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Cancers
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Liver Cancer: Improving Standard Diagnosis and Therapy: 2nd Edition
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Liver Cancer: Improving Standard Diagnosis and Therapy: 2nd Edition

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

Deadline for manuscript submissions: 25 July 2025 | Viewed by 8315

Special Issue Editors

Dr. Ryota Masuzaki

E-Mail Website
Guest Editor
Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan
Interests: hepatocellular carcinoma; liver diseases; liver transplantation; gastroenterology
Special Issues, Collections and Topics in MDPI journals
Dr. Tatsuo Kanda

E-Mail Website
Guest Editor
Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan
Interests: viral hepatitis; hepatocellular carcinoma; innate immunity; unfolded protein response
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the second edition of the Special Issue “Liver Cancer: Improving Standard Diagnosis and Therapy”, available at https://www.mdpi.com/journal/cancers/special_issues/LCISDAT.

Liver cancer is a common malignancy worldwide, responsible for 5% of all newly diagnosed cancers. Primary liver cancer ranked sixth for cancer incidence and third for deaths in 2020 globally. There have been significant advances in both the curative and palliative treatment of hepatocellular carcinoma (HCC), including liver resection, local ablation therapy, radiotherapy, systemic chemotherapy, and liver transplantation.

The indication of effective treatment depends on the stage of cancer and liver function. The detection of HCC in the early stage primarily depends on imaging studies, such as ultrasonography, computed tomography, and MRI. Sonazoid®, a new contrast agent that has been commercially available since 2007 in Japan, is very useful for detecting liver tumors, including primary liver cancer and metastatic liver cancer, because it enables long-lasting Kupffer phase imaging.

The treatment option is guided based on the Barcelona Clinic Liver Cancer (BCLC) stages. For BCLC A, curative treatments such as radiofrequency ablation, surgical resection, and liver transplantation are indicated. The long-term survival rates of liver cancer patients remain poor, and how to preserve the liver function reservoir and prevent the recurrence of tumors are challenging tasks in the field. For the patients with BCLC B and C, transarterial chemoembolization or systemic chemotherapy is indicated. Newly developed molecular targeted agents (MTA) and immuno-oncology drugs are now available. Anti-programmed death receptor-1, anti-programmed cell death ligand 1, and anti-cytotoxic lymphocyte antigen 4 are currently being investigated, and their combinations with MTA are expected to bring better clinical outcomes. Direct and indirect biomarkers for prediction and stratification are being extensively investigated and are expected to be applied in daily clinical practice.

This Special issue will focus on recent basic and clinical cancer research into liver cancer.

We welcome broad topics regarding the diagnosis and treatment of liver cancer from basic to clinical research.

Dr. Ryota Masuzaki
Dr. Tatsuo Kanda
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 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

  • liver cancer 
  • diagnosis 
  • treatment 
  • basic research 
  • clinical research

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Further information on MDPI's Special Issue polices can be found here.

Published Papers (5 papers)

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Research

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13 pages, 2625 KiB  
Article
Programmed Death 1 and Cytotoxic T-Lymphocyte-Associated Protein 4 Gene Expression in Peripheral Blood Mononuclear Cells Can Serve as Prognostic Biomarkers for Hepatocellular Carcinoma
by Ji Ah Lee, Hei-Gwon Choi, Hyuk Soo Eun, Jiyoon Bu, Tae Min Jang, Jeongdong Lee, Chae Yeon Son, Min Seok Kim, Woo Sun Rou, Seok Hyun Kim, Byung Seok Lee, Ha Neul Kim, Tae Hee Lee and Hong Jae Jeon
Cancers 2024, 16(8), 1493; https://doi.org/10.3390/cancers16081493 - 13 Apr 2024
Viewed by 1331
Abstract
Hepatocellular carcinoma (HCC) is a highly aggressive form of liver cancer with poor prognosis. The lack of reliable biomarkers for early detection and accurate diagnosis and prognosis poses a significant challenge to its effective clinical management. In this study, we investigated the diagnostic [...] Read more.
Hepatocellular carcinoma (HCC) is a highly aggressive form of liver cancer with poor prognosis. The lack of reliable biomarkers for early detection and accurate diagnosis and prognosis poses a significant challenge to its effective clinical management. In this study, we investigated the diagnostic and prognostic potential of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in peripheral blood mononuclear cells (PBMCs) in HCC. PD-1 and CTLA-4 gene expression was analyzed comparatively using PBMCs collected from HCC patients and healthy individuals. The results revealed higher PD-1 gene expression levels in patients with multifocal tumors, lymphatic invasion, or distant metastasis than those in their control counterparts. However, conventional serum biomarkers of liver function do not exhibit similar correlations. In conclusion, PD-1 gene expression is associated with OS and PFS and CTLA-4 gene expression is associated with OS, whereas the serum biomarkers analyzed in this study show no significant correlation with survival in HCC. Hence, PD-1 and CTLA-4 expressed in PBMCs are considered potential prognostic biomarkers for patients with HCC that can facilitate prediction of malignancy, response to currently available HCC treatments, and overall survival. Full article
(This article belongs to the Special Issue Liver Cancer: Improving Standard Diagnosis and Therapy: 2nd Edition)
►▼ Show Figures

