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Toyoda H, Hiraoka A, Ochi H, Tsuji K, Tajiri K, Tani J, Tada T, Okubo T, Atsukawa M, Hirooka M, Itobayashi E, Hatanaka T, Kariyama K, Ishikawa T, Kuroda H, Takaguchi K, Kosaka H, Kawada K, Kakizaki S, Yada Y, Ogawa C, Nishimura T, Yasuda S, Deguchi A, Morishita A, Itokawa N, Arai T, Tsutsui A, Naganuma A, Enomoto H, Kaibori M, Nouso K, Hiasa Y, Kumada T, Akita T, Tanaka J, Johnson PJ. Prognostic Significance of the BALAD Serological Model in Systemic Therapies for Hepatocellular Carcinoma: A Personalized Approach to the Prediction of Survival Benefit. JCO Clin Cancer Inform 2025; 9:e2400175. [PMID: 40354590 DOI: 10.1200/cci-24-00175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 01/27/2025] [Accepted: 03/05/2025] [Indexed: 05/14/2025] Open
Abstract
PURPOSE The BALAD model, a scoring system for staging hepatocellular carcinoma (HCC), is based on five serum markers: bilirubin, albumin, lens culinaris agglutinin-reactive alpha-fetoprotein [AFP], AFP, and des-gamma-carboxy prothrombin. It has shown good ability to predict survival in patients with HCC irrespective of stage and treatment, a high BALAD value being associated with a poor prognosis. However, its prognostic significance is unclear in patients with advanced unresectable HCC (uHCC) who undergo systemic therapies. We assessed the prognostic ability of BALAD in this subpopulation. METHODS In a multicenter cohort of 1,510 patients with advanced uHCC treated with first-line systemic therapies, the baseline BALAD score was calculated on the basis of pretreatment serum levels. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR) were calculated and related to the BALAD score. RESULTS In all, 502 patients were treated with sorafenib, 435 with lenvatinib, and 573 with atezolizumab plus bevacizumab. Irrespective of treatment regimen, OS, PFS, ORR, and DCR were all independently negatively correlated with the BALAD score. The beneficial effects of specific systemic therapy regimens differed according to the BALAD score. CONCLUSION The BALAD score had good prognostic ability for predicting OS and PFS in patients with advanced uHCC who underwent systemic therapies and was associated with treatment response. Application of the BALAD score offers increased precision in the prediction of outcome both for individual patients and for specific subgroups of patients with HCC.
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Affiliation(s)
- Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Hironori Ochi
- Hepato-biliary Center, Japanese Red Cross Matsuyama Hospital, Matsuyama, Japan
| | - Kunihiko Tsuji
- Center of Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Kazuto Tajiri
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan
| | - Joji Tani
- Department of Gastroenterology and Hepatology, Kagawa University, Kagawa, Japan
| | - Toshifumi Tada
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan
| | - Tomomi Okubo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School Chiba Hokuso Hospital, Inzai, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Ei Itobayashi
- Department of Gastroenterology, Asahi General Hospital, Asahi, Japan
| | - Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Maebashi, Japan
| | - Kazuya Kariyama
- Department of Hepatology, Okayama City Hospital, Okayama, Japan
| | - Toru Ishikawa
- Department of Hepatology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Hidekatsu Kuroda
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, School of Medicine, Morioka, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Hisashi Kosaka
- Department of Surgery, Kansai Medical University, Hirakata, Japan
| | - Kazuhito Kawada
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Satoru Kakizaki
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Yutaka Yada
- Department of Gastroenterology, Hanwa Memorial Hospital, Osaka, Japan
| | - Chikara Ogawa
- Department of Gastroenterology, Japanese Red Cross Takamatsu Hospital, Takamatsu, Japan
| | - Takashi Nishimura
- Department of Gastroenterology and Hepatology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Akihiro Deguchi
- Department of Gastroenterology and Hepatology, Kagawa University, Kagawa, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Hepatology, Kagawa University, Kagawa, Japan
| | - Norio Itokawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Taeang Arai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Akemi Tsutsui
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Hirayuki Enomoto
- Department of Gastroenterology and Hepatology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Masaki Kaibori
- Department of Surgery, Kansai Medical University, Hirakata, Japan
| | - Kazuhiro Nouso
- Department of Hepatology, Okayama City Hospital, Okayama, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Takashi Kumada
- Department of Nursing, Gifu Kyoritsu University, Ogaki, Japan
| | - Tomoyuki Akita
- Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan
| | - Junko Tanaka
- Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan
| | - Philip J Johnson
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom
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Al-Hasan M, Mehta N, Yang JD, Singal AG. Role of biomarkers in the diagnosis and management of HCC. Liver Transpl 2025; 31:384-394. [PMID: 38738964 DOI: 10.1097/lvt.0000000000000398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 05/06/2024] [Indexed: 05/14/2024]
Abstract
For many cancers, biomarkers have served as an important tool across the cancer care continuum from risk stratification and early detection to diagnosis and treatment. Alpha-fetoprotein (AFP) remains one of the few validated biomarkers for patients with HCC. Although AFP has shown potential for each of these steps, its performance, when used alone, has often been suboptimal. There continue to be discordant recommendations about AFP's value when combined with ultrasound for surveillance, as well as its role in diagnostic algorithms. Conversely, high AFP levels are associated with aggressive tumor biology and survival, so it remains a key factor for the selection of candidates for liver transplant. There have been immense efforts to identify and validate additional biomarkers for each of these steps in the HCC care continuum. Indeed, biomarker panels have shown promising data for HCC risk stratification and surveillance among patients with cirrhosis, as well as prognostication and detection of minimal residual disease in patients undergoing HCC treatment. Several large prospective studies are currently ongoing to evaluate the role of these emerging biomarkers in clinical practice.
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Affiliation(s)
- Mohammed Al-Hasan
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Neil Mehta
- Department of Internal Medicine, University of California San Francisco, San Francisco, California, USA
| | - Ju Dong Yang
- Department of Internal Medicine, Cedars Sinai, Los Angeles, California, USA
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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Zhang J, Wu Q, Zeng J, Zeng Y, Liu J, Zeng J. The APP Score: A simple serum biomarker model to enhance prognostic prediction in hepatocellular carcinoma. Biosci Trends 2025; 18:567-583. [PMID: 39631885 DOI: 10.5582/bst.2024.01228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
The prognosis for patients with hepatocellular carcinoma (HCC) depends on tumor stage and remnant liver function. However, it often includes tumor morphology, which is usually assessed with imaging studies or pathologic analysis, leading to limited predictive performance. Therefore, the aim of this study was to develop a simple and low-cost prognostic score for HCC based on serum biomarkers in routine clinical practice. A total of 3,100 patients were recruited. The least absolute shrinkage and selector operation (LASSO) algorithm was used to select the significant factors for overall survival. The prognostic score was devised based on multivariate Cox regression of the training cohort. Model performance was assessed by discrimination and calibration. Albumin (ALB), alkaline phosphatase (ALP), and alpha-fetoprotein (AFP) were selected by the LASSO algorithm. The three variables were incorporated into multivariate Cox regression to create the risk score (APP score = 0.390* ln (ALP) + 0.063* ln(AFP) - 0.033*ALB). The C-index, K-index, and time-dependent AUC of the score displayed significantly better predictive performance than 5 other models and 5 other staging systems. The model was able to stratify patients into three different risk groups. In conclusion, the APP score was developed to estimate survival probability and was used to stratify three strata with significantly different outcomes, outperforming other models in training and validation cohorts as well as different subgroups. This simple and low-cost model could help guide individualized follow-up.
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Affiliation(s)
- Jinyu Zhang
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
- Hepatobiliary Medical Center of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Qionglan Wu
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
- Hepatobiliary Medical Center of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Jinhua Zeng
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
- Hepatobiliary Medical Center of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Yongyi Zeng
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
- Hepatobiliary Medical Center of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Jingfeng Liu
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
- Hepatobiliary Medical Center of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Jianxing Zeng
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
- Hepatobiliary Medical Center of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
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Elgenidy A, Abubasheer TM, Odat RM, Abdelrahim MG, Jibril NS, Ramadan AM, Ballut L, Haseeb ME, Ragab A, Ismail AM, Afifi AM, Mohamed BJ, Jalal PK. Assessing the Predictive Accuracy of the aMAP Risk Score for Hepatocellular Carcinoma (HCC): Diagnostic Test Accuracy and Meta-analysis. J Clin Exp Hepatol 2025; 15:102381. [PMID: 39262566 PMCID: PMC11386263 DOI: 10.1016/j.jceh.2024.102381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 07/21/2024] [Indexed: 09/13/2024] Open
Abstract
Purpose We aimed to perform a meta-analysis with the intention of evaluating the reliability and test accuracy of the aMAP risk score in the identification of HCC. Methods A systematic search was performed in PubMed, Scopus, Cochrane, Embase, and Web of Science databases from inception to September 2023, to identify studies measuring the aMAP score in patients for the purpose of predicting the occurrence or recurrence of HCC. The meta-analysis was performed using the meta package in R version 4.1.0. The diagnostic accuracy meta-analysis was conducted using Meta-DiSc software. Results Thirty-five studies 102,959 participants were included in the review. The aMAP score was significantly higher in the HCC group than in the non-HCC group, with a mean difference of 6.15. When the aMAP score is at 50, the pooled sensitivity, specificity, negative likelihood ratio, and positive likelihood ratio with 95% CI was 0.961 (95% CI 0.936, 0.976), 0.344 (95% CI 0.227, 0.483), 0.114 (95% CI 0.087, 0.15), and 1.464 (95% CI 1.22, 1.756), respectively. At a cutoff value of 60, the pooled sensitivity, specificity, negative likelihood ratio, and positive likelihood ratio with 95% CI was 0.594 (95% CI 0.492, 0.689), 0.816 (95% CI 0.714, 0.888), 0.497 (95% CI 0.418, 0.591), and 3.235 (95% CI 2.284, 4.582), respectively. Conclusion The aMAP score is a reliable, accurate, and easy-to-use tool for predicting HCC patients of all stages, including early-stage HCC. Therefore, the aMAP score can be a valuable tool for surveillance of HCC patients and can help to improve early detection and reduce mortality.
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Affiliation(s)
| | - Tareq M Abubasheer
- Faculty of Medicine, Al-Quds University (Al-Azhar Branch), Gaza, Palestine
| | - Ramez M Odat
- Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | | | - Nada S Jibril
- Faculty of Medicine, Menofia University, Menofia, Egypt
| | - Aya M Ramadan
- Faculty of Medicine, Menofia University, Menofia, Egypt
| | | | | | | | | | - Ahmed M Afifi
- Department of Surgery, University of Toledo Medical Center, USA
| | - Benarad J Mohamed
- Oncology Department UClouvain, University Catholic Louvain, Brussels, Belgium
| | - Prasun K Jalal
- Division of Gastroenterology, Baylor College of Medicine, Houston, TX, 77030, USA
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Lu SY, Sun HY, Zhou Y, Luo X, Liu S, Zhou WZ, Shi HB, Yang W, Tian W. Prognosis of Patients with Hepatocellular Carcinoma Treated with TACE: A New Score Combining Alpha-Fetoprotein and Des-γ-Carboxy Prothrombin. J Hepatocell Carcinoma 2024; 11:1979-1992. [PMID: 39465043 PMCID: PMC11512524 DOI: 10.2147/jhc.s481393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 10/15/2024] [Indexed: 10/29/2024] Open
Abstract
Purpose Hepatocellular carcinoma (HCC) represents a significant global health problem, requiring precise prognostic tools for optimal treatment stratification. This study aimed to develop a new risk prediction score, called AD score, based on the serum markers alpha-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP), to offer an objective and accurate preoperative assessment of HCC in patients undergoing transarterial chemoembolization (TACE). Patients and Methods This was a retrospective study that included 295 HCC patients who were subjected to TACE (training set, n=147; testing set, n=148). Serum AFP and DCP levels were log-transformed to construct the AD score. Multivariate Cox regression analysis on cirrhosis subgroups validated the objectivity of the model. Performance comparison of established models (Child Pugh, BCLC, ALBI, Up-to-seven, Six-and-twelve, Four and seven, HAP score, mHAP-II, FAIL-T score), was assessed through time-dependent receiver operating characteristic (ROC) curves and risk stratification. Results The AD score, incorporating lgAFP and lgDCP, demonstrated superior predictive accuracy than the existing models. Time-dependent ROC curve revealed the consistent superiority of the AD score over a 5-year period. The risk stratification into low, intermediate, and high group based on the AD score showed a significant survival difference in both training and testing set. Conclusion For HCC patients undergoing TACE, the AD score serves as an objective and straightforward prognostic tool, enhancing predictive accuracy and showcasing its clinical utility. It demonstrates potential significance as a crucial addition to preoperative risk assessment for TACE.
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Affiliation(s)
- Shang-Yu Lu
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Han-Yao Sun
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Yan Zhou
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Xi Luo
- The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China
| | - Sheng Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Wei-Zhong Zhou
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Hai-Bin Shi
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Wei Yang
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Wei Tian
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
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Nakagawa S, Hayashi H, Itoyama R, Kitano Y, Mima K, Okabe H, Baba H. BALAD score predicts the recurrence and survival in the patients who underwent initial hepatectomy for HCC. Surg Oncol 2024; 55:102097. [PMID: 39029425 DOI: 10.1016/j.suronc.2024.102097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 06/03/2024] [Accepted: 06/28/2024] [Indexed: 07/21/2024]
Abstract
BACKGROUNDS Several studies have indicated that BALAD score which includes the HCC tumor markers of HCC, AFP, AFP-L3%, DCP, and serum albumin and bilirubin value were good predictors of HCC patients for all treatment modalities. In this study, we aim to clarify the impact of BALAD score as the prognostic factor for HCC patients after curative surgery. METHODS This study investigated 578 patients who underwent hepatectomy for HCC between January 2003 and May 2013. Cumulative recurrence rate, overall survival (OS), and clinicopathological parameters were analyzed according to the level of BALAD score. RESULTS In patients with higher BALAD score, recurrence rate and OS was poor (p = 0.0015 and p < 0.0001, respectively). Multivariate analyses revealed independent risk factors for recurrence to be male (hazard ratio [HR] 1.52, P = 0.011), HCV-antibody positive (HR 1.33, P = 0.019), multiple tumors (HR 2.16, P < 0.0001), microvascular invasion (HR 1.45, P = 0.0035) and higher BALAD score (RR 1.70, P = 0.015). The independent risk factors for OS were multiple tumors (HR 1.52, P = 0.014), microvascular invasion (HR 1.53, P = 0.012), and higher BALAD score (RR 2.51, P = 0.0012). CONCLUSION BALAD score is associated with high recurrence rate and poor overall survival of the patients who underwent curative liver resection for HCC.
