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Xu X, Jiang X, Jiang H, Yuan X, Zhao M, Wang Y, Chen G, Li G, Duan Y. Prediction of prognosis of immune checkpoint inhibitors combined with anti-angiogenic agents for unresectable hepatocellular carcinoma by machine learning-based radiomics. BMC Cancer 2025; 25:888. [PMID: 40389888 PMCID: PMC12087138 DOI: 10.1186/s12885-025-14247-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 04/29/2025] [Indexed: 05/21/2025] Open
Abstract
OBJECTIVES This study aims to develop and validate a novel radiomics model utilizing magnetic resonance imaging (MRI) to predict progression-free survival (PFS) in patients with unresectable hepatocellular carcinoma (uHCC) who are receiving a combination of immune checkpoint inhibitors (ICIs) and antiangiogenic agents. This is an area that has not been previously explored using MRI-based radiomics. METHODS 111 patients with uHCC were enrolled in this study. After performing univariate cox regression and the least absolute shrinkage and selection operator (LASSO) algorithms to extract radiological features, the Rad-score was calculated through a Cox proportional hazards regression model and a random survival forest (RSF) model. The optimal calculation method was selected by comparing the Harrell's concordance index (C-index) values. The Rad-score was then combined with independent clinical risk factors to create a nomogram. C-index, time-dependent receiver operating characteristics (ROC) curves, calibration curves, and decision curve analysis were employed to assess the forecast ability of the risk models. RESULTS The combined nomogram incorporated independent clinical factors and Rad-score calculated by RSF demonstrated better prognosis prediction for PFS, with C-index of 0.846, 0.845, separately in the training and the validation cohorts. This indicates that our model performs well and has the potential to enable more precise patient stratification and personalized treatment strategies. Based on the risk level, the participants were classified into two distinct groups: the high-risk signature (HRS) group and the low-risk signature (LRS) group, with a significant difference between the groups (P < 0.01). CONCLUSION The effective clinical-radiomics nomogram based on MRI imaging is a promising tool in predicting the prognosis in uHCC patients receiving ICIs combined with anti-angiogenic agents, potentially leading to more effective clinical outcomes.
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Affiliation(s)
- Xuni Xu
- Department of Radiology, Shaoxing Central Hospital, The Central Affiliated Hospital, Shaoxing University, Shaoxing, 312000, China
- Department of Radiation and Chemotherapy Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xue Jiang
- Department of Pathology, Jinhua Municipal Central Hospital, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
- Department of Radiation and Chemotherapy Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Haoran Jiang
- Department of Radiation and Chemotherapy Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xiaoye Yuan
- Department of Radiation and Chemotherapy Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Mengjing Zhao
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Yuqi Wang
- Department of Radiation and Chemotherapy Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Gang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
| | - Gang Li
- Department of Radiation and Chemotherapy Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Yuxia Duan
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
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Jiang Y, Dong X, Zhang Y, Su F, Zhao L, Shi X, Zhong J. Navigating the complexities: challenges and opportunities in conversion therapy for advanced hepatocellular carcinoma. Clin Exp Med 2025; 25:169. [PMID: 40382739 PMCID: PMC12086121 DOI: 10.1007/s10238-025-01698-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 04/14/2025] [Indexed: 05/20/2025]
Abstract
Primary liver cancer ranks as the sixth most prevalent malignant tumor and stands as the second leading cause of cancer-related mortality globally, posing a significant threat to public health. Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Surgical resection remains the cornerstone treatment for achieving radical cure and prolonged survival in HCC patients. Contrary to Western countries, the majority of HCC patients in China present with hepatitis B virus infection and consequent liver cirrhosis, with most cases diagnosed at an intermediate or advanced stage. This complexity results in a poor prognosis. Recent advancements in local therapeutic techniques and the introduction of systemic therapies, including targeted and immunotherapy agents, have provided new avenues for both clinical and basic conversion therapy for advanced HCC. Integrating multi-dimensional local and systemic therapies, multi-modal sequential, and comprehensive multidisciplinary approaches into the management of HCC patients has demonstrated promising conversion success rates. This holistic management strategy involves combining multiple treatment modalities vertically and coordinating various disciplines horizontally. However, significant challenges remain, including the precise selection of patients eligible for conversion therapy, the optimal choice of conversion therapy regimens, and the accurate determination of surgical timing post-conversion therapy. Addressing these challenges is crucial for hepatobiliary surgeons. High-quality, randomized controlled trials are urgently needed to generate robust evidence for clinical practice. This review aims to synthesize the latest research developments both in China and internationally and examines key issues in the realm of HCC conversion therapy.
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Affiliation(s)
- Yubo Jiang
- Department of Gastroenterology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Science, Jinan, Shandong Province, China
| | - Xiaofeng Dong
- Department of Hepatobiliary, Pancreas and Spleen Surgery, the People's Hospital of Guangxi Zhuang Autonomous Region (Guangxi Academy of Medical Sciences), Nanning, Guangxi Zhuang Autonomous Region, China
| | - Yingying Zhang
- Department of Oncology, Binzhou People's Hospital Affiliated to Shandong First Medical University, Binzhou, Shandong Province, China
| | - Feiyan Su
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Lei Zhao
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Xuetao Shi
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Jingtao Zhong
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
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Wu W, Mao H, Song J, Yang F. Bibliometric analysis of hepatocellular carcinoma and tyrosine kinase inhibitors. Medicine (Baltimore) 2025; 104:e42015. [PMID: 40388796 PMCID: PMC12091622 DOI: 10.1097/md.0000000000042015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 03/13/2025] [Indexed: 05/21/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common malignant tumor globally and in China, and its incidence and mortality rate are increasing year by year, and it faces many challenges and difficulties in treatment. Tyrosine kinase inhibitors (TKIs) have important roles in cell growth, proliferation, and differentiation, and have now become important drugs for cancer treatment. There are no bibliometric studies on liver cancer and TKIs to date. METHODS We retrieved 2848 records from the Web of Science™ Core Collection (WoSCC) database and analyzed them scientifically and metrically using CiteSpace and VOSviewer in terms of temporal and spatial distributions, author distributions, journal distributions, references, and keywords. RESULTS From January 1, 2004, to December 31, 2023, the WoSCC database documented 2848 publications related to tyrosinase inhibitors in HCC, comprising 2151 articles and 697 reviews. This literature involved 80 countries and regions, 3265 institutions, and 16,653 authors. Analysis shows a steady increase in publications annually since 2004, divided into 3 phases: 2004 to 2010 with fewer than 100 papers annually, suggesting minimal research attention; 2011 to 2019 with gradual growth, indicating increasing research interest; and a rapid surge post-2020, peaking in 2023, signaling heightened global interest in this field. CONCLUSION Our bibliometric analysis on TKIs and HCC spans years, countries, institutions, authors, disciplines, and journals. Since 2004, this field has gained attention, with current research focusing on inflammatory and immune mechanisms, associated diseases, cytokines, and TKIs' applications in liver cancer treatment, including combination therapies. These areas signify emerging research directions.
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Affiliation(s)
- Wurihan Wu
- Department of Neurology Department, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Hejun Mao
- Department of Hepatobiliary Surgery, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Jian Song
- Emergency Intensive Care Unit, Inner Mongolia Autonomous Region People’s Hospital, Hohhot, China
| | - Fan Yang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
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Zhou J, Gao M, Zhang S, Guo WW, He W, Zhang M, Chen X, Dongzhi C, Li X, Yuan Y, Ma W. PP1A Modulates the Efficacy of Lenvatinib Plus ICIs Therapy by Inhibiting Ferroptosis in Hepatocellular Carcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2501730. [PMID: 40344394 DOI: 10.1002/advs.202501730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 04/09/2025] [Indexed: 05/11/2025]
Abstract
Advanced hepatocellular carcinoma (HCC) is characterized by poor prognosis, primarily due to limited therapeutic options and resistance to treatment. Although the combination of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has shown promising potential, the underlying mechanisms remain inadequately understood. Here, serine/threonine-specific protein phosphatase (PP1A) is upregulated in Lenvatinib-resistant HCC cells and correlates with poor prognosis. Functional experiments revealed that PP1A promotes HCC progression both in vitro and in vivo. Transcriptomic analysis and ferroptosis metabolite profiling (e.g., ROS, Fe2⁺, lipid-ROS, and GSH) demonstrated that PP1A inhibits Lenvatinib-induced ferroptosis by dephosphorylating Keap1 at site 104. This disruption of the Keap1-Nrf2 interaction enhances the transcription of ferroptosis-related markers and immune checkpoint PD-L1. Notably, single-cell sequencing and co-culture experiments revealed that PP1A knockdown alleviates T cell exhaustion and immune evasion, thereby improving antitumor immunity. In vivo experiments further demonstrated that PP1A knockdown significantly enhances the efficacy of Lenvatinib-ICIs combination therapy. Overall, our findings highlight PP1A as a critical regulator of ferroptosis and antitumor immunity, suggesting its potential as a predictive biomarker and therapeutic target for improving outcomes in advanced HCC.
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Affiliation(s)
- Jitong Zhou
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, P. R. China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, P. R. China
| | - Meng Gao
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, P. R. China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, P. R. China
| | - Shikun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, P. R. China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, P. R. China
| | - Wing-Wa Guo
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, P. R. China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, P. R. China
| | - Wenzhi He
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, P. R. China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, P. R. China
| | - Minghe Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, P. R. China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, P. R. China
| | - Xi Chen
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, P. R. China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, P. R. China
| | - Cairang Dongzhi
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, P. R. China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, P. R. China
| | - Xiaomian Li
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, P. R. China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, P. R. China
| | - Yufeng Yuan
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, P. R. China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, P. R. China
- TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, P. R. China
| | - Weijie Ma
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, P. R. China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, P. R. China
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Lei W, Zhou K, Lei Y, Li Q, Zhu H. Pathogenesis and Systemic Treatment of Hepatocellular Carcinoma: Current Status and Prospects. Mol Cancer Ther 2025; 24:692-708. [PMID: 39417575 DOI: 10.1158/1535-7163.mct-24-0403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/14/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024]
Abstract
Hepatocellular carcinoma (HCC) remains one of the major threats to human health worldwide. The emergence of systemic therapeutic options has greatly improved the prognosis of patients with HCC, particularly those with advanced stages of the disease. In this review, we discussed the pathogenesis of HCC, genetic alterations associated with the development of HCC, and alterations in the tumor immune microenvironment. Then, important indicators and emerging technologies related to the diagnosis of HCC are summarized. Also, we reviewed the major advances in treatments for HCC, offering insights into future prospects for next-generation managements.
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Affiliation(s)
- Wanting Lei
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Kexun Zhou
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ye Lei
- College of Liberal Arts, Neijiang Normal University, Neijiang, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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Tong J, Tan Y, Ouyang W, Chang H. Targeting immune checkpoints in hepatocellular carcinoma therapy: toward combination strategies with curative potential. Exp Hematol Oncol 2025; 14:65. [PMID: 40317077 PMCID: PMC12046748 DOI: 10.1186/s40164-025-00636-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 03/07/2025] [Indexed: 05/04/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer characterized by poor immune cell infiltration and a strongly immunosuppressive microenvironment. Traditional treatments have often yielded unsatisfactory outcomes due to the insidious onset of the disease. Encouragingly, the introduction of immune checkpoint inhibitors (ICIs) has significantly transformed the approach to HCC treatment. Moreover, combining ICIs with other therapies or novel materials is considered the most promising opportunity in HCC, with some of these combinations already being evaluated in large-scale clinical trials. Unfortunately, most clinical trials fail to meet their endpoints, and the few successful ones also face challenges. This indicates that the potential of ICIs in HCC treatment remains underutilized, prompting a reevaluation of this promising therapy. Therefore, this article provides a review of the role of immune checkpoints in cancer treatment, the research progress of ICIs and their combination application in the treatment of HCC, aiming to open up avenues for the development of safer and more efficient immune checkpoint-related strategies for HCC treatment.
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Affiliation(s)
- Jing Tong
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
| | - Yongci Tan
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
| | - Wenwen Ouyang
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
| | - Haocai Chang
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China.
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China.
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Jiang K, Liu M, Zhao X, Wang S, Ling Y, Qiao L, Tu J, Peng Z. Evaluation of surrogate endpoints in phase III randomized control trials of advanced hepatocellular carcinoma treated with immune checkpoint inhibitors. Eur J Clin Pharmacol 2025; 81:727-737. [PMID: 40080137 DOI: 10.1007/s00228-025-03820-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] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 02/28/2025] [Indexed: 03/15/2025]
Abstract
PURPOSE Overall survival (OS) is recommended as a gold standard endpoint but has some limitations. We aimed to finding more effective surrogate endpoints for advanced hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICIs). METHODS Three online databases were searched for randomized control trials (RCTs) on HCC, published between January 2015 and July 2023, that evaluated ICIs and reported progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and OS. The correlation between the potential surrogate endpoints and OS was evaluated at the trial, arm, and patient levels. The prediction models were validated in single-arm or non-RCTs. Individual data were collected from a real-world (RW) cohort with advanced HCC underwent ICI monotherapy at three tertiary medical centers in China. RESULTS Ten RCTs (6023 participants) with 11 comparisons were included. PFS had a moderately significant association with OS (R2 = 0.50, p = 0.014). ORR, DCR, and OS showed weak correlations. On limiting the analysis to ICI monotherapy studies, the correlations of OS with PFS became stronger (R2 = 0.85, p = 0.02). The RW cohort also verified that PFS was closely related to OS when patient received with ICI monotherapy. CONCLUSION PFS are recommended as surrogate markers in patients with advanced HCC treated with ICI monotherapy.
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Affiliation(s)
- Ke Jiang
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2Nd Rd, Guangzhou, 510080, China
- Cancer Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Miaowen Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2Nd Rd, Guangzhou, 510080, China
- Cancer Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xiao Zhao
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2Nd Rd, Guangzhou, 510080, China
- Cancer Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Shutong Wang
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yunyan Ling
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2Nd Rd, Guangzhou, 510080, China
- Cancer Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Liangliang Qiao
- Department of Interventional Oncology, Jinshazhou Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510000, China
| | - Jianfei Tu
- Cancer Center, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China.
| | - Zhenwei Peng
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2Nd Rd, Guangzhou, 510080, China.
- Cancer Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China.
