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Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment
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Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment

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

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 33243

Special Issue Editor

Dr. Huei-Lung Liang

E-Mail Website
Guest Editor
Department of Radiology, Kaohsiung Veterans General Hospital, 386 Dazhong 1st Rd, Kaohsiung 813, Taiwan
Interests: hepatocellular carcinoma; metastatic hepatocellular carcinoma; multimodality treatment; novel therapy

Special Issue Information

Dear Colleagues,

Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide. Although the etiology of viral-hepatitis-related HCC has decreased due to the deployment of aggressive medication and/or vaccines, the etiologies of alcoholic- or nonalcoholic-fatty-liver-disease-related HCC are increasing. The importance of the clinical prevention and management of HCC still cannot be overstated. The new version of the BCLC guidelines recommends corresponding treatment strategies and clinical-outcome estimations for different stages of the disease. However, there still remain other unrecommended treatment modalities which may be beneficial, especially for the advanced HCC patients.

This Special Issue will reflect the recent advances in the research and treatment of HCC, including surgical resection, liver transplant, image-guided tumor ablation, conventional/drug-eluting chemoembolization, Y-90 radioembolization, new regimens of hepatic arterial infusion chemotherapy, proton beam radiotherapy, target/immunotherapy, and/or combination therapy.

Dr. Huei-Lung Liang
Guest Editor

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Keywords

  • research and treatment of HCC
  • surgical resection
  • liver transplant
  • image-guided tumor ablation
  • conventional/drug-eluting chemoembolization
  • new regimens of hepatic arterial infusion chemotherapy
  • proton beam radiotherapy
  • target/immunotherapy
  • combination therapy

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Published Papers (19 papers)