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Affiliation(s)
- Shigeki Nakagawa
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-0811, Japan.
| | - Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-0811, Japan
| | - Rumi Itoyama
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-0811, Japan
| | - Yuki Kitano
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-0811, Japan
| | - Kosuke Mima
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-0811, Japan
| | - Hirohisa Okabe
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-0811, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-0811, Japan
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Olbrich A, Niemeyer J, Seiffert H, Ebel S, Gros O, Lordick F, Forstmeyer D, Seehofer D, Rademacher S, Denecke T, Matz-Soja M, Berg T, van Bömmel F. The GALAD score and the BALAD-2 score correlate with transarterial and systemic treatment response and survival in patients with hepatocellular carcinoma. J Cancer Res Clin Oncol 2024; 150:81. [PMID: 38319485 PMCID: PMC10847183 DOI: 10.1007/s00432-023-05526-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 11/09/2023] [Indexed: 02/07/2024]
Abstract
PURPOSE The GALAD score and the BALAD-2 score are biomarker-based scoring systems used to detect hepatocellular carcinoma (HCC). Both incorporate levels of alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive AFP (AFP-L3), and des-gamma-carboxy prothrombin (DCP). Our objective was to examine the relationship between the GALAD score as well as the BALAD-2 score and treatment response to transarterial or systemic treatments in patients with HCC. METHODS A total of 220 patients with HCC treated with either transarterial (n = 121) or systemic treatments (n = 99; mainly Sorafenib) were retrospectively analyzed. The GALAD score and the BALAD-2 score were calculated based on AFP-L3, AFP, and DCP levels measured in serum samples collected before treatment. The results were correlated with 3-month treatment efficacy based on radiologic mRECIST criteria. RESULTS The GALAD score showed a strong correlation with BCLC stage (p < 0.001) and total tumor diameter before treatment (p < 0.001).The GALAD score at baseline was significantly lower in patients with a 3-month response to transarterial (p > 0.001) than in refractory patients. Among patients receiving systemic treatment, the median BALAD-2 score at baseline showed a strong association with response at month 3 (p < 0.001). In the transarterial treatment group, the GALAD score (AUC = 0.715; p < 0.001) as well as the BALAD score (AUC = 0.696; p < 0.001) were associated with overall survival, hereby outperforming AFP, AFP-L3 and DCP. CONCLUSION The GALAD score as well as the BALAD-2 score hold significant promise as a prognostic tool for patients with early or intermediate-stage HCC who are undergoing transarterial or systemic treatments.
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Affiliation(s)
- Anne Olbrich
- Laboratory for Clinical and Experimental Hepatology (LCEHep), Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Johannes Niemeyer
- Laboratory for Clinical and Experimental Hepatology (LCEHep), Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Hendrik Seiffert
- Laboratory for Clinical and Experimental Hepatology (LCEHep), Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Sebastian Ebel
- Department of Diagnostic and Interventional Radiology, Leipzig University Medical Center, Leipzig, Germany
- University Liver Tumor Center (ULTC), Leipzig University Medical Center, Leipzig, Germany
| | - Olga Gros
- Department of Anesthesia and Intensive Care, Helios Clinic Köthen, Köthen, Germany
| | - Florian Lordick
- University Cancer Center Leipzig (UCCL) and Division of Oncology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Dirk Forstmeyer
- University Cancer Center Leipzig (UCCL) and Division of Oncology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Daniel Seehofer
- Department of Visceral, Vascular, Thoracic and Transplant Surgery, Leipzig University Medical Center, Leipzig, Germany
- University Liver Tumor Center (ULTC), Leipzig University Medical Center, Leipzig, Germany
| | - Sebastian Rademacher
- Department of Visceral, Vascular, Thoracic and Transplant Surgery, Leipzig University Medical Center, Leipzig, Germany
- University Liver Tumor Center (ULTC), Leipzig University Medical Center, Leipzig, Germany
| | - Timm Denecke
- Department of Diagnostic and Interventional Radiology, Leipzig University Medical Center, Leipzig, Germany
- University Liver Tumor Center (ULTC), Leipzig University Medical Center, Leipzig, Germany
| | - Madlen Matz-Soja
- Laboratory for Clinical and Experimental Hepatology (LCEHep), Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
- Rudolf-Schönheimer-Institute for Biochemistry, University of Leipzig, Leipzig, Germany
| | - Thomas Berg
- Laboratory for Clinical and Experimental Hepatology (LCEHep), Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
- University Liver Tumor Center (ULTC), Leipzig University Medical Center, Leipzig, Germany
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Florian van Bömmel
- Laboratory for Clinical and Experimental Hepatology (LCEHep), Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany.
- University Liver Tumor Center (ULTC), Leipzig University Medical Center, Leipzig, Germany.
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany.
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Liu J, Park K, Shen Z, Lee H, Geetha P, Pakyari M, Chai L. Immunotherapy, targeted therapy, and their cross talks in hepatocellular carcinoma. Front Immunol 2023; 14:1285370. [PMID: 38173713 PMCID: PMC10762788 DOI: 10.3389/fimmu.2023.1285370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 12/05/2023] [Indexed: 01/05/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a challenging malignancy with limited treatment options beyond surgery and chemotherapy. Recent advancements in targeted therapies and immunotherapy, including PD-1 and PD-L1 monoclonal antibodies, have shown promise, but their efficacy has not met expectations. Biomarker testing and personalized medicine based on genetic mutations and other biomarkers represent the future direction for HCC treatment. To address these challenges and opportunities, this comprehensive review discusses the progress made in targeted therapies and immunotherapies for HCC, focusing on dissecting the rationales, opportunities, and challenges for combining these modalities. The liver's unique physiology and the presence of fibrosis in many HCC patients pose additional challenges to drug delivery and efficacy. Ongoing efforts in biomarker development and combination therapy design, especially in the context of immunotherapies, hold promise for improving outcomes in advanced HCC. Through exploring the advancements in biomarkers and targeted therapies, this review provides insights into the challenges and opportunities in the field and proposes strategies for rational combination therapy design.
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Affiliation(s)
- Jun Liu
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States
| | - Kevin Park
- Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | - Ziyang Shen
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States
| | - Hannah Lee
- University of California, San Diego, CA, United States
| | | | - Mohammadreza Pakyari
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States
| | - Li Chai
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States
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9
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Núñez K, Schneider M, Sandow T, Gimenez J, Hibino M, Fort D, Cohen A, Thevenot P. α-Fetoprotein, α-Fetoprotein-L3, and Des-γ-Carboxy Prothrombin Stratify Hepatocellular Carcinoma Treatment Response and Progression Risk. GASTRO HEP ADVANCES 2023; 3:316-325. [PMID: 39131145 PMCID: PMC11308544 DOI: 10.1016/j.gastha.2023.11.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 11/30/2023] [Indexed: 08/13/2024]
Abstract
Background and Aims Assessing aggressive biology at early-stage hepatocellular carcinoma (HCC) diagnosis remains challenging. Alpha-fetoprotein (AFP) is the only clinical biomarker of aggressive HCC. In this study, AFP, Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-γ-carboxy prothrombin (DCP) were measured at diagnosis prior to transplant evaluation and first cycle liver-directed therapy (LDT). Methods The prospective cohort included 207 patients who received LDT as a bridge/downstage to transplant or definitive treatment plan between 2016 and 2022. Plasma AFP, AFP-L3, and DCP levels were measured at diagnosis and analyzed with other factors associated with treatment response and time-to-progression. Results Biomarker phenotyping revealed 41% were triple negative, 30% expressed multiple biomarkers, and 12% express all 3 biomarkers. The biomarker profile was associated with target/overall response rate and time-to-progression (P < .001). Profiling stratified 1-year progression risk in nontransplant candidates, driven by coexpression of AFP and DCP in multivariate analysis controlling for tumor burden and staging. Conclusion The biomarker panel at diagnosis established prognosis for LDT response and stratified 1-year HCC progression risk. AFP, AFP-L3, and DCP profiling isolated aggressive HCC biology at diagnosis and may have important implications in post-LDT surveillance and transplant wait time.
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Affiliation(s)
- Kelley Núñez
- Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, Louisiana
| | - Michael Schneider
- Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, Louisiana
| | - Tyler Sandow
- Department of Radiology, Ochsner Health, New Orleans, Louisiana
| | - Juan Gimenez
- Department of Radiology, Ochsner Health, New Orleans, Louisiana
| | - Mina Hibino
- Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, Louisiana
| | - Daniel Fort
- Center for Outcomes Research, Ochsner Clinic Foundation, New Orleans, Louisiana
| | - Ari Cohen
- Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, Louisiana
- Multi-Organ Transplant Institute, Ochsner Health, New Orleans, Louisiana
- Faculty of Medicine, The University of Queensland, New Orleans, Louisiana
| | - Paul Thevenot
- Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, Louisiana
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10
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Huang DQ, Singal AG, Kanwal F, Lampertico P, Buti M, Sirlin CB, Nguyen MH, Loomba R. Hepatocellular carcinoma surveillance - utilization, barriers and the impact of changing aetiology. Nat Rev Gastroenterol Hepatol 2023; 20:797-809. [PMID: 37537332 DOI: 10.1038/s41575-023-00818-8] [Citation(s) in RCA: 76] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/30/2023] [Indexed: 08/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Surveillance for HCC is critical for early detection and treatment, but fewer than one-quarter of individuals at risk of HCC undergo surveillance. Multiple failures across the screening process contribute to the underutilization of surveillance, including limited disease awareness among patients and health-care providers, knowledge gaps, and difficulty recognizing patients who are at risk. Non-alcoholic fatty liver disease and alcohol-associated liver disease are the fastest-rising causes of HCC-related death worldwide and are associated with unique barriers to surveillance. In particular, more than one-third of patients with HCC related to non-alcoholic fatty liver disease do not have cirrhosis and therefore lack a routine indication for HCC surveillance on the basis of current practice guidelines. Semi-annual abdominal ultrasound with measurement of α-fetoprotein levels is recommended for HCC surveillance, but the sensitivity of this approach for early HCC is limited, especially for patients with cirrhosis or obesity. In this Review, we discuss the current status of HCC surveillance and the remaining challenges, including the changing aetiology of liver disease. We also discuss strategies to improve the utilization and quality of surveillance for HCC.
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Affiliation(s)
- Daniel Q Huang
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore.
| | - Amit G Singal
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Fasiha Kanwal
- Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Pietro Lampertico
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy
- CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Maria Buti
- Liver Unit, Department of Internal Medicine, Hospital Universitari Valle d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain
- CIBER-EHD del Instituto Carlos III, Barcelona, Spain
| | - Claude B Sirlin
- Liver Imaging Group, Department of Radiology, UCSD School of Medicine, San Diego, CA, USA
| | - Mindie H Nguyen
- Department of Epidemiology and Population Health, Stanford University Medical Center, Stanford University, Palo Alto, CA, USA
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford University, Palo Alto, CA, USA
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology and Hepatology, University of California at San Diego, San Diego, CA, USA
- Division of Epidemiology, Department of Family Medicine and Public Health, University of California at San Diego, San Diego, CA, USA
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11
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Zhou L, He L, Liu CH, Qiu H, Zheng L, Sample KM, Wu Q, Li J, Xie K, Ampuero J, Li Z, Lv D, Liu M, Romero-Gómez M, Hu Y, Tang H. Liver cancer stem cell dissemination and metastasis: uncovering the role of NRCAM in hepatocellular carcinoma. J Exp Clin Cancer Res 2023; 42:311. [PMID: 37993901 PMCID: PMC10664624 DOI: 10.1186/s13046-023-02893-w] [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: 08/10/2023] [Accepted: 11/10/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Liver cancer stem cells (LCSCs) play an important role in hepatocellular carcinoma (HCC), but the mechanisms that link LCSCs to HCC metastasis remain largely unknown. This study aims to reveal the contributions of NRCAM to LCSC function and HCC metastasis, and further explore its mechanism in detail. METHODS 117 HCC and 29 non-HCC patients with focal liver lesions were collected and analyzed to assess the association between NRCAM and HCC metastasis. Single-cell RNA sequencing (scRNA-seq) was used to explore the biological characteristics of cells with high NRCAM expression in metastatic HCC. The role and mechanism of NRCAM in LCSC dissemination and metastasis was explored in vitro and in vivo using MYC-driven LCSC organoids from murine liver cells. RESULTS Serum NRCAM is associated with HCC metastasis and poor prognosis. A scRNA-seq analysis identified that NRCAM was highly expressed in LCSCs with MYC activation in metastatic HCC. Moreover, NRCAM facilitated LCSC migration and invasion, which was confirmed in MYC-driven LCSC organoids. The in vivo tumor allografts demonstrated that NRCAM mediated intra-hepatic/lung HCC metastasis by enhancing the ability of LCSCs to escape from tumors into the bloodstream. Nrcam expression inhibition in LCSCs blocked HCC metastasis. Mechanistically, NRCAM activated epithelial-mesenchymal transition (EMT) and metastasis-related matrix metalloproteinases (MMPs) through the MACF1 mediated β-catenin signaling pathway in LCSCs. CONCLUSIONS LCSCs typified by high NRCAM expression have a strong ability to invade and migrate, which is an important factor leading to HCC metastasis.
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Affiliation(s)
- Lingyun Zhou
- Center of Infectious Diseases, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China.
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.
| | - Linye He
- Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China
| | - Chang-Hai Liu
- Center of Infectious Diseases, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Huandi Qiu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China
| | - Li Zheng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China
| | - Klarke Michael Sample
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China
| | - Qin Wu
- Center of Infectious Diseases, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China
| | - Jiaxin Li
- Department of Liver Surgery and Liver Transplantation Centre, West China Hospital of Sichuan University, Chengdu, China
| | - Kunlin Xie
- Department of Liver Surgery and Liver Transplantation Centre, West China Hospital of Sichuan University, Chengdu, China
| | - Javier Ampuero
- Digestive Diseases Unit, Virgen del Rocío University Hospital, SeLiver Group at Institute of Biomedicine of Seville (IBIS: HUVRocío/CSIC/US), University of Seville, Seville, Spain
| | - Zhihui Li
- Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China
| | - Duoduo Lv
- Center of Infectious Diseases, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Miao Liu
- Center of Infectious Diseases, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Manuel Romero-Gómez
- Digestive Diseases Unit, Virgen del Rocío University Hospital, SeLiver Group at Institute of Biomedicine of Seville (IBIS: HUVRocío/CSIC/US), University of Seville, Seville, Spain.
- Digestive Disease Department and CIBERehd, Virgen del Rocío University Hospital, Avenida Manuel Siurot S/N, 41013, Seville, Spain.
| | - Yiguo Hu
- Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China.
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China.
- National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China.
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China.
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.
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12
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Yen YH, Li WF, Liu YW, Yong CC, Wang CC, Lin CY. A simple preoperative model to predict overall survival of patients undergoing liver resection for hepatocellular carcinoma ≥10 cm. HPB (Oxford) 2023; 25:1373-1381. [PMID: 37517893 DOI: 10.1016/j.hpb.2023.07.881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/29/2023] [Accepted: 07/12/2023] [Indexed: 08/01/2023]
Abstract
BACKGROUND Studies have rarely reported on preoperative predictors of prognosis of patients undergoing liver resection (LR) for HCC ≥10 cm. We developed a simple model to predict overall survival (OS) of these patients. METHODS We enrolled 305 patients with HCC ≥10 cm undergoing LR. Cirrhosis and imaging-defined AJCC stage were used to develop a preoperative model. Patients were divided into three groups based on the Kaplan-Meier estimator. RESULTS Group 1 included patients with AJCC stage 1 and no cirrhosis (n = 86), group 2 those with AJCC stage 1 and cirrhosis plus those with AJCC stage 2 or 3 and no cirrhosis (n = 166), and group 3 those with AJCC stage 2 or 3 and cirrhosis (n = 51). The five-year OS of group 1, 2, and 3 was 55%, 32%, and 25%, respectively (p < 0.001). With group 1 as the reference, multivariate analysis of OS showed that group 2 (HR = 2.043; 95% CI = 1.332-3.134; p = 0.001) and group 3 (HR = 2.740; 95% CI = 1.645-4.564; p < 0.001) were independent predictors of OS. CONCLUSION We developed a simple model to predict OS of patients undergoing LR for HCC ≥10 cm.
