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Aggarwal M, Kuo M, Zhu Z, Gould S, Zhang K, Johnson P, Beheshtian S, Kuhlman L, Zhao Z, Fang H, Kallakury B, Creswell K, Mueller S, Kroemer A, He AR, Chung FL. Detection of γ-OHPdG in Circulating Tumor Cells of Patients With Hepatocellular Carcinoma as a Potential Prognostic Biomarker of Recurrence. GASTRO HEP ADVANCES 2024; 3:809-820. [PMID: 39280920 PMCID: PMC11401592 DOI: 10.1016/j.gastha.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 04/16/2024] [Indexed: 09/18/2024]
Abstract
Background and Aims Blood-based biomarkers for hepatocellular carcinoma (HCC) and its recurrence are lacking. We previously showed that hepatic γ-hydroxy-1,N 2 -propano-2'-deoxyguanosine (γ-OHPdG), an endogenous DNA adduct derived from acrolein by lipid peroxidation, increased during hepatocarcinogenesis. Additionally, higher hepatic γ-OHPdG from HCC patients after surgery were strongly associated with poor survival (P < .0001) and recurrence-free survival (P = .007) (Fu et al, Hepatology, 2018). These findings suggest that γ-OHPdG is a potential prognostic biomarker for HCC and its recurrence. To attain the goal of using γ-OHPdG as a biomarker in future preventive and therapeutic trials, we developed a blood-based method to detect γ-OHPdG in circulating liver tumor cells from HCC patient blood. Methods We first established the specificity of anti-γ-OHPdG antibody by determining its dose-response in HepG2 cells treated with acrolein. Then, HepG2 cells in spiked blood of healthy volunteers and circulating tumor cells (CTCs) from 32 HCC patients were isolated using a RosetteSep CD45 Depletion Cocktail and Ficoll Paque. The HCC CTCs identified with anti-asialoglycoprotein receptor 1, a surface protein expressed solely in hepatocytes, were stained with an anti-γ-OHPdG antibody. The number of total HCC CTCs and γ-OHPdG-positive CTCs, as well as the staining intensity, were quantified using MetaMorph software. As an initial effort toward its clinical application, we also evaluated γ-OHPdG in CTCs from these patients along with certain clinical features. Results The γ-OHPdG antibody specificity was demonstrated by an acrolein concentration-dependent increase of γ-OHPdG-positive HepG2 cells and the intensity of γ-OHPdG staining. The recovery of HepG2 cells from spiked blood was ∼50-60%, and the positivity rate of CTCs in blood from 32 patients with advanced HCC was 97%. The MetaMorph analysis showed a wide variation among patients in total number of CTCs, γ-OHPdG positivity, and staining intensity. Statistical analysis revealed that γ-OHPdG in CTCs of these patients appears to be associated with multifocality and poor differentiation. Conclusion A blood-based method was developed and applied to HCC patients to evaluate the potential of γ-OHPdG in CTCs as a prognostic biomarker.
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Affiliation(s)
- Monika Aggarwal
- Department of Oncology, Lombardi Comprehensive Cancer Centre, Georgetown University, Washington, District of Columbia
| | - Mark Kuo
- Department of Oncology, Lombardi Comprehensive Cancer Centre, Georgetown University, Washington, District of Columbia
| | - Zizhao Zhu
- Department of Oncology, Lombardi Comprehensive Cancer Centre, Georgetown University, Washington, District of Columbia
| | - Sophie Gould
- Department of Oncology, Lombardi Comprehensive Cancer Centre, Georgetown University, Washington, District of Columbia
| | - Kevin Zhang
- Department of Oncology, Lombardi Comprehensive Cancer Centre, Georgetown University, Washington, District of Columbia
| | - Peter Johnson
- Department of Oncology, Lombardi Comprehensive Cancer Centre, Georgetown University, Washington, District of Columbia
| | - Samira Beheshtian
- Department of Oncology, Lombardi Comprehensive Cancer Centre, Georgetown University, Washington, District of Columbia
| | - Laura Kuhlman
- Department of Oncology, Lombardi Comprehensive Cancer Centre, Georgetown University, Washington, District of Columbia
| | - Zijun Zhao
- Department of Oncology, Lombardi Comprehensive Cancer Centre, Georgetown University, Washington, District of Columbia
| | - Hongbin Fang
- Department of Oncology, Lombardi Comprehensive Cancer Centre, Georgetown University, Washington, District of Columbia
| | - Bhaskar Kallakury
- Department of Oncology, Lombardi Comprehensive Cancer Centre, Georgetown University, Washington, District of Columbia
| | - Karen Creswell
- Department of Oncology, Lombardi Comprehensive Cancer Centre, Georgetown University, Washington, District of Columbia
| | - Susette Mueller
- Department of Oncology, Lombardi Comprehensive Cancer Centre, Georgetown University, Washington, District of Columbia
| | - Alexander Kroemer
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Aiwu Ruth He
- Department of Oncology, Lombardi Comprehensive Cancer Centre, Georgetown University, Washington, District of Columbia
| | - Fung-Lung Chung
- Department of Oncology, Lombardi Comprehensive Cancer Centre, Georgetown University, Washington, District of Columbia
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Tang SC, Zhang KL, Lin KY, Tang YD, Fu J, Zhou WP, Zhang JX, Kong J, He XL, Sun ZH, Luo C, Liu HZ, Lai YP, Zeng YY. A multicenter propensity score analysis of significance of hepatic resection type for early-stage hepatocellular carcinoma. Hepatol Int 2024; 18:623-635. [PMID: 37880566 DOI: 10.1007/s12072-023-10602-0] [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: 07/10/2023] [Accepted: 09/24/2023] [Indexed: 10/27/2023]
Abstract
BACKGROUND The impact of hepatic resection type on long-term oncological prognosis of patients with early-stage hepatocellular carcinoma (HCC) has not been systematically investigated. We sought to determine risk factors, recurrence patterns, and survival outcomes after anatomical resection (AR) versus non-anatomical resection (NAR) for early-stage HCC. METHODS From a prospectively collected multicenter database, consecutive patients undergoing curative hepatectomy for early-stage HCC were identified. Recurrence patterns, overall survival (OS), recurrence-free survival (RFS), and risk factors were investigated in patients undergoing AR versus NAR using propensity score matching (PSM), subgroup analysis, and COX regression analysis. RESULTS A total of 3585 patients with early-stage HCC were enrolled, including 1287 and 2298 in the AR and NAR groups, respectively. After PSM, the OS and RFS of patients in the AR group were 58.8% and 42.7%, which were higher than those in the NAR group (52.2% and 30.6%, both p < 0.01). The benefits of AR were consistent across most subgroup analyses of OS and RFS. Multivariable COX regression analysis showed that AR was independently associated with better OS and RFS. Notably, although recurrence patterns were comparable, the risk factors for recurrence were not identical for AR versus NAR. Microvascular invasion and narrow resection margin were only associated with a higher recurrence rate after NAR. CONCLUSIONS This study demonstrated that AR decreases the risk of tumor recurrence and improves OS and RFS in patients with early-stage HCC. AR should be adopted as long as such a surgical maneuver is feasible for initial treatment of early-stage HCC.
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Affiliation(s)
- Shi-Chuan Tang
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, No. 312, Xihong Road, Fuzhou, 350025, Fujian Province, China
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Kai-Ling Zhang
- Department of Gastroenterology, Wenjiang District People's Hospital of Chengdu, Chengdu, China
| | - Kong-Ying Lin
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, No. 312, Xihong Road, Fuzhou, 350025, Fujian Province, China
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Yi-Dan Tang
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Jun Fu
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, No. 312, Xihong Road, Fuzhou, 350025, Fujian Province, China
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Wei-Ping Zhou
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University (Second Military Medical University), Shanghai, China
| | - Jian-Xi Zhang
- Department of Hepatobiliary Surgery, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, China
| | - Jie Kong
- Department of Hepatobiliary, Heze Municipal Hospital, Shandong, China
| | - Xiao-Lu He
- Department of Hepatobiliary Surgery, Chengdu Second People's Hospital, Chengdu, China
| | - Zheng-Hong Sun
- Department of General Surgery, Guizhou Maotai Hospital, Zunyi, China
| | - Cong Luo
- Department of Hepatopancreatobiliary Surgery, Zizhong County People's Hospital, Zizhong, China
| | - Hong-Zhi Liu
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, No. 312, Xihong Road, Fuzhou, 350025, Fujian Province, China
| | - Yong-Ping Lai
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, No. 312, Xihong Road, Fuzhou, 350025, Fujian Province, China.
| | - Yong-Yi Zeng
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, No. 312, Xihong Road, Fuzhou, 350025, Fujian Province, China.
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
- The Big Data Institute of Southeast Hepatobiliary Health Information, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China.
- The Liver Disease Research Center of Fujian Province, Fuzhou, China.
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Tang X, Xiang L, Li Q, Shao Y, Wan L, Zhao D, Li X, Wu S, Wang H, Li D, Ding K. Molecular evolution in different subtypes of multifocal hepatocellular carcinoma. Hepatol Int 2023; 17:1429-1443. [PMID: 37273168 DOI: 10.1007/s12072-023-10551-8] [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: 03/17/2023] [Accepted: 05/07/2023] [Indexed: 06/06/2023]
Abstract
BACKGROUND Multifocal hepatocellular carcinoma (MF-HCC) accounts for > 40% of HCCs, exhibiting a poor prognosis than single primary HCCs. Characterizing molecular features including dynamic changes of mutational signature along with clonal evolution, intrahepatic metastatic timing, and genetic footprint in the preneoplastic stage underlying different subtypes of MF-HCC are important for understanding their molecular evolution and developing a precision management strategy. METHODS We conducted whole-exome sequencing in 74 tumor samples from spatially distinct regions in 35 resected lesions and adjacent noncancerous tissues from 11 patients, 15 histologically confirmed preneoplastic lesions, and six samples from peripheral blood mononuclear cells. A previously published MF-HCC cohort (n = 9) was included as an independent validation dataset. We combined well-established approaches to investigate tumor heterogeneity, intrahepatic metastatic timing, and molecular footprints in different subtypes of MF-HCCs. RESULTS We classified MF-HCCs patients into three subtypes, including intrahepatic metastasis, multicentric occurrence, and mixed intrahepatic metastasis and multicentric occurrence. The dynamic changes in mutational signatures between tumor subclonal expansions demonstrated varied etiologies (e.g., aristolochic acid exposure) underlying the clonal progression in different MF-HCC subtypes. Furthermore, the clonal evolution in intrahepatic metastasis exhibited an early metastatic seeding at 10-4-0.01 cm3 in primary tumor volume (below the limits of clinical detection), further validated in an independent cohort. In addition, mutational footprints in the preneoplastic lesions for multicentric occurrence patients revealed common preneoplastic arising clones, evidently being ancestors of different tumor lesions. CONCLUSION Our study comprehensively characterized the varied tumor clonal evolutionary history underlying different subtypes of MF-HCC and provided important implications for optimizing personalized clinical management for MF-HCC.
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Affiliation(s)
- Xia Tang
- Shanghai Pudong Hospital and Pudong Medical Center of Fudan University, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200438, People's Republic of China
| | - Lei Xiang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Qingshu Li
- Department of Pathology, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Yue Shao
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Li Wan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Dachun Zhao
- Department of Pathology, Peking Union Medical College Hospital, Beijing, 100730, People's Republic of China
| | - Xiaoyuan Li
- Department of Oncology, Peking Union Medical College Hospital, Beijing, 100730, People's Republic of China
| | - Songfeng Wu
- Beijing Qinglian Biotech Co., Ltd, Beijing, 102206, People's Republic of China
| | - Haijian Wang
- Shanghai Pudong Hospital and Pudong Medical Center of Fudan University, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200438, People's Republic of China.
| | - Dewei Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China.