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Research

Jump to: Review, Other

13 pages, 1595 KiB  
Article
Proton Beam Therapy for Treating Patients with Hepatocellular Carcinoma with Major Portal Vein Tumor Invasion: A Single Center Retrospective Study
by Toshiki Ishida, Masashi Mizumoto, Takashi Saito, Toshiyuki Okumura, Kosei Miura, Hirokazu Makishima, Takashi Iizumi, Haruko Numajiri, Keiichiro Baba, Motohiro Murakami, Masatoshi Nakamura, Kei Nakai and Hideyuki Sakurai
Cancers 2024, 16(11), 2050; https://doi.org/10.3390/cancers16112050 - 29 May 2024
Cited by 1 | Viewed by 1088
Abstract
Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) has a poor prognosis and is generally not indicated for surgery. Proton beam therapy (PBT) may offer an alternative treatment. In this study, long-term outcomes were examined in 116 patients (median age 66 years, [...] Read more.
Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) has a poor prognosis and is generally not indicated for surgery. Proton beam therapy (PBT) may offer an alternative treatment. In this study, long-term outcomes were examined in 116 patients (median age 66 years, 100 males) with HCC with advanced PVTT (Vp3 or Vp4) who received PBT from April 2008 to March 2018. Of these patients, 63 received PBT as definitive treatment and 53 as palliative treatment. The representative dose was 72.6 Gy (RBE) in 22 fractions. Eight patients died in follow-up, including 72 due to tumor progression. The 5-year overall survival (OS) rate was 18.0% (95% CI 9.8–26.2%) and the 5-year local control (LC) rate was 86.1% (74.9–97.3%). In multivariate analyses, performance status and treatment strategy were significantly associated with OS. The median follow-up period for survivors with definitive treatment was 33.5 (2–129) months, and the 5-year OS rate was 25.1% (12.9–37.3%) in these cases. The median survival time after definitive irradiation was >20 months. The 5-year OS rate was 9.1% (0–19.7%) for palliative irradiation. These results compare favorably with those of other therapies and suggest that PBT is a useful option for cases of HCC with advanced PVTT that cannot undergo surgery, with an expected survival benefit and good local control. Determining the optimal indication for this treatment is a future challenge. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
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17 pages, 5600 KiB  
Article
The Impact of Statins on the Survival of Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib or Lenvatinib
by Ji Eun Han, Jisu Kim, Jae Youn Cheong, Soon Sun Kim, Sun Gyo Lim, Min Jae Yang, Choong-Kyun Noh, Gil Ho Lee, Jung Woo Eun, Bumhee Park and Hyo Jung Cho
Cancers 2024, 16(2), 249; https://doi.org/10.3390/cancers16020249 - 5 Jan 2024
Viewed by 1478
Abstract
We aimed to evaluate the survival benefits of coadministering statins and multityrosine kinase inhibitors (TKIs) in patients with advanced hepatocellular carcinoma (HCC). Data from the Health Insurance Review and Assessment Service in Korea (2010–2020) were utilized. Statin use (≥28 cumulative defined daily doses) [...] Read more.
We aimed to evaluate the survival benefits of coadministering statins and multityrosine kinase inhibitors (TKIs) in patients with advanced hepatocellular carcinoma (HCC). Data from the Health Insurance Review and Assessment Service in Korea (2010–2020) were utilized. Statin use (≥28 cumulative defined daily doses) was analyzed, with 1534 statin users matched to 6136 non-users (1:4 ratio) using propensity scores. Primary and secondary outcomes were overall survival (OS) and progression-free survival (PFS). Statin use significantly improved OS (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.72–0.82, p < 0.001) and PFS (HR 0.78, 95% CI 0.74–0.84, p < 0.001). Continuous or post-TKI statin users had better OS, while discontinuation after TKI use led to poorer OS. Both lipophilic and hydrophilic statins improved OS and PFS, particularly with ≥730 cumulative defined daily doses. In conclusion, combining statins and TKIs in patients with advanced HCC yielded significant survival benefits, influenced by statin dosage and duration. Continuous statin administration post-TKI treatment is crucial for improving outcomes in patients with HCC. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
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14 pages, 2565 KiB  
Article
Therapeutic Efficacy and Safety of Lenvatinib after Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma
by Shigeki Yano, Tomokazu Kawaoka, Shintaro Yamasaki, Yusuke Johira, Masanari Kosaka, Yuki Shirane, Ryoichi Miura, Kei Amioka, Kensuke Naruto, Kenji Yamaoka, Yasutoshi Fujii, Shinsuke Uchikawa, Hatsue Fujino, Atsushi Ono, Takashi Nakahara, Eisuke Murakami, Daiki Miki, Masataka Tsuge, Yuji Teraoka, Hirotaka Kouno, Shintaro Takaki, Nami Mori, Keiji Tsuji and Shiro Okaadd Show full author list remove Hide full author list