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Yu J, Li Y, Yang Y, Guo H, Chen Y, Yi P. PD-1 inhibitors improve the efficacy of tyrosine kinase inhibitors combined with transcatheter arterial chemoembolization in advanced hepatocellular carcinoma: a meta-analysis and trial sequential analysis. Scand J Gastroenterol 2025; 60:472-484. [PMID: 40152031 DOI: 10.1080/00365521.2025.2479193] [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: 11/20/2024] [Revised: 02/21/2025] [Accepted: 03/09/2025] [Indexed: 03/29/2025]
Abstract
BACKGROUND This meta-analysis and trial sequential analysis (TSA) aimed to evaluate the efficacy and safety of triple therapy with tyrosine kinase inhibitors (TKIs) combined with transcatheter arterial chemoembolization (TACE) plus programmed death 1 (PD-1) inhibitors (T-T-P) and dual therapy with TKIs combined with TACE (T-T) for the treatment of advanced unresectable hepatocellular carcinoma (uHCC). METHODS Literature related to the efficacy of TKIs combined with TACE plus PD-1 inhibitors in uHCC was searched using the Embase, PubMed, and Cocrane libraries. TSA was used to reduce false positive results due to random error. RESULTS Seventeen articles were included in this meta-analysis, including 2,561 patients. In the T-T-P group, OS [HR 0.45, 95% confidence interval (CI) 0.39-0.52; p = 0.000], PFS [HR 0.43, 95% CI 0.38 - 0.48; p = 0.000], were significantly prolonged compared to those in the T-T group; ORR (RR 1.59 [95% CI 1.39-1.81]; p = 0.000) and DCR (RR 1.26 [95% CI 1.15-1.37]; p = 0.000) were significantly higher. TSA analysis showed early results without further testing. Prognostic factor analysis demonstrated that portal vein tumor thrombus (PVTT) and extrahepatic metastasis were common independent risk factors for OS and PFS. Regarding grade 3/4 adverse events results showed no statistically significant differences in any of them. CONCLUSIONS Compared with T-T treatment group, the T-T-P treatment group exhibited a notable improvement in OS and PFS, particularly in cases of PVTT and extrahepatic metastasis. Furthermore, it can markedly enhance the ORR and DCR in patients with uHCC.
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Affiliation(s)
- Jiahui Yu
- Department of hepato-biliary-pancrease II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, P. R. China
| | - Yong Li
- Department of hepato-biliary-pancrease II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, P. R. China
| | - Yuting Yang
- Department of Educational Technology, Institute of Education, China West Normal University, Nanchong, Sichuan, P. R. China
| | - Hao Guo
- Department of hepato-biliary-pancrease II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, P. R. China
| | - Yimiao Chen
- Department of hepato-biliary-pancrease II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, P. R. China
| | - Pengsheng Yi
- Department of hepato-biliary-pancrease II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, P. R. China
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Almuradova E, Izzo D, Gandini S, Gaeta A, Giordano E, Valenza C, Antonarelli G, Trapani D, Curigliano G. From Dose-Finding to Dose-Optimization in Early-Phase oncology clinical trials. Cancer Treat Rev 2025; 136:102906. [PMID: 40157116 DOI: 10.1016/j.ctrv.2025.102906] [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: 01/22/2025] [Revised: 02/19/2025] [Accepted: 02/20/2025] [Indexed: 04/01/2025]
Abstract
Dose optimization in Phase I oncology trials balances therapeutic efficacy and patient safety. Traditional dose-escalation methods, such as the 3 + 3 design, primarily focus on safety, often resulting in prolonged exposure to subtherapeutic or excessively toxic doses. Additionally, these methods may fail to account for modern therapies' complex pharmacokinetics and pharmacodynamics, including targeted agents and immunotherapies. Contemporary approaches address these gaps by incorporating biomarkers, pharmacokinetic profiling, and patient-reported outcomes to guide personalized dosing strategies. Such methods improve the precision of dose selection and promote individualized cancer care. This review underscores the importance of distinguishing between dose-finding and dose optimization, advocating for designs that integrate patient perspectives and pharmacologic insights from early-phase trials. Additionally, we highlight the challenges of traditional methodologies and the importance of simplifying complex designs without compromising their scientific rigor. By embracing innovative approaches and patient-centered metrics, Phase I trials can evolve beyond safety assessments to expedite the delivery of effective and tailored cancer therapies.
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Affiliation(s)
- Elvina Almuradova
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Ege University Hospital, Department of Medical Oncology, Izmir, Turkey
| | - Davide Izzo
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Sara Gandini
- Experimental Oncology, European Institute of Oncology, IRCCS, Milan, Italy
| | - Aurora Gaeta
- Experimental Oncology, European Institute of Oncology, IRCCS, Milan, Italy
| | - Edoardo Giordano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Carmine Valenza
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; Harvard Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Gabriele Antonarelli
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Dario Trapani
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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10
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Maruyama Y, Saito M, Nakajima S, Saito K, Suzuki H, Kanoda R, Okayama H, Hanayama H, Sakamoto W, Saze Z, Momma T, Mimura K, Goto A, Kono K. Lenvatinib suppress FGF19-FGFR4 signaling to enhance antitumor immune response in gastric cancer. Gastric Cancer 2025; 28:397-408. [PMID: 39948303 DOI: 10.1007/s10120-025-01596-9] [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: 10/20/2024] [Accepted: 01/31/2025] [Indexed: 04/13/2025]
Abstract
BACKGROUND Fibroblast growth factor receptor (FGFR) 4 is overexpressed in gastric cancer (GC) and is a potential therapeutic target for GC. Since the FGF/FGFR signaling is involved in tumor microenvironment inducing the formation of an immunosuppression, lenvatinib is expected to inhibit FGFR4 leading to reduced tumor PD-L1 levels and regulatory T cell (Treg) infiltration, improving pembrolizumab efficacy. This study explored the background of the molecular mechanisms underlying the therapeutic efficacy of lenvatinib plus pembrolizumab. METHODS Expression of FGFR4 and its specific ligand FGF19 was assessed by immunohistochemical staining and clinicopathological relevance was also examined. The effect of lenvatinib on FGF19-FGFR4 signaling was evaluated using cellular experiments. Lastly, the expression of FGFR4 on Treg cells was evaluated by immunostaining and flow cytometry. The Cancer Genome Atlas cBioPortal and Gene Expression Omnibus microarray databases were accessed to support these results. RESULTS High FGFR4 expression was associated with histological type and venous invasion and predominantly detected in human epidermal growth factor receptor 2 and Epstein-Barr virus-positive GC. Bioinformatics data suggested that FGF19-FGFR4 signaling was activated in GC, and cellular experiments showed that lenvatinib reduced FGFR4 and PD-L1 expression in GC cells. Results of integrating various analyses suggested that FGFR4 did not seem to be enough expressed on Treg cells in GC. CONCLUSIONS The FGF19-FGFR4 signaling has a pivotal role in gastric tumorigenesis and may be involved in immunosuppression through PD-L1 modification. But, lenvatinib may not regulate immune editing by directly inhibiting FGFR4 on Treg cells.
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Affiliation(s)
- Yuya Maruyama
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
| | - Motonobu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan.
| | - Shotaro Nakajima
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
- Department of Multidisciplinary Treatment of Cancer and Regional Medical Support, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Katsuharu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
| | - Hiroya Suzuki
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
| | - Ryo Kanoda
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
| | - Hirokazu Okayama
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
| | - Hiroyuki Hanayama
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
| | - Wataru Sakamoto
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
| | - Zenichiro Saze
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
| | - Tomoyuki Momma
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
| | - Kosaku Mimura
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
- Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Akiteru Goto
- Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, Akita, Japan
| | - Koji Kono
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
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11
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Miri H, Rahimzadeh P, Hashemi M, Nabavi N, Aref AR, Daneshi S, Razzaghi A, Abedi M, Tahmasebi S, Farahani N, Taheriazam A. Harnessing immunotherapy for hepatocellular carcinoma: Principles and emerging promises. Pathol Res Pract 2025; 269:155928. [PMID: 40184729 DOI: 10.1016/j.prp.2025.155928] [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: 06/30/2024] [Revised: 03/12/2025] [Accepted: 03/26/2025] [Indexed: 04/07/2025]
Abstract
HCC is considered as one of the leadin causes of death worldwide, with the ability of resistance towards therapeutics. Immunotherapy, particularly ICIs, have provided siginficant insights towards harnessing the immune system. The present review introduces the concepts and possibilities of immunotherapy for HCC treatment, emphasizing its underlying mechanisms and capacity to enhance patient results, focusing on both pre-clinical and clinical insights. The functions of TME and immune evasion mechanisms typical of HCC would be evaluated along with how contemporary immunotherapeutic approaches are designed to address these challenges. Furthermore, the clinical application of immunotherapy in HCC is discussed, emphasizing recent trial findings demonstrating the effectiveness and safety of drugs. In addition, the problems caused by immune evasion and resistance would be discussed to increase potential of immunotherapy along with combination therapy.
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Affiliation(s)
- Hossein Miri
- Faculty of Medicine, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Amir Reza Aref
- Department of Vitro Vision, DeepkinetiX, Inc, Boston, MA, USA
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University Of Medical Sciences, Jiroft, Iran
| | - Alireza Razzaghi
- Social Determinants of Health Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Maryam Abedi
- Department of Pathology, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Safa Tahmasebi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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12
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Cai J, Zhang P, Cai Y, Zhu G, Chen S, Song L, Du J, Wang B, Dai W, Zhou J, Fan J, Yu Y, Dai Z. Lactylation-Driven NUPR1 Promotes Immunosuppression of Tumor-Infiltrating Macrophages in Hepatocellular Carcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2413095. [PMID: 40305758 DOI: 10.1002/advs.202413095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 04/13/2025] [Indexed: 05/02/2025]
Abstract
While checkpoint immunotherapy effectively mobilizes T-cell responses against tumors, its success in hepatocellular carcinoma (HCC) is frequently undermined by immunosuppressive myeloid cells within the tumor microenvironment. This study investigates the role of nuclear protein 1 (NUPR1), a gene prominently expressed in tumor-associated macrophages (TAMs), in mediating this suppression and influencing immunotherapy outcomes. Through comprehensive analysis of single-cell RNA sequencing (scRNA-seq) datasets and functional assays in vitro and in vivo, NUPR1 is identified as a critical regulator within TAMs. The upregulation of NUPR1 is associated with enhanced M2 macrophage polarization and increased expression of immune checkpoints PD-L1 and SIRPA, resulting in CD8+ T cell exhaustion and a diminished response to immunotherapy. Mechanistically, NUPR1 inhibits the ERK and JNK signaling pathways, thereby creating an immunosuppressive milieu conducive to tumor progression. Additionally, tumor-derived lactate is shown to upregulate NUPR1 expression in macrophages via histone lactylation, perpetuating a feedback loop that intensifies immune suppression. Pharmacological targeting of NUPR1 reverses M2 polarization, curtails tumor growth, and augments the efficacy of PD-1 blockade in preclinical models, positioning NUPR1 as both a potential biomarker for immunotherapy responsiveness and a therapeutic target to boost immunotherapy efficacy in HCC.
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Affiliation(s)
- Jialiang Cai
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China
| | - Peiling Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China
| | - Yufan Cai
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Guiqi Zhu
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, 100000, China
| | - Shiping Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China
| | - Lina Song
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China
| | - Junxian Du
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Biao Wang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Weixing Dai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, 100000, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, 100000, China
| | - Yiyi Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
- Cancer Center, Zhongshan Hospital Fudan University, Shanghai, 200032, China
| | - Zhi Dai
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China
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13
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Ding C, Ma L, Liang Y, Zhang Z, Wu Q, Lyu J, Su L. Gastrointestinal adverse events associated with Lenvatinib versus Lenvatinib plus Pembrolizumab: A pharmacovigilance study in FDA adverse event reporting system. Sci Rep 2025; 15:15047. [PMID: 40301541 PMCID: PMC12041505 DOI: 10.1038/s41598-025-99773-4] [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: 05/26/2024] [Accepted: 04/22/2025] [Indexed: 05/01/2025] Open
Abstract
This study aimed to empirically analyze gastrointestinal adverse events associated with Lenvatinib monotherapy and its combination with Pembrolizumab using FDA FAERS data (January 2015-December 2023), focusing on risk profiles, temporal patterns, and influencing factors. Proportional disproportionality analysis (ROR, PRR, BCPNN, EBGM) evaluated drug-AE associations. Kaplan-Meier curves characterized temporal distributions, while Wilcoxon rank-sum test compared median time-to-onset between regimens. Univariate logistic regression identified independent risk factors. A total of 291 severe gastrointestinal AEs reports were included. The gastrointestinal system had the most positive AE signals in both treatment groups. Perforation events showed strong positive signals in both regimens, while haemorrhage and fistula events were unique positive signals in the lenvatinib monotherapy group. In contrast, colitis and pancreatitis positive signals were more common in the combination therapy group. Most gastrointestinal AEs in both groups occurred within the first month of treatment. The monotherapy group had a significantly shorter median onset time than the combination therapy group (27 days vs. 38 days, P = 0.003). Logistic regression indicated that female sex (OR = 0.195, P = 0.022) and low-dose medication (OR = 0.240, P = 0.049) were independent protective factors for gastrointestinal AEs in the monotherapy group. This first comprehensive comparison reveals distinct gastrointestinal toxicity profiles: monotherapy predisposes to acute bleeding/fistulas, while combination therapy increases delayed tumor-related complications. Intensive monitoring during the first treatment month and gender/dosage-adjusted prevention strategies are recommended. These findings provide evidence-based insights for optimizing safety management of targeted-immunotherapy combinations.
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Affiliation(s)
- Chufeng Ding
- Department of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Lin Ma
- Department of Pharmacy, School of Food Science and Engineering, South China University of Technology, Guangzhou, Guangdong, China
- Department of Pharmacy, Guangdong Hospital of Traditional Chinese Medicine, Guangzhou, China
| | - Yankun Liang
- Department of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Zhenpo Zhang
- Department of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Qimin Wu
- Department of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Jun Lyu
- Department of Clinical Research, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China.
| | - Ling Su
- Department of Pharmacy, Jinan University, Guangzhou, Guangdong, China.
