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Tao R, Lu H, Dong X, Ren QQ, Fan H, Tang Z, Xia X. A nomogram based on quantitative MR signal intensity predicts early response to combined systemic treatment in patients with hepatocellular carcinoma. Front Oncol 2025; 15:1527108. [PMID: 40171262 PMCID: PMC11959652 DOI: 10.3389/fonc.2025.1527108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 02/24/2025] [Indexed: 04/03/2025] Open
Abstract
Objective This study aimed to develop and evaluate the value of a nomogram based on quantitative MR signal intensity to predict response to combined systemic therapy of anti-angiogenesis and immune checkpoint inhibitor (ICI) in hepatocellular carcinoma (HCC) patients. Methods 117 HCC patients who underwent the combined systemic treatment at a tertiary hospital between September 2020 and May 2024 were enrolled and divided into a development cohort (n = 82) and a validation cohort (n = 35). The predictive value of the relative signal intensity attenuation index (rSIAI) based on enhanced MR parameters and laboratory parameters on disease control was evaluated using receiver operating characteristic (ROC) curves, with the determination of optimal cut-off values (COVs) accomplished via Youden's index. Univariate and multivariable analyses were conducted to evaluate the association between COVs and disease control. The validity of the COVs was further confirmed through chi-square testing and calculation of Cramer's V coefficient (V). A nomogram was constructed based on the multivariable logistic regression model and evaluated for clinical applicability. Results rSIAI from arterial to portal phase (rSI_ap) in combination with peripheral T-cell subset (CD4+) achieved the most accurate predictive performance for outcome compared to rSI_ap or CD4+ alone, with an area under the curve (AUC) of the ROC of 0.845 (95% CI, 0.748-0.915). A nomogram based on rSI_ap and CD4+ was constructed. Calibration and decision curve analyses confirmed the clinical relevance and value of the nomogram. Conclusion The nomogram based on rSI_ap has the potential to be a non-invasive tool for predicting disease control in advanced HCC patients who have received combined anti-angiogenesis and ICI therapies.
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Affiliation(s)
- Ran Tao
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haohao Lu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangjun Dong
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Qian Ren
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongjie Fan
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhaoming Tang
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiangwen Xia
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Guo Y, Li RC, Xia WL, Yang X, Zhu WB, Li FT, Hu HT, Li HL. Immune effect and prognosis of transcatheter arterial chemoembolization and tyrosine kinase inhibitors therapy in patients with hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:3256-3269. [PMID: 39072154 PMCID: PMC11271774 DOI: 10.4251/wjgo.v16.i7.3256] [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: 03/06/2024] [Revised: 05/03/2024] [Accepted: 05/17/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND The combination of transcatheter arterial chemoembolization (TACE) and tyrosine kinase inhibitors (TKIs) has shown broad prospects in prolonging the survival of patients with hepatocellular carcinoma (HCC). TACE and TKIs can affect the immune microenvironment in patients with HCC. AIM To determine the overall effects and differences between TACE and different TKIs combinations on the immune microenvironment. METHODS Data and immune cell profile test results from 213 HCC patients treated with TACE combined with apatinib, lenvatinib, sorafenib, or donafenib before and after 3 wk of treatment were collected. Monocytes were co-cultured with LM3 liver cancer cells, and their ability to inhibit cancer cell growth was analyzed using the MTT method and a nude mouse subcutaneous tumorigenesis experiment. Simulated combined therapy was done using an in situ liver cancer C57BL/6 male mouse model, and the immune response of tumor tissues was analyzed using immunohistochemistry. RESULTS Compared to before combination therapy, the proportion of programmed cell death protein 1 (PD-1)+ mononuclear cells and the number of CD4+ T cells decreased in the TACE + apatinib group, while the number of absolute count of CD4+ and CD8+ T cells increased in the TACE + lenvatinib group. Furthermore, the number of regulatory cells decreased in the TACE + donafenib group, whereas the number of CD8+ T and natural killer cells increased. Additionally, monocytes in the TACE combined with donafenib or lenvatinib groups had a stronger ability to inhibit cancer cell growth than those in the other groups. Combining TACE with donafenib or lenvatinib increased CD8+ T cell infiltration into the tumor tissue. In addition, the proportion of PD-1+ in CD8+ cells, absolute CD8+ T lymphocyte count, and regulatory T cells proportion were independent prognostic factors affecting the survival time of patients with HCC. CONCLUSION TACE, in combination with different TKIs, produces different immune responses. Specifically, TACE combined with donafenib or lenvatinib may induce strong anti-tumor immune responses.
