|
1
|
Zhong J, Ding D, Liu J, Liu R, Chen P. SPNE: sample-perturbed network entropy for revealing critical states of complex biological systems. Brief Bioinform 2023; 24:7007928. [PMID: 36705581 DOI: 10.1093/bib/bbad028] [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: 11/22/2022] [Revised: 12/25/2022] [Accepted: 01/11/2023] [Indexed: 01/28/2023] Open
Abstract
Complex biological systems do not always develop smoothly but occasionally undergo a sharp transition; i.e. there exists a critical transition or tipping point at which a drastic qualitative shift occurs. Hunting for such a critical transition is important to prevent or delay the occurrence of catastrophic consequences, such as disease deterioration. However, the identification of the critical state for complex biological systems is still a challenging problem when using high-dimensional small sample data, especially where only a certain sample is available, which often leads to the failure of most traditional statistical approaches. In this study, a novel quantitative method, sample-perturbed network entropy (SPNE), is developed based on the sample-perturbed directed network to reveal the critical state of complex biological systems at the single-sample level. Specifically, the SPNE approach effectively quantifies the perturbation effect caused by a specific sample on the directed network in terms of network entropy and thus captures the criticality of biological systems. This model-free method was applied to both bulk and single-cell expression data. Our approach was validated by successfully detecting the early warning signals of the critical states for six real datasets, including four tumor datasets from The Cancer Genome Atlas (TCGA) and two single-cell datasets of cell differentiation. In addition, the functional analyses of signaling biomarkers demonstrated the effectiveness of the analytical and computational results.
Collapse
Affiliation(s)
- Jiayuan Zhong
- School of Mathematics and Big Data, Foshan University, Foshan 528000, China
- School of Mathematics, South China University of technology, Guangzhou 510640, China
| | - Dandan Ding
- Department of Thoracic Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China
| | - Juntan Liu
- School of Mathematics, South China University of technology, Guangzhou 510640, China
| | - Rui Liu
- School of Mathematics, South China University of technology, Guangzhou 510640, China
- Pazhou Lab, Guangzhou 510330, China
| | - Pei Chen
- School of Mathematics, South China University of technology, Guangzhou 510640, China
| |
Collapse
|
|
2
|
Abu El-Makarem MA, Kamel MF, Mohamed AA, Ali HA, Mohamed MR, Mohamed AEDM, El-Said AM, Ameen MG, Hassnine AA, Hassan HA. Down-regulation of hepatic expression of GHR/STAT5/IGF-1 signaling pathway fosters development and aggressiveness of HCV-related hepatocellular carcinoma: Crosstalk with Snail-1 and type 2 transforming growth factor-beta receptor. PLoS One 2022; 17:e0277266. [PMID: 36374927 PMCID: PMC9662744 DOI: 10.1371/journal.pone.0277266] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 10/24/2022] [Indexed: 11/16/2022] Open
Abstract
Background and aims So far, few clinical trials are available concerning the role of growth hormone receptor (GHR)/signal transducer and activator of transcription 5 (STAT5)/insulin like growth factor-1 (IGF-1) axis in hepatocarcinogenesis. The aim of this study was to evaluate the hepatic expression of GHR/STAT5/IGF-1 signaling pathway in hepatocellular carcinoma (HCC) patients and to correlate the results with the clinico-pathological features and disease outcome. The interaction between this signaling pathway and some inducers of epithelial-mesenchymal transition (EMT), namely Snail-1 and type 2 transforming growth factor-beta receptor (TGFBR2) was studied too. Material and methods A total of 40 patients with HCV-associated HCC were included in this study. They were compared to 40 patients with HCV-related cirrhosis without HCC, and 20 healthy controls. The hepatic expression of GHR, STAT5, IGF-1, Snail-1 and TGFBR2 proteins were assessed by immunohistochemistry. Results Compared with cirrhotic patients without HCC and healthy controls, cirrhotic patients with HCC had significantly lower hepatic expression of GHR, STAT5, and IGF-1proteins. They also displayed significantly lower hepatic expression of TGFBR2, but higher expression of Snail-1 versus the non-HCC cirrhotic patients and controls. Serum levels of alpha-fetoprotein (AFP) showed significant negative correlations with hepatic expression of GHR (r = -0.31; p = 0.029) and STAT5 (r = -0.29; p = 0.04). Hepatic expression of Snail-1 also showed negative correlations with GHR, STAT5, and IGF-1 expression (r = -0.55, p = 0.02; r = -0.472, p = 0.035, and r = -0.51, p = 0.009, respectively), whereas, hepatic expression of TGFBR2 was correlated positively with the expression of all these proteins (r = 0.47, p = 0.034; 0.49, p = 0.023, and r = 0.57, p<0.001, respectively). Moreover, we reported that decreased expression of GHR was significantly associated with serum AFP level>100 ng/ml (p = 0.048), increased tumor size (p = 0.02), vascular invasion (p = 0.002), and advanced pathological stage (p = 0.01). Similar significant associations were found between down-regulation of STAT5 expression and AFP level > 100 ng/ml (p = 0.006), vascular invasion (p = 0.009), and advanced tumor stage (p = 0.007). Also, attenuated expression of IGF-1 showed a significant association with vascular invasion (p < 0.001). Intriguingly, we detected that lower expression of GHR, STAT5 and IGF-1 were considered independent predictors for worse outcome in HCC. Conclusion Decreased expression of GHR/STAT5/IGF-1 signaling pathway may have a role in development, aggressiveness, and worse outcome of HCV-associated HCC irrespective of the liver functional status. Snail-1 and TGFBR2 as inducers of EMT may be key players. However, large prospective multicenter studies are needed to validate these results.
Collapse
Affiliation(s)
- Mona A. Abu El-Makarem
- Department of Internal Medicine, School of Medicine, Minia University, Minia, Egypt
- * E-mail:
| | - Mariana F. Kamel
- Department of Pathology, School of Medicine, Minia University, Minia, Egypt
- Department of Pathology, Minia Oncology Center, Minia, Egypt
| | - Ahmed A. Mohamed
- Department of Internal Medicine, School of Medicine, Minia University, Minia, Egypt
| | - Hisham A. Ali
- Department of Internal Medicine, School of Medicine, Minia University, Minia, Egypt
| | - Mahmoud R. Mohamed
- Department of Internal Medicine, School of Medicine, Minia University, Minia, Egypt
| | | | - Ahmed M. El-Said
- Department of Internal Medicine, School of Medicine, Minia University, Minia, Egypt
| | - Mahmoud G. Ameen
- Department of Pathology, South Egypt Cancer Institute, Assuit University, Assuit, Egypt
| | - Alshymaa A. Hassnine
- Department of Tropical Medicine and Gastroenterology, School of Medicine, Minia University, Minia, Egypt
| | - Hatem A. Hassan
- Department of Internal Medicine, School of Medicine, Minia University, Minia, Egypt
| |
Collapse
|
|
3
|
Suh YJ, Jin YJ, Jeong Y, Shin WY, Lee JM, Cho S, Yu JH, Lee JW. Resection or ablation versus transarterial therapy for Child-Pugh A patients with a single small hepatocellular carcinoma. Medicine (Baltimore) 2021; 100:e27470. [PMID: 34713824 PMCID: PMC8556049 DOI: 10.1097/md.0000000000027470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 09/19/2021] [Indexed: 01/05/2023] Open
Abstract
Data from a direct comparison of the long-term survival outcomes of surgical resection (SR) or radiofrequency ablation (RFA) versus transarterial therapy in Child-Turcotte-Pugh (CTP)-class A patients with a single small T1/T2 stage hepatocellular carcinoma (HCC) (≤3 cm) are still lacking. This study retrospectively compared the therapeutic outcomes of these treatment types for CTP-A patients with a single small HCC.Using a nationwide Korean registry, we identified 2314 CTP-A patients with SR (n = 722), RFA (n = 731), or transarterial therapy (n = 861) for a single (≤3 cm) T1/T2 stage HCC from 2008 to 2014. The posttreatment overall survival (OS) of transarterial therapy with either SR or RFA were compared using the Inverse Probability of treatment Weighting (IPW). The median follow-up period was 50 months (range 1-107 months).After IPW, the cumulative OS rates after SR or RFA were significantly higher than those after transarterial therapy in all subjects (all P values < .05). The OS rates after SR or RFA were better than those after transarterial therapy in patients with the hepatitis B or C virus (all P values < .05), and in patients aged <65 years (all P values < .05). The cumulative OSs between RFA and transarterial therapy were statistically comparable in patients with a 2 to 3 cm HCC and aged ≥65 years, respectively. For all subjects, the weighted Cox proportional hazards model using IPW provided the adjusted hazard ratios (95% confidence interval) for the OS after SR versus transarterial therapy and after RFA versus transarterial therapy of 0.42 (0.30-0.60) (P < .001) and 0.78 (0.61-0.99) (P = .044), respectively.In CTP-A patients with a single (≤3 cm) T1/T2 HCC, SR or RFA provides a better OS than transarterial therapy, regardless of the HCC etiology (hepatitis B virus or hepatitis C virus), especially in patients with HCC of <2 cm and aged <65 years.
Collapse
Affiliation(s)
- Young Ju Suh
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, South Korea
| | - Young-Joo Jin
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, South Korea
- The Korean Liver Cancer Study Group, South Korea
| | - Yujin Jeong
- Department of Biostatistics, Korea University, Seoul, South Korea
| | - Woo Young Shin
- Department of Surgery, Inha University Hospital, Inha University School of Medicine, Incheon, South Korea
| | - Jeong-min Lee
- Department of Radiology, Inha University Hospital, Inha University School of Medicine, Incheon, South Korea
| | - Soongu Cho
- Department of Radiology, Inha University Hospital, Inha University School of Medicine, Incheon, South Korea
| | - Jung Hwan Yu
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, South Korea
- The Korean Liver Cancer Study Group, South Korea
| | - Jin-Woo Lee
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, South Korea
- The Korean Liver Cancer Study Group, South Korea
| |
Collapse
|
|
4
|
Huang T, Yan T, Chen G, Zhang C. Development and Validation of a Gene Mutation-Associated Nomogram for Hepatocellular Carcinoma Patients From Four Countries. Front Genet 2021; 12:714639. [PMID: 34621291 PMCID: PMC8490742 DOI: 10.3389/fgene.2021.714639] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 09/03/2021] [Indexed: 01/07/2023] Open
Abstract
Background: Genomic alteration is the basis of occurrence and development of carcinoma. Specific gene mutation may be associated with the prognosis of hepatocellular carcinoma (HCC) patients without distant or lymphatic metastases. Hence, we developed a nomogram based on prognostic gene mutations that could predict the overall survival of HCC patients at early stage and provide reference for immunotherapy. Methods: HCC cohorts were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. The total patient was randomly assigned to training and validation sets. Univariate and multivariate cox analysis were used to select significant variables for construction of nomogram. The support vector machine (SVM) and principal component analysis (PCA) were used to assess the distinguished effect of significant genes. Besides, the nomogram model was evaluated by concordance index, time-dependent receiver operating characteristics (ROC) curve, calibration curve and decision curve analysis (DCA). Gene Set Enrichment Analysis (GSEA), CIBERSORT, Tumor Immune Dysfunction and Exclusion (TIDE) and Immunophenoscore (IPS) were utilized to explore the potential mechanism of immune-related process and immunotherapy. Results: A total of 695 HCC patients were selected in the process including 495 training patients and 200 validation patients. Nomogram was constructed based on T stage, age, country, mutation status of DOCK2, EYS, MACF1 and TP53. The assessment showed the nomogram has good discrimination and high consistence between predicted and actual data. Furthermore, we found T cell exclusion was the potential mechanism of malignant progression in high-risk group. Meanwhile, low-risk group might be sensitive to immunotherapy and benefit from CTLA-4 blocker treatment. Conclusion: Our research established a nomogram based on mutant genes and clinical parameters, and revealed the underlying association between these risk factors and immune-related process.
