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Llopiz D, Silva L, Ruiz M, Castro-Alejos C, Aparicio B, Vegas L, Infante S, Santamaria E, Sarobe P. MERTK inhibition improves therapeutic efficacy of immune checkpoint inhibitors in hepatocellular carcinoma. Oncoimmunology 2025; 14:2473165. [PMID: 40029206 PMCID: PMC11881874 DOI: 10.1080/2162402x.2025.2473165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 01/29/2025] [Accepted: 02/24/2025] [Indexed: 03/05/2025] Open
Abstract
Immunotherapy with immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) patients only achieves response rates of 25%-30%, indicating the necessity of new therapies for non-responder patients. Since myeloid-related suppressive factors are associated with poor responses to ICI in a subgroup of HCC patients, modulation of these targets may improve response rates. Our aim was to characterize the expression of the efferocytosis receptor MERTK in HCC and to analyze its potential as a new therapeutic target. In HCC patients, MERTK was expressed by myeloid cells and was associated with poorer survival. In a murine HCC model with progressive myeloid cell infiltration, MERTK was detected in dendritic cells and macrophages with an activated phenotype, which overexpressed the checkpoint ligand PD-L1. Concomitant expression of PD-1 in tumor T-cells suggested the pertinence of combined PD-1/PD-L1 and MERTK blockade. In vivo experiments in mice showed that inhibition of MERTK improved the therapeutic effect promoted by anti-PD-1 or by ICI combinations currently approved for HCC. This effect was associated with enhanced tumor infiltration and superior activity of antigen presenting cells and effector lymphocytes. Our results indicate that MERTK may behave as a relevant target for immunotherapeutic combinations in those HCC patients with tumors enriched in a myeloid component.
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Affiliation(s)
- Diana Llopiz
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Leyre Silva
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Marta Ruiz
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Carla Castro-Alejos
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Belen Aparicio
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Lucia Vegas
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
| | - Stefany Infante
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- DNA and RNA Medicine Division, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
- Facultad de Medicina Humana, Universidad de Piura, Lima, Peru
| | - Eva Santamaria
- DNA and RNA Medicine Division, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Pablo Sarobe
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
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2
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Song Q, Yu Z, Lu W, Zhuo Z, Chang L, Mei H, Cui Y, Zhang D. PD-1/PD-L1 inhibitors related adverse events: A bibliometric analysis from 2014 to 2024. Hum Vaccin Immunother 2025; 21:2424611. [PMID: 39757956 DOI: 10.1080/21645515.2024.2424611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/14/2024] [Accepted: 10/29/2024] [Indexed: 01/07/2025] Open
Abstract
Programmed cell death-1 (PD-1) inhibitors and programmed cell death ligand 1 (PD-L1) inhibitors are considered effective alternatives for the primary treatment of recurrent metastatic cancers. However, they can induce various adverse events affecting multiple organ systems, potentially diminishing patients' quality of life, and even leading to treatment interruptions. Adverse events related to PD-1/PD-L1 inhibitors differ from those associated with CTLA-4 inhibitors and are more commonly observed in the treatment of solid tumors. This study aimed to address the knowledge gap regarding adverse events related to PD-1/PD-L1 inhibitors. A visual bibliometric network was constructed using VOSviewer, CiteSpace, R software, and the Web of Science Core Collection (WoSCC) to quantitatively analyze this research field. Future research directions were also explored. The USA ranked first in publication count and total citations. Over time, publication types transitioned from case reports to clinical trials. Research on for nivolumab was the most prevalent. The spectrum of cancers treated by PD-1/PD-L1 inhibitors expanded beyond melanoma and lung cancer to include renal cell carcinoma, esophageal cancer, and others. Common adverse events included pneumonitis, myasthenia gravis, and vitiligo. There was a significant increase in multi-phase clinical trials and studies related to biomarkers. This study offers valuable insights for potential collaborators and institutions, highlighting trends in the study of adverse events related to PD-1/PD-L1 inhibitors. The management of these adverse events has become more refined and standardized. Biomarker research and multi-phase clinical trials are likely to be key areas of focus in future studies.
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Affiliation(s)
- Qingya Song
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zongliang Yu
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Wenping Lu
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhili Zhuo
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lei Chang
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Heting Mei
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Yongjia Cui
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Dongni Zhang
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Akabane M, Imaoka Y, Kawashima J, Pawlik TM. Advancing precision medicine in hepatocellular carcinoma: current challenges and future directions in liquid biopsy, immune microenvironment, single nucleotide polymorphisms, and conversion therapy. Hepat Oncol 2025; 12:2493457. [PMID: 40260687 DOI: 10.1080/20450923.2025.2493457] [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: 01/31/2025] [Accepted: 04/11/2025] [Indexed: 04/24/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains a health concern characterized by heterogeneity and high mortality. Surgical resection, radiofrequency ablation, trans-arterial chemoembolization, and liver transplantation offer potentially curative treatments for early-stage disease, but recurrence remains high. Most patients present with advanced-stage HCC, where locoregional therapies are less effective, and systemic treatments-primarily multi-kinase inhibitors and immune checkpoint inhibitors-often yield limited responses. Precision medicine aims to tailor therapy to molecular and genetic profiles, yet its adoption in HCC is hindered by inter-/intra-tumoral heterogeneity and limited biopsy availability. Advances in molecular diagnostics support reintroducing tissue sampling to better characterize genetic, epigenetic, and immunological features. Liquid biopsy offers a minimally invasive method for capturing real-time tumor evolution, overcoming spatial and temporal heterogeneity. Artificial intelligence and machine learning are revolutionizing biomarker discovery, risk stratification, and treatment planning by integrating multi-omics data. Immunological factors such as tumor-infiltrating lymphocytes, natural killer cells, macrophages, and fibroblasts have emerged as determinants of HCC progression and treatment response. Conversion therapy-combining systemic agents with locoregional treatments-has showndemonstrated promise in downstaging unresectable HCC. Ongoing efforts to refine biomarker-driven approaches and optimize multi-modality regimens underscore precision medicine's potential to improve outcomes. PubMed (January 2002-February 2025) was searched for relevant studies.
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Affiliation(s)
- Miho Akabane
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Yuki Imaoka
- Division of Abdominal Transplant, Department of Surgery, Stanford University, CA, USA
| | - Jun Kawashima
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
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Qiu N, Xu C, Zhang Z, Wang R, Wei X, Xie Y, Wang S, Lu D, Wang K, Xu S, Shen C, Su R, Cen B, Liu Y, Shen Y, Xu X. Autologous tumoral esterase-driven therapeutic polymers sequentially orchestrated antigen-induction, STING activation and anti-angiogenesis for systemic cancer immune therapy. Biomaterials 2025; 320:123260. [PMID: 40138966 DOI: 10.1016/j.biomaterials.2025.123260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 02/23/2025] [Accepted: 03/15/2025] [Indexed: 03/29/2025]
Abstract
Effective cancer immune therapy requires the orchestration of antigen induction, presentation and T-cell activation, further enhanced by anti-angiogenesis treatment; therefore, multiple therapeutics are generally used for such combination therapy. Herein, we report esterase-hydrolysable cationic polymers, N-[3-((4-acetoxy benzyl) oxy)-3-oxopropyl]-N-methyl-quaternized PEI (ERP) and poly{N-[2-(acryloyl-oxy) ethyl]-N-[p-acetyloxyphenyl]-N,N-dimethylammonium chloride} (PQDMA), capable of simultaneously inducing tumor cell immunogenic cell death (ICD) to release antigens, activating the cGAS-STING pathways of tumor macrophages and dendritic cells, and releasing antiangiogenic agent p-hydroxybenzyl alcohol (HBA). Thus, intratumoral injection of ERP or PQDMA systemically boosted the anti-cancer immunities and inhibited tumor angiogenesis in mouse hepatocellular carcinoma and melanoma bilateral tumor models, leading to more effective tumor growth inhibition of both treated and abscopal untreated tumors than ICD alone induced by mitoxantrone and control cationic polymers. Further study using gene knockout mice and transcriptome sequencing analysis confirmed the involvement of cGAS-STING and type I IFN signaling pathways. This work demonstrates ERP and PQDMA as the first examples of inherent therapeutic polymers, accomplishing systemic tumor inhibition without combining other therapeutic agents.
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Affiliation(s)
- Nasha Qiu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China.
| | - Chang Xu
- Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China
| | - Zhen Zhang
- Key Laboratory of Smart Biomaterials of Zhejiang Province and Key Laboratory of Biomass Chemical Engineering of the Ministry of Education of China, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310058, China
| | - Rui Wang
- Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China
| | - Xuyong Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Yangla Xie
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Shuai Wang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Di Lu
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, 310059, China
| | - Kai Wang
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, 310059, China
| | - Shengjun Xu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Chenchen Shen
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Renyi Su
- Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China
| | - Beini Cen
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Yanpeng Liu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Youqing Shen
- Key Laboratory of Smart Biomaterials of Zhejiang Province and Key Laboratory of Biomass Chemical Engineering of the Ministry of Education of China, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310058, China.
| | - Xiao Xu
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, 310059, China; Institute of Translational Medicine, Zhejiang University, Hangzhou, 310058, China.
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Singh SP, Kumar K, Kulkarni A, Arora V, Choudhury A, Chaubal A, Rathi S, Shah S, Taneja S, Kumar A, Duseja A, Kumar G, Nagaraja Rao P, Saraswat V, Sarin SK. Predictors of Non-response to Atezolizumab Plus Bevacizumab in Patients With Unresectable Hepatocellular Carcinoma: A Multicentre Real World Study (HCC-AB Study). J Clin Exp Hepatol 2025; 15:102513. [PMID: 40129631 PMCID: PMC11930068 DOI: 10.1016/j.jceh.2025.102513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 02/04/2025] [Indexed: 03/26/2025] Open
Abstract
Background The approved immunotherapies for patients with advanced HCC are Atezolizumab and Bevacizumab. However, patients in India present late and healthcare is often available through self-financing. To rationalise the therapy, we conducted a large multicentre study to identify the baseline predictors of non-response to atezolizumab and bevacizumab in advanced unresectable HCC. Methods A dose of atezolizumab 1200 mg and bevacizumab 15 mg/kg was used every 3 weeks from 6 centres across India. A total of 278 patients were screened, and 160 were included in the study. The study included patients with locally advanced metastatic or inoperable hepatocellular carcinoma who were at least 18 years of age and those who received <3 injections were excluded. Fifty-four percent of the included patients were BCLC-B and 46% were BCLC-C. The primary objective was to study overall survival and progression-free survival. While identifying radiological response, objective response rate and adverse effects were secondary objectives. Results The mean age was 61.9 ± 11.7 years, 88% were male, 55% had NASH, 16.3% had hepatitis C, 18.8% had hepatitis B and the rest were alcohol. The mean Model for End-Stage Liver Disease (MELD) is 12.05 ± 4.46, Albumin-Bilirubin Score (ALBI) is -2.04 ± 0.57. Fifty-five percent received first-line and 45% as second/other line therapy. The median overall survival was 10 (95% confidence interval [CI]: 6.1-15.6) months. Progression-free survival was found to be 8 (95%CI: 5.1-14.7) months overall. Eleven (6.9%) achieved complete response, 28 (17.5%) partial response, 33 (20.6%) had stable disease and 88 (55%) had progressive disease. On multivariate analysis, CRP>1 mg/dl (P-0.007), PIVKA-II>400 mAU/mL (P-0.019), AFP>100 ng/ml (P-0.009), presence of diabetes (P-0.042) were associated with non-response to atezolizumab and bevacizumab injection. Fifty-three percent of patients developed any grade of adverse effect, and 20% developed grade 3/4 adverse events amounting to the stoppage of therapy. Conclusion Non-response to atezolizumab and bevacizumab immunotherapy was predicted by CRP>1 mg/dl, PIVKA-II>400mAU/ml, AFP>100 ng/ml and the presence of diabetes.
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Affiliation(s)
- Satender P. Singh
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Karan Kumar
- Department of Hepatology and Liver Transplant, Mahatma Gandhi Hospital, Jaipur, India
| | - Anand Kulkarni
- Department of Hepatology and Liver Transplant, Asian Institute of Gastroenterology, Hyderabad, India
| | - Vinod Arora
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Ashok Choudhury
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Alisha Chaubal
- Department of Hepatology and Liver Intensive Care, Global Hospitals, Mumbai, India
| | - Sahaj Rathi
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Samir Shah
- Department of Hepatology and Liver Intensive Care, Global Hospitals, Mumbai, India
| | - Sunil Taneja
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashish Kumar
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital, New Delhi, India
| | - Ajay Duseja
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Guresh Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - P. Nagaraja Rao
- Department of Hepatology and Liver Transplant, Asian Institute of Gastroenterology, Hyderabad, India
| | - Vivek Saraswat
- Department of Hepatology and Liver Transplant, Mahatma Gandhi Hospital, Jaipur, India
| | - Shiv K. Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
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Pettas T, Lachanoudi S, Karageorgos FF, Ziogas IA, Fylaktou A, Papalois V, Katsanos G, Antoniadis N, Tsoulfas G. Immunotherapy and liver transplantation for hepatocellular carcinoma: Current and future challenges. World J Transplant 2025; 15:98509. [DOI: 10.5500/wjt.v15.i2.98509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 10/03/2024] [Accepted: 11/07/2024] [Indexed: 02/21/2025] Open
Abstract
Despite existing curative options like surgical removal, tissue destruction techniques, and liver transplantation for early-stage hepatocellular carcinoma (HCC), the rising incidence and mortality rates of this global health burden necessitate continuous exploration of novel therapeutic strategies. This review critically assesses the dynamic treatment panorama for HCC, focusing specifically on the burgeoning role of immunotherapy in two key contexts: early-stage HCC and downstaging advanced HCC to facilitate liver transplant candidacy. It delves into the unique immunobiology of the liver and HCC, highlighting tumor-mediated immune evasion mechanisms. Analyzing the diverse immunotherapeutic approaches including checkpoint inhibitors, cytokine modulators, vaccines, oncolytic viruses, antigen-targeting antibodies, and adoptive cell therapy, this review acknowledges the limitations of current diagnostic markers alpha-fetoprotein and glypican-3 and emphasizes the need for novel biomarkers for patient selection and treatment monitoring. Exploring the rationale for neoadjuvant and adjuvant immunotherapy in early-stage HCC, current research is actively exploring the safety and effectiveness of diverse immunotherapeutic approaches through ongoing clinical trials. The review further explores the potential benefits and challenges of combining immunotherapy and liver transplant, highlighting the need for careful patient selection, meticulous monitoring, and novel strategies to mitigate post-transplant complications. Finally, this review delves into the latest findings from the clinical research landscape and future directions in HCC management, paving the way for optimizing treatment strategies and improving long-term survival rates for patients with this challenging malignancy.
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Affiliation(s)
- Theodoros Pettas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Sofia Lachanoudi
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Filippos F Karageorgos
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Ioannis A Ziogas
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Asimina Fylaktou
- Department of Immunology, National Peripheral Histocompatibility Center, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Vassilios Papalois
- Department of Transplant Surgery, Imperial College Renal and Transplant Centre, London W12 0HS, United Kingdom
| | - Georgios Katsanos
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
| | - Nikolaos Antoniadis
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Georgios Tsoulfas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
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Zhang Z, Sun Y, Zeng Z, Li D, Cao W, Lei S, Chen T. Identification of the clinical value and biological effects of TTN mutation in liver cancer. Mol Med Rep 2025; 31:165. [PMID: 40242970 PMCID: PMC12012433 DOI: 10.3892/mmr.2025.13530] [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: 11/12/2024] [Accepted: 03/11/2025] [Indexed: 04/18/2025] Open
Abstract
Liver cancer, a malignant tumor of the digestive system, is a leading cause of cancer‑related mortality globally. Numerous genetic mutations associated with tumorigenesis have been identified, stemming from genomic instability. However, the clinical implications and therapeutic relevance of these mutations remain poorly understood. The present study evaluated the prognostic significance of titin (TTN) mutations in liver cancer by analyzing the mutation landscape of liver cancer tissues from The Cancer Genome Atlas (TCGA) database. The association between TTN mutations and drug susceptibility was subsequently examined using the OncoPredict algorithm and Cell Counting Kit‑8 (CCK‑8) assays. Furthermore, the impact of TTN mutations on hepatoma cell biology both in vivo and in vitro were assessed by reverse transcription‑quantitative PCR, protein stability assays, colony formation assays, tumor spheroid formation assays and subcutaneous tumor transplantation in BALB/c nude mice. Genetic analysis of the TCGA database revealed that TTN mutations are among the most frequent mutations in liver cancer. Patients with TTN mutations exhibited worse prognoses compared with those with the wild‑type allele. The OncoPredict algorithm and CCK‑8 assays revealed that TTN mutations are associated with altered drug sensitivity, particularly to GSK1904529A, nilotinib, 5‑fluorouracil (5‑FU) and sapitinib. Additionally, TTN mutations were shown to enhance TTN protein stability, decrease intracellular ferrous ion levels and significantly decrease liver cancer sensitivity to 5‑FU both in vitro and in vivo. The findings indicated that TTN mutations increase protein stability and lower intracellular ferrous ion levels, thereby suppressing ferroptosis and contributing to resistance to 5‑FU in hepatoma cells. These results suggest that TTN mutations are associated with poor prognosis in liver cancer and could serve as a predictive biomarker for liver cancer progression, prognosis and drug resistance.
