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Llopiz D, Silva L, Ruiz M, Castro-Alejos C, Aparicio B, Vegas L, Infante S, Santamaria E, Sarobe P. MERTK inhibition improves therapeutic efficacy of immune checkpoint inhibitors in hepatocellular carcinoma. Oncoimmunology 2025; 14:2473165. [PMID: 40029206 PMCID: PMC11881874 DOI: 10.1080/2162402x.2025.2473165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 01/29/2025] [Accepted: 02/24/2025] [Indexed: 03/05/2025] Open
Abstract
Immunotherapy with immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) patients only achieves response rates of 25%-30%, indicating the necessity of new therapies for non-responder patients. Since myeloid-related suppressive factors are associated with poor responses to ICI in a subgroup of HCC patients, modulation of these targets may improve response rates. Our aim was to characterize the expression of the efferocytosis receptor MERTK in HCC and to analyze its potential as a new therapeutic target. In HCC patients, MERTK was expressed by myeloid cells and was associated with poorer survival. In a murine HCC model with progressive myeloid cell infiltration, MERTK was detected in dendritic cells and macrophages with an activated phenotype, which overexpressed the checkpoint ligand PD-L1. Concomitant expression of PD-1 in tumor T-cells suggested the pertinence of combined PD-1/PD-L1 and MERTK blockade. In vivo experiments in mice showed that inhibition of MERTK improved the therapeutic effect promoted by anti-PD-1 or by ICI combinations currently approved for HCC. This effect was associated with enhanced tumor infiltration and superior activity of antigen presenting cells and effector lymphocytes. Our results indicate that MERTK may behave as a relevant target for immunotherapeutic combinations in those HCC patients with tumors enriched in a myeloid component.
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Affiliation(s)
- Diana Llopiz
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Leyre Silva
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Marta Ruiz
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Carla Castro-Alejos
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Belen Aparicio
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Lucia Vegas
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
| | - Stefany Infante
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- DNA and RNA Medicine Division, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
- Facultad de Medicina Humana, Universidad de Piura, Lima, Peru
| | - Eva Santamaria
- DNA and RNA Medicine Division, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Pablo Sarobe
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
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Song Q, Yu Z, Lu W, Zhuo Z, Chang L, Mei H, Cui Y, Zhang D. PD-1/PD-L1 inhibitors related adverse events: A bibliometric analysis from 2014 to 2024. Hum Vaccin Immunother 2025; 21:2424611. [PMID: 39757956 DOI: 10.1080/21645515.2024.2424611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/14/2024] [Accepted: 10/29/2024] [Indexed: 01/07/2025] Open
Abstract
Programmed cell death-1 (PD-1) inhibitors and programmed cell death ligand 1 (PD-L1) inhibitors are considered effective alternatives for the primary treatment of recurrent metastatic cancers. However, they can induce various adverse events affecting multiple organ systems, potentially diminishing patients' quality of life, and even leading to treatment interruptions. Adverse events related to PD-1/PD-L1 inhibitors differ from those associated with CTLA-4 inhibitors and are more commonly observed in the treatment of solid tumors. This study aimed to address the knowledge gap regarding adverse events related to PD-1/PD-L1 inhibitors. A visual bibliometric network was constructed using VOSviewer, CiteSpace, R software, and the Web of Science Core Collection (WoSCC) to quantitatively analyze this research field. Future research directions were also explored. The USA ranked first in publication count and total citations. Over time, publication types transitioned from case reports to clinical trials. Research on for nivolumab was the most prevalent. The spectrum of cancers treated by PD-1/PD-L1 inhibitors expanded beyond melanoma and lung cancer to include renal cell carcinoma, esophageal cancer, and others. Common adverse events included pneumonitis, myasthenia gravis, and vitiligo. There was a significant increase in multi-phase clinical trials and studies related to biomarkers. This study offers valuable insights for potential collaborators and institutions, highlighting trends in the study of adverse events related to PD-1/PD-L1 inhibitors. The management of these adverse events has become more refined and standardized. Biomarker research and multi-phase clinical trials are likely to be key areas of focus in future studies.
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Affiliation(s)
- Qingya Song
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zongliang Yu
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Wenping Lu
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhili Zhuo
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lei Chang
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Heting Mei
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Yongjia Cui
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Dongni Zhang
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Singh SP, Kumar K, Kulkarni A, Arora V, Choudhury A, Chaubal A, Rathi S, Shah S, Taneja S, Kumar A, Duseja A, Kumar G, Nagaraja Rao P, Saraswat V, Sarin SK. Predictors of Non-response to Atezolizumab Plus Bevacizumab in Patients With Unresectable Hepatocellular Carcinoma: A Multicentre Real World Study (HCC-AB Study). J Clin Exp Hepatol 2025; 15:102513. [PMID: 40129631 PMCID: PMC11930068 DOI: 10.1016/j.jceh.2025.102513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 02/04/2025] [Indexed: 03/26/2025] Open
Abstract
Background The approved immunotherapies for patients with advanced HCC are Atezolizumab and Bevacizumab. However, patients in India present late and healthcare is often available through self-financing. To rationalise the therapy, we conducted a large multicentre study to identify the baseline predictors of non-response to atezolizumab and bevacizumab in advanced unresectable HCC. Methods A dose of atezolizumab 1200 mg and bevacizumab 15 mg/kg was used every 3 weeks from 6 centres across India. A total of 278 patients were screened, and 160 were included in the study. The study included patients with locally advanced metastatic or inoperable hepatocellular carcinoma who were at least 18 years of age and those who received <3 injections were excluded. Fifty-four percent of the included patients were BCLC-B and 46% were BCLC-C. The primary objective was to study overall survival and progression-free survival. While identifying radiological response, objective response rate and adverse effects were secondary objectives. Results The mean age was 61.9 ± 11.7 years, 88% were male, 55% had NASH, 16.3% had hepatitis C, 18.8% had hepatitis B and the rest were alcohol. The mean Model for End-Stage Liver Disease (MELD) is 12.05 ± 4.46, Albumin-Bilirubin Score (ALBI) is -2.04 ± 0.57. Fifty-five percent received first-line and 45% as second/other line therapy. The median overall survival was 10 (95% confidence interval [CI]: 6.1-15.6) months. Progression-free survival was found to be 8 (95%CI: 5.1-14.7) months overall. Eleven (6.9%) achieved complete response, 28 (17.5%) partial response, 33 (20.6%) had stable disease and 88 (55%) had progressive disease. On multivariate analysis, CRP>1 mg/dl (P-0.007), PIVKA-II>400 mAU/mL (P-0.019), AFP>100 ng/ml (P-0.009), presence of diabetes (P-0.042) were associated with non-response to atezolizumab and bevacizumab injection. Fifty-three percent of patients developed any grade of adverse effect, and 20% developed grade 3/4 adverse events amounting to the stoppage of therapy. Conclusion Non-response to atezolizumab and bevacizumab immunotherapy was predicted by CRP>1 mg/dl, PIVKA-II>400mAU/ml, AFP>100 ng/ml and the presence of diabetes.
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Affiliation(s)
- Satender P. Singh
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Karan Kumar
- Department of Hepatology and Liver Transplant, Mahatma Gandhi Hospital, Jaipur, India
| | - Anand Kulkarni
- Department of Hepatology and Liver Transplant, Asian Institute of Gastroenterology, Hyderabad, India
| | - Vinod Arora
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Ashok Choudhury
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Alisha Chaubal
- Department of Hepatology and Liver Intensive Care, Global Hospitals, Mumbai, India
| | - Sahaj Rathi
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Samir Shah
- Department of Hepatology and Liver Intensive Care, Global Hospitals, Mumbai, India
| | - Sunil Taneja
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashish Kumar
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital, New Delhi, India
| | - Ajay Duseja
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Guresh Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - P. Nagaraja Rao
- Department of Hepatology and Liver Transplant, Asian Institute of Gastroenterology, Hyderabad, India
| | - Vivek Saraswat
- Department of Hepatology and Liver Transplant, Mahatma Gandhi Hospital, Jaipur, India
| | - Shiv K. Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
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Pettas T, Lachanoudi S, Karageorgos FF, Ziogas IA, Fylaktou A, Papalois V, Katsanos G, Antoniadis N, Tsoulfas G. Immunotherapy and liver transplantation for hepatocellular carcinoma: Current and future challenges. World J Transplant 2025; 15:98509. [DOI: 10.5500/wjt.v15.i2.98509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 10/03/2024] [Accepted: 11/07/2024] [Indexed: 02/21/2025] Open
Abstract
Despite existing curative options like surgical removal, tissue destruction techniques, and liver transplantation for early-stage hepatocellular carcinoma (HCC), the rising incidence and mortality rates of this global health burden necessitate continuous exploration of novel therapeutic strategies. This review critically assesses the dynamic treatment panorama for HCC, focusing specifically on the burgeoning role of immunotherapy in two key contexts: early-stage HCC and downstaging advanced HCC to facilitate liver transplant candidacy. It delves into the unique immunobiology of the liver and HCC, highlighting tumor-mediated immune evasion mechanisms. Analyzing the diverse immunotherapeutic approaches including checkpoint inhibitors, cytokine modulators, vaccines, oncolytic viruses, antigen-targeting antibodies, and adoptive cell therapy, this review acknowledges the limitations of current diagnostic markers alpha-fetoprotein and glypican-3 and emphasizes the need for novel biomarkers for patient selection and treatment monitoring. Exploring the rationale for neoadjuvant and adjuvant immunotherapy in early-stage HCC, current research is actively exploring the safety and effectiveness of diverse immunotherapeutic approaches through ongoing clinical trials. The review further explores the potential benefits and challenges of combining immunotherapy and liver transplant, highlighting the need for careful patient selection, meticulous monitoring, and novel strategies to mitigate post-transplant complications. Finally, this review delves into the latest findings from the clinical research landscape and future directions in HCC management, paving the way for optimizing treatment strategies and improving long-term survival rates for patients with this challenging malignancy.
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Affiliation(s)
- Theodoros Pettas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Sofia Lachanoudi
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Filippos F Karageorgos
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Ioannis A Ziogas
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Asimina Fylaktou
- Department of Immunology, National Peripheral Histocompatibility Center, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Vassilios Papalois
- Department of Transplant Surgery, Imperial College Renal and Transplant Centre, London W12 0HS, United Kingdom
| | - Georgios Katsanos
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
| | - Nikolaos Antoniadis
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Georgios Tsoulfas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
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Zhang D, Zhu Y, Shen Z, Ma S, Liu S, Lu Z. Immunosenescence and immunotherapy in elderly patients with hepatocellular carcinoma. Semin Cancer Biol 2025; 111:60-75. [PMID: 40020977 DOI: 10.1016/j.semcancer.2025.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 02/11/2025] [Accepted: 02/17/2025] [Indexed: 03/03/2025]
Abstract
Liver cancer, more specifically hepatocellular carcinoma (HCC), is a global health issue and one of the dominant causes of cancer death around the world. In the past few decades, remarkable advances have been achieved in the systemic therapy of HCC. Immune checkpoint inhibitors (ICIs) have become a therapy mainstay for advanced HCC and have shown promise in the neoadjuvant therapy before resection. Despite these significant advancements, the compositions and functions of the immune system occur various alterations with age, called "immunosenescence", which may affect the antitumor effects and safety of ICIs, thus raising concerns that immunosenescence may impair elderly patients' response to ICIs. Therefore, it is important to learn more about the immunosenescence characteristics of elderly patients. However, the real-world elderly HCC patients may be not accurately represented by the elderly patients included in the clinical trials, affecting the generalizability of the efficacy and safety profiles from the clinical trials to the real-world elderly patients. This review summarizes the characteristics of immunosenescence and its influence on HCC progression and immunotherapy efficacy as well as provides the latest progress in ICIs available for HCC and discusses their treatment efficacy and safety on elderly patients. In the future, more studies are needed to clarify the mechanisms of immunosenescence in HCC, and to find sensitive screening tools or biomarkers to identify the patients who may benefit from ICIs.
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Affiliation(s)
- Dengyong Zhang
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China
| | - Yan Zhu
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zhengchao Shen
- Department of General Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241001, China
| | - Shuoshuo Ma
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China
| | - Sihua Liu
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China
| | - Zheng Lu
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China.
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He M, Xie W, Yuan Z, Chen J, Wang J, Fu Y, Hu Z, Meng Q, Gao W, Hu D, Zhang Y, Pan Y, Zhou Z. Comparing PD-L1 and PD-1 inhibitors plus bevacizumab combined with hepatic arterial interventional therapies in unresetable hepatocellular carcinoma: A single-center, real-world study. Int J Cancer 2025; 156:1972-1985. [PMID: 39834172 DOI: 10.1002/ijc.35341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 12/18/2024] [Accepted: 01/02/2025] [Indexed: 01/22/2025]
Abstract
With the rise of anti-vascular endothelial growth factor antibody and programmed cell death-ligand 1 (PD-L1) regimens, particularly bevacizumab and atezolizumab, as first-line treatments for advanced hepatocellular carcinoma (HCC), there is a need to explore PD-L1 and programmed cell death 1 inhibitors in combination therapies for unresectable HCC (uHCC). Integrating systemic therapies with locoregional approaches is also emerging as a potent strategy. This study compares the outcomes of atezolizumab (PD-L1 inhibitor) and sintilimab (programmed cell death 1 inhibitor) with bevacizumab or its biosimilar, combined with hepatic arterial interventional therapies (HAIT) in uHCC patients. From January 2020 to September 2023, a retrospective analysis was conducted on 138 uHCC patients at Sun Yat-sen University Cancer Center. The cohort included 69 patients treated with atezolizumab with bevacizumab (Bev/Ate) and 69 with bevacizumab biosimilar with sintilimab (Bio/Sin), combined with HAIT. The propensity score matching was also employed to further explore the efficacy and safety. The median progression-free survival (mPFS) was 13.8 months for the Bev/Ate group and 10.0 months for the Bio/Sin group (p = 0.188). The Bev/Ate group showed significantly longer intrahepatic mPFS (HR 0.381; 95% confidence interval 0.176-0.824; p = .018) and higher overall response rates compared with the Bio/Sin group (60.87% vs. 31.88%, p = .001; 69.57% vs. 49.28%, p = .024) based on Response Evaluation Criteria in Solid Tumors v1.1 and modified Response Evaluation Criteria in Solid Tumors criteria. Treatment-related adverse events were similar between groups (p > .050). Combining atezolizumab or sintilimab with bevacizumab or its biosimilar alongside HAIT provided similar overall PFS in uHCC patients. However, the atezolizumab-bevacizumab combination with HAIT showed superior intrahepatic PFS and control rates, warranting further validation.