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14
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Huang S, Liu A, Yu X, Qiu Z, Weng G, Liu D, Wang Y, Zhuo Y, Yao L, Yang M, Lin H, Ke X. A prediction model for moderate to severe pain in primary hepatic carcinoma after chemotherapy: a multi-center prospective case‒control study. Sci Rep 2025; 15:14415. [PMID: 40280983 PMCID: PMC12032026 DOI: 10.1038/s41598-025-90814-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 02/17/2025] [Indexed: 04/29/2025] Open
Abstract
The incidence of moderate to severe pain after chemotherapy with primary hepatic carcinoma (PHC) patients is high. Although standardized treatment can effectively relieve pain, the control effect is poor. More attention should be paid to the prevention of pain at the beginning of symptoms, so as to reduce the incidence of pain and promote the health of patients. However, there are lack of a prospective design to predict pain before it occurs. The study is a prospective case‒control study. Population was PHC patients who received chemotherapy from April to August to 2024 in three grade 3 and first-class hospital. Data were collected in two periods (on the day of admission and within 24 h of chemotherapy). According to the Brief Pain Inventory, the patients were divided into case group and control group. Then the patients were randomly divided into a training group and an internal validation group at a 2:1 ratio. Single-factor logistics regression was used to analyze the risk factors, and the back-propagation artificial neural network (BP-ANN) model was constructed and verified. A total of 467 patients consisting of 312 training samples and 155 validation samples. BP-ANN model showed the AUC, sensitivity, specificity, and accuracy of prediction were 0.808, 70.6%, 81.7%, 93%, respectively. Internal verification also indicated these indicators were 0.783, 78.8%, 70.8%, and 94.2%, respectively. Significant predictors identified were age > 57.5, BMI > 19.9, symptoms of insomnia prior to illness, worker, Renvastinib, Child-Pugh = B, glutamic oxalacetic transaminase, other platinum drugs, cancer staging of IV, ECOG = 2, NRS-2002 = 3, Oxaliplatin, and Donafenib. The BP-ANN model holds high predictive value for the moderate to severe pain of PHC patients after chemotherapy. In the future, the model can be further visualized to facilitate clinical screening and to provide a basis for subsequent intervention.
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Affiliation(s)
- Siting Huang
- Department of Nursing, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350122, Fujian Province, China
| | - Aiqin Liu
- Department of Nursing, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350122, Fujian Province, China
| | - Xiaoruo Yu
- Department of Nursing, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Zhifeng Qiu
- Department of Nursing, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350122, Fujian Province, China
| | - Guizhen Weng
- Department of Oncology Nursing, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Dun Liu
- The School of Nursing, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Yan Wang
- Department of Nursing, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350122, Fujian Province, China
| | - Yan Zhuo
- Department of Nursing, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350122, Fujian Province, China
| | - Liuqing Yao
- Department of Nursing, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350122, Fujian Province, China
| | - Mei Yang
- Department of Nursing, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350122, Fujian Province, China
| | - Hui Lin
- Department of Nursing, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350122, Fujian Province, China.
| | - Xi Ke
- Department of Nursing, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350122, Fujian Province, China.
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15
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Wang W, Gao X, Niu W, Yin J, He K. Targeting Metabolism: Innovative Therapies for MASLD Unveiled. Int J Mol Sci 2025; 26:4077. [PMID: 40362316 PMCID: PMC12071536 DOI: 10.3390/ijms26094077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 04/01/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
The recent introduction of the term metabolic-dysfunction-associated steatotic liver disease (MASLD) has highlighted the critical role of metabolism in the disease's pathophysiology. This innovative nomenclature signifies a shift from the previous designation of non-alcoholic fatty liver disease (NAFLD), emphasizing the condition's progressive nature. Simultaneously, MASLD has become one of the most prevalent liver diseases worldwide, highlighting the urgent need for research to elucidate its etiology and develop effective treatment strategies. This review examines and delineates the revised definition of MASLD, exploring its epidemiology and the pathological changes occurring at various stages of the disease. Additionally, it identifies metabolically relevant targets within MASLD and provides a summary of the latest metabolically targeted drugs under development, including those in clinical and some preclinical stages. The review finishes with a look ahead to the future of targeted therapy for MASLD, with the goal of summarizing and providing fresh ideas and insights.
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Affiliation(s)
- Weixin Wang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
| | - Xin Gao
- School of Public Health, Jilin University, Changchun 130021, China;
| | - Wentong Niu
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
| | - Jinping Yin
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130041, China;
| | - Kan He
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
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16
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Xu P, Hong C, Liu L, Xiao L. PD-1/PD-L1 blockade therapy in hepatocellular carcinoma: Current status and potential biomarkers. Biochim Biophys Acta Rev Cancer 2025; 1880:189334. [PMID: 40280499 DOI: 10.1016/j.bbcan.2025.189334] [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: 09/21/2024] [Revised: 04/21/2025] [Accepted: 04/21/2025] [Indexed: 04/29/2025]
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death and the sixth most prevalent cancer worldwide. However, most patients with HCC are at an advanced stage at the time of clinical diagnosis, making surgery impossible. In the past, targeted therapeutic drugs such as sorafenib and lenvatinib were the main treatments. With recent breakthroughs in medicine, immunotherapy, particularly immune checkpoint inhibitors (ICIs), has garnered interest and has been extensively studied for clinical treatment. In addition to single-agent therapies, combination regimens involving ICIs have also been developed. Despite this progress, not all patients with HCC benefit from immunotherapy. Therefore, to improve the treatment response rates, it is crucial to identify patients with HCC who are suitable for immunotherapy. The exploration and validation of markers to predict the outcomes of immunotherapeutic treatments in patients with HCC are of clinical importance. In this article, we provide a comprehensive review of research progress in immunotherapy, particularly ICIs and combination therapies, for HCC. Furthermore, we summarize the clinical indicators and tumor markers discovered in recent years to forecast immunotherapy outcomes in patients with HCC. We also outline predictive markers for the occurrence of immune-related adverse events in patients with HCC receiving immunotherapy and discuss future research directions in the immunotherapeutic treatment landscape.
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Affiliation(s)
- Peishuang Xu
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Chang Hong
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Li Liu
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Lushan Xiao
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
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17
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Yao S, Huang Q, Zou Y, Liu T, Yang Y, Huang T, Zhao Y, Dong X. The efficacy and safety of thymosin alpha-1 combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma: a retrospective study. Sci Rep 2025; 15:13960. [PMID: 40263352 PMCID: PMC12015295 DOI: 10.1038/s41598-025-97160-7] [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: 07/18/2024] [Accepted: 04/02/2025] [Indexed: 04/24/2025] Open
Abstract
To validate the efficacy and safety of thymosin α-1 combined with lenvatinib plus sintilimab in the treatment of unresectable hepatocellular carcinoma. Patients with unresectable hepatocellular carcinoma treated with lenvatinib plus sintilimab at the People's Hospital of Guangxi Zhuang Autonomous Region from January 2020 to June 2022 were retrospectively analyzed. The patients were divided into an experimental group and a control group based on their therapeutic regimens: thymosin α-1 plus lenvatinib and sintilimab (experimental group), and lenvatinib plus sintilimab (control group). The primary endpoints were overall survival and progression-free survival. Tumor response was evaluated according to mRECIST criteria, and the partial response, complete response, stable disease, progressive disease, object response rate, and disease control rate of the two groups were compared. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events version 5.0. The median overall survival of all patients was 13.0 months (95% CI 10.587-15.413). The experimental group had a longer median overall survival than the control group (16 months vs. 11 months, P = 0.018). The median progression free survival of all patients was 5.0 months (95% CI 3.721-6.279). The experimental group had a longer median progression-free survival than the control group (7 months vs. 4 months, P = 0.006). The objective response rate of the experimental group was 55.8% (24/43), and of the control group's 34.7% (17/49) (P = 0.042). The disease control rate of the experimental group was 76.7% (33/43), while the control group had a rate of 59.2% (29/49) (P = 0.073). There was no significant difference in the incidence of grade 1-2 adverse events or grade 3-4 adverse events between the two groups (P > 0.05). Thymosin α-1 combined with lenvatinib plus sintilimab is an effective and safe therapeutic regimen in unresectable hepatocellular carcinoma.
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Affiliation(s)
- Siyang Yao
- Department of Hepatobiliary, Pancreas and Spleen Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, 6 Taoyuan Road, Nanning, 530021, China
| | - Qiangsong Huang
- Department of Hepatobiliary, Pancreas and Spleen Surgery, Wuming Hospital of Guangxi Medical University, 26 Yongning Road, Nanning, 530100, China
| | - Yan Zou
- Department of Hepatobiliary, Pancreas and Spleen Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, 6 Taoyuan Road, Nanning, 530021, China
| | - Tianqi Liu
- Department of General Surgery, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, 85 Hedi Road, Nanning, 530021, China
| | - Yongyu Yang
- Department of Hepatobiliary, Pancreas and Spleen Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, 6 Taoyuan Road, Nanning, 530021, China
| | - Tao Huang
- Department of Hepatobiliary, Pancreas and Spleen Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, 6 Taoyuan Road, Nanning, 530021, China
| | - Yuanquan Zhao
- Department of Hepatobiliary, Pancreas and Spleen Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, 6 Taoyuan Road, Nanning, 530021, China
| | - Xiaofeng Dong
- Department of Hepatobiliary, Pancreas and Spleen Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, 6 Taoyuan Road, Nanning, 530021, China.
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Miao YR, Yang XJ. Hepatocellular carcinoma resistance to tyrosine kinase inhibitors: Current status and perspectives. World J Gastrointest Oncol 2025; 17:101528. [PMID: 40235904 PMCID: PMC11995346 DOI: 10.4251/wjgo.v17.i4.101528] [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: 09/18/2024] [Revised: 12/31/2024] [Accepted: 01/08/2025] [Indexed: 03/25/2025] Open
Abstract
The study conducted by Wang et al, focuses on the role of Rho GTPase activating protein 12 (ARHGAP12), in hepatocellular carcinoma (HCC). This research reveals that ARHGAP12 expression, markedly elevated in malignant cells of HCC, correlates strongly with adverse outcomes for patients. Furthermore, the study illustrates that ARHGAP12 enhances the ability of HCC cells to invade and contributes to their resistance to tyrosine kinase inhibitors (TKIs) through modulation of the focal adhesion pathway. To comprehensively investigate the relationship between ARHGAP12 and TKI resistance, this study integrates single-cell and bulk RNA sequencing methodologies along with data from tumor immune single-cell hub 2, Gene Expression Omnibus, The Cancer Genome Atlas, CellMiner, Genomics of Drug Sensitivity in Cancer 2, as well as immunohistochemical staining and proteomic analyses. Statistical analyses, including the Wilcoxon rank-sum test and receiver operating characteristic curve analysis, were employed to evaluate the correlation between ARHGAP12 expression levels and clinical parameters, as well as drug sensitivity. It is evident that a more profound exploration of the molecular dynamics of HCC, especially those related to resistance against TKIs, is essential.
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Affiliation(s)
- Yu-Run Miao
- The First Clinical Medical School, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
- Second Ward of General Surgery, Gansu Province People Hospital, Lanzhou 730000, Gansu Province, China
| | - Xiao-Jun Yang
- Second Ward of General Surgery, Gansu Province People Hospital, Lanzhou 730000, Gansu Province, China
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Xiong T, Wang K. Reconstructing the hepatocellular carcinoma microenvironment: the current status and challenges of 3D culture technology. Discov Oncol 2025; 16:506. [PMID: 40208520 PMCID: PMC11985711 DOI: 10.1007/s12672-025-02290-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 04/01/2025] [Indexed: 04/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC), with high incidence and mortality rates among digestive system diseases, has become a focal point for researchers. However, the more we learn about HCC, the more apparent it becomes that our understanding is still superficial. The successes and failures of numerous studies underscore the urgent need for precision medicine in cancer treatment. A crucial aspect of preclinical research in precision medicine is the experimental model, particularly cell culture models. Among these, 3D cell culture models can effectively integrate and simulate the tumor microenvironment, closely reflecting the in vivo conditions of patients. This capability provides a solid theoretical foundation for personalized treatment approaches. In this review, we first outline the common in vitro 3D cell culture models and examine the essential elements within the tumor microenvironment, followed by insights into the current state and future developments of 3D in vitro cell models for HCC.
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Affiliation(s)
- Ting Xiong
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
- Jiangxi Province Engineering Research Center of Hepatobiliary Disease, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Kai Wang
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
- Jiangxi Provincial Clinical Research Center for General Surgery Disease, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
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20
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Choi J, Gordon A, Eresen A, Zhang Z, Borhani A, Bagci U, Lewandowski R, Kim DH. Current applications of radiomics in the assessment of tumor microenvironment of hepatocellular carcinoma. Abdom Radiol (NY) 2025:10.1007/s00261-025-04916-w. [PMID: 40208284 DOI: 10.1007/s00261-025-04916-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 02/10/2025] [Accepted: 03/25/2025] [Indexed: 04/11/2025]
Abstract
The tumor microenvironment (TME) of hepatocellular carcinoma (HCC) has garnered significant attention, especially with the rise of immunotherapy as a treatment strategy. Radiomics, an innovative technique, offers valuable insights into the intricate structure of the TME. This review highlights recent advancements in radiomics for analyzing the HCC TME, identifies key areas that warrant further research, and explores comprehensive multi-omics approaches that extend the potential of radiomics to new frontiers.
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Affiliation(s)
- Junghwa Choi
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, 60611, USA
| | - Andrew Gordon
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, 60611, USA
| | - Aydin Eresen
- Department of Radiological Sciences, University of California, Irvine, Irvine, USA
| | - Zhuoli Zhang
- Department of Radiological Sciences, University of California, Irvine, Irvine, USA
| | - Amir Borhani
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, 60611, USA
| | - Ulas Bagci
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, 60611, USA
| | - Robert Lewandowski
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, 60611, USA
| | - Dong-Hyun Kim
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, 60611, USA.
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, 60611, USA.
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21
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Zhan J, Huang H, Zhan T, Liu X, Cheng Q. Rare Gingival Metastasis Occurring After Conversion Therapy Followed by Resection of Initially Unresectable Hepatocellular Carcinoma: A Case Report. J Hepatocell Carcinoma 2025; 12:705-713. [PMID: 40226819 PMCID: PMC11994111 DOI: 10.2147/jhc.s514983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Accepted: 03/31/2025] [Indexed: 04/15/2025] Open
Abstract
Gingival metastases from hepatocellular carcinoma (HCC) are exceedingly rare and highly prone to be misdiagnosed without biopsy. Here, we report an initially unresectable HCC patient who received effective conversion therapy but discovered gingival metastasis within one-month post-hepatectomy. A 53-year-old male with a huge liver tumor diagnosed as unresectable HCC received conversion therapy of hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib and tislelizumab. During the conversion therapy, he experienced sore gingiva which was regarded as a side effect of lenvatinib. Considering the significant shrinkage of tumor after 10-month treatment, salvage resection was conducted with negative margin and no postoperative complications. Gingival oligometastases were identified and resected half month after surgery. Throughout the 1-year follow-up period, the patient remained alive; however, there was a recurrence of the gingival metastasis at the same site six months postoperatively. Hence, clinicians should regard gingival swelling and pain not merely as potential adverse events of conversion therapy but also as potential indicators of gingival metastasis.