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Affiliation(s)
- Zhixue Zhang
- Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
- Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
| | - Yating Sun
- Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
- Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
| | - Zhirui Zeng
- Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
- Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
| | - Dahuan Li
- Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
- Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
| | - Wenpeng Cao
- Department of Anatomy, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
| | - Shan Lei
- Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
- Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
| | - Tengxiang Chen
- Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
- Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
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Huang JC, Tong XL, Xiang MSW, Boumelhem BB, Foulis DP, Zhang M, McKenzie CA, McCaughan GW, Reinheckel T, Zhang HE, Gorrell MD. Dipeptidyl peptidase 9 (DPP9) depletion from hepatocytes in experimental primary liver cancer. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167819. [PMID: 40187163 DOI: 10.1016/j.bbadis.2025.167819] [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: 08/31/2024] [Revised: 03/13/2025] [Accepted: 03/25/2025] [Indexed: 04/07/2025]
Abstract
Dipeptidyl peptidase 9 (DPP9) is an indispensable intracellular protease. Among its many molecular functions is suppression of the NLRP1 inflammasome. Inhibitors targeting all four proteases of the DPP4 family, including DPP9, can reduce tumour burden, including in mouse liver. To explore hepatocyte DPP9 in experimental hepatocellular carcinoma (HCC), we generated hepatocyte-specific DPP9-KO mice by crossing albumin-Cre mice with DPP9 floxed mice and treated sequentially with diethylnitrosamine, then with thioacetamide combined with an atherogenic high-fat diet until 28 weeks of age. DPP9-KO mice had less body, liver and subcutaneous adipose tissue mass, lower fasting plasma glucose and fewer small macroscopic liver nodules compared to DPP9-WT control mice. However, there were no differences in the total number of macroscopic liver nodules, or of microscopic tumour burden, inflammation, fibrosis or steatosis. Consistent with the known function of DPP9 to suppress NLRP1 activation, activated caspase-1 protein and inflammation markers Nfkbib, Cxcl10 and Ccl5 were elevated in DPP9-KO liver. The tumour suppressor protein p53 was increased and the autophagy proteins beclin1, LC3B and p62 were altered. In conclusion, hepatocyte-specific DPP9 gene deletion in experimental primary liver cancer improved energy metabolism and may reduce liver cancer initiation, via mechanisms that may include increased autophagy and tumour suppression.
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MESH Headings
- Animals
- Hepatocytes/pathology
- Hepatocytes/metabolism
- Hepatocytes/enzymology
- Mice
- Mice, Knockout
- Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics
- Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism
- Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/deficiency
- Liver Neoplasms, Experimental/pathology
- Liver Neoplasms, Experimental/genetics
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/chemically induced
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Male
- Liver Neoplasms/pathology
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Diet, High-Fat/adverse effects
- Mice, Inbred C57BL
- Inflammasomes/metabolism
- Liver/pathology
- Liver/metabolism
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Affiliation(s)
- JiaLi Carrie Huang
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Xinlin Linda Tong
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Michelle Sui Wen Xiang
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Badwi B Boumelhem
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Diarmid P Foulis
- Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia
| | - MingChang Zhang
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Catriona A McKenzie
- Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Geoffrey W McCaughan
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia
| | - Thomas Reinheckel
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), partner site Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Centre for Biological Signalling Studies BIOSS, University of Freiburg, Freiburg, Germany
| | - Hui E Zhang
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Mark D Gorrell
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
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9
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Rao H, An X, Qu X, Yu J, Xie J, Ke J, Liu Z, You L, Qiu Z, Tian L, Du W, Li W, Jia J, Liu D, Li S. SGLT2i delays c-Myc-induced HCC progression via targeting mTOR. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167805. [PMID: 40113049 DOI: 10.1016/j.bbadis.2025.167805] [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: 11/27/2024] [Revised: 02/23/2025] [Accepted: 03/15/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) stands as a primary malignant liver tumor characterized by metabolic reprogramming. The oncogene c-Myc exerts substantial influence by driving the transcription of numerous genes. Empagliflozin (EMPA), a sodium-glucose cotransporter-2 inhibitor (SGLT2i), is widely used in the treatment of type 2 diabetes and has recently attracted attention for its potential anti-cancer effects. This study aims to unravel the complex interplay among c-Myc, EMPA, and the mammalian target of rapamycin (mTOR) in HCC development and progression. METHODS HCC induction in mice utilized high-pressure hydrodynamic transfection of the c-Myc plasmid. QPCR and immunohistochemistry experiments were performed to detect the expression of SGLT2 in HCC tissues. In vivo experiments were conducted to corroborate the upregulation of SGLT2 following c-Myc transfection. In invo and vitro investigations were conducted to evaluate the anti-cancer effects of two SGLT2i: EMPA and canagliflozin (CANA). Network pharmacology, molecular docking analyses, CETSA experiments, and additional western blot experiments were used to reveal EMPA's interaction inhibition with mTOR. RESULTS The study identified an increase in SGLT2 expression in HCC tissues as a result of c-Myc overexpression. In vitro experiments confirmed the upregulation of SGLT2 following c-Myc transfection. Notably, the administration of SGLT2i effectively curtailed liver cancer progression, and reduced hepatic fat accumulation in mice. EMPA exhibited significant suppression of cell proliferation in c-Myc-transfected cells. In vitro experiments unveiled EMPA's interaction and with inhibition the activation of mTOR. CONCLUSION Our study highlights EMPA's potential as a therapeutic agent in delaying the development and progression of HCC.
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Affiliation(s)
- Huiling Rao
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Department of Medical Engineering, The First Affiliated Hospital of Army Medical University, Chongqing 400000, People's Republic of China
| | - Xiaotong An
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Xinyang Qu
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Juan Yu
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Department of Anesthesiology, People's Hospital of Yunxi County of Hubei Province, Yunxi 442600, People's Republic of China
| | - Jin Xie
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Jing Ke
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Zhixin Liu
- Shiyan Key Laboratory of Virology, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Lei You
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Zhenpeng Qiu
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, People's Republic of China
| | - Lin Tian
- Department of Pathology, Renming Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Weixing Du
- Department of Pathology, Renming Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Wanrong Li
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Jie Jia
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China.
| | - Danwen Liu
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China.
| | - Shan Li
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China.
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10
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Zhang D, Zhu Y, Shen Z, Ma S, Liu S, Lu Z. Immunosenescence and immunotherapy in elderly patients with hepatocellular carcinoma. Semin Cancer Biol 2025; 111:60-75. [PMID: 40020977 DOI: 10.1016/j.semcancer.2025.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 02/11/2025] [Accepted: 02/17/2025] [Indexed: 03/03/2025]
Abstract
Liver cancer, more specifically hepatocellular carcinoma (HCC), is a global health issue and one of the dominant causes of cancer death around the world. In the past few decades, remarkable advances have been achieved in the systemic therapy of HCC. Immune checkpoint inhibitors (ICIs) have become a therapy mainstay for advanced HCC and have shown promise in the neoadjuvant therapy before resection. Despite these significant advancements, the compositions and functions of the immune system occur various alterations with age, called "immunosenescence", which may affect the antitumor effects and safety of ICIs, thus raising concerns that immunosenescence may impair elderly patients' response to ICIs. Therefore, it is important to learn more about the immunosenescence characteristics of elderly patients. However, the real-world elderly HCC patients may be not accurately represented by the elderly patients included in the clinical trials, affecting the generalizability of the efficacy and safety profiles from the clinical trials to the real-world elderly patients. This review summarizes the characteristics of immunosenescence and its influence on HCC progression and immunotherapy efficacy as well as provides the latest progress in ICIs available for HCC and discusses their treatment efficacy and safety on elderly patients. In the future, more studies are needed to clarify the mechanisms of immunosenescence in HCC, and to find sensitive screening tools or biomarkers to identify the patients who may benefit from ICIs.
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Affiliation(s)
- Dengyong Zhang
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China
| | - Yan Zhu
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zhengchao Shen
- Department of General Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241001, China
| | - Shuoshuo Ma
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China
| | - Sihua Liu
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China
| | - Zheng Lu
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China.
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11
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Zhao H, Mao Y, Wang H, Zhou A, Yang Z, Han Y, Li G, Bi X, Hao C, Wang X, Zhou J, Dai C, Wen F, Zhang J, Liu R, Li T, Zhao L, Niu Z, Wen T, Li Q, Zhang H, Chen X, Chen M, Zhao M, Chen Y, Yu J, Shen J, Li X, Liu L, Huang Z, Zhang W, Shen F, Zhou W, Yuan Z, Zhai J, Ge N, Chen Y, Sun H, Cai J. A Survey of Clinical Practices for Hepatocellular Carcinoma Among Experts at Tertiary Hospitals in China From 2020 to 2021. CANCER INNOVATION 2025; 4:e70006. [PMID: 40196745 PMCID: PMC11975463 DOI: 10.1002/cai2.70006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 07/08/2024] [Accepted: 08/03/2024] [Indexed: 04/09/2025]
Abstract
Background Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death in China. The rapid progress in systemic therapies has led to the approval of many therapeutic methods that have quickly changed clinical guidelines and practices. Because of the high heterogeneity of HCC, there are still some gaps between the guidelines and real-world clinical practice. The present study surveyed experts in China to investigate the current treatment concepts and clinical practice regarding HCC. Methods A questionnaire survey on the treatment concepts and clinical practice of HCC was administered to 310 experts with senior professional titles in 2020 and 312 experts in 2021. The results were analyzed and compared. Results For treating patients with resectable HCC, 28% of hepatobiliary surgeons indicated neoadjuvant therapy, and 7% chose systemic therapy ± locoregional therapy as 1 L therapy in 2021 compared with 20% and 1% in 2020. More experts chose adjuvant treatment within 1 month in 2021 compared with 2020, and 6 months and 12 months were the leading choices for the duration of adjuvant treatment. In 2021, 79% of surgeons and 19% of interventionalists were willing to conduct downstaging/conversion therapy for patients with potentially resectable HCC, and 78% chose tyrosine kinase inhibitors (TKI) + immunotherapy (IO) + locoregional therapy for cases in which R0 resection could not be achieved. For completely unresectable HCC, more experts preferred TKI + IO-based therapy as 1 L therapy in 2021 compared with 2020 (78% vs. 55%). The proportion of experts who indicated TKI + IO-based therapy as 2 L therapy increased from 32% in 2020 to 40% in 2021. Conclusion The survey results indicated that in 2021, compared with 2020, more experts opted to administer IO + TKI for the treatment of liver cancer, and more experts and patients were willing to participate in clinical research.
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Affiliation(s)
- Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College (PUMC) HospitalPUMC and Chinese Academy of Medical Sciences (CAMS)BeijingChina
| | - Hongguang Wang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Aiping Zhou
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Zhengqiang Yang
- Department of Interventional Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yue Han
- Department of Interventional Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Gong Li
- Department of Radiation Oncology, Beijing Tsinghua Changgung Hospital (BTCH)School of Clinical Medicine, Tsinghua UniversityBeijingChina
| | - Xinyu Bi
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Chunyi Hao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Sarcoma CenterPeking University Cancer Hospital & InstituteBeijingChina
| | - Xiaodong Wang
- Departments of Interventional OncologyPeking University Cancer Hospital & InstituteBeijingChina
| | - Jun Zhou
- Department of Medical OncologyPeking University Cancer Hospital & InstituteBeijingChina
| | - Chaoliu Dai
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Feng Wen
- Department of RadiologyShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Jingdong Zhang
- Medical Oncology Department of Gastrointestinal CancerLiaoning Cancer Hospital & Institute, Cancer Hospital of China Medical UniversityShenyangLiaoningChina
| | - Ruibao Liu
- Interventional Radiological DepartmentHarbin Medical University Cancer HospitalHarbinHeilongjiangChina
| | - Tao Li
- Department of General Surgery, Qilu HospitalThe Second Hospital of Shandong UniversityJinanShandongChina
| | - Lei Zhao
- Department of Hepatobiliary SurgeryShandong Cancer Hospital Affiliated to Shandong First Medical University and Shandong Academy of Medical ScienceJinanShandongChina
| | - Zuoxing Niu
- Department of Gastroenterology, Ward 2, Shandong Cancer Hospital and InstituteShandong First Medical UniversityJinanShandongChina
| | - Tianfu Wen
- Department of Liver Surgery, West China HospitalSichuan UniversityChengduSichuanChina
| | - Qiu Li
- Cancer Center, West China HospitalSichuan UniversityChengduSichuanChina
| | - Hongmei Zhang
- Department of Clinical Oncology, Xijing HospitalThe Air Force Military Medical UniversityXi'anShaanxiChina
| | - Xiaoming Chen
- Department of Interventional RadiologyGuangdong Provincial People's HospitalGuangzhouGuangdongChina
| | - Minshan Chen
- Department of Liver SurgerySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongChina
| | - Ming Zhao
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service GroupSun Yat‐sen University Cancer CenterGuangzhouGuangdongChina
| | - Yajin Chen
- Department of Hepatobiliary Surgery, Sun Yat‐sen Memorial HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
| | - Jun Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Jie Shen
- Department of OncologyThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingJiangsuChina
| | - Xiangchen Li
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsuChina
| | - Lianxin Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Zhiyong Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - Wei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery HospitalSecond Military Medical University (Naval Medical University)ShanghaiChina
| | - Weiping Zhou
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery HospitalSecond Military Medical University (Naval Medical University)ShanghaiChina
| | - Zhengang Yuan
- Department of Oncology, Eastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghaiChina
| | - Jian Zhai
- Department II of Interventional RadiologyEastern Hepatobiliary Surgery HospitalShanghaiChina
| | - Ningling Ge
- Department of Hepatic Oncology, Zhongshan Hospital, Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer InvasionFudan UniversityShanghaiChina
| | - Yongjun Chen
- Department of General Surgery, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Huichuan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan HospitalFudan UniversityShanghaiChina
| | - Jianqiang Cai
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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12
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He M, Xie W, Yuan Z, Chen J, Wang J, Fu Y, Hu Z, Meng Q, Gao W, Hu D, Zhang Y, Pan Y, Zhou Z. Comparing PD-L1 and PD-1 inhibitors plus bevacizumab combined with hepatic arterial interventional therapies in unresetable hepatocellular carcinoma: A single-center, real-world study. Int J Cancer 2025; 156:1972-1985. [PMID: 39834172 DOI: 10.1002/ijc.35341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 12/18/2024] [Accepted: 01/02/2025] [Indexed: 01/22/2025]
Abstract
With the rise of anti-vascular endothelial growth factor antibody and programmed cell death-ligand 1 (PD-L1) regimens, particularly bevacizumab and atezolizumab, as first-line treatments for advanced hepatocellular carcinoma (HCC), there is a need to explore PD-L1 and programmed cell death 1 inhibitors in combination therapies for unresectable HCC (uHCC). Integrating systemic therapies with locoregional approaches is also emerging as a potent strategy. This study compares the outcomes of atezolizumab (PD-L1 inhibitor) and sintilimab (programmed cell death 1 inhibitor) with bevacizumab or its biosimilar, combined with hepatic arterial interventional therapies (HAIT) in uHCC patients. From January 2020 to September 2023, a retrospective analysis was conducted on 138 uHCC patients at Sun Yat-sen University Cancer Center. The cohort included 69 patients treated with atezolizumab with bevacizumab (Bev/Ate) and 69 with bevacizumab biosimilar with sintilimab (Bio/Sin), combined with HAIT. The propensity score matching was also employed to further explore the efficacy and safety. The median progression-free survival (mPFS) was 13.8 months for the Bev/Ate group and 10.0 months for the Bio/Sin group (p = 0.188). The Bev/Ate group showed significantly longer intrahepatic mPFS (HR 0.381; 95% confidence interval 0.176-0.824; p = .018) and higher overall response rates compared with the Bio/Sin group (60.87% vs. 31.88%, p = .001; 69.57% vs. 49.28%, p = .024) based on Response Evaluation Criteria in Solid Tumors v1.1 and modified Response Evaluation Criteria in Solid Tumors criteria. Treatment-related adverse events were similar between groups (p > .050). Combining atezolizumab or sintilimab with bevacizumab or its biosimilar alongside HAIT provided similar overall PFS in uHCC patients. However, the atezolizumab-bevacizumab combination with HAIT showed superior intrahepatic PFS and control rates, warranting further validation.
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Affiliation(s)
- Minrui He
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Wa Xie
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Imaging Diagnostic and Interventional Center, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Ze Yuan
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Neurosurgery/NeuroOncology, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Jinbin Chen
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Juncheng Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Yizhen Fu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Zili Hu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Qi Meng
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Clinical Research, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Wenqing Gao
- Department of Oncology, Tengchong People's Hospital, Baoshan, PR China
| | - Dandan Hu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Yaojun Zhang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Yangxun Pan
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Zhongguo Zhou
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
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13
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Qiang N, Ao J, Nakamura M, Katayama K, Zhang J, Kogure T, Ogawa K, Kanzaki H, Kojima R, Koroki K, Kobayashi K, Inoue M, Kanogawa N, Kiyono S, Nakagawa R, Kondo T, Ogasawara S, Nakamoto S, Muroyama R, Kato J, Kato N. MEGF6 knockdown ameliorates lenvatinib-induced muscle differentiation suppression and enhances the antitumor effect of lenvatinib on hepatocellular carcinoma. Biochem Pharmacol 2025; 235:116829. [PMID: 40015652 DOI: 10.1016/j.bcp.2025.116829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 01/12/2025] [Accepted: 02/24/2025] [Indexed: 03/01/2025]
Abstract
Lenvatinib (LEN)-treated patients with hepatocellular carcinoma (HCC) are frequently accompanied by skeletal muscle loss, which is correlated with poor prognosis. Interactions between tumor and skeletal muscle may play a role in patient prognosis and tumor progression. We here demonstrated that LEN hindered proliferation and differentiation of the mouse myoblast cell line, C2C12 cells, by blocking the ERK1/2 and AKT signaling pathways. Transcriptome analysis revealed that multiple EGF-like domains 6 (Megf6) was upregulated in LEN-treated C2C12 cells. Furthermore, we observed that compared with normal adjacent tissues, MEGF6 was highly expressed in HCC tumor tissues according to the TCGA database, which suggested MEGF6-mediated interaction between tumor and skeletal muscle. The Megf6 knockdown restored the differentiation inhibition caused by LEN and ERK1/2 inhibitors; however, it had no significant impact on proliferation. Regarding mechanism, LEN increased Megf6 expression through the ERK1/2 signaling pathway, thereby resulting in myostatin expression elevation and myosin heavy chain protein expression repression. Furthermore, MEGF6 in LEN-treated C2C12 cell medium promoted tumor cell proliferation and impaired C2C12 cell differentiation when cultured with LEN-treated tumor cell medium. Clinically, patients who were accompanied by muscle mass loss and increased MEGF6 serum levels had shorter progression-free survival than those who were accompanied by muscle mass loss but no increased MEGF6 serum levels before and after LEN treatment. In conclusion, MEGF6 produced from muscle and tumor cells could impair muscle differentiation and enhance tumor proliferation. Therefore, MEGF6 is worth further investigating as a target for improving the prognosis of LEN-treated patients with HCC.
