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Hepatocellular Carcinoma
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Hepatocellular Carcinoma

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

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 54316

Special Issue Editor

Prof. Dr. Mario Scartozzi

E-Mail Website
Guest Editor
Medical Oncology Unit, University Hospital, University of Cagliari, 09042 Cagliari, Italy
Interests: pancreatic cancer; gastrointestinal cancer; clinical trials; predictive biomarkers; translational research; precision medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As we know, hepatocellular carcinoma (HCC) is the most common liver cancer with high morbidity and mortality worldwide. It is the fifth most common cause of cancer in men and the seventh in women. The most important causes of HCC are viral hepatitis B and hepatitis C, so their distributions are correlated.

Liver resection, orthotopic liver transplantation, and local treatments are curative options for patients with early and intermediate HCC.

Tyrosine kinase inhibitors are currently considered the standard of care for advanced or intermediate HCC patients’ refractory to locoregional therapy. In recent years, immunotherapy has also been showing promising results in this setting, although recent trials have failed to confirm preliminary results.

Nonetheless, not all patients seem to benefit from these treatments and are thus exposed to unnecessary toxicities without deriving any clinical benefit or survival improvement.

In this scenario, we urgently need clinical and/or biological markers which are able to identify responding patients as well as new treatment options.

Prof. Dr. Mario Scartozzi
Guest Editor

Manuscript Submission Information

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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
  • translational research
  • tyrosine kinase inhibitors
  • predictive factors

Published Papers (14 papers)

