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Darbà J, Ascanio M. Hepatocellular carcinoma: what are the differential costs compared to the general population? J Med Econ 2025; 28:471-478. [PMID: 40126406 DOI: 10.1080/13696998.2025.2484073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/20/2025] [Accepted: 03/21/2025] [Indexed: 03/25/2025]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC), which accounts for about 90% of all primary liver cancer cases, is the fifth most common malignancy and the second leading cause of cancer-related mortality worldwide. This study aims to analyse the differential costs of HCC-related hospital admissions compared to the general population in Spain. METHODS A retrospective multicenter study analyzed inpatient admissions from a Spanish national discharge database, covering 90% of hospitals between 2010 and 2022. HCC-related admissions were identified using ICD-9 and ICD-10 codes, while control admissions were selected from the general population in the same database without an HCC diagnosis. The direct hospitalization cost was included, covering medical examinations, procedures, medications, surgeries, personnel and equipment. Statistical methods, including nearest-neighbor matching, propensity score matching, and a generalized linear model, were used to estimate differential costs and to ensure comparability based on age, gender, and Charlson Comorbidity Index (CCI). RESULTS A total of 199,670 HCC-related hospital admissions and 200,000 control admissions were analyzed. Most HCC-related admissions involved male patients (78%) aged 66-85 years, with an average CCI of 5.18. HCC-related admissions incurred significantly higher costs, with an estimated differential cost of €1,303.68 using GLM, €1,804.25 via propensity score matching, and €1,767.77 using nearest-neighbor matching. Total costs per HCC admission ranged between €1,000 and €31,000. CONCLUSIONS HCC-related hospital admissions impose a significantly higher economic burden due to the complexity of care. Given the high mortality and resource utilization, advancements in early detection, treatment, and cost-effective interventions are needed to improve patient outcomes and reduce healthcare costs.
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Affiliation(s)
- Josep Darbà
- Department of Economics, Universitat de Barcelona, Barcelona, Spain
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Reierson MM, Acharjee A. Unsupervised machine learning-based stratification and immune deconvolution of liver hepatocellular carcinoma. BMC Cancer 2025; 25:853. [PMID: 40349011 PMCID: PMC12066050 DOI: 10.1186/s12885-025-14242-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 04/29/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer and a leading cause of cancer-related deaths globally. The tumour microenvironment (TME) influences treatment response and prognosis, yet its heterogeneity remains unclear. METHODS The unsupervised machine learning methods- agglomerative hierarchical clustering, Multi-Omics Factor Analysis with K-means++, and an autoencoder with K-means++ - stratified patients using microarray data from HCC samples. Immune deconvolution algorithms estimated the proportions of infiltrating immune cells across identified clusters. RESULTS Thirteen genes were found to influence HCC subtyping in both primary and validation datasets, with three genes-TOP2A, DCN, and MT1E-showing significant associations with survival and recurrence. DCN, a known tumour suppressor, was significant across datasets and associated with improved survival, potentially by modulating the TME and promoting an anti-tumour immune response. CONCLUSIONS The discovery of the 13 conserved genes is an important step toward understanding HCC heterogeneity and the TME, potentially leading to the identification of more reliable biomarkers and therapeutic targets. We have stratified and validated the liver cancer populations. The findings suggest further research is needed to explore additional factors influencing the TME beyond gene expression, such as tumour microbiome and stromal cell interactions.
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Affiliation(s)
- Mae Montserrat Reierson
- Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, B15 2TT, UK
| | - Animesh Acharjee
- Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, B15 2TT, UK.
- Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TT, UK.
- MRC Health Data Research UK (HDR), Midlands Site, UK.
- Centre for Health Data Research, University of Birmingham, Birmingham, B15 2TT, UK.
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You GR, Park SY, Cho SH, Cho SB, Koh YS, Lee CH, Jo HG, Choi SK, Yoon JH. Extrahepatic Recurrence After Surgical Resection of Hepatocellular Carcinoma Without Intrahepatic Recurrence: A Multi-Institutional Observational Study. Cancers (Basel) 2025; 17:1417. [PMID: 40361344 PMCID: PMC12070905 DOI: 10.3390/cancers17091417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 04/22/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND/OBJECTIVES Extrahepatic recurrence (EHR) is a significant negative prognostic factor in hepatocellular carcinoma (HCC). Although EHR is commonly observed in high-risk patients following HCC hepatectomy, its occurrence without concurrent intrahepatic HCC remains poorly understood. Therefore, this study aims to examine the clinical characteristics and risk factors associated with EHR in patients without intrahepatic HCC at diagnosis. METHODS This study included 1066 treatment-naïve patients who underwent curative hepatectomy for HCC at four tertiary academic centers between January 2004 and December 2019. After excluding those with intrahepatic recurrence (IHR), concurrent EHR, or incomplete clinical records, 569 patients were included in the final analysis. Risk factors for EHR were assessed using multivariate Cox regression over a median follow-up period of 3.91 years. RESULTS Among the cohort, 38 patients developed EHR post-surgery without residual intrahepatic HCC, with a median follow-up of 1.04 years. These patients experienced earlier initial HCC recurrence than those without EHR (1.73 vs. 4.43 years). Multivariate analysis revealed significant associations between EHR and microvascular invasion (hazard ratio [HR]: 2.418, p = 0.020), tumor necrosis (HR: 2.592, p = 0.009), and initial tumor staging beyond the Milan criteria (HR: 3.008, p = 0.001). Moreover, Cox regression analysis revealed that EHR strongly correlated with decreased post-hepatectomy survival (HR: 14.044, p < 0.001). Cumulative EHR and survival rates were closely linked to the number of risk factors present. CONCLUSIONS EHR without detectable IHR is significant and warrants close monitoring in high-risk patients.
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Affiliation(s)
- Ga Ram You
- Department of Gastroenterology and Hepatology, Chonnam National University Hwasun Hospital and Medical School, Hwasun 58128, Republic of Korea; (G.R.Y.); (S.B.C.)
| | - Shin Young Park
- Department of Gastroenterology and Hepatology, Chonnam National University Hospital and Medical School, Gwangju 61469, Republic of Korea; (S.Y.P.); (S.H.C.); (S.K.C.)
| | - Su Hyeon Cho
- Department of Gastroenterology and Hepatology, Chonnam National University Hospital and Medical School, Gwangju 61469, Republic of Korea; (S.Y.P.); (S.H.C.); (S.K.C.)
| | - Sung Bum Cho
- Department of Gastroenterology and Hepatology, Chonnam National University Hwasun Hospital and Medical School, Hwasun 58128, Republic of Korea; (G.R.Y.); (S.B.C.)
| | - Yang Seok Koh
- Department of Surgery, Chonnam National University Hwasun Hospital and Medical School, Hwasun 58128, Republic of Korea;
| | - Chang Hun Lee
- Department of Gastroenterology and Hepatology, Jeonbuk National University Hospital and Medical School, Jeonju 54907, Republic of Korea;
| | - Hoon Gil Jo
- Department of Gastroenterology and Hepatology, Wonkwang University Hospital and Medical School, Iksan 54538, Republic of Korea;
| | - Sung Kyu Choi
- Department of Gastroenterology and Hepatology, Chonnam National University Hospital and Medical School, Gwangju 61469, Republic of Korea; (S.Y.P.); (S.H.C.); (S.K.C.)
| | - Jae Hyun Yoon
- Department of Gastroenterology and Hepatology, Chonnam National University Hospital and Medical School, Gwangju 61469, Republic of Korea; (S.Y.P.); (S.H.C.); (S.K.C.)
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Akabane M, Kawashima J, Altaf A, Woldesenbet S, Cauchy F, Aucejo F, Popescu I, Kitago M, Martel G, Ratti F, Aldrighetti L, Poultsides GA, Imaoka Y, Ruzzenente A, Endo I, Gleisner A, Marques HP, Oliveira S, Balaia J, Lam V, Hugh T, Bhimani N, Shen F, Pawlik TM. Enhancing Recurrence-Free Survival Prediction in Hepatocellular Carcinoma: A Time-Updated Model Incorporating Tumor Burden and AFP Dynamics. Ann Surg Oncol 2025:10.1245/s10434-025-17303-y. [PMID: 40238062 DOI: 10.1245/s10434-025-17303-y] [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: 01/24/2025] [Accepted: 03/24/2025] [Indexed: 04/18/2025]
Abstract
BACKGROUND Existing models to predict recurrence-free survival (RFS) after hepatectomy for hepatocellular carcinoma (HCC) rely on static preoperative factors such as alpha-fetoprotein (AFP) and tumor burden score (TBS). These models overlook dynamic postoperative AFP changes, which may reflect evolving recurrence risk. We sought to develop a dynamic, real-time model integrating time-updated AFP values with TBS for improved recurrence prediction. PATIENTS AND METHODS Patients undergoing curative-intent hepatectomy for HCC (2000-2023) were identified from an international, multi-institutional database with RFS as the primary outcome. AFP trajectory was monitored from preoperative to 6- and 12-month postoperative values, using time-varying Cox regression with AFP as a time-dependent covariate. The predictive accuracy of this time-updated model was compared with a static preoperative Cox model excluding postoperative AFP. RESULTS Among 1911 patients, AFP trajectories differed between recurrent and nonrecurrent cases. While preoperative AFP values were similar, recurrent cases exhibited higher AFP at 6 and 12 months. Multivariable analysis identified TBS (hazard ratio (HR):1.043 [95% confidence interval (CI): 1.002-1.086]; p = 0.039) and postoperative log AFP dynamics (HR:1.216 [CI 1.132-1.305]; p < 0.001) as predictors. Contour plots depicted TBS's influence decreasing over time, while postoperative AFP became more predictive. The time-varying Cox model was created to update RFS predictions continuously on the basis of the latest AFP values. The preoperative Cox model, developed with age, AFP, TBS, and albumin-bilirubin score, had a baseline C-index of 0.61 [0.59-0.63]. At 6 months, the time-varying model's C-index was 0.70 [0.67-0.73] versus 0.59 [0.56-0.61] for the static model; at 12 months, it was 0.70 [0.66-0.73] versus 0.56 [0.53-0.59]. The model was made available online ( https://nm49jf-miho-akabane.shinyapps.io/AFPHCC/ ). CONCLUSIONS Incorporating postoperative AFP dynamics into RFS prediction after HCC resection enhanced prediction accuracy over time, as TBS's influence decreased. This adaptive, time-varying model provides refined RFS predictions throughout follow-up.
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Affiliation(s)
- Miho Akabane
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Jun Kawashima
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Abdullah Altaf
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Selamawit Woldesenbet
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - François Cauchy
- Department of Hepatobiliopancreatic Surgery, APHP, Beaujon Hospital, Clichy, France
| | - Federico Aucejo
- Department of General Surgery, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Irinel Popescu
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | - Minoru Kitago
- Department of Surgery, Keio University, Tokyo, Japan
| | | | | | | | | | - Yuki Imaoka
- Department of Surgery, Stanford University, Stanford, CA, USA
| | | | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Japan
| | - Ana Gleisner
- Department of Surgery, University of Colorado, Denver, CO, USA
| | - Hugo P Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - Sara Oliveira
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - Jorge Balaia
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - Vincent Lam
- Department of Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - Tom Hugh
- Department of Surgery, School of Medicine, The University of Sydney, Sydney, NSW, Australia
| | - Nazim Bhimani
- Department of Surgery, School of Medicine, The University of Sydney, Sydney, NSW, Australia
| | - Feng Shen
- The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA.
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Tian C, Ye C, Guo H, Lu K, Yang J, Wang X, Ge X, Yu C, Lu J, Jiang L, Zhang Q, Song C. Liver elastography-based risk score for predicting hepatocellular carcinoma risk. J Natl Cancer Inst 2025; 117:761-771. [PMID: 39576686 DOI: 10.1093/jnci/djae304] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 10/28/2024] [Accepted: 11/18/2024] [Indexed: 04/08/2025] Open
Abstract
BACKGROUND Liver stiffness measurement (LSM) via vibration-controlled transient elastography accurately assesses fibrosis. We aimed to develop a universal risk score for predicting hepatocellular carcinoma (HCC) development in patients with chronic hepatitis. METHODS We systematically selected predictors and developed the risk prediction model (HCC-LSM) in the hepatitis B virus (HBV) training cohort (n = 2251, median follow-up of 3.2 years). The HCC-LSM model was validated in an independent HBV validation cohort (n = 1191, median follow-up of 5.7 years) and a non-viral chronic liver disease (CLD) extrapolation cohort (n = 1189, median follow-up of 3.3 years). An HCC risk score was then constructed based on a nomogram. An online risk evaluation tool Liver Elastography-Based Hepatocellular Carcinoma Risk Score (LEBER) was developed using ChatGPT4.0. RESULTS Eight routinely available predictors were identified, with LSM levels showing a significant dose-response relationship with HCC incidence (P < .001 by log-rank test). The HCC-LSM model exhibited excellent predictive performance in the HBV training cohort (C-index = 0.866) and the HBV validation cohort (C-index = 0.852), with good performance in the extrapolation CLD cohort (C-index = 0.769). The model demonstrated significantly superior discrimination compared to 6 previous models across the 3 cohorts. Cut-off values of 87.2 and 121.1 for the HCC-LSM score categorized participants into low-, medium-, and high-risk groups. An online public risk evaluation tool (LEBER; http://ccra.njmu.edu.cn/LEBER669.html) was developed to facilitate the use of HCC-LSM. CONCLUSION The accessible, reliable risk score based on LSM accurately predicted HCC development in patients with chronic hepatitis, providing an effective risk assessment tool for HCC surveillance strategies.
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Affiliation(s)
- Chan Tian
- Health Management Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, P. R. China
| | - Chunyan Ye
- Department of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou 213000, Jiangsu, China
| | - Haiyan Guo
- Health Management Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, P. R. China
| | - Kun Lu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, P. R. China
| | - Juan Yang
- Health Management Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, P. R. China
| | - Xiao Wang
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Xinyuan Ge
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, P. R. China
| | - Chengxiao Yu
- Health Management Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, P. R. China
| | - Jing Lu
- Health Management Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, P. R. China
| | - Longfeng Jiang
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Qun Zhang
- Health Management Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Ci Song
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, P. R. China
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Ma L, Zhang Y, Fang Y, Hao C, Fan Q, Jiang D, Lu L, Su F, Yang C, Liu Z, Tian J, Sun X, Sun S, Cheng Y. Anti-PD-L1 envafolimab combined with anti-VEGF suvemcitug in pretreated solid tumors and hepatocellular carcinoma: an open-label phase II study with safety run-in stage. Invest New Drugs 2025; 43:181-190. [PMID: 39883265 DOI: 10.1007/s10637-025-01506-x] [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: 09/24/2024] [Accepted: 01/07/2025] [Indexed: 01/31/2025]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) combined with anti-vascular endothelial growth factor (VEGF) have been the standard first-line treatment of hepatocellular carcinoma (HCC). However, the efficacy of this combination in post-line treatment is still unknown. This study aimed to evaluate the efficacy and safety of the combination of anti-PD-L1 envafolimab and novel humanized anti-VEGF suvemcitug as second-line treatment for patients with HCC. METHODS This open-label, prospective phase II clinical study (NCT05148195) comprised safety run-in stage and dose expansion stage of HCC cohort. Eligible patients were aged ≥ 18 years and had undergone at least a prior line of treatment. Patients received fixed-dose envafolimab and suvemcitug until termination of disease progression, unacceptable toxicities, or withdrawal. The primary endpoint of safety run-in stage was recommended dose (RD), and dose expansion stage was objective response rate (ORR). RESULTS As of August 10, 2023, no dose-limiting toxicity was observed in six patients in the safety-run-in stage, and 2 mg/kg dose every 3 weeks was declared the RD of suvemcitug. Among 20 patients with HCC, the median age was 54.5 (range, 42-70) years. Of these patients, 20 (100.0%) received ≥ one prior line treatment, with 20 (100%) received tyrosine kinase inhibitor (TKI) treatment and 8 (40.0%) received prior ICI treatment. The ORR was 10.0% (95% confidence interval (CI), 1.2-31.7), DCR was 65.0% (95% CI, 40.8-84.6), and DoR was not reached (NR). With a median follow-up of 13.9 months, the median progression-free survival (PFS) and median overall survival (OS) were 4.3 months (95% CI, 1.4-8.1) and 10.7 months (95% CI, 6.0-not evaluable [NE]), respectively. Treatment-related adverse events (TRAEs) of grade ≥ 3 occurred in 40% patients, with proteinuria (20.0%, 4/20) being the most frequent. The ORR of no lung metastasis, prior first-line treatment and IO naïve treatment subgroup was 16.7%. CONCLUSIONS The combination of envafolimab and suvemcitug showed a tolerable safety profile and promising antitumor activity in HCC patients who failed later-line treatment.
