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Fan Q, Wei P, Ma D, Cheng Q, Gao J, Zhu J, Li Z. Therapeutic efficacy and prognostic indicators in re-resection for recurrent hepatocellular carcinoma: Insights from a retrospective study. Surg Open Sci 2025; 23:16-23. [PMID: 39816698 PMCID: PMC11733202 DOI: 10.1016/j.sopen.2024.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 12/05/2024] [Accepted: 12/16/2024] [Indexed: 01/18/2025] Open
Abstract
Aims To evaluate the efficacy of re-resection in recurrent hepatocellular carcinoma (rHCC), identify prognostic factors, and provide clinical guidance. Methods A retrospective analysis was conducted on 130 rHCC patients undergoing re-resection and 60 primary HCC patients undergoing initial hepatectomy at Peking University People's Hospital (2014-2022). Disease-free survival (DFS) and overall survival (OS) were compared. Prognostic factors were identified using univariate and multivariate COX regression analyses. Results Baseline characteristics were comparable between groups (P > 0.05). DFS was similar between groups (30.8 vs. 32.2 months, P = 0.612). The 1-year, 2-year, and 3-year DFS rates for the re-resection group were 88.5 %, 64.9 %, and 56.7 %, respectively, versus 88.3 %, 65.0 %, and 53.3 % for the primary resection group. OS was lower in the re-resection group (36.1 vs. 47.2 months, P = 0.041) with 1-year, 2-year, and 3-year OS rates of 90.8 %, 73.1 %, and 60.0 %, compared to 95.0 %, 80.0 %, and 68.3 % for the primary resection group. Significant factors affecting DFS were Child-Pugh classification (P = 0.044), time to recurrence (P = 0.002), tumor differentiation (P = 0.044), and satellite nodules (P = 0.019). Factors influencing OS included Child-Pugh classification (P = 0.040), time to recurrence (P = 0.002), and tumor differentiation (P = 0.032). Conclusions Re-resection is an effective treatment option for rHCC, with favorable outcomes as measured by DFS and OS, though OS is lower compared to initial hepatectomy. Key prognostic factors include Child-Pugh classification, time to recurrence, tumor differentiation, and satellite nodules.
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Affiliation(s)
- Qi Fan
- Department of General Surgery, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
| | - Pengcheng Wei
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
- Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Beijing, China
- Peking University Center of Liver Cancer Diagnosis and Treatment, Beijing, China
| | - Delin Ma
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
- Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Beijing, China
- Peking University Center of Liver Cancer Diagnosis and Treatment, Beijing, China
| | - Qian Cheng
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
- Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Beijing, China
- Peking University Center of Liver Cancer Diagnosis and Treatment, Beijing, China
| | - Jie Gao
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
- Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Beijing, China
- Peking University Center of Liver Cancer Diagnosis and Treatment, Beijing, China
- Peking University Institute of Organ Transplantation, Beijing, China
| | - Jiye Zhu
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
- Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Beijing, China
- Peking University Center of Liver Cancer Diagnosis and Treatment, Beijing, China
- Peking University Institute of Organ Transplantation, Beijing, China
| | - Zhao Li
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
- Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Beijing, China
- Peking University Center of Liver Cancer Diagnosis and Treatment, Beijing, China
- Peking University Institute of Organ Transplantation, Beijing, China
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Teng X, Shang J, Du L, Huang W, Wang Y, Liu M, Ma Y, Wang M, Tang H, Bai L. RNA-binding protein Trx regulates alternative splicing and promotes metastasis of HCC via interacting with LINC00152. J Gastroenterol Hepatol 2024; 39:2892-2902. [PMID: 39343436 PMCID: PMC11660213 DOI: 10.1111/jgh.16735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 08/19/2024] [Accepted: 08/29/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND Epithelial-mesenchymal transition (EMT) is central to HCC metastasis, in which RNA-binding proteins (RBPs) play a key role. METHODS To explore the role of RBPs in metastasis of hepatocellular carcinoma (HCC), whole transcriptome sequencing was conducted to identify differential RBPs between HCC with metastasis and HCC without metastasis. The influence of RBPs on metastasis of HCC was verified by in vitro and in vivo experiments. The interaction of RBPs with non-coding RNAs was evaluated by RNA immunoprecipitation and pull-down assays. RNA sequencing, whole-genome sequencing, and alternative splicing analysis were further performed to clarify post-transcriptional regulation mechanisms. RESULTS Whole transcriptome sequencing results showed that expression of thioredoxin (Trx) was significantly upregulated in HCC patients with metastasis. Trx was also found to be associated with poor prognosis in HCC patients. Overexpression of Trx could promote migration and invasion of HCC cells in vitro and increase the rate of lung metastasis of HCC cells in vivo. Moreover, binding assays showed that Trx could bind to LINC00152. As a result, LINC00152 was verified to determine the pro-metastasis function of Trx by knockdown assay. Furthermore, we revealed that Trx could regulate metastasis-associated alternative splicing program. Specifically, angiopoietin 1 (ANGPT1) was the splicing target; the splicing isoform switching of ANGPT1 could activate the PI3K-Akt pathway, upregulate EMT-associated proteins, and promote migration and invasion of HCC cells. CONCLUSIONS We found that Trx could interact with LINC00152 and promote HCC metastasis via regulating alternative splicing, indicating that Trx may serve as a novel therapeutic target for HCC treatment.
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Affiliation(s)
- Xiangnan Teng
- Center of Infectious DiseasesWest China Hospital, Sichuan UniversityChengduChina
| | - Jin Shang
- Center of Infectious DiseasesWest China Hospital, Sichuan UniversityChengduChina
- Liver Transplantation Center and HBP Surgery, Sichuan Clinical Research Center for Cancer Sichuan Cancer Hospital & Institute, Sichuan Cancer CenterAffiliated Cancer Hospital of University of Electronic Science and Technology of ChinaChengduChina
| | - Lingyao Du
- Center of Infectious DiseasesWest China Hospital, Sichuan UniversityChengduChina
| | - Wei Huang
- Center of Infectious DiseasesWest China Hospital, Sichuan UniversityChengduChina
| | - Yonghong Wang
- Center of Infectious DiseasesWest China Hospital, Sichuan UniversityChengduChina
| | - Miao Liu
- Center of Infectious DiseasesWest China Hospital, Sichuan UniversityChengduChina
| | - Yuanji Ma
- Center of Infectious DiseasesWest China Hospital, Sichuan UniversityChengduChina
| | - Ming Wang
- Center of Infectious DiseasesWest China Hospital, Sichuan UniversityChengduChina
| | - Hong Tang
- Center of Infectious DiseasesWest China Hospital, Sichuan UniversityChengduChina
| | - Lang Bai
- Center of Infectious DiseasesWest China Hospital, Sichuan UniversityChengduChina
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Wang Z, Pang C, Meng Q, Zhang DZ, Hong ZX, He GB, Yang H, Xiang BD, Li X, Jiang TA, Li K, Tang Z, Huang F, Lu M, Yu XL, Cheng ZG, Liu FY, Han ZY, Dou JP, Wu SS, Yu J, Liang P. Laparoscopic hepatectomy versus microwave ablation for multifocal 3-5 cm hepatocellular carcinoma: a multi-centre, real-world study. Int J Surg 2024; 110:6911-6921. [PMID: 39699863 DOI: 10.1097/js9.0000000000001398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 03/11/2024] [Indexed: 12/20/2024]
Abstract
BACKGROUND Researches comparing laparoscopic liver resection (LLR) with microwave ablation (MWA) for 3-5 cm multifocal hepatocellular carcinoma (MFHCC) are rare. MATERIALS AND METHODS From 2008 to 2019, 666 intrahepatic tumours in 289 patients from 12 tertiary medical centres in China were included in this retrospective study. Propensity score matching (PSM) was performed to balance variables between the two treatment groups over time frames 2008-2019 and 2013-2019 to observe the potential impact of advancements in intervention techniques on overall survival (OS), disease-free progression (DFS) of patients. complications, hospitalization, and cost were compared. RESULTS Among 289 patients, the median age was 59 years [interquartile range (IQR) 52-66]. 2008-2019, after PSM, the median OS was 97.4 months in the LLR group and 75.2 months (95% CI 47.8-102.6) in the MWA group during a follow-up period of 39.0 months. The 1-year, 3-year and 5-year OS rates in the two groups were 91.8%, 72.6%, 60.7% and 96.5%, 72.8%, 62.5% [hazard ratio (HR) 1.03, 95% CI 0.62-1.69, P =0.920]; The corresponding DFS rates were 75.9%, 57.2%, 46.9%, and 53.1%, 17.5%, 6.2% (HR 0.35, 95% CI 0.23-0.54, P <0.001). 2013-2019, the median OS time was not reached in either group during the 34.0 months of follow-up, the 1-year, 3-year and 5-year OS rates in the two groups were 90.2%, 67.6%, 56.7% and 96.5%, 76.7%, 69.7% (HR 1.54, 95% CI 0.79-3.01, P =0.210); The corresponding DFS rates were 69.6%, 53.9%, 43.3%, and 70.4%, 32.1%, 16.5% (HR 0.68, 95% CI 0.41-1.11, P =0.120). The incidence of major complications was similar in both groups (all P> 0.05). MWA had shorter intervention times, hospitalization, and lower costs. CONCLUSIONS For resectable MFHCC patients, LLR is preferable due to its lower recurrence rate. For patients who do not qualify for LLR, advances in ablation technology have promoted MWA as a promising alternative.
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Affiliation(s)
- Zhen Wang
- Departments ofInterventional Ultrasound
| | | | - Qiong Meng
- Department of Gynecology, Jinan Zhangqiu District People's Hospital, Jinan
| | - De-Zhi Zhang
- Abdominal ultrasound department, the first hospital of Jilin university, Changchun
| | - Zhi-Xian Hong
- Hepatobiliary Surgery, Fifth Medical Center of Chinese PLA General Hospital, Chinese PLA Medical School, Beijing
| | - Guang-Bin He
- Department of Ultrasound, Xijing Hospital, the Fourth Military Medical University, Xian
| | - Hong Yang
- Department of Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning
| | - Bang-de Xiang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning
| | - Xiao Li
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
| | - Tian-An Jiang
- Department of Ultrasound Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou
| | - Kai Li
- Department of Ultrasound, Guangdong Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou
| | - Zhe Tang
- Department of Surgery, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu
| | - Fei Huang
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning
| | - Man Lu
- Ultrasound Medical Center, Sichuan Cancer Hospital Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | | | | | | | | | | | - Song-Song Wu
- Department of Ultrasonography, Shengli Clinical Medical College of Fujian Medical University, Fuzhou
| | - Jie Yu
- Departments ofInterventional Ultrasound
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Voisin L, Lapouge M, Saba-El-Leil MK, Gombos M, Javary J, Trinh VQ, Meloche S. Syngeneic mouse model of YES-driven metastatic and proliferative hepatocellular carcinoma. Dis Model Mech 2024; 17:dmm050553. [PMID: 39051113 PMCID: PMC11552496 DOI: 10.1242/dmm.050553] [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: 10/17/2023] [Accepted: 05/24/2024] [Indexed: 07/27/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a disease of high unmet medical need that has become a global health problem. The development of targeted therapies for HCC has been hindered by the incomplete understanding of HCC pathogenesis and the limited number of relevant preclinical animal models. We recently unveiled a previously uncharacterized YES kinase (encoded by YES1)-dependent oncogenic signaling pathway in HCC. To model this subset of HCC, we established a series of syngeneic cell lines from liver tumors of transgenic mice expressing activated human YES. The resulting cell lines (referred to as HepYF) were enriched for expression of stem cell and progenitor markers, proliferated rapidly, and were characterized by high SRC family kinase (SFK) activity and activated mitogenic signaling pathways. Transcriptomic analysis indicated that HepYF cells are representative of the most aggressive proliferation class G3 subgroup of HCC. HepYF cells formed rapidly growing metastatic tumors upon orthotopic implantation into syngeneic hosts. Treatment with sorafenib or the SFK inhibitor dasatinib markedly inhibited the growth of HepYF tumors. The new HepYF HCC cell lines provide relevant preclinical models to study the pathogenesis of HCC and test novel small-molecule inhibitor and immunotherapy approaches.
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Affiliation(s)
- Laure Voisin
- Institute for Research in Immunology and Cancer, Montreal, Quebec H3T 1J4, Canada
| | - Marjorie Lapouge
- Institute for Research in Immunology and Cancer, Montreal, Quebec H3T 1J4, Canada
| | - Marc K. Saba-El-Leil
- Institute for Research in Immunology and Cancer, Montreal, Quebec H3T 1J4, Canada
| | - Melania Gombos
- Institute for Research in Immunology and Cancer, Montreal, Quebec H3T 1J4, Canada
| | - Joaquim Javary
- Institute for Research in Immunology and Cancer, Montreal, Quebec H3T 1J4, Canada
| | - Vincent Q. Trinh
- Institute for Research in Immunology and Cancer, Montreal, Quebec H3T 1J4, Canada
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec H2X 0A9, Canada
- Department of Pathology and Cell Biology, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
| | - Sylvain Meloche
- Institute for Research in Immunology and Cancer, Montreal, Quebec H3T 1J4, Canada
- Molecular Biology Program, Faculty of Medicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
- Department of Pharmacology and Physiology, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
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Mukherjee A, Sen R, Al Hoque A, Giri TK, Mukherjee B. H-ras-targeted genetic therapy remarkably surpassed docetaxel treatment in inhibiting chemically induced hepatic tumors in rats. Life Sci 2024; 348:122680. [PMID: 38697280 DOI: 10.1016/j.lfs.2024.122680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 04/19/2024] [Accepted: 04/27/2024] [Indexed: 05/04/2024]
Abstract
AIMS Hepatocellular carcinoma (HCC) is still a leading cause of cancer-related death worldwide. But its chemotherapeutic options are far from expectation. We here compared H-ras targeted genetic therapy to a commercial docetaxel formulation (DXT) in inhibiting HCC in rats. MAIN METHODS After the physicochemical characterization of phosphorothioate-antisense oligomer (PS-ASO) against H-ras mutated gene, the PS-ASO-mediated in vitro hemolysis, in vivo hepatic uptake, its pharmacokinetic profile, tissue distribution in some highly perfused organs, its effect in normal rats, antineoplastic efficacy in carcinogen-induced HCC in rats were evaluated and compared against DXT treatment. Mutated H-ras expression by in situ hybridization, hep-par-I, CK-7, CD-15, p53 expression patterns by immunohistochemical methods, scanning electron microscopic evaluation of hepatic architecture, various hepatic marker enzyme levels and caspase-3/9 apoptotic enzyme activities were also carried out in the experimental rats. KEY FINDINGS PS-ASO showed low in vitro hemolysis (<3 %), and had a sustained PS-ASO blood residence time in vivo compared to DTX, with a time-dependent hepatic uptake. It showed no toxic manifestations in normal rats. PS-ASO distribution was although initially less in the lung than liver and kidney, but at 8 h it accumulated more in lung than kidney. Antineoplastic potential of PS-ASO (treated for 6 weeks) excelled in inhibiting chemically induced tumorigenesis compared to DTX in rats, by inhibiting H-ras gene expression, some immonohistochemical modulations, and inducing caspase-3/9-mediated apoptosis. It prevented HCC-mediated lung metastatic tumor in the experimental rats. SIGNIFICANCE PS-ASO genetic therapy showed potential to inhibit HCC far more effectively than DXT in rats.
