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New Insights on Therapy in Hepatocellular Carcinoma

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (1 November 2023) | Viewed by 8271

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Special Issue Editor

Dr. Curtis J. Wray

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Guest Editor

McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Interests: hepatocellular carcinoma; duodenal adenocarcinoma; esophageal carcinoma; surgery; surgical outcome

Special Issue Information

Dear Colleagues,

Hepatocellular Carcinoma (HCC) remains a serious etiology of cancer-related mortality worldwide. Many solid malignancies (of the lung, gastric colorectal, and breast) have experienced improved survival outcomes over the past two decades. However, HCC-age-adjusted mortality rates have increased over the past 30 years, and this suboptimal trend is projected to worsen over the next 15 years. With the exception of pancreas cancer, HCC 5-year survival rates are the second lowest of any gastrointestinal malignancy.

Chronic inflammation and repetitive liver injury (primarily due to hepatitis B and C virus) are the main etiologies of hepatocarcinogenesis. For those with HCV-related cirrhosis, the annual incidence of HCC ranges from 2 to 8%. However, this statistic is difficult to interpret due the tendency of HCV cirrhosis to remain undiagnosed for many years. Meanwhile, cirrhosis has increasingly given rise to nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). NASH often develops in obesity, type 2 diabetes, dyslipidemia and hypertension patients and represents an emerging major additional risk factor for HCC in the United States; it is anticipated to replace viral hepatitis as the most common etiology of HCC in the US. Current estimates suggest the prevalence of NASH ranges from 3 to 5%, indicating a large percentage of the general population is at high for both cirrhosis and HCC.

These mechanisms lead to repetitive liver injury and repair, progressive hepatic dysfunction and eventual end-stage liver disease with cirrhosis. Thus, two significant disease processes (HCC and cirrhosis) limit treatment options and survival. In order to address this significant unmet need, improved strategies are needed for screening, diagnosis and treatment. This Special Issue will highlight the current efficiency of diagnosis and treatment of HC and provide an overview of the current ongoing clinical trials addressing these challenges.

Dr. Curtis J. Wray
Guest Editor

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

hepatocellular carcinoma (HCC)
hepatitis B and C virus
cirrhosis
nonalcoholic fatty liver disease
nonalcoholic steatohepatitis (NASH)
diagnosis
treatment
clinical trials

Published Papers (6 papers)

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Research

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25 pages, 11160 KiB

Open AccessArticle

Identification of Two Distinct Immune Subtypes in Hepatitis B Virus (HBV)-Associated Hepatocellular Carcinoma (HCC)

by Davide De Battista, Rylee Yakymi, Evangeline Scheibe, Shinya Sato, Hannah Gerstein, Tovah E. Markowitz, Justin Lack, Roberto Mereu, Cristina Manieli, Fausto Zamboni and Patrizia Farci

Cancers 2024, 16(7), 1370; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16071370 - 30 Mar 2024

Viewed by 836

Abstract

HBV is the most common risk factor for HCC development, accounting for almost 50% of cases worldwide. Despite significant advances in immunotherapy, there is limited information on the HBV-HCC tumor microenvironment (TME), which may influence the response to checkpoint inhibitors. Here, we characterize the TME in a unique series of liver specimens from HBV-HCC patients to identify who might benefit from immunotherapy. By combining an extensive immunohistochemistry analysis with the transcriptomic profile of paired liver samples (tumor vs. nontumorous tissue) from 12 well-characterized Caucasian patients with HBV-HCC, we identified two distinct tumor subtypes that we defined immune-high and immune-low. The immune-high subtype, seen in half of the patients, is characterized by a high number of infiltrating B and T cells in association with stromal activation and a transcriptomic profile featuring inhibition of antigen presentation and CTL activation. All the immune-high tumors expressed high levels of CTLA-4 and low levels of PD-1, while PD-L1 was present only in four of six cases. In contrast, the immune-low subtype shows significantly lower lymphocyte infiltration and stromal activation. By whole exome sequencing, we documented that four out of six individuals with the immune-low subtype had missense mutations in the CTNNB1 gene, while only one patient had mutations in this gene in the immune-high subtype. Outside the tumor, there were no differences between the two subtypes. This study identifies two distinctive immune subtypes in HBV-associated HCC, regardless of the microenvironment observed in the surrounding nontumorous tissue, providing new insights into pathogenesis. These findings may be instrumental in the identification of patients who might benefit from immunotherapy. Full article

