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Open AccessEditorial

Hepatocellular Carcinoma: Special Issue Highlights

by Medhavi Gupta and Renuka V. Iyer

Cancers 2020, 12(8), 2026; https://doi.org/10.3390/cancers12082026 - 24 Jul 2020

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Abstract

[...] Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

Research

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22 pages, 7850 KiB

Open AccessArticle

Protein Kinase B Inactivation Is Associated with Magnolol-Enhanced Therapeutic Efficacy of Sorafenib in Hepatocellular Carcinoma In Vitro and In Vivo

by Jiann-Hwa Chen, I-Tsang Chiang and Fei-Ting Hsu

Cancers 2020, 12(1), 87; https://doi.org/10.3390/cancers12010087 - 30 Dec 2019

Cited by 19 | Viewed by 3287

Abstract

Although sorafenib, an oral multikinase inhibitor, was approved as a treatment drug of advance hepatocellular carcinoma (HCC), treatment efficacy still requires improvement. Searching for the adjuvant reagent for enhancing sorafenib efficacy remains as a critical issue. Sorafenib has been proved to suppress extracellular [...] Read more.

Although sorafenib, an oral multikinase inhibitor, was approved as a treatment drug of advance hepatocellular carcinoma (HCC), treatment efficacy still requires improvement. Searching for the adjuvant reagent for enhancing sorafenib efficacy remains as a critical issue. Sorafenib has been proved to suppress extracellular signal-regulated kinases (ERK) in HCC; however, protein kinase B (AKT) was not affected by it. Targeting AKT in combination with sorafenib could be an important breakthrough point of HCC treatment. Many herbal compounds and composite formulas have been shown to enhance anti-HCC activity of sorafenib. Magnolol is a bioactive compound extracted from the bark of the Magnolia officinalis and has been shown to induce apoptosis and inhibit cell invasion in HCC in vitro. However, whether magnolol sensitizes HCC to sorafenib is ambiguous. In this study, we indicated that magnolol significantly enhanced sorafenib-diminished tumor cell growth, expression of anti-apoptotic proteins, and migration/invasion ability compared to sorafenib alone. Magnolol significantly boosted sorafenib-induced extrinsic/intrinsic dependent apoptosis pathways in HCC. Notably sorafenib could not reduce protein level of AKT (Ser473), but expression of AKT (Ser473) was significantly decreased by magnolol or magnolol combined with sorafenib. LY294002 as specific AKT inhibitor was used to confirm that AKT inactivation may promote anticancer effect of sorafenib. Taken together, AKT inhibition is associated with magnolol-enhanced the therapeutic effect of sorafenib in HCC. We suggested magnolol as the potential adjuvant which may enhance therapeutic benefits of sorafenib in patients with HCC. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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19 pages, 17443 KiB

Open AccessArticle

Calcium Regulates HCC Proliferation as well as EGFR Recycling/Degradation and Could Be a New Therapeutic Target in HCC

by Teresa Maria Elisa Modica, Francesco Dituri, Serena Mancarella, Claudio Pisano, Isabel Fabregat and Gianluigi Giannelli

Cancers 2019, 11(10), 1588; https://doi.org/10.3390/cancers11101588 - 18 Oct 2019

Cited by 8 | Viewed by 3429

Abstract

Calcium is the most abundant element in the human body. Its role is essential in physiological and biochemical processes such as signal transduction from outside to inside the cell between the cells of an organ, as well as the release of neurotransmitters from [...] Read more.

Calcium is the most abundant element in the human body. Its role is essential in physiological and biochemical processes such as signal transduction from outside to inside the cell between the cells of an organ, as well as the release of neurotransmitters from neurons, muscle contraction, fertilization, bone building, and blood clotting. As a result, intra- and extracellular calcium levels are tightly regulated by the body. The liver is the most specialized organ of the body, as its functions, carried out by hepatocytes, are strongly governed by calcium ions. In this work, we analyze the role of calcium in human hepatoma (HCC) cell lines harboring a wild type form of the Epidermal Growth Factor Receptor (EGFR), particularly its role in proliferation and in EGFR downmodulation. Our results highlight that calcium is involved in the proliferative capability of HCC cells, as its subtraction is responsible for EGFR degradation by proteasome machinery and, as a consequence, for EGFR intracellular signaling downregulation. However, calcium-regulated EGFR signaling is cell line-dependent. In cells responding weakly to the epidermal growth factor (EGF), calcium seems to have an opposite effect on EGFR internalization/degradation mechanisms. These results suggest that besides EGFR, calcium could be a new therapeutic target in HCC. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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21 pages, 2099 KiB

Open AccessArticle

Liver Cancer Cell Lines Treated with Doxorubicin under Normoxia and Hypoxia: Cell Viability and Oncologic Protein Profile

by Ilse R. Dubbelboer, Natasa Pavlovic, Femke Heindryckx, Erik Sjögren and Hans Lennernäs

Cancers 2019, 11(7), 1024; https://doi.org/10.3390/cancers11071024 - 20 Jul 2019

Cited by 40 | Viewed by 10247

Abstract

Hepatocellular carcinoma is often treated with a combination of doxorubicin and embolization, exposing it to high concentrations and hypoxia. Separation of the possible synergistic effect of this combination in vivo is difficult. Here, treatment with doxorubicin, under hypoxia or normoxia in different liver [...] Read more.