Collapse
Affiliation(s)
- Tingping Huang
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tao Yan
- Department of Thoracic Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Gonghai Chen
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chunqing Zhang
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| |
Collapse
|
|
5
|
Yu W, Dai Y. lncRNA LOXL1-AS1 promotes liver cancer cell proliferation and migration by regulating the miR-377-3p/NFIB axis. Oncol Lett 2021; 22:624. [PMID: 34267816 PMCID: PMC8258629 DOI: 10.3892/ol.2021.12885] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 05/11/2021] [Indexed: 12/11/2022] Open
Abstract
Liver cancer is becoming one of the most lethal malignancies due to its high incidence and mortality. Accumulating studies have indicated that long non-coding RNAs (lncRNAs) are critical regulators of the tumorigenesis and development of various types of cancer, including liver cancer. LncRNA LOXL1-antisense RNA 1 (LOXL1-AS1) has been identified as an oncogene in some types of human cancer; however, its role in liver cancer remains obscure. Reverse transcription-quantitative PCR was used to measure LOXL1-AS1 expression in liver cancer tissues and cells. Western blot, MTT, colony formation, glucose uptake and wound healing assays were used to explore the biological function of LOXL1-AS1 in liver cancer cells. Bioinformatics analysis and RNA pull-down and luciferase reporter assays were used to explore the molecular mechanism of LOXL1-AS1 in liver cancer cells. Statistical analysis was used to compare the experimental results of different groups. In the present study, LOXL1-AS1 expression was significantly upregulated in liver cancer tissues and cells compared with in normal liver tissues and cells, respectively. High LOXL1-AS1 expression was associated with poor clinical outcomes in patients with liver cancer. Furthermore, LOXL1-AS1-knockdown suppressed glucose metabolism, proliferation, migration and epithelial-mesenchymal transition (EMT) of liver cancer cells. Subsequently, LOXL1-AS1 acted as a microRNA (miR)-377-3p sponge, and nuclear factor I B (NFIB) was confirmed as the downstream target of miR-377-3p in liver cancer cells. Additionally, rescue assays suggested that NFIB overexpression countervailed the inhibitory influence of LOXL1-AS1 silencing on liver cancer cellular processes. The present study demonstrated that LOXL1-AS1 promoted glucose metabolism, proliferation, migration and EMT of liver cancer cells by sponging miR-377-3p and modulating NFIB, which may provide a novel insight for the treatment of liver cancer.
Collapse
Affiliation(s)
- Wei Yu
- Department of General Surgery, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225001, P.R. China
| | - Yong Dai
- Department of General Surgery, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225001, P.R. China
| |
Collapse
|
|
6
|
She WH, Chan ACY, Ma KW, Dai WC, Chok KSH, Cheung TT, Lo CM. Critical appraisal of TNM versus HKU staging system for postoperative prognostic evaluation of hepatocellular carcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:919. [PMID: 34350234 PMCID: PMC8263888 DOI: 10.21037/atm-20-7611] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 03/31/2021] [Indexed: 01/11/2023]
Abstract
BACKGROUND The 8th edition of the American Joint Committee on Cancer tumor-node-metastasis staging system (AJCC 8th) has been launched with modifications in T staging. The University of Hong Kong liver cancer staging system (HKUSS) has been proven to better categorize hepatocellular carcinoma (HCC) into different T stages. This study aimed to compare the two systems' predictive ability for HCC recurrence after primary surgical resection. METHODS Patients who had primary, curative resection for HCC between 1989 and 2017 were reviewed. The Kaplan-Meier plot was used to estimate disease-free survival (DFS), and the log-rank test was used for survival comparison between subgroups. The two systems' prediction of recurrence was evaluated by the Cox regression model. RESULTS Totally 1,815 patients were included. With AJCC 8th, the 5-year DFS was 58.9% for T1a, 52.3% for T1b, 30% for T2, 16.9% for T3, and 14.4% for T4. No survival difference was demonstrated between T1a and T1b (P=0.668) or between T3 and T4 (P=0.562). With HKUSS, the 5-year DFS was 57.7% for T1, 43.4% for T2, 28.9% for T3, and 15.7% for T4. The T staging in HKUSS showed significant survival differences (T1 vs. T2, T2 vs. T3, and T3 vs. T4; P<0.001). Using receiver operating characteristic curves to show the recurrence status in the two systems, HKUSS had the largest area under curve (AUC) (HKUSS: AUC =0.655, SE 0.014, P<0.001, 95% CI, 0.628-0.681; AJCC 8th: AUC =0.652, SE 0.013, P<0.001, 95% CI, 0.625-0.677). CONCLUSIONS HKUSS showed better categorization of HCC. In the context of primary surgical resection, HKUSS may be more appropriate for stratification of patients with HCC with various T stages, and thus the choice of staging system when primary surgical resection is considered for patients of HCC.
Collapse
Affiliation(s)
- Wong Hoi She
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Albert C. Y. Chan
- Department of Surgery, The University of Hong Kong, Hong Kong, China
- Department of Surgery, The University of Hong Kong–Shenzhen Hospital, Shenzhen, China
| | - Ka Wing Ma
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Wing Chiu Dai
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | | | - Tan To Cheung
- Department of Surgery, The University of Hong Kong, Hong Kong, China
- Department of Surgery, The University of Hong Kong–Shenzhen Hospital, Shenzhen, China
| | - Chung Mau Lo
- Department of Surgery, The University of Hong Kong, Hong Kong, China
- Department of Surgery, The University of Hong Kong–Shenzhen Hospital, Shenzhen, China
| |
Collapse
|
|
7
|
Beutler BD, Ulanja MB, Krishan R, Aluru V, Ndukwu ML, Hagen MM, Dupin ZD, Willyard CE, Moody AE, Boampong-Konam K, Zell SC. Sociodemographic Characteristics as Predictors of Outcomes in Hepatocellular Carcinoma: A Retrospective Cohort Study. Cancer Control 2021; 27:1073274820956615. [PMID: 32951450 PMCID: PMC7791478 DOI: 10.1177/1073274820956615] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Race, gender, insurance status, and income play important roles in predicting health care outcomes. However, the impact of these factors has yet to be fully elucidated in the setting of hepatocellular carcinoma (HCC). METHODS We designed a retrospective cohort study utilizing data from the Surveillance, Epidemiology, and End Results (SEER) program to identify patients diagnosed with resectable HCC (N = 28,518). Demographic factors of interest included race (Asian/Pacific Islander [API], African American [AA], Native American/Alaska Native [NA], or White [WH]) and gender (male [M] or female [F]). Insurance classifications included those having Medicare/Private Insurance [ME/PI], Medicaid [MAID], or No Insurance [NI]. Median household income was estimated for all diagnosed with HCC. Endpoints included: (1) overall survival; (2) likelihood of receiving a recommendation for surgery; and (3) specific surgical intervention performed. Multivariate multinomial logistic regression for relative risk ratio (RRR) and Cox regression models were used to identify pertinent associations. RESULTS Race, gender, insurance status, and income had statistically significant effects on the likelihood of surgical recommendation and overall survival. API were more likely to receive a recommendation for hepatic resection (RRR = 1.45; 95% CI: 1.31-1.61; Reference Race: AA) and exhibited prolonged overall survival (HR = 0.77; 95% CI: 0.73-0.82; Reference Race: AA) as compared to members of any other ethnic group; there was no difference in these endpoints between AA, NA, or WH individuals. Gender also had a significant effect on survival: Females exhibited superior overall survival (HR = 0.89; 95% CI: 0.85-0.93; Reference Gender: M) as compared to males. Patients who had ME/PI were more likely than those with MAID or NI to receive a surgical recommendation. ME/PI was also associated with superior overall survival. Conclusions: Race, gender, insurance status, and income have measurable effects on HCC management and outcomes. The underlying causes of these disparities warrant further investigation.
Collapse
Affiliation(s)
- Bryce D Beutler
- Department of Internal Medicine, Reno School of Medicine, University of Nevada, Reno, NV, USA
| | - Mark B Ulanja
- Department of Internal Medicine, Reno School of Medicine, University of Nevada, Reno, NV, USA
| | - Rohee Krishan
- Department of Internal Medicine, Reno School of Medicine, University of Nevada, Reno, NV, USA
| | - Vijay Aluru
- Department of Internal Medicine, Reno School of Medicine, University of Nevada, Reno, NV, USA
| | - Munachismo L Ndukwu
- Department of Internal Medicine, Reno School of Medicine, University of Nevada, Reno, NV, USA
| | - Molly M Hagen
- Office of Medical Research, Reno School of Medicine, University of Nevada, Reno, NV, USA
| | - Zachary D Dupin
- Miller Institute School of Public Health, George Washington University, Washington, DC, USA
| | - Charles E Willyard
- Department of Internal Medicine, Reno School of Medicine, University of Nevada, Reno, NV, USA
| | | | | | - Steven C Zell
- Department of Internal Medicine, Reno School of Medicine, University of Nevada, Reno, NV, USA
| |
Collapse
|
|
8
|
Satala CB, Jung I, Kobori L, Kovacs Z, Fodor D, Szodorai R, Gurzu S. Benefits of the 8th American Joint Committee on Cancer System for Hepatocellular Carcinoma Staging. J Gastrointest Cancer 2021; 52:243-248. [PMID: 32173767 DOI: 10.1007/s12029-020-00394-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
PURPOSE We aimed to emphasize the prognostic impact of differences included in the 8th versus the previous 7th edition of AJCC (American Joint Committee on Cancer) Cancer Staging manual for hepatocellular carcinoma (HCC). METHODS A number of 87 consecutive HCCs were retrospectively evaluated and staged, using the 7th and 8th edition of AJCC staging systems. The clinicopathological parameters were correlated with the overall survival rate. No preoperative chemotherapy was received by any of the patients. RESULTS According to the 7th edition of AJCC manual, 52 of the 87 cases were staged as pT2 and 35 as pT1. After restaging, according to the 8th edition, 23 of the 52 pT2 cases were understaged as pT1b, and the rest of the 29 remained as pT2. Regarding the 35 HCCs classified as pT1, using 7th edition, all of them were restaged as pT1a. Compared to the 7th staging system, using the 8th edition of AJCC manual, the percentage of pT2 tumors significantly decreased, from 59.77 to 33.33%. The patient's gender, age, tumor focality, and grade of differentiation did not prove to have any prognostic value. Regarding pT stage, it does not influence the overall survival rate, independently from the used staging system. CONCLUSION The staging criteria, in the most recent edition of AJCC, are simplified and allowed tumor understaging. These changes do not have independent prognostic value. The prognostic impact of pT understaging should be evaluated in larger cohorts.
Collapse
Affiliation(s)
- Catalin Bogdan Satala
- Department of Pathology, Emil Palade University of Medicine, Pharmacy, Sciences and Technology, 38 Gheorghe Marinescu Street, 530149, Targu-Mures, Romania
- Department of Pathology, Clinical County Emergency Hospital, Targu-Mures, Romania
| | - Ioan Jung
- Department of Pathology, Emil Palade University of Medicine, Pharmacy, Sciences and Technology, 38 Gheorghe Marinescu Street, 530149, Targu-Mures, Romania
| | - Laszlo Kobori
- Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary
| | - Zsolt Kovacs
- Department of Pathology, Clinical County Emergency Hospital, Targu-Mures, Romania
| | - Decebal Fodor
- Department of Pathology, Clinical County Emergency Hospital, Targu-Mures, Romania
- Department of Anatomy and Embryology, Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu-Mures, Romania
| | - Rita Szodorai
- Department of Pathology, Emil Palade University of Medicine, Pharmacy, Sciences and Technology, 38 Gheorghe Marinescu Street, 530149, Targu-Mures, Romania
| | - Simona Gurzu
- Department of Pathology, Emil Palade University of Medicine, Pharmacy, Sciences and Technology, 38 Gheorghe Marinescu Street, 530149, Targu-Mures, Romania.