- Hepatobiliary and Pancreatic Cancer Center, Chongqing University Cancer Hospital, Chongqing, 400030, People's Republic of China.
| | - Keyue Ding
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
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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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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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Histological Heterogeneity of Primary Liver Cancers: Clinical Relevance, Diagnostic Pitfalls and the Pathologist's Role. Cancers (Basel) 2021; 13:cancers13122871. [PMID: 34201284 PMCID: PMC8228556 DOI: 10.3390/cancers13122871] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 06/05/2021] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Primary liver cancers (PLCs) mainly comprise hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and combined (c)HCC-CCA. Both small duct types iCCA (a subtype pf iCCA) and cHCC-CCA are known to be tumors with histological heterogeneity. Understanding key tumor heterogeneity is crucial as it reflects tumor aggressiveness, patient outcome, treatment choice, and is predictive of treatment efficacy. In addition, PLCs often present with multiple liver tumors, which can be a combination of different types of PLCs or HCCs (intrahepatic metastasis or multicentric occurrence), and the pathological interpretation plays an important role in these cases. The aim of this review is to clarify the pathological features of HCC, iCCA, and cHCC-CCA, including their diagnostic pitfalls, molecular profiles, and the correlation between tumor subtypes and treatment choice. Abstract Primary liver cancers (PLCs) mainly comprise hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and cHCC-CCA. Combined HCC-CCA and small duct type iCCA show similar clinical presentations, and their histological features are more complex than seen in HCC. Therefore, while their treatment strategy differs, it is difficult to properly diagnose these tumors. Currently, HCC is the only tumor that can be treated by liver transplantation. In addition, small duct type iCCA harbors IDH1/2 mutations and FGFR2 fusions, which can be used for targeted therapy. Thus, improving diagnostic accuracy is crucial. A further point to note is that PLCs often present as multiple liver tumors, and they can be a combination of different types of PLCs or HCCs. In the case of HCCs, two different scenarios are possible, namely intrahepatic metastasis, or multicentric occurrence. Therefore, it is essential to characterize the type of multiple liver tumors. This review aims to clarify the pathological features of HCC, iCCA and cHCC-CCA, including their diagnostic pitfalls and clinical relevance. It is designed to be of use to clinicians who are dealing with PLCs, to provide a better understanding of the pathology of these tumors, and to enable a more accurate diagnosis and optimal treatment choice.
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Vij M, Calderaro J. Pathologic and molecular features of hepatocellular carcinoma: An update. World J Hepatol 2021; 13:393-410. [PMID: 33959223 PMCID: PMC8080551 DOI: 10.4254/wjh.v13.i4.393] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/27/2021] [Accepted: 03/31/2021] [Indexed: 02/06/2023] Open
Abstract
Morphological diversity and several new distinct pathologic subtypes of hepatocellular carcinoma (HCC) are now well-recognized. Recent advances in tumor genomics and transcriptomics have identified several recurrent somatic/genetic alterations that are closely related with histomorphological subtypes and have therefore, greatly improved our understanding of HCC pathogenesis. Pathologic subtyping allows for a diagnosis which is clinically helpful and can have important implication in patient prognostication as some of these subtypes are extremely aggressive with vascular invasion, early recurrence, and worst outcomes. Several targeted treatments are now being considered in HCC, and the reporting of subtypes may be quite useful for personalized therapeutic purpose. This manuscript reviews the recently identified histomorphological subtypes and molecular alterations in HCC.
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Affiliation(s)
- Mukul Vij
- Department ofPathology, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India.
| | - Julien Calderaro
- Department of Pathology, Groupe Hospitalier Henri Mondor, Creteil F-94010, France
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Brewer K, Nip I, Bellizzi J, Costa-Guda J, Arnold A. Molecular analysis of cyclin D1 modulators PRKN and FBX4 as candidate tumor suppressors in sporadic parathyroid adenomas. Endocr Connect 2021; 10:302-308. [PMID: 33617468 PMCID: PMC8052572 DOI: 10.1530/ec-21-0055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 02/17/2021] [Indexed: 11/10/2022]
Abstract
OBJECTIVE Primary hyperparathyroidism is most often caused by a sporadic single-gland parathyroid adenoma (PTA), a tumor type for which cyclin D1 is the only known and experimentally validated oncoprotein. However, the molecular origins of its frequent overexpression have remained mostly elusive. In this study, we explored a potential tumorigenic mechanism that could increase cyclin D1 stability through a defect in molecules responsible for its degradation. METHODS We examined two tumor suppressor genes known to modulate cyclin D1 ubiquitination, PRKN and FBXO4 (FBX4), for evidence of classic two-hit tumor suppressor inactivation within a cohort of 82 PTA cases. We examined the cohort for intragenic inactivating and splice site mutations by Sanger sequencing and for locus-associated loss of heterozygosity (LOH) by microsatellite analysis. RESULTS We identified no evidence of bi-allelic tumor suppressor inactivation of PRKN or FBXO4 via inactivating mutation or splice site perturbation, neither in combination with nor independent of LOH. Among the 82 cases, we encountered previously documented benign single nucleotide polymorphisms (SNPs) in 35 tumors at frequencies similar to those reported in the germlines of the general population. Eight cases exhibited intragenic LOH at the PRKN locus, in some cases extending to cover at least an additional 1.7 Mb of chromosome 6q25-26. FBXO4 was not affected by LOH. CONCLUSION The absence of evidence for specific bi-allelic inactivation in PRKN and FBXO4 in this sizeable cohort suggests that these genes only rarely, if ever, serve as classic driver tumor suppressors responsible for the growth of PTAs.
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Affiliation(s)
- Kelly Brewer
- Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut, USA
| | - Isabel Nip
- Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut, USA
| | - Justin Bellizzi
- Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut, USA
| | - Jessica Costa-Guda
- Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut, USA
- Center for Regenerative Medicine and Skeletal Development, Department of Reconstructive Sciences, University of Connecticut School of Dental Medicine, Farmington, Connecticut, USA
| | - Andrew Arnold
- Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut, USA
- Division of Endocrinology and Metabolism, University of Connecticut School of Medicine, Farmington, Connecticut, USA
- Correspondence should be addressed to A Arnold:
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Abstract
Hepatocellular carcinoma (HCC) is a morphologically heterogeneous tumor with variable architectural growth patterns and several distinct histologic subtypes. Large-scale attempts have been made over the past decade to identify targetable genomic alterations in HCC; however, its translation into clinical personalized care remains a challenge to precision oncology. The role of pathology is no longer limited to confirmation of diagnosis when radiologic features are atypical. Pathology is now in a position to predict the underlying molecular alteration, prognosis, and behavior of HCC. This review outlines various aspects of histopathologic diagnosis and role of pathology in cutting-edge diagnostics of HCC.
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Affiliation(s)
- Monika Vyas
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 303 Brookline Avenue, Boston, MA 02215, USA
| | - Xuchen Zhang
- Department of Pathology, Yale School of Medicine, 310 Cedar Street, PO Box 208023, New Haven, CT 06520-8023, USA.
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10
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Bekki T, Abe T, Amano H, Hattori M, Kobayashi T, Nakahara M, Ohdan H, Noriyuki T. Impact of low skeletal muscle mass index and perioperative blood transfusion on the prognosis for HCC following curative resection. BMC Gastroenterol 2020; 20:328. [PMID: 33028209 PMCID: PMC7539410 DOI: 10.1186/s12876-020-01472-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 09/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND This study aimed to assess the prognostic factors including low skeletal muscle mass index (SMI) and perioperative blood transfusion for patients with hepatocellular carcinoma (HCC) following curative surgery. METHODS This study included 139 patients with HCC who underwent hepatectomy between 2005 and 2016. Univariate and multivariate analyses were performed to identify variables associated with overall survival (OS) and recurrence-free survival (RFS). RESULTS Low SMI was significantly related with poor OS, while blood transfusion had a strong impact on RFS. The male ratio and body mass index in the low SMI group were significantly higher than those in the high SMI group. There were no significant differences in age, virus etiology, laboratory data, liver function, tumor makers, and operative variables between the groups. Tumor factors such as tumor diameter, tumor number, poor differentiation, and intrahepatic metastasis (IM) did not significantly differ between the two groups. Operation time, intraoperative blood loss volume, and recurrence ratio were significantly higher in the blood transfusion group than in the non-transfusion group. IM was associated with poor OS and RFS. CONCLUSIONS Low SMI and blood transfusion were independently related with long-term prognosis in patients with HCC following curative surgery.
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Affiliation(s)
- Tomoaki Bekki
- Department of Surgery, Onomichi General Hospital, 1-10-23 Hirahara, Onomichi, Hiroshima, Japan
| | - Tomoyuki Abe
- Department of Surgery, Onomichi General Hospital, 1-10-23 Hirahara, Onomichi, Hiroshima, Japan.
| | - Hironobu Amano
- Department of Surgery, Onomichi General Hospital, 1-10-23 Hirahara, Onomichi, Hiroshima, Japan.,Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3 Minami-ku, Hiroshima, Japan
| | - Minoru Hattori
- Advanced Medical Skills Training Center, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3 Minami-ku, Hiroshima, Japan
| | - Masahiro Nakahara
- Department of Surgery, Onomichi General Hospital, 1-10-23 Hirahara, Onomichi, Hiroshima, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3 Minami-ku, Hiroshima, Japan
| | - Toshio Noriyuki
- Department of Surgery, Onomichi General Hospital, 1-10-23 Hirahara, Onomichi, Hiroshima, Japan.,Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3 Minami-ku, Hiroshima, Japan
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11
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Frizziero M, McNamara MG, Lamarca A, Pihlak R, Kurup R, Hubner RA. Current Translational and Clinical Challenges in Advanced Hepatocellular Carcinoma. Curr Med Chem 2020; 27:4789-4805. [PMID: 32321391 DOI: 10.2174/0929867327666200422143847] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 03/16/2020] [Accepted: 04/13/2020] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a frequent and increasing cause of cancerrelated deaths worldwide. Reversing this trend is complicated by the varied aetiological factors leading to liver cirrhosis resulting in molecular genetic and clinical heterogeneity, combined with frequent presentation at advanced stage. Large-scale genomic studies have identified alterations in key signalling pathways for HCC development and progression, but these findings have not yet directly influenced patient management in the clinical setting. Despite these translational challenges, a small number of anti-angiogenic systemic therapy agents have succeeded in recent randomized trials enriching the repertoire of available treatments for advanced HCC. In addition, the early promise of immune checkpoint inhibition is now on the cusp of delivering changes to standard systemic therapy algorithms. This review focuses on recent translational and clinical developments that have advanced. current practice and explores the challenges encountered in attempting to improve the outcomes and experience of patients diagnosed with advanced HCC.
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Affiliation(s)
- Melissa Frizziero
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, United Kingdom
| | - Mairéad G McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, United Kingdom
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, United Kingdom
| | - Rille Pihlak
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, United Kingdom
| | - Roopa Kurup
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, United Kingdom
| | - Richard A Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, United Kingdom
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12
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Frizziero M, McNamara MG, Lamarca A, Pihlak R, Kurup R, Hubner RA. Current Translational and Clinical Challenges in Advanced Hepatocellular Carcinoma. Curr Med Chem 2020. [DOI: 10.10.2174/0929867327666200422143847] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Hepatocellular carcinoma (HCC) is a frequent and increasing cause of cancerrelated
deaths worldwide. Reversing this trend is complicated by the varied aetiological factors
leading to liver cirrhosis resulting in molecular genetic and clinical heterogeneity, combined
with frequent presentation at advanced stage. Large-scale genomic studies have identified
alterations in key signalling pathways for HCC development and progression, but these
findings have not yet directly influenced patient management in the clinical setting. Despite
these translational challenges, a small number of anti-angiogenic systemic therapy agents
have succeeded in recent randomized trials enriching the repertoire of available treatments for
advanced HCC. In addition, the early promise of immune checkpoint inhibition is now on the
cusp of delivering changes to standard systemic therapy algorithms. This review focuses on
recent translational and clinical developments that have advanced current practice and explores
the challenges encountered in attempting to improve the outcomes and experience of
patients diagnosed with advanced HCC.
