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Zhang L, Yang J, Li JJ, Chen CY, Wang XD, Xie Y, Jiang WT. Multidisciplinary tumor board is associated with improved survival in patients with hepatocellular carcinoma after liver transplantation. World J Clin Oncol 2025; 16:100729. [DOI: 10.5306/wjco.v16.i4.100729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 11/24/2024] [Accepted: 01/02/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) ranks as the sixth most common cancer and the third- leading cause of cancer-related deaths worldwide. The multidisciplinary tumor board (MDTB) has been recognized for improving outcomes in cancer management, but its role in patients with HCC undergoing liver transplantation (LT) remains underexplored.
AIM To evaluate the impact of an MDTB on survival outcomes in patients with HCC undergoing LT.
METHODS We retrospectively analyzed 393 patients with HCC who underwent LT at our institution from October 2015 to October 2021. Patients were categorized into the MDTB and non-MDTB groups. We compared preoperative and postoperative characteristics, overall survival (OS), and disease-free survival (DFS) between the two groups.
RESULTS Within the University of California, San Francisco (UCSF) criteria, no significant differences in OS and DFS were noted between the MDTB and non-MDTB groups. However, for patients who exceeded the UCSF criteria, the MDTB group exhibited a substantial improvement in both OS and DFS. The 1-year, 3-year, and 5-year OS rates for the MDTB group in this subgroup were 88.68%, 75.29%, and 61.78%, respectively, compared to 83.02%, 64.07%, and 38.25%, respectively in the non-MDTB group. Similarly, DFS rates were 89.47%, 71.35%, and 63.52%, respectively, vs 82.18%, 53.78%, and 34.04%, respectively.
CONCLUSION The MDTB approach was particularly beneficial for patients with HCC exceeding the UCSF criteria, significantly improving OS and DFS. These findings advocate for integrating MDTB into clinical practice for optimizing the management of high-risk patients with HCC undergoing LT.
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Affiliation(s)
- Li Zhang
- Department of Liver Transplantation, Tianjin First Center Hospital, Tianjin 300192, China
| | - Jian Yang
- Department of Liver Transplantation, Tianjin First Center Hospital, Tianjin 300192, China
| | - Jun-Jie Li
- Department of Liver Transplantation, Tianjin First Center Hospital, Tianjin 300192, China
| | - Chi-Yi Chen
- Department of Liver Transplantation, Tianjin First Center Hospital, Tianjin 300192, China
| | - Xiao-Dong Wang
- Department of Liver Transplantation, Tianjin First Center Hospital, Tianjin 300192, China
| | - Yan Xie
- Department of Liver Transplantation, Tianjin First Center Hospital, Tianjin 300192, China
| | - Wen-Tao Jiang
- Department of Liver Transplantation, Tianjin First Center Hospital, Tianjin 300192, China
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Zarlashat Y, Mushtaq H, Pham L, Abbas W, Sato K. Advancements in Immunotherapeutic Treatments for Hepatocellular Carcinoma: Potential of Combination Therapies. Int J Mol Sci 2024; 25:6830. [PMID: 38999940 PMCID: PMC11241106 DOI: 10.3390/ijms25136830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 06/16/2024] [Accepted: 06/17/2024] [Indexed: 07/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and a significant global health burden, with increasing incidence rates and limited treatment options. Immunotherapy has become a promising approach due to its ability to affect the immune microenvironment and promote antitumor responses. The immune microenvironment performs an essential role in both the progression and the development of HCC, with different characteristics based on specific immune cells and etiological factors. Immune checkpoint inhibitors, including programmed death-1/programmed death-ligand 1 inhibitors (pembrolizumab, nivolumab, and durvalumab) and cytotoxic T lymphocyte antigen-4 inhibitors (tremelimumab and ipilimumab), have the potential to treat advanced HCC and overcome adverse effects, such as liver failure and chemoresistance. Phase II and phase III clinical trials highlight the efficacy of pembrolizumab and nivolumab, respectively, in advanced HCC patients, as demonstrated by their positive effects on overall survival and progression-free survival. Tremelimumab has exhibited modest response rates, though it does possess antiviral activity. Thus, it is still being investigated in ongoing clinical trials. Combination therapies with multiple drugs have demonstrated potential benefits in terms of survival and tumor response rates, improving patient outcomes compared to monotherapy, especially for advanced-stage HCC. This review addresses the clinical trials of immunotherapies for early-, intermediate-, and advanced-stage HCC. Additionally, it highlights how combination therapy can significantly enhance overall survival, progression-free survival, and objective response rate in advanced-stage HCC, where treatment options are limited.
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Affiliation(s)
- Yusra Zarlashat
- Department of Biochemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan
| | - Hassan Mushtaq
- Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering-C (NIBGE), Faisalabad 38000, Pakistan
- Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad 45650, Pakistan
| | - Linh Pham
- Department of Science and Mathematics, Texas A&M University-Central Texas, Killeen, TX 76549, USA
| | - Wasim Abbas
- Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering-C (NIBGE), Faisalabad 38000, Pakistan
- Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad 45650, Pakistan
| | - Keisaku Sato
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Yao J, Tan X, Sha Y, Chen Y, Chen R, Shi D. An updated review of immunotherapy in esophageal cancer: PD-L1 footprint. Cent Eur J Immunol 2024; 49:77-90. [PMID: 38812606 PMCID: PMC11130989 DOI: 10.5114/ceji.2024.139269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 12/15/2023] [Indexed: 05/31/2024] Open
Abstract
Esophageal cancer is considered one of the most significant challenges to public health worldwide. While various therapeutic options exist for esophageal cancer, including chemotherapy, radiotherapy, and surgery, several adverse effects of these medications have been reported. Therefore, a new generation of therapeutic lines should be applied to minimize complications. In this regard, immunotherapy is a novel approach that aims to kill tumor cells directly by targeting them. Specifically, monoclonal antibodies can target specific markers of esophageal cancer tumor cells, keeping other normal cells safe. Multiple monoclonal antibodies optimized for esophageal cancer, such as pembrolizumab, ramucirumab, trastuzumab, nivolumab, and ipilimumab, are available. On the other hand, esophageal cancer tumor cells express a specific inhibitory ligand and its receptor called programmed cell death, which can suppress T cell immune responses. This receptor provides an inhibitory signal, causing the highest expression of the PD-L1 ligand on tumor cells. The outcomes of this interaction lead to the suppression of the activation and function of T lymphocytes. Therefore, immunotherapy for esophageal cancer targeting the PD-1/PD-L1 pathway has shown a remarkable correlation with cancer care. This study presents a comprehensive review of the latest findings related to immunotherapy in esophageal cancer.
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Affiliation(s)
- Juan Yao
- Department of Radiation Oncology, Huaian Hospital of Huaian City (Huai’a Cancer Hospital), Huaian, Jiangsu 223200, P.R. of China
| | - Xiaoyan Tan
- Department of Obstetrics and Gynecology, Huaian Hospital of Huaian City (Huai’an Cancer Hospital), Huaian, Jiangsu 223200, P.R. of China
| | - Yanping Sha
- Department of Radiation Oncology, Huaian Hospital of Huaian City (Huai’a Cancer Hospital), Huaian, Jiangsu 223200, P.R. of China
| | - Yurao Chen
- Department of Radiation Oncology, Huaian Hospital of Huaian City (Huai’a Cancer Hospital), Huaian, Jiangsu 223200, P.R. of China
| | - Ronghuai Chen
- Department of Radiation Oncology, Huaian Hospital of Huaian City (Huai’a Cancer Hospital), Huaian, Jiangsu 223200, P.R. of China
| | - Dongping Shi
- Department of Infection, Huaian Hospital of Huaian City (Huai’a Cancer Hospital), Huaian, Jiangsu 223200, P.R. of China
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Peng W, Pan Y, Xie L, Yang Z, Ye Z, Chen J, Wang J, Hu D, Xu L, Zhou Z, Chen M, Fang A, Zhang Y. The emerging therapies are reshaping the first-line treatment for advanced hepatocellular carcinoma: a systematic review and network meta-analysis. Therap Adv Gastroenterol 2024; 17:17562848241237631. [PMID: 38645513 PMCID: PMC11032067 DOI: 10.1177/17562848241237631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 02/12/2024] [Indexed: 04/23/2024] Open
Abstract
Background Given the superior performance of various therapies over sorafenib in advanced hepatocellular carcinoma (HCC) and the absence of direct comparisons, it is crucial to explore the efficacy of these treatments in phase III randomized clinical trials. Objectives The goal is to identify which patients are most likely to benefit significantly from these emerging therapies, contributing to more personalized and informed clinical decision-making. Design Systematic review and network meta-analysis. Data sources and methods PubMed, Embase, ClinicalTrials.gov, and international conference databases have been searched from 1 January 2010 to 1 December 2023. Results After screening, 17 phase III trials encompassing 18 treatments were included. In the whole-population network meta-analysis, the newly first-line tremelimumab plus durvalumab (Tre + Du) was found to be comparable with atezolizumab plus bevacizumab (Atezo + Beva) in providing the best overall survival (OS) benefit [hazard ratio (HR) 1.35, 95% confidence interval (CI): 0.93-1.92]. Concerning OS benefits, sintilimab plus bevacizumab biosimilar (Sint + Beva), camrelizumab plus rivoceranib (Camre + Rivo), and lenvatinib plus pembrolizumab (Lenva + Pemb) appear to exhibit similar effects to Tre + Du and Atezo + Beva. In the context of progression-free survival, Atezo + Beva seemed to outperform Tre + Du (HR: 0.66 CI: 0.49-0.87), while the effects are comparable to Sint + Beva, Camre + Rivo, and Lenva + Pemb. Upon comparison between Asia-Pacific and non-Asia-Pacific cohorts, as well as between hepatitis B virus (HBV)-infected and non-HBV-infected populations, immune checkpoint inhibitor (ICI)-based treatments seemed to exhibit heightened efficacy in the Asia-Pacific group and among individuals with HBV infection. However, combined ICI-based therapies did not show more effectiveness than molecular-targeted drugs in patients without macrovascular invasion and/or extrahepatic spread. As for grades 3-5 adverse events, combined therapies showed comparable safety to sorafenib and lenvatinib. Conclusion Compared with sorafenib and lenvatinib, combination therapies based on ICIs significantly improved the prognosis of advanced HCC and demonstrated similar safety. At the same time, the optimal treatment approach should be tailored to individual patient characteristics, such as etiology, tumor staging, and serum alpha-fetoprotein levels. With lower incidence rates of treatment-related adverse events and non-inferior efficacy compared to sorafenib, ICI monotherapies should be prioritized as a first-line treatment approach for patients who are not suitable candidates for ICI-combined therapies. Trial registration PROSPERO, CRD42022288172.
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Affiliation(s)
- Wei Peng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Yangxun Pan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Lan Xie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
- Department of Anesthesiology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Zhoutian Yang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Zhiwei Ye
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Jinbin Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Juncheng Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Dandan Hu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Li Xu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Zhongguo Zhou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Minshan Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Aiping Fang
- Department of Nutrition, School of Public Health, Sun Yat-sen University, 651 Dongfeng Road East, Guangzhou, Guangdong 510060, P. R. China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Yaojun Zhang
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong 510060, P. R. China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
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Chen H, Wang Z, Wang C. Lenvatinib Combined with the PD-1 Inhibitor Camrelizumab in the Treatment of Primary Liver Cancer Caused Hemorrhagic Exfoliative Gastritis. Case Rep Oncol 2024; 17:543-548. [PMID: 38595961 PMCID: PMC11003730 DOI: 10.1159/000538006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 02/19/2024] [Indexed: 04/11/2024] Open
Abstract
Introduction Patients with advanced primary liver cancer often lose the opportunity for surgery when they are found, and the treatment options are limited. Lenvatinib, as a multi-target tyrosine kinase inhibitor, has been used as the first-line treatment for advanced liver cancer. Immune checkpoint inhibitors, such as programmed cell death protein 1 inhibitors, have been successfully used in advanced or metastatic liver cancer. Case Presentation We report a case of combined lenvatinib and the programmed cell death protein 1 inhibitor camrelizumab in the treatment of primary liver cancer, in which the rare complication of full-thickness gastric mucosa exfoliation occurred. To the best of our knowledge, this is the first report of the side effect of hemorrhagic exfoliative gastritis with the combination of lenvatinib and camrelizumab. Conclusion Hemorrhagic exfoliative gastritis is an extremely rare clinical complication. Lenvatinib inhibits vascular proliferation and could cause gastrointestinal perforation, which is considered to be the main factor, but whether camrelizumab plays a role in it or only causes gastrointestinal reactions leading to nausea and vomiting, resulting in gastric mucosal exfoliation bleeding, remains to be further explored.
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Affiliation(s)
- Hong Chen
- Department of Clinical Pharmacy, Bethune International Peace Hospital, Shijiazhuang, China
| | - Zihua Wang
- Department of Oncology, Bethune International Peace Hospital, Shijiazhuang, China
| | - Chunhua Wang
- Department of Gastroenterology, Bethune International Peace Hospital, Shijiazhuang, China
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Wang Z, Zhou C, Zhang Y, Tian X, Wang H, Wu J, Jiang S. From synergy to resistance: Navigating the complex relationship between sorafenib and ferroptosis in hepatocellular carcinoma. Biomed Pharmacother 2024; 170:116074. [PMID: 38147732 DOI: 10.1016/j.biopha.2023.116074] [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: 11/04/2023] [Revised: 12/17/2023] [Accepted: 12/21/2023] [Indexed: 12/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains a major global health burden, and sorafenib, a multi-kinase inhibitor, has shown effectiveness in the treatment of HCC and is considered as the first-line therapy for advanced HCC. However, the response to sorafenib varies among patients, and the development of drug resistance poses a prevalent obstacle. Ferroptosis, a newly characterized form of cell death featured by iron-dependent lipid peroxidation, has emerged as a critical player in the reaction to sorafenib therapy in HCC. The induction of ferroptosis has been shown to augment the anticancer benefits of sorafenib. However, it has also been observed to contribute to sorafenib resistance. This review presents a comprehensive and thorough analysis that elucidates the intricate relationship between ferroptosis and sorafenib over recent years, aiming to formulate effective therapeutic approaches for liver cancer. Based on this exploration, we propose innovative strategies intended to overcome sorafenib resistance via targeted modulation of ferroptosis.