- Department of Pathology, Clinical County Emergency Hospital, Targu-Mures, Romania.
- Department of Pathology, Research Center (CCAMF) of the Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu-Mures, Romania.
| |
Collapse
|
|
9
|
Chemerin Is Induced in Non-Alcoholic Fatty Liver Disease and Hepatitis B-Related Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12102967. [PMID: 33066325 PMCID: PMC7602083 DOI: 10.3390/cancers12102967] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 10/08/2020] [Accepted: 10/12/2020] [Indexed: 12/14/2022] Open
Abstract
Chemerin is protective in experimental models of hepatocellular carcinoma (HCC). Noteworthy, chemerin mRNA and protein were reduced in HCC tissues of Asian patients with mostly hepatitis B disease etiology. The current study nevertheless showed that chemerin protein was induced in tumor tissues of European HCC patients with non-alcoholic fatty liver disease (NAFLD) and patients with unclear disease etiology. A similar regulation was observed in hepatitis B virus (HBV), but not in hepatitis C virus (HCV), related HCC. The apparent discrepancy between the regulation of chemerin in HBV-HCC obtained from our study and recent reports led us to use the chemerin antibodies applied in the previous assays. These antibodies could not equally detect different chemerin isoforms, which were overexpressed in HepG2 cells. Higher chemerin protein in HCC was nevertheless confirmed by the use of all antibodies. Chemerin protein was low in Huh7 and PLC/PRF/5 cells whereas HepG2 and Hep3B cells had chemerin protein similar as primary human hepatocytes. Besides, the anti-tumor effects of retinoids in hepatocyte cell lines did not enclose upregulation of chemerin, which was initially discovered as a tazarotene induced protein in the skin. Finally, protein levels of the chemerin receptor, chemokine-like receptor 1 (CMKLR1), declined in non-viral, and tended to be lower in HBV-HCC tissues suggesting reduced chemerin activity in the tumors. To sum up, our work showed an opposite regulation of chemerin and CMKLR1 in NAFLD and HBV associated HCC. In HCV-HCC neither chemerin nor its receptor were changed in the tumor tissues. Current findings do not support a critical role of total chemerin protein levels in HCC of non-viral and viral etiology. Accordingly, tumor-localized chemerin protein was not associated with tumor-node-metastasis classification.
Collapse
|
|
10
|
Zeng YL, Guo ZY, Su HZ, Zhong FD, Jiang KQ, Yuan GD. Diagnostic and prognostic value of lncRNA cancer susceptibility candidate 9 in hepatocellular carcinoma. World J Gastroenterol 2019; 25:6902-6915. [PMID: 31908394 PMCID: PMC6938724 DOI: 10.3748/wjg.v25.i48.6902] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 11/27/2019] [Accepted: 12/13/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common malignant gastrointestinal tumor. There are currently few clinical diagnostic and prognostic markers for HCC. LncRNA cancer susceptibility candidate 9 (CASC9) is a long-chain non-coding RNA discovered in recent years, and previous studies have found that lncRNA CASC9 participates in the occurrence and development of HCC, but its clinical value remains unclear. AIM To determine the expression of lncRNA CASC9 in HCC and its diagnostic and prognostic value. METHODS Data on CASC9 expression in patients with HCC were collected from the Cancer Genome Atlas (TCGA) database to analyze the relationship between CASC9 and patient survival. A total of 80 HCC patients treated in The First Affiliated Hospital of Guangxi Medical University from May 2012 to January 2014 were enrolled in the patient group, and 50 healthy subjects were enrolled in the control group during the same period. CASC9 expression in the two groups was determined using quantitative real-time polymerase chain reaction, and its diagnostic and prognostic value was analyzed based on the CASC9 data and pathological data in these HCC patients. The relationship between CASC9 and patient survival was assessed during the 5-year follow-up period. RESULTS Analysis of data from TCGA database revealed that control samples showed significantly lower CASC9 expression than carcinoma tissue samples (P < 0.001); the low CASC9 expression group had a higher survival rate than the high CASC9 expression group (P = 0.011), and the patient group showed significantly increased expression of serum CASC9, with the area under the curve (AUC) of 0.933. CASC9 expression was related to tumor size, combined hepatitis, tumor, node, metastasis (TNM) staging, lymph node metastasis, differentiation and alpha fetoprotein, and the high CASC9 expression group showed lower 1-year, 3-year and 5-year survival rates than the low CASC9 expression group (all a P < 0.05). Multivariate Cox regression analysis revealed that TNM staging, lymph node metastasis, differentiation, alpha fetoprotein and CASC9 were independent factors affecting the prognosis of patients. Stage I+II patients with lymph node metastasis, low differentiation, and alpha fetoprotein > 200 ng/mL had a poor 5-year survival rate. CONCLUSION High CASC9 expression is beneficial in the prognosis of HCC patients. CASC9 is expected to be a potential diagnostic and prognostic indicator of HCC.
Collapse
Affiliation(s)
- Yong-Lian Zeng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Zhen-Ya Guo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Hui-Zhao Su
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Fu-Di Zhong
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Ke-Qing Jiang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Guan-Dou Yuan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| |
Collapse
|
|
11
|
The Pre- and Postoperative FIB-4 Indexes Are Good Predictors to the Outcomes of HBV-Related HCC Patients after Resection. Gastroenterol Res Pract 2019; 2019:8945798. [PMID: 31885547 PMCID: PMC6914978 DOI: 10.1155/2019/8945798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 09/24/2019] [Indexed: 12/21/2022] Open
Abstract
Background and Aim Liver fibrosis is associated with the prognosis of patients with hepatocellular carcinoma (HCC) after resection. The fibrosis-4 (FIB-4) index is an accurate and noninvasive marker to determine the degree of liver fibrosis. Here, we evaluated the effect of pre- and postoperative FIB-4 index in predicting the outcomes after resection of HCC in patients who have chronic hepatitis B (CHB) infection. Methods A total of 534 CHB patients with HCC who received curative hepatectomy between 2001 and 2016 at Kaohsiung Chang Gung Memorial Hospital, Taiwan, were enrolled in this study. The impact of the FIB-4 index (preoperative and the 1st year after operation) on overall survival (OS) and recurrence-free survival (RFS) was evaluated. Results There was a significant association between the preoperative FIB-4 index and Metavir fibrosis stage (p < 0.01). The multivariate analysis showed that preoperative FIB‐4 > 2 is an independent risk factor for RFS and OS after HCC curative resection [hazard ratio (HR), 1.902; 95% CI, 1.491–2.460; p < 0.001, and HR, 2.207; 95% CI, 1.420–3.429; p < 0.001, respectively]. Notably, preoperative FIB-4 is also an independent risk factor for RFS (HR, 1.219; p = 0.035) in noncirrhotic patients. Furthermore, patients had deteriorated FIB-4 1 year after operation [definition: the value (the 1st year FIB‐4 after operation minus preoperative FIB‐4) > 1] and had an adverse outcome in RFS and OS (p < 0.001, both). Conclusion The pre and postoperative FIB-4 indexes are useful clinical markers to predict the prognosis in HBV-HCC patients after curative hepatectomy.
Collapse
|
|
12
|
Cao F, Shen L, Qi H, Xie L, Song Z, Chen S, Fan W. Tree-based classification system incorporating the HVTT-PVTT score for personalized management of hepatocellular carcinoma patients with macroscopic vascular invasion. Aging (Albany NY) 2019; 11:9544-9555. [PMID: 31682230 PMCID: PMC6874465 DOI: 10.18632/aging.102403] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 10/26/2019] [Indexed: 12/24/2022]
Abstract
Purpose: To develop a decision tree algorithm-based classification system for personalized management of hepatocellular carcinoma (HCC) patients with macroscopic vascular invasion. Results: The HVTT-PVTT score could differentiate two groups of patients (< 3 and ≥ 3 points) with different survival outcomes (7.4 vs 4.6 months, P < 0.001) and surgical proportion (24.4% vs 3.6%, P < 0.001). Using the Cox regression model and classification and regression tree (CART) algorithm, patients in the training set were automatically separated into three subgroups with different prognosis (10.3 vs 6.1 vs 3.3 months). The predictive accuracy was verified in the validation group (12.3 vs 6.9 vs 5.6 months) and was better than other commonly used staging systems. Conclusions: Our study proposed a new classification system for HCC patients with macroscopic vascular invasion that could be meaningful for personalized management of these patients. Methods: A total of 869 HCC patients initially diagnosed with macroscopic vascular invasion were randomly divided into training and validation sets. A comprehensive and simplified HVTT-PVTT score was set up for subdivision of vascular invasion according to the patients’ survival outcome. Then, a decision tree algorithm-based classification system was used to establish the refined subdivision system incorporating all independent prognostic factors.
Collapse
Affiliation(s)
- Fei Cao
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Guangdong, China
| | - Lujun Shen
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Guangdong, China
| | - Han Qi
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Guangdong, China
| | - Lin Xie
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Guangdong, China
| | - Ze Song
- Department of Oncology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China
| | - Shuanggang Chen
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Guangdong, China
| | - Weijun Fan
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Guangdong, China
| |
Collapse
|
|
13
|
Zhang L, Yan L, Niu H, Ma J, Yuan BY, Chen YH, Zhuang Y, Hu Y, Zeng ZC, Xiang ZL. A nomogram to predict prognosis of patients with unresected hepatocellular carcinoma undergoing radiotherapy: a population-based study. J Cancer 2019; 10:4564-4573. [PMID: 31528220 PMCID: PMC6746140 DOI: 10.7150/jca.30365] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 05/26/2019] [Indexed: 12/19/2022] Open
Abstract
Background: Radiotherapy is a primary treatment strategy for patients with unresectable hepatocellular carcinoma (HCC); however, the prognostic factors among HCC patients who have received radiotherapy but not undergone surgery have not been systematically studied. Thus, the prognostic factors were investigated in this study based on the Surveillance, Epidemiology, and End Results (SEER) Medicare database. Methods: A screening process was used for select cases from the SEER database. Survival was analyzed using the Kaplan-Meier method and log-rank test, the Cox proportional hazards regression model, and a competing risk model. A nomogram was established for predicting 1- and 3-year overall survival (OS) of patients. Results: A total of 1305 HCC patients who received radiotherapy but had not undergone surgery were included in this study and divided into training (n = 1175) and validation cohorts (n = 130). Patients in the training cohort had a 1-year OS rate of 30.9±1.3%, a 3-year OS rate of 10.0±1.0%, and a median survival rate of 6.0 months (range, 5.4-6.6 months). Race (p = 0.025), T stage (p < 0.001), N stage (p < 0.001), M stage (p < 0.001), and chemotherapy (p < 0.001) were identified as independent risk factors by multivariate analyses in the training cohort, while sex, age, grade, marital status, and insurance status were not independent factors. Survival in patients who received radiotherapy was worse with respect to the following characteristics: black race; higher T, N, or M stage; and no chemotherapy. A nomogram was established based on the results of the multivariate analysis, which was internally validated by a concordance index (C-index) of 0.731±0.016 and a group of calibration plots. External validation was carried out and the C-index was 0.738±0.049, which demonstrated the effectiveness of the nomogram we constructed. Conclusions: Race, T stage, N stage, M stage, and chemotherapy were independent risk factors for survival of HCC patients who received radiotherapy but had not undergone surgery. A validated nomogram was formulated to predict 1- and 3-year OS in these patients based on individual clinical characteristics.