Hepatocellular carcinoma is often treated with a combination of doxorubicin and embolization, exposing it to high concentrations and hypoxia. Separation of the possible synergistic effect of this combination in vivo is difficult. Here, treatment with doxorubicin, under hypoxia or normoxia in different liver cancer cell lines, was evaluated. Liver cancer cells HepG2, Huh7, and SNU449 were exposed to doxorubicin, hypoxia, or doxorubicin + hypoxia with different duration. Treatment response was evaluated with cell viability, apoptosis, oxidative stress, and summarized with IC₅₀. The protein profile of a 92-biomarker panel was analyzed on cells treated with 0 or 0.1 µM doxorubicin during 6 or 72 h, under normoxia or hypoxia. Hypoxia decreased viability of HepG2 and SNU499. HepG2 was least and SNU449 most tolerant to doxorubicin treatment. Cytotoxicity of doxorubicin increased over time in HepG2 and Huh7. The combination of doxorubicin + hypoxia affected the cells differently. Normalized protein expression was lower for HepG2 than Huh7 and SNU449. Hierarchical clustering separated HepG2 from Huh7 and SNU449. These three commonly used cell lines have critically different responses to chemotherapy and hypoxia, which was reflected in their different protein expression profile. These different responses suggest that tumors can respond differently to the combination of local chemotherapy and embolization. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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9 pages, 905 KiB

Open AccessArticle

Transarterial Chemoembolization of Hepatocellular Carcinoma with Idarubicin-Loaded Tandem Drug-Eluting Embolics

by Boris Guiu, Sebastien Colombat, Lauranne Piron, Margaux Hermida, Carole Allimant, Marie-Ange Pierredon-Foulongne, Ali Belgour, Laure Escal, Christophe Cassinotto and Mathieu Boulin

Cancers 2019, 11(7), 987; https://doi.org/10.3390/cancers11070987 - 15 Jul 2019

Cited by 11 | Viewed by 3207

Abstract

Objective: To describe the responses, toxicities and outcomes of HCC patients treated by transarterial chemoembolization (TACE) using idarubicin-loaded TANDEM beads. Materials and Methods: Seventy-two consecutive patients (mean age: 71 years (58–84 years)) with HCC were treated by TACE using idarubicin-loaded TANDEM [...] Read more.

Objective: To describe the responses, toxicities and outcomes of HCC patients treated by transarterial chemoembolization (TACE) using idarubicin-loaded TANDEM beads. Materials and Methods: Seventy-two consecutive patients (mean age: 71 years (58–84 years)) with HCC were treated by TACE using idarubicin-loaded TANDEM in a first line, over a five-year period. Most patients (89%) had liver cirrhosis classified as Child–Pugh A (90%). BCLC B classification applied in 85% of cases. Baseline tumor burden was limited to one to three nodules in 92% of cases, unilobar in 88% cases, with a median tumor diameter of 55 mm (range: 13–150 mm). Toxicity was assessed using NCI CTC AE v4.0. Response was assessed using mRECIST criteria. Time-to-treatment failure (TTTF) and overall survival (OS) were also calculated based on Kaplan–Meier method. Result: Of 141 TACE sessions performed with bead sizes of 100 and 75 µm in 42 (29.8%) and 99 (70.2%) sessions, respectively. In 78% of all TACE sessions, the full dose of idarubicin-loaded beads was injected. Grade 3–4 AE were observed after 73 (52%) sessions, most of them being biological. Multi-organ failure was observed three days after the first TACE in a Child B patients, unfortunately leading to death. Overall, the best objective response rate (ORR) was 65%. Median follow-up lasted 14.3 months (95% CI: 11.2–18.8 months). Median TTTF and OS were 14.4 months (95% CI: 7.2–24.6 months) and 34.6 months (95% CI: 24.7—not reached) respectively. Conclusion: In this retrospective study involving well-selected HCC patients, high ORR and long TTTF and OS are observed after TACE using idarubicin-loaded TANDEM. A randomized trial is needed. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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14 pages, 940 KiB

Open AccessArticle

Sorafenib with Transarterial Chemoembolization Achieves Improved Survival vs. Sorafenib Alone in Advanced Hepatocellular Carcinoma: A Nationwide Population-Based Cohort Study

by Victor C. Kok, Yu-Ching Chen, Yang-Yuan Chen, Yu-Chieh Su, Ming-Chang Ku, Jung-Tsung Kuo and Go J. Yoshida

Cancers 2019, 11(7), 985; https://doi.org/10.3390/cancers11070985 - 15 Jul 2019

Cited by 31 | Viewed by 4864

Abstract

We hypothesized that sorafenib plus transarterial chemoembolization (TACE) would confer survival benefits over sorafenib alone for advanced hepatocellular carcinoma (aHCC). We investigated this while using the population-based All-Cancer Dataset to assemble a cohort (n = 3674; median age, 60; 83% men) of [...] Read more.

We hypothesized that sorafenib plus transarterial chemoembolization (TACE) would confer survival benefits over sorafenib alone for advanced hepatocellular carcinoma (aHCC). We investigated this while using the population-based All-Cancer Dataset to assemble a cohort (n = 3674; median age, 60; 83% men) of patients receiving sorafenib for aHCC (Child-Pugh A) with macro-vascular invasion or nodal/distant metastases. The patients were classified into the sorafenib-TACE group (n = 426) or the propensity score-matched sorafenib-alone group (n = 1686). All of the participants were followed up until death or the end of the study. Time-dependent Cox model and the Mantel–Byar test were used for survival analysis. During the median follow-ups of 221 and 133 days for the sorafenib-TACE and sorafenib-alone groups, 164 (39%) and 916 (54%) deaths occurred, respectively; the corresponding median overall survivals (OS) were 381 and 204 days, respectively (hazard ratio, HR: 0.74; 95% confidence interval, CI, 0.63–0.88; p = 0.021). The one-year and six-month OS were 53.5% and 80.3% in the sorafenib-TACE group and 32.4% and 54.4% in the sorafenib-alone group, respectively. The major complications were comparable between the two groups. The addition of TACE to sorafenib improves survival, with a 26% reduction in mortality. These findings provide strong real-world evidence that supports this combination strategy for eligible Child-Pugh A aHCC patients. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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9 pages, 664 KiB

