|
1
|
Jiang Y, Qi S, Zhang R, Zhao R, Fu Y, Fang Y, Shao M. Diagnosis of hepatocellular carcinoma using liquid biopsy-based biomarkers: a systematic review and network meta-analysis. Front Oncol 2025; 14:1483521. [PMID: 39935848 PMCID: PMC11810725 DOI: 10.3389/fonc.2024.1483521] [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: 08/20/2024] [Accepted: 12/31/2024] [Indexed: 02/13/2025] Open
Abstract
Introduction The diagnostic performance of liquid biopsy-based biomarkers for HCC was comprehensively compared in this network meta-analysis (NMA). Methods A thorough literature search was conducted to identify all comparative studies from January 1, 2000, to January 11, 2024. The QUADAS-2 tool was utilized to appraise the quality of studies involving diagnostic performance. R (v4.3.3) and an ANOVA model-based NMA were used to assess the diagnostic accuracy of each biomarker. Results This study included 82 studies comprising a total of 15,024 patients.CircRNA demonstrated significantly superior performance in distinguishing HCC from healthy populations (superiority index: 3.550 (95% CI [0.143-3])) compared to other diagnostic biomarkers for HCC. "mRNA exhibited significantly superior performance in distinguishing HCC from liver disease patients (superiority index:10.621 (95% CI [7-11])) compared to other diagnostic biomarkers for HCC. Further subgroup analysis of the top-ranking liquid biopsy-based diagnostic biomarkers revealed that hsa_circ_000224 (superiority index: 3.091 (95% CI[0.143-9]) ranked remarkably higher in distinguishing HCC from both healthy populations and liver disease patients. Subgroup analysis of mRNA demonstrated that KIAA0101 mRNA (superiority index: 2.434 (95% CI [0.2-5]) ranked remarkably higher in distinguishing HCC from healthy populations and liver disease patients, respectively. Discussion The results of this meta-analysis show that circRNA and mRNA are the first choice for HCC diagnosis. Subsequent analysis of circRNA and mRNA highlighted hsa_circ_000224, hsa_circ_0003998, KIAA0101 mRNA and GPC-3mRNA as the optimal diagnostic biomarkers for distinguishing HCC from healthy populations and liver disease patients, respectively. Well-structured prospective studies are crucial to comprehensively validate these findings. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/,identifier CRD42024521299.
Collapse
Affiliation(s)
- Yutong Jiang
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, China
| | - Shangwen Qi
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, China
| | - Rongrong Zhang
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, China
| | - Ruixia Zhao
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yu Fu
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yuxuan Fang
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, China
| | - Mingyi Shao
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| |
Collapse
|
|
2
|
Mohd Haniff NS, Ng KH, Kamal I, Mohd Zain N, Abdul Karim MK. Systematic review and meta-analysis on the classification metrics of machine learning algorithm based radiomics in hepatocellular carcinoma diagnosis. Heliyon 2024; 10:e36313. [PMID: 39253167 PMCID: PMC11382069 DOI: 10.1016/j.heliyon.2024.e36313] [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: 09/21/2023] [Revised: 08/13/2024] [Accepted: 08/13/2024] [Indexed: 09/11/2024] Open
Abstract
The aim of this systematic review and meta-analysis is to evaluate the performance of classification metrics of machine learning-driven radiomics in diagnosing hepatocellular carcinoma (HCC). Following the PRISMA guidelines, a comprehensive search was conducted across three major scientific databases-PubMed, ScienceDirect, and Scopus-from 2018 to 2022. The search yielded a total of 436 articles pertinent to the application of machine learning and deep learning for HCC prediction. These studies collectively reflect the burgeoning interest and rapid advancements in employing artificial intelligence (AI)-driven radiomics for enhanced HCC diagnostic capabilities. After the screening process, 34 of these articles were chosen for the study. The area under curve (AUC), accuracy, specificity, and sensitivity of the proposed and basic models were assessed in each of the studies. Jamovi (version 1.1.9.0) was utilised to carry out a meta-analysis of 12 cohort studies to evaluate the classification accuracy rate. The risk of bias was estimated, and Logistic Regression was found to be the most suitable classifier for binary problems, with least absolute shrinkage and selection operator (LASSO) as the feature selector. The pooled proportion for HCC prediction classification was high for all performance metrics, with an AUC value of 0.86 (95 % CI: 0.83-0.88), accuracy of 0.83 (95 % CI: 0.78-0.88), sensitivity of 0.80 (95 % CI: 0.75-0.84) and specificity of 0.84 (95 % CI: 0.80-0.88). The performance of feature selectors, classifiers, and input features in detecting HCC and related factors was evaluated and it was observed that radiomics features extracted from medical images were adequate for AI to accurately distinguish the condition. HCC based radiomics has favourable predictive performance especially with addition of clinical features that may serve as tool that support clinical decision-making.