Collapse
Affiliation(s)
- Li Zhang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China
| | - Li Yan
- Department of Radiation Oncology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China
| | - Hao Niu
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China
| | - Jie Ma
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China
| | - Bao-Ying Yuan
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China
| | - Yu-Han Chen
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China
| | - Yuan Zhuang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China
| | - Yong Hu
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China
| | - Zhao-Chong Zeng
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China
| | - Zuo-Lin Xiang
- Department of Radiation Oncology, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China
| |
Collapse
|
|
14
|
Golfieri R, Bargellini I, Spreafico C, Trevisani F. Patients with Barcelona Clinic Liver Cancer Stages B and C Hepatocellular Carcinoma: Time for a Subclassification. Liver Cancer 2019; 8:78-91. [PMID: 31019899 PMCID: PMC6465743 DOI: 10.1159/000489791] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 04/27/2018] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The Barcelona Clinic Liver Cancer (BCLC) intermediate and advanced stages (BCLC B and C) of hepatocellular carcinoma (HCC) both include heterogeneous populations. Patients classified as BCLC stage B present with different tumour burdens, and the recommended treatment is transarterial chemoembolization (TACE). A similar heterogeneity of tumour burden and liver function can be found among patients classified as BCLC stage C, which includes diverse clinical features (performance status [PS] 1-2), macrovascular invasion (MVI) including portal vein tumour (PVT) thrombosis, and/or extra-hepatic spread. Nonetheless, the anti-tumoural treatment formally recommended by Western guidelines is systemic therapy with sorafenib. SUMMARY Several proposals of subclassification for both these stages have been suggested in recent years, differentiating the more appropriate treatments for each substage. In particular, for BCLC stage C patients with PVT, therapeutic indications, clinical outcomes, and response to locoregional therapy are notably different in the presence of subsegmental, segmental or main PVT. Accordingly, liver resection and transarterial therapies, such as TACE or transarterial embolization (TAE) and 90Y-radioembolization (TARE), can be performed in locally advanced HCC with intrahepatic MVI according to its extent. In fact, surgery and TACE/TAE/TARE have no contraindications in the presence of PVT limited to the subsegmental or segmental branches in Child-Pugh class A patients, whereas only TARE should be utilized when there is lobar branch involvement. The presence of PS 1 should not be sufficient to allocate patients to the advanced stage since this would preclude any potential treatment for HCC. Patients should be properly classified as BCLC C only in cases of main portal trunk PVT, and treated according to the guidelines, provided that they belong to Child-Pugh class A. KEY MESSAGES Subclassifications of BCLC B and C stages are urgently needed and require validation in order to guide clinicians towards the most effective treatment option.
Collapse
Affiliation(s)
- Rita Golfieri
- Radiology Unit, Department of Diagnostic and Preventive Medicine, S. Orsola-Malpighi Hospital, Alma Mater Studiorum – University of Bologna, Bologna, Italy
| | - Irene Bargellini
- Interventional Radiology Unit, Pisa University Hospital, Pisa, Italy
| | - Carlo Spreafico
- Interventional Radiology Unit, Department of Radiology, Istituto Tumori of Milan IRCCS Foundation, Milan, Italy
| | - Franco Trevisani
- Division of Semeiotics, Department of Medical and Surgical Sciences, Alma Mater Studiorum, Bologna, Italy
| |
Collapse
|
|
15
|
Kim IG, Hu XG, Wang HJ, Kim BW, Hong SY, Shen XY. The 7th/8th American Joint Committee on Cancer and the Modified Union for International Cancer Control Staging System for Hepatocellular Carcinoma. Yonsei Med J 2019; 60:140-147. [PMID: 30666835 PMCID: PMC6342718 DOI: 10.3349/ymj.2019.60.2.140] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 11/10/2018] [Accepted: 12/11/2018] [Indexed: 12/31/2022] Open
Abstract
PURPOSE Although many staging systems have been proposed for hepatocellular carcinoma (HCC), there is no globally accepted system due to the extreme heterogeneity of the disease. We aimed to compare the results of the 7th/8th American Joint Committee on Cancer (AJCC) and the modified Union for International Cancer Control (mUICC) staging systems in patients with HCC. MATERIALS AND METHODS We collected data from 792 patients who underwent hepatic resection at our center. The Kaplan-Meier method was used to determine disease-free survival and overall survival. To evaluate homogeneity, '-2 log likelihood' was calculated using Cox proportional hazards regression. To measure discriminatory ability, the linear trend chi method and the Cochran-Armitage test for trend were used. The ability to accurately predict survival was verified by cross-validation analysis. RESULTS Kaplan-Meier curves for disease-free survival and overall survival showed mUICC to be superior to the 7th/8th AJCC. The homogeneity test indicated that mUICC was the best for both disease-free survival and overall survival. In the discriminatory ability test, the chi-square value of mUICC was the best for disease-free survival, while the 7th AJCC had the best value for overall survival. In the cross-validation analysis, all three staging systems had significant predictive power. CONCLUSION mUICC seemed to be superior to the 7th/8th AJCC after analyzing the data of our surgical patients, although the geographic heterogeneity of HCC might result in differences between the staging systems. We believe that, while the three staging systems allow for the clear stratification of patients into prognostic groups, mUICC may be more appropriate in HCC.
Collapse
Affiliation(s)
- In Gyu Kim
- Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Ajou University School of Medicine, Suwon, Korea
| | - Xu Guang Hu
- Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Ajou University School of Medicine, Suwon, Korea
| | - Hee Jung Wang
- Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Ajou University School of Medicine, Suwon, Korea.
| | - Bong Wan Kim
- Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Ajou University School of Medicine, Suwon, Korea
| | - Sung Yeon Hong
- Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Ajou University School of Medicine, Suwon, Korea
| | - Xue Yin Shen
- Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Ajou University School of Medicine, Suwon, Korea
| |
Collapse
|
|
16
|
Zhu Z, Zhang Y, Huang C, Tang Y, Sun C, Ju W, He X. Overexpression of RALY promotes migration and predicts poor prognosis in hepatocellular carcinoma. Cancer Manag Res 2018; 10:5559-5572. [PMID: 30519104 PMCID: PMC6235007 DOI: 10.2147/cmar.s182996] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Introduction RALY plays a critical role in promoting invasiveness and is associated with poor prognosis in different types of cancers. However, the prognostic value of RALY and its precise role in hepatocellular carcinoma (HCC) remain unknown. Materials and methods We detected the expression of RALY in 127 clinical HCC tissue samples and seven HCC cell lines by immunohistochemical staining and Western blotting. The prognostic value of RALY expression was assessed using the Kaplan–Meier method. The expression and prognostic value of RALY were also studied by bioinformatics analysis of data from the Gene Expression Omnibus and The Cancer Genome Atlas. The biological influence of RALY on HCC cell lines was studied using proliferation, transwell migration, and invasion assays in vitro. Results The expression of RALY in HCC tissues was significantly higher than that in adjacent normal liver tissues. Abnormally high expression of RALY was associated with tumor size (P=0.031), TNM stage (P=0.026), presurgical serum AFP levels (P=0.025), and vascular invasion (P=0.001). Kaplan–Meier analysis demonstrated that higher expression of RALY correlated with poorer overall survival and disease-free survival in HCC patients. High RALY expression was an independent adverse prognostic factor for overall survival (HR =2.559, 95% CI: 1.710–3.827, P<0.001) and disease-free survival (HR =2.053, 95% CI: 1.384–3.047, P<0.001) in HCC. Moreover, knockdown of RALY expression using a specific shRNA suppressed the proliferation, migration, and invasion capabilities of HCC cells in vitro. Knockdown of RALY expression in HCC cell lines resulted in upregulation of E-cadherin and downregulation of N-cadherin, vimentin, and snail. Conclusion Taken together, our results indicate that RALY represents a biomarker for the prognosis of patients with HCC and highlight the importance of RALY as an oncogene in HCC.
Collapse
Affiliation(s)
- Zebin Zhu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China, , .,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou 510080, Guangdong, China, , .,Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou 510080, Guangdong, China, ,
| | - Yixi Zhang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China, , .,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou 510080, Guangdong, China, , .,Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou 510080, Guangdong, China, ,
| | - Chensong Huang
- Department of Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Yunhua Tang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China, , .,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou 510080, Guangdong, China, , .,Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou 510080, Guangdong, China, ,
| | - Chengjun Sun
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China, , .,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou 510080, Guangdong, China, , .,Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou 510080, Guangdong, China, ,
| | - Weiqiang Ju
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China, , .,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou 510080, Guangdong, China, , .,Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou 510080, Guangdong, China, ,
| | - Xiaoshun He
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China, , .,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou 510080, Guangdong, China, , .,Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou 510080, Guangdong, China, ,
| |
Collapse
|
|
17
|
Bao J, Chen X, Hou Y, Kang G, Li Q, Xu Y. LncRNA DBH-AS1 facilitates the tumorigenesis of hepatocellular carcinoma by targeting miR-138 via FAK/Src/ERK pathway. Biomed Pharmacother 2018; 107:824-833. [DOI: 10.1016/j.biopha.2018.08.079] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Revised: 08/13/2018] [Accepted: 08/15/2018] [Indexed: 12/18/2022] Open
|
|
18
|
Chang PY, Huang CC, Hung CH, Yu CY, Wu DK, Hwang JI, Liang PC, Wu RH, Tsai WL, Lin YJ, Liu YS, Liang HL, Lee RC, Chen CH. Multidisciplinary Taiwan Consensus Recommendations for the Use of DEBDOX-TACE in Hepatocellular Carcinoma Treatment. Liver Cancer 2018; 7:312-322. [PMID: 30488021 PMCID: PMC6249590 DOI: 10.1159/000487608] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 02/11/2018] [Indexed: 02/04/2023] Open
Abstract
Transarterial chemoembolization (TACE) is the first-line treatment in patients with unresectable hepatocellular carcinoma (HCC). In recent years, there has been increasing clinical evidence that drug-eluting beads provide a combined ischemic and cytotoxic effect that may be superior to conventional TACE, with low systemic toxicity. The therapeutic value of TACE performed using the embolic microsphere DC Bead loaded with doxorubicin (drug-eluting bead doxorubicin [DEBDOX]) has been shown by several randomized controlled trials. Since Lencioni et al. [Cardiovasc Intervent Radiol 2012; 35: 980-985] published the first widely accepted technical recommendations on HCC embolization with DEBDOX-TACE in 2012, new studies have contributed to a better understanding of when and how to apply this new therapeutic modality, and they have yet to be incorporated into an updated guideline. Additionally, differences in the underlying liver pathology and practice of transcatheter embolization between Asian and Western populations have not been adequately addressed, and there remain significant variations in the TACE protocols adopted in different parts of the world. These mainly revolve around the number and type of chemotherapeutic agents used, type of embolic material, reliance on Lipiodol, and selectivity of catheter positioning. As a result of these issues, it has been difficult to interpret and compare results obtained from different centers in a systematic fashion. To address these concerns, we convened a panel of experts specializing in different aspects of HCC treatment to craft an updated set of recommendations that better reflect recent clinical experiences and are tailored to the use of DEBDOX-TACE in Taiwan. The conclusions of this expert panel are described in the following article.
