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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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Xie B, Xie Y, Fang C, Zhong B, Ye R, Zhang J, Liu Q, Li H. Elevated FAM134B expression induces radiation-sensitive in hepatocellular carcinoma. BMC Cancer 2023; 23:671. [PMID: 37460952 PMCID: PMC10353116 DOI: 10.1186/s12885-023-11030-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 05/30/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND Previous studies have shown that Family with sequence similarity 134 member B (FAM134B) was involved in the occurrence and development of malignancy, however, the function and molecular mechanism of FAM134B in Hepatocellular Carcinoma (HCC) radiotherapy resistance remain unclear. Therefore, it may clinical effective to clarify the molecular mechanism and identify novel biomarker to overcome radiotherapy resistance in HCC. METHODS The protein and mRNA expression of FAM134B were determined using Real-time PCR and Western blot, respectively. IHC assay was performed to investigate the association between FAM134B expression and the clinicopathological characteristics of 132 HCC patients. Functional assays, such as in situ model, colon formation, FACS, and Tunel assay were used to determine the oncogenic role of FAM134B in human HCC progression. Furthermore, western blotting and luciferase assay were used to determine the mechanism of FAM134B promotes radiation-sensitive in HCC cells. RESULTS We noted that FAM134B was downregulated in HCC, which was correlated with the radiation resistance in patients with HCC. Overexpression of FAM134B contribute to radiation sensitive in HCC; however, inhibition of FAM134B confers HCC cell lines to radiation resistance both in vitro and in vivo. Moreover, we found that FAM134B interacts with FMS related receptor tyrosine kinase 3 (FLT3) and downregulation of FAM134B activated JAK/Stat3 signaling pathway. Importantly, pharmacological inhibition of JAK/Stat3 signaling pathway significantly counteracted downregulation of FAM134B-induced radiation resistance and enhanced radiation therapeutic efficacy in HCC. CONCLUSIONS Our findings suggest that FAM134B may be a potential therapeutic biomarker for the treatment of HCC patients with radiotherapy tolerance.
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Affiliation(s)
- Binhui Xie
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Gannan Medical University, 341000, Ganzhou, P R China
| | - Yuankang Xie
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Gannan Medical University, 341000, Ganzhou, P R China
| | - Cuifu Fang
- Department of general surgery III, the First Affiliated Hospital of Gannan Medical University, 341000, Ganzhou, P R China
| | - Baiyin Zhong
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Gannan Medical University, 341000, Ganzhou, P R China
| | - Rong Ye
- Department of general surgery III, the First Affiliated Hospital of Gannan Medical University, 341000, Ganzhou, P R China
| | - Jianhong Zhang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Gannan Medical University, 341000, Ganzhou, P R China
| | - Qingquan Liu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Gannan Medical University, 341000, Ganzhou, P R China
| | - Heping Li
- Department of Medical Oncology, the First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou, P R China.
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Chiang CC, Yeh H, Lim SN, Lin WR. Transcriptome analysis creates a new era of precision medicine for managing recurrent hepatocellular carcinoma. World J Gastroenterol 2023; 29:780-799. [PMID: 36816628 PMCID: PMC9932421 DOI: 10.3748/wjg.v29.i5.780] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/23/2022] [Accepted: 01/10/2023] [Indexed: 02/06/2023] Open
Abstract
The high incidence of hepatocellular carcinoma (HCC) recurrence negatively impacts outcomes of patients treated with curative intent despite advances in surgical techniques and other locoregional liver-targeting therapies. Over the past few decades, the emergence of transcriptome analysis tools, including real-time quantitative reverse transcription PCR, microarrays, and RNA sequencing, has not only largely contributed to our knowledge about the pathogenesis of recurrent HCC but also led to the development of outcome prediction models based on differentially expressed gene signatures. In recent years, the single-cell RNA sequencing technique has revolutionized our ability to study the complicated crosstalk between cancer cells and the immune environment, which may benefit further investigations on the role of different immune cells in HCC recurrence and the identification of potential therapeutic targets. In the present article, we summarized the major findings yielded with these transcriptome methods within the framework of a causal model consisting of three domains: primary cancer cells; carcinogenic stimuli; and tumor microenvironment. We provided a comprehensive review of the insights that transcriptome analyses have provided into diagnostics, surveillance, and treatment of HCC recurrence.
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Affiliation(s)
- Chun-Cheng Chiang
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, United States
| | - Hsuan Yeh
- School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, United States
| | - Siew-Na Lim
- Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Wey-Ran Lin
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
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Liang J, Bai Y, Ha FS, Luo Y, Deng HT, Gao YT. Combining local regional therapy and systemic therapy: Expected changes in the treatment landscape of recurrent hepatocellular carcinoma. World J Gastrointest Oncol 2023; 15:1-18. [PMID: 36684055 PMCID: PMC9850755 DOI: 10.4251/wjgo.v15.i1.1] [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: 09/24/2022] [Revised: 12/06/2022] [Accepted: 12/27/2022] [Indexed: 01/10/2023] Open
Abstract
Improvements in early screening, new diagnostic techniques, and surgical treatment have led to continuous downward trends in hepatocellular carcinoma (HCC) morbidity and mortality rates. However, high recurrence and refractory cancer after hepatectomy remain important factors affecting the long-term prognosis of HCC. The clinical characteristics and prognosis of recurrent HCC are heterogeneous, and guidelines on treatment strategies for recurrent HCC are lacking. Therapies such as surgical resection, radiofrequency ablation, and transhepatic arterial chemoembolization are effective for tumors confined to the liver, and targeted therapy is a very important treatment for unresectable recurrent HCC with systemic metastasis. With the deepening of the understanding of the immune microenvironment of HCC, blocking immune checkpoints to enhance the antitumor immune response has become a new direction for the treatment of HCC. In addition, improvements in the tumor immune microenvironment caused by local treatment may provide an opportunity to improve the therapeutic effect of HCC treatment. Ongoing and future clinical trial data of combined therapy may develop the new treatment scheme for recurrent HCC. This paper reviews the pattern of recurrent HCC and the characteristics of the immune microenvironment, demonstrates the basis for combining local treatment and systemic treatment, and reports current evidence to better understand current progress and future approaches in the treatment of recurrent HCC.
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Affiliation(s)
- Jing Liang
- Department of Hepatology, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Yi Bai
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin 300192, China
| | - Fu-Shuang Ha
- Department of Hepatology, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Ying Luo
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Hui-Ting Deng
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Ying-Tang Gao
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
- Tianjin Institute of Hepatobiliary Disease, The Third Central Clinical College of Tianjin Medical University, Tianjin 300170, China
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Milana F, Polidoro MA, Famularo S, Lleo A, Boldorini R, Donadon M, Torzilli G. Surgical Strategies for Recurrent Hepatocellular Carcinoma after Resection: A Review of Current Evidence. Cancers (Basel) 2023; 15:508. [PMID: 36672457 PMCID: PMC9856445 DOI: 10.3390/cancers15020508] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/07/2023] [Accepted: 01/10/2023] [Indexed: 01/17/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and both liver resection and liver transplantation are considered potentially curative options. However, high recurrence rates affect the prognosis depending both on the primary HCC pathology characteristics or on the type and time of the relapse. While great attention has been usually posted on treatment algorithms for the first HCC, treatment algorithms for recurrent HCC (rHCC) are lacking. In these cases, surgery still represents a curative option with both redo hepatectomy and/or salvage liver transplantation, which are considered valid treatments in selected patients. In the current era of personalised medicine with promises of new systemic-targeted immuno-chemotherapies, we wished to perform a narrative review of the literature on the role of surgical strategies for rHCC.