Collapse
Affiliation(s)
- Nurin Syazwina Mohd Haniff
- Department of Physics, Faculty of Science, Universiti Putra Malaysia, UPM, 43400 Serdang, Selangor, Malaysia
| | - Kwan Hoong Ng
- Department of Biomedical Imaging, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Izdihar Kamal
- Department of Physics, Faculty of Science, Universiti Putra Malaysia, UPM, 43400 Serdang, Selangor, Malaysia
- Research Management Centre, KPJ Healthcare University, 71800, Nilai, Negeri Sembilan, Malaysia
| | - Norhayati Mohd Zain
- Research Management Centre, KPJ Healthcare University, 71800, Nilai, Negeri Sembilan, Malaysia
| | - Muhammad Khalis Abdul Karim
- Department of Physics, Faculty of Science, Universiti Putra Malaysia, UPM, 43400 Serdang, Selangor, Malaysia
| |
Collapse
|
|
3
|
Ablefoni M, Richter T, Leonhardi J, Ehrengut C, Prasse G, Mehdorn M, Seehofer D, Höhn AK, Denecke T, Meyer HJ. Potential diagnostic value of high b-value computed diffusion-weighted imaging in hepatocellular carcinoma. Clin Exp Hepatol 2024; 10:129-136. [PMID: 39845353 PMCID: PMC11748228 DOI: 10.5114/ceh.2024.139651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 02/02/2024] [Indexed: 01/24/2025] Open
Abstract
Aim of the study Over the past few years, diffusion-weighted imaging (DWI) has become an increasingly important diagnostic tool in the diagnosis of liver lesions. The objective of the present study was to evaluate the diagnostic benefit of high b-value computed diffusion-weighted imaging (c-DWI) compared with standard DWI in patients with hepatocellular carcinoma (HCC) and whether there is an association with microvascular invasion (MVI). Material and methods In total, 37 patients with histopathologically confirmed HCC were retrospectively ana-lyzed. DWI was acquired with b-values of 50, 400, and 800 or 1000 s/mm² on a 1.5 T magnetic resonance imaging (MRI) scanner. The c-DWI was calculated using a monoexponential model with high b-values of 1000, 2000, 3000, 4000, and 5000 s/mm². All high b-value c-DWI images were compared to the standard DWI in terms of volume, detectability of hepatic lesions, and image quality. Results Regarding lesion volume and image quality there were no statistically significant differences between standard and c-DWI. HCC lesions measured on DWI images were statistically significantly larger compared to c-DWI images starting from a b value of 2000 s/mm2 (DWI vs. c-DWI b 2000 s/mm2: 2 cm3 [1-12] cm3 vs. 1 cm3 [0-17] cm3, p < 0.05). Moreover, there was deterioration of image quality starting at b = 2000 s/mm2. There were no significant differences in terms of lesion signal intensity in DWI and c-DWI images. There were no differences for the DWI parameters according to MVI status. Conclusions C-DWI images with high b-values up to b = 1000 s/mm2 demonstrate comparable detectability of HCC compared to standard DWI. The investigated DWI parameters were not associated with MVI status. Further research is needed to evaluate the potential benefit of high b-value c-DWI.
Collapse
Affiliation(s)
- Maxime Ablefoni
- Diagnostic and Interventional Radiology, University of Leipzig, Leipzig, Germany
| | - Theresa Richter
- Diagnostic and Interventional Radiology, University of Leipzig, Leipzig, Germany
| | - Jakob Leonhardi
- Diagnostic and Interventional Radiology, University of Leipzig, Leipzig, Germany
| | - Constantin Ehrengut
- Diagnostic and Interventional Radiology, University of Leipzig, Leipzig, Germany
| | - Gordian Prasse
- Diagnostic and Interventional Radiology, University of Leipzig, Leipzig, Germany
| | - Matthias Mehdorn
- Department of Visceral and Transplantation Surgery, University of Leipzig, Leipzig, Germany
| | - Daniel Seehofer
- Department of Visceral and Transplantation Surgery, University of Leipzig, Leipzig, Germany
| | | | - Timm Denecke
- Diagnostic and Interventional Radiology, University of Leipzig, Leipzig, Germany
| | - Hans-Jonas Meyer
- Diagnostic and Interventional Radiology, University of Leipzig, Leipzig, Germany
| |
Collapse
|
|
4
|
Liu M, Lai Z, Yuan X, Jin Q, Shen H, Rao D, Huang D. Role of exosomes in the development, diagnosis, prognosis and treatment of hepatocellular carcinoma. Mol Med 2023; 29:136. [PMID: 37848835 PMCID: PMC10580543 DOI: 10.1186/s10020-023-00731-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 09/17/2023] [Indexed: 10/19/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer. It is characterized by occult onset resulting in most patients being diagnosed at advanced stages and with poor prognosis. Exosomes are nanoscale vesicles with a lipid bilayer envelope released by various cells under physiological and pathological conditions, which play an important role in the biological information transfer between cells. There is growing evidence that HCC cell-derived exosomes may contribute to the establishment of a favorable microenvironment that supports cancer cell proliferation, invasion, and metastasis. These exosomes not only provide a versatile platform for diagnosis but also serve as a vehicle for drug delivery. In this paper, we review the role of exosomes involved in the proliferation, migration, and metastasis of HCC and describe their application in HCC diagnosis and treatment. We also discuss the prospects of exosome application in HCC and the research challenges.
