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Zhang D, Zhu Y, Shen Z, Ma S, Liu S, Lu Z. Immunosenescence and immunotherapy in elderly patients with hepatocellular carcinoma. Semin Cancer Biol 2025; 111:60-75. [PMID: 40020977 DOI: 10.1016/j.semcancer.2025.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 02/11/2025] [Accepted: 02/17/2025] [Indexed: 03/03/2025]
Abstract
Liver cancer, more specifically hepatocellular carcinoma (HCC), is a global health issue and one of the dominant causes of cancer death around the world. In the past few decades, remarkable advances have been achieved in the systemic therapy of HCC. Immune checkpoint inhibitors (ICIs) have become a therapy mainstay for advanced HCC and have shown promise in the neoadjuvant therapy before resection. Despite these significant advancements, the compositions and functions of the immune system occur various alterations with age, called "immunosenescence", which may affect the antitumor effects and safety of ICIs, thus raising concerns that immunosenescence may impair elderly patients' response to ICIs. Therefore, it is important to learn more about the immunosenescence characteristics of elderly patients. However, the real-world elderly HCC patients may be not accurately represented by the elderly patients included in the clinical trials, affecting the generalizability of the efficacy and safety profiles from the clinical trials to the real-world elderly patients. This review summarizes the characteristics of immunosenescence and its influence on HCC progression and immunotherapy efficacy as well as provides the latest progress in ICIs available for HCC and discusses their treatment efficacy and safety on elderly patients. In the future, more studies are needed to clarify the mechanisms of immunosenescence in HCC, and to find sensitive screening tools or biomarkers to identify the patients who may benefit from ICIs.
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Affiliation(s)
- Dengyong Zhang
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China
| | - Yan Zhu
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zhengchao Shen
- Department of General Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241001, China
| | - Shuoshuo Ma
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China
| | - Sihua Liu
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China
| | - Zheng Lu
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China.
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Zhang WC, Du KY, Yu SF, Guo XE, Yu HX, Wu DY, Pan C, Zhang C, Wu J, Bian LF, Cao LP, Yu J. Systemic chemotherapy improves outcome of hepatocellular carcinoma patients treated with transarterial chemoembolization. Hepatobiliary Pancreat Dis Int 2025; 24:157-163. [PMID: 39632156 DOI: 10.1016/j.hbpd.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 11/13/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND Transarterial chemoembolization (TACE) based neoadjuvant therapy was proven effective in hepatocellular carcinoma (HCC). Recently, tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) also showed promise in HCC treatment. However, the prognostic benefits associated with these treatments remain uncertain. This study aimed to explore the relationship between pathologic response and prognostic features in HCC patients who received neoadjuvant therapy. METHODS HCC patients who received TACE either with or without TKIs/ICIs as neoadjuvant therapy before liver resection were retrospectively collected from the First Affiliated Hospital, Zhejiang University School of Medicine in China. Pathologic response was determined by calculating the proportion of non-viable area within the tumor. Major pathologic response (MPR) was defined as the presence of non-viable tumor cells reaching a minimum of 90%. Complete pathologic response (CPR) was characterized by the absence of viable cells observed in the tumor. RESULTS A total of 481 patients meeting the inclusion criteria were enrolled, with 76 patients (15.8%) achieving CPR and 179 (37.2%) reaching MPR. The median recurrence-free survival (mRFS) in the CPR + MPR group was significantly higher than the non-MPR group (31.3 vs. 25.1 months). The difference in 3-year overall survival (OS) rate was not significant. Multivariate Cox regression analysis identified failure to achieve MPR (hazard ratio = 1.548, 95% confidence interval: 1.122-2.134; P = 0.008), HBsAg positivity (HR = 1.818, 95% CI: 1.062-3.115, P = 0.030), multiple lesions (HR = 2.278, 95% CI: 1.621-3.195, P < 0.001), and baseline tumor size > 5 cm (HR = 1.712, 95% CI: 1.031-2.849, P = 0.038) were independent risk factors for RFS. Subgroup analysis showed that 67 of 93 (72.0%) patients who received the combination of TACE, TKIs, and ICIs achieved MPR + CPR. CONCLUSIONS In individuals who received TACE-based neoadjuvant therapy for HCC, failure to achieve MPR emerges as an independent risk factor for RFS. Notably, the combination of TACE, TKIs, and ICIs demonstrated the highest rate of MPR.
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Affiliation(s)
- Wei-Chen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Ke-Yi Du
- Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Song-Feng Yu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xue-E Guo
- Department of Nursing, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Han-Xi Yu
- International Institutes of Medicine, Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, China
| | - Dong-Yan Wu
- Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Cheng Pan
- The 903rd Hospital of PLA, Hangzhou 310000, China
| | - Cheng Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jian Wu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Li-Fang Bian
- Department of Nursing, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Lin-Ping Cao
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jun Yu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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Li C, Diao YK, Li YF, Lv SD, Wang XM, Wang XD, Zheng QX, Wang H, Liu H, Lin KY, Liang YJ, Zhou YH, Gu WM, Wang MD, Yao LQ, Xu XF, Xu JH, Gu LH, Pawlik TM, Shen F, Yang T. α-Fetoprotein model versus Milan criteria in predicting outcomes after hepatic resection for hepatocellular carcinoma: multicentre study. BJS Open 2025; 9:zraf041. [PMID: 40202169 PMCID: PMC11979696 DOI: 10.1093/bjsopen/zraf041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 01/20/2025] [Accepted: 02/21/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND The Milan criteria and the French α-fetoprotein (AFP) model have both been validated for predicting outcomes after liver transplantation for hepatocellular carcinoma, with the Milan criteria also used for predicting outcomes after hepatic resection. The aim of this study was to evaluate the AFP model's predictive value for recurrence and survival following hepatocellular carcinoma resection and compare its performance with that of the Milan criteria. METHODS Data for patients who underwent hepatocellular carcinoma resection between 2002 and 2021 were analysed. For both the AFP model and Milan criteria, patients were divided into two groups: those with hepatocellular carcinoma within and beyond the AFP model (scores ≤ 2 and > 2 points, respectively) and the Milan criteria. Cumulative recurrence and overall survival rates were compared between patients within and beyond the AFP model. Predictions of recurrence and overall survival by the AFP model and Milan criteria were compared using net reclassification improvement and area under the receiver operating characteristic curve analyses. RESULTS Among 1968 patients evaluated, 1058 (53.8%) and 940 (47.8%) were classified as beyond on the AFP model and Milan criteria, respectively. After controlling for competing factors on multivariable analyses, being beyond the AFP model was independently associated with recurrence and worse overall survival after resection of hepatocellular carcinoma. Time-dependent net reclassification improvement and area under the receiver operating characteristic curve analyses demonstrated that the AFP model was superior to the Milan criteria in predicting recurrence. Of note, patients who were classified as beyond both the Milan criteria and AFP model had an even higher risk of postoperative recurrence and mortality (hazard ratios 1.51 and 1.47, respectively). CONCLUSION The French AFP model demonstrated superior prognostic accuracy to the Milan criteria in predicting recurrence and survival after hepatocellular carcinoma resection. The AFP model not only effectively stratified patient risk but also identified a subgroup of high-risk patients among those beyond the Milan criteria.
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Affiliation(s)
- Chao Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yong-Kang Diao
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yi-Fan Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Shao-Dong Lv
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Xian-Ming Wang
- Department of General Surgery, First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Xue-Dong Wang
- Hepatopancreatobiliary Centre, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing, China
| | - Qi-Xuan Zheng
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Hong Wang
- Department of General Surgery, Liuyang People’s Hospital, Liuyang, China
| | - Han Liu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Centre, First Hospital of Jilin University, Changchun, China
| | - Kong-Ying Lin
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fujian, China
| | - Ying-Jian Liang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ya-Hao Zhou
- Department of Hepatobiliary Surgery, Pu’er People’s Hospital, Pu’er, China
| | - Wei-Min Gu
- First Department of General Surgery, Fourth Hospital of Harbin, Harbin, Heilongjiang, China
| | - Ming-Da Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Lan-Qing Yao
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Xin-Fei Xu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jia-Hao Xu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Li-Hui Gu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Timothy M Pawlik
- Department of Surgery, Ohio State University, Wexner Medical Centre, Columbus, Ohio, USA
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
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Tabrizian P, Holzner ML, Ajmera V, Kim AK, Zhou K, Schnickel GT, Torosian K, Hoteit M, Marino R, Li M, Yao F, Florman SS, Schwartz ME, Mehta N. Intention-to-treat outcomes of patients with hepatocellular carcinoma receiving immunotherapy before liver transplant: The multicenter VITALITY study. J Hepatol 2025; 82:512-522. [PMID: 39255928 DOI: 10.1016/j.jhep.2024.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 08/23/2024] [Accepted: 09/03/2024] [Indexed: 09/12/2024]
Abstract
BACKGROUND & AIMS The use of immune checkpoint inhibitors (ICIs) in patients with advanced hepatocellular carcinoma (HCC) has become widespread with encouraging outcomes in the neoadjuvant setting. Safety and intention-to-treat (ITT) outcomes in the peri-transplant setting are currently based on small and heterogenous single-center reports. METHODS This first multiregional US study (2016-2023) included 117 consecutive patients with HCC assessed for liver transplantation (LT) and treated preoperatively with ICIs. ITT and survival analyses were conducted with evaluation of post-LT rejection rates. RESULTS In total, 86 (73.5%) patients exceeded Milan criteria (MC) and 65 (75.6%) were successfully downstaged within a median of 5.6 months; 43 (36.7%) underwent transplantation, including 18 (15.4%) within MC and 23 (19.7%) who were initially beyond but were downstaged. Overall, 94% of the cohort received concurrent ICIs and locoregional therapies. No grade 4-5 adverse events occurred on the waiting list. The 3-year cumulative probability of dropout was 28% for those within MC and 48% for those beyond. Independent predictors of dropout included being beyond MC (p <0.001), alpha-fetoprotein doubling from baseline (p = 0.014) and radiographic responses (p <0.001). The 3-year ITT survival rate was 71.1% (73.5% within MC vs. 69.7% beyond MC, p = 0.329), with a 3-year post-LT survival rate of 85%. Post-LT rejection occurred in seven patients, six received their last dose of ICI less than 3 months prior to LT, resulting in one graft loss. CONCLUSIONS The first multicenter evaluation of patients with HCC receiving ICIs pre-LT demonstrates favorable survival and safety outcomes, justifying continued utilization and further evaluation of this strategy in clinical practice. High tumor burden, doubling of alpha-fetoprotein levels, and radiographic response were identified as predictors of unfavorable oncologic outcomes. IMPACT AND IMPLICATIONS Herein, we report results from the first multicenter evaluation of pretransplant immune checkpoint inhibitors in hepatocellular carcinoma to show promising intention-to-treat survival, safety and rejection rates. Immune checkpoint inhibitors, either alone or combined with locoregional therapy, demonstrate reliable efficacy. This preoperative strategy could be particularly beneficial for high-risk patients, including those requiring downstaging or with elevated alpha-fetoprotein levels despite locoregional treatment. These findings fill current knowledge gaps and offer reassuring evidence for the feasibility of pretransplant use of immune checkpoint inhibitors, pending results from ongoing trials.
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Affiliation(s)
- Parissa Tabrizian
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
| | - Matthew L Holzner
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Veeral Ajmera
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, San Diego, California, USA
| | - Amy K Kim
- Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Kali Zhou
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Gabriel T Schnickel
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, University of California San Diego, San Diego, California, USA
| | - Kelly Torosian
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, San Diego, California, USA
| | - Maarouf Hoteit
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Rebecca Marino
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Michael Li
- Division of Gastroenterology/Hepatology, University of California San Francisco, San Francisco, California, USA
| | - Francis Yao
- Division of Gastroenterology/Hepatology, University of California San Francisco, San Francisco, California, USA; Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Sander S Florman
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Myron E Schwartz
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Neil Mehta
- Division of Gastroenterology/Hepatology, University of California San Francisco, San Francisco, California, USA
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Wu F, Cao H, Ren S, Wu J, Liu X, Li Q, Xu Q, Chen J, Wang R, Chen S, Kuang S, Xia B, Li Y, Wang L, Li J, Li B, Li J, Lan T. Tertiary lymphoid structure-related score as a predictor for survival prognosis and immunotherapy response in head and neck squamous cell carcinoma. Front Immunol 2024; 15:1483497. [PMID: 39493749 PMCID: PMC11527632 DOI: 10.3389/fimmu.2024.1483497] [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: 08/20/2024] [Accepted: 10/01/2024] [Indexed: 11/05/2024] Open
Abstract
Background Substantial studies reveal that tertiary lymphoid structure (TLS) correlate with prognosis and immunotherapy response in various types of cancers. However, the predictive value of TLS, the specific immune cell subtype within TLS and their anti-tumor mechanisms remain unclear. Methods Based on 23 TLS-related genes (TLSRGs), we utilized bioinformatics methods to construct a scoring system, named TLSscore. By integrating RNA and single-cell sequencing data, we assessed the utility of TLSscore in head and neck squamous cell carcinoma (HNSCC). Flow cytometric sorting was used to isolate specific T cells subtypes, in vivo and in vitro experiments were conducted to demonstrate its anti-tumor effects. Results The TLSscore model was constructed and specific TLSscore-genes were found to consistently align with the spatial location of TLS. TLSscore has proven to be a robust predictive model for predicting survival prognosis, immune cell infiltration, somatic mutation and immunotherapy response. Notably, a specific PD1+CXCL13+CD8+T cell subtype was identified within TLS. Both in vivo and in vitro experiments demonstrated that PD1+CXCL13+CD8+T cell might represent a functional cell subtype exerting anti-tumor effects during the process of immune surveillance. Conclusions Our study presents a predictive model for TLS, which can evaluate its presence and predicts survival prognosis and immunotherapy response in HNSSC patients. Additionally, we identify a specific subtype of T cells that might elucidate the mechanism of TLS function in anti-tumor activities. This T cell subtype holds the potential to be a prognostic marker and a target for adoptive cell therapy (ACT) in the future.
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Affiliation(s)
- Fan Wu
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Haotian Cao
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Siqi Ren
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jiaying Wu
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xin Liu
- Department of Stomatology, Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
- Department of Stomatology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, Guangdong, China
| | - Qunxing Li
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Qiuping Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jiali Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ruixin Wang
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Suling Chen
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shijia Kuang
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Binbin Xia
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yanyan Li
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Liansheng Wang
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jintao Li
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Bowen Li
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jinsong Li
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Tianjun Lan
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
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Hung HC, Lai Y, Lee JC, Wang YC, Cheng CH, Wu TH, Wu TJ, Chou HS, Chan KM, Lee WC, Lee CF. Optimal treatment strategy and prognostic analysis of salvage liver transplantation for patients with early hepatocellular carcinoma recurrence after hepatectomy. Hepatol Res 2024; 54:838-850. [PMID: 38451566 DOI: 10.1111/hepr.14033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 02/11/2024] [Accepted: 02/16/2024] [Indexed: 03/08/2024]
Abstract
AIM We aimed to investigate the prognostic factors for salvage liver transplant in patients with early hepatocellular carcinoma recurrence after hepatectomy. METHODS This retrospective analysis included 53 patients who underwent salvage living-donor liver transplantation between January 2007 and January 2018. There were 24 and 29 patients in the early (recurrence ≤24 months after primary liver resection) and the late recurrence groups, respectively. RESULTS In the multivariate Cox regression model, pre-liver transplant downstaging therapy, early recurrence (ER) after primary liver resection , and recurrence-to-liver-transplant ≥12 months were independent risks to predict recurrent hepatocellular carcinoma recurrence after salvage living-donor liver transplantation. Compared with the late recurrence group, the ER group showed lower disease-free survival rates (p < 0.001); however, the overall survival rates did not differ between the two groups (p = 0.355). The 1-, 3-, and 5-year disease-free survival rates were 83.3%, 70.6%, and 66.2%, and 96.0%, 91.6%, and 91.6% in the early and late recurrence groups, respectively. When stratified by recurrence-to-liver transplant time and pre-liver transplant downstaging therapy in the ER group, disease-free survival and overall survival rates were significantly different. CONCLUSION ER after primary liver resection with advanced tumor status and a longer period of recurrence-to-liver-transplant (≥12 months) have a negative impact on salvage liver transplant. Our findings provide novel recommendations for treatment strategies and eligibility for salvage liver transplant candidates.