Collapse
Affiliation(s)
- Pi-Yi Chang
- Department of Radiology, Taichung Veterans General Hospital, Taichung City, Taiwan
| | - Chun-Chieh Huang
- Department of Radiology, Far Eastern Memorial Hospital, Taipei, Taiwan
| | - Chao-Hung Hung
- Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan
| | - Chih-Yung Yu
- Department of Radiology, Tri-Service General Hospital, Taipei, Taiwan
| | - Ding-Kwo Wu
- Department of Radiology, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung City, Taiwan
| | - Jen-I Hwang
- Department of Radiology, Tungs' Taichung Metro Harbor Hospital, Taichung City, Taiwan
| | - Po-Chin Liang
- Department of Radiology, National Taiwan University Hospital, Taipei, Taiwan
| | - Reng-Hong Wu
- Department of Radiology, Chi Mei Hospital, Tainan City, Taiwan
| | - Wei-Lun Tsai
- Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung City, Taiwan
| | - Yih-Jyh Lin
- Department of Surgery, National Cheng Kung University Hospital, Tainan City, Taiwan
| | - Yi-Sheng Liu
- Department of Diagnostic Radiology, National Cheng Kung University Hospital, Tainan City, Taiwan
| | - Huei-Lung Liang
- Department of Radiology, Kaohsiung Veterans General Hospital, Kaohsiung City, Taiwan
| | - Rheun-Chuan Lee
- Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chien-Hung Chen
- Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch and National Taiwan University College of Medicine, Douliu City, Taiwan,*Chien-Hung Chen, MD, PhD, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, and National Taiwan University College of Medicine, No. 579, Sec. 2, Yunlin Road, Douliu City, Yunlin County 640 (Taiwan), E-Mail
| |
Collapse
|
|
19
|
A Data Mining-based Prognostic Algorithm for NAFLD-related Hepatoma Patients: A Nationwide Study by the Japan Study Group of NAFLD. Sci Rep 2018; 8:10434. [PMID: 29992975 PMCID: PMC6041283 DOI: 10.1038/s41598-018-28650-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
The prognosis of patients with nonalcoholic fatty liver disease-related hepatocellular carcinoma (NAFLD-HCC) is intricately associated with various factors. We aimed to investigate the prognostic algorithm of NAFLD-HCC patients using a data-mining analysis. A total of 247 NAFLD-HCC patients diagnosed from 2000 to 2014 were registered from 17 medical institutions in Japan. Of these, 136 patients remained alive (Alive group) and 111 patients had died at the censor time point (Deceased group). The random forest analysis demonstrated that treatment for HCC and the serum albumin level were the first and second distinguishing factors between the Alive and Deceased groups. A decision-tree algorithm revealed that the best profile comprised treatment with hepatectomy or radiofrequency ablation and a serum albumin level ≥3.7 g/dL (Group 1). The second-best profile comprised treatment with hepatectomy or radiofrequency ablation and serum albumin levels <3.7 g/dL (Group 2). The 5-year overall survival rate was significantly higher in the Group 1 than in the Group 2. Thus, we demonstrated that curative treatment for HCC and serum albumin level >3.7 g/dL was the best prognostic profile for NAFLD-HCC patients. This novel prognostic algorithm for patients with NAFLD-HCC could be used for clinical management.
Collapse
|
|
20
|
Yao C, Li G, Cai M, Qian Y, Wang L, Xiao L, Thaiss F, Shi B. Expression and genetic polymorphism of necroptosis related protein RIPK1 is correlated with severe hepatic ischemia-reperfusion injury and prognosis after hepatectomy in hepatocellular carcinoma patients. Cancer Biomark 2018; 20:23-29. [PMID: 28759952 DOI: 10.3233/cbm-170525] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVES The goal of our study was to assess the prognostic impact of the necroptosis relative protein RIPK1 genetic polymorphism in ischemia-reperfusion injury and survival after hepatectomy in hepatocellular carcinoma (HCC) patients. METHODS In this study, expression of RIPK1 and its genetic polymorphism(rs2272990) were examined in plasma of 44 HCC patients. All these patients were undergoing partial hepatectomy. The prognostic values of RIPK1 genetic polymorphism for tumor development and survival, and ischemia-reperfusion injury after hepatectomy were further determined. RESULTS Plasma RIPK1 expressions were significantly increased in HCC patients, compared to the healthy control group. Totally 19 patients have the GA + AA genotype in the RIPK1 rs2272990 SNP site and 25 have GG genotype. There were no statistically significant intergroup differences observed in age, gender, AFP value, HBV positive, tumor size or cirrhosis. GG genotype had positive correlation with TNM classification (p= 0.033) and lymphatic metastasis (p= 0.027) and was significantly associated with severe hepatic ischemia-reperfusion injury and decreased survival rate after hepatectomy. CONCLUSION In conclusion, the RIPK1 polymorphism is an indicator of hepatic injury and a novel prognostic biomarker for tumor development and survival of HCC recipients after hepatectomy.
Collapse
Affiliation(s)
- Chen Yao
- Organ Transplant Institute, Beijing, China.,Organ Transplant Institute, Beijing, China
| | - Gang Li
- Organ Transplant Institute, Beijing, China.,Organ Transplant Institute, Beijing, China
| | - Ming Cai
- Organ Transplant Institute, Beijing, China
| | | | - Liqin Wang
- Organ Transplant Institute, Beijing, China
| | - Li Xiao
- Organ Transplant Institute, Beijing, China
| | - Friedrich Thaiss
- IIII Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | - Bingyi Shi
- Organ Transplant Institute, Beijing, China
| |
Collapse
|
|
21
|
Zhang J, Zhou X, Chang H, Huang X, Guo X, Du X, Tian S, Wang L, Lyv Y, Yuan P, Xing J. Hsp60 exerts a tumor suppressor function by inducing cell differentiation and inhibiting invasion in hepatocellular carcinoma. Oncotarget 2018; 7:68976-68989. [PMID: 27677587 PMCID: PMC5356605 DOI: 10.18632/oncotarget.12185] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 08/08/2016] [Indexed: 01/08/2023] Open
Abstract
Heat shock protein 60 (Hsp60), a typical mitochondrial chaperone, is associated with progression of various cancers. However, its expression and significance in hepatocellular carcinoma (HCC) remain largely unclear. In the present study, the mRNA and protein expression of Hsp60 in HCC tissues were detected by quantitative RT-PCR (n=24), western blot (n=7), and immunohistochemical staining (n=295), respectively. The correlation between Hsp60 expression and clinicopathological characteristics of HCC patient was also analyzed. Meanwhile, the influence of Hsp60 on malignant phenotype of HCC cells was further investigated. We found that expression of Hsp60 was significantly downregulated in HCC tissues compared to peritumor tissues. Hsp60 expression was significantly correlated with serum alpha -foetoprotein (AFP) level and tumor differentiation grade. Moreover, high Hsp60 expression cancer/pericancer (C/P) ratio was associated with a better overall survival rate (P=0.035, n=295). The prognostic implication of Hsp60 in HCC was further confirmed in another cohort of 107 HCC patients (P=0.027). Up-regulation of Hsp60 remarkably induced the cell differentiation and inhibited the invasive potential of HCC in vitro and in vivo. Intriguingly, the down-regulation of Hsp60 significantly impaired mitochondrial biogenesis. Although more data are required to clarify the underling mechanism responsible for function of Hsp60, our results suggested that the effect of Hsp60 on differentiation and invasion of HCC cells might be associated with mitochondrial biogenesis. Collectively, our findings indicated that Hsp60 exerted a tumor suppressor function, and might serve as a potential therapeutic target in the treatment of HCC.
Collapse
Affiliation(s)
- Jing Zhang
- State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xingchun Zhou
- State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Hulin Chang
- Department of Hepatobiliary Surgery, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China
| | - Xiaojun Huang
- State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xu Guo
- State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xiaohong Du
- State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Siyuan Tian
- State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Lexiao Wang
- State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yinghua Lyv
- State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Peng Yuan
- Department of Pain Treatment, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jinliang Xing
- State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China
| |
Collapse
|
|
22
|
Assessment of the discriminating value of the 8th AJCC stage grouping for hepatocellular carcinoma. HPB (Oxford) 2018; 20:41-48. [PMID: 28882455 DOI: 10.1016/j.hpb.2017.08.017] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 07/24/2017] [Accepted: 08/02/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND This study seeks to validate the discriminating value of the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for Hepatocellular carcinoma (HCC) amongst patients registered within the surveillance, epidemiology and end results (SEER) database. METHODS Through SEER*Stat program, SEER database (2010-2013) was queried and 8th AJCC stage groups were reconstructed. Overall and cancer-specific survival analyses according to both 7th and 8th editions were conducted through Kaplan-Meier analysis/log-rank testing and multivariate analysis was conducted through a Cox proportional model. RESULTS For overall and cancer-specific survival assessment according to the 8th edition, P values for pair wise comparisons among different stages were significant (<0.001) in all comparisons except for stage IB vs. II/stage IIIB vs. stage IVA. A modified AJCC 8th staging system was suggested through collapsing stages IB/II into one stage and stages IIIB/IVA into one stage. Overall and cancer-specific survivals were compared according to this modified system and pair wise P value was significant in all comparisons (P < 0.001). CONCLUSION There is a minimal improvement in discriminating value for the 8th edition compared to the 7th edition; however, notable overlap in outcomes is still observed between stages IB/II and IIIB/IVA. A modified AJCC 8th system collapsing these overlapping stages may be more clinically relevant.
Collapse
|
|
23
|
Cai X, Chen Z, Chen J, Ma X, Bai M, Wang T, Chen X, Wu D, Wei L, Li X, Lin Q, Wen J, Ruan D, Lin Z, Dong M, Wu X. Albumin-to-Alkaline Phosphatase Ratio as an Independent Prognostic Factor for Overall Survival of Advanced Hepatocellular Carcinoma Patients without Receiving Standard Anti-Cancer Therapies. J Cancer 2018; 9:189-197. [PMID: 29290785 PMCID: PMC5743727 DOI: 10.7150/jca.21799] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 10/24/2017] [Indexed: 12/11/2022] Open
Abstract
Background Albumin-to-Alkaline Phosphatase Ratio (ALB/ALP ratio, AAPR), a newly developed index of liver function, has been rarely discussed about its prognostic value in malignancies. The current study attempted to evaluate the prognostic prediction of AAPR in advanced HCC. Methods 237 advanced HCC patients who refused any standard anti-cancer therapies were retrospectively analyzed. The threshold value of AAPR was determined by receiver operating characteristic (ROC) curve. Univariate analyses using Kaplan-Meier method and log-rank test, and multivariate analysis using Cox proportional hazards regression model were conducted. Comparisons of ROC curves and likelihood ratio test (LRT) were utilized to compare the value of different factors in predicting survival. Results ROC curve analysis confirmed 0.38 as the optimal cutoff value of AAPR in evaluating overall survival (OS). Patients with an AAPR > 0.38 exhibited significantly lower frequencies of ascites, portal vein tumor thrombus, Child-Pugh grade B & C, and KPS < 70 (all P < 0.05). These patients also displayed a longer median survival time than those with an AAPR ≤ 0.38 (5.8 m vs 2.4 m, P < 0.01). Univariate and multivariate analyses identified AAPR as an independent prognostic indicator (HR = 0.592, P = 0.007). Furthermore, we integrated AAPR with TNM system and found that area under curve of AAPR-TNM system was significantly larger than that of TNM system when predicting 3-month survival (0.670 vs 0.611, P < 0.01). Moreover, LRT indicated that AAPR-TNM system had a significantly larger χ2 (26.4 vs 16.4, P < 0.01) and a significantly smaller Akaike information criterion value (1936 vs 1948, P < 0.01) comparing with TNM system. Conclusions Our study implied that AAPR was a potentially valuable prognostic index for advanced HCC patients without receiving any standard anti-cancer therapies. AAPR-TNM system preceded TNM system in predicting overall survival in this study.