Open AccessArticle

Impact of Baseline ALBI Grade on the Outcomes of Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Study

by Kazuomi Ueshima, Naoshi Nishida, Satoru Hagiwara, Tomoko Aoki, Tomohiro Minami, Hirokazu Chishina, Masahiro Takita, Yasunori Minami, Hiroshi Ida, Mamoru Takenaka, Toshiharu Sakurai, Tomohiro Watanabe, Masahiro Morita, Chikara Ogawa, Atsushi Hiraoka, Philip Johnson and Masatoshi Kudo

Cancers 2019, 11(7), 952; https://doi.org/10.3390/cancers11070952 - 7 Jul 2019

Cited by 114 | Viewed by 5559

Abstract

Background: This study investigated the impact of baseline liver function according to the Child–Pugh score and ALBI (albumin-bilirubin) grade on the outcomes of patients with unresectable hepatocellular carcinoma treated with lenvatinib. Methods: A total of 82 lenvatinib treated patients were included. The correlations [...] Read more.

Background: This study investigated the impact of baseline liver function according to the Child–Pugh score and ALBI (albumin-bilirubin) grade on the outcomes of patients with unresectable hepatocellular carcinoma treated with lenvatinib. Methods: A total of 82 lenvatinib treated patients were included. The correlations of baseline liver function according to the Child–Pugh score and ALBI grade with treatment outcomes, including objective response rate per mRECIST (modified Response Evaluation Criteria in the Solid Tumor), time to treatment failure, treatment duration, and likelihood of treatment discontinuation due to adverse events, were assessed in patients with hepatocellular carcinoma treated with lenvatinib. Patients were divided into four groups: (1) Child–Pugh score 5 and ALBI grade 1 (group 1), (2) Child–Pugh score 5 and ALBI grade 2 (group 2), (3) Child–Pugh score 6 (group 3), and (4) Child–Pugh score ≥7 (group 4). Univariate and multivariate analyses were performed to identify the factors contributing to the objective response rate and likelihood of discontinuation due to adverse events. Results: Among the 82 patients analyzed, group 1 had the highest objective response rate (57.1%) and the lowest likelihood of treatment discontinuation because of adverse events (11.1%) among the four groups (p < 0.05 and p < 0.05). Multivariate analysis identified ALBI grade 1 and baseline AFP level <200 ng/mL as the significant predictors of a high objective response rate (p < 0.05 and p < 0.01), and confirmed that patients with ALBI grade 1 had the lowest probability of treatment discontinuation due to adverse events (p < 0.01). Conclusions: Patients with Child–Pugh score of 5 and ALBI grade 1 predicted a higher response rate and lower treatment discontinuation due to adverse events by lenvatinib treatment. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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20 pages, 5053 KiB

Open AccessArticle

Inhibition of Protein Phosphatase 1 Stimulates Noncanonical ER Stress eIF2α Activation to Enhance Fisetin-induced Chemosensitivity in HDAC Inhibitor-resistant Hepatocellular Carcinoma Cells

by Yi-Sheng Liu, Yu-Chun Chang, Wei-Wen Kuo, Ming-Cheng Chen, Hsi-Hsien Hsu, Chuan-Chou Tu, Yu-Lan Yeh, Vijaya Padma Viswanadha, Po-Hsiang Liao and Chih-Yang Huang

Cancers 2019, 11(7), 918; https://doi.org/10.3390/cancers11070918 - 29 Jun 2019

Cited by 16 | Viewed by 4367 | Correction

Abstract

Hepatocellular carcinoma (HCC) is a common fatal type of malignant tumor that has highly metastatic and recurrent properties. Fisetin is a natural flavonoid found in various vegetables and fruits which exhibits anti-cancer and anti-inflammatory properties, as well as other effects. Thus, we hypothesized [...] Read more.

Hepatocellular carcinoma (HCC) is a common fatal type of malignant tumor that has highly metastatic and recurrent properties. Fisetin is a natural flavonoid found in various vegetables and fruits which exhibits anti-cancer and anti-inflammatory properties, as well as other effects. Thus, we hypothesized that fisetin can act as an adjuvant therapy in cancer or drug-resistant cancer cells, and further investigated the molecular mechanisms underlying the development of drug-resistance in HCC cells. We found that fisetin effectively inhibited the cell viability of not only parental cells but also histone deacetylase inhibitors-resistant (HDACis-R) cells and enhanced the chemosensitivity of HCC cells. Interestingly, fisetin did not induce cell apoptosis through the activation of the endoplasmic reticulum (ER) stress sensor of protein kinase R (PKR)-like endoplasmic reticulum kinase, but rather through the non-canonical pathway of the protein phosphatase 1 (PP1)-mediated suppression of eIF2α phosphorylation. Moreover, fisetin-induced cell apoptosis was reversed by treatment with PP1 activator or eIF2α siRNA in HCC cells. Based on these observations, we suggest that PP1-eIF2α pathways are significantly involved in the effect of fisetin on HCC apoptosis. Thus, fisetin may act as a novel anticancer drug and new chemotherapy adjuvant which can improve the efficacy of chemotherapeutic agents and diminish their side-effects. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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13 pages, 2135 KiB

Open AccessArticle

Prognostic Role of Albumin, Bilirubin, and ALBI Scores: Analysis of 1000 Patients with Hepatocellular Carcinoma Undergoing Radioembolization

by Mark Antkowiak, Ahmed Gabr, Arighno Das, Rehan Ali, Laura Kulik, Daniel Ganger, Christopher Moore, Michael Abecassis, Nitin Katariya, Samdeep Mouli, Devalingam Mahalingam, Robert J. Lewandowski, Riad Salem and Ahsun Riaz

Cancers 2019, 11(6), 879; https://doi.org/10.3390/cancers11060879 - 24 Jun 2019

Cited by 41 | Viewed by 4585

Abstract

Introduction: We compared the efficacy of the ALBI (albumin–bilirubin) score to the established Child–Pugh (CP) grade in hepatocellular carcinoma (HCC) patients treated with yttrium-90 radioembolization (Y90). We further assessed the individual contributions of albumin and bilirubin to survival prediction. Methods: 1000 consecutive HCC [...] Read more.