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Affiliation(s)
- Hao-Chien Hung
- Division of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Yin Lai
- Division of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Jin-Chiao Lee
- Division of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Yu-Chao Wang
- Division of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Chih-Hsien Cheng
- Division of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Tsung-Han Wu
- Division of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Ting-Jung Wu
- Division of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Hong-Shiue Chou
- Division of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Kun-Ming Chan
- Division of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Wei-Chen Lee
- Division of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Chen-Fang Lee
- Division of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Chang-Gung University College of Medicine, Taoyuan, Taiwan
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7
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Fu Y, Guo X, Sun L, Cui T, Wu C, Wang J, Liu Y, Liu L. Exploring the role of the immune microenvironment in hepatocellular carcinoma: Implications for immunotherapy and drug resistance. eLife 2024; 13:e95009. [PMID: 39146202 PMCID: PMC11326777 DOI: 10.7554/elife.95009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 08/04/2024] [Indexed: 08/17/2024] Open
Abstract
Hepatocellular carcinoma (HCC), the most common type of liver tumor, is a leading cause of cancer-related deaths, and the incidence of liver cancer is still increasing worldwide. Curative hepatectomy or liver transplantation is only indicated for a small population of patients with early-stage HCC. However, most patients with HCC are not candidates for radical resection due to disease progression, leading to the choice of the conventional tyrosine kinase inhibitor drug sorafenib as first-line treatment. In the past few years, immunotherapy, mainly immune checkpoint inhibitors (ICIs), has revolutionized the clinical strategy for HCC. Combination therapy with ICIs has proven more effective than sorafenib, and clinical trials have been conducted to apply these therapies to patients. Despite significant progress in immunotherapy, the molecular mechanisms behind it remain unclear, and immune resistance is often challenging to overcome. Several studies have pointed out that the complex intercellular communication network in the immune microenvironment of HCC regulates tumor escape and drug resistance to immune response. This underscores the urgent need to analyze the immune microenvironment of HCC. This review describes the immunosuppressive cell populations in the immune microenvironment of HCC, as well as the related clinical trials, aiming to provide insights for the next generation of precision immunotherapy.
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Affiliation(s)
- Yumin Fu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, China
| | - Xinyu Guo
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Linmao Sun
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, China
| | - Tianming Cui
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, China
| | - Chenghui Wu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, China
| | - Jiabei Wang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, China
| | - Yao Liu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, China
| | - Lianxin Liu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, China
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8
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Li Z, Hong Q, Li K. Nomogram predicting survival in patients with lymph node-negative hepatocellular carcinoma based on the SEER database and external validation. Eur J Gastroenterol Hepatol 2024; 36:904-915. [PMID: 38652516 PMCID: PMC11136272 DOI: 10.1097/meg.0000000000002756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 02/19/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND The relationship between lymph node (LN) status and survival outcome in hepatocellular carcinoma (HCC) is a highly controversial topic. The aim of this study was to investigate the prognostic factors in patients without LN metastasis (LNM) and to construct a nomogram to predict cancer-specific survival (CSS) in this group of patients. METHODS We screened 6840 eligible HCC patients in the Surveillance, Epidemiology and End Results（SEER）database between 2010 and 2019 and randomized them into a training cohort and an internal validation cohort, and recruited 160 patients from Zhongnan Hospital of Wuhan University as an external validation cohort. Independent prognostic factors obtained from univariate and multivariate analysis were used to construct a nomogram prediction model. The concordance index (C-index), area under curve (AUC), calibration plots and decision curve analysis (DCA) were used to assess the predictive power and clinical application of the model. RESULTS Univariate and multivariate analysis revealed age, gender, bone metastasis, lung metastasis, AFP, T stage, surgery and chemotherapy as independent prognostic factors. The C-index of the constructed nomogram for the training cohort, internal validation cohort and external validation cohort are 0.746, 0.740, and 0.777, respectively. In the training cohort, the AUC at 1-, 3-, and 5-year were 0.81, 0.800, and 0.800, respectively. Calibration curves showed great agreement between the actual observations and predictions for the three cohorts. The DCA results suggest that the nomogram model has more clinical application potential. CONCLUSION We constructed a nomogram to predict CSS in HCC patients without LNM. The model has been internally and externally validated to have excellent predictive performance and can help clinicians determine prognosis and make treatment decisions.
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Affiliation(s)
- Ziqiang Li
- Department of Hepatobiliary and Pancreatic Surgery, Hubei Provincial Clinical Medicine Research Center for Minimally Invasive Diagnosis and Treatment of Hepatobiliary and Pancreatic Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qingyong Hong
- Department of Hepatobiliary and Pancreatic Surgery, Hubei Provincial Clinical Medicine Research Center for Minimally Invasive Diagnosis and Treatment of Hepatobiliary and Pancreatic Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Kun Li
- Department of Hepatobiliary and Pancreatic Surgery, Hubei Provincial Clinical Medicine Research Center for Minimally Invasive Diagnosis and Treatment of Hepatobiliary and Pancreatic Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
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9
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Zhang R, Dai J, Yao F, Zhou S, Huang W, Xu J, Yu K, Chen Y, Fan B, Zhang L, Xu J, Li Q. Hypomethylation-enhanced CRTC2 expression drives malignant phenotypes and primary resistance to immunotherapy in hepatocellular carcinoma. iScience 2024; 27:109821. [PMID: 38770131 PMCID: PMC11103543 DOI: 10.1016/j.isci.2024.109821] [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: 07/19/2023] [Revised: 11/22/2023] [Accepted: 04/24/2024] [Indexed: 05/22/2024] Open
Abstract
The cyclic AMP-responsive element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) is a crucial regulator of hepatic lipid metabolism and gluconeogenesis and correlates with tumorigenesis. However, the mechanism through which CRTC2 regulates hepatocellular carcinoma (HCC) progression is largely unknown. Here, we found that increased CRTC2 expression predicted advanced tumor grade and stage, as well as worse prognosis in patients with HCC. DNA promoter hypomethylation led to higher CRTC2 expression in HCC. Functionally, CRTC2 contributed to HCC malignant phenotypes through the activated Wnt/β-catenin pathway, which could be abrogated by the small-molecular inhibitor XAV-939. Moreover, Crtc2 facilitated tumor growth while concurrently downregulating the PD-L1/PD-1 axis, resulting in primary resistance to immunotherapy. In immunocompetent mice models of HCC, targeting Crtc2 in combination with anti-PD-1 therapy prominently suppressed tumor growth by synergistically enhancing responsiveness to immunotherapy. Collectively, targeting CRTC2 might be a promising therapeutic strategy to sensitize immunotherapy in HCC.
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Affiliation(s)
- Ruizhi Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Hepatobiliary Cancers, Nanjing, Jiangsu Province 210000, China
| | - Jingjing Dai
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210000, China
| | - Feifan Yao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Hepatobiliary Cancers, Nanjing, Jiangsu Province 210000, China
| | - Suiqing Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Hepatobiliary Cancers, Nanjing, Jiangsu Province 210000, China
| | - Wei Huang
- Department of General Surgery, The Friendship Hospital of Ili Kazakh Autonomous Prefecture, Ili & Jiangsu Joint Institute of Health, Ili 835000, China
| | - Jiali Xu
- Department of Anesthesiology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province 210000, China
| | - Kai Yu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Hepatobiliary Cancers, Nanjing, Jiangsu Province 210000, China
| | - Yining Chen
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210000, China
| | - Boqiang Fan
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210000, China
| | - Liren Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Hepatobiliary Cancers, Nanjing, Jiangsu Province 210000, China
| | - Jing Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210000, China
| | - Qing Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Hepatobiliary Cancers, Nanjing, Jiangsu Province 210000, China
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province 210000, China
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10
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Li Y, Lai Y, Luo X, Wu J, Wu K, Ma H. Case report: Massive hepatocellular carcinoma with complete response to the non-surgical systematic treatment strategy. Front Oncol 2024; 14:1291131. [PMID: 38800409 PMCID: PMC11116599 DOI: 10.3389/fonc.2024.1291131] [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: 09/08/2023] [Accepted: 04/23/2024] [Indexed: 05/29/2024] Open
Abstract
Background The five-year recurrence rate of hepatocellular carcinoma (HCC) remains as high as 70%. A complete clinical response has not been observed without surgical resection. Here, we report a rare case of clinical complete response and long-term survival in a patient with massive HCC receiving treatment with immunotherapy, anti-angiogenic therapy, and radiotherapy. Case description A 38-year-old woman presented to our hospital for abdominal pain that persisted for 3 months. She was diagnosed as Barcelona Clinic Liver Cancer(BCLC) stage A, with a Cancer of the Liver Italian Program (CLIP) score of 3, American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis (TNM) staging systems stage IB. She refused surgical resection and trans-arterial chemoembolization and accepted a non-invasive systematic treatment strategy involving immunotherapy, anti-angiogenic therapy, and radiotherapy. Her tumor burden decreased, and she experienced partial response before radiotherapy. Following radiotherapy, she experienced a complete clinical response and has been alive for more than 36 months after her initial presentation. She is currently alive. Conclusion A non-invasive systematic treatment strategy is a potential radical treatment option for patients with massive HCC.
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Affiliation(s)
- Yun Li
- Department of Oncology, Heyuan Hospital of Guangdong Provincial People’s Hospital, Heyuan People’s Hospital, Heyuan, Guangdong, China
- Heyuan Key Laboratory of Molecular Diagnosis & Disease Prevention and Treatment, Doctors Station of Guangdong Province, Heyuan People's Hospital, Heyuan, Guangdong, China
| | - Yanzhen Lai
- Department of Oncology, Heyuan Hospital of Guangdong Provincial People’s Hospital, Heyuan People’s Hospital, Heyuan, Guangdong, China
- Heyuan Key Laboratory of Molecular Diagnosis & Disease Prevention and Treatment, Doctors Station of Guangdong Province, Heyuan People's Hospital, Heyuan, Guangdong, China
| | - Xuqiang Luo
- Department of Oncology, Heyuan Hospital of Guangdong Provincial People’s Hospital, Heyuan People’s Hospital, Heyuan, Guangdong, China
- Heyuan Key Laboratory of Molecular Diagnosis & Disease Prevention and Treatment, Doctors Station of Guangdong Province, Heyuan People's Hospital, Heyuan, Guangdong, China
| | - Jian Wu
- Department of Oncology, Heyuan Hospital of Guangdong Provincial People’s Hospital, Heyuan People’s Hospital, Heyuan, Guangdong, China
- Heyuan Key Laboratory of Molecular Diagnosis & Disease Prevention and Treatment, Doctors Station of Guangdong Province, Heyuan People's Hospital, Heyuan, Guangdong, China
| | - Kunpeng Wu
- Department of Oncology, Heyuan Hospital of Guangdong Provincial People’s Hospital, Heyuan People’s Hospital, Heyuan, Guangdong, China
- Heyuan Key Laboratory of Molecular Diagnosis & Disease Prevention and Treatment, Doctors Station of Guangdong Province, Heyuan People's Hospital, Heyuan, Guangdong, China
| | - Haiqing Ma
- Department of Oncology, Heyuan Hospital of Guangdong Provincial People’s Hospital, Heyuan People’s Hospital, Heyuan, Guangdong, China
- Heyuan Key Laboratory of Molecular Diagnosis & Disease Prevention and Treatment, Doctors Station of Guangdong Province, Heyuan People's Hospital, Heyuan, Guangdong, China
- Medical Research Center, Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
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11
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Tao J, Shen L, Zhuang M, Zhai C, Zeng H, Mao Y, Liu X. Suppression of AGRN enhances CD8+ T cell recruitment and inhibits breast cancer progression. FASEB J 2024; 38:e23582. [PMID: 38568853 DOI: 10.1096/fj.202302288r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 01/24/2024] [Accepted: 03/15/2024] [Indexed: 04/05/2024]
Abstract
Breast cancer (BC) stands as a prominent contributor to global cancer-related mortality, with an increasing incidence annually. This study aims to investigate AGRN gene expression in BC, as well as explore its influence on the tumor immune microenvironment. AGRN displayed a pronounced upregulation in BC tissues relative to paracancerous tissues. Single-cell RNA analysis highlighted AGRN-specific elevation within cancer cell clusters and also showed expression expressed in stromal as well as immune cell clusters. AGRN upregulation was positively correlated with clinicopathological stage and negatively correlated with BC prognosis. As revealed by the in vitro experiment, AGRN knockdown effectively hinders BC cells in terms of proliferation, invasion as well as migration. AGRN protein, which may interact with EXT1, LRP4, RAPSN, etc., was primarily distributed in the cell cytoplasm. Notably, immune factors might interact with AGRN in BC, evidenced by its discernible associations with immunofactors like IL10, CD274, and PVRL2. Mass spectrometry and immunohistochemistry revealed that the reduction of AGRN led to an increase in CD8+ T cells with triple-negative breast cancer (TNBC). Mechanistically, the connection between TRIM7 and PD-L1 is improved by AGRN, acting as a scaffold, thereby facilitating the accelerated degradation of PD-L1 by TRIM7. Downregulation of AGRN inhibits BC progression and increases CD8+ T cell recruitment. Targeting AGRN may contribute to BC treatment. The biomarker AGRN, serving as a therapeutic target for BC, emerges as a prospective avenue for enhancing both diagnosis and prognosis in BC cases.