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Affiliation(s)
- Zijian Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chunyang Zhou
- Department of Radiation Oncology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China
| | - Yiming Zhang
- Clinical Medical Laboratory Center, Jining First People's Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Xinchen Tian
- Clinical Medical Laboratory Center, Jining First People's Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Haochen Wang
- Clinical Medical Laboratory Center, Jining First People's Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Jibiao Wu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Shulong Jiang
- Clinical Medical Laboratory Center, Jining First People's Hospital, Shandong First Medical University, Jining, Shandong, China; College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
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Sariyar E, Firtina Karagonlar Z. Modelling the Sorafenib-resistant Liver Cancer Microenvironment by Using 3-D Spheroids. Altern Lab Anim 2023; 51:301-312. [PMID: 37555318 DOI: 10.1177/02611929231193421] [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] [Indexed: 08/10/2023]
Abstract
Liver cancer is the third leading cause of cancer-related mortality, and hepatocellular carcinoma (HCC) is the most common form of liver cancer, and it usually occurs in the setting of chronic liver disease and cirrhosis. For patients with advanced HCC, systemic treatment is the first choice - however, resistance occurs frequently. Sorafenib was the first tyrosine kinase inhibitor approved for advanced HCC, and resistance to the therapy is a serious concern. When sorafenib therapy fails in a patient, it can be challenging to decide whether they can undergo a second-line therapy, and to determine which therapy they will be able to tolerate. Thus, physiologically relevant in vitro preclinical models are crucial for screening potential therapies, and 3-D tumour spheroids permit studies of tumour pathobiology. In this study, a drug-resistant 3-D tumour spheroid model was developed, based on sorafenib-resistant hepatocellular carcinoma cells, LX2 stellate cells and THP-1 monocytes. Model tumour spheroids that were formed with the sorafenib-resistant cells demonstrated lower diffusion of doxorubicin and exhibited increased resistance to regorafenib. Moreover, in the sorafenib-resistant spheroids, there was increased presence of CD68-positive cells and a reduction in inflammatory marker secretion. The sorafenib-resistant cell line-derived spheroids also showed a higher expression of FGF-19, PDGF-AA and GDF-15, which are known to be involved in malignancies. This multi-cell type spheroid model represents a potentially useful system to test drug candidates in a microenvironment that mimics the drug-resistant tumour microenvironment in HCC.
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Affiliation(s)
- Ece Sariyar
- Department of Genetics and Bioengineering, İzmir University of Economics, Izmir, Turkey
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Zhou S, Xu H, Wei T. Inhibition of stress proteins TRIB3 and STC2 potentiates sorafenib sensitivity in hepatocellular carcinoma. Heliyon 2023; 9:e17295. [PMID: 37389061 PMCID: PMC10300369 DOI: 10.1016/j.heliyon.2023.e17295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 06/10/2023] [Accepted: 06/13/2023] [Indexed: 07/01/2023] Open
Abstract
Sorafenib resistance is one of the main obstacles to the treatment of advanced hepatocellular carcinoma (HCC). Stress proteins TRIB3 and STC2 confer cell resistance to a variety of stresses, including hypoxia, nutritional deprivation, and other perturbations, which induce endoplasmic reticulum stress. However, the role of TRIB3 and STC2 in sorafenib sensitivity to HCC remains unclear. In this study, our results indicated that the common differentially expressed genes (DEGs) in sorafenib-treated HCC cells obtained from the NCBI-GEO database (Huh7 and Hep3B cells; GSE96796) included TRIB3, STC2, HOXD1, C2orf82, ADM2, RRM2, and UNC93A. The most significantly upregulated DEGs were TRIB3 and STC2, which were both stress protein genes. Bioinformatic analysis in NCBI public databases indicated that TRIB3 and STC2 were highly expressed in HCC tissues and closely associated with poor prognoses in HCC patients. Further investigation showed that inhibition of TRIB3 or STC2 with siRNA could enhance the anti-cancer effect of sorafenib in HCC cell lines. In conclusion, our study showed that stress proteins TRIB3 and STC2 are closely associated with sorafenib resistance in HCC. The combination of TRIB3 or STC2 inhibition and sorafenib may be a promising therapeutic strategy for HCC.
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Affiliation(s)
- Sheng Zhou
- Department of Ultrasound, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410000, China
| | - Huanji Xu
- Department of Abdominal Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China
| | - Tianhong Wei
- Department of Ultrasound, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410000, China
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Sarıyar E, Karpat O, Sezan S, Baylan SM, Kıpçak A, Guven K, Erdal E, Fırtına Karagonlar Z. EGFR and Lyn inhibition augments regorafenib induced cell death in sorafenib resistant 3D tumor spheroid model. Cell Signal 2023; 105:110608. [PMID: 36693455 DOI: 10.1016/j.cellsig.2023.110608] [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: 10/11/2022] [Revised: 01/18/2023] [Accepted: 01/19/2023] [Indexed: 01/22/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver and the third most lethal malignancy worldwide. Patients with unresectable HCC receive systemic therapies, traditionally sorafenib or lenvatinib as first line therapy. Despite its poor therapeutic response and high rates of resistance, in most countries, sorafenib still remains the globally used first-line treatment for advanced HCC. Thus, preclinical models demonstrating sorafenib resistance are crucial. 3D tumor spheroid models are becoming extremely important as screening platforms for drug therapies. In this paper, we utilized sorafenib resistant Huh7 cell line and LX2 hepatic stellate cell line to establish a sorafenib resistant 3D tumor spheroid model which can be used to test second-line treatment options. Our analysis demonstrated that sorafenib resistant 3D tumor spheroids are also more resistant to regorafenib and exhibit diverse features compared to parental tumor spheroids. Sorafenib resistant spheroids had higher CD24 and EpCAM positive cancer stem cell populations. In addition, several oncogenic kinases are upregulated in the sorafenib resistant spheroids. Importantly, combined inhibition of EGFR and Lyn kinase in sorafenib resistant tumor spheroids are effective in inducing cell death. Our model proved to be an affordable and useful model to mimic drug resistant tumor microenvironment in HCC and provided novel insights into candidates for new combinational therapies.
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Affiliation(s)
- Ece Sarıyar
- Division of Bioengineering, Graduate School, İzmir University of Economics, Sakarya Cad., İzmir 35330, Turkey; Izmir International Biomedicine and Genome Institute (IBG-Izmir), Dokuz Eylul University, Izmir, Turkey
| | - Ozum Karpat
- Department of Genetics and Bioengineering, İzmir University of Economics, Sakarya Cad., İzmir 35330, Turkey
| | - Sıla Sezan
- Department of Genetics and Bioengineering, İzmir University of Economics, Sakarya Cad., İzmir 35330, Turkey
| | - Sude Mısra Baylan
- Department of Genetics and Bioengineering, İzmir University of Economics, Sakarya Cad., İzmir 35330, Turkey
| | - Arda Kıpçak
- Department of Genetics and Bioengineering, İzmir University of Economics, Sakarya Cad., İzmir 35330, Turkey; Department of Psychology, University of Virginia, Charlottesville, VA 22903, USA
| | - Kadriye Guven
- Department of Medical Biology and Genetics, Faculty of Medicine, Dokuz Eylul University, Izmir 35340, Turkey
| | - Esra Erdal
- Izmir International Biomedicine and Genome Institute (IBG-Izmir), Dokuz Eylul University, Izmir, Turkey; Department of Medical Biology and Genetics, Faculty of Medicine, Dokuz Eylul University, Izmir 35340, Turkey; Izmir Biomedicine and Genome Center, Izmir 35340, Turkey
| | - Zeynep Fırtına Karagonlar
- Department of Genetics and Bioengineering, İzmir University of Economics, Sakarya Cad., İzmir 35330, Turkey.
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10
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Tsumura S, Shimose S, Niizeki T, Kuboyama E, Iwamoto H, Tanaka M, Moriyama E, Shirono T, Takaki K, Noda Y, Nakano M, Inoue M, Tsustumi K, Kuromatsu R, Koga H, Higuchi K, Kawaguchi T. Telephone follow-up contributes to improving adherence and treatment duration in patients with hepatocellular carcinoma treated with lenvatinib. J Gastroenterol Hepatol 2023. [PMID: 36880677 DOI: 10.1111/jgh.16168] [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: 12/30/2022] [Revised: 02/09/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023]
Abstract
BACKGROUND AND AIM This study aimed to investigate whether telephone follow-up by clinical pharmacists for unresectable hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN) contributes to improved adherence and treatment duration for LEN. METHODS This retrospective study enrolled 132 patients with HCC who were treated with LEN. The patients were classified into non-telephone follow-up (n = 32) or telephone follow-up groups (n = 100) [the latter group was further classified into family-pharmacist (FP) telephone follow-up (n = 18), or hospital family-pharmacist (HFP) telephone follow-up (n = 82) groups]. RESULTS The progression-free survival (PFS) in the telephone follow-up group was significantly higher than that in the non-telephone follow-up group (PFS 6.1 months vs 3.7 months, P = 0.001, respectively). Although treatment duration was significantly longer in the telephone follow-up group than in the non-telephone follow-up group [median treatment duration: 10.4 months vs 4.1 months, P = 0.001, respectively.], no significant differences were noted between the HFP telephone follow-up group and FP telephone follow-up groups (10.3 months vs 13.3 months, P = 0.543). Self-interruption and adverse-event discontinuation in the HFP-telephone follow-up group were significantly lower than those in the FP-telephone and non-telephone groups (0% vs 11.1% vs 18.8%; P < 0.001, 25.6% vs 33.3% vs 53.1%; P = 0.022, respectively). CONCLUSIONS Telephone follow-up contributes to prolonged treatment duration for LEN in patients with HCC treated. Moreover, telephone follow-up with an HFP may further improve treatment adherence.
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Affiliation(s)
- Sayo Tsumura
- Department of Pharmacy, Kurume University Hospital, Fukuoka, Japan
| | - Shigeo Shimose
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Fukuoka, Japan
| | - Takashi Niizeki
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Fukuoka, Japan
| | - Eri Kuboyama
- Department of Pharmacy, Kurume University Hospital, Fukuoka, Japan
| | - Hideki Iwamoto
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Fukuoka, Japan
| | | | - Etusko Moriyama
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Fukuoka, Japan
| | - Tomotake Shirono
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Fukuoka, Japan
| | - Kota Takaki
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Fukuoka, Japan
| | - Yu Noda
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Fukuoka, Japan
| | - Masahito Nakano
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Fukuoka, Japan
| | - Mitsutoshi Inoue
- Department of Pharmacy, Kurume University Hospital, Fukuoka, Japan
| | - Kazuki Tsustumi
- Department of Pharmacy, Kurume University Hospital, Fukuoka, Japan
| | - Ryoko Kuromatsu
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Fukuoka, Japan
| | - Hironori Koga
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Fukuoka, Japan
| | - Kyoko Higuchi
- Department of Pharmacy, Kurume University Hospital, Fukuoka, Japan
| | - Takumi Kawaguchi
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Fukuoka, Japan
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Metabolism as a New Avenue for Hepatocellular Carcinoma Therapy. Int J Mol Sci 2023; 24:ijms24043710. [PMID: 36835122 PMCID: PMC9964410 DOI: 10.3390/ijms24043710] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/08/2023] [Accepted: 02/10/2023] [Indexed: 02/16/2023] Open
Abstract
Hepatocellular carcinoma is today the sixth leading cause of cancer-related death worldwide, despite the decreased incidence of chronic hepatitis infections. This is due to the increased diffusion of metabolic diseases such as the metabolic syndrome, diabetes, obesity, and nonalcoholic steatohepatitis (NASH). The current protein kinase inhibitor therapies in HCC are very aggressive and not curative. From this perspective, a shift in strategy toward metabolic therapies may represent a promising option. Here, we review current knowledge on metabolic dysregulation in HCC and therapeutic approaches targeting metabolic pathways. We also propose a multi-target metabolic approach as a possible new option in HCC pharmacology.
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12
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Qi Y, Song Y, Cai M, Li J, Yu Z, Li Y, Huang J, Jiang Y, Peng C, Jiang B, Liu S. Vascular endothelial growth factor A is a potential prognostic biomarker and correlates with immune cell infiltration in hepatocellular carcinoma. J Cell Mol Med 2023; 27:538-552. [PMID: 36729917 PMCID: PMC9930434 DOI: 10.1111/jcmm.17678] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 09/30/2022] [Accepted: 01/06/2023] [Indexed: 02/03/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths among cancer patients. Vascular endothelial growth factor A (VEGFA) is involved in regulating biological processes, such as angiogenesis and vascular permeability, and is very closely related to the pathogenesis of various tumours, especially vascular-rich, solid tumours. Clinical data of patients with HCC and other tumours were analysed through public databases, such as the TCGA database, Gene Expression Omnibus database, Human Protein Atlas database, STRING, Tumour Immune Estimation Resource and Kaplan-Meier Plotter. The tumour tissues and adjacent normal tissues of patients with HCC from Hunan Provincial People's Hospital were collected to verify the expression of VEGFA by immunohistochemistry, immunofluorescence, Western blotting and qPCR. VEGFA expression is elevated in multiple tumour types and correlates with the prognosis of tumour patients. VEGFA is involved in regulating the tumour microenvironment and immune cell function in tumour development. Inhibition of VEGFA reduces proliferation, invasion, and migration and promotes apoptosis in HCC cells. VEGFA is a potential predictive biomarker for the diagnosis and prognosis of HCC.
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Affiliation(s)
- Yuchen Qi
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
- Department of CardiologyXiangdong Hospital Affiliated to Hunan Normal UniversityLilingChina
- Central Laboratory of Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
| | - Yinghui Song
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
- Central Laboratory of Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
| | - Mengting Cai
- Department of Nuclear MedicineHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
| | - Jianwen Li
- Department of CardiologyXiangdong Hospital Affiliated to Hunan Normal UniversityLilingChina
| | - Zhangtao Yu
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
| | - Yuhang Li
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
| | - Junkai Huang
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
| | - Yu Jiang
- Institute of Emergency Medicine/Hunan Provincial Key Laboratory of Emergency and Critical Care MetabonomicsHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
| | - Chuang Peng
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
| | - Bo Jiang
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
| | - Sulai Liu
- Department of Hepatobiliary SurgeryHunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
- Central Laboratory of Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangshaChina
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13
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Li S, Wu J, Wu J, Fu Y, Zeng Z, Li Y, Li H, Liao W, Yan M. Prediction of early treatment response to the combination therapy of TACE plus lenvatinib and anti-PD-1 antibody immunotherapy for unresectable hepatocellular carcinoma: Multicenter retrospective study. Front Immunol 2023; 14:1109771. [PMID: 36875116 PMCID: PMC9981935 DOI: 10.3389/fimmu.2023.1109771] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 02/01/2023] [Indexed: 02/19/2023] Open
Abstract
Background and aim The purpose of this study was to investigate and validate the efficacy of a nomogram model in predicting early objective response rate (ORR) in u-HCC patients receiving a combination of TACE, Lenvatinib, and anti-PD-1 antibody treatment after 3 months (triple therapy). Method This study included 169 u-HCC cases from five different hospitals. As training cohorts (n = 102), cases from two major centers were used, and external validation cohorts (n = 67) were drawn from the other three centers. The clinical data and contrast-enhanced MRI characteristics of patients were included in this retrospective study. For evaluating MRI treatment responses, the modified revaluation criteria in solid tumors (mRECIST) were used. Univariate and multivariate logistic regression analyses were used to select relevant variables and develop a nomogram model. Our as-constructed nomogram was highly consistent and clinically useful, as confirmed by the calibration curve and decision curve analysis (DCA); an independent external cohort also calibrated the nomogram. Results The ORR was 60.7% and the risk of early ORR was independently predicted by AFP, portal vein tumor thrombus (PVTT), tumor number, and size in both the training (C-index = 0.853) and test (C-index = 0.731) cohorts. The calibration curve revealed that the nomogram-predicted values were consistent with the actual response rates in both cohorts. Furthermore, DCA indicated that our developed nomogram performed well in clinical settings. Conclusion The nomogram model accurately predicts early ORR achieved by triple therapy in u-HCC patients, which aids in individual decision-making and modifying additional therapies for u-HCC cases.