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27 pages, 3241 KiB  
Article
Systematic Analysis of the Transcriptome Profiles and Co-Expression Networks of Tumour Endothelial Cells Identifies Several Tumour-Associated Modules and Potential Therapeutic Targets in Hepatocellular Carcinoma
by Thomas Mohr, Sonja Katz, Verena Paulitschke, Nadim Aizarani and Alexander Tolios
Cancers 2021, 13(8), 1768; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081768 - 07 Apr 2021
Cited by 9 | Viewed by 5975
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related death, with tumour associated liver endothelial cells being thought to be major drivers in HCC progression. This study aims to compare the gene expression profiles of [...] Read more.
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related death, with tumour associated liver endothelial cells being thought to be major drivers in HCC progression. This study aims to compare the gene expression profiles of tumour endothelial cells from the liver with endothelial cells from non-tumour liver tissue, to identify perturbed biologic functions, co-expression modules, and potentially drugable hub genes that could give rise to novel therapeutic targets and strategies. Gene Set Variation Analysis (GSVA) showed that cell growth-related pathways were upregulated, whereas apoptosis induction, immune and inflammatory-related pathways were downregulated in tumour endothelial cells. Weighted Gene Co-expression Network Analysis (WGCNA) identified several modules strongly associated to tumour endothelial cells or angiogenic activated endothelial cells with high endoglin (ENG) expression. In tumour cells, upregulated modules were associated with cell growth, cell proliferation, and DNA-replication, whereas downregulated modules were involved in immune functions, particularly complement activation. In ENG+ cells, upregulated modules were associated with cell adhesion and endothelial functions. One downregulated module was associated with immune system-related functions. Querying the STRING database revealed known functional-interaction networks underlying the modules. Several possible hub genes were identified, of which some (for example FEN1, BIRC5, NEK2, CDKN3, and TTK) are potentially druggable as determined by querying the Drug Gene Interaction database. In summary, our study provides a detailed picture of the transcriptomic differences between tumour and non-tumour endothelium in the liver on a co-expression network level, indicates several potential therapeutic targets and presents an analysis workflow that can be easily adapted to other projects. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma)
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17 pages, 3131 KiB  
Article
Remodeling Lipids in the Transition from Chronic Liver Disease to Hepatocellular Carcinoma
by Israa T. Ismail, Ashraf Elfert, Marwa Helal, Ibrahim Salama, Hala El-Said and Oliver Fiehn
Cancers 2021, 13(1), 88; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13010088 - 30 Dec 2020
Cited by 20 | Viewed by 3056
Abstract
Hepatocellular carcinoma (HCC) is a worldwide health problem. HCC patients show a 50% mortality within two years of diagnosis. To better understand the molecular pathogenesis at the level of lipid metabolism, untargeted UPLC MS—QTOF lipidomics data were acquired from resected human HCC tissues [...] Read more.
Hepatocellular carcinoma (HCC) is a worldwide health problem. HCC patients show a 50% mortality within two years of diagnosis. To better understand the molecular pathogenesis at the level of lipid metabolism, untargeted UPLC MS—QTOF lipidomics data were acquired from resected human HCC tissues and their paired nontumor hepatic tissues (n = 46). Blood samples of the same HCC subjects (n = 23) were compared to chronic liver disease (CLD) (n = 15) and healthy control (n = 15) blood samples. The participants were recruited from the National Liver Institute in Egypt. The lipidomics data yielded 604 identified lipids that were divided into six super classes. Five-hundred and twenty-four blood lipids were found as significantly differentiated (p < 0.05 and qFDR p < 0.1) between the three study groups. In the blood of CLD patients compared to healthy control subjects, almost all lipid classes were significantly upregulated. In CLD patients, triacylglycerides were found as the most significantly upregulated lipid class at qFDR p = 1.3 × 10−56, followed by phosphatidylcholines at qFDR p = 3.3 × 10−51 and plasmalogens at qFDR p = 1.8 × 10-46. In contrast, almost all blood lipids were significantly downregulated in HCC patients compared to CLD patients, and in HCC tissues compared to nontumor hepatic tissues. Ceramides were found as the most significant lipid class (qFDR p = 1 × 10−14) followed by phosphatidylglycerols (qFDR p = 3 × 10−9), phosphatidylcholines and plasmalogens. Despite these major differences, there were also common trends in the transitions between healthy controls, CLD and HCC patients. In blood, several mostly saturated triacylglycerides showed a continued increase in the trajectory towards HCC, accompanied by reduced levels of saturated free fatty acids and saturated lysophospatidylcholines. In contrast, the largest overlaps of lipid alterations that were found in both HCC tissue and blood comparisons were decreased levels of phosphatidylglycerols and sphingolipids. This study highlights the specific impact of HCC tumors on the circulating lipids. Such data may be used to target lipid metabolism for prevention, early detection and treatment of HCC in the background of viral-related CLD etiology. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma)
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10 pages, 1675 KiB  
Article
Novel Model to Predict HCC Recurrence after Liver Transplantation Obtained Using Deep Learning: A Multicenter Study
by Joon Yeul Nam, Jeong-Hoon Lee, Junho Bae, Young Chang, Yuri Cho, Dong Hyun Sinn, Bo Hyun Kim, Seoung Hoon Kim, Nam-Joon Yi, Kwang-Woong Lee, Jong Man Kim, Joong-Won Park, Yoon Jun Kim, Jung-Hwan Yoon, Jae-Won Joh and Kyung-Suk Suh
Cancers 2020, 12(10), 2791; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102791 - 29 Sep 2020
Cited by 30 | Viewed by 3431
Abstract
Several models have been developed using conventional regression approaches to extend the criteria for liver transplantation (LT) in hepatocellular carcinoma (HCC) beyond the Milan criteria. We aimed to develop a novel model to predict tumor recurrence after LT by adopting artificial intelligence (MoRAL-AI). [...] Read more.
Several models have been developed using conventional regression approaches to extend the criteria for liver transplantation (LT) in hepatocellular carcinoma (HCC) beyond the Milan criteria. We aimed to develop a novel model to predict tumor recurrence after LT by adopting artificial intelligence (MoRAL-AI). This study included 563 patients who underwent LT for HCC at three large LT centers in Korea. Derivation (n = 349) and validation (n = 214) cohorts were independently established. The primary outcome was time-to-recurrence after LT. A MoRAL-AI was derived from the derivation cohort with a residual block-based deep neural network. The median follow-up duration was 74.7 months (interquartile-range, 18.5–107.4); 204 patients (36.2%) had HCC beyond the Milan criteria. The optimal model consisted of seven layers including two residual blocks. In the validation cohort, the MoRAL-AI showed significantly better discrimination function (c-index = 0.75) than the Milan (c-index = 0.64), MoRAL (c-index = 0.69), University of California San Francisco (c-index = 0.62), up-to-seven (c-index = 0.50), and Kyoto (c-index = 0.50) criteria (all p < 0.001). The largest weighted parameter in the MoRAL-AI was tumor diameter, followed by alpha-fetoprotein, age, and protein induced by vitamin K absence-II. The MoRAL-AI had better predictability of tumor recurrence after LT than conventional models. The MoRAL-AI can also evolve with further data. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma)
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10 pages, 931 KiB  
Article
Prognostic Role of Serum Cytokeratin-19 Fragment (CYFRA 21-1) in Patients with Hepatocellular Carcinoma
by Gian Paolo Caviglia, Michela Ciruolo, Antonella Olivero, Patrizia Carucci, Emanuela Rolle, Chiara Rosso, Maria Lorena Abate, Alessandra Risso, Davide Giuseppe Ribaldone, Francesco Tandoi, Giorgio Maria Saracco, Elisabetta Bugianesi and Silvia Gaia
Cancers 2020, 12(10), 2776; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102776 - 28 Sep 2020
Cited by 15 | Viewed by 2339
Abstract
Keratin 19 (K19) is a cancer stem cell marker expressed by a subpopulation of hepatocellular carcinoma (HCC), associated with tumor aggressiveness. We evaluated the prognostic value of serum K19 fragment (CYFRA 21-1), in comparison or in combination with alpha-fetoprotein (AFP) and protein induced [...] Read more.
Keratin 19 (K19) is a cancer stem cell marker expressed by a subpopulation of hepatocellular carcinoma (HCC), associated with tumor aggressiveness. We evaluated the prognostic value of serum K19 fragment (CYFRA 21-1), in comparison or in combination with alpha-fetoprotein (AFP) and protein induced by vitamin-K absence or antagonist-II (PIVKA-II), in patients with HCC. A total of 160 patients (28F/132M; median age 62, range 44–86 years) with a new diagnosis of HCC and available serum samples collected at tumor diagnosis were analyzed retrospectively. Median overall survival (OS) after HCC diagnosis was 35.1, 95% CI 27.1–70.5 months. Multivariate Cox regression analysis showed that CYFRA 21-1 > 2.7 ng/mL (hazard ratio (HR) = 3.39, p < 0.001), AFP > 20 ng/mL (HR = 2.27, p = 0.007), and PIVKA-II > 200 mAU/mL (HR = 2.17, p = 0.020) were independent predictors of OS. The combination of biomarkers positivity allowed us to stratify patients with HCC into four risk categories associated with a progressively lower survival probability (log-rank test, p < 0.001). CYFRA 21-1 resulted an independent prognostic factor of patients with HCC and its combination with AFP and PIVKA-II might be useful to tailor personalized treatment strategies. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma)