Collapse
Affiliation(s)
- Xiurong Cai
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Zhanhong Chen
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
- Department of Medical Oncology of Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfengdong Road, Guangzhou, 510060, People's Republic of China
| | - Jie Chen
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Xiaokun Ma
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Mingjun Bai
- Department of Intervention and Radiology, Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Tiantian Wang
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Xiangwei Chen
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Donghao Wu
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Li Wei
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Xing Li
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Qu Lin
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Jingyun Wen
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Danyun Ruan
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Zexiao Lin
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Min Dong
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Xiangyuan Wu
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| |
Collapse
|
|
24
|
Shi C, Zhang Y, Yang H, Dong T, Chen Y, Xu Y, Yang X, Liu P. Ultrasound-targeted microbubble destruction-mediated Foxp3 knockdown may suppress the tumor growth of HCC mice by relieving immunosuppressive Tregs function. Exp Ther Med 2017; 15:31-38. [PMID: 29387180 PMCID: PMC5769241 DOI: 10.3892/etm.2017.5421] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 04/10/2017] [Indexed: 12/21/2022] Open
Abstract
The aim of the present study was to investigate the effect of Forkhead family transcription factor P3 (Foxp3) knockdown on the function of cluster of differentiation (CD)4+CD25+ regulatory T cell (Tregs) and the tumor growth of a hepatocellular carcinoma (HCC) mouse model. CD4+CD25+ Tregs and CD4+CD25- T cells were sorted from peripheral blood mononuclear cells (PBMCs) of patients with HCC. Then, ultrasound-targeted microbubble destruction (UTMD)-mediated Foxp3-microRNA (miRNA) was transfected into Tregs. Subsequently, CD4+CD25- T cells were co-cultured with PBMC and Tregs without Foxp3-miRNA (Foxp3+Tregs) or Tregs with Foxp3-miRNA (Foxp3-Tregs) and the proliferation-inhibition ratio of CD4+CD25- T cells was detected using a Cell Counting Kit-8. Additionally, HCC mice were treated with UTMD-mediated Foxp3-shRNA, the tumor volume was calculated and the content of CD4+ and CD25+ T cells in the blood were detected using flow cytometry. The content of interferon-γ (IFN-γ), interleukin (IL)-2, IL-10, transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) in cultural supernatant and serum were detected by ELISA analysis. Foxp3-Tregs significantly reduced the inhibition effect of Foxp3+Tregs on the proliferation of CD4+CD25- T cells (P<0.01). The content of IFN-γ and IL-2 significantly increased, while IL-10 and TGF-β significantly decreased in the co-cultured system of Foxp3-Tregs compared with the co-cultured system of Foxp3+Tregs (P<0.01). Following treatment with Foxp3-shRNA, the average tumor volume, ratio of Tregs/CD4+ T cells and level of IL-10, TGF-β and VEGF significantly decreased, however, the level of IFN-γ and IL-2 significantly increased compared with un-treated HCC mice (P<0.05). Foxp3 knockdown may suppress the tumor growth of HCC mice through relieving the immunosuppressive function of Tregs.
Collapse
Affiliation(s)
- Chunying Shi
- Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Heilongjiang, Harbin 150001, P.R. China
| | - Yu Zhang
- Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Heilongjiang, Harbin 150001, P.R. China
| | - Haichao Yang
- Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Heilongjiang, Harbin 150001, P.R. China
| | - Tianxiu Dong
- Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Heilongjiang, Harbin 150001, P.R. China
| | - Yaodong Chen
- Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Heilongjiang, Harbin 150001, P.R. China
| | - Yutong Xu
- Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Heilongjiang, Harbin 150001, P.R. China
| | - Xiuhua Yang
- Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Heilongjiang, Harbin 150001, P.R. China
| | - Pengfei Liu
- MRI Department, The First Affiliated Hospital of Harbin Medical University, Heilongjiang, Harbin 150001, P.R. China
| |
Collapse
|
|
25
|
Management consensus guideline for hepatocellular carcinoma: 2016 updated by the Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan. J Formos Med Assoc 2017; 117:381-403. [PMID: 29074347 DOI: 10.1016/j.jfma.2017.09.007] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 08/16/2017] [Accepted: 09/13/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality in Taiwan. To help clinical physicians to manage patients with HCC, the Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan produced the management consensus guideline for HCC. METHODS The recommendations focus on nine important issues on management of HCC, including surveillance, diagnosis, staging, surgery, local ablation, transarterial chemoembolization/transarterial radioembolization/hepatic arterial infusion chemotherapy, systemic therapy, radiotherapy, and prevention. RESULTS The consensus statements were discussed, debated and got consensus in each expert team. And then the statements were sent to all of the experts for further discussion and refinement. Finally, all of the experts were invited to vote for the statements, including the level of evidence and recommendation. CONCLUSION With the development of the management consensus guideline, HCC patients could benefit from the optimal therapeutic modality.
Collapse
|
|
26
|
Prognostic nomogram for hepatocellular carcinoma in adolescent and young adult patients after hepatectomy. Oncotarget 2017; 8:106393-106404. [PMID: 29290957 PMCID: PMC5739742 DOI: 10.18632/oncotarget.18192] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Accepted: 04/11/2017] [Indexed: 02/05/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) was rarely discussed in adolescent and young adult (AYA) patients. This study aimed to discuss the character of AYA HCC patients and establish an effective prognostic nomogram for patients after hepatectomy. Results For all of the patients, the median OS was 57 months with 5-year OS rate 60.4%, and DFS was 48 months with 5-year DFS rate 51.4%. The tumor size, vascular invasion status and the pathological differentiation were the independent predictors for both OS and DFS. Except for that, gender, Neutrophil-lymphocyte ratio, HbeAg, and α-Fetoprotein were the predictors for OS. The c-index for OS prognostic nomogram was 0.75 (95% CI, 0.71 to 0.79), and c-index was 0.70 (95% CI, 0.66 to 0.74) for DFS prognostic nomogram, which was better than American Joint Commission on Cancer 2002 and 2010, Okuda staging system, the Japanese Integrated Staging system, and Tokyo staging system. Materials And Methods This study was based on 423 AYA HCC patients (younger than 40 years old) undergoing hepatectomy in West China Hospital between 2008 to 2014. Based on the multivariate risk factors, the nomogram was constructed for predict the possibility for overall survival (OS) and disease-free survival (DFS) rate. Harrel’s concordance index (c-index) was used to compare the predictive accuracy and discriminative ability between the nomogram and eight contemporary staging systems. Conclusions Our prognostic nomogram could accurately and preciously provide individual prediction for AYA HCC patients in OS and DFS after hepatectomy.
Collapse
|
|
27
|
Bauschke A, Altendorf-Hofmann A, Malessa C, Schüle S, Zanow J, Settmacher U. Which factors affect the long-term survival of patients with hepatocellular carcinoma UICC stage IV? J Cancer Res Clin Oncol 2016; 142:2593-2601. [PMID: 27630023 DOI: 10.1007/s00432-016-2260-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 09/06/2016] [Indexed: 12/14/2022]
Abstract
AIM In the 7th edition of the TNM classification, not only HCC with distant metastases but also those with regional lymph node metastases are classified as stage IV. MATERIALS AND METHODS, RESULTS From our prospectively recorded tumor registry, 138 patients (17 %) with HCC were in stage IV. Among those were 68 and 70, respectively, in stage IVA (regional lymph node metastases) and IVB (distant metastases). The tumors were less frequently treated with resection or local ablative treatment (chemoembolization, RFA, SIRT, percutaneous radiation) than patients in stage I-III. Ten HCCs were resected. Five of the resected patients were in stage IVA and five in stage IVB. After tumor resection, patients lived longer than those who underwent local or systemic treatment only (p = 0.003 or p = 0.001, respectively). In the univariate survival analysis, the stage IV patients' long-term survival was decreased statistically significantly through elevated bilirubin, low albumin, Okuda stage III and BCLC stage D. Patients' age and sex, pre-treatment AFP level, Child stage and the presence of venous invasion did not influence survival. In the multivariate analysis (Cox regression), tumor resection and BCLC stage were independent prognostic factors. CONCLUSION Patients with HCC in TNM stage IV have a very poor prognosis. Only few patients are eligible for resection because of the extent of tumor growth, comorbidities and general condition. These, however, benefit markedly from tumor resection with lymph node dissection and possibly resection of distant metastases.
Collapse
Affiliation(s)
- A Bauschke
- Department of General, Visceral and Vascular Surgery, University Hospital Jena, Erlanger Allee 101, 07740, Jena, Germany.
| | - A Altendorf-Hofmann
- Department of General, Visceral and Vascular Surgery, University Hospital Jena, Erlanger Allee 101, 07740, Jena, Germany
| | - C Malessa
- Department of General, Visceral and Vascular Surgery, University Hospital Jena, Erlanger Allee 101, 07740, Jena, Germany
| | - S Schüle
- Department of General, Visceral and Vascular Surgery, University Hospital Jena, Erlanger Allee 101, 07740, Jena, Germany
| | - J Zanow
- Department of General, Visceral and Vascular Surgery, University Hospital Jena, Erlanger Allee 101, 07740, Jena, Germany
| | - U Settmacher
- Department of General, Visceral and Vascular Surgery, University Hospital Jena, Erlanger Allee 101, 07740, Jena, Germany
| |
Collapse
|
|
28
|
Kee KM, Wang JH, Wang CC, Cheng YF, Lu SN. Hepatocellular Carcinoma associated with Extra-hepatic Primary Malignancy: its Secular change, Clinical Manifestations and Survival. Sci Rep 2016; 6:30156. [PMID: 27444261 PMCID: PMC4957107 DOI: 10.1038/srep30156] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 06/29/2016] [Indexed: 12/17/2022] Open
Abstract
Clinical manifestations between hepatocellular carcinoma (HCC) and extra-hepatic primary malignancy (EHPM) are lack of large-scale study. We enrolled 14555 HCC patients between 1986 and 2013 retrospectively. The EHPM was classified as prior, synchronous and metachronous group based on before, within and after 6 months of HCC diagnosis, respectively. The incidence rate of EHPM is 3.91% (95% confidence interval [CI]: 3.60–4.23%). Urogenital cancers, kidney and bladder, were at unexpected higher ranks. Older in age, Child-Pugh A cirrhosis, negativity of HBsAg and anti-HCV, and earlier BCLC staging are independent factors associated with EHPM. The survival rates of EHPM improve over time and also better than HCC-alone. Cox proportional-hazards regression shows independent poor prognostic factors are age >60, male, AFP levels ≥400 ng/ml, positivity of HBsAg, Child-Pugh B vs. A, Non-metachronous group, respectively, treated with local ablation, transcatheter arterial embolization, radiotherapy and supportive care vs. surgery, respectively, TNM stage IIIA vs. I, and BCLC stages A, B, C and D vs. 0, respectively. Survival of EHPM improve could be explained by early diagnosis and improve treatment of cancers.
Collapse
Affiliation(s)
- Kwong Ming Kee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chih-Chi Wang
- Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yu-Fan Cheng
- Department of Radiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| |
Collapse
|
|
29
|
Ruiz E, Rojas Rojas T, Berrospi F, Chávez I, Luque C, Cano L, Doimi F, Pineau P, Deharo E, Bertani S. Hepatocellular carcinoma surgery outcomes in the developing world: A 20-year retrospective cohort study at the National Cancer Institute of Peru. Heliyon 2016; 2:e00052. [PMID: 27441236 PMCID: PMC4945847 DOI: 10.1016/j.heliyon.2015.e00052] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Revised: 10/31/2015] [Accepted: 12/03/2015] [Indexed: 12/18/2022] Open
Abstract
In the developing world, most patients with hepatocellular carcinoma present with advanced-stage disease, considered to be incurable based on current therapeutic algorithms. Here, we demonstrate that curative liver resection is achievable in a portion of Peruvian patients not addressed by these treatment algorithms. We conducted a retrospective cohort study of 253 hepatocellular carcinoma patients that underwent a curative hepatectomy between 1991 and 2011 at the National Cancer Institute of Peru. The median age of the cohort was 36 years, and merely 15.4% of the patients displayed cirrhosis. The average tumor size was over 14 cm in diameter, resulting in 76.3% of major hepatectomies performed. The 5- and 10-year survival probability estimates were 37.5% and 26.2%, respectively. Age (>44 vs. ≤44 years old; P = 0.005), tumor size (>10 cm vs. ≤10 cm in diameter; P = 0.009), cirrhosis (P < 0.001), satellite lesions (P < 0.001), macroscopic vascular invasion (P < 0.001), allogeneic blood transfusion (P = 0.011), and spontaneous rupture of the tumor (P = 0.006) were independent predictive factors for prognosis. Hepatocellular carcinomas in Peru are characterized by a distinct clinical presentation with notable features compared with those typically described throughout relevant literature. Despite a large number of advanced-stage hepatocellular carcinomas, the outcomes of liver resection observed in the present study were in good standing with the results previously described in other series. It thus appears that staging systems and associated therapeutic algorithms designed for use in the developed world remain inadequate in certain populations, especially in the context of Peruvian patients. Our findings suggest that clinicians in the developing world should reconsider management guidelines pertaining to hepatocellular carcinoma. Indeed, we hypothesize that, in developing countries, a strict adherence to these therapeutic algorithms might create a selection bias resulting in the dismissal of patients who could eventually be treated.