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Affiliation(s)
- Yuan Guo
- Department of Minimal Invasive Intervention, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450003, Henan Province, China
| | - Ru-Chun Li
- Department of Radiology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450003, Henan Province, China
| | - Wei-Li Xia
- Department of Minimal Invasive Intervention, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450003, Henan Province, China
| | - Xiong Yang
- Department of Minimal Invasive Intervention, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450003, Henan Province, China
| | - Wen-Bo Zhu
- Department of Minimal Invasive Intervention, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450003, Henan Province, China
| | - Fang-Ting Li
- Department of Minimal Invasive Intervention, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450003, Henan Province, China
| | - Hong-Tao Hu
- Department of Minimal Invasive Intervention, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450003, Henan Province, China
| | - Hai-Liang Li
- Department of Minimal Invasive Intervention, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450003, Henan Province, China
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Wang H, Huang H, Liu T, Chen Y, Li J, He M, Peng J, Liang E, Li J, Liu W. Peripheral blood lymphocyte subsets predict the efficacy of TACE with or without PD-1 inhibitors in patients with hepatocellular carcinoma: a prospective clinical study. Front Immunol 2024; 15:1325330. [PMID: 38404585 PMCID: PMC10884244 DOI: 10.3389/fimmu.2024.1325330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Accepted: 01/29/2024] [Indexed: 02/27/2024] Open
Abstract
Background Although peripheral blood lymphocyte subsets, particularly PD-1+ T cells, are promising prognostic indicators for patients with cancer. However, their clinical significance remains unclear. Methods We prospectively enrolled 157 patients with hepatocellular carcinoma (HCC) treated with transcatheter arterial chemoembolization combined with or without PD-1 inhibitors. Twenty peripheral lymphocyte subsets and cytokines were analyzed. We analyzed the differences in PD-1+ T cells between patients treated with and without PD-1 inhibitors and their associations with tumor response, survival prognosis, and clinical features. Results We found that the baseline CD8+PD-1+ and CD4+PD-1+ T-cell frequencies in patients who had received PD-1 inhibitors were lower than those in patients who had not received PD-1 inhibitors (p < 0.001). In the former patients, there were no differences in PD-1+ T-cell frequencies between the responder and non-responder subgroups (p > 0.05), whereas in the latter patients, the levels of CD8+PD-1+ T cells, CD4+PD-1+ T cells, and CD8+PD-1+/CD4+PD-1+ ratio did not predict tumor response, progression-free survival (PFS), or overall survival (OS) (p>0.05). Furthermore, in multivariate analysis of patients treated with or without PD-1 inhibitors revealed that the levels of CD8+CD38+ T cells (OR = 2.806, p = 0.006) were associated with tumor response, whereas those of CD8+CD28+ T cells (p = 0.038, p = 0.001) and natural killer (NK) cells (p = 0.001, p = 0.027) were associated with PFS and OS. Although, these independent prognostic factors were associated with progressive tumor characteristics (p<0.05), with the exception of CD8+CD28+ T cells, changes in these factors before and after treatment were unassociated with tumor response (p > 0.05). Conclusion Circulating CD8+CD38+ T cells, CD8+CD28+ T cells, and NK cells were identified as potential prognostic factors for tumor response and survival in patients with HCC. Contrastingly, although PD-1 inhibitors can effectively block the T cell PD-1 receptor, the baseline PD-1+ T-cell frequencies and changes in the frequency of these cells have limited prognostic value.