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13 pages, 1080 KiB  
Article
Pathway-Based Integrative Analysis of Metabolome and Microbiome Data from Hepatocellular Carcinoma and Liver Cirrhosis Patients
by Boram Kim, Eun Ju Cho, Jung-Hwan Yoon, Soon Sun Kim, Jae Youn Cheong, Sung Won Cho and Taesung Park
Cancers 2020, 12(9), 2705; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092705 - 21 Sep 2020
Cited by 7 | Viewed by 2622
Abstract
Aberrations of the human microbiome are associated with diverse liver diseases, including hepatocellular carcinoma (HCC). Even if we can associate specific microbes with particular diseases, it is difficult to know mechanistically how the microbe contributes to the pathophysiology. Here, we sought to reveal [...] Read more.
Aberrations of the human microbiome are associated with diverse liver diseases, including hepatocellular carcinoma (HCC). Even if we can associate specific microbes with particular diseases, it is difficult to know mechanistically how the microbe contributes to the pathophysiology. Here, we sought to reveal the functional potential of the HCC-associated microbiome with the human metabolome which is known to play a role in connecting host phenotype to microbiome function. To utilize both microbiome and metabolomic data sets, we propose an innovative, pathway-based analysis, Hierarchical structural Component Model for pathway analysis of Microbiome and Metabolome (HisCoM-MnM), for integrating microbiome and metabolomic data. In particular, we used pathway information to integrate these two omics data sets, thus providing insight into biological interactions between different biological layers, with regard to the host’s phenotype. The application of HisCoM-MnM to data sets from 103 and 97 patients with HCC and liver cirrhosis (LC), respectively, showed that this approach could identify HCC-related pathways related to cancer metabolic reprogramming, in addition to the significant metabolome and metagenome that make up those pathways. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma)
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17 pages, 1553 KiB  
Article
Immunotherapy in Hepatocellular Cancer Patients with Mild to Severe Liver Dysfunction: Adjunctive Role of the ALBI Grade
by David J. Pinato, Takahiro Kaneko, Anwaar Saeed, Tiziana Pressiani, Ahmed Kaseb, Yinghong Wang, David Szafron, Tomi Jun, Sirish Dharmapuri, Abdul Rafeh Naqash, Mahvish Muzaffar, Musharraf Navaid, Chieh-Ju Lee, Anushi Bulumulle, Bo Yu, Sonal Paul, Neil Nimkar, Dominik Bettinger, Hannah Hildebrand, Yehia I. Abugabal, Celina Ang, Thomas U. Marron, Uqba Khan, Nicola Personeni, Lorenza Rimassa and Yi-Hsiang Huangadd Show full author list remove Hide full author list
Cancers 2020, 12(7), 1862; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071862 - 10 Jul 2020
Cited by 47 | Viewed by 4204
Abstract
Immune checkpoint inhibitors (ICI) have shown positive results in patients with hepatocellular carcinoma (HCC). As liver function contributes to prognosis, its precise assessment is necessary for the safe prescribing and clinical development of ICI in HCC. We tested the accuracy of the albumin-bilirubin [...] Read more.
Immune checkpoint inhibitors (ICI) have shown positive results in patients with hepatocellular carcinoma (HCC). As liver function contributes to prognosis, its precise assessment is necessary for the safe prescribing and clinical development of ICI in HCC. We tested the accuracy of the albumin-bilirubin (ALBI) grade as an alternative prognostic biomarker to the Child-Turcotte-Pugh (CTP). In a prospectively maintained multi-centre dataset of HCC patients, we assessed safety and efficacy of ICI across varying levels of liver dysfunction described by CTP (A to C) and ALBI grade and evaluated uni- and multi-variable predictors of overall (OS) and post-immunotherapy survival (PIOS). We studied 341 patients treated with programmed-death pathway inhibitors (n = 290, 85%). Pre-treatment ALBI independently predicted for OS, with median OS of 22.5, 9.6, and 4.6 months across grades (p < 0.001). ALBI was superior to CTP in predicting 90-days mortality with area under the curve values of 0.65 (95% CI 0.57–0.74) versus 0.63 (95% CI 0.54–0.72). ALBI grade at ICI cessation independently predicted for PIOS (p < 0.001). Following adjustment for ICI regimen, neither ALBI nor CTP predicted for overall response rates or treatment-emerging adverse events (p > 0.05). ALBI grade identifies a subset of patients with prolonged survival prior to and after ICI therapy, lending itself as an optimal stratifying biomarker to optimise sequencing of systemic therapies in advanced HCC. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma)