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Affiliation(s)
- Shuqun Li
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China.,Department of Hepatobiliary Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Junyi Wu
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Jiayi Wu
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Yangkai Fu
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
| | - Zhenxin Zeng
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
| | - Yinan Li
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
| | - Han Li
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
| | - Weijia Liao
- Department of Hepatobiliary Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Maolin Yan
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian, China
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Jiang M, Liu M, Liu G, Ma J, Zhang L, Wang S. Advances in the structural characterization of complexes of therapeutic antibodies with PD-1 or PD-L1. MAbs 2023; 15:2236740. [PMID: 37530414 PMCID: PMC10399482 DOI: 10.1080/19420862.2023.2236740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 07/10/2023] [Accepted: 07/11/2023] [Indexed: 08/03/2023] Open
Abstract
Antibody-based immune checkpoint blockade (ICB)-based therapeutics have become effective clinical applications for cancers. Applications of monoclonal antibodies (mAbs) to de-activate the PD-1-PD-L1 pathway could effectively reverse the phenotype of depleted activated thymocytes (T cells) to recover their anti-tumoral activities. High-resolution structures of the complexes of the therapeutic monoclonal antibodies with PD-1 or PD-L1 have revealed the key inter-molecular interactions and provided valuable insights into the fundamental mechanisms by which these antibodies inhibit PD-L1-PD-1 binding. Each anti-PD-1 mAb exhibits a unique blockade mechanism, such as interference with large PD-1-PD-L1 contacting interfaces, steric hindrance by overlapping a small area of this site, or binding to an N-glycosylated site. In contrast, all therapeutic anti-PD-L1 mAbs bind to a similar area of PD-L1. Here, we summarized advances in the structural characterization of the complexes of commercial mAbs that target PD-1 or PD-L1. In particular, we focus on the unique characteristics of those mAb structures, epitopes, and blockade mechanisms. It is well known that the use of antibodies as anti-tumor drugs has increased recently and both PD-1 and PD-L1 have attracted substantial attention as target for antibodies derived from new technologies. By focusing on structural characterization, this review aims to aid the development of novel antibodies targeting PD-1 or PD-L1 in the future.
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Affiliation(s)
- Mengzhen Jiang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Man Liu
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Guodi Liu
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Jiawen Ma
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Lixin Zhang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Shenlin Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
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15
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Wei Q, Zhou H, Hou X, Liu X, Chen S, Huang X, Chen Y, Liu M, Duan Z. Current status of and barriers to the treatment of advanced-stage liver cancer in China: a questionnaire-based study from the perspective of doctors. BMC Gastroenterol 2022; 22:351. [PMID: 35871649 PMCID: PMC9310466 DOI: 10.1186/s12876-022-02425-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 07/13/2022] [Indexed: 12/05/2022] Open
Abstract
Background Liver cancer is a severe public health problem worldwide, and it creates a relatively higher disease burden in China than in the Western world. Despite achieving notable progress in China, potential differences in some aspects of medical services for liver cancer may persist across different regions and hospitals. This warrants serious consideration of the actual status of and barriers to liver cancer treatment. We intended to explore the present status of and obstacles in liver cancer treatment especially for advanced-stage liver cancer. Methods In February 2021, a national multicenter cross-sectional study was conducted among 1500 doctors from 31 provinces of mainland China using a self-administered online questionnaire. Participants completed the questionnaire about their general information, perspectives on the current status of liver cancer treatment, and expectations for future treatment. Chi-square and logistic regression analyses were performed to explore the differences associated with the regions, doctors’ professional ranks, and hospital levels. Results Treatment conditions, medications, and treatment strategies were inconsistent across different economic regions and hospital of different levels. With respect to obstacles in treatment, 76.6% of the doctors were unsatisfied with the current treatment for liver cancer. Important factors that influenced their satisfaction with the treatment for liver cancer included early diagnosis and the disclosure of true conditions to patients. Conclusions There persists differences in the treatment of liver cancer in China, besides barriers to treatment. More attention should be paid to the detection and treatment of liver cancer and the propagation of novel progress among doctors in underdeveloped areas. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-022-02425-4.
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Feng JK, Liu ZH, Fu ZG, Chai ZT, Sun JX, Wang K, Cheng YQ, Zhu HF, Xiang YJ, Zhou LP, Shi J, Guo WX, Zhai J, Cheng SQ. Efficacy and safety of transarterial chemoembolization plus antiangiogenic- targeted therapy and immune checkpoint inhibitors for unresectable hepatocellular carcinoma with portal vein tumor thrombus in the real world. Front Oncol 2022; 12:954203. [PMID: 36505818 PMCID: PMC9732723 DOI: 10.3389/fonc.2022.954203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 11/04/2022] [Indexed: 11/27/2022] Open
Abstract
Purpose This study aimed to assess the efficacy and safety of a triple therapy that comprises transarterial chemoembolization (TACE), antiangiogenic-targeted therapy, and programmed death-1 (PD-1) inhibitors in a real-world cohort of patients with unresectable hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Methods Consecutive patients treated with TACE combined with antiangiogenic therapy and PD-1 inhibitors at the Eastern Hepatobiliary Surgery Hospital between June 2019 and May 2021 were enrolled. The baseline characteristics and treatment course of the patients were recorded. The tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and HCC-specific modified RECIST (mRECIST). The overall survival (OS) and progression-free survival (PFS) of the patients were analyzed using the Kaplan-Meier method. Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Results As of the data cutoff on 30 August 2021, the median follow-up time was 10.0 (3.9-28.4) months. A total of 39 eligible patients were included. The objective response rate (ORR) and the disease control rate (DCR) were 35.9% and 74.4% according to the RECIST 1.1, and 48.7% and 84.6% according to mRECIST criteria, respectively. The median OS and PFS were 14.0 and 9.2 months, respectively. Moreover, 34 (87.2%) patients experienced at least one treatment-related AE and 8 (20.5%) patients experienced grade 3/4 treatment-related AEs. The most common treatment- and laboratory-related AEs were hypertension (46.2%) and decreased albumin (53.8%), respectively. No treatment-related mortality occurred during the study period. Conclusions TACE combined with antiangiogenic-targeted therapy and immune checkpoint inhibitors may have promising anticancer activity in unresectable HCC patients with PVTT. AEs were manageable, with no unexpected overlapping toxicities.
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Affiliation(s)
- Jin-Kai Feng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zong-Han Liu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zhi-Gang Fu
- Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zong-Tao Chai
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Ju-Xian Sun
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Kang Wang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yu-Qiang Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Hong-Fei Zhu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yan-Jun Xiang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China,Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Zhejiang, China
| | - Li-Ping Zhou
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jie Shi
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wei-Xing Guo
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jian Zhai
- Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China,*Correspondence: Shu-Qun Cheng, ; Jian Zhai,
| | - Shu-Qun Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China,*Correspondence: Shu-Qun Cheng, ; Jian Zhai,
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Peng W, Jiang X, Zhang W, Hu J, Zhang Y, Zhang L. A radiomics-based model can predict recurrence-free survival of hepatocellular carcinoma after curative ablation. Asian J Surg 2022:S1015-9584(22)01409-9. [DOI: 10.1016/j.asjsur.2022.09.130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 06/16/2022] [Accepted: 09/28/2022] [Indexed: 11/09/2022] Open
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Charonpongsuntorn C, Tanasanvimon S, Korphaisarn K, Payapwattanawong S, Siripoon T, Pakvisal N, Juengsamarn J, Phaibulvatanapong E, Chindaprasirt J, Prasongsook N, Udomdamrongkul K, Ngamphaiboon N, Sirachainan E. Efficacy, Safety, and Patient-Reported Outcomes of Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma in Thailand: A Multicenter Prospective Study. JCO Glob Oncol 2022; 8:e2200205. [PMID: 36455172 PMCID: PMC10166432 DOI: 10.1200/go.22.00205] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
PURPOSE Atezolizumab plus bevacizumab treatment is a first-line therapy for unresectable hepatocellular carcinoma (HCC) worldwide. The efficacy, safety, and patient-reported outcomes (PROs) of HCC in Thailand have not yet been reported. This study aimed to evaluate the efficacy, safety, and PROs of atezolizumab plus bevacizumab. MATERIALS AND METHODS From September 2020 to August 2021, 30 patients with unresectable HCC who met the inclusion criteria of atezolizumab plus bevacizumab as first-line treatment were enrolled. Analysis was assessed for progression-free survival, overall survival, adverse events (AEs), and quality of life (QoL). RESULTS The median progression-free survival and overall survival periods were 6.7 and 10.2 months, respectively. The disease control rate was 63.3%. The frequent AEs were proteinuria, hypertension, and hepatitis. Serious AEs included gastrointestinal bleeding, but none of the patients died from serious AEs. The discontinuation rate was 23.3%, and the median number of treatment cycles was 10.5 cycles. In total, 23.3% of the patients continued treatment after 1 year of therapy. The global health status/QoL and physical function scores showed less deterioration at baseline than at 3 and 6 months (median scores = 76.7, 71.6, and 64.1 in QoL and 84.7, 79.6, and 79.0 in physical function, respectively). The HCC18 symptom score index data showed a slow progression of symptom scores from baseline to 3 and 6 months (12.7, 19.6, and 22.3, respectively). CONCLUSION This study demonstrates that atezolizumab plus bevacizumab is effective and has a safety profile comparable with that of previous studies as first-line therapy for unresectable HCC in a real-world setting and in Thai populations. Data on PROs also demonstrate benefits in terms of patients' QoL and symptoms.
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Affiliation(s)
- Chanchai Charonpongsuntorn
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Srinakharinwirot University, Nakhon Nayok, Thailand
| | - Suebpong Tanasanvimon
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Krittiya Korphaisarn
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital Mahidol University, Bangkok, Thailand
| | - Songwit Payapwattanawong
- Oncology Unit, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Lak Hok, Thailand
| | - Teerada Siripoon
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Ramathibodi Hospital Mahidol University, Bangkok, Thailand
| | - Nussara Pakvisal
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Jitlada Juengsamarn
- Oncology Unit, Department of Medicine, Sunpasitthiprasong Hospital, Ubon Ratchathani, Thailand
| | | | - Jarin Chindaprasirt
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Naiyarat Prasongsook
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Phramongkutklao University, Bangkok, Thailand
| | | | - Nuttapong Ngamphaiboon
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Ramathibodi Hospital Mahidol University, Bangkok, Thailand
| | - Ekaphop Sirachainan
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Ramathibodi Hospital Mahidol University, Bangkok, Thailand
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Comparison of Efficacy and Safety of Atezolizumab Plus Bevacizumab and Lenvatinib as First-Line Therapy for Unresectable Hepatocellular Carcinoma: A Propensity Score Matching Analysis. Target Oncol 2022; 17:643-653. [PMID: 36272060 DOI: 10.1007/s11523-022-00921-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/19/2022] [Indexed: 11/26/2022]
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20
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Amioka K, Kawaoka T, Kinami T, Yamasaki S, Kosaka M, Johira Y, Yano S, Naruto K, Ando Y, Fujii Y, Uchikawa S, Ono A, Yamauchi M, Imamura M, Kosaka Y, Ohya K, Mori N, Takaki S, Tsuji K, Masaki K, Honda Y, Kouno H, Kohno H, Morio K, Moriya T, Naeshiro N, Nonaka M, Aisaka Y, Azakami T, Hiramatsu A, Aikata H, Oka S. Analysis of Lenvatinib's Efficacy against Intermediate-Stage Unresectable Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14205066. [PMID: 36291850 PMCID: PMC9600304 DOI: 10.3390/cancers14205066] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/12/2022] [Accepted: 10/14/2022] [Indexed: 11/16/2022] Open
Abstract
Transarterial chemoembolization (TACE) has been the standard treatment for intermediate-stage, unresectable hepatocellular carcinoma (u-HCC). However, with recent advances in systemic therapy and the emergence of the concept of TACE-refractory or -unsuitable, the effectiveness of systemic therapy, as well as TACE, has been demonstrated for patients judged to be TACE-refractory or -unsuitable. In this study, the efficacy of lenvatinib and its combination with TACE after lenvatinib was investigated in 140 patients with intermediate-stage u-HCC treated with lenvatinib mainly because of being judged to be TACE-refractory or -unsuitable. Median overall survival (OS) and progression-free survival (PFS) were 24.4 and 9.0 months, respectively, indicating a good response rate. In multivariate analysis, modified albumin-bilirubin (mALBI) grade and up to seven criteria were identified as independent factors for OS, and mALBI grade and tumor morphology were identified as independent factors for PFS. While 95% of all patients were TACE-refractory or -unsuitable, the further prognosis was prolonged by the combination with TACE after lenvatinib initiation. These findings suggest that systemic therapy should be considered for intermediate-stage u-HCC, even in patients judged to be TACE-refractory or -unsuitable. The use of TACE after the start of systemic therapy may further improve prognosis.
