigneurin, Celine Coppard, Laurissa Ouaguia, Caroline Aspord, Patrice N. Marche, Vincent Leroy and Thomas Decaens

Cancers 2020, 12(12), 3820; https://doi.org/10.3390/cancers12123820 - 18 Dec 2020

Cited by 8 | Viewed by 1881

Abstract

Direct-acting antivirals (DAAs) are highly effective in targeting hepatitis C virus (HCV) infections, but the incidence of HCV-related hepatocellular carcinoma (HCC) remains still high. In this study, we investigated a cohort of HCV-infected patients treated with DAAs who were followed up for 4 years after sustained virological response (SVR) achievement. Patients who developed de novo HCC following DAA treatment were compared to matched controls who did not develop HCC. These control patients were selected based on DAA treatment, sex, age, fibrosis status, and platelet counts. We evaluated serum levels of 30 immune mediators before, during, at the end of, and three months after DAA treatment using Luminex technology. We identified the immune factors associated with de novo HCC occurrence following DAA treatment. Specifically, interleukin (IL)-4 and IL-13 levels were significantly higher before start of the DAA treatment in the serum of patients who later developed HCC than in controls and stayed higher at each subsequent time point. Least absolute shrinkage and selection operator (LASSO) regression revealed IL-13 as the only strong factor associated with HCC development in this cohort of HCV patients. The difference was observed already at baseline of DAA treatment, which confirms the existence of a specific immune profile in these patients who later develop HCC. Full article

(This article belongs to the Special Issue Hepatitis C Virus and Hepatocellular Carcinoma (HCV & HCC))

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Review

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29 pages, 16948 KiB

Open AccessReview

Role of Virus-Related Chronic Inflammation and Mechanisms of Cancer Immune-Suppression in Pathogenesis and Progression of Hepatocellular Carcinoma

by Melissa Borgia, Michele Dal Bo and Giuseppe Toffoli

Cancers 2021, 13(17), 4387; https://doi.org/10.3390/cancers13174387 - 30 Aug 2021

Cited by 14 | Viewed by 4956

Abstract

Hepatocellular carcinoma (HCC) can be classified as a prototypical inflammation-driven cancer that generally arises from a background of liver cirrhosis, but that in the presence of nonalcoholic steatohepatitis (NASH), could develop in the absence of fibrosis or cirrhosis. Tumor-promoting inflammation characterizes HCC pathogenesis, with an epidemiology of the chronic liver disease frequently encompassing hepatitis virus B (HBV) or C (HCV). HCC tumor onset and progression is a serial and heterogeneous process in which intrinsic factors, such as genetic mutations and chromosomal instability, are closely associated with an immunosuppressive tumor microenvironment (TME), which may have features associated with the etiopathogenesis and expression of the viral antigens, which favor the evasion of tumor neoantigens to immune surveillance. With the introduction of direct-acting antiviral (DAA) therapies for HCV infection, sustained virological response (SVR) has become very high, although occurrence of HCC and reactivation of HBV in patients with co-infection, who achieved SVR in short term, have been observed in a significant proportion of treated cases. In this review, we discuss the main molecular and TME features that are responsible for HCC pathogenesis and progression. Peculiar functional aspects that could be related to the presence and treatment of HCV/HBV viral infections are also dealt with. Full article

(This article belongs to the Special Issue Hepatitis C Virus and Hepatocellular Carcinoma (HCV & HCC))

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22 pages, 1572 KiB

Open AccessReview

HCV Proteins Modulate the Host Cell miRNA Expression Contributing to Hepatitis C Pathogenesis and Hepatocellular Carcinoma Development

by Devis Pascut, Minh Hoang, Nhu N. Q. Nguyen, Muhammad Yogi Pratama and Claudio Tiribelli

Cancers 2021, 13(10), 2485; https://doi.org/10.3390/cancers13102485 - 19 May 2021

Cited by 12 | Viewed by 3627

Abstract

Hepatitis C virus (HCV) genome encodes for one long polyprotein that is processed by cellular and viral proteases to generate 10 polypeptides. The viral structural proteins include the core protein, and the envelope glycoproteins E1 and E2, present at the surface of HCV particles. Non-structural (NS) proteins consist of NS1, NS2, NS3, NS4A, NS4B, NS5a, and NS5b and have a variable function in HCV RNA replication and particle assembly. Recent findings evidenced the capacity of HCV virus to modulate host cell factors to create a favorable environment for replication. Indeed, increasing evidence has indicated that the presence of HCV is significantly associated with aberrant miRNA expression in host cells, and HCV structural and non-structural proteins may be responsible for these alterations. In this review, we summarize the recent findings on the role of HCV structural and non-structural proteins in the modulation of host cell miRNAs, with a focus on the molecular mechanisms responsible for the cell re-programming involved in viral replication, immune system escape, as well as the oncogenic process. In this regard, structural and non-structural proteins have been shown to modulate the expression of several onco-miRNAs or tumor suppressor miRNAs. Full article

(This article belongs to the Special Issue Hepatitis C Virus and Hepatocellular Carcinoma (HCV & HCC))

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