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Affiliation(s)
- Alankar Mukherjee
- Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
| | - Ramkrishna Sen
- Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India; Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa city, IA 52242, USA
| | - Ashique Al Hoque
- Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
| | - Tapan Kumar Giri
- Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
| | - Biswajit Mukherjee
- Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India.
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Kim NR, Rho SY, Navarro J, An C, Han DH, Choi JS, Kim MJ, Choi GH. Additional nodules detected using EOB-MRI in patients with resectable single hepatocellular carcinoma: an implication for active treatment strategy. JOURNAL OF LIVER CANCER 2024; 24:92-101. [PMID: 38351675 PMCID: PMC10990668 DOI: 10.17998/jlc.2024.01.25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 01/16/2024] [Accepted: 01/25/2024] [Indexed: 04/05/2024]
Abstract
BACKGROUND/AIM Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOBMRI) further enhances the identification of additional hepatic nodules compared with computed tomography (CT) alone; however, the optimal treatment for such additional nodules remains unclear. We investigated the long-term oncological effect of aggressive treatment strategies for additional lesions identified using EOB-MRI in patients with hepatocellular carcinoma (HCC). METHODS Data from 522 patients diagnosed with solitary HCC using CT between January 2008 and December 2012 were retrospectively reviewed. Propensity score-matched (PSM) analysis was used to compare the oncologic outcomes between patients with solitary HCC and those with additional nodules on EOB-MRI after aggressive treatment (resection or radiofrequency ablation [RFA]). RESULTS Among the 383 patients included, 59 had additional nodules identified using EOB-MRI. Compared with patients with solitary HCC, those with additional nodules on EOB-MRI had elevated total bilirubin, aspartate transaminase, and alanine transaminase; had a lower platelet count, higher MELD score, and highly associated with liver cirrhosis (P<0.05). Regarding long-term outcomes, 59 patients with solitary HCC and those with additional nodules after PSM were compared. Disease-free survival (DFS) and overall survival (OS) were comparable between the two groups (DFS, 60.4 vs. 44.3 months, P=0.071; OS, 82.8 vs. 84.8 months, P=0.986). CONCLUSION The aggressive treatment approach, either resection or RFA, for patients with additional nodules identified on EOBMRI was associated with long-term survival comparable with that for solitary HCC. However, further studies are required to confirm these findings.
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Affiliation(s)
- Na Reum Kim
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Seoung Yoon Rho
- Department of Surgery, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
| | - Jonathan Navarro
- Division of Surgical Oncology, Department of Surgery, Vicente Sotto Memorial Medical Center, Cebu, Philippines
| | - Chansik An
- Department of Radiology, CHA University Bundang Medical Center, Seongnam, Korea
| | - Dai Hoon Han
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Jin Sub Choi
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Myeong-Jin Kim
- Department of Radiology, Yonsei University College of Medicine, Seoul, Korea
| | - Gi Hong Choi
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
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Sun Y, Wu P, Zhang Z, Wang Z, Zhou K, Song M, Ji Y, Zang F, Lou L, Rao K, Wang P, Gu Y, Gu J, Lu B, Chen L, Pan X, Zhao X, Peng L, Liu D, Chen X, Wu K, Lin P, Wu L, Su Y, Du M, Hou Y, Yang X, Qiu S, Shi Y, Sun H, Zhou J, Huang X, Peng DH, Zhang L, Fan J. Integrated multi-omics profiling to dissect the spatiotemporal evolution of metastatic hepatocellular carcinoma. Cancer Cell 2024; 42:135-156.e17. [PMID: 38101410 DOI: 10.1016/j.ccell.2023.11.010] [Citation(s) in RCA: 35] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 09/27/2023] [Accepted: 11/21/2023] [Indexed: 12/17/2023]
Abstract
Comprehensive molecular analyses of metastatic hepatocellular carcinoma (HCC) are lacking. Here, we generate multi-omic profiling of 257 primary and 176 metastatic regions from 182 HCC patients. Primary tumors rich in hypoxia signatures facilitated polyclonal dissemination. Genomic divergence between primary and metastatic HCC is high, and early dissemination is prevalent. The remarkable neoantigen intratumor heterogeneity observed in metastases is associated with decreased T cell reactivity, resulting from disruptions to neoantigen presentation. We identify somatic copy number alterations as highly selected events driving metastasis. Subclones without Wnt mutations show a stronger selective advantage for metastasis than those with Wnt mutations and are characterized by a microenvironment rich in activated fibroblasts favoring a pro-metastatic phenotype. Finally, metastases without Wnt mutations exhibit higher enrichment of immunosuppressive B cells that mediate terminal exhaustion of CD8+ T cells via HLA-E:CD94-NKG2A checkpoint axis. Collectively, our results provide a multi-dimensional dissection of the complex evolutionary process of metastasis.
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Affiliation(s)
- Yunfan Sun
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
| | - Pin Wu
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200032, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China; BGI Research, Shenzhen 518083, China
| | - Zefan Zhang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Zejian Wang
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200032, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Kaiqian Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Minfang Song
- Research Center for Intelligent Computing Platforms, Zhejiang Lab, Hangzhou, Zhejiang 311121, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Fenglin Zang
- Department of Pathology, Liver Cancer Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Limu Lou
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200032, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China
| | - Keqiang Rao
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Pengxiang Wang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Yutong Gu
- Department of Orthopaedic Surgery, Zhongshan Hospital Fudan University, Shanghai 200032, China
| | - Jie Gu
- Department of Thoracic Surgery, Zhongshan Hospital Fudan University, Shanghai 200032, China
| | - Binbin Lu
- Dunwill Med-Tech, Shanghai 200032, China
| | | | - Xiuqi Pan
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200032, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China
| | - Xiaojing Zhao
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200032, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China
| | - Lihua Peng
- BGI Research, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI Research, Shenzhen 518083, China
| | - Dongbing Liu
- BGI Research, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI Research, Shenzhen 518083, China
| | - Xiaofang Chen
- BGI Research, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI Research, Shenzhen 518083, China
| | - Kui Wu
- BGI Research, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI Research, Shenzhen 518083, China
| | - Penghui Lin
- BGI Research, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI Research, Shenzhen 518083, China
| | - Liang Wu
- BGI Research, Shenzhen 518083, China
| | - Yulin Su
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200032, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China
| | - Min Du
- Department of Pathology, Huadong Hospital, Fudan University, Shanghai 200032, China
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xinrong Yang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Shuangjian Qiu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Yinghong Shi
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Huichuan Sun
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Jian Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Xingxu Huang
- Research Center for Intelligent Computing Platforms, Zhejiang Lab, Hangzhou, Zhejiang 311121, China
| | | | - Liye Zhang
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200032, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China.
| | - Jia Fan
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
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Xie ZS, Han XY, Zhou ZY, Li SY, Zhu JY, Zhang L, Xue ST. Design and synthesis of dabigatran etexilate derivatives with inhibiting thrombin activity for hepatocellular carcinoma treatment. Biomed Pharmacother 2024; 170:116018. [PMID: 38113628 DOI: 10.1016/j.biopha.2023.116018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 12/11/2023] [Accepted: 12/14/2023] [Indexed: 12/21/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most fatal solid malignancies worldwide. Evidence suggests that thrombin stimulates tumor progression via fibrin formation and platelet activation. Meanwhile, we also found a correlation between thrombin and HCC through bioinformatics analysis. Dabigatran is a selective, direct thrombin inhibitor that reversibly binds to thrombin. Dabigatran was used as the lead agent in this study, and 19 dabigatran derivatives were designed and synthesized based on docking mode. The thrombin-inhibitory activity of the derivative AX-2 was slightly better than that of dabigatran. BX-2, a prodrug of AX-2, showed a fairly strong inhibitory effect on thrombin-induced platelet aggregation, and effectively antagonized proliferation of HCC tumor cells induced by thrombin at the cellular level. Furthermore, BX-2 reduced tumor volume, weight, lung metastasis, and secondary tumor occurrence in nude mouse models. BX-2 combined with sorafenib increased sorafenib efficacy. This study lays the foundation for discovering new anti-HCC mechanism based on thrombin. BX-2 can be used as an anti-HCC drug lead for further research.
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Affiliation(s)
- Zhuo-Song Xie
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiao-Yang Han
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zi-Ying Zhou
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Si-Yan Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jiang-Yi Zhu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Lei Zhang
- School of Biological & Chemical Engineering, Zhejiang University of Science and Technology, Zhejiang, China.
| | - Si-Tu Xue
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
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9
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Tao C, Zhang K, Tao Z, Liu Y, Wu A, Wang L, Feng Q, Wu F, Rong W, Wu J. Clinical benefits of intraoperative radiotherapy for the recurrence of centrally located hepatocellular carcinoma with microvascular invasion. Cancer Rep (Hoboken) 2024; 7:e1928. [PMID: 37906430 PMCID: PMC10809203 DOI: 10.1002/cnr2.1928] [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: 03/23/2023] [Revised: 09/29/2023] [Accepted: 10/16/2023] [Indexed: 11/02/2023] Open
Abstract
BACKGROUND Although the efficacy and safety of intraoperative radiotherapy (IORT) in the treatment of malignant tumours, such as breast cancer, have been documented, it remains unclear whether this treatment is effective for centrally located hepatocellular carcinoma (HCC) with microvascular invasion (MVI). AIMS This study aimed to explore the efficacy and safety of IORT in the treatment of centrally located HCC with MVI. METHODS AND RESULTS Patients with centrally located HCC, who underwent surgery between January 2016 and January 2020, were enrolled. The patient cohort was then allocated to two groups: those who underwent IORT combined with liver resection (IORT+LR); or LR alone (LR). Propensity score matching and Cox proportional hazards regression analyses were performed. The Kaplan-Meier method was used to estimate recurrence-free survival (RFS), and the log-rank test was used to determine whether RFS differed between the groups. Subgroup analysis was performed to evaluate differences in RFS and early recurrence rates in patients with different MVI grades. E-values were generated to measure the sensitivity to unmeasured confounding factors. In total, 97 patients were enrolled, 27 of whom underwent IORT+LR and 70 underwent LR alone. The 1-, 3-, and 5-year RFS rates in the IORT+LR group were 66%, 50%, and 32%, respectively, whereas those in the LR group were 54%, 37%, and 26%, respectively. After matching analysis, 23 patients were successfully matched, and RFS was found to be significantly different between the two groups (p = .04). IORT was an independent prognostic factor for RFS (hazard ratio 0.46 [95% confidence interval 0.21-0.99]). In subgroup analysis, RFS between the IORT+LR and LR groups was significantly different in patients with MVI (M1 grade) (p = .0067). The postoperative early recurrence rate was significantly reduced with IORT (p < .05). No serious complications were reported in either group following surgery. Based on E-values, the results appeared to be robust against unmeasured confounding factors. CONCLUSION IORT+LR provided safe, feasible treatment for patients with centrally located HCC with MVI, along with an improvement in prognosis and lower early recurrence rates.
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Affiliation(s)
- Changcheng Tao
- Department of Hepatobiliary SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Kai Zhang
- Department of Interventional TherapyTianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for CancerTianjinChina
| | - Zonggui Tao
- Department of ImagingJinan City People's Hospital, Shandong First Medical UniversityJinanChina
| | - Yue Liu
- Department of Hepatobiliary SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Anke Wu
- Department of Hepatobiliary SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Liming Wang
- Department of Hepatobiliary SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Qinfu Feng
- Department of Radiation OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Fan Wu
- Department of Hepatobiliary SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Weiqi Rong
- Department of Hepatobiliary SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Jianxiong Wu
- Department of Hepatobiliary SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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10
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Xiang J, Zhang N, Du A, Li J, Luo M, Wang Y, Liu M, Yang L, Li X, Wang L, Liu Q, Chen D, Wang T, Bian X, Qin Z, Su L, Wen L, Wang B. A Ubiquitin-Dependent Switch on MEF2D Senses Pro-Metastatic Niche Signals to Facilitate Intrahepatic Metastasis of Liver Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2305550. [PMID: 37828611 PMCID: PMC10724427 DOI: 10.1002/advs.202305550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Indexed: 10/14/2023]
Abstract
Effective treatment for metastasis, a leading cause of cancer-associated death, is still lacking. To seed on a distal organ, disseminated cancer cells (DCCs) must adapt to the local tissue microenvironment. However, it remains elusive how DCCs respond the pro-metastatic niche signals. Here, systemic motif-enrichment identified myocyte enhancer factor 2D (MEF2D) as a critical sensor of niche signals to regulate DCCs adhesion and colonization, leading to intrahepatic metastasis and recurrence of liver cancer. In this context, MEF2D transactivates Itgb1 (coding β1-integrin) and Itgb4 (coding β4-integrin) to execute temporally unique functions, where ITGB1 recognizes extracellular matrix for early seeding, and ITGB4 acts as a novel sensor of neutrophil extracellular traps-DNA (NETs-DNA) for subsequent chemotaxis and colonization. In turn, an integrin-FAK circuit promotes a phosphorylation-dependent USP14-orchastrated deubiquitination switch to stabilize MEF2D via circumventing degradation by the E3-ubiquitin-ligase MDM2. Clinically, the USP14(pS432)-MEF2D-ITGB1/4 feedback loop is often hyper-active and indicative of inferior outcomes in human malignancies, while its blockade abrogated intrahepatic metastasis of DCCs. Together, DCCs exploit a deubiquitination-dependent switch on MEF2D to integrate niche signals in the liver mesenchyme, thereby amplifying the pro-metastatic integrin-FAK signaling. Disruption of this feedback loop is clinically applicable with fast-track potential to block microenvironmental cues driving metastasis.