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Affiliation(s)
- Kei Amioka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Takahiro Kinami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Shintaro Yamasaki
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Masanari Kosaka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Yusuke Johira
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Shigeki Yano
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Kensuke Naruto
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Yuwa Ando
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Yasutoshi Fujii
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Yumi Kosaka
- Department of Gastroenterology, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima 730-8619, Japan
| | - Kazuki Ohya
- Department of Gastroenterology, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima 730-8619, Japan
| | - Nami Mori
- Department of Gastroenterology, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima 730-8619, Japan
| | - Shintaro Takaki
- Department of Gastroenterology, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima 730-8619, Japan
| | - Keiji Tsuji
- Department of Gastroenterology, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima 730-8619, Japan
| | - Keiichi Masaki
- Department of Gastroenterology, Hiroshima City Asa Citizens Hospital, Hiroshima 731-0293, Japan
| | - Yoji Honda
- Department of Gastroenterology, Hiroshima City Asa Citizens Hospital, Hiroshima 731-0293, Japan
| | - Hirotaka Kouno
- Department of Gastroenterology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Hiroshima 737-0023, Japan
| | - Hioshi Kohno
- Department of Gastroenterology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Hiroshima 737-0023, Japan
| | - Kei Morio
- Department of Gastroenterology, Chugoku Rosai Hospital, Hiroshima 737-0193, Japan
| | - Takashi Moriya
- Department of Gastroenterology, Chugoku Rosai Hospital, Hiroshima 737-0193, Japan
| | - Noriaki Naeshiro
- Department of Gastroenterology, National Hospital Organization Higashihiroshima Medical Center, Hiroshima 739-0041, Japan
| | - Michihiro Nonaka
- Department of Gastroenterology, JA Hiroshima General Hospital, Hiroshima 738-8503, Japan
| | - Yasuyuki Aisaka
- Department of Gastroenterology, JA Hiroshima General Hospital, Hiroshima 738-8503, Japan
| | - Takahiro Azakami
- Department of Gastroenterology, Hiroshima Memorial Hospital, Hiroshima 730-0802, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology, Hiroshima Memorial Hospital, Hiroshima 730-0802, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
- Correspondence: ; Tel.: +81-82-257-5192; Fax: +81-82-257-5194
| | - Shiro Oka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
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Iwamoto H, Niizeki T, Nagamatsu H, Ueshima K, Tani J, Kuzuya T, Kasai K, Kooka Y, Hiraoka A, Sugimoto R, Yonezawa T, Tanaka S, Deguchi A, Shimose S, Shirono T, Sakai M, Suzuki H, Moriyama E, Koga H, Torimura T, Kawaguchi T. The Clinical Impact of Hepatic Arterial Infusion Chemotherapy New-FP for Hepatocellular Carcinoma with Preserved Liver Function. Cancers (Basel) 2022; 14:cancers14194873. [PMID: 36230795 PMCID: PMC9562659 DOI: 10.3390/cancers14194873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/01/2022] [Accepted: 10/03/2022] [Indexed: 11/18/2022] Open
Abstract
Background: Systemic treatments are recommended for advanced hepatocellular carcinoma (HCC) in preserved liver function. However, their effects are unsatisfactory in some tumor conditions, particularly macrovascular invasion (MVI) including major portal vein tumor thrombus (PVTT). We compared the efficacy of hepatic arterial infusion chemotherapy (HAIC) regimens New-FP and sorafenib for various tumor conditions in preserved liver function. Methods: We retrospectively collected the data of 1709 patients with HCC who were treated with New-FP or sorafenib. Survival was assessed after propensity score matching. Subgroup analyses were conducted: cohort 1 (no MVI or extrahepatic spread (EHS)), cohort 2 (MVI only), cohort 3 (EHS only), cohort 4 (MVI and EHS), and cohort 5 (major PVTT). Results: The New-FP group had a longer median survival time (MST) than the sorafenib in the whole analysis (18 vs. 9 months; p < 0.0001). New-FP demonstrated a longer MST compared with sorafenib in cohort 2 and cohort 4. In cohort 5, the MST of the New-FP group was 16 months, while that of sorafenib was 6 months (p < 0.0001). For major PVTT-HCC, the response rate of New-FP was 73.0%. The MST of patients who achieved complete response with New-FP was 59 months. Conclusions: HAIC using New-FP is promising for patients with MVI- and major PVTT-HCC in preserved liver function.
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Affiliation(s)
- Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
- Iwamoto Internal Medicine Clinic, Kitakyusyu 802-0832, Japan
- Correspondence: ; Tel.: +81-942-35-3311; Fax: 81-942-31-7747
| | - Takashi Niizeki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Hiroaki Nagamatsu
- Department of Gastroenterology, Juntendo University, Bunkyo-ku 113-8421, Japan
| | - Kazuomi Ueshima
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka 589-8511, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki 761-0793, Japan
| | - Teiji Kuzuya
- Department of Gastroenterology and Hepatology, Fujita Healthy University, Toyoake 470-1101, Japan
| | - Kazuhiro Kasai
- Division of Gastroenterology, IMS Sapporo Digestive Disease Center General Hospital, Sapporo 063-0842, Japan
| | - Youhei Kooka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Iwate 028-3695, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama 790-0024, Japan
| | - Rie Sugimoto
- Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, Fukuoka 811-1395, Japan
| | - Takehiro Yonezawa
- Department of Gastroenterology, Hachinohe Red Cross Hospital, Aomori 039-1104, Japan
| | - Satoshi Tanaka
- Department of Gastroenterology and Hepatology, National Hospital Organization Osaka National Hospital, Osaka 540-0006, Japan
| | - Akihiro Deguchi
- Department of Gastroenterology, Kagawa Rosai Hospital, Marugame 763-8502, Japan
| | - Shigeo Shimose
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Tomotake Shirono
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Miwa Sakai
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Hiroyuki Suzuki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Etsuko Moriyama
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Takuji Torimura
- Department of Gastroenterology, Omuta City Hospital, Omuta 836-0861, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
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Wu JY, Wu JY, Li YN, Qiu FN, Zhou SQ, Yin ZY, Chen YF, Li B, Zhou JY, Yan ML. Lenvatinib combined with anti-PD-1 antibodies plus transcatheter arterial chemoembolization for neoadjuvant treatment of resectable hepatocellular carcinoma with high risk of recurrence: A multicenter retrospective study. Front Oncol 2022; 12:985380. [PMID: 36212494 PMCID: PMC9534527 DOI: 10.3389/fonc.2022.985380] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 09/06/2022] [Indexed: 01/27/2023] Open
Abstract
Background Early recurrence is common after surgical resection (SR) for hepatocellular carcinoma (HCC) with high risk of recurrence and is associated with poor prognosis. The combinations of lenvatinib (LEN), anti-PD-1 antibodies (PD-1) and transcatheter arterial chemoembolization (TACE) (triple therapy) has shown better trend in tumor response and survival outcomes on unresectable HCC. It is unknown whether triple therapy for neoadjuvant treatment of resectable HCC with high risk of recurrence is effective. This article aimed to compare the outcomes of surgery alone and neoadjuvant combination treatment with triple therapy before SR in patients with HCC with high risk of recurrence. Methods A retrospective study was conducted on patients diagnosed with HCC with high risk of recurrence who received treatment with or without triple therapy. The records of 24 patients in the triple therapy group and 76 patients in the surgery-alone group were analyzed. Propensity score matching (PSM) was performed to minimize the influence of potential confounders. Results One hundred patients were enrolled. In the triple therapy group, 8 (33.3%) and 12 (50.0%) patients had complete and partial responses, respectively, as assessed by an investigator. Before PSM, the overall survival (OS) rates for the triple therapy group at 6, 12, 18, and 24 months were 100.0%, 100.0%, 100.0%, and 85.7%, respectively, compared with corresponding 92.1%, 73.7%, 53.9%, and 48.7% for the surgery-alone group (P<0.001). The disease-free survival (DFS) rates were 82.2%, 66.95%, 48.8%, and 48.8% for the triple therapy and 41.92%, 28.34%, 27.05%, and 22.99% for the surgery-alone group (P=0.003). After PSM, DFS and OS were significantly longer in the triple therapy group than in the surgery-alone group (DFS, p=0.019; OS, p=0.003). Conclusions Neoadjuvant combination treatment before SR had a high rate of tumor response and provided significantly better postoperative survival outcomes than surgery alone in patients with HCC with high risk of recurrence.
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Affiliation(s)
- Jun-Yi Wu
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Jia-Yi Wu
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Yi-Nan Li
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Fu-Nan Qiu
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Song-Qiang Zhou
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Zhen-Yu Yin
- Department of Hepatobiliary Surgery, Xiamen Traditional Chinese Medical Hospital, Xiamen, China
| | - Yu-Feng Chen
- Department of Hepatobiliary Surgery, The Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China
| | - Bin Li
- Department of Hepato-Biliary-Pancreatic and Vascular Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Jian-Yin Zhou
- Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China
| | - Mao-Lin Yan
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
- *Correspondence: Mao-Lin Yan,
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23
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Gnocchi D, Kurzyk A, Mintrone A, Lentini G, Sabbà C, Mazzocca A. Inhibition of LPAR6 overcomes sorafenib resistance by switching glycolysis into oxidative phosphorylation in hepatocellular carcinoma. Biochimie 2022; 202:180-189. [PMID: 35952946 DOI: 10.1016/j.biochi.2022.07.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 07/20/2022] [Accepted: 07/26/2022] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most threatening tumours in the world today. Pharmacological treatments for HCC mainly rely on protein kinase inhibitors, such as sorafenib and regorafenib. Even so, these approaches exhibit side effects and acquired drug resistance, which is an obstacle to HCC treatment. We have previously shown that selective lysophosphatidic acid receptor 6 (LPAR6) chemical antagonists inhibit HCC growth. Here, we investigated whether LPAR6 mediates resistance to sorafenib by affecting energy metabolism in HCC. To uncover the role of LPAR6 in drug resistance and cancer energy metabolism, we used a gain-of-function and loss-of-function approach in 2D tissue and 3D spheroids. LPAR6 was ectopically expressed in HLE cells (HLE-LPAR6) and knocked down in HepG2 (HepG2 LPAR6-shRNA). Measurements of oxygen consumption and lactate and pyruvate production were performed to assess the energy metabolism response of HCC cells to sorafenib treatment. We found that LPAR6 mediates the resistance of HCC cells to sorafenib by promoting lactic acid fermentation at the expense of oxidative phosphorylation (OXPHOS) and that the selective LPAR6 antagonist 9-xanthenyl acetate (XAA) can effectively overcome this resistance. Our study shows for the first time that an LPAR6-mediated metabolic mechanism supports sorafenib resistance in HCC and proposes a pharmacological approach to overcome it.
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Affiliation(s)
- Davide Gnocchi
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11 - 70124, Bari, Italy
| | - Agata Kurzyk
- Department of Cancer Biology, Maria Sklodowska-Curie National Research Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland
| | - Antonella Mintrone
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11 - 70124, Bari, Italy
| | - Giovanni Lentini
- Department of Pharmacy - Drug Sciences, University of Bari Aldo Moro, via Orabona, 4 - 70125, Bari, Italy
| | - Carlo Sabbà
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11 - 70124, Bari, Italy
| | - Antonio Mazzocca
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11 - 70124, Bari, Italy.
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Zheng Y, Ji S, Li X, Feng Q. Active ingredients and molecular targets of Taraxacum mongolicum against hepatocellular carcinoma: network pharmacology, molecular docking, and molecular dynamics simulation analysis. PeerJ 2022; 10:e13737. [PMID: 35873910 PMCID: PMC9302432 DOI: 10.7717/peerj.13737] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 06/25/2022] [Indexed: 01/17/2023] Open
Abstract
Background Taraxacum mongolicum (TM) is a widely used herb. Studies have reported that TM exhibits growth-inhibitory and apoptosis-inducing on multiple tumors, including hepatocellular carcinoma (HCC). The active ingredients, targets, and molecular mechanisms of TM against HCC need to be further elucidated. Methods We identified the active ingredients and targets of TM via HERB, PubChem, SwissADME, SwissTargetPrediction, and PharmMapper. We searched HCC targets from GeneCards, Comparative Toxicogenomics Database (CTD), and DisGeNET. Then, the intersection of drug targets and disease targets was uploaded to the STRING database to construct protein-protein interactions (PPI) networking whose topology parameters were analyzed in Cytoscape software to screen hub targets. Next, we used Metascape for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and we employed AutoDock vina, AMBER18 and PyMOL software along with several auxiliary tools for molecular docking and molecular dynamics (MD) simulation. Finally, based on the in silico findings, cellular experiments were conducted to investigate the effect of TM on HSP90AA1 gene expression. Results A total of 228 targets and 35 active ingredients were identified. Twenty two hub targets were selected through PPI networking construction for further investigation. The enrichment analysis showed that protein kinase binding, mitogenactivated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways were mainly involved. Molecular docking and MD simulation results supported good interaction between HSP90 protein and Austricin/Quercetin. The in vitro assay showed that TM inhibited the proliferation of HepG2 cells and the expression of HSP90AA1 gene. Conclusions This study is the first to use network pharmacology, molecular docking, MD simulation and cellular experiments to elucidate the active ingredients, molecular targets, and key biological pathways responsible for TM anti-HCC, providing a theoretical basis for further research.
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Affiliation(s)
- Yanfeng Zheng
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Shaoxiu Ji
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xia Li
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Quansheng Feng
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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Wang D, Zhang L, Zhang Y, Zhang Y, Xu S. A ferroptosis-associated lncRNAs signature predicts the prognosis of hepatocellular carcinoma. Medicine (Baltimore) 2022; 101:e29546. [PMID: 35839000 PMCID: PMC11132323 DOI: 10.1097/md.0000000000029546] [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: 09/27/2021] [Accepted: 04/20/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Long noncoding RNAs (lncRNAs) have been implicated in the development of hepatocellular carcinoma (HCC). Mounting evidence shows that lncRNAs can be used as prognostic biomarkers of HCC. Here, we developed a multi-lncRNA prognostic signature comprising ferroptosis-related lncRNAs in HCC. METHODS Gene expression data and clinical information of HCC were obtained from the TCGA dataset. Differentially expressed genes of ferroptosis (DE-Ferrs) were screened. Correlation analysis was carried between lncRNAs and DE-Ferrs to identify ferroptosis-related lncRNAs. lncRNAs associated with prognosis and ferroptosis were identified using Univariate Cox analysis. Data from a TCGA dataset were randomly grouped into training and verification sets. The least absolute shrinkage and selection operator method analysis was carried out to identify lncRNAs with prognostic value. These lncRNAs were used to construct a prognostic signature using the training set. The signature was validated in the verification set. RESULTS A total of 90 DE-Ferrs-related lncRNAs were identified which were significantly correlated with HCC prognosis. Seven lncRNAs were used to construct a 7-lncRNA signature. The area under the curves for 1-, 3-, and 5-year overall survival (OS) were 0.748, 0.681, and 0.659 in the training set, and 0.791, 0.731, and 0.815 in the validation set, respectively. The results demonstrated that a high-risk score was significantly associated with a high tumor grade, high infiltration of macrophages and fibroblasts in the tumor, and high expression of m6A methylation regulatory factors. A nomogram was constructed using the risk score and clinical features for predicting the prognosis of HCC. The nomogram showed high prediction accuracy. CONCLUSION In conclusion, the established 7 ferroptosis-related lncRNAs signature can accurately predict HCC prognosis.
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Affiliation(s)
- Dengchuan Wang
- Office of Medical Ethics, Shenzhen Longhua District Central Hospital, Shenzhen, China
| | - Limei Zhang
- Oncology Department, Shenzhen Longhua District Central Hospital, Shenzhen, China
| | - YingJie Zhang
- Department of Rehabilitation Medicine, Shenzhen Longhua District Central Hospital, Shenzhen, China
| | - Yonggang Zhang
- Department of Clinical Laboratory, Shenzhen Longhua District Central Hospital, Shenzhen, China
| | - Shi Xu
- Department of Burn and Plastic Surgery, Shenzhen Longhua District Central Hospital, Shenzhen, China
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Zhang M, Lai W, Zhang J, Hu B, Huang L, Chu C. Efficacy Investigation of TACE Combined with Lenvatinib and Sintilimab in Intermediate-Stage Hepatocellular Carcinoma. DISEASE MARKERS 2022; 2022:6957580. [PMID: 35845129 PMCID: PMC9279099 DOI: 10.1155/2022/6957580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 06/22/2022] [Indexed: 12/24/2022]
Abstract
Objective To evaluate the effectiveness of transarterial chemoembolization (TACE) combined with lenvatinib and sintilimab in treating patients with midstage hepatocellular carcinoma (HCC). Methods Sixty-two patients with midstage HCC were enrolled in this study. All of them were firstly treated in our hospital between September 1, 2019, and March 1, 2020. According to different treatment regimens, they were divided into the control group (31 cases, TACE group) and the observation group (31 cases, TACE combined with lenvatinib and sintilimab group). Each patient was followed up for at least 30 months to compare the short-term clinical efficacy and survival rate between the two groups. Results The objective response rate (ORR) and disease control rate (DCR) of the observation group at 3 months were 77.4% and 93.5%, respectively, which were higher than those of the control group (P < 0.05). The 2-year cumulative overall survival rate of the observation group was 64.5%, which was significantly higher than that of the control group (P < 0.05). The survival curve of the disease-free survival rate in the observation group was higher than that in the control group, and the difference was statistically significant (X 2 = 4.313, P < 0.05). Conclusion TACE combined with lenvatinib and sintilimab in the treatment of Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma can effectively control the tumor progression and prolong the survival time of patients. Those preliminary findings need validation in larger studies, with a prospective design and longer follow-up.