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Affiliation(s)
- Na Qiang
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China; Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Junjie Ao
- Cancer Center, Department of Gastroenterology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China; Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Keichi Katayama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Jiaqi Zhang
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tadayoshi Kogure
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Keita Ogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroaki Kanzaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan; Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ryuta Kojima
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Keisuke Koroki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kazufumi Kobayashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masanori Inoue
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kanogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Soichiro Kiyono
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ryo Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takayuki Kondo
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ryosuke Muroyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kato
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
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14
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Wang J, Chen Q, Shan Q, Liang T, Forde P, Zheng L. Clinical development of immuno-oncology therapeutics. Cancer Lett 2025; 617:217616. [PMID: 40054657 PMCID: PMC11930610 DOI: 10.1016/j.canlet.2025.217616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 03/03/2025] [Accepted: 03/05/2025] [Indexed: 03/15/2025]
Abstract
Immuno-oncology (IO) is one of the fastest growing therapeutic areas within oncology. IO agents work indirectly via the host's adaptive and innate immune system to recognize and eradicate tumor cells. Despite checkpoint inhibitors being only introduced to the market since 2011, they have become the second most approved product category. Current Food and Drug Administration (FDA)-approved classes of IO agents include: immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapy (CAR-T), bi-specific T-cell engager (BiTE) antibody therapy, T-cell receptor (TCR) engineered T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, cytokine therapy, cancer vaccine therapy, and oncolytic virus therapy. Cancer immunotherapy has made progress in multiple cancer types including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma; however, several cancers remain refractory to immunotherapy. Future directions of IO include exploration in the neoadjuvant/perioperative setting, combination strategies, and optimizing patient selection through improved biomarkers.
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Affiliation(s)
- Jianxin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Qi Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Qiang Shan
- Department of General Surgery, Haining People's Hospital, Haining, 314400, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Patrick Forde
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Mays Cancer Center at the University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Lei Zheng
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Mays Cancer Center at the University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
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Chai J, Li L, Wu Q, Zhang S. CD96: immunoregulation and its role and prospect in immunotherapy of primary hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2025; 37:534-539. [PMID: 39976070 DOI: 10.1097/meg.0000000000002916] [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] [Indexed: 02/21/2025]
Abstract
Recently, immune checkpoint inhibitors have been widely used in the treatment of advanced liver cancer. Immune checkpoints are a type of molecules that play an important role in the self-regulation of the immune system. In tumor immunity, their activation by immune checkpoints leads to the inhibition of effector lymphocyte activation or the mediation of cytotoxic T cell dysfunction, resulting in immune escape. These immune checkpoints include programmed death receptor 1 (PD-1) and its ligand PD-L1, as well as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and others. Immune checkpoint inhibitors block the interaction between immune checkpoint receptors and ligands, thereby relieving the immune suppression caused by immune checkpoints, and reactivating immune cells to exert antitumor effects. With the continuous progress of immunotherapy research, drugs targeting PDL-1, PD-1, and CTLA-4 have played an important role in clinical treatment. However, some patients still cannot benefit from immunotherapy; therefore, multitarget immunotherapy is an important way to improve the response rate of immunotherapy. CD96 is one of the members of the immunoglobulin superfamily receptors, which mainly functions by regulating natural killer cells and CD8+ T cells, and is expected to become a new generation of immune checkpoints. This article reviews the molecular structure of CD96, its role in tumor immunity, and its application in hepatocellular carcinoma, hoping to provide reference for related research.
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Affiliation(s)
- Jiaqi Chai
- Department of Colorectal Surgery, 731 Hospital of China Aerospace Science and Industry Group
| | - Luyang Li
- Department of Hepatobiliary Surgery, Air Force Medical Center, Air Force Medical University Beijing
| | - Qimei Wu
- Graduate School of China Medical University, Shenyang, China
| | - Shuhan Zhang
- Department of Hepatobiliary Surgery, Air Force Medical Center, Air Force Medical University Beijing
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Kohya R, Suda G, Ohara M, Hosoda S, Sho T, Chuma M, Komori A, Kugiyama Y, Yasui Y, Tsuchiya K, Kurosaki M, Tani J, Kaneko S, Nakagawa M, Asahina Y, Maekawa S, Enomoto N, Yamamoto Y, Baba M, Yamada R, Sasaki T, Yoda T, Yoshida S, Fu Q, Yang Z, Maehara O, Ohnishi S, Tokuchi Y, Kitagataya T, Kawagishi N, Nakai M, Natsuizaka M, Ogawa K, Sakamoto N. Serum FGF21 as a predictor of response to atezolizumab and bevacizumab in HCC. JHEP Rep 2025; 7:101364. [PMID: 40242310 PMCID: PMC11999275 DOI: 10.1016/j.jhepr.2025.101364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 02/01/2025] [Accepted: 02/13/2025] [Indexed: 04/18/2025] Open
Abstract
Background & Aims Fibroblast growth factor 21 (FGF21) is a crucial regulator of cell metabolism. Tumour-secreted FGF21 has shown immune-checkpoint factor functions, and high FGF21 levels are associated with a poor prognosis for patients. However, its prognostic value and impact on treatment response in patients with hepatocellular carcinoma (HCC) treated with immune-checkpoint inhibitors (ICIs) remain unclear. Thus, this study investigated the potential of high FGF21 levels as a prognostic marker and whether traditional ICI-based therapy can improve the prognosis of patients with high FGF21 levels. Methods In this retrospective multicentre study, patients with unresectable HCC who received atezolizumab/bevacizumab in the NORTE study group (n = 117) were classified into high (≥915 pg/ml; n = 29) and non-high (n = 88) FGF21 groups. For validation, we investigated patients treated with atezolizumab/bevacizumab in an independent cohort (n = 285). Overall survival, progression-free survival, and treatment response were compared between patients with and without high baseline FGF21 levels. Results The median overall survival (p <0.001) and progression-free survival (p = 0.045) were significantly shorter in the high FGF21 group than in the non-high FGF21 group. Independent cohort analysis validated these results. In the overall cohort, the median progression-free survival (5.75 vs. 8.84 months; p = 0.027) and median overall survival (14.13 vs. 22.08 months; p <0.001) were significantly shorter in the high FGF21 group than in the non-high FGF21 group. The durable response (≥6 months) + complete response rate was significantly decreased in the high FGF21 group (p = 0.045). No patient with a high FGF21 level achieved a complete response, whereas this was achieved in 4.1% (13/319) of patients with non-high FGF21 levels. Multivariate Cox regression analysis identified high baseline serum FGF21 as an independent poor prognostic factor for overall survival (hazard ratio 2.20, p <0.001). Conclusions Serum FGF21 may be a robust, non-invasive prognostic and treatment response marker for unresectable HCC treated with atezolizumab/bevacizumab. Impact and implications FGF21 has been reported to act as a secreted immune-checkpoint factor, and elevated levels of FGF21 are associated with a poor prognosis in patients with HCC. It is not fully understood whether ICIs can overcome the impact of high FGF21 levels on the shortened prognosis of patients with HCC. In this multicentre retrospective study, patients with HCC and high baseline levels of serum FGF21 who received atezolizumab/bevacizumab treatment exhibited a significantly shorter overall survival and shorter progression-free survival. These findings suggest serum FGF21 as a robust prognostic marker and an indicator of treatment response in unresectable HCC treated with ICI-based therapy. These findings could be crucial for the implementation of personalised treatment strategies for unresectable HCC. However, identifying optimal therapeutic options for patients with unresectable HCC and high serum FGF21 levels remains an urgent and critical clinical issue.
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Affiliation(s)
- Risako Kohya
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Shunichi Hosoda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Makoto Chuma
- Gastroenterology Centre, Yokohama City University Medical Centre, Minami-ku, Yokohama, Japan
| | - Atsumasa Komori
- Hepatology Division, NHO Nagasaki Medical Centre, Ōmura, Nagasaki, Japan
| | - Yuki Kugiyama
- Hepatology Division, NHO Nagasaki Medical Centre, Ōmura, Nagasaki, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Takamatsu, Kagawa, Japan
| | - Shun Kaneko
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Mina Nakagawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
- Department of Liver Disease Control, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Shinya Maekawa
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, Kofu City, Yamanashi, Japan
| | - Nobuyuki Enomoto
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, Kofu City, Yamanashi, Japan
| | - Yoshiya Yamamoto
- Department of Gastroenterology and Hepatology, Hakodate Municipal Hospital, Hakodate, Hokkaido, Japan
| | - Masaru Baba
- Centre for Gastroenterology and Hepatology, Japan Community Healthcare Organisation Hokkaido Hospital, Sapporo, Hokkaido, Japan
| | - Ren Yamada
- Kushiro Rosai Hospital, Kushiro, Hokkaido, Japan
| | - Takashi Sasaki
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Tomoka Yoda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Sonoe Yoshida
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Qingjie Fu
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Zijian Yang
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Osamu Maehara
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Shunsuke Ohnishi
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Yoshimasa Tokuchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
- Department of Gastroenterology and Hepatology, Hakodate Municipal Hospital, Hakodate, Hokkaido, Japan
| | - Takashi Kitagataya
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Naoki Kawagishi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
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Piñero F, Anders M, Bermudez C, Arufe D, Varón A, Palazzo A, Rodriguez J, Beltrán O, Simian D, da Fonseca LG, Ridruejo E, Tamagnone N, Cheinquer H, Bejarano D, Marín JI, Orozco F, Pages J, Poniachik J, Marciano S, Reggiardo V, Silva M, Mendizabal M. Hepatic Recompensation Before Systemic Therapy for Hepatocellular Carcinoma Yields Comparable Survival to Compensated Cirrhosis. Liver Int 2025; 45:e70092. [PMID: 40208044 DOI: 10.1111/liv.70092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 03/06/2025] [Accepted: 03/29/2025] [Indexed: 04/11/2025]
Abstract
BACKGROUND AND AIMS The survival outcomes associated with hepatic recompensation in patients with advanced hepatocellular carcinoma (HCC) treated with first-line systemic therapies remain unclear. We compared survival from the initiation of first-line systemic treatments for advanced HCC among patients with compensated, decompensated, and recompensated cirrhosis. METHODS A Latin American multicenter, prospective cohort study was conducted from 2018 to 2024, involving patients with HCC and Child-Pugh class A or B who received systemic therapy. At the time of first-line therapy, patients with cirrhosis were categorised as compensated (never decompensated), decompensated, or recompensated. Cox proportional hazards models were estimated. RESULTS Among 306 patients receiving first-line systemic therapy (sorafenib: 60.5%, atezolizumab + bevacizumab: 29.7%, lenvatinib: 9.1%), 240 had cirrhosis, with 30.4% having a history of hepatic decompensation. Of these, 57.5% (95% CI 45.4%-69.0%) achieved hepatic recompensation over a median period of 12 months. At the time of first-line therapy, 69.6% were compensated, 17.5% recompensated, and 12.9% decompensated. Metabolic-associated steatotic liver disease (MASLD) was the most common underlying aetiology in the recompensated group. Median survival was significantly shorter in the decompensated group (8.6 months) compared to the compensated group (17.2 months) [aHR 1.91 (95% CI 1.04-3.5); p = 0.03], without a significant difference between the recompensated and compensated groups [aHR 1.28 (95% CI 0.79-2.1); p = 0.31]. Tumour progression was the primary reason for treatment discontinuation, and similar access to second-line therapies was observed between the compensated and recompensated groups. CONCLUSION Patients with cirrhosis and advanced HCC who achieved hepatic recompensation might benefit from systemic therapies after a cautious observation period.
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Affiliation(s)
| | | | - Carla Bermudez
- Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Diego Arufe
- Sanatorio Sagrado Corazón, Buenos Aires, Argentina
| | | | | | | | | | - Daniela Simian
- Hospital Clínico de la Universidad de Chile, Santiago, Chile
| | - Leonardo Gomes da Fonseca
- Instituto Do Cancer do Estado de São Paulo, Hospital das Clínicas Universidade São Paulo, São Paulo, Brazil
| | - Ezequiel Ridruejo
- Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Buenos Aires, Argentina
| | | | - Hugo Cheinquer
- Hospital das Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Diana Bejarano
- Hospital Universitario Fundación Santa Fe de Bogotá, Bogotá, Colombia
| | | | | | | | - Jaime Poniachik
- Hospital Clínico de la Universidad de Chile, Santiago, Chile
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Tsakiridis EE, Ahmadi E, Gautam J, Hannah She YR, Fayyazi R, Lally JS, Wang S, Di Pastena F, Valvano CM, Del Rosso D, Biziotis OD, Meyers B, Muti P, Tsakiridis T, Steinberg GR. Salsalate improves the anti-tumor efficacy of lenvatinib in MASH-driven hepatocellular carcinoma. JHEP Rep 2025; 7:101354. [PMID: 40276482 PMCID: PMC12018114 DOI: 10.1016/j.jhepr.2025.101354] [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: 08/09/2024] [Revised: 01/23/2025] [Accepted: 02/06/2025] [Indexed: 04/26/2025] Open
Abstract
Background & Aims Metabolic dysfunction-associated steatohepatitis (MASH) is a growing cause of hepatocellular carcinoma (HCC) worldwide. The complex microenvironment of these tumors, characterized by metabolic dysfunction, hypoxia, steatosis, and fibrosis, limits the effectiveness of standard-of-care therapies, such as the multi-tyrosine kinase inhibitor lenvatinib (LEN). Salsalate (SAL), is a rheumatoid arthritis therapy that enhances fatty acid oxidation and reduces de novo lipogenesis, fibrosis and cell proliferation pathways. We hypothesize that addition of SAL could improve the efficacy of LEN in MASH-HCC. Methods We assessed the efficacy of combination therapy using clinically relevant concentrations of LEN and SAL in human HCC cell models, orthotopic xenograft and MASH-HCC mouse models. In addition, assays assessing fatty acid oxidation and lipogenesis, protein immunoblotting and RNA-sequencing were used to understand mechanisms involved. Results LEN + SAL synergistically suppressed the proliferation and clonogenic survival of cells (p ≤0.0001), prolonged survival in an orthotopic xenograft model (p = 0.02), and reduced angiogenesis, fibrosis, and steatosis (p ≤0.05) in a MASH-HCC model. These effects were associated with activation of AMPK and inhibition of the mTOR-HIF1α and Erk1/2 signaling pathways. RNA-sequencing analysis in both Hep3B cells and livers of the MASH-HCC mouse model revealed that SAL enhanced fatty acid oxidation and suppressed fibrosis and cell cycle progression, while LEN reduced angiogenesis with regulatory network analysis, suggesting a potential role for activating transcription factor 3 (ATF3) and ETS-proto-oncogene-1 (ETS-1). Conclusions These data indicate that combining LEN and SAL, which exert distinct effects leading to improvements in the liver microenvironment (steatosis, angiogenesis, and fibrosis) and inhibition of tumor proliferation, may have therapeutic potential for MASH-driven HCC. Impact and implications Although rates of MASH-HCC are on the rise globally, standard-of-care multi-tyrosine kinase inhibitors and immunotherapy have limited efficacy in this HCC etiology. Metabolic targeting with SAL inhibits cancer growth kinetics while also alleviating drivers of MASH by increasing fatty acid oxidation and reducing de novo lipogenesis and fibrosis. Combined LEN and SAL improved survival and MASH-HCC pathology in mouse models without adverse effects. Given that SAL is a safe, economical, and approved medication, this concept holds great translational potential that could provide a new treatment avenue for patients with unresected MASH-HCC.