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Affiliation(s)
- Melissa Frizziero
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, United Kingdom
| | - Mairéad G. McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, United Kingdom
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, United Kingdom
| | - Rille Pihlak
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, United Kingdom
| | - Roopa Kurup
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, United Kingdom
| | - Richard A. Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, United Kingdom
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13
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Increased both PD-L1 and PD-L2 expressions on monocytes of patients with hepatocellular carcinoma was associated with a poor prognosis. Sci Rep 2020; 10:10377. [PMID: 32587357 PMCID: PMC7316832 DOI: 10.1038/s41598-020-67497-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 06/08/2020] [Indexed: 12/31/2022] Open
Abstract
Anti-programmed cell death-1 (PD-1) antibodies has been approved to treat HCC. Some PD-1 ligands (PD–L1 and PD–L2) negative tumors respond to treatment of anti-PD-1 antibodies, and this fact may be caused by the expression of PD-1 ligands on non-tumor cells. PD–L1 was recently found to be expressed on CD14+ cells from cancer patients. We investigate PD-1 ligands expression on CD14+ cells of patients with HCC and the role of CD14+ cells in an antitumor response. In this study, 87 patients diagnosed with HCC were enrolled. CD14+ cells from patients with HCC expressed PD–L1 (4.5–95.5%) and PD–L2 (0.2–95.0%). According to cut-off values, we classified patients as those either with PD–L1+PD–L2+CD14+ cells or other types of CD14+ cells. The overall survival of patients with PD–L1+PD–L2+CD14+ cells was shorter than that of patients with other types of CD14+ cells (p = 0.0023). PD–L1+PD–L2+CD14+ cells produced IL-10 and CCL1, and showed little tumoricidal activity against HepG2 cells. The tumoricidal activity of CD8+ cells from patients with PD–L1+PD–L2+CD14+ cells were suppressed by co-cultivation with CD14+ cells from the syngeneic patient. Furthermore, anti-PD-1 antibody restored their tumoricidal activity of CD8+ cells. In conclusion, some patients with HCC have PD–L1+PD–L2+CD14+ cells that suppress their antitumor response. These inhibitory functions of CD14+ cells may be associated with a poor prognosis in these patients.
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14
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Xing H, Zhang WG, Cescon M, Liang L, Li C, Wang MD, Wu H, Lau WY, Zhou YH, Gu WM, Wang H, Chen TH, Zeng YY, Schwartz M, Pawlik TM, Serenari M, Shen F, Wu MC, Yang T. Defining and predicting early recurrence after liver resection of hepatocellular carcinoma: a multi-institutional study. HPB (Oxford) 2020; 22:677-689. [PMID: 31607637 DOI: 10.1016/j.hpb.2019.09.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 09/12/2019] [Accepted: 09/14/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND A clear definition of "early recurrence" after hepatocellular carcinoma (HCC) resection is still lacking. This study aimed to determine the optimal cutoff between early and late HCC recurrence, and develop nomograms for pre- and postoperative prediction of early recurrence. METHODS Patients undergoing HCC resection were identified from a multi-institutional Chinese database. Minimum P-value approach was adopted to calculate optimal cut-off to define early recurrence. Pre- and postoperative risk factors for early recurrence were identified and further used for nomogram construction. The results were externally validated by a Western cohort. RESULTS Among 1501 patients identified, 539 (35.9%) were recurrence-free. The optimal length to distinguish between early (n = 340, 35.3%) and late recurrence (n = 622, 64.7%) was 8 months. Multivariable logistic regression analyses identified 5 preoperative and 8 postoperative factors for early recurrence, which were further incorporated into preoperative and postoperative nomograms (C-index: 0.785 and 0.834). The calibration plots for the probability of early recurrence fitted well. The nomogram performance was maintained using the validation dataset (C-index: 0.777 for preoperative prediction and 0.842 for postoperative prediction). CONCLUSIONS An interval of 8 months was the optimal threshold for defining early HCC recurrence. The two web-based nomograms have been published to allow accurate pre- and postoperative prediction of early recurrence. These may offer useful guidance for individual treatment or follow up for patients with resectable HCC.
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Affiliation(s)
- Hao Xing
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wan-Guang Zhang
- Department of Hepatic Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Matteo Cescon
- Department of Medical and Surgical Sciences, General Surgery and Transplantation Unit, University of Bologna, Italy
| | - Lei Liang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Chao Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Ming-Da Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Han Wu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wan Yee Lau
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong Special Administrative Region
| | - Ya-Hao Zhou
- Department of Hepatobiliary Surgery, Pu'er People's Hospital, Yunnan, China
| | - Wei-Min Gu
- The First Department of General Surgery, The Fourth Hospital of Harbin, Heilongjiang, China
| | - Hong Wang
- Department of General Surgery, Liuyang People's Hospital, Hunan, China
| | - Ting-Hao Chen
- Department of General Surgery, Ziyang First People's Hospital, Sichuan, China
| | - Yong-Yi Zeng
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fujian, China
| | - Myron Schwartz
- Liver Cancer Program, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, United States
| | - Timothy M Pawlik
- Department of Surgery, Ohio State University, Wexner Medical Center, Columbus, OH, United States
| | - Matteo Serenari
- Department of Medical and Surgical Sciences, General Surgery and Transplantation Unit, University of Bologna, Italy
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Meng-Chao Wu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
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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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16
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Sakon M, Kobayashi S, Wada H, Eguchi H, Marubashi S, Takahashi H, Akita H, Gotoh K, Yamada D, Asukai K, Hasegawa S, Ohue M, Yano M, Nagano H. "Logic-Based Medicine" Is More Feasible than "Evidence-Based Medicine" in the Local Treatment for Hepatocellular Carcinoma. Oncology 2020; 98:259-266. [PMID: 32045926 DOI: 10.1159/000505554] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 12/12/2019] [Indexed: 01/18/2023]
Abstract
The optimal type of surgery (e.g., anatomic or non-anatomic resection) or radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is still under debate despite numerous comparative studies based on overall survival. This debate continues not only because these endpoints are influenced by non-surgical factors, such as liver function, but because the definition of non-anatomic resection for HCC has remained unclear. The optimal surgery could be logically determined based on the mechanism of local intrahepatic metastasis, that is, the drainage of tumour blood flow (TBF), because HCC spreads locally through tumour blood flowing to the peri-tumourous liver parenchyma. Since TBF is clearly demonstrated by CT scan under hepatic arteriography, the surgical margin can be determined individually based on the drainage of TBF without deteriorating local curability. Controversy regarding RFA and surgery does not result from the curability of treatment itself but from the lack of scientific evidence on safety margins. Based on proper concepts and self-evident truths, an algorithm of loco-regional treatment for HCC is proposed.
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Affiliation(s)
- Masato Sakon
- Department of Surgery, Osaka International Cancer Institute, Osaka, Japan,
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Hiroshi Wada
- Department of Surgery, Osaka International Cancer Institute, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Shigeru Marubashi
- Department of Hepato-Biliary-Pancreatic and Transplant Surgery, Fukushima Medical University, Fukushima, Japan
| | - Hidenori Takahashi
- Department of Surgery, Osaka International Cancer Institute, Osaka, Japan
| | - Hirofumi Akita
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Kunihito Gotoh
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Daisaku Yamada
- Department of Surgery, Osaka International Cancer Institute, Osaka, Japan
| | - Kei Asukai
- Department of Surgery, Osaka International Cancer Institute, Osaka, Japan
| | | | - Masayuki Ohue
- Department of Surgery, Osaka International Cancer Institute, Osaka, Japan
| | - Masahiko Yano
- Department of Surgery, Osaka International Cancer Institute, Osaka, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University, Yamaguchi, Japan
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17
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Yamamoto S, Midorikawa Y, Nagae G, Tatsuno K, Ueda H, Moriyama M, Takayama T, Aburatani H. Spatial and temporal expansion of intrahepatic metastasis by molecularly-defined clonality in multiple liver cancers. Cancer Sci 2020; 111:601-609. [PMID: 31845427 PMCID: PMC7004543 DOI: 10.1111/cas.14282] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 12/09/2019] [Accepted: 12/10/2019] [Indexed: 12/17/2022] Open
Abstract
Multiple hepatocellular carcinoma (HCC) is divided into two categories: intrahepatic metastasis (IM), which is a true relapse of HCC, and multicentric origin (MO), which is a second primary tumor. Clinical diagnosis of multiple HCC is usually made based on tumor location and/or time to recurrence; however, it is often difficult to distinguish the two types of multiple HCC. Using 41 matched pairs of multiple HCC specimens, we confirmed the accuracy of clinical diagnoses using exome sequence data and investigated the importance of discriminating the type of multiple HCC. Genomic analysis revealed that 18 (43.9%) patients diagnosed as having genomic IM had common mutations in a pair of HCC tumors with the main tumor of these patients being more progressive compared to those with genomic MO. The accuracy of clinical diagnosis based on lobe (Definition 1) and segment (Definition 2) were 68.3% and 78.0%, respectively. Intriguingly, recurrence ≥2 years after initial surgery for 3 patients was IM. The survival of patients with clinical IM was significantly shorter than for those with clinical MO based on both Definition 1 (P = 0.045) and Definition 2 (P = 0.043). However, mean survival was not different between the patients with genomic IM and those with MO (P = 0.364). Taken together, genomic analysis elucidated that liver cancer may spread more extensively and more slowly than previously thought. In addition, distinguishing multiple HCC as IM or MC may have provided biological information but was not of clinical importance with respect to patient prognosis.
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Affiliation(s)
- Shogo Yamamoto
- Genome Science Division, RCAST, University of Tokyo, Tokyo, Japan
| | - Yutaka Midorikawa
- Genome Science Division, RCAST, University of Tokyo, Tokyo, Japan.,Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Genta Nagae
- Genome Science Division, RCAST, University of Tokyo, Tokyo, Japan
| | - Kenji Tatsuno
- Genome Science Division, RCAST, University of Tokyo, Tokyo, Japan
| | - Hiroki Ueda
- Genome Science Division, RCAST, University of Tokyo, Tokyo, Japan
| | - Mitsuhiko Moriyama
- Gastroenterology and Hepatology, Nihon University School of Medicine, Tokyo, Japan
| | - Tadatoshi Takayama
- Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
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18
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Insights into the success and failure of systemic therapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2019; 16:617-630. [PMID: 31371809 DOI: 10.1038/s41575-019-0179-x] [Citation(s) in RCA: 144] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/26/2019] [Indexed: 02/08/2023]
Abstract
Systemic treatment for hepatocellular carcinoma (HCC) has been boosted by the incorporation of new agents after many negative phase III trials in the decade since the approval of sorafenib. Sorafenib introduced the concept that targeting specific hallmarks of hepatocarcinogenesis could modify the dismal prognosis of this disease, with the drug remaining a cornerstone in the upfront therapy for advanced HCC. The design of clinical trials in this malignancy is complicated by important obstacles related to patient selection, prognostic assessment and the need for endpoints that correlate with improvement in survival outcomes. In addition, the currently used criteria to determine treatment response or progression might prevent physicians from making appropriate clinical judgements and interpreting evidence arising from trials. In this Review, we discuss the advances in systemic therapy for HCC and critically review trial designs in HCC. Although novel therapies, such as new targeted agents and immunotherapies, are being rapidly incorporated, it is paramount to design future clinical trials based on the lessons learned from past failures and successes.
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19
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Zhang H, Han J, Xing H, Li ZL, Schwartz ME, Zhou YH, Chen TH, Wang H, Gu WM, Lau WY, Wu H, Wu MC, Shen F, Yang T. Sex difference in recurrence and survival after liver resection for hepatocellular carcinoma: A multicenter study. Surgery 2019; 165:516-524. [PMID: 30337048 DOI: 10.1016/j.surg.2018.08.031] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 08/15/2018] [Accepted: 08/28/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND There is a striking sex difference in the incidence of hepatocellular carcinoma, with a strong predominance for men; however, the impact of sex on the incidence of recurrence after curative resection of hepatocellular carcinoma remains controversial. This study aimed to assess sex differences in the risks of recurrence and mortality for patients treated with curative resection of hepatocellular carcinoma. METHODS We retrospectively reviewed data from 1,435 hepatocellular carcinoma patients treated with curative resection (1,228 men and 207 women) between 2004 and 2014 at 5 institutions in China. Patients' baseline characteristics, operative variables, and rates of early recurrence (≤2 years after resection), late recurrence (>2 years after resection), and cancer-specific mortality were evaluated and compared. To clarify the true oncologic impact of sex, multivariable competing-risks regression analyses were performed to identify predictors associated with early and late recurrence, as well as cancer-specific mortality. RESULTS The early recurrence rates between men and women were similar (43.3% vs 42.0%, P = .728), but the late recurrence and rates of cancer-specific mortality in men were greater compared with women (17.2% vs 11.2%, P = .044; and 42.8% vs 34.3%, P = .022, respectively). Multivariable competing-risks regression analyses revealed no sex difference in early recurrence; however, men had greater late recurrence rate (hazard ratio, 1.752; 95% confidence interval, 1.145-2.682; P = .010) and rate of cancer-specific mortality (hazard ratio, 1.307; 95% confidence interval, 1.015-1.683; P = .038). CONCLUSION There was no difference in early recurrence rate (≤2 years after resection between men and women, but men had significantly greater late recurrence (>2 years) and rates of cancer-specific mortality after hepatocellular carcinoma resection than women.