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Affiliation(s)
- Yi-Hao Yen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
| | - Wei-Feng Li
- Liver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Yueh-Wei Liu
- Liver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chee-Chien Yong
- Liver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chih-Chi Wang
- Liver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
| | - Chih-Yun Lin
- Biostatistics Center of Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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13
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Gradel KO. Interpretations of the Role of Plasma Albumin in Prognostic Indices: A Literature Review. J Clin Med 2023; 12:6132. [PMID: 37834777 PMCID: PMC10573484 DOI: 10.3390/jcm12196132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/18/2023] [Accepted: 09/21/2023] [Indexed: 10/15/2023] Open
Abstract
This review assesses how publications interpret factors that influence the serum or plasma albumin (PA) level in prognostic indices, focusing on inflammation and nutrition. On PubMed, a search for "albumin AND prognosis" yielded 23,919 results. From these records, prognostic indices were retrieved, and their names were used as search strings on PubMed. Indices found in 10 or more original research articles were included. The same search strings, restricted to "Review" or "Systematic review", retrieved yielded on the indices. The data comprised the 10 latest original research articles and up to 10 of the latest reviews. Thirty indices had 294 original research articles (6 covering two indices) and 131 reviews, most of which were from recent years. A total of 106 articles related the PA level to inflammation, and 136 related the PA level to nutrition. For the reviews, the equivalent numbers were 54 and 65. In conclusion, more publications mention the PA level as a marker of nutrition rather than inflammation. This is in contrast to several general reviews on albumin and nutritional guidelines, which state that the PA level is a marker of inflammation but not nutrition. Hypoalbuminemia should prompt clinicians to focus on the inflammatory aspects in their patients.
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Affiliation(s)
- Kim Oren Gradel
- Center for Clinical Epidemiology, Odense University Hospital, 5000 Odense, Denmark; ; Tel.: +45-21-15-80-85
- Research Unit of Clinical Epidemiology, Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark
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14
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Yu J, Park R, Kim R. Promising Novel Biomarkers for Hepatocellular Carcinoma: Diagnostic and Prognostic Insights. J Hepatocell Carcinoma 2023; 10:1105-1127. [PMID: 37483311 PMCID: PMC10362916 DOI: 10.2147/jhc.s341195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 07/07/2023] [Indexed: 07/25/2023] Open
Abstract
The systemic therapy landscape for hepatocellular carcinoma is rapidly evolving, as the recent approvals of checkpoint inhibitor-based regimens such as atezolizumab-bevacizumab and durvalumab-tremelimumab in advanced disease have led to an expanding therapeutic armamentarium. The development of biomarkers, however, has not kept up with the approvals of new agents. Nevertheless, biomarker research for hepatocellular carcinoma has recently been growing at a rapid pace. The most active areas of research are biomarkers for early detection and screening, accurate prognostication, and detection of minimal residual disease following curative intent therapies, and, perhaps most importantly, predictive markers to guide selection and sequencing of the individual agents, including tyrosine kinase inhibitors and immunotherapy. In this review, we briefly summarize the recent developments in systemic therapeutics for hepatocellular carcinoma, introduce the key completed and ongoing prospective and retrospective studies evaluating diagnostic, prognostic, and predictive biomarkers with high clinical relevance, highlight several potentially important areas of future research, and share our insights for each biomarker.
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Affiliation(s)
- James Yu
- Division of Hematology and Medical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Robin Park
- Division of Hematology and Medical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Richard Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
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15
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Xu FQ, Zhang Z, Hu A, Huang DS. Circulating biomarkers for diagnosis and management of hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2023; 31:404-411. [DOI: 10.11569/wcjd.v31.i10.404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/26/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, but the prognosis of HCC patients is poor due to the difficulty of early diagnosis and high recurrence rate. Therefore, it is particularly important to seek effective methods for early diagnosis and early recurrence monitoring after treatment. Circulating biomarkers play an important role in the diagnosis, progression monitoring, and prognosis evaluation of HCC. In recent years, with the discovery of a variety of new biomarkers, the development of biomarkers-related models, and the emergence of liquid biopsy technology, the diagnosis and treatment of HCC have been greatly improved. This article reviews the latest research advances of biomarkers in the diagnosis and treatment of HCC, aiming to provide new ideas for improving the prognosis of HCC patients.
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16
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Yang C, Wu X, Liu J, Wang H, Jiang Y, Wei Z, Cai Q. Nomogram Based on Platelet-Albumin-Bilirubin for Predicting Tumor Recurrence After Surgery in Alpha-Fetoprotein-Negative Hepatocellular Carcinoma Patients. J Hepatocell Carcinoma 2023; 10:43-55. [PMID: 36660412 PMCID: PMC9844149 DOI: 10.2147/jhc.s396433] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 01/08/2023] [Indexed: 01/15/2023] Open
Abstract
Purpose In this study, we developed a nomogram based on the platelet-albumin-bilirubin (PALBI) score to predict recurrence-free survival (RFS) after curative resection in alpha-fetoprotein (AFP)-negative (≤20 ng/mL) hepatocellular carcinoma (HCC) patients. Patients and Methods A total of 194 pathologically confirmed AFP-negative HCC patients were retrospectively analyzed. Univariate and multivariate Cox regression analyses were performed to screen the independent risk factors associated with RFS, and a nomogram prediction model for RFS was established according to the independent risk factors. The receiver operating characteristic (ROC) curve and the C-index were used to evaluate the accuracy and the efficacy of the model prediction. The correction curve was used to assess the calibration of the prediction model, and decision curve analysis was performed to evaluate the clinical application value of the prediction model. Results PALBI score, MVI, and tumor size were independent risk factors for postoperative tumor recurrence (P < 0.05). A nomogram prediction model based on the independent predictive factors was developed to predict RFS, and it achieved a good C-index of 0.704 with an area under the ROC curve of 0.661 and the sensitivity was 73.2%. Patients with AFP-negative HCC could be divided into the high-risk group or the low-risk group by the risk score calculated by the nomogram, and there was a significant difference in RFS between the two groups (P < 0.05). Decision curve analysis (DCA) showed that the nomogram increased the net benefit in predicting the recurrence of AFP-negative HCC and exhibited a wider range of threshold probabilities than the independent risk factors (PALBI score, MVI, and tumor size) by risk stratification. Conclusion The nomogram based on the PALBI score can predict RFS after curative resection in AFP-negative HCC patients and can help clinicians to screen out high-risk patients for early intervention.
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Affiliation(s)
- Chengkai Yang
- The Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Xiaoya Wu
- Eastern Hospital Affiliated to Xiamen University, Fuzhou, 350025, People’s Republic of China
| | - Jianyong Liu
- Department of Hepatobiliary Surgery, 900 Hospital of The Joint Logistics Team, Fuzhou, 350025, People’s Republic of China
| | - Huaxiang Wang
- The Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Yi Jiang
- Department of Hepatobiliary Surgery, 900 Hospital of The Joint Logistics Team, Fuzhou, 350025, People’s Republic of China
| | - Zhihong Wei
- Department of Hepatobiliary Surgery, 900 Hospital of The Joint Logistics Team, Fuzhou, 350025, People’s Republic of China
| | - Qiucheng Cai
- Department of Hepatobiliary Surgery, 900 Hospital of The Joint Logistics Team, Fuzhou, 350025, People’s Republic of China
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Stulpinas R, Zilenaite-Petrulaitiene D, Rasmusson A, Gulla A, Grigonyte A, Strupas K, Laurinavicius A. Prognostic Value of CD8+ Lymphocytes in Hepatocellular Carcinoma and Perineoplastic Parenchyma Assessed by Interface Density Profiles in Liver Resection Samples. Cancers (Basel) 2023; 15:cancers15020366. [PMID: 36672317 PMCID: PMC9857181 DOI: 10.3390/cancers15020366] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 12/28/2022] [Accepted: 01/04/2023] [Indexed: 01/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) often emerges in the setting of long-standing inflammatory liver disease. CD8 lymphocytes are involved in both the antitumoral response and hepatocyte damage in the remaining parenchyma. We investigated the dual role of CD8 lymphocytes by assessing density profiles at the interfaces of both HCC and perineoplastic liver parenchyma with surrounding stroma in whole-slide immunohistochemistry images of surgical resection samples. We applied a hexagonal grid-based digital image analysis method to sample the interface zones and compute the CD8 density profiles within them. The prognostic value of the indicators was explored in the context of clinicopathological, peripheral blood testing, and surgery data. Independent predictors of worse OS were a low standard deviation of CD8+ density along the tumor edge, high mean CD8+ density within the epithelial aspect of the perineoplastic liver-stroma interface, longer duration of surgery, a higher level of aspartate transaminase (AST), and a higher basophil count in the peripheral blood. A combined score, derived from these five independent predictors, enabled risk stratification of the patients into three prognostic categories with a 5-year OS probability of 76%, 40%, and 8%. Independent predictors of longer RFS were stage pT1, shorter duration of surgery, larger tumor size, wider tumor-free margin, and higher mean CD8+ density in the epithelial aspect of the tumor-stroma interface. We conclude that (1) our computational models reveal independent and opposite prognostic impacts of CD8+ cell densities at the interfaces of the malignant and non-malignant epithelium interfaces with the surrounding stroma; and (2) together with pathology, surgery, and laboratory data, comprehensive prognostic models can be constructed to predict patient outcomes after liver resection due to HCC.
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Affiliation(s)
- Rokas Stulpinas
- Faculty of Medicine, Institute of Biomedical Sciences, Department of Pathology, Forensic Medicine and Pharmacology, Vilnius University, 03101 Vilnius, Lithuania
- National Center of Pathology, Affiliate of Vilnius University Hospital Santaros Clinics, 08406 Vilnius, Lithuania
- Correspondence:
| | - Dovile Zilenaite-Petrulaitiene
- Faculty of Medicine, Institute of Biomedical Sciences, Department of Pathology, Forensic Medicine and Pharmacology, Vilnius University, 03101 Vilnius, Lithuania
- National Center of Pathology, Affiliate of Vilnius University Hospital Santaros Clinics, 08406 Vilnius, Lithuania
| | - Allan Rasmusson
- Faculty of Medicine, Institute of Biomedical Sciences, Department of Pathology, Forensic Medicine and Pharmacology, Vilnius University, 03101 Vilnius, Lithuania
- National Center of Pathology, Affiliate of Vilnius University Hospital Santaros Clinics, 08406 Vilnius, Lithuania
| | - Aiste Gulla
- Faculty of Medicine, Institute of Clinical Medicine, Vilnius University, 03101 Vilnius, Lithuania
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Agne Grigonyte
- Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania
| | - Kestutis Strupas
- Faculty of Medicine, Institute of Clinical Medicine, Vilnius University, 03101 Vilnius, Lithuania
| | - Arvydas Laurinavicius
- Faculty of Medicine, Institute of Biomedical Sciences, Department of Pathology, Forensic Medicine and Pharmacology, Vilnius University, 03101 Vilnius, Lithuania
- National Center of Pathology, Affiliate of Vilnius University Hospital Santaros Clinics, 08406 Vilnius, Lithuania
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Li L, Lu F, Chen P, Song H, Xu W, Guo J, Wang J, Zhou J, Kang X, Jin C, Cai Y, Feng Z, Gao H. Validation of the GALAD model and establishment of a new model for HCC detection in Chinese patients. Front Oncol 2022; 12:1037742. [PMID: 36620588 PMCID: PMC9817025 DOI: 10.3389/fonc.2022.1037742] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 11/24/2022] [Indexed: 12/25/2022] Open
Abstract
Background GALAD model is a statistical model used to estimate the possibility of hepatocellular carcinoma (HCC) in patients with chronic liver disease. Many studies with other ethnic populations have shown that it has high sensitivity and specificity. However, whether this model can be used for Chinese patients remains to be determined. Our study was conducted to verify the performance of GALAD model in a Chinese cohort and construct a new model that is more appropriately for Chinese populations. Methods There are total 512 patients enrolled in the study, which can be divided into training set and validation set. 80 patients with primary liver cancer, 139 patients with chronic liver disease and 87 healthy people were included in the training set. Through the ROC(receiver operating characteristic) curve analysis, the recognition performance of GALAD model for liver cancer was evaluated, and the GAADPB model was established by logistic regression, including gender, age, AFP, DCP, total protein, and total bilirubin. The validation set (75 HCC patients and 130 CLD patients) was used to evaluate the performance of the GAADPB model. Result The GALAD and GAADPB achieved excellent performance (area under the receiver operating characteristic curve [AUC], 0.925, 0.945), and were better than GAAP, Doylestown, BALAD-2, aMAP, AFP, AFP-L3%, DCP and combined detection of AFP, AFP-L3 and DCP (AUCs: 0.894, 0.870, 0.648, 0.545, 0.879, 0.782, 0.820 and 0.911) for detecting HCC from CLD in the training set. As for early stage of HCC (BCLC 0/A), GAADPB had the best sensitivity compared to GALAD, ADP and DCP (56.3%, 53.1%, 40.6%, 50.0%). GAADPB had better performance than GALAD in the test set, AUC (0.896 vs 0.888). Conclusions The new GAADPB model was powerful and stable, with better performance than the GALAD and other models, and it also was promising in the area of HCC prognosis prediction. Further study on the real-world HCC patients in China are needed.
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Affiliation(s)
- Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China,National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China,Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China,*Correspondence: Lanjuan Li, ; Fengmin Lu,
| | - Fengmin Lu
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China,Hepatology Institute, Peking University People's Hospital, Beijing, China,*Correspondence: Lanjuan Li, ; Fengmin Lu,
| | - Ping Chen
- Department of Infectious Diseases, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
| | - Haolin Song
- College of Medicine, Zhejiang University, Hangzhou, China
| | - Wei Xu
- College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jin Guo
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Jianfei Wang
- Research and Development Division, Oriomics Biotech Inc, Hangzhou, China
| | - Juhong Zhou
- Research and Development Division, Oriomics Biotech Inc, Hangzhou, China
| | - Xiang Kang
- Research and Development Division, Oriomics Biotech Inc, Hangzhou, China
| | - Chaolei Jin
- Infection and Immunity Institute and Translational Medical Center of Huaihe Hospital, Henan University, Kaifeng, China
| | - Yubo Cai
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China,National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China,Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zixuan Feng
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Hainv Gao
- Department of Infectious Diseases, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
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19
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Circulating biomarkers in the diagnosis and management of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2022; 19:670-681. [PMID: 35676420 DOI: 10.1038/s41575-022-00620-y] [Citation(s) in RCA: 153] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/20/2022] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal causes of cancer-related death worldwide. The treatment of HCC remains challenging and is largely predicated on early diagnosis. Surveillance of high-risk groups using abdominal ultrasonography, with or without serum analysis of α-fetoprotein (AFP), can permit detection of early, potentially curable tumours, but is limited by its insensitivity. Reviewed here are two current approaches that aim to address this limitation. The first is to use old re-emerged empirically derived biomarkers such as AFP, now applied within statistical models. The second is to use circulating nucleic acid biomarkers, which include cell-free DNA (for example, circulating tumour DNA, cell-free mitochondrial DNA and cell-free viral DNA) and cell-free RNA, applying modern molecular biology-based technologies and machine learning techniques closely allied to the underlying biology of cancer. Taken together, these approaches are likely to be complementary. Both hold considerable promise for achieving earlier diagnosis as well as offering additional functionalities including improved monitoring of therapy and prediction of response thereto.