Cancers 2023, 15(22), 5406; https://doi.org/10.3390/cancers15225406 - 14 Nov 2023
Cited by 5 | Viewed by 2161
Abstract
A total of 137 HCC patients treated with atezolizumab plus bevacizumab from October 2020 to September 2022 were enrolled. The median overall survival (OS) and progression-free survival (PFS) from the beginning of atezolizumab plus bevacizumab were 21.1 months (range, 18.8 months–not reached) and [...] Read more.
A total of 137 HCC patients treated with atezolizumab plus bevacizumab from October 2020 to September 2022 were enrolled. The median overall survival (OS) and progression-free survival (PFS) from the beginning of atezolizumab plus bevacizumab were 21.1 months (range, 18.8 months–not reached) and 10.5 months (range, 8.2–12.1 months), respectively. Fifty patients were diagnosed with progressive disease after atezolizumab plus bevacizumab. Of this group, 24 patients were administered lenvatinib, and the median OS and PFS from the beginning of lenvatinib were 15.3 months (range, 10.5 months–not reached) and 4.0 months (range, 2.5–6.4 months), respectively. The objective response rates based on the response evaluation criteria in solid tumors (RECISTs) criteria version 1.1 and modified RECISTs were 33.3% and 54.2%, respectively. There was no significant difference in the median serum alpha-fetoprotein level between before and after lenvatinib. In the multivariate analysis, Child–Pugh class A (hazard ratio 0.02, 95% confidence interval (CI) 0.02–0.76, p = 0.02) and intrahepatic tumor occupancy rate < 50% (hazard ratio < 0.01, 95% CI 0.003–0.35, p < 0.01) were the significant factors for OS. There were some frequent adverse events (AEs) in patients treated with lenvatinib such as hypertension, fatigue, anorexia, proteinuria, and so on, but none directly caused death. In conclusion, lenvatinib after atezolizumab plus bevacizumab for unresectable HCC should be considered an effective treatment option. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
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15 pages, 1854 KiB  
Article
Primary versus Salvage Liver Transplantation after Curative-Intent Resection or Radiofrequency Ablation for Hepatocellular Carcinoma: Long-Term Oncological Outcomes
by Alessandro Anselmo, Leandro Siragusa, Paolo Brigato, Camilla Riccetti, Andrea Collini, Bruno Sensi and Giuseppe Tisone
Cancers 2023, 15(20), 5030; https://doi.org/10.3390/cancers15205030 - 18 Oct 2023
Cited by 3 | Viewed by 1268
Abstract
Liver transplantation for hepatocellular carcinoma (HCC) may be performed ab initio, primary liver transplantation (PLT), or for HCC recurrence after previous treatments such as liver resection (LR) or radiofrequency ablation (RFA), salvage liver transplantation (SLT). The aim of this study was to evaluate [...] Read more.
Liver transplantation for hepatocellular carcinoma (HCC) may be performed ab initio, primary liver transplantation (PLT), or for HCC recurrence after previous treatments such as liver resection (LR) or radiofrequency ablation (RFA), salvage liver transplantation (SLT). The aim of this study was to evaluate the oncological outcomes of SLT vs. PLT. For this, a retrospective study was carried out on patients undergoing liver transplantation for HCC. The outcomes of PLT were compared with those of SLT. The primary outcome was disease-free survival (DFS). The secondary outcomes included overall survival (OS), cancer-specific survival (CSS), and major postoperative complications. A sub-analysis of SLT-LR and SLT-RFA was also performed. In total, 141 patients were included: 96 underwent PLT and 45 SLT. Among the SLT group, 25 patients had undergone previous LR while 20 had had RFA. There were no differences in the major postoperative complications. Unadjusted DFS was significantly longer in the PLT group (p = 0.02), as were OS (p = 0.025) and CSS (p = 0.001). There was no difference in DFS between PLT and SLT-LR groups, while a significant difference was found between the PLT and SLT-RFA groups (p = 0.035). Nonetheless, DFS was no different between the SLT-LR and SLT-RFA groups. PLT appears to offer superior long-term oncological outcomes to SLT. Both SLT-LR and SLT-RFA offer acceptable OS and CSS. Further prospective studies are needed to confirm these results, but the re-direction of grafts and transplant philosophy towards PLT rather than SLT may need to be considered. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
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14 pages, 2196 KiB  
Article