Introduction: We compared the efficacy of the ALBI (albumin–bilirubin) score to the established Child–Pugh (CP) grade in hepatocellular carcinoma (HCC) patients treated with yttrium-90 radioembolization (Y90). We further assessed the individual contributions of albumin and bilirubin to survival prediction. Methods: 1000 consecutive HCC patients treated with Y90 were included. Overall survival (OS) was assessed using Kaplan Meier analysis. Sub-stratification analyses were performed using CP and ALBI and in subgroups determined by United Network for Organ Sharing (UNOS) or Barcelona Clinic Liver Cancer (BCLC) staging. The independent impact (hazard ratio (HR)) of ALBI, CP, albumin, and bilirubin on survival was assessed using Cox proportional hazards analysis. Results: Median OS for ALBI 1, 2, and 3 grades was 46.7, 19.1, and 8.8 months, respectively. The HR for death for ALBI 2 vs. ALBI 1 was 3.39 (1.75–6.57); ALBI 3 vs. ALBI 1 was 7.58 (3.89–14.79); and the c-index was 0.623. Median OS for CP A, B, and C was 21.7, 11.3, and 6.0 months, respectively. The HR for death for CP B vs. CP A was 2.04 (1.71–2.43); CP C vs. CP A was 3.27 (2.08–5.14); and the c-index was 0.616. Stratified OS showed unique prognostic groups identified by ALBI within CP-B and CP-C. Median OS for albumin grades 1, 2, and 3 was 46.0, 17.1, and 9.1 months, respectively. Median OS for bilirubin grades 1, 2, and 3 was 15.6, 21.0, and 5.8 months, respectively. The HR for death for albumin 2 vs. 1 was 2.48 (1.81–3.41); albumin 3 vs. 1 was 4.74 (3.44–6.54); and the c-index was 0.640. The HR for death for bilirubin 2 vs. 1 was 1.09 (0.82–1.44); bilirubin 3 vs. 1 was 2.37 (1.66–3.40); and the c-index was 0.533. Conclusions: ALBI outperforms CP in survival prognosis in Y90 treated patients. On sub-analyses, serum albumin (not bilirubin) appears to be the main driver of survival prediction. Our study supports the prognostic ability of ALBI and may suggest a role of albumin alone as a biomarker for patients with HCC. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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15 pages, 1748 KiB

Open AccessArticle

A Phase II, Multicenter, Single-Arm Study of Mipsagargin (G-202) as a Second-Line Therapy Following Sorafenib for Adult Patients with Progressive Advanced Hepatocellular Carcinoma

by Devalingam Mahalingam, Julio Peguero, Putao Cen, Sukeshi P. Arora, John Sarantopoulos, Julie Rowe, Victoria Allgood, Benjamin Tubb and Luis Campos

Cancers 2019, 11(6), 833; https://doi.org/10.3390/cancers11060833 - 17 Jun 2019

Cited by 53 | Viewed by 4886

Abstract

Background: Mipsagargin (G-202) is a thapsigargin-based prodrug with cytotoxic activity masked by a peptide that is cleaved by prostate-specific membrane antigen (PSMA), a protease expressed in prostate cancer cells and the endothelium of tumor vasculature. It was hypothesized that PSMA-mediated activation of [...] Read more.

Background: Mipsagargin (G-202) is a thapsigargin-based prodrug with cytotoxic activity masked by a peptide that is cleaved by prostate-specific membrane antigen (PSMA), a protease expressed in prostate cancer cells and the endothelium of tumor vasculature. It was hypothesized that PSMA-mediated activation of mipsagargin would result in disruption of the tumor vasculature, leading to a decrease in blood flow, and in direct cytotoxic effects on tumor cells, resulting in anti-tumor activity. Method: In this open-label, Phase II study, mipsagargin was administered intravenously on Days 1, 2, and 3 of a 28-day cycle to patients with hepatocellular carcinoma (HCC) who progressed on or after treatment with sorafenib or intolerant of sorafenib. Assessments included time to disease progression (TTP), response rate, progression-free survival (PFS), overall survival (OS), and safety. Blood flow metrics in hepatic lesions were evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: Of 25 treated patients, 19 were evaluable for efficacy. None had an objective response, 12 (63.2%) had a best response of stable disease, and 12 (63.2%) showed radiologic progression; seven patients (36.8%) were censored. The median TTP was 134.0 days, median PFS was 129.0 days, and median OS was 205.0 days. Of five patients with DCE-MRI data for 11 HCC lesions, all demonstrated a reduced K_trans (mean, 52%). The most common treatment-emergent AEs were Grade 1–2 and consisted of increased blood creatinine (68.0%), fatigue (56.0%), and nausea (44.0%). Conclusions: Mipsagargin is relatively well tolerated and promotes prolonged disease stabilization in patients with advanced HCC that had progressed on prior treatment with sorafenib. A significant decrease in K_trans upon treatment suggests mipsagargin reduces blood flow in hepatic lesions. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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17 pages, 1450 KiB

Open AccessArticle

Dose-Dependent Sorafenib-Induced Immunosuppression Is Associated with Aberrant NFAT Activation and Expression of PD-1 in T Cells

by Renuka V. Iyer, Orla Maguire, Minhyung Kim, Leslie I. Curtin, Sandra Sexton, Daniel T. Fisher, Sarah A. Schihl, Gerald Fetterly, Stephan Menne and Hans Minderman

Cancers 2019, 11(5), 681; https://doi.org/10.3390/cancers11050681 - 16 May 2019

Cited by 33 | Viewed by 3681

Abstract

The multikinase inhibitor sorafenib is the only standard first-line therapy for hepatocellular carcinoma (HCC). Here, we report the dose-dependent effects of sorafenib on the immune response, which is related to nuclear factor of activated T cells 1 (NFAT1) activity. In vitro and in [...] Read more.