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Affiliation(s)
- Lixia Ma
- Department of Internal Medicine, Jilin Cancer Hospital, Changchun, China
| | - Yu Zhang
- Department of Oncology, Mianyang Central Hospital, Mianyang, China
| | - Yong Fang
- Medical Oncology Dept, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chunyi Hao
- Department of Hepato-Pancreato-Biliary Surgery, Key Laboratory of Carcinogenesis and Translational Research, MinistryofEducation/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Qingxia Fan
- Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Da Jiang
- Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Liqin Lu
- Department of Medical Oncology, Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Fang Su
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Chen Yang
- Clinical Science, Shandong Simcere Biopharmaceutical Co., Ltd, Shandong, China
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China
| | - Zhenru Liu
- Clinical Science, Shandong Simcere Biopharmaceutical Co., Ltd, Shandong, China
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China
| | - Ji Tian
- Clinical Science, Shandong Simcere Biopharmaceutical Co., Ltd, Shandong, China
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China
| | - Xiyang Sun
- Clinical Pharmacology, Shandong Simcere Biopharmaceutical Co., Ltd, Shandong, China
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China
| | - Shuguang Sun
- Clinical Statistics, Shandong Simcere Biopharmaceutical Co., Ltd, Shandong, China
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China
| | - Ying Cheng
- Department of Internal Medicine, Jilin Cancer Hospital, Changchun, China.
- Department of Thoracic Oncology, Jilin Cancer Hospital, No.1066 Jinhu Road, Changchun City, Jilin Province, 130000, China.
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7
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Zhang F, Wang YS, Li SP, Zhao B, Huang N, Song RP, Meng FZ, Feng ZW, Zhang SY, Song HC, Chen XP, Liu LX, Wang JZ. Alpha-fetoprotein combined with initial tumor shape irregularity in predicting the survival of patients with advanced hepatocellular carcinoma treated with immune-checkpoint inhibitors: a retrospective multi-center cohort study. J Gastroenterol 2025; 60:442-455. [PMID: 39714631 PMCID: PMC11922967 DOI: 10.1007/s00535-024-02202-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 12/07/2024] [Indexed: 12/24/2024]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) are playing a significant role in the treatment of hepatocellular carcinoma (HCC). This study aims to explore the prognostic value of alpha-fetoprotein (AFP) and initial tumor shape irregularity in patients treated with ICIs. METHODS In this retrospective, multi-center study, 296 HCC patients were randomly divided into the training set and the validation set in a 3:2 ratio. The training set was used to evaluate prognostic factors and to develop an easily applicable ATSI (AFP and Tumor Shape Irregularity) score, which was verified in the validation set. RESULTS The ATSI score was developed from two independent prognostic risk factors: baseline AFP ≥ 400 ng/ml (HR 1.73, 95% CI 1.01-2.96, P = 0.046) and initial tumor shape irregularity (HR 1.94, 95% CI 1.03-3.65, P = 0.041). The median overall survival (OS) was not reached (95% CI 28.20-NA) in patients who met no criteria (0 points), 25.8 months (95% CI 14.17-NA) in patients who met one criterion (1 point), and 17.03 months (95% CI 11.73-23.83) in patients who met two criteria (2 points) (P = 0.001). The median progression-free survival (PFS) was 10.83 months (95% CI 9.27-14.33) for 0 points, 8.03 months (95% CI 6.77-10.57) for 1 point, and 5.03 months (95% CI 3.83-9.67) for 2 points (P < 0.001). The validation set effectively verified these results (median OS, 37.43/24.27/14.03 months for 0/1/2 points, P = 0.028; median PFS, 13.93/8.30/4.90 months for 0/1/2 points, P < 0.001). CONCLUSIONS The ATSI score can effectively predict prognosis in HCC patients receiving ICIs.
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Affiliation(s)
- Feng Zhang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Yong-Shuai Wang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Shao-Peng Li
- Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Bin Zhao
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Nan Huang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Rui-Peng Song
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Fan-Zheng Meng
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Zhi-Wen Feng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, 241000, China
| | - Shen-Yu Zhang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Hua-Chuan Song
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Xiao-Peng Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, 241000, China.
| | - Lian-Xin Liu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China.
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China.
| | - Ji-Zhou Wang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China.
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China.
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8
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Shin H, Yu SJ. A concise review of updated global guidelines for the management of hepatocellular carcinoma: 2017-2024. JOURNAL OF LIVER CANCER 2025; 25:19-30. [PMID: 39925090 PMCID: PMC12010826 DOI: 10.17998/jlc.2025.02.03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 01/30/2025] [Accepted: 02/03/2025] [Indexed: 02/11/2025]
Abstract
Many guidelines for hepatocellular carcinoma (HCC) have been published and are regularly updated worldwide. HCC management involves a broad range of treatment options and requires multidisciplinary care, resulting in significant heterogeneity in management practices across international communities. To support standardized care for HCC, we systematically appraised 13 globally recognized guidelines and expert consensus statements, including five from Asia, four from Europe, and four from the United States. These guidelines share similarities but reveal notable discrepancies in surveillance strategies, treatment allocation, and other recommendations. Geographic differences in tumor biology (e.g., prevalence of viral hepatitis, alcohol-related liver disease, or metabolic dysfunction-associated steatotic liver disease) and disparities in available medical resources (e.g., organ availability, healthcare infrastructure, and treatment accessibility) complicate the creation of universally applicable guidelines. Previously, significant gaps existed between Asian and Western guidelines, particularly regarding treatment strategies. However, these differences have diminished over the years. Presently, variations are often more attributable to publication dates than to regional differences. Nonetheless, Asia-Pacific experts continue to diverge from the Barcelona Clinic Liver Cancer system, particularly with respect to surgical resection and locoregional therapies, which are viewed as overly conservative in Western guidelines. Advancements in systemic therapies have prompted ongoing updates to these guidelines. Given that each set of guidelines reflects distinct regional characteristics, strengths, and limitations, fostering collaboration and mutual complementarity is essential for addressing discrepancies and advancing global HCC care.
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Affiliation(s)
- Hyunjae Shin
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Liver Research Institute, Seoul National University, Seoul, Korea
| | - Su Jong Yu
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Liver Research Institute, Seoul National University, Seoul, Korea
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Seven İ, Bayram D, Arslan H, Köş FT, Gümüşlü K, Aktürk Esen S, Şahin M, Şendur MAN, Uncu D. Predicting hepatocellular carcinoma survival with artificial intelligence. Sci Rep 2025; 15:6226. [PMID: 39979406 PMCID: PMC11842547 DOI: 10.1038/s41598-025-90884-6] [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: 12/16/2024] [Accepted: 02/17/2025] [Indexed: 02/22/2025] Open
Abstract
Despite the extensive research on hepatocellular carcinoma (HCC) exploring various treatment strategies, the survival outcomes have remained unsatisfactory. The aim of this research was to evaluate the ability of machine learning (ML) methods in predicting the survival probability of HCC patients. The study retrospectively analyzed cases of patients with stage 1-4 HCC. Demographic, clinical, pathological, and laboratory data served as input variables. The researchers employed various feature selection techniques to identify the key predictors of patient mortality. Additionally, the study utilized a range of machine learning methods to model patient survival rates. The study included 393 individuals with HCC. For early-stage patients (stages 1-2), the models reached recall values of up to 91% for 6-month survival prediction. For advanced-stage patients (stage 4), the models achieved accuracy values of up to 92% for 3-year overall survival prediction. To predict whether patients are ex or not, the accuracy was 87.5% when using all 28 features without feature selection with the best performance coming from the implementation of weighted KNN. Further improvements in accuracy, reaching 87.8%, were achieved by applying feature selection methods and using a medium Gaussian SVM. This study demonstrates that machine learning techniques can reliably predict survival probabilities for HCC patients across all disease stages. The research also shows that AI models can accurately identify a high proportion of surviving individuals when assessing various clinical and pathological factors.
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Affiliation(s)
- İsmet Seven
- Ankara Bilkent City Hospital, Medical Oncology Clinic, Ankara, Turkey.
| | - Doğan Bayram
- Ankara Bilkent City Hospital, Medical Oncology Clinic, Ankara, Turkey
| | - Hilal Arslan
- Computer Engineering Department, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| | - Fahriye Tuğba Köş
- Ankara Bilkent City Hospital, Medical Oncology Clinic, Ankara, Turkey
| | - Kübranur Gümüşlü
- Computer Engineering Department, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| | - Selin Aktürk Esen
- Ankara Bilkent City Hospital, Medical Oncology Clinic, Ankara, Turkey
| | - Mücella Şahin
- Department of Internal Medicine, Ankara Bilkent City Hospital, Ankara, Turkey
| | | | - Doğan Uncu
- Ankara Bilkent City Hospital, Medical Oncology Clinic, Ankara, Turkey
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10
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Park J, Lee YT, Agopian VG, Liu JS, Koltsova EK, You S, Zhu Y, Tseng HR, Yang JD. Liquid biopsy in hepatocellular carcinoma: Challenges, advances, and clinical implications. Clin Mol Hepatol 2025; 31:S255-S284. [PMID: 39604328 PMCID: PMC11925447 DOI: 10.3350/cmh.2024.0541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 11/15/2024] [Accepted: 11/25/2024] [Indexed: 11/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive primary liver malignancy often diagnosed at an advanced stage, resulting in a poor prognosis. Accurate risk stratification and early detection of HCC are critical unmet needs for improving outcomes. Several blood-based biomarkers and imaging tests are available for early detection, prediction, and monitoring of HCC. However, serum protein biomarkers such as alpha-fetoprotein have shown relatively low sensitivity, leading to inaccurate performance. Imaging studies also face limitations related to suboptimal accuracy, high cost, and limited implementation. Recently, liquid biopsy techniques have gained attention for addressing these unmet needs. Liquid biopsy is non-invasive and provides more objective readouts, requiring less reliance on healthcare professional's skills compared to imaging. Circulating tumor cells, cell-free DNA, and extracellular vesicles are targeted in liquid biopsies as novel biomarkers for HCC. Despite their potential, there are debates regarding the role of these novel biomarkers in the HCC care continuum. This review article aims to discuss the technical challenges, recent technical advancements, advantages and disadvantages of these liquid biopsies, as well as their current clinical application and future directions of liquid biopsy in HCC.
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Affiliation(s)
- Jaeho Park
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yi-Te Lee
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Vatche G. Agopian
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
- Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA
| | - Jessica S Liu
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Ekaterina K. Koltsova
- Smidt Heart Institute, Department of Medicine, Department of Biomedical Sciences, 8700 Beverly Blvd, Los Angeles, CA, USA
| | - Sungyong You
- Department of Urology and Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yazhen Zhu
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA
| | - Hsian-Rong Tseng
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Zhang C, Sun D, Zhou H, Liu C, Ruan J, Kang J, Xie Y. Autophagy-related long non-coding RNA MIR210HG plays a therapeutic role in hepatocellular carcinoma. Discov Oncol 2025; 16:75. [PMID: 39838125 PMCID: PMC11751285 DOI: 10.1007/s12672-025-01765-3] [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: 07/18/2024] [Accepted: 01/02/2025] [Indexed: 01/23/2025] Open
Abstract
OBJECTIVE This study aimed to investigate the role of the autophagy-related long noncoding RNA (lncRNA) MIR210HG in hepatocellular carcinoma and its potential as a therapeutic target. METHODS LncRNA MIR210HG expression and its correlation with survival outcomes in hepatocellular carcinoma patients were analyzed using data from The Cancer Genome Atlas (TCGA). Kaplan-Meier and Cox regression analyses were conducted to assess survival correlations. Quantitative reverse transcription PCR was used to measure lncRNA MIR210HG expression in liver cancer cells and normal liver cells. Functional assays, including CCK-8, Transwell, flow cytometry, and western blot, were performed to evaluate the effects of lncRNA MIR210HG on cell proliferation, invasion, apoptosis, and autophagy in hepatocellular carcinoma. RESULTS Elevated lncRNA MIR210HG expression correlated with poor overall survival in hepatocellular carcinoma patients. LncRNA MIR210HG expression was significantly up-regulated in hepatocellular carcinoma cells compared to normal liver cells. Knockdown of lncRNA MIR210HG inhibited cell proliferation and autophagy, while promoting apoptosis in hepatocellular carcinoma cells, findings that were confirmed through both in vitro and in vivo studies. CONCLUSION The findings suggest that lncRNA MIR210HG contributes to hepatocellular carcinoma progression by regulating autophagy and could serve as a promising therapeutic target in hepatocellular carcinoma treatment strategies.
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Affiliation(s)
- Chaoqun Zhang
- Hebei Key Laboratory of Laboratory Animal Science, Hebei Medical University, No. 361 East Zhongshan Road, Changan District, Shijiazhuang, 050017, China
| | - Dianxing Sun
- Hebei Key Laboratory of Laboratory Animal Science, Hebei Medical University, No. 361 East Zhongshan Road, Changan District, Shijiazhuang, 050017, China.
- Department of Infection, The 980, Hospital of PLA Joint Logistics Support Force, Shijiazhuang, 050082, China.
| | - Huifang Zhou
- Department of Infection, The 980, Hospital of PLA Joint Logistics Support Force, Shijiazhuang, 050082, China
| | - Chao Liu
- Hebei Key Laboratory of Laboratory Animal Science, Hebei Medical University, No. 361 East Zhongshan Road, Changan District, Shijiazhuang, 050017, China
| | - Jie Ruan
- Hebei Key Laboratory of Laboratory Animal Science, Hebei Medical University, No. 361 East Zhongshan Road, Changan District, Shijiazhuang, 050017, China
| | - Jiwen Kang
- Department of Infection, The 980, Hospital of PLA Joint Logistics Support Force, Shijiazhuang, 050082, China
| | - Ying Xie
- Hebei Key Laboratory of Laboratory Animal Science, Hebei Medical University, No. 361 East Zhongshan Road, Changan District, Shijiazhuang, 050017, China.
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12
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Liu B, Yang J, Wu Y, Chen X, Wu X. Application of dynamic enhanced scanning with GD-EOB-DTPA MRI based on deep learning algorithm for lesion diagnosis in liver cancer patients. Front Oncol 2025; 14:1423549. [PMID: 39834934 PMCID: PMC11743610 DOI: 10.3389/fonc.2024.1423549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 12/09/2024] [Indexed: 01/22/2025] Open
Abstract
Background Improvements in the clinical diagnostic use of magnetic resonance imaging (MRI) for the identification of liver disorders have been made possible by gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA). Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) technology is in high demand. Objectives The purpose of the study is to segment the liver using an enhanced multi-gradient deep convolution neural network (EMGDCNN) and to identify and categorize a localized liver lesion using a Gd-EOB-DTPA-enhanced MRI. Methods We provided the classifier images of the liver in five states (unenhanced, arterial, portal venous, equilibrium, and hepatobiliary) and labeled them with localized liver diseases (hepatocellular carcinoma, metastasis, hemangiomas, cysts, and scarring). The Shanghai Public Health Clinical Center ethics committee recruited 132 participants between August 2021 and February 2022. Fisher's exact test analyses liver lesion Gd-EOB-DTPA-enhanced MRI data. Results Our method could identify and classify liver lesions at the same time. On average, 25 false positives and 0.6 real positives were found in the test instances. The percentage of correct answers was 0.790. AUC, sensitivity, and specificity evaluate the procedure. Our technique outperforms others in extensive testing. Conclusion EMGDCNN may identify and categorize a localized hepatic lesion in Gd-EOB-DTPA-enhanced MRI. We found that one network can detect and classify. Radiologists need higher detection capability.