Figure 1

Figure 1
<p>Diagnostic capability of PD-1 and CTLA-4 genes in PBMCs for the detection of HCC compared to the serum AFP level: (<b>A</b>) PD-1 gene expressions, CTLA-4 gene expressions, and serum AFP levels between HCC patients and healthy donors; (<b>B</b>) the ROC analysis of gene expressions and serum AFP level for discriminating HCC patients from healthy individuals. Note that the significance levels are indicated as *** <span class="html-italic">p</span> &lt; 0.010.</p> Full article ">Figure 2
<p>The expression profiles of PD-1 and CTLA-4 genes in PBMCs and serum antigens depending on (<b>A</b>) the tumor multifocality and (<b>B</b>) the existence of nodal invasion or distant metastasis. Note that the significance levels are indicated as <sup>#</sup> <span class="html-italic">p</span> &lt; 0.100, and * <span class="html-italic">p</span> &lt; 0.050.</p> Full article ">Figure 3
<p>The Kaplan–Meier method for estimating the (<b>A</b>) OS and (<b>B</b>) PFS of patients with HCC using PD-1 and CTLA-4 gene expressions in PBMC. The results were compared with the standard serum tests for liver function, including AFP, AST, ALT, and albumin.</p> Full article ">Figure 4
<p>The univariate Cox regression analysis of the immune checkpoint genes and serum biomarkers for estimating OS and PFS.</p> Full article ">
15 pages, 1024 KiB  
Article
Promising Outcomes of Modified ALPPS for Staged Hepatectomy in Cholangiocarcinoma
by Arianeb Mehrabi, Mohammad Golriz, Ali Ramouz, Elias Khajeh, Ahmed Hammad, Thilo Hackert, Beat Müller-Stich, Oliver Strobel, Sadeq Ali-Hasan-Al-Saegh, Omid Ghamarnejad, Mohammed Al-Saeedi, Christoph Springfeld, Christian Rupp, Philipp Mayer, Markus Mieth, Benjamin Goeppert, Katrin Hoffmann and Markus W. Büchler
Cancers 2023, 15(23), 5613; https://doi.org/10.3390/cancers15235613 - 28 Nov 2023
Cited by 3 | Viewed by 3922
Abstract
Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage procedure that can potentially cure patients with large cholangiocarcinoma. The current study evaluates the impact of modifications on the outcomes of ALPPS in patients with cholangiocarcinoma. In this single-center [...] Read more.
Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage procedure that can potentially cure patients with large cholangiocarcinoma. The current study evaluates the impact of modifications on the outcomes of ALPPS in patients with cholangiocarcinoma. In this single-center study, a series of 30 consecutive patients with cholangiocarcinoma (22 extrahepatic and 8 intrahepatic) who underwent ALPPS between 2011 and 2021 was evaluated. The ALPPS procedure in our center was modified in 2016 by minimizing the first stage of the surgical procedure through biliary externalization after the first stage, antibiotic administration during the interstage phase, and performing biliary reconstructions during the second stage. The rate of postoperative major morbidity and 90-day mortality, as well as the one- and three-year disease-free and overall survival rates were calculated and compared between patients operated before and after 2016. The ALPPS risk score before the second stage of the procedure was lower in patients who were operated on after 2016 (before 2016: median 6.4; after 2016: median 4.4; p = 0.010). Major morbidity decreased from 42.9% before 2016 to 31.3% after 2016, and the 90-day mortality rate decreased from 35.7% before 2016 to 12.5% after 2016. The three-year survival rate increased from 40.8% before 2016 to 73.4% after 2016. Our modified ALPPS procedure improved perioperative and postoperative outcomes in patients with extrahepatic and intrahepatic cholangiocarcinoma. Minimizing the first step of the ALPPS procedure was key to these improvements. Full article
(This article belongs to the Special Issue Liver Cancer: Improving Standard Diagnosis and Therapy: 2nd Edition)
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Figure 1