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Affiliation(s)
- Junyu Xiang
- Department of GastroenterologyChongqing Key Laboratory of Digestive MalignanciesDaping HospitalArmy Medical University (Third Military Medical University)Chongqing400042China
| | - Ni Zhang
- Department of GastroenterologyChongqing Key Laboratory of Digestive MalignanciesDaping HospitalArmy Medical University (Third Military Medical University)Chongqing400042China
| | - Aibei Du
- Department of GastroenterologyChongqing Key Laboratory of Digestive MalignanciesDaping HospitalArmy Medical University (Third Military Medical University)Chongqing400042China
| | - Jinyang Li
- Department of GastroenterologyChongqing Key Laboratory of Digestive MalignanciesDaping HospitalArmy Medical University (Third Military Medical University)Chongqing400042China
| | - Mengyun Luo
- Department of GastroenterologyChongqing Key Laboratory of Digestive MalignanciesDaping HospitalArmy Medical University (Third Military Medical University)Chongqing400042China
| | - Yuzhu Wang
- Department of GastroenterologyChongqing Key Laboratory of Digestive MalignanciesDaping HospitalArmy Medical University (Third Military Medical University)Chongqing400042China
| | - Meng Liu
- Department of GastroenterologyChongqing Key Laboratory of Digestive MalignanciesDaping HospitalArmy Medical University (Third Military Medical University)Chongqing400042China
| | - Luming Yang
- Department of GastroenterologyChongqing Key Laboratory of Digestive MalignanciesDaping HospitalArmy Medical University (Third Military Medical University)Chongqing400042China
| | - Xianfeng Li
- Department of GastroenterologyChongqing Key Laboratory of Digestive MalignanciesDaping HospitalArmy Medical University (Third Military Medical University)Chongqing400042China
| | - Lin Wang
- Department of GastroenterologyChongqing Key Laboratory of Digestive MalignanciesDaping HospitalArmy Medical University (Third Military Medical University)Chongqing400042China
| | - Qin Liu
- Department of GastroenterologyChongqing Key Laboratory of Digestive MalignanciesDaping HospitalArmy Medical University (Third Military Medical University)Chongqing400042China
| | - Dongfeng Chen
- Department of GastroenterologyChongqing Key Laboratory of Digestive MalignanciesDaping HospitalArmy Medical University (Third Military Medical University)Chongqing400042China
| | - Tao Wang
- Department of GastroenterologyChongqing Key Laboratory of Digestive MalignanciesDaping HospitalArmy Medical University (Third Military Medical University)Chongqing400042China
| | - Xiu‐wu Bian
- Institute of Pathology and Southwest Cancer Centerand Key Laboratory of Tumor Immunopathology of Ministry of Education of ChinaSouthwest HospitalArmy Medical University (Third Military Medical University)Chongqing400038China
| | - Zhong‐yi Qin
- Department of GastroenterologyChongqing Key Laboratory of Digestive MalignanciesDaping HospitalArmy Medical University (Third Military Medical University)Chongqing400042China
- Institute of Pathology and Southwest Cancer Centerand Key Laboratory of Tumor Immunopathology of Ministry of Education of ChinaSouthwest HospitalArmy Medical University (Third Military Medical University)Chongqing400038China
| | - Li Su
- Department of Oncology and HematologyChongqing Hospital of Traditional Chinese MedicineChongqing400030China
| | - Liangzhi Wen
- Department of GastroenterologyChongqing Key Laboratory of Digestive MalignanciesDaping HospitalArmy Medical University (Third Military Medical University)Chongqing400042China
| | - Bin Wang
- Department of GastroenterologyChongqing Key Laboratory of Digestive MalignanciesDaping HospitalArmy Medical University (Third Military Medical University)Chongqing400042China
- Institute of Pathology and Southwest Cancer Centerand Key Laboratory of Tumor Immunopathology of Ministry of Education of ChinaSouthwest HospitalArmy Medical University (Third Military Medical University)Chongqing400038China
- Jinfeng LaboratoryChongqing401329China
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11
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Xu Y, Li Z, Zhou Y, Yang Y, Ouyang J, Li L, Huang Z, Ye F, Ying J, Zhao H, Zhou J, Zhao X. Using immunovascular characteristics to predict very early recurrence and prognosis of resectable intrahepatic cholangiocarcinoma. BMC Cancer 2023; 23:1009. [PMID: 37858111 PMCID: PMC10588260 DOI: 10.1186/s12885-023-11476-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 10/03/2023] [Indexed: 10/21/2023] Open
Abstract
OBJECTIVE To predict the very early recurrence (VER) of patients with intrahepatic cholangiocarcinoma (ICC) based on TLSs and MVI status, and further perform prognosis stratifications. METHODS A total of 160, 51 ICC patients from two institutions between May 2012 and July 2022 were retrospectively included as training, external validation cohort. Clinical, radiological and pathological variables were evaluated and collected. Univariate and multivariate analysis were applied to select the significant factors related to VER of ICC. The factors selected were combined to perform stratification of overall survival (OS) using the Kaplan-Meier method with the log-rank test. RESULTS Overall, 39 patients (24.4%) had VER, whereas 121 (75.6%) did not (non-VER group). In the training cohort, the median OS was 40.5 months (95% CIs: 33.2-47.7 months). The VER group showed significantly worse OS than the non-VER group (median OS: 14.8, 95% CI:11.6-18.0 months vs. 53.4, 34.3-72.6 months; p<0.001), and it was confirmed in the validation cohort (median OS: 22.1, 95% CI: 8.8-35.4 months vs. 40.1, 21.2-59.0 months; p = 0.003). According to the univariate analysis, four variables were significantly different between the VER group and non-VER group (TLSs status, p = 0.028; differentiation, p = 0.023; MVI status, p = 0.012; diameter, p = 0.028). According to the multivariate analysis, MVI-positive status was independently associated with a higher probability of VER (odds ratio [OR], 2.5; 95% CIs,1.16-5.18; p = 0.018), whereas intra-tumoral TLSs-positive status was associated with lower odds of VER (OR, 0.43; 95% CIs, 0.19-0.97; p = 0.041). Based on the TLSs and MVI status, patients of ICC were categorized into four groups: TLSs-positive and MVI-negative (TP/MN); TLSs-negative and MVI-negative (TN/MN); TLSs-positive and MVI-positive (TP/MP), TLSs-negative and MVI-positive groups (TN/MP). In the training cohort, the four groups could be correlated with OS significantly (p<0.001), and it was confirmed in the validation cohort (p<0.001). CONCLUSION Intra-tumoral TLSs and MVI status are independent predictive factors of VER after surgery, based on which immunovascular stratifications are constructed and associated with OS significantly of resectable intrahepatic cholangiocarcinoma.
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Affiliation(s)
- Ying Xu
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhuo Li
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanzhao Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Yi Yang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Key Laboratory of Gene Editing Screening and Research and Development (R&D) of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jingzhong Ouyang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Lu Li
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhen Huang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Key Laboratory of Gene Editing Screening and Research and Development (R&D) of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Feng Ye
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Jianming Ying
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- Key Laboratory of Gene Editing Screening and Research and Development (R&D) of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- Key Laboratory of Gene Editing Screening and Research and Development (R&D) of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Jinxue Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, China.
| | - Xinming Zhao
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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12
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Nan Y, Xu X, Dong S, Yang M, Li L, Zhao S, Duan Z, Jia J, Wei L, Zhuang H. Consensus on the tertiary prevention of primary liver cancer. Hepatol Int 2023; 17:1057-1071. [PMID: 37369911 PMCID: PMC10522749 DOI: 10.1007/s12072-023-10549-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 05/04/2023] [Indexed: 06/29/2023]
Abstract
To effectively prevent recurrence, improve the prognosis and increase the survival rate of primary liver cancer (PLC) patients with radical cure, the Chinese Society of Hepatology, Chinese Medical Association, invited clinical experts and methodologists to develop the Consensus on the Tertiary Prevention of Primary Liver Cancer, which was based on the clinical and scientific advances on the risk factors, histopathology, imaging finding, clinical manifestation, and prevention of recurrence of PLC. The purpose is to provide a current basis for the prevention, surveillance, early detection and diagnosis, and the effective measures of PLC recurrence.
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Affiliation(s)
- Yuemin Nan
- Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051 China
| | - Xiaoyuan Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034 China
| | - Shiming Dong
- Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051 China
| | - Ming Yang
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing, China
| | - Ling Li
- Department of Intervention, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 China
| | - Suxian Zhao
- Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051 China
| | - Zhongping Duan
- Artificial Liver Centre, Beijing You-An Hospital, Capital Medical University, Beijing, 100069 China
| | - Jidong Jia
- Liver Research Centre, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050 China
| | - Lai Wei
- Hepatopancreatobiliary Centre, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, 102218 China
| | - Hui Zhuang
- Department of Microbiology and Centre for Infectious Diseases, Peking University Health Science Centre, Beijing, 100191 China
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13
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Wu F, Sun H, Shi Z, Zhou C, Huang P, Xiao Y, Yang C, Zeng M. Estimating Microvascular Invasion in Patients with Resectable Multinodular Hepatocellular Carcinoma by Using Preoperative Contrast-Enhanced MRI: Establishment and Validation of a Risk Score. J Hepatocell Carcinoma 2023; 10:1143-1156. [PMID: 37492267 PMCID: PMC10364817 DOI: 10.2147/jhc.s410237] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 07/07/2023] [Indexed: 07/27/2023] Open
Abstract
Objective To determine the preoperative clinicoradiological factors to predict microvascular invasion (MVI) in patients with resectable multinodular hepatocellular carcinoma (mHCC), and further to establish and validate a stratified risk scoring system. Methods Two hundred and seventy-three patients with pathologically confirmed mHCC (≥2 lesions) without major vascular invasion and biliary tract tumor thrombosis, who underwent preoperative contrast-enhanced MRI and hepatectomy, were consecutively enrolled (training/validation cohort=193/80). Preoperative clinicoradiological variables were collected and analyzed. The multivariable logistic regression was performed to determine the independent predictors of MVI and create a risk score system. The C-index, calibration curve and decision curve were used to evaluate the performance of the risk score. A risk score-based prognostic stratification system was performed in mHCC patients. The risk score system was further verified in the validation cohort. Results AFP > 400 ng/mL, presence of satellite nodule, mosaic architecture and increased total tumor diameter were independent predictors of MVI while fat in mass was an independent protective factor of MVI. The risk score yielded satisfactory C-index values (training/validation cohort: 0.777/0.758) and fitted well in calibration curves. Decision curve analysis further confirmed its clinical utility. Based on the risk score, mHCC patients were stratified into high-/low-MVI-risk subgroups with significantly different recurrence-free survival (both P < 0.001). Conclusion The presented risk score incorporating clinicoradiological parameters could stratify mHCC patients into high-risk and low-risk subgroups and predict prognosis in patients with resectable mHCC.
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Affiliation(s)
- Fei Wu
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Haitao Sun
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Zhang Shi
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Changwu Zhou
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
- Shanghai Institute of Medical Imaging, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Peng Huang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Yuyao Xiao
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Chun Yang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Mengsu Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
- Shanghai Institute of Medical Imaging, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
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14
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Preoperative Predictors of Early Recurrence After Liver Resection for Multifocal Hepatocellular Carcinoma. J Gastrointest Surg 2023:10.1007/s11605-023-05592-1. [PMID: 36857014 DOI: 10.1007/s11605-023-05592-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 01/07/2023] [Indexed: 03/02/2023]
Abstract
BACKGROUND Liver transplantation remains the optimal treatment for multifocal hepatocellular carcinoma (HCC). However, due to resource constrains, other therapeutic modalities such as liver resection (LR), are frequently utilized. LR, however, has to be balanced against potential morbidity and mortality along with the risks of early recurrence leading to futile surgery. In this study, we evaluated preoperative factors, including inflammatory indices, in predicting early (< 1 year) recurrence in patients who underwent LR for multifocal HCC. METHODS This was a post hoc analysis of 250 consecutive patients with multifocal HCC who underwent LR. RESULTS After exclusion of 10 patients with 30-day/in-hospital mortality, 240 were included of which 134 (55.8%) developed early recurrence. Hepatitis B/C aetiology, 3/ > more hepatic nodules and elevated alpha-fetoprotein (AFP) ≥ 200 ng/ml were significant independent preoperative predictors of early recurrence. The early recurrence rate was 72.1% when 2 out of 3 significant predictive factors were present. The conglomerate of all 3 factors predicted early recurrence of 100% with a statistically significant association between number of predictive factors and early recurrence (p < 0.001). CONCLUSION Better patient selection via the use of preoperative predictive factors of early recurrence such as hepatitis B/C aetiology, ≥ 3 nodules and elevated AFP ≥ 200 ng/ml may assist in identifying patients in whom LR is deemed futile and improve resource allocation.