Collapse
Affiliation(s)
- Meijin Liu
- Ganzhou Jingkai District People's Hospital, Ganzhou, China
| | - Zhonghong Lai
- Department of Traumatology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Xiaoying Yuan
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Qing Jin
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Haibin Shen
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Dingyu Rao
- Department of Cardiothoracic Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
| | - Defa Huang
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
| |
Collapse
|
|
5
|
Zeng Y, Hu S, Luo Y, He K. Exosome Cargos as Biomarkers for Diagnosis and Prognosis of Hepatocellular Carcinoma. Pharmaceutics 2023; 15:2365. [PMID: 37765333 PMCID: PMC10537613 DOI: 10.3390/pharmaceutics15092365] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 09/14/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Due to the insidiousness of HCC onset and the lack of specific early-stage markers, the early diagnosis and treatment of HCC are still unsatisfactory, leading to a poor prognosis. Exosomes are a type of extracellular vesicle containing various components, which play an essential part in the development, progression, and metastasis of HCC. A large number of studies have demonstrated that exosomes could serve as novel biomarkers for the diagnosis of HCC. These diagnostic components mainly include proteins, microRNAs, long noncoding RNAs, and circular RNAs. The exosome biomarkers showed high sensitivity and high specificity in distinguishing HCC from health controls and other liver diseases, such as chronic HBV and liver cirrhosis. The expression of these biomarkers also exhibits correlations with various clinical factors such as tumor size, TMN stage, overall survival, and recurrence rate. In this review, we summarize the function of exosomes in the development of HCC and highlight their application as HCC biomarkers for diagnosis and prognosis prediction.
Collapse
Affiliation(s)
- Yulai Zeng
- Department of Liver Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai 200127, China; (Y.Z.); (S.H.)
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200127, China
- Shanghai Institute of Transplantation, Shanghai 200127, China
| | - Shuyu Hu
- Department of Liver Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai 200127, China; (Y.Z.); (S.H.)
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200127, China
- Shanghai Institute of Transplantation, Shanghai 200127, China
| | - Yi Luo
- Department of Liver Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai 200127, China; (Y.Z.); (S.H.)
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200127, China
- Shanghai Institute of Transplantation, Shanghai 200127, China
| | - Kang He
- Department of Liver Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai 200127, China; (Y.Z.); (S.H.)
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200127, China
- Shanghai Institute of Transplantation, Shanghai 200127, China
| |
Collapse
|
|
6
|
Koh B, Danpanichkul P, Wang M, Tan DJH, Ng CH. Application of artificial intelligence in the diagnosis of hepatocellular carcinoma. EGASTROENTEROLOGY 2023; 1:e100002. [PMID: 39944000 PMCID: PMC11770452 DOI: 10.1136/egastro-2023-100002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 09/20/2023] [Indexed: 05/29/2025]
Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. This review explores the recent progress in the application of artificial intelligence (AI) in radiological diagnosis of HCC. The Barcelona Classification of Liver Cancer criteria guides treatment decisions based on tumour characteristics and liver function indicators, but HCC often remains undetected until intermediate or advanced stages, limiting treatment options and patient outcomes. Timely and accurate diagnostic methods are crucial for enabling curative therapies and improving patient outcomes. AI, particularly deep learning and neural network models, has shown promise in the radiological detection of HCC. AI offers several advantages in HCC diagnosis, including reducing diagnostic variability, optimising data analysis and reallocating healthcare resources. By providing objective and consistent analysis of imaging data, AI can overcome the limitations of human interpretation and enhance the accuracy of HCC diagnosis. Furthermore, AI systems can assist healthcare professionals in managing the increasing workload by serving as a reliable diagnostic tool. Integration of AI with information systems enables comprehensive analysis of patient data, facilitating more informed and reliable diagnoses. The advancements in AI-based radiological diagnosis hold significant potential to improve early detection, treatment selection and patient outcomes in HCC. Further research and clinical implementation of AI models in routine practice are necessary to harness the full potential of this technology in HCC management.