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Affiliation(s)
- Jing Tao
- Department of General Surgery, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Li Shen
- Department of General Surgery, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Minyu Zhuang
- Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Changyuan Zhai
- Department of General Surgery, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Hanling Zeng
- Department of General Surgery, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Yuan Mao
- Department of General Surgery, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Xiaoan Liu
- Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Tabrizian P, Zeitlhoefler M, Hassan AT, Marino R. Immunotherapy for transplantation of hepatocellular carcinoma: the next frontier in adjunctive therapy. Curr Opin Organ Transplant 2024; 29:144-154. [PMID: 38164882 DOI: 10.1097/mot.0000000000001133] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
PURPOSE OF REVIEW The increasing success of liver transplantation in hepatocellular carcinoma (HCC) drives an ever-evolving search for innovative strategies to broaden eligible patients' pools. Recent advances in immuno-oncology have turned the spotlight on immune checkpoint inhibitors (ICIs). This review offers an updated overview of ICIs in liver transplantation for HCC, exploring neoadjuvant and adjuvant approaches and addressing unanswered questions on safety, patients' selection, and response predictors. RECENT FINDINGS ICIs have transitioned from being a last-chance therapeutic hope to becoming an integral cornerstone in the treatment of advanced HCC, holding great promise as a compelling option not only to downstage patients for transplantation but also as an alternative strategy in addressing posttransplantation disease recurrence. Despite ongoing refinements in immunotherapeutic agents, the complex molecular pathways involved emphasize the need for a comprehensive approach to integrate immunotherapy in liver transplantation. SUMMARY Initial concerns about graft rejection, with ICIs as a bridging therapy to liver transplantation, were successfully addressed using adequate immunosuppressants strategies and minimized with a sufficient washout period. Post-liver transplantation disease recurrence remains challenging, requiring a balance between effective therapy and preserving graft function. Emphasis should be placed on clinical trials validating the risk-benefit ratio of ICIs for liver transplantation, guiding appropriate patients' selection, and establishing clear management pathways.
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Affiliation(s)
- Parissa Tabrizian
- Liver Transplant and Hepatobiliary Surgery, Recanati-Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Gupta T, Jarpula NS. Hepatocellular carcinoma immune microenvironment and check point inhibitors-current status. World J Hepatol 2024; 16:353-365. [PMID: 38577535 PMCID: PMC10989304 DOI: 10.4254/wjh.v16.i3.353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/24/2024] [Accepted: 03/04/2024] [Indexed: 03/27/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and has a high mortality rate. The Barcelona Clinic Liver Cancer staging system in addition to tumor staging also links the modality of treatment available to a particular stage. The recent description of the tumor microenvironment (TME) in HCC has provided a new concept of immunogenicity within the HCC. Virus-related HCC has been shown to be more immunogenic with higher expression of cytotoxic T lymphocytes and decreased elements for immunosuppression such as regulatory T cells. This immunogenic milieu provides a better response to immunotherapy especially immune checkpoint inhibitors (ICIs). In addition, the recent data on combining locoregional therapies and other strategies may convert the less immunogenic state of the TME towards higher immunogenicity. Therefore, data are emerging on the use of combinations of locoregional therapy and ICIs in unresectable or advanced HCC and has shown better survival outcomes in this difficult population.
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Affiliation(s)
- Tarana Gupta
- Division of Hepatology, Department of Medicine, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak 124001, Haryana, India.
| | - Nikhil Sai Jarpula
- Division of Hepatology, Department of Medicine, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak 124001, Haryana, India
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14
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Wang K, Xiang YJ, Yu HM, Cheng YQ, Liu ZH, Qin YY, Shi J, Guo WX, Lu CD, Zheng YX, Zhou FG, Yan ML, Zhou HK, Liang C, Zhang F, Wei WJ, Lau WY, Li JJ, Liu YF, Cheng SQ. Adjuvant sintilimab in resected high-risk hepatocellular carcinoma: a randomized, controlled, phase 2 trial. Nat Med 2024; 30:708-715. [PMID: 38242982 DOI: 10.1038/s41591-023-02786-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 12/21/2023] [Indexed: 01/21/2024]
Abstract
Hepatocellular carcinoma (HCC), particularly when accompanied by microvascular invasion (MVI), has a markedly high risk of recurrence after liver resection. Adjuvant immunotherapy is considered a promising avenue. This multicenter, open-label, randomized, controlled, phase 2 trial was conducted at six hospitals in China to assess the efficacy and safety of adjuvant sintilimab, a programmed cell death protein 1 inhibitor, in these patients. Eligible patients with HCC with MVI were randomized (1:1) into the sintilimab or active surveillance group. The sintilimab group received intravenous injections every 3 weeks for a total of eight cycles. The primary endpoint was recurrence-free survival (RFS) in the intention-to-treat population. Key secondary endpoints included overall survival (OS) and safety. From September 1, 2020, to April 23, 2022, a total of 198 eligible patients were randomly allocated to receive adjuvant sintilimab (n = 99) or undergo active surveillance (n = 99). After a median follow-up of 23.3 months, the trial met the prespecified endpoints. Sintilimab significantly prolonged RFS compared to active surveillance (median RFS, 27.7 versus 15.5 months; hazard ratio 0.534, 95% confidence interval 0.360-0.792; P = 0.002). Further follow-up is needed to confirm the difference in OS. In the sintilimab group, 12.4% of patients experienced grade 3 or 4 treatment-related adverse events, the most common of which were elevated alanine aminotransferase levels (5.2%) and anemia (4.1%). These findings support the potential of immune checkpoint inhibitors as effective adjuvant therapy for these high-risk patients. Chinese Clinical Trial Registry identifier: ChiCTR2000037655 .
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Affiliation(s)
- Kang Wang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- Shanghai Hepatobiliary Cancer Research Center, Naval Medical University, Shanghai, China
| | - Yan-Jun Xiang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Key Laboratory of Medical Immunology, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Hong-Ming Yu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- Shanghai Hepatobiliary Cancer Research Center, Naval Medical University, Shanghai, China
| | - Yu-Qiang Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- Shanghai Hepatobiliary Cancer Research Center, Naval Medical University, Shanghai, China
| | - Zong-Han Liu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Ying-Yi Qin
- Department of Health Statistics, Naval Medical University, Shanghai, China
| | - Jie Shi
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Wei-Xing Guo
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Chong-De Lu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Ya-Xin Zheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Fei-Guo Zhou
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Mao-Lin Yan
- Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Hong-Kun Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing College, Jiaxing, China
| | - Chao Liang
- Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fan Zhang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Binzhou Medical College, Binzhou, China
| | - Wen-Jing Wei
- Department of General Surgery, Taiyuan People's Hospital, Taiyuan, China
| | - Wan Yee Lau
- Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Jing-Jing Li
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yan-Fang Liu
- National Key Laboratory of Medical Immunology, Institute of Immunology, Naval Medical University, Shanghai, China.
- Department of Pathology, Changhai Hospital, Naval Medical University, Shanghai, China.
| | - Shu-Qun Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
- Shanghai Hepatobiliary Cancer Research Center, Naval Medical University, Shanghai, China.
- Department of Cell Biology, College of Medicine, Jiaxing University, Jiaxing, China.
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15
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Tian C, Yu Y, Wang Y, Yang L, Tang Y, Yu C, Feng G, Zheng D, Wang X. Neoadjuvant Immune Checkpoint Inhibitors in hepatocellular carcinoma: a meta-analysis and systematic review. Front Immunol 2024; 15:1352873. [PMID: 38440727 PMCID: PMC10909934 DOI: 10.3389/fimmu.2024.1352873] [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: 12/09/2023] [Accepted: 01/29/2024] [Indexed: 03/06/2024] Open
Abstract
BACKGROUND Neoadjuvant immunotherapy has demonstrated beneficial outcomes in various cancer types; however, standardized protocols for neoadjuvant immunotherapy in hepatocellular carcinoma (HCC) are currently lacking. This systematic review and meta-analysis aims to investigate the reliability of neoadjuvant immunotherapy's efficacy and safety in the context of HCC. METHODS A systematic search was conducted across PubMed (MEDLINE), EMBASE, the Web of Science, the Cochrane Library, and conference proceedings to identify clinical trials involving resectable HCC and neoadjuvant immunotherapy. Single-arm meta-analyses were employed to compute odds ratios and 95% confidence intervals (CIs). Heterogeneity analysis, data quality assessment, and subgroup analyses based on the type of immunotherapy drugs and combination therapies were performed. This meta-analysis is registered in PROSPERO (identifier CRD42023474276). RESULTS This meta-analysis included 255 patients from 11 studies. Among resectable HCC patients, neoadjuvant immunotherapy exhibited an overall major pathological response (MPR) rate of 0.47 (95% CI 0.31-0.70) and a pathological complete response (pCR) rate of 0.22 (95% CI 0.14-0.36). The overall objective response rate (ORR) was 0.37 (95% CI 0.20-0.69), with a grade 3-4 treatment-related adverse event (TRAE) incidence rate of 0.35 (95% CI 0.24-0.51). Furthermore, the combined surgical resection rate was 3.08 (95% CI 1.66-5.72). Subgroup analysis shows no significant differences in the efficacy and safety of different single-agent immunotherapies; the efficacy of dual ICIs (Immune Checkpoint Inhibitors) combination therapy is superior to targeted combined immunotherapy and monotherapy, while the reverse is observed in terms of safety. DISCUSSION Neoadjuvant immunotherapy presents beneficial outcomes in the treatment of resectable HCC. However, large-scale, high-quality experiments are warranted in the future to provide robust data support.
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Affiliation(s)
- Chunhong Tian
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yifan Yu
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuqing Wang
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lunwei Yang
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ying Tang
- Institute of Tumor, Guangzhou University of Chinese Medicine, Guangzhou, China
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chengyang Yu
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Gaofei Feng
- Department of Oncology, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Dayong Zheng
- Department of Hepatology, TCM-Integrated Hospital of Southern Medical University, Guangzhou, China
- Department of Hepatopancreatobiliary, Cancer Center, Southern Medical University, Guangzhou, China
- Department of Oncology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiongwen Wang
- Beibei District Traditional Chinese Medicine Hospital (Chongqing Hospital, The First Affiliated Hospital of Guangzhou University of Chinese Medicine), Chongqing, China
- Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
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16
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Tabrizian P, Yu A, Debnath N, Myers B, Marron T. Immunotherapy and Liver Transplantation: The Future or the Failure? Surg Clin North Am 2024; 104:163-182. [PMID: 37953034 DOI: 10.1016/j.suc.2023.07.009] [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: 11/14/2023]
Abstract
A quarter century has passed since the milestone study by Mazzaferro and colleagues on liver transplantation (LT) for hepatocellular carcinoma (HCC). The increasing demand for LT for HCC has led to the continued efforts to expand LT indications. Downstaging to within Milan criteria has been incorporated into the organ allocation policy for HCC in the United States in 2017 and provides acceptable long-term survival. The present review focuses on the rationale of neoadjuvant immune checkpoint inhibitor (ICI) in HCC, the experience of ICI in the pre- and posttransplant setting.
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Affiliation(s)
- Parissa Tabrizian
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy, New York, NY 10029, USA.
| | - Allen Yu
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy, New York, NY 10029, USA
| | - Neha Debnath
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy, New York, NY 10029, USA
| | - Bryan Myers
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy, New York, NY 10029, USA
| | - Thomas Marron
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy, New York, NY 10029, USA
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17
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Gu XY, Huo JL, Yu ZY, Jiang JC, Xu YX, Zhao LJ. Immunotherapy in hepatocellular carcinoma: an overview of immune checkpoint inhibitors, drug resistance, and adverse effects. ONCOLOGIE 2024; 26:9-25. [DOI: 10.1515/oncologie-2023-0412] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Abstract
Hepatocellular carcinoma (HCC) is a concerning liver cancer with rising incidence and mortality rates worldwide. The effectiveness of traditional therapies in managing advanced HCC is limited, necessitating the development of new therapeutic strategies. Immune checkpoint inhibitors (ICIs) have emerged as a promising strategy for HCC management. By preventing tumor cells from evading immune surveillance through immunological checkpoints, ICIs can restore the immune system’s ability to target and eliminate tumors. While ICIs show promise in enhancing the immune response against malignancies, challenges such as drug resistance and adverse reactions hinder their efficacy. To address these challenges, developing individualized ICI treatment strategies is critical. Combining targeted therapy and immunotherapy holds the potential for comprehensive therapeutic effects. Additionally, biomarker-based individualized ICI treatment strategies offer promise in predicting treatment response and guiding personalized patient care. Future research should explore emerging ICI treatment methods to optimize HCC immunotherapy. This review provides an overview of ICIs as a new treatment for HCC, demonstrating some success in promoting the tumor immune response. However, drug resistance and adverse reactions remain important considerations that must be addressed. As tailored treatment plans evolve, the prospect of immunotherapy for HCC is expected to grow, offering new opportunities for improved patient outcomes.
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Affiliation(s)
- Xuan-Yu Gu
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Jin-Long Huo
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Zhi-Yong Yu
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Ji-Chang Jiang
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Ya-Xuan Xu
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Li-Jin Zhao
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
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18
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Loosen SH, Leyh C, Neumann UP, Bock H, Weigel C, Luedde T, Roderburg C. Liver transplantation meets gastrointestinal cancer. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:62-72. [PMID: 38195110 DOI: 10.1055/a-2226-0123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2024]
Abstract
Liver transplantation (LT) has emerged as a standard of care for patients with end-stage liver disease, providing a life-saving intervention for patients with severely compromised liver function in both the acute and chronic setting. While LT has also become a routine procedure for early-stage hepatocellular carcinoma (HCC), offering a potential cure by treating both the tumor and the underlying liver disease, its relevance in the context of other malignancies such as cholangiocellular carcinoma (CCA), combined hepatocellular-cholangiocarcinoma (cHCC-CCA) or liver metastases is still the subject of intense debate and no definite recommendations have yet been established. This review summarizes the current therapeutic standards in the context of LT for gastrointestinal malignancies and provides a reflection and outlook on current scientific and clinical developments.
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Affiliation(s)
- Sven H Loosen
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Catherine Leyh
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Ulf Peter Neumann
- Department of General, Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, Germany
- Department of Surgery and Transplantation, University Hospital Essen, Essen, Germany
| | - Hans Bock
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Christian Weigel
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Christoph Roderburg
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
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19
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Dopazo C, Søreide K, Rangelova E, Mieog S, Carrion-Alvarez L, Diaz-Nieto R, Primavesi F, Stättner S. Hepatocellular carcinoma. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2024; 50:107313. [PMID: 38086315 DOI: 10.1016/j.ejso.2023.107313] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 11/30/2023] [Indexed: 01/16/2024]
Abstract
An update on the management of Hepatocellular carcinoma (HCC) is provided in the present article for those interested in the UEMS/EBSQ exam in Surgical Oncology. The most recent publications in HCC, including surveillance, guidelines, and indications for liver resection, liver transplantation, and locoregional or systemic therapies, are summarised. The objective is to yield a set of main points regarding HCC that are required in the core curriculum of hepatobiliary oncological surgery.