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15
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Wu F, Sun H, Zhou C, Huang P, Xiao Y, Yang C, Zeng M. Prognostic factors for long-term outcome in bifocal hepatocellular carcinoma after resection. Eur Radiol 2023; 33:3604-3616. [PMID: 36700957 DOI: 10.1007/s00330-023-09398-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 12/14/2022] [Accepted: 12/23/2022] [Indexed: 01/27/2023]
Abstract
OBJECTIVES This study aimed to evaluate whether the radiological similarity and clinicopathological factors determine the prognosis in bifocal hepatocellular carcinoma (bHCC) stratified by the Milan criteria. METHODS Consecutive patients with pathologically confirmed bHCC examined between January 2016 and December 2018 were retrospectively enrolled and grouped based on the Milan criteria. Two radiologists independently evaluated whether the imaging features of both tumors were consistent or not, which was defined as the radiological similarity. The clinicopathological data were also collected. The multivariable Cox regression was applied to separately identify the independent factors for recurrence-free survival (RFS) and overall survival (OS) in bHCC within and beyond the Milan criteria. RESULTS A total of 193 patients were evaluated and divided into the within the Milan criteria group (n = 72) and the beyond the Milan criteria group (n = 121). bHCC within the Milan criteria showed a significantly better prognosis than those beyond the criteria. In the within the Milan criteria group, HBV-DNA load >104 IU/mL, microvascular invasion (MVI), and different enhancement patterns were independently associated with poor RFS. MVI was an independent prognostic factor for poor OS. In the beyond the Milan criteria group, HBV infection, MVI, increased ratio of the larger to the smaller tumor diameter (RLSD) value, and low comprehensive similarity were associated with shorter RFS, whereas MVI and increased RLSD value were independent predictors for poor OS. CONCLUSIONS Our study revealed that in addition to MVI- and HBV-related factors, similarity in imaging features between lesions of bHCC is associated with the long-term prognosis. KEY POINTS • The prognosis of bifocal HCC patients within the Milan criteria is significantly better than those beyond the criteria. • The similarity in imaging features between lesions of bHCC was an independent prognostic factor. • The more similar the bifocal lesions are in imaging features, the better the prognosis is.
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Affiliation(s)
- Fei Wu
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Cancer Center, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Haitao Sun
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Cancer Center, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Changwu Zhou
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Cancer Center, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.,Shanghai Institute of Medical Imaging, Shanghai, China
| | - Peng Huang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Cancer Center, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Yuyao Xiao
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Cancer Center, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Chun Yang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China. .,Department of Cancer Center, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.
| | - Mengsu Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China. .,Department of Cancer Center, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China. .,Shanghai Institute of Medical Imaging, Shanghai, China.
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16
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Milana F, Polidoro MA, Famularo S, Lleo A, Boldorini R, Donadon M, Torzilli G. Surgical Strategies for Recurrent Hepatocellular Carcinoma after Resection: A Review of Current Evidence. Cancers (Basel) 2023; 15:508. [PMID: 36672457 PMCID: PMC9856445 DOI: 10.3390/cancers15020508] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/07/2023] [Accepted: 01/10/2023] [Indexed: 01/17/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and both liver resection and liver transplantation are considered potentially curative options. However, high recurrence rates affect the prognosis depending both on the primary HCC pathology characteristics or on the type and time of the relapse. While great attention has been usually posted on treatment algorithms for the first HCC, treatment algorithms for recurrent HCC (rHCC) are lacking. In these cases, surgery still represents a curative option with both redo hepatectomy and/or salvage liver transplantation, which are considered valid treatments in selected patients. In the current era of personalised medicine with promises of new systemic-targeted immuno-chemotherapies, we wished to perform a narrative review of the literature on the role of surgical strategies for rHCC.
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Affiliation(s)
- Flavio Milana
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, MI, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Michela Anna Polidoro
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Simone Famularo
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, MI, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, MI, Italy
- Department of Internal Medicine, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Renzo Boldorini
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, NO, Italy
- Department of Pathology, University Maggiore Hospital, 28100 Novara, NO, Italy
| | - Matteo Donadon
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, NO, Italy
- Department of General Surgery, University Maggiore Hospital, 28100 Novara, NO, Italy
| | - Guido Torzilli
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, MI, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
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17
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Repeat hepatectomy versus microwave ablation for solitary and small (≤3 cm) recurrent hepatocellular carcinoma with early or late recurrence: A propensity score matched study. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2022; 49:1001-1008. [PMID: 36585301 DOI: 10.1016/j.ejso.2022.12.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 12/24/2022] [Indexed: 12/27/2022]
Abstract
BACKGROUND Repeat hepatectomy (RH) and microwave ablation (MWA) are frequently used procedures for the treatment of recurrent hepatocellular carcinoma (HCC) after curative resection. This study aimed to compare the long-term outcomes of RH and MWA for solitary and small HCC with early or late recurrence. METHOD This retrospective study enrolled patients who underwent RH or MWA for solitary and small (≤3 cm) recurrent HCC at Tongji hospital between April 2006 and December 2020. Propensity score matching (PSM) was further employed to analyze the prognosis of different treatment methods. RESULTS A total of 256 patients were analyzed, of whom 94 and 162 underwent RH and MWA, respectively. The overall treatment-related complication rate was higher in the RH group. Both recurrence-free survival (RFS) and overall survival (OS) rates of RH were significantly better than those of MWA. Multivariate analysis showed that MWA, early recurrence (within 24 months after initial resection), cirrhosis, and AFP >400 ng/ml were independent risk factors for poor prognoses of recurrent HCC. The stratified analysis demonstrated that MWA and RH had similar long-term outcomes in patients with early recurrence. Nevertheless, MWA had worse RFS and OS than RH in patients with late recurrence. The same results were obtained in the PSM analysis. CONCLUSION The long-term outcomes of HCC patients with late recurrence were significantly better than those with early recurrence. RH should be the first choice for solitary small recurrent HCC patients with late recurrence, while MWA should be selected for those with early recurrence.
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18
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Testa U, Pelosi E, Castelli G. Clinical value of identifying genes that inhibit hepatocellular carcinomas. Expert Rev Mol Diagn 2022; 22:1009-1035. [PMID: 36459631 DOI: 10.1080/14737159.2022.2154658] [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: 12/05/2022]
Abstract
INTRODUCTION Primary liver cancer is a major health problem being the sixth most frequent cancer in the world and the fourth most frequent cause of cancer-related death in the world. The most common histological type of liver cancer is hepatocellular carcinoma (HCC, 75-80%). AREAS COVERED Based on primary literature, this review provides an updated analysis of studies of genetic characterization of HCC at the level of gene mutation profiling, copy number alterations and gene expression, with definition of molecular subgroups and identification of some molecular biomarkers and therapeutic targets. EXPERT OPINION A detailed and comprehensive study of the genetic abnormalities characterizing different HCC subsets represents a fundamental tool for a better understanding of the disease heterogeneity and for the identification of subgroups of patients responding or resistant to targeted treatments and for the discovery of new therapeutic targets. It is expected that a comprehensive characterization of these tumors may provide a fundamental contribution to improve the survival of a subset of HCC patients. Immunotherapy represents a new fundamental strategy for the treatment of HCC.
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Affiliation(s)
- Ugo Testa
- Department of Oncology, Istituto Superiore Di Sanità, ROME, ITALY
| | - Elvira Pelosi
- Department of Oncology, Istituto Superiore Di Sanità, ROME, ITALY
| | - Germana Castelli
- Department of Oncology, Istituto Superiore Di Sanità, ROME, ITALY
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19
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Yoon JH, Choi SK, Cho SB, Kim HJ, Ko YS, Jun CH. Early extrahepatic recurrence as a pivotal factor for survival after hepatocellular carcinoma resection: A 15-year observational study. World J Gastroenterol 2022; 28:5351-5363. [PMID: 36185633 PMCID: PMC9521522 DOI: 10.3748/wjg.v28.i36.5351] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 08/11/2022] [Accepted: 09/08/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Surgical resection is one of the most widely used modalities for the treatment of hepatocellular carcinoma (HCC). Early extrahepatic recurrence (EHR) of HCC after surgical resection is considered to be closely associated with poor prognosis. However, data regarding risk factors and survival outcomes of early EHR after surgical resection remain scarce. AIM To investigate the clinical features and risk factors of early EHR and elucidate its association with survival outcomes. METHODS From January 2004 to December 2019, we enrolled treatment-naïve patients who were ≥ 18 years and underwent surgical resection for HCC in two tertiary academic centers. After excluding patients with tumor types other than HCC and/or ineligible data, this retrospective study finally included 779 patients. Surgical resection of HCC was performed according to the physicians' decisions and the EHR was diagnosed based on contrast-enhanced computed tomography or magnetic resonance imaging, and pathologic confirmation was performed in selected patients. Multivariate Cox regression analysis was performed to identify the variables associated with EHR. RESULTS Early EHR within 2 years after surgery was diagnosed in 9.5% of patients during a median follow-up period of 4.4 years. The recurrence-free survival period was 5.2 mo, and the median time to EHR was 8.8 mo in patients with early EHR. In 52.7% of patients with early EHR, EHR occurred as the first recurrence of HCC after surgical resection. On multivariate analysis, serum albumin < 4.0 g/dL, serum alkaline phosphatase > 100 U/L, surgical margin involvement, venous and/or lymphatic involvement, satellite nodules, tumor necrosis detected by pathology, tumor size ≥ 7 cm, and macrovascular invasion were determined as risk factors associated with early EHR. After sub-categorizing the patients according to the number of risk factors, the rates of both EHR and survival showed a significant correlation with the risk of early EHR. Furthermore, multivariate analysis revealed that early EHR was associated with substantially worse survival outcomes (Hazard ratio, 6.77; 95% confidence interval, 4.81-9.52; P < 0.001). CONCLUSION Early EHR significantly deteriorates the survival of patients with HCC, and our identified risk factors may predict the clinical outcomes and aid in postoperative strategies for improving survival.
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Affiliation(s)
- Jae Hyun Yoon
- Department of Gastroenterology and Hepatology, Chonnam National University Hospital and College of Medicine, Gwangju 61469, South Korea
| | - Sung Kyu Choi
- Department of Gastroenterology and Hepatology, Chonnam National University Hospital and College of Medicine, Gwangju 61469, South Korea
| | - Sung Bum Cho
- Department of Gastroenterology and Hepatology, Hwasun Chonnam National University Hospital and College of Medicine, Hwasun 58128, South Korea
| | - Hee Joon Kim
- Department of Surgery, Chonnam National University Hospital and College of Medicine, Gwangju 61469, South Korea
| | - Yang Seok Ko
- Department of Surgery, Hwasun Chonnam National University Hospital and College of Medicine, Hwasun 58128, South Korea
| | - Chung Hwan Jun
- Department of Internal Medicine, Mokpo Hankook Hospital, Mokpo 58643, South Korea
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20
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Surgical resection versus radiofrequency ablation for early recurrent hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2022; 34:844-851. [PMID: 35694799 DOI: 10.1097/meg.0000000000002393] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND Surgical resection (SR) and radiofrequency ablation (RFA) are reasonable treatment options for early recurrent hepatocellular carcinoma (rHCC), but it is still uncertain which treatment is better. The purpose of this study was to compare the therapeutic effects of SR and RFA on patients with early rHCC. METHODS This study enrolled 168 patients with early rHCC who underwent SR or RFA. The progression-free survival (PFS), overall survival (OS), and complications between the treatment groups for the total and propensity score-matched (PSM) cohorts were compared. RESULTS Before PSM, the 1-, 3-, 5-year OS (94.8%, 63.0%, 36.1% vs. 93.8%, 58.5%, 35.4%, P = 0.580) and PFS (50.7%, 22.7%, 12.0% vs. 68.8%, 30.3%, 15.9%, P = 0.224) were similar in RFA group and the SR group. After PSM, the 1-, 3-, 5-year OS (95.5%, 71.1%, 53.3% vs. 95.5%, 58.0%, 42.1%, P = 0.285) and PFS (50%, 36.4%, 27.3% vs. 68.2%, 25.6%, 12.8%, P = 0.999) were similar in the RFA group and the SR group. For patients with early recurrent tumors ≤3 cm, RFA and SR could achieve similar curative effects. However, SR was superior to RFA in terms PFS for patients with early recurrent tumors >3 cm, but the OS was similar. For all patients, RFA had significantly fewer complications and shorter hospitalization time compared with SR. CONCLUSION SR achieves better tumor control compared with RFA for patients with early rHCC (>3 cm) after SR. RFA had significantly fewer complications and shorter hospitalization time compared with SR for all patients.
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21
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Wu Y, Peng W, Shen J, Zhang X, Li C, Wen T. The impact of tumor burden at the initial hepatectomy on the recurrence-to-death survival after repeat surgical resection/radiofrequency ablation: a retrospective study. BMC Surg 2022; 22:193. [PMID: 35585534 PMCID: PMC9118788 DOI: 10.1186/s12893-022-01643-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 05/10/2022] [Indexed: 02/08/2023] Open
Abstract
Background Previous studies have reported the surgical resection (SR) and radiofrequency ablation (RFA) could achieve comparable recurrence-to-death survival (RTDS). However, the impact of primary tumor burden on RTDS of patients with recurrent hepatocellular carcinoma (HCC) following SR or RFA has not been clarified. Methods From January 2009 to March 2015, 171 patients who underwent initial hepatectomy and second curative treatments in West China Hospital were retrospectively analyzed. Survival analysis was performed by the Kaplan–Meier method. Risk factors were identified using the Cox proportional hazard model. Results At initial hepatectomy, 96 patients (56.1%) were diagnosed with HCC within the Milan criteria (MC), and 75 patients (43.9%) were HCC beyond the MC. The clinicopathological features and re-treatment methods of recurrent HCC were similar between patients with primary HCC within or beyond the MC. Patients with primary HCC within the MC had longer recurrence time (31.4 ± 24.2 months vs. 20.2 ± 16 months, P < 0.001). The 1- and 3- year RTDS within and beyond the MC group were 88.8%, 57.6% and 79.0%, 46.3%, respectively (P = 0.093). In multivariate analysis, the recurrence time, tumor size and AFP > 400 ng/mL at the time of recurrence were associated with RTDS. Conclusions The primary tumor burden had no impact on RTDS, but had an impact on recurrence time. The recurrence time had an impact on RTDS and might be a good index to reflect the biology of recurrent HCC.