Collapse
Affiliation(s)
- Benjamin Koh
- Department of Medicine, National University of Singapore Yong Loo Lin School of Medicine, Singapore
| | | | - Meng Wang
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore
| | - Darren Jun Hao Tan
- Department of Medicine, National University of Singapore Yong Loo Lin School of Medicine, Singapore
| | - Cheng Han Ng
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore
| |
Collapse
|
|
7
|
Salama DE, Shash LS, Shakweer MM, Abdel-Maqsoud RR, Ahmed Abosaif AI, Elgohary SA. Interpretation of Farnesoid X Receptor Immunohistochemical Expression in Discriminating Hepatocellular Carcinoma from Its Non-Neoplastic Mimics as an Adjunct to Glypican 3. Asian Pac J Cancer Prev 2023; 24:3221-3227. [PMID: 37774075 PMCID: PMC10762761 DOI: 10.31557/apjcp.2023.24.9.3221] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 09/10/2023] [Indexed: 10/01/2023] Open
Abstract
AIMS Differentiating hepatocellular carcinoma (HCC) and non-neoplastic lesions may be challenging. Immunohistochemistry (IHC) can help in the comparative morphologic evaluation of HCC and its mimics. Farnesoid X receptor (FXR) is a nuclear metabolic receptor essential for bile salts homeostasis and other biological functions of liver cells. Preliminary studies have shown that FXR can be useful for diagnosing HCC. This study aimed to assess the role of Farnesoid X receptor (FXR) combined with Glypican 3 (GPC3) in differentiation between HCC and non-neoplastic hepatic lesions. MATERIAL AND METHODS Immunohistochemistry of GPC3 and FXR was performed in 38 cases of primary hepatic lesions using an automated immunohistochemical stainer. The study included 17 primary HCC cases and 21 non-neoplastic hepatic lesions (5 cases were focal nodular hyperplasia, 7 were regenerative nodules and 9 were dysplastic nodules). RESULTS The percentage of positive GPC3 and low or negative FXR expression was significantly higher in HCC cases than non-neoplastic hepatic lesions (P value <0.001). The sensitivity and specificity of GPC3 in differentiating HCC from non-neoplastic hepatic lesions were 70.6% and 85.7%, respectively, while the sensitivity and specificity of FXR were 58.8% and 100%, respectively. CONCLUSION The present work revealed that FXR could be combined with GPC3 in distinguishing between HCC and non-neoplastic hepatic lesions with improved specificity rather than using an individual marker.
Collapse
Affiliation(s)
- Doaa E.A. Salama
- Department of Pathology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt.
- Department of Pathology, School of Medicine, Badr University in Cairo (BUC), Egypt.
| | - Lobna Sadek Shash
- Department of Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Marwa Mosaad Shakweer
- Department of Pathology, School of Medicine, Badr University in Cairo (BUC), Egypt.
- Department of Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | | | | | | |
Collapse
|
|
8
|
The mesenchymal circulating tumor cells as biomarker for prognosis prediction and supervision in hepatocellular carcinoma. J Cancer Res Clin Oncol 2023:10.1007/s00432-022-04526-9. [PMID: 36633681 PMCID: PMC10356895 DOI: 10.1007/s00432-022-04526-9] [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: 10/31/2022] [Accepted: 12/07/2022] [Indexed: 01/13/2023]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of death worldwide. Accurate prognosis prediction tools are urgently needed. While the use of circulating tumor cells (CTCs) as prognostic prediction tool has a clear potential. METHODS We established a comprehensive, negative enrichment-based strategy for CTCs analysis in patients with HCC, involving identification of epithelial CTCs (E-CTCs) and mesenchymal CTCs (M-CTCs) through specific biomarker. This strategy was performed in 127 HCC cases, 21 nonmalignant liver disease (NMLD) patients and 42 health control to analyze the relevance between CTCs and tumor recurrence. RESULTS The total CTC number and M-CTC percent were positively correlated with tumor malignancy and high recurrence risk. Individually, preoperative total CTC number and M-CTC percent could robustly distinguish relapse cases from those with no relapse, with sensitivity of 80.95% and 90.48%, specificity of 74.12% and 84.71%, respectively. Levels of preoperative total CTC number and M-CTC percent can both be regarded as independent risk factors for HCC with early recurrence (P = 0.0053, P < 0.0001), and are both significantly correlated with worse recurrence-free survival (RFS) (log rank P < 0.0001; HR 7.78, 95% CI = 3.59-16.87; log rank P < 0.0001; HR 24.4, 95% CI = 8.67-68.77). The levels of total CTC number and M-CTC number had higher effectiveness than alpha fetal protein (AFP) in HCC longitudinal supervision (77.78% vs 88.89% vs 22.22%). CONCLUSION Preoperative and postoperative CTCs with higher effectiveness than AFP in prognosis prediction and recurrence supervision, indicating that CTCs could work as the biomarker for HCC clinical management.
Collapse
|
|
9
|
Chan LWC, Wong SCC, Cho WCS, Huang M, Zhang F, Chui ML, Lai UNY, Chan TYK, Cheung ZHC, Cheung JCY, Tang KF, Tse ML, Wong HK, Kwok HMF, Shen X, Zhang S, Chiu KWH. Primary Tumor Radiomic Model for Identifying Extrahepatic Metastasis of Hepatocellular Carcinoma Based on Contrast Enhanced Computed Tomography. Diagnostics (Basel) 2022; 13:102. [PMID: 36611394 PMCID: PMC9818425 DOI: 10.3390/diagnostics13010102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 12/22/2022] [Accepted: 12/24/2022] [Indexed: 01/01/2023] Open
Abstract
This study aimed to identify radiomic features of primary tumor and develop a model for indicating extrahepatic metastasis of hepatocellular carcinoma (HCC). Contrast-enhanced computed tomographic (CT) images of 177 HCC cases, including 26 metastatic (MET) and 151 non-metastatic (non-MET), were retrospectively collected and analyzed. For each case, 851 radiomic features, which quantify shape, intensity, texture, and heterogeneity within the segmented volume of the largest HCC tumor in arterial phase, were extracted using Pyradiomics. The dataset was randomly split into training and test sets. Synthetic Minority Oversampling Technique (SMOTE) was performed to augment the training set to 145 MET and 145 non-MET cases. The test set consists of six MET and six non-MET cases. The external validation set is comprised of 20 MET and 25 non-MET cases collected from an independent clinical unit. Logistic regression and support vector machine (SVM) models were identified based on the features selected using the stepwise forward method while the deep convolution neural network, visual geometry group 16 (VGG16), was trained using CT images directly. Grey-level size zone matrix (GLSZM) features constitute four of eight selected predictors of metastasis due to their perceptiveness to the tumor heterogeneity. The radiomic logistic regression model yielded an area under receiver operating characteristic curve (AUROC) of 0.944 on the test set and an AUROC of 0.744 on the external validation set. Logistic regression revealed no significant difference with SVM in the performance and outperformed VGG16 significantly. As extrahepatic metastasis workups, such as chest CT and bone scintigraphy, are standard but exhaustive, radiomic model facilitates a cost-effective method for stratifying HCC patients into eligibility groups of these workups.