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10 pages, 1047 KiB  
Article
Rapid Depletion of Subcutaneous Adipose Tissue during Sorafenib Treatment Predicts Poor Survival in Patients with Hepatocellular Carcinoma
by Kenji Imai, Koji Takai, Takao Miwa, Daisuke Taguchi, Tatsunori Hanai, Atsushi Suetsugu, Makoto Shiraki and Masahito Shimizu
Cancers 2020, 12(7), 1795; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071795 - 04 Jul 2020
Cited by 14 | Viewed by 1926
Abstract
The aim of this study was to assess the annualized changes in body composition, including skeletal muscle, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) before, during, and after sorafenib treatment in patients with hepatocellular carcinoma (HCC). This retrospective study evaluated 61 [...] Read more.
The aim of this study was to assess the annualized changes in body composition, including skeletal muscle, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) before, during, and after sorafenib treatment in patients with hepatocellular carcinoma (HCC). This retrospective study evaluated 61 HCC patients treated with sorafenib. Annualized changes (Δ; cm2/m2/year) in skeletal muscle index (SMI), SAT index (SATI), and VAT index (VATI), which were defined as the cross-sectional areas (cm2) of those areas on computed tomography normalized by the square of one’s height (m2), before (pre), during (during), and after (post) sorafenib treatment, were calculated. Patients within the 20th percentile cutoffs for these indices were classified into the rapid depletion group and the effects of these values on survival were analyzed using the Kaplan-Meier analysis and Cox proportional-hazards model. Annualized depletion rates of SMI (ΔSMIpre: −3.5, ΔSMIduring: −3.5, ΔSMIpost: −8.0) and VATI (ΔVATIpre: −3.2, ΔVATIduring: −2.8, ΔVATIpost: −15.1) accelerated after the cancellation of sorafenib, whereas that of SATI (ΔSATIpre: −4.8, ΔSATIduring; −7.6, ΔSATIpost; −8.0) had already accelerated during sorafenib treatment. Patients with rapid depletion of ΔSATIduring experienced significantly worse survival rates (p < 0.001), and it was an independent predictor of survival (p = 0.009), together with therapeutic effect (p < 0.001). Rapid depletion of SAT during sorafenib treatment can be used to predict survival in patients with HCC. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma)
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14 pages, 4715 KiB  
Article
Sorafenib for the Treatment of Unresectable Hepatocellular Carcinoma: Preliminary Toxicity and Activity Data in Dogs
by Laura Marconato, Silvia Sabattini, Giorgia Marisi, Federica Rossi, Vito Ferdinando Leone and Andrea Casadei-Gardini
Cancers 2020, 12(5), 1272; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12051272 - 18 May 2020
Cited by 14 | Viewed by 6884
Abstract
Unresectable nodular and diffuse hepatocellular carcinoma (HCC) have a poor prognosis with limited treatment options. Systemic traditional chemotherapy has been only rarely reported, with unsatisfactory results. The aim of this prospective, non-randomized, non-blinded, single center clinical trial was to investigate safety profile, objective [...] Read more.
Unresectable nodular and diffuse hepatocellular carcinoma (HCC) have a poor prognosis with limited treatment options. Systemic traditional chemotherapy has been only rarely reported, with unsatisfactory results. The aim of this prospective, non-randomized, non-blinded, single center clinical trial was to investigate safety profile, objective response rate, time to progression and overall survival of sorafenib in comparison with metronomic chemotherapy (MC) consisting of thalidomide, piroxicam and cyclophosphamide in dogs with advanced, unresectable HCC. Between December 2011 and June 2017, 13 dogs were enrolled: seven received sorafenib, and six were treated with MC. Median time to progression was 363 days (95% CI, 191–535) in dogs treated with sorafenib versus 27 days (95% CI, 0–68) in dogs treated with MC (p = 0.044). Median overall survival was 361 days (95% CI, 0–909) in dogs receiving sorafenib, while 32 days (95% CI, 0–235) in those receiving MC (p = 0.079). Sorafenib seems to be a good candidate for the treatment of dogs with advanced HCC, due to a benefit in disease control and an acceptable safety profile, offering a good basis on which new randomized prospective clinical trials should be undertaken to compare the efficacy and drawback of sorafenib versus MC or traditional chemotherapy. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma)
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13 pages, 4342 KiB  
