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Medicina
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Advance in the Diagnosis, Treatment and Prognosis of Hepatocellular Carcinoma
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Advance in the Diagnosis, Treatment and Prognosis of Hepatocellular Carcinoma

A special issue of Medicina (ISSN 1648-9144). This special issue belongs to the section "Gastroenterology & Hepatology".

Deadline for manuscript submissions: 15 May 2025 | Viewed by 19317

Special Issue Editor

Dr. Emdio Scarpellini

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Guest Editor
Departement Chronische Ziekten, Metabolisme en Veroudering, Leuven, Belgium
Interests: gut microbiota; nutrition; liver disease; probiotic; dyspepsia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Hepatocellular carcinoma (HCC) is the third leading cause of death worldwide, and its incidence is expected to rise significantly in the coming years because of the Westernization taking place around the world. In fact, the growing impact of metabolic disease has reshaped the feature of hepatology. Metabolic-associated fatty liver disease (MAFLD) has become the leading cause of liver cirrhosis and hepatocellular carcinoma. The latter can occur also in the absence of cirrhotic evolution of hepatic disease.

Thus, early HCC diagnosis is a must for clinical and bench research. Over anti-angiogenetic treatment, HCC prognosis and life expectancy are improved by the use of check-point inhibitors. However, the lack of a genetic mutation fingerprint of HCC requires newer biomarkers for more personalized medicine. In this context, the growing role of gut microbiota dysbiosis in liver disease and in HCC physiopathology can be an efficacious tool in the diagnostic and therapeutic armamentarium.

This Special Issue calls for contributions on:

  • HCC prevalence and incidence;
  • HCC pathophysiology;
  • Updates on HCC diagnosis;
  • The role of gut microbiota and its dysbiosis in HCC natural history;
  • Updates on HCC treatments;
  • Special focus on gut microbiota modulation in HCC treatment.

Dr. Emdio Scarpellini
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. Medicina is an international peer-reviewed open access monthly 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 2200 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

  • metabolic-associated fatty liver disease
  • hepatic disease

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Published Papers (7 papers)