Collapse
Affiliation(s)
- Lawrence Wing Chi Chan
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Sze Chuen Cesar Wong
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | | | - Mohan Huang
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Fei Zhang
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Man Lik Chui
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Una Ngo Yin Lai
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Tiffany Yuen Kwan Chan
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Zoe Hoi Ching Cheung
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Jerry Chun Yin Cheung
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Kin Fu Tang
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Man Long Tse
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Hung Kit Wong
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Hugo Man Fung Kwok
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Xinping Shen
- Department of Radiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
| | - Sailong Zhang
- Department of Diagnostic Radiology, The University of Hong Kong, Hong Kong SAR, China
| | - Keith Wan Hang Chiu
- Department of Diagnostic Radiology, The University of Hong Kong, Hong Kong SAR, China
- Department of Radiology & Imaging, Queen Elizabeth Hospital, Hong Kong SAR, China
| |
Collapse
|
|
10
|
El-Badrawy A. Multi-detector computed tomography evaluation of synchronous hepatocellular carcinoma and other solid malignancies. Clin Exp Hepatol 2022; 8:219-225. [PMID: 36685262 PMCID: PMC9850313 DOI: 10.5114/ceh.2022.119224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 06/30/2022] [Indexed: 01/25/2023] Open
Abstract
Aim of the study To review the findings of multi-detector computed tomography (MDCT) in synchronous hepatocellular carcinoma (HCC) and other solid malignancies. Material and methods A total of 74 cases were included in this retrospective analysis, all of them confirmed with a diagnosis of synchronous HCC and other solid malignancies. They were 41 women and 33 men (mean age, 63.36 years). The whole body and triphasic abdominal CT scanning utilized 128 MDCT scanners in all 74 patients. The pathological diagnoses of all 148 malignancies were confirmed in all 74 cases. Results Out of 3480 patients with HCC, 74 patients (2.1%) were diagnosed with another synchronous primary solid malignancy. The pathology of all 148 cancers was verified, and each one was correctly characterized, assessed, and staged. Hepatocellular carcinoma was detected in all 74 patients. The most frequent extra-hepatic primary malignant sites were breast (18/74, 24.3%), followed by kidney (15/74, 20.3%), lymphoma (9/74, 12.2%), uterus (7/74, 9.5%), ovary (5/74, 6.8%), colon (5/74, 6.8%), prostate (5/74, 6.8%), urinary bladder (3/74, 4.1%), thyroid (2/74, 2.7%), gall bladder (1/74, 1.4%), stomach (1/74, 1.4%), pancreas (1/74, 1.4%), esophagus (1/74, 1.4%) and lung (1/74, 1.4%). Conclusions The possibility of synchronous double malignancies with HCC should always be considered during pretreatment evaluation. Using an MDCT scanner, researchers were able to assess this occurrence accurately. An increased number of such findings may lead to an improved therapeutic method for these patients.
Collapse
|
|
11
|
Survarachakan S, Prasad PJR, Naseem R, Pérez de Frutos J, Kumar RP, Langø T, Alaya Cheikh F, Elle OJ, Lindseth F. Deep learning for image-based liver analysis — A comprehensive review focusing on malignant lesions. Artif Intell Med 2022; 130:102331. [DOI: 10.1016/j.artmed.2022.102331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 05/23/2022] [Accepted: 05/30/2022] [Indexed: 11/26/2022]
|
|
12
|
Zelli V, Compagnoni C, Capelli R, Corrente A, Di Vito Nolfi M, Zazzeroni F, Alesse E, Tessitore A. Role of exosomal microRNAs in cancer therapy and drug resistance mechanisms: focus on hepatocellular carcinoma. Front Oncol 2022; 12:940056. [PMID: 35912267 PMCID: PMC9334682 DOI: 10.3389/fonc.2022.940056] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 06/27/2022] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs), defined as intercellular messengers that carry their cargos between cells, are involved in several physiological and pathological processes. These small membranous vesicles are released by most cells and contain biological molecules, including nucleic acids, proteins and lipids, which can modulate signaling pathways of nearby or distant recipient cells. Exosomes, one the most characterized classes of EVs, include, among others, microRNAs (miRNAs), small non-coding RNAs able to regulate the expression of several genes at post-transcriptional level. In cancer, exosomal miRNAs have been shown to influence tumor behavior and reshape tumor microenvironment. Furthermore, their possible involvement in drug resistance mechanisms has become evident in recent years. Hepatocellular carcinoma (HCC) is the major type of liver cancer, accounting for 75-85% of all liver tumors. Although the improvement in HCC treatment approaches, low therapeutic efficacy in patients with intermediate-advanced HCC is mainly related to the development of tumor metastases, high risk of recurrence and drug resistance. Exosomes have been shown to be involved in pathogenesis and progression of HCC, as well as in drug resistance, by regulating processes such as cell proliferation, epithelial-mesenchymal transition and immune response. Herein, we summarize the current knowledge about the involvement of exosomal miRNAs in HCC therapy, highlighting their role as modulators of therapeutic response, particularly chemotherapy and immunotherapy, as well as possible therapeutic tools.