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Affiliation(s)
- Bo Liu
- Department of Radiology, Ordos Central Hospital, Ordos, Inner Mongolia, China
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13
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Li YT, Zeng XZ. Establishment and Validation of the Novel Necroptosis-related Genes for Predicting Stemness and Immunity of Hepatocellular Carcinoma via Machine-learning Algorithm. Comb Chem High Throughput Screen 2025; 28:146-165. [PMID: 39641162 DOI: 10.2174/0113862073271292231108113547] [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: 07/26/2023] [Revised: 08/21/2023] [Accepted: 09/21/2023] [Indexed: 12/07/2024]
Abstract
BACKGROUND Necroptosis, a recently identified mechanism of programmed cell death, exerts significant influence on various aspects of cancer biology, including tumor cell proliferation, stemness, metastasis, and immunosuppression. However, the role of necroptosis-related genes (NRGs) in Hepatocellular Carcinoma (HCC) remains elusive. METHODS In this study, we assessed the mutation signature, copy number variation, and expression of 37 NRGs in HCC using the TCGA-LIHC dataset. We further validated our results using the ICGC-LIRI-JP dataset. To construct our prognostic model, we utilized the least absolute shrinkage and selection operator (LASSO), and evaluated the predictive efficacy of the NRGs-score using various machine learning algorithms, including K-M curves, time-ROC curves, univariate and multivariate Cox regression, and nomogram. In addition, we analyzed immune infiltration using the CIBERSOFT and ssGSEA algorithms, calculated the stemness index through the one-class logistic regression (OCLR) algorithm, and performed anti-cancer stem cells (CSCs) drug sensitivity analysis using oncoPredict. Finally, we validated the expression of the prognostic NRGs through qPCR both in vitro and in vivo. RESULTS About 18 out of 37 NRGs were found to be differentially expressed in HCC and correlated with clinical outcomes. To construct a prognostic model, six signature genes (ALDH2, EZH2, PGAM5, PLK1, SQSTM1, and TARDBP) were selected using LASSO analysis. These genes were then employed to categorize HCC patients into two subgroups based on NRGs-score (low vs. high). A high NRGs score was associated with a worse prognosis. Furthermore, univariate and multivariate Cox regression analyses were performed to confirm the NRGs-score as an independent risk factor. These analyses revealed strong associations between NRGs-score and critical factors, such as AFP, disease stage, and tumor grade in the HCC cohort. NRGs-score effectively predicted the 1-, 3-, and 5-year survival of HCC patients. Immune infiltration analysis further revealed that the expression of immune checkpoint molecules was significantly enhanced in the high NRGs-score group. Stemness analysis in the HCC cohort showed that NRGs-score was positively correlated with mRNA stemness index, and patients with high NRGs-score were sensitive to CSCs inhibitors. The findings from the external validation cohort provided confirmation that the NRGs-score presented a trait with universal applicability in accurately predicting the survival of HCC. Additionally, the six prognostic genes were consistently differentially expressed in both the HCC cell line and the mouse HCC model. CONCLUSION Our study demonstrated the pivotal role of NRGs in promoting stemness and immune suppression in HCC and established a robust model which could successfully predict HCC prognosis.
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Affiliation(s)
- Yao-Ting Li
- Department of Forensic Science, Guangdong Police College, 500 Binjiang East Road, Guangzhou 510230, Guangdong, China
| | - Xue-Zhen Zeng
- Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China
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14
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Haga Y, Ray R, Ray RB. Silmitasertib in Combination With Cabozantinib Impairs Liver Cancer Cell Cycle Progression, Induces Apoptosis, and Delays Tumor Growth in a Preclinical Model. Mol Carcinog 2025; 64:72-82. [PMID: 39377735 DOI: 10.1002/mc.23827] [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: 08/06/2024] [Revised: 09/18/2024] [Accepted: 09/19/2024] [Indexed: 10/09/2024]
Abstract
The rising incidence of hepatocellular carcinoma (HCC) is a global problem. Several approved treatments, including immune therapy and multi-tyrosine kinase inhibitors, are used for treatment, although the results are not optimum. There is an unmet need to develop highly effective chemotherapies for HCC. Targeting multiple pathways to attack cancer cells is beneficial. Cabozantinib is an orally available bioactive multikinase inhibitor and has a modest effect on HCC treatment. Silmitasertib is an orally bioavailable, potent CK2 inhibitor with a direct role in DNA damage repair and is in clinical trials for other cancers. In this study, we planned to repurpose these existing drugs on HCC treatment. We observed a stronger antiproliferative effect of these two combined drugs on HCC cells generated from different etiologies as compared to the single treatment. Global RNA-seq analyses revealed a decrease in the expression of G2/M cell cycle transition genes in HCC cells following combination treatment, suggesting G2 phase cell arrest. We observed G2/M cell cycle phase arrest in HCC cells upon combination treatment compared to the single-treated or vehicle-treated control cells. The downregulation of CCNA2 and CDC25C following combination therapy further supported the observation. Subsequent analyses demonstrated that combination treatment inhibited 70 kDa ribosomal protein S6 kinase (p70S6K) phosphorylation, and increased Bim expression. Apoptosis of HCC cells were accompanied by increased poly (ADP-ribose) polymerase cleavage and caspase-9 activation. Next, we observed that a combination therapy significantly delayed the progression of HCC xenograft growth as compared to vehicle control. Together, our results suggested combining cabozantinib and silmitasertib would be a promising treatment option for HCC.
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Affiliation(s)
- Yuki Haga
- Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA
| | - Ranjit Ray
- Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA
- Department of Molecular Microbiology & Immunology, Saint Louis University, St. Louis, Missouri, USA
| | - Ratna B Ray
- Department of Molecular Microbiology & Immunology, Saint Louis University, St. Louis, Missouri, USA
- Department of Pathology, Saint Louis University, St. Louis, Missouri, USA
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15
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Wu Q, Chen Q, Yang J, Zhang J, Yang A. Material basis revelation of anti-hepatoma effect of Huachansu (Cinobufacini) through down-regulation of thymidylate synthase. CHINESE HERBAL MEDICINES 2025; 17:127-138. [PMID: 39949800 PMCID: PMC11814253 DOI: 10.1016/j.chmed.2024.04.002] [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: 05/06/2023] [Revised: 01/11/2024] [Accepted: 04/30/2024] [Indexed: 02/16/2025] Open
Abstract
Objective Hepatocellular carcinoma (HCC) is a leading cause of mortality worldwide. Huachansu (Cinobufacini) is active extract isolated from the dry skin of Bufo Bufo gargarizans. It has now been widely used in clinical treatment of cancer, this study is to clarify the material basis of down-regulation of thymidylate synthase (TYMS) induced by Huachansu. Methods Our study utilized UPLC-MS/MS to identify major bioactive components from Huachansu. Cell Counting Kit 8 (CCK-8) assay and clone formation assay were used to examine the cell viability of tumor cells. TYMS and γ-H2AX level were detected by using quantitative real-time RT-PCR and/or western blotting. Small interfering RNA (siRNA) transfection was used to explore whether inhibition of TYMS could enhance the suppressive effect of Huachansu on cell growth of HCC cells. Results In our study, firstly, we identify 21 major bioactive components from Huachansu. CCK-8 assay results showed that Huachansu and its bioactive bufadienolides (Bufalin, Bufotalin, Cinobufotalin, Desacetylcinobufagin, Arenobufagin, Telocinobufagin, and Resibufogenin) significantly inhibited the proliferation of HepG2 and SK-HEP-1 cells in a dose- and time-dependent manner. Further molecular mechanistic investigation demonstrates that Huachansu significantly suppresses thymidylate synthase (TYMS), the enzyme which provides the sole de novo source of thymidylate for DNA synthesis. The inhibition of TYMS could lead to cell-cycle block and DNA damage of HCC cells. Furthermore, we identified that Huachansu markedly increased γ-H2AX expression, which indicated the presence of DNA damage. Moreover, we confirmed that transfection of cells with small interfering RNA specific to TYMS could increase the suppressive effects of Huachansu on the HCC cells proliferation. Quantitative RT-PCR analysis showed that Huachansu treatment had no effect on the transcription level of TYMS. Furthermore, proteasomal inhibitor MG132 could block TYMS inhibition induced by Huachansu, and concomitant administration of protein synthesis inhibitor cycloheximide (CHX) with Huachansu could further suppress the protein level of TYMS, indicating that Huachansu promotes proteasome-dependent degradation of TYMS in liver cancer cells. More importantly, the bioactive bufadienolides of Huachansu such as Bufalin, Bufotalin, Cinobufotalin, Desacetylcinobufagin, Arenobufagin, Telocinobufagin, and Resibufogenin could also significantly restrain the protein level of TYMS, revealing the material basis of inhibition of TYMS exposed to Huachansu. 5-Fluorouracil (5-FU) is a TYMS inhibitor, we also evaluate the effects of the combined treatment of Huachansu with 5-FU, the results show that interactions between Huachansu and 5-FU are synergistic or antagonistic. Thus, in clinical, attention should be paid to the dosage of Huachansu in combination with 5-FU. Conclusion Huachansu inhibits the growth and induces DNA damage of human HCC cells through proteasome-dependent degradation of TYMS, bioactive bufadienolides are the material basis of down-regulation of TYMS induced by Huachansu.
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Affiliation(s)
- Qi Wu
- School of Pharmacy, Binzhou Medical University, Yantai 264003, China
| | - Qimei Chen
- School of Pharmacy, Binzhou Medical University, Yantai 264003, China
| | - Jingyi Yang
- School of Pharmacy, Binzhou Medical University, Yantai 264003, China
| | - Jiayu Zhang
- School of Pharmacy, Binzhou Medical University, Yantai 264003, China
| | - Ailin Yang
- School of Pharmacy, Binzhou Medical University, Yantai 264003, China
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16
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Maher S, Kabir A, Behary J, Conway DP, Akon AC, Barr M, Zekry A. New South Wales data linkage study reveals a shift in HCC mortality risk: Time for broader strategies. Cancer Epidemiol 2024; 93:102690. [PMID: 39486273 DOI: 10.1016/j.canep.2024.102690] [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: 02/25/2024] [Revised: 10/04/2024] [Accepted: 10/21/2024] [Indexed: 11/04/2024]
Abstract
BACKGROUND This study aims to examine the impact of sociodemographic and clinical factors on hepatocellular carcinoma (HCC) mortality in New South Wales (NSW), Australia. METHODS We conducted a 15-year retrospective study (2001-2015) using data linkage of health records and cancer registry databases, to identify all HCC cases and analyse HCC-related and all-cause mortality rates. Location-based socioeconomic status (SES) was determined using the Socioeconomic Indexes for Areas (SEIFA). Multivariable Cox regression analysis was used to determine the effect of key variables on mortality. RESULTS 5564 cases of HCC were diagnosed during the study period. A study cohort of 5454 cases was analysed after excluding cases with key missing data. More than half of the chronic liver disease cases were due to non-viral causes. During the study period, 4033 deaths occurred, of which 2862 were HCC-related. The median survival time for HCC-related deaths was 547 days, and the 5-year survival rate was 31.3 %. Higher HCC-related mortality rates were observed in SEIFA quintiles 2, 3 and 4, when compared to 5 (where SEIFA 1 is most disadvantaged, and SEIFA 5 is most advantaged). Furthermore, significantly increased HCC-related mortality was observed for those aged ≥65, male gender, Australian-born, hospitalisation due to complications of alcohol use, having metastatic HCC at diagnosis, and not receiving surgery for HCC. CONCLUSIONS There is higher prevalence of non-viral-related HCC than viral-related HCC in NSW, Australia, where HCC-related mortality risk is greatest among those Australian-born and lower to higher SES, when compared to highest SES. Identifying factors contributing to these emerging disparities is crucial for developing effective prevention programs and allocating research and health resources.
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Affiliation(s)
- Salim Maher
- Gastroenterology and Hepatology Department, St George Hospital, Sydney, NSW, Australia; School of Clinical Medicine, St George and Sutherland Clinical Campus, UNSW Sydney, NSW, Australia.
| | - Alamgir Kabir
- Centre for Primary Health Care and Equity, UNSW Sydney, NSW, Australia; The George Institute for Global Health, UNSW Sydney, NSW, Australia.
| | - Jason Behary
- Gastroenterology and Hepatology Department, St George Hospital, Sydney, NSW, Australia; School of Clinical Medicine, St George and Sutherland Clinical Campus, UNSW Sydney, NSW, Australia.
| | - Damian P Conway
- Population and Community Health, South Eastern Sydney Local Health District, NSW, Australia; The Kirby Institute, UNSW Sydney, NSW, Australia.
| | - Anna C Akon
- Gastroenterology and Hepatology Department, St George Hospital, Sydney, NSW, Australia.
| | - Margo Barr
- Centre for Primary Health Care and Equity, UNSW Sydney, NSW, Australia.
| | - Amany Zekry
- Gastroenterology and Hepatology Department, St George Hospital, Sydney, NSW, Australia; School of Clinical Medicine, St George and Sutherland Clinical Campus, UNSW Sydney, NSW, Australia.
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Yahia Y, Qasem M, Abbarh S, Saffo H, Obeidat IM, Barjas HH, Faisal MM, Halabiya M, Chandra P, Derbala M. Risk of Malignancy in Indeterminate Liver Nodules Among Patients with Cirrhosis: A Retrospective Cohort Study. J Gastrointest Cancer 2024; 56:1. [PMID: 39414724 PMCID: PMC11485135 DOI: 10.1007/s12029-024-01122-7] [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] [Accepted: 09/29/2024] [Indexed: 10/18/2024]
Abstract
BACKGROUND Several studies have shown a higher risk of liver cancer from indeterminate liver nodules, but the exact occurrence and predictors of liver cancer in this group are still unclear. Our aim is to study the development of liver cancer in this population and identify any potential risk factors. METHODS This retrospective study evaluated cirrhotic patients with indeterminate liver nodules from 2013 to 2023.Data from electronic patient records was analyzed to assess the association between HCC and baseline factors. Subgroup exploratory analysis compared characteristics of patients with de novo HCC and those with nodule transformation HCC. RESULTS Out of 116 patients with liver nodules, 19 (16%) developed HCC in up to 7.5-year follow-up. Univariate Cox regression analysis showed a significant association between HCC incidence and smoking [hazard ratio (HR) 2.60, 95% Confidence Interval [CI] 1.01-6.74), nodule diameter exceeding 2 cm (HR 5.41, 95% CI 1.45-20.18), and baseline LI-RADS score 3 (HR 3.78, 95% CI 1.36-19.52). Multivariate Cox regression analysis revealed significant independent associations with nodule diameters 1 cm to < 2 cm (adjusted HR 3.35, 95% CI 1.06-10.60) and greater than 2 cm (adjusted HR 5.85, 95% CI 1.10-31.16), as well as with LI-RADS 3 lesions (adjusted HR 3.75, 95% CI 1.16-12.11) with adjusting other potential predictors and covariates. CONCLUSION Our findings show a higher incidence of HCC in patients with indeterminate liver nodules, increasing over time and reaching 30% at seven years. Nodules larger than 1-2 cm or LI-RADS 3 lesions pose increased risk for HCC. Enhanced surveillance is necessary given the lack of clear management guidelines.
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Affiliation(s)
- Yousef Yahia
- Gastroenterology and Hepatology Department, Hamad Medical Corporation, Doha, Qatar.
| | - Ma'mon Qasem
- Radiology Department, Hamad Medical Corporation, Doha, Qatar
| | - Shahem Abbarh
- Internal Medicine Department, Hamad Medical Corporation, Doha, Qatar
| | - Husam Saffo
- Gastroenterology and Hepatology Department, Hamad Medical Corporation, Doha, Qatar
| | - Ibrahim M Obeidat
- Gastroenterology and Hepatology Department, Hamad Medical Corporation, Doha, Qatar
| | | | | | - Malik Halabiya
- Gastroenterology and Hepatology Department, Hamad Medical Corporation, Doha, Qatar
| | - Prem Chandra
- Medical Research Centre, Hamad Medical Corporation, Doha, Qatar
| | - Moutaz Derbala
- Gastroenterology and Hepatology Department, Hamad Medical Corporation, Doha, Qatar
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Tang H, Li YX, Lian JJ, Ng HY, Wang SSY. Personalized treatment using predictive biomarkers in solid organ malignancies: A review. TUMORI JOURNAL 2024; 110:386-404. [PMID: 39091157 DOI: 10.1177/03008916241261484] [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: 08/04/2024]
Abstract
In recent years, the influence of specific biomarkers in the diagnosis and prognosis of solid organ malignancies has been increasingly prominent. The relevance of the use of predictive biomarkers, which predict cancer response to specific forms of treatment provided, is playing a more significant role than ever before, as it affects diagnosis and initiation of treatment, monitoring for efficacy and side effects of treatment, and adjustment in treatment regimen in the long term. In the current review, we explored the use of predictive biomarkers in the treatment of solid organ malignancies, including common cancers such as colorectal cancer, breast cancer, lung cancer, prostate cancer, and cancers associated with high mortalities, such as pancreatic cancer, liver cancer, kidney cancer and cancers of the central nervous system. We additionally analyzed the goals and types of personalized treatment using predictive biomarkers, and the management of various types of solid organ malignancies using predictive biomarkers and their relative efficacies so far in the clinical settings.