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Affiliation(s)
- Minrui He
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Wa Xie
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Imaging Diagnostic and Interventional Center, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Ze Yuan
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Neurosurgery/NeuroOncology, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Jinbin Chen
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Juncheng Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Yizhen Fu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Zili Hu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Qi Meng
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Clinical Research, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Wenqing Gao
- Department of Oncology, Tengchong People's Hospital, Baoshan, PR China
| | - Dandan Hu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Yaojun Zhang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Yangxun Pan
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Zhongguo Zhou
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
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Qiang N, Ao J, Nakamura M, Katayama K, Zhang J, Kogure T, Ogawa K, Kanzaki H, Kojima R, Koroki K, Kobayashi K, Inoue M, Kanogawa N, Kiyono S, Nakagawa R, Kondo T, Ogasawara S, Nakamoto S, Muroyama R, Kato J, Kato N. MEGF6 knockdown ameliorates lenvatinib-induced muscle differentiation suppression and enhances the antitumor effect of lenvatinib on hepatocellular carcinoma. Biochem Pharmacol 2025; 235:116829. [PMID: 40015652 DOI: 10.1016/j.bcp.2025.116829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 01/12/2025] [Accepted: 02/24/2025] [Indexed: 03/01/2025]
Abstract
Lenvatinib (LEN)-treated patients with hepatocellular carcinoma (HCC) are frequently accompanied by skeletal muscle loss, which is correlated with poor prognosis. Interactions between tumor and skeletal muscle may play a role in patient prognosis and tumor progression. We here demonstrated that LEN hindered proliferation and differentiation of the mouse myoblast cell line, C2C12 cells, by blocking the ERK1/2 and AKT signaling pathways. Transcriptome analysis revealed that multiple EGF-like domains 6 (Megf6) was upregulated in LEN-treated C2C12 cells. Furthermore, we observed that compared with normal adjacent tissues, MEGF6 was highly expressed in HCC tumor tissues according to the TCGA database, which suggested MEGF6-mediated interaction between tumor and skeletal muscle. The Megf6 knockdown restored the differentiation inhibition caused by LEN and ERK1/2 inhibitors; however, it had no significant impact on proliferation. Regarding mechanism, LEN increased Megf6 expression through the ERK1/2 signaling pathway, thereby resulting in myostatin expression elevation and myosin heavy chain protein expression repression. Furthermore, MEGF6 in LEN-treated C2C12 cell medium promoted tumor cell proliferation and impaired C2C12 cell differentiation when cultured with LEN-treated tumor cell medium. Clinically, patients who were accompanied by muscle mass loss and increased MEGF6 serum levels had shorter progression-free survival than those who were accompanied by muscle mass loss but no increased MEGF6 serum levels before and after LEN treatment. In conclusion, MEGF6 produced from muscle and tumor cells could impair muscle differentiation and enhance tumor proliferation. Therefore, MEGF6 is worth further investigating as a target for improving the prognosis of LEN-treated patients with HCC.
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Affiliation(s)
- Na Qiang
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China; Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Junjie Ao
- Cancer Center, Department of Gastroenterology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China; Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Keichi Katayama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Jiaqi Zhang
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tadayoshi Kogure
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Keita Ogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroaki Kanzaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan; Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ryuta Kojima
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Keisuke Koroki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kazufumi Kobayashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masanori Inoue
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kanogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Soichiro Kiyono
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ryo Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takayuki Kondo
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ryosuke Muroyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kato
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
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8
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Wang J, Chen Q, Shan Q, Liang T, Forde P, Zheng L. Clinical development of immuno-oncology therapeutics. Cancer Lett 2025; 617:217616. [PMID: 40054657 PMCID: PMC11930610 DOI: 10.1016/j.canlet.2025.217616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 03/03/2025] [Accepted: 03/05/2025] [Indexed: 03/15/2025]
Abstract
Immuno-oncology (IO) is one of the fastest growing therapeutic areas within oncology. IO agents work indirectly via the host's adaptive and innate immune system to recognize and eradicate tumor cells. Despite checkpoint inhibitors being only introduced to the market since 2011, they have become the second most approved product category. Current Food and Drug Administration (FDA)-approved classes of IO agents include: immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapy (CAR-T), bi-specific T-cell engager (BiTE) antibody therapy, T-cell receptor (TCR) engineered T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, cytokine therapy, cancer vaccine therapy, and oncolytic virus therapy. Cancer immunotherapy has made progress in multiple cancer types including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma; however, several cancers remain refractory to immunotherapy. Future directions of IO include exploration in the neoadjuvant/perioperative setting, combination strategies, and optimizing patient selection through improved biomarkers.
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Affiliation(s)
- Jianxin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Qi Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Qiang Shan
- Department of General Surgery, Haining People's Hospital, Haining, 314400, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Patrick Forde
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Mays Cancer Center at the University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Lei Zheng
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Mays Cancer Center at the University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
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Zhang X, Zhang X, Luo QK, Fu Q, Liu P, Pan CJ, Liu CJ, Zhang HW, Qin T. Pretreatment radiomic imaging features combined with immunological indicators to predict targeted combination immunotherapy response in advanced hepatocellular carcinoma. World J Clin Oncol 2025; 16:102735. [DOI: 10.5306/wjco.v16.i4.102735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 12/16/2024] [Accepted: 01/23/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Early symptoms of hepatocellular carcinoma (HCC) are not obvious, and more than 70% of which does not receive radical hepatectomy, when first diagnosed. In recent years, molecular-targeted drugs combined with immunotherapy and other therapeutic methods have provided new treatment options for middle and advanced HCC (aHCC). Predicting the effect of targeted combined immunotherapy has become a hot topic in current research.
AIM To explore the relationship between nodule enhancement in hepatobiliary phase and the efficacy of combined targeted immunotherapy for aHCC.
METHODS Data from 56 patients with aHCC for magnetic resonance imaging with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid were retrospectively collected. Signal intensity of intrahepatic nodules was measured, and the hepatobiliary relative enhancement ratio (RER) was calculated. Progression-free survival (PFS) of patients with high and low reinforcement of HCC nodules was compared. The model was validated using receiver operating characteristic curves. Univariate and multivariate logistic regression and Kaplan-Meier analysis were performed to explore factors influencing the efficacy of targeted immunization and PFS.
RESULTS Univariate and multivariate analyses revealed that the RER, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index were significantly associated with the efficacy of tyrosine kinase inhibitors combined with immunotherapy (P < 0.05). The area under the curve of the RER for predicting the efficacy of tyrosine kinase inhibitors combined with anti-programmed death 1 antibody in patients with aHCC was 0.876 (95% confidence interval: 0.781-0.971, P < 0.05), the optimal cutoff value was 0.904, diagnostic sensitivity was 87.5%, and specificity was 79.2%. Kaplan-Meier analysis showed that neutrophil-to-lymphocyte ratio < 5, platelet-to-lymphocyte ratio < 300, prognostic nutritional index < 45, and RER < 0.9 significantly improved PFS.
CONCLUSION AHCC nodules enhancement in the hepatobiliary stage was significantly correlated with PFS. Imaging information and immunological indicators had high predictive efficacy for targeted combined immunotherapy and were associated with PFS.
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Affiliation(s)
- Xu Zhang
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Xu Zhang
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Qian-Kun Luo
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Qiang Fu
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Pan Liu
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Chang-Jie Pan
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Chuan-Jiang Liu
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Hong-Wei Zhang
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Tao Qin
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
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Wang J, Liu ZX, Huang ZH, Wen J, Rao ZZ. Long non-coding RNA in the regulation of cell death in hepatocellular carcinoma. World J Clin Oncol 2025; 16:104061. [DOI: 10.5306/wjco.v16.i4.104061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 02/02/2025] [Accepted: 02/25/2025] [Indexed: 03/26/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer, accounting for 90% of all cases. Currently, early diagnosis of HCC can be achieved through serum alpha-fetoprotein detection, B-ultrasound, and computed tomography scanning; however, their specificity and sensitivity are suboptimal. Despite significant advancements in HCC biomarker detection, the prognosis for patients with HCC remains unfavorable due to tumor heterogeneity and limited understanding of its pathogenesis. Therefore, it is crucial to explore more sensitive HCC biomarkers for improved diagnosis, monitoring, and management of the disease. Long non-coding RNA (lncRNA) serves as an auxiliary carrier of genetic information and also plays diverse intricate regulatory roles that greatly contribute to genome complexity. Moreover, investigating gene expression regulation networks from the perspective of lncRNA may provide insights into the diagnosis and prognosis of HCC. We searched the PubMed database for literature, comprehensively classified regulated cell death mechanisms and systematically reviewed research progress on lncRNA-mediated cell death pathways in HCC cells. Furthermore, we prospectively summarize its potential implications in diagnosing and treating HCC.
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Affiliation(s)
- Jiang Wang
- Children Medical Center, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Zi-Xuan Liu
- Children Medical Center, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Zhi-Hong Huang
- Children Medical Center, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Jie Wen
- Department of Pediatric Orthopedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Zhou-Zhou Rao
- Department of Physiology, Hunan Normal University School of Medicine, Changsha 410003, Hunan Province, China
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Gao LL, Gao DN, Yuan HT, Chen WQ, Yang J, Peng JQ. Combining anti-PD-1 antibodies with surufatinib for gastrointestinal neuroendocrine carcinoma: Two cases report and review of literature. World J Clin Oncol 2025; 16:102297. [DOI: 10.5306/wjco.v16.i4.102297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/20/2024] [Accepted: 02/27/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Gastrointestinal neuroendocrine carcinoma (GI NEC) has a low incidence rate and poor prognosis. Most patients already have metastatic disease when they are diagnosed. Platinum chemotherapy is the main means of treating metastatic GI NECs. There is a lack of effective treatment methods after chemotherapy failure. Therefore, Therefore, selecting appropriate posterior-line treatment programs to improve the prognosis of patients is urgently needed.
CASE SUMMARY A 64-year-old female was diagnosed with stage IV NEC of the rectum due to abdominal pain and rectal bleeding. After multiline chemotherapy, the condition progressed, and the patient was treated with a combination of camrelizumab and surufatinib. The efficacy evaluation revealed partial remission (PR) and stable conditions, with the expression of the tumor marker neuron-specific enolase (NSE) returning to normal. The adverse reactions were controllable, and the overall condition was good, with weight gain achieved in the past four years. Another 51-year-old female experienced recurrence and metastasis of a duodenal NEC after surgery. After multiline chemotherapy, she received sintilimab combined with surufatinib. The curative effect fluctuated between PR and stability. During treatment, she recovered from immune-related diabetes and later died due to deterioration of her condition. During the treatment, the patient’s NSE level returned to normal.
CONCLUSION The combination of antiangiogenic targeted drugs and immunotherapy provides a new therapeutic approach for the treatment of metastatic GI-NECs.
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Affiliation(s)
- Lou-Lu Gao
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Dong-Ni Gao
- Department of Oncology, Shandong Public Health Clinical Center, Jinan 250100, Shandong Province, China
| | - Hong-Tu Yuan
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China
| | - Wen-Qiang Chen
- Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Jing Yang
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China
| | - Jie-Qiong Peng
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China
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12
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Liang LW, Luo RH, Huang ZL, Tang LN. Clinical observation of nivolumab combined with cabozantinib in the treatment of advanced hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:103631. [DOI: 10.4251/wjgo.v17.i4.103631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/25/2024] [Accepted: 02/07/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a particularly serious kind of liver cancer. Liver cancer ranks third in terms of mortality rate worldwide, putting it among the leading causes of deaths from cancer. HCC is the primary kind of liver cancer and makes up the vast majority of cases, accounting for approximately 90% of occurrences. Numerous research have verified this information. the progress of fatty liver, alcohol induced cirrhosis, smoking habits, obesity caused by overweight, and metabolic diseases such as diabetes. The treatment strategies for HCC can be divided into two categories: One is curative treatment, including liver transplantation, surgical resection, and ablation therapy or selective arterial radiation embolization, aimed at completely eliminating the lesion; Another type is non curative treatment options, including transarterial chemoembolization and systemic therapy, which focus on controlling disease progression and prolonging patient survival. The majority of HCC patients are found to be in an advanced stage and need systemic therapy. Sorafenib and lenvatinib are frequently used as first-line medications in traditional HCC treatment to slow the disease's progression. For second-line treatment, regorafenib, cabozantinib, or remdesizumab are used to inhibit tumors through different mechanisms and prolong survival. In recent years, with the in-depth exploration of the pathogenesis and progression mechanism of HCC, as well as the rapid progress within the domain of tumor immunotherapy, the treatment prospects for advanced HCC patients have shown a positive transformation. This transformation is reflected in the fact that more and more patients are gradually gaining significant and considerable therapeutic advantages from advanced immunotherapy regimens, bringing unprecedented improvements to their treatment outcomes. In order to enable activated T cells to attack tumor cells, immune checkpoint inhibitors interfere with the inhibitory.
AIM To evaluate the effects of nivolumab in combination with cabozantinib on patient tumor markers and immune function, as well as the therapeutic efficacy of this combination in treating advanced HCC, a study was conducted.
METHODS In all, 100 patients with advanced HCC who were brought to our hospital between July 2022 and July 2023 and who did not match the requirements for surgical resection had their clinical data thoroughly analyzed retrospectively in this study. Among them, half of the patients (50 cases) only received oral cabozantinib as a single treatment regimen (set as the control group), while the other half of the patients (50 cases) received intravenous infusion of nivolumab in addition to oral cabozantinib (set as the observation group). The objective of the probe is to examine the variations in disease control rate (DCR) and objective response rate (ORR) between two groups; At the same time, changes in the levels of T lymphocyte subsets (CD3+, CD4+, CD8+) and tumor markers, including AFP, GP-73, and AFP-L3, were evaluated; In addition, changes in liver and kidney function indicators and adverse reactions during treatment were also monitored. For patients with advanced HCC, this research also calculated and analyzed the progression free survival of two patient groups throughout the course of a 12-month follow-up to assess the effectiveness and safety of this therapeutic approach.