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Affiliation(s)
- Hongyu Wang
- Department of Interventional Therapy, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Huijie Huang
- Department of Laboratory Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ting Liu
- Department of Laboratory Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yaoming Chen
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jinwei Li
- Department of Interventional Therapy, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Min He
- Department of Laboratory Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jianxin Peng
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Enyu Liang
- Department of Laboratory Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiaping Li
- Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Wendao Liu
- Department of Interventional Therapy, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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Duan Y, Zhang H, Tan T, Ye W, Yin K, Yu Y, Kang M, Yang J, Liao R. The immune response of hepatocellular carcinoma after locoregional and systemic therapies: The available combination option for immunotherapy. Biosci Trends 2024; 17:427-444. [PMID: 37981319 DOI: 10.5582/bst.2023.01275] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2023]
Abstract
Hepatocellular carcinoma (HCC) is associated with a highly heterogeneous immune environment that produces an immune response to various locoregional treatments (LRTs), which in turn affects the effectiveness of immunotherapy. Although LRTs still dominate HCC therapies, 50-60% of patients will ultimately be treated with systemic therapies and might receive those treatments for the rest of their life. TACE, SIRT, and thermal ablation can dramatically increase the immunosuppressive state of HCC, a condition that can be addressed by combination with immunotherapy to restore the activity of lymphocytes and the secretion of cellular immune factors. Immune treatment with locoregional and systemic treatments has dramatically changed the management of HCC. In this review, we examine the research on the changes in the immune microenvironment after locoregional or systemic treatment. We also summarize the regulation of various immune cells and immune factors in the tumor microenvironment and discuss the different infiltration degrees of immune cells and factors on the prognosis of HCC to better compare the efficacy between different treatment methods from the perspective of the tumor microenvironment. This information can be used to help develop treatment options for the upcoming new era of HCC treatment in the future.
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Affiliation(s)
- Yuxin Duan
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hua Zhang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tao Tan
- Chongqing Health Statistics Information Center, Chongqing, China
| | - Wentao Ye
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Kunli Yin
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yanxi Yu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Meiqing Kang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jian Yang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Rui Liao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Zhao M, Duan X, Mi L, Shi J, Li N, Yin X, Han X, Wang J, Han G, Hou J, Yin F. Prognosis of hepatocellular carcinoma and its association with immune cells using systemic inflammatory response index. Future Oncol 2022; 18:2269-2288. [PMID: 35440159 DOI: 10.2217/fon-2021-1087] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 04/04/2022] [Indexed: 11/21/2022] Open
Abstract
Aim: To explore the prognostic value of the systemic inflammatory response index (SIRI) and peripheral blood T-cell subsets in patients with hepatocellular carcinoma (HCC) and the relationship between them. Materials & methods: We treated 352 patients with HCC with sorafenib and/or immune checkpoint inhibitors (ICIs) and analyzed SIRI and peripheral blood T cells. Results: SIRI was an independent prognostic factor for patients with HCC receiving systemic therapy. Patients with high SIRI and low baseline peripheral blood T-cell counts showed a poor response to ICIs. SIRI was significantly and negatively correlated with CD3+, CD4+ and CD8+ T-cell counts. Conclusion: SIRI markers can be employed to noninvasively assess the presence of cancer-promoting inflammation in the tumor microenvironment and predict the efficacy of targeted therapy and immunotherapy.