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Affiliation(s)
- Han Zhang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jun Han
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Hao Xing
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zhen-Li Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Myron E Schwartz
- Liver Cancer Program, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Ya-Hao Zhou
- Department of Hepatobiliary Surgery, Pu'er People's Hospital, Yunnan, China
| | - Ting-Hao Chen
- Department of General Surgery, Ziyang First People's Hospital, Sichuan, China
| | - Hong Wang
- Department of General Surgery, Liuyang People's Hospital, Hunan, China
| | - Wei-Min Gu
- The First Department of General Surgery, the Fourth Hospital of Harbin, Heilongjiang, China
| | - Wan Yee Lau
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; Faculty of Medicine, the Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China
| | - Han Wu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Meng-Chao Wu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; Liver Cancer Program, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
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20
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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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21
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Chan AWH, Zhong J, Berhane S, Toyoda H, Cucchetti A, Shi K, Tada T, Chong CCN, Xiang BD, Li LQ, Lai PBS, Mazzaferro V, García-Fiñana M, Kudo M, Kumada T, Roayaie S, Johnson PJ. Development of pre and post-operative models to predict early recurrence of hepatocellular carcinoma after surgical resection. J Hepatol 2018; 69:1284-1293. [PMID: 30236834 DOI: 10.1016/j.jhep.2018.08.027] [Citation(s) in RCA: 391] [Impact Index Per Article: 55.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 08/22/2018] [Accepted: 08/28/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Resection is the most widely used potentially curative treatment for patients with early hepatocellular carcinoma (HCC). However, recurrence within 2 years occurs in 30-50% of patients, being the major cause of mortality. Herein, we describe 2 models, both based on widely available clinical data, which permit risk of early recurrence to be assessed before and after resection. METHODS A total of 3,903 patients undergoing surgical resection with curative intent were recruited from 6 different centres. We built 2 models for early recurrence, 1 using preoperative and 1 using pre and post-operative data, which were internally validated in the Hong Kong cohort. The models were then externally validated in European, Chinese and US cohorts. We developed 2 online calculators to permit easy clinical application. RESULTS Multivariable analysis identified male gender, large tumour size, multinodular tumour, high albumin-bilirubin (ALBI) grade and high serum alpha-fetoprotein as the key parameters related to early recurrence. Using these variables, a preoperative model (ERASL-pre) gave 3 risk strata for recurrence-free survival (RFS) in the entire cohort - low risk: 2-year RFS 64.8%, intermediate risk: 2-year RFS 42.5% and high risk: 2-year RFS 20.7%. Median survival in each stratum was similar between centres and the discrimination between the 3 strata was enhanced in the post-operative model (ERASL-post) which included 'microvascular invasion'. CONCLUSIONS Statistical models that can predict the risk of early HCC recurrence after resection have been developed, extensively validated and shown to be applicable in the international setting. Such models will be valuable in guiding surveillance follow-up and in the design of post-resection adjuvant therapy trials. LAY SUMMARY The most effective treatment of hepatocellular carcinoma is surgical removal of the tumour but there is often recurrence. In this large international study, we develop a statistical method that allows clinicians to estimate the risk of recurrence in an individual patient. This facility enhances communication with the patient about the likely success of the treatment and will help in designing clinical trials that aim to find drugs that decrease the risk of recurrence.
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Affiliation(s)
- Anthony W H Chan
- State Key Laboratory in Oncology in South China, Sir Y. K. Pao Centre for Cancer, Department of Anatomical & Cellular Pathology, and Department of Surgery, The Chinese University of Hong Kong, Hong Kong
| | - Jianhong Zhong
- Department of Hepatobiliary Surgery, Affiliated Tumour Hospital of Guangxi Medical University, Nanning, China
| | - Sarah Berhane
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki, Gifu 503-8052, Japan
| | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Italy
| | - KeQing Shi
- Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Toshifumi Tada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki, Gifu 503-8052, Japan
| | - Charing C N Chong
- State Key Laboratory in Oncology in South China, Sir Y. K. Pao Centre for Cancer, Department of Anatomical & Cellular Pathology, and Department of Surgery, The Chinese University of Hong Kong, Hong Kong
| | - Bang-De Xiang
- Department of Hepatobiliary Surgery, Affiliated Tumour Hospital of Guangxi Medical University, Nanning, China
| | - Le-Qun Li
- Department of Hepatobiliary Surgery, Affiliated Tumour Hospital of Guangxi Medical University, Nanning, China
| | - Paul B S Lai
- State Key Laboratory in Oncology in South China, Sir Y. K. Pao Centre for Cancer, Department of Anatomical & Cellular Pathology, and Department of Surgery, The Chinese University of Hong Kong, Hong Kong
| | - Vincenzo Mazzaferro
- University of Milan and Gastrointestinal Surgery and Liver Transplantation Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Takashi Kumada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki, Gifu 503-8052, Japan
| | - Sasan Roayaie
- Liver Cancer Program, White Plains Hospital - Montefiore Health System, White Plains, NY, United States
| | - Philip J Johnson
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
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22
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Xu D, Liu X, Wang L, Xing B. Hepatectomy plus adjuvant transcatheter arterial chemoembolization improves the survival rate of patients with multicentric occurrence of hepatocellular carcinoma. Oncol Lett 2018; 16:5882-5890. [PMID: 30344739 PMCID: PMC6176366 DOI: 10.3892/ol.2018.9333] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 06/29/2018] [Indexed: 01/27/2023] Open
Abstract
The aim of the present study was to evaluate the role of hepatectomy plus adjuvant transcatheter arterial chemoembolization (TACE) in patients with multicentric occurrence (MO) or intrahepatic metastases (IM) of hepatocellular carcinoma (HCC). Patients with multifocal HCC who underwent hepatic resection only (HR) or HR plus adjuvant TACE (HRT) between January 2005 and December 2015 were divided into MO or IM groups. The patient characteristics and outcomes were retrospectively analyzed. A total of 103 patients (59 and 44 in the MO and IM groups, respectively) were included in the analysis. The 1-, 3- and 5-year overall survival (OS) rates were 92.7, 76.8 and 56.8% for the MO group, and 93.1, 41.6 and 18.5% for the IM group, respectively (OS, P=0.001), and the 1-, 3- and 5-year disease-free survival (DFS) rates were 84.1, 44.6 and 40.5% for the MO group and 51.7, 22.5 and 15.0% for the IM group, respectively (DFS, P<0.001). In the subgroup analysis, the overall survival were significantly better in the MO-HRT group compared with those in the MO-HR group (P=0.019), which was also observed between the IM-HRT and IM-HR groups (P=0.132). Furthermore, the 1-, 3- and 5-year OS demonstrated non-significant differences between patients with <3 and ≥3 tumors in the MO-HR group (P=0.300), but significantly reduced OS for patients with ≥3 tumors in the IM-HR group compared with that for patients with <3 tumors (P=0.132). In conclusion, surgical resection combined with adjuvant TACE may result in significantly increased survival rates of patients with MO-HCC. Tumor number should not be an absolute contradiction to hepatectomy in patients with MO-HCC.
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Affiliation(s)
- Da Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Xiaofeng Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Lijun Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Baocai Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
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23
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Famularo S, Di Sandro S, Giani A, Lauterio A, Sandini M, De Carlis R, Buscemi V, Romano F, Gianotti L, De Carlis L. Long-term oncologic results of anatomic vs. parenchyma-sparing resection for hepatocellular carcinoma. A propensity score-matching analysis. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2018; 44:1580-1587. [PMID: 29861336 DOI: 10.1016/j.ejso.2018.05.018] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 04/30/2018] [Accepted: 05/11/2018] [Indexed: 12/29/2022]
Abstract
PURPOSE The extent of liver resection for the optimal treatment of hepatocellular carcinoma (HCC) is debated. The purpose of this study was to compare the impact of anatomic resection (AR) vs. parenchyma-sparing resection (PSR) on disease recurrence and patient survival. METHODS We retrospectively analyzed patients with HCC who underwent liver resection from January 2001 to August 2015. Patients receiving AR or PSR were compared by a propensity score analysis (PSA) (caliper = 0.1). The primary outcomes were disease-free survival (DFS) and overall survival (OS) rates, and assessed by the Kaplan-Meier method. RESULTS 455 consecutive patients were evaluated. After PSA 354 patient were studied (177 pairs for each group). The median follow-up time was 28.2 months. The median OS was 47.5 months (95% CI: 30.0-65.9) for AR and 56.5 months (95% CI 33.2-79.6) for PSR (p = 0.169). The median DFS was 29.2 months (95% CI 17.6-40.8) for AR and 24.8 months (95% CI: 15.2-34.2) for PSR (p = 0.337). The multivariate regression model showed that cirrhosis (HR 2.85, 95% CI: 1.53-5.32; p = 0.001), BCLC grade B (HR 4.15, 95% CI: 1.33-12.95; p = 0.014), microvascular invasion (HR 1.55, 95% CI: 1.03-2.31; p = 0.033), presence of satellitosis (HR 1.94, 95% CI: 1.25-3.01; p = 0.003), severe complications (HR 6.09, 95% CI: 2.26-16.40; p > 0.001) were independently associated with poor long-term oncologic outcomes. CONCLUSIONS The extent of resection did not significantly affect overall and disease-free survival while tumor characteristics and underlying liver function appeared significant determinants.
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Affiliation(s)
- Simone Famularo
- School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy; Department of Surgery, San Gerardo Hospital, Monza, Italy
| | - Stefano Di Sandro
- Department of General Surgery and Transplantation, Ca'Granda Niguarda Hospital, 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, Ca'Granda Niguarda Hospital, 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, Ca'Granda Niguarda Hospital, Milan, Italy
| | - Vincenzo Buscemi
- Department of General Surgery and Transplantation, Ca'Granda Niguarda Hospital, Milan, 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, Ca'Granda Niguarda Hospital, Milan, Italy
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24
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Wen T, Jin C, Facciorusso A, Donadon M, Han HS, Mao Y, Dai C, Cheng S, Zhang B, Peng B, Du S, Jia C, Xu F, Shi J, Sun J, Zhu P, Nara S, Millis JM. Multidisciplinary management of recurrent and metastatic hepatocellular carcinoma after resection: an international expert consensus. Hepatobiliary Surg Nutr 2018; 7:353-371. [PMID: 30498711 DOI: 10.21037/hbsn.2018.08.01] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is the sixth-most common cancer and the third leading cause of cancer-related death in the world. However, 40-70% patients eventually suffer from postoperative recurrence within 5 years. HCC recurrence after surgery severely affects prognosis of the patients. Nevertheless, there is an opportunity to improve patients' prognosis if doctors and researchers can recognize the importance of a standardized perioperative management and study it in clinical and pre-clinical settings. Hence, based on our own experience and published studies from other researchers, we develop this consensus regarding multidisciplinary management of locally recurrent and metastatic hepatocellular carcinoma after resection. This consensus consists of the entire course of recurrent hepatocellular carcinoma (RHCC) management, including prediction of recurrence, prevention, diagnosis, treatment and surveillance of RHCC. Consensus recommendations are presented with grades of evidences (Ia, Ib, IIa, IIb, III and IV), and strength of recommendations (A, B, C, D and E). We also develop a decision-making path for RHCC treatment, which can intuitively demonstrate the management for RHCC. It is hoped that we may make some effort to standardize the management of RHCC and ultimately understand how to improve outcomes.