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Affiliation(s)
- Flavio Milana
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, MI, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Michela Anna Polidoro
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Simone Famularo
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, MI, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, MI, Italy
- Department of Internal Medicine, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Renzo Boldorini
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, NO, Italy
- Department of Pathology, University Maggiore Hospital, 28100 Novara, NO, Italy
| | - Matteo Donadon
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, NO, Italy
- Department of General Surgery, University Maggiore Hospital, 28100 Novara, NO, Italy
| | - Guido Torzilli
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, MI, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
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LR-3 and LR-4 Lesions Are More Likely to Be Hepatocellular Carcinoma in Transplant Patients with LR-5 or LR-TR Lesions. Dig Dis Sci 2022; 67:5345-5352. [PMID: 35257246 DOI: 10.1007/s10620-022-07428-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 01/23/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Liver Imaging Reporting and Data System (LI-RADS) classifies liver nodules from LR-1 to LR-5 based on risk for hepatocellular carcinoma (HCC). It is challenging to know the nature of the LR-3 and LR-4 lesions. AIMS To test our hypothesis that in patients with a definite HCC (LR-5) or treated HCC (LR-TR), a coexisting LR-3 or LR-4 lesion is more likely to represent HCC compared to patients without LR-5 or LR-TR lesions. METHODS We conducted a retrospective study including all adult patients who received liver transplantation in our institution from 1/1/2014 to 3/3/2020 who had any LR-3 or LR-4 lesion on pre-transplant MRI. RESULTS Seventy-eight patients were included in the final cohort (115 LR-3 and LR-4 lesions total). When accompanied by LR-5 or LR-TR lesions, 41% (28/69) of LR-3 lesions were HCC compared to 12% (3/25) when not accompanied by LR-5 LR-TR lesions. When accompanied by LR-5 or LR-TR lesions, 83% (10/12) of LR-4 lesions were HCC, versus 33% (3/9) when not accompanied by LR-5 or LR-TR lesions. In a multivariable analysis of all lesions, the presence of a LR-5 or LR-TR lesion was significantly associated with LR-3 or LR-4 lesions representing HCC (OR 6.4, p = 0.01). CONCLUSION LR-3 and LR-4 lesions are more likely to be HCC in patients with LR-5 or LR-TR lesions. The presence of coexisting definite HCC may be a useful diagnostic feature to improve risk stratification of lesions without typical imaging features of HCC. This may also affect decision-making prior to liver transplant when HCC burden must be accurately determined.
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Prognostic significance of preoperative hyaluronic acid level in patients with hepatocellular carcinoma. HPB (Oxford) 2022; 24:525-534. [PMID: 34654620 DOI: 10.1016/j.hpb.2021.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 08/15/2021] [Accepted: 09/02/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Serum hyaluronic acid (HA) levels are increased in patients with solid tumors, and may predict outcomes. However, as HA levels also correlate with the degree of liver fibrosis, the prognostic significance of serum HA levels in patients with hepatocellular carcinoma (HCC) is unclear. METHODS A total of 656 consecutive patients who underwent hepatic resection for HCC were divided into two groups by serum HA level (high HA [≥200 ng/mL], n = 248; low HA [<200 ng/mL], n = 408). Clinicopathological characteristics and postoperative survival were compared between groups. Moreover, 1:1 propensity score matching analysis was applied to adjust characteristics between groups. RESULTS Both the 5-year overall and relapse-free survival rates (OSR and RFSR) in the low HA group were significantly better than those in the high HA group (59.8% vs. 38.6%, respectively, p < 0.001 and 24.5% vs. 13.1%, respectively, p < 0.001). After propensity score matching, two comparable groups of 124 patients each were obtained. However, both the 5-year OSR and RFSR in the low HA group remained significantly better than those in the high HA group (57.4% vs. 38.3%, respectively, p = 0.006 and 22.5% vs. 14.7%, respectively, p = 0.003). CONCLUSION High preoperative HA level predicts poor postoperative survival of patients with HCC. undergoing hepatic resection.
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Margonis GA, Andreatos N, Wang J, Weiss MJ, Wolfgang CL. Lessons learned from hepatocellular carcinoma may cause a paradigm shift in intraductal papillary mucinous neoplasms: a narrative review and discussion of conceptual similarities in tumor progression and recurrence. JOURNAL OF PANCREATOLOGY 2022; 5:36-40. [PMID: 39640535 PMCID: PMC11619816 DOI: 10.1097/jp9.0000000000000083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Although the natural history of recurrence/progression in patients with intraductal papillary mucinous neoplasms (IPMN) of the pancreas has not been studied thoroughly, the three principal mechanisms have been identified: (a) presence of residual disease at the transection margin, (b) presence of intraductal/intraparenchymal metastases and (c) development of new primary lesions. Mechanisms (a) and (b) result in metastatic lesions that are genetically related to the primary, while new primary lesions (mechanism c) are genetically distinct. Interestingly, recurrence/progression in IPMN displays conceptual parallels with the well-established paradigm of disease recurrence in patients with hepatocellular carcinoma (HCC). Specifically, patients with HCC may also develop recurrent tumors due to microscopic residual disease/intrahepatic metastasis which are genetically similar to the primary while the development of genetically unrelated, de novo HCC after curative-intent resection is also common. The latter has been attributed to the presence of a widespread genetic abnormality ("field defect") in the liver (ie, cirrhosis). Given the conceptual similarities between IPMN and HCC, a pancreatic "field defect"may also be hypothesized to exist. This review does not suggest that HCC and IPMN have identical pathogeneses, but rather that they have conceptual similarities in tumor recurrence/progression; thus, lessons learned from HCC could be applied to IPMN research and subsequent management. Conceptual similarities in tumor progression and recurrence may also be observed between IPMN and other malignancies. However, HCC was selected because it is well studied and can serve as a paradigm.