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Research

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19 pages, 8176 KiB  
Article
Fatty Acid Synthase Promotes Hepatocellular Carcinoma Growth via S-Phase Kinase-Associated Protein 2/p27KIP1 Regulation
by Antonio Cigliano, Maria M. Simile, Gianpaolo Vidili, Giovanni M. Pes, Maria P. Dore, Francesco Urigo, Eleonora Cossu, Li Che, Claudio Feo, Sara M. Steinmann, Silvia Ribback, Rosa M. Pascale, Matthias Evert, Xin Chen and Diego F. Calvisi
Medicina 2024, 60(7), 1160; https://doi.org/10.3390/medicina60071160 - 18 Jul 2024
Viewed by 1247
Abstract
Background and Objectives: Aberrant upregulation of fatty acid synthase (FASN), catalyzing de novo synthesis of fatty acids, occurs in various tumor types, including human hepatocellular carcinoma (HCC). Although FASN oncogenic activity seems to reside in its pro-lipogenic function, cumulating evidence suggests that FASN’s [...] Read more.
Background and Objectives: Aberrant upregulation of fatty acid synthase (FASN), catalyzing de novo synthesis of fatty acids, occurs in various tumor types, including human hepatocellular carcinoma (HCC). Although FASN oncogenic activity seems to reside in its pro-lipogenic function, cumulating evidence suggests that FASN’s tumor-supporting role might also be metabolic-independent. Materials and Methods: In the present study, we show that FASN inactivation by specific small interfering RNA (siRNA) promoted the downregulation of the S-phase kinase associated-protein kinase 2 (SKP2) and the consequent induction of p27KIP1 in HCC cell lines. Results: Expression levels of FASN and SKP2 directly correlated in human HCC specimens and predicted a dismal outcome. In addition, forced overexpression of SKP2 rendered HCC cells resistant to the treatment with the FASN inhibitor C75. Furthermore, FASN deletion was paralleled by SKP2 downregulation and p27KIP1 induction in the AKT-driven HCC preclinical mouse model. Moreover, forced overexpression of an SKP2 dominant negative form or a p27KIP1 non-phosphorylatable (p27KIP1-T187A) construct completely abolished AKT-dependent hepatocarcinogenesis in vitro and in vivo. Conclusions: In conclusion, the present data indicate that SKP2 is a critical downstream effector of FASN and AKT-dependent hepatocarcinogenesis in liver cancer, envisaging the possibility of effectively targeting FASN-positive liver tumors with SKP2 inhibitors or p27KIP1 activators. Full article
(This article belongs to the Special Issue Advance in the Diagnosis, Treatment and Prognosis of Hepatocellular Carcinoma)
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14 pages, 1704 KiB  
Article
The Role of Epithelial Cell Adhesion Molecule Cancer Stem Cell Marker in Evaluation of Hepatocellular Carcinoma
by Marwa A. El-Kholy, Shimaa S. Abu-Seadah, Abdulkarim Hasan, Mohammed E. A. Elhussiny, Mohammed S. Abdelwahed, Mehenaz Hanbazazh, Abdulhadi Samman, Saeed A. Alrashdi, Zaky F. Rashed, Diaa Ashmawy, Alyaa E. Othman, Mohamed F. Abdelaleem, Amany I. A. Abo-Saif, Rania R. Abdel-Maqsoud, Samah M. Attiah, Eissa Saeed Assiri, Mohamed Nasr, Khadiga Ahmed Ismail, Diana Z. Saad and Marwa M. El-Mosely
Medicina 2024, 60(6), 915; https://doi.org/10.3390/medicina60060915 - 30 May 2024
Cited by 1 | Viewed by 1399
Abstract
Background and Objectives: Hepatocellular carcinoma (HCC) is a prevalent form of malignancy that is characterized by high mortality rates and prognosis that remain suboptimal, largely due to treatment resistance mechanisms. Recent studies have implicated cancer stem cells (CSCs), particularly those expressing epithelial cell [...] Read more.