Article
Chemoembolization Plus Radiotherapy versus Chemoembolization Plus Sorafenib for the Treatment of Hepatocellular Carcinoma Invading the Portal Vein: A Propensity Score Matching Analysis
by Hee Ho Chu, Jin Hyoung Kim, Ju Hyun Shim, Sang Min Yoon, Pyeong Hwa Kim and Ibrahim Alrashidi
Cancers 2020, 12(5), 1116; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12051116 - 29 Apr 2020
Cited by 24 | Viewed by 3465
Abstract
A combination of transarterial chemoembolization (TACE) plus sorafenib or radiotherapy (RT) has demonstrated efficacy in patients with advanced hepatocellular carcinoma (HCC). Here, the two combined treatment approaches were compared in patients with HCC and portal vein tumor thrombus (PVTT). Data from 307 patients [...] Read more.
A combination of transarterial chemoembolization (TACE) plus sorafenib or radiotherapy (RT) has demonstrated efficacy in patients with advanced hepatocellular carcinoma (HCC). Here, the two combined treatment approaches were compared in patients with HCC and portal vein tumor thrombus (PVTT). Data from 307 patients treated with TACE plus RT (n = 203) or TACE plus sorafenib (n = 104) as first-line treatment for HCC with PVTT were retrospectively evaluated. Using the propensity model to correct selection bias, 87 patients were included from each treatment group. During follow up (median, 12 months) in the entire study population, the median progression-free survival (PFS) and overall survival (OS) were significantly longer in the TACE plus RT group than in the TACE plus sorafenib group (6.5 vs. 4.3 months, respectively; p = 0.017 and 16.4 vs. 12 months, respectively; p = 0.007). Following propensity score matching, the median PFS and OS in the two groups showed no statistically significant difference. Multivariable analysis found no significant association between PFS or OS and the treatment type. In conclusion, this retrospective study of data from patients with advanced HCC with PVTT shows that PFS and OS did not differ significantly in patients treated with TACE plus RT and TACE plus sorafenib. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma)
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12 pages, 932 KiB  
Article
Early Tumor Shrinkage as a Predictive Factor for Outcomes in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Analysis
by Aya Takahashi, Michihisa Moriguchi, Yuya Seko, Toshihide Shima, Yasuhide Mitsumoto, Hidetaka Takashima, Hiroyuki Kimura, Hideki Fujii, Hiroki Ishikawa, Takaharu Yo, Hiroshi Ishiba, Atsuhiro Morita, Masayasu Jo, Yasuyuki Nagao, Masahiro Arai, Tasuku Hara, Akira Okajima, Akira Muramatsu, Naomi Yoshinami, Tomoki Nakajima, Hironori Mitsuyoshi, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Takeshi Okanoue and Yoshito Itohadd Show full author list remove Hide full author list
Cancers 2020, 12(3), 754; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030754 - 23 Mar 2020
Cited by 16 | Viewed by 3507
Abstract
We investigated the association between early tumor shrinkage (ETS) and treatment outcome in patients with hepatocellular carcinoma treated with lenvatinib (LEN). A retrospective analysis was performed in 104 patients. ETS was defined as tumor shrinkage at the first evaluation in the sum of [...] Read more.
We investigated the association between early tumor shrinkage (ETS) and treatment outcome in patients with hepatocellular carcinoma treated with lenvatinib (LEN). A retrospective analysis was performed in 104 patients. ETS was defined as tumor shrinkage at the first evaluation in the sum of target lesions’ longest diameters from baseline according to the Response Evaluation Criteria in Solid Tumors (RECIST). The median overall survival (OS) was not reached, whereas the median progression-free survival (PFS) was 5.0 months. The receiver operating characteristic curve analysis in differentiating long-term responders (PFS ≥ 5.0 months) from short-term responders (PFS < 5.0 months) revealed an ETS cut-off value of 10%. ETS ≥ 10% was significantly correlated with better PFS and OS compared with ETS < 10%. Additionally, ETS ≥ 10% showed a better discrimination ability on prognosis compared with modified RECIST-based objective response at the first evaluation. Multivariate analysis confirmed ETS ≥ 10% as an independent predictor of better OS, as well as a Child–Pugh score of 5 and macrovascular invasion. In conclusion, ETS ≥ 10% was strongly associated with outcome in patients treated with LEN. This biomarker could allow earlier assessment of the treatment response and guide treatment decision-making for HCC. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma)
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16 pages, 1559 KiB  
Article
Early Changes in Circulating FGF19 and Ang-2 Levels as Possible Predictive Biomarkers of Clinical Response to Lenvatinib Therapy in Hepatocellular Carcinoma