The multikinase inhibitor sorafenib is the only standard first-line therapy for hepatocellular carcinoma (HCC). Here, we report the dose-dependent effects of sorafenib on the immune response, which is related to nuclear factor of activated T cells 1 (NFAT1) activity. In vitro and in vivo experiments were performed with low and high doses of sorafenib using human T cells and spontaneous developed woodchuck HCC models. In vitro studies demonstrated that following exposure to a high dose of sorafenib the baseline activity of NFAT1 in T cells was significantly increased. In a parallel event, high dose sorafenib resulted in a significant decrease in T cell proliferation and increased the proportion of PD-1 expressing CD8+ T cells with NFAT1 activation. In the in vivo model, smaller tumors were detected in the low-dose sorafenib treated group compared to the placebo and high-dose treated groups. The low-dose sorafenib group showed a significant tumor growth delay with significantly more CD3+ cells in tumor. This study demonstrates that sorafenib has immunomodulatory effects in a dose- and time-dependent manner. Higher dose of sorafenib treatment was associated with immunosuppressive action. This observed effect of sorafenib should be taken into consideration in the selection of optimum starting dose for future trials. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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12 pages, 412 KiB

Open AccessArticle

Development of a New Nomogram Including Neutrophil-to-Lymphocyte Ratio to Predict Survival in Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization

by Young Eun Chon, Hana Park, Hye Kyung Hyun, Yeonjung Ha, Mi Na Kim, Beom Kyung Kim, Joo Ho Lee, Seung Up Kim, Do Young Kim, Sang Hoon Ahn, Seong Gyu Hwang, Kwang-Hyub Han, Kyu Sung Rim and Jun Yong Park

Cancers 2019, 11(4), 509; https://doi.org/10.3390/cancers11040509 - 10 Apr 2019

Cited by 39 | Viewed by 3193

Abstract

The neutrophil-to-lymphocyte ratio (NLR) has recently been reported to predict the prognosis of hepatocellular carcinoma (HCC). We explored whether NLR predicted the survival of patients with HCC undergoing transarterial chemoembolization (TACE), and developed a predictive model. In total, 1697 patients with HCC undergoing [...] Read more.

The neutrophil-to-lymphocyte ratio (NLR) has recently been reported to predict the prognosis of hepatocellular carcinoma (HCC). We explored whether NLR predicted the survival of patients with HCC undergoing transarterial chemoembolization (TACE), and developed a predictive model. In total, 1697 patients with HCC undergoing TACE as first-line therapy at two university hospitals were enrolled (derivation set n = 921, internal validation set n = 395, external validation set n = 381). The tumor size, tumor number, AFP level, vascular invasion, Child–Pugh score, objective response after TACE, and NLR, selected as predictors of overall survival (OS) via multivariate Cox’s regression model, were incorporated into a 14-point risk prediction model (SNAVCORN score). The time-dependent areas under the receiver-operating characteristic curves for OS at 1, 3, and 5 years predicted by the SNAVCORN score were 0.812, 0.734, and 0.700 in the derivation set. Patients were stratified into three risk groups by SNAVCORN score (low, 0–4; intermediate, 5–9; high, 10–14). Compared with the low-risk group, the intermediate-risk (HR 3.10, p < 0.001) and high-risk (HR 7.37, p < 0.001) groups exhibited significantly greater mortality. The prognostic performance of the SNAVCORN score including NLR in patients with HCC treated with TACE was remarkable, much better than those of the conventional scores. The SNAVCORN score will guide future HCC treatment decisions. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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Review

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16 pages, 276 KiB

Open AccessReview

Treatment of Combined Hepatocellular and Cholangiocarcinoma

by Simona Leoni, Vito Sansone, Stefania De Lorenzo, Luca Ielasi, Francesco Tovoli, Matteo Renzulli, Rita Golfieri, Daniele Spinelli and Fabio Piscaglia

Cancers 2020, 12(4), 794; https://doi.org/10.3390/cancers12040794 - 26 Mar 2020

Cited by 27 | Viewed by 4347

Abstract

Combined hepatocellular and cholangiocarcinoma (HCC-CC) is a rare primary liver cancer. It is constituted by neoplastic cells of both hepatocellular and cholangiocellular derivation. Different histology types of HCC-CC have been reported, hinting at heterogeneous carcinogenic pathways leading to the development of this cancer. [...] Read more.