RESULTS Upon comparing baseline information for both groups of subjects before treatment, it was found that no statistically significant alterations had occurred (P > 0.05). After the therapeutic intervention, the observation group and control group's ORR and DCR differed statistically significantly (P < 0.05). The observation group's scores significantly improved. Subsequent examination revealed that the observation group's T lymphocyte subset levels had significantly changed, mostly exhibiting an increase in CD3+, CD4+, and CD4+/CD8+ levels while CD8+ levels had comparatively dropped. There was a significant difference (P < 0.05) between these changes and those in the control group. The observation group also showed positive improvements in tumor markers; AFP, GP-73, and AFP-L3 levels were considerably lower in the group under observation than in the control group, with statistically significant differences (P < 0.05). When liver function was assessed, total bilirubin and alanine aminotransferase were found to be considerably lower in the observation group than in the control group (P < 0.05). The incidence of adverse responses was not statistically significant (P > 0.05), indicating that the incidence of adverse responses did not differ significantly between the two groups.
CONCLUSION When treating advanced HCC, nivolumab and cabozantinib together have the ability to increase T lymphocyte numbers, reduce tumor marker levels, effectively prolong survival time, and have better efficacy than simple control treatment, with good safety.
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Affiliation(s)
- Lu-Wen Liang
- Infection and Liver Disease Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400000, China
| | - Rong-Hong Luo
- Department of Infectious Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Zhi-Li Huang
- Department of Infectious Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Li-Na Tang
- Department of Infectious Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
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Huang M, Song C, Zhou X, Wang H, Lin Y, Wang J, Cai H, Wang M, Peng Z, Dong Z, Feng S. Tissue-matched analysis of MRI evaluating the tumor infiltrating lymphocytes in hepatocellular carcinoma. Int J Cancer 2025; 156:1634-1643. [PMID: 39635936 PMCID: PMC11826122 DOI: 10.1002/ijc.35281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 10/14/2024] [Accepted: 10/31/2024] [Indexed: 12/07/2024]
Abstract
Tumor-infiltrating lymphocytes (TILs) play critical roles in the tumor microenvironment and immunotherapy response. This study aims to explore the feasibility of multi-parametric magnetic resonance imaging (MRI) in evaluating TILs and to develop an evaluation model that considers spatial heterogeneity. Multi-parametric MRI was performed on hepatocellular carcinoma (HCC) mice (N = 28). Three-dimensional (3D) printing was employed for tissue sampling, to match the multi-parametric MRI data with tumor tissues, followed by flow cytometry analysis and next-generation RNA-sequencing. Pearson's correlation, multivariate logistic regression, and receiver operating characteristic (ROC) curve analyses were utilized to model TIL-related MRI parameters. MRI quantitative parameters, including T1 relaxation times and perfusion, were correlated with the infiltration of leukocytes, T-cells, CD4+ T-cells, CD8+ T-cells, PD1 + CD8+ T-cells, B-cells, macrophages, and regulatory T-cells (correlation coefficients ranged from -0.656 to 0.482, p <.05) in tumor tissues. TILs were clustered into inflamed and non-inflamed subclasses, with the proportion of T-cells, CD8+ T-cells, and PD1 + CD8+ T-cells significantly higher in the inflamed group compared to the non-inflamed group (43.37% vs. 25.45%, 50.83% vs. 34.90%, 40.45% vs. 29.47%, respectively; p <.001). The TIL evaluation model, based on the Z-score combining Kep and T1post, was able to distinguish between these subgroups, yielding an area under the curve of 0.816 (95% confidence interval 0.721-0.910) and a cut-off value of -0.03 (sensitivity 68.4%, specificity 91.3%). Additionally, the Z-score was related to the gene expression of T-cell activation, chemokine production, and cell adhesion. The tissue-matched analysis of multi-parametric MRI offers a feasible method of regional evaluation and can distinguish between TIL subclasses.
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Affiliation(s)
- Mengqi Huang
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Department of Radiology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Chenyu Song
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Xiaoqi Zhou
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Huanjun Wang
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Yingyu Lin
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Jifei Wang
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Huasong Cai
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Meng Wang
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Zhenpeng Peng
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Zhi Dong
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Shi‐Ting Feng
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
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Park K, Lee HW, Kim E, Choi WM, Lee D, Shim JH, Kim KM, Lim YS, Lee HC, Yoo C, Ryoo BY, Han S, Choi J. Risk of Variceal Bleeding in Patients Receiving Atezolizumab-Bevacizumab Treatment for Hepatocellular Carcinoma. Aliment Pharmacol Ther 2025; 61:1310-1317. [PMID: 39871662 DOI: 10.1111/apt.18526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 11/15/2024] [Accepted: 01/18/2025] [Indexed: 01/29/2025]
Abstract
BACKGROUND AND AIMS Real-world data on the variceal bleeding (VB) risk in patients receiving atezolizumab-bevacizumab (Atezo-Bev) treatment remain limited. This study aimed to assess the risk of VB and identify risk factors in patients with advanced hepatocellular carcinoma (HCC) receiving Atezo-Bev treatment. METHODS This retrospective study included 640 patients with HCC who underwent endoscopy before Atezo-Bev treatment at two hospitals in Korea. The primary outcome was the occurrence of VB, with non-VB events considered as competing events. RESULTS Of the 640 patients, the mean age was 61.3 years, and 528 (82.5%) patients were male. The main aetiology of HCC was chronic hepatitis B virus (69.5%), and 563 (88.0%) had BCLC stage C. Portal vein invasion (PVI) was present in 313 (48.9%). During a median follow-up of 5.6 months, 45 (7.0%) patients developed VB. The cumulative incidence of VB was 6.3% at 6 months and 7.4% at 12 months. No patient died from VB. Multivariable analysis revealed that the main PVI (subdistribution hazard ratio [SHR]: 3.49, 95% confidence interval [CI]: 1.63-7.44), low platelet count (SHR: 0.994, 95% CI: 0.99-1.00), a history of gastrointestinal (GI) bleeding (SHR: 3.70, 95% CI: 1.49-9.16) and varices needing treatment (VNT; SHR: 2.67, 95% CI: 1.26-5.64) increased the risk of VB. CONCLUSION A low platelet count, main PVI, history of GI bleeding and VNT were significant risk factors for VB in patients receiving Atezo-Bev treatment for HCC. Identifying these factors can guide clinicians in assessing and managing VB risk in clinical settings.
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Affiliation(s)
- Kanghee Park
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Euichang Kim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Won-Mook Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Danbi Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ju Hyun Shim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Han Chu Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Baek-Yeol Ryoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seungbong Han
- Department of Biostatistics, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jonggi Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Tomooka F, Kitagawa K, Mitoro A, Fujinaga Y, Nishimura N, Namisaki T, Akahane T, Kaji K, Asada S, Sato S, Hanatani J, Mori H, Motokawa Y, Iwata T, Kachi H, Osaki Y, Yoshiji H. Unilateral drainage and chemotherapy prolong the patency of a plastic stent placed above the sphincter of Oddi in patients with malignant hilar biliary obstruction. DEN OPEN 2025; 5:e404. [PMID: 39011511 PMCID: PMC11248713 DOI: 10.1002/deo2.404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 06/17/2024] [Accepted: 06/24/2024] [Indexed: 07/17/2024]
Abstract
Objectives To evaluate the results of inside stent therapy for unresectable malignant hilar biliary obstruction and identify factors related to stent patency duration. Methods Of 44 patients who underwent initial inside-stent placement above the sphincter of Oddi from April 2017 to December 2022, 42 with the resolution of jaundice (clinical success rate, 95.5%) were retrospectively analyzed. Univariate and multivariate logistic regression analysis identified factors associated with stent patency duration. Results Univariate analysis revealed significant differences in the drainage method (406 days for unilateral drainage vs. 305 days for bilateral drainage of the right and left liver lobes, p = 0.022) with or without chemotherapy (406 days with vs. 154 days without, p = 0.038). Multivariate analysis (Cox proportional hazards analysis) revealed similar results, with unilateral drainage (p = 0.031) and chemotherapy (p = 0.048) identified as independent factors associated with prolonged stent patency. Early adverse events were observed in two patients (4.8%; one cholangitis, one pancreatitis). Conclusions Inside-stent therapy was safely performed in patients with malignant hilar biliary obstruction. Simple unilateral drainage and chemotherapy may prolong stent patency.
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Affiliation(s)
| | - Koh Kitagawa
- Department of GastroenterologyNara Medical UniversityNaraJapan
| | - Akira Mitoro
- Division of EndoscopyNara Medical UniversityNaraJapan
| | | | | | | | - Takemi Akahane
- Department of GastroenterologyNara Medical UniversityNaraJapan
| | - Kosuke Kaji
- Department of GastroenterologyNara Medical UniversityNaraJapan
| | - Shohei Asada
- Department of GastroenterologyNara Medical UniversityNaraJapan
| | - Shinya Sato
- Department of GastroenterologyNara Medical UniversityNaraJapan
| | | | - Hitoshi Mori
- Department of GastroenterologyNara Medical UniversityNaraJapan
| | - Yuki Motokawa
- Department of GastroenterologyNara Medical UniversityNaraJapan
| | - Tomihiro Iwata
- Department of GastroenterologyNara Medical UniversityNaraJapan
| | - Hiroki Kachi
- Department of GastroenterologyNara Medical UniversityNaraJapan
| | - Yui Osaki
- Department of GastroenterologyNara Medical UniversityNaraJapan
| | - Hitoshi Yoshiji
- Department of GastroenterologyNara Medical UniversityNaraJapan
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Magyar CTJ, Rajendran L, Li Z, Banz V, Vogel A, O'Kane GM, Chan ACY, Sapisochin G. Precision surgery for hepatocellular carcinoma. Lancet Gastroenterol Hepatol 2025; 10:350-368. [PMID: 39993401 DOI: 10.1016/s2468-1253(24)00434-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 12/12/2024] [Accepted: 12/17/2024] [Indexed: 02/26/2025]
Abstract
Hepatocellular carcinoma arises in the setting of cirrhosis in most cases, requiring multidisciplinary input to define resectability. In this regard, more precise surgical management considers patient factors and anatomical states, including resection margins, tumour biology, and perioperative therapy. Together with advances in surgical techniques, this integrated approach has resulted in considerable improvements in patient morbidity and oncological outcomes. Despite this, recurrence rates in hepatocellular carcinoma remain high. As the systemic treatment landscape in hepatocellular carcinoma continues to evolve and locoregional options are increasingly used, we review current and future opportunities to individualise the surgical management of patients with hepatocellular carcinoma.
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Affiliation(s)
- Christian Tibor Josef Magyar
- HPB Surgical Oncology, University Health Network, Toronto, ON, Canada; Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada; Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Luckshi Rajendran
- HPB Surgical Oncology, University Health Network, Toronto, ON, Canada; Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada; Division of Transplant Surgery, Henry Ford Hospital, Detroit, MI, USA
| | - Zhihao Li
- HPB Surgical Oncology, University Health Network, Toronto, ON, Canada; Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Vanessa Banz
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Arndt Vogel
- Medical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada; Division of Gastroenterology and Hepatology, Toronto General Hospital, Toronto, ON, Canada; Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Grainne Mary O'Kane
- Medical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada; Department of Medicine Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; St Vincent's University Hospital and School of Medicine, University College Dublin, Dublin, Ireland
| | - Albert Chi-Yan Chan
- Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Gonzalo Sapisochin
- HPB Surgical Oncology, University Health Network, Toronto, ON, Canada; Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada.
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Yang X, Deng B, Zhao W, Guo Y, Wan Y, Wu Z, Su S, Gu J, Hu X, Feng W, Hu C, Li J, Xu Y, Huang X, Lin Y. FABP5 + lipid-loaded macrophages process tumour-derived unsaturated fatty acid signal to suppress T-cell antitumour immunity. J Hepatol 2025; 82:676-689. [PMID: 39357545 DOI: 10.1016/j.jhep.2024.09.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 09/12/2024] [Accepted: 09/20/2024] [Indexed: 10/04/2024]
Abstract
BACKGROUND & AIMS Tumour-associated macrophages (TAMs) contribute to hepatocellular carcinoma (HCC) progression. However, while the pro-tumour and immunosuppressive roles of lipid-loaded macrophages are well established, the mechanisms by which lipid metabolism enhances the tumour-promoting effects of TAMs remain unclear. METHODS Single-cell RNA sequencing was performed on mouse and human HCC tumour samples to elucidate the landscape of HCC TAMs. Macrophages were stimulated with various long-chain unsaturated fatty acids (UFAs) to assess immunosuppressive molecule expression in vitro. Additionally, in vivo and in vitro studies were conducted using mice with macrophage-specific deficiencies in fatty acid-binding protein 5 (FABP5) or peroxisome proliferator-activated receptor γ (PPARγ). RESULTS Single-cell RNA sequencing identified a subpopulation of FABP5+ lipid-loaded TAMs characterized by enhanced immune checkpoint blocker ligands and immunosuppressive molecules in an oncogene-mutant HCC mouse model and human HCC tumours. Mechanistically, long-chain UFAs released by tumour cells activate PPARγ via FABP5, resulting in immunosuppressive properties in TAMs. FABP5 deficiency in macrophages decreases immunosuppressive molecule expression, enhances T cell-dependent antitumour immunity, diminishes HCC growth, and improves immunotherapy efficacy. CONCLUSIONS This study demonstrates that UFAs promote tumourigenesis by enhancing the immunosuppressive tumour microenvironment via FABP5-PPARγ signalling and provides a proof-of-concept for targeting this pathway to improve the efficacy of tumour immunotherapy. IMPACT AND IMPLICATIONS Despite the role of tumour-associated macrophages (TAMs) in promoting tumour progression being well established, the mechanisms by which lipid metabolism enhances the tumour-promoting effects of TAMs remain unclear. Our study reveals that FABP5-mediated unsaturated fatty acid metabolism in TAMs is crucial for modulating antitumour T-cell immunity and influencing the efficacy of immunotherapy. This finding provides novel insights into the immunomodulatory roles of FABP5+ lipid-loaded TAMs in hepatocellular carcinoma and suggests that targeting FABP5 could offer a new approach to liver cancer treatment.