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Gedallovich SM, Kwo PY. Reply to correspondence on "Metformin and statins reduce hepatocellular carcinoma risk in chronic hepatitis C patients with failed antiviral therapy". Clin Mol Hepatol 2024; 30:1050-1052. [PMID: 38993076 PMCID: PMC11540377 DOI: 10.3350/cmh.2024.0546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 07/11/2024] [Indexed: 07/13/2024] Open
Affiliation(s)
- Seren M. Gedallovich
- Division of Gastroenterology and Hepatology, Stanford University Medical School, Stanford, CA, USA
| | - Paul Y. Kwo
- Division of Gastroenterology and Hepatology, Stanford University Medical School, Stanford, CA, USA
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Zheng Y, Wagner PD, Singal AG, Hanash SM, Srivastava S, Huang Y, Zhao YQ, Chari ST, Marquez G, Etizioni R, Marsh TL, Feng Z. Designing Rigorous and Efficient Clinical Utility Studies for Early Detection Biomarkers. Cancer Epidemiol Biomarkers Prev 2024; 33:1150-1157. [PMID: 39223980 PMCID: PMC11534000 DOI: 10.1158/1055-9965.epi-23-1594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 03/11/2024] [Accepted: 06/07/2024] [Indexed: 09/04/2024] Open
Abstract
Before implementing a biomarker in routine clinical care, it must demonstrate clinical utility by leading to clinical actions that positively affect patient-relevant outcomes. Randomly controlled early detection utility trials, especially those targeting mortality endpoint, are challenging due to their high costs and prolonged duration. Special design considerations are required to determine the clinical utility of early detection assays. This commentary reports on discussions among the National Cancer Institute's Early Detection Research Network investigators, outlining the recommended process for carrying out single-organ biomarker-driven clinical utility studies. We present the early detection utility studies in the context of phased biomarker development. We describe aspects of the studies related to the features of biomarker tests, the clinical context of endpoints, the performance criteria for later phase evaluation, and study size. We discuss novel adaptive design approaches for improving the efficiency and practicality of clinical utility trials. We recommend using multiple strategies, including adopting real-world evidence, emulated trials, and mathematical modeling to circumvent the challenges in conducting early detection utility trials.
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Affiliation(s)
- Yingye Zheng
- Biostatistics Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Paul D. Wagner
- Division of Cancer Prevention, National Cancer Institute, Rockville, MD
| | - Amit G. Singal
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas TX
| | - Samir M Hanash
- Department of Clinical Cancer Prevention, McCombs Institute for Cancer Detection and Treatment at MD Anderson Cancer Center, Houston, TX
| | - Sudhir Srivastava
- Division of Cancer Prevention, National Cancer Institute, Rockville, MD
| | - Ying Huang
- Biostatstics, Bioinformatics and Epidemiology Program, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Ying-Qi Zhao
- Biostatistics Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Suresh T Chari
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Guillermo Marquez
- Division of Cancer Prevention, National Cancer Institute, Rockville, MD
| | - Ruth Etizioni
- Biostatistics Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Tracey L Marsh
- Biostatistics Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Ziding Feng
- Biostatistics Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
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21
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Agudile EP, Vega EA, Salirrosas O, Agudile UM, Chirban AM, Lathan C, Sorescu GP, Odisio BC, Panettieri E, Conrad C. Temporal trends of health disparity in the utilization of curative-intent treatments for hepatocellular carcinoma: are we making progress? J Gastrointest Surg 2024; 28:1392-1399. [PMID: 38754809 DOI: 10.1016/j.gassur.2024.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 04/17/2024] [Accepted: 05/11/2024] [Indexed: 05/18/2024]
Abstract
BACKGROUND Liver-directed treatments - ablative therapy (AT), surgical resection (SR), liver transplantation (LT), and transarterial chemoembolization (TACE) - improve the overall survival of patients with early-stage hepatocellular carcinoma (HCC). Although racial and socioeconomic disparities affect access to liver-directed therapies, the temporal trends for the curative-intent treatment of HCC remain to be elucidated. METHODS This study performed chi-square, logistic regression, and temporal trends analyses on data from the Nationwide Inpatient Sample from 2011 to 2019. The outcome of interest was the rate of AT, SR, LT (curative-intent treatments), and TACE utilization, and the primary predictors were racial/ethnic group and socioeconomic status (SES; insurance status). RESULTS African American and Hispanic patients had lower odds of receiving AT (African American: odds ratio [OR], 0.78; P < .001; Hispanic: OR, 0.84; P = .005) and SR (African American: OR, 0.71; P < .001; Hispanics: OR, 0.64; P < .001) than White patients. Compared with White patients, the odds of LT was lower in African American patients (OR, 0.76; P < .001) but higher in Hispanic patients (OR, 1.25; P = .001). Low SES was associated with worse odds of AT (OR, 0.79; P = .001), SR (OR, 0.66; P < .001), and LT (OR, 0.84; P = .028) compared with high SES. Although curative-intent treatments showed significant upward temporal trends among White patients (10.6%-13.9%; P < .001) and Asian and Pacific Islander/other patients (14.4%-15.7%; P = .007), there were nonsignificant trends among African American patients (10.9%-10.1%; P = .825) or Hispanic patients (12.2%-13.7%; P = .056). CONCLUSION Our study demonstrated concerning disparities in the utilization of curative-intent treatment for HCC based on race/ethnicity and SES. Moreover, racial/ethnic disparities have widened rather than improved over time.
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Affiliation(s)
- Emeka P Agudile
- Department of Medicine, Steward Carney Hospital, Dorchester, Massachusetts, United States; Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States
| | - Eduardo A Vega
- Department of Surgery, St. Elizabeth's Medical Center, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, United States
| | - Oscar Salirrosas
- Department of Surgery, St. Elizabeth's Medical Center, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, United States
| | - Ukamaka M Agudile
- Department of Medicine, Steward Carney Hospital, Dorchester, Massachusetts, United States
| | - Ariana M Chirban
- Department of Surgery, St. Elizabeth's Medical Center, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, United States; Department of Surgery, School of Medicine, University of California San Diego, La Jolla, California, United States
| | - Christopher Lathan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard School of Medicine, Boston, Massachusetts, United States
| | - George P Sorescu
- Department of Medicine, Lemuel Shattuck Hospital, Boston, Massachusetts, United States
| | - Bruno C Odisio
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Elena Panettieri
- Department of Surgery, St. Elizabeth's Medical Center, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, United States; Hepatobiliary Surgery Unit, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Claudius Conrad
- Division of Surgical Oncology, Carle Illinois College of Medicine, University of Illinois Urbana Champaign, Illinois, United States.
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Guan Y, Gan Y, An J. Clinical Characteristics and Prognosis of Early-Onset Hepatocellular Carcinoma: A Retrospective Cohort Study Based on Population Data. Dig Dis Sci 2024; 69:3563-3573. [PMID: 38965157 DOI: 10.1007/s10620-024-08549-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 06/22/2024] [Indexed: 07/06/2024]
Abstract
BACKGROUND The incidence of young patients diagnosed with hepatocellular carcinoma (HCC) is projected to rise. This study aimed to investigate the distinctive characteristics of adolescent and young adult (AYA) patients with HCC and identify the risk factors that impact their survival. METHODS This study included 1005 AYA patients and 55,435 older adult (OA) patients with HCC, using data from the Surveillance, Epidemiology, and End Results database. Propensity score matching was used to adjust for baseline differences in patient characteristics. The Kaplan-Meier curve and log-rank test are utilized to compare the overall survival between the two groups. The Cox proportional hazards regression model was used for subgroup analysis to identify risk factors for overall survival in AYA patients. RESULTS AYA patients exhibited a higher proportion of advanced clinical stage (49.15% vs 37.57%, P < 0.001) and fibrolamellar hepatocellular carcinoma (14.13% vs 0.09%, P < 0.001), but a lower incidence of alpha-fetoprotein positivity (32.04% vs 45.32%, P < 0.001) and cirrhosis (8.86% vs 18.32%, P < 0.001). The subgroup analysis results indicated that AYA patients had a more favorable prognosis than OA patients in most subgroups. Undifferentiated carcinoma emerged as the predominant risk factor for AYA patients (Hazard Ratio [HR], 6.08 [2.53-14.62]), whereas partial hepatectomy was determined to be the most advantageous factor (HR, 0.29 [0.23-0.37]). CONCLUSIONS AYA patients with HCC exhibit more aggressive characteristics but demonstrate a better prognosis compared to the OA group, necessitating personalized surveillance and treatment.
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Affiliation(s)
- Yufan Guan
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, 169 Changle Xi Lu, Xi'an, 710032, China
| | - Yu Gan
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, 169 Changle Xi Lu, Xi'an, 710032, China
| | - Jiaze An
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, 169 Changle Xi Lu, Xi'an, 710032, China.
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23
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Liang Y, Wu H, Wei X. Development and validation of a CT-based nomogram for accurate hepatocellular carcinoma detection in high risk patients. Front Oncol 2024; 14:1374373. [PMID: 39165686 PMCID: PMC11333883 DOI: 10.3389/fonc.2024.1374373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 07/18/2024] [Indexed: 08/22/2024] Open
Abstract
Purpose To establish and validate a CT-based nomogram for accurately detecting HCC in patients at high risk for the disease. Methods A total of 223 patients were divided into training (n=161) and validation (n=62) cohorts between January of 2017 and May of 2022. Logistic analysis was performed, and clinical model and radiological model were developed separately. Finally, a nomogram was established based on clinical and radiological features. All models were evaluated using the area under the curve (AUC). DeLong's test was used to evaluate the differences among these models. Results In the multivariate analysis, gender (p = 0.014), increased Alpha-fetoprotein (AFP) (p = 0.017), non-rim arterial phase hyperenhancement (APHE) (p = 0.011), washout (p = 0.011), and enhancing capsule (p = 0.001) were the independent differential predictors of HCC. A nomogram was formed with well-fitted calibration curves based on these five factors. The area under the curve (AUC) of the nomogram in the training and validation cohorts was 0.961(95%CI: 0.935~0.986) and 0.979 (95% CI: 0.949~1), respectively. The nomogram outperformed the clinical and the radiological models in training and validation cohorts. Conclusion The nomogram incorporating clinical and CT features can be a simple and reliable tool for detecting HCC and achieving risk stratification in patients at high risk for HCC.
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Affiliation(s)
- Yingying Liang
- The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
- Department of Radiology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Hongzhen Wu
- Department of Radiology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Xinhua Wei
- The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
- Department of Radiology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
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24
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Gong L, Wu S, Liu J, Zhang M, Zhuang J, Xu D. Construction of an immunosensor based on Cys/Au@TiO 2 modification for the detection of liver cancer marker PIVKA-II. Talanta 2024; 275:126082. [PMID: 38677167 DOI: 10.1016/j.talanta.2024.126082] [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: 07/12/2023] [Revised: 04/02/2024] [Accepted: 04/08/2024] [Indexed: 04/29/2024]
Abstract
An ultrasensitive immunosensor of Cys/Au@TiO2 based on disposable screen-printed electrodes (SPE) for PIVKA-II detection for hepatocellular carcinoma (HCC) diagnosis was developed by utilizing Cystine (Cys) and nanocomposite Au@TiO2. Firstly, HAuCl4 underwent a reduction reaction with NaBH4, then Au nanoparticles were coated onto TiO2 nanoparticles. Followed, Cys/Au@TiO2 was formed through self-assembly of cysteine to allow the monoclonal antibody of abnormal thrombospondin to bound to the amino group on the surface of the composite by covalent bonding. The mechanism is to determine the changes in the current of the sensor caused by the specific binding of the abnormal prothrombin monoclonal antibody adsorbed by the complex with its antigen. The Cys/Au@TiO2 immunosensor was fully characterized by various analytical approaches and it showed a wide linear testing range of 1-10000 pg mL-1 (R2 = 0.991) and the limit of detection down to 0.77 pg ml-1, with highly sensitivity and specificity. The results showed that the developed immunosensor platform can effectively detect trace amounts of PIVKA-II protein and has potent clinical application for HCC diagnosis.
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Affiliation(s)
- Lvhong Gong
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Shengxi Wu
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China.
| | - Junjie Liu
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Mingjun Zhang
- Laboratory Department of Chongqing Jiulongpo District People's Hospital, Chongqing, 400050, China
| | - Jinghao Zhuang
- Department of Physics and Energy, Chongqing University of Technology, Chongqing 400054, China
| | - Doudou Xu
- NMPA Key Laboratory for Quality Monitoring of Narcotic Drugs and Psychotropic Substances, Chongqing Institute for Food and Drug Control, Chongqing, 401121, China.
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25
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Zhang DY, Bai FH. Research trends and hotspots in the immune microenvironment related to hepatocellular carcinoma: A bibliometric and visualization study. World J Gastrointest Oncol 2024; 16:3321-3330. [PMID: 39072164 PMCID: PMC11271783 DOI: 10.4251/wjgo.v16.i7.3321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 04/16/2024] [Accepted: 04/28/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND The immune microenvironment (IME) in hepatocellular carcinoma (HCC) plays a pivotal role in determining patient outcomes and responses to treatment. This area is witnessing rapid growth in research interest. However, there is a lack of comprehensive bibliometric analyses that dissect trends and potential focal points in this field. AIM To explore the evolution of research on the IME in HCC from January 1, 2004, to December 31, 2023, using bibliometric methodologies. METHODS English articles and reviews concerning the IME of HCC were retrieved from the Web of Science Core Collection with a search date of December 31, 2023. The R package Bibliometrix was employed to compute basic bibliometric characteristics, illustrate collaborations among countries and authors, and create a three-field diagram illustrating the connections between authors, affiliations, and keywords. Analyses of country and institutional co-authorship, as well as keyword co-occurrence, were conducted using VOSviewer. Additionally, CiteSpace was utilized for the cite burst analysis of keywords and cited literature. RESULTS The study encompassed 3125 documents in the research areas related to HCC of IME, revealing a substantial and continuous increase in the annual publication trend over time. China and Fudan University emerged as leading contributors, with 2103 and 165 publications, respectively. Frontiers in immunology was the most prolific journal in this domain. Among the top ten researchers in the field, eight are based in China. Key research terms identified include tumour microenvironment, expression, immunotherapy, and prognosis. CONCLUSION The relationship between HCC and IME is receiving increasing attention, and related research is in a highly developed stage. Key focus areas, including IME and immune checkpoint inhibitors, immunotherapy are poised to be central to future research endeavors, offering promising pathways for further exploration.
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Affiliation(s)
- Da-Ya Zhang
- Department of Graduate School, Hainan Medical University, Haikou 571199, Hainan Province, China
| | - Fei-Hu Bai
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou 570216, Hainan Province, China
- Department of Gastroenterology, The Gastroenterology Clinical Medical Center of Hainan Province, Haikou 570216, Hainan Province, China
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Chen Z, Ding C, Chen K, Gu Y, Qiu X, Li Q. Investigating the causal association between obesity and risk of hepatocellular carcinoma and underlying mechanisms. Sci Rep 2024; 14:15717. [PMID: 38977823 PMCID: PMC11231137 DOI: 10.1038/s41598-024-66414-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 07/01/2024] [Indexed: 07/10/2024] Open
Abstract
Obesity is a global health concern and independent risk factor for cancers including hepatocellular carcinoma (HCC). However, evidence on the causal links between obesity and HCC is limited and inconclusive. This study aimed to investigate the causal relationship between obesity-related traits and HCC risk and explore underlying mechanisms using bioinformatics approaches. Two-sample Mendelian randomization analysis was conducted leveraging publicly available genome-wide association study summary data on obesity traits (body mass index, body fat percentage, waist circumference, waist-to-hip ratio, visceral adipose tissue volume) and HCC. Associations of obesity with primary mechanisms (insulin resistance, adipokines, inflammation) and their effects on HCC were examined. Differentially expressed genes in obesity and HCC were identified and functional enrichment analyses were performed. Correlations with tumor microenvironment (TME) and immunotherapy markers were analyzed. Genetically predicted higher body mass index and body fat percentage showed significant causal relationships with increased HCC risk. Overall obesity also demonstrated causal links with insulin resistance, circulating leptin levels, C-reactive protein levels and risk of severe insulin resistant type 2 diabetes. Four differentially expressed genes (ESR1, GCDH, FAHD2A, DCXR) were common in obesity and HCC. Enrichment analyses indicated their roles in processes like RNA capping, viral transcription, IL-17 signaling and endocrine resistance. They exhibited negative correlations with immune cell infiltration and immunotherapy markers in HCC. Overall obesity likely has a causal effect on HCC risk in Europeans, possibly via influencing primary mechanisms. The identified differentially expressed genes may be implicated in obesity-induced hepatocarcinogenesis through regulating cell cycle, inflammation and immune evasion. Further research on precise mechanisms is warranted.
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Affiliation(s)
- Zhitao Chen
- Department of Hepatobiliary Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, 848# Dongxin Road, Hangzhou, 310003, Zhejiang Province, China
| | - Chenchen Ding
- Child and Adolescent Psychology, Affiliated Mental Health Centre & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310013, Zhejiang, China
| | - Kailei Chen
- School of Medicine, Zhejiang Shuren University, Hangzhou, 310003, China
| | - Yangjun Gu
- Department of Hepatobiliary Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, 848# Dongxin Road, Hangzhou, 310003, Zhejiang Province, China
| | - Xiaoxia Qiu
- Department of Hepatobiliary Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, 848# Dongxin Road, Hangzhou, 310003, Zhejiang Province, China
| | - Qiyong Li
- Department of Hepatobiliary Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, 848# Dongxin Road, Hangzhou, 310003, Zhejiang Province, China.