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Affiliation(s)
- Juncheng Zhan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People’s Republic of China
- Department of Clinical Medicine, Bengbu Medical University, Bengbu, Anhui Province, 233004, People’s Republic of China
| | - Hongwei Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People’s Republic of China
| | - Tianao Zhan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People’s Republic of China
| | - Xinkang Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People’s Republic of China
| | - Qi Cheng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People’s Republic of China
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22
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Liu GM, Guo R, Xu JW. A bibliometric and visual analysis based on immune checkpoint inhibitors for hepatocellular carcinoma: 2014 - 2024. Front Pharmacol 2025; 16:1520055. [PMID: 40260385 PMCID: PMC12009821 DOI: 10.3389/fphar.2025.1520055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 03/24/2025] [Indexed: 04/23/2025] Open
Abstract
Background Immune checkpoint inhibitors (ICIs) have changed the treatment landscape of hepatocellular carcinoma (HCC), especially those with unresectable advanced stages. The field has progressed rapidly, and the research hotspots have significantly changed compared to previous years. The study aims to comprehensively review and analyze the development history, knowledge structure, current research focus, and emerging trends in ICIs for HCC. Materials and methods Reviews and articles published in English from The Web of Science Core Collection (WoSCC) database from 2014 to 2024 were systemically retrieved. Citespace, VOSviewer, and Bibliometrix R package were used for further bibliometric analysis and visualization for countries, institutions, authors, references, and keywords. Results 2,941 records were included for analysis. The literature on ICIs for HCC has continued to grow steadily over the past decade. Three major research centers have emerged: North America, Europe, and East Asia. The Chinese institution has the highest publication volume, but Kudo Masatoshi from Japan has the highest number of publications. At the same time, Richard S. Finn from the United States leads in citations and co-citations. The most prolific journal is "Cancers". The clustering and Timeline view of critical literature and keywords indicated that research on ICIs for HCC is rapidly advancing toward a more evidence-based, personalized, and multimodal approach. Immune evasion mechanisms, predictive biomarkers, and high-quality clinical trials focusing on Novel combination, conversion, and perioperative therapies, including ICIs, are emerging hotspots. Conclusion This study highlights the groundbreaking advancements of ICIs in treating HCC and shows a trend rapidly advancing towards a more evidence-based, personalized, and multimodal approach. The study updated the current understanding of ICIs in hepatocellular carcinoma and identified vital future directions for research, such as the exploration of mechanisms of immune evasion, developing predictive biomarkers, and combining therapy strategies.
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Affiliation(s)
- Gao-Min Liu
- Meizhou Clinical Medical College of Shantou University Medical College, Meizhou, China
- Department of Hepatobiliary Surgery, Meizhou People’s Hospital, Meizhou, China
| | - Rui Guo
- Department of Hepatobiliary Surgery, Meizhou People’s Hospital, Meizhou, China
| | - Ji-Wei Xu
- Meizhou Clinical Medical College of Shantou University Medical College, Meizhou, China
- Department of Hepatobiliary Surgery, Meizhou People’s Hospital, Meizhou, China
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23
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Jiang J, Zhang H, Ou Y, Lai J, Huang Y, Cai W, Li C, Zhang L, Fu Y. The immune-reinforcements of Lenvatinib plus anti-PD-1 and their rationale to unite with TACE for unresectable hepatocellular carcinoma treatment. Immunol Lett 2025; 275:107003. [PMID: 40189154 DOI: 10.1016/j.imlet.2025.107003] [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: 12/17/2024] [Revised: 03/05/2025] [Accepted: 03/26/2025] [Indexed: 04/12/2025]
Abstract
BACKGROUND Despite encouraging clinical benefits have gained by anti-PD-1 and Lenvatinib combination, in-depth characterizations about the mechanisms of action remain poorly characterized. Furthermore, although the combination of systemic anti-PD-1 or Lenvatinib treatment and locoregional transcatheter arterial chemoembolization (TACE) is widely carried out to treat unresectable HCC in clinical, the efficacies of different combination regimens are uncertain due to limited researches. METHODS We firstly generated murine HCC models to validate the enhanced anti-tumor effects of anti-PD-1 and Lenvatinib combination therapy. Then single cell mass cytometry (CyTOF) was employed to phenotypically reveal their mechanisms of action. After that, we further compared the effectiveness of TACE plus Lenvatinib (i.e., TACE-Len) dual therapy with TACE, Lenvatinib plus anti-PD-1 (i.e., TACE-Len-PD-1) triple therapy as conversion therapy for unresectable HCC. RESULTS Lenvatinib and anti-PD-1 combination could generate activated immune profiles not only by increasing systemic CD4+, CD8+T cells and B cells proportions, but also by weakening the immune-tolerance functions derived from both immunosuppressive cells (i.e., MDSCs) and co-inhibitory mediators (i.e., PD-L1 and LAG-3). Meanwhile, our study also suggested that TACE-Len-PD-1 triple therapy could achieve better clinical responses with powerful immune profiles for unresectable HCC compared to TACE-Len dual therapy. CONCLUSIONS Our study provided a delicate immune landscape of anti-PD-1and Lenvatinib combination, and we also offered scientific evidences that TACE-Len-PD-1 triple therapy could fulfill better clinical benefits than TACE-Len dual therapy, which is anticipated to provide objective and effective evidences for clinical use.
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Affiliation(s)
- Jiayun Jiang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University/Army Medical University, Chongqing, 400038, PR China
| | - Hui Zhang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University/Army Medical University, Chongqing, 400038, PR China
| | - Yanjiao Ou
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University/Army Medical University, Chongqing, 400038, PR China
| | - Jiejuan Lai
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University/Army Medical University, Chongqing, 400038, PR China
| | - Yulan Huang
- Medical Research Institute, College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, PR China
| | - Wenyun Cai
- Medical Research Institute, College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, PR China
| | - Chong Li
- Medical Research Institute, College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, PR China.
| | - Leida Zhang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University/Army Medical University, Chongqing, 400038, PR China.
| | - Yu Fu
- Medical Research Institute, College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, PR China.
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24
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Xu J, Li J, Wang T, Luo X, Zhu Z, Wang Y, Wang Y, Zhang Z, Song R, Yang LZ, Wang H, Wong STC, Li H. Predicting treatment response and prognosis of immune checkpoint inhibitors-based combination therapy in advanced hepatocellular carcinoma using a longitudinal CT-based radiomics model: a multicenter study. BMC Cancer 2025; 25:602. [PMID: 40181337 PMCID: PMC11967134 DOI: 10.1186/s12885-025-13978-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 03/19/2025] [Indexed: 04/05/2025] Open
Abstract
BACKGROUND Identifying effective predictive strategies to assess the response of immune checkpoint inhibitors (ICIs)-based combination therapy in advanced hepatocellular carcinoma (HCC) is crucial. This study presents a new longitudinal CT-based radiomics model to predict treatment response and prognosis in advanced HCC patients undergoing ICIs-based combination therapy. METHODS Longitudinal CT images were collected before and during the treatment for HCC patients across three institutions from January 2019 to April 2022. A total of 1316 radiomic features were extracted from arterial and portal venous phase abdominal CT images for each patient. A model called Longitudinal Whole-liver CT-based Radiomics (LWCTR) was developed to categorize patients into responders or non-responders using radiomic features and clinical information through support vector machine (SVM) classifiers. The area under the curve (AUC) was used as the performance metric and subsequently applied for risk stratification and prognostic assessment. The Shapley Additive explanations (SHAP) method was used to calculate the Shapley value, which explains the contribution of each feature in the SVM model to the prediction. RESULTS This study included 395 eligible participants, with a median age of 57 years (IQR 51-66), comprising 344 males and 51 females. The LWCTR model performed well in predicting treatment response, achieving an AUC of 0.883 (95% confidence interval [CI] 0.881-0.888) in the training cohort, 0.876 (0.858-0.895) in the internal validation cohort, and 0.875 (0.860-0.887) in the external test cohort. The Rad-Nomo model, integrating the LWCTR model's prediction score (Rad-score) with the modified Response Evaluation Criteria in Solid Tumors (mRECIST), demonstrated strong prognostic performance. It achieved time-dependent AUC values of 0.902, 0.823, and 0.850 at 1, 2, and 3 years in the internal validation cohort and 0.893, 0.848, and 0.762 at the same intervals in the external test cohort. CONCLUSION The proposed LWCTR model performs well in predicting treatment response and prognosis in patients with HCC receiving ICIs-based combination therapy, potentially contributing to personalized and timely treatment decisions.
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Affiliation(s)
- Jun Xu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, People's Republic of China
- University of Science and Technology of China, Hefei, 230026, People's Republic of China
- Department of Intervention, The First Affiliated Hospital of University of Science and Technology of China, Hefei, 230001, People's Republic of China
- Department of Oncology, Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, People's Republic of China
| | - Junjun Li
- Department of Radiology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, 230001, People's Republic of China
| | - Tengfei Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, People's Republic of China.
- University of Science and Technology of China, Hefei, 230026, People's Republic of China.
- Department of Oncology, Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, People's Republic of China.
| | - Xin Luo
- Yangtze Delta Region Institute (Huzhou) & School of Resources and Environment, University of Electronic Science and Technology of China, Huzhou, Chengdu, 313099, 611731, China
| | - Zhangxiang Zhu
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People's Republic of China
| | - Yimou Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, People's Republic of China
- University of Science and Technology of China, Hefei, 230026, People's Republic of China
| | - Yong Wang
- Department of Radiology, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241001, People's Republic of China
| | - Zhenglin Zhang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, People's Republic of China
- University of Science and Technology of China, Hefei, 230026, People's Republic of China
| | - Ruipeng Song
- Department of Hepatobiliary Surgerydivision of Life Sciences and Medicineanhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, The First Affiliated Hospital of USTC, the University of Science and Technology of China, Hefei, 230001, People's Republic of China
| | - Li-Zhuang Yang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, People's Republic of China
- University of Science and Technology of China, Hefei, 230026, People's Republic of China
- Department of Oncology, Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, People's Republic of China
| | - Hongzhi Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, People's Republic of China
- University of Science and Technology of China, Hefei, 230026, People's Republic of China
- Department of Oncology, Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, People's Republic of China
| | - Stephen T C Wong
- Department of Systems Medicine and Bioengineering, Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, TX, 77030, USA
- Department of Radiology, Weill Cornell Medical College, New York, NY, 10065, United States
| | - Hai Li
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, People's Republic of China.
- University of Science and Technology of China, Hefei, 230026, People's Republic of China.
- Department of Oncology, Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, People's Republic of China.
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25
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Xie D, Liu Y, Xu F, Dang Z, Li M, Zhang Q, Dang Z. Immune microenvironment and immunotherapy in hepatocellular carcinoma: mechanisms and advances. Front Immunol 2025; 16:1581098. [PMID: 40242773 PMCID: PMC12000014 DOI: 10.3389/fimmu.2025.1581098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Accepted: 03/17/2025] [Indexed: 04/18/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally. The tumor microenvironment (TME) plays a pivotal role in HCC progression, characterized by dynamic interactions between stromal components, immune cells, and tumor cells. Key immune players, including tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), cytotoxic T lymphocytes (CTLs), regulatory T cells (Tregs), MDSCs, dendritic cells (DCs), and natural killer (NK) cells, contribute to immune evasion and tumor progression. Recent advances in immunotherapy, such as immune checkpoint inhibitors (ICIs), cancer vaccines, adoptive cell therapy (ACT), and combination therapies, have shown promise in enhancing anti-tumor responses. Dual ICI combinations, ICIs with molecular targeted drugs, and integration with local treatments or radiotherapy have demonstrated improved outcomes in HCC patients. This review highlights the evolving understanding of the immune microenvironment and the therapeutic potential of immunotherapeutic strategies in HCC management.
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Affiliation(s)
- Dong Xie
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
| | - Yang Liu
- College of Traditional Chinese Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Fangbiao Xu
- Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhibo Dang
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
| | - Mengge Li
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
| | - Qinsheng Zhang
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
| | - Zhongqin Dang
- Diagnosis and Treatment Center for Digestive Diseases of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
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26
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Lu Y, Liu Y, Zuo X, Li G, Wang J, Liu J, Wang X, Wang S, Zhang W, Zhang K, Lei X, Hao Q, Li W, Liu L, Li M, Zhang C, Zhang HM, Zhang Y, Gao Y. CXCL12 + tumor-associated endothelial cells promote immune resistance in hepatocellular carcinoma. J Hepatol 2025; 82:634-648. [PMID: 39393439 DOI: 10.1016/j.jhep.2024.09.044] [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: 03/25/2024] [Revised: 09/05/2024] [Accepted: 09/25/2024] [Indexed: 10/13/2024]
Abstract
BACKGROUND & AIMS The tumor microenvironment (TME) plays a crucial role in the limited efficacy of existing treatments for hepatocellular carcinoma (HCC), with tumor-associated endothelial cells (TECs) serving as fundamental TME components that substantially influence tumor progression and treatment efficacy. However, the precise roles and mechanisms of TECs in HCC remain inadequately understood. METHODS We employed a multi-omics profiling strategy to investigate the single-cell and spatiotemporal evolution of TECs within the microenvironment of HCC tumors, showcasing varied responses to immunotherapy. Through an analysis of a clinical cohort of patients with HCC, we explored the correlation between TEC subpopulations and immunotherapy outcomes. The influence of TEC subsets on the immune microenvironment was confirmed through comprehensive in vitro and in vivo studies. To further explore the mechanisms of distinct TEC subpopulations in microenvironmental modulation and their impact on immunotherapy, we utilized TEC subset-specific knockout mouse models as well as humanized mouse models. RESULTS In this study, we identified a new subset of CXCL12+ TECs that exert a crucial role in immune suppression within the HCC TME. Functionally, CXCL12+ TECs impede the differentiation of CD8+ naïve T cells into CD8+ cytotoxic T cells by secreting CXCL12. Furthermore, they attract myeloid-derived suppressor cells (MDSCs). A bispecific antibody was developed to target both CXCL12 and PD1 specifically, showing significant promise in bolstering anti-tumor immune responses and advancing HCC therapy. CONCLUSIONS CXCL12+ TECs are pivotal in mediating immunosuppression within the HCC microenvironment and targeting CXCL12+ TECs presents a promising approach to augment the efficacy of immunotherapies in patients with HCC. IMPACT AND IMPLICATIONS This investigation reveals a pivotal mechanism wherein CXCL12+ tumor-associated endothelial cells (TECs) emerge as crucial modulators of immune suppression in the tumor microenvironment of hepatocellular carcinoma (HCC). The discovery of CXCL12+ TECs as inhibitors of CD8+ naïve T cell activation and recruiters of myeloid-derived suppressor cells significantly advances our grasp of the dynamic between HCC and immune regulation. Moreover, the development and application of a bispecific antibody precisely targeting CXCL12 and PD1 has proven to enhance immune responses in a humanized mouse HCC model. This finding underscores a promising therapeutic direction for HCC, offering the potential to amplify the impact of current immunotherapies.