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Affiliation(s)
- Man Zhao
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Xiaoling Duan
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Lili Mi
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Jianfei Shi
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Ning Li
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Xiaolei Yin
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Xin Han
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Jinfeng Wang
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Guangjie Han
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Jiaojiao Hou
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
| | - Fei Yin
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Heibei, PR China
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Wang H, Zhang G, Fan W, Wu Y, Zhang J, Xue M, Zhao Y, Yao W, Li J. Clinical Significance of Peripheral Blood Lymphocyte Subtypes and Cytokines in Patients with Hepatocellular Carcinoma Treated with TACE. Cancer Manag Res 2022; 14:451-464. [PMID: 35153515 PMCID: PMC8827642 DOI: 10.2147/cmar.s342527] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 12/24/2021] [Indexed: 12/12/2022] Open
Affiliation(s)
- Hongyu Wang
- Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China
| | - Guixiong Zhang
- Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China
| | - Wenzhe Fan
- Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China
| | - Yanqin Wu
- Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China
| | - Jiang Zhang
- Department of Clinical Laboratory, The first Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China
| | - Miao Xue
- Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China
| | - Yue Zhao
- Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China
| | - Wang Yao
- Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China
| | - Jiaping Li
- Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China
- Correspondence: Jiaping Li, Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China, Tel +86-20-13352890908, Fax +86-20-87755766, Email
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Biondetti P, Saggiante L, Ierardi AM, Iavarone M, Sangiovanni A, Pesapane F, Fumarola EM, Lampertico P, Carrafiello G. Interventional Radiology Image-Guided Locoregional Therapies (LRTs) and Immunotherapy for the Treatment of HCC. Cancers (Basel) 2021; 13:5797. [PMID: 34830949 PMCID: PMC8616392 DOI: 10.3390/cancers13225797] [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: 10/08/2021] [Revised: 11/16/2021] [Accepted: 11/16/2021] [Indexed: 12/12/2022] Open
Abstract
Image-guided locoregional therapies (LRTs) are a crucial asset in the treatment of hepatocellular carcinoma (HCC), which has proven to be characterized by an impaired antitumor immune status. LRTs not only directly destroy tumor cells but also have an immunomodulating role, altering the tumor microenvironment with potential systemic effects. Nevertheless, the immune activation against HCC induced by LRTs is not strong enough on its own to generate a systemic significant antitumor response, and it is incapable of preventing tumor recurrence. Currently, there is great interest in the possibility of combining LRTs with immunotherapy for HCC, as this combination may result in a mutually beneficial and synergistic relationship. On the one hand, immunotherapy could amplify and prolong the antitumoral immune response of LRTs, reducing recurrence cases and improving outcome. On the other hand, LTRs counteract the typical immunosuppressive HCC microenvironment and status and could therefore enhance the efficacy of immunotherapy. Here, after reviewing the current therapeutic options for HCC, we focus on LRTs, describing for each of them the technique and data on its effect on the immune system. Then, we describe the current status of immunotherapy and finally report the recently published and ongoing clinical studies testing this combination.
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Affiliation(s)
- Pierpaolo Biondetti
- Diagnostic and Interventional Radiology Department, IRCCS Cà Granda Fondazione Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy; (A.M.I.); (G.C.)
| | - Lorenzo Saggiante
- Postgraduate School in Radiodiagnostics, Università degli Studi di Milano, 20122 Milan, Italy;
| | - Anna Maria Ierardi
- Diagnostic and Interventional Radiology Department, IRCCS Cà Granda Fondazione Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy; (A.M.I.); (G.C.)
| | - Massimo Iavarone
- Gastroenterology Department, IRCCS Cà Granda Fondazione Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy; (M.I.); (A.S.); (P.L.)
| | - Angelo Sangiovanni
- Gastroenterology Department, IRCCS Cà Granda Fondazione Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy; (M.I.); (A.S.); (P.L.)
| | - Filippo Pesapane
- Radiology Department, IEO European Institute of Oncology IRCCS, 20122 Milan, Italy;
| | - Enrico Maria Fumarola
- Diagnostic and Interventional Radiology Department, ASST Santi Paolo e Carlo, 20122 Milan, Italy;
| | - Pietro Lampertico
- Gastroenterology Department, IRCCS Cà Granda Fondazione Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy; (M.I.); (A.S.); (P.L.)
| | - Gianpaolo Carrafiello
- Diagnostic and Interventional Radiology Department, IRCCS Cà Granda Fondazione Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy; (A.M.I.); (G.C.)