The Prognostic Impact of ABO Blood Group in Hepatocellular Carcinoma Following Hepatectomy
by Masaki Kaibori, Kengo Yoshii, Kosuke Matsui, Hideyuki Matsushima, Hisashi Kosaka, Hidekazu Yamamoto, Takayoshi Nakajima, Kazunori Aoi, Takashi Yamaguchi, Katsunori Yoshida and Mitsugu Sekimoto
Cancers 2023, 15(11), 2905; https://doi.org/10.3390/cancers15112905 - 25 May 2023
Cited by 1 | Viewed by 1479
Abstract
Background/Purpose: The effect of the ABO blood group on the survival of patients with hepatocellular carcinoma (HCC) is unclear. The aim of the present study is to determine the prognostic impact of ABO blood types on the survival of a Japanese population of [...] Read more.
Background/Purpose: The effect of the ABO blood group on the survival of patients with hepatocellular carcinoma (HCC) is unclear. The aim of the present study is to determine the prognostic impact of ABO blood types on the survival of a Japanese population of patients with HCC who underwent surgical resection. Methods: Patients with HCC (n = 480) who underwent an R0 resection between 2010 and 2020 were retrospectively analyzed. Survival outcomes were investigated according to ABO blood type (A, B, O, or AB). Outcomes for type A (n = 173) and non-type A (n = 173) groups after surgery were compared using 1-to-1 propensity score matching to control for variables. Results: In the study cohort, 173 (36.0%), 133 (27.7%), 131 (27.3%), and 43 (9.0%) of participants had Type A, O, B, and AB, respectively. Type A and non-type A patients were successfully matched based on liver function and tumor characteristics. Recurrence-free survival (RFS; hazard ratio [HR] 0.75, 95% confidence interval [Cl] 0.58–0.98, p = 0.038) and overall survival (OS; HR: 0.67, 95% Cl: 0.48–0.95, p = 0.023) for patients with blood type A were both significantly decreased relative to non-type A patients. Cox proportional hazard analysis demonstrated that patients with HCC who have blood type A had a worse prognosis than those with non-type A blood. Conclusion: ABO blood type may have a prognostic impact on patients with HCC after hepatectomy. Blood type A is an independent unfavorable prognostic factor for recurrence-free and overall survival (RFS and OS) after hepatectomy. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
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10 pages, 1166 KiB  
Article
Predictive Factors of Complete Response to Transarterial Chemoembolization in Intermediate Stage Hepatocellular Carcinoma beyond Up-To-7 Criteria
by Natsuhiko Saito, Hideyuki Nishiofuku, Takeshi Sato, Shinsaku Maeda, Kiyoyuki Minamiguchi, Ryosuke Taiji, Takeshi Matsumoto, Yuto Chanoki, Tetsuya Tachiiri, Hideki Kunichika, Nagaaki Marugami and Toshihiro Tanaka
Cancers 2023, 15(9), 2609; https://doi.org/10.3390/cancers15092609 - 4 May 2023
Cited by 5 | Viewed by 1985
Abstract
Aim: To clarify the prognosis and identify predictors for obtaining a complete response (CR) by transarterial chemoembolization (TACE) in intermediate stage HCC beyond up-to-7 criteria. Methods: Of the 120 patients with intermediate stage HCC who were treated by TACE as the initial treatment [...] Read more.
Aim: To clarify the prognosis and identify predictors for obtaining a complete response (CR) by transarterial chemoembolization (TACE) in intermediate stage HCC beyond up-to-7 criteria. Methods: Of the 120 patients with intermediate stage HCC who were treated by TACE as the initial treatment from February 2007 to January 2016, 72 finally matched the following inclusion criteria: beyond up-to-7 criteria; Child–Pugh score under 7; and no combined therapy within 4 weeks after the initial TACE. The CR rate and overall survival (OS) were evaluated. Logistic regression analysis was performed to identify predictors of CR. The deterioration of liver function after TACE was also evaluated. Results: The CR rate was 56.9%, and the overall median survival time (MST) was 37.7 months. The MST was 38.7 months in the CR group and 28.0 months in the non-CR group (p = 0.018). HCC within up-to-11 criteria was the only predictor of CR. The CR rate and MST were 70.7% and 37.7 months, respectively, in patients with HCC within up-to-11 criteria and 38.7% and 32.7 months, respectively, in the patients beyond up-to-11 criteria. Deterioration of the Child–Pugh score after the initial TACE and the 2nd TACE occurred in 24.2% and 12.0%, respectively, and deterioration of the modified albumin-bilirubin (mALBI) grade occurred in 17.6% and 7.4%, respectively. Conclusion: TACE can achieve high CR rates with prolonged overall survival for intermediate stage HCC beyond up-to-7 criteria. The predictor of CR was within up-to-11 criteria. Deterioration of liver function was not severe, but requires caution. Multidisciplinary approach as additional treatment after TACE is important. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