Collapse
Affiliation(s)
- Eloy Ruiz
- Instituto Nacional de Enfermedades Neoplásicas, Departamento de Cirugía en Abdomen, Lima, Peru
| | - Teresa Rojas Rojas
- Aix Marseille Université, UMR912 SESSTIM INSERM-IRD-AMU, Centre d'Epidémiologie et de Santé Publique des Armées, Marseille, France
| | - Francisco Berrospi
- Instituto Nacional de Enfermedades Neoplásicas, Departamento de Cirugía en Abdomen, Lima, Peru
| | - Ivan Chávez
- Instituto Nacional de Enfermedades Neoplásicas, Departamento de Cirugía en Abdomen, Lima, Peru
| | - Carlos Luque
- Instituto Nacional de Enfermedades Neoplásicas, Departamento de Cirugía en Abdomen, Lima, Peru
| | - Luis Cano
- Instituto Nacional de Enfermedades Neoplásicas, Departamento de Patología, Lima, Peru
| | - Franco Doimi
- Instituto Nacional de Enfermedades Neoplásicas, Departamento de Patología, Lima, Peru
| | - Pascal Pineau
- Institut Pasteur, Unité Organisation Nucléaire et Oncogenèse, Paris, France; Institut National de la Santé et de la Recherche Médicale, Paris U993, France
| | - Eric Deharo
- Université de Toulouse, UPS, UMR152 PHARMADEV, Université Toulouse 3, Toulouse, France; Institut de Recherche pour le Développement, UMR152 PHARMADEV, Vientiane, Laos
| | - Stéphane Bertani
- Université de Toulouse, UPS, UMR152 PHARMADEV, Université Toulouse 3, Toulouse, France; Institut de Recherche pour le Développement, UMR152 PHARMADEV, Lima, Peru
| |
Collapse
|
|
30
|
Zhang TT, Zhao XQ, Liu Z, Mao ZY, Bai L. Factors affecting the recurrence and survival of hepatocellular carcinoma after hepatectomy: a retrospective study of 601 Chinese patients. Clin Transl Oncol 2015; 18:831-40. [PMID: 26577107 DOI: 10.1007/s12094-015-1446-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 11/03/2015] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Indications for resection of hepatocellular carcinoma (HCC) remain controversial. This study aimed to identify prognostic factors that affect overall survival (OS) and disease-free survival (DFS) in patients with HCC after hepatectomy. METHODS From 2004 to 2010, 601 patients with HCC who underwent resection were enrolled. Factors stratified into the host, biochemical, surgical treatment and tumor-related features in terms of recurrence and overall survival were analyzed. Prognostic factors were evaluated by univariate and multivariate analyses, with Kaplan-Meier survival analyses and Cox proportional hazard model. RESULTS The overall survival rates of 1-, 3- and 5- year were 79, 62, and 54 %, and the corresponding DFS rates were 51, 38 and 31 %, respectively. In a multivariate analysis, Child-Pugh, serum AFP level, ALT level, time for hepatic resection, tumor differentiation, maximum size of tumors, local necrosis, portal vein tumor thrombus, and TNM Stage were correlated significantly with patients' OS. Gender (P = 0.046), cigarette smoking (P = 0.007), serum AFP level (P = 0.001), GGT level (P = 0.002), maximum size of tumors (P = 0.009), liver cirrhosis (P = 0.025), portal vein tumor thrombus (P = 0.022), microvascular tumor thrombus (P = 0.007) and TNM Stage (P = 0.001) were significantly affected DFS. CONCLUSION Preoperative AFP level, maximum size of tumors, portal vein tumor thrombus and TNM Stage were revealed as important prognostic factors for OS and DFS through follow-up of a relatively large cohort of Chinese HCC patients.
Collapse
Affiliation(s)
- T T Zhang
- Department of Oncology, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China
| | - X Q Zhao
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Z Liu
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Z Y Mao
- Department of Oncology, Air Force General Hospital of Chinese PLA, Beijing, People's Republic of China
| | - L Bai
- Department of Oncology, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China.
| |
Collapse
|
|
31
|
Sinn DH, Cho JY, Gwak GY, Paik YH, Choi MS, Lee JH, Koh KC, Paik SW, Yoo BC. Different survival of Barcelona clinic liver cancer stage C hepatocellular carcinoma patients by the extent of portal vein invasion and the type of extrahepatic spread. PLoS One 2015; 10:e0124434. [PMID: 25923439 PMCID: PMC4414501 DOI: 10.1371/journal.pone.0124434] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2015] [Accepted: 03/15/2015] [Indexed: 12/18/2022] Open
Abstract
Portal vein invasion (PVI) and extrahepatic spread (ES) are two tumor-related factors that define advanced stage in the Barcelona Clinic Liver Cancer (BCLC) staging system (BCLC stage C), and the recommended first line therapy in this stage is sorafenib. However, the extent of PVI and the type of ES may affect patient prognosis as well as treatment outcome. This study analyzed survival of BCLC stage C HCC patients in order to see whether sub-classification of BCLC stage C is necessary. A total of 582 treatment naïve, BCLC stage C HCC patients [age: 54.3 ± 10.8 years, males = 494 (84.9%), hepatitis B virus (458, 78.7%)], defined by PVI and/or ES, were analyzed. Extent of PVI was divided into none, type I-segmental/sectoral branches, type II-left and/or right portal vein, and type III-main portal vein trunk. Type of ES was divided into nodal and distant metastasis. The extent of PVI and type of ES were independent factors for survival. When patients were sub-classified according to the extent of PVI and type of ES, the median survival was significantly different [11.7 months, 5.7 months, 4.9 months and 2.3 months for C1 (PVI-O/I without distant ES), C2 (PVI-II/III without distant ES), C3 (PVI-0/I with distant ES), and C4 (PVI-II/III with distant ES), respectively, P = 0.01]. Patients' survival was different according to the treatment modality in each sub-stage. Sub-classification of BCLC stage C according to the extent of PVI and type of ES resulted in a better prediction of survival. Also, different outcome was observed by treatment modalities in each sub-stage. Sub-classification of BCLC stage C is required to minimize heterogeneity within the same tumor stage, that will help better predict survival and to select optimal treatment strategies.
Collapse
Affiliation(s)
- Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Ju-Yeon Cho
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
- * E-mail:
| | - Yong-Han Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Moon Seok Choi
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Joon Hyeok Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Kwang Cheol Koh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Seung Woon Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Byung Chul Yoo
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| |
Collapse
|
|
32
|
Yim HJ, Suh SJ, Um SH. Current management of hepatocellular carcinoma: an Eastern perspective. World J Gastroenterol 2015; 21:3826-42. [PMID: 25852267 PMCID: PMC4385529 DOI: 10.3748/wjg.v21.i13.3826] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 12/11/2014] [Accepted: 02/12/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death, especially in Eastern areas. With advancements in diagnosis and treatment modalities for HCC, the survival and prognosis of HCC patients are improving. However, treatment patterns are not uniform between areas despite efforts to promote a common protocol. Although many hepatologists in Asian countries may adopt the principles of the Barcelona Clinic Liver Cancer staging system, they are also independently making an effort to expand the indications of each treatment and to combine therapies for better outcomes. Several expanded criteria for liver transplantation in HCC have been developed in Asian countries. Living donor liver transplantation is much more commonly performed in these countries than deceased donor liver transplantation, and it may be preceded by other treatments such as the down-staging of tumors. Local ablation therapies are often combined with transarterial chemoembolization (TACE) and the outcome is comparable to that of surgical resection. The indications of TACE are expanding, and there are new types of transarterial therapies. Although data on drug-eluting beads, TACE, and radioembolization in Asian countries are still relatively sparse compared with Western countries, these methods are gradually gaining popularity because of better tolerability and the possibility of improved response rates. Hepatic arterial infusion chemotherapy and radiotherapy are not included in Western guidelines, but are currently being used actively in several Asian countries. For more advanced HCCs, appropriate combinations of TACE, radiotherapy, and sorafenib can be considered, and emerging data indicate improved outcomes of combination therapies compared with single therapies. To include these paradigm shifts into newer treatment guidelines, more studies may be needed, but they are certainly in progress.
Collapse
|
|
33
|
Kim M. Evaluation of a Web-Based App Demonstrating an Exclusionary Algorithmic Approach to TNM Cancer Staging. JMIR Cancer 2015; 1:e3. [PMID: 28410163 PMCID: PMC5367667 DOI: 10.2196/cancer.4019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 03/17/2015] [Accepted: 03/17/2015] [Indexed: 11/29/2022] Open
Abstract
Background TNM staging plays a critical role in the evaluation and management of a range of different types of cancers. The conventional combinatorial approach to the determination of an anatomic stage relies on the identification of distinct tumor (T), node (N), and metastasis (M) classifications to generate a TNM grouping. This process is inherently inefficient due to the need for scrupulous review of the criteria specified for each classification to ensure accurate assignment. An exclusionary approach to TNM staging based on sequential constraint of options may serve to minimize the number of classifications that need to be reviewed to accurately determine an anatomic stage. Objective Our aim was to evaluate the usability and utility of a Web-based app configured to demonstrate an exclusionary approach to TNM staging. Methods Internal medicine residents, surgery residents, and oncology fellows engaged in clinical training were asked to evaluate a Web-based app developed as an instructional aid incorporating (1) an exclusionary algorithm that polls tabulated classifications and sorts them into ranked order based on frequency counts, (2) reconfiguration of classification criteria to generate disambiguated yes/no questions that function as selection and exclusion prompts, and (3) a selectable grid of TNM groupings that provides dynamic graphic demonstration of the effects of sequentially selecting or excluding specific classifications. Subjects were asked to evaluate the performance of this app after completing exercises simulating the staging of different types of cancers encountered during training. Results Survey responses indicated high levels of agreement with statements supporting the usability and utility of this app. Subjects reported that its user interface provided a clear display with intuitive controls and that the exclusionary approach to TNM staging it demonstrated represented an efficient process of assignment that helped to clarify distinctions between tumor, node, and metastasis classifications. High overall usefulness ratings were bolstered by supplementary comments suggesting that this app might be readily adopted for use in clinical practice. Conclusions A Web-based app that utilizes an exclusionary algorithm to prompt the assignment of tumor, node, and metastasis classifications may serve as an effective instructional aid demonstrating an efficient and informative approach to TNM staging.
Collapse
Affiliation(s)
- Matthew Kim
- Brigham and Women's Hospital, Division of Endocrinology, Diabetes and Hypertension, Boston, MA, United States
| |
Collapse
|
|
34
|
Kinoshita A, Onoda H, Fushiya N, Koike K, Nishino H, Tajiri H. Staging systems for hepatocellular carcinoma: Current status and future perspectives. World J Hepatol 2015; 7:406-424. [PMID: 25848467 PMCID: PMC4381166 DOI: 10.4254/wjh.v7.i3.406] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 11/08/2014] [Accepted: 12/10/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a major health concern worldwide and the third cause of cancer-related death. Despite advances in treatment as well as careful surveillance programs, the mortality rates in most countries are very high. In contrast to other cancers, the prognosis and treatment of HCC depend on the tumor burden in addition to patient’s underlying liver disease and liver functional reserve. Moreover, there is considerable geographic and institutional variation in both risk factors attributable to the underlying liver diseases and the management of HCC. Therefore, although many staging and/or scoring systems have been proposed, there is currently no globally accepted system for HCC due to the extreme heterogeneity of the disease. The aim of this review is to focus on currently available staging systems as well as those newly reported in the literatures since 2012. Moreover, we describe problems with currently available staging systems and attempts to modify and/or add variables to existing staging systems.