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Affiliation(s)
- Cristina Dopazo
- Department of HPB Surgery and Transplants, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autónoma de Barcelona, Barcelona, Spain.
| | - Kjetil Søreide
- Department of Gastrointestinal Surgery, HPB unit, Stavanger University Hospital, Stavanger, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of HPB Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Elena Rangelova
- Section of Upper GI Surgery at Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Sven Mieog
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
| | - Lucia Carrion-Alvarez
- Department of General Surgery, HPB Unit, Fuenlabrada University Hospital, Madrid, Spain
| | - Rafael Diaz-Nieto
- Hepatobiliary Surgery Unit, Liverpool University Hospital, Liverpool, UK
| | - Florian Primavesi
- Department of General, Visceral and Vascular Surgery, Salzkammergut Klinikum, OÖG, Dr. Wilhelm Bock Strasse 1, 4840, Vöcklabruck, Austria
| | - Stefan Stättner
- Department of General, Visceral and Vascular Surgery, Salzkammergut Klinikum, OÖG, Dr. Wilhelm Bock Strasse 1, 4840, Vöcklabruck, Austria
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20
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Elderkin J, Al Hallak N, Azmi AS, Aoun H, Critchfield J, Tobon M, Beal EW. Hepatocellular Carcinoma: Surveillance, Diagnosis, Evaluation and Management. Cancers (Basel) 2023; 15:5118. [PMID: 37958294 PMCID: PMC10647678 DOI: 10.3390/cancers15215118] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/11/2023] [Accepted: 10/13/2023] [Indexed: 11/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) ranks fourth in cancer-related deaths worldwide. Semiannual surveillance of the disease for patients with cirrhosis or hepatitis B virus allows for early detection with more favorable outcomes. The current underuse of surveillance programs demonstrates the need for intervention at both the patient and provider level. Mail outreach along with navigation provision has proven to increase surveillance follow-up in patients, while provider-targeted electronic medical record reminders and compliance reports have increased provider awareness of HCC surveillance. Imaging is the primary mode of diagnosis in HCC with The Liver Imaging Reporting and Data System (LI-RADS) being a widely accepted comprehensive system that standardizes the reporting and data collection for HCC. The management of HCC is complex and requires multidisciplinary team evaluation of each patient based on their preference, the state of the disease, and the available medical and surgical interventions. Staging systems are useful in determining the appropriate intervention for HCC. Early-stage HCC is best managed by curative treatment modalities, such as liver resection, transplant, or ablation. For intermediate stages of the disease, transarterial local regional therapies can be applied. Advanced stages of the disease are treated with systemic therapies, for which there have been recent advances with new drug combinations. Previously sorafenib was the mainstay systemic treatment, but the recent introduction of atezolizumab plus bevacizumab proves to have a greater impact on overall survival. Although there is a current lack of improved outcomes in Phase III trials, neoadjuvant therapies are a potential avenue for HCC management in the future.
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Affiliation(s)
- Jessica Elderkin
- Wayne State University School of Medicine, Detroit, MI 48201, USA;
| | - Najeeb Al Hallak
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (N.A.H.); (A.S.A.)
| | - Asfar S. Azmi
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (N.A.H.); (A.S.A.)
| | - Hussein Aoun
- Department of Radiology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (H.A.); (J.C.)
| | - Jeffrey Critchfield
- Department of Radiology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (H.A.); (J.C.)
| | - Miguel Tobon
- Department of Surgery, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA;
| | - Eliza W. Beal
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (N.A.H.); (A.S.A.)
- Department of Surgery, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA;
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21
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Claasen MPAW, Sneiders D, Rakké YS, Adam R, Bhoori S, Cillo U, Fondevila C, Reig M, Sapisochin G, Tabrizian P, Toso C. European Society of Organ Transplantation (ESOT) Consensus Report on Downstaging, Bridging and Immunotherapy in Liver Transplantation for Hepatocellular Carcinoma. Transpl Int 2023; 36:11648. [PMID: 37779513 PMCID: PMC10533675 DOI: 10.3389/ti.2023.11648] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 08/22/2023] [Indexed: 10/03/2023]
Abstract
Liver transplantation offers the best chance of cure for most patients with non-metastatic hepatocellular carcinoma (HCC). Although not all patients with HCC are eligible for liver transplantation at diagnosis, some can be downstaged using locoregional treatments such as ablation and transarterial chemoembolization. These aforementioned treatments are being applied as bridging therapies to keep patients within transplant criteria and to avoid them from dropping out of the waiting list while awaiting a liver transplant. Moreover, immunotherapy might have great potential to support downstaging and bridging therapies. To address the contemporary status of downstaging, bridging, and immunotherapy in liver transplantation for HCC, European Society of Organ Transplantation (ESOT) convened a dedicated working group comprised of experts in the treatment of HCC to review literature and to develop guidelines pertaining to this cause that were subsequently discussed and voted during the Transplant Learning Journey (TLJ) 3.0 Consensus Conference that took place in person in Prague. The findings and recommendations of the working group on Downstaging, Bridging and Immunotherapy in Liver Transplantation for Hepatocellular Carcinoma are presented in this article.
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Affiliation(s)
- Marco Petrus Adrianus Wilhelmus Claasen
- Department of Surgery, Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, University Medical Centre Rotterdam, Rotterdam, Netherlands
- Multi-Organ Transplant Program, University Health Network (UHN), Toronto, ON, Canada
| | - Dimitri Sneiders
- Department of Surgery, Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, University Medical Centre Rotterdam, Rotterdam, Netherlands
| | - Yannick Sebastiaan Rakké
- Department of Surgery, Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, University Medical Centre Rotterdam, Rotterdam, Netherlands
| | - René Adam
- Centre Hépato-Biliaire, APHP Hôpital Universitaire Paul Brousse, Université Paris-Saclay, Paris, France
| | - Sherrie Bhoori
- Hepatology, Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Umberto Cillo
- Chirurgia Generale 2, Epato-Bilio-Pancreatica e Centro Trapianto di Fegato, Azienda Ospedale Università Padova, Padova, Italy
| | | | - Maria Reig
- BCLC Group, Liver Unit, Digestive Disease Institute, Hospital Clínic, IDIBAPS CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, University Health Network (UHN), Toronto, ON, Canada
| | - Parissa Tabrizian
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Christian Toso
- Division of Abdominal Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
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22
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Liu X, Huangfu Y, Wang J, Kong P, Tian W, Liu P, Fang C, Li S, Nie Y, Feng Z, Huang P, Shi S, Zhang C, Dong A, Wang W. Supramolecular Polymer-Nanomedicine Hydrogel Loaded with Tumor Associated Macrophage-Reprogramming polyTLR7/8a Nanoregulator for Enhanced Anti-Angiogenesis Therapy of Orthotopic Hepatocellular Carcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300637. [PMID: 37229748 PMCID: PMC10401096 DOI: 10.1002/advs.202300637] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 04/07/2023] [Indexed: 05/27/2023]
Abstract
Anti-angiogenic therapies targeting inhibition of vascular endothelial growth factor (VEGF) pathway show clinical benefit in hypervascular hepatocellular carcinoma (HCC) tumors. However, HCC expresses massive pro-angiogenic factors in the tumor microenvironment (TME) in response to anti-angiogenic therapy, recruiting tumor-associated macrophages (TAMs), leading to revascularization and tumor progression. To regulate cell types in TME and promote the therapeutic efficiency of anti-angiogenic therapy, a supramolecular hydrogel drug delivery system (PLDX-PMI) co-assembled by anti-angiogenic nanomedicines (PCN-Len nanoparticles (NPs)) and oxidized dextran (DX), and loaded with TAMs-reprogramming polyTLR7/8a nanoregulators (p(Man-IMDQ) NRs) is developed for orthotopic liver cancer therapy. PCN-Len NPs target tyrosine kinases of vascular endothelial cells and blocked VEGFR signaling pathway. p(Man-IMDQ) NRs repolarize pro-angiogenic M2-type TAMs into anti-angiogenic M1-type TAMs via mannose-binding receptors, reducing the secretion of VEGF, which further compromised the migration and proliferation of vascular endothelial cells. On highly malignant orthotopic liver cancer Hepa1-6 model, it is found that a single administration of the hydrogel formulation significantly decreases tumor microvessel density, promotes tumor vascular network maturation, and reduces M2-subtype TAMs, thereby effectively inhibiting tumor progression. Collectively, findings in this work highlight the great significance of TAMs reprogramming in enhancing anti-angiogenesis treatment for orthotopic HCC, and provides an advanced hydrogel delivery system-based synergistic approach for tumor therapy.
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Affiliation(s)
- Xiang Liu
- Department of Polymer Science and EngineeringKey Laboratory of Systems Bioengineering (Ministry of Education)School of Chemical Engineering and TechnologyTianjin UniversityTianjin300072P. R. China
| | - Yini Huangfu
- Department of Polymer Science and EngineeringKey Laboratory of Systems Bioengineering (Ministry of Education)School of Chemical Engineering and TechnologyTianjin UniversityTianjin300072P. R. China
| | - Jingrong Wang
- Tianjin Key Laboratory of Biomaterial ResearchInstitute of Biomedical EngineeringChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin300192P. R. China
| | - Pengxu Kong
- Department of Structural Heart DiseaseFuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100037P. R. China
| | - Weijun Tian
- Department of General SurgeryTianjin Medical University General HospitalTianjin300052P. R. China
| | - Peng Liu
- Department of General SurgeryTianjin Medical University General HospitalTianjin300052P. R. China
| | - Chuang Fang
- Department of General SurgeryTianjin Medical University General HospitalTianjin300052P. R. China
| | - Shuangyang Li
- Department of Polymer Science and EngineeringKey Laboratory of Systems Bioengineering (Ministry of Education)School of Chemical Engineering and TechnologyTianjin UniversityTianjin300072P. R. China
| | - Yu Nie
- Department of Gastrointestinal OncologyShandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandong250117P. R. China
| | - Zujian Feng
- Tianjin Key Laboratory of Biomaterial ResearchInstitute of Biomedical EngineeringChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin300192P. R. China
| | - Pingsheng Huang
- Tianjin Key Laboratory of Biomaterial ResearchInstitute of Biomedical EngineeringChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin300192P. R. China
| | - Shengbin Shi
- Department of Gastrointestinal OncologyShandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandong250117P. R. China
| | - Chuangnian Zhang
- Tianjin Key Laboratory of Biomaterial ResearchInstitute of Biomedical EngineeringChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin300192P. R. China
| | - Anjie Dong
- Department of Polymer Science and EngineeringKey Laboratory of Systems Bioengineering (Ministry of Education)School of Chemical Engineering and TechnologyTianjin UniversityTianjin300072P. R. China
- Frontiers Science Center for Synthetic BiologyKey Laboratory of Systems Bioengineering (MOE)Tianjin UniversityTianjin300072P. R. China
| | - Weiwei Wang
- Tianjin Key Laboratory of Biomaterial ResearchInstitute of Biomedical EngineeringChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin300192P. R. China
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23
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Qu X, Zhou D, Lu J, Qin D, Zhou J, Liu HJ. Cancer nanomedicine in preoperative therapeutics: Nanotechnology-enabled neoadjuvant chemotherapy, radiotherapy, immunotherapy, and phototherapy. Bioact Mater 2023; 24:136-152. [PMID: 36606253 PMCID: PMC9792706 DOI: 10.1016/j.bioactmat.2022.12.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 12/10/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
Surgical resection remains a mainstay in the treatment of malignant solid tumors. However, the use of neoadjuvant treatments, including chemotherapy, radiotherapy, phototherapy, and immunotherapy, either alone or in combination, as a preoperative intervention regimen, have attracted increasing attention in the last decade. Early randomized, controlled trials in some tumor settings have not shown a significant difference between the survival rates in long-term neoadjuvant therapy and adjuvant therapy. However, this has not hampered the increasing use of neoadjuvant treatments in clinical practice, due to its evident downstaging of primary tumors to delineate the surgical margin, tailoring systemic therapy response as a clinical tool to optimize subsequent therapeutic regimens, and decreasing the need for surgery, with its potential for increased morbidity. The recent expansion of nanotechnology-based nanomedicine and related medical technologies provides a new approach to address the current challenges of neoadjuvant therapy for preoperative therapeutics. This review not only summarizes how nanomedicine plays an important role in a range of neoadjuvant therapeutic modalities, but also highlights the potential use of nanomedicine as neoadjuvant therapy in preclinical and clinic settings for tumor management.
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Affiliation(s)
- Xiaogang Qu
- Department of General Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, 215500, China
| | - Dong Zhou
- Department of General Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, 215500, China
| | - Jianpu Lu
- Department of General Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, 215500, China
| | - Duotian Qin
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Jun Zhou
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Hai-Jun Liu
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
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24
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Integrated Analysis of N1-Methyladenosine Methylation Regulators-Related lncRNAs in Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:cancers15061800. [PMID: 36980686 PMCID: PMC10046959 DOI: 10.3390/cancers15061800] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 03/07/2023] [Accepted: 03/14/2023] [Indexed: 03/19/2023] Open
Abstract
N1-methyladenosine (m1A) and long non-coding RNAs (lncRNAs) play significant roles in tumor progression in hepatocellular carcinoma (HCC). However, their association with HCC is still unclear. In this study, lncRNAs related to m1A were extracted from the mRNA expression matrix in The Cancer Genome Atlas (TCGA) database. Five m1A-related lncRNAs (AL031985.3, NRAV, WAC-AS1, AC026412.3, and AC099850.4) were identified based on lasso Cox regression and they generated a prognostic signature of HCC. The prognostic signature was identified as an independent prognosis factor in HCC patients. Moreover, the prognostic signature achieved better performance than TP53 mutation status or tumor mutational burden (TMB) scores in the stratification of patient survival. The immune landscape indicated that most immune checkpoint genes and immune cells were distributed differently between both risk groups. A higher IC50 of chemotherapeutics (sorafenib, nilotinib, sunitinib, and gefitinib) was observed in the high-risk group, and a lower IC50 of gemcitabine in the low-risk group, suggesting the potential of the prognostic signature in chemosensitivity. In addition, fifty-five potential small molecular drugs were found based on drug sensitivity and NRAV expression. Together, five m1A-related lncRNAs generated a prognostic signature that could be a promising prognostic prediction approach and therapeutic response assessment tool for HCC patients.
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25
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Pinter M, Pinato DJ, Ramadori P, Heikenwalder M. NASH and Hepatocellular Carcinoma: Immunology and Immunotherapy. Clin Cancer Res 2023; 29:513-520. [PMID: 36166660 PMCID: PMC9890137 DOI: 10.1158/1078-0432.ccr-21-1258] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 06/29/2022] [Accepted: 09/20/2022] [Indexed: 02/05/2023]
Abstract
The last 10 years have revolutionized our basic understanding of nonalcoholic fatty liver disease and consequent liver cancer. It has become clear that several innate and adaptive immune cells play an important role in initiating, maintaining, or exacerbating nonalcoholic steatohepatitis (NASH)-a disease that has been recently defined as autoaggressive. Despite improved disease management aimed at reducing the progression of fibrosis, NASH is set to become a leading cause for hepatocellular carcinoma (HCC). Preliminary data from preclinical studies suggest that immunotherapy efficacy may be reduced in NASH-related HCC compared with viral HCC; however, conclusive evidence supporting clinical translation of these findings is lacking. Comprehensive clinical and immunologic phenotyping of mechanisms linking NASH progression with carcinogenesis and therapeutic resistance is key to prevent progression to cirrhosis, improve monitoring and stratification of NASH according to predicted cancer risk, and ultimately increase survival of patients with NASH-HCC. In this review, we summarize the state of the art in the field of NASH and NASH-HCC with focus on immunobiology. We discuss preclinical and clinical findings underpinning NASH as an immunologically distinct pro-tumorigenic disease entity, and explore areas of potential therapeutic vulnerabilities in NASH-associated HCC.
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Affiliation(s)
- Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - David J. Pinato
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, United Kingdom
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Pierluigi Ramadori
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany
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Abstract
This is a review of current practices and upcoming developments regarding hepatocellular carcinoma (HCC). This includes a contemporary review of the diagnosis, staging, and treatment of HCC. Furthermore, the authors provide a review of certain ongoing trials and future directions of various treatment modalities for HCC.