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Affiliation(s)
| | - Nikolaos Andreatos
- Department of Internal Medicine and Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
| | - Jane Wang
- Department of Surgery, University of California San Francisco, San Francisco, CA
| | - Matthew J. Weiss
- Department of Surgery, Northwell Health Cancer Institute and Zucker School of Medicine at Hofstra, Lake Success
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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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Kuo MJ, Mo LR, Chen CL. Factors predicting long-term outcomes of early-stage hepatocellular carcinoma after primary curative treatment: the role of surgical or nonsurgical methods. BMC Cancer 2021; 21:250. [PMID: 33685409 PMCID: PMC7941925 DOI: 10.1186/s12885-021-07948-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 02/15/2021] [Indexed: 02/06/2023] Open
Abstract
Background We quantified the elusive effects of putative factors on the clinical course of early hepatocellular carcinoma (HCC) after primary surgical or nonsurgical curative treatment. Methods Patients with newly diagnosed early HCC who received surgical resection (SR) or percutaneous radiofrequency ablation (RFA) with or without transcatheter arterial chemoembolization (TACE) from January 2003 to December 2016 were enrolled. The cumulative overall survival (OS) and disease-free survival (DFS) rates were compared. A polytomous logistic regression was used to estimate factors for early and late recurrence. Independent predictors of OS were identified using Cox proportional hazard regression. Results One hundred twenty-five patients underwent SR, and 176 patients underwent RFA, of whom 72 were treated with TACE followed by RFA. Neither match analysis based on propensity score nor multiple adjustment regression yielded a significant difference in DFS and OS between the two groups. Multivariate analysis showed high AFP (> 20 ng/mL), and multinodularity significantly increased risk of early recurrence (< 1 year). In contrast, hepatitis B virus, hepatitis C virus and multinodularity were significantly associated with late recurrence (> 1 year). Multivariate Cox regression with recurrent events as time-varying covariates identified older age (HR = 1.55, 95% CI:1.01–2.36), clinically significant portal hypertension (CSPH) (HR = 1.97, 95% CI:1.26–3.08), early recurrence (HR = 6.62, 95% CI:3.79–11.6) and late recurrence (HR = 3.75, 95% CI:1.99–7.08) as independent risk factors of mortality. A simple risk score showed fair calibration and discrimination in early HCC patients after primary curative treatment. In the Barcelona Clinic Liver Cancer (BCLC) stage A subgroup, SR significantly improved DFS compared to RFA with or without TACE. Conclusion Host and tumor factors rather than the initial treatment modalities determine the outcomes of early HCC after primary curative treatment. Statistical models based on recurrence types can predict early HCC prognosis but further external validation is necessary. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-07948-9.
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Affiliation(s)
- Ming-Jeng Kuo
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan 701, Taiwan. No. 670, Chon-De Road, Tainan, 701, Taiwan.
| | - Lein-Ray Mo
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan 701, Taiwan. No. 670, Chon-De Road, Tainan, 701, Taiwan
| | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, College of Medicine, and Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei 100, 7 Chung-Shan South Road, Taipei, 100, Taiwan.
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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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Huang M, He M, Guo Y, Li H, Shen S, Xie Y, Li X, Xiao H, Fang L, Li D, Peng B, Liang L, Yu J, Kuang M, Xu L, Peng S. The Influence of Immune Heterogeneity on the Effectiveness of Immune Checkpoint Inhibitors in Multifocal Hepatocellular Carcinomas. Clin Cancer Res 2020; 26:4947-4957. [PMID: 32527942 DOI: 10.1158/1078-0432.ccr-19-3840] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Revised: 03/17/2020] [Accepted: 06/04/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE Immune checkpoint inhibitor therapy is emerging as the promising option for patients with advanced hepatocellular carcinoma. We aimed to investigate the heterogeneity of different tumor nodules of the same patient with multifocal hepatocellular carcinomas in response to immunotherapy and its molecular mechanisms. EXPERIMENTAL DESIGN We attained 45 surgical tumor samples including 33 small and 12 large nodules from 12 patients with multifocal hepatocellular carcinoma and evaluated genomic and immune heterogeneity among tumors through whole-genome sequencing and RNA sequencing. IHC was performed to validate the expression of immune markers. The responses to anti-programmed cell death protein-1 (PD-1) therapy in patients with multifocal hepatocellular carcinoma were evaluated. RESULTS The small and large tumors within the same patient presented with similar genomic characteristics, indicating their same genomic origin. We further found the small tumors had higher immune cell infiltration including more CD8+ T cells, M1 macrophages, and monocytes as compared with large tumors. Besides, the expression of interferon signature predictive of response to anti-PD-1 therapy was significantly upregulated in the small tumors. Moreover, the immune pathways were more vigorous along with less active proliferation pathways in the small tumors. In keeping with this, we found that small nodules were more sensitive to anti-PD-1 therapy than large nodules in patients with multifocal hepatocellular carcinoma. CONCLUSIONS The small tumors in patients with multifocal hepatocellular carcinoma had higher immune cell infiltration and upregulation of immune pathways as compared with the large tumors, which can partially explain the different responses of small and large tumors in the same case to anti-PD-1 therapy.
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Affiliation(s)
- Manling Huang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Minghui He
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yu Guo
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Heping Li
- Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shunli Shen
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yubin Xie
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoxing Li
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Han Xiao
- Division of Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lujing Fang
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dongming Li
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Baogang Peng
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lijian Liang
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jun Yu
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ming Kuang
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Division of Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lixia Xu
- Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. .,Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Sui Peng
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. .,Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Clinical Trial Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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14
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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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15
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Weidle UH, Schmid D, Birzele F, Brinkmann U. MicroRNAs Involved in Metastasis of Hepatocellular Carcinoma: Target Candidates, Functionality and Efficacy in Animal Models and Prognostic Relevance. Cancer Genomics Proteomics 2020; 17:1-21. [PMID: 31882547 PMCID: PMC6937123 DOI: 10.21873/cgp.20163] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/31/2019] [Accepted: 11/04/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is responsible for the second-leading cancer-related death toll worldwide. Although sorafenib and levantinib as frontline therapy and regorafenib, cabazantinib and ramicurimab have now been approved for second-line therapy, the therapeutic benefit is in the range of only a few months with respect to prolongation of survival. Aggressiveness of HCC is mediated by metastasis. Intrahepatic metastases and distant metastasis to the lungs, lymph nodes, bones, omentum, adrenal gland and brain have been observed. Therefore, the identification of metastasis-related new targets and treatment modalities is of paramount importance. In this review, we focus on metastasis-related microRNAs (miRs) as therapeutic targets for HCC. We describe miRs which mediate or repress HCC metastasis in mouse xenograft models. We discuss 18 metastasis-promoting miRs and 35 metastasis-inhibiting miRs according to the criteria as outlined. Six of the metastasis-promoting miRs (miR-29a, -219-5p, -331-3p, 425-5p, -487a and -1247-3p) are associated with unfavourable clinical prognosis. Another set of six down-regulated miRs (miR-101, -129-3p, -137, -149, -503, and -630) correlate with a worse clinical prognosis. We discuss the corresponding metastasis-related targets as well as their potential as therapeutic modalities for treatment of HCC-related metastasis. A subset of up-regulated miRs -29a, -219-5p and -425-5p and down-regulated miRs -129-3p and -630 were evaluated in orthotopic metastasis-related models which are suitable to mimic HCC-related metastasis. Those miRNAs may represent prioritized targets emerging from our survey.