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Araz F, Soydaş B, Özer B, Karadeli E, Erbay G. Comparison of Characteristics and Survival of New-Onset Hepatocellular Carcinomas With or Without Cirrhosis in a Tertiary Center. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2024; 35:539-550. [PMID: 39128067 PMCID: PMC11363398 DOI: 10.5152/tjg.2024.23451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 03/04/2024] [Indexed: 08/13/2024]
Abstract
BACKGROUND/AIMS Although hepatocellular carcinoma (HCC) usually develops in cirrhotic livers, HCCs could also arise in non-cirrhotic livers. We aimed to compare the characteristics and survival of cirrhotic- and non-cirrhotic HCCs. MATERIALS AND METHODS Data of HCC patients between 2011 and 2021 in a single tertiary center was evaluated retrospectively. Demographic, clinical, laboratory, tumoral and pathological features, and survival outcomes of cirrhotic and non-cirrhotic HCCs were compared. RESULTS The study included 188 HCC patients. Median age was 64 (26-92) years and similar for study groups (P = .208). Both groups had similar male/female ratio. Forty-two patients (22.3%) had HCC in non-cirrhotic liver. Non-cirrhotic HCCs had similar tumor differentiation type, radiological characteristics, Milan, University of California San Francisco, and the Barcelona Clinic Liver Cancer stages, but more unifocal lesion (78.6% vs. 59.6%) and larger tumor size (89.5 (16-240) mm vs. 59.0 (12-290) mm) at presentation compared to non-cirrhotic HCCs. Despite larger tumor size, non-cirrhotic HCC patients had better overall, disease-free and progression-free survival rates than cirrhotic HCCs. Overall survivals for 1 and 3 years were 71.4% and 49.7% for non-cirrhotic and 54% and 28.3% for cirrhotic HCCs, respectively (P = .035). According to Cox analyses, Eastern Cooperative Oncology Group score (P <.001, hazards ratio (HR): 4.05) and curative treatments (P < .001, HR: 0.21) were predictive for overall survival in cirrhotic HCCs. Curative treatment (P = .027, HR: 0.31) was found to be a significant predictor for overall survival in non-cirrhotic HCCs. Vascular invasion was the only independent predictor for disease-free survival (HR: 2.62, 95% CI 1.01-6.93, P = .049) for non-cirrhotic HCCs. CONCLUSION Despite larger tumor size and similar tumor stages, compared to cirrhotic HCCs, non-cirrhotic HCCs were associated with better survival outcomes.
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Affiliation(s)
- Filiz Araz
- Department of Gastroenterology, Başkent University, Adana Turgut Noyan Training and Research Hospital, Adana, Türkiye
| | - Barış Soydaş
- Department of Gastroenterology, Başkent University, Adana Turgut Noyan Training and Research Hospital, Adana, Türkiye
| | - Birol Özer
- Department of Gastroenterology, Başkent University, Adana Turgut Noyan Training and Research Hospital, Adana, Türkiye
| | - Elif Karadeli
- Department of Radiology, Başkent University, Adana Turgut Noyan Training and Research Hospital, Adana, Türkiye
| | - Gürcan Erbay
- Department of Radiology, Başkent University, Adana Turgut Noyan Training and Research Hospital, Adana, Türkiye
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Amador A, Salord S, Xiol X, Garcia-Guix M, Cachero A, Rota R, Hernandez Aretxabaleta N, Baliellas C, Castellote J. Improvement of quality of care provided to outpatients with hepatic cirrhosis after an educational intervention. Eur J Gastroenterol Hepatol 2024; 36:941-944. [PMID: 38625820 DOI: 10.1097/meg.0000000000002778] [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] [Indexed: 04/18/2024]
Abstract
OBJECTIVE A set of indicators has been reported to measure the quality of care for cirrhotic patients, and previously published studies report variable adherence rates to these indicators. This study aimed to assess the quality of care provided to cirrhotic outpatients before and after an educational intervention by determining its impact on adherence to quality indicators. METHODS We conducted a quasi-experimental, cross-sectional study including 324 cirrhotic patients seen in 2017 and 2019 at a tertiary teaching hospital in Spain. Quality indicators were assessed in five domains: documentation of cirrhosis etiology, disease severity assessment, hepatocellular carcinoma (HCC) screening, variceal bleeding prophylaxis, and vaccination. After identifying areas for improvement, an educational intervention was implemented. A second evaluation was performed after the intervention to assess changes in adherence rates. RESULTS Before the intervention, adherence rates were excellent (>90%) for indicators related to variceal bleeding prophylaxis and documentation of cirrhosis etiology, acceptable (60-80%) for HCC screening and disease severity assessment, and poor (<50%) for vaccinations. After the educational intervention, there was a statistically significant improvement in adherence rates for eight indicators related to HCC screening (70-90%), disease severity assessment (90%), variceal bleeding prophylaxis (>90%), and vaccinations (60-90%). CONCLUSION Our study demonstrates a significant improvement in the quality of care provided to cirrhotic outpatients after an educational intervention. The findings highlight the importance of targeted educational interventions to enhance adherence to quality indicators in the management of cirrhosis.
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Affiliation(s)
- Alberto Amador
- Hepatology Unit, Gastroenterology Department, Hospital Universitari de Bellvitge, Institut Català de la Salut, Hepatobiliary and Pancreatic Diseases Research Group, IDIBELL, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
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Wang M, Zhuang B, Yu S, Li G. Ensemble learning enhances the precision of preliminary detection of primary hepatocellular carcinoma based on serological and demographic indices. Front Oncol 2024; 14:1397505. [PMID: 38952558 PMCID: PMC11215019 DOI: 10.3389/fonc.2024.1397505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 06/04/2024] [Indexed: 07/03/2024] Open
Abstract
Primary hepatocellular carcinoma (PHC) is associated with high rates of morbidity and malignancy in China and throughout the world. In clinical practice, a combination of ultrasound and alpha-fetoprotein (AFP) measurement is frequently employed for initial screening. However, the accuracy of this approach often falls short of the desired standard. Consequently, this study aimed to investigate the enhancement of precision of preliminary detection of PHC by ensemble learning techniques. To achieve this, 712 patients with PHC and 1887 healthy controls were enrolled for the assessment of four ensemble learning methods, namely, Random Forest (RF), LightGBM, Xgboost, and Catboost. A total of eleven characteristics, comprising nine serological indices and two demographic indices, were selected from the participants for use in detecting PHC. The findings identified an optimal feature subset consisting of eight features, namely AFP, albumin (ALB), alanine aminotransferase (ALT), platelets (PLT), age, alkaline phosphatase (ALP), hemoglobin (Hb), and body mass index (BMI), that achieved the highest classification accuracy of 96.62%. This emphasizes the importance of the collective use of these features in PHC diagnosis. In conclusion, the results provide evidence that the integration of serological and demographic indices together with ensemble learning models, can contribute to the precision of preliminary diagnosis of PHC.
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Affiliation(s)
- Mengxia Wang
- School of Medicine, Shaoxing University, Shaoxing, Zhejiang, China
| | - Bo Zhuang
- Department of Hepatobiliary Surgery, The Affliated Jinhua Hospital of Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Shian Yu
- Department of Hepatobiliary Surgery, The Affliated Jinhua Hospital of Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Gang Li
- College of Mathematical Medicine, Zhejiang Normal University, Jinhua, China
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He L, Zhang C, Liu LL, Huang LP, Lu WJ, Zhang YY, Zou DY, Wang YF, Zhang Q, Yang XL. Development of a diagnostic nomogram for alpha-fetoprotein-negative hepatocellular carcinoma based on serological biomarkers. World J Gastrointest Oncol 2024; 16:2451-2463. [DOI: 10.4251/wjgo.v16.i6.2451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 02/12/2024] [Accepted: 04/01/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Serum biomarkers play an important role in the early diagnosis and prognosis of HCC. Because a certain percentage of HCC patients are negative for alpha-fetoprotein (AFP), the diagnosis of AFP-negative HCC is essential to improve the detection rate of HCC.
AIM To establish an effective model for diagnosing AFP-negative HCC based on serum tumour biomarkers.
METHODS A total of 180 HCC patients were enrolled in this study. The expression levels of GP73, des-γ-carboxyprothrombin (DCP), CK18-M65, and CK18-M30 were detected by a fully automated chemiluminescence analyser. The variables were selected by logistic regression analysis. Several models were constructed using stepwise backward logistic regression. The performance of the models was compared using the C statistic, integrated discrimination improvement, net reclassification improvement, and calibration curves. The clinical utility of the nomogram was assessed using decision curve analysis (DCA).
RESULTS The results showed that the expression levels of GP73, DCP, CK18-M65, and CK18-M30 were significantly greater in AFP-negative HCC patients than in healthy controls (P < 0.001). Multivariate logistic regression analysis revealed that GP73, DCP, and CK18-M65 were independent factors for diagnosing AFP-negative HCC. By comparing the diagnostic performance of multiple models, we included GP73 and CK18-M65 as the model variables, and the model had good discrimination ability (area under the curve = 0.946) and good goodness of fit. The DCA curves indicated the good clinical utility of the nomogram.
CONCLUSION Our study identified GP73 and CK18-M65 as serum biomarkers with certain application value in the diagnosis of AFP-negative HCC. The diagnostic nomogram based on CK18-M65 combined with GP73 demonstrated good performance and effectively identified high-risk groups of patients with HCC.
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Affiliation(s)
- Li He
- School of Clinical Medicine, Weifang Medical University, Weifang 261053, Shandong Province, China
- Department of Organ Transplantation, The Third Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
| | - Cui Zhang
- Department of Laboratory Medicine, The Third Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
| | - Lan-Lan Liu
- Department of Laboratory Medicine, The Third Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
| | - Li-Ping Huang
- Department of Laboratory Medicine, Jingyu County People’s Hospital, Baishan 135200, Jilin Province, China
| | - Wen-Jing Lu
- Department of Laboratory Medicine, The Third Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
| | - Yuan-Yuan Zhang
- Department of Laboratory Medicine, The Third Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
| | - De-Yong Zou
- Department of Laboratory Medicine, The Third Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
| | - Yu-Fei Wang
- Department of Laboratory Medicine, The Third Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
| | - Qing Zhang
- School of Clinical Medicine, Weifang Medical University, Weifang 261053, Shandong Province, China
- Department of Organ Transplantation, The Third Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
| | - Xiao-Li Yang
- Department of Laboratory Medicine, The Third Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
- School of Laboratory Medicine, Weifang Medical University, Weifang 261053, Shandong Province, China
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He L, Zhang C, Liu LL, Huang LP, Lu WJ, Zhang YY, Zou DY, Wang YF, Zhang Q, Yang XL. Development of a diagnostic nomogram for alpha-fetoprotein-negative hepatocellular carcinoma based on serological biomarkers. World J Gastrointest Oncol 2024; 16:2463-2475. [PMID: 38994169 PMCID: PMC11236252 DOI: 10.4251/wjgo.v16.i6.2463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 02/12/2024] [Accepted: 04/01/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Serum biomarkers play an important role in the early diagnosis and prognosis of HCC. Because a certain percentage of HCC patients are negative for alpha-fetoprotein (AFP), the diagnosis of AFP-negative HCC is essential to improve the detection rate of HCC. AIM To establish an effective model for diagnosing AFP-negative HCC based on serum tumour biomarkers. METHODS A total of 180 HCC patients were enrolled in this study. The expression levels of GP73, des-γ-carboxyprothrombin (DCP), CK18-M65, and CK18-M30 were detected by a fully automated chemiluminescence analyser. The variables were selected by logistic regression analysis. Several models were constructed using stepwise backward logistic regression. The performance of the models was compared using the C statistic, integrated discrimination improvement, net reclassification improvement, and calibration curves. The clinical utility of the nomogram was assessed using decision curve analysis (DCA). RESULTS The results showed that the expression levels of GP73, DCP, CK18-M65, and CK18-M30 were significantly greater in AFP-negative HCC patients than in healthy controls (P < 0.001). Multivariate logistic regression analysis revealed that GP73, DCP, and CK18-M65 were independent factors for diagnosing AFP-negative HCC. By comparing the diagnostic performance of multiple models, we included GP73 and CK18-M65 as the model variables, and the model had good discrimination ability (area under the curve = 0.946) and good goodness of fit. The DCA curves indicated the good clinical utility of the nomogram. CONCLUSION Our study identified GP73 and CK18-M65 as serum biomarkers with certain application value in the diagnosis of AFP-negative HCC. The diagnostic nomogram based on CK18-M65 combined with GP73 demonstrated good performance and effectively identified high-risk groups of patients with HCC.
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Affiliation(s)
- Li He
- School of Clinical Medicine, Weifang Medical University, Weifang 261053, Shandong Province, China
- Department of Organ Transplantation, The Third Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
| | - Cui Zhang
- Department of Laboratory Medicine, The Third Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
| | - Lan-Lan Liu
- Department of Laboratory Medicine, The Third Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
| | - Li-Ping Huang
- Department of Laboratory Medicine, Jingyu County People’s Hospital, Baishan 135200, Jilin Province, China
| | - Wen-Jing Lu
- Department of Laboratory Medicine, The Third Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
| | - Yuan-Yuan Zhang
- Department of Laboratory Medicine, The Third Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
| | - De-Yong Zou
- Department of Laboratory Medicine, The Third Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
| | - Yu-Fei Wang
- Department of Laboratory Medicine, The Third Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
| | - Qing Zhang
- School of Clinical Medicine, Weifang Medical University, Weifang 261053, Shandong Province, China
- Department of Organ Transplantation, The Third Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
| | - Xiao-Li Yang
- Department of Laboratory Medicine, The Third Medical Centre of Chinese PLA General Hospital, Beijing 100039, China
- School of Laboratory Medicine, Weifang Medical University, Weifang 261053, Shandong Province, China
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Panettieri E, Campisi A, De Rose AM, Mele C, Giuliante F, Vauthey JN, Ardito F. Emerging Prognostic Markers in Patients Undergoing Liver Resection for Hepatocellular Carcinoma: A Narrative Review. Cancers (Basel) 2024; 16:2183. [PMID: 38927889 PMCID: PMC11201456 DOI: 10.3390/cancers16122183] [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: 03/12/2024] [Revised: 05/27/2024] [Accepted: 05/27/2024] [Indexed: 06/28/2024] Open
Abstract
In patients with hepatocellular carcinoma (HCC), liver resection is potentially curative. Nevertheless, post-operative recurrence is common, occurring in up to 70% of patients. Factors traditionally recognized to predict recurrence and survival after liver resection for HCC include pathologic factors (i.e., microvascular and capsular invasion) and an increase in alpha-fetoprotein level. During the past decade, many new markers have been reported to correlate with prognosis after resection of HCC: liquid biopsy markers, gene signatures, inflammation markers, and other biomarkers, including PIVKA-II, immune checkpoint molecules, and proteins in urinary exosomes. However, not all of these new markers are readily available in clinical practice, and their reproducibility is unclear. Liquid biopsy is a powerful and established tool for predicting long-term outcomes after resection of HCC; the main limitation of liquid biopsy is represented by the cost related to its technical implementation. Numerous patterns of genetic expression capable of predicting survival after curative-intent hepatectomy for HCC have been identified, but published findings regarding these markers are heterogenous. Inflammation markers in the form of prognostic nutritional index and different blood cell ratios seem more easily reproducible and more affordable on a large scale than other emerging markers. To select the most effective treatment for patients with HCC, it is crucial that the scientific community validate new predictive markers for recurrence and survival after resection that are reliable and widely reproducible. More reports from Western countries are necessary to corroborate the evidence.
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Affiliation(s)
- Elena Panettieri
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Andrea Campisi
- Hepatobiliary Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (A.C.); (A.M.D.R.); (C.M.); (F.G.); (F.A.)
| | - Agostino M. De Rose
- Hepatobiliary Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (A.C.); (A.M.D.R.); (C.M.); (F.G.); (F.A.)
| | - Caterina Mele
- Hepatobiliary Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (A.C.); (A.M.D.R.); (C.M.); (F.G.); (F.A.)
| | - Felice Giuliante
- Hepatobiliary Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (A.C.); (A.M.D.R.); (C.M.); (F.G.); (F.A.)
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Francesco Ardito
- Hepatobiliary Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (A.C.); (A.M.D.R.); (C.M.); (F.G.); (F.A.)