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Xu L, Chen L, Zhang B, Liu Z, Liu Q, Liang H, Chen Y, Chen X, Leng C, Zhang B. Alkaline phosphatase combined with γ-glutamyl transferase is an independent predictor of prognosis of hepatocellular carcinoma patients receiving programmed death-1 inhibitors. Front Immunol 2023; 14:1115706. [PMID: 36761721 PMCID: PMC9905229 DOI: 10.3389/fimmu.2023.1115706] [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: 12/04/2022] [Accepted: 01/09/2023] [Indexed: 01/27/2023] Open
Abstract
Background Immunotherapy plays an increasingly critical role in the systemic treatment of HCC. This current study aimed to establish a novel prognostic predictor of Programmed death 1 (PD-1) inhibitor therapy in hepatocellular carcinoma (HCC) independent of Child-Pugh grade. Methods Our study screened patients with HCC who received PD-1 inhibitors at Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology from January 2018 to December 2020. ALG grade was determined by the patient's serum ALP and GGT levels before the initiation of PD-1 inhibitors. The endpoints of our study were overall survival (OS) and progression free survival (PFS). Follow-up ended at May 31, 2022. Results Eighty- five patients (77 with Child-Pugh grade A, 8 with Child-Pugh grade B at baseline) were enrolled according to the inclusion criteria. Patients with Child-Pugh grade A achieved longer PFS and OS than those with Child-Pugh grade B. Patients with ALG grade 3 at baseline showed worse tumor response and poorer survival, and ALG grade could stratify patients with Child-Pugh grade A into subgroups with significantly different prognosis. Conclusions ALG grade, combining ALP and GGT, is a novel and readily available prognostic marker and the predictive effect of ALG grade on patient prognosis is independent of Child-Pugh grade.
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Affiliation(s)
- Lei Xu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lin Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Bin Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhichen Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qiumeng Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yifa Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Xiaoping Chen, ; Chao Leng, ; Bixiang Zhang,
| | - Chao Leng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Xiaoping Chen, ; Chao Leng, ; Bixiang Zhang,
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Xiaoping Chen, ; Chao Leng, ; Bixiang Zhang,
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Zhao M, Chen S, Li C, Du Y, Li P. Neoadjuvant Immune Checkpoint Inhibitors for Resectable Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. Cancers (Basel) 2023; 15:600. [PMID: 36765557 PMCID: PMC9913451 DOI: 10.3390/cancers15030600] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/12/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Resectable hepatocellular carcinoma (HCC) has poor prognosis because of its high recurrence rate. Immunotherapy has been tried for neoadjuvant therapy as it has shown excellent performance in the treatment of advanced HCC. This systematic review and meta-analysis aimed to assess the reported efficacy and safety of neoadjuvant immune checkpoint inhibitors (ICIs) for resectable HCC. Electronic databases, including PubMed (MEDLINE), Embase, the Cochrane Library, and ClinicalTrials.gov were systematically searched to identify published and ongoing studies evaluating the efficacy and safety of neoadjuvant ICIs for resectable HCC up to October 2022. The odds ratio (OR) and 95% confidence interval (CI) were calculated. Heterogeneity and subgroup analyses were performed, and data quality was assessed. The study was registered with PROSPERO (registration number: CRD42022371495). A total of 193 patients from 9 studies were included in this meta-analysis. The overall pathological complete response (pCR) rate was 12.9% (95%CI, 6.7-19.1%), and major pathological response (MPR) rate was 27.3% (95%CI, 15.1-39.4%), indicating a favorable association with neoadjuvant ICIs (pCR: OR = 0.17, p < 0.00001; MPR: OR = 0.38, p = 0.001). The pooled OR values for the incidence of grade 3 to 4 treatment-related adverse events and surgical delay rate were 0.26 and 0.05, respectively, which were significantly in favor of neoadjuvant ICIs (p < 0.0001; p < 0.00001, respectively). The subgroup analyses did not demonstrate superiority of one ICI over another ICI or combination therapy. The present study found that neoadjuvant ICIs were well tolerated by patients with resectable HCC and conferred therapeutic benefits in view of histopathological response results.
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Affiliation(s)
- Mei Zhao
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
- Department of Integrated Traditional Chinese and Western Medicine, Anhui Medical University, Hefei 230032, China
| | - Shanwen Chen
- Department of Otorhinolaryngology—Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Conggui Li
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Yingying Du
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Ping Li
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
- Department of Integrated Traditional Chinese and Western Medicine, Anhui Medical University, Hefei 230032, China
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Yang SC, Liang L, Wang MD, Wang XM, Gu LH, Lin KY, Zhou YH, Chen TH, Gu WM, Li J, Wang H, Chen Z, Li C, Yao LQ, Diao YK, Sun LY, Zhang CW, Zeng YY, Lau WY, Huang DS, Shen F, Yang T. Prospective validation of the Eastern Staging in predicting survival after surgical resection for patients with hepatocellular carcinoma: a multicenter study from China. HPB (Oxford) 2023; 25:81-90. [PMID: 36167767 DOI: 10.1016/j.hpb.2022.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 08/29/2022] [Accepted: 09/06/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND The Eastern Staging System, which was specially developed for patients undergoing surgical resection for hepatocellular carcinoma (HCC), has been proposed for more than ten years. To prospectively validate the predictive accuracy of the Eastern staging on long-term survival after HCC resection. METHODS Patients who underwent hepatectomy for HCC from 2011 to 2020 at 10 Chinese hospitals were identified from a prospectively collected database. The survival predictive accuracy was evaluated and compared between the Eastern Staging with six other staging systems, including the JIS, BCLC, Okuda, CLIP, 8th AJCC TNM, and HKLC staging. RESULTS Among 2365 patients, the 1-, 3-, and 5-year overall survival rates were 84.2%, 64.5%, and 52.6%, respectively. Among these seven staging systems, the Eastern staging was associated with the best monotonicity of gradients (linear trend χ2: 408.5) and homogeneity (likelihood ratio χ2: 447.3), and the highest discriminatory ability (the areas under curves for 1-, 3-, and 5-year mortality: 0.776, 0.787, and 0.768, respectively). In addition, the Eastern staging was the most informative staging system in predicting survival (Akaike information criterion: 2982.33). CONCLUSION Using a large multicenter prospectively collected database, the Eastern Staging was found to show the best predictive accuracy on long-term overall survival in patients with resectable HCC than the other 6 commonly-used staging systems.
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Affiliation(s)
- Shun-Chao Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University (Second Military Medical University), Shanghai, China; Graduate School, Hebei North University, Hebei, China
| | - Lei Liang
- Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Ming-Da Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University (Second Military Medical University), Shanghai, China
| | - Xian-Ming Wang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong, China
| | - Li-Hui Gu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University (Second Military Medical University), Shanghai, China
| | - Kong-Ying Lin
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fujian, China
| | - Ya-Hao Zhou
- Department of Hepatobiliary Surgery, Pu'er People's Hospital, Yunnan, China
| | - Ting-Hao Chen
- Department of General Surgery, Ziyang First People's Hospital, Sichuan, China
| | - Wei-Min Gu
- The First Department of General Surgery, The Fourth Hospital of Harbin, Heilongjiang, China
| | - Jie Li
- Department of Hepatobiliary Surgery, Fuyang People's Hospital, Anhui, China
| | - Hong Wang
- Department of General Surgery, Liuyang People's Hospital, Hunan, China
| | - Zhong Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Chao Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University (Second Military Medical University), Shanghai, China
| | - Lan-Qing Yao
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University (Second Military Medical University), Shanghai, China
| | - Yong-Kang Diao
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University (Second Military Medical University), Shanghai, China
| | - Li-Yang Sun
- Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Cheng-Wu Zhang
- Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yong-Yi Zeng
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fujian, China
| | - Wan Yee Lau
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University (Second Military Medical University), Shanghai, China; Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China
| | - Dong-Sheng Huang
- Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China; School of Public Health, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University (Second Military Medical University), Shanghai, China; Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Medical University, Shanghai, China.
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University (Second Military Medical University), Shanghai, China; Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China; School of Public Health, Hangzhou Medical College, Hangzhou, Zhejiang, China; Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Medical University, Shanghai, China.
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Li Q, Zhang L, You W, Xu J, Dai J, Hua D, Zhang R, Yao F, Zhou S, Huang W, Dai Y, Zhang Y, Baheti T, Qian X, Pu L, Xu J, Xia Y, Zhang C, Tang J, Wang X. PRDM1/BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells. Nat Commun 2022; 13:7677. [PMID: 36509766 PMCID: PMC9744896 DOI: 10.1038/s41467-022-35469-x] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 12/06/2022] [Indexed: 12/14/2022] Open
Abstract
Programmed death receptor-1 (PD-1) blockade have achieved some efficacy but only in a fraction of patients with hepatocellular carcinoma (HCC). Programmed cell death 1 ligand 1 (PD-L1) binds to its receptor PD1 on T cells to dampen antigen-tumor immune responses. However, the mechanisms underlying PD-L1 regulation are not fully elucidated. Herein, we identify that tumoral Prdm1 overexpression inhibits cell growth in immune-deficient mouse models. Further, tumoral Prdm1 overexpression upregulates PD-L1 levels, dampening anti-tumor immunity in vivo, and neutralizes the anti-tumor efficacy of Prdm1 overexpression in immune-competent mouse models. Mechanistically, PRDM1 enhances USP22 transcription, thus reducing SPI1 protein degradation through deubiquitination, which enhances PD-L1 transcription. Functionally, PD-1 mAb treatment reinforces the efficacy of Prdm1-overexpressing HCC immune-competent mouse models. Collectively, we demonstrate that the PRDM1-USP22-SPI1 axis regulates PD-L1 levels, resulting in infiltrated CD8+ T cell exhaustion. Furthermore, PRDM1 overexpression combined with PD-(L)1 mAb treatment provides a therapeutic strategy for HCC treatment.
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Affiliation(s)
- Qing Li
- grid.89957.3a0000 0000 9255 8984Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province China
| | - Liren Zhang
- grid.89957.3a0000 0000 9255 8984Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province China
| | - Wenhua You
- grid.263826.b0000 0004 1761 0489School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu Province China ,grid.89957.3a0000 0000 9255 8984Department of Immunology, Key Laboratory of Immune Microenvironment and Disease, Nanjing Medical University, Nanjing, Jiangsu Province China
| | - Jiali Xu
- grid.412676.00000 0004 1799 0784Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province China
| | - Jingjing Dai
- grid.412676.00000 0004 1799 0784Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province China
| | - Dongxu Hua
- grid.89957.3a0000 0000 9255 8984The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Ruizhi Zhang
- grid.89957.3a0000 0000 9255 8984Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province China
| | - Feifan Yao
- grid.89957.3a0000 0000 9255 8984Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province China
| | - Suiqing Zhou
- grid.89957.3a0000 0000 9255 8984Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province China
| | - Wei Huang
- grid.411610.30000 0004 1764 2878Department of General Surgery, The Friendship Hospital of Ili Kazakh Autonomous Prefecture, Ili & Jiangsu Joint Institute of Health, Ili, China
| | - Yongjiu Dai
- grid.89957.3a0000 0000 9255 8984Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province China
| | - Yu Zhang
- grid.411610.30000 0004 1764 2878Department of General Surgery, The Friendship Hospital of Ili Kazakh Autonomous Prefecture, Ili & Jiangsu Joint Institute of Health, Ili, China
| | - Tasiken Baheti
- grid.411610.30000 0004 1764 2878Department of General Surgery, The Friendship Hospital of Ili Kazakh Autonomous Prefecture, Ili & Jiangsu Joint Institute of Health, Ili, China
| | - Xiaofeng Qian
- grid.89957.3a0000 0000 9255 8984Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province China
| | - Liyong Pu
- grid.89957.3a0000 0000 9255 8984Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province China
| | - Jing Xu
- grid.412676.00000 0004 1799 0784Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province China
| | - Yongxiang Xia
- grid.89957.3a0000 0000 9255 8984Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province China
| | - Chuanyong Zhang
- grid.89957.3a0000 0000 9255 8984Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province China
| | - Jinhai Tang
- grid.412676.00000 0004 1799 0784Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province China
| | - Xuehao Wang
- grid.89957.3a0000 0000 9255 8984Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province China
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Zhou Q, Chen L, Yang L, Zhou H, Chen Y, Guo Y. Integrated systemic analysis of FAM72A to identify its clinical relevance, biological function, and relationship to drug sensitivity in hepatocellular carcinoma. Front Oncol 2022; 12:1046473. [DOI: 10.3389/fonc.2022.1046473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 11/07/2022] [Indexed: 11/24/2022] Open
Abstract
BackgroundThe family with sequence similarity 72 member A (FAM72A) protein has been identified as an effector of multiple pathological processes in many cancers. The value of FAM72A in HCC remains largely unknown.MethodsData from TCGA-LIHC, ICGC-LIRI-JP, IMvigor210, cBioPortal, GeneMANIA, and TIMER were processed and visualized to explore the association between FAM72A and the prognosis, stemness phenotype, mutational burden, immune cell infiltration, and drug sensitivity in HCC patients. Potential pathways were also revealed. Furthermore, we experimentally verified the results in vivo and in vitro using immunohistochemistry, western blotting, and CCK-8 assays.ResultsFirst, FAM72A mRNA expression was significantly upregulated in HCC. High FAM72A expression was independently associated with a poor prognosis. Experimental validation confirmed that FAM72A was remarkably overexpressed in HCC patients and mice. Moreover, FAM72A knockdown suppressed HCC cell proliferation. In addition, the frequency of TP53 mutations was significantly higher in the high FAM72A expression group. Subsequently, the enrichment analysis revealed that FAM72A was closely related to immune processes and mTOR pathways. Silencing FAM72A increased the expression levels of mTOR in HCC cell lines. The FAM72A-mTOR pathway was strongly associated with a poor prognosis for patients with HCC. Patients with high FAM72A expression levels might be more resistant to sorafenib. Furthermore, the expression of FAM72A and mTOR was significantly associated with the abundance of some tumor-infiltrating immune cells, especially CD4+ T cells. Finally, patients with high levels of FAM72A and mTOR were more sensitive to immunotherapy.ConclusionsFAM72A, a member of the FAM72 family, might be a prognostic and immunotherapeutic target for HCC patients.
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Ouranos K, Chatziioannou A, Goulis I, Sinakos E. Role of immunotherapy in downsizing hepatocellular carcinoma prior to liver transplantation. World J Transplant 2022; 12:331-346. [PMID: 36437845 PMCID: PMC9693898 DOI: 10.5500/wjt.v12.i11.331] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/10/2022] [Accepted: 10/19/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive primary liver neoplasm that, according to tumor stage, can be treated with resection, transplantation, locoregional treatment options, or systemic therapy. Although interventions only in early-stage disease can offer complete tumor regression, systemic therapy in advanced disease can significantly prolong overall survival, according to published clinical trials. The emergence of immunotherapy in the field of cancer therapy has had a positive impact on patients with HCC, resulting in atezolizumab–bevacizumab currently being the first-line option for treatment of advanced HCC. In light of this, application of immunotherapy in the preoperative process could increase the number of patients fulfilling the criteria for liver transplantation (LT). Implementation of this approach is faced with challenges regarding the safety of immunotherapy and the possibly increased risk of rejection in the perioperative period. Case reports and clinical trials assessing the safety profile and effectiveness of neoadjuvant immunotherapy, highlight important aspects regarding this newly evolving approach to HCC management. More studies need to be conducted in order to reach a consensus regarding the optimal way to administer immunotherapy prior to LT. In this review, we summarize the role, safety profile and future considerations regarding the use of neoadjuvant immunotherapy prior to LT in patients with HCC.