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Immune Responses Following Locoregional Treatment for Hepatocellular Carcinoma: Possible Roles of Adjuvant Immunotherapy. Pharmaceutics 2021; 13:pharmaceutics13091387. [PMID: 34575463 PMCID: PMC8471821 DOI: 10.3390/pharmaceutics13091387] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/29/2021] [Accepted: 08/30/2021] [Indexed: 12/22/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common cause of cancer-related deaths worldwide. Unlike other types of cancer, HCC can be treated with locoregional treatments (LRTs) such as radiofrequency ablation (RFA) or transarterial chemoembolization (TACE). However, recurrences following LRTs are common, and strategies to improve long-term outcomes need to be developed. The exhaustion of anti-tumor immunity in HCC has been well established in many reports and the immunomodulatory effects of LRTs (enhancement of tumor antigen-specific T cell responses after RFA, reduction of effector regulatory T cells after TACE) have also been reported in several previous studies. However, a comprehensive review of previous studies and the possible roles of immunotherapy following LRTs in HCC are not known. In this review, we discuss the immunological evidence of current clinical trials using LRTs and combined immunotherapies, and the possible role of this strategy.
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9
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Mahgoub S, Abosalem H, Emara M, Kotb N, Maged A, Soror S. Restoring NK cells functionality via cytokine activation enhances cetuximab-mediated NK-cell ADCC: A promising therapeutic tool for HCC patients. Mol Immunol 2021; 137:221-227. [PMID: 34284214 DOI: 10.1016/j.molimm.2021.07.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/08/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022]
Abstract
Natural Killer (NK) cells are considered the first line of defense against viral infections and tumors. Several factors affect NK cytotoxic activity rendering it dysfunctional and thereby impeding the ability to scavenge abnormal cells as a part of immune escaping mechanisms induced by different types of cancers. NK cells play a crucial role augmenting the activity of various types of anticancer mAb since dysfunctional NK cells are the main reason for the low response to these therapies. To this light, we examined the phenotypic characters of the circulating NK cells isolated from HCC patients compared to healthy controls. Then, dysfunctional NK cells, from HCC patients, were reactivated with cytokines cocktail and their cytotoxic activity with the anti-EGFR mAb "cetuximab" was investigated. This showed a downregulation of patients NK cells activating receptors (NKP30, NKP46, NKG2D and CD16) as well as CD56 and up-regulation of NKG2A inhibitory receptor. We also reported an increase in aberrant CD56- NK cells subset in peripheral blood of HCC patients compared to healthy controls. Thus, confirming the dysfunctionality of peripheral NK cells isolated from HCC patients. Cytokines re-activation of those NK cells lead to upregulation of NK activating receptors and downregulation of inhibitory receptor. Moreover, the percentage of aberrant CD56- NK cells subset was reduced. Here, we proved that advanced HCC patients have an increased percentage of more immature and noncytotoxic NK cell subsets in their peripheral blood, which might account for the low cytotoxicity noticed in those patients. A significant improvement in the cytotoxicity against HCC was noticed upon using reactivated NK cells combined with cetuximab. Therefore, this study highlights the potential recruitment of NK immune cells along with cetuximab to enhance cytotoxicity against HCC.
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Affiliation(s)
- Shahenda Mahgoub
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Ein-Helwan, Cairo, 11795, Egypt.
| | - Hadeer Abosalem
- Deputy of Technical Manager, Biotechnology Unit, Egyptian Drug Authority (EDA), Giza, 12654, Egypt.
| | - Mohamed Emara
- Department of Microbiology and Immunology, Faculty of Pharmacy, Helwan University, Ein-Helwan, Cairo, 11795, Egypt.
| | - Nahla Kotb
- Manager of Blood Derivative Unit, Egyptian Drug Authority (EDA), Giza, 12654, Egypt.
| | - A Maged
- National Hepatology and Tropical Medicine Research Institute (NHTMRI), 11441, Cairo, Egypt.
| | - Sameh Soror
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Ein-Helwan, Cairo, 11795, Egypt.