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Affiliation(s)
- Ulrich H Weidle
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Daniela Schmid
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Fabian Birzele
- Pharmaceutical Sciences, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland
| | - Ulrich Brinkmann
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
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16
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Zhou X, Wang X, Zhou Y, Cheng L, Zhang Y, Zhang Y. Long Noncoding RNA NEAT1 Promotes Cell Proliferation And Invasion And Suppresses Apoptosis In Hepatocellular Carcinoma By Regulating miRNA-22-3p/akt2 In Vitro And In Vivo. Onco Targets Ther 2019; 12:8991-9004. [PMID: 31802908 PMCID: PMC6827517 DOI: 10.2147/ott.s224521] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 09/28/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most aggressive cancers that is associated with cirrhosis and other chronic liver diseases. Although remarkable progress has been made in past decades, it is still necessary to continue exploring the pathology and development of HCC. OBJECTIVE In this study, we elucidated the effect of long noncoding RNA (lncRNA) NEAT1 on HCC development and underlying mechanisms. METHODS Clinicopathological features of HCC patients were collected and the correlations with NEAT1 expression were assessed. To determine cell activities, CCK-8, flow cytometry, invasion assays, and TUNEL assays were performed. Real-time PCR, Western blot, and luciferase reporter assays were performed to investigate the related mechanism of HCC. RESULTS The results revealed that NEAT1 expression was associated with tumor size and differentiation where NEAT1 was upregulated in both HCC tissues and cell lines. Overexpression of NEAT1 promoted proliferation and invasion while inhibited apoptosis in HCC cells, which was opposite to the effect of NEAT1 knockdown. Also, AKT2 was increased in HCC tissues. Downregulation of AKT2 was associated with reduced cell proliferation and invasion while increased apoptosis, while overexpression of AKT2 exerted opposite roles. In addition, the expression of miRNA-22-3p displayed an inverse association with NEAT1. miRNA-22-3p mimic and inhibitor suppressed and promoted HCC development, respectively. The luciferase assay revealed that both NEAT1 and AKT2 were direct target genes of miRNA-22-3p. Furthermore, knockdown and overexpression of NEAT1 suppressed and promoted tumor growth in the HCC mouse model, which were abolished by the miRNA-22-3p inhibitor and mimic, respectively. CONCLUSION In conclusion, the results demonstrate that NEAT1 promotes the development of HCC, both in vitro and in vivo, through regulating miRNA-22-3p/AKT2, and provides insight into developing a new strategy for HCC treatment.
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Affiliation(s)
- Xichang Zhou
- Department of Intervention, Xuzhou Central Hospital, Xuzhou Medical University, XuZhou221009, People’s Republic of China
| | - Xiang Wang
- Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou Medical University, XuZhou221009, People’s Republic of China
| | - Yizhou Zhou
- Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou Medical University, XuZhou221009, People’s Republic of China
| | - Long Cheng
- Department of Intervention, Xuzhou Central Hospital, Xuzhou Medical University, XuZhou221009, People’s Republic of China
| | - Youwei Zhang
- Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou Medical University, XuZhou221009, People’s Republic of China
| | - Yangmei Zhang
- Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou Medical University, XuZhou221009, People’s Republic of China
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou215006, People’s Republic of China
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17
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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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18
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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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19
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Chapman WC, Korenblat KM, Fowler KJ, Saad N, Khan AS, Subramanian V, Doyle MBM, Dageforde LA, Tan B, Grierson P, Lin Y, Xu M, Brunt EM. Hepatocellular carcinoma: Where are we in 2018? Curr Probl Surg 2018; 55:450-503. [PMID: 30526875 DOI: 10.1067/j.cpsurg.2018.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- William C Chapman
- Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO.
| | - Kevin M Korenblat
- Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO
| | | | - Nael Saad
- University of Rochester, Rochester, NY
| | - Adeel S Khan
- Division of Abdominal Transplant Surgery, Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO
| | - Vijay Subramanian
- Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO
| | - Maria B Majella Doyle
- Barnes-Jewish Hospital, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO
| | - Leigh Anne Dageforde
- Harvard Medical School, Division of Transplant Surgery, Massachusetts General Hospital, Boston, MA
| | - Benjamin Tan
- Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO
| | - Patrick Grierson
- Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO
| | - Yiing Lin
- Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO
| | - Min Xu
- Department of Surgery, Washington University School of Medicine, St. Louis, MO
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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, 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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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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Distinct Recurrence Risk Factors for Intrahepatic Metastasis and Multicenter Occurrence After Surgery in Patients with Hepatocellular Carcinoma: What Is More Is About Different Therapeutic Strategies. J Gastrointest Surg 2017; 21:2148-2149. [PMID: 28861802 DOI: 10.1007/s11605-017-3553-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 08/16/2017] [Indexed: 02/05/2023]
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Liver transplantation for hepatocellular carcinoma: current update on treatment and allocation. Curr Opin Organ Transplant 2017; 22:128-134. [PMID: 27926548 DOI: 10.1097/mot.0000000000000385] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW This review discusses the current imaging modalities and criteria used to diagnose, and the role of liver transplantation as well as nonsurgical hepatic-directed therapies to treat hepatocellular carcinoma in the setting of chronic liver disease. RECENT FINDINGS There has been continual evolution of guidelines, policies, and algorithms for the imaging diagnosis of hepatocellular carcinoma, particularly the Liver Imaging Reporting and Data System. The use of liver-directed therapy as a bridge to transplant is now common practice. Recently, patients have waited 6 months from listing before being granted a Model for End-Stage Liver Disease exception score of 28, with an increase every 3 months to a maximum score of 34. This policy change was developed to reduce disparities in outcomes for patients undergoing liver transplantation. SUMMARY The use of liver transplantation to treat hepatocellular carcinoma within the Milan criteria has good outcomes with a 5-year disease-free survival rate comparable to patients transplanted without malignancy. The development of guidelines both for the radiologic diagnosis and staging of the primary tumor and guidelines for assessing response to treatment allows for a more unified approach to the management of patients. With the partnership of oncologists, hepatologists, radiologists, pathologists, and surgeons, the outcomes of liver transplantation as treatment for hepatocellular continue to improve.
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Abstract
Local recurrence of pancreatic cancer (PC) can occur in the pancreatic remnant. In addition, new primary PC can develop in the remnant. There are limited data available regarding this so-called remnant PC. The aim of this review was to describe the characteristics and therapeutic strategy regarding remnant PC. A literature search was performed using Medline published in English according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The incidence of remnant PC has been reported to be 3% to 5%. It is difficult to distinguish local recurrence from new primary PC. Genetic diagnosis such as Kirsten rat sarcoma viral oncogene homolog mutation may resolve this problem. For patients with remnant PC, repeated pancreatectomy can be performed. Residual total pancreatectomy is the most common procedure. Recent studies have described the safety of the operation because of recent surgical progress and perioperative care. The patients with remnant PC without distant metastasis have shown good long-term outcomes, especially those who underwent repeated pancreatectomy. Adjuvant chemotherapy may contribute to longer survival. In conclusion, this review found that both local recurrence and new primary PC can develop in the pancreatic remnant. Repeated pancreatectomy for the remnant PC is a feasible procedure and can prolong patient survival.