Figure 1
<p>Three-year recurrence-free survival of patients who underwent ALPPS (Solid lines present the actual survival curve, and dash lines define the confidence intervals).</p> Full article ">Figure 2
<p>Three-year overall survival of patients who underwent ALPPS (Solid lines present the actual survival curve, and dash lines define the confidence intervals).</p> Full article ">
13 pages, 1438 KiB  
Article
Impact of Low Skeletal Muscle Mass on Long-Term Outcomes in Hepatocellular Carcinoma Treated with Trans-Arterial Radioembolization: A Retrospective Multi-Center Study
by Heechul Nam, Hyun Yang, Ho Soo Chun, Han Ah Lee, Joon Yeul Nam, Jeong Won Jang, Yeon Seok Seo, Do Young Kim, Yoon Jun Kim and Si Hyun Bae
Cancers 2023, 15(21), 5195; https://doi.org/10.3390/cancers15215195 - 28 Oct 2023
Cited by 2 | Viewed by 1427
Abstract
Trans-arterial radioembolization (TARE) is a form of radiation therapy performed for hepatocellular carcinoma (HCC) via selective intra-arterial injection of Yttrium-90-loaded microspheres. This was a multi-center retrospective study of consecutive patients with HCC who underwent TARE between July 2009 and May 2019. Using pre-treatment [...] Read more.
Trans-arterial radioembolization (TARE) is a form of radiation therapy performed for hepatocellular carcinoma (HCC) via selective intra-arterial injection of Yttrium-90-loaded microspheres. This was a multi-center retrospective study of consecutive patients with HCC who underwent TARE between July 2009 and May 2019. Using pre-treatment computed tomography imaging, the total cross-sectional area (cm2) of the abdominal skeletal muscle at the third lumbar vertebra was measured. The skeletal muscle index (SMI) was calculated by normalizing the muscle area to patient height. In total, 347 patients (median age, 65 years; 284 male) were included in the study. A total of 108 (31.1%) patients had portal vein tumor thrombus (PVTT), and 126 (36.3%) were classified as LSMM. The median overall survival (OS) was 28.1 months (95% CI, 24.8–35.7), and median progression-free survival was 8.0 months (95% CI, 6.4–9.4). Multivariate Cox regression analysis revealed that LSMM (hazard ratio [HR], 1.36; 95% CI, 1.00–1.85, p = 0.05), PVTT (HR, 1.82; 95% CI, 1.33–2.49, p < 0.01), alpha-fetoprotein (AFP) (≥200 ng/mL) (HR 1.41; 95% CI, 1.04–1.92, p = 0.03), and albumin–bilirubin grade (2–3) (HR 1.74; 95% CI, 1.24–2.43, p < 0.01) were independently associated with poor OS. TARE provided favorable long-term outcomes for patients with advanced HCC. Pre-treatment LSMM independently associated with survival, suggesting its utility as a surrogate biomarker for identifying TARE candidates. Full article
(This article belongs to the Special Issue Liver Cancer: Improving Standard Diagnosis and Therapy: 2nd Edition)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Assessment of body composition using body mass index measurement software, showing the proportions of skeletal muscle (green), subcutaneous fat (red), and visceral fat (blue) in a representative patient.</p> Full article ">Figure 2
<p>Kaplan–Meier curve for overall survival. (<b>A</b>) Total patients; (<b>B</b>) subgroup analysis stratified according to LSMM; (<b>C</b>) subgroup analysis stratified according to PVTT. LSMM, low skeletal muscle mass; PVTT, portal vein tumor thrombus.</p> Full article ">Figure 2 Cont.
<p>Kaplan–Meier curve for overall survival. (<b>A</b>) Total patients; (<b>B</b>) subgroup analysis stratified according to LSMM; (<b>C</b>) subgroup analysis stratified according to PVTT. LSMM, low skeletal muscle mass; PVTT, portal vein tumor thrombus.</p> Full article ">Figure 3
<p>Kaplan–Meier curve for progression-free survival. (<b>A</b>) Total patients; (<b>B</b>) subgroup analysis stratified according to LSMM; (<b>C</b>) subgroup analysis stratified according to PVTT. LSMM, low skeletal muscle mass; PVTT, portal vein tumor thrombus.</p> Full article ">