Collapse
Affiliation(s)
- Veronica Zelli
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
- Center for Molecular Diagnostics and Advanced Therapies, University of L’Aquila, L’Aquila, Italy
| | - Chiara Compagnoni
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
| | - Roberta Capelli
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
| | - Alessandra Corrente
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
| | - Mauro Di Vito Nolfi
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
| | - Francesca Zazzeroni
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
| | - Edoardo Alesse
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
| | - Alessandra Tessitore
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
- Center for Molecular Diagnostics and Advanced Therapies, University of L’Aquila, L’Aquila, Italy
- *Correspondence: Alessandra Tessitore,
| |
Collapse
|
|
13
|
Garg T, Shrigiriwar A, Habibollahi P, Cristescu M, Liddell RP, Chapiro J, Inglis P, Camacho JC, Nezami N. Intraarterial Therapies for the Management of Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14143351. [PMID: 35884412 PMCID: PMC9322128 DOI: 10.3390/cancers14143351] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 07/05/2022] [Accepted: 07/07/2022] [Indexed: 12/11/2022] Open
Abstract
Image-guided locoregional therapies play a crucial role in the management of patients with hepatocellular carcinoma (HCC). Transarterial therapies consist of a group of catheter-based treatments where embolic agents are delivered directly into the tumor via their supplying arteries. Some of the transarterial therapies available include bland embolization (TAE), transarterial chemoembolization (TACE), drug-eluting beads-transarterial chemoembolization (DEB-TACE), selective internal radioembolization therapy (SIRT), and hepatic artery infusion (HAI). This article provides a review of pre-procedural, intra-procedural, and post-procedural aspects of each therapy, along with a review of the literature. Newer embolotherapy options and future directions are also briefly discussed.
Collapse
Affiliation(s)
- Tushar Garg
- Division of Vascular and Interventional Radiology, Russell H Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (T.G.); (R.P.L.)
| | - Apurva Shrigiriwar
- Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA;
| | - Peiman Habibollahi
- Department of Interventional Radiology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Mircea Cristescu
- Vascular and Interventional Radiology Division, Department of Radiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
| | - Robert P. Liddell
- Division of Vascular and Interventional Radiology, Russell H Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (T.G.); (R.P.L.)
| | - Julius Chapiro
- Section of Vascular and Interventional Radiology, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06510, USA;
| | - Peter Inglis
- Division of Vascular and Interventional Radiology, Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Juan C. Camacho
- Department of Clinical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA;
- Vascular and Interventional Radiology, Radiology Associates of Florida, Sarasota, FL 34239, USA
| | - Nariman Nezami
- Division of Vascular and Interventional Radiology, Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
- Experimental Therapeutics Program, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
- Correspondence:
| |
Collapse
|
|
14
|
Shi Y, Men J, Sun H, Tan J. The Identification and Analysis of MicroRNAs Combined Biomarkers for Hepatocellular Carcinoma Diagnosis. Med Chem 2022; 18:1073-1085. [PMID: 35379158 DOI: 10.2174/1573406418666220404084532] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 12/22/2021] [Accepted: 01/24/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common malignant tumor with high morbidity and mortality globally. Compared with traditional diagnostic methods, microRNAs (miRNAs) were novel biomarkers with higher accuracy. OBJECTIVE We aimed to identify combinatorial biomarkers of miRNAs to construct a classification model for the diagnosis of HCC. METHOD The mature miRNAs expression profile data of six cancers (liver, lung, gastric, breast, prostate and colon) were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database with accession number GSE36915, GSE29250, GSE99417, GSE41970, GSE64333 and GSE35982. The messenger RNA (mRNA) expression profile data of these six cancers were obtained from TCGA. Three R software packages, student's t-test and a normalized fold-change method were utilized to identify HCC-specific differentially expressed miRNAs (DEMs). Using all combinations of obtained HCC- specific DEMs as input features, we construct a classification model by support vector machine searching for the optimal combination. Furthermore, target genes prediction was conducted on the miRWalk 2.0 website to obtain differentially expressed mRNAs (DEmRNAs), and KEGG pathway enrichment was analyzed on the DAVID website. RESULTS The optimal combination consisted of four miRNAs (hsa-miR-130a-3p, hsa-miR-450b-5p, hsa-miR-136-5p and hsa-miR-24-1-5p), of which the last one has not been currently reported to be relevant to HCC. The target genes of hsa-miR-24-1-5p (CDC7, ACACA, CTNNA1, and NF2) were involved in the cell cycle, AMPK signaling pathway, Hippo signaling pathway and insulin signaling pathway, which affect the proliferation, metastasis, and apoptosis of cancer cells. Moreover, the area under the receiver operating characteristic curves of the four miRNAs were all higher than 0.85. CONCLUSION These results suggest that the miRNAs combined biomarkers were reliable for the diagnosis of HCC. Hsa-miR-24-1-5p was a novel biomarker for HCC diagnosis identified in this study.