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Affiliation(s)
- Youwei Wu
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Wei Peng
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Junyi Shen
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xiaoyun Zhang
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Chuan Li
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Tianfu Wen
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
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22
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Szlasa W, Wilk K, Knecht-Gurwin K, Gurwin A, Froń A, Sauer N, Krajewski W, Saczko J, Szydełko T, Kulbacka J, Małkiewicz B. Prognostic and Therapeutic Role of CD15 and CD15s in Cancer. Cancers (Basel) 2022; 14:cancers14092203. [PMID: 35565333 PMCID: PMC9101515 DOI: 10.3390/cancers14092203] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 04/26/2022] [Accepted: 04/27/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary CD15 (Lewis X) is a typical myeloid antigen presented in myeloid and monocytic lineages of cells. This molecule interacts with E-, L- and P-selectins, which allows for adhesion with endothelial cells. CD15 is found on various cancer cells, including renal cancer, prostate and bladder cancers, acute leukaemias, hepatocellular carcinoma, breast cancer and melanoma cells. Its high expression can serve as a prognostic marker for patients and is a potentially valuable target for immunotherapy against cancer. Blockage of the antigen’s function results in reduced metastatic potential and it may be an immunotherapeutic target. CD15s is a sialyl derivative of CD15; however, unlike the high expression of CD15, which is a prognostic factor in Hodgkin lymphoma, CD15s relates to poor prognosis for patients. CD15 is considered a marker of cancer stem cells. This review presents a comprehensive description of the prognostic role of CD15 and CD15s and their use in anticancer therapy. Abstract CD15 (Lewis X/Lex) is a fucosyl (3-fucosly-N-acetyl-lactosamine) moiety found on membrane proteins of various cancer cells. These cancers include renal cancer, prostate and bladder cancers, acute leukaemias, hepatocellular carcinoma, breast cancer and melanoma. The biological role of CD15 is interaction with E-, L- and P-selectins (adhesion molecules), allowing for adhesion with endothelial cells. In this way, cancer cells start to interact with the endothelia of blood vessels and consequently move out from the blood flow to the surrounding tissues. Blockage of the antigen’s function results in reduced metastatic potential. Moreover, the molecule may be a therapeutic target against cancer in monoclonal antibody-based therapies. CD15 may serve as a prognostic marker for patients and there are high hopes for its use in the immunotherapeutic treatment of tumours. CD15s is a sialyl derivative of CD15 that possesses its own unique characteristics. Its soluble form may act as a competitive inhibitor of the interaction of cancer cells with epithelial cells and thus disallow migration through the vessels. However, the prognostic relevance of CD15 and CD15s expression is very complex. This review presents a comprehensive description of the role of CD15 and CD15s in cancer development and metastasis and overviews its significance for clinical applications.
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Affiliation(s)
- Wojciech Szlasa
- Department of Minimally Invasive and Robotic Urology, University Center of Excellence in Urology, Wroclaw Medical University, 50-556 Wroclaw, Poland; (K.W.); (A.G.); (A.F.); (W.K.); (T.S.)
- Correspondence: (W.S.); (B.M.)
| | - Karol Wilk
- Department of Minimally Invasive and Robotic Urology, University Center of Excellence in Urology, Wroclaw Medical University, 50-556 Wroclaw, Poland; (K.W.); (A.G.); (A.F.); (W.K.); (T.S.)
| | - Klaudia Knecht-Gurwin
- Department of Dermatology, Venerology and Allergology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland;
| | - Adam Gurwin
- Department of Minimally Invasive and Robotic Urology, University Center of Excellence in Urology, Wroclaw Medical University, 50-556 Wroclaw, Poland; (K.W.); (A.G.); (A.F.); (W.K.); (T.S.)
| | - Anita Froń
- Department of Minimally Invasive and Robotic Urology, University Center of Excellence in Urology, Wroclaw Medical University, 50-556 Wroclaw, Poland; (K.W.); (A.G.); (A.F.); (W.K.); (T.S.)
| | - Natalia Sauer
- Department of Drugs Form Technology, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland;
| | - Wojciech Krajewski
- Department of Minimally Invasive and Robotic Urology, University Center of Excellence in Urology, Wroclaw Medical University, 50-556 Wroclaw, Poland; (K.W.); (A.G.); (A.F.); (W.K.); (T.S.)
| | - Jolanta Saczko
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland; (J.S.); (J.K.)
| | - Tomasz Szydełko
- Department of Minimally Invasive and Robotic Urology, University Center of Excellence in Urology, Wroclaw Medical University, 50-556 Wroclaw, Poland; (K.W.); (A.G.); (A.F.); (W.K.); (T.S.)
| | - Julita Kulbacka
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland; (J.S.); (J.K.)
| | - Bartosz Małkiewicz
- Department of Minimally Invasive and Robotic Urology, University Center of Excellence in Urology, Wroclaw Medical University, 50-556 Wroclaw, Poland; (K.W.); (A.G.); (A.F.); (W.K.); (T.S.)
- Correspondence: (W.S.); (B.M.)
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Ohni S, Yamaguchi H, Hirotani Y, Nakanishi Y, Midorikawa Y, Sugitani M, Naruse H, Nakayama T, Makishima M, Esumi M. Direct molecular evidence for both multicentric and monoclonal carcinogenesis followed by transdifferentiation from hepatocellular carcinoma to cholangiocarcinoma in a case of metachronous liver cancer. Oncol Lett 2022; 23:22. [PMID: 34868359 PMCID: PMC8630812 DOI: 10.3892/ol.2021.13140] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 10/18/2021] [Indexed: 01/21/2023] Open
Abstract
Frequent recurrence is a major issue in liver cancer and histological heterogeneity frequently occurs in this cancer type. However, it has remained elusive whether such cancers are multicentric or monoclonal. To elucidate the clonal evolution of hepatocellular carcinoma (HCC) recurrence and combined hepatocellular-cholangiocarcinoma (cHCC-CCA) development, the somatic mutation frequency and signatures in a patient with triple occurrence of liver cancer every three years were examined, with samples designated as #1HCC, #2HCC and #3cHCC-CCA, respectively. A total of four tumor regions, including HCC (#3HCC) and intrahepatic CCA (#3iCCA) components of #3cHCC-CCA, and three nontumor regions (#1N, #2N and #3N) were precisely dissected from formalin-fixed paraffin-embedded tissues of each surgical specimen. DNA was extracted and subjected to tumor-specific somatic mutation determination. Of note, five nonsynonymous single-nucleotide variants (SNVs), namely those of KMT2D, TP53, DNMT3A, PKHD1 and TLR4, were identified in #3cHCC-CCA. All five SNVs were detected in both #3HCC and #3iCCA and #2HCC but not in #1HCC. The telomerase reverse transcriptase (TERT) promoter mutation C228T, but not C250T, was observed in all tumors. Digital PCR of C228T also indicated the presence of the TERT promoter mutation C228T in nontumorous liver tissues (#1N, #2N and #3N) at a frequency of 0.11-0.83% compared with normal liver and blood samples. These results suggest the following phylogenetic evolution of three metachronous liver cancers: #1HCC was not related to #2HCC, #3HCC and #3iCCA; both #3HCC and #3iCCA arose from #2HCC. From the above, three novel findings were deduced: i) Both multicentric occurrence and intrahepatic metastasis may be involved in liver cancer in a three-year interval; ii) transdifferentiation from HCC to iCCA is a possible pathogenic mechanism of cHCC-CCA; and iii) a nontumorous, noncirrhotic liver may contain a preneoplastic region with a cancer driver mutation in the TERT promoter.
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Affiliation(s)
- Sumie Ohni
- Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Hiromi Yamaguchi
- Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Yukari Hirotani
- Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Yoko Nakanishi
- Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Yutaka Midorikawa
- Department of Surgery, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Masahiko Sugitani
- Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Hiromu Naruse
- Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Tomohiro Nakayama
- Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Makoto Makishima
- Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Mariko Esumi
- Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo 173-8610, Japan
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Hu X, Yuan G, Li Q, Huang J, Cheng X, Chen J. DEAH-box polypeptide 32 promotes hepatocellular carcinoma progression via activating the β-catenin pathway. Ann Med 2021; 53:437-447. [PMID: 33729094 PMCID: PMC7971220 DOI: 10.1080/07853890.2021.1898674] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 02/28/2021] [Indexed: 02/03/2023] Open
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is refractory cancer with high morbidity and high mortality. DEAH-box polypeptide 32 (DHX32) was upregulated in several types of malignancies and predicted poor prognosis. Herein, we investigated the role of DHX32 in HCC progression. METHODS The expression of DHX32, β-catenin, and epithelial-mesenchymal transition (EMT)-related makers were determined by Western blot and quantitative real-time PCR assays. Cell proliferation was tested by EdU cell proliferation assay. The effect of DHX32 and β-catenin on cell migration and invasion were detected by wound-healing and Traswell invasion assays. Tumour xenografts were performed to determine the effect of DHX32 on HCC tumour growth. RESULTS High level of DHX32 expression was associated with reduced overall survival in HCC patients. DHX32 expression was upregulated in human HCC cells and ectopic expression of DHX32 induced EMT, promoted the mobility and proliferation of HCC cells, and enhanced tumour growth in vivo. Silencing DHX32 reversed EMT, inhibited the malignancy behaviors of HCC cells, and suppressed tumour growth. Mechanistically, silencing DHX32 decreased the expression of β-cateninin in nucleus and β-catenin siRNA abrogated DHX32-mediated HCC progression. CONCLUSION DHX32 was an attractive regulator of HCC progression and indicated DHX32 canserve as a potential biomarker and therapeutic target for HCC patients.
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Affiliation(s)
- Xiaoyun Hu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Guosheng Yuan
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qi Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jing Huang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiao Cheng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinzhang Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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25
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Endo M, Honda K, Saito T, Shiraiwa K, Sueshige Y, Tokumaru T, Iwao M, Tokoro M, Arakawa M, Tanaka R, Tatsuta R, Seike M, Itoh H, Murakami K. Maximum Plasma Concentration of Lenvatinib Is Useful for Predicting Thrombocytopenia in Patients Treated for Hepatocellular Carcinoma. World J Oncol 2021; 12:165-172. [PMID: 34804279 PMCID: PMC8577601 DOI: 10.14740/wjon1399] [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: 07/13/2021] [Accepted: 09/10/2021] [Indexed: 11/11/2022] Open
Abstract
Background Although lenvatinib treatment has a favorable efficacy for unresectable hepatocellular carcinoma (HCC), it is associated with adverse events (AEs) that must be closely monitored and managed. Thrombocytopenia is one of the major AEs. The aim of this study was to clarify whether thrombocytopenia can be predicted by the plasma concentration of lenvatinib. Methods This was a single-center retrospective observational study. Twenty-three patients with unresectable HCC and pharmacokinetics data at the initial lenvatinib administration between May 2018 and September 2020 at Oita University Hospital were enrolled. The AEs during the 4 weeks after the initiation of treatment were evaluated, and the correlations between the thrombocytopenia and the plasma concentration of lenvatinib were examined. Spearman's correlation was used to evaluate the correlation between two continuous variables. Results The rate of platelet count decrease correlated with the maximum plasma concentration (Cmax) (r = 0.65, P = 0.001), whereas it did not with the minimum plasma concentration (Cmin) (r = 0.29, P = 0.206). After stepwise multiple linear regression analysis, the starting dose of lenvatinib and the serum albumin concentration were identified as independent explanatory variables. Next, a formula for predicting the Cmax using these two variables was created. The predicted Cmax was strongly correlated with the Cmax (r = 0.87, P < 0.0001) and the rate of platelet count decrease (r = 0.67, P = 0.001). Conclusions This study identified the usefulness of the drug Cmax to predict the rate of platelet count decrease within 4 weeks after the initiation of treatment. Although it is difficult to measure the plasma concentration of lenvatinib in community hospitals, the predicted Cmax is useful for predicting the rate of platelet count decrease with this treatment.
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Affiliation(s)
- Mizuki Endo
- Department of Gastroenterology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan
| | - Koichi Honda
- Department of Gastroenterology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan
| | - Tomoko Saito
- Department of Gastroenterology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan
| | - Ken Shiraiwa
- Department of Clinical Pharmacy, Oita University Hospital, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan
| | - Yoshio Sueshige
- Department of Clinical Pharmacy, Oita University Hospital, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan
| | - Tomoko Tokumaru
- Department of Gastroenterology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan
| | - Masao Iwao
- Department of Gastroenterology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan
| | - Masanori Tokoro
- Department of Gastroenterology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan
| | - Mie Arakawa
- Department of Gastroenterology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan
| | - Ryota Tanaka
- Department of Clinical Pharmacy, Oita University Hospital, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan
| | - Ryosuke Tatsuta
- Department of Clinical Pharmacy, Oita University Hospital, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan
| | - Masataka Seike
- Department of Gastroenterology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan
| | - Hiroki Itoh
- Department of Clinical Pharmacy, Oita University Hospital, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan
| | - Kazunari Murakami
- Department of Gastroenterology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan
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26
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Fang Y, Yang Y, Li N, Zhang XL, Huang HF. Emerging role of long noncoding RNAs in recurrent hepatocellular carcinoma. World J Clin Cases 2021; 9:9699-9710. [PMID: 34877309 PMCID: PMC8610931 DOI: 10.12998/wjcc.v9.i32.9699] [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: 04/18/2021] [Revised: 06/08/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the most frequent types of liver cancer and is characterized by a high recurrence rate. Recent studies have proposed that long non-coding RNAs (lncRNAs) are potential biomarkers in several recurrent tumor types. It is now well understood that invasion, migration, and metastasis are important factors for tumor recurrence. Moreover, some of the known risk factors for HCC may affect the expression levels of several types of lncRNAs and thus affect the recurrence of liver cancer through lncRNA regulation. In this paper, we review the biological functions, molecular mechanisms, and roles of lncRNAs in HCC and summarize current knowledge about lncRNAs as potential biomarkers in recurrent HCC.