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Affiliation(s)
- Yajie Lu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China; The Department of Clinical Oncology, Xijing Hospital, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China; Innovation Research Institute, Xijing Hospital, Air Force Medical University, 710032 Xi'an, People's Republic of China
| | - Yunpeng Liu
- The Department of Clinical Oncology, Xijing Hospital, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China
| | - Xiaoshuang Zuo
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China
| | - Guodong Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China
| | - Jianlin Wang
- The Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China
| | - Jianshan Liu
- The Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China
| | - Xiangxu Wang
- The Department of Clinical Oncology, Xijing Hospital, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China; Innovation Research Institute, Xijing Hospital, Air Force Medical University, 710032 Xi'an, People's Republic of China
| | - Shuning Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China
| | - Wangqian Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China
| | - Kuo Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China
| | - Xiaoying Lei
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China
| | - Qiang Hao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China
| | - Weina Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China
| | - Lei Liu
- Innovation Research Institute, Xijing Hospital, Air Force Medical University, 710032 Xi'an, People's Republic of China
| | - Meng Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China
| | - Cun Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China.
| | - Hong-Mei Zhang
- The Department of Clinical Oncology, Xijing Hospital, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China.
| | - Yingqi Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China.
| | - Yuan Gao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China; Innovation Research Institute, Xijing Hospital, Air Force Medical University, 710032 Xi'an, People's Republic of China.
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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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Xu B, Wang LN, Wang ZY, He T, Zhu XD, Shen YH, Zhou J, Fan J, Sun HC, Huang C. Depth of Radiographic Response as an Independent Prognostic Factor for Patients with Initially Unresectable Hepatocellular Carcinoma Receiving Hepatectomy following Targeted Therapy plus Immunotherapy. Liver Cancer 2025; 14:142-157. [PMID: 40255871 PMCID: PMC12005705 DOI: 10.1159/000541300] [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: 04/08/2024] [Accepted: 09/03/2024] [Indexed: 04/22/2025] Open
Abstract
Introduction Surgical resection following systemic therapy is feasible in patients with initially unresectable hepatocellular carcinoma (HCC). However, postoperative tumor recurrence is common after surgery, and the factors affecting this recurrence remain unclear. This study aimed to assess factors influencing postoperative outcomes in patients with initially unresectable HCC undergoing hepatectomy after systemic therapy. Methods This study retrospectively enrolled patients with initially unresectable HCC who underwent hepatectomy after targeted therapy plus immunotherapy (with or without locoregional therapy). Multivariate Cox regression analyses were used to identify the independent prognostic factors for recurrence-free survival (RFS) and overall survival (OS). Machine learning was used to determine the RFS rates at different intervals for different radiographic responses. Results Eighty-one patients who underwent R0 hepatectomy after systemic therapy were included. With a median follow-up of 17.4 (interquartile range: 7.2-22.3) months, median RFS and OS were not reached. Preoperative tumor downstaging and achieving pathological complete response were associated with improved RFS and OS. Multivariate Cox analyses identified radiographic response as an independent prognostic factor for RFS and OS. Furthermore, a radiographic response >40% (assessed using the Response Evaluation Criteria in Solid Tumors, version 1.1) or >50% (assessed using the modified Response Evaluation Criteria in Solid Tumors) was associated with a longer RFS (p = 0.006 and 0.003, respectively). Conclusion Radiographic response depth was an independent prognostic factor in patients with initially unresectable HCC who underwent hepatectomy following targeted therapy plus immunotherapy, and the response to systemic therapy may be the determining factor for patient prognosis after surgery.
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Affiliation(s)
- Bin Xu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lu-Na Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zi-Yi Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tian He
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiao-Dong Zhu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ying-Hao Shen
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hui-Chuan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Cheng Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
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Hong H, Han H, Wang L, Cao W, Hu M, Li J, Wang J, Yang Y, Xu X, Li G, Zhang Z, Zhang C, Xu M, Wang H, Wang Q, Yuan Y. ABCF1-K430-Lactylation promotes HCC malignant progression via transcriptional activation of HIF1 signaling pathway. Cell Death Differ 2025; 32:613-631. [PMID: 39753865 PMCID: PMC11982231 DOI: 10.1038/s41418-024-01436-w] [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: 05/28/2024] [Revised: 12/08/2024] [Accepted: 12/16/2024] [Indexed: 01/12/2025] Open
Abstract
Lysine lactylation plays critical roles in various diseases, including cancer. Our previous study showed that lactylation of non-histone ABCF1 may be involved in hepatocellular carcinoma (HCC) progression. In this study, we evaluated the prognostic value of ABCF1-K430la in HCC using immunohistochemical staining and performed amino acid point mutations, multi-omics crossover, and biochemical experiments to investigate its biological role and underlying mechanism. Additionally, we performed molecular docking on lactylation sites. ABCF1-K430la was highly expressed in HCC tissues and correlated with poor patient prognosis. Functionally, ABCF1-K430la promoted HCC growth and lung metastasis. Mechanistically, upon lactylation, E2 ubiquitin ligase activity of ABCF1 remained unaffected, and ABCF1 entered the nucleus, bound to the KDM3A promoter to upregulate its expression, and activated the KDM3A-H3K9me2-HIF1A axis, challenging the notion that ABCF1 functions exclusively in cytoplasmic protein translation. Notably, we discovered the existence of a lactate-ABCF1(430Kla)-HIF1A-lactate in HCC. A small-molecule drug screen targeting ABCF1-K430la revealed that tubuloside A inhibits ABCF1-K430la and suppresses HCC development. These findings demonstrate that elevated ABCF1-K430la expression promotes HCC development, suggesting it as a potential prognostic biomarker and therapeutic target for HCC.
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Affiliation(s)
- Han Hong
- Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
- Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Hexu Han
- Department of Gastroenterology of the affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China
| | - Lei Wang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wen Cao
- Department of Liver Disease of the affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China
| | - Minjie Hu
- Department of Hepatobiliary Surgery of the affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China
| | - Jindong Li
- Department of Pharmacy of the affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China
| | - Jiawei Wang
- Department of Hepatobiliary Surgery of the affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China
| | - Yijin Yang
- Department of Oncology, Suzhou Kowloon Hospital, Shanghai Jiao Tong University, School of Medicine, Suzhou, China
| | - XiaoYong Xu
- Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Gaochao Li
- Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Zixiang Zhang
- Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Changhe Zhang
- Department of Hepatobiliary Surgery of the affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China.
| | - Minhui Xu
- Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
| | - Honggang Wang
- Department of Gastrointestinal Surgery of the affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China.
| | - Qiang Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University; Innovative Institute of Tumor Immunity and Medicine (ITIM); Anhui Provincial Innovation Institute for Pharmaceutical Basic Research; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, China.
| | - Yin Yuan
- Department of Hepatobiliary Surgery of the affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China.
- Department of Clinical research center, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China.
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Yan H, Xu J, Li Z, Li N, Guo X, Wu M, Wang D, Lin N, Dong J, Xu X. Efficacy of radiotherapy combined with targeted therapy and immunotherapy for lymph node metastasis of liver cancer. J Cancer Res Clin Oncol 2025; 151:129. [PMID: 40169437 PMCID: PMC11961524 DOI: 10.1007/s00432-025-06182-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 03/24/2025] [Indexed: 04/03/2025]
Abstract
PURPOSE To investigate the efficacy and safety of radiotherapy combined with targeted therapy and immunotherapy for liver cancer with lymph node metastasis (LNM). METHODS We analysed patients who received radiotherapy for liver cancer with LNM in our hospital from June 2020 to June 2023. 62 patients were enrolled in this study, who received radiotherapy with a median radiation dose of 60.0 Gy, combined with targeted therapy and/or immunotherapy. The objective response rate (ORR), overall survival (OS), progression free survival (PFS), and adverse events were observed to evaluate treatment efficacy and safety. RESULTS With a median follow-up of 18.5 months, the best ORR was 90.3%. The median OS was 26.0 months. The 1-year and 2-year OS rates were 78.93% and 57.37%, respectively. The median PFS was 17.0 months, and the 1-year and 2-year PFS rates were 59.06% and 49.22%, respectively. Multivariate analysis showed that alanine aminotransferase (HR = 2.34, 95% CI 1.07-5.11, P = 0.033), prothrombin time (HR = 4.51, 95% CI 1.76-11.57, P = 0.002), alpha fetal protein (HR = 2.94, 95% CI 1.34-6.45, P = 0.007), and the volume of LNM (HR = 3.05, 95% CI 1.25-7.46, P = 0.014) were independent predictors for OS, while non-regional LNM (HR = 3.19, 95% CI 1.24-8.16, P = 0.016) was an independent predictor for PFS. Toxicity was generally mild and moderate. CONCLUSIONS Radiotherapy combined with targeted therapy and immunotherapy is an effective treatment option, and expected to become new treatment strategy for liver cancer with LNM.
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Affiliation(s)
- Huamei Yan
- Department of Radiation Oncology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Jianliang Xu
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Zhenghuan Li
- Department of Radiation Oncology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Nuoya Li
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Xianyu Guo
- Department of Radiation Oncology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Manya Wu
- Department of Radiation Oncology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Donghui Wang
- Department of Radiation Oncology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Nan Lin
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
| | - Jie Dong
- Department of Radiation Oncology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
| | - Xiangying Xu
- Department of Radiation Oncology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
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Kong Q, Wang X, Chen Z, Peng W. Efficacy and challenges of combining transarterial chemoembolization with pembrolizumab in advanced hepatocellular carcinoma: insights from the PETAL study. Hepatobiliary Surg Nutr 2025; 14:301-304. [PMID: 40342779 PMCID: PMC12057501 DOI: 10.21037/hbsn-2025-36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 03/04/2025] [Indexed: 05/11/2025]
Affiliation(s)
- Qingyan Kong
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Xiankun Wang
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
- Department of General Surgery, Tibet Hospital, West China Hospital, Sichuan University, Lhasa, China
| | - Zhuyu Chen
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Peng
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
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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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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. [PMID: 40162395 PMCID: PMC11948109 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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Tang P, Zhou F. Efficacy and safety of PD-1/PD-L1 inhibitors combined with tyrosine kinase inhibitors as first-line treatment for hepatocellular carcinoma: a meta-analysis and trial sequential analysis of randomized controlled trials. Front Pharmacol 2025; 16:1535444. [PMID: 40196369 PMCID: PMC11973308 DOI: 10.3389/fphar.2025.1535444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 03/04/2025] [Indexed: 04/09/2025] Open
Abstract
Background The use of immune checkpoint inhibitors (ICIs) in treating hepatocellular carcinoma (HCC) has grown significantly. However, the therapeutic benefits of ICIs alone are notably modest. This meta-analysis assesses the efficacy and safety of using PD-1/PD-L1 inhibitors in conjunction with tyrosine kinase inhibitors (TKIs) for patients with advanced or unresectable HCC. Methods An extensive search of the literature was performed using databases such as PubMed, Web of Science, Embase, and the Cochrane Library, capturing randomized controlled trials (RCTs) until 16 October 2024. Efficacy was measured by progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Safety was gauged through the occurrence of treatment-related adverse events (TRAEs). Hazard ratios (HRs) for PFS and OS, along with risk ratios (RRs) for ORR, DCR, and TRAEs, were calculated, each with 95% confidence intervals (CIs). Heterogeneity among studies was quantified using Cochran's Q test, I2 statistics, and 95% prediction intervals (PIs). Results This analysis incorporated 4 studies with a total of 2,174 patients. Treatment regimens combining PD-1/PD-L1 inhibitors with TKIs significantly improved PFS (HR = 0.694, 95% CI: 0.527-0.914; 95% PI: 0.228-2.114) and ORR (RR = 2.303, 95% CI: 1.360-3.902; 95% PI: 0.408-12.991) compared with first-line monotherapy or TKI monotherapy in the overall population. Subgroup analysis indicated that the improvements in PFS and OS were particularly significant among patients of Asian descent or those with hepatitis B virus (HBV) infection (all p < 0.05). While the occurrence of any grade TRAEs did not differ significantly between the two groups (RR = 1.016, 95% CI: 0.996-1.036; 95% PI: 0.941-1.097), the incidence of serious (RR = 2.068, 95% CI: 1.328-3.222; 95% PI: 0.487-8.776) and grade ≥3 TRAEs (RR = 1.287, 95% CI: 1.020-1.624; 95% PI: 0.574-2.883) increased in patients treated with the combination of PD-1/PD-L1 inhibitors and TKIs. Conclusion This study revealed that combining PD-1/PD-L1 inhibitors with TKIs in the treatment of advanced or unresectable HCC leads to superior clinical outcomes compared to first-line monotherapy or TKIs alone, particularly in patients with HBV infection and those of Asian descent. Clinicians are advised to be vigilant regarding the potential for TRAEs in clinical settings.