Collapse
Affiliation(s)
- Yi Shi
- Department of Biomedical Engineering, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China
| | - Jingrui Men
- Department of Biomedical Engineering, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China
| | - Hongliang Sun
- Department of Biomedical Engineering, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China
| | - Jianjun Tan
- Department of Biomedical Engineering, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China
| |
Collapse
|
|
15
|
Lucatelli P, Burrel M, Guiu B, de Rubeis G, van Delden O, Helmberger T. CIRSE Standards of Practice on Hepatic Transarterial Chemoembolisation. Cardiovasc Intervent Radiol 2021; 44:1851-1867. [PMID: 34694454 DOI: 10.1007/s00270-021-02968-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 09/04/2021] [Indexed: 12/15/2022]
Abstract
This CIRSE Standards of Practice document is aimed at interventional radiologists and provides best practices for performing transarterial chemoembolisation. It has been developed by an expert writing group under the guidance of the CIRSE Standards of Practice Committee. It will encompass all technical details reflecting European practice of different TACE procedures (Lp-TACE, DEM-TACE, DSM-TACE, b-TACE) as well as revising the existing literature on the various clinical indications (HCC, mCRC, ICC, NET). Finally, new frontiers of development will also be discussed.
Collapse
Affiliation(s)
- Pierleone Lucatelli
- Vascular and Interventional Radiology Unit, Department of Radiological Oncological and Anatomo-Pathological Sciences, Sapienza University of Rome, Rome, Italy.
| | - Marta Burrel
- Radiology Department, Hospital Clínic of Barcelona, Barcelona, Spain
| | - Boris Guiu
- Department of Radiology, Montpellier School of Medicine, St-Eloi University Hospital, Montpellier, France
| | - Gianluca de Rubeis
- Vascular and Interventional Radiology Unit, Department of Radiological Oncological and Anatomo-Pathological Sciences, Sapienza University of Rome, Rome, Italy
- Department of Diagnostic Radiology, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
| | - Otto van Delden
- Department of Interventional Radiology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Thomas Helmberger
- Institute for Diagnostic and Interventional Radiology and Neuroradiology, Bogenhausen Hospital, Munich, Germany
| |
Collapse
|
|
16
|
Rahimi A, Khalil A, Faisal A, Lai KW. CT-MRI Dual Information Registration for the Diagnosis of Liver Cancer: A Pilot Study Using Point-Based Registration. Curr Med Imaging 2021; 18:61-66. [PMID: 34433403 DOI: 10.2174/1573405617666210825155659] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 05/17/2021] [Accepted: 06/01/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND Early diagnosis of liver cancer may increase life expectancy. Computed tomography (CT) and magnetic resonance imaging (MRI) play a vital role in diagnosing liver cancer. Together, both modalities offer significant individual and specific diagnosis data to physicians; however, they lack the integration of both types of information. To address this concern, a registration process has to be utilized for the purpose, as multimodal details are crucial in providing the physician with complete information. OBJECTIVE The aim was to present a model of CT-MRI registration used to diagnose liver cancer, specifically for improving the quality of the liver images and provide all the required information for earlier detection of the tumors. This method should concurrently address the issues of imaging procedures for liver cancer to fasten the detection of the tumor from both modalities. METHODS In this work, a registration scheme for fusing the CT and MRI liver images is studied. A feature point-based method with normalized cross-correlation has been utilized to aid in the diagnosis of liver cancer and provide multimodal information to physicians. Data on ten patients from an online database were obtained. For each dataset, three planar views from both modalities were interpolated and registered using feature point-based methods. The registration of algorithms was carried out by MATLAB (vR2019b, Mathworks, Natick, USA) on an Intel(R) Core (TM) i5-5200U CPU @ 2.20 GHz computer. The accuracy of the registered image is being validated qualitatively and quantitatively. RESULTS The results show that an accurate registration is obtained with minimal distance errors by which CT and MRI were accurately registered based on the validation of the experts. The RMSE ranges from 0.02 to 1.01 for translation, which is equivalent in magnitude to approximately 0 to 5 pixels for CT and registered image resolution. CONCLUSION The CT-MRI registration scheme can provide complementary information on liver cancer to physicians, thus improving the diagnosis and treatment planning process.