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Affiliation(s)
- Menglong Zhang
- Ganzhou People's Hospital, No. 16, MeiGuan Road, Zhanggong District, Ganzhou, 341000 Jiangxi, China
| | - Weiguo Lai
- Ganzhou People's Hospital, No. 16, MeiGuan Road, Zhanggong District, Ganzhou, 341000 Jiangxi, China
| | - Jian Zhang
- Ganzhou People's Hospital, No. 16, MeiGuan Road, Zhanggong District, Ganzhou, 341000 Jiangxi, China
| | - Bijuan Hu
- Ganzhou People's Hospital, No. 16, MeiGuan Road, Zhanggong District, Ganzhou, 341000 Jiangxi, China
| | - Liyin Huang
- Ganzhou People's Hospital, No. 16, MeiGuan Road, Zhanggong District, Ganzhou, 341000 Jiangxi, China
| | - Cunkun Chu
- Library, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, 271000 Shandong Province, China
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27
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Hou JY, Xiao YT, Huang JB, Jiang XH, Jiang K, Li X, Xu L, Chen MS. Real-Life Experience of Regorafenib in Patients With Advanced Hepatocellular Carcinoma. Front Pharmacol 2022; 13:917384. [PMID: 35734398 PMCID: PMC9207200 DOI: 10.3389/fphar.2022.917384] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 05/16/2022] [Indexed: 12/24/2022] Open
Abstract
Background: The RESORCE trial reported that regorafenib was effective as the second-line treatment for patients with hepatocellular carcinoma (HCC) after progression on sorafenib. Real-world data are needed to assess clinical outcomes and adverse events in the setting of daily practice. Objective: We aimed to evaluate the efficacy and safety of regorafenib after disease progression with sorafenib in Chinese patients with advanced HCC. Patients and Methods: A total of 41 patients with advanced HCC who did not respond to sorafenib and followed a regorafenib regimen were enrolled in this retrospective study. Overall survival (OS), progression-free survival (PFS), radiological responses, and adverse events (AEs) were evaluated. Survival curves were compared by using the log-rank test and constructed with the Kaplan–Meier method. Results: The median PFS with regorafenib was 6.6 months (range: 5.0–8.2 months), and the median OS with regorafenib was not reached. The 1-year OS rate of regorafenib was 66.4%. The median OS of sequential sorafenib to regorafenib treatment was 35.3 months [95% confidence interval (CI), 24.3–46.3], and the 2-year OS rate of sequential sorafenib to regorafenib treatment was 74.4%. The most common AEs of regorafenib treatment were elevated aspartate aminotransferase [17/41 patients (41.5%)], elevated alanine aminotransferase [16/41 patients (39%)] and hand-foot syndrome [14/41 patients (34.1%)]. Conclusion: Regorafenib appears to be safe and clinically effective in patients with advanced HCC who progressed on first-line sorafenib.
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Affiliation(s)
- Jing-Yu Hou
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Ya-ting Xiao
- School of Molecular Medicine, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, China
| | - Jing-Bo Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, China
| | - Xin-Hua Jiang
- Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Kai Jiang
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xun Li
- School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Li Xu
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
- *Correspondence: Li Xu, ; Min-Shan Chen,
| | - Min-Shan Chen
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
- *Correspondence: Li Xu, ; Min-Shan Chen,
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Li Z, Bu J, Zhu X, Zhou H, Ren K, Chu PK, Li L, Hu X, Ding X. Anti-tumor immunity and ferroptosis of hepatocellular carcinoma are enhanced by combined therapy of sorafenib and delivering modified GO-based PD-L1 siRNAs. BIOMATERIALS ADVANCES 2022; 136:212761. [PMID: 35929305 DOI: 10.1016/j.bioadv.2022.212761] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 03/08/2022] [Accepted: 03/11/2022] [Indexed: 06/15/2023]
Abstract
Programmed cell death receptor ligand 1 (PD-L1)/PD-1 signaling has been exploited to design inhibitors that deliver promising clinical outcome albeit with limited efficacy. Herein, we prepare graphene oxide (GO)-PEI-PEG with low cytotoxicity and long stability and GO-PEI-PEG delivers PD-L1 siRNAs to hepatocellular carcinoma (HCC) cells by the endocytosis-lysosome pathway. The functional GO-PEI-PEG/PD-L1 siRNAs decrease PD-L1 and PD-1 abundance, increase pro-inflammation cytokine IFN-γ and TNF-α release, and improve the proliferation activity of Jurkat T cells. Since GO-PEI-PEG targets the mouse liver effectively, the intrahepatic tumors in C57BL/6 mice are treated with GO-PEI-PEG/Pd-l1 siRNAs via the tail vein, resulting in shrinkage of the HCC tumors and boosting the anti-tumor efficacy in combination with oral sorafenib. A single treatment improves the total CD3+ and cytotoxic CD8+ T cell infiltration in the HCC tumor tissues and even spleen and upregulates the expression of Perforin, Gzmb, Ifng, Il-1b and Tnfa in the tumors after the combined treatment. Both the single and combined treatments enhance reactive oxygen species (ROS) accumulation, and improved HCC ferroptosis. The results suggest that GO-PEI-PEG delivered PD-L1 siRNAs combined with oral sorafenib can activate the adaptive immunity and tumor ferroptosis and reveal an effective therapy to treat advanced HCC patients.
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Affiliation(s)
- Zhiwei Li
- National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha 410081, China
| | - Jiaqi Bu
- College of Chemistry, Hunan Normal University, Changsha 410081, China
| | - Xinyu Zhu
- National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha 410081, China
| | - Hao Zhou
- National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha 410081, China
| | - Kaiqun Ren
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha 410013, China
| | - Paul K Chu
- Department of Physics, Department of Materials Science and Engineering, and Department of Biomedical Engineering, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China
| | - Limin Li
- College of Engineering and Design, Hunan Normal University, Changsha 410081, China.
| | - Xiang Hu
- National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha 410081, China.
| | - Xiaofeng Ding
- National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha 410081, China.
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Comparative assessment of standard and immune response criteria for evaluation of response to PD-1 monotherapy in unresectable HCC. Abdom Radiol (NY) 2022; 47:969-980. [PMID: 34964909 DOI: 10.1007/s00261-021-03386-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 12/09/2021] [Accepted: 12/10/2021] [Indexed: 12/31/2022]
Abstract
PURPOSE To assess response to programmed death-1 (PD-1) monotherapy (nivolumab) in hepatocellular carcinoma (HCC) patients using RECIST1.1, modified RECIST (mRECIST), and immune RECIST (iRECIST). A secondary objective was to identify clinicolaboratory and imaging variables predictive of progressive disease (PD) and overall survival (OS). METHODS Patients with HCC treated with nivolumab at a single institution from 5/2016 to 12/2019 with MRI or CT performed ≥ 4 weeks post treatment were retrospectively assessed. Patients who received concurrent locoregional, radiation, or other systemic therapies were excluded. Response was assessed by 2 observers in consensus using RECIST1.1, mRECIST, and iRECIST at 3/6/9/12-month time points. Time to progression (TTP) and OS were recorded. Clinicolaboratory and imaging variables were evaluated as predictors of PD and OS using uni-/multivariable and Cox regression analyses. RESULTS Fifty-eight patients (42M/16F) were included. 118 target lesions (TL) were identified before treatment. Baseline mean TL size was 49.1 ± 43.5 mm (range 10-189 mm) for RECIST1.1/iRECIST and 46.3 ± 42.3 mm (range 10-189 mm) for mRECIST. Objective response rate (ORR) was 21% for mRECIST/iRECIST/RECIST1.1, with no cases of pseudoprogression. Median OS and median TTP were 717 days and 127 days for RECIST1.1/mRECIST/iRECIST-iUPD (unconfirmed PD). Older age, MELD/Child-Pugh scores, AFP, prior transarterial radioembolization (TARE), and larger TL size were predictive of PD and/or poor OS using mRECIST/iRECIST. The strongest predictor of PD (HR = 2.49, 95% CI 1.29-4.81, p = 0.007) was TARE. The strongest predictor of poor OS was PD by mRECIST/iRECIST at 3 months (HR = 2.26, 95% CI 1.00-5.10, p = 0.05) with borderline significance. CONCLUSION Our results show ORR of 21%, equivalent for mRECIST, iRECIST, and RECIST1.1 in patients with advanced HCC clinically treated with nivolumab.
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Huang X, Zhu S, Zhang K, Tan W, Chen Y, Shang C. High Expression of Long Non-Coding RNA TMCO1-AS1 is Associated With Poor Prognosis of Hepatocellular Carcinoma. Front Mol Biosci 2022; 9:814058. [PMID: 35141283 PMCID: PMC8819098 DOI: 10.3389/fmolb.2022.814058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 01/07/2022] [Indexed: 12/24/2022] Open
Abstract
Background: The molecular pathways along with the clinical significance of long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC) remain uncertain. Our study sought to identify and characterize lncRNAs associated with HCC. Methods: LncRNA TMCO1-AS1 was identified by differential expression analysis, receiver operating characteristic (ROC) analysis, and univariate analysis using RNA sequencing and clinical information of HCC from the public database. Then clinical correlations and survival analysis were conducted to further appraise the prognostic significance of lncRNA TMCO1-AS1 in HCC. Hepatoma and adjoining normal tissues from 66 patients who received surgical operation at our center were used to verify the results of the bioinformatics analysis. A survival prognostic model was established combining TMCO1-AS1 expression and other clinical characteristics. Results: Bioinformatics analysis showed the aberrant high expression of TMCO1-AS1 in HCC tissue. TMCO1-AS1 expression was positively correlated with alpha-fetoprotein (AFP) level, vascular invasion, tumor stage, as well as tumor differentiation. Moreover, survival analysis found a significant inverse association between the expression of TMCO1-AS1 and the survival of patients with HCC. Cox analysis indicated that TMCO1-AS1 was an independent factor for HCC prognosis. Analysis of the HCC tissues from patients at our center provided results similar to those of the bioinformatics analysis. Risk models for overall survival (OS) and recurrence-free survival (RFS) incorporating TMCO1-AS1 exhibited better sensitivity and specificity than using clinical characteristics alone. Conclusion: High TMCO1-AS1 expression is significantly correlated with the unfavorable poor prognosis of HCC, indicating its potential of being a novel prognostic marker for HCC.
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Affiliation(s)
- Xuelian Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Sicong Zhu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Surgical Intensive Care Unit, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Kelin Zhang
- Department of Surgical Intensive Care Unit, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wenliang Tan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yajin Chen
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Yajin Chen, ; Changzhen Shang,
| | - Changzhen Shang
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Yajin Chen, ; Changzhen Shang,
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A Meta-Analysis of Efficacy and Safety of PD-1/PD-L1 Inhibitors in Triple-Negative Breast Cancer. JOURNAL OF ONCOLOGY 2022; 2022:2407211. [PMID: 35096057 PMCID: PMC8799355 DOI: 10.1155/2022/2407211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/20/2021] [Accepted: 12/27/2021] [Indexed: 11/30/2022]
Abstract
Objective To evaluate the efficacy and safety of programmed cell death receptor-1 (PD-1)/programmed cell death-ligand protein-1 (PD-L1) inhibitors in triple-negative breast cancer (TNBC) to provide a treatment basis for TNBC. Methods Published case-control studies on PD-1/PD-L1 inhibitors in the treatment of TNBC were retrieved from PubMed, Embase, and Cochrane Library databases, and collected data were processed by RevMan 5.4. Results A total of 7 studies with 4340 study subjects were obtained, including 2092 PD-L1-negative cases, 1375 PD-L1-positive cases, and 847 PD-L1 unidentified cases. The use of PD-1/PD-L1 inhibitors showed no significant impact on patients' progression-free survival (PFS) and overall survival (OS). The use of PD-1/PD-L1 inhibitors in the PD-L1-positive subgroup significantly improved patients' PFS and OS. Treatment with PD-1/PD-L1 inhibitors presented no significant effect on the incidence of adverse events (AEs) but increased the risk of AE grade ≥3 and severe AEs (SAEs). Conclusion PD-1/PD-L1 inhibitors are effective in the treatment of TNBC, which is strongly correlated with the expression of PD-L1; patient selection and clinical application require further investigation and verification.
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Vitale G, Gitto S, Campani C, Turco L, Baldan A, Marra F, Morelli MC. Biological therapies in patients with liver disease: are they really lifesavers? Expert Opin Biol Ther 2021; 22:473-490. [PMID: 34860629 DOI: 10.1080/14712598.2022.2013799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION The liver plays a key role in the setting of immune tolerance. Targeting antigens for presentation by antigen-presenting cells in the liver can induce immune tolerance to either autoantigens from the liver itself or organs outside of the liver. Despite its non-conventional capacity for tolerance induction, the liver remains a target organ for autoimmune diseases. Whereas chronic inflammation and intra-hepatic immuno-suppressive microenvironment occurring during liver fibrosis lead to hepatocellular carcinoma. Monoclonal antibodies have revolutionized the therapeutic strategies of many autoimmune diseases and some cancers. AREAS COVERED We review data from literature regarding the safety and efficacy of biologics in treating hepatobiliary autoimmune diseases and primary liver cancers. Furthermore, we describe their potential use in the setting of liver transplants and their main immune-related liver adverse events. EXPERT OPINION Biological therapies have changed the natural history of main autoimmune diseases and solid cancers. Compared to other organs and disease settings, the liver lags behind in biologics and their applications. The development of novel diagnostic and therapeutic strategies based on the immunological and antigenic characteristics of the hepatobiliary system could reduce mortality and transplant rates linked to chronic liver diseases.
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Affiliation(s)
- Giovanni Vitale
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Claudia Campani
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Laura Turco
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Anna Baldan
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Maria Cristina Morelli
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
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Fan Z, Zhuang C, Wang S, Zhang Y. Photodynamic and Photothermal Therapy of Hepatocellular Carcinoma. Front Oncol 2021; 11:787780. [PMID: 34950591 PMCID: PMC8688153 DOI: 10.3389/fonc.2021.787780] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 11/22/2021] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver tumor. It is ranked the sixth most common neoplasm and the third most common cause of cancer mortality. At present, the most common treatment for HCC is surgery, but the 5-year recurrence rates are still high. Patients with early stage HCC with few nodules can be treated with resection or radiofrequency ablation (RFA); while for multinodular HCC, transarterial chemoembolization (TACE) has been the first-line treatment. In recent years, based on medical engineering cooperation, nanotechnology has been increasingly applied to the treatment of cancer. Photodynamic therapy and photothermal therapy are effective for cancer. This paper summarizes the latest progress of photodynamic therapy and photothermal therapy for HCC, with the aim of providing new ideas for the treatment of HCC.