Combined hepatocellular and cholangiocarcinoma (HCC-CC) is a rare primary liver cancer. It is constituted by neoplastic cells of both hepatocellular and cholangiocellular derivation. Different histology types of HCC-CC have been reported, hinting at heterogeneous carcinogenic pathways leading to the development of this cancer. Due to its rarity and complexity, mixed HCC-CC is a scantly investigated condition with unmet needs and unsatisfactory outcomes. Surgery remains the preferred treatment in resectable patients. The risk of recurrence, however, is high, especially in comparison with other primary liver cancers such as hepatocellular carcinoma. In unresectable or recurring patients, the therapeutic options are challenging due to the dual nature of the neoplastic cells. Consequently, the odds of survival of patients with HCC-CC remains poor. We analysed the literature systematically about the treatment of mixed HCC-CC, reviewing the main therapeutic options and their outcomes and analysing the most interesting developments in this topic with a focus on new potential therapeutic avenues. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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13 pages, 993 KiB

Open AccessReview

Glypican 3-Targeted Therapy in Hepatocellular Carcinoma

by Takahiro Nishida and Hiroaki Kataoka

Cancers 2019, 11(9), 1339; https://doi.org/10.3390/cancers11091339 - 10 Sep 2019

Cited by 77 | Viewed by 12126

Abstract

Glypican-3 (GPC3) is an oncofetal glycoprotein attached to the cell membrane by a glycophosphatidylinositol anchor. GPC3 is overexpressed in some kinds of tumors, particularly hepatocellular carcinoma (HCC). The prognostic significance of serum GPC3 levels and GPC3 immunoreactivity in tumor cells has been defined [...] Read more.

Glypican-3 (GPC3) is an oncofetal glycoprotein attached to the cell membrane by a glycophosphatidylinositol anchor. GPC3 is overexpressed in some kinds of tumors, particularly hepatocellular carcinoma (HCC). The prognostic significance of serum GPC3 levels and GPC3 immunoreactivity in tumor cells has been defined in patients with HCC. In addition to its usefulness as a biomarker, GPC3 has attracted attention as a novel therapeutic target molecule, and clinical trials targeting GPC3 are in progress. The major mechanism of anti-GPC3 antibody (GPC3Ab) against cancer cells is antibody-dependent cellular cytotoxicity and/or complement-dependent cytotoxicity. Since GPC3Ab is associated with immune responses, a combination of protocols with immune checkpoint inhibitors has also been investigated. Moreover, some innovative approaches for GPC3-targeting therapy have emerged in recent years. This review introduces the results of recent clinical trials targeting GPC3 in HCC and summarizes the latest knowledge regarding the role of GPC3 in HCC progression and clinical application targeting GPC3. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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21 pages, 649 KiB

Open AccessReview

Current Status of Gene Therapy in Hepatocellular Carcinoma

by Saranya Chidambaranathan Reghupaty and Devanand Sarkar

Cancers 2019, 11(9), 1265; https://doi.org/10.3390/cancers11091265 - 28 Aug 2019

Cited by 46 | Viewed by 15636

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer related deaths world-wide. Liver transplantation, surgical resection, trans-arterial chemoembolization, and radio frequency ablation are effective strategies to treat early stage HCC. Unfortunately, HCC is usually diagnosed at [...] Read more.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer related deaths world-wide. Liver transplantation, surgical resection, trans-arterial chemoembolization, and radio frequency ablation are effective strategies to treat early stage HCC. Unfortunately, HCC is usually diagnosed at an advanced stage and there are not many treatment options for late stage HCC. First-line therapy for late stage HCC includes sorafenib and lenvatinib. However, these treatments provide only an approximate three month increase in survival. Besides, they cannot specifically target cancer cells that lead to a wide array of side effects. Patients on these drugs develop resistance within a few months and have to rely on second-line therapy that includes regorafenib, pembrolizumab, nivolumab, and cabometyx. These disadvantages make gene therapy approach to treat HCC an attractive option. The two important questions that researchers have been trying to answer in the last 2–3 decades are what genes should be targeted and what delivery systems should be used. The objective of this review is to analyze the changing landscape of HCC gene therapy, with a focus on these two questions. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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18 pages, 757 KiB

Open AccessReview

Current State of Liver-Directed Therapies and Combinatory Approaches with Systemic Therapy in Hepatocellular Carcinoma (HCC)

by Pedro Viveiros, Ahsun Riaz, Robert J. Lewandowski and Devalingam Mahalingam

Cancers 2019, 11(8), 1085; https://doi.org/10.3390/cancers11081085 - 31 Jul 2019

Cited by 61 | Viewed by 6375

Abstract

The increasing set of liver-directed therapies (LDT) have become an integral part of hepatocellular carcinoma (HCC) treatment. These range from percutaneous ablative techniques to arterial embolization, and varied radiotherapy strategies. They are now used for local disease control, symptom palliation, and bold curative [...] Read more.

The increasing set of liver-directed therapies (LDT) have become an integral part of hepatocellular carcinoma (HCC) treatment. These range from percutaneous ablative techniques to arterial embolization, and varied radiotherapy strategies. They are now used for local disease control, symptom palliation, and bold curative strategies. The big challenge in the face of these innovative and sometimes overlapping technologies is to identify the best opportunity of use. In real practice, many patients may take benefit from LDT used as a bridge to curative treatment such as resection and liver transplantation. Varying trans-arterial embolization strategies are used, and comparison between established and developing technologies is scarce. Also, radioembolization utilizing yttrium-90 (Y-90) for locally advanced or intermediate-stage HCC needs further evidence of clinical efficacy. There is increasing interest on LDT-led changes in tumor biology that could have implications in systemic therapy efficacy. Foremost, additional to its apoptotic and necrotic properties, LDT could warrant changes in vascular endothelial growth factor (VEGF) expression and release. However, trans-arterial chemoembolization (TACE) used alongside tyrosine-kinase inhibitor (TKI) sorafenib has had its efficacy contested. Most recently, interest in associating Y-90 and TKI has emerged. Furthermore, LDT-led differences in tumor immune microenvironment and immune cell infiltration could be an opportunity to enhance immunotherapy efficacy for HCC patients. Early attempts to coordinate LDT and immunotherapy are being made. We here review LDT techniques exposing current evidence to understand its extant reach and future applications alongside systemic therapy development for HCC. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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16 pages, 253 KiB