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Chen G, Zhang G, Zhu Y, Wu A, Fang J, Yin Z, Chen H, Cao K. Identifying disulfidptosis subtypes in hepatocellular carcinoma through machine learning and preliminary exploration of its connection with immunotherapy. Cancer Cell Int 2024; 24:194. [PMID: 38831301 PMCID: PMC11149214 DOI: 10.1186/s12935-024-03387-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 05/25/2024] [Indexed: 06/05/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a highly prevalent and deadly cancer, with limited treatment options for advanced-stage patients. Disulfidptosis is a recently identified mechanism of programmed cell death that occurs in SLC7A11 high-expressing cells due to glucose starvation-induced disintegration of the cellular disulfide skeleton. We aimed to explore the potential of disulfidptosis, as a prognostic and therapeutic marker in HCC. METHODS We classified HCC patients into two disulfidptosis subtypes (C1 and C2) based on the transcriptional profiles of 31 disulfrgs using a non-negative matrix factorization (NMF) algorithm. Further, five genes (NEIL3, MMP1, STC2, ADH4 and CFHR3) were screened by Cox regression analysis and machine learning algorithm to construct a disulfidptosis scoring system (disulfS). Cell proliferation assay, F-actin staining and PBMC co-culture model were used to validate that disulfidptosis occurs in HCC and correlates with immunotherapy response. RESULTS Our results suggests that the low disulfidptosis subtype (C2) demonstrated better overall survival (OS) and progression-free survival (PFS) prognosis, along with lower levels of immunosuppressive cell infiltration and activation of the glycine/serine/threonine metabolic pathway. Additionally, the low disulfidptosis group showed better responses to immunotherapy and potential antagonism with sorafenib treatment. As a total survival risk factor, disulfS demonstrated high predictive efficacy in multiple validation cohorts. We demonstrated the presence of disulfidptosis in HCC cells and its possible relevance to immunotherapeutic sensitization. CONCLUSION The present study indicates that novel biomarkers related to disulfidptosis may serve as useful clinical diagnostic indicators for liver cancer, enabling the prediction of prognosis and identification of potential treatment targets.
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Affiliation(s)
- Guanjun Chen
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Ganghua Zhang
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Yuxing Zhu
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Anshan Wu
- Department of Oncology,, Zhuzhou Hospital Xiangya School of Medicine, Zhuzhou, 412000, China
| | - Jianing Fang
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Zhijing Yin
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Haotian Chen
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Ke Cao
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, 410013, China.
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Wu Q, Fan C, Liu K, Tang J. GDF11 inhibits the malignant progression of hepatocellular carcinoma via regulation of the mTORC1‑autophagy axis. Exp Ther Med 2024; 27:252. [PMID: 38682112 PMCID: PMC11046183 DOI: 10.3892/etm.2024.12540] [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: 10/07/2023] [Accepted: 02/19/2024] [Indexed: 05/01/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignant tumor, which is associated with a poor prognosis and high mortality rate. It is well known that growth differentiation factor 11 (GDF11) acts as a tumor suppressor in various types of cancer, including HCC. The present study aimed to determine the tumor-suppressive properties of GDF11 in HCC and to assess the intrinsic mechanisms. In the present study, the human hepatoma cell line Huh-7 was transfected with the GDF11 overexpression plasmid (Oe-GDF11) for gain-of-function experiments to investigate the effects of GDF11 on the biological behaviors of HCC cells, including proliferation, colony formation, apoptosis, cell cycle arrest, migration, invasion, epithelial-mesenchymal transition (EMT) and angiogenesis. The proliferation, colony formation, apoptosis, cell cycle, migration, invasion and angiogenesis of HCC cells were assessed by CCK-8, EdU staining, colony formation, flow cytometry, wound healing, Transwell and tube formation assays, respectively. Apoptosis-, cell cycle-, EMT-related key factors were also determined by western blot assay. Furthermore, Oe-GDF11-transfected Huh-7 cells were treated with the mammalian target of rapamycin (mTOR) activator MHY1485 for rescue experiments to explore whether GDF11 could exert antitumor effects against HCC via mediating the mTOR complex 1 (mTORC1)-autophagy axis. In the present study, GDF11 was verified to be lowly expressed in HCC cells. Overexpression of GDF11 inhibited the proliferation, colony formation, migration, invasion, EMT and angiogenesis of HCC cells, and facilitated the apoptosis and cell cycle arrest of HCC cells. Additionally, it was verified that overexpression of GDF11 inactivated the mTORC1 signaling pathway to enhance autophagy in HCC cells. Treatment with the mTOR activator MHY1485 partially reversed the tumor-suppressive effects of GDF11 overexpression on HCC. In conclusion, GDF11 may exert tumor-suppressive properties in HCC cells through inactivating the mTORC1 signaling pathway to strengthen autophagy.
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Affiliation(s)
- Qingyi Wu
- School of Public Health and Laboratory Medicine, Hunan University of Medicine, Huaihua, Hunan 418000, P.R. China
| | - Chan Fan
- School of Public Health and Laboratory Medicine, Hunan University of Medicine, Huaihua, Hunan 418000, P.R. China
| | - Kebo Liu
- Department of Neurosurgery, Hunan University of Medicine General Hospital, Huaihua, Hunan 418000, P.R. China
| | - Jiefu Tang
- Spine and Spinal Cord Center, The First Affiliated Hospital of Hunan University of Medicine, Huaihua, Hunan 418000, P.R. China
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Wu WK, Patel K, Padmanabhan C, Idrees K. Hepatocellular carcinoma presenting as an extrahepatic mass: A case report and review of literature. World J Gastrointest Oncol 2024; 16:2241-2252. [PMID: 38764834 PMCID: PMC11099426 DOI: 10.4251/wjgo.v16.i5.2241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 02/03/2024] [Accepted: 03/20/2024] [Indexed: 05/09/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a primary liver tumor generally diagnosed based on radiographic findings. Metastatic disease is typically associated with increased tumor diameter, multifocality, and vascular invasion. We report a case of a patient who presented with extrahepatic HCC metastasis to a portocaval lymph node with occult hepatic primary on computed tomography (CT). We review the literature for cases of extrahepatic HCC presentation without known hepatic lesions and discuss strategies to differentiate between metastatic and ectopic HCC. CASE SUMMARY A 67-year-old male with remotely treated hepatis C was referred for evaluation of an enlarging portocaval, mixed cystic-solid mass. Serial CT evaluations demonstrated steatosis, but no cirrhosis or liver lesions. Endoscopic ultrasound demonstrated a normal-appearing pancreas, biliary tree, and liver. Fine needle aspiration yielded atypical cells. The differential diagnosis included duodenal or pancreatic cyst, lymphoproliferative cyst, stromal or mesenchymal lesions, nodal involvement from gastrointestinal or hematologic malignancy, or duodenal gastro-intestinal stromal tumor. After review by a multidisciplinary tumor board, the patient underwent open surgical resection of a 5.2 cm × 5.5 cm retroperitoneal mass with pathology consistent with moderately-differentiated HCC. Magnetic resonance imaging (MRI) subsequently demonstrated a 1.2 cm segment VIII hepatic lesion with late arterial enhancement, fatty sparing, and intrinsic T1 hyperintensity. Alpha fetoprotein was 23.3 ng/mL. The patient was diagnosed with HCC with portocaval nodal involvement. Review: We surveyed the literature for HCC presenting as extrahepatic masses without history of concurrent or prior intrahepatic HCC. We identified 18 cases of extrahepatic HCC ultimately found to represent metastatic lesions, and 30 cases of extrahepatic HCC found to be primary, ectopic HCC. CONCLUSION Hepatocellular carcinoma can seldomly present with extrahepatic metastasis in the setting of occult primary. In patients with risk factors for HCC and lesions suspicious for metastatic disease, MRI may be integral to identifying small hepatic lesions and differentiating from ectopic HCC. Tumor markers may also have utility in establishing the diagnosis.
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Affiliation(s)
- Wei Kelly Wu
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, United States
| | - Krutika Patel
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, United States
| | - Chandrasekhar Padmanabhan
- Division of Surgical Oncology and Endocrine Surgery, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, United States
| | - Kamran Idrees
- Division of Surgical Oncology and Endocrine Surgery, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, United States
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Sadler L, Jones H, Whiting P, Rogers M, Watt K, Cramp M, Ryder S, Stein K, Welton N, Oppe F, Bell J, Rogers G. Diagnostic accuracy of serological and imaging tests used in surveillance for hepatocellular carcinoma in adults with cirrhosis: a systematic review protocol. NIHR OPEN RESEARCH 2024; 3:23. [PMID: 39139275 PMCID: PMC11320044 DOI: 10.3310/nihropenres.13409.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/13/2024] [Indexed: 08/15/2024]
Abstract
Background Liver cirrhosis is the largest risk factor for developing hepatocellular carcinoma (HCC), and surveillance is therefore recommended among this population. Current guidance recommends surveillance with ultrasound, with or without alpha-fetoprotein (AFP). This review is part of a larger project looking at benefits, harms and costs of surveillance for HCC in people with cirrhosis. It aims to synthesise the evidence on the diagnostic accuracy of imaging or biomarker tests, alone or in combination, to identify HCC in adults with liver cirrhosis in a surveillance programme. Methods We will identify studies through a 2021 Cochrane review with similar eligibility criteria, and a database search of MEDLINE, Embase and the Cochrane Database of Systematic Reviews. We will include diagnostic test accuracy studies with adult cirrhosis patients of any aetiology. Studies must assess at least one of the following index tests: ultrasound (US), magnetic resonance imaging (MRI), computerised tomography (CT), alpha-fetoprotein (AFP), des-gamma-carboxyprothrombin (DCP), lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), a genomic biomarker, or a diagnostic prediction model incorporating at least one of the above-mentioned tests. We will assess studies for risk of bias using QUADAS-2 and QUADAS-C. We will combine data using bivariate random effects meta-analyses. For tests evaluated across varying diagnostic thresholds, we will produce pooled estimates of sensitivity and specificity across the full range of numerical thresholds, where possible. Where sufficient studies compare two or more index tests, we will perform additional analyses to compare the accuracy of different tests. Where feasible, we will stratify all meta-analyses by tumour size and patient characteristics, including cirrhosis aetiology and liver disease severity. Discussion This review will synthesise evidence across the full range of possible surveillance tests, using advanced statistical methods to summarise accuracy across all thresholds and to compare the accuracy of different tests. PROSPERO registration CRD42022357163.
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Affiliation(s)
- Libby Sadler
- Population Health Sciences, University of Bristol, Bristol, England, UK
| | - Hayley Jones
- Population Health Sciences, University of Bristol, Bristol, England, UK
| | - Penny Whiting
- Population Health Sciences, University of Bristol, Bristol, England, UK
| | | | - Kelsey Watt
- Radiology Department, Nevill Hall Hospital, Abergavenny, Wales, UK
| | - Matthew Cramp
- Peninsula Medical School, University of Plymouth, Plymouth, England, UK
| | - Stephen Ryder
- Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Ken Stein
- Medical School, University of Exeter, Exeter, England, UK
| | - Nicky Welton
- Population Health Sciences, University of Bristol, Bristol, England, UK
| | - Felicity Oppe
- Patient and Public Involvement, NIHR Nottingham Biomedical Research Centre, Nottingham, UK
| | - John Bell
- Patient and Public Involvement, NIHR Nottingham Biomedical Research Centre, Nottingham, UK
| | - Gabriel Rogers
- Manchester Centre for Health Economics, The University of Manchester, Manchester, England, N13 NPL, UK
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Guo DZ, Huang A, Wang YC, Zhou S, Wang H, Xing XL, Zhang SY, Cheng JW, Xie KH, Yang QC, Ma CC, Li Q, Chen Y, Su ZX, Fan J, Liu R, Liu XL, Zhou J, Yang XR. Early detection and prognosis evaluation for hepatocellular carcinoma by circulating tumour DNA methylation: A multicentre cohort study. Clin Transl Med 2024; 14:e1652. [PMID: 38741204 DOI: 10.1002/ctm2.1652] [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: 01/27/2024] [Revised: 03/07/2024] [Accepted: 03/21/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Early diagnosis of hepatocellular carcinoma (HCC) can significantly improve patient survival. We aimed to develop a blood-based assay to aid in the diagnosis, detection and prognostic evaluation of HCC. METHODS A three-phase multicentre study was conducted to screen, optimise and validate HCC-specific differentially methylated regions (DMRs) using next-generation sequencing and quantitative methylation-specific PCR (qMSP). RESULTS Genome-wide methylation profiling was conducted to identify DMRs distinguishing HCC tumours from peritumoural tissues and healthy plasmas. The twenty most effective DMRs were verified and incorporated into a multilocus qMSP assay (HepaAiQ). The HepaAiQ model was trained to separate 293 HCC patients (Barcelona Clinic Liver Cancer (BCLC) stage 0/A, 224) from 266 controls including chronic hepatitis B (CHB) or liver cirrhosis (LC) (CHB/LC, 96), benign hepatic lesions (BHL, 23), and healthy controls (HC, 147). The model achieved an area under the curve (AUC) of 0.944 with a sensitivity of 86.0% in HCC and a specificity of 92.1% in controls. Blind validation of the HepaAiQ model in a cohort of 523 participants resulted in an AUC of 0.940 with a sensitivity of 84.4% in 205 HCC cases (BCLC stage 0/A, 167) and a specificity of 90.3% in 318 controls (CHB/LC, 100; BHL, 102; HC, 116). When evaluated in an independent test set, the HepaAiQ model exhibited a sensitivity of 70.8% in 65 HCC patients at BCLC stage 0/A and a specificity of 89.5% in 124 patients with CHB/LC. Moreover, HepaAiQ model was assessed in paired pre- and postoperative plasma samples from 103 HCC patients and correlated with 2-year patient outcomes. Patients with high postoperative HepaAiQ score showed a higher recurrence risk (Hazard ratio, 3.33, p < .001). CONCLUSIONS HepaAiQ, a noninvasive qMSP assay, was developed to accurately measure HCC-specific DMRs and shows great potential for the diagnosis, detection and prognosis of HCC, benefiting at-risk populations.
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Affiliation(s)
- De-Zhen Guo
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Ao Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Ying-Chao Wang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
| | | | - Hui Wang
- Singlera Genomics Ltd., Shanghai, China
| | - Xiang-Lei Xing
- Biliary Tract Surgery Department IV, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Shi-Yu Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Jian-Wen Cheng
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | | | | | | | - Qing Li
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yan Chen
- XiangYa Medical Laboratory, Central South University, Changsha, Hunan, China
| | - Zhi-Xi Su
- Singlera Genomics Ltd., Shanghai, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Rui Liu
- Singlera Genomics Ltd., Shanghai, China
| | - Xiao-Long Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Xin-Rong Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
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Zou Y, Zhu J, Song C, Li T, Wang K, Shi J, Ye H, Wang P. A polygenetic risk score combined with environmental factors better predict susceptibility to hepatocellular carcinoma in Chinese population. Cancer Med 2024; 13:e7230. [PMID: 38698686 PMCID: PMC11066500 DOI: 10.1002/cam4.7230] [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: 01/09/2024] [Revised: 04/11/2024] [Accepted: 04/18/2024] [Indexed: 05/05/2024] Open
Abstract
AIMS This study aimed to investigate environmental factors and genetic variant loci associated with hepatocellular carcinoma (HCC) in Chinese population and construct a weighted genetic risk score (wGRS) and polygenic risk score (PRS). METHODS A case-control study was applied to confirm the single nucleotide polymorphisms (SNPs) and environmental variables linked to HCC in the Chinese population, which had been screened by meta-analyses. wGRS and PRS were built in training sets and validation sets. Area under the curve (AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), Akaike information criterion (AIC), and Bayesian information criterion (BIC) were applied to evaluate the performance of the models. RESULTS A total of 13 SNPs were included in both risk prediction models. Compared with wGRS, PRS had better accuracy and discrimination ability in predicting HCC risk. The AUC for PRS in combination with drinking history, cirrhosis, HBV infection, and family history of HCC in training sets and validation sets (AUC: 0.86, 95% CI: 0.84-0.89; AUC: 0.85, 95% CI: 0.81-0.89) increased at least 20% than the AUC for PRS alone (AUC: 0.63, 95% CI: 0.60-0.67; AUC: 0.65, 95% CI: 0.60-0.71). CONCLUSIONS A novel model combining PRS with alcohol history, HBV infection, cirrhosis, and family history of HCC could be applied as an effective tool for risk prediction of HCC, which could discriminate at-risk individuals for precise prevention.