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Affiliation(s)
- Konstantinos Ouranos
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Anthi Chatziioannou
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Ioannis Goulis
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Emmanouil Sinakos
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
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Ivanics T, Murillo Perez CF, Claasen MPAW, Patel MS, Morgenshtern G, Erdman L, Shwaartz C, Rajendran L, O'Kane GM, Hansen BE, Cleary SP, Sapisochin G. Dynamic risk profiling of HCC recurrence after curative intent liver resection. Hepatology 2022; 76:1291-1301. [PMID: 35178739 DOI: 10.1002/hep.32411] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 02/07/2022] [Accepted: 02/08/2022] [Indexed: 12/28/2022]
Abstract
BACKGROUND AND AIMS Following liver resection (LR) for HCC, the likelihood of survival is dynamic, in that multiple recurrences and/or metastases are possible, each having variable impacts on outcomes. We sought to evaluate the natural progression, pattern, and timing of various disease states after LR for HCC using multistate modeling and to create a practical calculator to provide prognostic information for patients and clinicians. APPROACH AND RESULTS Adult patients undergoing LR for HCC between January 2000 and December 2018 were retrospectively identified at a single center. Multistate analysis modeled post-LR tumor progression by describing transitions between distinct disease states. In this model, the states included surgery, intrahepatic recurrence (first, second, third, fourth, fifth), distant metastasis with or without intrahepatic recurrence, and death. Of the 486 patients included, 169 (34.8%) remained recurrence-free, 205 (42.2%) developed intrahepatic recurrence, 80 (16.5%) developed distant metastasis, and 32 (7%) died. For an average patient having undergone LR, there was a 33.1% chance of remaining disease-free, a 31.0% chance of at least one intrahepatic recurrence, a 16.3% chance of distant metastasis, and a 19.8% chance of death within the first 60 months post-LR. The transition probability from surgery to first intrahepatic recurrence, without a subsequent state transition, increased from 3% (3 months) to 17.4% (30 months) and 17.2% (60 months). Factors that could modify these probabilities included tumor size, satellite lesions, and microvascular invasion. The online multistate model calculator can be found on https://multistatehcc.shinyapps.io/home/. CONCLUSIONS In contrast to standard single time-to-event estimates, multistate modeling provides more realistic prognostication of outcomes after LR for HCC by taking into account many postoperative disease states and transitions between them. Our multistate modeling calculator can provide meaningful data to guide the management of patients undergoing postoperative surveillance and therapy.
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Affiliation(s)
- Tommy Ivanics
- Multi-Organ Transplant Program, University Health Network Toronto, Toronto, Ontario, Canada
- Department of Surgery, Henry Ford Hospital, Detroit, Michigan, USA
- Department of Surgical Sciences, Akademiska Sjukhuset, Uppsala University, Uppsala, Sweden
| | - Carla Fiorella Murillo Perez
- Multi-Organ Transplant Program, University Health Network Toronto, Toronto, Ontario, Canada
- Toronto Centre for Liver Disease, Toronto Western & General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Marco P A W Claasen
- Multi-Organ Transplant Program, University Health Network Toronto, Toronto, Ontario, Canada
- Department of Surgery, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands
| | - Madhukar S Patel
- Multi-Organ Transplant Program, University Health Network Toronto, Toronto, Ontario, Canada
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | | | - Lauren Erdman
- Department of Computer Science, University of Toronto, Toronto, Ontario, Canada
| | - Chaya Shwaartz
- Multi-Organ Transplant Program, University Health Network Toronto, Toronto, Ontario, Canada
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Luckshi Rajendran
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Grainne M O'Kane
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, Toronto Western & General Hospital, University Health Network, Toronto, Ontario, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Sean P Cleary
- Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, University Health Network Toronto, Toronto, Ontario, Canada
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada
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Izzo F, Mason MC, Silberfein EJ, Massarweh NN, Hsu C, Tran Cao HS, Palaia R, Piccirillo M, Belli A, Patrone R, Fusco R, Granata V, Curley SA. Long-Term Survival and Curative-Intent Treatment in Hepatitis B or C Virus-Associated Hepatocellular Carcinoma Patients Diagnosed during Screening. BIOLOGY 2022; 11:biology11111597. [PMID: 36358298 PMCID: PMC9687526 DOI: 10.3390/biology11111597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/24/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022]
Abstract
Background: We initiated a prospective screening trial in patients with hepatitis to diagnose HCC in the early stage and to evaluate the impact on long-term survival. Methods: From 1993−2006, 10,372 patients with chronic hepatitis B (14%), hepatitis C (81%), or both (5%) were enrolled in an HCC screening program. All patients underwent liver biopsy at enrollment. Transabdominal ultrasonography and serum alpha-fetoprotein were evaluated every 6 months. Abnormal screening results led to axial imaging and tumor biopsy. Results: Cirrhosis was confirmed on biopsy in 2074 patients (20%). HCC was diagnosed in 1016 patients (9.8%), all of whom had cirrhosis (49.0% HCC incidence in patients with cirrhosis). HCC was diagnosed at the initial screening in 165 patients (16.2%) and on follow-up in 851 patients (83.8%). The HCC diagnosis median time during follow-up screening was 6 years (range 4−10). Curative-intent treatment (resection, ablation, or transplant) was performed in 713 patients (70.2%). Overall survival at 5 and 10 years in those 713 patients was 30% and 4%, respectively, compared to no 5-year survivors in the 303 patients with advanced-stage disease (p < 0.001). Cause of death at 5 years in the 713 patients treated with curative intent was HCC in 371 patients (52%), progressive cirrhosis in 116 patients (16%), and other causes in 14 patients (2%). At 10 years, 456 patients (64%) had died from HCC, 171 (24%) from progressive cirrhosis, and 57 (8%) from other causes. Conclusions: Our screening program diagnosed early-stage HCC, permitting curative-intent treatment in 70%, but the 10-year survival rate is 4% due to HCC recurrence and progressive cirrhosis.
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Affiliation(s)
- Francesco Izzo
- Department of Surgical Oncology, IRCCS Fondazione “G. Pascale” National Cancer Institute, 80131 Naples, Italy
| | - Meredith C. Mason
- Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
| | - Eric J. Silberfein
- Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
| | - Nader N. Massarweh
- Surgical and Perioperative Care, Atlanta VA Health Care System, Decatur, GA 30033, USA
- Division of Surgical Oncology, Department of Surgery, Emory University School of Medicine, Atlanta, GA 30307, USA
- Department of Surgery, Morehouse School of Medicine, Atlanta, GA 30310, USA
| | - Cary Hsu
- Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
| | - Hop S. Tran Cao
- Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
| | - Raffaele Palaia
- Department of Surgical Oncology, IRCCS Fondazione “G. Pascale” National Cancer Institute, 80131 Naples, Italy
| | - Mauro Piccirillo
- Department of Surgical Oncology, IRCCS Fondazione “G. Pascale” National Cancer Institute, 80131 Naples, Italy
| | - Andrea Belli
- Department of Surgical Oncology, IRCCS Fondazione “G. Pascale” National Cancer Institute, 80131 Naples, Italy
| | - Renato Patrone
- Department of Surgical Oncology, IRCCS Fondazione “G. Pascale” National Cancer Institute, 80131 Naples, Italy
| | - Roberta Fusco
- Medical Oncolody Division, Igea SpA, 80013 Naples, Italy
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, via della Signora 2, 20122 Milan, Italy
| | - Vincenza Granata
- Division of Radiology, Istituto Nazionale Tumori IRCCS Fondazione Pascale—IRCCS di Napoli, 80131 Naples, Italy
- Correspondence:
| | - Steven A. Curley
- Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
- Oncology Institute, Christus Trinity Mother Frances Health System, Tyler, TX 75702, USA
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A Macrophage Differentiation-Mediated Gene: DDX20 as a Molecular Biomarker Encompassing the Tumor Microenvironment, Disease Staging, and Prognoses in Hepatocellular Carcinoma. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9971776. [PMID: 36246406 PMCID: PMC9556188 DOI: 10.1155/2022/9971776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/03/2022] [Accepted: 09/17/2022] [Indexed: 11/18/2022]
Abstract
Background DDX20 involves the mechanism of cell proliferate, mitogenic Ets transcriptional suppressor (METS), which can arrest the cell cycle of macrophages. However, little is known about DDX20 expression, clinical values, and the relationship with tumor microenvironment in HCC. Methods We mined the transcriptional, protein expression and survival data of DDX20 in HCC from online databases. The immunological effects of DDX20 were estimated by bioinformatic algorithms. The RNAi and CRISPR screening were used to assess the gene effect of DDX20 for the EGFR gene in liver tumor cell. Results We found that the DDX20 was highly expressed in HCC. The qRT-PCR result shows a significantly upregulated DDX20 expression in HCC samples from the West China Hospital. The high mRNA expression of DDX20 is associated with a poor survival. DDX20 expression is positively correlated with MDSCs in HCC tissues. Moreover, DDX20 has a high predicted ability for the response to immunotherapy. Furthermore, hsa-mir-324-5p could regulate the macrophage differentiation by interacting with DDX20. Meanwhile, the EGFR gene gets a high dependency score for DDX20. Conclusion In sum, DDX20 may serve as a prognostic marker for worse clinical outcomes with HCC and potentially enable more precise and personalized immunotherapeutic strategies in the future.
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Liu H, Yang XL, Dong ZR, Chen ZQ, Hong JG, Wang DX, Li T. Clinical benefits of direct-acting antivirals therapy in hepatitis C virus patients with hepatocellular carcinoma: A systematic review and meta-analysis. J Gastroenterol Hepatol 2022; 37:1654-1665. [PMID: 35722709 DOI: 10.1111/jgh.15915] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 05/07/2022] [Accepted: 06/14/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIM The purpose of the present study was to evaluate the effect of direct-acting antivirals (DAAs) therapy on the clinical outcomes of hepatitis C virus (HCV) patients with hepatocellular carcinoma (HCC). METHODS We searched multiple electronic databases from database inception to June 14, 2021. Meta-analyses were performed separately for HCC recurrence and overall survival (OS). RESULTS A total of 23 studies were identified for the primary analysis. Compared with no intervention, pooled data showed significant benefit from DAAs therapy in reducing recurrence (adjusted HR = 0.55, 95% CI 0.41-0.74, P < 0.001; I2 = 66.6%, P < 0.001) and improving OS (adjusted HR = 0.36, 95% CI 0.16-0.83, P = 0.017; I2 = 90.7%, P < 0.001) of HCV-related HCC patients. Compared with non-responders, patients with sustained virologic response (SVR) had greater benefit from DAAs therapy in reducing recurrence (HR = 0.37, 95% CI 0.16-0.84, P = 0.017; I2 = 58.8%, P = 0.088) and improving OS (HR = 0.17; 95% CI 0.06-0.50; P = 0.001; I2 = 56.4%, P = 0.130). Though DAAs did not show significant advantages over IFN in reducing recurrence (adjusted HR = 0.96, 95% CI 0.72-1.28, P = 0.784; I2 = 0.0%, P = 0.805), there seems to be a trend toward OS benefit from DAAs therapy (adjusted HR = 0.11, 95% CI 0.01-1.19, P = 0.059). CONCLUSION DAAs therapy can prevent recurrence and improve OS of HCV-related HCC patients, especially for patients with SVR. Further prospective randomized controlled trial is warranted to validate these results.
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Affiliation(s)
- Hui Liu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Xiao-Li Yang
- Department of Nephrology, Jinan Central Hospital, Shandong University, Jinan, China
| | - Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Zhi-Qiang Chen
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Jian-Guo Hong
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Dong-Xu Wang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Tao Li
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China.,Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China
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Yin Z, Chen D, Liang S, Li X. Neoadjuvant Therapy for Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022; 9:929-946. [PMID: 36068876 PMCID: PMC9441170 DOI: 10.2147/jhc.s357313] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 06/15/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is characterized by low resection and high postoperative recurrence rates, and conventional treatment strategies have failed to meet clinical needs. Neoadjuvant therapy (NAT) is widely employed in the routine management of several solid tumors because it increases resectability and reduces the rate of postoperative recurrence. However, a consensus has not been reached regarding the effects of NAT on HCC. As systemic therapy, particularly targeted therapy and immunotherapy, is given for HCC treatment, accumulating evidence shows that the "spring" of NAT for HCC is imminent. In the future, HCC researchers should focus on identifying biomarkers for treatment response, explore the mechanisms of resistance, and standardize the endpoints of NAT.
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Affiliation(s)
- Zongyi Yin
- Department of Hepatobiliary Surgery, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, People’s Republic of China
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases & Carson International Cancer, Shenzhen University, Shenzhen, 518055, People’s Republic of China
- Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, 518055, People’s Republic of China
| | - Dongying Chen
- Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, 518055, People’s Republic of China
- Department of Anesthesiology, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, People’s Republic of China
| | - Shuang Liang
- Department of Hepatobiliary Surgery, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, People’s Republic of China
| | - Xiaowu Li
- Department of Hepatobiliary Surgery, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, People’s Republic of China
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases & Carson International Cancer, Shenzhen University, Shenzhen, 518055, People’s Republic of China
- Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, 518055, People’s Republic of China
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Marzi L, Mega A, Gitto S, Pelizzaro F, Seeber A, Spizzo G. Impact and Novel Perspective of Immune Checkpoint Inhibitors in Patients with Early and Intermediate Stage HCC. Cancers (Basel) 2022; 14:cancers14143332. [PMID: 35884392 PMCID: PMC9313349 DOI: 10.3390/cancers14143332] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/27/2022] [Accepted: 07/02/2022] [Indexed: 02/04/2023] Open
Abstract
Surgery and radiofrequency ablation remain the gold standard to achieve cure in patients with hepatocellular carcinoma (HCC). After a decade in which only sorafenib was available for advanced and metastatic HCC, the emergence of other molecularly targeted drugs and immune checkpoint inhibitors (ICIs) has significantly improved the patients` prognosis. In particular, the use of ICIs has shown promising results and has revolutionized the treatment algorithm in HCC patients. Indeed, preclinical and clinical data have documented a high density of immunosuppressive cells and an increased expression of the programmed death-1 (PD-1) receptor and cytotoxic T-cell associated protein-4 (CTLA-4) in HCC. However, despite these observations, no validated biomarker is available and the molecular groundwork responsible for response to ICIs remains elusive. The anti-CTLA4 monoclonal antibody tremelimumab and the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab were the first ICIs to be tested in HCC. Recently, the combination of the anti-programmed death-ligand 1 (PD-L1) inhibitor atezolizumab and the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab demonstrated an improvement in patient outcome compared to sorafenib, becoming the standard of care in the frontline setting of advanced disease. Other immunotherapeutic agents such as pembrolizumab or the combination nivolumab-ipilimumab have shown promising results that have to be confirmed in phase III studies. Currently, the combination of different ICIs (i.e., ipilimumab, durvalumab) and anti-angiogenic agents (i.e., regorafenib, lenvatinib) is currently being tested in several trials and will hopefully revolutionize the treatment of HCC. To date, numerous studies are underway evaluating ICIs in adjuvant and neoadjuvant settings to improve survival in early and intermediate stages. Thus, this review focuses on the rationale for ICIs and their potential use for early or intermediate HCC stages.