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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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Distinct Recurrence Risk Factors for Intrahepatic Metastasis and Multicenter Occurrence After Surgery in Patients with Hepatocellular Carcinoma. J Gastrointest Surg 2017; 21:312-320. [PMID: 27815759 DOI: 10.1007/s11605-016-3311-z] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 10/13/2016] [Indexed: 01/31/2023]
Abstract
BACKGROUND AND OBJECTIVES Intrahepatic recurrence after hepatectomy for hepatocellular carcinoma (HCC) includes intrahepatic metastasis (IM) and multicenter occurrence (MO). The risk factors for these two types of intrahepatic recurrence have not been well defined. METHODS The type of intrahepatic recurrence was determined based on histopathological features of 93 HCC patients who underwent a repeat hepatectomy for recurrent HCC. Various clinical and pathological factors were analyzed to define distinct risk factors for different types of intrahepatic recurrence. RESULTS The recurrence rates at 1, 2, 3, 5, and 8 years postoperatively were 22.4, 42.9, 61.2, 85.7, and 100 %, respectively, in patients with IM and 5.0, 25.0, 45.5, 67.5, and 100 %, respectively, in patients with MO (p = 0.005). A total of 16 clinical and pathological factors were tested in univariable and multivariable analyses. We found that large-size tumor (>5 cm), multiple tumors (two or more), and vascular invasion were significantly associated with IM recurrence, and liver cirrhosis and Ishak hepatic inflammatory activity were highly associated with MO recurrence. In addition, blood transfusion and a high hepatitis B virus (HBV)-DNA load (>2000 IU/ml) were independent risk factors common to both IM and MO recurrences. CONCLUSIONS IM and MO recurrences were associated with distinct risk factors, while blood transfusion and high HBV-DNA load (>2000 IU/ml) were independent risk factors common to both IM and MO recurrences.
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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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28
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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: 207] [Impact Index Per Article: 23.0] [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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29
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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: 95] [Impact Index Per Article: 10.6] [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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30
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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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31
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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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32
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Chapman WC, Klintmalm G, Hemming A, Vachharajani N, Majella Doyle MB, DeMatteo R, Zaydfudim V, Chung H, Cavaness K, Goldstein R, Zendajas I, Melstrom LG, Nagorney D, Jarnagin W. Surgical treatment of hepatocellular carcinoma in North America: can hepatic resection still be justified? J Am Coll Surg 2015; 220:628-37. [PMID: 25728142 DOI: 10.1016/j.jamcollsurg.2014.12.030] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 12/16/2014] [Indexed: 12/22/2022]
Abstract
BACKGROUND The incidence of hepatocellular cancer (HCC) is increasing dramatically worldwide. Optimal management remains undefined, especially for well-compensated cirrhosis and HCC. STUDY DESIGN This retrospective analysis included 5 US liver cancer centers. Patients with surgically treated HCC between 1990 and 2011 were analyzed; demographics, tumor characteristics, and survival rates were included. RESULTS There were 1,765 patients who underwent resection (n = 884, 50.1%) or transplantation (n = 881, 49.9%). Overall, 248 (28.1%) resected patients were transplant eligible (1 tumor <5 cm or 2 to 3 tumors all <3 cm, no major vascular invasion); these were compared with 496 transplant patients, matched based on year of transplantation and tumor status. Overall survivals at 5 and 10 years were significantly improved for transplantation patients (74.3% vs 52.8% and 53.7% vs 21.7% respectively, p < 0.001), with greater differences in disease-free survival (71.8% vs 30.1% at 5 years and 53.4% vs 11.7% at 10 years, p < 0.001). Ninety-seven of the 884 (11%) resected patients were within Milan criteria and had cirrhosis; these were compared with the 496 transplantation patients, with similar results to the overall group. On multivariate analysis, type of surgery was an independent variable affecting all survival outcomes. CONCLUSIONS The increasing incidence of HCC stresses limited resources. Although transplantation results in better long-term survival, limited donor availability precludes widespread application. Hepatic resection will likely remain a standard therapy in selected patients with HCC. In this large series, only about 10% of patients with cirrhosis were transplant-eligible based on tumor status. Although liver transplantation results are significantly improved compared with resection, transplantation is available only for a minority of patients with HCC.
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Affiliation(s)
- William C Chapman
- Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, St Louis, MO.
| | | | - Alan Hemming
- Department of Surgery, University of California San Diego Health System, San Diego, CA
| | - Neeta Vachharajani
- Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, St Louis, MO
| | - Maria B Majella Doyle
- Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, St Louis, MO
| | - Ron DeMatteo
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Victor Zaydfudim
- Department of Surgery, University of Virginia Health System, Charlottesville, VA
| | - Haniee Chung
- Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, St Louis, MO
| | | | | | - Ivan Zendajas
- Department of Surgery, University of Florida Health, Gainesville, FL
| | - Laleh G Melstrom
- Department of Surgery, The Cancer Institute of New Jersey, Rutgets Robert Wood Johnson Medical School, New Brunswick, NJ
| | | | - William Jarnagin
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY
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Sehn JK, Abel HJ, Duncavage EJ. Copy number variants in clinical next-generation sequencing data can define the relationship between simultaneous tumors in an individual patient. Exp Mol Pathol 2014; 97:69-73. [PMID: 24886963 DOI: 10.1016/j.yexmp.2014.05.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Accepted: 05/29/2014] [Indexed: 12/30/2022]
Abstract
Targeted next-generation sequencing (NGS) cancer panels have become a popular method for the identification of clinically predictive mutations in cancer. Such methods typically detect single nucleotide variants (SNVs) and small insertions/deletions (indels) in known cancer genes and can provide further information regarding diagnosis in challenging surgical pathology cases, as well as identify therapeutic targets and prognostically significant mutations. However, in addition to SNVs and indels, other mutation classes, including copy number variants (CNVs) and translocations, can be simultaneously detected from targeted NGS data. Here, as proof of methods, we present clinical data which demonstrate that targeted NGS panels can separate synchronous liver tumors based on CNV status, in the absence of distinct SNVs and indels. Such CNV-based analysis can be performed without additional cost using existing targeted cancer panel data and publically available software.
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Affiliation(s)
- Jennifer K Sehn
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
| | - Haley J Abel
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Eric J Duncavage
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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Wang B, Xia CY, Lau WY, Lu XY, Dong H, Yu WL, Jin GZ, Cong WM, Wu MC. Determination of clonal origin of recurrent hepatocellular carcinoma for personalized therapy and outcomes evaluation: a new strategy for hepatic surgery. J Am Coll Surg 2014; 217:1054-62. [PMID: 24246620 DOI: 10.1016/j.jamcollsurg.2013.07.402] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Revised: 07/16/2013] [Accepted: 07/21/2013] [Indexed: 12/23/2022]
Abstract
BACKGROUND Recurrent hepatocellular carcinoma (RHCC) after curative resection is a major challenge for hepatic surgeons. A better understanding of the clonal origin of RHCC will help clinicians design personalized therapy and assess postoperative outcomes. The current study was performed to determine the clonal origin of RHCC and its clinical significance. STUDY DESIGN Fifteen high-frequency of loss of heterozygosity of DNA microsatellites were determined on 100 tumor nodules in 60 matched pairs of RHCC from 40 patients who underwent liver re-resections. The relationships among the origin of clonal patterns of RHCC and the surgicopathologic features and clinical outcomes were analyzed. RESULTS Of 60 pairs of RHCC, there were 2 clonal patterns with 6 subclonal types. Pattern I was multicentric occurrence (MO type) in 14 pairs (23.3%) and pattern II was intrahepatic metastasis (IM type) in 46 pairs (76.7%). The clinicopathologic features, including recurrence time, tumor size, vascular invasion, histological grading, and associated chronic liver diseases in patients with the MO type of RHCC were significantly different from those with the IM type of RHCC (p < 0.05 to 0.001). Compared with patients in the IM group, patients in the MO group had significantly better overall survival (130.8 ± 8.5 months vs 80.8 ± 8.5 months; p < 0.05) and recurrence-free survival (33.8 ± 4.5 months vs 14.2 ± 2.5 months; p < 0.001). CONCLUSIONS The MO-type RHCC was closely associated with better postoperative outcomes when compared with the IM-type RHCC. Generally, we recommend liver re-resection for MO-type RHCC, and interventional therapy for IM-type RHCC. Microdissection-based microsatellite loss of heterozygosity protocol has advantages in assessing the clonal origin, modes of personalized treatment, and clinical outcomes of RHCC.