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Affiliation(s)
- Yuanlin Zou
- Department of Epidemiology and Statistics, College of Public HealthZhengzhou UniversityZhengzhouHenan ProvinceChina
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & TreatmentZhengzhou UniversityZhengzhouHenan ProvinceChina
| | - Jicun Zhu
- Department of PharmacyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina
| | - Caijuan Song
- The Institution for Chronic and Noncommunicable Disease Control and PreventionZhengzhou Center for Disease Control and PreventionZhengzhouHenan ProvinceChina
| | - Tiandong Li
- Department of Epidemiology and Statistics, College of Public HealthZhengzhou UniversityZhengzhouHenan ProvinceChina
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & TreatmentZhengzhou UniversityZhengzhouHenan ProvinceChina
| | - Keyan Wang
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & TreatmentZhengzhou UniversityZhengzhouHenan ProvinceChina
- Henan Institute of Medical and Pharmaceutical SciencesZhengzhou UniversityZhengzhouHenan ProvinceChina
| | - Jianxiang Shi
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & TreatmentZhengzhou UniversityZhengzhouHenan ProvinceChina
- Henan Institute of Medical and Pharmaceutical SciencesZhengzhou UniversityZhengzhouHenan ProvinceChina
| | - Hua Ye
- Department of Epidemiology and Statistics, College of Public HealthZhengzhou UniversityZhengzhouHenan ProvinceChina
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & TreatmentZhengzhou UniversityZhengzhouHenan ProvinceChina
| | - Peng Wang
- Department of Epidemiology and Statistics, College of Public HealthZhengzhou UniversityZhengzhouHenan ProvinceChina
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & TreatmentZhengzhou UniversityZhengzhouHenan ProvinceChina
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Mazza S, Frigerio C, Alfieri D, Mauro A, Torello Viera F, Scalvini D, Barteselli C, Sgarlata C, Veronese L, Bardone M, Rovedatti L, Agazzi S, Strada E, Pozzi L, Maestri M, Ravetta V, Anderloni A. Prognostic Role of Basal Serum Alpha-Fetoprotein in Patients with Hepatocellular Carcinoma Suitable for Curative Treatment. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:692. [PMID: 38792876 PMCID: PMC11123130 DOI: 10.3390/medicina60050692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 04/07/2024] [Accepted: 04/20/2024] [Indexed: 05/26/2024]
Abstract
Background and Objectives: Serum alpha-fetoprotein (AFP) is a recognized affordable oncological marker in patients with hepatocellular carcinoma (HCC). However, AFP's prognostic role has been assessed mainly after specific treatments, and no unanimously recognized cut-offs have been identified. The aim of this study is to investigate the prognostic role of different basal AFP cut-offs on survival and HCC course. Materials and Methods: In this single-center, retrospective study, all patients newly diagnosed with HCC between January 2009 and December 2021 were prospectively enrolled. Only patients suitable for curative HCC treatments were included in the analyses. Patients were stratified according to AFP cut-offs of 20, 200, 400, and 1000 ng/mL, which were correlated with survival outcomes and clinical parameters. Results: A total of 266 patients were analyzed, with a median follow-up time of 41.5 months. Median overall survival (OS) of all cohort was 43 months. At the multivariate Cox-regression analysis, AFP value ≥ 1000 ng/mL correlated with impaired OS (1-year OS: 67% vs. 88%, 5-year OS: 1% vs. 43%; p = 0.005); other risk factors were tumor dimension ≥ 5 cm (HR 1.73; p = 0.002), Child-Pugh class B-C (HR 1.72; p = 0.002), BCLC stage A (vs. 0) (HR 2.4; p = 0.011), and malignant portal vein thrombosis (HR 2.57; p = 0.007). AFP ≥ 1000 ng/mL was also associated with a reduced recurrence-free survival (HR 2.0; p = 0.038), while starting from AFP ≥ 20 ng/mL, a correlation with development of HCC metastases over time (HR 3.5; p = 0.002) was seen. AFP values ≥ 20 ng/mL significantly correlated with tumor size and higher histological grading; starting from AFP values ≥ 400 ng/mL, a significant correlation with Child-Pugh class B-C and female gender was also observed. Conclusions: Basal AFP correlates with relevant outcomes in patients with HCC. It could help identify patients at a higher risk of worse prognosis who might benefit from personalized surveillance and treatment programs. Prospective studies are needed to confirm these results.
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Affiliation(s)
- Stefano Mazza
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Chiara Frigerio
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Daniele Alfieri
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Aurelio Mauro
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Francesca Torello Viera
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Davide Scalvini
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Chiara Barteselli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Carmelo Sgarlata
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Letizia Veronese
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Marco Bardone
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Laura Rovedatti
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Simona Agazzi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Elena Strada
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Lodovica Pozzi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Marcello Maestri
- General Surgery I, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Valentina Ravetta
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Andrea Anderloni
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
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Ross-Driscoll K, Ayuk-Arrey AT, Lynch R, McCullough LE, Roccaro G, Nephew L, Hundley J, Rubin RA, Patzer R. Disparities in Access to Liver Transplant Referral and Evaluation among Patients with Hepatocellular Carcinoma in Georgia. CANCER RESEARCH COMMUNICATIONS 2024; 4:1111-1119. [PMID: 38517133 PMCID: PMC11034460 DOI: 10.1158/2767-9764.crc-23-0541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/16/2024] [Accepted: 03/15/2024] [Indexed: 03/23/2024]
Abstract
Liver transplantation offers the best survival for patients with early-stage hepatocellular carcinoma (HCC). Prior studies have demonstrated disparities in transplant access; none have examined the early steps of the transplant process. We identified determinants of access to transplant referral and evaluation among patients with HCC with a single tumor either within Milan or meeting downstaging criteria in Georgia.Population-based cancer registry data from 2010 to 2019 were linked to liver transplant centers in Georgia. Primary cohort: adult patients with HCC with a single tumor ≤8 cm in diameter, no extrahepatic involvement, and no vascular involvement. Secondary cohort: primary cohort plus patients with multiple tumors confined to one lobe. We estimated time to transplant referral, evaluation initiation, and evaluation completion, accounting for the competing risk of death. In sensitivity analyses, we also accounted for non-transplant cancer treatment.Among 1,379 patients with early-stage HCC in Georgia, 26% were referred to liver transplant. Private insurance and younger age were associated with increased likelihood of referral, while requiring downstaging was associated with lower likelihood of referral. Patients living in census tracts with ≥20% of residents in poverty were less likely to initiate evaluation among those referred [cause-specific hazard ratio (csHR): 0.62, 95% confidence interval (CI): 0.42-0.94]. Medicaid patients were less likely to complete the evaluation once initiated (csHR: 0.53, 95% CI: 0.32-0.89).Different sociodemographic factors were associated with each stage of the transplant process among patients with early-stage HCC in Georgia, emphasizing unique barriers to access and the need for targeted interventions at each step. SIGNIFICANCE Among patients with early-stage HCC in Georgia, age and insurance type were associated with referral to liver transplant, race, and poverty with evaluation initiation, and insurance type with evaluation completion. Opportunities to improve transplant access include informing referring providers about insurance requirements, addressing barriers to evaluation initiation, and streamlining the evaluation process.
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Affiliation(s)
- Katherine Ross-Driscoll
- Division of Transplantation, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
- Center for Health Services Research, Regenstrief Institute, Indianapolis, Indiana
- Department of Epidemiology, Rollins School of Public Health, Atlanta, Georgia
| | | | - Raymond Lynch
- Division of Transplantation, Department of Surgery, Pennsylvania State University School of Medicine, Hershey, Pennsylvania
| | - Lauren E. McCullough
- Department of Epidemiology, Rollins School of Public Health, Atlanta, Georgia
- Winship Cancer Institute, Emory University, Atlanta, Georgia
| | - Giorgio Roccaro
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Lauren Nephew
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, Indiana
| | - Jonathan Hundley
- Piedmont Transplant Institute, Piedmont Healthcare, Atlanta, Georgia
| | - Raymond A. Rubin
- Piedmont Transplant Institute, Piedmont Healthcare, Atlanta, Georgia
| | - Rachel Patzer
- Division of Transplantation, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
- Regenstrief Institute, Indianapolis, Indiana
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Xu J, Zhao Y, Chen Z, Wei L. Clinical Application of Different Liquid Biopsy Components in Hepatocellular Carcinoma. J Pers Med 2024; 14:420. [PMID: 38673047 PMCID: PMC11051574 DOI: 10.3390/jpm14040420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 03/26/2024] [Accepted: 04/04/2024] [Indexed: 04/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, usually occurring in the background of chronic liver disease. HCC lethality rate is in the third highest place in the world. Patients with HCC have concealed early symptoms and possess a high-level of heterogeneity. Once diagnosed, most of the tumors are in advanced stages and have a poor prognosis. The sensitivity and specificity of existing detection modalities and protocols are suboptimal. HCC calls for more sophisticated and individualized therapeutic regimens. Liquid biopsy is non-invasive, repeatable, unaffected by location, and can be monitored dynamically. It has emerged as a useable aid in achieving precision malignant tumor treatment. Circulating tumor cells (CTCs), circulating nucleic acids, exosomes and tumor-educated platelets are the commonest components of a liquid biopsy. It possesses the theoretical ability to conquer the high heterogeneity and the difficulty of early detection for HCC patients. In this review, we summarize the common enrichment techniques and the clinical applications in HCC for different liquid biopsy components. Tumor recurrence after HCC-related liver transplantation is more insidious and difficult to treat. The clinical use of liquid biopsy in HCC-related liver transplantation is also summarized in this review.
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Affiliation(s)
| | | | | | - Lai Wei
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China; (J.X.); (Y.Z.); (Z.C.)
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Ramos-Santillan V, Oshi M, Nelson E, Endo I, Takabe K. High Ki67 Gene Expression Is Associated With Aggressive Phenotype in Hepatocellular Carcinoma. World J Oncol 2024; 15:257-267. [PMID: 38545476 PMCID: PMC10965267 DOI: 10.14740/wjon1751] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Accepted: 12/20/2023] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) with high Ki67 protein expression, the most commonly used cell proliferation marker, is associated with an aggressive biologic phenotype; however, conventional immunostaining is hampered by variability in institutional protocol, specific antibody probe, and by assessor subjectivity. To this end, we hypothesized that Ki67 gene (MKi67) expression would identify highly proliferative HCC, and clarify its association with oncologic outcome, tumor progression, and immune cell population in the tumor microenvironment (TME). Furthermore, we sought to identify the cell-cycle gene expression profile that confers this aggressive phenotype. METHODS A total of 473 HCC patients with clinicopathological data associated with transcriptome were selected for this study: 358 patients from The Cancer Genome Atlas (TCGA) as the testing cohort, and 115 from GSE76427 as the validation cohort. Each cohort was divided into a highly proliferative group (MKi67-high) and the low MKi67 group (MKi67-low) by the median of Ki67 gene (MKi67) expression levels. RESULTS MKi67-high HCC patients had worse disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS) independent of histological grade in the TCGA cohort. MKi67 expression correlated with histological grade and tumor size. MKi67 expression increased throughout the HCC carcinomatous sequence from normal liver, cirrhotic liver, early HCC, and advanced HCC. MKi67-high HCC was associated with higher intratumor heterogeneity, homologous recombination deficiency, and altered fraction as well as intratumoral infiltration of T helper type 1 (Th1) and Th2 cells, but lower interferon-gamma response and M2 macrophage infiltration. Cell proliferation-related gene sets in the Hallmark collection (E2F targets, G2M checkpoint, Myc target v1 and mitotic spindle), MTORC1 signaling, DNA repair, PI3K MTOR signaling, and unfolded protein response were all enriched in the MKi67-high HCC (false discovery rate (FDR) < 0.25). CONCLUSIONS High MKi67 gene expression identified highly proliferative HCC with aggressive biology involving classical pathways in cell cycle regulation and DNA repair, as well as poor overall oncologic outcomes. This suggests potential for personalized treatment strategies, but validation and refinement of these observations require further research to elucidate the underlying mechanisms and validate therapeutic targeting of these pathways in MKi67-high HCC tumors.
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Affiliation(s)
- Vicente Ramos-Santillan
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- These authors contributed equally to this work
| | - Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Surgery, Yokohama City University, Yokohama, Japan
- These authors contributed equally to this work
| | - Erek Nelson
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Itaru Endo
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Surgery, Yokohama City University, Yokohama, Japan
- Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, VA, USA
- Department of Surgery, University at Buffalo Jacob School of Medicine and Biomedical Sciences, the State University of New York, Buffalo, NY, USA
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
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Li ZC, Wang J, Liu HB, Zheng YM, Huang JH, Cai JB, Zhang L, Liu X, Du L, Yang XT, Chai XQ, Jiang YH, Ren ZG, Zhou J, Fan J, Yu DC, Sun HC, Huang C, Liu F. Proteomic and metabolomic features in patients with HCC responding to lenvatinib and anti-PD1 therapy. Cell Rep 2024; 43:113877. [PMID: 38421869 DOI: 10.1016/j.celrep.2024.113877] [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: 06/07/2023] [Revised: 12/16/2023] [Accepted: 02/13/2024] [Indexed: 03/02/2024] Open
Abstract
Combination therapy (lenvatinib/programmed death-1 inhibitor) is effective for treating unresectable hepatocellular carcinoma (uHCC). We reveal that responders have better overall and progression-free survival, as well as high tumor mutation burden and special somatic variants. We analyze the proteome and metabolome of 82 plasma samples from patients with hepatocellular carcinoma (HCC; n = 51) and normal controls (n = 15), revealing that individual differences outweigh treatment differences. Responders exhibit enhanced activity in the alternative/lectin complement pathway and higher levels of lysophosphatidylcholines (LysoPCs), predicting a favorable prognosis. Non-responders are enriched for immunoglobulins, predicting worse outcomes. Compared to normal controls, HCC plasma proteins show acute inflammatory response and platelet activation, while LysoPCs decrease. Combination therapy increases LysoPCs/phosphocholines in responders. Logistic regression/random forest models using metabolomic features achieve good performance in the prediction of responders. Proteomic analysis of cancer tissues unveils molecular features that are associated with side effects in responders receiving combination therapy. In conclusion, our analysis identifies plasma features associated with uHCC responders to combination therapy.
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Affiliation(s)
- Zhong-Chen Li
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China; Department of Hepatic Oncology, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China; Minhang Hospital, Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical of Sciences, Fudan University, 131 DongAn Road, Shanghai 200032, China
| | - He-Bin Liu
- Shanghai Omicsolution Co., Ltd., 28 Yuanwen Road, Shanghai 201199, China
| | - Yi-Min Zheng
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China
| | - Jian-Hang Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China; Minhang Hospital, Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical of Sciences, Fudan University, 131 DongAn Road, Shanghai 200032, China
| | - Jia-Bin Cai
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China
| | - Lei Zhang
- Institutes of Biomedical of Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China
| | - Xin Liu
- Department of Central Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Road, Shanghai 200071, China
| | - Ling Du
- Minhang Hospital, Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical of Sciences, Fudan University, 131 DongAn Road, Shanghai 200032, China
| | - Xue-Ting Yang
- Minhang Hospital, Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical of Sciences, Fudan University, 131 DongAn Road, Shanghai 200032, China
| | - Xiao-Qiang Chai
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China
| | - Ying-Hua Jiang
- Minhang Hospital, Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical of Sciences, Fudan University, 131 DongAn Road, Shanghai 200032, China
| | - Zheng-Gang Ren
- Department of Hepatic Oncology, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China
| | - De-Cai Yu
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China.
| | - Hui-Chuan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China.
| | - Cheng Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China.
| | - Feng Liu
- Minhang Hospital, Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical of Sciences, Fudan University, 131 DongAn Road, Shanghai 200032, China.
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Bracco C, Gallarate M, Badinella Martini M, Magnino C, D'Agnano S, Canta R, Racca G, Melchio R, Serraino C, Polla Mattiot V, Gollè G, Fenoglio L. Epidemiology, therapy and outcome of hepatocellular carcinoma between 2010 and 2019 in Piedmont, Italy. World J Gastrointest Oncol 2024; 16:761-772. [PMID: 38577451 PMCID: PMC10989369 DOI: 10.4251/wjgo.v16.i3.761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/19/2023] [Accepted: 12/28/2023] [Indexed: 03/12/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the second leading cause of cancer deaths worldwide. It is often diagnosed at an advanced stage and therefore its prognosis remains poor with a low 5-year survival rate. HCC patients have increasingly complex and constantly changing characteristics, thus up-to-date and comprehensive data are fundamental.
AIM To analyze the epidemiology and main clinical characteristics of HCC patients in a referral center hospital in the northwest of Italy between 2010 and 2019.
METHODS In this retrospective study, we analyzed the clinical data of all consecutive patients with a new diagnosis of HCC recorded at "Santa Croce e Carle" Hospital in Cuneo (Italy) between 1 January 2010 and 31 December 2019. To highlight possible changes in HCC patterns over the 10-year period, we split the population into two 5-year groups, according to the diagnosis period (2010-2014 and 2015-2019).