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Affiliation(s)
- Luca Marzi
- Department of Gastroenterology, Bolzano Regional Hospital (SABES-ASDAA), 39100 Bolzano-Bozen, Italy; (L.M.); (A.M.)
| | - Andrea Mega
- Department of Gastroenterology, Bolzano Regional Hospital (SABES-ASDAA), 39100 Bolzano-Bozen, Italy; (L.M.); (A.M.)
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Firenze, 50134 Firenze, Italy;
| | - Filippo Pelizzaro
- Department of Gastroenterology, Medical University of Padova, 35128 Padova, Italy;
| | - Andreas Seeber
- Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, 6020 Innsbruck, Austria
- Correspondence: (A.S.); (G.S.)
| | - Gilbert Spizzo
- Department of Internal Medicine, Oncologic Day Hospital, Hospital of Bressanone (SABES-ASDAA), 39042 Bressanone-Brixen, Italy
- Correspondence: (A.S.); (G.S.)
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Marron TU, Schwartz M, Corbett V, Merad M. Neoadjuvant Immunotherapy for Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022; 9:571-581. [PMID: 35794901 PMCID: PMC9252295 DOI: 10.2147/jhc.s340935] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 06/23/2022] [Indexed: 11/23/2022] Open
Abstract
The treatment paradigm for hepatocellular carcinoma (HCC) had been stagnant until recently, with new combinations of targeted and immunotherapies entering the first- and second-line setting for patients with advanced disease. This improvement in therapeutic options is well timed given the rise in rates of HCC globally; additionally, screening high-risk patients has also led to an increase in detection of early HCC lesions, identifying patients who can be treated with curative intent approaches such as surgery. Unfortunately, the vast majority of patients who undergo surgical resection develop recurrent HCC, either due to disease recurrence from residual micrometastatic disease or de novo primaries, and there are no perioperative therapies that have demonstrated the ability to significantly improve survival for these patients. Given the survival benefit that immunotherapy has imparted to patients with advanced HCC, and recent studies in other tumor types demonstrating perioperative-in particular neoadjuvant-immunotherapy significantly improves outcomes, there is substantial interest in neoadjuvant immunotherapy for patients with resectable HCC. Three recently reported small studies looking at anti-PD-1 antibodies alone or in combination have demonstrated significant pathologic response to brief pre-operative interventions, and support exploring this approach in larger registrational studies. With these developments the clinical outlook for HCC patients, with both early and advanced disease, is rapidly improving.
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Affiliation(s)
- Thomas U Marron
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Early Phase Trials Unit, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Myron Schwartz
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Early Phase Trials Unit, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Virginia Corbett
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Miriam Merad
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Early Phase Trials Unit, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Su YY, Liu YS, Hsiao CF, Hsu C, Chen LT. Trial Designs for Integrating Novel Therapeutics into the Management of Intermediate-Stage Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022; 9:517-536. [PMID: 35677350 PMCID: PMC9170176 DOI: 10.2147/jhc.s220978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 04/23/2022] [Indexed: 11/23/2022] Open
Abstract
Intermediate-stage hepatocellular carcinoma (HCC) consists of heterogeneous groups of patients in terms of tumor burden and organ function reserves. Although liver-directed therapy (LDT), including trans-catheter arterial chemoembolization, radiofrequency ablation or even surgical resection, is the recommended frontline treatment modality, intrahepatic and distant failures are common. The recent advances in systemic treatment, notably the introduction of immune checkpoint inhibitor (ICI)-based therapy, have significantly improved the objective tumor response rate, quality of response and overall survival in patients with recurrent and advanced HCC. Whether the combination of systemic treatment and LDT can further improve the outcome of patients with intermediate-stage HCC is currently being extensively evaluated. In this article, the recent clinical trials incorporating different ICI-based combinations with different LDT for intermediate-stage HCC were reviewed focusing on trial design issues, including patient selection, endpoint definition, and biomarker development. The strength and caveats of different combination strategies and novel biomarker development were discussed.
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Affiliation(s)
- Yung-Yeh Su
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Sheng Liu
- Department of Medical Imaging, National Cheng Kung University Hospital, College of Medical College, National Cheng Kung University, Tainan, Taiwan
| | - Chin-Fu Hsiao
- Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan
| | - Chiun Hsu
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan
- National Taiwan University Cancer Center, Taipei, Taiwan
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Internal Medicine, Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
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Shen YH, Huang C, Zhu XD, Xu MH, Chen ZS, Tan CJ, Zhou J, Fan J, Sun HC. The Safety Profile of Hepatectomy Following Preoperative Systemic Therapy with Lenvatinib Plus Anti-PD-1 Antibodies Versus Hepatectomy Alone in Patients With Hepatocellular Carcinoma. ANNALS OF SURGERY OPEN 2022; 3:e163. [PMID: 37601608 PMCID: PMC10431521 DOI: 10.1097/as9.0000000000000163] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 04/12/2022] [Indexed: 10/18/2022] Open
Abstract
Objective To determine the safety of hepatectomy after combined lenvatinib and anti-PD-1 preoperative systemic therapy (PST) in patients with marginally resectable hepatocellular carcinoma (HCC). Background PST followed by hepatectomy (PSTH) is an emerging treatment for HCC. However, the impact of PST with lenvatinib plus anti-PD-1 antibodies on surgical safety is unknown. Methods Medical records from consecutive patients with marginally resectable advanced HCC who underwent hepatectomy after PST with lenvatinib and anti-PD-1 antibodies between January 2018 and August 2021 were retrieved from a prospectively designed database. Propensity score matching (1:2) was performed with a further 2318 HCC patients who underwent upfront hepatectomy (UH) without initial antitumor treatment during the same period. Results In total, 49 and 98 matched patients were included in the PSTH and UH groups, respectively. Compared to the UH group, individuals in the PSTH group experienced more intraoperative blood loss, blood transfusions, and longer postoperative hospital stays. Moreover, posthepatectomy liver failure was more common in the PSTH group, who also had worse albumin-bilirubin (ALBI) scores on postoperative days 1-7. A significantly greater amount of drainage was also required in the PSTH group. However, the 30-day morbidity and 90-day mortality were similar among the two groups. Additionally, the duration of surgery, use of hepatic inflow occlusion during surgery, and the levels of postoperative inflammation-based markers were not statistically different between the two groups. Conclusions Despite more intraoperative and postoperative adverse events, PSTH had comparable 30-day morbidity and 90-day mortality as UH. Thus, PSTH appears to be a viable treatment option for marginally resectable HCC patients with careful preoperative evaluation.
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Affiliation(s)
- Ying-Hao Shen
- From the Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Cheng Huang
- From the Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiao-Dong Zhu
- From the Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ming-Hao Xu
- From the Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhao-Shuo Chen
- Department of Hepatobiliary Pancreatic Surgery, Fujian Medical University Cancer Hospital, Fuzhou, China
| | - Chang-Jun Tan
- From the Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Zhou
- From the Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia Fan
- From the Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hui-Chuan Sun
- From the Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
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Yan X, Duan H, Ni Y, Zhou Y, Wang X, Qi H, Gong L, Liu H, Tian F, Lu Q, Sun J, Yang E, Zhong D, Wang T, Huang L, Wang J, Chaoyang Wang, Wang Y, Wan Z, Lei J, Zhao J, Jiang T. Tislelizumab combined with chemotherapy as neoadjuvant therapy for surgically resectable esophageal cancer: A prospective, single-arm, phase II study (TD-NICE). Int J Surg 2022; 103:106680. [PMID: 35595021 DOI: 10.1016/j.ijsu.2022.106680] [Citation(s) in RCA: 112] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 04/18/2022] [Accepted: 05/07/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Clinical benefit of neoadjuvant immunotherapy in resectable esophageal squamous cell carcinoma (ESCC). remains unclear. This study evaluated the efficacy and safety of the programmed death 1 (PD-1) inhibitor tislelizumab combined with chemotherapy as neoadjuvant therapy in patients with resectable ESCC. METHODS Treatment-naïve patients were enrolled and eligible patients received 3 cycles of neoadjuvant therapy with tislelizumab, carboplatin, and nab-paclitaxel. The primary endpoint was surgery patients major pathological response (MPR). Subgroup analysis was stratified by tumor downstaging, circumferential resection margin (CRM), PD-ligand 1 (PD-L1) expression, and tumor mutation burden (TMB). Safety was assessed by adverse events (AEs) and postoperative complications. RESULTS Between September 2020 and March 2021, 45 patients were enrolled. Thirty-six (80.0%) of 45 patients underwent surgery, and 29 (80.5%) underwent successful R0 resection. MPR and pathological complete response (pCR) for surgery patients were 72.0% and 50.0%, respectively. Intention to treatment (ITT) patients MPR and PCR were 57.5% and 40%. Downgrading occurred in 75% of 36 patients. MPR and pCR were identified to be associated with tumor downstaging and CRM but not PD-L1 expression or TMB. TPS levels in MPR and pCR group were significantly higher than that in Non-MPR and Non-pCR group, respectively. Treatment-related AEs of grade 3-4 and immune-related AEs occurred in 42.2% and 22.2% of 45 patients, respectively, and postoperative complications occurred in 77.8% of 36 patients. No treatment-related surgical delay or death occurred. No associations between gene mutation and pathological efficacy were observed. CONCLUSIONS Tislelizumab plus chemotherapy as neoadjuvant therapy demonstrates promising antitumor activity for resectable ESCC with high rates of MPR, pCR, and R0 resection, as well as acceptable tolerability.
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Affiliation(s)
- Xiaolong Yan
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Hongtao Duan
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Yunfeng Ni
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Yongan Zhou
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Xiaoping Wang
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Haini Qi
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Li Gong
- Department of Pathology, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Honggang Liu
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Feng Tian
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Qiang Lu
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Jianyong Sun
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Ende Yang
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Daixing Zhong
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Tao Wang
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Lijun Huang
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Jian Wang
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Chaoyang Wang
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Yuanyong Wang
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Zhiyi Wan
- Genecast Biotechnology Co., Ltd, 88 Danshan Road, Xidong Chuangrong Building, Suite C 1310-1318, Xishan District, Wuxi City, Jiangsu, 214104, China.
| | - Jie Lei
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Jinbo Zhao
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
| | - Tao Jiang
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Military Medical University, No.1. Xinsi Road, Xi'an, Shaanxi, China.
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Wang Z, Yu Y, Wu P, Ye Q, Guo Y, Zhang X, Xi L, Li Q, Jin Y, Zhou D, Luo Y, Peng S, Li J. Lactate promotes the growth of patient-derived organoids from hepatopancreatobiliary cancers via ENO1/HIF1α pathway and does not affect their drug sensitivities. Cell Death Discov 2022; 8:214. [PMID: 35443744 PMCID: PMC9021221 DOI: 10.1038/s41420-022-01014-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 03/30/2022] [Accepted: 03/30/2022] [Indexed: 11/28/2022] Open
Abstract
The long culture duration of patient-derived organoids (PDOs) have severely limited their clinical applications. The aim of this study was to determine the effect of lactate supplementation on the growth, genetic profiles and drug sensitivities of PDOs from hepatopancreatobiliary tumors. LM3, Huh7, Panc02, and RBE cell lines were cultured as organoids in the presence or absence of lactate, and total protein was extracted to measure the expression of α-enolase (ENO1), hypoxia-inducible factor-1α (HIF1α), AKT, and PI3 kinase (PI3K). Thirteen hepatopancreatobiliary tumor specimens were collected during surgical resection and cultured as PDOs with or without L-lactate. Hematoxylin and eosin (H&E) staining and immunohistochemical staining were performed on the original tissues and PDOs to compare their pathological structures, and their genetic profiles were analyzed by whole-exome sequencing (WES). The sensitivity of the PDOs to gemcitabine, 5-fluorouracil, cisplatin, paclitaxel, ivosidenib, infigratinib, and lenvatinib were evaluated in terms of cell viability. Peripheral blood mononuclear cells (PBMCs) were isolated and co-cultured with PDOs to test the sensitivity of PDOs to tislelizumab. The addition of 20 mM lactate significantly promoted the growth of LM3 and Huh 7 organoids by 217% and 36%, respectively, compared to the control group, and the inhibition of lactate transporter decreased their growth. The HIF1α/ENO1/AKT/PI3K pathway was also activated by lactate. The inhibition of enolase also partly decreased the growth of organoids treated with lactate. Furthermore, 20 mM lactate increased the viability of 9 PDOs from 135% to 317% without affecting their pathological features. The genetic similarity, in terms of single nucleotide variations, insertions, and deletions, between original tissues and lactate-treated PDOs ranged from 83.2% to 94.1%, and that between the untreated and lactate-treated PDOs was at least 93.2%. Furthermore, the addition of lactate did not significantly change the dose-response curves of the PDOs to chemotherapeutic drugs, targeted drugs, and immune checkpoint inhibitor, especially for the drugs to which the cells were sensitive. Thus, lactate can be added to the culture medium of PDOs to promote their growth without altering their genetic profiles and drug sensitivities.
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Affiliation(s)
- Zhiwei Wang
- Department of Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang Province, China
| | - Yuanquan Yu
- Department of Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang Province, China
| | - Peiyao Wu
- Gastroenterology Endoscopy Center, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, 210029, Nanjing, Jiangsu Province, China
| | - Qinghuang Ye
- Department of Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang Province, China
| | - Yinghao Guo
- Department of Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang Province, China
| | - Xiaoxiao Zhang
- Department of Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang Province, China
| | - Longfu Xi
- Department of Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang Province, China
| | - Qi Li
- Department of Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang Province, China
| | - Yun Jin
- Department of Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang Province, China
| | - Donger Zhou
- Department of Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang Province, China
| | - Yan Luo
- Department of Biochemistry and Cancer Institute of the Second Affiliated Hospital (Key Laboratory of Cancer Prevention and Intervention of China National MOE), Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Shuyou Peng
- Department of Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang Province, China
| | - Jiangtao Li
- Department of Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang Province, China.
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Marron TU, Galsky MD, Taouli B, Fiel MI, Ward S, Kim E, Yankelevitz D, Doroshow D, Guttman-Yassky E, Ungar B, Mehandru S, Golas BJ, Labow D, Sfakianos J, Nair SS, Chakravarty D, Buckstein M, Song X, Kenigsberg E, Gnjatic S, Brown BD, Sparano J, Tewari A, Schwartz M, Bhardwaj N, Merad M. Neoadjuvant clinical trials provide a window of opportunity for cancer drug discovery. Nat Med 2022; 28:626-629. [PMID: 35347282 PMCID: PMC9901535 DOI: 10.1038/s41591-022-01681-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Window-of-opportunity trials, during which patients receive short-duration pre-surgical therapies, provide a platform for understanding the therapies’ mechanisms of action, but will require a paradigm shift in trial design, specimen collection and analysis.