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17 pages, 629 KiB  
Article
Baveno VII Criteria Is an Accurate Risk Stratification Tool to Predict High-Risk Varices Requiring Intervention and Hepatic Events in Patients with Advanced Hepatocellular Carcinoma
by Claudia Wing-Kwan Wu, Rashid Nok-Shun Lui, Vincent Wai-Sun Wong, Tsz-Fai Yam, Terry Cheuk-Fung Yip, Ken Liu, Jimmy Che-To Lai, Yee-Kit Tse, Tony Shu-Kam Mok, Henry Lik-Yuen Chan, Kelvin Kwok-Chai Ng, Grace Lai-Hung Wong and Stephen Lam Chan
Cancers 2023, 15(9), 2480; https://doi.org/10.3390/cancers15092480 - 26 Apr 2023
Cited by 9 | Viewed by 3239
Abstract
The Baveno VII criteria are used in patients with liver cirrhosis to predict high-risk varices in patients with liver cirrhosis. Yet its use in patients with advanced hepatocellular carcinoma (HCC) has not been validated. HCC alone is accompanied with a higher variceal bleeding [...] Read more.
The Baveno VII criteria are used in patients with liver cirrhosis to predict high-risk varices in patients with liver cirrhosis. Yet its use in patients with advanced hepatocellular carcinoma (HCC) has not been validated. HCC alone is accompanied with a higher variceal bleeding risk due to its association with liver cirrhosis and portal vein thrombosis. The use of systemic therapy in advanced HCC has been thought to further augment this risk. Upper endoscopy is commonly used to evaluate for the presence of varices before initiation of treatment with systemic therapy. Yet it is associated with procedural risks, waiting time and limited availability in some localities which may delay the commencement of systemic therapy. Our study successfully validated the Baveno VI criteria with a 3.5% varices needing treatment (VNT) missed rate, also with acceptable <5% VNT missed rates when considering alternative liver stiffness (LSM) and platelet cut-offs. The Baveno VII clinically significant portal hypertension rule-out criteria (LSM < 15 kPa and platelet >150 × 109/L) also revealed a low frequency (2%) of hepatic events, whilst the rule-in criteria (LSM > 25 kPa) was predictive of a higher proportion of hepatic events (14%). Therefore, our study has successfully validated the Baveno VII criteria as a non-invasive stratification of the risk of variceal bleeding and hepatic decompensation in the HCC population. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
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9 pages, 1310 KiB  
Article
Prognostic Value of Simple Non-Invasive Tests for the Risk Stratification of Incident Hepatocellular Carcinoma in Cirrhotic Individuals with Non-Alcoholic Fatty Liver Disease
by Angelo Armandi, Gian Paolo Caviglia, Amina Abdulle, Chiara Rosso, Kamela Gjini, Gabriele Castelnuovo, Marta Guariglia, Nuria Perez Diaz del Campo, Daphne D’Amato, Davide Giuseppe Ribaldone, Giorgio Maria Saracco and Elisabetta Bugianesi
Cancers 2023, 15(6), 1659; https://doi.org/10.3390/cancers15061659 - 8 Mar 2023
Cited by 3 | Viewed by 1598
Abstract
Hepatocellular carcinoma (HCC) represents a relevant disease burden in cirrhotic patients with non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the prognostic value of simple non-invasive tests (NITs) (AAR, APRI, BARD, FIB-4) for the stratification of HCC risk development in a cohort [...] Read more.
Hepatocellular carcinoma (HCC) represents a relevant disease burden in cirrhotic patients with non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the prognostic value of simple non-invasive tests (NITs) (AAR, APRI, BARD, FIB-4) for the stratification of HCC risk development in a cohort of 122 consecutive cirrhotic individuals with NAFLD. Over a median follow up of 5.9 (3.2–9.3) years, 13 (10.7%) developed HCC. Only FIB-4 was associated with HCC risk (HR = 1.27, 95% CI 1.03–1.58, p = 0.027). After evaluating different established FIB-4 cut-offs, the lowest cut-off of 1.45 allowed the ruling out of a greater number of patients with a minimal risk of HCC than the 1.3 cut-off (23 vs. 18 patients). Conversely, the cumulative incidence of HCC using the highest cut-off of 3.25 (rule in) was distinctly higher than the 2.67 cut-off (19.4% vs. 13.3%). After multivariate Cox regression analysis, these cut-offs were independently associated with HCC after adjusting for sex, BMI and T2DM (HR = 6.40, 95% CI 1.71–24.00, p = 0.006). In conclusion, FIB-4 values of <1.3 and >3.25 could allow for the optimal stratification of long-term HCC risk in cirrhotic individuals with NAFLD. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
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Review