Background and Objectives: Hepatocellular carcinoma (HCC) is a prevalent form of malignancy that is characterized by high mortality rates and prognosis that remain suboptimal, largely due to treatment resistance mechanisms. Recent studies have implicated cancer stem cells (CSCs), particularly those expressing epithelial cell adhesion molecule (EpCAM), in HCC progression and resistance. In the present study, we sought to assess EpCAM expression in HCC patients and its correlation with various clinicopathological parameters. Materials and Methods: Tissue samples from 42 HCC patients were subjected to immunohistochemical staining to evaluate EpCAM expression. Clinicopathological data were obtained including the size, grade and stage of tumors, vascular invasion status, alpha-fetoprotein levels, and cirrhosis status. The Chi square and Fisher’s exact tests were employed to assess the association between categorical groups. Independent Student-t test or Mann–Whitney U test was used to investigate the association between continuous patient characteristics and survival. Results: Immunohistochemical analysis revealed EpCAM expression in 52.5% of HCC cases. EpCAM-positive tumors exhibited characteristics indicative of aggressive disease, including larger tumor sizes (p = 0.006), greater tumor multiplicity (p = 0.004), higher grades (p = 0.002), more advanced stages (p = 0.003), vascular invasion (p = 0.023), elevated alpha-fetoprotein levels (p = 0.013), and cirrhosis (p = 0.052). Survival analysis demonstrated that EpCAM expression was significantly associated with lower overall rates of survival and higher rates of recurrence in HCC patients. Conclusions: Our findings suggest that EpCAM expression may serve as a prognostic biomarker for HCC with a potential role in patient management. Targeting EpCAM-positive CSCs may represent a promising approach to overcome treatment resistance and improve clinical outcomes in HCC. However, further investigation into the molecular mechanisms underlying EpCAM’s role in HCC progression is warranted to facilitate the development of personalized therapeutic interventions. Full article
(This article belongs to the Special Issue Advance in the Diagnosis, Treatment and Prognosis of Hepatocellular Carcinoma)
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11 pages, 1583 KiB  
Article
Efficacy of Transarterial Chemoembolization (TACE) for Early-Stage Hepatocellular Carcinoma
by Moonhyung Lee and Hyun Phil Shin
Medicina 2023, 59(12), 2174; https://doi.org/10.3390/medicina59122174 - 14 Dec 2023
Cited by 2 | Viewed by 2613
Abstract
Backgound and Objectives: The treatments of choice for patients with early-stage hepatocellular carcinoma (HCC) are surgical resection, local ablation therapy, and liver transplantation; however, transarterial chemoembolization (TACE) is commonly performed due to variations among patients and liver diseases. This study aimed to assess [...] Read more.
Backgound and Objectives: The treatments of choice for patients with early-stage hepatocellular carcinoma (HCC) are surgical resection, local ablation therapy, and liver transplantation; however, transarterial chemoembolization (TACE) is commonly performed due to variations among patients and liver diseases. This study aimed to assess the efficacy of TACE in patients with early-stage HCC. Materials and Methods: A retrospective analysis was performed of all TACE procedures performed at Kyung Hee University Hospital at Gangdong over a 15-year period (July 2006 to November 2021). The study included a total of 97 eligible patients with early-stage HCC ≤ 5 cm initially treated with TACE. The mean participant age was 63.47 ± 11.02 years; 69 were men (71.1%). The number of Child–Pugh class A patients was the highest (74 patients [76.3%]), followed by Child–Pugh class B (19 patients [19.6%]) and Child–Pugh class C (4 patients [4.12%]). Results: A complete response was achieved in 84 (86.6%) patients after the first TACE procedure, with 1-, 2-, and 3-year survival rates of 91.8%, 87.3%, and 75.4%, respectively. In the multivariate analysis, the patients with a low initial alpha-fetoprotein (AFP) ≤ 20 ng/mL (p = 0.02) and a complete response after the first TACE (p = 0.03) were associated with favorable overall survival. Conclusions: TACE can be used to treat patients with early-stage HCC who are unsuitable for ablation or surgery. If patients are well selected, TACE may be an alternative treatment for patients with low AFP levels who respond well to the initial TACE procedure. Full article
(This article belongs to the Special Issue Advance in the Diagnosis, Treatment and Prognosis of Hepatocellular Carcinoma)
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Review