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Affiliation(s)
- Tianfu Wen
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Chen Jin
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Antonio Facciorusso
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Matteo Donadon
- Department of Hepatobiliary & General Surgery, Humanitas University, Humanitas Clinical and Research Center, Milan, Italy
| | - Ho-Seong Han
- Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Chaoliu Dai
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang 110000, China
| | - Shuqun Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Baogang Peng
- Department of Liver Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Changjun Jia
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang 110000, China
| | - Feng Xu
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang 110000, China
| | - Jie Shi
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Juxian Sun
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Peng Zhu
- Hepatic Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Satoshi Nara
- Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan
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25
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Tokumitsu Y, Sakamoto K, Tokuhisa Y, Matsui H, Matsukuma S, Maeda Y, Sakata K, Wada H, Eguchi H, Ogihara H, Fujita Y, Hamamoto Y, Iizuka N, Ueno T, Nagano H. A new prognostic model for hepatocellular carcinoma recurrence after curative hepatectomy. Oncol Lett 2018; 15:4411-4422. [PMID: 29556288 PMCID: PMC5844062 DOI: 10.3892/ol.2018.7821] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 10/10/2017] [Indexed: 02/06/2023] Open
Abstract
We previously reported the effectiveness of the product of tumor number and size (NxS factor) for the prognosis of hepatocellular carcinoma (HCC) in patients following hepatectomy. The present study aimed to propose a new score based on the NxS factor to predict HCC recurrence following hepatectomy. A total of 406 patients who underwent hepatectomy for HCC at Osaka University Graduate School of Medicine were retrospectively analyzed to develop the new score. Among clinicopathological factors, including the NxS factor, the marker subset that achieved the best performance for prediction of early recurrence was assessed, and a prognostic model for HCC recurrence after curative hepatectomy (REACH) was developed. As the validation set, 425 patients who underwent hepatectomy for HCC at Yamaguchi University Graduate School of Medicine and Shimonoseki Medical Center were analyzed, and the prognostic ability of the REACH score was compared with that of well-known staging systems. Following analysis, the REACH score was constructed using six covariates (NxS factor, microscopic hepatic vein invasion, differentiation, serum albumin, platelet count and indocyanine green retention rate at 15 min). In the validation set, the REACH score predicted early recurrence in 73 of 81 samples, with a sensitivity of 89% and a specificity of 58%. The area under the curve (AUC) of the receiver operating characteristic curve of the REACH score was 0.78 and 0.74, respectively, for 1- and 2-year recurrence after hepatectomy; each AUC was higher than that of any of the other staging systems. Survival analysis indicated the REACH score had the best predictive value in disease-free and overall survival. The present findings demonstrated that the REACH score may be used to classify patients with HCC into high- and low-risk of recurrence, and to predict subsequent survival following hepatic resection.
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Affiliation(s)
- Yukio Tokumitsu
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
| | - Kazuhiko Sakamoto
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
| | - Yoshihiro Tokuhisa
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
| | - Hiroto Matsui
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
| | - Satoshi Matsukuma
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
| | - Yoshinari Maeda
- Department of Surgery, Kanmon Medical Center, National Hospital Organization, Shimonoseki, Yamaguchi 752-8510, Japan
| | - Koichiro Sakata
- Department of Surgery, Shimonoseki Medical Center, Japan Community Health Care Organization, Shimonoseki, Yamaguchi 750-0061, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Hiroyuki Ogihara
- Department of Biomolecular Engineering Applied Molecular Bioscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8611, Japan
| | - Yusuke Fujita
- Department of Information Science and Engineering, Yamaguchi University Graduate School of Sciences and Technology for Innovation, Ube, Yamaguchi 755-8611, Japan
| | - Yoshihiko Hamamoto
- Department of Information Science and Engineering, Yamaguchi University Graduate School of Sciences and Technology for Innovation, Ube, Yamaguchi 755-8611, Japan
| | - Norio Iizuka
- Department of Kampo Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
| | - Tomio Ueno
- Department of Digestive Surgery, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
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26
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Zhang X, Li C, Wen T, Peng W, Yan L, Yang J. Outcomes of Salvage Liver Transplantation and Re-resection/Radiofrequency Ablation for Intrahepatic Recurrent Hepatocellular Carcinoma: A New Surgical Strategy Based on Recurrence Pattern. Dig Dis Sci 2018; 63:502-514. [PMID: 29238896 DOI: 10.1007/s10620-017-4861-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 11/19/2017] [Indexed: 02/05/2023]
Abstract
BACKGROUND The treatment of intrahepatic recurrent hepatocellular carcinoma (HCC) has been poorly investigated, and the optimal treatment strategy remains unclear. AIMS The aim of this study was to compare outcomes between salvage liver transplantation (SLT) and re-resection (RR)/radiofrequency ablation (RFA) for intrahepatic recurrent HCC according to recurrence pattern. METHODS Based on postoperative histopathological examination, 122 patients with intrahepatic recurrent HCC were divided into an intrahepatic metastasis (IM, n = 75) group and a multicentric occurrence (MO, n = 47) group. The demographic, clinical, and primary and recurrent tumor characteristics of the IM group and the MO group were collected and compared. Overall survival (OS) and disease-free survival (DFS) were analyzed, and subgroup analysis according to retreatment type (SLT vs. RR/RFA) was conducted. Twenty-nine clinicopathological variables potentially related to prognostic factors affecting survival were analyzed using a Cox proportional hazard model. RESULTS The patients that received SLT treatment exhibited favorable DFS compared to patients that received RR/RFA (P = 0.002). OS (P < 0.001) and DFS (P = 0.008) rates were significantly increased in the MO group compared with in the IM group. Subgroup analysis revealed that DFS was significantly improved for patients in the MO group treated with SLT compared to patients treated with RR/RFA (P = 0.017). Recurrence pattern was an independent prognostic factor for both OS [hazard ratio (HR) = 0.093, 95% confidence interval (CI): 0.026-0.337, P < 0.001] and DFS (HR = 0.318, 95% CI: 0.125-0.810, P = 0.016; HR = 3.334, 95% CI: 1.546-7.18, P = 0.002). CONCLUSIONS For patients with intrahepatic recurrent HCC, an MO recurrence pattern is associated with better long-term outcomes than the IM pattern. SLT is the preferred option for intrahepatic recurrent HCC, especially for MO cases.
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Affiliation(s)
- Xiaoyun Zhang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Guoxuexiang 37, Chengdu, 610041, Sichuan Province, China
| | - Chuan Li
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Guoxuexiang 37, Chengdu, 610041, Sichuan Province, China
| | - Tianfu Wen
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Guoxuexiang 37, Chengdu, 610041, Sichuan Province, China.
| | - Wei Peng
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Guoxuexiang 37, Chengdu, 610041, Sichuan Province, China
| | - Lunan Yan
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Guoxuexiang 37, Chengdu, 610041, Sichuan Province, China
| | - Jiayin Yang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Guoxuexiang 37, Chengdu, 610041, Sichuan Province, China
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27
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Chianchiano P, Pezhouh MK, Kim A, Luchini C, Cameron A, Weiss MJ, He J, Voltaggio L, Oshima K, Anders RA, Wood LD. Distinction of intrahepatic metastasis from multicentric carcinogenesis in multifocal hepatocellular carcinoma using molecular alterations. Hum Pathol 2018; 72:127-134. [PMID: 29180252 PMCID: PMC6435273 DOI: 10.1016/j.humpath.2017.11.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 11/10/2017] [Accepted: 11/15/2017] [Indexed: 02/07/2023]
Abstract
Patients with hepatocellular carcinoma (HCC) frequently have multiple anatomically distinct tumors. In these patients, multifocal HCC could represent intrahepatic metastases (IMs) of a single cancer or multicentric carcinogenesis (MC) with multiple independent neoplasms. To determine the frequency and clinical implications of these 2 possibilities, we performed histological and molecular analysis of 70 anatomically distinct HCCs from 24 patients. We assayed mutations in the TERT promoter region by Sanger sequencing and used next-generation sequencing to analyze the entire coding regions of 7 well-characterized HCC driver genes-based on shared or discordant mutations in these genes, we classified the HCCs in each patient as IM, MC, or indeterminate. Mutations in the TERT promoter were the most common alteration in our cohort, present in 71% of tumors analyzed. Mutations in the remaining genes occurred in less than 20% of analyzed tumors. We were able to determine the relatedness in 58% of the patients analyzed: MC occurred in 41% of patients, with 33% with exclusively MC and 8% with both MC and IM. IM occurred exclusively in 17% of patients, whereas the remainder were indeterminate. This study highlights the utility of molecular analyses to determine relatedness in multifocal HCC; however, targeted sequencing can only resolve this distinction in approximately 60% of patients with multifocal HCC.
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Affiliation(s)
- Peter Chianchiano
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Maryam Kherad Pezhouh
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Amy Kim
- Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona 37134, Italy
| | - Andrew Cameron
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21231
| | - Matthew J Weiss
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21231
| | - Jin He
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21231
| | - Lysandra Voltaggio
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Kiyoko Oshima
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Robert A Anders
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Laura D Wood
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
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28
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Sonohara F, Inokawa Y, Hayashi M, Yamada S, Sugimoto H, Fujii T, Kodera Y, Nomoto S. Prognostic Value of Long Non-Coding RNA HULC and MALAT1 Following the Curative Resection of Hepatocellular Carcinoma. Sci Rep 2017; 7:16142. [PMID: 29170515 PMCID: PMC5700934 DOI: 10.1038/s41598-017-16260-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 11/08/2017] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) were shown to be the crucial regulators of the many diseases. In this study, the expressions of lncRNAs were investigated in resected 158 hepatocellular carcinomas (HCCs) to evaluate the effects of their expression levels on prognosis. The expression levels of HULC and MALAT1 were shown to be significantly higher in the normal background tissue of HCC than those in the normal liver tissue of metastatic liver tumor without hepatitis (HULC: fold change 14.9, P = 1.7e-06; MALAT1: fold change 17.5, P = 1.2e-06. The formation of capsule was shown to be correlated with the increased expression of HULC (P = 0.041), while the size of HCC under 2 cm was correlated with a decrease in MALAT1 expression (P = 0.019). The levels of serum alpha-fetoprotein above 20 ng/mL indicated a decreased expression of both HULC and MALAT1 (HULC: P = 0.017; MALAT1: P = 0.0036). The increase in the expression levels of MALAT1 in HCC tissues was significantly correlated with better overall survival (HULC: P = 0.099, MALAT1: P = 0.028). Thus, the expression of these lncRNAs in HCC potentially correlates with the HCC malignancy and they represent potential prognostic biomarkers of the resected HCC.
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Affiliation(s)
- Fuminori Sonohara
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Department of Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Japan
| | - Yoshikuni Inokawa
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Department of Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroyuki Sugimoto
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shuji Nomoto
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan. .,Department of Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Japan.
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Yang SL, Luo YY, Chen M, Zhou YP, Lu FR, Deng DF, Wu YR. A systematic review and meta-analysis comparing the prognosis of multicentric occurrence and vs. intrahepatic metastasis in patients with recurrent hepatocellular carcinoma after hepatectomy. HPB (Oxford) 2017; 19:835-842. [PMID: 28734693 DOI: 10.1016/j.hpb.2017.06.002] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Revised: 06/02/2017] [Accepted: 06/07/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND The aim of this meta-analysis was to evaluate the prognosis of patients with different types of hepatocellular cancer (HCC) recurrence following hepatectomy. Specifically, it evaluated overall survival and disease-free survival in HCC patients with multicentric occurrence (MO) or intrahepatic metastasis (IM). METHODS Medline, Cochrane, EMBASE, and Google Scholar were searched until August 22, 2016 using the following search terms: hepatocellular carcinoma, multicentric occurrence, intrahepatic metastasis, early recurrence, and late recurrence. Prospective, retrospective, and case control studies were included. RESULTS The pooled results showed that patients in the MO group had lower risk of death than the IM group (pooled HR = 0.495, 95% CI = 0.378 to 0.648, P < 0.001). The MO group also had significantly longer disease-free survival than the IM group (pooled HR = 0.774, 95% CI = 0.663 to 0.903, P = 0.001). Sensitivity analysis indicated that no one study dominated the findings and that the data are robust. Overall the included studies were of good quality. CONCLUSION This study found that MO patients have greater survival following surgery than IM patients, indicating the prognosis of MO patients is significantly better than that for IM patients.
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Affiliation(s)
- Sheng-Lan Yang
- Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, PR China
| | - Ying-Ying Luo
- Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, PR China
| | - Min Chen
- Department of Geriatric, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, PR China.
| | - Yan-Ping Zhou
- Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, PR China
| | - Fu-Rong Lu
- Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, PR China
| | - Dan-Fang Deng
- Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, PR China
| | - Yan-Ran Wu
- Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, PR China
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Zhang X, Li C, Wen T, Peng W, Yan L, Yang J. Treatment for intrahepatic recurrence after curative resection of hepatocellular carcinoma: Salvage liver transplantation or re-resection/radiofrequency ablation? A Retrospective Cohort Study. Int J Surg 2017; 46:178-185. [PMID: 28890407 DOI: 10.1016/j.ijsu.2017.09.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Revised: 08/25/2017] [Accepted: 09/03/2017] [Indexed: 02/05/2023]
Abstract
OBJECTIVE The optimal treatment strategy for patients with recurrent hepatocellular carcinoma (HCC) remains unclear. This study was designed to investigate the outcomes of salvage liver transplantation (SLT) and re-resection (RR)/radiofrequency ablation (RFA) with respect to the time to recurrence after initial curative resection. METHODS Between 2007 and 2016, 756 patients underwent curative hepatectomy for HCC in accordance with the Milan criteria. Among them, 152 experienced an intrahepatic recurrence and underwent SLT (n = 36) and RR/RFA (n = 116). Clinical data, overall survival (OS), and disease-free survival (DFS) (including subgroup analyses) according to the time to recurrence were statistically compared between the 2 groups, and prognostic factors were identified. RESULTS The DFS of the patients who underwent SLT was much better than that of the patients who underwent RR/RFA (P = 0.002), particularly those with late recurrence (more than 12 months, P = 0.004). The time to recurrence from initial hepatectomy was found to be an independent predictor of OS and DFS. CONCLUSIONS SLT, rather than re-resection or RFA, should be the preferred treatment option for patients with late recurrence.