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20
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Li Z, Gao H, Zhang X, Liu Q, Chen G. Mutational and transcriptional alterations and clinicopathological factors predict the prognosis of stage I hepatocellular carcinoma. BMC Gastroenterol 2022; 22:427. [PMID: 36153509 PMCID: PMC9509563 DOI: 10.1186/s12876-022-02496-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 09/07/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The prognosis of hepatocellular carcinoma (HCC) has been extensively studied. However, the impact on prognosis of stage I HCC has not been well studied at clincopathological, mutational and transcriptional levels.
Methods
Here we first characterized the influencing factors of prognosis of stage I HCC patients by downloading and analyzing the whole-exome somatic mutation data, messenger ribonucleic acid (mRNA) transcription data, along with demographic and clinical information of 163 stage I HCC patients from the TCGA database. The relationship between the influencing factors and HCC prognosis was studied in detail, and a prediction Nomogram model was established. Figures and tables were plotted using the R software.
Results
TP53, CTNNB1, TTN, MUC16 and ALB were the top mutated genes in stage I HCC. A series of co-mutations and mutually exclusive mutations were identified. Twenty-nine genes with significant stratification on prognosis were identified, including highly mutated LRP1B, ARID1A and PTPRQ. Patients with wild type (WT) genes unanimously exhibited significantly better overall survival rate than those with mutants. Patients with the top 10% tumor mutational burden (TMB) exhibited significantly worse prognosis than the rest 90%. Further characterization of transcriptional profile revealed that membrane functions, cell skeleton proteins, ion channels, receptor function and cell cycle were comprehensively altered in stage I HCC. Univariate and multivariate analyses were performed at clinicopathological, mutational and transcriptional levels. The combined analysis revealed sex, race, TMB, neoplasm histologic grade, Child–Pugh grade, MMRN1, OXT and COX6A2 transcription as independent risk factors. These factors were used to establish a Nomogram model to predict the prognosis of individual HCC patients.
Conclusions
The influencing factors of prognosis of stage I HCC have been characterized for the first time at clinicopathological, mutational and transcriptional levels. A Nomogram model has been established to predict the prognosis. Further validation is needed to confirm the effectiveness and reliability of the model.
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21
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Cerrito L, Ainora ME, Mosoni C, Borriello R, Gasbarrini A, Zocco MA. Prognostic Role of Molecular and Imaging Biomarkers for Predicting Advanced Hepatocellular Carcinoma Treatment Efficacy. Cancers (Basel) 2022; 14:4647. [PMID: 36230569 PMCID: PMC9564154 DOI: 10.3390/cancers14194647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/19/2022] [Accepted: 09/20/2022] [Indexed: 11/30/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the fourth cause of tumor-related death. Imaging biomarkers are based on computed tomography, magnetic resonance, and contrast-enhanced ultrasound, and are widely applied in HCC diagnosis and treatment monitoring. Unfortunately, in the field of molecular biomarkers, alpha-fetoprotein (AFP) is still the only recognized tool for HCC surveillance in both diagnostic and follow-up purposes. Other molecular biomarkers have little roles in clinical practice regarding HCC, mainly for the detection of early-stage HCC, monitoring the response to treatments and analyzing tumor prognosis. In the last decades no important improvements have been achieved in this field and imaging biomarkers maintain the primacy in HCC diagnosis and follow-up. Despite the still inconsistent role of molecular biomarkers in surveillance and early HCC detection, they could play an outstanding role in prognosis estimation and treatment monitoring with a potential reduction in health costs faced by standard radiology. An important challenge resides in identifying sufficiently sensitive and specific biomarkers for advanced HCC for prognostic evaluation and detection of tumor progression, overcoming imaging biomarker sensitivity. The aim of this review is to analyze the current molecular and imaging biomarkers in advanced HCC.
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Affiliation(s)
- Lucia Cerrito
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Elena Ainora
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Carolina Mosoni
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Raffaele Borriello
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Assunta Zocco
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
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22
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Kim JY, Kim J, Lim YS, Gwak GY, Yeo I, Kim Y, Lee J, Shin D, Lee JH, Kim Y. Proteome Multimarker Panel for the Early Detection of Hepatocellular Carcinoma: Multicenter Derivation, Validation, and Comparison. ACS OMEGA 2022; 7:29934-29943. [PMID: 36061641 PMCID: PMC9434733 DOI: 10.1021/acsomega.2c02926] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 08/08/2022] [Indexed: 06/15/2023]
Abstract
Conventional methods for the surveillance of hepatocellular carcinoma (HCC) by imaging, with and without serum tumor markers, are suboptimal with regard to accuracy. We aimed to develop and validate a reliable serum biomarker panel for the early detection of HCC using a proteomic technique. This multicenter case-control study comprised 727 patients with HCC and patients with risk factors but no HCC. We developed a multiple reaction monitoring-mass spectrometry (MRM-MS) multimarker panel using 17 proteins from the sera of 398 patients. Area under the receiver operating characteristics curve (AUROC) values of this MRM-MS panel with and without α-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) were compared. The combination and standalone MRM-MS panels had higher AUROC values than AFP in the training (0.940 and 0.929 vs 0.775, both P < 0.05), test (0.894 and 0.893 vs 0.593, both P < 0.05), and confirmation sets (0.961 and 0.937 vs 0.806, both P < 0.05) in detecting small single HCC. The combination and standalone MRM-MS panels had significantly higher AUROC values than the GALAD score (0.945 and 0.931 vs 0.829, both P < 0.05). Our proteome 17-protein multimarker panel distinguished HCC patients from high-risk controls and had high accuracy in the early detection of HCC.
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Affiliation(s)
- Ju Yeon Kim
- Department
of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Jaenyeon Kim
- Interdisciplinary
Program of Bioengineering, Graduate School,
Seoul National University, Seoul 08826, Republic of Korea
| | - Young-Suk Lim
- Department
of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 44610, Republic of Korea
| | - Geum-Youn Gwak
- Department
of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic
of Korea
| | - Injoon Yeo
- Interdisciplinary
Program of Bioengineering, Graduate School,
Seoul National University, Seoul 08826, Republic of Korea
| | - Yoseop Kim
- Interdisciplinary
Program of Bioengineering, Graduate School,
Seoul National University, Seoul 08826, Republic of Korea
| | - Jihyeon Lee
- Department
of Biomedical Sciences, Seoul National University
College of Medicine, Seoul 03080, Republic of Korea
| | - Dongyoon Shin
- Department
of Biomedical Sciences, Seoul National University
College of Medicine, Seoul 03080, Republic of Korea
| | - Jeong-Hoon Lee
- Department
of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Youngsoo Kim
- Interdisciplinary
Program of Bioengineering, Graduate School,
Seoul National University, Seoul 08826, Republic of Korea
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23
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Chan HLY, Vogel A, Berg T, De Toni EN, Kudo M, Trojan J, Eiblmaier A, Klein H, Hegel JK, Sharma A, Madin K, Rolny V, Lisy M, Piratvisuth T. Performance evaluation of the Elecsys
PIVKA‐II
and Elecsys AFP assays for hepatocellular carcinoma diagnosis. JGH Open 2022; 6:292-300. [PMID: 35601131 PMCID: PMC9120909 DOI: 10.1002/jgh3.12720] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 02/03/2022] [Indexed: 12/12/2022]
Abstract
Background and Aims Prothrombin induced by vitamin K absence‐II (PIVKA‐II) is a serum biomarker linked to hepatocellular carcinoma (HCC), showing superiority to alpha‐fetoprotein (AFP) for early disease detection. We aimed to assess the clinical and analytical performance of the Elecsys® PIVKA‐II immunoassay in diagnosing HCC and evaluate PIVKA‐II's technical performance. Methods Serum samples from adult cases (i.e. patients with a first‐time HCC diagnosis; n = 168) and disease controls (i.e. patients without HCC with an at‐risk condition; n = 208) were assessed. An AFP cut‐off of 20 ng/mL was used to differentiate between HCC cases and disease controls. Clinical performance of the Elecsys PIVKA‐II assay was compared with that of comparator assays (Lumipulse G PIVKA‐II, μTASWako DCP, ARCHITECT PIVKA‐II) using receiver operating characteristic curve analysis to determine the area under the curve (AUC) values. Results The Elecsys PIVKA‐II assay compared favorably with comparator assays. Using a 28.4 ng/mL cut‐off, the Elecsys PIVKA‐II assay detected HCC with 86.9% sensitivity and 83.7% specificity. Clinical performance of the Elecsys PIVKA‐II assay (AUC: 90.8%) was equivalent to that of comparator assays (AUC: 88.3–89.6%). Relatively high PIVKA‐II concentrations were observed for cholangiocarcinoma and pancreatic cancer with the Elecsys assay in specificity panel analyses, indicating that high PIVKA‐II concentrations should not be used alone in the absence of other clinical data. Conclusions The Elecsys PIVKA‐II assay showed good analytical performance under routine laboratory conditions, comparing favorably with comparator assays. These findings support the suitability of the Elecsys PIVKA‐II assay as an aid in HCC diagnosis.
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Affiliation(s)
- Henry L Y Chan
- Faculty of Medicine The Chinese University of Hong Kong Hong Kong China
| | - Arndt Vogel
- Clinic for Gastroenterology, Hepatology and Endocrinology Medizinische Hochschule Hannover Hannover Germany
| | - Thomas Berg
- Division of Hepatology, Department of Medicine II Leipzig University Medical Center Leipzig Germany
| | - Enrico N De Toni
- Department of Medicine II University Hospital, Ludwig Maximilian University of Munich Munich Germany
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology Kindai University Faculty of Medicine Osaka Japan
| | - Jörg Trojan
- Department of Gastrointestinal Oncology Goethe Universitat Frankfurt Frankfurt Germany
| | - Anja Eiblmaier
- Laboratory Services Microcoat Biotechnologie GmbH Bernried Germany
| | | | - Johannes Kolja Hegel
- Studies, Collaborations, and Innovation Management Labor Berlin Charité Vivantes Services GmbH Berlin Germany
| | - Ashish Sharma
- Global Medical and Scientific Affairs Roche Diagnostics International Ltd Rotkreuz Switzerland
| | - Kairat Madin
- Global Study Management Roche Diagnostics GmbH Penzberg Germany
| | - Vinzent Rolny
- New Technology Statistics Roche Diagnostics GmbH Penzberg Germany
| | - Marcus‐Rene Lisy
- Research and Development Roche Diagnostics GmbH Penzberg Germany
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24
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Huang C, Fang M, Xiao X, Wang H, Gao Z, Ji J, Liu L, Gu E, Li Y, Wang M, Gao C. Validation of the GALAD model for early diagnosis and monitoring of hepatocellular carcinoma in Chinese multicenter study. Liver Int 2022; 42:210-223. [PMID: 34679250 DOI: 10.1111/liv.15082] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 10/18/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND GALAD is an algorithm model estimating the presence of hepatocellular carcinoma (HCC). However, the participants enrolled in the GALAD differ from those of Chinese subjects whose HCCs are mainly hepatitis B virus infection related. Therefore, the cross-sectional as well as longitudinal multicenter study was designed to assess the clinical performances of GALAD in the Chinese population. METHODS A case-control study of 602 patients with HCC (34.10% within Barcelona Clinic Liver Cancer 0-A stage) and 923 subjects without HCC from five Chinese medical centres was conducted. Longitudinally the performances of GALAD identifying HCC were assessed using receiver operating characteristic curves analyses. Furthermore, the surveillance performance of GALAD for 204 HCC patients after radical surgery and for the early detection of HCC prospectively in an independent cohort of chronic hepatitis B were analysed, respectively. RESULTS We found the GALAD identified early stage HCC at an area under the receiver operating characteristic curve (AUC) above 0.85 and outperformed significantly than AFP, PIVKAII, AFP-L3 and BALAD-2 respectively. Meanwhile the GALAD could stratify HCC into two distinct subgroups with high or low risks of overall survival and recurrence. The GALAD could detection HCC 24 (AUC: 0.848) or even 48 (AUC: 0.833) weeks before clinical diagnosis. CONCLUSIONS Our study indicates that the GALAD exhibits outstanding performance in the early diagnosis, prognosis prediction as well as risk monitoring of HCC in our cross-sectional and longitudinal multicenter study of 1561 patients. GALAD should be implanted into clinical practice early so as to improve the clinical efficacy of individual biomarkers in HCC early monitoring and prognosis prediction.
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Affiliation(s)
- Chenjun Huang
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China.,Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Meng Fang
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Xiao Xiao
- Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hong Wang
- Department of Hepatology and Gastroenterology, Jing'an District Centre Hospital, Fudan University, P.R. China
| | - Zhiyuan Gao
- Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jun Ji
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Lijuan Liu
- Department of Laboratory Medicine, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Erli Gu
- Department of Hepatology and Gastroenterology, Jing'an District Centre Hospital, Fudan University, P.R. China
| | - Ya Li
- Department of Laboratory Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, P.R. China
| | - Mengmeng Wang
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, P.R. China
| | - Chunfang Gao
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China.,Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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25
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Han JW, Sung PS, Jang JW, Choi JY, Yoon SK. Whole blood viscosity is associated with extrahepatic metastases and survival in patients with hepatocellular carcinoma. PLoS One 2021; 16:e0260311. [PMID: 34855786 PMCID: PMC8638904 DOI: 10.1371/journal.pone.0260311] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 11/05/2021] [Indexed: 12/12/2022] Open
Abstract
Whole blood viscosity (WBV) is increased in cancer patients and associated with the advanced stage with systemic metastases. However, relevance of WBV in hepatocellular carcinoma (HCC) remains unclear. This pilot study included a discovery cohort of 148 treatment-naïve HCC patients with preserved liver function, and a validation cohort of 33 treatment-experienced HCC patients with nivolumab. Systolic and diastolic WBV was measured using an automated scanning capillary tube viscometer at diagnosis or before the nivolumab treatment. Extrahepatic metastases were observed in 15 treatment-naïve patients (11.3%) at diagnosis. Portal vein tumor thrombosis (PVTT), tumor size, number of tumors, and systolic/diastolic WBV were factors associated with extrahepatic metastases. Systolic WBV and diastolic WBV were significantly increased in patients with metastases compared with patients without metastases. Multivariate logistic regression showed that high diastolic WBV > 16 cP was an independent factor associated with metastases. Notably, patients who developed extrahepatic metastases during the observation period among patients without metastases at diagnosis had higher diastolic WBV initially. Patients with high diastolic WBV had poor survival, and multivariate Cox regression analyses showed high diastolic WBV was an independent risk factor for poor survival with the Child-Pugh B7 and PVTT. High diastolic WBV also predicted poor survival in patients with low alpha-fetoprotein (AFP) and proteins induced by vitamin K antagonist-II (PIVKA-II) levels. In 33 nivolumab-treated patients, high diastolic WBV before the treatment was also tended to be associated with overall and progression-free survival. Our study is the first in which high WBV is associated with the distant metastases and survival in patients with HCC, but future prospective, large cohort studies are necessary to validate the results.