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Affiliation(s)
- Evangelia E. Tsakiridis
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
| | - Elham Ahmadi
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
- Juravinski Cancer Center, Hamilton Health Sciences, 699 Concession Street, Hamilton, ONT, L8V 5CV, Canada
| | - Jaya Gautam
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
| | - Yi Ran Hannah She
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
| | - Russta Fayyazi
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
| | - James S.V. Lally
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
| | - Simon Wang
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
- Juravinski Cancer Center, Hamilton Health Sciences, 699 Concession Street, Hamilton, ONT, L8V 5CV, Canada
- Department of Oncology, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
| | - Fiorella Di Pastena
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
| | - Celina M. Valvano
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
| | - Daniel Del Rosso
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
- Department of Oncology, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
| | - Olga-Demetra Biziotis
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
- Juravinski Cancer Center, Hamilton Health Sciences, 699 Concession Street, Hamilton, ONT, L8V 5CV, Canada
- Department of Oncology, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
| | - Brandon Meyers
- Juravinski Cancer Center, Hamilton Health Sciences, 699 Concession Street, Hamilton, ONT, L8V 5CV, Canada
- Department of Oncology, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
| | - Paola Muti
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
- Department of Oncology, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
| | - Theodoros Tsakiridis
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
- Juravinski Cancer Center, Hamilton Health Sciences, 699 Concession Street, Hamilton, ONT, L8V 5CV, Canada
- Department of Oncology, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
| | - Gregory R. Steinberg
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ONT, L8S 4K1, Canada
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Monsel A, Sitbon A, Roux C, Eyraud D, Scatton O, Vezinet C, Oré MV, Gallet J, Wagner M, Thabut D, Boughdad S, Renaud F, Mazzola A, Goumard C, Allaire M. Current insights into anaesthesia and critical care management of patients with hepatocellular carcinoma: Multifaceted implications for the anaesthesiologist and intensive care physician. Eur J Anaesthesiol 2025; 42:435-448. [PMID: 39945138 DOI: 10.1097/eja.0000000000002141] [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: 10/10/2024] [Accepted: 01/23/2025] [Indexed: 04/03/2025]
Abstract
BACKGROUND The incidence of hepatocellular carcinoma (HCC) is on the rise worldwide, due to the increasing prevalence of liver diseases associated with metabolic dysfunction and better management of cirrhosis and its complications. The diversification of HCC treatments has recently increased, with the choice of strategy based on HCC characteristics, liver function and comorbidities. The combination of new therapies has transformed the prognosis, with up to 70% survival at 5 years. OBJECTIVE The aim of this review was to analyse the most recent data on preoperative evaluation, peri-operative anaesthetic management of liver resection, liver transplantation and other types of procedures, and to highlight the multidisciplinary aspect of such management. MAIN FINDINGS AND DISCUSSION The importance of preanaesthetic evaluation will depend largely on the procedure proposed, associated co-morbidities and the stage of liver disease. This assessment should verify stabilisation of all comorbidities, and evaluate the degree of portal hypertension, cirrhosis severity and sarcopenia. Liver resection and liver transplantation for HCC present specific surgical challenges, and minimally invasive techniques improve recovery. Nonsurgical procedures considered as therapeutic (ablation) or standby (regional embolisation) are diverse, and all expose patients to specific intra-anaesthetic complications, sometimes requiring intensive care management. Peri-operative anaesthetic strategies deployed in the management of liver resection or nonsurgical procedures involve specific management of fluids, coagulation, narcosis and analgesia, which can impact on patients' overall, and cancer prognosis. Lastly, new down-staging strategies combining several types of procedure and possibly immunotherapy, also call for collegial reflection on posthepatic transplant immunosuppression, which must remain tailored to each individual patient.
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Affiliation(s)
- Antoine Monsel
- From the Multidisciplinary Intensive Care Unit, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP) Sorbonne University, Paris, France (AM, AS, DE, CV, MVO, JG), Sorbonne Université-INSERM UMRS_959, Immunology-Immunopathology-Immunotherapy (I3), 75013 Paris, France (AM), Sorbonne Université, INSERM, Centre de Recherche de Saint-Antoine (CRSA), UMRS-938, 75012, Paris, France (AM, AS, OS, CG), Department of Advanced Interventional Radiology, APHP, Sorbonne University, Hôpital Pitié-Salpétrière, Paris, France (CR), Hepatology and gastrenterology Unit, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP) Sorbonne University, Paris, France (DT, AM, MA), Department of Hepatobiliary and Liver Transplantation Surgery, AP-HP, Pitié-Salpêtrière Hospital, Sorbonne Université, Paris, France (OS, CG), Department of Radiology (SISU), APHP, Sorbonne University, Laboratoire d'imagerie biomédicale, Hôpital Pitié-Salpétrière, Paris, France (MW, SB), Nuclear Medicine Department, AP-HP, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France (SB), Pathology Department, AP-HP, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France (FR), Genomic Instability, Metabolism, Immunity and Liver Tumorigenesis laboratory, Equipe Labellisée LIGUE 2023, Paris, France (MA), Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France (MA), Radiotherapy Department, AP-HP, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France
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20
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Sequeira LM, Ozturk NB, Sierra L, Gurakar M, Toruner MD, Zheng M, Simsek C, Gurakar A, Kim AK. Hepatocellular Carcinoma and the Role of Liver Transplantation: An Update and Review. J Clin Transl Hepatol 2025; 13:327-338. [PMID: 40206277 PMCID: PMC11976436 DOI: 10.14218/jcth.2024.00432] [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: 11/18/2024] [Revised: 01/25/2025] [Accepted: 02/08/2025] [Indexed: 04/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. Multiple treatment modalities are available for the management of HCC, depending on its stage as determined by the Barcelona Clinic Liver Cancer staging system. Because liver transplantation (LT) theoretically removes the cancer and replaces the organ at risk for future malignancy, LT is often considered the most definitive and one of the most efficacious treatment options for HCC. Nevertheless, the success and efficacy of liver transplantation depend on various tumor characteristics. As a result, multiple criteria have been developed to assess the appropriateness of a case of HCC for LT, with the pioneering Milan Criteria established in 1996. Over the past 20 to 30 years, these criteria have been critically evaluated, expanded, and often liberalized to make LT for patients with HCC a more universally applicable option. Furthermore, the development of other treatment modalities has enabled downstaging and bridging strategies for HCC prior to LT. In this narrative and comprehensive review, we provided an update on recent trends in the epidemiology of HCC, selection criteria for LT, implementation of LT across different regions, treatment modalities available as bridges, downstaging strategies, alternatives to LT, and, finally, post-LT surveillance.
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Affiliation(s)
- Lynette M. Sequeira
- Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - N. Begum Ozturk
- Department of Internal Medicine, Beaumont Hospital, Royal Oak, MI, USA
| | - Leandro Sierra
- Department of Internal Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Merve Gurakar
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Melanie Zheng
- Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Cem Simsek
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ahmet Gurakar
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Amy K. Kim
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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21
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Chok KSH, Joeng TYT, Poon DMC. Proton beam therapy in the management of hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2025:1-10. [PMID: 40272863 DOI: 10.1080/17474124.2025.2495080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 04/15/2025] [Indexed: 04/26/2025]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. Photon radiotherapy shows efficacy in treating HCC but carries risks of high exit dose and radiation-induced liver disease. Additionally, HCCs with portal vein tumor thrombosis (PVTT) have a poor prognosis and are associated with higher risk of death. In recent years, proton beam therapy (PBT) has emerged as a novel treatment with the ability to downstage HCC for liver transplant (LT). AREAS COVERED This review will provide an overview of dosimetric benefits of PBT, efficacy of PBT in treating HCC, downstaging HCC-PVTT for LT, and a comparison of PBT with other non-surgical techniques. A search of PubMed until 3 September 2024 was conducted using free search and the following keywords: hepatocellular carcinoma, proton beam therapy, portal vein tumor thrombosis, local ablative therapy, trans-arterial chemoembolization, stereotactic body radiotherapy, Y-90 radioembolization. EXPERT OPINION Various clinical trials using PBT have shown promising tumor local control and overall survival rates. PBT is mostly safe and efficacious for downstaging HCC-PVTT for LT. PBT has also been shown to be non-inferior to various other treatment modalities. Future research should focus on combinations of PBT with other modalities.
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Affiliation(s)
- Kenneth S H Chok
- Department of Surgery, The Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Tiffany Y T Joeng
- Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Darren M C Poon
- Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong, China
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22
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Zhang X, Zhang X, Luo QK, Fu Q, Liu P, Pan CJ, Liu CJ, Zhang HW, Qin T. Pretreatment radiomic imaging features combined with immunological indicators to predict targeted combination immunotherapy response in advanced hepatocellular carcinoma. World J Clin Oncol 2025; 16:102735. [DOI: 10.5306/wjco.v16.i4.102735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 12/16/2024] [Accepted: 01/23/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Early symptoms of hepatocellular carcinoma (HCC) are not obvious, and more than 70% of which does not receive radical hepatectomy, when first diagnosed. In recent years, molecular-targeted drugs combined with immunotherapy and other therapeutic methods have provided new treatment options for middle and advanced HCC (aHCC). Predicting the effect of targeted combined immunotherapy has become a hot topic in current research.
AIM To explore the relationship between nodule enhancement in hepatobiliary phase and the efficacy of combined targeted immunotherapy for aHCC.
METHODS Data from 56 patients with aHCC for magnetic resonance imaging with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid were retrospectively collected. Signal intensity of intrahepatic nodules was measured, and the hepatobiliary relative enhancement ratio (RER) was calculated. Progression-free survival (PFS) of patients with high and low reinforcement of HCC nodules was compared. The model was validated using receiver operating characteristic curves. Univariate and multivariate logistic regression and Kaplan-Meier analysis were performed to explore factors influencing the efficacy of targeted immunization and PFS.
RESULTS Univariate and multivariate analyses revealed that the RER, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index were significantly associated with the efficacy of tyrosine kinase inhibitors combined with immunotherapy (P < 0.05). The area under the curve of the RER for predicting the efficacy of tyrosine kinase inhibitors combined with anti-programmed death 1 antibody in patients with aHCC was 0.876 (95% confidence interval: 0.781-0.971, P < 0.05), the optimal cutoff value was 0.904, diagnostic sensitivity was 87.5%, and specificity was 79.2%. Kaplan-Meier analysis showed that neutrophil-to-lymphocyte ratio < 5, platelet-to-lymphocyte ratio < 300, prognostic nutritional index < 45, and RER < 0.9 significantly improved PFS.
CONCLUSION AHCC nodules enhancement in the hepatobiliary stage was significantly correlated with PFS. Imaging information and immunological indicators had high predictive efficacy for targeted combined immunotherapy and were associated with PFS.
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Affiliation(s)
- Xu Zhang
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Xu Zhang
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Qian-Kun Luo
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Qiang Fu
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Pan Liu
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Chang-Jie Pan
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Chuan-Jiang Liu
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Hong-Wei Zhang
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Tao Qin
- Department of Hepato-Biliary-Pancreatic Surgery, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
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23
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Liu H, Wang G, Li Z, Zhang X, Zhang W, Zhang X, Liu F, Gao J. Exosome-based immunotherapy in hepatocellular carcinoma. Clin Exp Med 2025; 25:127. [PMID: 40274634 DOI: 10.1007/s10238-025-01659-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 03/29/2025] [Indexed: 04/26/2025]
Abstract
Hepatocellular carcinoma (HCC) is a significant global health concern and ranks as the third leading cause of cancer-associated mortality. Systemic therapy faces the emergence of resistance, which hinders the clinical benefits. Recent evidence suggests that exosomes, measuring between 30 and 150 nm in size, which impact the antitumor immune responses, making them a promising candidate for cancer immunotherapy. Owing to their unique physical and chemical characteristics, exosomes can be tailored and engineered for a range of therapeutic objectives. In the present review, we outline the immunomodulatory functions of exosomes in the tumor microenvironment (TME) of HCC, aiming to decipher the underlying mechanisms of exosomes in remodeling suppressive TME. Moreover, we provide detailed and intuitive resource for leveraging the potential of exosomes in immunotherapy, presenting valuable strategies to improve and optimize HCC treatment. Despite the huge therapeutic potential of exosomes, significant challenges persist, including the need for standardization in exosome production, optimization of cargo loading techniques, and the assurance of safety and effectiveness in clinical applications. Addressing these challenges may pave the way for exosome-based immunotherapy for HCC patients.
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Affiliation(s)
- Hong Liu
- Department of Pathology, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China
| | - GuoWei Wang
- Department of Radiology, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China
| | - ZhaoYi Li
- Department of Scientific Research and Education, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China
| | - XianTu Zhang
- Department of Pathology, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China
| | - WeiDong Zhang
- Department of General Surgery I, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China
| | - Xia Zhang
- Medical Laboratory, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China.
| | - Fang Liu
- Xixi Hospital Biobank, Xixi Hospital of Hangzhou, Zhejiang Province, Hangzhou, 310023, China.
| | - Jing Gao
- Department of Pathology, Xixi Hospital of Hangzhou, Hangzhou, 310023, Zhejiang Province, China.
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Wang J, Liu ZX, Huang ZH, Wen J, Rao ZZ. Long non-coding RNA in the regulation of cell death in hepatocellular carcinoma. World J Clin Oncol 2025; 16:104061. [DOI: 10.5306/wjco.v16.i4.104061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 02/02/2025] [Accepted: 02/25/2025] [Indexed: 03/26/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer, accounting for 90% of all cases. Currently, early diagnosis of HCC can be achieved through serum alpha-fetoprotein detection, B-ultrasound, and computed tomography scanning; however, their specificity and sensitivity are suboptimal. Despite significant advancements in HCC biomarker detection, the prognosis for patients with HCC remains unfavorable due to tumor heterogeneity and limited understanding of its pathogenesis. Therefore, it is crucial to explore more sensitive HCC biomarkers for improved diagnosis, monitoring, and management of the disease. Long non-coding RNA (lncRNA) serves as an auxiliary carrier of genetic information and also plays diverse intricate regulatory roles that greatly contribute to genome complexity. Moreover, investigating gene expression regulation networks from the perspective of lncRNA may provide insights into the diagnosis and prognosis of HCC. We searched the PubMed database for literature, comprehensively classified regulated cell death mechanisms and systematically reviewed research progress on lncRNA-mediated cell death pathways in HCC cells. Furthermore, we prospectively summarize its potential implications in diagnosing and treating HCC.
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Affiliation(s)
- Jiang Wang
- Children Medical Center, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Zi-Xuan Liu
- Children Medical Center, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Zhi-Hong Huang
- Children Medical Center, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Jie Wen
- Department of Pediatric Orthopedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Zhou-Zhou Rao
- Department of Physiology, Hunan Normal University School of Medicine, Changsha 410003, Hunan Province, China
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25
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Gao LL, Gao DN, Yuan HT, Chen WQ, Yang J, Peng JQ. Combining anti-PD-1 antibodies with surufatinib for gastrointestinal neuroendocrine carcinoma: Two cases report and review of literature. World J Clin Oncol 2025; 16:102297. [DOI: 10.5306/wjco.v16.i4.102297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/20/2024] [Accepted: 02/27/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Gastrointestinal neuroendocrine carcinoma (GI NEC) has a low incidence rate and poor prognosis. Most patients already have metastatic disease when they are diagnosed. Platinum chemotherapy is the main means of treating metastatic GI NECs. There is a lack of effective treatment methods after chemotherapy failure. Therefore, Therefore, selecting appropriate posterior-line treatment programs to improve the prognosis of patients is urgently needed.
CASE SUMMARY A 64-year-old female was diagnosed with stage IV NEC of the rectum due to abdominal pain and rectal bleeding. After multiline chemotherapy, the condition progressed, and the patient was treated with a combination of camrelizumab and surufatinib. The efficacy evaluation revealed partial remission (PR) and stable conditions, with the expression of the tumor marker neuron-specific enolase (NSE) returning to normal. The adverse reactions were controllable, and the overall condition was good, with weight gain achieved in the past four years. Another 51-year-old female experienced recurrence and metastasis of a duodenal NEC after surgery. After multiline chemotherapy, she received sintilimab combined with surufatinib. The curative effect fluctuated between PR and stability. During treatment, she recovered from immune-related diabetes and later died due to deterioration of her condition. During the treatment, the patient’s NSE level returned to normal.
CONCLUSION The combination of antiangiogenic targeted drugs and immunotherapy provides a new therapeutic approach for the treatment of metastatic GI-NECs.
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Affiliation(s)
- Lou-Lu Gao
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Dong-Ni Gao
- Department of Oncology, Shandong Public Health Clinical Center, Jinan 250100, Shandong Province, China
| | - Hong-Tu Yuan
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China
| | - Wen-Qiang Chen
- Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Jing Yang
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China
| | - Jie-Qiong Peng
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China
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Xu R, Guo S, Song Q, Wang X, Li Q. PD-1/PD-L1 inhibitors combined with anti-angiogenic drugs for advanced triple-negative breast cancer: synergistic mechanisms and research progress. Crit Rev Oncol Hematol 2025; 211:104740. [PMID: 40268075 DOI: 10.1016/j.critrevonc.2025.104740] [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: 03/15/2025] [Revised: 04/15/2025] [Accepted: 04/19/2025] [Indexed: 04/25/2025] Open
Abstract
Triple-negative breast cancer (TNBC), a subtype of breast cancer that is highly aggressive and lacks effective therapeutic targets, has a particularly grim prognosis, with advanced patients having a significantly shorter median survival and showing resistance to chemotherapy. The introduction of immunotherapy has brought new hope for cancer treatment, but the use of immune checkpoint inhibitors（ ICI） alone in TNBC is ineffective, and there is an urgent need to explore more effective combination therapies.The combination of PD-1/PD-L1 inhibitors and anti-angiogenic drugs（AADs） can produce synergistic effects and open up new therapeutic avenues for TNBC patients. Specifically, inhibition of the vascular endothelial growth factor（VEGF） signaling pathway induces normalization of tumor vasculature, which in turn promotes infiltration of CD8+ T lymphocytes(CD8+ T cells）. Meanwhile, PD-1/PD-L1 inhibitors can similarly promote normalization of tumor vasculature and enhance the function of effector T cells by activating effector T cells and upregulating γ-interferon (IFN-γ) secretion. This combination regimen has demonstrated encouraging efficacy in several clinical studies. In this article, we comprehensively analyze the latest advances in the field,and provides insights into the application, mechanism of action, signaling pathways, clinical translational prospects, and shortcomings of anti-PD-1/PD-L1 drugs combined with anti-angiogenic drugs in advanced TNBC. This study aims to provide clues for the individualized treatment of TNBC, with a view to realizing precision medicine, reducing the risk of recurrence and metastasis in patients, and improving the poor prognosis, which has an important clinical practice value.