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Affiliation(s)
- Xiaoyun Zhang
- Department of Liver Surgery and Liver Transplantation Centre, West China Hospital of Sichuan University, Guoxuexiang 37, Chengdu 610041, Sichuan Province, China
| | - Chuan Li
- Department of Liver Surgery and Liver Transplantation Centre, West China Hospital of Sichuan University, Guoxuexiang 37, Chengdu 610041, Sichuan Province, China
| | - Tianfu Wen
- Department of Liver Surgery and Liver Transplantation Centre, West China Hospital of Sichuan University, Guoxuexiang 37, Chengdu 610041, Sichuan Province, China.
| | - Wei Peng
- Department of Liver Surgery and Liver Transplantation Centre, West China Hospital of Sichuan University, Guoxuexiang 37, Chengdu 610041, Sichuan Province, China
| | - Lunan Yan
- Department of Liver Surgery and Liver Transplantation Centre, West China Hospital of Sichuan University, Guoxuexiang 37, Chengdu 610041, Sichuan Province, China
| | - Jiayin Yang
- Department of Liver Surgery and Liver Transplantation Centre, West China Hospital of Sichuan University, Guoxuexiang 37, Chengdu 610041, Sichuan Province, China
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Liu T, Kan XF, Ma C, Chen LL, Cheng TT, Zou ZW, Li Y, Cao FJ, Zhang WJ, Yao J, Li PD. GPX2 overexpression indicates poor prognosis in patients with hepatocellular carcinoma. Tumour Biol 2017. [PMID: 28635398 DOI: 10.1177/1010428317700410] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Glutathione peroxidase 2 has important role of tumor progression in lots of carcinomas, yet little is known about the prognosis of glutathione peroxidase 2 in hepatocellular carcinoma. Glutathione peroxidase 2 expression was assessed by immunohistochemistry in hepatocellular carcinoma tissues. The association between glutathione peroxidase 2 expression with clinicopathological/prognostic value was examined. Glutathione peroxidase 2 overexpression was correlated with alpha-fetoprotein level, larger tumor, BCLC stage, and tumor recurrence. Kaplan-Meier analysis showed that glutathione peroxidase 2 was an independent predictor for overall survival and time to recurrence. glutathione peroxidase 2 overexpression was correlated with poor prognosis in patient subgroups stratified by tumor size, differentiation, tumor-node-metastasis, and BCLC stage. Moreover, stratified analysis showed that tumor-node-metastasis stage-I patients with high glutathione peroxidase 2 expression had poor prognosis than those with low glutathione peroxidase 2 expression. Additionally, combination of glutathione peroxidase 2 and serum alpha-fetoprotein was correlated with prognosis in hepatocellular carcinoma. In conclusion, glutathione peroxidase 2 overexpression contributes to poor prognosis of hepatocellular carcinoma patients and helps to identify the high-risk hepatocellular carcinoma patients.
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Affiliation(s)
- Ting Liu
- 1 Department of Infectious Diseases, Institute of Infection and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xue-Feng Kan
- 2 Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Charlie Ma
- 3 The Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Li-Li Chen
- 3 The Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Tian-Tian Cheng
- 4 Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Zhen-Wei Zou
- 5 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Li
- 6 Cancer Center, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Feng-Jun Cao
- 6 Cancer Center, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Wen-Jie Zhang
- 7 Department of Pathology, Shihezi University School of Medicine, Shihezi, China
| | - Jing Yao
- 5 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Pin-Dong Li
- 5 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Lee EC, Kim SH, Park H, Lee SD, Lee SA, Park SJ. Survival analysis after liver resection for hepatocellular carcinoma: A consecutive cohort of 1002 patients. J Gastroenterol Hepatol 2017; 32:1055-1063. [PMID: 27797420 DOI: 10.1111/jgh.13632] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 10/06/2016] [Accepted: 10/22/2016] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND AIM The improvements in surgical technique and perioperative management in the recent decades may warrant revisit for survival outcomes and prognostic factors after liver resection for hepatocellular carcinoma (HCC). This study aimed to analyze the survival outcomes after liver resection for HCC for a consecutive cohort of 1002 patients. METHODS This study was performed by analyzing the clinicopathological and follow-up data of 1002 consecutive patients who underwent liver resection for HCC from April 2001 to December 2013. Prognostic factors were investigated by univariate and multivariate analysis, using the Cox's proportional hazards model. RESULTS The overall incidence of postoperative complications was 16.1% (n = 161), with an in-hospital mortality rate of 0.3% (n = 3). The rates of 1-, 3-, and 5-year overall survival were 91.9%, 78.9%, and 69.5%, while the rates of 1-, 3-, and 5-year recurrence-free survival were 71.7%, 51.7%, and 43.7%, respectively. Multivariate analysis showed that patient age, platelet count, intraoperative estimated blood loss (EBL), tumor number, Edmond-Steiner grade, microvascular invasion, major vessel invasion, and intrahepatic metastasis were independent significant prognostic factors affecting the overall survival. Platelet count, intraoperative EBL, maximal tumor size, major vessel invasion, capsule formation, intrahepatic metastasis, cirrhosis, and the pathological stage were independent prognostic factors for recurrence-free survival. CONCLUSIONS Survival of patients with HCC after resection should be stratified by various perioperative clinicopathological factors. Platelet count and intraoperative EBL could be considered as one of the powerful predictors of the prognosis and recurrence of HCC in such patients.
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Affiliation(s)
- Eung Chang Lee
- Center for Liver Cancer, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Seong Hoon Kim
- Center for Liver Cancer, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Hyeongmin Park
- Center for Liver Cancer, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Seung Duk Lee
- Center for Liver Cancer, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Soon-Ae Lee
- Center for Liver Cancer, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Sang-Jae Park
- Center for Liver Cancer, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
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Whole genome sequencing discriminates hepatocellular carcinoma with intrahepatic metastasis from multi-centric tumors. J Hepatol 2017; 66:363-373. [PMID: 27742377 DOI: 10.1016/j.jhep.2016.09.021] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 09/01/2016] [Accepted: 09/21/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Patients with hepatocellular carcinoma (HCC) have a high-risk of multi-centric (MC) tumor occurrence due to a strong carcinogenic background in the liver. In addition, they have a high risk of intrahepatic metastasis (IM). Liver tumors withIM or MC are profoundly different in their development and clinical outcome. However, clinically or pathologically discriminating between IM and MC can be challenging. This study investigated whether IM or MC could be diagnosed at the molecular level. METHODS We performed whole genome and RNA sequencing analyses of 49 tumors including two extra-hepatic metastases, and one nodule-in-nodule tumor from 23 HCC patients. RESULTS Sequencing-based molecular diagnosis using somatic single nucleotide variation information showed higher sensitivity compared to previous techniques due to the inclusion of a larger number of mutation events. This proved useful in cases, which showed inconsistent clinical diagnoses. In addition, whole genome sequencing offered advantages in profiling of other genetic alterations, such as structural variations, copy number alterations, and variant allele frequencies, and helped to confirm the IM/MCdiagnosis. Divergent alterations between IM tumors with sorafenib treatment, long time-intervals, or tumor-in-tumor nodules indicated high intra-tumor heterogeneity, evolution, and clonal switching of liver cancers. CONCLUSIONS It is important to analyze the differences between IM tumors, in addition to IM/MC diagnosis, before selecting a therapeutic strategy for multiple tumors in the liver. LAY SUMMARY Whole genome sequencing of multiple liver tumors enabled the accuratediagnosis ofmulti-centric occurrence and intrahepatic metastasis using somatic single nucleotide variation information. In addition, genetic discrepancies between tumors help us to understand the physical changes during recurrence and cancer spread.
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Genetic profiling of hepatocellular carcinoma using next-generation sequencing. J Hepatol 2016; 65:1031-1042. [PMID: 27262756 DOI: 10.1016/j.jhep.2016.05.035] [Citation(s) in RCA: 214] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 04/05/2016] [Accepted: 05/25/2016] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, both clinically and from a molecular standpoint. The advent of next-generation sequencing technologies has provided new opportunities to extensively analyze molecular defects in HCC samples. This has uncovered major cancer driver genes and associated oncogenic pathways operating in HCC. More sophisticated analyses of sequencing data have linked specific nucleotide patterns to external toxic agents and defined so-called 'mutational signatures' in HCC. Molecular signatures, taking into account intra- and inter-tumor heterogeneity, and their functional validation could provide useful data to predict treatment response to molecular therapies. In this review we will focus on the current knowledge of deep sequencing in HCC and its foreseeable clinical impact.
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35
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Sonohara F, Inokawa Y, Hishida M, Kanda M, Nishikawa Y, Yamada S, Fujii T, Sugimoto H, Kodera Y, Nomoto S. Prognostic significance of AKR1B10 gene expression in hepatocellular carcinoma and surrounding non-tumorous liver tissue. Oncol Lett 2016; 12:4821-4828. [PMID: 28105190 DOI: 10.3892/ol.2016.5240] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 09/30/2016] [Indexed: 02/06/2023] Open
Abstract
When assessing outcome in hepatocellular carcinoma (HCC), it is important to consider prognostic factors in background non-tumorous liver tissue as well as in the tumor, since multiple occurrence is associated with background liver status such as hepatitis. The current study aimed to elucidate molecular prognostic predictors that have an association with HCC background non-tumorous tissue. Microarray expression profiling identified aldo-keto reductase family 1, member B10 (AKR1B10) as a putative non-tumorous prognostic factor, and AKR1B10 gene expression was investigated in 158 curatively resected HCC cases by reverse transcription-quantitative polymerase chain reaction. AKR1B10 expression (AKR1B10 value/GAPDH value × 1,000) was significantly higher in tumor tissue (median, 9.2200; range, 0.0003-611.0200; n=158) than in the corresponding non-tumorous tissue (median, 0.5461; range, 0.0018-69.0300; n=158) (P<0.001). When the samples were grouped according to AKR1B10 expression in tumor tissue relative to non-tumorous tissue, tumor<non-tumorous expression (n=26) significantly correlated with poor recurrence-free survival (P=0.0074) and overall survival (OS) (P<0.0001), and was an independent prognostic factor for OS (P=0.0011) in a multivariate analysis. The ratio of AKR1B10 messenger RNA levels in HCC and corresponding non-tumorous tissues may predict prognosis after curative hepatectomy, with low expression in HCC tissue relative to non-tumorous tissue indicative of poor prognosis.
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Affiliation(s)
- Fuminori Sonohara
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan; Department of Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi 464-8651, Japan
| | - Yoshikuni Inokawa
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan; Department of Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi 464-8651, Japan
| | - Mitsuhiro Hishida
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Yoko Nishikawa
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Hiroyuki Sugimoto
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Shuji Nomoto
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan; Department of Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi 464-8651, Japan
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Wang JH, Wei W, Xu J, Guo ZX, Xiao CZ, Zhang YF, Jian PE, Wu XL, Shi M, Guo RP. Elevated expression of Cripto-1 correlates with poor prognosis in hepatocellular carcinoma. Oncotarget 2016; 6:35116-28. [PMID: 26375669 PMCID: PMC4741514 DOI: 10.18632/oncotarget.5057] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Accepted: 08/24/2015] [Indexed: 01/06/2023] Open
Abstract
Cripto-1 could promote tumorigenesis in a wide range of carcinomas, yet little is known in hepatocellular carcinoma (HCC). The expression of Cripto-1 and MMP-9 were assessed by immunohistochemistry in 205 HCC specimens. The correlation between Cripto-1 and MMP-9, clinicopathological/prognostic value in HCC was examined. Cripto-1 overexpression was correlated with larger tumor, TNM stage, BCLC stage and tumor recurrence. In multivariate analyses, Cripto-1 was an independent predictor for overall survival (OS) and time to recurrence (TTR). Cripto-1 expression was increased in TNM and BCLC stage-dependent manner. Cripto-1 overexpression was associated with poor prognosis in patients subgroups stratified by tumor size, tumor differentiation, TNM and BCLC stage. In addition, Cripto-1 was positively correlated with MMP-9 among 205 HCC samples. Patients with Cripto-1 upregulation had poor OS and shorter TTR in low and high aggressiveness groups. Furthermore, Cripto-1 had predictive validity for early and late recurrence in HCC patients. Combination of Cripto-1 and serum AFP was correlated with OS and TTR. In conclusion, Cripto-1 overexpression contributes to aggressiveness and poor prognosis of HCC. Cripto-1/AFP expression could be a potential prognostic biomarker for survival in HCC patients.