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Affiliation(s)
- Ji Won Han
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
| | - Pil Soo Sung
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jeong Won Jang
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jong Young Choi
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung Kew Yoon
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
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26
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Lin K, Huang Q, Zeng J, Ding Z, Wang L, Chen Z, Guo P, Zeng Y, Zhou W, Liu J. Clinical Significance of Alpha-Fetoprotein in Alpha-Fetoprotein Negative Hepatocellular Carcinoma Underwent Curative Resection. Dig Dis Sci 2021; 66:4545-4556. [PMID: 33723698 PMCID: PMC8589766 DOI: 10.1007/s10620-020-06797-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 12/16/2020] [Indexed: 01/27/2023]
Abstract
BACKGROUND The clinical value of alpha-fetoprotein (AFP) in patients with AFP-negative (< 20 ng/ml) hepatocellular carcinoma (HCC) who underwent curative resection remained controversial. AIMS To investigate clinical relevance and prognostic effect of preoperative serum AFP level in this subgroup. METHODS A total of 1879 patients with AFP-negative HCC who underwent curative resection were included in the study. Overall survival (OS) and disease-free survival (DFS) rate were displayed by Kaplan-Meier method and compared by log-rank test. Multivariate cox proportional hazard regression analysis was used to identify the independent prognostic factors. The prognostic predictive performance was analyzed by time-dependent areas under receiver operating characteristic curve (AUC). RESULTS Even in AFP-negative HCC, patients with high preoperative serum AFP level tended to have multiple tumor (P < 0.001), poorer differentiation of tumor cell (P < 0.001), presence of satellite nodules (P < 0.001), and MVI (P = 0.002). Kaplan-Meier analysis showed the adverse impact of AFP level on prognosis, especially for DFS. Multivariate analysis identified AFP as the independent unfavorable factor for OS and DFS (P < 0.001 for both). Time-dependent AUC analysis showed that the combination with AFP could improve the prognostic predictive performance of 8th AJCC and BCLC staging system. CONCLUSIONS AFP was still the surrogate of aggressive behavior of HCC and independent prognostic factor for patients with AFP-negative HCC underwent curative resection. Even combining with such a low level of AFP could significantly improve the predictive performance of conventional staging system.
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Affiliation(s)
- Kongying Lin
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, 350025 Fujian China
| | - Qizhen Huang
- Department of Radiation Oncology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian China
| | - Jianxing Zeng
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, 350025 Fujian China
| | - Zongren Ding
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, 350025 Fujian China
| | - Lei Wang
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fuzhou, Fujian China
| | - Zhenwei Chen
- The Big Data Institute of Southeast Hepatobiliary Health Information, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian China
| | - Pengfei Guo
- The Big Data Institute of Southeast Hepatobiliary Health Information, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian China
| | - Yongyi Zeng
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, 350025 Fujian China
| | - Weiping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, No. 225 Changhai Road, Shanghai, 200438 China
| | - Jingfeng Liu
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, 350025 Fujian China
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fuzhou, Fujian China
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27
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Sagar VM, Herring K, Curbishley S, Hodson J, Fletcher P, Karkhanis S, Mehrzad H, Punia P, Shah T, Shetty S, Ma YT. The potential of PIVKA-II as a treatment response biomarker in hepatocellular carcinoma: a prospective United Kingdom cohort study. Oncotarget 2021; 12:2338-2350. [PMID: 34853657 PMCID: PMC8629402 DOI: 10.18632/oncotarget.28136] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 11/10/2021] [Indexed: 11/25/2022] Open
Abstract
Prothrombin induced by vitamin K absence II (PIVKA-II) has recently been validated internationally as a diagnostic biomarker for hepatocellular carcinoma (HCC), as part of the GALAD model. However, its role as a treatment response biomarker has been less well explored. We, therefore, undertook a prospective study at a tertiary centre in the UK to evaluate the role of PIVKA-II as a treatment response biomarker in patients with early, intermediate and advanced stage HCC. In a cohort of 141 patients, we found that PIVKA-II levels tracked concordantly with treatment response in the majority of patients, across a range of different treatment modalities. We also found that rises in PIVKA-II levels almost always predated radiological progression. Among AFP non-secretors, PIVKA-II was found to be informative in 60% of cases. In a small cohort of patients undergoing liver transplantation, pre-transplant PIVKA-II levels predicted for microvascular invasion and poorer differentiation. Our results demonstrate the potential utility of PIVKA-II as a treatment response biomarker and in predicting microvascular invasion, in a Western population. PIVKA-II demonstrated improved performance over AFP but, as a single biomarker, its performance was still limited. Further larger prospective studies are recommended to evaluate PIVKA-II as a treatment response biomarker, within the GALAD model.
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Affiliation(s)
- Vandana M. Sagar
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- These authors contributed equally to this work (joint first authors)
| | - Kathyrn Herring
- The Cancer Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- These authors contributed equally to this work (joint first authors)
| | - Stuart Curbishley
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - James Hodson
- Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Peter Fletcher
- Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK
| | - Salil Karkhanis
- Department of Radiology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Homoyon Mehrzad
- Department of Radiology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Pankaj Punia
- The Cancer Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Tahir Shah
- The Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Shishir Shetty
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- The Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- These authors contributed equally to this work (joint senior authors)
| | - Yuk Ting Ma
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- The Cancer Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- These authors contributed equally to this work (joint senior authors)
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Yang Y, Li G, Lu Z, Liu Y, Kong J, Liu J. Progression of Prothrombin Induced by Vitamin K Absence-II in Hepatocellular Carcinoma. Front Oncol 2021; 11:726213. [PMID: 34900676 PMCID: PMC8660097 DOI: 10.3389/fonc.2021.726213] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 10/11/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related death worldwide. Due to the lack of efficient tools for early detection, asymptomatic HCC patients are diagnosed at an advanced stage, leading to a poor prognosis. To improve survival, serum biomarker prothrombin induced by vitamin K absence-II (PIVKA-II) was under investigation. PIVKA-II is an abnormal protein produced in HCC. The coagulation function was insufficient due to the lack of Gla residues. Elevated PIVKA-II was associated with bad tumor behavior in terms of proliferation, metastasis, and invasion. Three major signaling pathways were proposed to clarify the mechanism. With the advantages including affordability, minimal invasiveness, convenience, and efficiency, PIVKA-II could improve HCC management consisting of four aspects. First, PIVKA-II was an effective and dynamic tool for improving HCC surveillance in high-risk population. Changes in the serum levels of PIVKA-II provided valuable molecular alteration information before imaging discovery. Second, PIVKA-II offered a complementary approach for HCC early detection. Compared to traditional diagnostic approaches, the combination of PIVKA-II and other biomarkers had better performance. Third, PIVKA-II was an indicator for the assessment of response to treatment in HCC. Preoperative assessment was for selecting personalized therapy, and postoperative measurement was for assessing treatment efficacy. Fourth, PIVKA-II was considered as a prognostic predictor for HCC. Patients with elevated PIVKA-II were more likely to develop microvascular invasion, metastasis, and recurrence.
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Affiliation(s)
- Yang Yang
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Guangbing Li
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Ziwen Lu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yong Liu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Junjie Kong
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jun Liu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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Ahn KS, O'Brien DR, Kim YH, Kim TS, Yamada H, Park JW, Park SJ, Kim SH, Zhang C, Li H, Kang KJ, Roberts LR. Associations of Serum Tumor Biomarkers with Integrated Genomic and Clinical Characteristics of Hepatocellular Carcinoma. Liver Cancer 2021; 10:593-605. [PMID: 34950182 PMCID: PMC8647136 DOI: 10.1159/000516957] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/29/2021] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION Serum α-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-γ-carboxy-pro-thrombin (DCP) are useful biomarkers of hepatocellular carcinoma (HCC). However, associations among molecular characteristics and serum biomarkers are unclear. We analyzed RNA expression and DNA variant data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) to examine their associations with serum biomarker levels and clinical data. METHODS From 371 TCGA-LIHC patients, we selected 91 seen at 3 institutions in Korea and the USA and measured AFP, AFP-L3, and DCP from preoperatively obtained serum. We conducted an integrative clinical and molecular analysis, focusing on biomarkers, and validated the findings with the remaining 280 patients in the TCGA-LIHC cohort. RESULTS Patients were categorized into 4 subgroups: elevated AFP or AFP-L3 alone (↑AFP&L3), elevated DCP alone (↑DCP), elevation of all 3 biomarkers (elevated levels of all 3 biomarkers [↑All]), and reference range values for all biomarkers (RR). CTNNB1 variants were frequently observed in ↑DCP patients (53.8%) and RR patients (38.5%), but ↑DCP patients with a CTNNB1 variant had worse survival than RR patients. TP53 sequence variants were associated with ↑AFP (30.8%) and ↑DCP (30.8%). The Wnt-β-catenin signaling pathway was activated in the ↑AFP&L3, whereas liver-related Wnt signaling was activated in the RR. TGF-β and VEGF signaling were activated in ↑AFP&L3, whereas dysregulated bile acid and fatty acid metabolism were dominant in ↑DCP. We validated these findings by showing similar results between the test cohort and the remainder of the TCGA-LIHC cohort. CONCLUSIONS Serum AFP, AFP-L3, and DCP levels can help predict variants in the genetic profile of HCC, especially for TP53 and CTNNB1. These findings may facilitate development of an evidence-based approach to treatment.
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Affiliation(s)
- Keun Soo Ahn
- Department of Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Daniel R. O'Brien
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
| | - Yong Hoon Kim
- Department of Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Tae-Seok Kim
- Department of Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Hiroyuki Yamada
- Global Clinical Research Management, FUJIFILM Wako Pure Chemical Corporation, Tokyo, Japan
| | - Joong-Won Park
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Republic of Korea
| | - Sang-Jae Park
- Department of Surgery, National Cancer Center, Goyang, Republic of Korea
| | - Seoung Hoon Kim
- Department of Surgery, National Cancer Center, Goyang, Republic of Korea
| | - Cheng Zhang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA
| | - Hu Li
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA
| | - Koo Jeong Kang
- Department of Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Lewis R. Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Núñez KG, Sandow T, Fort D, Patel J, Hibino M, Carmody I, Cohen AJ, Thevenot P. Baseline Alpha-Fetoprotein, Alpha-Fetoprotein-L3, and Des-Gamma-Carboxy Prothrombin Biomarker Status in Bridge to Liver Transplant Outcomes for Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:4765. [PMID: 34638251 PMCID: PMC8507524 DOI: 10.3390/cancers13194765] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/08/2021] [Accepted: 09/20/2021] [Indexed: 11/16/2022] Open
Abstract
The biomarkers α-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP fraction (AFP-L3), and des-γ-carboxy prothrombin (DCP) have emerging implications in hepatocellular carcinoma (HCC) surveillance, overall prognosis, and post-surgical recurrence risk. This retrospective study investigated treatment and bridge to liver transplant (LT) prognosis associated with AFP, AFP-L3%, and DCP biomarker profiles prior to liver-directed therapy (LDT). In a 140-patient cohort, each biomarker was associated with HCC progression risk using the established thresholds of AFP > 20 ng/mL, AFP-L3 > 15%, and DCP > 7.5 ng/mL. Over 60% of the cohort expressed at least one biomarker at baseline. Although most biomarker-positive patients expressed the clinical standard AFP (57/87), only 32% were positive for AFP alone. Biomarker accumulation increased HCC progression risk but was not associated with demographic factors or preserved liver function. Biomarker triple negative patients had smaller index HCC (p = 0.003), decreased multifocal burden (p = 0.010), and a higher objective response rate (ORR, 62% compared to 46%, p = 0.011). Expressing all three biomarkers at baseline was associated with dismal first-line ORR (12%) with a median time to progression (TTP) of only 181 days post-LDT. Patients with triple negative status for the HCC biomarkers AFP, AFP-L3%, and DCP have the highest first-line ORR with < 5% HCC progression 1-year post-LDT. Biomarker profiling can establish baseline prognosis for identifying optimal bridge to LT and downstaging to LT candidates with triple negative biomarker status and providing an ideal post-LDT target as a compliment to radiographic response.
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Affiliation(s)
- Kelley G. Núñez
- Institute of Translational Research, Ochsner Health, New Orleans, LA 70121, USA; (K.G.N.); (J.P.); (M.H.); (A.J.C.)
| | - Tyler Sandow
- Department of Radiology, Ochsner Health, New Orleans, LA 70121, USA;
| | - Daniel Fort
- Center for Outcomes and Health Services Research, Ochsner Health, New Orleans, LA 70121, USA;
| | - Jai Patel
- Institute of Translational Research, Ochsner Health, New Orleans, LA 70121, USA; (K.G.N.); (J.P.); (M.H.); (A.J.C.)
| | - Mina Hibino
- Institute of Translational Research, Ochsner Health, New Orleans, LA 70121, USA; (K.G.N.); (J.P.); (M.H.); (A.J.C.)
| | - Ian Carmody
- Multi-Organ Transplant Institute, Ochsner Health, New Orleans, LA 70121, USA;
| | - Ari J. Cohen
- Institute of Translational Research, Ochsner Health, New Orleans, LA 70121, USA; (K.G.N.); (J.P.); (M.H.); (A.J.C.)
- Multi-Organ Transplant Institute, Ochsner Health, New Orleans, LA 70121, USA;
- Faculty of Medicine, The University of Queensland, New Orleans, LA 70121, USA
| | - Paul Thevenot
- Institute of Translational Research, Ochsner Health, New Orleans, LA 70121, USA; (K.G.N.); (J.P.); (M.H.); (A.J.C.)