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Affiliation(s)
- Xuguang Yang
- Clinical Research Center, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China; Department of Immunology of Basic Medical Sciences; Shanghai Pudong Hospital, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - Bo Deng
- Division of Nephrology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Weiwei Zhao
- Department of Integrated Therapy, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yangyang Guo
- Department of Immunology of Basic Medical Sciences; Shanghai Pudong Hospital, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yaqi Wan
- Department of Immunology of Basic Medical Sciences; Shanghai Pudong Hospital, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Zhihao Wu
- Clinical Research Center, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Sheng Su
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jingyan Gu
- Department of Neurosurgery, Shanghai General Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Xiaoqian Hu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200032, China
| | - Wenxue Feng
- Department of Immunology of Basic Medical Sciences; Shanghai Pudong Hospital, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Chencheng Hu
- Frontier Innovation Center, Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Pathology of School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Jia Li
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yanyong Xu
- Frontier Innovation Center, Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Pathology of School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Xiaowu Huang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Clinical Center for Biotherapy, Zhongshan Hospital (Xiamen), Fudan University, Shanghai, 200032, China.
| | - Yuli Lin
- Department of Immunology of Basic Medical Sciences; Shanghai Pudong Hospital, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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18
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Zhang WC, Du KY, Yu SF, Guo XE, Yu HX, Wu DY, Pan C, Zhang C, Wu J, Bian LF, Cao LP, Yu J. Systemic chemotherapy improves outcome of hepatocellular carcinoma patients treated with transarterial chemoembolization. Hepatobiliary Pancreat Dis Int 2025; 24:157-163. [PMID: 39632156 DOI: 10.1016/j.hbpd.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 11/13/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND Transarterial chemoembolization (TACE) based neoadjuvant therapy was proven effective in hepatocellular carcinoma (HCC). Recently, tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) also showed promise in HCC treatment. However, the prognostic benefits associated with these treatments remain uncertain. This study aimed to explore the relationship between pathologic response and prognostic features in HCC patients who received neoadjuvant therapy. METHODS HCC patients who received TACE either with or without TKIs/ICIs as neoadjuvant therapy before liver resection were retrospectively collected from the First Affiliated Hospital, Zhejiang University School of Medicine in China. Pathologic response was determined by calculating the proportion of non-viable area within the tumor. Major pathologic response (MPR) was defined as the presence of non-viable tumor cells reaching a minimum of 90%. Complete pathologic response (CPR) was characterized by the absence of viable cells observed in the tumor. RESULTS A total of 481 patients meeting the inclusion criteria were enrolled, with 76 patients (15.8%) achieving CPR and 179 (37.2%) reaching MPR. The median recurrence-free survival (mRFS) in the CPR + MPR group was significantly higher than the non-MPR group (31.3 vs. 25.1 months). The difference in 3-year overall survival (OS) rate was not significant. Multivariate Cox regression analysis identified failure to achieve MPR (hazard ratio = 1.548, 95% confidence interval: 1.122-2.134; P = 0.008), HBsAg positivity (HR = 1.818, 95% CI: 1.062-3.115, P = 0.030), multiple lesions (HR = 2.278, 95% CI: 1.621-3.195, P < 0.001), and baseline tumor size > 5 cm (HR = 1.712, 95% CI: 1.031-2.849, P = 0.038) were independent risk factors for RFS. Subgroup analysis showed that 67 of 93 (72.0%) patients who received the combination of TACE, TKIs, and ICIs achieved MPR + CPR. CONCLUSIONS In individuals who received TACE-based neoadjuvant therapy for HCC, failure to achieve MPR emerges as an independent risk factor for RFS. Notably, the combination of TACE, TKIs, and ICIs demonstrated the highest rate of MPR.
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Affiliation(s)
- Wei-Chen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Ke-Yi Du
- Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Song-Feng Yu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xue-E Guo
- Department of Nursing, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Han-Xi Yu
- International Institutes of Medicine, Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, China
| | - Dong-Yan Wu
- Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Cheng Pan
- The 903rd Hospital of PLA, Hangzhou 310000, China
| | - Cheng Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jian Wu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Li-Fang Bian
- Department of Nursing, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Lin-Ping Cao
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jun Yu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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Hashimoto K, Nishimura S, Goto K. PD‑1/PD‑L1 immune checkpoint in bone and soft tissue tumors (Review). Mol Clin Oncol 2025; 22:31. [PMID: 39989606 PMCID: PMC11843085 DOI: 10.3892/mco.2025.2826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 01/22/2025] [Indexed: 02/25/2025] Open
Abstract
Anti-programmed cell death 1 (PD-1)/PD-1 ligand-1 (PD-L1) drugs have been used clinically, including those for skin cancer, with reasonable efficacy. Despite extensive ongoing research on bone and soft tissue sarcomas, there is a paucity of reviews that present a coherent picture. The present article is a comprehensive narrative review on the role of the PD-1/PD-L1 immune checkpoint in bone and soft tissue tumors. The review outlines the biological functions and mechanisms of action of PD-1/PD-L1 and its expression and clinical significance in various tumor types, including osteosarcoma and soft tissue sarcoma. Clinical trial results of immune checkpoint inhibitors, their association with prognosis, mechanisms of resistance to therapy, immune-related adverse events, and their potential in combination therapies, were also discussed.
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Affiliation(s)
- Kazuhiko Hashimoto
- Department of Orthopedic Surgery, Kindai University Hospital, Osaka-Sayama, Osaka 589-8511, Japan
| | - Shunji Nishimura
- Department of Orthopedic Surgery, Kindai University Hospital, Osaka-Sayama, Osaka 589-8511, Japan
| | - Koji Goto
- Department of Orthopedic Surgery, Kindai University Hospital, Osaka-Sayama, Osaka 589-8511, Japan
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20
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Zhong BY, Fan W, Guan JJ, Peng Z, Jia Z, Jin H, Jin ZC, Chen JJ, Zhu HD, Teng GJ. Combination locoregional and systemic therapies in hepatocellular carcinoma. Lancet Gastroenterol Hepatol 2025; 10:369-386. [PMID: 39993404 DOI: 10.1016/s2468-1253(24)00247-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 07/20/2024] [Accepted: 07/25/2024] [Indexed: 02/26/2025]
Abstract
Locoregional therapies play a fundamental role in the treatment of patients with early and intermediate and locally advanced hepatocellular carcinomas. With encouraging recent advances in immunotherapy-based systemic therapies, locoregional therapies are being both promoted and challenged by new systemic therapy options. Combined locoregional and systemic therapies might enhance treatment outcomes compared with either option alone. This Series paper summarises the existing data on locoregional and systemic therapies for hepatocellular carcinoma, and discusses evidence from studies investigating their combination with a focus on their synergistic efficacy and safety.
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Affiliation(s)
- Bin-Yan Zhong
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China; Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Wenzhe Fan
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Justin J Guan
- Division of Interventional Radiology, Department of Radiology, Cleveland Clinic, Cleveland, OH, USA
| | - Zhenwei Peng
- Department of Radiation Oncology, Cancer Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhongzhi Jia
- Department of Interventional and Vascular Surgery, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, China
| | - Haojie Jin
- Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhi-Cheng Jin
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Jian-Jian Chen
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Hai-Dong Zhu
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Gao-Jun Teng
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China.
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21
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Salimi S, Liu K. Editorial: Variceal Bleeding in Patients Receiving Atezolizumab-Bevacizumab for Hepatocellular Carcinoma-Don't Ignore the Risk Factors! Aliment Pharmacol Ther 2025; 61:1404-1405. [PMID: 39957603 DOI: 10.1111/apt.70017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 01/30/2025] [Accepted: 01/30/2025] [Indexed: 02/18/2025]
Affiliation(s)
- Shirin Salimi
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Ken Liu
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
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22
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Mauro E, Rodríguez-Perálvarez M, D'Alessio A, Crespo G, Piñero F, De Martin E, Colmenero J, Pinato DJ, Forner A. New Scenarios in Liver Transplantation for Hepatocellular Carcinoma. Liver Int 2025; 45:e16142. [PMID: 39494583 DOI: 10.1111/liv.16142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 10/03/2024] [Accepted: 10/09/2024] [Indexed: 11/05/2024]
Abstract
BACKGROUND AND AIMS Despite liver transplantation (LT) is considered the optimal treatment for hepatocellular carcinoma (HCC), particularly in patients with impaired liver function, the shortage of donors has forced the application of very restrictive criteria for selecting ideal candidates for whom LT can offer the best outcome. With the evolving LT landscape due to the advent of direct-acting antivirals (DAAs) and the steady increase in donors, major efforts have been made to expand the transplant eligibility criteria for HCC. In addition, the emergence of immune checkpoint inhibitors (ICIs) for the treatment of HCC, with demonstrated efficacy in earlier stages, has revolutionized the therapeutic approach for these patients, and their integration in the setting of LT is challenging. Management of immunological compromise from ICIs, including the wash-out period before LT and post-LT immunosuppression adjustments, is crucial to balance the risk of graft rejection against HCC recurrence. Additionally, the effects of increased immunosuppression on non-hepatic complications must be understood to prevent them from becoming obstacles to long-term OS. METHODS AND RESULTS In this review, we will evaluate the emerging evidence and its implications for the future of LT in HCC. Addressing these novel challenges and opportunities, while integrating the current clinical evidence with predictive algorithms, would ensure a fair balance between individual patient needs and the overall population benefit in the LT system.
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Affiliation(s)
- Ezequiel Mauro
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Manuel Rodríguez-Perálvarez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
- Department of Hepatology and Liver Transplantation, Hospital Universitario Reina Sofía, Universidad de Córdoba, IMIBIC, CIBERehd, Córdoba, Spain
| | - Antonio D'Alessio
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Gonzalo Crespo
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
- Liver Transplant Unit, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Federico Piñero
- School of Medicine, Hospital Universitario Austral, Austral University, Buenos Aires, Argentina
| | - Eleonora De Martin
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, INSERM Unit 1193, Université Paris-Saclay, FHU Hepatinov, Villejuif, France
| | - Jordi Colmenero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
- Liver Transplant Unit, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - David James Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Alejandro Forner
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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Liu Q, Zhang X, Qi J, Tian X, Dovjak E, Zhang J, Du H, Zhang N, Zhao J, Zhang Y, Wang L, Wei Y, Liu C, Qian R, Xiang L, Li W, Xiu P, Ma C, Yu Y, Jiang S. Comprehensive profiling of lipid metabolic reprogramming expands precision medicine for HCC. Hepatology 2025; 81:1164-1180. [PMID: 38899975 PMCID: PMC11902616 DOI: 10.1097/hep.0000000000000962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 05/11/2024] [Indexed: 06/21/2024]
Abstract
BACKGROUND AND AIMS Liver HCC is the second leading cause of cancer-related deaths worldwide. The heterogeneity of this malignancy is driven by a wide range of genetic alterations, leading to a lack of effective therapeutic options. In this study, we conducted a systematic multi-omics characterization of HCC to uncover its metabolic reprogramming signature. APPROACH AND RESULTS Through a comprehensive analysis incorporating transcriptomic, metabolomic, and lipidomic investigations, we identified significant changes in metabolic pathways related to glucose flux, lipid oxidation and degradation, and de novo lipogenesis in HCC. The lipidomic analysis revealed abnormal alterations in glycerol-lipids, phosphatidylcholine, and sphingolipid derivatives. Machine-learning techniques identified a panel of genes associated with lipid metabolism as common biomarkers for HCC across different etiologies. Our findings suggest that targeting phosphatidylcholine with saturated fatty acids and long-chain sphingolipid biosynthesis pathways, particularly by inhibiting lysophosphatidylcholine acyltransferase 1 ( LPCAT1 ) and ceramide synthase 5 ( CERS5 ) as potential therapeutic strategies for HCC in vivo and in vitro. Notably, our data revealed an oncogenic role of CERS5 in promoting tumor progression through lipophagy. CONCLUSIONS In conclusion, our study elucidates the metabolic reprogramming nature of lipid metabolism in HCC, identifies prognostic markers and therapeutic targets, and highlights potential metabolism-related targets for therapeutic intervention in HCC.