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Wang H, Lin C, Fan W, Zhang J, Zhang Y, Yao W, Li J. Dynamic Changes in the Neutrophil-to-Lymphocyte Ratio Predict the Prognosis of Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization. Cancer Manag Res 2020; 12:3433-3444. [PMID: 32523374 PMCID: PMC7234956 DOI: 10.2147/cmar.s245396] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 04/21/2020] [Indexed: 12/24/2022] Open
Abstract
Purpose To examine the effect of dynamic changes in neutrophil-to-lymphocyte ratio (NLR) on tumor response and overall survival (OS) in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). Patients and Methods Data from 181 patients with HCC were retrospectively collected. White blood cell, neutrophil and lymphocyte counts, and the NLR were obtained 1–3 days before as well as 3–6 weeks and 3 months after TACE. Patients were divided into two groups at each time point according to the mean value of NLR, and also divided into continuous decrease, fluctuating increase-decrease (I-D), fluctuating decrease-increase (D-I), and continuous increase groups according to the dynamic changes in the NLR. The dynamic changes in blood counts and NLR were analyzed using repeated-measures ANOVA. The odds ratios (ORs) for tumor response in different NLR groups were examined using a multivariate logistic regression model. Finally, the prognostic value of the dynamic changes in the NLR was examined using Cox regression models. Results Continuous decline of white blood cell counts, neutrophil counts and lymphocyte counts were observed at 3–6 weeks and 3 months after TACE treatment. The NLR increased slightly and then decreased substantially in responders, while it increased slightly and then significantly in non-responders, with a significant interaction effect of Time × Tumor response (P = 0.005). NLR grouping before TACE, 3–6 weeks and 3 months after TACE was not associated with tumor response, and only 3 months after TACE did, it shows a significant difference in univariate survival analyses (NLR > 2.5 vs NLR ≤ 2.5, hazard ratio [HR] = 2.442, 95% confidence interval (CI): 1.545, 3.860). The changes in the NLR were significantly correlated with tumor response and OS. Non-responders for TACE were more common in the continuous NLR increase group (OR = 6.230, 95% CI: 1.848–21.001) and in the fluctuating D-I group (OR = 5.702, 95% CI: 1.480–21.957). Multivariate analyses revealed that these two patient groups also showed poorer OS (HR = 2.351, 95% CI: 1.120–4.605 and HR = 2.320, 95% CI: 1.187–4.533, respectively). Conclusion Dynamic changes in the NLR may be better predictors of tumor response and OS than static NLR values, but more data are needed.
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Affiliation(s)
- Hongyu Wang
- Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, People's Republic of China
| | - Chuyang Lin
- Department of Cancer Prevention Center, Sun Yat-sen University Cancer Center, Guangzhou 510080, People's Republic of China
| | - Wenzhe Fan
- Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, People's Republic of China
| | - Jiang Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, People's Republic of China
| | - Yingqiang Zhang
- Department of Interventional Radiology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, People's Republic of China
| | - Wang Yao
- Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, People's Republic of China
| | - Jiaping Li
- Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, People's Republic of China
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11
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Lewis AR, Padula CA, McKinney JM, Toskich BB. Ablation plus Transarterial Embolic Therapy for Hepatocellular Carcinoma Larger than 3 cm: Science, Evidence, and Future Directions. Semin Intervent Radiol 2019; 36:303-309. [PMID: 31680721 DOI: 10.1055/s-0039-1697641] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Thermal ablation is widely regarded as definitive therapy for early-stage hepatocellular carcinoma, but its efficacy decreases in tumors greater than 3 cm. Extensive clinical studies have supported improved outcomes provided through combining transarterial embolic therapy with ablation in the treatment of larger tumors. This article will provide a survey of the science and data for combination therapy in both thermal and nonthermal ablation modalities, as well as describe emerging applications.