Review

Jump to: Research

30 pages, 3560 KiB  
Review
Resistance to Tyrosine Kinase Inhibitors in Hepatocellular Carcinoma (HCC): Clinical Implications and Potential Strategies to Overcome the Resistance
by Ali Gawi Ermi and Devanand Sarkar
Cancers 2024, 16(23), 3944; https://doi.org/10.3390/cancers16233944 (registering DOI) - 25 Nov 2024
Viewed by 112
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, and the development of effective treatment strategies remains a significant challenge in the management of advanced HCC patients. The emergence of tyrosine kinase inhibitors (TKIs) has been a significant advancement in the [...] Read more.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, and the development of effective treatment strategies remains a significant challenge in the management of advanced HCC patients. The emergence of tyrosine kinase inhibitors (TKIs) has been a significant advancement in the treatment of HCC, as these targeted therapies have shown promise in prolonging the survival of patients with advanced disease. Although immunotherapy is currently considered as the first line of treatment for advanced HCC patients, many such patients do not meet the clinical criteria to be eligible for immunotherapy, and in many parts of the world there is still lack of accessibility to immunotherapy. As such, TKIs still serve as the first line of treatment and play a major role in the treatment repertoire for advanced HCC patients. However, the development of resistance to these agents is a major obstacle that must be overcome. In this review, we explore the underlying mechanisms of resistance to TKIs in HCC, the clinical implications of this resistance, and the potential strategies to overcome or prevent the emergence of resistance. Full article
(This article belongs to the Special Issue Liver Cancer: Improving Standard Diagnosis and Therapy: 2nd Edition)
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Figure 1

Figure 1
<p>Mechanism of receptor tyrosine kinase (RTK) activation. Created in <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p> Full article ">Figure 2
<p>Cartoon showing common tyrosine kinase receptors and their downstream signaling pathways. Created in <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p> Full article ">Figure 3
<p>Chemical structures of commonly used TKIs approved by the FDA for treatment of HCC. Created in <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p> Full article ">Figure 4
<p>Schematic of m6A RNA modification and its contribution to resistance to TKIs. See text for details. Created in <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p> Full article ">Figure 5
<p>Schematic of metabolic changes contributing to resistance to TKIs. See text for details. Created in <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p> Full article ">Figure 6
<p>Important mechanisms of TKI resistance and strategies to overcome them. Please see text for details. Created in <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p> Full article ">
17 pages, 886 KiB  
Review
Racial/Ethnic Disparities and Immunotherapeutic Advances in the Treatment of Hepatocellular Carcinoma
by Alexsis Garcia and Stephen O. Mathew
Cancers 2024, 16(13), 2446; https://doi.org/10.3390/cancers16132446 - 3 Jul 2024
Viewed by 1052
Abstract
Hepatocellular carcinoma (HCC) remains one of the leading causes of death among many associated liver diseases. Various conventional strategies have been utilized for treatment, ranging from invasive surgeries and liver transplants to radiation therapy, but fail due to advanced disease progression, late screening/staging, [...] Read more.
Hepatocellular carcinoma (HCC) remains one of the leading causes of death among many associated liver diseases. Various conventional strategies have been utilized for treatment, ranging from invasive surgeries and liver transplants to radiation therapy, but fail due to advanced disease progression, late screening/staging, and the various etiologies of HCC. This is especially evident within racially distinct populations, where incidence rates are higher and treatment outcomes are worse for racial/ethnic minorities than their Caucasian counterparts. However, with the rapid development of genetic engineering and molecular and synthetic biology, many novel strategies have presented promising results and have provided potential treatment options. In this review, we summarize past treatments, how they have shaped current treatments, and potential treatment strategies for HCC that may prove more effective in the future. Full article
(This article belongs to the Special Issue Liver Cancer: Improving Standard Diagnosis and Therapy: 2nd Edition)
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Figure 1

Figure 1
<p>Currently approved FDA biomarkers, biomarkers currently being evaluated in clinical trials, and a list of the challenges associated with evaluating biomarkers.</p> Full article ">Figure 2
<p>Current treatments for hepatocellular carcinoma (HCC).</p> Full article ">
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