Open AccessReview

Immunotherapy in Hepatocellular Carcinoma: Is There a Light at the End of the Tunnel?

by Amit Mahipal, Sri Harsha Tella, Anuhya Kommalapati, Alexander Lim and Richard Kim

Cancers 2019, 11(8), 1078; https://doi.org/10.3390/cancers11081078 - 30 Jul 2019

Cited by 36 | Viewed by 4902

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with dismal prognosis when diagnosed at advanced stages. Surgical resection of the primary tumor or orthotropic liver transplantation serves as a potential curative option. However, this approach is highly dependent on the hepatic [...] Read more.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with dismal prognosis when diagnosed at advanced stages. Surgical resection of the primary tumor or orthotropic liver transplantation serves as a potential curative option. However, this approach is highly dependent on the hepatic reserve and baseline functional status of the patient. Liver directed therapies such as portal vein embolization (PVE), trans-arterial chemoembolization (TACE), and systemic chemotherapy are employed in non-surgical candidates. Sorafenib was the only approved systemic therapeutic agent for almost a decade until the recent approval of lenvatinib by the United States Food and Drug Administration (FDA) as an alternate first-line agent. Regorafenib, nivolumab, pembrolizumab and cabozantinib are approved by the FDA as second-line agents in patients who failed or could not tolerate sorafenib. Ramucirumab was recently FDA approved for the subset of patients that have high alfa-fetoprotein levels (>400 ng/mL). A better understanding of tumorigenesis and encouraging clinical trial results that evaluated immune-checkpoint inhibitors opened doors for immunotherapy in HCC. Immune checkpoint inhibitors have demonstrated a prolonged median overall and progression-free survival in a subset of patients with HCC. On-going translational and clinical research will hopefully provide us with a better understanding of tumor markers, genetic aberrations and other factors that determine the immunotherapy response in HCC. In this review, we sought to summarize the potential role and future directions of immunotherapy in the management of HCC. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

17 pages, 812 KiB

Open AccessReview

Platelets as Key Factors in Hepatocellular Carcinoma

by Natasa Pavlovic, Bhavna Rani, Pär Gerwins and Femke Heindryckx

Cancers 2019, 11(7), 1022; https://doi.org/10.3390/cancers11071022 - 20 Jul 2019

Cited by 59 | Viewed by 6672

Abstract

Hepatocellular carcinoma (HCC) is a primary liver cancer that usually develops in the setting of chronic inflammation and liver damage. The hepatic microenvironment plays a crucial role in the disease development, as players such as hepatic stellate cells, resident liver macrophages (Kupffer cells), [...] Read more.

Hepatocellular carcinoma (HCC) is a primary liver cancer that usually develops in the setting of chronic inflammation and liver damage. The hepatic microenvironment plays a crucial role in the disease development, as players such as hepatic stellate cells, resident liver macrophages (Kupffer cells), endothelial cells, extracellular matrix, and a variety of immune cells interact in highly complex and intertwined signaling pathways. A key factor in these cross-talks are platelets, whose role in cancer has gained growing evidence in recent years. Platelets have been reported to promote HCC cell proliferation and invasion, but their involvement goes beyond the direct effect on tumor cells, as they are known to play a role in pro-fibrinogenic signaling and the hepatic immune response, as well as in mediating interactions between these factors in the stroma. Anti-platelet therapy has been shown to ameliorate liver injury and improve the disease outcome. However, platelets have also been shown to play a crucial role in liver regeneration after organ damage. Therefore, the timing and microenvironmental setting need to be kept in mind when assessing the potential effect and therapeutic value of platelets in the disease progression, while further studies are needed for understanding the role of platelets in patients with HCC. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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12 pages, 210 KiB

Open AccessReview

Multidisciplinary Management of Patients with Unresectable Hepatocellular Carcinoma: A Critical Appraisal of Current Evidence

by Pierre M. Gholam, Renuka Iyer and Matthew S. Johnson

Cancers 2019, 11(6), 873; https://doi.org/10.3390/cancers11060873 - 22 Jun 2019

Cited by 21 | Viewed by 3657

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of new cancer diagnoses in the United States, with an incidence that is expected to rise. The etiology of HCC is varied and can lead to differences between patients in terms of presentation and natural history. [...] Read more.

Hepatocellular carcinoma (HCC) is a leading cause of new cancer diagnoses in the United States, with an incidence that is expected to rise. The etiology of HCC is varied and can lead to differences between patients in terms of presentation and natural history. Subsequently, physicians treating these patients need to consider a variety of disease and patient characteristics when they select from the many different treatment options that are available for these patients. At the same time, the treatment landscape for patients with HCC, particularly those with unresectable HCC, has been rapidly evolving as new, evidence-based options become available. The treatment plan for patients with HCC can include surgery, transplant, ablation, transarterial chemoembolization, transarterial radioembolization, radiation therapy, and/or systemic therapies. Implementing these different modalities, where the optimal sequence and/or combination has not been defined, requires coordination between physicians with different specialties, including interventional radiologists, hepatologists, and surgical and medical oncologists. As such, the implementation of a multidisciplinary team is necessary to develop a comprehensive care plan for patients, especially those with unresectable HCC. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

17 pages, 263 KiB

Open AccessReview

Outcomes and Quality of Life of Systemic Therapy in Advanced Hepatocellular Carcinoma

by Kehua Zhou and Christos Fountzilas

Cancers 2019, 11(6), 861; https://doi.org/10.3390/cancers11060861 - 21 Jun 2019

Cited by 26 | Viewed by 4287

Abstract

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide; most patients are diagnosed with advanced disease for which there is no known cure. Tremendous progress has been made over the past decade in the development of new agents for HCC, [...] Read more.