Jump to: Research, Other

17 pages, 328 KiB  
Review
Decoding the Prognostic Significance and Therapeutic Implications of Inflammation-Based Scores in Hepatocellular Carcinoma: A Comprehensive Review
by Evgenia Kotsifa, Nikolaos Machairas, Apostolos Angelis, Nikolaos I. Nikiteas, Dimitrios Dimitroulis and Georgios C. Sotiropoulos
Cancers 2024, 16(14), 2549; https://doi.org/10.3390/cancers16142549 - 15 Jul 2024
Viewed by 778
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, posing a significant global health challenge with an increasing incidence. In recent years, multiple staging systems and scores have been proposed, emphasising the necessity for the development of precise prognostic tools. The well-documented [...] Read more.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, posing a significant global health challenge with an increasing incidence. In recent years, multiple staging systems and scores have been proposed, emphasising the necessity for the development of precise prognostic tools. The well-documented etiological relationship between chronic inflammation and carcinogenesis has prompted researchers to explore novel prognostic markers associated with the inflammatory status of HCC patients. This review summarises the current data about inflammation-based scores in the context of HCC. We discuss established scores like the Glasgow Prognostic Score (GPS), modified GPS (mGPS) and the neutrophil-to-lymphocyte ratio (NLR) and others not as extensively studied, examining their utility in predicting survival outcomes and treatment response in HCC patients. Furthermore, we explore emerging scores, including the prognostic nutritional index (PNI) and other lymphocyte-based scores, assessing their potential in refining risk stratification and guiding therapeutic decisions in the era of precision medicine. As research progresses and these scores undergo further refinement and integration into the evolving landscape of HCC management, they carry significant potential for improving patient outcomes. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
12 pages, 752 KiB  
Review
Transarterial Chemoembolization Treatment Paradigms for Hepatocellular Carcinoma
by Elliott L. Fite and Mina S. Makary
Cancers 2024, 16(13), 2430; https://doi.org/10.3390/cancers16132430 - 1 Jul 2024
Cited by 3 | Viewed by 1405
Abstract
Hepatocellular carcinoma (HCC) accounts for 90% of liver cancer cases worldwide and is currently the most quickly increasing cause of cancer-related deaths in the United States. The 5-year survival rate for primary liver cancer is estimated to be below 20%, and HCC mortality [...] Read more.
Hepatocellular carcinoma (HCC) accounts for 90% of liver cancer cases worldwide and is currently the most quickly increasing cause of cancer-related deaths in the United States. The 5-year survival rate for primary liver cancer is estimated to be below 20%, and HCC mortality is expected to increase by 41% by 2040. Currently, surgical resection is the first-line approach to definitive treatment of early-stage HCC. However, the majority of patients present with late-stage, unresectable disease due to the asymptomatic nature of early HCC. For patients who present with unresectable HCC, locoregional therapies such as transarterial chemoembolization (TACE) represent an alternative approach to HCC treatment. TACE is a minimally invasive, catheter-based technique that allows for targeted delivery of chemotherapy to tumor sites while occluding tumor-feeding blood vessels. In appropriately selected patients, outcomes for TACE therapy have been shown to be more favorable than supportive care or conservative management. The increasing incidence and mortality of HCC, in addition to the late-stage presentation of most HCC patients, demonstrates the need to expand the role of locoregional therapies in the treatment of HCC. TACE represents an appealing approach to HCC management, including disease control, palliation, and potentially curative-intent strategies. In this review, we will describe the current utility of TACE in the treatment of HCC, characterize the outcomes of patients treated with TACE across different HCC stages, and outline future applications of TACE in the treatment paradigm. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
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21 pages, 535 KiB  
Review
The Negative Impact of Sarcopenia on Hepatocellular Carcinoma Treatment Outcomes
by Annalisa Cespiati, Daniel Smith, Rosa Lombardi and Anna Ludovica Fracanzani
Cancers 2024, 16(13), 2315; https://doi.org/10.3390/cancers16132315 - 24 Jun 2024
Viewed by 996
Abstract
Introduction: Hepatocellular carcinoma (HCC) represents a major global health concern, characterized by evolving etiological patterns and a range of treatment options. Among various prognostic factors, sarcopenia, characterized by loss of skeletal muscle mass, strength, and function, has emerged as a pivotal contributor to [...] Read more.
Introduction: Hepatocellular carcinoma (HCC) represents a major global health concern, characterized by evolving etiological patterns and a range of treatment options. Among various prognostic factors, sarcopenia, characterized by loss of skeletal muscle mass, strength, and function, has emerged as a pivotal contributor to HCC outcomes. Focusing on liver transplantation, surgical resection, locoregional treatments, and systemic therapies, this review aims to analyze the impact of sarcopenia on HCC treatment outcomes, shedding light on an underexplored subject in the pursuit of more personalized management. Methods: A comprehensive literature review was conducted by searching peer-reviewed articles on sarcopenia and treatment outcomes in patients with HCC from inception up to October 2023. Results: Sarcopenia was found to be prevalent among HCC patients, exhibiting different occurrence, possibly attributable to diverse diagnostic criteria. Notably, despite variations in studies utilizing skeletal muscle indices, sarcopenia independently correlated with lower overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS) across surgical (both transplantation and resection), locoregional, and systemic therapies, including tyrosine-kinase inhibitors (TKIs) and immune-checkpoint inhibitors (ICIs). Moreover, a link between sarcopenia and increased rate and severity of adverse events, particularly in surgery and TKIs recipients, and larger tumor size at diagnosis was observed. While baseline sarcopenia negatively influenced treatment outcomes, alterations in muscle mass post-treatment emerged as primary determinants of reduced OS. Conclusions: Sarcopenia, either present before or after HCC treatment, negatively correlates with response to it, across all etiologies and therapeutic strategies. Although only a few studies have evaluated the impact of supervised physical activity training on muscle mass and OS after HCC treatment, it is crucial to evaluate the presence of sarcopenia before treatment initiation, to better stratify patients’ prognosis, thus performing a more tailored approach, and identify therapies able to restore muscle mass in HCC patients. Conversely, the impact of sarcopenia on HCC recurrence and extrahepatic spread remains inadequately explored. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