by Makoto Chuma, Haruki Uojima, Kazushi Numata, Hisashi Hidaka, Hidenori Toyoda, Atsushi Hiraoka, Toshifumi Tada, Shunji Hirose, Masanori Atsukawa, Norio Itokawa, Taeang Arai, Makoto Kako, Takahide Nakazawa, Naohisa Wada, Shuitirou Iwasaki, Yuki Miura, Satoshi Hishiki, Shuhei Nishigori, Manabu Morimoto, Nobuhiro Hattori, Katsuaki Ogushi, Akito Nozaki, Hiroyuki Fukuda, Tatehiro Kagawa, Kojiro Michitaka, Takashi Kumada and Shin Maedaadd Show full author list remove Hide full author list
Cancers 2020, 12(2), 293; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12020293 - 26 Jan 2020
Cited by 36 | Viewed by 3950
Abstract
Predictive biomarkers of the response of hepatocellular carcinoma (HCC) to Lenvatinib therapy have not yet been clarified. The aim of this study was to identify clinically significant biomarkers of response to Lenvatinib therapy, to target strategies against HCC. Levels of circulating angiogenic factors [...] Read more.
Predictive biomarkers of the response of hepatocellular carcinoma (HCC) to Lenvatinib therapy have not yet been clarified. The aim of this study was to identify clinically significant biomarkers of response to Lenvatinib therapy, to target strategies against HCC. Levels of circulating angiogenic factors (CAFs) were analyzed in blood samples collected at baseline and after introducing lenvatinib, from 74 Child-Pugh class A HCC patients who received lenvatinib. As CAF biomarkers, serum vascular endothelial growth factor (VEGF), fibroblast growth factor 19 (FGF19), FGF23, and angiopoietin-2 (Ang-2) were measured using enzyme-linked immunosorbent assays. Results: Significantly increased FGF19 (FGF19-i) levels and decreased Ang-2 (Ang-2-d) levels were seen in Lenvatinib responders as compared to non-responders (ratio of FGF19 level at 4 weeks/baseline in responders vs. non-responders: 2.09 vs. 1.32, respectively, p = 0.0004; ratio of Ang-2 level at four weeks/baseline: 0.584 vs. 0.810, respectively, p = 0.0002). Changes in FGF23 and VEGF levels at four weeks versus baseline, however, were not significantly different in responders versus non-responders. In multivariate analysis, the combination of serum FGF19-i and Ang-2-d was the most independent predictive factor for Lenvatinib response (Odds ratio, 9.143; p = 0.0012). Furthermore, this combination biomarker showed the greatest independent association with progression-free survival (Hazard ratio, 0.171; p = 0.0240). Early changes in circulating FGF19 and Ang-2 levels might be useful for predicting clinical response and progression-free survival in HCC patients on Lenvatinib therapy. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma)
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16 pages, 4743 KiB  
Article
Overexpression of p62/IMP2 can Promote Cell Migration in Hepatocellular Carcinoma via Activation of the Wnt/β-Catenin Pathway
by Mengtao Xing, Pei Li, Xiao Wang, Jitian Li, Jianxiang Shi, Jiejie Qin, Xiaojun Zhang, Yangcheng Ma, Giulio Francia and Jian-Ying Zhang
Cancers 2020, 12(1), 7; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010007 - 18 Dec 2019
Cited by 24 | Viewed by 3400
Abstract
p62/IMP2 is an oncofetal protein that was first reported as a tumor-associated antigen in hepatocellular carcinoma (HCC). In our previous studies, we demonstrated a high frequency of p62/IMP2 autoantibodies appearing in various types of cancer. Therefore, we hypothesize that p62/IMP2 plays an important [...] Read more.
p62/IMP2 is an oncofetal protein that was first reported as a tumor-associated antigen in hepatocellular carcinoma (HCC). In our previous studies, we demonstrated a high frequency of p62/IMP2 autoantibodies appearing in various types of cancer. Therefore, we hypothesize that p62/IMP2 plays an important role in the progression of HCC, although the mechanism remains to be explored. In this study, we evaluated the expression of p62/IMP2 protein both in human tissues and liver cancer cell lines by immunohistochemistry and western blotting analysis and found that p62/IMP2 protein is overexpressed in human HCC tissue in comparison to normal human liver tissue. To explore the role that p62/IMP2 plays in HCC, p62/IMP2 was knocked out in two p62/IMP2-positive liver cancer cell lines (SNU449 and HepG2). Due to the low expression level of p62/IMP2 in SNU449, we overexpressed p62/IMP2 in this cell line. We subsequently demonstrated that high expression of p62/IMP2 in both cell lines can promote cell migration and invasion abilities in vitro by activating the Wnt/β-catenin pathway. We also used the Wnt/β-catenin pathway inhibitor, XAV 939, and a phosphoproteome assay to confirm our findings. Conclusion: Our results suggest that p62/IMP2 is an essential regulator of Wnt signaling pathways and plays an important role in HCC progression and metastasis. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma)
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Review