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Affiliation(s)
- Andrew R Lewis
- Division of Interventional Radiology, Department of Radiology, Mayo Clinic, Jacksonville, Florida
| | - Carlos A Padula
- Division of Interventional Radiology, Department of Radiology, Mayo Clinic, Jacksonville, Florida
| | - J Mark McKinney
- Division of Interventional Radiology, Department of Radiology, Mayo Clinic, Jacksonville, Florida
| | - Beau B Toskich
- Division of Interventional Radiology, Department of Radiology, Mayo Clinic, Jacksonville, Florida
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12
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Li W, Ni CF. Current status of the combination therapy of transarterial chemoembolization and local ablation for hepatocellular carcinoma. Abdom Radiol (NY) 2019; 44:2268-2275. [PMID: 31016345 DOI: 10.1007/s00261-019-01943-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW To review the current status and ideal time interval of the combination therapy of transarterial chemoembolization (TACE) and local ablation for patients with HCCs. RECENT FINDINGS In recent years, local ablation has been proposed as an alternative curative treatment in the management of HCC. Additionally, many treatment options are available including TACE molecular targeted agents and immune checkpoint inhibitors. Similar overall survival rates and prognoses have been obtained with radiofrequency ablation (RFA) microwave ablation (MWA) and cryoablation for patients with HCCs up to 3 cm in diameter. Yet, MWA has shown superiority in treating large HCCs while cryoablation has several advantages compared with RFA or MWA. Furthermore, the treatment strategy of TACE combined with local ablation is widely accepted by many physicians in order to further increase the survival rate and improve the prognosis of patients with HCCs. However, the time interval between the two sessions of combination therapy remains uncertain in the current guidelines. Combination therapy of TACE and local ablation has advantages on survival and prognosis in patients with HCC compared with monotherapy. Good patient selection for the right modality needs to be carried out to guarantee the most efficacious treatment for HCC patients. Further studies are needed to find the ideal time interval between TACE and local ablation for HCC patients.
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13
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Greten TF, Mauda-Havakuk M, Heinrich B, Korangy F, Wood BJ. Combined locoregional-immunotherapy for liver cancer. J Hepatol 2019; 70:999-1007. [PMID: 30738077 PMCID: PMC6462230 DOI: 10.1016/j.jhep.2019.01.027] [Citation(s) in RCA: 151] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 01/23/2019] [Accepted: 01/26/2019] [Indexed: 02/07/2023]
Abstract
Locoregional therapies are commonly used to treat patients with hepatocellular carcinoma. It has been noted for many years that locoregional therapies may have additional systemic effects other than simple tumour elimination. Immunological "side effects" have been described in response to locoregional therapies in animal studies and in patients. With the advent of immunotherapy for hepatocellular carcinoma, there is increasing interest in determining the best way to combine immunotherapy with locoregional therapies. Herein, we provide a compact summary of answered and unanswered questions in the field, including: What animal model is best suited to test combined immune-locoregional treatments? How does tumour cell death affect immune responses? What type of immune responses have been observed in patients treated with different types of locoregional therapies? What can be surmised from the results of the first study testing the combination of locoregional therapy with immune checkpoint blockade? Finally, we discuss the outlook for this rapidly growing area of research, focussing on the issues which must be overcome to bridge the gap between interventional radiology and cancer immunology.
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Affiliation(s)
- Tim F Greten
- Gastrointestinal Malignancies Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, United States; NCI CCR Liver Cancer Program, United States.
| | - Michal Mauda-Havakuk
- Center for Interventional Oncology, Radiology and Imaging Sciences, NIH Clinical Center & Center for Cancer Research, National Institutes of Health, United States; NIBIB & NIH Clinical Center Clinical Translational Research Fellowship Program, United States
| | - Bernd Heinrich
- Gastrointestinal Malignancies Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, United States
| | - Firouzeh Korangy
- Gastrointestinal Malignancies Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, United States
| | - Bradford J Wood
- Center for Interventional Oncology, Radiology and Imaging Sciences, NIH Clinical Center & Center for Cancer Research, National Institutes of Health, United States; NCI CCR Liver Cancer Program, United States
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14
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Cui W, Fan W, Huang K, Wang Y, Lu M, Yao W, Li J. Large hepatocellular carcinomas: treatment with transarterial chemoembolization alone or in combination with percutaneous cryoablation. Int J Hyperthermia 2018; 35:239-245. [PMID: 30200796 DOI: 10.1080/02656736.2018.1493235] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Affiliation(s)
- Wei Cui
- Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wenzhe Fan
- Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Kunbo Huang
- Department of Ultrasonography, the First Hospital of China Medical University, ShenYang, China
| | - Yu Wang
- Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Mingjian Lu
- Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wang Yao
- Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiaping Li
- Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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15
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Impact of Interventional Oncology Therapies on Tumor Microenvironment and Strategies to Enhance Their Efficacy. AJR Am J Roentgenol 2018; 210:648-656. [PMID: 29364726 DOI: 10.2214/ajr.16.17677] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE We provide a brief review of the tumor microenvironment, the impact of six interventional radiology treatments on the tumor microenvironment, and potential methods to improve treatment efficacy. CONCLUSION Interventional oncology plays a unique role in cancer therapy, contributing to both antitumorigenic and protumorigenic effects.