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Affiliation(s)
- Qingbin Liu
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
- Post-Doctoral Research Center, Cisen Pharmaceutical Co. Ltd, Jining, Shandong, China
- School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
| | - Xiangyu Zhang
- Pathology Department, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Jingjing Qi
- Medical Faculty, Medical Faculty, Johannes Kepler University Linz, Linz, Austria
| | - Xinchen Tian
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Eva Dovjak
- Medical Faculty, Medical Faculty, Johannes Kepler University Linz, Linz, Austria
| | - Jiaqi Zhang
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Honghuan Du
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Ni Zhang
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jing Zhao
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Yiming Zhang
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Lijuan Wang
- Department of Ultrasonic Medicine, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Yangang Wei
- Post-Doctoral Research Center, Cisen Pharmaceutical Co. Ltd, Jining, Shandong, China
| | - Chenqiao Liu
- Hepatobiliary Surgery Department, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Ruikun Qian
- Hepatobiliary Surgery Department, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Longquan Xiang
- Pathology Department, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Weiyang Li
- School of Biological Sciences, Jining Medical University, Rizhao, Shandong, China
| | - Peng Xiu
- Department of General Surgery, Shandong Province Qianfoshan Hospital, The First Hospital Affiliated With Shandong First Medical University, Jinan, Shandong, China
| | - Changlin Ma
- Hepatobiliary Surgery Department, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Yong Yu
- Medical Faculty, Medical Faculty, Johannes Kepler University Linz, Linz, Austria
| | - Shulong Jiang
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Shandong First Medical University, Jining, Shandong, China
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24
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Liu Z, Zhu M, Peng Z. Reply: Interpreting the 100% disease control rate of Sin-Bev-RT in HCC with PVTT. Hepatology 2025; 81:E127-E128. [PMID: 39908188 DOI: 10.1097/hep.0000000000001230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 12/05/2024] [Indexed: 02/07/2025]
Affiliation(s)
- Zelong Liu
- Department of Radiation Oncology, Cancer Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Meiyan Zhu
- Department of Radiation Oncology, Cancer Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhenwei Peng
- Department of Radiation Oncology, Cancer Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
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Nault JC, Boubaya M, Wartski M, Dohan A, Pol S, Pop G, Soussan M, Sutter O, Costentin C, Roux J, Sengel C, Lequoy M, Montravers F, Menu Y, Pageaux GP, Goulart DM, Guiu B, Luciani A, Nahon P, Dioguardi Burgio M, Wagner M, Maksud P, Mulé S, Allaire M, Sidali S, Coilly A, Besson FL, Lewin M, Regnault H, Hollande C, Amaddeo G, Ronot M, Ganne-Carrié N, Itti E, Bloch-Queyrat C, Levy V, Lebtahi R, Chalaye J, Bouattour M. [ 18F]fluorodeoxyglucose and [ 18F]fluorocholine PET-CT for staging optimisation and treatment modification in hepatocellular carcinoma (PET-HCC01): a prospective multicentre study. Lancet Gastroenterol Hepatol 2025; 10:306-314. [PMID: 39987937 DOI: 10.1016/s2468-1253(25)00011-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 01/11/2025] [Accepted: 01/13/2025] [Indexed: 02/25/2025]
Abstract
BACKGROUND The role of PET-CT with [18F]fluorodeoxyglucose ([18F]FDG) and [18F]fluorocholine ([18F]FCH) in staging hepatocellular carcinoma and treatment decisions has, to our knowledge, never been prospectively assessed. METHODS We conducted a multicentre prospective study (PET-HCC01) in nine hospitals in France, including patients aged 18 years or older with a first diagnosis of hepatocellular carcinoma classified as Barcelona Clinic Liver Cancer (BCLC) classification A to C (without metastasis). At study inclusion, patients underwent contrast-enhanced liver MRI and liver, chest, and pelvis CT scans. Patients subsequently underwent [18F]FCH and [18F]FDG PET-CT. A first tumour staging and treatment decision was recorded by the multidisciplinary tumour board at each centre using morphological imaging, blind to the results of the PET-CTs. After the results of the PET-CTs were revealed, a second tumour staging and treatment decision was recorded. The primary endpoint was the proportion of patients whose treatment was modified by PET-CTs. Analyses were done in the intention-to-image population, consisting of all patients who had undergone at least one PET-CT and were discussed by the multidisciplinary tumour board. This study was registered with ClinicalTrials.gov, NCT04391348. FINDINGS Between July 20, 2020, and April 27, 2023, 230 patients were enrolled. Among the 215 patients included in the intention-to-image population, the median age was 66·0 years (IQR 60·0-71·5), 193 (90%) were male, and 155 (73%) had cirrhosis. Hepatocellular carcinoma was classified as BCLC stage A in 140 (65%) patients, B in 48 (22%), and C without metastasis in 27 (13%) on the basis of morphological imaging. Potential new lesions were identified in 19 (9%) patients by PET-CT (eight by both tracers, six by [18F]FCH only, and five by [18F]FDG only) and in six of these patients, follow-up confirmed the diagnosis of hepatocellular carcinoma (one lesion in the adrenal gland, two in bones, two in the lymph node, and one intrahepatic). PET-CT modified BCLC stage in ten patients: disease stage for two patients moved from BCLC A to B, from BCLC A to C for two patients, from BCLC B to C for two patients, and from BCLC C without metastasis to BCLC C with metastasis for four patients. Planned treatment was modified for four patients (2% [95% CI 1-5]), below the prespecified threshold of clinical significance (10%). INTERPRETATION [18F]FDG and [18F]FCH-PET-CTs should not be systematically performed for staging a first diagnosis of hepatocellular carcinoma, as they modified treatment decisions only in a minority of patients. FUNDING Programme Hospitalier de Recherche Clinique Inter-regional-PHRC-I2018 (Ministère de la Santé).
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Affiliation(s)
- Jean-Charles Nault
- Service d'Hépatologie, Hôpital Avicenne, Bobigny, France; Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Functional Genomics of Solid Tumors, Paris, France.
| | | | - Myriam Wartski
- Department of Nuclear Medicine, Hôpital Cochin, AP-HP, Paris, France
| | - Anthony Dohan
- Department of Radiology, Hôpital Cochin, AP-HP, Paris, France; Université Paris Cité, Faculté de Médecine, Paris, France
| | - Stanislas Pol
- Centre Université Paris Centre, Groupe Hospitalier Cochin Port Royal, AP-HP, DMU Cancérologie et spécialités médico-chirurgicales, Service des Maladies du foie, Université Paris Cité, Paris, France
| | - Gabriel Pop
- Université Paris 13, AP-HP, Service de Médecine nucléaire, Hôpital universitaire Avicenne, Bobigny, France
| | - Michael Soussan
- Université Paris 13, AP-HP, Service de Médecine nucléaire, Hôpital universitaire Avicenne, Bobigny, France
| | - Olivier Sutter
- Interventional Radiology Unit, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, AP-HP, Bobigny, France
| | - Charlotte Costentin
- Institute for Advanced Biosciences, Research Center UGA/Inserm U 1209/CNRS 5309; Gastroenterology, hepatology and GI oncology department, Digidune, Grenoble Alpes University Hospital, La Tronche, France
| | - Julie Roux
- Department of Nuclear Medicine, Grenoble Alpes University Hospital, Grenoble, France
| | - Christian Sengel
- Department of Radiology, Grenoble Alpes University Hospital, Grenoble, France
| | - Marie Lequoy
- Hepatology Department, Saint Antoine Hospital, AP-HP, Paris, France; INSERM UMRS 938 - Centre de Recherche Saint Antoine, APHP Sorbonne Université, Paris, France
| | | | - Yves Menu
- Département d'imagerie, Gustave Roussy, Villejuif, France; SIRIC CURAMUS, INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Paris, France
| | | | - Denis Mariano Goulart
- Department of Nuclear Medicine, CHU of Montepellier, PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France
| | - Boris Guiu
- Department of Radiology, St-Eloi University Hospital, Montpellier, France
| | - Alain Luciani
- Université Paris-Est Créteil, Créteil, France; INSERM, U955, Virus Hépatologie Cancer, Créteil, France; Department of Medical Imaging, Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Créteil, France
| | - Pierre Nahon
- Service d'Hépatologie, Hôpital Avicenne, Bobigny, France; Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Functional Genomics of Solid Tumors, Paris, France
| | - Marco Dioguardi Burgio
- Department of Radiology, Hôpital Beaujon, AP-HP Nord, Paris, France; INSERM U1149 Centre de Recherche sur l'Inflammation, Université Paris Cité, Paris, France
| | - Mathilde Wagner
- Department of Radiology, Hospital Pitié Salpêtrière, Paris; UMR 7371, Université Sorbonne, CNRS, Inserm U114615, rue de l'École de Médecine, 75006, Paris, France
| | - Philippe Maksud
- Service de médecine nucléaire, AP-HP Sorbonne Université, Hôpital Universitaire Pitié-Salpêtrière, Paris, France
| | - Sebastien Mulé
- Université Paris-Est Créteil, Créteil, France; INSERM, U955, Virus Hépatologie Cancer, Créteil, France; Department of Medical Imaging, Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Créteil, France
| | - Manon Allaire
- Service d'Hépato-gastroentérologie, AP-HP Sorbonne Université, Hôpital Universitaire Pitié-Salpêtrière, Paris, France; INSERM UMR 1138, Centre de recherche des Cordeliers, Paris, France
| | - Sabrina Sidali
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Functional Genomics of Solid Tumors, Paris, France; Liver Unit, Paris Cité University, Beaujon Hospital, APHP, DMU DIGEST, Clichy, France
| | - Audrey Coilly
- Centre Hépato-Biliaire, AP-HP, Hôpital Paul Brousse, Villejuif, France; Université Paris-Saclay, INSERM, UMR_S 1193, Hepatinov, Orsay, France
| | - Florent L Besson
- Department of Nuclear Medicine-Molecular Imaging, Hôpitaux Universitaires Paris-Saclay, AP-HP, DMU SMART IMAGING, CHU Bicêtre, Le Kremlin-Bicêtre, France; Université Paris-Saclay, Commissariat à l'énergie atomique et aux énergies alternatives, Centre National de la Recherche Scientifique, Inserm, BioMaps, Orsay, France; Université Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France
| | - Maïté Lewin
- Department of Radiology, Paul Brousse University Hospital, AP-HP-University Paris Saclay, Villejuif, France
| | - Hélène Regnault
- Hepatology Department, Henri Mondor Hospital, AP-HP, Créteil, France; Virus Hépatologie Cancer, Institut Mondor de Recherche Biomédicale, INSERM U955, Hôpital Henri Mondor, AP-HP, Université Paris-Est, Créteil, France
| | - Clémence Hollande
- Centre Université Paris Centre, Groupe Hospitalier Cochin Port Royal, AP-HP, DMU Cancérologie et spécialités médico-chirurgicales, Service des Maladies du foie, Université Paris Cité, Paris, France
| | - Giuliana Amaddeo
- Hepatology Department, Henri Mondor Hospital, AP-HP, Créteil, France; Virus Hépatologie Cancer, Institut Mondor de Recherche Biomédicale, INSERM U955, Hôpital Henri Mondor, AP-HP, Université Paris-Est, Créteil, France
| | - Maxime Ronot
- Department of Radiology, Hôpital Beaujon, AP-HP Nord, Paris, France; INSERM U1149 Centre de Recherche sur l'Inflammation, Université Paris Cité, Paris, France
| | - Nathalie Ganne-Carrié
- Service d'Hépatologie, Hôpital Avicenne, Bobigny, France; Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Functional Genomics of Solid Tumors, Paris, France
| | - Emmanuel Itti
- Nuclear Medicine Department, Henri Mondor Hospital, AP-HP, Créteil, France
| | | | - Vincent Levy
- URC-CRC GHPSS, Hôpital Avicenne, AP-HP, Bobigny, France
| | - Rachida Lebtahi
- Department of Nuclear Medicine, Hôpital Beaujon, AP-HP Nord, Paris, France; DMU DIGEST, Hôpital Beaujon, AP-HP Nord, Paris, France; Université Paris Cité, INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France
| | - Julia Chalaye
- Nuclear Medicine Department, Henri Mondor Hospital, AP-HP, Créteil, France
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Li Z, Chen ICY, Centonze L, Magyar CTJ, Choi WJ, Shah S, O'Kane GM, Vogel A, De Carlis L, Lerut J, Lai Q, Mehta N, Chen CL, Sapisochin G. Analysis of treatment benefits and prognostic factors for posttransplant HCC recurrence in a large Euro-American-Asian cohort. Liver Transpl 2025; 31:450-463. [PMID: 39356515 DOI: 10.1097/lvt.0000000000000501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 09/16/2024] [Indexed: 10/03/2024]
Abstract
Posttransplant HCC recurrence significantly impacts survival, yet its management is challenging due to limited evidence. With recent advancements in HCC treatment, updated data on managing recurrent diseases are needed. In this retrospective study across 6 centers (2000-2022), we employed Cox proportional-hazards regression and log-rank tests to assess survival differences. A prognostic score model was developed to categorize patient survival. The efficacy of tyrosine kinase inhibitors was evaluated through propensity score matching. In our study, 431 of 3349 (14%) patients with HCC who underwent transplantation developed recurrence within a median interval of 18 (IQR: 9-32) months. One hundred forty-seven (34%) underwent curative-intent treatments, 207 (48%) received palliative treatments, and 77 (18%) were given best-supportive care. Patients undergoing curative-intent treatments had better survival from the time of recurrence with a median survival of 45 (95% CI: 36-63) months and 1/3/5-year survival of 90%/56%/43% compared to those receiving noncurative treatments (median: 11 [95% CI: 10-13] mo, 1/3/5-y survival of 46%/10%/7%, log-rank p < 0.001). Patients with recurrence diagnosed in the era 2018-2022 showed improved survival over the previous era (HR 0.64 [95% CI: 0.47-0.86]). Multivariable analysis identified 5 prognostic factors: ineligibility for curative-intent treatment (HR: 3.5 [95% CI: 2.7-4.6]), recurrence within 1 year (HR: 1.7 [95% CI: 1.3-2.1]), poor tumor differentiation (HR: 1.5 [95% CI: 1.1-1.9]), RETREAT score ≥3 (HR: 1.4 [95% CI: 1.1-1.8]), and alpha-fetoprotein at recurrence ≥400 ng/mL (HR: 1.4 [95% CI: 1.1-1.9]). These factors contributed to a prognostic scoring system (0-9) that stratified patients into 3 prognosis groups. Both propensity score-matched analysis and multivariable regression indicated that lenvatinib was not statistically superior to sorafenib in terms of efficacy. Curative-intent treatments should be advocated for patients with posttransplant recurrence whenever possible. Prognostic factors linked to aggressive tumor biology significantly influence survival. Advancements in HCC management have improved survival outcomes over the past 5 years.
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Affiliation(s)
- Zhihao Li
- HBP & Multi-Organ Transplant Program, Department of Surgery, University Health Network, Toronto, Ontario, Canada
| | - Itsuko Chih-Yi Chen
- Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Leonardo Centonze
- Department of General Surgery and Transplantation, Niguarda Ca' Granda Hospital, Milan, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy
| | - Christian T J Magyar
- HBP & Multi-Organ Transplant Program, Department of Surgery, University Health Network, Toronto, Ontario, Canada
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Woo Jin Choi
- HBP & Multi-Organ Transplant Program, Department of Surgery, University Health Network, Toronto, Ontario, Canada
| | - Sachin Shah
- Department of Medicine, Division of Gastroenterology, University of California San Francisco, San Francisco, California, USA
| | - Grainne M O'Kane
- Department of Medical Oncology, St. Vincent's University Hospital and School of Medicine University College Dublin, Dublin, Republic of Ireland
- Wallace McCain Centre for Pancreatic Cancer, Division of Medical Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - Arndt Vogel
- Division of Gastroenterology and Hepatology, University Health Network, Toronto, Ontario, Canada
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Luciano De Carlis
- Department of General Surgery and Transplantation, Niguarda Ca' Granda Hospital, Milan, Italy
- School of Medicine and Surgery, Department of Surgery, University of Milan-Bicocca, Milan, Italy
| | - Jan Lerut
- Institut de Recherche Expérimentale et Clinique, Department of Surgery, Université catholique de Louvain, Brussels, Belgium
| | - Quirino Lai
- General Surgery and Organ Transplantation Unit, Department of Surgery, Sapienza University of Rome, Rome, Italy
| | - Neil Mehta
- Department of Medicine, Division of Gastroenterology, University of California San Francisco, San Francisco, California, USA
| | - Chao-Long Chen
- Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Gonzalo Sapisochin
- HBP & Multi-Organ Transplant Program, Department of Surgery, University Health Network, Toronto, Ontario, Canada
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Ziogas DC, Theocharopoulos C, Aravantinou K, Boukouris AE, Stefanou D, Anastasopoulou A, Lialios PP, Lyrarakis G, Gogas H. Clinical benefit of immune checkpoint inhibitors in elderly cancer patients: Current evidence from immunosenescence pathophysiology to clinical trial results. Crit Rev Oncol Hematol 2025; 208:104635. [PMID: 39889861 DOI: 10.1016/j.critrevonc.2025.104635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 01/20/2025] [Accepted: 01/21/2025] [Indexed: 02/03/2025] Open
Abstract
The age-related decline in immunity appears to be associated not only with cancer development but also with differential responses to immune checkpoint inhibitors (ICIs). Despite their increasing utility across various malignancies and therapeutic settings, limited data -derived primarily from subgroup analyses of randomized controlled trials (RCTs), pooled meta-analyses, and retrospective studies- are available on the effects of aging on their efficacy and toxicity. Immunosenescence, characterized by the progressive decline of the function of the immune system, and inflammaging, a state of persistent low-grade sterile inflammation, may influence ICI outcomes. Additionally, the incidence, severity, and subtypes of immune-related adverse events (irAEs) may differ between older and younger individuals due to loss of immunotolerance. In the current review, starting from a a comprehensive discussion of the pathophysiology of immunosenescence, we proceed to critically review age-related retrospective and randomized evidence supporting FDA-approved ICIs. We highlight similarities or differences across age groups and the clinical benefit of ICIs in elderly versus younger cancer patients. The optimal integration of ICIs in geriatric oncology necessitates greater inclusion of this patient demographic in RCTs along with real-world data in order to acquire robust data which will guide evidence-based treatment decisions for this population.