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19 pages, 938 KiB  
Review
Clinical Characterisation and Management of the Main Treatment-Induced Toxicities in Patients with Hepatocellular Carcinoma and Cirrhosis
by Fausto Meriggi and Massimo Graffeo
Cancers 2021, 13(3), 584; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13030584 - 02 Feb 2021
Cited by 6 | Viewed by 2142
Abstract
The incidence of hepatocellular carcinoma (HCC) continues to increase worldwide, particularly in Western countries. In almost all cases, HCC develops in subjects with hepatic cirrhosis, often as the result of hepatitis B or C virus infection, alcohol abuse or metabolic forms secondary to [...] Read more.
The incidence of hepatocellular carcinoma (HCC) continues to increase worldwide, particularly in Western countries. In almost all cases, HCC develops in subjects with hepatic cirrhosis, often as the result of hepatitis B or C virus infection, alcohol abuse or metabolic forms secondary to non-alcoholic steatohepatitis. Patients with HCC and hepatic symptoms can therefore present symptoms that are attributable to both conditions. These patients require multidisciplinary management, calling for close interaction between the hepatologist and the oncologist. Indeed, the treatment of HCC requires, depending on the disease stage and the degree of hepatic impairment, locoregional therapies that can in turn be broken down into surgical and nonsurgical treatments and systemic treatments used in the event of progression after the administration of locoregional treatments. The past decade has seen the publication of countless papers of great interest that have radically changed the scenario of treatment for HCC. Novel therapies with biological agents and immunotherapy have come to be standard options in the approach to treatment of this cancer, obtaining very promising results where in the past chemotherapy was almost never able to have an impact on the course of the disease. However, in addition to being costly, these drugs are not devoid of adverse effects and their management cannot forgo the consideration of the underlying hepatic impairment. Patients with HCC and cirrhosis therefore require special attention, starting from the initial characterisation needed for an appropriate selection of those to be referred for treatment, as these patients are almost never fit. In this chapter, we will attempt to investigate and clarify the key points of the management of the main toxicities induced by locoregional and systemic treatments for HCC secondary to cirrhosis. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma)
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17 pages, 3004 KiB  
Review
Statin Use and the Risk of Hepatocellular Carcinoma: A Meta-Analysis of Observational Studies
by Md. Mohaimenul Islam, Tahmina Nasrin Poly, Bruno Andreas Walther, Hsuan-Chia Yang and Yu-Chuan (Jack) Li
Cancers 2020, 12(3), 671; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030671 - 13 Mar 2020
Cited by 59 | Viewed by 6227
Abstract
Background and Aims: Statins are the first-line medication to treating hypercholesterolemia. Several studies have investigated the impact of statins on the risk of hepatocellular carcinoma (HCC). However, the extent to which statins may prevent HCC remains uncertain. Therefore, we performed a meta-analysis [...] Read more.
Background and Aims: Statins are the first-line medication to treating hypercholesterolemia. Several studies have investigated the impact of statins on the risk of hepatocellular carcinoma (HCC). However, the extent to which statins may prevent HCC remains uncertain. Therefore, we performed a meta-analysis of relevant studies to quantify the magnitude of the association between statins use and the risk of HCC. Methods: A systematic literature search of PubMed, EMBASE, Google Scholar, Web of Science, and Scopus was performed for studies published between January 1, 1990, and September 1, 2019, with no restriction of language. Two reviewers independently evaluated the literature and included observational and experimental studies that reported the association between statin use and HCC risk. The random-effect model was used to calculate the overall risk ratio (RR) with a 95% confidence interval (CI), and the heterogeneity among the studies was assessed using the Q statistic and I2 statistic. The Newcastle Ottawa Scale (NOS) was also used to evaluate the quality of the included studies. Results: A total of 24 studies with 59,073 HCC patients was identified. Statin use was associated with a reduced risk of HCC development (RR: 0.54, 95% CI: 0.47–0.61, I2 = 84.39%) compared with nonusers. Moreover, the rate of HCC reduction was also significant among patients with diabetes (RR: 0.44, 95% CI: 0.28–0.70), liver cirrhosis (RR: 0.36, 95% CI: 0.30–0.42), and antiviral therapy (RR: 0.21, 95% CI: 0.08–0.59) compared with nonusers. Conclusion: This study serves as additional evidence supporting the beneficial inhibitory effect of statins on HCC incidence. The subgroup analyses of this study also highlight that statins are significantly associated with a reduced risk of HCC and may help to direct future prevention efforts. Additional large clinical studies are needed to determine whether statins are associated with a lower risk of HCC. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma)
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