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Yan QH, Xu DG, Shen YF, Yuan DL, Bao JH, Li HB, Lv YG. Observation of the effect of targeted therapy of 64-slice spiral CT combined with cryoablation for liver cancer. World J Gastroenterol 2017; 23:4080-4089. [PMID: 28652661 PMCID: PMC5473127 DOI: 10.3748/wjg.v23.i22.4080] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Revised: 02/15/2017] [Accepted: 03/06/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To observe the effect of targeted therapy with 64-slice spiral computed tomography (CT) combined with cryoablation for liver cancer.
METHODS A total of 124 patients (142 tumors) were enrolled into this study. According to the use of dual-slice spiral CT or 64-slice spiral CT as a guide technology, patients were divided into two groups: dual-slice group (n = 56, 65 tumors) and 64-slice group (n = 8, 77 tumors). All patients were accepted and received targeted therapy by an argon-helium superconducting surgery system. The guided scan times of the two groups was recorded and compared. In the two groups, the lesion ice coverage in diameter of ≥ 3 cm and < 3 cm were recorded, and freezing effective rate was compared. Hepatic perfusion values [hepatic artery perfusion (HAP), portal vein perfusion (PVP), and the hepatic arterial perfusion index (HAPI)] of tumor tissues, adjacent tissues and normal liver tissues at preoperative and postoperative four weeks in the two groups were compared. Local tumor changes were recorded and efficiency was compared at four weeks post-operation. Adverse events were recorded and compared between the two groups, including fever, pain, frostbite, nausea, vomiting, pleural effusion and abdominal bleeding.
RESULTS Guided scan times in the dual-slice group was longer than that in the 64-slice group (t = 11.445, P = 0.000). The freezing effective rate for tumors < 3 cm in diameter in the dual-slice group (81.58%) was lower than that in the 64-slice group (92.86%) (χ2 = 5.707, P = 0.017). The HAP and HAPI of tumor tissues were lower at four weeks post-treatment than at pre-treatment in both groups (all P < 0.05), and those in the 64-slice group were lower than that in the dual-slice group (all P < 0.05). HAP and PVP were lower and HAPI was higher in tumor adjacent tissues at post-treatment than at pre-treatment (all P < 0.05). Furthermore, the treatment effect and therapeutic efficacy in the dual-slice group were lower than the 64-slice group at four weeks post-treatment (all P < 0.05). Moreover, pleural effusion and intraperitoneal hemorrhage occurred in patients in the dual-slice group, while no complications occurred in the 64-slice group (all P < 0.05).
CONCLUSION 64-slice spiral CT applied with cryoablation in targeted therapy for liver cancer can achieve a safe and effective freezing treatment, so it is worth being used.
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12-O-Tetradecanoylphorbol-13-acetate (TPA) is anti-tumorigenic in liver cancer cells via inhibiting YAP through AMOT. Sci Rep 2017; 7:44940. [PMID: 28322318 PMCID: PMC5359578 DOI: 10.1038/srep44940] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 02/15/2017] [Indexed: 12/22/2022] Open
Abstract
TPA stimulates carcinogenesis in various types of cancers. However, we found that TPA inhibits transformative phenotypes in liver cancer cells via the translocation of YAP from the nucleus, where it functions as a transcriptional co-factor, to the cytoplasm. Such effects led to a separation of YAP from its dependent transcription factors. The inhibitory effects of TPA on YAP were AMOT dependent. Without AMOT, TPA was unable to alter YAP activity. Importantly, the depletion of YAP and AMOT blocked the TPA-reduced transformative phenotypes. In sum, TPA has been established as an anti-tumorigenic drug in liver cancer cells via YAP and AMOT.
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