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Affiliation(s)
- Jia-Hong Wang
- Department of Hepatobilliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Wei Wei
- Department of Hepatobilliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jing Xu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zhi-Xing Guo
- Department of Ultrasonics, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Cheng-Zuo Xiao
- Department of Hepatobilliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yong-Fa Zhang
- Department of Hepatobilliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Pei-En Jian
- Department of Hepatobilliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xiao-Liang Wu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Ming Shi
- Department of Hepatobilliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Rong-Ping Guo
- Department of Hepatobilliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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Zhao Q, Yu WL, Lu XY, Dong H, Gu YJ, Sheng X, Cong WM, Wu MC. Combined hepatocellular and cholangiocarcinoma originating from the same clone: a pathomolecular evidence-based study. CHINESE JOURNAL OF CANCER 2016; 35:82. [PMID: 27552844 PMCID: PMC4995671 DOI: 10.1186/s40880-016-0146-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 08/05/2016] [Indexed: 12/30/2022]
Abstract
Background Combined hepatocellular and cholangiocarcinoma (CHC) is a unique subtype of liver cancer comprising both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC); however, its cellular origin remains unclear. The purpose of this study was to investigate the clinicopathologic features and the clonal relationship between HCC and ICC in 34 patients with CHC. Methods The clinicopathologic features and prognosis of the 34 CHC patients were compared with those of 29 patients with separated HCC and ICC (SHC). Loss of heterozygosity (LOH) at 10 highly polymorphic microsatellite markers was detected in 16 CHC and 10 SHC tissues for determination of the clonal origin of CHC. Expression of hepatocyte markers [hepatocyte paraffin 1 (Hep Par 1) and glypican 3 (GPC3)] and cholangiocyte markers [cytokeratin (CK)7 and 19] in tumor tissues was examined by immuno histochemical analysis. Results In the 16 CHC specimens, the difference in LOH patterns between HCC and ICC was less than 30%, suggesting the same clonal origin of HCC and ICC. Consistent with this finding, immunohistochemical analysis revealed that hepatocyte markers (Hep Par 1 and GPC3) and cholangiocyte markers (CK7 and CK19) were simultaneously expressed in both the HCC and ICC components in 52.9% of CHC specimens, suggesting that the two components shared a similar phenotype with hepatic progenitor cells (HPCs). On the contrary, in all 10 SHC cases, the difference in LOH patterns between the HCC and ICC components was greater than 30%, suggesting different clonal origins of HCC and ICC. Overall survival and disease-free survival were shorter for patients with CHC than for patients with SHC (P < 0.05). Conclusions Our results suggest that the HCC and ICC components of CHC may originate from the same clone, having the potential for dual-directional differentiation similar to HPCs. CHC tended to exhibit the biological behaviors of both HCC and ICC, which may enhance the infiltrative capacity of tumor cells, leading to poor clinical outcomes for patients with CHC.
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Affiliation(s)
- Qian Zhao
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, P. R. China
| | - Wen-Long Yu
- Department of Biliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, P. R. China
| | - Xin-Yuan Lu
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, P. R. China
| | - Hui Dong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, P. R. China
| | - Yi-Jin Gu
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, P. R. China
| | - Xia Sheng
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, P. R. China
| | - Wen-Ming Cong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, P. R. China.
| | - Meng-Chao Wu
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, P. R. China
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Lee PC, Yeh CM, Hu YW, Chen CC, Liu CJ, Su CW, Huo TI, Huang YH, Chao Y, Chen TJ, Lin HC, Wu JC. Antiplatelet Therapy is Associated with a Better Prognosis for Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma after Liver Resection. Ann Surg Oncol 2016; 23:874-883. [PMID: 27541812 DOI: 10.1245/s10434-016-5520-9] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Recurrence of hepatocellular carcinoma (HCC) with unsatisfactory survival is common after surgical resection. Antiplatelet therapy with aspirin or clopidogrel was recently shown to prevent hepatic carcinogenesis in a murine model, but its effect in humans had not been clarified. This study aimed to investigate the association between antiplatelet therapy and the outcomes for patients with hepatitis B virus (HBV)-related HCC after liver resection. METHODS By analyzing data from the Taiwan National Health Insurance Research Database, 9461 HBV-related HCC patients who had undergone liver resection between January 1997 and December 2011 were identified. After one-to-four matching by sex, age, and propensity score, 442 patients with antiplatelet therapy and 1768 patients without antiplatelet therapy were enrolled for the analysis. The Kaplan-Meier method and modified Cox proportional hazards models were used for survival and multivariable, stratified analyses. RESULTS Recurrence-free survival and overall survival after resection surgery were significantly better after 5 years in the treated cohort than in the untreated cohort (52.8 vs 47.9 %; p = 0.021 and 80.3 vs 65.4 %; p < 0.001, respectively). Besides, antiplatelet therapy reduced the risk of HCC recurrence (hazard ratio [HR] 0.73; p < 0.001) and overall mortality (HR 0.57; p < 0.001) in the multivariable analysis. However, antiplatelet use significantly increased the risk of upper gastrointestinal bleeding (odds ratio [OR] 1.91; p < 0.001). CONCLUSIONS Use of aspirin or clopidogrel was associated with better recurrence-free survival and overall survival among patients with HBV-related HCC after liver resection. However, these agents should be used with caution due to the adverse effects of upper gastrointestinal bleeding.
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Affiliation(s)
- Pei-Chang Lee
- Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Yuanshan Branch, Taipei Veterans General Hospital, Yilan, Taiwan
| | - Chiu-Mei Yeh
- Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yu-Wen Hu
- Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.,Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan.,Institute of Public Health, National Yang-Ming University, Taipei, Taiwan
| | - Chun-Chia Chen
- Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chia-Jen Liu
- Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan. .,Institute of Public Health, National Yang-Ming University, Taipei, Taiwan. .,Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
| | - Chien-Wei Su
- Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan. .,Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
| | - Teh-Ia Huo
- Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.,Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Yee Chao
- Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.,Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Tzeng-Ji Chen
- Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.,Institute of Hospital and Health Care Administration, National Yang-Ming University, Taipei, Taiwan
| | - Han-Chieh Lin
- Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jaw-Ching Wu
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
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Lu LC, Hsu CH, Hsu C, Cheng AL. Tumor Heterogeneity in Hepatocellular Carcinoma: Facing the Challenges. Liver Cancer 2016; 5:128-38. [PMID: 27386431 PMCID: PMC4906428 DOI: 10.1159/000367754] [Citation(s) in RCA: 106] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Tumor heterogeneity in hepatocellular carcinoma (HCC), such as that found in second primary tumors after curative treatment, synchronous multifocal tumors of different clonality, or intratumor heterogeneity, poses severe challenges for the development and administration of systemic molecular targeted therapies. Various methodologies, including historical DNA ploidy analysis, integrated hepatitis B virus DNA analysis, DNA fingerprinting, and next-generation sequencing technologies, are used to explore tumor heterogeneity in HCC. It is estimated that 30%-60% of recurrent or metastatic tumors harbor clones different from the primary tumor, 22%-79% of synchronous tumors vary clonally, and 12%-66% of single tumors contain intratumor heterogeneity. Substantial intertumor and intratumor heterogeneity renders biomarker identification, which is critical for the development and administration of molecular targeted therapy, challenging when applied to a single tumor biopsy specimen. The use of circulating tumor cells or circulating tumor DNA to evaluate overall tumor heterogeneity may help resolve this problem. This article reviews previous studies of tumor heterogeneity and discusses the implications and future opportunities regarding tumor heterogeneity in HCC.
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Affiliation(s)
- Li-Chun Lu
- Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan (ROC),Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan (ROC)
| | - Chih-Hung Hsu
- Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan (ROC),Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan (ROC)
| | - Chiun Hsu
- Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan (ROC),Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan (ROC)
| | - Ann-Lii Cheng
- Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan (ROC),Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan (ROC),Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan (ROC),*Ann-Lii Cheng, MD, PhD, Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 10002, Taiwan (ROC), Tel. +886 2 2312 3456 ext. 67251, E-Mail
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Abstract
The nuances of determining resectability for liver tumors can be difficult to navigate, owing to the variety of primary and secondary malignancies involving the liver, the range of patient-specific factors to consider, and the hepatic anatomic and functional variability that seems inevitable. The basic principles, however, are simple;if surgery is deemed appropriate from an oncologic standpoint, the patient is in reasonably good health, and the tumor can be safely removed without compromising the integrity of the future remnant, nearly all patients will be candidates for resection.
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Affiliation(s)
- Cecilia G Ethun
- Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, 1365C Clifton Road NE, Building C, 2nd Floor, Atlanta, GA 30322, USA
| | - Shishir K Maithel
- Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, 1365C Clifton Road NE, Building C, 2nd Floor, Atlanta, GA 30322, USA.
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41
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Pretransplant serum levels of C-reactive protein predict prognoses in patients undergoing liver transplantation for hepatocellular carcinoma. Transplant Proc 2015; 47:686-93. [PMID: 25891712 DOI: 10.1016/j.transproceed.2014.11.048] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Revised: 11/12/2014] [Accepted: 11/25/2014] [Indexed: 12/28/2022]
Abstract
BACKGROUND Preoperative absolute C-reactive protein (CRP) has been shown to correlate with prognoses in various malignancies, including hepatocellular carcinoma (HCC). METHODS The aim of this study was to investigate whether pretransplant CRP levels predict prognoses in patients undergoing liver transplantation (LT) for HCC. We retrospectively analyzed clinicopathological factors in 211 patients with available pretransplant serum CRP levels who underwent LT for HCC between January 2005 and April 2012. RESULTS By means of receiver operating characteristic curve analysis, a CRP level of >0.3 mg/dL was considered to be elevated. By multivariate analysis, the high CRP level, the maximal tumor size >5 cm, the presence of intrahepatic metastasis, and positive findings in pretransplant (18)fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) were related to tumor recurrence, whereas the high CRP level, the presence of intrahepatic metastasis, and positive findings in pretransplant (18)F-FDG PET/CT were related to poor overall survival. When subgroup analysis was conducted according to the Milan criteria, the high CRP level was an independent factor for predicting poor outcomes in patients with HCC beyond the Milan criteria (P = .001 for recurrence-free survival and P = .010 for overall survival), and not for patients within the criteria. CONCLUSIONS Pretransplant serum CRP levels can predict prognoses in patients undergoing LT for HCC, especially in patients with HCC exceeding the Milan criteria.
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Liu HP, Zhao Q, Jin GZ, Qian YW, Gu YJ, Dong H, Lu XY, Cong WM, Wu MC. Unique genetic alterations and clinicopathological features of hepatocellular adenoma in Chinese population. Pathol Res Pract 2015; 211:918-24. [DOI: 10.1016/j.prp.2015.09.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Accepted: 09/02/2015] [Indexed: 01/09/2023]
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43
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Liu G, Wang K, Li J, Xia Y, Lu L, Wan X, Yan Z, Shi L, Lau WY, Wu M, Shen F. Changes in serum alpha fetoprotein in patients with recurrent hepatocellular carcinoma following hepatectomy. J Gastroenterol Hepatol 2015; 30:1405-1411. [PMID: 25801981 DOI: 10.1111/jgh.12953] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/11/2015] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIM To study the change in serum alpha fetoprotein (AFP) of patients with recurrent hepatocellular carcinoma (HCC) after curative resection and to analyze its effect on the survival. METHODS We prospectively collected 981 consecutive patients with post-resectional recurrent HCC between 2005 and 2010 at the Eastern Hepatobiliary Surgery Hospital. According to the change of AFP from the initial stage to recurrent stage, the patients were divided into stable-L (20 ng/mL to 20 ng/mL, n = 296), stable-M (20-400 ng/mL to 20-400 ng/mL, n = 102), stable-H (400 ng/mL to 400 ng/mL, n = 212), decreasing (n = 287), and increasing (n = 84) groups. The overall survival (OS) and recurrence to death survival (RTDS) were analyzed using Kaplan-Meier method. Multivariate analysis was performed by Cox proportional hazards regression. RESULTS The stable-H/increasing and stable-L/decreasing groups had the lowest and highest 5-year OS and RTDS rates (10.8%/18.8% vs 56.3%/55.0%; 3.4%/5.1% vs 37.7%/33.2%; both P < 0.001), while the stable-M group had the lower rates, which were 29.8% and 23.6% (for OS and RTDS: vs stable-L, P < 0.001 and 0.002; vs deceasing, P = 0.001 and 0.012; vs increasing, P = 0.113 and 0.011; vs stable-H, both P < 0.001). Cox regression analysis showed that AFP inconsistency was an independent factor affecting RTDS (decreasing vs stable-L, hazard ratio: 1.10, 95% confidence interval: 0.79-1.54, P = 0.575; increasing vs stable-L, 2.93, 2.06-4.16, P < 0.001). CONCLUSIONS The AFP inconsistency was an important prognostic factor for recurrent HCC.