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Affiliation(s)
- Yuan Fang
- Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Yang Yang
- Department of Otorhinolaryngology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Na Li
- Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Xiao-Li Zhang
- Department of Gastrointestinal and Hernia Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Han-Fei Huang
- Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
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27
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Single-Shot Local Injection of Microfragmented Fat Tissue Loaded with Paclitaxel Induces Potent Growth Inhibition of Hepatocellular Carcinoma in Nude Mice. Cancers (Basel) 2021; 13:cancers13215505. [PMID: 34771667 PMCID: PMC8583409 DOI: 10.3390/cancers13215505] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 10/29/2021] [Accepted: 10/30/2021] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is poorly beneficiated by intravenous chemotherapy due to inadequate availability of drugs at the tumor site. We previously demonstrated that human micro-fragmented adipose tissue (MFAT) and its devitalized counterpart (DMFAT) could be effective natural scaffolds to deliver Paclitaxel (PTX) to tumors in both in vitro and in vivo tests, affecting cancer growth relapse. Here we tested the efficacy of DMFAT-PTX in a well-established HCC in nude mice. MFAT-PTX and DMFAT-PTX preparations were tested for anti-cancer activity in 2D and 3D assays using Hep-3B tumor cells. The efficacy of DMFAT-PTX was evaluated after a single-shot subcutaneous injection near a Hep-3B growing tumor by assessing tumor volumes, apoptosis rate, and drug pharmacokinetics in an in vivo model. Potent antiproliferative activity was seen in both in vitro 2D and 3D tests. Mice treated with DMFAT-PTX (10 mg/kg) produced potent Hep-3B growth inhibition with 33% complete tumor regressions. All treated animals experienced tumor ulceration at the site of DMFAT-PTX injection, which healed spontaneously. Lowering the drug concentration (5 mg/kg) prevented the formation of ulcers, maintaining statistically significant efficacy. Histology revealed a higher number of apoptotic cancer cells intratumorally, suggesting prolonged presence of PTX that was confirmed by the pharmacokinetic analysis. DMFAT may be a potent and valid new tool for local chemotherapy of HCC in an advanced stage of progression, also suggesting potential effectiveness in other human primary inoperable cancers.
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28
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Intrinsic and Extrinsic Control of Hepatocellular Carcinoma by TAM Receptors. Cancers (Basel) 2021; 13:cancers13215448. [PMID: 34771611 PMCID: PMC8582520 DOI: 10.3390/cancers13215448] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 10/22/2021] [Accepted: 10/26/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Tyro3, Axl, and MerTK are receptor tyrosine kinases of the TAM family, which are activated by their ligands Gas6 and Protein S. TAM receptors have large physiological implications, including the removal of dead cells, activation of immune cells, and prevention of bleeding. In the last decade, TAM receptors have been suggested to play a relevant role in liver fibrogenesis and the development of hepatocellular carcinoma. The understanding of TAM receptor functions in tumor cells and their cellular microenvironment is of utmost importance to advances in novel therapeutic strategies that conquer chronic liver disease including hepatocellular carcinoma. Abstract Hepatocellular carcinoma (HCC) is the major subtype of liver cancer, showing high mortality of patients due to limited therapeutic options at advanced stages of disease. The receptor tyrosine kinases Tyro3, Axl and MerTK—belonging to the TAM family—exert a large impact on various aspects of cancer biology. Binding of the ligands Gas6 or Protein S activates TAM receptors causing homophilic dimerization and heterophilic interactions with other receptors to modulate effector functions. In this context, TAM receptors are major regulators of anti-inflammatory responses and vessel integrity, including platelet aggregation as well as resistance to chemotherapy. In this review, we discuss the relevance of TAM receptors in the intrinsic control of HCC progression by modulating epithelial cell plasticity and by promoting metastatic traits of neoplastic hepatocytes. Depending on different etiologies of HCC, we further describe the overt role of TAM receptors in the extrinsic control of HCC progression by focusing on immune cell infiltration and fibrogenesis. Additionally, we assess TAM receptor functions in the chemoresistance against clinically used tyrosine kinase inhibitors and immune checkpoint blockade in HCC progression. We finally address the question of whether inhibition of TAM receptors can be envisaged for novel therapeutic strategies in HCC.
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Gupta S, Khan S, Kawka M, Gujjuri R, Chau I, Starling N, Cunningham D, Jiao LR, Gall T. Clinical utility of clonal origin determination in managing recurrent hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:1159-1167. [PMID: 34402366 DOI: 10.1080/17474124.2021.1967144] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
INTRODUCTION Recurrence is the driving factor for reduced long-term survival in patients following resected hepatocellular carcinoma (HCC). Extensive research efforts have been conducted to understand the molecular processes precipitating disease recurrence. Modern genomic techniques have identified two distinct mechanisms for recurrent HCC (RHCC): Intrahepatic metastasis (IM-HCC); and multicentric origin (MO-HCC). Medline, EMBASE and Cochrane library were methodically searched for primary research articles in English with the aim of appraising existing literature on the identification of clonal origin of RHCC and its potential clinical utility. AREAS COVERED Molecular and next-generation sequencing techniques, when applied to clonal origin identification, yield superior accuracy than traditional clinicopathological criteria. Despite various treatment modalities, no optimal therapy has yet been identified for treating clonally differentiated RHCC. Patients with MO-HCC appear to experience improved long-term survival following re-treatment compared to their IM-HCC counterparts (91.7% vs 22.9% 5-year survival, p < 0.001). However, cautious interpretation is advised as heterogeneous classification criteria and small sample sizes restrict the generalizability of such findings. EXPERT OPINION Improved identification of clonal origin in RHCC may facilitate further research on RHCC treatment strategies and enable the development of novel therapeutic targets, potentially leading to individualized treatment approaches in the future.
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Affiliation(s)
- Shubham Gupta
- Department of Medicine, Imperial College London, South Kensington Campus, London, UK
| | - Sikandar Khan
- Department of Medicine, Imperial College London, South Kensington Campus, London, UK
| | - Michal Kawka
- Department of Medicine, Imperial College London, South Kensington Campus, London, UK
| | - Rohan Gujjuri
- Department of Medicine, Imperial College London, South Kensington Campus, London, UK
| | - Ian Chau
- Department Of Oncology And Surgery, The Royal Marsden Hospital, London, UK
| | - Naureen Starling
- Department Of Oncology And Surgery, The Royal Marsden Hospital, London, UK
| | - David Cunningham
- Department Of Oncology And Surgery, The Royal Marsden Hospital, London, UK
| | - Long R Jiao
- Department of Medicine, Imperial College London, South Kensington Campus, London, UK.,Department Of Oncology And Surgery, The Royal Marsden Hospital, London, UK
| | - Tamara Gall
- Department of Medicine, Imperial College London, South Kensington Campus, London, UK.,Department Of Oncology And Surgery, The Royal Marsden Hospital, London, UK
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30
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Lin J, Zhao S, Wang D, Song Y, Che Y, Yang X, Mao J, Xie F, Long J, Bai Y, Yang X, Zhang L, Bian J, Lu X, Sang X, Pan J, Wang K, Zhao H. Targeted Next-Generation Sequencing Combined With Circulating-Free DNA Deciphers Spatial Heterogeneity of Resected Multifocal Hepatocellular Carcinoma. Front Immunol 2021; 12:673248. [PMID: 34211467 PMCID: PMC8240639 DOI: 10.3389/fimmu.2021.673248] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 05/27/2021] [Indexed: 01/10/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) has a high risk of recurrence after surgical resection, particularly among patients with multifocal HCC. Genomic heterogeneity contributes to the early recurrence. Few studies focus on targeted next-generation sequencing (tNGS) to depict mutational footprints of heterogeneous multifocal HCC. Methods We conducted tNGS with an ultra-deep depth on 31 spatially distinct regions from 11 resected multifocal HCC samples. Matched preoperative peripheral circulating-free DNA (cfDNA) were simultaneously collected. Genomic alterations were identified and compared to depict the heterogeneity of multifocal HCC. Results Widespread intertumoral heterogeneity of driver mutations was observed in different subfoci of multifocal HCC. The identified somatic mutations were defined as truncal drivers or branchy drivers according to the phylogenetic reconstruction. TP53 and TERT were the most commonly altered truncal drivers in multifocal HCC, while the most frequently mutated branchy driver was TSC2. HCC patients with a higher level of intertumoral heterogeneity, defined by the ratio of truncal drivers less than 50%, had a shorter RFS after surgical resection (HR=0.17, p=0.028). Genome profiling of cfDNA could effectively capture tumor-derived driver mutations, suggesting cfDNA was a non-invasive strategy to gain insights of genomic alterations in patients with resected multifocal HCC. Conclusions Truncal mutations and the level of genomic heterogeneity could be identified by tNGS panel in patients with resected multifocal HCC. cfDNA could serve as a non-invasive and real-time auxiliary method to decipher the intertumoral heterogeneity and identify oncodrivers of multifocal HCC.
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Affiliation(s)
- Jianzhen Lin
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Songhui Zhao
- Department of Bioinformatics, OrigiMed, Shanghai, China
| | - Dongxu Wang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yang Song
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yue Che
- Department of Bioinformatics, OrigiMed, Shanghai, China
| | - Xu Yang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jinzhu Mao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fucun Xie
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Junyu Long
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yi Bai
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaobo Yang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lei Zhang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jin Bian
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xin Lu
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinting Sang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie Pan
- Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Kai Wang
- Department of Bioinformatics, OrigiMed, Shanghai, China
| | - Haitao Zhao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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31
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Barcena-Varela M, Lujambio A. The Endless Sources of Hepatocellular Carcinoma Heterogeneity. Cancers (Basel) 2021; 13:2621. [PMID: 34073538 PMCID: PMC8198457 DOI: 10.3390/cancers13112621] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 05/20/2021] [Accepted: 05/21/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) represents a global health problem. The incidence keeps increasing and current therapeutic options confer limited benefits to the patients. Tumor heterogeneity plays a central role in this context, limiting the availability of predictive biomarkers and complicating the criteria used to choose the most suitable therapeutic option. HCC heterogeneity occurs at different levels: within the population (inter-patient heterogeneity) and within tumors from the same patient (intra-patient and intra-tumor heterogeneity). Experts in the field have made many efforts to classify the patients based on clinicopathological characteristics and molecular signatures; however, there is still much work ahead to be able to integrate the extra-tumor heterogeneity that emerges from the complexity of the tumor microenvironment, which plays a critical role in the pathogenesis of the disease and therapy responses. In this review, we summarize tumor intrinsic and extrinsic sources of heterogeneity of the most common etiologies of HCC and summarize the most recent discoveries regarding the evolutionary trajectory of liver cancer cells and the influence of tumor-extrinsic factors such as the microbiome and the host immune system. We further highlight the potential of novel high-throughput methodologies to contribute to a better understanding of this devastating disease and to the improvement of the clinical management of patients.
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Affiliation(s)
- Marina Barcena-Varela
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Amaia Lujambio
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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32
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Intrahepatic recurrence of hepatocellular carcinoma after resection: an update. Clin J Gastroenterol 2021; 14:699-713. [PMID: 33774785 DOI: 10.1007/s12328-021-01394-7] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 03/19/2021] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma recurrence occurs in 40-70% of patients after hepatic resection. Despite the high frequency of hepatocellular cancer relapse, there is no established guidance for the management of such cases. The evaluation of prognostic factors that indicate a high risk of recurrence after surgery such as the tumor number and size and the presence of microvascular invasion may guide the therapeutic strategy and point out which patients should be strictly monitored. Additionally, the administration of adjuvant treatment or ab initio liver transplantation in selected patients with high-risk characteristics could have a significant impact on the prevention of relapse and overall survival. Once the recurrence has occurred in the liver remnant, the available therapeutic options include re-resection, salvage liver transplantation and locoregional treatments, although the therapeutic choice is often challenging and should be based on the characteristics of the recurrent tumor, the patient profile and most importantly the timing of relapse. Aggressive combination treatments are often required in challenging cases of early relapse. The results of the above treatment strategies are reviewed and compared to determine the optimal management of patients with recurrent hepatocellular cancer following liver resection.
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33
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Abstract
Hepatocellular carcinoma (HCC) is a lethal malignancy with poor prognosis. More than 80% of patients are diagnosed at an advanced stage, and most patients with HCC also have liver cirrhosis that complicates cancer management. No targeted treatment options currently exist outside genomics-based clinical trials. Multiple tyrosine kinase inhibitors (mTKIs) such as sorafenib, lenvatinib, cabozantinib, and regorafenib have been used to treat advanced hepatocellular carcinoma (aHCC). Immune checkpoint inhibitors including nivolumab and pembrolizumab have shown survival benefit. More recently, atezolizumab in combination with bevacizumab resulted in improved overall survival and progression-free survival, compared with sorafenib in patients with aHCC in the first-line setting. The combination of nivolumab with ipilimumab as an alternative in the treatment of patients treated with sorafenib has inspired various combination studies of immune checkpoint inhibitors. Currently, ongoing studies of systemic therapy consist of various immune-based combination therapies. Finally, there is no established adjuvant and neoadjuvant therapy although a few early phase studies show promising results. In this chapter, we summarize current approaches of systemic treatment in patients with liver cancer.
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Affiliation(s)
- Tarik Demir
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
| | - Sunyoung S Lee
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
| | - Ahmed O Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
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34
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Tan HL, Goh BKP. Management of recurrent hepatocellular carcinoma after resection. Hepatobiliary Surg Nutr 2020; 9:780-783. [PMID: 33299834 PMCID: PMC7720055 DOI: 10.21037/hbsn.2020.03.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 02/24/2020] [Indexed: 01/27/2023]
Affiliation(s)
- Hwee Leong Tan
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Brian K. P. Goh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
- Duke-NUS Medical School Singapore, Singapore, Singapore
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35
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Li CL, Ho MC, Lin YY, Tzeng ST, Chen YJ, Pai HY, Wang YC, Chen CL, Lee YH, Chen DS, Yeh SH, Chen PJ. Cell-Free Virus-Host Chimera DNA From Hepatitis B Virus Integration Sites as a Circulating Biomarker of Hepatocellular Cancer. Hepatology 2020; 72:2063-2076. [PMID: 32171027 DOI: 10.1002/hep.31230] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 02/21/2020] [Accepted: 02/29/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Early recurrence of hepatocellular carcinoma (HCC) after surgical resection compromises patient survival. Timely detection of HCC recurrence and its clonality is required to implement salvage therapies appropriately. This study examined the feasibility of virus-host chimera DNA (vh-DNA), generated from junctions of hepatitis B virus (HBV) integration in the HCC chromosome, as a circulating biomarker for this clinical setting. APPROACH AND RESULTS HBV integration in 50 patients with HBV-related HCC was determined by the Hybridization capture-based next-generation sequencing (NGS) platform. For individual HCC, the vh-DNA was quantified by specific droplet digital PCR (ddPCR) assay in plasma samples collected before and 2 months after surgery. HBV integrations were identified in 44 out of 50 patients with HBV-related HCC. Tumor-specific ddPCR was developed to measure the corresponding vh-DNA copy number in baseline plasma from each patient immediately before surgery. vh-DNA was detected in 43 patients (97.7%), and the levels correlated with the tumor sizes (detection limit at 1.5 cm). Among the plasma collected at 2 months after surgery, 10 cases (23.3%) still contained the same signature vh-DNA detected at baseline, indicating the presence of residual tumor cells. Nine of them (90%) experienced HCC recurrence within 1 year, supporting vh-DNA as an independent risk factor in predicting early recurrence. Analysis of circulating vh-DNA at recurrence further helped identify the clonal origin. A total of 81.8% of recurrences came from original HCC clones sharing the same plasma vh-DNA, whereas 18.2% were from de novo HCC. CONCLUSIONS vh-DNA was shown to be a circulating biomarker for detecting the tumor load in majority of patients with HBV-related HCC and aided in monitoring residual tumor and recurrence clonality after tumor resection.