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Affiliation(s)
- Thomas U Marron
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Immunotherapy and Novel TargEt Research Across Clinical Teams (INTERACT), Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Early Phase Trials Unit, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Matthew D Galsky
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Early Phase Trials Unit, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Bachir Taouli
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Maria Isabel Fiel
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Stephen Ward
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Edward Kim
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - David Yankelevitz
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Deborah Doroshow
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Early Phase Trials Unit, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Emma Guttman-Yassky
- Immunotherapy and Novel TargEt Research Across Clinical Teams (INTERACT), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Benjamin Ungar
- Immunotherapy and Novel TargEt Research Across Clinical Teams (INTERACT), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Saurabh Mehandru
- Immunotherapy and Novel TargEt Research Across Clinical Teams (INTERACT), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Benjamin J Golas
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Surgical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Daniel Labow
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Surgical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - John Sfakianos
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sujit S Nair
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Dimple Chakravarty
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Michael Buckstein
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Xiaoyu Song
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Effi Kenigsberg
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sacha Gnjatic
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Brian D Brown
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Joseph Sparano
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ashutosh Tewari
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Myron Schwartz
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Surgical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Nina Bhardwaj
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Immunotherapy and Novel TargEt Research Across Clinical Teams (INTERACT), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Early Phase Trials Unit, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Miriam Merad
- The neoAdjuvant Research Group to Evaluate Therapeutics (TARGET), Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Immunotherapy and Novel TargEt Research Across Clinical Teams (INTERACT), Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Early Phase Trials Unit, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Liu TH, Shen YC, Cheng AL. Immune checkpoint inhibitors for hepatocellular carcinoma – A game changer in treatment landscape. J Formos Med Assoc 2022; 121:1371-1383. [PMID: 35400583 DOI: 10.1016/j.jfma.2022.03.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 03/02/2022] [Accepted: 03/21/2022] [Indexed: 11/25/2022] Open
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Abstract
Liver cancer, more specifically hepatocellular carcinoma (HCC), is the second leading cause of cancer-related death and its incidence is increasing globally. Around 50% of patients with HCC receive systemic therapies, traditionally sorafenib or lenvatinib in the first line and regorafenib, cabozantinib or ramucirumab in the second line. In the past 5 years, immune-checkpoint inhibitors have revolutionized the management of HCC. The combination of atezolizumab and bevacizumab has been shown to improve overall survival relative to sorafenib, resulting in FDA approval of this regimen. More recently, durvalumab plus tremelimumab yielded superior overall survival versus sorafenib and atezolizumab plus cabozantinib yielded superior progression-free survival. In addition, pembrolizumab monotherapy and the combination of nivolumab plus ipilimumab have received FDA Accelerated Approval in the second-line setting based on early efficacy data. Despite these major advances, the molecular underpinnings governing immune responses and evasion remain unclear. The immune microenvironment has crucial roles in the development and progression of HCC and distinct aetiology-dependent immune features have been defined. Inflamed and non-inflamed classes of HCC and genomic signatures have been associated with response to immune-checkpoint inhibitors, yet no validated biomarker is available to guide clinical decision-making. This Review provides information on the immune microenvironments underlying the response or resistance of HCC to immunotherapies. In addition, current evidence from phase III trials on the efficacy, immune-related adverse events and aetiology-dependent mechanisms of response are described. Finally, we discuss emerging trials assessing immunotherapies across all stages of HCC that might change the management of this disease in the near future.
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Marron TU, Fiel MI, Hamon P, Fiaschi N, Kim E, Ward SC, Zhao Z, Kim J, Kennedy P, Gunasekaran G, Tabrizian P, Doroshow D, Legg M, Hammad A, Magen A, Kamphorst AO, Shareef M, Gupta NT, Deering R, Wang W, Wang F, Thanigaimani P, Mani J, Troncoso L, Tabachnikova A, Chang C, Akturk G, Buckup M, Hamel S, Ioannou G, Hennequin C, Jamal H, Brown H, Bonaccorso A, Labow D, Sarpel U, Rosenbloom T, Sung MW, Kou B, Li S, Jankovic V, James N, Hamon SC, Cheung HK, Sims JS, Miller E, Bhardwaj N, Thurston G, Lowy I, Gnjatic S, Taouli B, Schwartz ME, Merad M. Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial. Lancet Gastroenterol Hepatol 2022; 7:219-229. [PMID: 35065058 PMCID: PMC9901534 DOI: 10.1016/s2468-1253(21)00385-x] [Citation(s) in RCA: 127] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 01/05/2023]
Abstract
BACKGROUND Surgical resection of early stage hepatocellular carcinoma is standard clinical practice; however, most tumours recur despite surgery, and no perioperative intervention has shown a survival benefit. Neoadjuvant immunotherapy has induced pathological responses in multiple tumour types and might decrease the risk of postoperative recurrence in hepatocellular carcinoma. We aimed to evaluate the clinical activity of neoadjuvant cemiplimab (an anti-PD-1) in patients with resectable hepatocellular carcinoma. METHODS For this single-arm, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma (stage Ib, II, and IIIb) were enrolled and received two cycles of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by surgical resection. Eligible patients were aged 18 years or older, had confirmed resectable hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate liver function. Patients were excluded if they had metastatic disease, if the surgery was not expected to be curative, if they had a known additional malignancy requiring active treatment, or if they required systemic steroid treatment or any other immunosuppressive therapy. After resection, patients received an additional eight cycles of cemiplimab 350 mg intravenously every 3 weeks in the adjuvant setting. The primary endpoint was significant tumour necrosis on pathological examination (defined as >70% necrosis of the resected tumour). Secondary endpoints included delay of surgery, the proportion of patients with an overall response, change in CD8+ T-cell density, and adverse events. Tumour necrosis and response were analysed in all patients who received at least one dose of cemiplimab and completed surgical resection; safety and other endpoints were analysed in the intention-to-treat population. Patients underwent pre-treatment biopsies and blood collection throughout treatment. This trial is registered with ClinicalTrials.gov (NCT03916627, Cohort B) and is ongoing. FINDINGS Between Aug 5, 2019, and Nov 25, 2020, 21 patients were enrolled. All patients received neoadjuvant cemiplimab, and 20 patients underwent successful resection. Of the 20 patients with resected tumours, four (20%) had significant tumour necrosis. Three (15%) of 20 patients had a partial response, and all other patients maintained stable disease. 20 (95%) patients had a treatment-emergent adverse event of any grade during the neoadjuvant treatment period. The most common adverse events of any grade were increased aspartate aminotransferase (in four patients), increased blood creatine phosphokinase (in three), constipation (in three), and fatigue (in three). Seven patients had grade 3 adverse events, including increased blood creatine phosphokinase (in two patients) and hypoalbuminaemia (in one). No grade 4 or 5 events were observed. One patient developed pneumonitis, which led to a delay in surgery by 2 weeks. INTERPRETATION This report is, to our knowledge, the largest clinical trial of a neoadjuvant anti-PD-1 monotherapy reported to date in hepatocellular carcinoma. The observed pathological responses to cemiplimab in this cohort support the design of larger trials to identify the optimal treatment duration and definitively establish the clinical benefit of preoperative PD-1 blockade in patients with hepatocellular carcinoma. FUNDING Regeneron Pharmaceuticals.
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MESH Headings
- Aged
- Aged, 80 and over
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/adverse effects
- Antineoplastic Agents, Immunological/administration & dosage
- Antineoplastic Agents, Immunological/adverse effects
- Aspartate Aminotransferases/blood
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/surgery
- Creatine Kinase/blood
- Female
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/pathology
- Liver Neoplasms/surgery
- Male
- Middle Aged
- Neoadjuvant Therapy
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Affiliation(s)
- Thomas U Marron
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Early Phase Trials Unit, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Maria Isabel Fiel
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Pauline Hamon
- The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Edward Kim
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Stephen C Ward
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Zhen Zhao
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Joel Kim
- The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Paul Kennedy
- Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; BioMedical Engineering and Imaging Institute (BMEII), Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ganesh Gunasekaran
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Surgical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Parissa Tabrizian
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Surgical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Deborah Doroshow
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Early Phase Trials Unit, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Meredith Legg
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Early Phase Trials Unit, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ashley Hammad
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Early Phase Trials Unit, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Assaf Magen
- The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alice O Kamphorst
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Muhammed Shareef
- Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | | | - Wei Wang
- Regeneron Pharmaceuticals, Tarrytown, NY, USA
| | - Fang Wang
- Regeneron Pharmaceuticals, Tarrytown, NY, USA
| | | | | | - Leanna Troncoso
- The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alexandra Tabachnikova
- The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Christie Chang
- The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Guray Akturk
- The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Human Immune Monitoring Core, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mark Buckup
- The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Steven Hamel
- The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Human Immune Monitoring Core, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Giorgio Ioannou
- The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Human Immune Monitoring Core, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Clotilde Hennequin
- The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Hajra Jamal
- The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Haley Brown
- The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Antoinette Bonaccorso
- The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Surgical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Daniel Labow
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Surgical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Umut Sarpel
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Surgical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Talia Rosenbloom
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Early Phase Trials Unit, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Max W Sung
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Baijun Kou
- Regeneron Pharmaceuticals, Tarrytown, NY, USA
| | - Siyu Li
- Regeneron Pharmaceuticals, Tarrytown, NY, USA
| | | | | | | | | | | | | | - Nina Bhardwaj
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Israel Lowy
- Regeneron Pharmaceuticals, Tarrytown, NY, USA
| | - Sacha Gnjatic
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Human Immune Monitoring Core, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Bachir Taouli
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; BioMedical Engineering and Imaging Institute (BMEII), Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Myron E Schwartz
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Surgical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Miriam Merad
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The neoAdjuvant Research Group to Evaluate Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center of Excellence for Liver and Bile Duct Cancer, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases and RM Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Human Immune Monitoring Core, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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48
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Cammarota A, Zanuso V, D'Alessio A, Pressiani T, Bozzarelli S, Personeni N, Rimassa L. The dual checkpoint blockade in unresectable hepatocellular carcinoma: Opportunities emerging in clinical trials. Expert Opin Investig Drugs 2022; 31:425-435. [PMID: 35152830 DOI: 10.1080/13543784.2022.2042253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
INTRODUCTION To prevent damage from an immune response against autoantigens and toxins originating from the gut, the liver promotes an immune-tolerant milieu providing fertile ground for immune escape of cancer cells. Therefore, the use and evaluation of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) is a treatment rationale. AREA COVERED In this article, we discuss the role of the dual ICIs blockade in advanced HCC, covering the biological basis for their combination, their mechanism of action, and the results of the early phase studies testing nivolumab plus ipilimumab and durvalumab plus tremelimumab. Furthermore, we provide the results of the phase III HIMALAYA trial and an overview of the ongoing trials investigating the dual ICIs in different disease stages. EXPERT OPINION The potential approval of the dual ICIs blockade strategies for advanced HCC will set the entry of antiangiogenic-free options, expanding the proportion of patients eligible for a first-line treatment. However, it will pose a series of clinical challenges with a sizeable proportion of patients, namely Child-Pugh B, elderly, and immunocompromised patients, still marginalized. Also, given the rate of disease progression, identifying reliable predictive biomarkers is crucial to inform treatment choice and sequences. Finally, the compelling response rate of such combinations is paving the way for their evaluation in earlier stages.
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Affiliation(s)
- Antonella Cammarota
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Valentina Zanuso
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Antonio D'Alessio
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy.,Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, W120HS, United Kingdom
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Silvia Bozzarelli
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Nicola Personeni
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
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49
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Wei YG, Yang CK, Wei ZL, Liao XW, He YF, Zhou X, Huang HS, Lan CL, Han CY, Peng T. High-Mobility Group AT-Hook 1 Served as a Prognosis Biomarker and Associated with Immune Infiltrate in Hepatocellular Carcinoma. Int J Gen Med 2022; 15:609-621. [PMID: 35058711 PMCID: PMC8765458 DOI: 10.2147/ijgm.s344858] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 12/23/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The protein high-mobility group AT-hook 1 (HMGA1) has been demonstrated that modulated cellular proliferation, invasion, and apoptosis with a poor prognosis in miscellaneous carcinomas. However, the mechanism of circumstantial carcinogenesis and association with the immune microenvironment of HMGA1 in hepatocellular carcinoma (HCC) had not been extensively explored. METHODS The gene expression, clinicopathological correlation, and prognosis analysis were performed in the data obtained from TCGA. The results were further validated by ICGC and GEO database and external validation cohort from Guangxi. The HMGA1 protein expression was further examined in the HPA database. Biological function analyses were conducted by GSEA, STRING database, and Coexpedia online tool. Using TIMER and CIBERSORT method, the relationship between immune infiltrate and HMGA1 was investigated. RESULTS In HCC, HMGA1 had much higher transcriptional and proteomic expression than in corresponding paraneoplastic tissue. Patients with high HMGA1 expression had a poor prognosis and unpromising clinicopathological features. High HMGA1 expression was closely related to the cell cycle, tumorigenesis, substance metabolism, and immune processes by regulating complex signaling pathways. Notably, HMGA1 may be associated with TP53 mutational carcinogenesis. Moreover, increased HMGA1 expression may lead to an increase in immune infiltration and a decrease in tumor purity in HCC. CIBERSORT analysis elucidated that the amount of B cell naive, B cell memory, T cells gamma delta, macrophages M2, and mast cell resting decreased when HMGA1 expression was high, whereas T cells follicular helper, macrophages M0, and Dendritic cells resting increased. CONCLUSION In conclusions, HMGA1 is a potent prognostic biomarker and a sign of immune infiltration in HCC, which may be a potential immunotherapy target for HCC.
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Affiliation(s)
- Yong-Guang Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Cheng-Kun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Zhong-Liu Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Xi-Wen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Yong-Fei He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Hua-Sheng Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Chen-Lu Lan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Chuang-Ye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
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50
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Fulgenzi CAM, D'Alessio A, Talbot T, Gennari A, Openshaw MR, Demirtas CO, Cortellini A, Pinato DJ. New Frontiers in the Medical Therapy of Hepatocellular Carcinoma. Chemotherapy 2022; 67:164-172. [PMID: 34999584 DOI: 10.1159/000521837] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 12/20/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common primary liver tumor, and it rates fourth as a cause of cancer-related death. The presence of underlying liver disease and poor chemosensitivity pose major treatment challenges in the management of HCC. However, in the last few years, the therapeutic scenario has substantially changed, and immunotherapy in the form of immune checkpoint inhibitors (ICPIs) has become an essential therapeutic strategy in this field. SUMMARY After controversial results of monotherapy, ICPIs have been mainly investigated in association with antiangiogenic agents or as dual checkpoint inhibition. The combination of atezolizumab plus bevacizumab has become the new therapeutic standard for unresectable HCC. Currently, a number of ICPI-based combinations are being studied in phase III clinical trials as front-line therapy for advanced HCC, with growing interest in integration of early-stage disease management in the form of adjuvant or neoadjuvant therapies. With most of the trials investigating ICPIs as first-line treatment, the second-line scenario relies mainly on tyrosine kinase inhibitors, which however have not been formally trialed after ICPIs. KEY MESSAGES In this review, we summarize the main therapeutic advances in the systemic management of HCC focusing on the most relevant ongoing trials. We also discuss the main issues arising from a such rapidly evolving field including therapeutic sequencing and patient stratification.
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Affiliation(s)
- Claudia Angela Maria Fulgenzi
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Department of Medical Oncology, University Campus Bio-Medico, Rome, Italy
| | - Antonio D'Alessio
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Thomas Talbot
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Alessandra Gennari
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Mark R Openshaw
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Coskun O Demirtas
- Department of Gastroenterology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Alessio Cortellini
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Department of Biotechnology and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - David J Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
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