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Affiliation(s)
- Zhe Fan
- Department of General Surgery, the Third People's Hospital of Dalian, Dalian Medical University, Dalian, China.,Department of Central Laboratory, the Third People's Hospital of Dalian, Dalian Medical University, Dalian, China
| | - Chengjun Zhuang
- Department of Critical Care Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shuang Wang
- Department of Endocrinology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yewei Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Bakrania A, Zheng G, Bhat M. Nanomedicine in Hepatocellular Carcinoma: A New Frontier in Targeted Cancer Treatment. Pharmaceutics 2021; 14:41. [PMID: 35056937 PMCID: PMC8779722 DOI: 10.3390/pharmaceutics14010041] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/17/2021] [Accepted: 12/22/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and is associated with a dismal median survival of 2-9 months. The fundamental limitations and ineffectiveness of current HCC treatments have led to the development of a vast range of nanotechnologies with the goal of improving the safety and efficacy of treatment for HCC. Although remarkable success has been achieved in nanomedicine research, there are unique considerations such as molecular heterogeneity and concomitant liver dysfunction that complicate the translation of nanotheranostics in HCC. This review highlights the progress, challenges, and targeting opportunities in HCC nanomedicine based on the growing literature in recent years.
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Affiliation(s)
- Anita Bakrania
- Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada;
- Ajmera Transplant Program, University Health Network, Toronto, ON M5G 2N2, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada;
| | - Gang Zheng
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada;
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Mamatha Bhat
- Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada;
- Ajmera Transplant Program, University Health Network, Toronto, ON M5G 2N2, Canada
- Division of Gastroenterology, Department of Medicine, University Health Network, Toronto, ON M5G 2C4, Canada
- Department of Medical Sciences, University of Toronto, Toronto, ON M5S 1A1, Canada
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Wang Z, Qu K, Zhou L, Ren L, Ren B, Meng F, Yu W, Wang H, Fan H. Apaf1 nanoLuc biosensors identified lentinan as a potent synergizer of cisplatin in targeting hepatocellular carcinoma cells. Biochem Biophys Res Commun 2021; 577:45-51. [PMID: 34507064 DOI: 10.1016/j.bbrc.2021.08.030] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 08/10/2021] [Indexed: 12/25/2022]
Abstract
Liver cancer is one of the most common malignancies that is difficult to treat due to late diagnosis and chemo-resistance. In the present study, we developed and validated a cell based split nanoLuc biosensor to monitor the Apaf1-Apaf1 interactions in response to apoptosis-inducing drugs such as cisplatin. We showed that the activity of split nanoLuc is reconstituted only in response to apoptotic inducer, cisplatin and in a dose-dependent manner. Apaf1 mutants which were unable to oligomerize failed to recover nanoLuc activity while constitutively active variant increased the nanoLuc activity. Generation of Apaf1 knockout HepG2 and treatment with cisplatin showed dramatic reduction in cell death suggesting that cisplatin mainly targets liver cancer cells through apoptosis. As the natural products are potent sources of compounds for adjuvant therapy, we screened a collection of natural products and identified lentinan as an inducer of apoptosome formation, a key step for induction of apoptosis. Lentinan is a polysaccharide with antitumor, pro-apoptotic properties that functions with poorly understood mechanisms. Lentinan was shown to have cytotoxic effects with the IC50 of 650 μM. Sub-lethal lentinan concentration doubled the nanoLuc activity when co-treated with cisplatin. We also showed that lentinan hugely reduced the dose of cisplatin to induce certain amount of death and that lentinan co-treatment with cisplatin enhanced the Apaf1 transcription in HepG2 cells while lentinan or cisplatin alone failed to alter the transcription. In addition, lentinan and cisplatin co-treatment induced mitochondrial depolarization. This suggested that lentinan combinatorial therapy with cisplatin engaged a different signalling pathway to kill the liver cancer cells and that adjuvant therapy with lentinan can reduce the dose of cisplatin and thus reduce the possibility of chemo-resistance.
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Affiliation(s)
- Zhixin Wang
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, China
| | - Kai Qu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi 'an Jiaotong University, China
| | - Lei Zhou
- Department of Hepatobiliary Surgery, Binzhou Medical University Hospital, China
| | - Li Ren
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, China
| | - Bin Ren
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, China
| | - Fandi Meng
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi 'an Jiaotong University, China
| | - Wenhao Yu
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, China
| | - Haijiu Wang
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, China
| | - Haining Fan
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, China.
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Wu JY, Yin ZY, Bai YN, Chen YF, Zhou SQ, Wang SJ, Zhou JY, Li YN, Qiu FN, Li B, Yan ML. Lenvatinib Combined with Anti-PD-1 Antibodies Plus Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Study. J Hepatocell Carcinoma 2021; 8:1233-1240. [PMID: 34676181 PMCID: PMC8502053 DOI: 10.2147/jhc.s332420] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 09/23/2021] [Indexed: 12/11/2022] Open
Abstract
Background Lenvatinib (LEN) combined with anti-PD-1 antibodies (PD-1) exerted promising effects on unresectable hepatocellular carcinoma (uHCC). We assessed the safety and clinical efficacy of triple therapy [LEN+PD-1+transcatheter arterial chemoembolization (TACE)] in uHCC. Methods uHCC patients with an ECOG PS score of 0–1 and Child–Pugh class A who underwent triple therapy were included. The primary endpoint was objective response rate (ORR) based on mRECIST. Secondary endpoints were conversion rate to liver resection and treatment-related adverse events. Results Between November 2018 and December 2020, 62 uHCC patients who underwent triple therapy at four major cancer centers in China were analyzed, including 35 in BCLC-C, 21 in BCLC-B, and 6 in BCLC-A. With a median follow-up of 12.2 months (range, 7.6–33.3 months), the investigator and blinded independent central review-assessed ORR were 80.6% and 77.4%, respectively. A total of 33 patients (53.2%) reached the standard of conversion to resectable HCC and 29 patients underwent resection. The median interval between start of triple therapy and resection was 123 days (range, 55–372 days). Pathological complete response and major pathological response were observed in 16 and 24 patients, respectively. Median overall survival and progression-free survival were not reached. Treatment-related adverse events occurred in 74.2% of the patients (grade ≥3, 14.5%; grade ≥4, 4.8%). Conclusion Combination of LEN, PD-1 and TACE showed a high rate of tumor response and convert resection in uHCC patients, with manageable toxicity.
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Affiliation(s)
- Jia-Yi Wu
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, 350001, People's Republic of China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian Province, 350001, People's Republic of China
| | - Zhen-Yu Yin
- Department of Hepatobiliary Surgery, Xiamen Traditional Chinese Medical Hospital, Xiamen, Fujian Province, 361000, People's Republic of China
| | - Yan-Nan Bai
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, 350001, People's Republic of China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian Province, 350001, People's Republic of China
| | - Yu-Feng Chen
- Department of Hepatobiliary Surgery, The Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian Province, 363000, People's Republic of China
| | - Song-Qiang Zhou
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, 350001, People's Republic of China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian Province, 350001, People's Republic of China
| | - Shuang-Jia Wang
- Department of Hepato-Biliary-Pancreatic and Vascular Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian Province, 361000, People's Republic of China
| | - Jian-Yin Zhou
- Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian Province, 361000, People's Republic of China
| | - Yi-Nan Li
- Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian Province, 350001, People's Republic of China
| | - Fu-Nan Qiu
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, 350001, People's Republic of China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian Province, 350001, People's Republic of China
| | - Bin Li
- Department of Hepato-Biliary-Pancreatic and Vascular Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian Province, 361000, People's Republic of China
| | - Mao-Lin Yan
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, 350001, People's Republic of China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian Province, 350001, People's Republic of China
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Chu PY, Chan SH. Cure the Incurable? Recent Breakthroughs in Immune Checkpoint Blockade for Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:5295. [PMID: 34771459 PMCID: PMC8582442 DOI: 10.3390/cancers13215295] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 10/20/2021] [Accepted: 10/20/2021] [Indexed: 12/12/2022] Open
Abstract
HCC usually arises from a chronic inflammation background, driven by several factors including fatty liver, HBV/HCV viral infection and metabolic syndrome. Systemic treatment for advanced HCC remains disappointing due to its strong resistance to chemotherapy and even to tyrosine kinase inhibitors (TKIs). Recently, the use of ICI therapy has revolutionized the systemic treatment of advanced HCC. For the first time, clinical trials testing ICIs, anti-CTLA-4 and anti-PD1/PDL1 reported a survival benefit in patients with sorafenib resistance. However, it took four more years to find the right combination regimen to use ICI in combination with the anti-angiogenic agent bevacizumab to substantially prolong overall survival (OS) of patients with advanced HCC after sorafenib. This review provides a comprehensive history of ICI therapy in HCC, up-to-date information on the latest ICI clinical trials, and discusses the recent development of novel ICIs that would potentially lead to a new checkpoint blockade therapy for advanced HCC.
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Affiliation(s)
- Pei-Yi Chu
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan;
- College of Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Department of Pathology, Show Chwan Memorial Hospital, Changhua 500, Taiwan
- School of Medicine, College of Medicine, Fu Jen Catholic University, Taipei 242, Taiwan
- Department of Health Food, Chung Chou University of Science and Technology, Changhua 510, Taiwan
| | - Shih-Hsuan Chan
- Graduate Institute of Integrated Medicine, China Medial University, Taichung 402, Taiwan
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Fan X, Wu H, Zhao L, Guo X. A Poly-Chitosan and Cis-Platinum Conjugated Composite Nanoparticle System for Liver Cancer Therapy. J Biomed Nanotechnol 2021; 17:1726-1734. [PMID: 34688317 DOI: 10.1166/jbn.2021.3157] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The aim of this study was to test an effective nano-pole capsule loaded cis-platinum (CP) transplantation device for liver cancer (LC) therapy. A novel nano-pole capsule was designed as a new vector for storing CP. HepG2 cells and a B6/J mouse model were used to test the efficiency of polyethyleneimine-cis-platinum (PEI-CP) and poly-chitosan-cis-platinum (PC-CP). Infiltration efficiency and transplantation efficiency tests were performed to study the performance of the delivery system, and fibroblast reactions and macrophage numbers were observed, to test for immune rejection and foreign body reactions. The apoptosis rate and tumor diameter of hepatocellular carcinoma cells were used to evaluate the effect of the tumor therapy. We also studied the functional mechanism of different CP delivery systems. The infiltration and transplantation efficiencies of PC-CP were higher than that of PEI-CP; Less foreign body reaction appeared in PC system, with less fibroblast reaction and lower macrophage reaction. The clinical efficacy of PC-CP in terms of tumor apoptosis and diameter reduction was superior to that of PEI-CP. We demonstrated that PC-CP had a more significant alteration effect on mTOR, P-Ak, LC3 and P53. The PC system can better deliver and release drugs than PEI-CP, and may be a better choice for LC therapy in the future.
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Affiliation(s)
- Xiangyu Fan
- Department of Radiation Oncology, The Fourth Hospital of Harbin Medical University, Harbin 150001, Heilongjiang, PR China
| | - Haiyun Wu
- Department of Medical Imaging, The Fourth Hospital of Harbin Medical University, Harbin 150001, Heilongjiang, PR China
| | - Lisong Zhao
- Department of Radiation Oncology, The Fourth Hospital of Harbin Medical University, Harbin 150001, Heilongjiang, PR China
| | - Xu Guo
- Department of Radiation Oncology, The Fourth Hospital of Harbin Medical University, Harbin 150001, Heilongjiang, PR China
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Wu K, Teng M, Zhou W, Lu F, Zhou Y, Zeng J, Yang J, Liu X, Zhang Y, Ding Y, Shen W. Wogonin Induces Cell Cycle Arrest and Apoptosis of Hepatocellular Carcinoma Cells by Activating Hippo Signalling. Anticancer Agents Med Chem 2021; 22:1551-1560. [PMID: 34431466 DOI: 10.2174/1871520621666210824105915] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 07/07/2021] [Accepted: 07/12/2021] [Indexed: 01/14/2023]
Abstract
OBJECTIVE The current study aimed to illustrate whether wogonin influences HCC cell cycle progression and apoptosis by regulating Hippo signaling. <P> Methods: The effects of wogonin on HCC cell viability, cell cycle progression and apoptosis were analyzed by utilizing CCK-8 and flow cytometry. RNA-seq was employed to analyze the expression profiles between wogonin-treated and control HCC cells, and the selected RNA-seq transcripts were validated by reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR). Immunofluorescence staining was performed to detect the distribution of YAP/TAZ in the nucleus and cytoplasm in HCC cells. Western blotting and human apoptosis array were performed to examine the expression of the indicated genes. <P> Results: We demonstrated that wogonin induced cell cycle arrest and apoptosis of HCC cell lines SMMC7721 and HCCLM3. RNA-seq analysis showed enrichment in genes associated with cell cycle progression and apoptosis following incubation with wogonin in HCC cells, and the pathways analysis further identified that Hippo signaling pathways highly altered in wogonin-treated cells. Specifically, wogonin increased the phosphorylation of MOB1 and LATS1, promoted translocation of endogenous YAP and TAZ from the nucleus to the cytoplasm, and facilitated phosphorylation of YAP and TAZ. Notably, overexpression of YAP or TAZ partially abrogated the wogonin-mediated HCC cell cycle arrest and apoptosis, and reversed wogonin-mediated suppression of Claspin. <P> Conclusion: Wogonin induced HCC cell cycle arrest and apoptosis probably by activating MOB1-LATS1 signaling to inhibit the activation of YAP and TAZ, and then decrease the expression of Claspin, suggesting that the understanding of the molecular mechanisms underlying wogonin-induced cell cycle arrest and apoptosis may be useful in HCC therapeutics.