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide; most patients are diagnosed with advanced disease for which there is no known cure. Tremendous progress has been made over the past decade in the development of new agents for HCC, including small-molecule kinase inhibitors such as sorafenib, lenvatinib, cabozantinib, regorafenib, and monoclonal antibodies like ramucirumab, nivolumab, and pembrolizumab. Ideal use of these agents in clinics has improved the long-term outcome of patients with advanced HCC as well as introduced unique toxicities that can affect quality of life. These toxicities usually are thought to be partially related to cirrhosis, a major risk factor for the development of HCC and a pathophysiological barrier complicating the optimal delivery of antineoplastic therapy. Additionally, side effects of medications together with advanced HCC symptoms not only decrease quality of life, but also cause treatment interruptions and dose reductions that can potentially decrease efficacy. Physicians caring for patients with advanced HCC are called to optimally manage HCC along with cirrhosis in order to prolong life while at the same time preserve the quality of life. In this review, we aimed to summarize outcomes and quality of life with the use of modern systemic treatments in advanced HCC and provide a physician reference for treatment toxicity and cirrhosis management. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

18 pages, 576 KiB

Open AccessReview

Current Treatment Landscape for Advanced Hepatocellular Carcinoma: Patient Outcomes and the Impact on Quality of Life

by Daneng Li, Sabrina Sedano, Rebecca Allen, Jun Gong, May Cho and Sunil Sharma

Cancers 2019, 11(6), 841; https://doi.org/10.3390/cancers11060841 - 18 Jun 2019

Cited by 63 | Viewed by 6974

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer mortality worldwide. Heterogeneity of clinical conditions contributes to the complex management of care for patients with advanced HCC. Recently, the treatment landscape for advanced HCC has expanded [...] Read more.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer mortality worldwide. Heterogeneity of clinical conditions contributes to the complex management of care for patients with advanced HCC. Recently, the treatment landscape for advanced HCC has expanded rapidly, with the additional FDA approvals of several oral tyrosine kinase inhibitors (lenvatinib, regorafenib, and cabozantinib), as well as immunotherapies such as immune check point inhibitors (nivolumab and pembrolizumab) and the monoclonal IgG1 antibody, ramucirumab. This expansion has generated a need for novel treatment sequencing strategies in this patient population. In light of these developments, an evaluation of the impact of FDA-approved therapeutics on patient-centered outcomes such as health-related quality of life (HRQoL) is warranted. An increased understanding of HRQoL in patients included in advanced HCC clinical trials could potentially help physician decision-making for treatment sequencing in patients with advanced HCC. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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16 pages, 1212 KiB

Open AccessReview

The Role of AMP-Activated Protein Kinase as a Potential Target of Treatment of Hepatocellular Carcinoma

by Xue Jiang, Hor-Yue Tan, Shanshan Teng, Yau-Tuen Chan, Di Wang and Ning Wang

Cancers 2019, 11(5), 647; https://doi.org/10.3390/cancers11050647 - 10 May 2019

Cited by 56 | Viewed by 5739

Abstract

Background: Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide with a very high recurrence rate and very dismal prognosis. Diagnosis and treatment in HCC remain difficult, and the identification of new therapeutic targets is necessary for a better outcome of [...] Read more.

Background: Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide with a very high recurrence rate and very dismal prognosis. Diagnosis and treatment in HCC remain difficult, and the identification of new therapeutic targets is necessary for a better outcome of HCC treatment. AMP-Activated Protein Kinase (AMPK) is an essential intracellular energy sensor that plays multiple roles in cellular physiology and the pathological development of chronic diseases. Recent studies have highlighted the important regulation of AMPK in HCC. This review aims to comprehensively and critically summarize the role of AMPK in HCC. Methods: Original studies were retrieved from NCBI database with keywords including AMPK and HCC, which were analyzed with extensive reading. Results: Dysregulation of the kinase activity and expression of AMPK was observed in HCC, which was correlated with survival of the patients. Loss of AMPK in HCC cells may proceed cell cycle progression, proliferation, survival, migration, and invasion through different oncogenic molecules and pathways. Conclusions: We identified several AMPK activators which may possess potential anti-HCC function, and discussed the clinical perspective on the use of AMPK activators for HCC therapy. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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9 pages, 2442 KiB

Open AccessPerspective

The Utility of Anatomical Liver Resection in Hepatocellular Carcinoma: Associated with Improved Outcomes or Lack of Supportive Evidence?

by Michelle Ju and Adam C. Yopp

Cancers 2019, 11(10), 1441; https://doi.org/10.3390/cancers11101441 - 26 Sep 2019

Cited by 17 | Viewed by 2984

Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Surgical resection of HCC remains one of the mainstays of curative therapies and is associated with five-year overall survival rates approaching 60%. Despite improved perioperative outcomes, locoregional recurrence within the first [...] Read more.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Surgical resection of HCC remains one of the mainstays of curative therapies and is associated with five-year overall survival rates approaching 60%. Despite improved perioperative outcomes, locoregional recurrence within the first two years following hepatic resection is of significant concern with recurrence rates of up to 50%. The use of anatomical resection surgical approaches, whereby the portal venous blood flow is ligated proximal to the tumor bed, is postulated to reduce recurrence rates due to reduction of micrometastatic disease. The aim of this review is to characterize the definition of an anatomical resection (AR) during partial hepatectomy, discuss the theoretical advantages of AR during hepatic resection for HCC, and to present evidence of the impact of AR on outcome measures in patients with HCC. Based on current data, there is a lack of conclusive evidence to support the universal use of AR in cirrhotic patients with HCC. A randomized clinical trial is warranted to further clarify the debate between AR versus non-anatomical resection (NAR) for HCC. Full article

(This article belongs to the Special Issue Hepatocellular Cancer Treatment)

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