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Affiliation(s)
- Bin Wang
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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35
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Tsuji N, Ishiguro S, Sasaki Y, Kudo M. CD34 expression in noncancerous liver tissue predicts multicentric recurrence of hepatocellular carcinoma. Dig Dis 2013; 31:467-71. [PMID: 24281022 DOI: 10.1159/000355246] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Metachronous multicentric recurrence of hepatocellular carcinoma (HCC) is a common cause of morbidity and mortality following curative surgical resection. Clinical and laboratory predictors of these processes can markedly aid in managing these patients. Capillarization of hepatic sinusoids is also a well-known phenomenon in many liver diseases, especially in neoplastic liver diseases. Here, we investigated the clinical features, fibrosis scores and distribution of CD34 in noncancerous hepatic tissues of postresection patients with and without multicentric recurrence. METHODS Eighteen patients with multicentric recurrence of HCC diagnosed by histological examination of repeated hepatectomy specimens and 72 HCC patients with more than 5-year disease-free survival postresection participated in the study. We compared the clinicopathological features of these two groups. We examined noncancerous hepatic tissues for iron deposition by Prussian blue staining and computed the CD34-labeling index (LI) through immunohistochemistry using anti-CD34 antibody. RESULTS CD34-LI was significantly higher in the multicentric recurrence group (p < 0.001) and staging scores of fibrosis were also significantly higher in the recurrence group (p = 0.035). A high histological activity grade (p = 0.057) and a high alanine aminotransferase level (p = 0.060) were also associated with recurrence. There were no significant differences between the two groups in age, sex, hepatitis B virus surface antigen and anti-hepatitis C virus antibody levels, or grade of iron deposition. On multivariate analysis, high CD34-LI was the only independent risk factor (p = 0.001) for metachronous multicentric recurrence. CONCLUSION CD34 expression in the capillaries and sinusoids of noncancerous hepatic tissue is a risk factor for multicentric recurrence of HCC. Histologic assessment of hepatic tissue with CD34 immunohistochemistry might be useful for the prognostic evaluation of HCC patients after surgery.
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Affiliation(s)
- Naoko Tsuji
- Department of Gastroenterology, Sakai Hospital, Kinki University Faculty of Medicine, Sakai, Japan
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36
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Downregulation of microRNA-214 and overexpression of FGFR-1 contribute to hepatocellular carcinoma metastasis. Biochem Biophys Res Commun 2013; 439:47-53. [PMID: 23962428 DOI: 10.1016/j.bbrc.2013.08.032] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Accepted: 08/09/2013] [Indexed: 12/16/2022]
Abstract
miR-214 is one of the most significantly downregulated microRNAs (miRNAs) in hepatocellular carcinoma (HCC). Fibroblast growth factor receptor 1 (FGFR-1) is a miR-214 target gene implicated in the progression of HCC. However, the roles of miR-214 and FGFR-1 in HCC are not fully understood. Here, we analyzed the expression of miR-214 and FGFR-1 in 65 cases of HCC and paired non-neoplastic tissue specimens using real-time PCR and Western blot (WB), respectively. Our data indicated that miR-214 was downregulated and FGFR-1 was overexpressed in HCC compared to the paired non-neoplastic tissues. The low miR-214 expression was correlated with portal vein invasion (p=0.016) and early recurrence (p=0.045) in HCC patients. Moreover, the low miR-214 expression was correlated with high positive rate of FGFR-1 in HCC cases (p=0.020). Our data further demonstrated that miR-214 overexpression in SK-HEP1 and HepG2 cells downregulated FGFR-1 expression and inhibited liver cancer cell invasion. The Luciferase assay results further demonstrated the targeted regulation of FGFR-1 by miR-214. In conclusion, our data indicate that the downregulation of miR-214 in HCC and the upregulation of its target gene FGFR-1 is associated with HCC progression. Therefore, miR-214 and FGFR-1 are potential prognostic markers and therapeutic targets in HCC.
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Sakon M, Ogawa H, Fujita M, Nagano H. Hepatic resection for hepatocellular carcinoma based on tumor hemodynamics. Hepatol Res 2013. [PMID: 23194466 DOI: 10.1111/hepr.12001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Survival or disease-free survival is not considered an appropriate surrogate outcome for the locoregional curability (i.e. surgical margin) of hepatectomy for hepatocellular carcinoma because these are greatly influenced by non-metastatic factors like multicentric carcinogenesis (MC) or liver function. Hepatocellular carcinoma metastasizes by hematogenous seeding; therefore, the tumor blood flow (TBF) drainage area is a high-risk area for intrahepatic metastasis, and can be identified by computed tomography under hepatic arteriography and completely resected as part of the surgical margin. The TBF pattern is classified into marginal, portal vein or hypovascular types. Partial hepatectomies were mostly performed in patients with marginal or hypovascular type, whereas anatomical surgery was frequently performed in those with portal vein type. Pathologically, nodules inside the TBF drainage area were moderately or poorly differentiated carcinomas, suggesting intrahepatic metastasis. In contrast, those outside the drainage area were frequently solitary and contained well-differentiated carcinoma, which is consistent with MC. The pattern of tumor recurrences after TBF-based hepatectomy is divided into two distinct groups - "a few nodules" and "many nodules in multiple segments or extrahepatic" - indicating that intrahepatic recurrences develop from MC and from circulating tumor cells in peripheral blood, respectively. Anatomical resection has not shown a survival benefit over that of TBF-based partial hepatectomy. TBF-based hepatectomy enables us to preserve liver function without compromising locoregional curability.
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Affiliation(s)
- Masato Sakon
- Department of Surgery, Nishinomiya Municipal Central Hospital, Nishinomiya, Japan
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Surgical resection for small hepatocellular carcinoma in cirrhosis: the Eastern experience. Recent Results Cancer Res 2013; 190:69-84. [PMID: 22941014 DOI: 10.1007/978-3-642-16037-0_5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Detection of small Hepatocarcinoma (HCC) by screening of high-risk populations is important to increase the percentage of patients suitable for curative treatment, which would lead to prolongation of the mean survival of patients with HCC. It should be remembered that small HCC is not always necessarily equivalent to early HCC as defined histologically. With recent advances in diagnostic imaging modalities, including contrast-enhanced ultrasonography and magnetic resonance imaging with liver-specific contrast enhancement, accurate differential diagnosis of early HCCs from dysplastic nodules has become possible. Because a certain proportion of small HCCs is known to show microscopic vascular invasion, surgical resection would be the treatment of first choice. To minimize potential microscopic invasion, anatomic resection and/or resection with a wide margin should be performed, while preserving liver function to the maximum extent possible. Surgical resection, however, cannot prevent multicentric occurrence of HCC, which remains a major issue precluding curative treatment of HCC.