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Affiliation(s)
- Keyan Wu
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, Jiangsu. China
| | - Man Teng
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, Jiangsu. China
| | - Wei Zhou
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, Jiangsu. China
| | - Fanglin Lu
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, Jiangsu. China
| | - Yang Zhou
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, Jiangsu. China
| | - Jing Zeng
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, Jiangsu. China
| | - Jie Yang
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, Jiangsu. China
| | - Xinnong Liu
- Department of General Surgery, Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu. China
| | - Yu Zhang
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, Jiangsu. China
| | - Yanbing Ding
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu. China
| | - Weigan Shen
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, Jiangsu. China
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Lim J, Choi H, Ahn J, Jeon NL. 3D High‐Content Culturing and Drug Screening Platform to Study Vascularized Hepatocellular Carcinoma in Hypoxic Condition. ADVANCED NANOBIOMED RESEARCH 2021. [DOI: 10.1002/anbr.202100078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
- Jungeun Lim
- School of Mechanical and Aerospace Engineering Seoul National University Seoul 08826 South Korea
| | - Hyeri Choi
- Interdisciplinary Program in Bioengineering Seoul National University Seoul 08826 South Korea
| | - Jungho Ahn
- School of Mechanical and Aerospace Engineering Seoul National University Seoul 08826 South Korea
| | - Noo Li Jeon
- School of Mechanical and Aerospace Engineering Seoul National University Seoul 08826 South Korea
- Interdisciplinary Program in Bioengineering Seoul National University Seoul 08826 South Korea
- Institute of Advanced Machinery and Design Seoul National University Seoul 08826 South Korea
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Yacoub JH, Mauro D, Moon A, He AR, Bashir MR, Hsu CC, Fishbein TM, Burke LMB. Therapies for hepatocellular carcinoma: overview, clinical indications, and comparative outcome evaluation. Part two: noncurative intention. Abdom Radiol (NY) 2021; 46:3540-3548. [PMID: 33864107 DOI: 10.1007/s00261-021-03074-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 03/21/2021] [Accepted: 03/25/2021] [Indexed: 12/12/2022]
Abstract
Locoregional therapies can be offered to hepatocellular carcinoma patients as a bridge to transplant, to downstage disease burden for transplant eligibility, or for disease control to prolong survival. Systemic therapies also play a large role in HCC treatment, occasionally in conjunction with other methods. This manuscript reviews the various treatment options for HCC with a historically noncurative intent.
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42
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Hao J, Peng Q, Wang K, Yu G, Pan Y, Du X, Hu N, Zhang X, Qin Y, Li H. Antitumor Effect of Lenvatinib Combined with Alisertib in Hepatocellular Carcinoma by Targeting the DNA Damage Pathway. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6613439. [PMID: 34337035 PMCID: PMC8324353 DOI: 10.1155/2021/6613439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 06/12/2021] [Accepted: 07/09/2021] [Indexed: 12/24/2022]
Abstract
METHODS Immunohistochemical staining, sequencing, and genetic analysis of liver cancer tissues were performed. The antitumor efficacy of single-agent or combination treatment was measured by cell counting kit-8 assay and colony formation assays. Their antiproliferative and apoptosis activity is evaluated by cell cycle analyses and wound healing assays. The DNA-related proteins were also measured by Western blotting and immunohistochemical staining. The HepG2 xenograft model was used to detect the effects of lenvatinib-alisertib on the antitumor activity. RESULTS AURKA was found to be upregulated in HCC tissues (77.3%, 17/22). Combined alisertib and lenvatinib treatment significantly enhanced the inhibition of proliferation and migration in HepG2 and Hep3B cell lines compared to single-agent treatments (all Ps < 0.01). Alisertib alone or in combination with lenvatinib demonstrated a significant increase in the percentage of super-G2 cells (lenvatinib 1 μM vs. lenvatinib 1 μM + alisertib 0.1 μM 8.84 ± 0.84 vs. 34.0 ± 1.54, P < 0.001). Discontinuous spindles and missegregated chromosomes in HCC cells treated with alisertib in combination with lenvatinib were observed. We further revealed that combined treatment inhibited the expression of DNA damage pathway proteins compared to those of single-agent treatments. In nude mice, combined administration of alisertib combined with lenvatinib significantly enhanced the suppression of tumor growth and induced apoptosis (all Ps < 0.01). CONCLUSIONS Our findings provide evidence for the possible use of alisertib in combination with lenvatinib in the treatment of HCC for better therapeutic outcomes.
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Affiliation(s)
- Jianwen Hao
- Department of Radiology, Tianjin Chest Hospital, Tianjin 300350, China
| | - Qizhen Peng
- Department of Radiology, Tungwah Hospital of Sun Yat-Sen University, Dongguan, 523000 Guangdong, China
| | - Keruo Wang
- Department of Diagnostics, Tianjin Medical University, Tianjin 300070, China
| | - Ge Yu
- Department of Hepatobiliary, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Clinical Research Center for Cancer, Tianjin 300070, China
| | - Yi Pan
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Clinical Research Center for Cancer, Tianjin 300070, China
| | - Xiaoling Du
- Department of Diagnostics, Tianjin Medical University, Tianjin 300070, China
| | - Na Hu
- Department of Diagnostics, Tianjin Medical University, Tianjin 300070, China
| | - Xuening Zhang
- Department of Radiology Second Hospital of Tianjin Medical University, Tianjin 300070, China
| | - Yu Qin
- Department of Diagnostics, Tianjin Medical University, Tianjin 300070, China
| | - Huikai Li
- Department of Hepatobiliary, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Clinical Research Center for Cancer, Tianjin 300070, China
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Manganelli M, Grossi I, Ferracin M, Guerriero P, Negrini M, Ghidini M, Senti C, Ratti M, Pizzo C, Passalacqua R, Molfino S, Baiocchi G, Portolani N, Marchina E, De Petro G, Salvi A. Longitudinal Circulating Levels of miR-23b-3p, miR-126-3p and lncRNA GAS5 in HCC Patients Treated with Sorafenib. Biomedicines 2021; 9:813. [PMID: 34356875 PMCID: PMC8301380 DOI: 10.3390/biomedicines9070813] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/08/2021] [Accepted: 07/09/2021] [Indexed: 01/10/2023] Open
Abstract
Human hepatocellular carcinoma (HCC) is the most frequent primary tumor of the liver and the third cause of cancer-related deaths. The multikinase inhibitor sorafenib is a systemic drug for unresectable HCC. The identification of molecular biomarkers for the early diagnosis of HCC and responsiveness to treatment are needed. In this work, we performed an exploratory study to investigate the longitudinal levels of cell-free long ncRNA GAS5 and microRNAs miR-126-3p and -23b-3p in a cohort of 7 patients during the period of treatment with sorafenib. We used qPCR to measure the amounts of GAS5 and miR-126-3p and droplet digital PCR (ddPCR) to measure the levels of miR-23b-3p. Patients treated with sorafenib displayed variable levels of GAS5, miR-126-3p and miR-23b-3p at different time-points of follow-up. miR-23b-3p was further measured by ddPCR in 37 healthy individuals and 25 untreated HCC patients. The amount of miR-23b-3p in the plasma of untreated HCC patients was significantly downregulated if compared to healthy individuals. The ROC curve analysis underlined its diagnostic relevance. In conclusion, our results highlight a potential clinical significance of circulating miR-23b-3p and an exploratory observation on the longitudinal plasmatic levels of GAS5, miR-126-3p and miR-23b-3p during sorafenib treatment.
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Affiliation(s)
- Michele Manganelli
- Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, 25123 Brescia, Italy; (M.M.); (I.G.); (E.M.)
| | - Ilaria Grossi
- Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, 25123 Brescia, Italy; (M.M.); (I.G.); (E.M.)
| | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40126 Bologna, Italy;
| | - Paola Guerriero
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy; (P.G.); (M.N.)
| | - Massimo Negrini
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy; (P.G.); (M.N.)
| | - Michele Ghidini
- Department of Oncology, Azienda Socio Sanitaria Territoriale of Cremona, 26100 Cremona, Italy; (M.G.); (C.S.); (M.R.); (C.P.); (R.P.)
| | - Chiara Senti
- Department of Oncology, Azienda Socio Sanitaria Territoriale of Cremona, 26100 Cremona, Italy; (M.G.); (C.S.); (M.R.); (C.P.); (R.P.)
| | - Margherita Ratti
- Department of Oncology, Azienda Socio Sanitaria Territoriale of Cremona, 26100 Cremona, Italy; (M.G.); (C.S.); (M.R.); (C.P.); (R.P.)
| | - Claudio Pizzo
- Department of Oncology, Azienda Socio Sanitaria Territoriale of Cremona, 26100 Cremona, Italy; (M.G.); (C.S.); (M.R.); (C.P.); (R.P.)
| | - Rodolfo Passalacqua
- Department of Oncology, Azienda Socio Sanitaria Territoriale of Cremona, 26100 Cremona, Italy; (M.G.); (C.S.); (M.R.); (C.P.); (R.P.)
| | - Sarah Molfino
- Department of Clinical and Experimental Sciences, Surgical Clinic, University of Brescia, 25123 Brescia, Italy; (S.M.); (G.B.); (N.P.)
| | - Gianluca Baiocchi
- Department of Clinical and Experimental Sciences, Surgical Clinic, University of Brescia, 25123 Brescia, Italy; (S.M.); (G.B.); (N.P.)
| | - Nazario Portolani
- Department of Clinical and Experimental Sciences, Surgical Clinic, University of Brescia, 25123 Brescia, Italy; (S.M.); (G.B.); (N.P.)
| | - Eleonora Marchina
- Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, 25123 Brescia, Italy; (M.M.); (I.G.); (E.M.)
| | - Giuseppina De Petro
- Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, 25123 Brescia, Italy; (M.M.); (I.G.); (E.M.)
| | - Alessandro Salvi
- Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, 25123 Brescia, Italy; (M.M.); (I.G.); (E.M.)
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Zeng Z, Lu Q, Liu Y, Zhao J, Zhang Q, Hu L, Shi Z, Tu Y, Xiao Z, Xu Q, Huang D. Effect of the Hypoxia Inducible Factor on Sorafenib Resistance of Hepatocellular Carcinoma. Front Oncol 2021; 11:641522. [PMID: 34307125 PMCID: PMC8292964 DOI: 10.3389/fonc.2021.641522] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 06/16/2021] [Indexed: 12/11/2022] Open
Abstract
Sorafenib a multi-target tyrosine kinase inhibitor, is the first-line drug for treating advanced hepatocellular carcinoma (HCC). Mechanistically, it suppresses tumor angiogenesis, cell proliferation and promotes apoptosis. Although sorafenib effectively prolongs median survival rates of patients with advanced HCC, its efficacy is limited by drug resistance in some patients. In HCC, this resistance is attributed to multiple complex mechanisms. Previous clinical data has shown that HIFs expression is a predictor of poor prognosis, with further evidence demonstrating that a combination of sorafenib and HIFs-targeted therapy or HIFs inhibitors can overcome HCC sorafenib resistance. Here, we describe the molecular mechanism underlying sorafenib resistance in HCC patients, and highlight the impact of hypoxia microenvironment on sorafenib resistance.
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Affiliation(s)
- Zhi Zeng
- The Medical College of Qingdao University, Qingdao, China.,Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
| | - Qiliang Lu
- The Medical College of Qingdao University, Qingdao, China.,Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
| | - Yang Liu
- The Medical College of Qingdao University, Qingdao, China.,Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
| | - Junjun Zhao
- Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China.,Graduate Department, Bengbu Medical College, Bengbu, China
| | - Qian Zhang
- The Medical College of Qingdao University, Qingdao, China
| | - Linjun Hu
- The Medical College of Qingdao University, Qingdao, China.,Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
| | - Zhan Shi
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yifeng Tu
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Zunqiang Xiao
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiuran Xu
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
| | - Dongsheng Huang
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
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Luo Y, Li H, Huang H, Xue L, Li H, Liu L, Fu H. Integrated analysis of ceRNA network in hepatocellular carcinoma using bioinformatics analysis. Medicine (Baltimore) 2021; 100:e26194. [PMID: 34087888 PMCID: PMC8183720 DOI: 10.1097/md.0000000000026194] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 05/13/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Long noncoding RNAs (lncRNAs) can work as microRNA (miRNA) sponges through a competitive endogenous RNA (ceRNA) mechanism. LncRNAs and miRNAs are important components of competitive endogenous binding, and their expression imbalance in hepatocellular carcinoma (HCC) is closely related to tumor development, diagnosis, and prognosis. This study explored the potential impact of the ceRNA regulatory network in HCC on the prognosis of HCC patients. METHODS We thoroughly researched the differential expression profiles of lncRNAs, miRNAs, and mRNAs from 2 HCC Gene Expression Omnibus datasets (GSE98269 and GSE60502). Then, a dysregulated ceRNA network was constructed by bioinformatics. In addition, hub genes in the ceRNA network were screened by Cytoscape, these hub genes functional analysis was performed by gene set enrichment analysis, and the expression of these hub genes in tumors and their correlation with patient prognosis were verified with Gene Expression Profiling Interactive Analysis. RESULTS A ceRNA network was successfully constructed in this study including 4 differentially expressed (DE) lncRNAs, 7 DEmiRNAs, and 166 DEmRNAs. Importantly, 4 core genes (CCNA2, CHEK1, FOXM1, and MCM2) that were significantly associated with HCC prognosis were identified. CONCLUSIONS Our study provides comprehensive and meaningful insights into HCC tumorigenesis and the underlying molecular mechanisms of ceRNA. Furthermore, the specific ceRNAs can be further used as potential therapeutic targets and prognostic biomarkers for HCC.
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Affiliation(s)
| | | | | | | | | | - Li Liu
- Department of Liver Disease, The 3rd People's Hospital of Kunming, Kunming, Yunnan, China
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Iwamoto H, Shimose S, Noda Y, Shirono T, Niizeki T, Nakano M, Okamura S, Kamachi N, Suzuki H, Sakai M, Kajiwara A, Itano S, Tanaka M, Yamaguchi T, Kuromatsu R, Koga H, Torimura T. Initial Experience of Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma in Real-World Clinical Practice. Cancers (Basel) 2021; 13:cancers13112786. [PMID: 34205099 PMCID: PMC8199943 DOI: 10.3390/cancers13112786] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 05/24/2021] [Accepted: 06/02/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Although the clinical trial of atezolizumab plus bevacizumab have revealed its efficacy for HCC, the outcomes in the real-world clinical practice are unclear. In the study, we retorspectively evaluated the efficacy and safety of atezoizumab plus bevacizumab for HCC. Atezorizumab plus bevacizumab was effective and safe even in the real-world clinical practice including patients with HCC in a previous MTA history or other than ALBI grade 1. Abstract Background: Atezolizumab plus bevacizumab was approved for patients with hepatocellular carcinoma (HCC). Although clinical trials have revealed its efficacy, the outcomes in the real-world clinical practice are unclear. We retrospectively evaluated the efficacy and safety of atezolizumab plus bevacizumab for HCC. Materials and Methods: This is a multicenter study conducted between November 2020 and March 2021. Among the 61 patients, 51 were assessed for progression-free survival (PFS), therapeutic response, and adverse events (AEs). Results: The median PFS was 5.4 months. The objective response rate (ORR) was 35.3%. The disease control rate (DCR) was 86.3%. The incidence rates of AEs at any grade and grade >3 were 98.0% and 29.4%, respectively. The most frequent AE at any grade and grade >3 was hepatic disorder. In patients with a previous history of molecular targeted agent (MTA) or the degree of albumin-bilirubin (ALBI) grade, there were no significant differences in the PFS, ORR, DCR, and incidence rates of AEs. Conclusion: The study demonstrated that atezolizumab plus bevacizumab was effective and safe for patients with HCC even in the real-world setting including patients with a previous MTA history or other than ALBI grade 1.
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Affiliation(s)
- Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (S.S.); (Y.N.); (T.S.); (T.N.); (M.N.); (S.O.); (N.K.); (H.S.); (M.S.); (A.K.); (R.K.); (H.K.); (T.T.)