RESULTS Of the 328 HCC patients who were included (M/F 255/73; mean age 68.9 ± 11.3 years), 154 in the first period, and 174 in the second. Hepatitis C virus infection was the most common HCC risk factor (41%, 135 patients). The alcoholic etiology rate was 18%, the hepatitis B virus infection etiology was 5%, and the non-viral/non-alcoholic etiology rate was 22%. The Child-Pugh score distribution of the patients was: class A 75%, class B 21% and class C 4%. The average Mayo end-stage liver disease score was 10.6 ± 3.7. A total of 55 patients (17%) were affected by portal vein thrombosis and 158 (48%) by portal hypertension. The average nodule size of the HCC was 4.6 ± 3.1 cm. A total of 204 patients (63%) had more than one nodule < 3, and 92% (305 patients) had a non-metastatic stage of the disease. The Barcelona Clinic Liver Cancer (BCLC) staging distribution of all patients was: 4% very early, 32% early, 23% intermediate, 34% advanced, and 7% terminal. Average survival rate was 1.6 ± 0.3 years. Only 20% of the patients underwent treatment. Age, presence of ascites, BCLC stage and therapy were predictors of a better prognosis (P < 0.01). A comparison of the two 5-year groups revealed a statistically significant difference only in global etiology (P < 0.05) and alpha-fetoprotein (AFP) levels (P < 0.01).
CONCLUSION In this study analyzing patients with a new diagnosis of HCC between 2010-2019, hepatitis C virus infection was the most common etiology. Most patients presented with an advanced stage disease and a poor prognosis. When comparing the two 5-year groups, we observed a statistically significant difference only in global etiology (P < 0.05) and AFP levels (P < 0.01).
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Affiliation(s)
- Christian Bracco
- Department of Internal Medicine, Santa Croce e Carle General Hospital, Cuneo 12100, Italy
| | - Marta Gallarate
- Department of Medical Sciences, "City of Health and Science" University Hospital, Torino 10100, Italy
| | | | - Corrado Magnino
- Department of Internal Medicine, Santa Croce e Carle General Hospital, Cuneo 12100, Italy
| | - Salvatore D'Agnano
- Department of Internal Medicine, Santa Croce e Carle General Hospital, Cuneo 12100, Italy
| | - Roberta Canta
- Department of Internal Medicine, Santa Croce e Carle General Hospital, Cuneo 12100, Italy
| | - Giulia Racca
- Department of Internal Medicine, Santa Croce e Carle General Hospital, Cuneo 12100, Italy
| | - Remo Melchio
- Department of Internal Medicine, Santa Croce e Carle General Hospital, Cuneo 12100, Italy
| | - Cristina Serraino
- Department of Internal Medicine, Santa Croce e Carle General Hospital, Cuneo 12100, Italy
| | | | - Giovanni Gollè
- Department of Internal Medicine, Santa Croce e Carle General Hospital, Cuneo 12100, Italy
| | - Luigi Fenoglio
- Department of Internal Medicine, Santa Croce e Carle General Hospital, Cuneo 12100, Italy
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Lin H, Li G, Delamarre A, Ahn SH, Zhang X, Kim BK, Liang LY, Lee HW, Wong GLH, Yuen PC, Chan HLY, Chan SL, Wong VWS, de Lédinghen V, Kim SU, Yip TCF. A Liver Stiffness-Based Etiology-Independent Machine Learning Algorithm to Predict Hepatocellular Carcinoma. Clin Gastroenterol Hepatol 2024; 22:602-610.e7. [PMID: 37993034 DOI: 10.1016/j.cgh.2023.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 10/30/2023] [Accepted: 11/01/2023] [Indexed: 11/24/2023]
Abstract
BACKGROUND & AIMS The existing hepatocellular carcinoma (HCC) risk scores have modest accuracy, and most are specific to chronic hepatitis B infection. In this study, we developed and validated a liver stiffness-based machine learning algorithm (ML) for prediction and risk stratification of HCC in various chronic liver diseases (CLDs). METHODS MLs were trained for prediction of HCC in 5155 adult patients with various CLDs in Korea and further tested in 2 prospective cohorts from Hong Kong (HK) (N = 2732) and Europe (N = 2384). Model performance was assessed according to Harrell's C-index and time-dependent receiver operating characteristic (ROC) curve. RESULTS We developed the SMART-HCC score, a liver stiffness-based ML HCC risk score, with liver stiffness measurement ranked as the most important among 9 clinical features. The Harrell's C-index of the SMART-HCC score in HK and Europe validation cohorts were 0.89 (95% confidence interval, 0.85-0.92) and 0.91 (95% confidence interval, 0.87-0.95), respectively. The area under ROC curves of the SMART-HCC score for HCC in 5 years was ≥0.89 in both validation cohorts. The performance of SMART-HCC score was significantly better than existing HCC risk scores including aMAP score, Toronto HCC risk index, and 7 hepatitis B-related risk scores. Using dual cutoffs of 0.043 and 0.080, the annual HCC incidence was 0.09%-0.11% for low-risk group and 2.54%-4.64% for high-risk group in the HK and Europe validation cohorts. CONCLUSIONS The SMART-HCC score is a useful machine learning-based tool for clinicians to stratify HCC risk in patients with CLDs.
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Affiliation(s)
- Huapeng Lin
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Guanlin Li
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Adèle Delamarre
- Hepatology Unit, Hôpital Haut Lévêque, Bordeaux University Hospital, Bordeaux, France; INSERM U1312, Bordeaux University, Bordeaux, France
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Xinrong Zhang
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Lilian Yan Liang
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Grace Lai-Hung Wong
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Pong-Chi Yuen
- Department of Computer Science, Hong Kong Baptist University, Hong Kong
| | - Henry Lik-Yuen Chan
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong; Union Hospital, Hong Kong
| | - Stephen Lam Chan
- Department of Clinical Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong
| | - Vincent Wai-Sun Wong
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Victor de Lédinghen
- Hepatology Unit, Hôpital Haut Lévêque, Bordeaux University Hospital, Bordeaux, France; INSERM U1312, Bordeaux University, Bordeaux, France.
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; Yonsei Liver Center, Severance Hospital, Seoul, Korea.
| | - Terry Cheuk-Fung Yip
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.
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Long L, Chen B, Zheng X, Wu F, Wang L, Rong W, Wu J, Li Y, Wang W. Postoperative radiotherapy following null-margin hepatectomy in patients with hepatocellular carcinoma adhering to the major vessels: A propensity score-matched survival analysis cohort study. Clin Transl Radiat Oncol 2024; 45:100727. [PMID: 38292331 PMCID: PMC10825561 DOI: 10.1016/j.ctro.2024.100727] [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: 04/08/2023] [Revised: 12/18/2023] [Accepted: 01/11/2024] [Indexed: 02/01/2024] Open
Abstract
Background & Aims This study aims to analyze the prognosis of null-margin (≤1.0 mm) hepatectomy (NH) in patients with hepatocellular carcinoma (HCC) adhering to the major vessels and explore the value of postoperative radiotherapy (RT) in these patients. Methods HCC patients who underwent null-margin or wide-margin (≥1.0 cm) hepatectomy (WH) by our team from January 2008 to March 2016 were recruited and analyzed retrospectively. The patients were divided into the NH, NH + RT, and WH groups. Propensity score matching (PSM) was performed to balance baseline characteristics. Results A total of 357 patients were recruited. Of these, 84, 49, and 224 patients were given NH alone, NH plus RT, and WH, respectively. After PSM, the 5-year overall survival (OS) and disease-free survival (DFS) rates of the NH group were significantly worse than those of the WH group (51.5 % vs. 71.4 %, P = 0.003; 32.2 % vs. 50.9 %, P = 0.005). The OS and DFS rates of the NH + RT group were significantly higher than those of the NH group (75.6 % vs. 56.1 %, P = 0.012; 46.6 % vs. 30.2 %, P = 0.015) and similar to those of the WH group (75.6 % vs. 75.1 %, P = 0.354; 46.6 % vs. 56.6 %, P = 0.717). In addition, patients in the NH + RT group experienced significantly lower early (P = 0.023) and intrahepatic (P = 0.015) recurrences than those in the NH group. Conclusions Patients with HCC adhering to the major vessels who underwent NH alone had a poorer prognosis, and the addition of RT to NH provide a significant survival benefit for these patients, which may yield outcomes comparable to the efficacy of WH.
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Affiliation(s)
- Liuhua Long
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing, PR China
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Bo Chen
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Xuan Zheng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing, PR China
| | - Fan Wu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Liming Wang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Weiqi Rong
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Jianxiong Wu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Yexiong Li
- State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Weihu Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing, PR China
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Ricker AB, Baker EH, Strand MS, Kalabin A, Butano V, Wells A, Phillips M, Wang H, McKillop I, Iannitti G, Casingal J, Martinie JB, Vrochides D, Iannitti DA. Surgical microwave ablation for the treatment of hepatocellular carcinoma in 791 operations. HPB (Oxford) 2024; 26:379-388. [PMID: 38102029 DOI: 10.1016/j.hpb.2023.11.009] [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: 09/12/2023] [Revised: 11/03/2023] [Accepted: 11/17/2023] [Indexed: 12/17/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality and often arises in the setting of cirrhosis. The present series reviews outcomes following 791 operations. METHODS Retrospective review surgical MWA for HCC from March 2007 through December 2022 at a high-volume institution was performed using a prospective database. Primary outcome was overall survival. RESULTS A total of 791 operations in 623 patients and 1156 HCC tumors were treated with surgical MWA. Median tumor size was 2 cm (range 0.25-10 cm) with an average of 1 tumor ablated per operation (range 1-7 tumors). Nearly 90 % of patients had cirrhosis with a median MELD score of 8 (IQR = 6-11). Mortality within 30 days occurred in 13 patients (1.6 %). Per tumor, the rate of incomplete ablation was 2.25 % and local recurrence was 2.95 %. Previous ablation and tumor size were risk factors for recurrence. One-year overall survival was 82.0 % with a median overall survival of 36.5 months (95 % CI 15.7-93.7) and median disease-free survival of 15.9 months (range 5.7-37.3 months). CONCLUSION Surgical MWA offers a low-morbidity approach for treatment of HCC, affording low rates of incomplete ablation and local recurrence.
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Affiliation(s)
- Ansley B Ricker
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC, USA
| | - Erin H Baker
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC, USA
| | - Matthew S Strand
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC, USA
| | - Aleksandr Kalabin
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC, USA
| | - Vincent Butano
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC, USA
| | - Alexandra Wells
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC, USA
| | - Michael Phillips
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC, USA
| | - Huaping Wang
- Carolinas Center for Surgical Outcomes Science, Atrium Health, Charlotte, NC, USA
| | - Iain McKillop
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC, USA
| | - Giuliana Iannitti
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC, USA
| | - Joel Casingal
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC, USA
| | - John B Martinie
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC, USA
| | - Dionisios Vrochides
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC, USA
| | - David A Iannitti
- Division of HPB Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC, USA.
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Tavabie OD, Salehi S, Aluvihare VR. The challenges and potential of microRNA-based therapy for patients with liver failure syndromes and hepatocellular carcinoma. Expert Opin Ther Targets 2024; 28:179-191. [PMID: 38487923 DOI: 10.1080/14728222.2024.2331598] [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: 12/21/2023] [Accepted: 03/13/2024] [Indexed: 03/20/2024]
Abstract
INTRODUCTION Morbidity and mortality from liver disease continues to rise worldwide. There are currently limited curative treatments for patients with liver failure syndromes, encompassing acute liver failure and decompensated cirrhosis states, outside of transplantation. Whilst there have been improvements in therapeutic options for patients with hepatocellular carcinoma (HCC), there remain challenges necessitating novel therapeutic agents. microRNA have long been seen as potential therapeutic targets but there has been limited clinical translation. AREAS COVERED We will discuss the limitations of conventional non-transplant management of patients with liver failure syndromes and HCC. We will provide an overview of microRNA and the challenges in developing and delivering microRNA-based therapeutic agents. We will finally provide an overview of microRNA-based therapeutic agents which have progressed to clinical trials. EXPERT OPINION microRNA have great potential to be developed into therapeutic agents due to their association with critical biological processes which govern health and disease. Utilizing microRNA sponges to target multiple microRNA associated with specific biological processes may improve their therapeutic efficacy. However, there needs to be significant improvements in delivery systems to ensure the safe delivery of microRNA to target sites and minimize systemic distribution. This currently significantly impacts the clinical translation of microRNA-based therapeutic agents.
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Affiliation(s)
| | - Siamak Salehi
- Institute of Liver Studies, King's College Hospital, London, UK
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Beal EW, McNamara M, Owen M, McAlearney AS, Tsung A. Interventions to Improve Surveillance for Hepatocellular Carcinoma in High-Risk Patients: A Scoping Review. J Gastrointest Cancer 2024; 55:1-14. [PMID: 37328730 DOI: 10.1007/s12029-023-00944-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2023] [Indexed: 06/18/2023]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is most often a sequela of chronic liver disease or chronic hepatitis B infection. Among high-risk patients, surveillance for HCC every 6 months is recommended by international guidelines. However, rates of HCC surveillance are suboptimal (11-64%). Barriers at the patient, provider, and healthcare delivery system levels have been identified. METHODS We performed a systemic scoping review to identify and characterize interventions to improve HCC surveillance that has previously been evaluated. Searches using key terms in PubMed and Embase were performed to identify studies examining interventions designed to improve the surveillance rate for HCC in patients with cirrhosis or chronic liver disease that were published in English between January 1990 and September 2021. RESULTS Included studies (14) had the following study designs: (1) randomized clinical trials (3, 21.4%), (2) quasi-experimental (2, 14.3%), (3) prospective cohort (6, 42.8%), and (4) retrospective cohort (3, 21.4%). Interventions included mailed outreach invitations, nursing outreach, patient education with or without printed materials, provider education, patient navigation, chronic disease management programs, nursing-led protocols for image ordering, automated reminders to physicians and nurses, web-based clinical management tools, HCC surveillance databases, provider compliance reports, radiology-led surveillance programs, subsidized HCC surveillance, and the use of oral medications. It was found that HCC surveillance rates increased after intervention implementation in all studies. CONCLUSION Despite improvements in HCC surveillance rates with intervention, compliance remained suboptimal. Further analysis of which interventions yield the greatest increases in HCC surveillance, design of multi-pronged strategies, and improved implementation are needed.
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Affiliation(s)
- Eliza W Beal
- Departments of Surgery and Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, Mailcode: HW04HO, Detroit, MI, 48201, USA.
| | - Molly McNamara
- The Ohio State University College of Medicine, Columbus, OH, 43210, USA
| | - Mackenzie Owen
- The Ohio State University College of Medicine, Columbus, OH, 43210, USA
| | - Ann Scheck McAlearney
- The Center for the Advancement of Team Science, Analytics, and Systems Thinking in Health Services and Implementation Science Research (CATALYST), The Ohio State University College of Medicine, Columbus, OH, 43210, USA
- Department of Family and Community Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Allan Tsung
- Department of Surgery, Division of Surgical Oncology, University of Virginia, Charlottsville, VA, 22908, USA
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Zhang Y, Sui P, Zhong C, Liu J. Development and Validation of the novel Cuproptosis- and Immune-related Signature for Predicting Prognosis in Hepatocellular Carcinoma. J Cancer 2024; 15:2260-2275. [PMID: 38495502 PMCID: PMC10937287 DOI: 10.7150/jca.92558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 02/19/2024] [Indexed: 03/19/2024] Open
Abstract
Background: Hepatocellular carcinoma often results in late-stage diagnosis, leading to decreased treatment success. To improve prognosis, this study integrates cuproptosis with immune risk scoring models for HCC patients. Method: We identified differentially expressed genes connected to cuproptosis and immune responses using Pearson correlation. A risk signature was then constructed via LASSO regression, and its robustness was validated in the International Cancer Genome Consortium dataset. Additionally, qPCR confirmed findings in tumor and normal tissues. Results: Eight genes emerged as key prognostic markers from the 110 differentially expressed genes linked to cuproptosis and immunity. A risk-scoring model was developed using gene expression, effectively categorizing patients into low- or high-risk groups. Validated in the ICGC dataset, high-risk patients had significantly reduced survival times. Multivariate Cox regression affirmed the risk signature's independent predictive capability. A clinical nomogram based on the risk signature was generated. Notably, low-risk patients might benefit more from immune checkpoint inhibitors. qPCR and western blotting results substantiated our bioinformatics findings. Conclusions: The genetic risk signature linked to cuproptosis and immunity holds potential as a vital prognostic biomarker for Hepatocellular carcinoma, providing avenues for tailored therapeutic strategies.
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Affiliation(s)
- Yongping Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Ping Sui
- Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shandong, China
| | - Cheng Zhong
- Department of Orthopedics, The first clinical medical college of Guangzhou University of Chinese Medicine, Guangzhou, 515000, China
- Department of Orthopedics, Jiangmen Hospital of Traditional Chinese Medicine Affiliated to Jinan University, Jiangmen, 52900, China
| | - Jiansheng Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
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