(This article belongs to the Special Issue New Insights on Therapy in Hepatocellular Carcinoma)

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12 pages, 1630 KiB

Open AccessArticle

Impact of Pre-Liver Transplant Treatments on the Imaging Accuracy of HCC Staging and Their Influence on Outcomes

by Eloisa Franchi, Daniele Eliseo Dondossola, Giulia Maria Francesca Marini, Massimo Iavarone, Luca Del Prete, Clara Di Benedetto, Maria Francesca Donato, Barbara Antonelli, Pietro Lampertico and Lucio Caccamo

Cancers 2024, 16(5), 1043; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16051043 - 4 Mar 2024

Viewed by 620

Abstract

The outcome of liver transplantation (LT) for hepatocarcinoma (HCC) is strongly influenced by HCC staging, which is based on radiological examinations in a pre-LT setting; concordance between pre-LT radiological and definitive pathological staging remains controversial. To address this issue, we retrospectively analyzed our LT series to assess concordance between radiology and pathology and to explore the factors associated with poor concordance and outcomes. We included all LTs with an HCC diagnosis performed between 2013 and 2018. Concordance (Co group) was defined as a comparable tumor burden in preoperative imaging and post-transplant pathology; otherwise, non-concordance was diagnosed (nCo group). Concordance between radiology and pathology was observed in 32/134 patients (Co group, 24%). The number and diameter of the nodules were higher when nCo was diagnosed, as was the number of pre-LT treatments. Although concordance did not affect survival, more than three pre-LT treatments led to a lower disease-free survival. Patients who met the Milan Criteria (Milan-in patients) were more likely to receive ≥three prior treatments, leading to a lower survival in multi-treated Milan-in patients than in other Milan-in patients. In conclusion, the concordance rate between the pre-LT imaging and histopathological results was low in patients with a high number of nodules. Multiple bridging therapies reduce the accuracy of pre-LT imaging in predicting HCC stages and negatively affect outcomes after LT. Full article

(This article belongs to the Special Issue New Insights on Therapy in Hepatocellular Carcinoma)

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18 pages, 4955 KiB

Open AccessArticle

Improving HCC Prognostic Models after Liver Resection by AI-Extracted Tissue Fiber Framework Analytics

by Rokas Stulpinas, Mindaugas Morkunas, Allan Rasmusson, Julius Drachneris, Renaldas Augulis, Aiste Gulla, Kestutis Strupas and Arvydas Laurinavicius

Cancers 2024, 16(1), 106; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16010106 - 24 Dec 2023

Cited by 1 | Viewed by 1101

Abstract

Despite advances in diagnostic and treatment technologies, predicting outcomes of patients with hepatocellular carcinoma (HCC) remains a challenge. Prognostic models are further obscured by the variable impact of the tumor properties and the remaining liver parenchyma, often affected by cirrhosis or non-alcoholic fatty liver disease that tend to precede HCC. This study investigated the prognostic value of reticulin and collagen microarchitecture in liver resection samples. We analyzed 105 scanned tissue sections that were stained using a Gordon and Sweet’s silver impregnation protocol combined with Picric Acid–Sirius Red. A convolutional neural network was utilized to segment the red-staining collagen and black linear reticulin strands, generating a detailed map of the fiber structure within the HCC and adjacent liver tissue. Subsequent hexagonal grid subsampling coupled with automated epithelial edge detection and computational fiber morphometry provided the foundation for region-specific tissue analysis. Two penalized Cox regression models using LASSO achieved a concordance index (C-index) greater than 0.7. These models incorporated variables such as patient age, tumor multifocality, and fiber-derived features from the epithelial edge in both the tumor and liver compartments. The prognostic value at the tumor edge was derived from the reticulin structure, while collagen characteristics were significant at the epithelial edge of peritumoral liver. The prognostic performance of these models was superior to models solely reliant on conventional clinicopathologic parameters, highlighting the utility of AI-extracted microarchitectural features for the management of HCC. Full article

(This article belongs to the Special Issue New Insights on Therapy in Hepatocellular Carcinoma)