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16 pages, 1124 KiB  
Review
Perspective on the Role of Gut Microbiome in the Treatment of Hepatocellular Carcinoma with Immune Checkpoint Inhibitors
by Ludovico Abenavoli, Michele Montori, Gianluca Svegliati Baroni, Maria Eva Argenziano, Francesca Giorgi, Giuseppe Guido Maria Scarlata, Francesca Ponziani and Emidio Scarpellini
Medicina 2023, 59(8), 1427; https://doi.org/10.3390/medicina59081427 - 6 Aug 2023
Cited by 11 | Viewed by 3656
Abstract
Background and Objectives: Hepatocellular carcinoma (HCC) is the leading cause of liver cancer worldwide and has a high mortality rate. Its incidence has increased due to metabolic-associated liver disease (MAFLD) epidemics. Liver transplantation and surgery remain the most resolute measures. Despite the optimistic [...] Read more.
Background and Objectives: Hepatocellular carcinoma (HCC) is the leading cause of liver cancer worldwide and has a high mortality rate. Its incidence has increased due to metabolic-associated liver disease (MAFLD) epidemics. Liver transplantation and surgery remain the most resolute measures. Despite the optimistic use of multi-kinase inhibitors, namely sorafenib, the co-existence of chronic liver disease made the response rate low in these patients. Immune checkpoint inhibitors (ICIs) have become a promising hope for certain advanced solid tumors and, also, for advanced HCC. Unfortunately, a large cohort of patients with HCC fail to respond to immunotherapy. Materials and Methods: We conducted a narrative search on the main medical databases for original articles, reviews, meta-analyses, randomized clinical trials, and case series using the following keywords and acronyms and their associations: hepatocellular carcinoma, immunotherapy, checkpoint inhibitors, gut microbiota, and fecal microbiota transplantation. Results: ICIs are a promising and sufficiently safe treatment option for HCC. In detail, they have significantly improved survival and prognosis in these patients vs. sorafenib. Although there are several highlighted mechanisms of resistance, the gut microbiota signature can be used both as a response biomarker and as an effect enhancer. Practically, probiotic dose-finding and fecal microbiota transplantation are the weapons that can be used to increase ICI’s treatment-response-reducing resistance mechanisms. Conclusion: Immunotherapy has been a significant step-up in HCC treatment, and gut microbiota modulation is an effective liaison to increase its efficacy. Full article
(This article belongs to the Special Issue Advance in the Diagnosis, Treatment and Prognosis of Hepatocellular Carcinoma)
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13 pages, 659 KiB  
Review
The Role of Transjugular Intrahepatic Portosystemic Shunt (TIPS) in Treating Portal Hypertension in Patients with Hepatocellular Carcinoma
by Daniele Balducci, Michele Montori, Federico De Blasio, Alessandro Di Bucchianico, Maria Eva Argenziano, Gianluca Svegliati Baroni and Emidio Scarpellini
Medicina 2023, 59(6), 1150; https://doi.org/10.3390/medicina59061150 - 15 Jun 2023
Cited by 3 | Viewed by 2922
Abstract
Liver cancer is very frequent, and hepatocellular carcinoma (HCC) accounts for the majority of liver cancer cases. Its growing incidence has been greatly affected by the increasing prevalence of metabolic-associated fatty liver disease (MAFLD). The latter is a new epidemic in our era. [...] Read more.
Liver cancer is very frequent, and hepatocellular carcinoma (HCC) accounts for the majority of liver cancer cases. Its growing incidence has been greatly affected by the increasing prevalence of metabolic-associated fatty liver disease (MAFLD). The latter is a new epidemic in our era. In fact, HCC is often generated from noncirrhotic liver and its treatment benefits from surgical and nonsurgical approaches, potentially bridged by transjugular intrahepatic portosystemic shunt (TIPS) use. TIPS use is an effective treatment for portal hypertension complications, but its application in patients with HCC and clinically significant portal hypertension (CSPH) remains controversial due to concerns about tumor rupture, dissemination, and increased toxicity. The technical feasibility and safety of TIPS use in HCC patients have been evaluated in several studies. Despite concerns about intraprocedural complications, retrospective studies have shown high success rates and low complication rates in TIPS placement for HCC patients. TIPS use in combination with locoregional treatments, such as transarterial chemoembolization (TACE) or transarterial radioembolization (TARE), has been explored as a treatment option for HCC patients with portal hypertension. These studies have shown improved survival rates in patients undergoing TIPS in combination with locoregional treatments. However, the efficacy and toxicity of TACE in combination with TIPS use require careful evaluation, as changes in venous and arterial flow can affect treatment outcomes and complications. The results from studies evaluating the impact of TIPS on systemic therapy and surgical options are also promising. In conclusion, the TIPS is a sufficiently safe, useful item available for physicians treating complications of portal hypertension. Moreover, a TIPS can be used in combination with locoregional therapy in HCC patients. Systemic chemotherapy can also benefit of the use of TIPS placement. A complex interplay affects TIPS use with surgery. The latter needs further data. The TIPS is a useful and safe add-on treatment, changing the natural course of HCC progression. Its use is regulated by a sophisticated physiologic and pathophysiologic flow of evidence. Full article