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Wang J, Li J, Shen J, Wang C, Yang L, Zhang X. MicroRNA-182 downregulates metastasis suppressor 1 and contributes to metastasis of hepatocellular carcinoma. BMC Cancer 2012; 12:227. [PMID: 22681717 PMCID: PMC3492170 DOI: 10.1186/1471-2407-12-227] [Citation(s) in RCA: 123] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2012] [Accepted: 06/01/2012] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND miR-182 is one of the most significantly up-regulated miRNAs in hepatocellular carcinoma (HCC). Metastasis suppressor 1 (MTSS1), one target gene of miR-182, plays an important role in the metastasis of cancers. However, it remains unclear what role does function and mechanism of miR-182 and MTSS1play in HCC. METHODS miR-182 expression was tested in 86 cases of paired HCC and normal tissues by real-time PCR and the relationships between miR-182 expression and clinicopathological parameters were analyzed. The expression of MTSS1 was evaluated by immunohistochemistry and western blot in the above tissues and its correlation with miR-182 expression was analyzed. Moreover, western blot and invasion assays were performed after transfection of pre-miR-182 or anti-miR-182 to HCC cell lines. In addition, luciferase assays was performed to confirm the regulation of miR-182 on MTSS1. RESULTS Compared with normal tissue, miR-182 was up-regulated and MTSS1 was down-regulated in HCC tissues. Moreover, the over-expression of miR-182 was correlated with intrahepatic metastasis (p = 0.034) and poor prognosis (p = 0.039) of HCC patients. There was a negative correlation between miR-182 and MTSS1 expression in both HCC tissues (r = -0.673, p < 0.01) and HCC cell lines (r = -0.931, p = 0.021). Furthermore, the up-regulation of miR-182 resulted in the down-regulation of MTSS1 and increased invasive potential of HUH-1, and reverse results were also confirmed when the expression of miR-182 was inhibited. In addition, the results of the luciferase assay demonstrated the targeted regulation of miR-182 on MTSS1. CONCLUSIONS miR-182 could promote metastasis of HCC and inhibit the expression of MTSS1. miR-182 and MTSS1 are potential prognostic markers and/or therapeutic targets in HCC.
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Affiliation(s)
- Jian Wang
- Department of 4th Abdominal Oncology, Cancer Hospital and Institute of Tianjin Medical University, Tianjin, 300060, China.
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Huang ZY, Liang BY, Xiong M, Zhan DQ, Wei S, Wang GP, Chen YF, Chen XP. Long-term outcomes of repeat hepatic resection in patients with recurrent hepatocellular carcinoma and analysis of recurrent types and their prognosis: a single-center experience in China. Ann Surg Oncol 2012; 19:2515-25. [PMID: 22395985 DOI: 10.1245/s10434-012-2269-7] [Citation(s) in RCA: 96] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Indexed: 12/13/2022]
Abstract
BACKGROUND Recurrent hepatocellular carcinoma (HCC) after curative resection usually originates from intrahepatic metastasis (IM) or multicentric occurrence (MO). The long-term outcomes of repeat hepatic resection in patients with different types of recurrence have not been evaluated in a large number of patients. The surgical indications for recurrent HCC remain controversial. The purpose of this study was to investigate long-term outcomes of repeat hepatic resection and clinicopathologic factors associated with different types of recurrent HCC, and to single out principle differentiating factors between IM and MO. METHODS 82 patients who underwent repeat hepatic resection for recurrent HCC were retrospectively studied. The recurrent type was evaluated by histopathologic analysis of primary and recurrent HCC. The recurrence and survival rates as well as clinicopathologic factors associated with different types of recurrence were analyzed. RESULTS 45 patients (54.9%) had confirmed with IM, and 37 patients (45.1%) had with MO. The recurrence rates in the MO patients after initial or repeat resection were significantly lower than those in the IM patients (p < 0.001). The overall survival rates in the MO patients after initial or repeat resection were significantly higher than those in the IM patients (p < 0.001). Recurrence-free time was identified as the most significant differentiating factor between IM and MO. A recurrence-free time of 18 months after initial resection was a significant cutoff time point for differentiating between IM and MO. A recurrence-free time of less than or equal to 18 months and microvascular invasion at repeat resection were independent adverse prognostic factors for overall survival after repeat hepatic resection. CONCLUSIONS Repeat hepatic resection resulted in much higher survival rates in the MO patients than in the IM patients. Repeat hepatic resection could be recommended for those patients in whom the recurrent HCC occurs more than 18 months after initial resection.
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Affiliation(s)
- Zhi-Yong Huang
- Research Laboratory and Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Takaki H, Yamakado K, Sakurai H, Nakatsuka A, Shiraki K, Isaji S, Takeda K. Radiofrequency ablation combined with chemoembolization: treatment of recurrent hepatocellular carcinomas after hepatectomy. AJR Am J Roentgenol 2011; 197:488-494. [PMID: 21785099 DOI: 10.2214/ajr.10.4933] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/01/2025]
Abstract
OBJECTIVE The purpose of this study is to evaluate the treatment effect and prognostic factors of radiofrequency ablation (RFA) combined with chemoembolization for patients with recurrent hepatocellular carcinomas (HCCs) after hepatectomy. MATERIALS AND METHODS Fifty-five consecutive patients who received combination therapy as a curative treatment of recurrent HCCs after hepatectomy were included in this retrospective study. The mean maximum tumor diameter was 2.2 cm (range, 1.0-4.8 cm). Under CT fluoroscopic guidance, RFA was performed 1-2 weeks after chemoembolization. Technique effectiveness rates, complications, local tumor progression rates, survival rates, and prognostic factors were evaluated. RESULTS Tumor enhancement disappeared on contrast-enhanced CT images in all patients after 72 RFA sessions (technique effectiveness rate, 100%). Pneumothorax requiring chest drainage was the only major complication that developed in one RFA session (1%). Four of 55 patients (7%) showed local tumor progression. New tumors emerged in the untreated liver in 27 patients (49%) during the mean follow-up of 35 months (range, 1-82 months). The 5-year overall and recurrence-free survival rates after combination therapy were 74% (95% CI, 54-87%) and 28% (95% CI, 14-45%), respectively. The presence of a single tumor at initial hepatectomy and a low α-fetoprotein level (≤ 100 ng/mL) at recurrence were significantly favorable independent factors affecting overall and recurrence-free survival. CONCLUSION For treatment of recurrent HCCs after hepatectomy, RFA combined with chemoembolization is a useful therapeutic option. This study identified prognostic factors that will help to stratify patients with recurrent HCCs after hepatectomy.
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Affiliation(s)
- Haruyuki Takaki
- Department of Radiology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
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Gehrau R, Mas V, Archer KJ, Maluf D. Molecular classification and clonal differentiation of hepatocellular carcinoma: the step forward for patient selection for liver transplantation. Expert Rev Gastroenterol Hepatol 2011; 5:539-52. [PMID: 21780900 DOI: 10.1586/egh.11.48] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Liver transplantation is a successful treatment for hepatocellular carcinoma (HCC). However, advanced stages are not selected for transplant, based on the United Network for Organ Sharing selection criteria's. Nowadays, molecular biology-based techniques constitute an excellent option to better understand HCC origin differentiation and biological behavior. Moreover, microarray technology is a powerful tool to address a variety of tumor tissues at molecular level and is actively used for the discovery of biomarkers in cancer research. This article will discuss published data in the field of HCC origin differentiation and its potential impact on outcomes following liver transplantation. Although preliminary results are presented, these findings encourage the use of gene-expression profiling microarrays for studying HCC biology and behavior and ultimately optimizing treatment success.