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20 pages, 8909 KiB

Open AccessArticle

Mannose-Binding Lectin 2 as a Potential Therapeutic Target for Hepatocellular Carcinoma: Multi-Omics Analysis and Experimental Validation

by Hangyu Liao, Jun Yang, Yuyan Xu, Juncheng Xie, Ke Li, Kunling Chen, Jingyuan Pei, Qiong Luo and Mingxin Pan

Cancers 2023, 15(19), 4900; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15194900 - 9 Oct 2023

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Abstract

Mannose-binding lectin 2 (MBL2), a member of the multimeric lectin family, is crucial in immune regulation and tumor development. MBL2 gene polymorphisms are associated with the risk and prognosis of various tumors, including hepatocellular carcinoma (HCC). Its functional role in HCC remains largely unclear. In this study, we aimed to identify whether MBL2 is a key regulator and a potential therapeutic target for HCC. A bioinformatics analysis revealed close relationships among MBL2 downregulation, the tumor-associated proliferation and metastasis pathway, and tumor immunosuppressive microenvironments. Lower expression of MBL2 in HCC patients was linked to an unfavorable prognosis. A cell counting kit-8 assay, colony formation assay, transwell migration assay, and wound healing assay further confirmed that the overexpression of MBL2 could directly inhibit the proliferation and metastasis of HCC. Moreover, MBL2 expression was regulated by miR-34c-3p, as confirmed by the dual-luciferase reporter assay, thereby demonstrating tumor progression in HCC cells. Thus, our study offers the first comprehensive confirmation of the role of MBL2 in the development of HCC through multi-omics analysis and experimental validation. Furthermore, miR-34c-3p was found to be an upstream mechanism of the downregulation of MBL2 expression and could be a promising therapeutic target, expanding treatment options for patients with HCC. Full article

(This article belongs to the Special Issue New Insights on Therapy in Hepatocellular Carcinoma)

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Review

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23 pages, 1652 KiB

Open AccessReview

Management of Hepatocellular Carcinoma in 2024: The Multidisciplinary Paradigm in an Evolving Treatment Landscape

by Emily Kinsey and Hannah M. Lee

Cancers 2024, 16(3), 666; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16030666 - 4 Feb 2024

Cited by 1 | Viewed by 2812

Abstract

Liver cancer is the third most common cause of cancer-related deaths worldwide, and hepatocellular carcinoma (HCC) makes up the majority of liver cancer cases. Despite the stabilization of incidence rates in recent years due to effective viral hepatitis treatments, as well as improved outcomes from early detection and treatment advances, the burden of HCC is anticipated to rise again due to increasing rates of metabolic dysfunction-associated steatotic liver disease and alcohol-related liver disease. The treatment landscape is evolving and requires a multidisciplinary approach, often involving multi-modal treatments that include surgical resection, transplantation, local regional therapies, and systemic treatments. The optimal approach to the care of the HCC patient requires a multidisciplinary team involving hepatology, medical oncology, diagnostic and interventional radiology, radiation oncology, and surgery. In order to determine which approach is best, an individualized treatment plan should consider the patient’s liver function, functional status, comorbidities, cancer stage, and preferences. In this review, we provide an overview of the current treatment options and key trials that have revolutionized the management of HCC. We also discuss evolving treatment paradigms for the future. Full article

(This article belongs to the Special Issue New Insights on Therapy in Hepatocellular Carcinoma)

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16 pages, 11067 KiB

Open AccessReview

New Insights on Liver-Directed Therapies in Hepatocellular Carcinoma

by Christina G. Dalzell, Amy C. Taylor and Sarah B. White

Cancers 2023, 15(24), 5749; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15245749 - 8 Dec 2023

Cited by 1 | Viewed by 1332

Abstract

The incidence of hepatocellular carcinoma (HCC) has been increasing over the past decades, but improvements in systemic and locoregional therapies is increasing survival. Current locoregional treatment options include ablation, transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and stereotactic body radiotherapy (SBRT). There is ongoing research regarding the combination of systemic and local therapies to maximize treatment effect as well as in new non-invasive, image-guided techniques such as histotripsy. There is also active research in optimizing the delivery of therapy to tumors via nanostructures and viral-vector-mediated gene therapies. In many cases, patients require a combination of therapies to achieve tumor control and prolong survival. This article provides an overview of the most common liver-directed therapies for HCC as well as insight into more recent advances in personalized medicine and emerging techniques. Full article

(This article belongs to the Special Issue New Insights on Therapy in Hepatocellular Carcinoma)

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