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Affiliation(s)
- Peng Tang
- Department of Gastroenterology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Fei Zhou
- Department of Obstetrics and Gynaecology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
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Xu J, Wang X, Jia Z, Sun G. Effectiveness and safety of angiogenesis inhibitors combined with PD-1/PD-L1 blockades in the first-line treatment of patients with advanced hepatocellular carcinoma: A single-center retrospective study. Medicine (Baltimore) 2025; 104:e41814. [PMID: 40101095 PMCID: PMC11922473 DOI: 10.1097/md.0000000000041814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 02/21/2025] [Indexed: 03/20/2025] Open
Abstract
The combination of immune checkpoint inhibitors targeting anti-programmed cell death-1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) with antiangiogenic agents has emerged as a revolutionary therapy for advanced hepatocellular carcinoma (aHCC). Key antiangiogenic medications encompass monoclonal antibodies targeting vascular endothelial growth factor (anti-VEGF mAbs) and multiple kinase inhibitors (MKIs). The aim of this study is to assess the difference of efficacy and safety between 2 combination therapies. This study retrospectively examined the outcomes of 57 patients with aHCC who underwent first-line treatment with a combination of immune checkpoint inhibitors and antiangiogenic therapy at the First Affiliated Hospital of Anhui Medical University, from September 2018 to July 2023. The analysis, conducted using SPSS software, focused on patient outcomes such as tumor response (assessed according to modified Response Evaluation Criteria in Solid Tumors criteria), objective response rate, disease control rate, progression-free survival, overall survival, and safety. Comparisons among different groups were also made. The anti-PD-1/anti-PD-L1-anti-VEGF mAbs group showed a trend of higher partial response rate (37.50% vs 22.45%), objective response rate (37.50% vs 24.49%), disease control rate (62.50% vs 59.18%), and seemed to achieve longer median progression-free survival (14.93 vs 14.90 months) and median overall survival (15.80 vs 11.10 months) without higher grade 3 or higher adverse events comparing to anti-PD-1/anti-PD-L1-MKIs group. Subgroup analysis showed that the anti-PD-1-lenvatinib group achieved longer median progression-free survival (23.97 months), while the anti-PD-1-regorafenib group achieved longer median overall survival (37.97 months). The anti-PD-1/anti-PD-L1 combined with anti-VEGF mAbs was effective and tolerable compared to anti-PD-1/anti-PD-L1-MKIs in aHCC. The addition of lenvatinib or regorafenib may provide promising incremental benefit for patients with aHCC.
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Affiliation(s)
- Jing Xu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Xin Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Zhenya Jia
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Guoping Sun
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
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Li S, Wen Q, Huang W, Qiu Z, Feng L, Yi F. A real-world study of the efficacy of second-line treatment of unresectable hepatocellular carcinoma with esophagogastric varices after progression on first-line lenvatinib combined with PD-1 inhibitor. World J Surg Oncol 2025; 23:83. [PMID: 40082982 PMCID: PMC11905572 DOI: 10.1186/s12957-025-03742-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 03/07/2025] [Indexed: 03/16/2025] Open
Abstract
PURPOSE The incidence and mortality of hepatocellular carcinoma are still high according to National Cancer Center of China. Atezolizumab plus bevacizumab has become one of the standard regimens for the first-line treatment of unresectable hepatocellular carcinoma. However, some patients still use lenvatinib in combination with immunotherapy instead of a standard "atezolizumab-bevacizumab" regimen as a lower risk of bleeding in patients with esophagogastric varices. However, there is no evidence for second-line therapy after progression on lenvatinib combined with PD-1 inhibitor in unresectable hepatocellular carcinoma till now. Herein, we aim to investigate second-line treatment among these patients. PATIENTS AND METHODS Thirty-three patients with unresectable hepatocellular carcinoma with esophagogastric varices were admitted to the Second Affiliated Hospital of Nanchang University from January 2019 to December 2023. They were treated with lenvatinib in combination with PD-1 inhibitor as first line. The efficacy was conducted according to the RECIST1.1 criteria. The endpoints included objective response rate (ORR), disease control rate (DCR), median overall survival (OS), and median progression free survival (PFS). RESULTS We identified a total of 225 patients with unresectable hepatocellular carcinoma with esophagogastric varices who received first-line lenvatinib in combination with PD-1 inhibitor, of whom 33 (14.7%) received second-line therapy. 21 patients (63.6%) were treated with regorafenib combined with PD-1 inhibitor, 6 patients (18.2%) with apatinib plus PD-1 inhibitor, 4 patients (12.1%) with bevacizumab plus PD-1 inhibitor, and the remaining 2 patients with regorafenib or sorafenib as monotherapy, respectively. Of the 33 patients, 2 (6.1%) were evaluated as partial response (PR), 16 (48.5%) had stable disease (SD), and 15 (45.4%) experienced progression (PD). The ORR was 6.1%, and the DCR was 54.6%. Median PFS was 4.5 months, median OS was 7.2 months, and the 12-month OS rate was 27.3%. Overall survival follow-up was done in 37 patients without second line treatment whose baseline levels were matched with those of the treatment group. The OS was 7.2 months in second line treatment group versus 3.0 months in control group (p = 0.04). As for different treatments in a second line, The ORR of regorafenib in combination with PD-1 inhibitor was 9.5%, the DCR was 47.6%, the median PFS was 4.2 months, and the median OS was 5.9 months. None of the patients treated with apatinib plus PD-1 inhibitor got PR, the DCR was 83.3%, the median PFS was 8.7 months, and the median OS was 9.1 months. None of the patients treated with bevacizumab plus PD-1 inhibitor got PR, the DCR was 25.0%, the median PFS was 2.2 months, and the median OS was 6.0 months. CONCLUSION The second-line treatment of unresectable hepatocellular carcinoma with esophagogastric varices after progression on first-line lenvatinib combined with PD-1 inhibitor is effective. Regorafenib or apatinib combined with PD-1 inhibitor might be the preferred options.
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Affiliation(s)
- Saifeng Li
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Minde Road 1, Nanchang, 330006, P. R. China
- Jiangxi Medical College of Nanchang University, Nanchang, 330006, P. R. China
| | - Qin Wen
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Minde Road 1, Nanchang, 330006, P. R. China
- Jiangxi Medical College of Nanchang University, Nanchang, 330006, P. R. China
| | - Wenwu Huang
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Minde Road 1, Nanchang, 330006, P. R. China
- Jiangxi Medical College of Nanchang University, Nanchang, 330006, P. R. China
| | - Zeyu Qiu
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Minde Road 1, Nanchang, 330006, P. R. China
| | - Long Feng
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Minde Road 1, Nanchang, 330006, P. R. China.
| | - Fengming Yi
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Minde Road 1, Nanchang, 330006, P. R. China.
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Zhou Q, Li H, Liang Y, Li R, Wang X, Wang W, Liu M, Duan F, Huang Z. Hepatic arterial infusion chemotherapy combined with lenvatinib and immune checkpoint inhibitor versus lenvatinib for advanced hepatocellular carcinoma: a multicenter study with propensity score and coarsened exact matching. LA RADIOLOGIA MEDICA 2025:10.1007/s11547-025-01975-3. [PMID: 40072804 DOI: 10.1007/s11547-025-01975-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 02/14/2025] [Indexed: 03/14/2025]
Abstract
PURPOSE Hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib (Len) and immune checkpoint inhibitor (ICI) in treating advanced hepatocellular carcinoma (HCC) still needs further confirmation. We aimed to evaluate the efficacy of HAIC combined with Len and ICI (HAIC + Len + ICI) versus Len alone in advanced HCC. METHODS A total of 290 patients in Len group and 349 patients in HAIC + Len + ICI group were analysed. Propensity score matching (PSM), inverse probability treatment weighting (IPTW), and coarsened exact matching (CEM) analyses were used to balance the bias between two groups. Mediation analysis of treatment type in survival was performed for analysis. RESULTS The median progression-free survival (PFS) was 5.9 ± 0.2 months in Len group and 9.2 ± 0.5 months in HAIC + Len + ICI group. The HAIC + Len + ICI group demonstrated significantly better PFS than the Len group across the entire cohort (hazard ratio [HR], 0.50; 95% CI 0.43-0.60; P < 0.001). This advantage in PFS was sustained in the PSM, IPTW, and CEM cohorts. HAIC + Len + ICI group also showed better overall survival (OS) than the Len group (HR, 0.38; 95% CI 0.31-0.46; P < 0.001). The OS was also superior in the PSM, IPTW, and CEM cohorts. The objective response rate (ORR) in HAIC + Len + ICI group was twice as high as that in Len group. Further mediation analysis showed tumor response at 3 and 6 months had different mediation effect on survival. CONCLUSIONS HAIC combined with Len and ICI showed improved better OS and PFS than Len alone. This triple therapy could be considered as a first-line treatment for advanced HCC.
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Affiliation(s)
- Qunfang Zhou
- Department of Interventional Radiology, 5th Medical Center of Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China
| | - Hui Li
- Department of Minimally Invasive Interventional Radiology, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Dongfeng East Road 651, Guangzhou, 510260, Guangdong Province, China
| | - Ye Liang
- Department of Interventional Radiology, 5th Medical Center of Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China
| | - Ruixia Li
- Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Er Road, Guangzhou, 510080, Guangdong Province, China
| | - Xiaohui Wang
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, 61 Jiefang West Road, Changsha, Hunan Province, China
| | - Wei Wang
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Renmin Road No. 2, Jinzhou, 121000, Liaoning Province, China
| | - Mingyu Liu
- Department of Interventional Radiology, The Affiliated Shunde Hospital of Jinan University, Guizhou East Road 50, Foshan, Guangdong Province, China
| | - Feng Duan
- Department of Interventional Radiology, 5th Medical Center of Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China.
| | - Zhimei Huang
- Department of Minimally Invasive Interventional Radiology, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Dongfeng East Road 651, Guangzhou, 510260, Guangdong Province, China.
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Pan S, Wang J, Tian J, Wang Y, Wang S, Yu Y, Li F, Jiao YM, Shen Y, Yang L, Liu X, Qiu Q, Luan J, Wang FS, Meng F. Safety and efficacy of PD-1 inhibitors plus tyrosine kinase inhibitors combination therapy in patients with advanced hepatocellular carcinoma combined with hyperbilirubinemia: a retrospective cohort study. Front Immunol 2025; 16:1530477. [PMID: 40134422 PMCID: PMC11932989 DOI: 10.3389/fimmu.2025.1530477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 02/21/2025] [Indexed: 03/27/2025] Open
Abstract
Background Programmed death-1 (PD-1) inhibitors plus tyrosine kinase inhibitors (TKIs) combination therapy are considered as a first-line treatment recommendation for advanced hepatocellular carcinoma (HCC). However, patients with hyperbilirubinemia are excluded from this therapeutic option due to limitations in indications. There is a notable absence of published studies evaluating the safety and efficacy of the PD-1 inhibitors plus TKIs combination therapy in patients with HCC combined with hyperbilirubinemia. Methods Patients with HCC complicated with hyperbilirubinemia who received combination therapy with PD-1 inhibitors and TKIs were retrospectively analyzed. Adverse events, tumor response, and laboratory parameters were recorded to assess the safety and efficacy of the treatment, as well as to identify potential risk factors influencing survival. Results A total of 108 participants were included in the study, with 56 patients (51.9%) reporting at least one adverse event, the majority of which were mild. The objective response rate (ORR) for the enrolled participants was 11.9%, and the disease control rate(DCR) reached 61.2%. The median overall survival (OS) for the entire cohort was 5.03 months, while the median progression-free survival (PFS) was 3.63 months. Multifactorial analysis showed that MELD score >18 and increased total bilirubin (TBIL) levels within one week were significant risk factors for OS. Patients with a decrease in TBIL levels within one week had significantly prolonged median OS (not reached vs 3.3months, P =0.013) and median PFS (7.03 months vs 2.77 months, P =0.010). Conclusion Combination therapy demonstrated favorable safety and tolerability among patients with HCC combined with hyperbilirubinemia. Patients who experienced a rapid decline in TBIL levels during the early phase of treatment with PD-1 inhibitors and TKIs were observed to derive clinical benefits. Early initiation of aggressive interventions aimed at reducing TBIL levels is recommended to optimize treatment outcomes.
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Affiliation(s)
- Shida Pan
- Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Jianing Wang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- Peking University 302 Clinical Medical School, Beijing, China
| | - Jiahe Tian
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- Peking University 302 Clinical Medical School, Beijing, China
| | - Yilin Wang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- Chinese People's Liberation Army (PLA) Medical School, Beijing, China
| | - Siyu Wang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Yingying Yu
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Fengyi Li
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Yan-Mei Jiao
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Yingjuan Shen
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Luo Yang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Xiaomeng Liu
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Qin Qiu
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Junqing Luan
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Fu-Sheng Wang
- Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- Peking University 302 Clinical Medical School, Beijing, China
- Chinese People's Liberation Army (PLA) Medical School, Beijing, China
| | - Fanping Meng
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- Peking University 302 Clinical Medical School, Beijing, China
- Chinese People's Liberation Army (PLA) Medical School, Beijing, China
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Pan H, Ruan M, Jin R, Zhang J, Li Y, Wu D, Zhang L, Sun W, Wang R. Immune checkpoint inhibitor plus tyrosine kinase inhibitor with or without transarterial chemoembolization for unresectable hepatocellular carcinoma. Front Oncol 2025; 15:1385304. [PMID: 40129919 PMCID: PMC11930818 DOI: 10.3389/fonc.2025.1385304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 02/11/2025] [Indexed: 03/26/2025] Open
Abstract
Background and aims Transcatheter arterial chemoembolization (TACE) has been combined with immune checkpoint inhibitor (ICI)-based systemic therapies for unresectable hepatocellular carcinoma (uHCC) with promising efficacy. However, whether the addition of TACE to the combination of ICI and tyrosine kinase inhibitor (TKI) (ICI+TKI+TACE) is superior to ICI+TKI combination therapy is still not clear. Thus, this study compares the efficacy of ICI+TKI+TACE triple therapy and ICI+TKI doublet therapy in patients with uHCC. Methods uHCC patients treated with either ICI+TKI+TACE triple therapy or ICI+TKI doublet therapy were retrospectively recruited between January 2016 and December 2021 at Eastern Hepatobiliary Surgery Hospital. The patients from ICI+TKI+TACE group and ICI+TKI group were further subjected to propensity score matching (PSM). The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS) and objective response rate (ORR). Post-progression survival (PPS) as well as treatment-related adverse events (TRAEs) were also assessed. Results A total of 120 patients were matched. The median PFS was 8.4 months in ICI+TKI+TACE triple therapy group versus 6.6 months in ICI+TKI doublet therapy group (HR 0.72, 95%CI 0.48-1.08; p=0.115). Similar results were obtained in term of OS (26.9 versus 24.2 months, HR 0.88, 95% CI 0.51-1.52; p=0.670). The ORR in the triple therapy group was comparable with that in the doublet therapy group (16.6% versus 21.6%, p=0.487). Further subgroup analysis for PFS illustrated that patients without previous locoregional treatment (preLRT) (10.5 versus 3.7 months, HR 0.35 [0.16-0.76]; p=0.009), without previous treatment (10.5 versus 3.5 months, HR 0.34 [0.14-0.81]; p=0.015) or treated with lenvatinib (14.8 versus 6.9 months, HR 0.52 [0.31-0.87]; p=0.013) can significantly benefit from triple therapy compared with doublet therapy. A remarkable interaction between treatment and preLRT (p=0.049) or TKIs-combined (p=0.005) was also detected in term of PFS. Post progression treatment significantly improved PPS in both groups. The incidence of TRAEs was comparable between two groups. Conclusions The addition of TACE to ICI+TKI combination therapy did not result in a substantial improvement in efficacy and prognosis of patients. However, in selected uHCC patients (without preLRT or treated with lenvatinib as combination), ICI+TKI+TACE triple therapy may remarkably improve PFS.