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Kudo M. Surveillance, Diagnosis, and Treatment Outcomes of Hepatocellular Carcinoma in Japan: 2021 Update. Liver Cancer 2021; 10:167-180. [PMID: 34239807 PMCID: PMC8237798 DOI: 10.1159/000516491] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 04/13/2021] [Indexed: 02/04/2023] Open
Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
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32
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Kudo M, Kawamura Y, Hasegawa K, Tateishi R, Kariyama K, Shiina S, Toyoda H, Imai Y, Hiraoka A, Ikeda M, Izumi N, Moriguchi M, Ogasawara S, Minami Y, Ueshima K, Murakami T, Miyayama S, Nakashima O, Yano H, Sakamoto M, Hatano E, Shimada M, Kokudo N, Mochida S, Takehara T. Management of Hepatocellular Carcinoma in Japan: JSH Consensus Statements and Recommendations 2021 Update. Liver Cancer 2021; 10:181-223. [PMID: 34239808 PMCID: PMC8237791 DOI: 10.1159/000514174] [Citation(s) in RCA: 429] [Impact Index Per Article: 107.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 12/23/2020] [Indexed: 02/06/2023] Open
Abstract
The Clinical Practice Manual for Hepatocellular Carcinoma was published based on evidence confirmed by the Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma along with consensus opinion among a Japan Society of Hepatology (JSH) expert panel on hepatocellular carcinoma (HCC). Since the JSH Clinical Practice Guidelines are based on original articles with extremely high levels of evidence, expert opinions on HCC management in clinical practice or consensus on newly developed treatments are not included. However, the practice manual incorporates the literature based on clinical data, expert opinion, and real-world clinical practice currently conducted in Japan to facilitate its use by clinicians. Alongside each revision of the JSH Guidelines, we issued an update to the manual, with the first edition of the manual published in 2007, the second edition in 2010, the third edition in 2015, and the fourth edition in 2020, which includes the 2017 edition of the JSH Guideline. This article is an excerpt from the fourth edition of the HCC Clinical Practice Manual focusing on pathology, diagnosis, and treatment of HCC. It is designed as a practical manual different from the latest version of the JSH Clinical Practice Guidelines. This practice manual was written by an expert panel from the JSH, with emphasis on the consensus statements and recommendations for the management of HCC proposed by the JSH expert panel. In this article, we included newly developed clinical practices that are relatively common among Japanese experts in this field, although all of their statements are not associated with a high level of evidence, but these practices are likely to be incorporated into guidelines in the future. To write this article, coauthors from different institutions drafted the content and then critically reviewed each other's work. The revised content was then critically reviewed by the Board of Directors and the Planning and Public Relations Committee of JSH before publication to confirm the consensus statements and recommendations. The consensus statements and recommendations presented in this report represent measures actually being conducted at the highest-level HCC treatment centers in Japan. We hope this article provides insight into the actual situation of HCC practice in Japan, thereby affecting the global practice pattern in the management of HCC.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan,*Masatoshi Kudo,
| | | | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuya Kariyama
- Department of Gastroenterology, Okayama City Hospital, Okayama, Japan
| | - Shuichiro Shiina
- Department of Gastroenterology, Juntendo University, Tokyo, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, Japan
| | - Yasuharu Imai
- Department of Gastroenterology, Ikeda Municipal Hospital, Osaka, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Michihisa Moriguchi
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yasunori Minami
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kazuomi Ueshima
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Takamichi Murakami
- Department of Radiology, Kobe University Graduate School of Medicine, Hyogo, Japan
| | - Shiro Miyayama
- Department of Diagnostic Radiology, Fukui-ken Saiseikai Hospital, Fukui, Japan
| | - Osamu Nakashima
- Department of Clinical Laboratory Medicine, Kurume University Hospital, Kurume, Japan
| | - Hirohisa Yano
- Department of Pathology, Kurume University School of Medicine, Kurume, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Etsuro Hatano
- Department of Gastroenterological Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Norihiro Kokudo
- Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
| | - Satoshi Mochida
- Department of Gastroenterology and Hepatology, Saitama Medical University, Saitama, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
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BALAD and BALAD-2 predict survival of hepatocellular carcinoma patients: a North American cohort study. HPB (Oxford) 2021; 23:762-769. [PMID: 33023823 PMCID: PMC8018983 DOI: 10.1016/j.hpb.2020.09.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 09/09/2020] [Accepted: 09/14/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND The BALAD score and BALAD-2 class derived from bilirubin, albumin, AFP, AFP-L3, and des-gamma-carboxyprothrombin (DCP) are effective in predicting mortality in HCC, but have not been validated in North America. METHODS 148 HCC patients from 2000 to 2015 who had all five biomarkers tested at diagnosis were included. Hazard ratios (HR) were calculated. RESULTS 75 patients died during a median follow-up of 21.9 months. 1-and 3-year survival rates were 70.8% and 47.6%. 114 (77%) had cirrhosis. The HR (95%CI) for death were 1.24 (0.42-3.67), 1.79 (0.61-5.26), 2.83 (0.95-8.38), and 7.19 (2.26-22.91) for BALAD scores 1, 2, 3, and 4 vs. BALAD 0. The HR (95%CI) for death were 1.25 (0.65-2.40), 1.75 (0.94-3.23), and 6.20 (3.29-11.68) for BALAD-2 classes 2, 3, and 4 vs. BALAD-2 class 1. A multivariate model incorporating maximal tumor diameter, tumor number, neutrophil-lymphocyte ratio, and BALAD had HR of 1.43 (1.14-1.81) per increase of 1 BALAD score. A similar model with BALAD-2 had HR of 1.50 (1.18-1.90) per increase of 1 BALAD-2 class. CONCLUSION BALAD models at diagnosis can predict the survival of HCC patients in North America. AFP, AFP-L3, and DCP reflect tumor progression and metastasis of HCC and distinguish the BALAD model from other predictive models.
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Xu XF, Liang L, Xing H, Shen F, Huang DS, Lau WY, Yang T. Clinical utility of serum biomarkers for hepatocellular carcinoma. Biomark Med 2021; 15:151-155. [PMID: 33470867 DOI: 10.2217/bmm-2020-0474] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 09/25/2020] [Indexed: 02/07/2023] Open
Affiliation(s)
- Xin-Fei Xu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Lei Liang
- Department of Hepatobiliary, Pancreatic & Minimal Invasive Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Zhejiang, China
| | - Hao Xing
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Dong-Sheng Huang
- Department of Hepatobiliary, Pancreatic & Minimal Invasive Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Zhejiang, China
| | - Wan Yee Lau
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
- Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
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He H, Ji B, Jia Z, Zhang Y, Wang X, Tao X, Liu Y, Jiang J. A Practical Model is Equivalent to the BALAD or BALAD-2 Score in Predicting Long-term Survival after Hepatectomy in Chinese Patients with Hepatocellular Carcinoma. J Cancer 2021; 12:1474-1482. [PMID: 33531992 PMCID: PMC7847645 DOI: 10.7150/jca.51593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 12/18/2020] [Indexed: 11/21/2022] Open
Abstract
Aim: To evaluate the predictive value of the BALAD and BALAD-2 scores on long-term survival after hepatectomy in Chinese hepatocellular carcinoma (HCC) patients and to attempt to establish a more practical or effective model. Methods: A total of 251 HCC patients underwent hepatectomy were recruited. The BALAD and BALAD-2 scores were calculated with total bilirubin, albumin, alpha-fetoprotein, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein and des-gamma-carboxyprothrombin. The associations of the two scores and their components with the overall survival were analyzed. Finally, three prediction models were explored and constructed. Results: We observed that HCC patients had 5-year survival rates that worsened with increasement of BALAD and BALAD-2 scores. The BALAD and BALAD-2 scores demonstrated fine value in predicting overall survival with Harrell-C statistics of 0.665 (0.618-0.712) and 0.603 (0.554-0.636). After two variables, largest tumor size and BMI, were included in BALAD [0.720 (0.671-0.769)] or BALAD-2 [0.701 (0.649-0.751)] multivariate models, the Harrell-C statistic increased significantly than BALAD (P=0.048) or BALAD-2 (P<0.001) alone. Taking into account availability and expense, an equivalent BAA-BS model was established based on total bilirubin, albumin, AFP, BMI and largest tumor size. The Harrell-C statistic of BAA-BS model [0.723(0.674-0.772)] was similar to that of BALAD (P=0.820) or BALAD-2 (P=0.209) multivariate model. And, the continuous net reclassification index and integrated discriminatory improvement were not statistically different. Finally, a nomogram of the equivalent BAA-BS model was constructed to assist surgeons and patients in predicting 5-year survival rates. Conclusion: Both BALAD and BALAD-2 scores were highly suitable for predicting long-term survival after hepatectomy in Chinese HCC patients. A significant increase in predictive efficacy was observed after the addition of largest tumor size and BMI to BALAD or BALAD-2 score. Even if AFP-L3 and DCP are not detected, an equivalent BAA-BS model also obtained an excellent discriminatory performance.
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Affiliation(s)
- Hua He
- Division of Clinical Research, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun 130021, Jilin Province, China
| | - Bai Ji
- Department of Hepatobiliary and Pancreatic Surgery, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Zhifang Jia
- Division of Clinical Research, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Yangyu Zhang
- Division of Clinical Research, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Xueying Wang
- Division of Clinical Research, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun 130021, Jilin Province, China
| | - Xuerong Tao
- Division of Clinical Research, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Yahui Liu
- Department of Hepatobiliary and Pancreatic Surgery, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Jing Jiang
- Division of Clinical Research, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun 130021, Jilin Province, China
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Czauderna C, Schmidtmann I, Koch S, Pilz L, Heinrich S, Otto G, Mittler J, Lang H, Kloeckner R, Düber C, Sprinzl MF, Worns MA, Galle PR, Marquardt JU, Weinmann A. High pre-treatment static and dynamic alpha-fetoprotein values predict reduced overall survival in hepatocellular carcinoma. United European Gastroenterol J 2020; 9:2050640620972611. [PMID: 33226301 PMCID: PMC8259127 DOI: 10.1177/2050640620972611] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 10/13/2020] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma is one of the most lethal cancers worldwide. Novel prognostic and/or predictive biomarkers are urgently needed to improve patient management. Alpha-fetoprotein is a well-established and widely used biomarker for hepatocellular carcinoma. However, diagnostic accuracy of static alpha-fetoprotein values is limited and the clinical potential is a matter of ongoing scientific discussion. OBJECTIVE We here evaluated the prognostic impact of pre-treatment static and dynamic alpha-fetoprotein variables on overall survival of hepatocellular carcinoma patients in a Western cohort. METHODS Patients with confirmed hepatocellular carcinoma (n = 809) treated at the Johannes Gutenberg-University Mainz between 1998 and 2014 and two available pre-treatment alpha-fetoprotein-values (AFP-slope) were retrospectively analysed. Clinico-pathological baseline parameters, pre-treatment static values and AFP-slope were assessed. Prognostic impact was determined by Kaplan-Meier analyses and Cox regression models. RESULTS High static and dynamic alpha-fetoprotein variables prior to therapy were associated with reduced survival rates of hepatocellular carcinoma patients. Several known clinical parameters such as Child-Pugh B (p < 0.01) and C stage (p < 0.001), portal vein thrombosis (p < 0.001) and extrahepatic spread (p < 0.001) were confirmed as independent predictors for overall survival. Addition of static and/or dynamic alpha-fetoprotein variable resulted in higher time-dependent area under the curves. Notably, in patients with more favourable prognosis, AFP-slope prior to therapy was a slightly stronger predictor for overall survival compared with static alpha-fetoprotein values. CONCLUSION Static and dynamic alpha-fetoprotein variables prior to therapy are predictive for overall survival of hepatocellular carcinoma patients. Addition of AFP-slope to established prognostic parameters might improve prognostic classification for a subgroup of hepatocellular carcinoma patients with preserved liver function and without portal vein tumour thrombosis.
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Affiliation(s)
- Carolin Czauderna
- Department of Internal Medicine IJohannes Gutenberg UniversityMainzGermany
- Department of Medicine IUniversity Medical Centre SchleswigHolstein—Campus LübeckLübeckGermany
| | - Irene Schmidtmann
- Institute of Medical BiostatisticsEpidemiology and Informatics (IMBEI)Johannes Gutenberg UniversityMainzGermany
- Department of General, Visceral and Transplant SurgeryJohannes Gutenberg UniversityMainzGermany
| | - Sandra Koch
- Department of Internal Medicine IJohannes Gutenberg UniversityMainzGermany
| | - Lukas Pilz
- Department of Internal Medicine IJohannes Gutenberg UniversityMainzGermany
| | - Sophia Heinrich
- Department of Internal Medicine IJohannes Gutenberg UniversityMainzGermany
| | - Gerd Otto
- Department of General, Visceral and Transplant SurgeryJohannes Gutenberg UniversityMainzGermany
| | - Jens Mittler
- Department of General, Visceral and Transplant SurgeryJohannes Gutenberg UniversityMainzGermany
| | - Hauke Lang
- Department of General, Visceral and Transplant SurgeryJohannes Gutenberg UniversityMainzGermany
| | - Roman Kloeckner
- Department of Diagnostic and Interventional RadiologyJohannes Gutenberg UniversityMainzGermany
| | - Christoph Düber
- Department of Diagnostic and Interventional RadiologyJohannes Gutenberg UniversityMainzGermany
| | - Martin F. Sprinzl
- Department of Internal Medicine IJohannes Gutenberg UniversityMainzGermany
| | - Marcus A. Worns
- Department of Internal Medicine IJohannes Gutenberg UniversityMainzGermany
| | - Peter R. Galle
- Department of Internal Medicine IJohannes Gutenberg UniversityMainzGermany
| | - Jens U. Marquardt
- Department of Internal Medicine IJohannes Gutenberg UniversityMainzGermany
- Department of Medicine IUniversity Medical Centre SchleswigHolstein—Campus LübeckLübeckGermany
| | - Arndt Weinmann
- Department of Internal Medicine IJohannes Gutenberg UniversityMainzGermany
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Abstract
Hepatocellular carcinoma (HCC) is increasing in prevalence and is the third leading cause of cancer-related death worldwide. Unlike other malignancies, HCC can be diagnosed with dynamic imaging with very high accuracy, and tissue diagnosis is not needed for cancer therapy. There is a unique role of established as well as developing biomarkers in diagnosis, prognosis, and management of HCC. Sequencing HCC tumors has yielded substantial insights into HCC tumor biology and has raised the possibility of precision oncology in which therapy decisions are guided by cancer genetics. However, it is not ready for prime time yet.
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Affiliation(s)
- Vincent L Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 3912 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Pratima Sharma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 3912 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
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38
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Singh G, Yoshida EM, Rathi S, Marquez V, Kim P, Erb SR, Salh BS. Biomarkers for hepatocellular cancer. World J Hepatol 2020; 12:558-573. [PMID: 33033565 PMCID: PMC7522562 DOI: 10.4254/wjh.v12.i9.558] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/06/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. If diagnosed early, curative treatment options such as surgical resection, loco-regional therapies, and liver transplantation are available to patients, increasing their chances of survival and improving their quality of life. Unfortunately, most patients are diagnosed with late stage HCC where only palliative treatment is available. Therefore, biomarkers which could detect HCC early with a high degree of sensitivity and specificity, may play a crucial role in the diagnosis and management of the disease. This review will aim to provide an overview of the different biomarkers of HCC comprising those used in the diagnosis of HCC in at risk populations, as well as others with potential for prognosis, risk predisposition and prediction of response to therapeutic intervention.
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Affiliation(s)
- Gurjot Singh
- Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
| | - Eric M Yoshida
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
| | - Sahaj Rathi
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
| | - Vladimir Marquez
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
| | - Peter Kim
- Division of Oncological Surgery, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
| | - Siegfried R Erb
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
| | - Baljinder S Salh
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
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39
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Piñero F, Dirchwolf M, Pessôa MG. Biomarkers in Hepatocellular Carcinoma: Diagnosis, Prognosis and Treatment Response Assessment. Cells 2020; 9:1370. [PMID: 32492896 PMCID: PMC7349517 DOI: 10.3390/cells9061370] [Citation(s) in RCA: 311] [Impact Index Per Article: 62.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 05/28/2020] [Accepted: 05/28/2020] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the main cancer-related causes of death worldwide. Thus, there is a constant search for improvement in screening, diagnosis, and treatment strategies to improve the prognosis of this malignancy. The identification of useful biomarkers for surveillance and early HCC diagnosis is still deficient, with available serum biomarkers showing low sensitivity and heterogeneous specificity despite different cut-off points, even when assessed longitudinally, or with a combination of serum biomarkers. In contrast, HCC biomarkers used for prognostic (when associated with clinical outcomes) or predictive purposes (when associated with treatment response) may have an increased clinical role in the near future. Furthermore, some serum biomarkers are already implicated as a treatment selection tool, whether to provide access to certain therapies or to assess clinical benefit after treatment. In the present review we will discuss the clinical utility and foreseen future of HCC biomarkers implicated in surveillance, diagnosis, prognosis, and post-treatment assessment.