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Affiliation(s)
- Ricardo Gehrau
- Department of Surgery, Hume Lee Transplant Center, Virginia Commonwealth University, 1200 E Broad Street, Richmond, VA 23219-0645, USA
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Earl TM, Chapman WC. Conventional Surgical Treatment of Hepatocellular Carcinoma. Clin Liver Dis 2011; 15:353-70, vii-x. [PMID: 21689618 DOI: 10.1016/j.cld.2011.03.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Liver resection remains the standard therapy for solitary hepatocellular carcinoma in patients with preserved hepatic function. In well-selected patients, 5-year survival rates are good and can approach that of liver transplantation for early-stage disease. Patient selection is critical to optimizing therapeutic benefit, and the health of the native liver must be considered in addition to tumor characteristics. Hepatic recurrence after resection is common. The difficulty lies in deciding which patients with chronic liver disease and small solitary tumors are best served by resection and which should proceed with transplant evaluation; this is the focus of this article.
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Affiliation(s)
- T Mark Earl
- Section of Transplantation, Department of Surgery, Washington University School of Medicine, Washington University, 660 South Euclid Avenue, Campus Box 8109, St Louis, MO 63130, USA
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Hodges KB, Cummings OW, Saxena R, Wang M, Zhang S, Lopez-Beltran A, Montironi R, Nour H, Cheng L. Clonal origin of multifocal hepatocellular carcinoma. Cancer 2010; 116:4078-85. [PMID: 20564142 DOI: 10.1002/cncr.25258] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Hepatocellular carcinoma is the most common primary tumor of the liver. Patients frequently have multiple histologically similar, but anatomically separate tumors. The clonal origin of multiple hepatocellular carcinomas is uncertain. METHODS The authors analyzed 31 tumors from 12 different patients (11 women, 1 man), who had multiple hepatocellular carcinomas involving 1 or both lobes. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue using laser capture microdissection. DNA was analyzed for loss of heterozygosity (LOH), X chromosome inactivation status, and TP53 gene mutations. RESULTS Ten (83%) of the 12 patients showed LOH in at least 1 of the analyzed microsatellite markers. Concordant LOH patterns between separate hepatocellular carcinomas in individual patients were seen in 8 (80%) of 10 cases, whereas discordant patterns were seen in 2 (20%) of 10 cases. Five (50%) of 10 informative female patients showed identical nonrandom X chromosome inactivation patterns in multiple tumors; 1 case showed discordant nonrandom X chromosome inactivation pattern. TP53 mutations were identified in 8 (67%) of 12 patients. Tumors in 7 (88%) of these 8 patients showed different point mutations. Three patients (Cases 4, 5, and 10) had tumors with additional TP53 point mutations, indicating additional genetic abnormalities in these tumors. CONCLUSIONS The data suggested that the significant proportion of patients with multifocal hepatocellular carcinomas have tumors of common clonal origin.
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Affiliation(s)
- Kurt B Hodges
- Departments of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
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Application of tumor-node-metastasis staging 2002 version in locally advanced hepatocellular carcinoma: is it predictive of surgical outcome? BMC Cancer 2010; 10:535. [PMID: 20925965 PMCID: PMC2958946 DOI: 10.1186/1471-2407-10-535] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2010] [Accepted: 10/07/2010] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Locally advanced (pT3-4N0M0) hepatocellular carcinoma (HCC) is a heterogeneous group of tumors, which consists of four different categories, including HCC with "multiple tumors more than 5 cm", "major vascular invasion", "invasion of adjacent organs", and "perforation of visceral peritoneum". The aim of our study was to verify whether the 2002 version of the Tumor-Node-Metastasis staging system could predict surgical outcomes in patients with locally advanced HCC. METHODS We retrospectively reviewed 298 patients with pT3-4N0M0 HCC who underwent hepatic resection from 1993 to 2000 in an academic tertiary hospital. Overall survival (OS) and cumulative recurrence rate (CRR) of the four categories of locally advanced HCC patients were compared. RESULTS In multivariate analysis, major vascular invasion was identified as the most significant factor (HR = 3.291, 95% CI 2.362-4.584, P < 0.001) followed by cirrhosis status on OS, and was found to be the only independent factor of CRR (HR = 2.242, 95% CI 1.811-3.358, P < 0.001) in patients with locally advanced HCC. Among the four categories of locally advanced HCC, OS was significantly worse, and CRR was significantly higher in patients with HCC with major vascular invasion (pT3) than with multiple tumors more than 5 cm (pT3); or tumor invasion of adjacent organs (pT4); or perforation of visceral peritoneum (pT4). No significant differences were observed in OS or CRR between the latter three groups of patients. CONCLUSIONS HCC with major vascular invasion, which are classified as pT3 under the current TNM staging, have the worst prognosis when compared with the other categories of pT3-4 disease. There is a need to redefine the T classification and to stratify locally advanced HCC.
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Ju MJ, Qiu SJ, Gao Q, Fan J, Cai MY, Li YW, Tang ZY. Combination of peritumoral mast cells and T-regulatory cells predicts prognosis of hepatocellular carcinoma. Cancer Sci 2009; 100:1267-74. [PMID: 19432885 PMCID: PMC11159676 DOI: 10.1111/j.1349-7006.2009.01182.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2009] [Revised: 03/28/2009] [Accepted: 03/29/2009] [Indexed: 12/12/2022] Open
Abstract
The peritumoral inflammatory environment is critical for the progression of intrahepatic recurrence of hepatocellular carcinoma (HCC) after curative resections. Here, we investigated the relevance of peritumoral mast cells (MCs) to HCC outcomes. Peritumoral tryptase(+) MCs in addition to Foxp3(+) T-regulatory cells (Tregs) were evaluated using immunohistochemistry enumeration in tissue microarrays containing 207 randomly selected HCC patients. Clinicopathological factors and postoperative outcomes were compared between high and low subgroups of MCs or Tregs. Compared to low denstiy, higher peritumoral MCs were associated with poorer clinical outcomes, and independently related to elevated 5-year recurrence incidence (54.1%vs 39.2%, P = 0.026). High-dense MCs were especially related to increased probability of early recurrence (within 2 years) (P = 0.004). We also found that peritumoral Tregs were positively correlated with MCs in density (r = 0.353, P < 0.001) and reversely related to HCC outcomes. Notably, MCs in combination with Tregs displayed better prognostic performances than MCs alone (area under curve [AUC](survival) = 0.629 vs 0.589, AUC(recurrence) = 0.632 vs 0.591). Moreover, MCs were positively correlated to alanine aminotransferase, a serum inflammatory marker (P = 0.014). Therefore, peritumoral MCs are promising prognostic parameters for HCC mainly through inflammation response-related mechanisms, and we propose that MCs and Tregs may cooperate with each other and result in poorer prognosis.
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Affiliation(s)
- Min-Jie Ju
- Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School of Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, China
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