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21 pages, 353 KiB  
Review
Immune Checkpoint Inhibitors in Hepatocellular Carcinoma and Their Hepatic-Related Side Effects: A Review
by Thomas M. Ruli, Jr., Ethan D. Pollack, Atul Lodh, Charles D. Evers III, Christopher A. Price and Mohamed Shoreibah
Cancers 2024, 16(11), 2042; https://doi.org/10.3390/cancers16112042 - 28 May 2024
Cited by 3 | Viewed by 1668
Abstract
Primary liver cancer is one of the leading causes of cancer mortality worldwide, with hepatocellular carcinoma (HCC) being the most prevalent type of liver cancer. The prognosis of patients with advanced, unresectable HCC has historically been poor. However, with the emergence of immunotherapy, [...] Read more.
Primary liver cancer is one of the leading causes of cancer mortality worldwide, with hepatocellular carcinoma (HCC) being the most prevalent type of liver cancer. The prognosis of patients with advanced, unresectable HCC has historically been poor. However, with the emergence of immunotherapy, specifically immune checkpoint inhibitors (ICIs), there is reason for optimism. Nevertheless, ICIs do not come without risk, especially when administered in patients with HCC, given their potential underlying poor hepatic reserve. Given their novelty in the management of HCC, there are few studies to date specifically investigating ICI-related side effects on the liver in patients with underlying HCC. This review will serve as a guide for clinicians on ICIs’ role in the management of HCC and their potential side effect profile. There will be a discussion on ICI-related hepatotoxicity, the potential for hepatitis B and C reactivation with ICI use, the potential for the development of autoimmune hepatitis with ICI use, and the risk of gastrointestinal bleeding with ICI use. As ICIs become more commonplace as a treatment option in patients with advanced HCC, it is imperative that clinicians not only understand the mechanism of action of such agents but also understand and are able to identify hepatic-related side effects. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
29 pages, 1578 KiB  
Review
Understanding the Role of Connexins in Hepatocellular Carcinoma: Molecular and Prognostic Implications
by Stavros P. Papadakos, Elena Chatzikalil, Konstantinos Arvanitakis, Georgios Vakadaris, Ioanna E. Stergiou, Maria-Loukia Koutsompina, Alexandra Argyrou, Vasileios Lekakis, Ippokratis Konstantinidis, Georgios Germanidis and Stamatios Theocharis
Cancers 2024, 16(8), 1533; https://doi.org/10.3390/cancers16081533 - 17 Apr 2024
Cited by 1 | Viewed by 1862
Abstract
Connexins, a family of tetraspan membrane proteins forming intercellular channels localized in gap junctions, play a pivotal role at the different stages of tumor progression presenting both pro- and anti-tumorigenic effects. Considering the potential role of connexins as tumor suppressors through multiple channel-independent [...] Read more.
Connexins, a family of tetraspan membrane proteins forming intercellular channels localized in gap junctions, play a pivotal role at the different stages of tumor progression presenting both pro- and anti-tumorigenic effects. Considering the potential role of connexins as tumor suppressors through multiple channel-independent mechanisms, their loss of expression may be associated with tumorigenic activity, while it is hypothesized that connexins favor the clonal expansion of tumor cells and promote cell migration, invasion, and proliferation, affecting metastasis and chemoresistance in some cases. Hepatocellular carcinoma (HCC), characterized by unfavorable prognosis and limited responsiveness to current therapeutic strategies, has been linked to gap junction proteins as tumorigenic factors with prognostic value. Notably, several members of connexins have emerged as promising markers for assessing the progression and aggressiveness of HCC, as well as the chemosensitivity and radiosensitivity of hepatocellular tumor cells. Our review sheds light on the multifaceted role of connexins in HCC pathogenesis, offering valuable insights on recent advances in determining their prognostic and therapeutic potential. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
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15 pages, 2312 KiB  
Review
Selecting the Appropriate Downstaging and Bridging Therapies for Hepatocellular Carcinoma: What Is the Role of Transarterial Radioembolization? A Pooled Analysis
by Victor Lopez-Lopez, Kohei Miura, Christoph Kuemmerli, Antonio Capel, Dilmurodjon Eshmuminov, David Ferreras, Alberto Baroja-Mazo, Pedro Cascales-Campos, María Isabel Jiménez-Mascuñán, José Antonio Pons, Maria Isabel Castellon, Francisco Sánchez-Bueno, Ricardo Robles-Campos and Pablo Ramírez
Cancers 2023, 15(7), 2122; https://doi.org/10.3390/cancers15072122 - 2 Apr 2023
Cited by 8 | Viewed by 2293
Abstract
Background: Transarterial radioembolization in HCC for LT as downstaging/bridging has been increasing in recent years but some indication criteria are still unclear. Methods: We conducted a systematic literature search of primary research publications conducted in PubMed, Scopus and ScienceDirect databases until November 2022. [...] Read more.
Background: Transarterial radioembolization in HCC for LT as downstaging/bridging has been increasing in recent years but some indication criteria are still unclear. Methods: We conducted a systematic literature search of primary research publications conducted in PubMed, Scopus and ScienceDirect databases until November 2022. Relevant data about patient selection, HCC features and oncological outcomes after TARE for downstaging or bridging in LT were analyzed. Results: A total of 14 studies were included (7 downstaging, 3 bridging and 4 mixed downstaging and bridging). The proportion of whole liver TARE was between 0 and 1.6%. Multiple TARE interventions were necessary for 16.7% up to 28% of the patients. A total of 55 of 204 patients across all included studies undergoing TARE for downstaging were finally transplanted. The only RCT included presents a higher tumor response with the downstaging rate for LT of TARE than TACE (9/32 vs. 4/34, respectively). Grade 3 or 4 adverse effects rate were detected between 15 and 30% of patients. Conclusions: TARE is a safe therapeutic option with potential advantages in its capacity to necrotize and reduce the size of the HCC for downstaging or bridging in LT. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