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Affiliation(s)
- Federico Piñero
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629AHJ Buenos Aires, Argentina;
- Latin American Liver Research Educational and Awareness Network (LALREAN), B1629AHJ Buenos Aires, Argentina
| | - Melisa Dirchwolf
- Liver Unit, Hospital Privado de Rosario, 2000 Rosario, Santa Fe, Argentina;
| | - Mário G. Pessôa
- Division of Gastroenterology and Hepatology, University of São Paulo School of Medicine, 05403-000 São Paulo, Brazil
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40
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Miura M, Fujinami N, Shimizu Y, Mizuno S, Saito K, Suzuki T, Konishi M, Takahashi S, Gotohda N, Suto K, Yoshida T, Nakatsura T. Usefulness of plasma full-length glypican-3 as a predictive marker of hepatocellular carcinoma recurrence after radial surgery. Oncol Lett 2020; 19:2657-2666. [PMID: 32218816 PMCID: PMC7068289 DOI: 10.3892/ol.2020.11371] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 10/31/2019] [Indexed: 02/07/2023] Open
Abstract
Predicting the risk of hepatocellular carcinoma (HCC) recurrence before treatment is necessary for developing subsequent treatment policies. Several tumor markers found in blood, such as alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II), are presently used to determine the occurrence and recurrence of HCC and to predict patient prognosis. However, these markers are insufficient for these purposes as certain patients have HCC recurrence despite exhibiting negative AFP and PIVKA-II. The present study identified glypican-3 (GPC3), an embryonal carcinoma antigen that is expressed specifically in HCC and is secreted into blood. Although the N-terminal domain of GPC3 in sera may be a potential prognostic factor for HCC, its biological role remains unclear. By contrast, full-length GPC3 (FL-GPC3) is reported to serve important roles in cell differentiation, proliferation and signaling events that cause HCC. Given the biological roles of FL-GPC3 in HCC progression, the present study evaluated its potential as a predictive marker of HCC recurrence. In the present study, a novel measurement system was constructed to specifically measure plasma FL-GPC3. Subsequently, its ability to predict recurrence after radical surgery in 39 HCC patients was evaluated. The results revealed that preoperative FL-GPC3 levels in patients with recurrence were significantly higher than those in patients without recurrence, suggesting that FL-GPC3 could be a better predictive maker of risk of recurrence than AFP or PIVKA-II. Furthermore, it was determined that the combination of FL-GPC3, AFP and PIVKA-II could predict recurrence within one year of radical surgery with high sensitivity and specificity. Based on these results, the validation of FL-GPC3 as a predictive marker of HCC recurrence in a larger population is warranted.
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Affiliation(s)
- Masahiro Miura
- Central Research Laboratories, Sysmex Corporation, Kobe, Hyōgo 651-2271, Japan
| | - Norihiro Fujinami
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Yasuhiro Shimizu
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Shoichi Mizuno
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Keigo Saito
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Toshihiro Suzuki
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Masaru Konishi
- Division of Hepatobiliary Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
| | - Shinichiro Takahashi
- Division of Hepatobiliary Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
| | - Naoto Gotohda
- Division of Hepatobiliary Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
| | - Kouzou Suto
- Central Research Laboratories, Sysmex Corporation, Kobe, Hyōgo 651-2271, Japan
| | - Tomokazu Yoshida
- Central Research Laboratories, Sysmex Corporation, Kobe, Hyōgo 651-2271, Japan
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
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Galle PR, Foerster F, Kudo M, Chan SL, Llovet JM, Qin S, Schelman WR, Chintharlapalli S, Abada PB, Sherman M, Zhu AX. Biology and significance of alpha-fetoprotein in hepatocellular carcinoma. Liver Int 2019; 39:2214-2229. [PMID: 31436873 DOI: 10.1111/liv.14223] [Citation(s) in RCA: 390] [Impact Index Per Article: 65.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 07/19/2019] [Accepted: 08/03/2019] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths globally due, in part, to the majority of patients being diagnosed with intermediate or advanced stage disease. Our increased understanding of the heterogeneous molecular pathogenesis of HCC has led to significant developments in novel targeted therapies. Despite these advances, there remains a high unmet need for new treatment options. HCC is a complex disease with multiple pathogenic mechanisms caused by a variety of risk factors, making it difficult to characterize with a single biomarker. In fact, numerous biomarkers have been studied in HCC, but alpha-fetoprotein (AFP) remains the most widely used and accepted serum marker since its discovery over 60 years ago. This review summarizes the most relevant studies associated with the regulation of AFP at the gene and protein levels; the pathophysiology of AFP as a pro-proliferative protein; and the correlation of AFP with molecular HCC subclasses, the vascular endothelial growth factor pathway and angiogenesis. Also described are the historical and current uses of AFP for screening and surveillance, diagnosis, its utility as a prognostic and predictive biomarker and its role as a tumour antigen in HCC. Taken together, these data demonstrate the relevance of AFP for patients with HCC and identify several remaining questions that will benefit from future research.
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Affiliation(s)
- Peter R Galle
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Friedrich Foerster
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | | | | | - Josep M Llovet
- Translational Research in Hepatic Oncology, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.,Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Shukui Qin
- Cancer Center of Bayi Hospital, Nanjing Chinese Medicine University, Nanjing, China
| | | | | | | | | | - Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Harvard Medical Center, Boston, MA, USA
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42
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Hiraoka A, Kumada T, Michitaka K, Kudo M. Newly Proposed ALBI Grade and ALBI-T Score as Tools for Assessment of Hepatic Function and Prognosis in Hepatocellular Carcinoma Patients. Liver Cancer 2019; 8:312-325. [PMID: 31768342 PMCID: PMC6873026 DOI: 10.1159/000494844] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 10/08/2018] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Because of the rapid progression of antiviral treatment options and the increasing frequency of nonviral-related hepatocellular carcinoma (HCC) due to the aging of society, the number of HCC patients with good hepatic function has been increasing and a more detailed method of assessment of hepatic function is needed. The Child-Pugh classification (CP) is used worldwide as an assessment tool for hepatic reserve function, even though it has some weaknesses. Recently, the albumin-bilirubin (ALBI) grade, calculated based on only albumin and total bilirubin, was proposed, and recent investigations have suggested that ALBI grade instead of CP can be used as an assessment tool for hepatic function as part of therapeutic strategies such as Barcelona Clinic Liver Cancer staging and a practical guideline presented by the Japan Society of Hepatology as well for total staging scoring systems. There has been an increasing number of reports showing that it has better capability than CP for HCC patients who undergo not only curative but also palliative treatments. Transcatheter arterial chemoembolization (TACE) is a major palliative treatment used for unresectable HCC, and the idea of TACE-refractory status has been proposed to indicate the possibility of switching to a tyrosine kinase inhibitor (TKI). However, TKI administration requires a maintained hepatic reserve function, thus the importance of assessment of hepatic function in patients undergoing TACE treatments has increased. We consider that ALBI grade might also play a significant role as part of a detailed assessment of relative changes in hepatic function during treatment. In this review, we evaluate the practical usefulness of ALBI grade for assessing hepatic function and HCC prognosis. KEY MESSAGE A detailed assessment of hepatic function is required for recent HCC therapeutic strategies. ALBI grade may be a powerful tool to improve treatment options for affected patients.
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Affiliation(s)
- Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Takashi Kumada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, Japan
| | - Kojiro Michitaka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan
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Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 2019; 16:589-604. [PMID: 31439937 PMCID: PMC6813818 DOI: 10.1038/s41575-019-0186-y] [Citation(s) in RCA: 2804] [Impact Index Per Article: 467.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/04/2019] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Risk factors for HCC include chronic hepatitis B and hepatitis C, alcohol addiction, metabolic liver disease (particularly nonalcoholic fatty liver disease) and exposure to dietary toxins such as aflatoxins and aristolochic acid. All these risk factors are potentially preventable, highlighting the considerable potential of risk prevention for decreasing the global burden of HCC. HCC surveillance and early detection increase the chance of potentially curative treatment; however, HCC surveillance is substantially underutilized, even in countries with sufficient medical resources. Early-stage HCC can be treated curatively by local ablation, surgical resection or liver transplantation. Treatment selection depends on tumour characteristics, the severity of underlying liver dysfunction, age, other medical comorbidities, and available medical resources and local expertise. Catheter-based locoregional treatment is used in patients with intermediate-stage cancer. Kinase and immune checkpoint inhibitors have been shown to be effective treatment options in patients with advanced-stage HCC. Together, rational deployment of prevention, attainment of global goals for viral hepatitis eradication, and improvements in HCC surveillance and therapy hold promise for achieving a substantial reduction in the worldwide HCC burden within the next few decades.
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Affiliation(s)
- Ju Dong Yang
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Pierre Hainaut
- Tumor Molecular Biology and Biomarkers Group, Institute for Advanced Biosciences, Inserm U 1209 CNRS UMR5309, Université Grenoble Alpes, Grenoble, France
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Amina Amadou
- Tumor Molecular Biology and Biomarkers Group, Institute for Advanced Biosciences, Inserm U 1209 CNRS UMR5309, Université Grenoble Alpes, Grenoble, France
| | - Amelie Plymoth
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
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44
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Ke K, Chen G, Cai Z, Huang Y, Zhao B, Wang Y, Liao N, Liu X, Li Z, Liu J. Evaluation and prediction of hepatocellular carcinoma prognosis based on molecular classification. Cancer Manag Res 2018; 10:5291-5302. [PMID: 30464626 PMCID: PMC6225913 DOI: 10.2147/cmar.s178579] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE Prediction of hepatocellular carcinoma (HCC) prognosis faced great difficulty due to tumor heterogeneity. We aimed to identify the prognosis-associated molecular subtypes existing in HCC patients and construct an evaluation model based on identified molecular classification. MATERIALS AND METHODS Non-negative matrix factorization consensus clustering was performed using 371 HCC patients from The Cancer Genome Atlas (TCGA) to identify molecular subtypes, based on the expression profile of the survival-associated genes. Signature genes for different subtypes were identified by Significance Analysis of Microarray and Prediction Analysis for Microarrays. Model for subtype discrimination and prognosis evaluation was established using binary logistic regression. The model and its clinical implications were further validated in GSE5436 cohort and Fujian cohort. RESULTS Based on TCGA data, we observed two molecular subtypes with distinct clinical outcomes including significantly different overall survival, tumor differentiation, TNM stage, and vascular invasion (all P<0.05). The existence of these two molecular subtypes was further validated in five other Gene Expression Omnibus datasets. Furthermore, we constructed an evaluation model based on six subtype signature genes, which can discriminate different subtypes with the cutoff of 0.385. Meanwhile, both Cox regression analysis and stratification analysis showed that the calculated continuous prognostic value could also effectively indicate HCC prognosis, regardless of patients' clinical conditions. The prognostic evaluation model was successfully validated in GSE54236 cohort and Fujian cohort. CONCLUSION Two prognostic molecular subtypes existed among HCC patients, which provided promising strategies for overcoming HCC heterogeneity and could be utilized in future clinical application for predicting HCC prognosis.
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Affiliation(s)
- Kun Ke
- The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China,
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China, ;
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou 350025, China, ;
| | - Geng Chen
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China, ;
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou 350025, China, ;
- School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Zhixiong Cai
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China, ;
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou 350025, China, ;
- School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Yanbing Huang
- The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China,
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China, ;
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou 350025, China, ;
| | - Bixing Zhao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China, ;
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou 350025, China, ;
| | - Yingchao Wang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China, ;
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou 350025, China, ;
| | - Naishun Liao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China, ;
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou 350025, China, ;
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China, ;
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou 350025, China, ;
| | - Zhenli Li
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China, ;
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou 350025, China, ;
| | - Jingfeng Liu
- The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China,
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China, ;
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou 350025, China, ;
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China,
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Ofuji K, Saito K, Suzuki S, Shimomura M, Shirakawa H, Nobuoka D, Sawada Y, Yoshimura M, Tsuchiya N, Takahashi M, Yoshikawa T, Tada Y, Konishi M, Takahashi S, Gotohda N, Nakamoto Y, Nakatsura T. Perioperative plasma glypican-3 level may enable prediction of the risk of recurrence after surgery in patients with stage I hepatocellular carcinoma. Oncotarget 2018; 8:37835-37844. [PMID: 28035063 PMCID: PMC5514954 DOI: 10.18632/oncotarget.14271] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 11/30/2016] [Indexed: 12/15/2022] Open
Abstract
Glypican-3 (GPC3) is a glycosylphosphatidylinositol-anchored cell surface protein overexpressed in hepatocellular carcinoma(HCC), and its overexpression is associated with poor prognosis. The diagnostic potential of GPC3 as a serum marker has been reported. In the present study, we evaluated the usefulness of plasma GPC3 as a predictor for recurrence after surgical resection in stage I HCC patients by newly developed an enzyme-linked immunosorbent assay (ELISA) system. Current study demonstrated that high levels of preoperative plasma GPC3 patients tended to experience postoperative recurrence. On the other hand, pre- and postoperative plasma GPC3 positivity of non-recurrence patients was very low. Moreover, even after surgery, approximately half of patients who experienced recurrence were positive for plasma GPC3. Postoperative plasma GPC3 positivity was significantly correlated with worse recurrence-free survival. Immuohistochemical analysis also showed positive rate of GPC3-expression in HCC was higher in recurrence patients than in non-recurrence patients. These results suggested that both pre- and postoperative plasma GPC3 levels may be accurate predictors for recurrence after curative resection of early-stage HCC. It should be noted that the current study only examined a small number of cases; thus, a larger sample size is necessary to validate GPC3 as a predictor for HCC recurrence.