- Department of Gastroenterology, Iwamoto Internal Medicine Clinic, Kitakyushu 802-0832, Japan;
- Correspondence: ; Tel.: +81-942-353-311
| | - Shigeo Shimose
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (S.S.); (Y.N.); (T.S.); (T.N.); (M.N.); (S.O.); (N.K.); (H.S.); (M.S.); (A.K.); (R.K.); (H.K.); (T.T.)
| | - Yu Noda
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (S.S.); (Y.N.); (T.S.); (T.N.); (M.N.); (S.O.); (N.K.); (H.S.); (M.S.); (A.K.); (R.K.); (H.K.); (T.T.)
| | - Tomotake Shirono
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (S.S.); (Y.N.); (T.S.); (T.N.); (M.N.); (S.O.); (N.K.); (H.S.); (M.S.); (A.K.); (R.K.); (H.K.); (T.T.)
| | - Takashi Niizeki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (S.S.); (Y.N.); (T.S.); (T.N.); (M.N.); (S.O.); (N.K.); (H.S.); (M.S.); (A.K.); (R.K.); (H.K.); (T.T.)
| | - Masahito Nakano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (S.S.); (Y.N.); (T.S.); (T.N.); (M.N.); (S.O.); (N.K.); (H.S.); (M.S.); (A.K.); (R.K.); (H.K.); (T.T.)
| | - Shusuke Okamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (S.S.); (Y.N.); (T.S.); (T.N.); (M.N.); (S.O.); (N.K.); (H.S.); (M.S.); (A.K.); (R.K.); (H.K.); (T.T.)
| | - Naoki Kamachi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (S.S.); (Y.N.); (T.S.); (T.N.); (M.N.); (S.O.); (N.K.); (H.S.); (M.S.); (A.K.); (R.K.); (H.K.); (T.T.)
| | - Hiroyuki Suzuki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (S.S.); (Y.N.); (T.S.); (T.N.); (M.N.); (S.O.); (N.K.); (H.S.); (M.S.); (A.K.); (R.K.); (H.K.); (T.T.)
| | - Miwa Sakai
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (S.S.); (Y.N.); (T.S.); (T.N.); (M.N.); (S.O.); (N.K.); (H.S.); (M.S.); (A.K.); (R.K.); (H.K.); (T.T.)
| | - Akira Kajiwara
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (S.S.); (Y.N.); (T.S.); (T.N.); (M.N.); (S.O.); (N.K.); (H.S.); (M.S.); (A.K.); (R.K.); (H.K.); (T.T.)
| | - Satoshi Itano
- Department of Gastroenterology, Kurume Central Hospital, Kurume 830-0001, Japan;
| | - Masatoshi Tanaka
- Department of Gastroenterology, Yokokura Hospital, Miyama 839-0295, Japan;
| | - Taizo Yamaguchi
- Department of Gastroenterology, Iwamoto Internal Medicine Clinic, Kitakyushu 802-0832, Japan;
| | - Ryoko Kuromatsu
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (S.S.); (Y.N.); (T.S.); (T.N.); (M.N.); (S.O.); (N.K.); (H.S.); (M.S.); (A.K.); (R.K.); (H.K.); (T.T.)
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (S.S.); (Y.N.); (T.S.); (T.N.); (M.N.); (S.O.); (N.K.); (H.S.); (M.S.); (A.K.); (R.K.); (H.K.); (T.T.)
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (S.S.); (Y.N.); (T.S.); (T.N.); (M.N.); (S.O.); (N.K.); (H.S.); (M.S.); (A.K.); (R.K.); (H.K.); (T.T.)
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Gnocchi D, Cavalluzzi MM, Mangiatordi GF, Rizzi R, Tortorella C, Spennacchio M, Lentini G, Altomare A, Sabbà C, Mazzocca A. Xanthenylacetic Acid Derivatives Effectively Target Lysophosphatidic Acid Receptor 6 to Inhibit Hepatocellular Carcinoma Cell Growth. ChemMedChem 2021; 16:2121-2129. [PMID: 33831272 DOI: 10.1002/cmdc.202100032] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/02/2021] [Indexed: 12/22/2022]
Abstract
Despite the increasing incidence of hepatocellular carcinoma (HCC) worldwide, current pharmacological treatments are still unsatisfactory. We have previously shown that lysophosphatidic acid receptor 6 (LPAR6) supports HCC growth and that 9-xanthenylacetic acid (XAA) acts as an LPAR6 antagonist inhibiting HCC growth without toxicity. Here, we synthesized four novel XAA derivatives, (±)-2-(9H-xanthen-9-yl)propanoic acid (compound 4 - MC9), (±)-2-(9H-xanthen-9-yl)butanoic acid (compound 5 - MC6), (±)-2-(9H-xanthen-9-yl)hexanoic acid (compound 7 - MC11), and (±)-2-(9H-xanthen-9-yl)octanoic acid (compound 8 - MC12, sodium salt) by introducing alkyl groups of increasing length at the acetic α-carbon atom. Two of these compounds were characterized by X-ray powder diffraction and quantum mechanical calculations, while molecular docking simulations suggested their enantioselectivity for LPAR6. Biological data showed anti-HCC activity for all XAA derivatives, with the maximum effect observed for MC11. Our findings support the view that increasing the length of the alkyl group improves the inhibitory action of XAA and that enantioselectivity can be exploited for designing novel and more effective XAA-based LPAR6 antagonists.
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Affiliation(s)
- Davide Gnocchi
- Interdisciplinary Department of Medicine, University of Bari, School of Medicine, Piazza G. Cesare, 11, 70124, Bari, Italy
| | - Maria M Cavalluzzi
- Department of Pharmacy - Drug Sciences, University of Bari Aldo Moro, via Orabona, 4, 70125, Bari, Italy
| | | | - Rosanna Rizzi
- Institute of Crystallography CNR, Via Amendola 122/o, 70126, Bari, Italy
| | - Cosimo Tortorella
- Interdisciplinary Department of Medicine, University of Bari, School of Medicine, Piazza G. Cesare, 11, 70124, Bari, Italy
| | - Mauro Spennacchio
- Department of Pharmacy - Drug Sciences, University of Bari Aldo Moro, via Orabona, 4, 70125, Bari, Italy.,Institute of Crystallography CNR, Via Amendola 122/o, 70126, Bari, Italy
| | - Giovanni Lentini
- Department of Pharmacy - Drug Sciences, University of Bari Aldo Moro, via Orabona, 4, 70125, Bari, Italy
| | - Angela Altomare
- Institute of Crystallography CNR, Via Amendola 122/o, 70126, Bari, Italy
| | - Carlo Sabbà
- Interdisciplinary Department of Medicine, University of Bari, School of Medicine, Piazza G. Cesare, 11, 70124, Bari, Italy
| | - Antonio Mazzocca
- Interdisciplinary Department of Medicine, University of Bari, School of Medicine, Piazza G. Cesare, 11, 70124, Bari, Italy
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48
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Shibata O, Kamimura K, Ko M, Sakai N, Abe H, Morita S, Mizusawa T, Sato H, Sakamaki A, Terai S. Effect of Lenvatinib on a Hepatocellular Carcinoma with Fibroblast Growth Factor Receptor 4 Expression: A Case Report and Review of the Literature. Intern Med 2021; 60:1709-1715. [PMID: 33390501 PMCID: PMC8222122 DOI: 10.2169/internalmedicine.6580-20] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Basic and clinical research have shown that the expression of molecules involved in the hepatocellular carcinoma (HCC) cell signaling pathway is related to the sensitivity to molecular-targeted agents. We herein report a case of HCC that was effectively treated with lenvatinib after a poor response to sorafenib. The tumor showed a high expression of fibroblast growth factor receptor 4, which is reportedly related to the sensitivity to lenvatinib in vitro. The information obtained from this case and from our literature review highlights the importance of assessing the expression of the molecules involved in tumors for effective precision medicine.
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Affiliation(s)
- Osamu Shibata
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Japan
| | - Kenya Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Japan
| | - Masayoshi Ko
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Japan
| | - Norihiro Sakai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Japan
| | - Hiroyuki Abe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Japan
| | - Shinichi Morita
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Japan
| | - Takeshi Mizusawa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Japan
| | - Hiroki Sato
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Japan
| | - Akira Sakamaki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Japan
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Tsuchiya H, Shiota G. Immune evasion by cancer stem cells. Regen Ther 2021; 17:20-33. [PMID: 33778133 PMCID: PMC7966825 DOI: 10.1016/j.reth.2021.02.006] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 02/10/2021] [Accepted: 02/21/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor immunity represents a new avenue for cancer therapy. Immune checkpoint inhibitors have successfully improved outcomes in several tumor types. In addition, currently, immune cell-based therapy is also attracting significant attention. However, the clinical efficacy of these treatments requires further improvement. The mechanisms through which cancer cells escape the immune response must be identified and clarified. Cancer stem cells (CSCs) play a central role in multiple aspects of malignant tumors. CSCs can initiate tumors in partially immunocompromised mice, whereas non-CSCs fail to form tumors, suggesting that tumor initiation is a definitive function of CSCs. However, the fact that non-CSCs also initiate tumors in more highly immunocompromised mice suggests that the immune evasion property may be a more fundamental feature of CSCs rather than a tumor-initiating property. In this review, we summarize studies that have elucidated how CSCs evade tumor immunity and create an immunosuppressive milieu with a focus on CSC-specific characteristics and functions. These profound mechanisms provide important clues for the development of novel tumor immunotherapies.
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Key Words
- ADCC, antibody-dependent cell mediated cytotoxicity
- ALDH, alcohol dehydrogenase
- AML, acute myeloid leukemia
- ARID3B, AT-rich interaction domain-containing protein 3B
- CCR7, C–C motif chemokine receptor 7
- CIK, cytokine-induced killer cell
- CMV, cytomegalovirus
- CSC, cancer stem cell
- CTL, cytotoxic T lymphocytes
- CTLA-4, cytotoxic T-cell-associated antigen-4
- Cancer stem cells
- DC, dendritic cell
- DNMT, DNA methyltransferase
- EMT, epithelial–mesenchymal transition
- ETO, fat mass and obesity associated protein
- EV, extracellular vesicle
- HNSCC, head and neck squamous cell carcinoma
- Immune checkpoints
- Immune evasion
- KDM4, lysine-specific demethylase 4C
- KIR, killer immunoglobulin-like receptor
- LAG3, lymphocyte activation gene 3
- LILR, leukocyte immunoglobulin-like receptor
- LMP, low molecular weight protein
- LOX, lysyl oxidase
- MDSC, myeloid-derived suppressor cell
- MHC, major histocompatibility complex
- MIC, MHC class I polypeptide-related sequence
- NGF, nerve growth factor
- NK cells
- NK, natural killer
- NOD, nonobese diabetic
- NSG, NOD/SCID IL-2 receptor gamma chain null
- OCT4, octamer-binding transcription factor 4
- PD-1, programmed death receptor-1
- PD-L1/2, ligands 1/2
- PI9, protease inhibitor 9
- PSME3, proteasome activator subunit 3
- SCID, severe combined immunodeficient
- SOX2, sex determining region Y-box 2
- T cells
- TAM, tumor-associated macrophage
- TAP, transporter associated with antigen processing
- TCR, T cell receptor
- Treg, regulatory T cell
- ULBP, UL16 binding protein
- uPAR, urokinase-type plasminogen activator receptor
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Affiliation(s)
- Hiroyuki Tsuchiya
- Division of Medical Genetics and Regenerative Medicine, Department of Genomic Medicine and Regenerative Therapy, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Goshi Shiota
- Division of Medical Genetics and Regenerative Medicine, Department of Genomic Medicine and Regenerative Therapy, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
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50
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Han Y, Zhi WH, Xu F, Zhang CB, Huang XQ, Luo JF. Selection of first-line systemic therapies for advanced hepatocellular carcinoma: A network meta-analysis of randomized controlled trials. World J Gastroenterol 2021; 27:2415-2433. [PMID: 34040331 PMCID: PMC8130040 DOI: 10.3748/wjg.v27.i19.2415] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/10/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The majority of clinical trials of first-line systemic treatments for hepatocellular carcinoma (HCC) used placebo or sorafenib as comparators, and there are limited data providing a cross comparison of treatments in this setting, especially for newly-approved immune checkpoint inhibitor and vascular endothelial growth factor inhibitor combination treatments. AIM To systematically review and compare response rates, survival outcomes, and safety of first-line systemic therapies for advanced hepatocellular carcinoma. METHODS We searched PubMed, Science Direct, the Cochrane Database, Excerpta Medica Database, and abstracts from the American Society of Clinical Oncology 2020 annual congress. Eligible studies were randomized controlled trials of systemic therapy enrolling adults with advanced/unresectable HCC. Risk of bias was assessed with the Cochrane risk of bias tool for randomized controlled trials. A network meta-analysis was used to synthesize data and perform direct and indirect comparisons between treatments. P value, a frequentist analog to the surface under the cumulative ranking curve, was used to rank treatments. RESULTS In total, 1398 articles were screened and 27 included. Treatments compared were atezolizumab plus bevacizumab, brivanib, donafenib, dovitinib, FOLFOX4, lenvatinib, linifanib, nintedanib, nivolumab, sorafenib, sunitinib, vandetanib, 11 sorafenib combination therapies, and three other combination therapies. For overall response rate, lenvatinib ranked 1/19, followed by atezolizumab plus bevacizumab and nivolumab. For progression-free survival (PFS), atezolizumab + bevacizumab was ranked 1/15, followed by lenvatinib. With the exception of atezolizumab + bevacizumab [hazard ratios (HR)PFS = 0.90; 95% confidence interval (CI): 0.64-1.25], the estimated HRs for PFS for all included treatments vs lenvatinib were > 1; however, the associated 95%CI passed through unity for bevacizumab plus erlotinib, linifanib, and FOLFOX4. For overall survival, atezolizumab plus bevacizumab was ranked 1/25, followed by vandetanib 100 mg/d and donafinib, with lenvatinib ranked 6/25. Atezolizumab + bevacizumab was associated with a lower risk of death vs lenvatinib (HRos = 0.63; 95%CI: 0.44-0.89), while the HR for overall survival for most other treatments vs lenvatinib had associated 95%CIs that passed through unity. Vandetanib 300 mg/d and 100 mg/d were ranked 1/13 and 2/13, respectively, for the lowest incidence of treatment terminations due to adverse events, followed by sorafenib (5/13), lenvatinib (10/13), and atezolizumab + bevacizumab (13/13). CONCLUSION There is not one single first-line treatment for advanced HCC associated with superior outcomes across all outcome measurements. Therefore, first-line systemic treatment should be selected based on individualized treatment goals.
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Affiliation(s)
- Yue Han
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wei-Hua Zhi
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Fei Xu
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Chen-Bo Zhang
- Department of Biostatistics, School of Public Health, Fudan University, Shanghai 200034, China
| | - Xiao-Qian Huang
- Department of Biostatistics, School of Public Health, Fudan University, Shanghai 200034, China
| | - Jian-Feng Luo
- Department of Biostatistics, School of Public Health, Fudan University, Shanghai 200034, China
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