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Affiliation(s)
- Rui Xu
- Hebei North University, Zhangjiakou, Hebei Province, China; Hebei Provincial People's Hospital, Shijiazhuang,Hebei Province, China
| | - Shaowei Guo
- Hebei Provincial People's Hospital, Shijiazhuang,Hebei Province, China
| | - Qingle Song
- Hebei Provincial People's Hospital, Shijiazhuang,Hebei Province, China; Hebei Medical University, Shijiazhuang,Hebei Province, China
| | - Xiaotong Wang
- Hebei Provincial People's Hospital, Shijiazhuang,Hebei Province, China; Hebei Medical University, Shijiazhuang,Hebei Province, China
| | - Qingxia Li
- Hebei Provincial People's Hospital, Shijiazhuang,Hebei Province, China; Hebei Key Laboratory of Molecular Medicine, Shijiazhuang,Hebei Province, China.
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Lee JW, Lee SM, Kang B, Kim JS, An C, Chon HJ, Jang SJ. Prognostic Significance of Volumetric Parameters on Pretreatment FDG PET/CT in Patients With Hepatocellular Carcinoma Receiving Atezolizumab Plus Bevacizumab Therapy. Clin Nucl Med 2025:00003072-990000000-01659. [PMID: 40254801 DOI: 10.1097/rlu.0000000000005896] [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: 11/21/2024] [Accepted: 03/06/2025] [Indexed: 04/22/2025]
Abstract
BACKGROUND This study aimed to assess prognostic significance of FDG PET/CT parameters in predicting progression-free survival (PFS) and overall survival (OS) in patients with hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab therapy. PATIENTS AND METHODS We retrospectively enrolled 78 patients with HCC who underwent FDG PET/CT before atezolizumab plus bevacizumab therapy and identified intrahepatic target tumor lesions on pretreatment imaging studies. From PET/CT images, we measured SUVmax, tumor-to-normal liver uptake ratio, metabolic tumor volume, and total lesion glycolysis (TLG) for intrahepatic tumor lesions, as well as SUVmax for extrahepatic metastatic lesions (extrahepatic SUVmax). RESULTS In comparisons of PET/CT parameters, patients with progressive disease demonstrated significantly higher TLG values than those achieving complete or partial response (P < 0.05). In the multivariate survival analysis, TLG independently predicted both PFS (P = 0.019) and OS (P = 0.003). Metabolic tumor volume was significantly associated with OS alone (P = 0.010), and extrahepatic SUVmax was significantly associated with only PFS (P = 0.045). Patients with high TLG values experienced poorer PFS and OS than those with low TLG values (P < 0.05). CONCLUSIONS TLG in intrahepatic HCC lesions was significantly associated with treatment response and served as an independent prognostic factor for PFS and OS. TLG could be a potential imaging biomarker for predicting clinical outcomes in patients with HCC receiving atezolizumab plus bevacizumab therapy.
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Affiliation(s)
- Jeong Won Lee
- Department of Nuclear Medicine, Soonchunhyang University Cheonan Hospital, Cheonan
| | - Sang Mi Lee
- Department of Nuclear Medicine, Soonchunhyang University Cheonan Hospital, Cheonan
| | - Beodeul Kang
- Department of Internal Medicine, Division of Medical Oncology
| | - Jung Sun Kim
- Department of Nuclear Medicine, Soonchunhyang University Cheonan Hospital, Cheonan
| | | | - Hong Jae Chon
- Department of Internal Medicine, Division of Medical Oncology
| | - Su Jin Jang
- Department of Nuclear Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongam, Republic of Korea
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Lee SM, Choi JH, Yoon JH, Kim YJ, Yu SJ, Lee JH, Kang HC, Chie EK, Kim KS. Efficacy and safety of image-guided hypofractionated radiotherapy for hepatocellular carcinoma with portal vein tumor thrombosis: a retrospective, multicenter study. BMC Cancer 2025; 25:736. [PMID: 40254568 PMCID: PMC12010600 DOI: 10.1186/s12885-025-13739-3] [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: 08/21/2023] [Accepted: 02/14/2025] [Indexed: 04/22/2025] Open
Abstract
BACKGROUND External beam radiation therapy (RT) has shown promising effects for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) in recent studies. However, there is still a lack of consensus on the optimal RT scheme for PVTT treatment. We evaluated the efficacy and safety of image-guided 10-fraction hypofractionated RT in these patients. METHODS Between January 2016 and March 2022, a total of 95 HCC patients with PVTT received 10-fraction hypofractionated image-guided radiation therapy (IGRT) at two institutes, and 69 patients were analyzed. Follow-up imaging was performed at three-month intervals after the completion of RT. The extent of PVTT was described according to the Liver Cancer Study Group of Japan classification: Vp1 = segmental portal vein branch, Vp2 = right/left anterior/posterior portal vein, Vp3 = right/left portal vein, and Vp4 = main portal vein. Response evaluation was performed using Response Evaluation Criteria in Solid Tumors, version 1.1. Freedom from local progression (FFLP), progression-free survival (PFS), and overall survival (OS) were calculated from the start date of RT. RESULTS The median prescribed dose of 50 Gy (range: 40-50 Gy; biologically effective dose [BED]: 56-75Gy10) was delivered in 10 fractions. In this cohort, 4.3% of patients had Vp1, 20.3% had Vp2, 37.7% had Vp3, and 37.7% had Vp4. Median Planning target volume was 105.3 cc (interquartile range [IQR], 74.1-179.4 cc). Fifty-two (75.4%) patients received 50 Gy. With a median follow-up of 10.2 months (IQR, 6-21 months), the median OS was 20.3 months, and 1-year FFLP, PFS, and OS rates were 88.7%, 26.9%, and 62.2%, respectively. At 3 months follow-up, 13.0% had a complete response, 36.2% had a partial response, 46.4% had a stable disease and 4.4% had a progressive disease. In the multivariate analysis, alpha-fetoprotein level ≥ 600 IU/ml (hazard ratio [HR] 2.06, p = 0.03), Child-Pugh Class B or C (HR 2.30, p = 0.02), and stage IVA or IVB (4.05, p = 0.02) were significantly related to OS. During the follow-up period, there were 2 (2.9%) cases of grade ≥ 3 toxicity: grade 3 liver enzyme elevation (n = 1), and acute cholangitis (n = 1). CONCLUSIONS Hypofractionated RT demonstrated promising local PVTT control and OS rates with acceptable toxicity. These data suggest that 10-fraction image-guided hypofractionated RT (BED: 56-75 Gy10) is a feasible treatment option for PVTT in HCC patients.
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Affiliation(s)
- Sang Min Lee
- Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jin Hwa Choi
- Department of Radiation Oncology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Hyun-Cheol Kang
- Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
| | - Eui Kyu Chie
- Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
| | - Kyung Su Kim
- Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
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Li L, Wu ZT, Duan WH, Liu J, Zhu YR. Machine learning-based prognostic modelling of NK cells in PAAD for immunotherapy guidance. Discov Oncol 2025; 16:577. [PMID: 40253675 PMCID: PMC12009793 DOI: 10.1007/s12672-025-02266-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 03/28/2025] [Indexed: 04/22/2025] Open
Abstract
Pancreatic cancer's high incidence and mortality rates are underscored by ineffective treatments, particularly immunotherapy's poor performance. This could stem from an unclear immune microenvironment, where NK cells may play a unique role. Analyzing the NK cell-differentially expressed genes (NKDEGs) from the PAAD_GSE162708 single-cell dataset and utilizing the TCGA-PAAD and ICGC-PACA-AU datasets, we identified 11 NKDEGs linked to pancreatic adenocarcinoma (PAAD) prognosis and developed a prognostic model. This model's risk scores significantly outperformed traditional grading and TNM staging systems, validated through clinical and pathological analyses. Functional enrichment analysis pointed to the Neuroactive ligand-receptor interaction and MAPK signaling pathways, suggesting NK cells' distinctive role in PAAD. High-risk groups showed decreased overall NK cells but increased activated NK cells, which may mediate adverse inflammatory responses. NK cells exhibit synergistic interactions with plasma cells and macrophages and negative regulation by monocytes and naive B cells. Our model accurately predicts immunotherapy responses, indicating potential for targeted drugs to enhance treatment. Additionally, we introduced an NKDEGs-based immunotyping approach for personalized medicine and clinical decision-making in PAAD. This study emphasizes NK cells' potential in PAAD treatment, offering precise patient stratification and therapeutic targets for immunotherapy.
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Affiliation(s)
- Li Li
- The People'S Hospital of Wenshan Prefecture, Kunming University of Science and Technology, No. 228, Kaihua East Road, Wenshan, 663000, Yunnan, China
| | - Zu-Tao Wu
- The People'S Hospital of Wenshan Prefecture, Kunming University of Science and Technology, No. 228, Kaihua East Road, Wenshan, 663000, Yunnan, China
| | - Wen-Hong Duan
- The People'S Hospital of Wenshan Prefecture, Kunming University of Science and Technology, No. 228, Kaihua East Road, Wenshan, 663000, Yunnan, China
| | - Jiang Liu
- The People'S Hospital of Wenshan Prefecture, Kunming University of Science and Technology, No. 228, Kaihua East Road, Wenshan, 663000, Yunnan, China
| | - Yin-Rong Zhu
- The People'S Hospital of Wenshan Prefecture, Kunming University of Science and Technology, No. 228, Kaihua East Road, Wenshan, 663000, Yunnan, China.
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Fu X, Guo Y, Zhang K, Cheng Z, Liu C, Ren Y, Miao L, Liu W, Jiang S, Zhou C, Su Y, Yang L. Prognostic impact of extracellular volume fraction derived from equilibrium contrast-enhanced CT in HCC patients receiving immune checkpoint inhibitors. Sci Rep 2025; 15:13643. [PMID: 40254627 PMCID: PMC12009984 DOI: 10.1038/s41598-025-97677-x] [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: 01/06/2025] [Accepted: 04/07/2025] [Indexed: 04/22/2025] Open
Abstract
This study aimed to investigate whether extracellular volume (ECV) fraction derived from equilibration contrast-enhanced computed tomography (CECT) affects prognosis in HCC patients receiving ICIs. This retrospective study ultimately included 211 HCC patients undergoing ICIs, of whom 60 were included in an internal validation to assess the reproducibility of the results. Baseline unenhanced and equilibrated CECT were used to measure CT values of the tumor, liver and aorta, which were combined with hematocrit to calculate the ECV fraction. Correlation analysis was used to investigate the association between tumor ECV and liver ECV fractions. The effects of clinical variables and ECV fraction on progression-free survival (PFS) and overall survival (OS) were evaluated using Cox proportional hazards models and Kaplan-Meier curves. Of these 151 patients, tumor ECV fraction positively correlated with liver ECV fraction. In the Lower tumor ECV group, PFS (5.6 vs. 7.6 months) and OS (10.5 vs. 15.5 months) were notably shorter than in the Higher tumor ECV group, while no significant differences were found between the Higher and Lower liver ECV groups. Furthermore, the multivariable Cox regression model demonstrated that higher tumor ECV fraction level was an independent protective factor for PFS and OS (all P < 0.001). Internal validation cohort preliminary demonstrated reproducibility of results. The tumor ECV fraction is expected to become a routine indicator before ICIs therapy for HCC patients in contrast to liver ECV fraction, contributing to their subsequent management.
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Affiliation(s)
- Xiaona Fu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yusheng Guo
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Kailu Zhang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Zhixuan Cheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Chanyuan Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yi Ren
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Lianwei Miao
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Weiwei Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Shanshan Jiang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Chen Zhou
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
| | - Yangbo Su
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
| | - Lian Yang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
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Liu X, Zhang J, Yi T, Li H, Tang X, Liu D, Wu D, Li Y. Decoding tumor angiogenesis: pathways, mechanisms, and future directions in anti-cancer strategies. Biomark Res 2025; 13:62. [PMID: 40251641 PMCID: PMC12007322 DOI: 10.1186/s40364-025-00779-x] [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: 11/26/2024] [Accepted: 04/13/2025] [Indexed: 04/20/2025] Open
Abstract
Angiogenesis, a crucial process in tumor growth and metastasis, necessitates targeted therapeutic intervention. This review reviews the latest knowledge of anti-angiogenesis targets in tumors, with emphasis on the molecular mechanisms and signaling pathways that regulate this process. We emphasize the tumor microenvironment's role in angiogenesis, examine endothelial cell metabolic changes, and evaluated potential therapeutic strategies targeting the tumor vascular system. At the same time, we analyzed the signaling pathway and molecular mechanism of tumor angiogenesis in detail. In addition, this paper also looks at the development trend of tumor anti-angiogenesis drugs, including their future development direction and challenges, aiming to provide prospective insight into the development of this field. Despite their potential, anti-angiogenic therapies encounter challenges like drug resistance and side effects, necessitating ongoing research to enhance cancer treatment strategies and the efficacy of these therapies.
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Affiliation(s)
- Xueru Liu
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Juan Zhang
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Ting Yi
- Department of Trauma Center, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Hui Li
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Xing Tang
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Dan Liu
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Daichao Wu
- Laboratory of Structural Immunology, Department of Hepatopancreatobiliary Surgery, Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang, 421001, Hunan, China.
| | - Yukun Li
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China.
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Tan Y, Yang L, Xu T, Wang Q, Huang M, Zhao Z, Chen X, Tang C, Tan W. GPX2 inhibition enhances antitumor efficacy of lenvatinib via promoting immunogenic cell death in hepatocellular carcinoma. J Transl Med 2025; 23:456. [PMID: 40251668 PMCID: PMC12007242 DOI: 10.1186/s12967-025-06468-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 04/06/2025] [Indexed: 04/20/2025] Open
Abstract
BACKGROUND Immunogenic cell death (ICD) is a distinct subtype of regulatory cell death, and represents a potential mechanism to remodel the tumor microenvironment. Lenvatinib is established as the first-line therapy for advanced hepatocellular carcinoma (HCC), but drug resistance limits its efficiency. Our previous research showed that lenvatinib can inhibit GPX2 expression and induce reactive oxygen species (ROS)-related cell apoptosis in HCC. The present study intends to explore whether lenvatinib can induce ICD and clarify its underlying mechanisms in HCC. METHODS Flow cytometry was utilized to detect the expression levels of CRT and CD markers, measure intracellular ROS levels, and assess cell apoptosis. Western blot analysis was employed to determine changes in protein levels, while qRT-PCR analysis was used to quantify alterations in mRNA levels. Subcutaneous allograft tumor models were established to investigate the mechanism of lenvatinib against HCC. Immunohistochemical (IF) staining were used to detect the ratio of CD8+GZMB+ cells. RESULTS Herein, we found that HCC cells treated with lenvatinib or si-GPX2 showed increased ICD markers, such as CRT exposure, ATP secretion, and HMGB1 release. Notably, we demonstrated that lenvatinib promoted dendritic cells (DCs) maturation and CD8+ T cells activation, thus inducing HCC cell apoptosis when co-cultured with peripheral blood mononuclear cells. Additionally, we further demonstrated that lenvatinib or GPX2 inhibition triggers endoplasmic reticulum stress (ERS) in HCC cells, which is mediated by the accumulation of ROS. Our findings indicate that pre-treatment with the antioxidant N-acetylcysteine suppressed lenvatinib-induced expression of CRT on the cell membrane, ATP secretion and HMGB1 release, and inhibited lenvatinib-induced cell apoptosis. Furthermore, we also found that ERS inhibitor ISRIB could reverse lenvatinib-induced upregulation of ICD biomarkers. Moreover, we further identified that downregulation of GPX2 enhanced the efficacy of lenvatinib via triggering ERS-mediated ICD in HCC. CONCLUSIONS This study uncovered that lenvatinib could be a potent ICD inducer, which could trigger ERS via increasing ROS levels in HCC cells, which present valuable insights into the mechanism of lenvatinib-induced ICD in HCC cells. Collectively, our findings highlight the significant therapeutic potential of the combination of targeting GPX2 and treatment with lenvatinib for HCC.
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Affiliation(s)
- Yingzheng Tan
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412007, Hunan, China
| | - Lei Yang
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230000, Anhui, China
| | - Tao Xu
- Department of Hepatobiliary and Pancreatic Surgery, Medical Center of Digestive Disease, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412007, Hunan, China
| | - Qingbin Wang
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong, China
| | - Meiyuan Huang
- Department of Pathology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412007, Hunan, China
| | - Zhijian Zhao
- Department of Hepatobiliary and Pancreatic Surgery, Medical Center of Digestive Disease, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412007, Hunan, China
| | - Xun Chen
- Department of Hepatobiliary and Pancreatic Surgery, Medical Center of Digestive Disease, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412007, Hunan, China.
| | - Caixi Tang
- Department of Hepatobiliary and Pancreatic Surgery, Medical Center of Digestive Disease, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412007, Hunan, China.
| | - Wenliang Tan
- Department of Hepatobiliary and Pancreatic Surgery, Medical Center of Digestive Disease, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412007, Hunan, China.