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Affiliation(s)
- Dimitrios C Ziogas
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Charalampos Theocharopoulos
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Katerina Aravantinou
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Aristeidis E Boukouris
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Dimitra Stefanou
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Amalia Anastasopoulou
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Panagiotis-Petros Lialios
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - George Lyrarakis
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Helen Gogas
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
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Hoteit MA, Weinfurtner K. Recurrent HCC after liver transplantation: Small steps, while awaiting a breakthrough. Liver Transpl 2025; 31:421-422. [PMID: 39916602 DOI: 10.1097/lvt.0000000000000571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 12/11/2024] [Indexed: 03/20/2025]
Affiliation(s)
- Maarouf A Hoteit
- Department of Medicine, Division of Gastroenterology and Hepatology, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Zhang YJ, Zhou DJ, Li H, Pan Q, Cheng Y. Prolongated and large dose of r-ATG relieves PD-L1 inhibitor-induced allograft rejection in liver transplant recipient. Hepatobiliary Pancreat Dis Int 2025; 24:221-224. [PMID: 38845248 DOI: 10.1016/j.hbpd.2024.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 05/06/2024] [Indexed: 03/22/2025]
Affiliation(s)
- Yi-Jie Zhang
- Department of Hepatobiliary Surgery and Organ Transplantation, the First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Dian-Jie Zhou
- Department of Hepatobiliary Surgery and Organ Transplantation, the First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Hong Li
- Department of Hepatobiliary Surgery and Organ Transplantation, the First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Qi Pan
- Department of Hepatobiliary Surgery and Organ Transplantation, the First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Ying Cheng
- Department of Hepatobiliary Surgery and Organ Transplantation, the First Affiliated Hospital of China Medical University, Shenyang 110001, China.
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Zanuso V, Rimassa L, Braconi C. The rapidly evolving landscape of HCC: Selecting the optimal systemic therapy. Hepatology 2025; 81:1365-1386. [PMID: 37695554 DOI: 10.1097/hep.0000000000000572] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 08/04/2023] [Indexed: 09/12/2023]
Abstract
Over the past years, there has been a remarkable advance in the systemic treatment options for advanced HCC. The overall survival has gradually increased over time, with larger benefits for patients with sensitive tumors and preserved liver function, the latter being an essential condition for the delivery of sequential lines of treatment and optimization of clinical outcomes. With the approval of new first-line agents and the introduction of immune checkpoint inhibitor-based therapies, the treatment landscape of advanced HCC is becoming wider than ever. Atezolizumab plus bevacizumab and, more recently, durvalumab plus tremelimumab have entered the clinical practice and are the current standard of care for treatment-naïve patients, surpassing sorafenib and lenvatinib monopoly. As no head-to-head comparisons are available among all the first-line treatment options, the recommendation for the most appropriate choice and sequence is patient-driven and integrates efficacy data with clinical comorbidities, background liver disease, and the safety profile of available drugs. In addition, predictive biomarkers for successful patients' stratification are yet to be available and constitute the focus of ongoing research. The treatment algorithm is likely to become even more complex since systemic therapeutic approaches are now being translated into earlier stages of the disease, with an impact on the evolution of the sequential treatment of patients with HCC.
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Affiliation(s)
- Valentina Zanuso
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Chiara Braconi
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Beatson West of Scotland Cancer Centre, Glasgow, UK
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Deng Z, Xiao S, He YY, Guo Y, Tang LJ. Sorafenib-induced cardiovascular toxicity: A cause for concern. Chem Biol Interact 2025; 410:111388. [PMID: 39889871 DOI: 10.1016/j.cbi.2025.111388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 12/22/2024] [Accepted: 01/15/2025] [Indexed: 02/03/2025]
Abstract
Sorafenib, a multi-target tyrosine kinase inhibitor, is primarily used to manage hepatocellular carcinoma, advanced renal cell carcinoma, and differentiated thyroid cancer. Although this drug extends patient survival and slows tumor progression, its cardiovascular toxicity substantially impacts of quality of life. Effective the prevention and treatment of the resulting complications are needed. The mechanisms underlying of sorafenib-induced cardiovascular toxicity are complex, and remain incompletely understood despite extensive research. In this review, we discuss the incidence of sorafenib-induced cardiovascular toxicity, including hypertension, thromboembolism, and heart failure in clinical settings. We also summarize current research on the underlying mechanisms, such as ferroptosis, necroptosis, autophagy, mitochondrial damage, and endoplasmic reticulum stress. Additionally, we explore studies regarding the protective effects of various drugs against sorafenib-induced cardiovascular toxicity. This in-depth synthesis of data regarding the clinical manifestations and mechanisms of sorafenib-induced cardiotoxicity provides a valuable scientific foundation for developing therapeutic drugs to combat these adverse effects.
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Affiliation(s)
- Zheng Deng
- Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, Department of Pharmacy, Institute of Pharmacy and Pharmacology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Shuang Xiao
- Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, Department of Pharmacy, Institute of Pharmacy and Pharmacology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Ying-Ying He
- Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, Department of Pharmacy, Institute of Pharmacy and Pharmacology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Yu Guo
- Institute of Pharmacy and Pharmacology, Cooperative Innovation Center for Molecular Target New Drug Study, College of Pharmacy, Hengyang Medical School, University of South China, Hengyang, 421001, China.
| | - Li-Jing Tang
- Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, Department of Pharmacy, Institute of Pharmacy and Pharmacology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
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Zhang F, Wang YS, Li SP, Zhao B, Huang N, Song RP, Meng FZ, Feng ZW, Zhang SY, Song HC, Chen XP, Liu LX, Wang JZ. Alpha-fetoprotein combined with initial tumor shape irregularity in predicting the survival of patients with advanced hepatocellular carcinoma treated with immune-checkpoint inhibitors: a retrospective multi-center cohort study. J Gastroenterol 2025; 60:442-455. [PMID: 39714631 PMCID: PMC11922967 DOI: 10.1007/s00535-024-02202-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 12/07/2024] [Indexed: 12/24/2024]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) are playing a significant role in the treatment of hepatocellular carcinoma (HCC). This study aims to explore the prognostic value of alpha-fetoprotein (AFP) and initial tumor shape irregularity in patients treated with ICIs. METHODS In this retrospective, multi-center study, 296 HCC patients were randomly divided into the training set and the validation set in a 3:2 ratio. The training set was used to evaluate prognostic factors and to develop an easily applicable ATSI (AFP and Tumor Shape Irregularity) score, which was verified in the validation set. RESULTS The ATSI score was developed from two independent prognostic risk factors: baseline AFP ≥ 400 ng/ml (HR 1.73, 95% CI 1.01-2.96, P = 0.046) and initial tumor shape irregularity (HR 1.94, 95% CI 1.03-3.65, P = 0.041). The median overall survival (OS) was not reached (95% CI 28.20-NA) in patients who met no criteria (0 points), 25.8 months (95% CI 14.17-NA) in patients who met one criterion (1 point), and 17.03 months (95% CI 11.73-23.83) in patients who met two criteria (2 points) (P = 0.001). The median progression-free survival (PFS) was 10.83 months (95% CI 9.27-14.33) for 0 points, 8.03 months (95% CI 6.77-10.57) for 1 point, and 5.03 months (95% CI 3.83-9.67) for 2 points (P < 0.001). The validation set effectively verified these results (median OS, 37.43/24.27/14.03 months for 0/1/2 points, P = 0.028; median PFS, 13.93/8.30/4.90 months for 0/1/2 points, P < 0.001). CONCLUSIONS The ATSI score can effectively predict prognosis in HCC patients receiving ICIs.
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Affiliation(s)
- Feng Zhang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Yong-Shuai Wang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Shao-Peng Li
- Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Bin Zhao
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Nan Huang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Rui-Peng Song
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Fan-Zheng Meng
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Zhi-Wen Feng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, 241000, China
| | - Shen-Yu Zhang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Hua-Chuan Song
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Xiao-Peng Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, 241000, China.
| | - Lian-Xin Liu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China.
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China.
| | - Ji-Zhou Wang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China.
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China.
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Cillo U, Gringeri E, D'Amico FE, Lanari J, Furlanetto A, Vitale A. Hepatocellular carcinoma: Revising the surgical approach in light of the concept of multiparametric therapeutic hierarchy. Dig Liver Dis 2025; 57:809-818. [PMID: 39828438 DOI: 10.1016/j.dld.2024.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 11/20/2024] [Accepted: 12/02/2024] [Indexed: 01/22/2025]
Abstract
The clinical management of hepatocellular carcinoma (HCC) is strongly influenced by several prognostic factors, mainly tumor stage, patient's health, liver function and specific characteristics of each intervention. The interplay between these factors should be carefully evaluated by a multidisciplinary tumor board. To support this, the novel "multiparametric therapeutic hierarchy" (MTH) concept has been recently proposed. This review will present the main features of available surgical treatments for HCC (liver transplantation, liver resection, ablation). Strengths and weaknesses are reported in the light of clinical decision making and of treatment allocation, with a special focus on the collocation of each treatment in the MTH framework and on how MTH may be useful in supporting clinical decision. Sequential treatments and their role to allow further surgical treatments will also be analyzed.
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Affiliation(s)
- Umberto Cillo
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy.
| | - Enrico Gringeri
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Francesco Enrico D'Amico
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Jacopo Lanari
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Alessandro Furlanetto
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Alessandro Vitale
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
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Grigg S, Lade S, Ryland G, Grimmond S, Dickinson M, Blombery P. Genomic mechanisms associated with resistance to PDL1-blockade in a patient with mantle cell lymphoma. Leuk Lymphoma 2025; 66:790-793. [PMID: 39709635 DOI: 10.1080/10428194.2024.2443561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 12/02/2024] [Accepted: 12/12/2024] [Indexed: 12/24/2024]
Affiliation(s)
- Samuel Grigg
- Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
- Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Stephen Lade
- Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Georgina Ryland
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
- Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia
| | - Sean Grimmond
- Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia
| | - Michael Dickinson
- Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Piers Blombery
- Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
- Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia
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35
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Tabrizian P. Advances in Understanding the Complexities of Recurrent HCC Following Liver Transplantation. Transplantation 2025; 109:e190-e191. [PMID: 39531341 DOI: 10.1097/tp.0000000000005255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Affiliation(s)
- Parissa Tabrizian
- Mount Sinai Medical Center NY, Recanati/Miller Transplantation Institute, Transplantation, New York, NY
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Lim J, Goh MJ, Song BG, Sinn DH, Kang W, Gwak GY, Choi MS, Lee JH, Cha DI, Gu K, Ha SY, Hwang I, Park WY, Paik YH. Unraveling the immune-activated tumor microenvironment correlated with clinical response to atezolizumab plus bevacizumab in advanced HCC. JHEP Rep 2025; 7:101304. [PMID: 40124166 PMCID: PMC11929055 DOI: 10.1016/j.jhepr.2024.101304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 12/05/2024] [Accepted: 12/10/2024] [Indexed: 03/25/2025] Open
Abstract
Background & Aims Despite atezolizumab plus bevacizumab being a standard treatment for advanced hepatocellular carcinoma (HCC), a significant proportion of patients do not achieve durable benefit. This study aimed to identify predictive biomarkers for this therapy by investigating the role of immune activation within the tumor microenvironment (TME). Methods We characterized the intratumoral TME of patients with advanced HCC treated with atezolizumab plus bevacizumab using single cell transcriptomics on pretreatment tumor biopsies from 12 patients. To complement and support these findings, we integrated our single cell data with publicly available bulk RNA-sequencing data from independent clinical trial cohorts. Results Patients who responded to combination therapy with atezolizumab plus bevacizumab demonstrated an immune-activated TME, marked by enhanced cytotoxicity and a tumor-specific T cell response. These patients also exhibited an increased proportion of inflammatory cytokine-enriched tumor-associated macrophage clusters with stronger interactions with T cells, an increased population of conventional dendritic cells, and activated antigen-presenting function in tumor endothelial cells. When publicly available bulk RNA-sequencing data from independent clinical trial cohorts were analyzed, these immune activation features were associated with improved progression-free survival (median 10.8 months, 95% CI: 7.3-not reached versus 5.5 months, 95% CI: 4.0-6.7; p <0.001). Conclusions These findings suggest that the existence of an activated immune TME before treatment is crucial for a favorable clinical response in patients with HCC treated with atezolizumab plus bevacizumab. Impact and implications Only a subset of patients with HCC benefit from combination therapy with atezolizumab plus bevacizumab, limiting its clinical utility. In this study, we used single cell RNA analysis to identify TME features associated with a clinical response to this therapy. Our findings suggest that a pre-existing immune-activated TME is crucial for predicting the response to atezolizumab plus bevacizumab. Specifically, features such as enhanced T cell cytotoxicity, inflammatory cytokine-enriched macrophage clusters, active antigen presentation in endothelial cells, and an increased presence of dendritic cells may aid patient selection and inform therapeutic strategies.