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22 pages, 1816 KiB  
Review
Update on PET Radiopharmaceuticals for Imaging Hepatocellular Carcinoma
by Nozipho Nyakale, Luca Filippi, Colleen Aldous and Mike Sathekge
Cancers 2023, 15(7), 1975; https://doi.org/10.3390/cancers15071975 - 25 Mar 2023
Cited by 5 | Viewed by 2591
Abstract
Numerous positron emission tomography (PET) targets for detection and staging of hepatocellular cancer have been developed in recent years. Hepatocellular carcinomas (HCCs) are clinically and pathologically heterogeneous tumours with a high tendency to be aggressive and unresponsive to chemotherapy. Early detection is essential, [...] Read more.
Numerous positron emission tomography (PET) targets for detection and staging of hepatocellular cancer have been developed in recent years. Hepatocellular carcinomas (HCCs) are clinically and pathologically heterogeneous tumours with a high tendency to be aggressive and unresponsive to chemotherapy. Early detection is essential, and the need for an adequate imaging biomarker, which can overcome some of the limitations of conventional radiological imaging, is persistent. Flourine-18 (18F) flourodeoxyglucose (FDG), the most widely used PET radiopharmaceutical, has proven disappointing as a possible staple in the evaluation of HCC. This disappointment had led to experimentation with carious radiotracers, such as the choline derivatives, acetate, and prostate-specific membrane antigen, which appear to complement and/or enhance the role of FDG. In this study, we look at the various PET radiopharmaceuticals that have been used for imaging HCC and the particular pathways that they target in HCC and liver cancers. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
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12 pages, 279 KiB  
Review
Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease: The Prognostic Role of Liver Stiffness Measurement
by Lucia Cerrito, Irene Mignini, Maria Elena Ainora, Carolina Mosoni, Antonio Gasbarrini and Maria Assunta Zocco
Cancers 2023, 15(3), 637; https://doi.org/10.3390/cancers15030637 - 19 Jan 2023
Cited by 2 | Viewed by 1777
Abstract
Nonalcoholic fatty liver disease (NAFLD), which is nowadays the most common etiology of chronic liver disease, is associated with an increased risk of hepatocellular carcinoma (HCC), with or without cirrhosis. Owing to the high prevalence of NAFLD worldwide, it becomes crucial to develop [...] Read more.
Nonalcoholic fatty liver disease (NAFLD), which is nowadays the most common etiology of chronic liver disease, is associated with an increased risk of hepatocellular carcinoma (HCC), with or without cirrhosis. Owing to the high prevalence of NAFLD worldwide, it becomes crucial to develop adequate strategies for surveillance of HCC and new prediction models aiming at stratifying NAFLD population for HCC risk. To this purpose, several noninvasive tests (NITs) have been proposed in the several last years, including clinical parameters, serum biomarkers, and imaging techniques. Most of these tools are focused on the assessment of liver fibrosis. Both ultrasound (US) elastography (especially transient elastography) and magnetic resonance (MR) elastography have been evaluated to estimate HCC risk in NAFLD patients. Recently, the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) include these techniques among the recommended NITs for the assessment of liver fibrosis. The aim of this review is to summarize the most recent data on the role of US and MR elastography in HCC risk stratification in patients with NAFLD. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
17 pages, 2049 KiB  
Review
P-21 Activated Kinases in Liver Disorders
by Xun Qiu, Hanzhi Xu, Kai Wang, Fengqiang Gao, Xiao Xu and Hong He
Cancers 2023, 15(2), 551; https://doi.org/10.3390/cancers15020551 - 16 Jan 2023
Cited by 4 | Viewed by 2267
Abstract
The p21 Activated Kinases (PAKs) are serine threonine kinases and play important roles in many biological processes, including cell growth, survival, cytoskeletal organization, migration, and morphology. Recently, PAKs have emerged in the process of liver disorders, including liver cancer, hepatic ischemia-reperfusion injury, hepatitis, [...] Read more.
The p21 Activated Kinases (PAKs) are serine threonine kinases and play important roles in many biological processes, including cell growth, survival, cytoskeletal organization, migration, and morphology. Recently, PAKs have emerged in the process of liver disorders, including liver cancer, hepatic ischemia-reperfusion injury, hepatitis, and liver fibrosis, owing to their effects in multiple signaling pathways in various cell types. Activation of PAKs promotes liver cancer growth and metastasis and contributes to the resistance of liver cancer to radiotherapy and chemotherapy, leading to poor survival of patients. PAKs also play important roles in the development and progression of hepatitis and other pathological processes of the liver such as fibrosis and ischemia-reperfusion injury. In this review, we have summarized the currently available studies about the role of PAKs in liver disorders and the mechanisms involved, and further explored the potential therapeutic application of PAK inhibitors in liver disorders, with the aim to provide a comprehensive overview on current progress and perspectives of PAKs in liver disorders. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
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4 pages, 543 KiB  
Reply
Reply to Allaire, M.; Thabut, D. Comment on “Wu et al. Baveno VII Criteria Is an Accurate Risk Stratification Tool to Predict High-Risk Varices Requiring Intervention and Hepatic Events in Patients with Advanced Hepatocellular Carcinoma. Cancers 2023, 15, 2480”
by Claudia Wing-Kwan Wu, Terry Cheuk-Fung Yip, Vincent Wai-Sun Wong, Grace Lai-Hung Wong, Ken Liu and Rashid Nok-Shun Lui
Cancers 2024, 16(4), 725; https://doi.org/10.3390/cancers16040725 - 9 Feb 2024
Viewed by 873
Abstract
We thank Allaire et al [...] Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
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2 pages, 157 KiB  
Comment
Comment on Wu et al. Baveno VII Criteria Is an Accurate Risk Stratification Tool to Predict High-Risk Varices Requiring Intervention and Hepatic Events in Patients with Advanced Hepatocellular Carcinoma. Cancers 2023, 15, 2480
by Manon Allaire and Dominique Thabut
Cancers 2024, 16(3), 661; https://doi.org/10.3390/cancers16030661 - 4 Feb 2024
Cited by 1 | Viewed by 905
Abstract
We read with great interest the original research conducted by Wu et al [...] Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Advances and Challenges in Research and Treatment)
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