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Lin Z, Long JW, Zhao MC, Guo P, Wen J, Chen GL. Purinosomes as a therapeutic target in hepatocellular carcinoma: insights and opportunities. Discov Oncol 2025; 16:564. [PMID: 40251459 PMCID: PMC12008087 DOI: 10.1007/s12672-025-02366-w] [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: 08/27/2024] [Accepted: 04/11/2025] [Indexed: 04/20/2025] Open
Abstract
The formation of purinosomes, dynamic complexes involved in de novo purine biosynthesis, has been recognized as a critical process for cell growth. Although their upregulation in cancer cells suggests their potential as a therapeutic target, the specific role of purinosomes in hepatocellular carcinoma (HCC) remains uncertain. The purinosome score was found to have prognostic value. Enrichment analyses indicated a connection between purinosome-related genes and cell cycle regulation. Moreover, our research has demonstrated a correlation between the upregulation of genes associated with purinosomes and the enhanced formation of purinosomes in Huh-7 cells. Pyrimethamine has been identified as a promising therapeutic option for targeting purinosome to exert anti-cancer effects. Furthermore, the purinosome score exhibited an positive relationship with the response to immunotherapy. It may guide the stratification of liver cancer patients and screen for populations that may benefit from immunotherapy. This study examines the prognostic and predictive value of purinosome in liver cancer, suggesting that targeting purinosome formation with pyrimethamine or immunotherapy could benefit patients with high purinosome scores.
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Affiliation(s)
- Zhen Lin
- Department of Medical Oncology, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, China
| | - Jia-Wei Long
- Department of Respiratory Medicine, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China
| | - Ming-Chun Zhao
- Department of Pathology, Guilin Hospital of Chinese Traditional and Western Medicine, Guilin, 541004, China
| | - Pin Guo
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Jin Wen
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, 55905, USA.
| | - Guang-Liang Chen
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College Fudan University, Shanghai, 200032, China.
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Yao RR, Zhang QB, Ge MX, Li L, Li J, Zhou XL, Wang ZX, Liang XH. The safety and efficacy of atezolizumab for recurrent primary liver cancer after liver transplantation. Discov Oncol 2025; 16:553. [PMID: 40244542 PMCID: PMC12006625 DOI: 10.1007/s12672-025-02299-4] [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: 11/20/2024] [Accepted: 04/02/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have been proved to have certain therapeutic effects for primary liver cancer. However, the efficacy and safety of their applications in liver transplantation (LT) recipients with recurrent tumor remained unclear and even controversial. METHODS A retrospective study was conducted to evaluate the safety and efficacy of atezolizumab in LT recipients with recurrent PLC from August 1, 2019, to July 1, 2022. The primary endpoint was the incidence of allograft rejection, while secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Additionally, risk factors associated with ICI-related rejection were analyzed. RESULTS A total of eight LT recipients with recurrent PLC were included in the study, comprising six cases of hepatocellular carcinoma (HCC) and two cases of intrahepatic cholangiocarcinoma (ICC). The median number of atezolizumab treatment cycles was 3 (range, 1-10). Graft rejection occurred in 25% of patients (2/8). The median overall survival (mOS) from the initiation of atezolizumab was 6.2 months (range, 0.7-12.5 months), with a mortality rate of 75% (6/8). The ORR (complete response [CR] + partial response [PR]) was 28.5% (2/7), and the disease control rate (DCR; CR + PR + stable disease [SD]) was 42.9% (3/7). Time from LT to recurrence (P = 0.008) and Interval time from LT to atezolizumab (P = 0.005) were associated with liver rejection. CONCLUSIONS Atezolizumab demonstrated a certain degree of efficacy as a salvage treatment for patients with recurrent HCC and ICC after LT. However, given the potential risk of allograft rejection, careful evaluation of safety is essential before initiating ICI therapy. Moreover, close monitoring and timely intervention are necessary during treatment to mitigate the risk of rejection. Future studies should further explore the optimal timing and strategies for ICI administration in this patient population.
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Grants
- (2020QD010) Scientific Research Foundation of Huashan Hospital, Fudan University
- (2020QD010) Scientific Research Foundation of Huashan Hospital, Fudan University
- (2020QD010) Scientific Research Foundation of Huashan Hospital, Fudan University
- (2020QD010) Scientific Research Foundation of Huashan Hospital, Fudan University
- (2020QD010) Scientific Research Foundation of Huashan Hospital, Fudan University
- 82071797, 82173093, 82241225 Natural Science Foundation of China
- 82071797, 82173093, 82241225 Natural Science Foundation of China
- 82071797, 82173093, 82241225 Natural Science Foundation of China
- (SHDC2020CR2021B) the Shanghai Hospital Development Center
- (SHDC2020CR2021B) the Shanghai Hospital Development Center
- (SHDC2020CR2021B) the Shanghai Hospital Development Center
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Affiliation(s)
- Rong-Rong Yao
- Department of Oncology, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China
| | - Quan-Bao Zhang
- Liver Transplantation Center, Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China
- Institute of Organ Transplantation, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China
| | - Meng-Xi Ge
- Department of Oncology, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China
| | - Li Li
- Liver Transplantation Center, Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China
- Institute of Organ Transplantation, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China
| | - Jing Li
- Department of Oncology, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China
| | - Xin-Li Zhou
- Department of Oncology, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China
| | - Zheng-Xin Wang
- Liver Transplantation Center, Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China.
- Institute of Organ Transplantation, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China.
| | - Xiao-Hua Liang
- Department of Oncology, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China.
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Nihei S, Saito K, Ikeda T, Oikawa T, Asahi K, Asaka J, Kudo K. Potential role of endothelial dysfunction in hypertension and proteinuria in patients with hepatocellular carcinoma receiving atezolizumab plus bevacizumab: a pilot prospective observational study. Cancer Chemother Pharmacol 2025; 95:55. [PMID: 40244305 DOI: 10.1007/s00280-025-04776-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Accepted: 04/04/2025] [Indexed: 04/18/2025]
Abstract
PURPOSE Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), is the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). Its inhibition of VEGF signaling may lead to proteinuria due to endothelial dysfunction but the association between endothelial function and clinical outcomes has not been established. This study aimed to investigate vascular endothelial function in patients with HCC receiving atezolizumab plus bevacizumab, and to assess the correlation between reactive hyperemia index (RHI) and adverse renal outcomes. METHODS This pilot prospective observational study included 20 patients with HCC who received atezolizumab plus bevacizumab. We used reactive hyperemia-peripheral arterial tonometry (RH-PAT) and evaluated vascular endothelial function on the basis of RHI. RHI, blood pressure, and proteinuria were recorded at baseline and at 3 and 6 months after initiation of atezolizumab plus bevacizumab treatment. Statistical analyses were performed to investigate the relationship of RHI to blood pressure and proteinuria. RESULTS Following initiation of atezolizumab plus bevacizumab treatment, systolic blood pressure and urine protein-creatinine ratio increased significantly, and RHI decreased. Patients with borderline or low baseline RHI had a higher incidence of grade ≥ 2 proteinuria than those with normal baseline RHI but not hypertension. A significant inverse correlation was found between RHI and urine protein-creatinine ratio. CONCLUSION Bevacizumab administration may cause endothelial dysfunction in patients with HCC. The vascular endothelial function status before and during atezolizumab plus bevacizumab treatment is associated with the risk of bevacizumab-induced proteinuria.
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Affiliation(s)
- Satoru Nihei
- Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3695, Japan.
- Division of Clinical Pharmaceutics and Pharmacy Practice, Department of Clinical Pharmacy, School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan.
| | - Kazuki Saito
- Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3695, Japan
| | - Tatsuki Ikeda
- Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3695, Japan
| | - Takayoshi Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan
| | - Koichi Asahi
- Division of Nephrology and Hypertension, Department of Internal Medicine, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan
| | - Junichi Asaka
- Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3695, Japan
- Division of Clinical Pharmaceutics and Pharmacy Practice, Department of Clinical Pharmacy, School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan
| | - Kenzo Kudo
- Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3695, Japan
- Division of Clinical Pharmaceutics and Pharmacy Practice, Department of Clinical Pharmacy, School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan
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Vithayathil M, Koku D, Campani C, Nault JC, Sutter O, Carrié NG, Aboagye EO, Sharma R. Machine learning based radiomic models outperform clinical biomarkers in predicting outcomes after immunotherapy for hepatocellular carcinoma. J Hepatol 2025:S0168-8278(25)00244-2. [PMID: 40246150 DOI: 10.1016/j.jhep.2025.04.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 04/07/2025] [Accepted: 04/08/2025] [Indexed: 04/19/2025]
Abstract
BACKGROUND Atezolizumab plus bevacizumab (A/B) is a first-line therapy for unresectable hepatocellular carcinoma (HCC). Only a small proportion of patients respond to treatment. This study integrated radiomic and clinical data derived from routine pre-treatment imaging to predict outcomes after immunotherapy. METHODS 152 patients from two international centres receiving A/B were retrospectively reviewed. Deep learning autosegmentation generated whole liver masks from pre-treatment CTs. Radiomic features combined with clinical variables were used to predict 12-month mortality post A/B. Radiomic and integrated radiomic-clinical models were developed using 7 machine learning models in combination with 13 feature selection techniques in the Imperial College London (ICL) cohort. K-means clustering identified high- and low-risk groups and predicted overall survival (OS), progression-free survival (PFS) and response. Model performance was assessed in the independent Assistance Publique-Hôpitaux de Paris (AP-HP) cohort. RESULTS The integrated radiomic-clinical model outperformed BCLC stage (AUC 0.61, p<0.001) and ALBI grade (AUC 0.48, p<0.001) in ICL (AUC 0.89, 95% CI 0.75-0.99) and AP-HP (AUC 0.75, 95% CI 0.64-0.85) cohorts. Integrated model-stratified high-risk patients had significantly shorter median OS (ICL: 5.6 months vs. 28.2 months; p<0.001; AP-HP: 5.8 months vs. 15.7 months; p<0.001) and PFS (ICL: 2.4 months vs. 14.6 months; p<0.001; AP-HP: 2.1 months vs. 6.1 months; p=0.046). Low-risk patients had significantly higher ICI response rates compared to high-risk patients (35.6% vs. 21.4%; p=0.038). In multivariable analysis, radiomic group was the strongest predictor of OS (HR 3.22, 95% CI 1.99-5.20; p<0.001) and PFS (HR 1.82, 95% CI 1.18-2.80; p=0.010). CONCLUSION Radiomic-based models predict survival outcomes and response to immunotherapy in patients with advanced HCC. Deep learning in combination with machine learning can stratify patients and allows for precision treatment strategies. IMPACT AND IMPLICATIONS There is a lack of prognostic markers predicting survival and response after immunotherapy in hepatocellular carcinoma. This study used deep learning and machine learning to develop and validate an integrated radiomic-clinical model which can predict survival and response to atezolizumab plus bevacizumab from pre-treatment imaging. Radiomic-based machine learning models can risk-stratify advanced HCC patients receiving atezolizumab plus bevacizumab.
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Affiliation(s)
| | - Deniz Koku
- Department of Surgery & Cancer, Imperial College London, London, UK
| | - Claudia Campani
- Cordeliers Research Center, Sorbonne University, Inserm, Paris Citẻ University, "Functional Genomics of Solid Tumours" team, Ligue Nationale Contre le Cancer accredited team, Labex OncoImmunology, Paris, France; Department of Experimental and Clinical Medicine, Internal Medicine and Hepatology Unit, University of Firenze, Florence, Italy
| | - Jean-Charles Nault
- Cordeliers Research Center, Sorbonne University, Inserm, Paris Citẻ University, "Functional Genomics of Solid Tumours" team, Ligue Nationale Contre le Cancer accredited team, Labex OncoImmunology, Paris, France; Liver Unit, Avicenne Hospital, Paris-Seine-Saint-Denis Universitary Hospitas, AP-HP, Bobigny, France
| | - Olivier Sutter
- Diagnostic and Interventional Imaging Department, Avicenne Hospital, AP-HP, France; University of Bordeaux, IMB, UMR CNRS 5251, INRIA Project team Monc, Talence, France
| | - Nathalie Ganne Carrié
- Cordeliers Research Center, Sorbonne University, Inserm, Paris Citẻ University, "Functional Genomics of Solid Tumours" team, Ligue Nationale Contre le Cancer accredited team, Labex OncoImmunology, Paris, France; Liver Unit, Avicenne Hospital, Paris-Seine-Saint-Denis Universitary Hospitas, AP-HP, Bobigny, France
| | - Eric O Aboagye
- Department of Surgery & Cancer, Imperial College London, London, UK
| | - Rohini Sharma
- Department of Surgery & Cancer, Imperial College London, London, UK.
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Liang LW, Luo RH, Huang ZL, Tang LN. Clinical observation of nivolumab combined with cabozantinib in the treatment of advanced hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:103631. [PMID: 40235875 PMCID: PMC11995320 DOI: 10.4251/wjgo.v17.i4.103631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 12/25/2024] [Accepted: 02/07/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a particularly serious kind of liver cancer. Liver cancer ranks third in terms of mortality rate worldwide, putting it among the leading causes of deaths from cancer. HCC is the primary kind of liver cancer and makes up the vast majority of cases, accounting for approximately 90% of occurrences. Numerous research have verified this information. the progress of fatty liver, alcohol induced cirrhosis, smoking habits, obesity caused by overweight, and metabolic diseases such as diabetes. The treatment strategies for HCC can be divided into two categories: One is curative treatment, including liver transplantation, surgical resection, and ablation therapy or selective arterial radiation embolization, aimed at completely eliminating the lesion; Another type is non curative treatment options, including transarterial chemoembolization and systemic therapy, which focus on controlling disease progression and prolonging patient survival. The majority of HCC patients are found to be in an advanced stage and need systemic therapy. Sorafenib and lenvatinib are frequently used as first-line medications in traditional HCC treatment to slow the disease's progression. For second-line treatment, regorafenib, cabozantinib, or remdesizumab are used to inhibit tumors through different mechanisms and prolong survival. In recent years, with the in-depth exploration of the pathogenesis and progression mechanism of HCC, as well as the rapid progress within the domain of tumor immunotherapy, the treatment prospects for advanced HCC patients have shown a positive transformation. This transformation is reflected in the fact that more and more patients are gradually gaining significant and considerable therapeutic advantages from advanced immunotherapy regimens, bringing unprecedented improvements to their treatment outcomes. In order to enable activated T cells to attack tumor cells, immune checkpoint inhibitors interfere with the inhibitory. AIM To evaluate the effects of nivolumab in combination with cabozantinib on patient tumor markers and immune function, as well as the therapeutic efficacy of this combination in treating advanced HCC, a study was conducted. METHODS In all, 100 patients with advanced HCC who were brought to our hospital between July 2022 and July 2023 and who did not match the requirements for surgical resection had their clinical data thoroughly analyzed retrospectively in this study. Among them, half of the patients (50 cases) only received oral cabozantinib as a single treatment regimen (set as the control group), while the other half of the patients (50 cases) received intravenous infusion of nivolumab in addition to oral cabozantinib (set as the observation group). The objective of the probe is to examine the variations in disease control rate (DCR) and objective response rate (ORR) between two groups; At the same time, changes in the levels of T lymphocyte subsets (CD3+, CD4+, CD8+) and tumor markers, including AFP, GP-73, and AFP-L3, were evaluated; In addition, changes in liver and kidney function indicators and adverse reactions during treatment were also monitored. For patients with advanced HCC, this research also calculated and analyzed the progression free survival of two patient groups throughout the course of a 12-month follow-up to assess the effectiveness and safety of this therapeutic approach. RESULTS Upon comparing baseline information for both groups of subjects before treatment, it was found that no statistically significant alterations had occurred (P > 0.05). After the therapeutic intervention, the observation group and control group's ORR and DCR differed statistically significantly (P < 0.05). The observation group's scores significantly improved. Subsequent examination revealed that the observation group's T lymphocyte subset levels had significantly changed, mostly exhibiting an increase in CD3+, CD4+, and CD4+/CD8+ levels while CD8+ levels had comparatively dropped. There was a significant difference (P < 0.05) between these changes and those in the control group. The observation group also showed positive improvements in tumor markers; AFP, GP-73, and AFP-L3 levels were considerably lower in the group under observation than in the control group, with statistically significant differences (P < 0.05). When liver function was assessed, total bilirubin and alanine aminotransferase were found to be considerably lower in the observation group than in the control group (P < 0.05). The incidence of adverse responses was not statistically significant (P > 0.05), indicating that the incidence of adverse responses did not differ significantly between the two groups. CONCLUSION When treating advanced HCC, nivolumab and cabozantinib together have the ability to increase T lymphocyte numbers, reduce tumor marker levels, effectively prolong survival time, and have better efficacy than simple control treatment, with good safety.
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Affiliation(s)
- Lu-Wen Liang
- Infection and Liver Disease Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400000, China
| | - Rong-Hong Luo
- Department of Infectious Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Zhi-Li Huang
- Department of Infectious Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Li-Na Tang
- Department of Infectious Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
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Pomej K, Frick A, Scheiner B, Balcar L, Pajancic L, Klotz A, Kreuter A, Lampichler K, Regnat K, Zinober K, Trauner M, Tamandl D, Gasche C, Pinter M. Study protocol: Fecal Microbiota Transplant combined with Atezolizumab/Bevacizumab in Patients with Hepatocellular Carcinoma who failed to achieve or maintain objective response to Atezolizumab/Bevacizumab - the FAB-HCC pilot study. PLoS One 2025; 20:e0321189. [PMID: 40233040 PMCID: PMC11999108 DOI: 10.1371/journal.pone.0321189] [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: 11/06/2024] [Accepted: 02/13/2025] [Indexed: 04/17/2025] Open
Abstract
BACKGROUND The gut microbiota is often altered in chronic liver diseases and hepatocellular carcinoma (HCC), and increasing evidence suggests that it may influence response to cancer immunotherapy. Strategies to modulate the gut microbiome (i.e., fecal microbiota transplant (FMT)) may help to improve efficacy of immune checkpoint inhibitors (ICIs) or even overcome resistance to ICIs. Here, we describe the design and rationale of FAB-HCC, a single-center, single-arm, phase II pilot study to assess safety, feasibility, and efficacy of FMT from patients with HCC who responded to PD-(L)1-based immunotherapy or from healthy donors to patients with HCC who failed to achieve or maintain a response to atezolizumab plus bevacizumab. METHODS In this single-center, single-arm, phase II pilot study (ClinicalTrials.gov identifier: NCT05750030), we plan to include 12 patients with advanced HCC who failed to achieve or maintain a response to atezolizumab/bevacizumab. Patients will receive a single FMT via colonoscopy from donors with HCC who responded to PD-(L)1-based immunotherapy or from healthy individuals, followed by atezolizumab/bevacizumab every 3 weeks. The primary endpoint is safety, measured by incidence and severity of treatment-related adverse events. The main secondary endpoint is efficacy, as assessed by best radiological response according to RECISTv1.1 and mRECIST. Additional exploratory endpoints include data on the effect of FMT on recipient gut microbiota, as well as metagenomic analysis of stool samples, analyses of circulating immune cells and serum and stool proteomic, metabolomic and lipidomic signatures. DISCUSSION The results of this study will help to define the potential of FMT as add-on intervention in the systemic treatment of advanced HCC, with the potential to improve efficacy of immunotherapy or even overcome resistance. TRIAL REGISTRATION EudraCT Number: 2022-000234-42 Clinical trial registry & ID: ClinicalTrials.gov identifier: NCT05750030 (Registration date: 16.01.2023).