(This article belongs to the Special Issue Advance in the Diagnosis, Treatment and Prognosis of Hepatocellular Carcinoma)
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21 pages, 892 KiB  
Review
Angiogenesis and Hepatocellular Carcinoma: From Molecular Mechanisms to Systemic Therapies
by Elisa Pinto, Filippo Pelizzaro, Fabio Farinati and Francesco Paolo Russo
Medicina 2023, 59(6), 1115; https://doi.org/10.3390/medicina59061115 - 9 Jun 2023
Cited by 12 | Viewed by 3230
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The hypervascular nature of the majority of HCCs and the peculiar vascular derangement occurring during liver carcinogenesis underscore the importance of angiogenesis in the development and progression of these tumors. Indeed, several angiogenic [...] Read more.
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The hypervascular nature of the majority of HCCs and the peculiar vascular derangement occurring during liver carcinogenesis underscore the importance of angiogenesis in the development and progression of these tumors. Indeed, several angiogenic molecular pathways have been identified as deregulated in HCC. The hypervascular nature and the peculiar vascularization of HCC, as well as deregulated angiogenic pathways, represent major therapeutic targets. To a large extent, intra-arterial locoregional treatments (transarterial-(chemo)embolization) rely on tumor ischemia caused by embolization of tumor feeding arteries, even though this may represent the “primum movens” of tumor recurrence through the activation of neoangiogenesis. Considering systemic therapies, the currently available tyrosine kinase inhibitors (sorafenib, regorafenib, cabozantinib and lenvatinib) and monoclonal antibodies (ramucirumab and bevacizumab, in combination with the anti-PD-L1, atezolizumab) primarily target, among others, angiogenic pathways. Considering the importance of angiogenesis in the pathogenesis and treatment of liver cancer, in this paper, we aim to review the role of angiogenesis in HCC, addressing the molecular mechanisms, available antiangiogenic therapies and prognostic biomarkers in patients receiving these treatments. Full article
(This article belongs to the Special Issue Advance in the Diagnosis, Treatment and Prognosis of Hepatocellular Carcinoma)
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11 pages, 331 KiB  
Review
Predicting Post-Hepatectomy Liver Failure in HCC Patients: A Review of Liver Function Assessment Based on Laboratory Tests Scores
by Alessio Morandi, Matteo Risaliti, Michele Montori, Simone Buccianti, Ilenia Bartolini and Luca Moraldi
Medicina 2023, 59(6), 1099; https://doi.org/10.3390/medicina59061099 - 7 Jun 2023
Cited by 9 | Viewed by 3073
Abstract
The assessment of liver function is crucial in predicting the risk of post-hepatectomy liver failure (PHLF) in patients undergoing liver resection, especially in cases of hepatocellular carcinoma (HCC) which is often associated with cirrhosis. There are currently no standardized criteria for predicting the [...] Read more.
The assessment of liver function is crucial in predicting the risk of post-hepatectomy liver failure (PHLF) in patients undergoing liver resection, especially in cases of hepatocellular carcinoma (HCC) which is often associated with cirrhosis. There are currently no standardized criteria for predicting the risk of PHLF. Blood tests are often the first- and least invasive expensive method for assessing hepatic function. The Child–Pugh score (CP score) and the Model for End Stage Liver Disease (MELD) score are widely used tools for predicting PHLF, but they have some limitations. The CP score does not consider renal function, and the evaluation of ascites and encephalopathy is subjective. The MELD score can accurately predict outcomes in cirrhotic patients, but its predictive capabilities diminish in non-cirrhotic patients. The albumin–bilirubin score (ALBI) is based on serum bilirubin and albumin levels and allows the most accurate prediction of PHLF for HCC patients. However, this score does not consider liver cirrhosis or portal hypertension. To overcome this limitation, researchers suggest combining the ALBI score with platelet count, a surrogate marker of portal hypertension, into the platelet–albumin–bilirubin (PALBI) grade. Non-invasive markers of fibrosis, such as FIB-4 and APRI, are also available for predicting PHLF but they focus only on cirrhosis related aspects and are potentially incomplete in assessing the global liver function. To improve the predictive power of the PHLF of these models, it has been proposed to combine them into a new score, such as the ALBI-APRI score. In conclusion, blood test scores may be combined to achieve a better predictive value of PHLF. However, even if combined, they may not be sufficient to evaluate liver function and to predict PHLF; thus, the inclusion of dynamic and imaging tests such as liver volumetry and ICG r15 may be helpful to potentially improve the predictive capacity of these models. Full article
(This article belongs to the Special Issue Advance in the Diagnosis, Treatment and Prognosis of Hepatocellular Carcinoma)
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