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Affiliation(s)
- Chiao-Ling Li
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ming-Chih Ho
- Department of Surgery, National Taiwan University College of Medicine, Taipei, Taiwan
| | - You-Yu Lin
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | | | - Yun-Ju Chen
- TCM Biotech International Corp., Taipei, Taiwan
| | | | | | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yu-Hsin Lee
- Department of Surgery, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ding-Shinn Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Shiou-Hwei Yeh
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan.,National Taiwan University Center for Genomic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Laboratory Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,National Taiwan University Center for Genomic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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36
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Prognostic factors of gadoxetic acid-enhanced MRI for postsurgical outcomes in multicentric hepatocellular carcinoma. Eur Radiol 2020; 31:3405-3416. [PMID: 33146795 DOI: 10.1007/s00330-020-07419-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/14/2020] [Accepted: 10/13/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVES The primary aim of this study was to determine the clinical and histopathological prognostic factors for patients who underwent surgical resection of multiple hepatocellular carcinomas (HCCs) of multicentric occurrence. The secondary aim of this study was to evaluate whether specific imaging-related factors, including arterial phase hyperenhancement (APHE) and the LI-RADS category of each lesion on gadoxetic acid-enhanced MRI, would provide additional prognostic information about multicentric HCCs. METHODS In this retrospective study, 54 patients with 120 multicentric HCCs were diagnosed by surgical resection at a single tertiary hospital between 2009 and 2014. Two independent readers evaluated patients' preoperative gadoxetic acid-enhanced MR images and recorded APHE and LI-RADS category for each HCC, with discrepancies resolved through consensus sessions if necessary. Potential clinicopathologic and imaging parameters for predicting disease-free survival (DFS) and overall survival (OS) were analyzed using Cox regression analysis. RESULTS Presence of microvascular invasion (MVI) (p = 0.003) and of three or more HCCs (p = 0.013) were both independent predictors of a shorter DFS. Patients with concurrent MVI and three or more HCCs had the shortest DFS. MVI was the only statistically significant parameter (p = 0.023) predicting OS. The number of HCCs with APHE or LR-5/M category was not associated with survival. CONCLUSIONS Presence of MVI and of three or more HCCs were associated with poorer outcomes after surgical resection of multicentric HCCs. Imaging parameters on gadoxetic acid-enhanced MRI such as APHE or LI-RADS category were not associated with postsurgical outcomes. KEY POINTS • Patients with three or more hepatocellular carcinomas showed worse disease-free survival than those with two hepatocellular carcinomas after surgical resection. • Microvascular invasion was the only significant factor to affect both the disease-free and overall survivals of patients after surgical resection of multicentric hepatocellular carcinomas. • Preoperative MRI findings related to multicentric hepatocellular carcinomas such as arterial phase hyperenhancement and LI-RADS category of lesions did not provide significant prognostic information.
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Wakizaka K, Kamiyama T, Wakayama K, Orimo T, Shimada S, Nagatsu A, Kamachi H, Yokoo H, Fukai M, Kobayashi N, Mitsuhashi T, Taketomi A. Role of Wnt5a in suppressing invasiveness of hepatocellular carcinoma via epithelial-mesenchymal transition. Oncol Lett 2020; 20:268. [PMID: 32989402 PMCID: PMC7517569 DOI: 10.3892/ol.2020.12131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 07/14/2020] [Indexed: 02/05/2023] Open
Abstract
Inappropriate activation of the canonical Wnt signaling pathway is associated with progression of hepatocellular carcinoma (HCC). However, the association between the non-canonical pathway activated by Wnt5a and HCC is not well known. The present study investigated the significance of Wnt5a expression in HCC. Immunohistochemical staining of Wnt5a was performed on specimens from 243 patients who underwent hepatic resection for HCC. The present study investigated whether Wnt5a expression was associated with clinical and pathological factors and prognosis. Wnt5a expression in human HCC cell lines was investigated using western blotting. The effects of overexpression or knockdown of Wnt5a were evaluated using proliferation and invasion assays. Changes in epithelial-mesenchymal transition (EMT)-related molecules were investigated using western blotting. Wnt5a negativity was significantly associated with poor tumor differentiation and positive vascular invasion. In univariate analysis, Wnt5a negativity was identified as a significant prognostic factor for overall survival (OS). Multivariate analysis of OS demonstrated that Wnt5a negativity was an independent prognostic factor. Wnt5a expression was lower in HLE and HLF cells than in HepG2 and Huh7 cells. Knockdown of Wnt5a by short hairpin RNA transfection increased the proliferation and invasiveness of Huh7 cells, and decreased the expression levels of E-cadherin. In HLF cells, overexpression of Wnt5a inhibited invasiveness and decreased the expression levels of vimentin. Wnt5a negativity was associated with poor tumor differentiation and positive vascular invasion, and was an independent poor prognostic factor in patients with HCC. Wnt5a may be a tumor suppressor involved in EMT-mediated changes in invasiveness.
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Affiliation(s)
- Kazuki Wakizaka
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan
| | - Toshiya Kamiyama
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan
| | - Kenji Wakayama
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan
| | - Tatsuya Orimo
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan
| | - Shingo Shimada
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan
| | - Akihisa Nagatsu
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan
| | - Hirofumi Kamachi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan
| | - Hideki Yokoo
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan
| | - Moto Fukai
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan
| | - Nozomi Kobayashi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan
| | - Tomoko Mitsuhashi
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Hokkaido 060-8648, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan
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Ruff SM, Rothermel LD, Diggs LP, Wach MM, Ayabe RI, Martin SP, Boulware D, Anaya D, Davis JL, Mullinax JE, Hernandez JM. Tumor grade may be used to select patients with multifocal hepatocellular carcinoma for resection. HPB (Oxford) 2020; 22:1004-1010. [PMID: 31734237 PMCID: PMC7771330 DOI: 10.1016/j.hpb.2019.10.1531] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 07/23/2019] [Accepted: 10/13/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND While resection is a recommended treatment for patients with stage 1 hepatocellular carcinoma (HCC), it remains controversial for multifocal disease. We sought to identify patients with multifocal HCC with survival after resection similar to patients with clinical stage 1 HCC. METHODS The National Cancer Database was queried to identify patients that underwent resection for HCC. RESULTS In this study, 2990 patients with a single tumor, and 1087 patients with multifocal disease confined to one lobe underwent resection. In the multifocal cohort, patients with clinical stage 3 (HR 1.54, CI 1.31-1.81, p < 0.0001) or 4 (HR 2.27, CI 1.57-3.29, p < 0.0001) disease, and those with moderately-differentiated (HR 1.32, CI 1.06-1.64, p = 0.012) or poorly differentiated/undifferentiated tumors (HR 1.53, CI 1.20-1.95, p = 0.0006) were associated with worse overall survival (OS). There was no difference in OS between patients with well-differentiated clinical stage 2 multifocal HCC and those with all grades of clinical stage 1 HCC (median of 84.8 (CI 66.3-107.2) vs 76.2 months (CI 71.2-81.3), respectively, p = 0.356). CONCLUSIONS Patients with well-differentiated, clinical stage 2 multifocal HCC confined to one lobe experience similar OS following hepatic resection to patients with clinical stage 1 disease. These findings may impact the management of select patients with multifocal HCC.
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Affiliation(s)
- Samantha M Ruff
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, 10 Center Drive Bethesda, MD, 20892, USA
| | - Luke D Rothermel
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, 12902 USF Magnolia Drive Tampa, FL, 33612, USA
| | - Laurence P Diggs
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, 10 Center Drive Bethesda, MD, 20892, USA
| | - Michael M Wach
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, 10 Center Drive Bethesda, MD, 20892, USA
| | - Reed I Ayabe
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, 10 Center Drive Bethesda, MD, 20892, USA
| | - Sean P Martin
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, 10 Center Drive Bethesda, MD, 20892, USA
| | - David Boulware
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, 12902 USF Magnolia Drive Tampa, FL, 33612, USA
| | - Daniel Anaya
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, 12902 USF Magnolia Drive Tampa, FL, 33612, USA
| | - Jeremy L Davis
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, 10 Center Drive Bethesda, MD, 20892, USA
| | - John E Mullinax
- Sarcoma Department, H. Lee Moffitt Cancer Center & Research Institute, 12902 USF Magnolia Drive Tampa, FL, 33612, USA
| | - Jonathan M Hernandez
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, 10 Center Drive Bethesda, MD, 20892, USA.
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Abstract
Hepatocellular carcinoma (HCC) is characterized by high prevalence of multifocality. Multifocal HCC can arise synchronously or metachronously either from intrahepatic metastasis (IM) or multicentric occurrence (MO). To date, there have been no established criteria to accurately distinguish whether multifocal HCC originates from IM or MO. Histopathological features remain the most convenient strategy but with subjectivity and limited accuracy. Various molecular biological techniques involving assessment of TP53 mutation status, hepatitis B virus integration sites, and chromosomal alterations have been applied to determine the clonal origin. The introduction of next-generation sequencing facilitates a more comprehensive annotation of intertumor heterogeneity, resulting in more sensitive and accurate clonal discrimination. Generally, MO-HCC has better overall survival than IM-HCC after curative resection. Adjuvant antiviral treatment has been proved to decrease post-treatment recurrence probably by reducing MO-HCC recurrence, whereas adjuvant sorafenib treatment targeting prior micrometastasis failed to reduce IM-HCC recurrence. Recent studies recommended transcatheter arterial chemoembolization (TACE) and traditional Chinese medicine Huaier granule as effective adjuvant treatments probably by preventing IM and both types of recurrences respectively. Immunotherapy that inhibits immune checkpoint interaction may be an optimal choice for both MO- and IM-HCC. In the future, effective personalized therapy against multifocal HCC may be achieved.
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Weidle UH, Schmid D, Birzele F, Brinkmann U. MicroRNAs Involved in Metastasis of Hepatocellular Carcinoma: Target Candidates, Functionality and Efficacy in Animal Models and Prognostic Relevance. Cancer Genomics Proteomics 2020; 17:1-21. [PMID: 31882547 PMCID: PMC6937123 DOI: 10.21873/cgp.20163] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/31/2019] [Accepted: 11/04/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is responsible for the second-leading cancer-related death toll worldwide. Although sorafenib and levantinib as frontline therapy and regorafenib, cabazantinib and ramicurimab have now been approved for second-line therapy, the therapeutic benefit is in the range of only a few months with respect to prolongation of survival. Aggressiveness of HCC is mediated by metastasis. Intrahepatic metastases and distant metastasis to the lungs, lymph nodes, bones, omentum, adrenal gland and brain have been observed. Therefore, the identification of metastasis-related new targets and treatment modalities is of paramount importance. In this review, we focus on metastasis-related microRNAs (miRs) as therapeutic targets for HCC. We describe miRs which mediate or repress HCC metastasis in mouse xenograft models. We discuss 18 metastasis-promoting miRs and 35 metastasis-inhibiting miRs according to the criteria as outlined. Six of the metastasis-promoting miRs (miR-29a, -219-5p, -331-3p, 425-5p, -487a and -1247-3p) are associated with unfavourable clinical prognosis. Another set of six down-regulated miRs (miR-101, -129-3p, -137, -149, -503, and -630) correlate with a worse clinical prognosis. We discuss the corresponding metastasis-related targets as well as their potential as therapeutic modalities for treatment of HCC-related metastasis. A subset of up-regulated miRs -29a, -219-5p and -425-5p and down-regulated miRs -129-3p and -630 were evaluated in orthotopic metastasis-related models which are suitable to mimic HCC-related metastasis. Those miRNAs may represent prioritized targets emerging from our survey.
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Affiliation(s)
- Ulrich H Weidle
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Daniela Schmid
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Fabian Birzele
- Pharmaceutical Sciences, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland
| | - Ulrich Brinkmann
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
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Matsuda M, Ichikawa S, Matsuda M, Amemiya H, Ichikawa D, Onishi H, Motosugi U. Hepatobiliary phase hypointense nodule without arterial phase hyperenhancement as a risk factor for late recurrence (>1 year) of hepatocellular carcinoma after surgery. Clin Radiol 2019; 74:975.e1-975.e9. [PMID: 31540704 DOI: 10.1016/j.crad.2019.08.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 08/08/2019] [Indexed: 11/19/2022]
Abstract
AIM To evaluate the value of magnetic resonance imaging (MRI) features, including liver stiffness measured by magnetic resonance elastography (MRE) and the presence of hepatobiliary phase (HBP) hypointense nodule without arterial phase hyperenhancement (APHE), for predicting late recurrence (>1 year) after surgery for hepatocellular carcinoma (HCC). MATERIALS AND METHODS This retrospective study included 124 consecutive patients who had undergone surgery for HCC and preoperative MRI. After excluding patients with early recurrence within 1 year after surgery, 89 patients were analysed. Preoperative MRI images were reviewed by a radiologist to record imaging findings, including (1) liver stiffness by MRE, (2) size of the HCCs, (3) number of HCCs, and (4) presence of HBP hypointense nodule without APHE. Pathological findings included tumour grade, vascular/biliary/capsule invasion, and fibrosis stage of the liver. Considering imaging/pathological findings and patients' characteristics as dependent variables, Cox proportional hazards model analysis was performed to identify independent factors associated with late recurrence after surgery. RESULTS The median follow-up period was 37.3 months. During follow-up, 29 patients (32.5%) developed late recurrence after surgery. In multivariate analysis, underlying liver disease (viral hepatitis) and presence of HBP hypointense nodules without APHE (p=0.010 and 0.033, respectively) were independently associated with disease-free survival (DFS). Kaplan-Meier analysis revealed that patients with HBP hypointense nodules without APHE had a significantly lower DFS rate than those without the nodule (39.2% versus 74.1% at 3 years after surgery, p=0.008). CONCLUSION The presence of HBP hypointense nodules without APHE was an indicator of late recurrence after surgery for HCC.