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Affiliation(s)
- Kazuya Ofuji
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan.,Second Department of Internal Medicine, University of Fukui, Eiheiji-cho Yoshida-gun, Fukui 910-1193, Japan
| | - Keigo Saito
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Shiro Suzuki
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Manami Shimomura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Hirofumi Shirakawa
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Daisuke Nobuoka
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Yu Sawada
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Mayuko Yoshimura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Nobuhiro Tsuchiya
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Mari Takahashi
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Toshiaki Yoshikawa
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Yoshitaka Tada
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Masaru Konishi
- Division of Hepatobiliary Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
| | - Shinichiro Takahashi
- Division of Hepatobiliary Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
| | - Naoto Gotohda
- Division of Hepatobiliary Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
| | - Yasunari Nakamoto
- Second Department of Internal Medicine, University of Fukui, Eiheiji-cho Yoshida-gun, Fukui 910-1193, Japan
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
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Wongjarupong N, Negron-Ocasio GM, Chaiteerakij R, Addissie BD, Mohamed EA, Mara KC, Harmsen WS, Theobald JP, Peters BE, Balsanek JG, Ward MM, Giama NH, Venkatesh SK, Harnois DM, Charlton MR, Yamada H, Algeciras-Schimnich A, Snyder MR, Therneau TM, Roberts LR. Model combining pre-transplant tumor biomarkers and tumor size shows more utility in predicting hepatocellular carcinoma recurrence and survival than the BALAD models. World J Gastroenterol 2018; 24:1321-1331. [PMID: 29599607 PMCID: PMC5871827 DOI: 10.3748/wjg.v24.i12.1321] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Revised: 03/10/2018] [Accepted: 03/18/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To assess the performance of BALAD, BALAD-2 and their component biomarkers in predicting outcome of hepatocellular carcinoma (HCC) patients after liver transplant. METHODS BALAD score and BALAD-2 class are derived from bilirubin, albumin, alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-gamma-carboxyprothrombin (DCP). Pre-transplant AFP, AFP-L3 and DCP were measured in 113 patients transplanted for HCC from 2000 to 2008. Hazard ratios (HR) for recurrence and death were calculated. Univariate and multivariate regression analyses were conducted. C-statistics were used to compare biomarker-based to predictive models. RESULTS During a median follow-up of 12.2 years, 38 patients recurred and 87 died. The HRs for recurrence in patients with elevated AFP, AFP-L3, and DCP defined by BALAD cut-off values were 2.42 (1.18-5.00), 1.86 (0.98-3.52), and 2.83 (1.42-5.61), respectively. For BALAD, the HRs for recurrence and death per unit increased score were 1.48 (1.15-1.91) and 1.59 (1.28-1.97). For BALAD-2, the HRs for recurrence and death per unit increased class were 1.45 (1.06-1.98) and 1.38 (1.09-1.76). For recurrence prediction, the combination of three biomarkers had the highest c-statistic of 0.66 vs. 0.64, 0.61, 0.53, and 0.53 for BALAD, BALAD-2, Milan, and UCSF, respectively. Similarly, for death prediction, the combination of three biomarkers had the highest c-statistic of 0.66 vs 0.65, 0.61, 0.52, and 0.50 for BALAD, BALAD-2, Milan, and UCSF. A new model combining biomarkers with tumor size at the time of transplant (S-LAD) demonstrated the highest predictive capability with c-statistics of 0.71 and 0.69 for recurrence and death. CONCLUSION BALAD and BALAD-2 are valid in transplant HCC patients, but less predictive than the three biomarkers in combination or the three biomarkers in combination with maximal tumor diameter (S-LAD).
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Affiliation(s)
- Nicha Wongjarupong
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
- Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10400, Thailand
| | - Gabriela M Negron-Ocasio
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
- University of Puerto Rico Medical Sciences Campus, San Juan 00921, Puerto Rico
| | - Roongruedee Chaiteerakij
- Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10400, Thailand
| | - Benyam D Addissie
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
| | - Essa A Mohamed
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
| | - Kristin C Mara
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, United States
| | - William S Harmsen
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, United States
| | - J Paul Theobald
- Division of Laboratory Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, United States
| | - Brian E Peters
- Division of Laboratory Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, United States
| | - Joseph G Balsanek
- Division of Laboratory Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, United States
| | - Melissa M Ward
- Division of Laboratory Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, United States
| | - Nasra H Giama
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
| | - Sudhakar K Venkatesh
- Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN 55905, United States
| | - Denise M Harnois
- Department of Transplantation, Mayo Clinic Florida, Jacksonville, FL 32224, United States
| | - Michael R Charlton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
| | - Hiroyuki Yamada
- Wako Life Sciences, Incorporated, Mountain View, CA 94043, United States
| | - Alicia Algeciras-Schimnich
- Division of Laboratory Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, United States
| | - Melissa R Snyder
- Division of Laboratory Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, United States
| | - Terry M Therneau
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, United States
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
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Hiraoka A, Michitaka K, Kumada T, Izumi N, Kadoya M, Kokudo N, Kubo S, Matsuyama Y, Nakashima O, Sakamoto M, Takayama T, Kokudo T, Kashiwabara K, Kudo M. Validation and Potential of Albumin-Bilirubin Grade and Prognostication in a Nationwide Survey of 46,681 Hepatocellular Carcinoma Patients in Japan: The Need for a More Detailed Evaluation of Hepatic Function. Liver Cancer 2017; 6:325-336. [PMID: 29234636 PMCID: PMC5704689 DOI: 10.1159/000479984] [Citation(s) in RCA: 231] [Impact Index Per Article: 28.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND/AIM Recently, albumin-bilirubin (ALBI) scoring/grading, consisting of only albumin and total bilirubin, has been proposed. We examined the efficacy of this grading system for determining hepatic function in patients with hepatocellular carcinoma (HCC). METHODS/MATERIALS The prognoses of 46,681 HCC patients based on results obtained from a nationwide survey conducted in Japan from 2001 to 2007 were evaluated using (1) Japan Integrated Staging (JIS), consisting of Child-Pugh classification and TNM staging (TNM), (2) modified JIS (m-JIS), consisting of liver damage grading and TNM, and (3) ALBI-TNM (ALBI-T), consisting of ALBI grading and TNM, and the results were compared. A subanalysis was also performed to define a cutoff value for ALBI scores for a more detailed stratification of hepatic function. RESULTS ALBI-T, JIS, and m-JIS each showed good capacity for the stratification of prognoses. Although the Akaike information criterion for ALBI-T was nearly equal to that for JIS and m-JIS, the Kaplan-Meier curves and median survival times obtained with ALBI-T were always superior to the corresponding scores. When the indocyanine green retention test (<30%) was used as an additional cutoff value for ALBI score (-2.270, area under the curve 0.828) to divide ALBI grade into 4 levels (modified ALBI [mALBI] grade), mALBI grade was able to stratify the prognosis of patients at any TNM stage in order of grade. Modified ALBI-T (mALBI-T), using mALBI grading and TNM, produced a more detailed stratification for prognosis. CONCLUSION The predictive value for prognosis of ALBI-T was found to be equal to that of JIS and m-JIS. In addition, mALBI grading and mALBI-T, as proposed in the present study, might provide a more detailed assessment of the hepatic function and prognosis of HCC patients.
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Affiliation(s)
- Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama
| | - Kojiro Michitaka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama
| | - Takashi Kumada
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki
| | - Namiki Izumi
- Department of Gastroenterology, Musashino Red Cross Hospital, Tokyo
| | - Masumi Kadoya
- Department of Radiology, Shinshu University School of Medicine, Matsumoto
| | | | - Shoji Kubo
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, Osaka
| | - Yutaka Matsuyama
- Department of Biostatistics, School of Public Health, University of Tokyo, Tokyo
| | - Osamu Nakashima
- Department of Clinical Laboratory Medicine, Kurume University Hospital, Kurume
| | | | - Tadatoshi Takayama
- Department of Digestive Surgery, Nihon University School of Medicine and Hepato-Biliary-Pancreatic Surgery Division
| | | | - Kosuke Kashiwabara
- Department of Biostatistics, School of Public Health, Graduate School of Medicine, University of Tokyo, Tokyo
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University School of Medicine, Osaka, Japan
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48
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Validation of serological models for staging and prognostication of HCC in patients from a Japanese nationwide survey. J Gastroenterol 2017; 52:1112-1121. [PMID: 28224228 DOI: 10.1007/s00535-017-1321-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 02/07/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Two serology-based scoring models for prognostication of patients with hepatocellular carcinoma (HCC), the BALAD and BALAD-2 models, were applied to a Japanese cohort of a nationwide follow-up survey of HCC. The ability of these models to predict the progression of HCC and the deterioration of liver function and to assess prognosis was evaluated. METHODS BALAD and BALAD-2 scores were calculated in 24,029 patients from a cohort of Japanese nationwide survey based on the serum levels of five markers (bilirubin, albumin, lens culinaris agglutinin-reactive alpha-fetoprotein, alpha-fetoprotein, and des-gamma-carboxy prothrombin) measured at the time of HCC diagnosis. The associations of these scores with the progression of HCC and liver function and with survival rates were analyzed. RESULTS There were good correlations between BALAD and BALAD-2 scores and the progression of HCC and Child-Pugh class. Both scores accurately categorized patients into risk groups with different survival rates. BALAD-2 showed superior discrimination of patient survival compared with the original BALAD. CONCLUSIONS Serology-based scoring models for prognostication, especially the BALAD-2 model, were useful for staging and prognostication of survival in a cohort of Japanese patients with HCC from a nationwide survey.
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49
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Chen ZH, Hong YF, Lin J, Li X, Wu DH, Wen JY, Chen J, Ruan DY, Lin Q, Dong M, Wei L, Wang TT, Lin ZX, Ma XK, Wu XY, Xu R. Validation and ranking of seven staging systems of hepatocellular carcinoma. Oncol Lett 2017; 14:705-714. [PMID: 28693224 PMCID: PMC5494763 DOI: 10.3892/ol.2017.6222] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 03/17/2017] [Indexed: 12/15/2022] Open
Abstract
The aim of the present study was to evaluate the ability of seven staging systems to predict 3- and 6-month and cumulative survival rates of patients with advanced hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). Data were collected from 220 patients with HBV-associated HCC who did not receive any standard anticancer treatment. Participants were patients at The Third Affiliated Hospital of Sun Yat-sen University from September 2008 to June 2010. The participants were classified according to the Chinese University Prognostic Index (CUPI), the Cancer of the Liver Italian Program (CLIP), Japan Integrated Staging (JIS), China Integrated Score (CIS) systems, Barcelona Clinic Liver Cancer (BCLC), Okuda and tumor-node-metastasis (TNM) staging systems at the time of diagnosis and during patient follow-up. The sensitivity and specificity of the predictive value of each staging system for 3- and 6-month mortality were analyzed by relative operating characteristic (ROC) curve analysis with a non-parametric test being used to compare the area under curve (AUC) of the ROC curves. In addition, log-rank tests and Kaplan-Meier estimator survival curves were applied to compare the overall survival rates of the patients with HCC defined as advanced using the various staging systems, and the Akaike information criterion (AIC) and likelihood ratio tests (LRTs) were used to evaluate the predictive value for overall survival in patients with advanced HCC. Using univariate and multivariate Cox's model analyses, the factors predictive of survival were also identified. A total of 220 patients with HBV-associated HCC were analyzed. Independent prognostic factors identified by multivariate analyses included tumor size, α-fetoprotein levels, blood urea nitrogen levels, the presence or absence of portal vein thrombus, Child-Pugh score and neutrophil count. When predicting 3-month survival, the AUCs of CLIP, CIS, CUPI, Okuda, TNM, JIS and BCLC were 0.806, 0.772, 0.751, 0.731, 0.643, 0.754 and 0.622, respectively. When predicting 6-month survival, the AUCs of CLIP, CIS, CUPI, Okuda, TNM, JIS and BCLC were 0.828, 0.729, 0.717, 0.692, 0.664, 0.746 and 0.575, respectively. For 3-month mortality, the prognostic value of CLIP ranked highest, followed by CIS; for 6-month mortality, the prognostic value of CLIP also ranked highest, followed by JIS. No significant difference between the AUCs of CLIP and CIS (P>0.05) in their predictive value for 3-month mortality was observed. The AUC of CLIP was significantly higher compared with that of the other staging systems (P<0.05) for predicting 6-month mortality. The χ2 values from the LRTs of CLIP, CIS, CUPI, Okuda, TNM, JIS and BCLC were 75.6, 48.4, 46.7, 36.0, 21.0, 46.8 and 7.24, respectively. The AIC values of CLIP, CIS, CUPI, Okuda, TNM, JIS and BCLC were 1601.5, 1632.3, 1629.9, 1641.1, 1654.8, 1627.4 and 1671.1, respectively. CLIP exhibited the highest χ2 value and lowest AIC value, indicating that CLIP has the highest predictive value of cumulative survival rate. In the selected patients of the present study, CLIP was the staging system best able to predict 3- and 6-month and overall survival rates. CIS ranked second in predicting 3-month mortality.
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Affiliation(s)
- Zhan-Hong Chen
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. 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, Guangzhou, Guangdong 510060, P.R. China
| | - Ying-Fen Hong
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Jinxiang Lin
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Xing Li
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Dong-Hao Wu
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Jing-Yun Wen
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Jie Chen
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Dan-Yun Ruan
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Qu Lin
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Min Dong
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Li Wei
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Tian-Tian Wang
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Ze-Xiao Lin
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Xiao-Kun Ma
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Xiang-Yuan Wu
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Ruihua Xu
- 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, Guangzhou, Guangdong 510060, P.R. China
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50
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Johnson P, Berhane S, Kagebayashi C, Satomura S, Teng M, Fox R, Yeo W, Mo F, Lai P, Chan SL, Tada T, Toyoda H, Kumada T. Impact of disease stage and aetiology on survival in hepatocellular carcinoma: implications for surveillance. Br J Cancer 2017; 116:441-447. [PMID: 28081537 PMCID: PMC5318967 DOI: 10.1038/bjc.2016.422] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Revised: 11/08/2016] [Accepted: 11/28/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Variation in survival in hepatocellular carcinoma (HCC) has been attributed to different aetiologies or disease stages at presentation. While international guidelines recommend surveillance of high-risk groups to permit early diagnosis and curative treatment, the evidence that surveillance decreases disease-specific mortality is weak. METHODS We compared HCC survival figures from Japan (n=1174) and Hong Kong (n=1675) over similar time periods (Japan 2000-2013, Hong Kong, China 2003-2014). The former has an intensive national surveillance programme, while the latter has none. We also analysed changes in survival in Japan over a 50-year period including data from before and after institution of a national HCC surveillance programme. RESULTS In Japan, over 75% of cases are currently detected by surveillance, whereas in Hong Kong <20% of cases are detected presymptomatically. Median survival was 52 months in Japan and 17.8 months in Hong Kong; this survival advantage persisted after allowance for lead-time bias. Sixty-two per cent of Japanese patients had early disease at diagnosis and 63% received curative treatment. The comparable figures for Hong Kong were 31.7% and 44.1%, respectively. These differences could not be accounted for by disease aetiology, and patients in Hong Kong who were detected at an early stage had a similar survival to the analogous patients in Japan. CONCLUSIONS The variation in survival is largely accounted for by stage at diagnosis, which in turn relates to the intensity of surveillance programmes and the consequent variation in curative therapeutic options.
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Affiliation(s)
- Philip Johnson
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool and Clatterbridge Cancer Centre NHS Foundation Trust, Sherrington Building, Ashton Street, Liverpool, Merseyside L69 3GA, UK
- The Clatterbridge Cancer Centre NHS Foundation Trust, Clatterbridge Road, Bebington, Wirral CH63 4JY, UK
| | - Sarah Berhane
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool and Clatterbridge Cancer Centre NHS Foundation Trust, Sherrington Building, Ashton Street, Liverpool, Merseyside L69 3GA, UK
| | - Chiaki Kagebayashi
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Shinji Satomura
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Mabel Teng
- Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Hills Road, Cambridge CB2 0QQ, UK
| | - Richard Fox
- Cancer Research UK Clinical Trials Unit, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK
| | - Winnie Yeo
- State Key Laboratory in Oncology in South China, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong Cancer Institute, Hong Kong, China
| | - Frankie Mo
- State Key Laboratory in Oncology in South China, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong Cancer Institute, Hong Kong, China
| | - Paul Lai
- Department of Surgery, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China
| | - Stephen L Chan
- State Key Laboratory in Oncology in South China, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong Cancer Institute, Hong Kong, China
| | - Toshifumi Tada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki, Gifu 503-8052, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki, Gifu 503-8052, Japan
| | - Takashi Kumada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki, Gifu 503-8052, Japan
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