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Affiliation(s)
- Katharina Pomej
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Division of Gastroenterology and Hepatology, Department of Medicine III, Vienna Liver Cancer Study Group, Medical University of Vienna, Vienna, Austria
| | - Adrian Frick
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Division of Gastroenterology and Hepatology, Department of Medicine III, Vienna Liver Cancer Study Group, Medical University of Vienna, Vienna, Austria
| | - Lorenz Balcar
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Division of Gastroenterology and Hepatology, Department of Medicine III, Vienna Liver Cancer Study Group, Medical University of Vienna, Vienna, Austria
| | - Larissa Pajancic
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Division of Gastroenterology and Hepatology, Department of Medicine III, Vienna Liver Cancer Study Group, Medical University of Vienna, Vienna, Austria
| | - Anton Klotz
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Abelina Kreuter
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Division of Gastroenterology and Hepatology, Department of Medicine III, Vienna Liver Cancer Study Group, Medical University of Vienna, Vienna, Austria
| | - Katharina Lampichler
- Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Katharina Regnat
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Kerstin Zinober
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Dietmar Tamandl
- Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Christoph Gasche
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Division of Gastroenterology and Hepatology, Department of Medicine III, Vienna Liver Cancer Study Group, Medical University of Vienna, Vienna, Austria
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Huang M, Song C, Zhou X, Wang H, Lin Y, Wang J, Cai H, Wang M, Peng Z, Dong Z, Feng S. Tissue-matched analysis of MRI evaluating the tumor infiltrating lymphocytes in hepatocellular carcinoma. Int J Cancer 2025; 156:1634-1643. [PMID: 39635936 PMCID: PMC11826122 DOI: 10.1002/ijc.35281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 10/14/2024] [Accepted: 10/31/2024] [Indexed: 12/07/2024]
Abstract
Tumor-infiltrating lymphocytes (TILs) play critical roles in the tumor microenvironment and immunotherapy response. This study aims to explore the feasibility of multi-parametric magnetic resonance imaging (MRI) in evaluating TILs and to develop an evaluation model that considers spatial heterogeneity. Multi-parametric MRI was performed on hepatocellular carcinoma (HCC) mice (N = 28). Three-dimensional (3D) printing was employed for tissue sampling, to match the multi-parametric MRI data with tumor tissues, followed by flow cytometry analysis and next-generation RNA-sequencing. Pearson's correlation, multivariate logistic regression, and receiver operating characteristic (ROC) curve analyses were utilized to model TIL-related MRI parameters. MRI quantitative parameters, including T1 relaxation times and perfusion, were correlated with the infiltration of leukocytes, T-cells, CD4+ T-cells, CD8+ T-cells, PD1 + CD8+ T-cells, B-cells, macrophages, and regulatory T-cells (correlation coefficients ranged from -0.656 to 0.482, p <.05) in tumor tissues. TILs were clustered into inflamed and non-inflamed subclasses, with the proportion of T-cells, CD8+ T-cells, and PD1 + CD8+ T-cells significantly higher in the inflamed group compared to the non-inflamed group (43.37% vs. 25.45%, 50.83% vs. 34.90%, 40.45% vs. 29.47%, respectively; p <.001). The TIL evaluation model, based on the Z-score combining Kep and T1post, was able to distinguish between these subgroups, yielding an area under the curve of 0.816 (95% confidence interval 0.721-0.910) and a cut-off value of -0.03 (sensitivity 68.4%, specificity 91.3%). Additionally, the Z-score was related to the gene expression of T-cell activation, chemokine production, and cell adhesion. The tissue-matched analysis of multi-parametric MRI offers a feasible method of regional evaluation and can distinguish between TIL subclasses.
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Affiliation(s)
- Mengqi Huang
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Department of Radiology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Chenyu Song
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Xiaoqi Zhou
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Huanjun Wang
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Yingyu Lin
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Jifei Wang
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Huasong Cai
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Meng Wang
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Zhenpeng Peng
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Zhi Dong
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Shi‐Ting Feng
- Department of Radiology, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
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40
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Otomo K, Fujita M, Sekine R, Sato H, Abe N, Sugaya T, Watanabe C, Takahata Y, Hayashi M, Abe K, Takahashi A, Ohira H. Patient with Atezolizumab-induced Encephalitis in Hepatocellular Carcinoma. Intern Med 2025; 64:1181-1187. [PMID: 39261064 DOI: 10.2169/internalmedicine.4321-24] [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] [Indexed: 09/13/2024] Open
Abstract
A 65-year-old man treated with atezolizumab plus bevacizumab for hepatocellular carcinoma was admitted to our hospital with a fever, difficulty in moving, and aphasia. The patient became comatose immediately after admission. Imaging and cerebral fluid tests revealed no evidence of malignancy or infection. A diagnosis of atezolizumab-induced encephalitis was made, and steroid pulse therapy was initiated on admission, immediately after which the patient regained consciousness and was able to talk and walk. He was discharged with slight paralysis of his legs and was able to resume chemotherapy. An early diagnosis and treatment are required to improve the prognosis of encephalitis.
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Affiliation(s)
- Kakeru Otomo
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Masashi Fujita
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Ryoji Sekine
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Hidenori Sato
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Naoto Abe
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Tatsuro Sugaya
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Chiharu Watanabe
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Yosuke Takahata
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Manabu Hayashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Kazumichi Abe
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
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Yasukawa K, Shimada S, Akiyama Y, Taniai T, Igarashi Y, Tsukihara S, Tanji Y, Umemura K, Kamachi A, Nara A, Yamane M, Akahoshi K, Shimizu A, Soejima Y, Tanabe M, Tanaka S. ACVR2A attenuation impacts lactate production and hyperglycolytic conditions attracting regulatory T cells in hepatocellular carcinoma. Cell Rep Med 2025; 6:102038. [PMID: 40139191 DOI: 10.1016/j.xcrm.2025.102038] [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: 01/18/2024] [Revised: 10/01/2024] [Accepted: 03/03/2025] [Indexed: 03/29/2025]
Abstract
Although ACVR2A mutations are prevalent in non-viral hepatocellular carcinomas (HCCs), the underlying mechanism remains unelucidated. Our molecular investigation reveals that ACVR2A impairment induces hyperglycolysis through the inactivation of the SMAD signaling pathway. Using syngeneic transplantation models and human clinical samples, we clarify that ACVR2A-deficient HCC cells produce and secrete lactate via the upregulation of lactate dehydrogenase A (LDHA) and monocarboxylate transporter 4 (MCT4) expression levels, which promotes regulatory T (Treg) cell accumulation and then acquires resistance to immune checkpoint inhibitors. Remarkably, genetic knockdown and pharmacological inhibition of MCT4 ameliorate the high-lactate milieu in ACVR2A-deficient HCC, resulting in the suppression of intratumoral Treg cell recruitment and the restoration of the sensitivity to PD-1 blockade. These findings furnish compelling evidence that lactate attenuates anti-tumor immunity and that therapeutics targeting this pathway present a promising strategy for mitigating immunotherapy resistance in ACVR2A-deficient HCC.
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Affiliation(s)
- Koya Yasukawa
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Shu Shimada
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
| | - Yoshimitsu Akiyama
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
| | - Tomohiko Taniai
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo 105-8471, Japan
| | - Yosuke Igarashi
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo 105-8471, Japan
| | - Shu Tsukihara
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Department of Surgery, The Jikei University School of Medicine, Tokyo 105-8471, Japan
| | - Yoshiaki Tanji
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo 105-8471, Japan
| | - Kentaro Umemura
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Atsushi Kamachi
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Atsushi Nara
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
| | - Masahiro Yamane
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
| | - Keiichi Akahoshi
- Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
| | - Akira Shimizu
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Yuji Soejima
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Minoru Tanabe
- Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
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Biswas S, Samanta A. Immune therapies in intermediate-advanced unresectable hepatocellular carcinoma: Changing the therapeutic landscape. World J Gastroenterol 2025; 31:103267. [PMID: 40248376 PMCID: PMC12001191 DOI: 10.3748/wjg.v31.i14.103267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 03/13/2025] [Accepted: 03/19/2025] [Indexed: 04/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. A substantial proportion of patients are diagnosed with advanced or intermediate-advanced stage disease at presentation and are often ineligible for curative surgery. The mainstay of treatment of this unique intermediate-advanced stage patients who have a liver-limited disease but unresectable due to large tumor burden, number of lesions or technical difficulties, have traditionally been locoregional therapies. However, the response has not been satisfactory in the majority of patients. With the advent of immune therapies and the remarkable progress it has made over the past decade, the management of intermediate-advanced HCC has undergone a paradigm change. Till 2020, sorafenib, a multi-targeted inhibitor of vascular endothelial growth factor, platelet-derived growth factor and rapidly accelerated fibrosarcoma was the one approved immune therapy. However, since 2021, nine more drugs have been approved, based on studies showing improved survival in advanced-stage HCC patients. However, the challenge clinicians face now is to determine the best choice/combination of available drugs to achieve long-term success and survival while maintaining preserved liver function. In light of emerging literature concerning immune therapies, including the relevant randomized controlled trial by Han et al, this editorial aims to review the currently available treatment strategies for the intermediate-advanced stage HCC.
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Affiliation(s)
- Sagnik Biswas
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Arghya Samanta
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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Li Y, Liu X, Dong Y, Zhou Y. Angiogenesis causes and vasculogenic mimicry formation in the context of cancer stem cells. Biochim Biophys Acta Rev Cancer 2025; 1880:189323. [PMID: 40239849 DOI: 10.1016/j.bbcan.2025.189323] [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: 11/14/2024] [Revised: 04/10/2025] [Accepted: 04/10/2025] [Indexed: 04/18/2025]
Abstract
Tumor occurrence, development, invasion, and metastasis are regulated by multiple mechanisms. Among these, angiogenesis promotes tumor progression mainly by supplying tumor tissue and providing channels for tumor metastasis. Cancer stem cells (CSCs) are another important factor affecting tumor progression by involving in tumor initiation and development, while remaining insensitive to conventional antitumor treatments. Among treatment strategies for them, owing to the existence of alternative angiogenic pathways or the risk of damaging normal stem cells, the clinical effect is not ideal. Angiogenesis and CSCs may influence each other in this process. Tumor angiogenesis can support CSC self-renewal by providing a suitable microenvironment, whereas CSCs can regulate tumor neovascularization and mediate drug resistance to anti-angiogenic therapy. This review summarized the role of vascular niche formed by angiogenesis in CSC self-renewal and stemness maintenance, and the function of CSCs in endothelial progenitor cell differentiation and pro-angiogenic factor upregulation. We also elucidated the malignant loop between CSCs and angiogenesis promoting tumor progression. Additionally, we summarized and proposed therapeutic targets, including blocking tumor-derived endothelial differentiation, inhibiting pro-angiogenic factor upregulation, and directly targeting endothelial-like cells comprising CSCs. And we analyzed the feasibility of these strategies to identify more effective methods to improve tumor treatment.
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Affiliation(s)
- Ying Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Xiaofang Liu
- Department of Anus and Intestine Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Yaodong Dong
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
| | - Yingying Zhou
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
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Du B, Qin J, Lin B, Zhang J, Li D, Liu M. CAR-T therapy in solid tumors. Cancer Cell 2025; 43:665-679. [PMID: 40233718 DOI: 10.1016/j.ccell.2025.03.019] [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: 12/14/2024] [Revised: 02/17/2025] [Accepted: 03/12/2025] [Indexed: 04/17/2025]
Abstract
While chimeric antigen receptor (CAR) T cell therapy has shown great success in hematologic malignancies, the effectiveness in solid tumors has been limited by several factors, including antigenic heterogeneity and the immunosuppressive nature of the tumor microenvironment (TME). In this review, we discuss the advancements made in clinical studies and challenges faced by CAR-T therapy for solid tumors. To enhance CAR-T cell efficacy in solid tumors, we explore strategies such as enhancing T cell persistence and cytotoxicity, targeting multiple antigens, and utilizing innovative allogeneic CAR-T cell manufacturing. Additionally, we highlight the potential benefits of combining CAR-T therapies with immune checkpoint inhibitors and other treatment modalities to overcome TME limitations. We remain optimistic about the future of CAR-T cell therapy in solid tumors, emphasizing the need for continued research to refine therapeutic approaches and address the clinical needs of patients with cancer.
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Affiliation(s)
- Bing Du
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
| | - Juliang Qin
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Boxu Lin
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Jiqin Zhang
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Dali Li
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Mingyao Liu
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
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Fu L, Li S, Mei J, Li Z, Yang X, Zheng C, Li N, Lin Y, Cao C, Liu L, Huang L, Shen X, Huang Y, Yun J. BIRC2 blockade facilitates immunotherapy of hepatocellular carcinoma. Mol Cancer 2025; 24:113. [PMID: 40223121 PMCID: PMC11995630 DOI: 10.1186/s12943-025-02319-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 04/01/2025] [Indexed: 04/15/2025] Open
Abstract
BACKGROUND The effectiveness of immunotherapy in hepatocellular carcinoma (HCC) is limited, however, the molecular mechanism remains unclear. In this study, we identified baculoviral IAP repeat-containing protein 2 (BIRC2) as a key regulator involved in immune evasion of HCC. METHODS Genome-wide CRISPR/Cas9 screening was conducted to identify tumor-intrinsic genes pivotal for immune escape. In vitro and in vivo models demonstrated the role of BIRC2 in protecting HCC cells from immune killing. Then the function and relevant signaling pathways of BIRC2 were explored. The therapeutic efficacy of BIRC2 inhibitor was examined in different in situ and xenograft HCC models. RESULTS Elevated expression of BIRC2 correlated with adverse prognosis and resistance to immunotherapy in HCC patients. Mechanistically, BIRC2 interacted with and promoted the ubiquitination-dependent degradation of NFκB-inducing kinase (NIK), leading to the inactivation of the non-canonical NFκB signaling pathway. This resulted in the decrease of major histocompatibility complex class I (MHC-I) expression, thereby protecting HCC cells from T cell-mediated cytotoxicity. Silencing BIRC2 using shRNA or inhibiting it with small molecules increased the sensitivity of HCC cells to immune killing. Meanwhile, BIRC2 blockade improved the function of T cells both in vitro and in vivo. Targeting BIRC2 significantly inhibited tumor growth, and enhanced the efficacy of anti-programmed death protein 1 (PD-1) therapy. CONCLUSIONS Our findings suggested that BIRC2 blockade facilitated immunotherapy of HCC by simultaneously sensitizing tumor cells to immune attack and boosting the anti-tumor immune response of T cells.
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Affiliation(s)
- Lingyi Fu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Shuo Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Jie Mei
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Ziteng Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Xia Yang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Chengyou Zheng
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Nai Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Yansong Lin
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Chao Cao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Lixuan Liu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Liyun Huang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Xiujiao Shen
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Yuhua Huang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Jingping Yun
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China.
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Fortuny M, García-Calonge M, Arrabal Ó, Sanduzzi-Zamparelli M, Castaño-García A, Cascos E, Mesa A, Piedra-Cerezal AM, Llarch N, Iserte G, Campos M, González M, Marsal A, Lorca R, Rodríguez M, Torres F, Varela M, Reig M. Cardiological adverse events in hepatocellular carcinoma patients receiving immunotherapy: Influence of comorbidities and clinical outcomes. Eur J Cancer 2025; 221:115404. [PMID: 40245453 DOI: 10.1016/j.ejca.2025.115404] [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: 01/22/2025] [Revised: 03/21/2025] [Accepted: 03/28/2025] [Indexed: 04/19/2025]
Abstract
INTRODUCTION Immunotherapy-based combinations have revolutionized the first-line treatment for advanced hepatocellular carcinoma (HCC), improving overall survival (OS). However, these therapies are associated with adverse events (AEs), particularly cardiological complications and major adverse cardiovascular events (MACE), which may adversely affect outcomes. The influence of comorbid conditions such as arterial hypertension (AHT) and type 2 diabetes mellitus (T2DM) on the incidence and prognosis of cardiological AEs in HCC patients remains understudied. METHODS This retrospective study included 109 HCC patients treated with atezolizumab-bevacizumab, tremelimumab-durvalumab, or durvalumab as first-line therapy at two Spanish medical centers from 2017-2023. Patients were stratified by comorbidities, AE incidence, and cardiological risk (CARDIOSOR scale). The primary endpoints were the incidence of treatment-modifying AEs and MACE, and their association with survival. RESULTS Among the cohort, 50.5 % experienced AEs of special interest (AESI), with 34 % considered immune-related (irAE). MACE occurred in 7.3 % of patients, including myocarditis (3.7 %). The CARDIOSOR scale identified a higher risk of MACE in patients with AHT, T2DM, or both (OR: 5.07, p = 0.034). Early cardiological AEs were independently associated with worse OS (HR: 3.38, p = 0.04). Patients with both AHT and T2DM exhibited higher rates of MACE (16.7 %) and treatment discontinuation (25.9 %). The CARDIOSOR scale effectively stratified patients into high-risk groups, correlating with increased MACE rates and poor survival outcomes. CONCLUSIONS Comorbid conditions, particularly AHT and T2DM, amplify the risk of MACE and influence treatment discontinuation. The CARDIOSOR scale is a valuable tool for personalized risk assessment, guiding tailored therapeutic strategies. Integrating cardiovascular risk management into HCC care is crucial for optimizing both oncological and cardiovascular outcomes.