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Affiliation(s)
- Hongyu Pan
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Minghao Ruan
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Riming Jin
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Jin Zhang
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Yao Li
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Dong Wu
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Lijie Zhang
- The Department of Information, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Wen Sun
- National Center for Liver Cancer, The Naval Medical University, Shanghai, China
| | - Ruoyu Wang
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
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Zhang Y, Xie M, Wen J, Liang C, Song Q, Liu W, Liu Y, Song Y, Lau HCH, Cheung AHK, Man K, Yu J, Zhang X. Hepatic TM6SF2 activates antitumour immunity to suppress metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma and boosts immunotherapy. Gut 2025; 74:639-651. [PMID: 39667906 PMCID: PMC12014897 DOI: 10.1136/gutjnl-2024-333154] [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: 06/21/2024] [Accepted: 11/19/2024] [Indexed: 12/14/2024]
Abstract
BACKGROUND Transmembrane 6 superfamily member 2 (TM6SF2) has a protective role against metabolic dysfunction-associated steatotic liver disease (MASLD). OBJECTIVE We aim to investigate the mechanistic role and therapeutic potential of hepatic TM6SF2 in MASLD-related hepatocellular carcinoma (HCC). DESIGN Hepatocyte-specific Tm6sf2 knockout (Tm6sf2 ∆hep) mice were fed with high-fat/high-cholesterol (HFHC) diet or diethylnitrosamine plus HFHC diet to induce MASLD-HCC. TM6SF2 function was also evaluated in orthotopic MASLD-HCC mice. Human MASLD-HCC specimens were included to evaluate clinical significance. RESULTS TM6SF2 was downregulated in tumours compared with adjacent normal tissues from MASLD-HCC patients. Hepatocyte-specific Tm6sf2 knockout exacerbated tumour formation in mice with diet-induced or diet-induced and carcinogen-induced MASLD-HCC. The tumour-promoting effect of Tm6sf2 knockout was verified in orthotopic MASLD-HCC mice, while mice bearing Tm6sf2-overexpressing tumours had opposite phenotypes. We observed the reduction of interferon-gamma (IFN-γ)+CD8+ T cells in the tumours of Tm6sf2 ∆hep mice and orthotopic Tm6sf2 knockout mice, while the tumour-suppressive effect of Tm6sf2 was abolished after depleting CD8+ T cells. The correlation between TM6SF2 and CD8+ T cells was confirmed in human MASLD-HCC tissues, inferring that TM6SF2 could promote antitumour immunity. Mechanistically, TM6SF2 directly bound to IKKβ and inhibited NF-κB signalling pathway to reduce interleukin (IL)-6 secretion, thereby activating cytotoxic CD8+ T cells. IL-6 neutralisation abolished the tumour-promoting and immunosuppressive effects of Tm6sf2 knockout in mice. Moreover, introducing Tm6sf2 by adenovirus improved immunotherapy response against MASLD-HCC in mice. CONCLUSION Hepatic TM6SF2 protects against MASLD-HCC and activates cytotoxic CD8+ T cells via NF-κB-IL-6 axis. TM6SF2 is a promising strategy for sensitising MASLD-HCC to immunotherapy.
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Affiliation(s)
- Yating Zhang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Mingxu Xie
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jun Wen
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Cong Liang
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guang Zhou, China
| | - Qian Song
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Weixin Liu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yali Liu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yang Song
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Harry Cheuk Hay Lau
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Alvin Ho-Kwan Cheung
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Kwan Man
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Xiang Zhang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
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Wu Y, Zeng Z, Chen S, Zhou D, Tong G, Du D. Adverse events associated with hepatic arterial infusion chemotherapy and its combination therapies in hepatocellular carcinoma: a systematic review. Front Immunol 2025; 16:1531249. [PMID: 40098973 PMCID: PMC11911461 DOI: 10.3389/fimmu.2025.1531249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 02/21/2025] [Indexed: 03/19/2025] Open
Abstract
Background Hepatic arterial infusion chemotherapy (HAIC) has emerged as a promising treatment for unresectable hepatocellular carcinoma (HCC). However, the safety profiles of HAIC and its various combination therapies remain to be systematically evaluated. Methods We systematically searched PubMed, Embase, Cochrane Library, and Web of Science databases from inception to November 2024. Studies reporting adverse events (AEs) of HAIC monotherapy or combination therapies in HCC were included. The severity and frequency of AEs were analyzed according to different treatment protocols. Results A total of 58 studies (11 prospective, 47 retrospective) were included. HAIC monotherapy demonstrated relatively mild toxicity, primarily affecting hepatobiliary (transaminase elevation 53.2%, hypoalbuminemia 57.2%) and hematological systems (anemia 43.0%, thrombocytopenia 35.2%). HAIC with targeted therapy showed increased adverse events, including characteristic reactions like hand-foot syndrome (48.0%) and hypertension (49.9%). HAIC combined with targeted, and immunotherapy exhibited the highest adverse reaction rates (neutropenia 82.9%, transaminase elevation 97.1%), while HAIC with anti-angiogenic and immunotherapy showed a relatively favorable safety profile. Prospective studies consistently reported higher incidence rates than retrospective studies, suggesting potential underreporting in clinical practice. Conclusions Different HAIC-based regimens exhibit distinct safety profiles requiring individualized management approaches. We propose a comprehensive framework for patient selection, monitoring strategies, and AE management. These recommendations aim to optimize treatment outcomes while minimizing adverse impacts on patient quality of life.
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Affiliation(s)
- Ying Wu
- Department of Interventional Therapy, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Zhenpeng Zeng
- Department of Interventional Therapy, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Shuanggang Chen
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
- StateKey Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Danyang Zhou
- Department of Oncology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Gangling Tong
- Department of Oncology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Duanming Du
- Department of Interventional Therapy, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
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Lin LW, Nian YX, Lin X, Ke K, Yang WZ, Lin JQ, Huang N. Efficacy and Safety of Transarterial Chemoembolization Combined with Lenvatinib Plus Programmed Death-1 Inhibitor for Hepatocellular Carcinoma with the Hepatic Vein and/or Inferior Vena Cava Tumor Thrombus. Cardiovasc Intervent Radiol 2025; 48:314-326. [PMID: 39658748 DOI: 10.1007/s00270-024-03919-2] [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: 07/18/2024] [Accepted: 11/12/2024] [Indexed: 12/12/2024]
Abstract
PURPOSE The aim of this study was to assess the safety and effectiveness of transarterial chemoembolization (TACE) plus lenvatinib with a programmed death-1 (PD-1) inhibitor compared with TACE plus lenvatinib and TACE alone for hepatocellular carcinoma (HCC) with the hepatic vein and/or inferior vena cava tumor thrombus (HVTT and IVCTT). METHODS Data on HCC accompanied by HVTT and IVCTT from June 2015 to August 2022 were analyzed in this single-center retrospective study. Drug-eluting bead TACE (DEB-TACE) or conventional TACE (cTACE) was used. The primary study outcomes were overall survival (OS) and progression-free survival (PFS). Univariate and multivariate Cox analyses were performed to determine the predictive factors for OS and PFS. A subgroup analysis was conducted. RESULTS Overall, 214 patients were enrolled. Among them, 60 received triple therapy consisting of TACE, lenvatinib, and PD-1 inhibitors (TACE + L + P), 72 received dual therapy consisting of TACE and lenvatinib (TACE + L), and 82 received TACE alone. The TACE + L + P group (16.2; 95% confidence interval [CI]: 12.8-19.5 months) had a significantly longer median OS compared with the TACE + L group (11.2; 95% CI: 10.0-12.3 months) (P = 0.001) and the TACE group (8.3; 95% CI: 7.7-8.5 months) (P < 0.001); the TACE + L + P group (12.3; 95% CI: 10.9-13.7 months) had a significantly longer median PFS compared with the TACE + L group (8.5; 95% CI: 7.7-9.2 months) (P < 0.001) and the TACE group (6.2; 95% CI: 5.8 ~ 6.3 months) (P < 0.001). Multivariate Cox analysis demonstrated that treatment strategy was a significant factor for OS and PFS. Skin rash was more common in the triple therapy group and might be attributed to PD-1 ligand inhibitor therapy (33.33% vs. 16.66%, P = 0.026). CONCLUSIONS Triple therapy consisting of TACE plus lenvatinib with a PD-1 inhibitor showed promising efficacy for advanced HCC patients with HVTT and IVCTT, with manageable safety profiles.
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Affiliation(s)
- Long-Wang Lin
- Department of Interventional Radiology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Yu-Xia Nian
- Department of Prevention and Healthcare, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Xin Lin
- Department of Interventional Radiology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Kun Ke
- Department of Interventional Radiology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Wei-Zhu Yang
- Department of Interventional Radiology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Jun-Qing Lin
- Department of Interventional Radiology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Ning Huang
- Department of Interventional Radiology, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
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Yao Y, Zhang M, Liu D, Liu X, Li Q, Wang X. Changes in systemic immune-inflammation index (SII) predict the prognosis of patients with hepatitis B-related hepatocellular carcinoma treated with lenvatinib plus PD-1 inhibitors. Clin Transl Oncol 2025; 27:1155-1165. [PMID: 39153177 DOI: 10.1007/s12094-024-03596-0] [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: 04/30/2024] [Accepted: 07/03/2024] [Indexed: 08/19/2024]
Abstract
PURPOSE This study aimed to evaluate the prognostic significance of changes in inflammatory markers in patients with Hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) treated with first-line lenvatinib plus a programmed cell death protein 1 (PD-1) inhibitor. METHODS This study retrospectively included 117 HBV-HCC patients treated with first-line lenvatinib in combination with a PD-1 inhibitor. Independent factors affecting progression-free survival (PFS) and overall survival (OS) were explored based on baseline indicators and inflammatory markers changes after one treatment cycle. RESULTS Multivariate analysis revealed that an alpha-fetoprotein (AFP) level ⩾ 400 ng/mL [hazard ratio (HR), 1.69; 95% confidence interval (CI), 1.11-2.58; P = 0.01] was identified as an independent risk factor, platelet-to-neutrophil ratio (PNR) ⩽ 65.43 (HR 0.50; 95% CI 0.30-0.84; P < 0.01 ) and SII ⩽ 539.47 (HR 0.54; 95% CI 0.30-0.96; P = 0.03) were identified as independent protective factors for PFS. Additionally, multivariate analysis demonstrated that AFP ⩾ 400 ng/mL, HBV-HCC patients with diabetes mellitus (DM), and SII > 303.66 were independent risk factors of OS. The patients whose SII had increased after one cycle of treatment showed a poorer PFS (HR 1.61; 95 %CI 1.10-2.37; P = 0.015) and OS (HR 1.76; 95 % CI 1.15-2.70; P = 0.009) than patients whose SII had decreased. The objective response rate (ORR) was higher in the SII-decreased patients (47.5% vs 32.5%, P = 0.11). Mann-Whitney test found a significant difference in therapeutic response between the SII-increased patients and the SII-decreased patients (P = 0.04). CONCLUSION SII can be associated with outcomes in patients with HBV-HCC treated with first-line lenvatinib plus PD-1 inhibitors.
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Affiliation(s)
- Yang Yao
- Department of Integrated Traditional Chinese and Western Medicine, Beijing Youan Hospital, Capital Medical University, No. 8 Xi Tou Tiao, You An Men Wai, Feng Tai District, Beijing, 100069, China
| | - Minyue Zhang
- Department of Integrated Traditional Chinese and Western Medicine, Beijing Youan Hospital, Capital Medical University, No. 8 Xi Tou Tiao, You An Men Wai, Feng Tai District, Beijing, 100069, China
| | - Di Liu
- Department of Integrated Traditional Chinese and Western Medicine, Beijing Youan Hospital, Capital Medical University, No. 8 Xi Tou Tiao, You An Men Wai, Feng Tai District, Beijing, 100069, China
| | - Xiaoni Liu
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8 Xi Tou Tiao, You An Men Wai, Feng Tai District, Beijing, 100069, China
| | - Quanwei Li
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8 Xi Tou Tiao, You An Men Wai, Feng Tai District, Beijing, 100069, China
| | - Xiaojun Wang
- Department of Integrated Traditional Chinese and Western Medicine, Beijing Youan Hospital, Capital Medical University, No. 8 Xi Tou Tiao, You An Men Wai, Feng Tai District, Beijing, 100069, China.
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Yin X, Deng N, Chen J, Ding X. Mono-TKI and TKI Plus ICI in Unresectable Hepatocellular Carcinoma Progression on First-Line Treatment of Lenvatinib: A Real-World Study. Cancer Med 2025; 14:e70711. [PMID: 40047078 PMCID: PMC11883418 DOI: 10.1002/cam4.70711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 02/11/2025] [Accepted: 02/12/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND Lenvatinib (LEN) is the recommended first-line therapy for unresectable hepatocellular carcinoma (uHCC), but resistance frequently develops, and limited data exist on second-line treatments. This study evaluated the efficacy and safety with a focus on the sorafenib (SOR) or regorafenib (REG)- based monotherapy or combination therapy in patients with uHCC after failure of first-line LEN. METHODS Patients with first-line LEN failure between May 2018 and December 2023 were retrospectively collected. Based on second-line regimens, 70 patients were divided into two groups: the TKI group (n = 21) and the TKI-ICI group (n = 49). Overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier methods, and multivariate analysis was performed to identify prognostic factors. RESULTS In the TKI-ICI group, median PFS was 5.27 months and median OS was 12.53 months. In the TKI group, median PFS was 3.10 months and median OS was 7.50 months. The objective response rate (ORR) was 19.1% in the TKI group and 16.3% in the TKI-ICI group. The disease control rate (DCR) was 85.7% in the TKI-ICI group and 61.9% in the TKI group. In the TKI-ICI cohort, multivariable Cox analysis revealed the high albumin to neutrophil ratio index (ANRI) was an independent predictor for PFS, while alpha-fetoprotein > 400 ng/mL was the independent predictor for OS. Safety profiles in both cohorts showed manageable toxicity, with no treatment-related deaths. CONCLUSIONS The combination of TKI and ICI presents a promising second-line treatment option after LEN failure, regardless of the specific second-line TKI used.