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Affiliation(s)
- Jinyeong Lim
- Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sunkyunkwan University, Seoul, South Korea
- Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea
| | - Myung Ji Goh
- Division of Gastroenterology and Hepatology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Byeong Geun Song
- Division of Gastroenterology and Hepatology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Dong Hyun Sinn
- Division of Gastroenterology and Hepatology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Wonseok Kang
- Division of Gastroenterology and Hepatology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Geum-Youn Gwak
- Division of Gastroenterology and Hepatology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Moon Seok Choi
- Division of Gastroenterology and Hepatology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Joon Hyeok Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Dong Ik Cha
- Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Kyowon Gu
- Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Sang Yun Ha
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Inwoo Hwang
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Woong-Yang Park
- Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sunkyunkwan University, Seoul, South Korea
- Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea
| | - Yong-Han Paik
- Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sunkyunkwan University, Seoul, South Korea
- Division of Gastroenterology and Hepatology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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Jiang X, Ge X, Huang Y, Xie F, Chen C, Wang Z, Tao W, Zeng S, Lv L, Zhan Y, Bao L. Drug resistance in TKI therapy for hepatocellular carcinoma: Mechanisms and strategies. Cancer Lett 2025; 613:217472. [PMID: 39832650 DOI: 10.1016/j.canlet.2025.217472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 01/14/2025] [Accepted: 01/16/2025] [Indexed: 01/22/2025]
Abstract
Tyrosine kinase inhibitors (TKIs) are such as sorafenib the first-line therapeutic drugs for patients with advanced hepatocellular carcinoma. However, patients with TKI-resistant advanced liver cancer are insensitive to TKI treatment, resulting in limited survival benefits. This paper comprehensively reviewed the mechanisms underlying TKI resistance in hepatocytes, investigating activation of tumor signaling pathways, epigenetic regulation, tumor microenvironment, and metabolic reprogramming. Based on resistance mechanisms, it also reviews preclinical and clinical studies of drug resistance strategies and summarizes targeted therapy combined with immunotherapy currently in investigational clinical trials. Understanding the interactions and clinical studies of these resistance mechanisms offers new hope for improving and prolonging patient survival.
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Affiliation(s)
- Xue Jiang
- Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China.
| | - Xiaoying Ge
- Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China.
| | - Yueying Huang
- Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China.
| | - Fangyuan Xie
- Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China.
| | - Chun Chen
- Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China.
| | - Zijun Wang
- Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China.
| | - Wanru Tao
- Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China.
| | - Sailiang Zeng
- Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China.
| | - Lei Lv
- Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China.
| | - Yangyang Zhan
- Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China.
| | - Leilei Bao
- Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China.
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Zhou XQ, Huang S, Shi XM, Liu S, Zhang W, Shi L, Lv MH, Tang XW. Global trends in artificial intelligence applications in liver disease over seventeen years. World J Hepatol 2025; 17:101721. [DOI: 10.4254/wjh.v17.i3.101721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 01/01/2025] [Accepted: 02/10/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND In recent years, the utilization of artificial intelligence (AI) technology has gained prominence in the field of liver disease.
AIM To analyzes AI research in the field of liver disease, summarizes the current research status and identifies hot spots.
METHODS We searched the Web of Science Core Collection database for all articles and reviews on hepatopathy and AI. The time spans from January 2007 to August 2023. We included 4051 studies for further collection of information, including authors, countries, institutions, publication years, keywords and references. VOS viewer, CiteSpace, R 4.3.1 and Scimago Graphica were used to visualize the results.
RESULTS A total of 4051 articles were analyzed. China was the leading contributor, with 1568 publications, while the United States had the most international collaborations. The most productive institutions and journals were the Chinese Academy of Sciences and Frontiers in Oncology. Keywords co-occurrence analysis can be roughly summarized into four clusters: Risk prediction, diagnosis, treatment and prognosis of liver diseases. "Machine learning", "deep learning", "convolutional neural network", "CT", and "microvascular infiltration" have been popular research topics in recent years.
CONCLUSION AI is widely applied in the risk assessment, diagnosis, treatment, and prognosis of liver diseases, with a shift from invasive to noninvasive treatment approaches.
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Affiliation(s)
- Xue-Qin Zhou
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou 646099, Sichuan Province, China
| | - Shu Huang
- Department of Gastroenterology, Lianshui People’ Hospital of Kangda College Affiliated to Nanjing Medical University, Huaian 223499, Jiangsu Province, China
| | - Xia-Min Shi
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou 646099, Sichuan Province, China
| | - Sha Liu
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou 646099, Sichuan Province, China
| | - Wei Zhang
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou 646099, Sichuan Province, China
| | - Lei Shi
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou 646099, Sichuan Province, China
| | - Mu-Han Lv
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou 646099, Sichuan Province, China
| | - Xiao-Wei Tang
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou 646099, Sichuan Province, China
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Zhang XD, Zhang LY, Luo JL, Yu KH, Zhu KL. Neoadjuvant therapy: Dawn of reducing the high post-surgery recurrence rate of hepatocellular carcinoma. World J Gastrointest Surg 2025; 17:103740. [DOI: 10.4240/wjgs.v17.i3.103740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/01/2025] [Accepted: 01/14/2025] [Indexed: 02/24/2025] Open
Abstract
The high postoperative recurrence rate remains a major challenge in the treatment of hepatocellular carcinoma (HCC) following resection. Increasing research has been delved into investigating the role of neoadjuvant therapy on the prognosis of resectable HCC. Recent trends in combination therapy with molecularly targeted agents and immune checkpoint inhibitors have significantly improved the efficacy of systemic antitumor treatments, yielding survival benefits exceeding 40%. Neoadjuvant therapy for HCC, whether based on systemic antitumor treatments, locoregional therapies, or their combination, has emerged as a promising research direction. However, there remains a matter of debate on neoadjuvant therapy. In this review, we summarize and discuss the research progress and challenges of neoadjuvant therapy for HCC over the past five years from the perspective of Chinese guidelines to provide new insights and future directions in this field.
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Affiliation(s)
- Xiao-Dong Zhang
- Department of Hepatopancreatobiliary Surgery, The Affiliated People's Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China
| | - Lu-Yi Zhang
- Zhejiang Provincial Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo 315211, Zhejiang Province, China
| | - Jia-Liang Luo
- Department of Hepatopancreatobiliary Surgery, The Affiliated People's Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China
| | - Ke-Heng Yu
- Department of Hepatopancreatobiliary Surgery, The Affiliated People's Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China
| | - Ke-Lei Zhu
- Department of Hepatopancreatobiliary Surgery, The Affiliated People's Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China
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Wong CCL, Wong CM. ETV5-S100A9 feed-forward loop connecting HCC and MDSCs to shape the immunosuppressive tumour microenvironment. Gut 2025:gutjnl-2025-335078. [PMID: 40147932 DOI: 10.1136/gutjnl-2025-335078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Accepted: 03/18/2025] [Indexed: 03/29/2025]
Affiliation(s)
- Carmen Chak-Lui Wong
- State Key Laboratory of Liver Reserarch, The Unviersity of Hong Kong, Hong Kong, People's Republic of China
- Departtment of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China
- Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong, People's Republic of China
| | - Chun Ming Wong
- State Key Laboratory of Liver Reserarch, The Unviersity of Hong Kong, Hong Kong, People's Republic of China
- Departtment of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China
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Wang CD, Liu RD, Liu MJ, Song J. Lung metastasis following temporary discontinuation of lenvatinib and tislelizumab in hepatocellular carcinoma: A case report. World J Gastrointest Surg 2025; 17:100951. [DOI: 10.4240/wjgs.v17.i3.100951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 12/04/2024] [Accepted: 01/10/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a prevalent malignancy in China, primarily diagnosed at advanced stages, which limits treatment options and increases mortality rates. Conversion therapy, which includes systemic and locoregional treatments, aims to render unresectable tumors resectable. Nonetheless, research is scant on the risks of disease progression during the temporary cessation of targeted drugs and immune checkpoint inhibitors before surgery.
CASE SUMMARY This report describes a 58-year-old male with HCC who developed lung metastases following the discontinuation of lenvatinib and tislelizumab, revealing the necessity for further investigation into the management of HCC patients during the perioperative period, particularly concerning the timing and duration of targeted therapy and immunotherapy.
CONCLUSION Our study highlights the complex challenges in managing advanced HCC and emphasizes the critical need for ongoing research to refine treatment strategies and improve patient outcomes.
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Affiliation(s)
- Chen-Dong Wang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Run-Dong Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Ming-Jie Liu
- Department of Oncology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430062, Hubei Province, China
| | - Jia Song
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
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Tharwat M, Tawheed A, El-Kassas M. Atezolizumab and bevacizumab combination in advanced hepatocellular carcinoma patients: The imperative for safety assessment studies. World J Clin Cases 2025; 13:99043. [PMID: 40144486 PMCID: PMC11670025 DOI: 10.12998/wjcc.v13.i9.99043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 11/18/2024] [Accepted: 12/02/2024] [Indexed: 12/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent cancer of the hepatobiliary tract and the third leading cause of cancer-related mortality worldwide. Atezolizumab and bevacizumab combination is currently considered among the front-line treatment modalities for advanced unresectable HCC. Most studies examining this combination were focused on evaluating its effectiveness. Despite numerous case reports documenting some side effects, there is a limited number of large-scale studies assessing these side effects. In this article, we comment on the case report by Park et al published recently, reporting a fatal intra-tumoral hemorrhage in a patient with HCC who received systemic therapy in the form of the combination of atezolizumab and bevacizumab.
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Affiliation(s)
- Mina Tharwat
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Aswan University, Aswan 81528, Egypt
| | - Ahmed Tawheed
- Department of Endemic Medicine, Faculty of Medicine, Helwan University, Cairo 11795, Egypt
| | - Mohamed El-Kassas
- Department of Endemic Medicine, Faculty of Medicine, Helwan University, Cairo 11795, Egypt
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Chan LL, Chan SL. Future perspectives on immunotherapy for hepatocellular carcinoma. Ther Adv Med Oncol 2025; 17:17588359251323199. [PMID: 40144682 PMCID: PMC11938898 DOI: 10.1177/17588359251323199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Accepted: 02/05/2025] [Indexed: 03/28/2025] Open
Abstract
In recent years, several global phase III trials have shown that combinations of immune checkpoint inhibitors (ICIs) offer superior efficacy and survival compared to multi-kinase inhibitors, establishing them as the gold standard for treating patients with advanced hepatocellular carcinoma (HCC). This success has led to investigations into expanding the use of immunotherapy into various other settings and populations, including neoadjuvant and adjuvant therapies, patients with decompensated liver function and those awaiting liver transplantation. Despite its proven efficacy, a significant number of patients still develop resistance to immunotherapy, highlighting the need for innovative strategies to address this challenge. Approaches aimed at enhancing tumour immunogenicity, such as combining immunotherapy with transarterial chemoembolization or radiation therapies, show significant promise. Additionally, novel immunotherapeutics - such as triplet therapy, bispecific antibodies, adoptive T-cell therapy and cancer vaccines - are in early development for HCC. These agents have demonstrated potential for synergistic effects with existing ICIs, with initial studies yielding positive outcomes. In this review, we offer our future perspective on immunotherapy, emphasizing emerging indications, novel combination strategies and the development of new immunotherapeutic agents. Overall, the future of immunotherapy in HCC is brimming with extraordinary potential, set to transform the treatment landscape and redefine the possibilities for managing this challenging disease.
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Affiliation(s)
- Landon L. Chan
- State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Sir YK Pao Centre for Cancer, SIRT, Hong Kong Cancer Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Stephen L. Chan
- State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Sir YK Pao Centre for Cancer, SIRT, Hong Kong Cancer Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, Hong Kong, China
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44
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Ramirez CFA, Akkari L. Myeloid cell path to malignancy: insights into liver cancer. Trends Cancer 2025:S2405-8033(25)00054-8. [PMID: 40140328 DOI: 10.1016/j.trecan.2025.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 02/12/2025] [Accepted: 02/24/2025] [Indexed: 03/28/2025]
Abstract
Clinically approved treatments for advanced liver cancer often lack potency because of the heterogeneous characteristics of hepatocellular carcinoma (HCC). This complexity is largely driven by context-dependent inflammatory responses brought on by diverse etiologies, such as metabolic dysfunction-associated steatohepatitis (MASH), the genetic makeup of cancer cells, and the versatile adaptability of immune cells, such as myeloid cells. In this review, we discuss the evolutionary dynamics of the immune landscape, particularly that of liver-resident Kupffer cells (KCs), TREM2+, and SPP1+ macrophages with an active role during liver disease progression, which eventually fuels hepatocarcinogenesis. We highlight exploitable immunomodulatory avenues amenable to mitigate both the inherent pathological characteristics of liver cancers and the associated external factors that favor malignancy, paving a roadmap toward improving the management and therapeutic outcome for patients with HCC.
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Affiliation(s)
- Christel F A Ramirez
- Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
| | - Leila Akkari
- Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
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Shao YY, Chen CT, Chuang CH, Su TH, Ho MC, Tseng TC, Liu TH, Wu TC, Cheng AL, Hsu CH. Prompt initiation of durvalumab and tremelimumab for unresectable hepatocellular carcinoma in patients with chronic active hepatitis B: a phase 2 clinical trial. Br J Cancer 2025:10.1038/s41416-025-02978-7. [PMID: 40128285 DOI: 10.1038/s41416-025-02978-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 02/10/2025] [Accepted: 03/10/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection is an etiology of HCC, but clinical trials using immune checkpoint inhibitors (ICIs) usually exclude patients with chronic active hepatitis B (serum HBV viral load > 2000 IU/mL). This study examined the safety and efficacy of concurrently administering the ICI and anti-HBV medications in this patient population. METHODS In this single-arm phase 2 clinical trial, we enrolled patients with advanced HCC and untreated chronic active hepatitis B. Patients received 1500 mg of durvalumab every 4 weeks alone or in combination with 300 mg of tremelimumab on day 1 (the STRIDE regimen). Anti-HBV treatment with entecavir was simultaneously initiated. The primary endpoint was the rate of HBV reactivation. RESULTS We enrolled 30 patients, whose mean baseline HBV viral load was 770,986 IU/mL. No patients experienced HBV reactivation or HBV-associated hepatitis. Hepatitis flare was noted in 8 (26.7%) patients, but none of them were associated with HBV reactivation. The objective tumor response rate was 10% and 25% for the durvalumab treatment alone and the STRIDE regimen, respectively. CONCLUSION For patients with chronic active hepatitis B, ICI therapy could be promptly initiated as long as anti-HBV medications were administered simultaneously. CLINICAL TRIAL REGISTRATION NCT04294498.