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Affiliation(s)
- M Matsuda
- Department of Radiology, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi, 409-3898, Japan
| | - S Ichikawa
- Department of Radiology, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi, 409-3898, Japan.
| | - M Matsuda
- First Department of Surgery, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi, 409-3898, Japan; Fujiyoshida Municipal Medical Center, 6530 Kamiyoshida, Yujiyoshida-shi, Yamanashi, 403-0005, Japan
| | - H Amemiya
- First Department of Surgery, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi, 409-3898, Japan
| | - D Ichikawa
- First Department of Surgery, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi, 409-3898, Japan
| | - H Onishi
- Department of Radiology, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi, 409-3898, Japan
| | - U Motosugi
- Department of Radiology, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi, 409-3898, Japan
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Bai Y, Liang W. Postoperative Recurrence of Hepatocellular Carcinoma: The Importance of Distinguishing between Intrahepatic Metastasis and Multicentric Occurrence-Letter. Clin Cancer Res 2019; 25:5426. [PMID: 31481486 DOI: 10.1158/1078-0432.ccr-19-0948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 06/27/2019] [Indexed: 11/16/2022]
Affiliation(s)
- Yanjun Bai
- Department of Radiology, the People's Hospital of Beilun District, Ningbo, Zhejiang Province, China
| | - Wenjie Liang
- Department of Radiology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, China.
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The strengths and weaknesses of gross and histopathological evaluation in hepatocellular carcinoma: a brief review. SURGICAL AND EXPERIMENTAL PATHOLOGY 2019. [DOI: 10.1186/s42047-019-0047-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
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Wang MD, Li C, Li J, Zhang WG, Jiang WQ, Yu JJ, Xing H, Wu H, Han J, Li ZL, Xu XF, Chen TH, Zhou YH, Gu WM, Wang H, Zeng YY, Zhang YM, Pawlik TM, Lau WY, Wu MC, Yang JM, Shen F, Yang T. Long-Term Survival Outcomes After Liver Resection for Binodular Hepatocellular Carcinoma: A Multicenter Cohort Study. Oncologist 2019; 24:e730-e739. [PMID: 31127021 PMCID: PMC6693721 DOI: 10.1634/theoncologist.2018-0898] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 04/05/2019] [Accepted: 04/17/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The long-term prognosis after liver resection for multinodular (≥3 nodules) hepatocellular carcinoma (HCC) is generally considered to be unfavorable. However, the role of liver resection for binodular HCC is less investigated. SUBJECTS, MATERIALS, AND METHODS From a multicenter database, consecutive patients who underwent curative-intent liver resection for binodular HCC and without macrovascular invasion between 2003 and 2015 were retrospectively reviewed. Patients' clinical variables as well as perioperative and long-term survival outcomes were analyzed. Univariable and multivariable analyses were performed to identify the risk factors associated with overall survival (OS) and recurrence-free survival (RFS) after curative resection. RESULTS Of 263 enrolled patients, the perioperative 30-day mortality and morbidity rates were 1.5% and 28.5%. The 1-, 3-, and 5-year OS and RFS rates were 81.5%, 52.4%, and 39.1% and 57.1%, 35.8%, and 26.6%, respectively. Multivariable Cox-regression analyses identified preoperative alpha-fetoprotein level >400 μg/L, tumor size with a sum of two nodules >8 cm, tumor size ratio of large/small nodule >1.5 (asymmetrical proportion), unilateral hemiliver distribution of two nodules, distance of ≤3 cm between two nodules, and microvascular invasion in any nodule as independent risk factors associated with decreased OS and RFS. CONCLUSION Liver resection was safe and feasible in patients with binodular HCC, with acceptable perioperative and long-term outcomes. Sum of two tumor sizes, size ratio and distribution, and distance between two nodules were independent risk factors associated with long-term survival outcomes after surgery. These results may guide clinicians to make individualized surgical decisions and estimate long-term prognosis for these patients. IMPLICATIONS FOR PRACTICE Liver resection was safe and feasible in patients with binodular hepatocellular carcinoma, with acceptable perioperative and long-term outcomes. The sum of two tumor sizes, the size ratio and distribution of the two nodules, and the distance between two nodules were independent risk factors associated with long-term overall survival and recurrence-free survival after liver resection. The results of this study may guide clinicians to make individualized surgical decisions, estimate long-term prognosis, and plan recurrence surveillance and adjuvant therapy for these patients.
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Affiliation(s)
- Ming-Da Wang
- The 1st Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Chao Li
- The 1st Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Jun Li
- The 1st Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Wan-Guang Zhang
- Department of Hepatic Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Wei-Qin Jiang
- Cancer Biotherapy Center, First Affiliated Hospital, School of Medicine of Zhejiang University, Zhejiang, People's Republic of China
| | - Jiong-Jie Yu
- The 1st Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Hao Xing
- The 1st Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Han Wu
- The 1st Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Jun Han
- The 1st Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Zhen-Li Li
- The 1st Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Xin-Fei Xu
- The 1st Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Ting-Hao Chen
- Department of General Surgery, Ziyang First People's Hospital, Sichuan, People's Republic of China
| | - Ya-Hao Zhou
- Department of Hepatobiliary Surgery, Pu'er People's Hospital, Yunnan, People's Republic of China
| | - Wei-Min Gu
- The First Department of General Surgery, the Fourth Hospital of Harbin, Heilongjiang, People's Republic of China
| | - Hong Wang
- Department of General Surgery, Liuyang People's Hospital, Hunan, People's Republic of China
| | - Yong-Yi Zeng
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fujian, People's Republic of China
| | - Yao-Ming Zhang
- The Second Department of Hepatobiliary Surgery, Meizhou People's Hospital (Huangtang Hosptial), Meizhou Hospital to Sun Yat-sen University, Meizhou, People's Republic of China
| | - Timothy M Pawlik
- Department of Surgery, Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
| | - Wan Yee Lau
- The 1st Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People's Republic of China
- Faculty of Medicine, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR
| | - Meng-Chao Wu
- The 1st Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Jia-Mei Yang
- The 1st Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Feng Shen
- The 1st Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Tian Yang
- The 1st Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People's Republic of China
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Shimizu T, Ishizuka M, Park KH, Shiraki T, Sakuraoka Y, Mori S, Iso Y, Kato M, Aoki T, Kubota K. Preoperative lymphocyte-to-monocyte ratio is useful for stratifying the prognosis of hepatocellular carcinoma patients with a low Cancer of the Liver Italian Program score undergoing curative resection. Ann Gastroenterol Surg 2019; 3:325-335. [PMID: 31131362 PMCID: PMC6524078 DOI: 10.1002/ags3.12251] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 03/18/2019] [Accepted: 03/26/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND AND AIM Although the Cancer of the Liver Italian Program (CLIP) score is useful for prognostication of patients with hepatocellular carcinoma (HCC), a previous study has reported that the CLIP score was unable to stratify the postoperative outcomes of HCC patients in whom the score was low (0-1). Recent studies have reported that the preoperative lymphocyte-to-monocyte ratio (LMR) is useful for prognostication of patients with various cancer. METHODS We reviewed 329 HCC patients with a low CLIP score (0-1) undergoing curative resection. This study had the approval of the Institutional Review Board (28068). Multivariate analyses were carried out to detect clinical factors correlating with overall survival (OS). Kaplan-Meier analysis and the log-rank test were used for comparison of OS. RESULTS Multivariate analysis showed that LMR (<4.35/≥4.35) was significantly associated with OS (hazard ratio [HR], 2.022; 95% CI, 1.141-3.583; P = 0.016) as well as portal vein invasion (HR, 2.410; 95%CI, 1.258-4.618; P = 0.008). Kaplan-Meier analysis and the log-rank test showed a significant difference in OS and relapse-free survival between patients with high LMR and those with low LMR. CONCLUSION Preoperative LMR is useful for stratifying the prognosis of HCC patients with a low CLIP score (0-1) undergoing curative resection.
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Affiliation(s)
- Takayuki Shimizu
- Second Department of SurgeryDokkyo Medical UniversityTochigiJapan
| | - Mitsuru Ishizuka
- Second Department of SurgeryDokkyo Medical UniversityTochigiJapan
| | - Kyung Hwa Park
- Second Department of SurgeryDokkyo Medical UniversityTochigiJapan
| | - Takayuki Shiraki
- Second Department of SurgeryDokkyo Medical UniversityTochigiJapan
| | - Yuhki Sakuraoka
- Second Department of SurgeryDokkyo Medical UniversityTochigiJapan
| | - Shozo Mori
- Second Department of SurgeryDokkyo Medical UniversityTochigiJapan
| | - Yukihiro Iso
- Second Department of SurgeryDokkyo Medical UniversityTochigiJapan
| | - Masato Kato
- Second Department of SurgeryDokkyo Medical UniversityTochigiJapan
| | - Taku Aoki
- Second Department of SurgeryDokkyo Medical UniversityTochigiJapan
| | - Keiichi Kubota
- Second Department of SurgeryDokkyo Medical UniversityTochigiJapan
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Famularo S, Di Sandro S, Giani A, Lauterio A, Sandini M, De Carlis R, Buscemi V, Uggeri F, Romano F, Gianotti L, De Carlis L. Recurrence Patterns After Anatomic or Parenchyma-Sparing Liver Resection for Hepatocarcinoma in a Western Population of Cirrhotic Patients. Ann Surg Oncol 2018; 25:3974-3981. [PMID: 30244421 DOI: 10.1245/s10434-018-6730-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Indexed: 08/29/2023]
Abstract
BACKGROUND The optimal surgical strategy to lessen the risk of hepatocarcinoma (HCC) recurrence is debated. This study aimed to investigate the role of anatomic resection (AR) and parenchyma-sparing resection (PSR) in HCC recurrence patterns. METHODS The study analyzed 384 cirrhotic patients with a first diagnosis of HCC. Of these patients, 142 underwent AR, and 242 underwent PSR. The two groups were unbalanced at the univariate analysis. To minimize this bias, a 1:1 propensity score-matching analysis (PSA) was used. Disease-free survival (DFS) curves were analyzed by the Kaplan-Maier method. RESULTS The PSA allowed pairing of 200 patients (100 for AR and 100 for PSR). In this study, 59 patients (62.8%) had recurrence after AR compared with 58 patients (63.7%) after PSR (p = 0.891). The rates of local recurrence were respectively 15.3% and 15.5% (p = 0.968). When microvascular invasion was considered, the median DFS was 10.7 months for AR and 9.4 months for PSR (p = 0.607). In comparisons of AR and PSR, DFS did not differ significantly between subgroups with high histologic grading (p = 0.520), multiple nodules (p = 0.307), and Child-Pugh B (p = 0.679). CONCLUSION Excision of the anatomic segment did not seem to reduce the rate of relapse or recurrence patterns significantly, even in high-risk subgroups.
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Affiliation(s)
- Simone Famularo
- School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
- Department of General Surgery and Transplantation, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Stefano Di Sandro
- Department of General Surgery and Transplantation, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Alessandro Giani
- School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
- Department of Surgery, San Gerardo Hospital, Monza, Italy
| | - Andrea Lauterio
- Department of General Surgery and Transplantation, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Marta Sandini
- School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
- Department of Surgery, San Gerardo Hospital, Monza, Italy
| | - Riccardo De Carlis
- Department of General Surgery and Transplantation, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Vincenzo Buscemi
- Department of General Surgery and Transplantation, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Fabio Uggeri
- School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
- Department of Surgery, San Gerardo Hospital, Monza, Italy
| | - Fabrizio Romano
- School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
- Department of Surgery, San Gerardo Hospital, Monza, Italy
| | - Luca Gianotti
- School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy.
- Department of Surgery, San Gerardo Hospital, Monza, Italy.
| | - Luciano De Carlis
- School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
- Department of General Surgery and Transplantation, Grande Ospedale Metropolitano Niguarda, Milan, Italy
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Zhang W, Qian S, Yang G, Zhu L, Zhou B, Qu X, Yan Z, Liu R, Wang J. Establishment and characterization of McA-RH7777 cells using virus-mediated stable overexpression of enhanced green fluorescent protein. Exp Ther Med 2018; 16:3149-3154. [PMID: 30250518 DOI: 10.3892/etm.2018.6580] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 06/29/2018] [Indexed: 12/31/2022] Open
Abstract
Hepatocellular carcinoma (HCC), the most common primary tumor of the liver, has a poor prognosis, rapid progression. The aim of the current study was to establish a stable lentiviral expression vector for enhanced green fluorescent protein (EGFP) and to evaluate biological characteristics on HCC growth and migration following transfection of HCC cells with EGFP. McA-RH7777 cells were transfected with EGFP overexpression lentiviral vector. Cell activity and mobility were monitored with a Cell-IQ Analyzer. Transwell assays were performed to detect invasiveness and flow cytometry was performed for cell cycle analysis. A subcutaneous tumor rat model was established to analyze the stability of fluorescent protein expression. The result suggested no significant differences between wild-type and EGFP-overexpressing McA-RH7777 cells with regards to cell proliferation, activity, mobility, invasiveness and cell cycle. Green fluorescence was detected over 108 days of culturing. The subcutaneous tumor rat model demonstrated that EGFP expression had no influence on tumor growth and long-term expression was stable. The stable EGFP expression of the HCC transplanted tumor rat model may share biological characteristics with human liver cancer. The model established in the current study may be suitable for various applications, including research focusing on liver cancer metastasis and recurrence, interventional therapy, imaging diagnosis and drug screenings.
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Affiliation(s)
- Wei Zhang
- Department of Intervention Radiology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Sheng Qian
- Department of Intervention Radiology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Guowei Yang
- Department of Intervention Radiology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Liang Zhu
- Department of Intervention Radiology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Bo Zhou
- Department of Intervention Radiology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Xudong Qu
- Department of Intervention Radiology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Zhiping Yan
- Department of Intervention Radiology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Rong Liu
- Department of Intervention Radiology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
| | - Jianhua Wang
- Department of Intervention Radiology, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
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