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Affiliation(s)
- Marta Fortuny
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Liver Oncology Unit, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Marta García-Calonge
- Servicio de Digestivo, Sección de Hepatología, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Óscar Arrabal
- Biostatistics Unit, Medical School, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Marco Sanduzzi-Zamparelli
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Liver Oncology Unit, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Andrés Castaño-García
- Servicio de Digestivo, Sección de Hepatología, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Enric Cascos
- Cardiology Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Alicia Mesa
- Radiodiagnostic Department, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Ana María Piedra-Cerezal
- Servicio de Digestivo, Sección de Hepatología, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Neus Llarch
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Liver Oncology Unit, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; Universitat de Barcelona, Barcelona, Spain
| | - Gemma Iserte
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Liver Oncology Unit, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Marta Campos
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Liver Oncology Unit, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Melina González
- Liver Oncology Unit, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Aida Marsal
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Rebeca Lorca
- Área del Corazón, Servicio de Cardiología, Hospital Universitario Central de Asturias, Spain; Universidad de Oviedo, Oviedo, Asturias, Spain; IUOPA, ISPA, FINBA, Oviedo, Spain; Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORs), Madrid, Spain
| | - Manuel Rodríguez
- Servicio de Digestivo, Sección de Hepatología, Hospital Universitario Central de Asturias, Oviedo, Spain; Universidad de Oviedo, Oviedo, Asturias, Spain; IUOPA, ISPA, FINBA, Oviedo, Spain
| | - Ferran Torres
- Biostatistics Unit, Medical School, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - María Varela
- Servicio de Digestivo, Sección de Hepatología, Hospital Universitario Central de Asturias, Oviedo, Spain; Universidad de Oviedo, Oviedo, Asturias, Spain; IUOPA, ISPA, FINBA, Oviedo, Spain.
| | - María Reig
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Liver Oncology Unit, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; Universitat de Barcelona, Barcelona, Spain.
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Wen Y, Zhou S, Xu Y, Zhang C, Feng Z, Song Y, Ding B, Peng C, Tan H, Wang C, Feng J, Pei J, He G, Fu S, Wang L, Cai L, Liu S, Pan M. Donafenib versus sorafenib in triple therapy for unresectable hepatocellular carcinoma: a propensity score-matched multicenter analysis. World J Surg Oncol 2025; 23:143. [PMID: 40221746 PMCID: PMC11993997 DOI: 10.1186/s12957-025-03767-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 03/23/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND In recent years, triple therapy (molecular targeted agent + PD-1 inhibitor + transarterial therapy) has emerged as a promising strategy for unresectable hepatocellular carcinoma (uHCC). However, the optimal molecular targeted agent choice within triple therapy remains unclear. Donafenib is currently the only targeted drug with superior survival benefits compared with sorafenib monotherapy. This study aimed to compare donafenib-based versus sorafenib-based triple therapy in patients with uHCC, providing preliminary evidence to guide molecular targeted agent selection in this emerging treatment paradigm. METHODS This retrospective study enrolled 106 patients with initially uHCC who received triple therapy combining either donafenib or sorafenib with PD-1 inhibitors and transarterial therapies. A 1:2 nearest neighbour propensity score matching was used to minimize selection bias. The primary endpoints were overall survival (OS) and progression-free survival (PFS) based on Kaplan-Meier analysis. The secondary endpoints included objective response rate (ORR), surgical conversion rate and adverse events (AEs). Statistical comparisons used Cox regression for survival data and chi-squared/ t-tests for other metrics, with p < 0.05 indicating significance. RESULTS After matching, 30 patients received sorafenib-based triple therapy (Sor-P-T/H group) and 50 patients received donafenib-based triple therapy (Don-P-T/H group). Although the median OS was not attained, the Don-P-T/H regimen demonstrated a statistically significant survival advantage (HR = 0.317, P = 0.004). Moreover, the Don-P-T/H group demonstrated significantly higher median PFS (9.00 vs. 4.62 months, P = 0.005), ORR (64% vs. 40%, P = 0.037) and surgical conversion rate (26.0% vs. 3.3%, P = 0.01) compared to the Sor-P-T/H group. The two groups showed no notable difference in the overall severity of adverse events but the Don-P-T/H group demonstrated less liver impairment. CONCLUSION Donafenib may be more advantageous than sorafenib in triple therapy for patients with uHCC.
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Affiliation(s)
- Yaohong Wen
- General Surgery Center, Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, No.253 Gongye Dadao Zhong, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Shuyi Zhou
- Department of Hepatobiliary Surgery/Central Laboratory, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan Province, People's Republic of China
| | - Yuyan Xu
- General Surgery Center, Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, No.253 Gongye Dadao Zhong, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Cheng Zhang
- General Surgery Center, Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, No.253 Gongye Dadao Zhong, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Zhoubin Feng
- General Surgery Center, Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, No.253 Gongye Dadao Zhong, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Yinghui Song
- Department of Hepatobiliary Surgery/Central Laboratory, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan Province, People's Republic of China
| | - Bai Ding
- Department of Hepatobiliary Surgery/Central Laboratory, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan Province, People's Republic of China
| | - Chuang Peng
- Department of Hepatobiliary Surgery/Central Laboratory, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan Province, People's Republic of China
- Hunan Provincial Key Laboratory of Biliary Disease Prevention and Treatment, Changsha, Hunan Province, China
- Clinical Medical Technology Research Center of Hunan Provincial for Biliary Disease Prevention and Treatment, Changsha, Hunan Province, China
| | - Hongkun Tan
- General Surgery Center, Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, No.253 Gongye Dadao Zhong, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Chunming Wang
- General Surgery Center, Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, No.253 Gongye Dadao Zhong, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Jianan Feng
- General Surgery Center, Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, No.253 Gongye Dadao Zhong, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Jingyuan Pei
- General Surgery Center, Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, No.253 Gongye Dadao Zhong, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Guolin He
- General Surgery Center, Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, No.253 Gongye Dadao Zhong, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Shunjun Fu
- General Surgery Center, Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, No.253 Gongye Dadao Zhong, Haizhu District, Guangzhou, 510280, Guangdong Province, China
| | - Lvhuan Wang
- Suzhou Zelgen Biopharmaceuticals Co, Ltd, Suzhou, China
| | - Lei Cai
- General Surgery Center, Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, No.253 Gongye Dadao Zhong, Haizhu District, Guangzhou, 510280, Guangdong Province, China.
| | - Sulai Liu
- Department of Hepatobiliary Surgery/Central Laboratory, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan Province, People's Republic of China.
- Hunan Engineering Research Center of Digital Hepatobiliary Medicine, Changsha, Hunan Province, China.
- Hunan Provincial Key Laboratory of Biliary Disease Prevention and Treatment, Changsha, Hunan Province, China.
| | - Mingxin Pan
- General Surgery Center, Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, No.253 Gongye Dadao Zhong, Haizhu District, Guangzhou, 510280, Guangdong Province, China.
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Li C, Hu J, Li M, Mao Y, Mao Y. Integrated multi-omics analysis and machine learning refine molecular subtypes and clinical outcome for hepatocellular carcinoma. Hereditas 2025; 162:61. [PMID: 40221783 PMCID: PMC11992824 DOI: 10.1186/s41065-025-00431-6] [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: 01/25/2025] [Accepted: 04/04/2025] [Indexed: 04/14/2025] Open
Abstract
The high morbidity and mortality of hepatocellular carcinoma (HCC) impose a substantial economic burden on patients' families and society, and the majority of HCC patients are detected at advanced stages and experience poor therapeutic outcomes, whereas early-stage patients exhibit the most favorable prognosis following radical treatment. In this study, we utilized a computational framework to integrate multi-omics data from HCC patients using the latest 10 different clustering algorithms, which were then employed a diverse set of 101 combinations derived from 10 different machine learning algorithms to develop a consensus machine learning-based signature (CMLBS). Using multi-omics consensus clustering, we distinguished two cancer subtypes (CSs) of HCC, and found that CS2 patients exhibited superior overall survival (OS) outcomes. In TCGA-LIHC, ICGC-LIRI, and multiple immunotherapy cohorts, low-CMLBS patients demonstrated favorable clinical outcomes and enhanced responsiveness to immunotherapy. Encouragingly, we observed that the high-CMLBS patients may exhibit increased sensitivity to Alpelisib, AZD7762, BMS-536,924, Carmustine, and GDC0810, whereas they may demonstrate reduced sensitivity to Axitinib, AZD6482, AZD8055, Entospletinib, GSK269962A, GSK1904529A, and GSK2606414, suggesting that CMLBS may contribute to the selection of chemotherapeutic agents for HCC patients. Therefore, in-depth examination of data from multi-omics data can provide valuable insights and contribute to the refinement of the molecular classification of HCC. In addition, the CMLBS model demonstrates potential as a screening tool for identifying HCC patients who may derive benefit from immunotherapy, and it possesses practical utility in the clinical management of HCC.
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Affiliation(s)
- Chunhong Li
- Central Laboratory, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, Guangxi, China.
- Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, Guangxi, China.
| | - Jiahua Hu
- Central Laboratory, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, Guangxi, China
- Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, Guangxi, China
| | - Mengqin Li
- College of pharmacy, Guilin Medical University, Guilin, 541199, Guangxi, China
| | - Yiming Mao
- Department of thoracic surgery, Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine, Suzhou, 215028, China
| | - Yuhua Mao
- Department of Obstetrics, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, Guangxi, China.
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Guo X, Zhao Z, Zhu L, Liu S, Zhou L, Wu F, Fang S, Chen M, Zheng L, Ji J. The evolving landscape of biomarkers for systemic therapy in advanced hepatocellular carcinoma. Biomark Res 2025; 13:60. [PMID: 40221793 PMCID: PMC11993949 DOI: 10.1186/s40364-025-00774-2] [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: 01/26/2025] [Accepted: 03/29/2025] [Indexed: 04/14/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the most prevalent and deadliest cancers. With the approval of multiple first- and second-line agents, especially the combination therapies based on immune checkpoint inhibitor (ICI) regimens, the landscape of systemic therapy for advanced HCC (aHCC) is more diverse than ever before. The efficacy of current systemic therapies shows great heterogeneity in patients with aHCC, thereby identifying biomarkers for response prediction and patient stratification has become an urgent need. The main biomarkers for systemic therapy in hepatocellular carcinoma are derived from peripheral blood, tissues, and imaging. Currently, the understanding of the clinical response to systemic therapy indicates unequivocally that a single biomarker cannot be used to identify patients who are likely to benefit from these treatments. In this review, we provide an integrated landscape of the recent development in molecular targeted therapies and ICIs-based therapies, especially focusing on the role of clinically applicable predictive biomarkers. Additionally, we further highlight the latest advancements in biomarker-driven therapies, including targeted treatments, adoptive cell therapies, and bispecific antibodies.
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Affiliation(s)
- Xinyu Guo
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Zhongwei Zhao
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Lingyi Zhu
- The 2nd Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, China
| | - Shuang Liu
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Lingling Zhou
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Fazong Wu
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Shiji Fang
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Minjiang Chen
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Liyun Zheng
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China.
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China.
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China.
| | - Jiansong Ji
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China.
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China.
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China.
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Rimassa L, Chan SL, Sangro B, Lau G, Kudo M, Reig M, Breder V, Ryu MH, Ostapenko Y, Sukeepaisarnjaroen W, Varela M, Tougeron D, Crysler OV, Bouattour M, Van Dao T, Tam VC, Faccio A, Furuse J, Jeng LB, Kang YK, Kelley RK, Paskow MJ, Ran D, Xynos I, Kurland JF, Negro A, Abou-Alfa GK. Five-year overall survival update from the HIMALAYA study of tremelimumab plus durvalumab in unresectable HCC. J Hepatol 2025:S0168-8278(25)00226-0. [PMID: 40222621 DOI: 10.1016/j.jhep.2025.03.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 03/25/2025] [Accepted: 03/30/2025] [Indexed: 04/15/2025]
Abstract
BACKGROUND & AIMS In the phase III HIMALAYA study (NCT03298451), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) versus sorafenib in unresectable HCC (uHCC) and demonstrated long-term survival benefits. We report an updated exploratory analysis of OS with 5 years of follow-up, including survival by multiple tumour response measures. METHODS Participants were randomised to STRIDE (tremelimumab plus durvalumab), durvalumab or sorafenib. OS, depth of response and serious adverse events (AEs) were assessed. Extended long-term survivors (eLTS; ≥48 months beyond randomisation) were described. Updated data cut-off: 01 March 2024. RESULTS Median (95% CI) follow-up durations were 62.49 (59.47-64.79) months (STRIDE) and 59.86 (58.32-61.54) months (sorafenib). The OS HR (95% CI) for STRIDE versus sorafenib was 0.76 (0.65-0.89). OS rates at 60 months for STRIDE versus sorafenib were 19.6% versus 9.4% overall, 28.7% versus 12.7% in participants achieving disease control per RECIST v1.1 and 50.7% versus 26.3% in participants achieving >25% tumour shrinkage. No late-onset treatment-related serious AEs were reported for STRIDE. There were more eLTS with STRIDE (83/393, 21.1%) than sorafenib (45/389, 11.6%), and extended long-term survival occurred across all clinically relevant subgroups. CONCLUSIONS At 5 years, STRIDE sustained an OS benefit versus sorafenib and maintained a manageable safety profile. OS benefit with STRIDE was improved in participants with disease control. Data suggest that any degree of tumour shrinkage with STRIDE can be associated with improved OS, indicating that conventional response measures may not fully capture STRIDE benefits. Nevertheless, participants experiencing deep responses appear to have the greatest benefit. STRIDE continues to set new benchmarks in uHCC with 1 in 5 patients alive at 5 years. IMPACT AND IMPLICATIONS The phase III HIMALAYA study showed that STRIDE (Single Tremelimumab Regular Interval Durvalumab) improved overall survival (OS) versus sorafenib in participants with unresectable HCC (uHCC), including after 4 years of follow-up. Understanding the efficacy and safety of STRIDE over the longer term is important for healthcare providers; here, we demonstrate that STRIDE sustained an OS benefit versus sorafenib and maintained a manageable safety profile after 5 years of follow-up. OS benefit with STRIDE was improved in participants with disease control and any degree of tumour shrinkage, indicating that conventional response measures may not fully capture the benefits of STRIDE. These findings are important as they set new benchmarks in uHCC and may help guide clinical decisions in the future.
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Affiliation(s)
- Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
| | - Stephen L Chan
- State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Sir Yue-Kong Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Bruno Sangro
- Liver Unit and HPB Oncology Area, Clínica Universidad de Navarra and CIBEREHD, Pamplona - Madrid, Spain
| | - George Lau
- Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, Hong Kong SAR, China
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Maria Reig
- Barcelona Clinic Liver Cancer (BCLC), Liver Unit, Hospital Clinic de Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Valeriy Breder
- Department of Chemotherapy, N. N. Blokhin National Medical Research Center of Oncology, Moscow, Russian Federation
| | - Min-Hee Ryu
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yuriy Ostapenko
- Department of Minimally Invasive and Endoscopic Surgery, Interventional Radiology, National Cancer Institute, Kyiv, Ukraine
| | | | - Maria Varela
- Liver Unit, Hospital Universitario Central de Asturias, IUOPA, ISPA, FINBA, Universidad de Oviedo, Oviedo, Spain
| | - David Tougeron
- Department of Gastroenterology and Hepatology, Poitiers University Hospital, Poitiers, France
| | - Oxana V Crysler
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Tu Van Dao
- Cancer Research and Clinical Trials Center, Department of Optimal Therapy, National Cancer Hospital, Hanoi, Vietnam
| | - Vincent C Tam
- Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta, Canada
| | - Adilson Faccio
- Department of Oncology, CEON - Centro Especializado em Oncologia, Ribeirao Preto, Brazil
| | - Junji Furuse
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
| | - Long-Bin Jeng
- Department of Surgery, China Medical University and Hospital, Taichung, Taiwan, Republic of China
| | - Yoon Koo Kang
- Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Robin K Kelley
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
| | - Michael J Paskow
- Global Medical Affairs, AstraZeneca, Gaithersburg, Maryland, USA
| | - Di Ran
- Statistics, AstraZeneca, Gaithersburg, Maryland, USA
| | - Ioannis Xynos
- Oncology R&D, Late-Stage Development, AstraZeneca, Cambridge, UK
| | - John F Kurland
- Oncology R&D, Late-Stage Development, AstraZeneca, Gaithersburg, Maryland, USA
| | - Alejandra Negro
- Oncology R&D, Late-Stage Development, AstraZeneca, Gaithersburg, Maryland, USA
| | - Ghassan K Abou-Alfa
- Department of Medicine, Memorial Sloan Kettering Cancer Center, Cornell University, New York, New York, USA; Weill Medical College, Cornell University, New York, New York, USA; Trinity College Dublin, Dublin, Ireland
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