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Affiliation(s)
- Yu-Yun Shao
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.
| | - Ching-Tso Chen
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Oncology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan
| | - Chien-Huai Chuang
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Tung-Hung Su
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Ming-Chih Ho
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- Department of Surgery, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan
| | - Tai-Chung Tseng
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Tsung-Hao Liu
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Tsung-Che Wu
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Oncology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan
| | - Ann-Lii Cheng
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chih-Hung Hsu
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
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Tanaka K, Sugisaka J, Shiraishi Y, Watanabe Y, Daga H, Azuma K, Nishino K, Mori M, Ota T, Saito H, Hata A, Sakaguchi T, Kozuki T, Akamatsu H, Matsumoto H, Tachihara M, Wakuda K, Sato Y, Ozaki T, Tsuchiya-Kawano Y, Yamamoto N, Nakagawa K, Okamoto I. Serum VEGF-A as a biomarker for the addition of bevacizumab to chemo-immunotherapy in metastatic NSCLC. Nat Commun 2025; 16:2825. [PMID: 40121197 PMCID: PMC11929838 DOI: 10.1038/s41467-025-58186-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 03/07/2025] [Indexed: 03/25/2025] Open
Abstract
Anti-vascular endothelial growth factor (VEGF) agents in combination with immunotherapies have improved outcomes for cancer patients, but predictive biomarkers have not been elucidated. We report here a preplanned analysis in the previously reported APPLE study, a phase 3 trial evaluating the efficacy of the bevacizumab in combination with atezolizumab, plus platinum chemotherapy in metastatic, nonsquamous non-small cell lung cancer (NSCLC). We investigated the correlation of serum VEGF-A and its isoforms at baseline with treatment response by using an enzyme-linked immunosorbent assay. We reveal that the addition of bevacizumab significantly improves the progression-free survival in patients with the low VEGF-A level. Our results demonstrate that measuring serum VEGF-A or its isoforms may identify NSCLC patients who are likely to benefit from the addition of bevacizumab to immunotherapy. These assays are easy to measure and have significant potential for further clinical development.
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Affiliation(s)
- Kentaro Tanaka
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
| | - Jun Sugisaka
- Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Japan
| | - Yoshimasa Shiraishi
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | - Haruko Daga
- Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan
| | - Koichi Azuma
- Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Kazumi Nishino
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Masahide Mori
- Department of Thoracic Oncology, NHO Osaka Toneyama Medical Center, Toyonaka, Japan
| | - Takayo Ota
- Department of Breast Medical Oncology, Izumi City General Hospital, Izumi, Japan
| | - Haruhiro Saito
- Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan
| | - Akito Hata
- Division of Thoracic Oncology, Kobe Minimally Invasive Cancer Center, Kobe, Japan
| | | | - Toshiyuki Kozuki
- Department of Thoracic Oncology and Medicine, NHO Shikoku Cancer Center, Matsuyama, Japan
| | - Hiroaki Akamatsu
- Internal Medicine III, Wakayama Medical University, Wakayama, Japan
| | - Hirotaka Matsumoto
- Department of Respiratory Medicine, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Japan
| | - Motoko Tachihara
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kazushige Wakuda
- Division of Thoracic Oncology, Shizuoka Cancer Center Hospital, Nagaizumi, Japan
| | - Yuki Sato
- Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan
| | - Tomohiro Ozaki
- Department of Medical Oncology, Kishiwada City Hospital, Osaka, Japan
| | - Yuko Tsuchiya-Kawano
- Department of Respiratory Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | - Nobuyuki Yamamoto
- Department of Thoracic Oncology and Medicine, NHO Shikoku Cancer Center, Matsuyama, Japan
| | - Kazuhiko Nakagawa
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Isamu Okamoto
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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47
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Liu D, Liu L, Zhao X, Zhang X, Chen X, Che X, Wu G. A comprehensive review on targeting diverse immune cells for anticancer therapy: Beyond immune checkpoint inhibitors. Crit Rev Oncol Hematol 2025; 210:104702. [PMID: 40122356 DOI: 10.1016/j.critrevonc.2025.104702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/02/2025] [Accepted: 03/07/2025] [Indexed: 03/25/2025] Open
Abstract
Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, primary resistance and acquired resistance continue to limit their efficacy for many patients. To address resistance and enhance the anti-tumor activity within the tumor immune microenvironment (TIME), numerous therapeutic strategies targeting both innate and adaptive immune cells have emerged. These include combination therapies with ICIs, chimeric antigen receptor T-cell (CAR-T), chimeric antigen receptor macrophages (CAR-Ms) or chimeric antigen receptor natural killer cell (CAR-NK) therapy, colony stimulating factor 1 receptor (CSF1R) inhibitors, dendritic cell (DC) vaccines, toll-like receptor (TLR) agonists, cytokine therapies, and chemokine inhibition. These approaches underscore the significant potential of the TIME in cancer treatment. This article provides a comprehensive and up-to-date review of the mechanisms of action of various innate and adaptive immune cells within the TIME, as well as the therapeutic strategies targeting each immune cell type, aiming to deepen the understanding of their therapeutic potential.
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Affiliation(s)
- Dequan Liu
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Lei Liu
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Xinming Zhao
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Xiaoman Zhang
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Xiaochi Chen
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
| | - Xiangyu Che
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
| | - Guangzhen Wu
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
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Hu H, Ning S, Liu F, Zhang Z, Zeng W, Liu Y, Liao Z, Zhang H, Zhang Z. Hafnium Metal-Organic Framework-Based Glutamine Metabolism Disruptor For Potentiating Radio-Immunotherapy in MYC-Amplified Hepatocellular Carcinoma. ACS APPLIED MATERIALS & INTERFACES 2025. [PMID: 40116395 DOI: 10.1021/acsami.4c21998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/23/2025]
Abstract
Hepatocellular carcinoma (HCC) with MYC oncogene amplification remains a serious challenge in clinical practice. Recent advances in comprehensive treatment strategies, particularly the combination of radiotherapy and immunotherapy, offer new hope. To further improve efficacy while lowering radiation doses, nanopharmaceuticals based on high-Z elements have been extensively studied in radio-immunotherapy. In this work, a hafnium-based metal-organic framework (Hf-MOF), UiO-66-Hf(2OH)-CB-839/BSO@HA (UiO-66-Hf(2OH)-C/B@HA), was designed to codeliver telaglenastat (CB-839) and buthionine sulfoximine (BSO), which synergistically inhibited glutamine metabolism and alleviated tumor hypoxia. Further modification with hyaluronic acid (HA) enhanced tumor targeting, ultimately strengthening the efficacy of radiotherapy in MYC-amplified HCC. Beyond increasing reactive oxygen species (ROS) generation, promoting DNA damage, and inducing tumor apoptosis, more importantly, UiO66-Hf(2OH)-C/B@HA triggered immunogenic cell death (ICD), driving the antitumor immune response. Combination with immune checkpoint blockade (ICB) further enhanced the efficacy, accompanied by increased infiltration of T cells with high granzyme B expression (GZMB+ T cells) within the tumor microenvironment (TME). In the orthotopic HCC model, established with MYC-amplified tumor cells, intravenous administration of UiO66-Hf(2OH)-C/B@HA significantly potentiated the efficacy of radio-immunotherapy, resulting in superior tumor regression. In summary, our study provides insights into the design of Hf-MOF for radio-immunotherapy and proposes a promising therapeutic approach for MYC-amplified HCC.
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Affiliation(s)
- Haofan Hu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan 430030, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences; NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China
| | - Shangwu Ning
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan 430030, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences; NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China
| | - Furong Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan 430030, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences; NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China
| | - Ze Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan 430030, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences; NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China
| | - Weifeng Zeng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan 430030, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences; NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China
| | - Yachong Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan 430030, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences; NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China
| | - Zhibin Liao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan 430030, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences; NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China
| | - Hongwei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan 430030, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences; NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan 430030, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences; NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China
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49
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Anders M, Mattos AZ, Debes JD, Beltran O, Coste P, Marín JI, Chagas AL, Menéndez J, Estupiñan EC, Ferrer JD, Mattos AA, Piñero F. Latin American expert opinion letter on the feasibility of systemic therapies in combination with locoregional therapies for hepatocellular carcinoma. Ann Hepatol 2025:101905. [PMID: 40122521 DOI: 10.1016/j.aohep.2025.101905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 12/26/2024] [Accepted: 01/10/2025] [Indexed: 03/25/2025]
Abstract
Recent advances in the systemic treatment of advanced hepatocellular carcinoma (HCC) with immunotherapy have once again reignited discussion over the role of combined therapy in earlier stages. This year, different international meetings have presented recent results from clinical trials on adjuvant therapy alone (IMBrave-050) and combined with transarterial chemoembolization (EMERALD-1 and LEAP-12). Increased enthusiasm for the use of adjuvant and neoadjuvant therapy for liver transplantation, surgery, and local-regional treatment of HCC has been shown. However, the initial results from these trials should be interpreted cautiously as we wait for final analyses and effects on overall survival. In this position paper from the special interest group from the Latin American Association for the Study of Liver Diseases (ALEH), we underline the caveats of the applicability of these potential treatments in our region, explore points of agreement, and highlight areas of uncertainty. Moreover, we underscore the role of hepatologists in the clinical decision-making process and management of these patients.
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Affiliation(s)
- Margarita Anders
- Hepatología y trasplante hepático. Hospital Alemán, Buenos Aires, Argentina.
| | - Angelo Z Mattos
- Graduate Program in Medicine: Hepatology. Federal University of Health Sciences of Porto Alegre, Brazil
| | - José D Debes
- Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | | | - Pablo Coste
- Programa Nacional de Trasplante Hepático, Hospital R.A. Calderón Guardia, Costa Rica
| | | | - Aline Lopes Chagas
- Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Josemaría Menéndez
- Programa Nacional de Trasplante Hepático, Hospital Militar, Montevideo, Uruguay
| | - Enrique Carrera Estupiñan
- Hospital Eugenio Espejo, Departamento de Gastroenterología. Universidad San Francisco de Quito, Ecuador
| | | | - Angelo A Mattos
- Graduate Program in Medicine: Hepatology. Federal University of Health Sciences of Porto Alegre, Brazil
| | - Federico Piñero
- Hospital Universitario Austral, Austral University, School of Medicine, Buenos Aires, Argentina
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50
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Vargas-Accarino E, Higuera M, Bermúdez-Ramos M, Soriano-Varela A, Torrens M, Pons M, Aransay AM, Martín JE, Rodríguez-Frías F, Merino X, Mínguez B. Harnessing Plasma Biomarkers to Predict Immunotherapy Outcomes in Hepatocellular Carcinoma: The Role of cfDNA, ctDNA, and Cytokines. Int J Mol Sci 2025; 26:2794. [PMID: 40141436 PMCID: PMC11942713 DOI: 10.3390/ijms26062794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/07/2025] [Accepted: 03/17/2025] [Indexed: 03/28/2025] Open
Abstract
Immunotherapy has improved survival in patients with advanced hepatocellular carcinoma (HCC); yet, objective radiological responses occur in only about 20% of cases, suggesting variable benefits. This study aimed to identify serologic markers predictive of response to immune checkpoint inhibitors (ICIs). A cohort of 38 advanced HCC patients receiving immunotherapy was prospectively analyzed. Levels of cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), and cytokines were measured pre-treatment and three months post-treatment initiation. Genomic profiling of ctDNA was also conducted. Baseline levels of cfDNA and ctDNA effectively discriminated HCC patients based on their radiological response to ICIs. Additionally, individuals with pathologic mutations in the CDKN2A gene exhibited significantly reduced survival. Patients with progressive disease (PD) as their best radiological response had significantly fewer copy number variations (CNVs) than those with a radiological response. Furthermore, levels of IL10, PD1, and TGFβ assessed after three months of treatment showed significant variations correlating with survival status. In conclusion, the analysis of cfDNA, ctDNA, and cytokines may improve treatment selection for HCC patients by predicting their expected response to immunotherapies.
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Affiliation(s)
- Elena Vargas-Accarino
- Liver Cancer Research Group, Liver Diseases, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (M.B.-R.); (A.S.-V.); (M.T.)
- Department of Medicine, Campus de la UAB, Universitat Autònoma de Barcelona (UAB), Bellaterra, 08193 Cerdanyola del Vallès, Spain
| | - Mónica Higuera
- Liver Cancer Research Group, Liver Diseases, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (M.B.-R.); (A.S.-V.); (M.T.)
| | - María Bermúdez-Ramos
- Liver Cancer Research Group, Liver Diseases, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (M.B.-R.); (A.S.-V.); (M.T.)
- Department of Medicine, Campus de la UAB, Universitat Autònoma de Barcelona (UAB), Bellaterra, 08193 Cerdanyola del Vallès, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.P.); (F.R.-F.)
| | - Agnès Soriano-Varela
- Liver Cancer Research Group, Liver Diseases, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (M.B.-R.); (A.S.-V.); (M.T.)
- Liver Unit, Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - María Torrens
- Liver Cancer Research Group, Liver Diseases, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (M.B.-R.); (A.S.-V.); (M.T.)
- Liver Unit, Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - Mònica Pons
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.P.); (F.R.-F.)
- Liver Unit, Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - Ana María Aransay
- Genome Analysis Platform, CIC bioGUNE, 48160 Derio, Spain; (A.M.A.); (J.E.M.)
| | | | - Francisco Rodríguez-Frías
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.P.); (F.R.-F.)
- Microbiology and Biochemistry Department, Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - Xavier Merino
- Radiology Department, Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain;
| | - Beatriz Mínguez
- Liver Cancer Research Group, Liver Diseases, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (M.B.-R.); (A.S.-V.); (M.T.)
- Department of Medicine, Campus de la UAB, Universitat Autònoma de Barcelona (UAB), Bellaterra, 08193 Cerdanyola del Vallès, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.P.); (F.R.-F.)
- Liver Unit, Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
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