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Affiliation(s)
- Guanghua Liu
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
- Department of Interventional Radiology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Kui Wang
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jun Li
- Department of Clinical Database, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yong Xia
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Lihua Lu
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xuying Wan
- Department of Clinical Database, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zhenlin Yan
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Lehua Shi
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wan Yee Lau
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
- Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Mengchao Wu
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Feng Shen
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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Pineda-Solis K, McAlister V. Wading through the noise of "multi-omics" to identify prognostic biomarkers in hepatocellular carcinoma. Hepatobiliary Surg Nutr 2015; 4:293-4. [PMID: 26312246 DOI: 10.3978/j.issn.2304-3881.2015.04.05] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 03/23/2015] [Indexed: 12/27/2022]
Abstract
Multi-omics, the molecular analysis of genes, transcriptional RNA and proteins, allows researchers document the mechanism of action of a target gene. However multi-omics may result in an avalanche of information when used to screen a population. It is very difficult to discern a pattern or signal related to a disease or its progression. Differential multi-omics exploits our ability to see differences between subjects who are similar in all respects except for the outcome being tested. Twin studies are an example of this. Miao and colleagues compared two patients who had diverse outcomes following treatment of multi-focal hepatocellular carcinoma (HCC) to identify seven candidates as the responsible genes. In a larger cohort of patients with HCC they narrowed the field down to a single target down. By looking at progression of HCC, they isolated TTK, a protein kinase which disrupts the interaction of the tumour suppressor p53 with the oncogene MDM2. TTK-high tumours recurred 3 times faster than TTK-low tumours.
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Affiliation(s)
- Karen Pineda-Solis
- Department of Surgery, University of Western Ontario, London, ON, Canada
| | - Vivian McAlister
- Department of Surgery, University of Western Ontario, London, ON, Canada
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ITPKA expression is a novel prognostic factor in hepatocellular carcinoma. Diagn Pathol 2015; 10:136. [PMID: 26249031 PMCID: PMC4528344 DOI: 10.1186/s13000-015-0374-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2015] [Accepted: 07/29/2015] [Indexed: 12/15/2022] Open
Abstract
Background Inositol-1,4,5-trisphosphate-3-kinase-A (ITPKA) has recently been found to be implicated in the tumor progression of various cancers. However, the expression and the prognostic value of ITPKA in hepatocellular carcinoma (HCC) remains unexplored. The aim of this study is to investigate the clinical significance of ITPKA expression in HCC. Methods We determined the expression level of ITPKA in 135 cases of HCC tissues and the matched adjacent nontumorous tissues by quantitative real-time RT-PCR. The correlation between ITPKA expression and prognosis of HCC patients was further evaluated by univariate and multivariate analysis. Multivariate analysis of the prognostic factors was performed with Cox proportional hazards model. Results Up-regulation of ITPKA occurred in 48.9 % of primary HCCs compared with their nontumor counterparts (P < 0.001). In addition, high expression of ITPKA was significantly associated with vascular invasion (P = 0.001) and TNM stage (P = 0.005). Kaplan–Meier analysis showed that the 5-year overall survival (OS) and relapse-free survival (RFS) rate in the group with high expression of ITPKA is poorer than that in low expression group (32.2 and 26.8 % versus 59.2 and 57.7 %). Univariate and multivariate analyses revealed that ITPKA was an independent prognostic factor for OS and RFS. Moreover, Stratified analysis revealed that its prognostic significance still existed within the subgroup of patients with early clinical stage (TNM stage I) or normal serum AFP level (≤25 μg/L). Conclusion Our data indicated that ITPKA expression was significantly up-regulated in HCC and could serve as a potential novel prognostic biomarker for HCC patients after surgery.
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46
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Baffy G. Decoding multifocal hepatocellular carcinoma: an opportune pursuit. Hepatobiliary Surg Nutr 2015; 4:206-10. [PMID: 26151061 DOI: 10.3978/j.issn.2304-3881.2014.12.05] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 12/03/2014] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with major worldwide prevalence and a poor overall prognosis. About 75% of all HCC cases are initially diagnosed as multiple tumors, presenting a particular challenge for aggressive surgical therapy. Multiple HCC may result from multicentric occurrence (MO-HCC) or intrahepatic metastases (IM-HCC), corresponding to highly dissimilar clinical outcomes. Reliable distinction of these two mechanisms is therefore paramount in optimizing the management of multiple HCC. In a recent work, Miao et al. adopted a multi-omics approach to find key parameters of different clonality in MO-HCC vs. IM-HCC and link these data to tumor behavior and prognosis in a cohort of patients with HBV-related HCC. The mitotic checkpoint regulator TTK has emerged from this analysis as a novel biomarker that may predict aggressive behavior and early postoperative recurrence of HCC.
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Affiliation(s)
- György Baffy
- Department of Medicine, VA Boston Healthcare System and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02130, USA
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47
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Hepatectomy Versus Hepatectomy With Lymphadenectomy in Hepatocellular Carcinoma: A Prospective, Randomized Controlled Clinical Trial. J Clin Gastroenterol 2015; 49:520-8. [PMID: 25564411 DOI: 10.1097/mcg.0000000000000277] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
GOALS AND BACKGROUND The role of preventive lymphadenectomy has not yet been determined for hepatocellular carcinoma (HCC) patients. We designed a study to evaluate the effect of hepatectomy combined with preventive lymphadenectomy on HCC patients. STUDY Patients were randomly divided into group A (treated with hepatectomy alone) and group B (underwent hepatectomy combined with lymphadenectomy). The postoperative complications and oncologic prognoses were analyzed. RESULTS Of the 85 patients enrolled into this study, 79 cases (38 in group A and 41 in group B) were pathologically confirmed to have HCC and received curative resection. One hundred and sixteen lymph nodes were dissected and evaluated as negative by the pathologist. The 12-, 36-, and 60-month disease-free survival rates of group A were 81.6%, 68.4%, and 63.2%, respectively, whereas they were 78.0%, 65.9%, and 63.4%, respectively, for group B. The 12-, 36-, and 60-month overall survival rates in group A were 94.7%, 78.9%, and 65.8%, respectively, whereas they were 87.8%, 78.0%, and 70.7%, respectively, in group B. The differences in the disease-free survival and overall survival between the 2 groups were not statistically significant according to the log-rank test (P=0.811 and P=0.881, respectively). The difference in the surgical complication rate between groups A and B was not statistically significant (47.4% vs. 36.6%, P=0.332). CONCLUSIONS Although hepatectomy combined with regional lymphadenectomy is a safe procedure, preventive lymphadenectomy may not decrease the rate of tumor recurrence nor improve the prognosis in early-stage HCC patients.
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Fitzmorris P, Shoreibah M, Anand BS, Singal AK. Management of hepatocellular carcinoma. J Cancer Res Clin Oncol 2015; 141:861-876. [PMID: 25158999 DOI: 10.1007/s00432-014-1806-0] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Accepted: 08/08/2014] [Indexed: 02/07/2023]
Abstract
PURPOSE Hepatocellular carcinoma (HCC), a common cause for cancer-related death, is increasing worldwide. Over the past decade, survival and quality of life of HCC patients have significantly improved due to better prevention strategies, early diagnosis, and improved treatment options. We performed this narrative review to synthesize current status on the HCC management. METHODS Literature search for publications especially over the last decade, which has changed the paradigm on the management of HCC. RESULTS Hepatitis B vaccination and treatment of chronic hepatitis B and C are important measures for HCC prevention. Screening and surveillance for HCC using ultrasonogram and alpha-fetoprotein estimation are directed toward cirrhotics and hepatitis B patients at high risk of HCC. If detected at an early stage, curative treatments for HCC can be used such as tumor resection, ablation and liver transplantation. HCC patients without curative options are managed by loco-regional therapies and systemic chemotherapy. Loco-regional treatments include trans-arterial chemoembolization, radioembolization and combinations of loco-regional plus systemic therapies. Currently, sorafenib is the only FDA-approved systemic therapy and newer better chemotherapeutic agents are being investigated. Palliative care for terminally ill patients with metastatic disease and/or poor functional status focusses on comfort care and symptom control. CONCLUSIONS In spite of significant advancement in HCC management, its incidence continues to rise. There remains an urgent need to continue refining understanding of HCC and develop strategies to increase utilization of the available preventive measures and curative treatment modalities for HCC.
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MESH Headings
- Antineoplastic Agents/therapeutic use
- Antiviral Agents/therapeutic use
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/prevention & control
- Carcinoma, Hepatocellular/virology
- Disease Management
- Hepatitis B/complications
- Hepatitis C/complications
- Hepatitis, Viral, Human/complications
- Hepatitis, Viral, Human/drug therapy
- Hepatitis, Viral, Human/prevention & control
- Humans
- Incidence
- Liver Neoplasms/drug therapy
- Liver Neoplasms/epidemiology
- Liver Neoplasms/prevention & control
- Liver Neoplasms/virology
- Mass Screening/methods
- Niacinamide/analogs & derivatives
- Niacinamide/therapeutic use
- Palliative Care/methods
- Phenylurea Compounds/therapeutic use
- Population Surveillance/methods
- Quality of Life
- Sorafenib
- Viral Hepatitis Vaccines/administration & dosage
- alpha-Fetoproteins/metabolism
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Affiliation(s)
- P Fitzmorris
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
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49
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Hsu YC, Wu CY, Lin JT. Hepatitis C Virus Infection, Antiviral Therapy, and Risk of Hepatocellular Carcinoma. Semin Oncol 2015; 42:329-38. [PMID: 25843737 DOI: 10.1053/j.seminoncol.2014.12.023] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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50
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Feo F, Pascale RM. Multifocal hepatocellular carcinoma: intrahepatic metastasis or multicentric carcinogenesis? ANNALS OF TRANSLATIONAL MEDICINE 2015; 3:4. [PMID: 25705636 DOI: 10.3978/j.issn.2305-5839.2014.12.08] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 12/08/2014] [Indexed: 12/28/2022]
Abstract
Multifocal Hepatocellular carcinoma (HCC) may be multiple HCCs of multicentric origin (MO) or intrahepatic metastases (IM) arising from a primary HCC. Numerous attempts to differentiate the two types of multifocal HCC have been made including the valuation of the clinicopathologic characteristics of MO and IM patients and the recurrence time, loss-of-heterozygosity analysis of specific DNA microsatellite loci to distinguish multiclonal MO from IM of monoclonal origin, and the research of diagnostic and progression markers through genomic and proteomic analyses. These approaches, however, have been unsatisfactory hitherto. Recently, a multi-omic analysis of HBV-related multifocal HCCs, including intergraded genomics and transcriptomics, was performed and the results, validated by a cohort of 174 HCC patients, were correlated with HCC clinicopathological data. The two multifocal HCC types were effectively discerned by multi-omics profiling that could predict HCC clonality and aggressiveness. Further, the dual-specificity protein kinase TTK was recognized as a prognostic marker for HCC. Multi-omics strategy potentially opens new perspectives for the diagnosis, prognosis and personalized treatment of multi-focal HCC. Further work aimed at extending this strategy to HCC with other etiology, simplifying the analysis, and reducing its costs is necessary for its routine clinical application.
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Affiliation(s)
- Francesco Feo
- Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy
| | - Rosa M Pascale
- Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy
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