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Affiliation(s)
- Xue Yin
- Department of Cancer Center, Beijing Ditan HospitalCapital Medical UniversityBeijingChina
| | - Na Deng
- Department of Cancer Center, Beijing Ditan HospitalCapital Medical UniversityBeijingChina
| | - Jinglong Chen
- Department of Cancer Center, Beijing Ditan HospitalCapital Medical UniversityBeijingChina
| | - Xiaoyan Ding
- Department of Cancer Center, Beijing Ditan HospitalCapital Medical UniversityBeijingChina
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Di Marco L, Romanzi A, Pivetti A, De Maria N, Ravaioli F, Salati M, Villa E, Di Benedetto F, Magistri P, Dominici M, Colecchia A, Di Sandro S, Spallanzani A. Suppressing, stimulating and/or inhibiting: The evolving management of HCC patient after liver transplantation. Crit Rev Oncol Hematol 2025; 207:104607. [PMID: 39725094 DOI: 10.1016/j.critrevonc.2024.104607] [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: 05/23/2024] [Revised: 12/20/2024] [Accepted: 12/22/2024] [Indexed: 12/28/2024] Open
Abstract
Liver transplantation (LT) is a curative strategy for hepatocellular carcinoma (HCC), but the risk of HCC recurrence remains a challenging problem. In patients with HCC recurrence after LT (HCC-R_LT), the locoregional and surgical approaches are complex, and the guidelines do not report evidence-based strategies for the management of immunosuppression. In recent years, immunotherapy has become an effective option for patients with advanced HCC in pre-transplant settings. However, due to the risk of potentially fatal allograft rejection, the use of immunotherapy is avoided in post-transplant settings. Combining immunosuppressants with immunotherapy in transplant patients is also challenging due to the complex tumor microenvironment and immunoreactivity. The fear of acute liver rejection and the lack of predictive factors hinder the successful clinical application of immunotherapy for post-liver transplantation HCC recurrence. This review aims to comprehensively summarize the risk of HCC-R_LT, the available evidence for the efficacy of immunotherapy in patients with HCC-R_LT, and the clinical issues regarding the innovative management of this patient population.
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Affiliation(s)
- Lorenza Di Marco
- Department of Oncology and Hematology, Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41124, Italy; Department of Biomedical, Metabolic and Neural Sciences, Clinical and Experimental Medicine Program, University of Modena and Reggio Emilia, Modena 41124, Italy.
| | - Adriana Romanzi
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Alessandra Pivetti
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Nicola De Maria
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Federico Ravaioli
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, Bologna 40138, Italy.
| | - Massimiliano Salati
- Department of Oncology and Hematology, Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41124, Italy.
| | - Erica Villa
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy; National Institute of Gastroenterology IRCCS "Saverio de Bellis", Research Hospital, Castellana Grotte 70013, Italy.
| | - Fabrizio Di Benedetto
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Paolo Magistri
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Massimo Dominici
- Department of Oncology and Hematology, Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41124, Italy.
| | - Antonio Colecchia
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Stefano Di Sandro
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Andrea Spallanzani
- Department of Oncology and Hematology, Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41124, Italy.
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Yu J, Li Y, Yu J, Yang Y, Chen Y, Yi P. Hepatic arterial infusion chemotherapy enhances the efficacy of lenvatinib and PD-1 inhibitors for advanced hepatocellular carcinoma: A meta-analysis and trial sequential analysis. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:109573. [PMID: 39793379 DOI: 10.1016/j.ejso.2025.109573] [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: 12/18/2024] [Accepted: 01/02/2025] [Indexed: 01/13/2025]
Abstract
BACKGROUND Hepatic arterial infusion chemotherapy (HAIC) was an effective treatment for advanced hepatocellular carcinoma (HCC), and its effectiveness in combination with targeted immunotherapy regimens was controversial. This meta-analysis was performed to evaluate the efficacy of adding HAIC to lenvatinib in combination with programmed death-1 (PD-1) inhibitors. METHODS Literature related to the efficacy of HAIC in combination with lenvatinib plus PD-1 inhibitors in the treatment of advanced HCC was searched through PubMed, Cochrane Library, Embase, and Web of Science databases. TSA was used to control for the risk of random error and assess whether the meta-analysis evidence was conclusive. RESULTS Eight relevant papers with a total of 1244 patients. Compared with the L-P treatment group, the H-L-P treatment group significantly prolonged OS (hazard ratio [HR] 2.11 [95 % confidence interval (CI) 1.82-2.44]; p < 0.001) and PFS (HR 1.91 [95 % CI 1.67-2.17]; p < 0.001) and improved ORR (risk ratio [RR] 2.20 [95 % CI 1.74-2.78]; p < 0.001) and DCR (RR 1.28 [95 % CI 1.15-1.42]; p < 0.001) in patients with advanced HCC. TSA analysis indicated that further trials were unnecessary, preliminary positive results were promptly obtained. Prognostic factor analysis demonstrated that extrahepatic metastasis were common independent risk factor for OS and PFS. The rate of adverse events (AEs) was higher in the H-L-P treatment group than in the L-P treatment group. CONCLUSION HAIC combined with lenvatinib plus PD-1 inhibitors markedly extended OS and PFS, particularly in patients without extrahepatic metastases. Furthermore, it markedly enhanced ORR and DCR in patients with HCC.
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Affiliation(s)
- Jiahui Yu
- Department of Hepato-biliary-pancrease II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, 637000, PR China
| | - Yong Li
- Department of Hepato-biliary-pancrease II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, 637000, PR China
| | - Jinxin Yu
- North Sichuan Medical College, Nanchong, Sichuan, 637000, PR China
| | - Yuting Yang
- Department of Educational Technology, Institute of Education, China West Normal University, Nanchong, Sichuan, 637000, PR China; Nanchong Gaoping District Wangcheng Primary School, Nanchong, Sichuan, 637100, PR China
| | - Yimiao Chen
- Department of Hepato-biliary-pancrease II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, 637000, PR China
| | - Pengsheng Yi
- Department of Hepato-biliary-pancrease II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, 637000, PR China.
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Chen QF, Jiang XY, Chen MS, Lyu N, Zhao M. A Metrology Informatics Investigation of Conversion Therapy in Hepatocellular Carcinoma: 2014-2023. ANNALS OF SURGERY OPEN 2025; 6:e562. [PMID: 40134489 PMCID: PMC11932632 DOI: 10.1097/as9.0000000000000562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 02/07/2025] [Indexed: 03/27/2025] Open
Abstract
Background With advancements in drug therapy, local treatments, and evolving concepts, conversion therapy has shown benefits for patients initially diagnosed with unresectable hepatocellular carcinoma (HCC). Over the past 10 years, the conversion therapy field has accumulated a vast amount of underutilized data, necessitating in-depth bibliometric evaluation. Methods This cross-sectional retrospective study collected a substantial amount of research on conversion therapy published between 2014 and 2023, adhering to strict search criteria. The primary outcomes were publication volume, citation count, and interstudy relationships. Comprehensive analysis was conducted using unsupervised hierarchical clustering, spatiotemporal analysis, regression model, and the Walktrap algorithm. Results Over the past decade, conversion therapy has demonstrated significant progress, with an annual growth rate of 23.0%. Post-2020, these metrics saw a marked increase, reaching 116 publications and 1943 citations by 2023. Cluster analysis grouped 244 authors into 17 clusters, highlighting early and sustained contributions from Western authors compared with later-emerging Eastern authors. Research characteristics in HCC conversion therapy were classified into 5 clusters, with Cluster 2 (Target Therapy and Immunotherapy) emerging as a new focus. Thematic analysis categorized research characteristics into 4 quadrants, identifying "immune checkpoint inhibitor" and "combination therapy" as highly relevant and rapidly developing themes, while "hepatic arterial infusion chemotherapy" and "radioembolization" show high potential for future research. Conclusions This study highlights key contributors and emerging trends and provides important predictions for future research directions. To achieve effective conversion therapy for HCC, researchers may prioritize immunotherapy and locoregional treatments such as hepatic arterial infusion chemotherapy or radioembolization.
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Affiliation(s)
- Qi-Feng Chen
- From the Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiong-Ying Jiang
- From the Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Min-Shan Chen
- Department of Liver Surgery, Liver Cancer Study and Service Group, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ning Lyu
- From the Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ming Zhao
- From the Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
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Sun R, Wu C, Gou Y, Zhao Y, Huang P. Advancements in second-line treatment research for hepatocellular carcinoma. Clin Transl Oncol 2025; 27:837-857. [PMID: 39162977 DOI: 10.1007/s12094-024-03653-8] [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: 05/08/2024] [Accepted: 07/29/2024] [Indexed: 08/21/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, characterized by high incidence and mortality rates. Due to its insidious onset, most patients are diagnosed at an advanced stage, often missing the opportunity for surgical resection. Consequently, systemic treatments play a pivotal role. In recent years, an increasing number of drugs have been approved for first-line systemic treatment of HCC. However, their efficacy is limited, and some patients develop drug resistance after a period of treatment. For such patients, there is currently a lack of standard second-line systemic treatment options. This review summarizes the latest advancements in second-line systemic treatment research for HCC patients who have developed resistance to various first-line systemic treatments, aiming to provide more rational and personalized second-line treatment strategies.
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Affiliation(s)
- Ruirui Sun
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Chenrui Wu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Yang Gou
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Yaowu Zhao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Ping Huang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China.
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Zhang T, Du S, Zhang Y, Liu R, Li J, Zhao C, Xu J. Correlation Between Treatment-Related Adverse Events and Efficacy of Camrelizumab in Combination With Apatinib in Patients With Unresectable Hepatocellular Carcinoma. Cancer Med 2025; 14:e70713. [PMID: 40123149 PMCID: PMC11930853 DOI: 10.1002/cam4.70713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 02/10/2025] [Accepted: 02/12/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND The relationship between treatment-related adverse events (TRAEs) and efficacy in patients receiving immune checkpoint inhibitors (ICIs) combined with anti-angiogenic therapy remains unclear. This study aims to investigate the potential correlation between TRAEs and efficacy in patients with unresectable hepatocellular carcinoma (uHCC) treated with the combination of camrelizumab and apatinib. METHODS We conducted an analysis of efficacy and safety data obtained from 189 patients with uHCC enrolled in a phase II trial. All patients received intravenous camrelizumab 200 mg every 2 weeks and oral apatinib 250 mg once daily in 4-week cycles. Efficacy was evaluated based on objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). We described the profiles of TRAEs and analyzed the correlation between TRAEs and treatment efficacy. To mitigate the impact of immortal time bias, landmark analysis and time-dependent Cox regression analysis were employed to assess the correlation between immune-related adverse events (irAEs) and survival outcomes. RESULTS As of March 10, 2021, irAEs of any grade were reported in 88 (46.6%) patients, with 17 (9.0%) patients experiencing grade 3-4 irAEs. The median onset time for any grade irAEs was 17.4 weeks. Apatinib-related adverse events (AEs) of any grade were reported in 188 (99.5%) patients. Among them, 139 (73.5%) patients experienced any grade of apatinib-related hypertension, while 65 (34.4%) patients had grade 3-4 hypertension. Patients who experienced irAEs exhibited significantly higher ORR and DCR, but the onset of irAEs occurred later than the time of PR or CR in 75.0% (30/40) of patients. Furthermore, in the landmark analysis and time-dependent Cox regression analysis, no significant differences in survival outcomes were observed between patients with irAEs and those without. Notably, patients with apatinib-related hypertension demonstrated better ORR (38.1% vs. 18.0%, p = 0.009) and DCR (84.2% vs. 60.0%, p < 0.001), as well as longer PFS (6.5 vs. 3.7 months, p = 0.001) and OS (23.0 vs. 15.1 months, p = 0.03). CONCLUSIONS In this study, the occurrence of irAEs did not predict the efficacy of camrelizumab in combination with apatinib, likely due to the decreased incidence and delayed occurrence. On the other hand, apatinib-related hypertension was associated with improved treatment efficacy.
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Affiliation(s)
- Ting Zhang
- Chinese People's Liberation Army (PLA) Medical SchoolBeijingChina
- Department of Gastrointestinal Oncology, The First Medical CenterChinese PLA General HospitalBeijingChina
| | - Sicheng Du
- Chinese People's Liberation Army (PLA) Medical SchoolBeijingChina
- Department of Gastrointestinal Oncology, The First Medical CenterChinese PLA General HospitalBeijingChina
| | - Ying Zhang
- Chinese People's Liberation Army (PLA) Medical SchoolBeijingChina
- Department of Gastrointestinal Oncology, The First Medical CenterChinese PLA General HospitalBeijingChina
| | - Rongrui Liu
- Department of Gastrointestinal Oncology, The First Medical CenterChinese PLA General HospitalBeijingChina
| | - Juan Li
- Department of Gastrointestinal Oncology, The First Medical CenterChinese PLA General HospitalBeijingChina
| | - Chuanhua Zhao
- Department of Gastrointestinal Oncology, The Fifth Medical CenterChinese PLA General HospitalBeijingChina
| | - Jianming Xu
- Department of Gastrointestinal Oncology, The Fifth Medical CenterChinese PLA General HospitalBeijingChina
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Zhu XD, Zhao L, Li B, Cheng Y, Sun HC. Systemic Treatment for Unresectable Hepatocellular Carcinoma: A Surgeon's Perspective. J Hepatocell Carcinoma 2025; 12:399-413. [PMID: 40034975 PMCID: PMC11873029 DOI: 10.2147/jhc.s504457] [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: 11/11/2024] [Accepted: 02/08/2025] [Indexed: 03/05/2025] Open
Abstract
In recent years, the standard treatment for hepatocellular carcinoma (HCC) has changed dramatically due to the emergence of potent systemic treatment options. These advanced therapies have led to increased survival benefits for patients with advanced or intermediate-stage HCC. Advancements in HCC treatments also offer the possibility of conversion therapy for initially unresectable HCC. However, the treatment of HCC is becoming increasingly complex, due to the expanding availability of systemic therapies, their use in combination with locoregional therapies, and their perioperative applications. Patient characteristics such as liver function, esophageal and gastric variceal status, and treatment goal (downstaging resection or long-term maintenance treatment), are the most critical factors when selecting a systemic treatment strategy. Consequently, the necessity to tailor a personalized and comprehensive treatment strategy for individual patients is growing. This review briefly summarizes the current systemic treatment regimens for HCC from a surgeon's perspective. It is based on results from clinical studies as well as personal experience and introduces the concept of a patient-centered, treatment goals-driven, individualized systemic treatment strategy for managing HCC.
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Affiliation(s)
- Xiao-Dong Zhu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Lei Zhao
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People’s Republic of China
| | - Binkui Li
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Yuan Cheng
- Department of Medical Oncology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China
| | - Hui-Chuan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
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