Collapse
|
|
35
|
Tejeda-Maldonado J, García-Juárez I, Aguirre-Valadez J, González-Aguirre A, Vilatobá-Chapa M, Armengol-Alonso A, Escobar-Penagos F, Torre A, Sánchez-Ávila JF, Carrillo-Pérez DL. Diagnosis and treatment of hepatocellular carcinoma: An update. World J Hepatol 2015; 7:362-376. [PMID: 25848464 PMCID: PMC4381163 DOI: 10.4254/wjh.v7.i3.362] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 12/11/2014] [Accepted: 12/31/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies leading to high mortality rates in the general population; in cirrhotic patients, it is the primary cause of death. The diagnosis is usually delayed in spite of at-risk population screening recommendations, i.e., patients infected with hepatitis B or C virus. Hepatocarcinogenesis hinges on a great number of genetic and molecular abnormalities that lead to tumor angiogenesis and foster their dissemination potential. The diagnosis is mainly based on imaging studies such as computed tomography and magnetic resonance, in which lesions present a characteristic classical pattern of early arterial enhancement followed by contrast medium “washout” in late venous phase. On occasion, when imaging studies are not conclusive, biopsy of the lesion must be performed to establish the diagnosis. The Barcelona Clinic Liver Cancer staging method is the most frequently used worldwide and recommended by the international guidelines of HCC management. Currently available treatments include tumor resection, liver transplant, sorafenib and loco-regional therapies (alcoholization, radiofrequency ablation, chemoembolization). The prognosis of hepatocarcinoma is determined according to the lesion’s stage and in cirrhotic patients, on residual liver function. Curative treatments, such as liver transplant, are sought in patients diagnosed in early stages; patients in more advanced stages, were not greatly benefitted by chemotherapy in terms of survival until the advent of target molecules such as sorafenib.
Collapse
|
|
36
|
Hung HH, Chao Y, Chiou YY, Li CP, Lee RC, Huo TI, Huang YH, Chau GY, Su CW, Yeh YC, Lin HC, Lee SD, Wu JC. A comparison of clinical manifestations and prognoses between patients with hepatocellular carcinoma and Child-Pugh scores of 5 or 6. Medicine (Baltimore) 2014; 93:e348. [PMID: 25546689 PMCID: PMC4602592 DOI: 10.1097/md.0000000000000348] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The objective of this work is to compare the outcomes between the Child-Pugh score 5 (A5 group) and Child-Pugh score 6 (A6 group) in patients with hepatocellular carcinoma (HCC). Whether HCC patients with A5 and A6 groups have different prognoses is still obscure. We enrolled 2462 consecutive treatment-naive HCC patients from 2007 to 2012. Among them, 1486 patients had Child-Pugh grade A, including 1016 in the A5 group and 470 in the A6 group. Factors in the prognoses were analyzed by multivariate analysis. Compared with those in the A6 group, patients in the A5 group were younger, had higher proportions of tumors within the Milan criteria, and more of them underwent curative therapies. The cumulative survival rates at 5 years were 51.3% and 37.1% for patients in the A5 and A6 groups, respectively (P < 0.001). Multivariate analysis showed that the independent risk factors associated with poor overall survival were nonhepatitis C virus carrier, serum albumin ≤ 4 g/dL, aspartate aminotransferase > 45 U/L, α-fetoprotein > 20 ng/mL, multinodularity, tumor size > 3 cm, vascular invasion, and noncurative therapies, but not the Child-Pugh numeric score. The Child-Pugh numeric score had a significant prognostic effect only in patients who had tumors beyond the Milan criteria and received noncurative therapies. HCC patients with A5 group had a better overall survival rate than those with A6 group due to the early tumor stage and higher rate of receiving curative treatments. Tumor factors and treatment modalities were more important than the Child-Pugh numeric score.
Collapse
Affiliation(s)
- Hung-Hsu Hung
- From the Division of Gastroenterology (H-HH, S-DL), Department of Medicine, Cheng Hsin General Hospital; Faculty of Medicine, School of Medicine (H-HH, YC, Y-YC, C-PL, R-CL, G-YC, C-WS, Y-CY, H-CL, S-DL); Institute of Clinical Medicine and Genomic Research Center (H-HH, Y-HH, J-CW), National Yang-Ming University; Division of Chemoradiotherapy (YC), Department of Oncology Medicine; Division of Gastrointestinal Radiology (Y-YC), Department of Radiology; Division of Gastroenterology (C-PL, T-IH, Y-HH, C-WS, H-CL), Department of Medicine; Division of Pediatric Radiology (R-CL), Department of Radiology, Taipei Veterans General Hospital; Institute of Pharmacology (T-IH), School of Medicine, National Yang-Ming University; Division of General Surgery (G-YC), Department of Surgery; Department of Pathology and Laboratory Medicine (Y-CY); and Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan (J-CW)
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Ho CM, Hu RH, Lee PH, Wu YM, Ho MC. Long-term survival in patients with T2 hepatocellular carcinoma after primary curative resection can be further stratified by tumor size. Medicine (Baltimore) 2014; 93:e203. [PMID: 25501076 PMCID: PMC4602780 DOI: 10.1097/md.0000000000000203] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Insufficient data are available regarding the validation of long-term survival in patients with T2 (solitary tumor with microvascular invasion [MVI] or multiple tumors, none >5 cm) hepatocellular carcinoma (HCC) after primary hepatectomy. We aim to evaluate the survival and relevant risk factors for T2 HCC patients. Between 2001 and 2007, 312 T2 HCC patients who underwent primary hepatectomy were included. Survival was estimated using the Kaplan-Meier method and compared using Cox proportional hazard model with adjusted independent prognostic factors. The 1, 3, and 5-year overall survival rates of patients with MVI were 85.7%, 68.7%, and 64.8%, respectively; these were inferior to the rates in patients without MVI, which were 93.0%, 89.3%, and 73.7%, respectively (P = 0.037). Within the with-MVI group, the survival rate of patients with tumor sizes ≥ 5 cm was inferior to that of patients with tumors <5 cm (overall, P = 0.01; recurrence-free, P < 0.0001). For patients with the largest tumors in the <5-cm group, those without MVI tended to have a higher probability of recurrence for 2 years after resection (P = 0.088) but a similar overall survival rate relative to those with MVI (P = 0.31). The crude metastasis-free survival was higher in the without-MVI group than in the with-MVI group (P = 0.012). The T2 HCC category comprised heterogeneous patients with differences in survival rates. Extrahepatic recurrence occurred more frequently in patients with MVI than in those without MVI. These results provide evidence for an updated definition of T2 HCC.
Collapse
Affiliation(s)
- Cheng-Maw Ho
- From the Department of Surgery (C-MH, R-HH, P-HL, Y-MW, M-CH), National Taiwan University Hospital; and Graduate Institute of Clinical Medicine (C-MH, P-HL), College of Medicine, National Taiwan University, Taipei, Taiwan
| | | | | | | | | |
Collapse
|
|
38
|
Huang X, Qu P, Chen Y, Zhou X, Wu Y, Liu F, Wang D, Zhang J, An J. Low expression of CD112 is associated with poor overall survival in patients with hepatocellular carcinoma. Hum Pathol 2014; 45:1944-50. [DOI: 10.1016/j.humpath.2014.06.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 06/02/2014] [Accepted: 06/04/2014] [Indexed: 10/25/2022]
|
|
39
|
Yu SJ, Won JK, Ryu HS, Choi WM, Cho H, Cho EJ, Lee JH, Kim YJ, Suh KS, Jang JJ, Kim CY, Lee HS, Yoon JH, Cho KH. A novel prognostic factor for hepatocellular carcinoma: protein disulfide isomerase. Korean J Intern Med 2014; 29:580-7. [PMID: 25228833 PMCID: PMC4164721 DOI: 10.3904/kjim.2014.29.5.580] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2014] [Revised: 07/01/2014] [Accepted: 07/02/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIMS Protein disulfide isomerase (PDI) has been implicated in the survival and progression of some cancer cells, by compensating for endoplasmic reticulum stress by upregulating the protein-folding capacity. However, its prognostic role in patients with hepatocellular carcinoma (HCC) has not been investigated. METHODS We collected HCC tissues from 83 HCC patients who underwent surgical resection for an immunohistochemical study of PDI. Overall survival (OS) was measured from the date of surgical resection until the date of death from any cause. Radiological progression was evaluated using the modified Response Evaluation Criteria in Solid Tumors in an independent radiological assessment. RESULTS PDI expression was found to be increased in human HCC compared to adjacent nontumor tissues. Increased immunopositivity for PDI was associated with a high Edmondson-Steiner grade (p = 0.028). Univariate analysis of patients who had undergone surgical resection for HCC showed that tumor PDI upregulation is a significant risk factor for poor OS (p = 0.016; hazard ratio [HR], 1.980) and time to progression (TTP; p = 0.007; HR, 1.971). Multivariate analyses revealed that high PDI expression was an independent predictor of a shorter TTP (p = 0.015; HR, 1.865) and poor OS (p = 0.012; HR, 2.069). CONCLUSIONS Upregulated PDI expression is associated with aggressive clinicopathological features of HCC; thus, PDI might serve as an independent prognostic factor and a potential therapeutic target for HCC patients.
Collapse
Affiliation(s)
- Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jae-Kyung Won
- Laboratory for Systems Biology and Bio-Inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Han Suk Ryu
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Won-Mook Choi
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyeki Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Eun-Ju Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Ja-June Jang
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Chung Yong Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyo-Suk Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Kwang-Hyun Cho
- Laboratory for Systems Biology and Bio-Inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
| |
Collapse
|
|
40
|
Yu L, Guo X, Zhang P, Qi R, Li Z, Zhang S. Cyclic adenosine monophosphate-responsive element-binding protein activation predicts an unfavorable prognosis in patients with hepatocellular carcinoma. Onco Targets Ther 2014; 7:873-9. [PMID: 24926200 PMCID: PMC4049914 DOI: 10.2147/ott.s63594] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Aim To investigate the clinical significance of cyclic adenosine monophosphate-responsive element-binding (CREB) and phosphorylated CREB (pCREB) expression in human hepatocellular carcinoma (HCC). Materials and methods Immunohistochemistry and Western blot analyses were performed to detect the expression and subcellular localizations of CREB and pCREB proteins in 130 pairs of HCC and adjacent nonneoplastic liver tissues. Results Both immunohistochemistry and Western blot analyses showed that the expression levels of CREB and pCREB proteins in HCC tissues were significantly higher than those in the adjacent nonneoplastic liver tissues (both P<0.001). In addition, the combined upregulation of CREB and pCREB proteins (CREB-high/pCREB-high) was significantly associated with serum α-fetoprotein (P=0.02), tumor stage (P<0.001), and tumor grade (P=0.01). Moreover, HCC patients with CREB-high/pCREB-high expression showed shortest 5-year disease-free survival and 5-year overall survival (both P<0.001). Furthermore, the multivariate survival analysis found that the combined upregulation of CREB and pCREB proteins may be an independent unfavorable prognostic factor for both 5-year disease-free survival and 5-year overall survival (both P=0.01) in HCC. Conclusion Our data indicate for the first time that the activation of the CREB protein may be associated with tumor progression in HCC, and may serve as a valuable marker of prognosis for patients with this malignancy.
Collapse
Affiliation(s)
- Lingxiang Yu
- Department of Hepatobiliary Surgery, 302 Military Hospital of China, Beijing, People's Republic of China
| | - Xiaodong Guo
- Department of Hepatobiliary Surgery, 302 Military Hospital of China, Beijing, People's Republic of China
| | - Peirui Zhang
- Department of Hepatobiliary Surgery, 302 Military Hospital of China, Beijing, People's Republic of China
| | - Ruizhao Qi
- Department of Hepatobiliary Surgery, 302 Military Hospital of China, Beijing, People's Republic of China
| | - Zhiwei Li
- Department of Hepatobiliary Surgery, 302 Military Hospital of China, Beijing, People's Republic of China
| | - Shaogeng Zhang
- Department of Hepatobiliary Surgery, 302 Military Hospital of China, Beijing, People's Republic of China
| |
Collapse
|