Collapse
Affiliation(s)
- Aisyah Rahimi
- Faculty of Science and Technology, Universiti Sains Islam Malaysia, 71800 Nilai, Negeri Sembilan. Malaysia
| | - Azira Khalil
- Faculty of Science and Technology, Universiti Sains Islam Malaysia, 71800 Nilai, Negeri Sembilan. Malaysia
| | - Amir Faisal
- Biomedical Engineering, Institut Teknologi Sumatera, Lampung Selatan, 35365. Indonesia
| | - Khin Wee Lai
- Department of Biomedical Engineering, Faculty of Engineering, University of Malaya, 50603 Kuala Lumpur. Malaysia
| |
Collapse
|
|
17
|
Granata V, Grassi R, Fusco R, Belli A, Cutolo C, Pradella S, Grazzini G, La Porta M, Brunese MC, De Muzio F, Ottaiano A, Avallone A, Izzo F, Petrillo A. Diagnostic evaluation and ablation treatments assessment in hepatocellular carcinoma. Infect Agent Cancer 2021; 16:53. [PMID: 34281580 PMCID: PMC8287696 DOI: 10.1186/s13027-021-00393-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 07/06/2021] [Indexed: 02/07/2023] Open
Abstract
This article provides an overview of diagnostic evaluation and ablation treatment assessment in Hepatocellular Carcinoma (HCC). Only studies, in the English language from January 2010 to January 202, evaluating the diagnostic tools and assessment of ablative therapies in HCC patients were included. We found 173 clinical studies that satisfied the inclusion criteria.HCC may be noninvasively diagnosed by imaging findings. Multiphase contrast-enhanced imaging is necessary to assess HCC. Intravenous extracellular contrast agents are used for CT, while the agents used for MRI may be extracellular or hepatobiliary. Both gadoxetate disodium and gadobenate dimeglumine may be used in hepatobiliary phase imaging. For treatment-naive patients undergoing CT, unenhanced imaging is optional; however, it is required in the post treatment setting for CT and all MRI studies. Late arterial phase is strongly preferred over early arterial phase. The choice of modality (CT, US/CEUS or MRI) and MRI contrast agent (extracelllar or hepatobiliary) depends on patient, institutional, and regional factors. MRI allows to link morfological and functional data in the HCC evaluation. Also, Radiomics is an emerging field in the assessment of HCC patients.Postablation imaging is necessary to assess the treatment results, to monitor evolution of the ablated tissue over time, and to evaluate for complications. Post- thermal treatments, imaging should be performed at regularly scheduled intervals to assess treatment response and to evaluate for new lesions and potential complications.
Collapse
Affiliation(s)
- Vincenza Granata
- Division of Radiology, Istituto Nazionale Tumori IRCCS Fondazione Pascale - IRCCS di Napoli, Naples, Italy
| | - Roberta Grassi
- Division of Radiology, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy
- Italian Society of Medical and Interventional Radiology SIRM, SIRM Foundation, Milan, Italy
| | | | - Andrea Belli
- Division of Hepatobiliary Surgical Oncology, Istituto Nazionale Tumori IRCCS Fondazione Pascale - IRCCS di Napoli, Naples, Italy
| | - Carmen Cutolo
- Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy
| | - Silvia Pradella
- Radiology Division, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Giulia Grazzini
- Radiology Division, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | | | - Maria Chiara Brunese
- Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, Campobasso, Italy
| | - Federica De Muzio
- Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, Campobasso, Italy
| | - Alessandro Ottaiano
- Abdominal Oncology Division, Istituto Nazionale Tumori IRCCS Fondazione Pascale - IRCCS di Napoli, Naples, Italy
| | - Antonio Avallone
- Abdominal Oncology Division, Istituto Nazionale Tumori IRCCS Fondazione Pascale - IRCCS di Napoli, Naples, Italy
| | - Francesco Izzo
- Division of Hepatobiliary Surgical Oncology, Istituto Nazionale Tumori IRCCS Fondazione Pascale - IRCCS di Napoli, Naples, Italy
| | - Antonella Petrillo
- Division of Radiology, Istituto Nazionale Tumori IRCCS Fondazione Pascale - IRCCS di Napoli, Naples, Italy
| |
Collapse
|
|
18
|
Guo S, Hu C, Zhai X, Sun D. Circular RNA 0006602 in plasma exosomes: a new potential diagnostic biomarker for hepatocellular carcinoma. Am J Transl Res 2021; 13:6001-6015. [PMID: 34306340 PMCID: PMC8290788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 03/02/2021] [Indexed: 06/13/2023]
Abstract
Circular RNAs (circRNAs) in exosomes exhibit stable expression and are not easily degraded in plasma; a characteristic that makes them ideal as novel non-invasive tumor diagnostic markers. In this study, we examined different expression of circRNA in plasma exosomes of primary hepatocellular carcinoma patient and healthy volunteer by full transcriptome sequencing. Five circRNAs with up-regulated expression were selected, and large sample size verified their expression. Among them, it is further confirmed that exo_circ_0006602 is up-regulated in the large sample cohort. In addition, the expression level of exo_circ_0006602 was correlated with HBsAg (P<0.011), HBeAg (P=0.048), liver cirrhosis (P=0.001) and Edmondson-Steiner grade (P<0.001). The receiver operating characteristic (ROC) was used to evaluate the accuracy of exo_circ_0006602 as a diagnostic marker. The AUC value of exo_circ_0006602 was significantly highter than common serum tumor markers AFP and CEA. Exo_circ_0006602 combined with AFP can significantly improve the diagnostic accuracy. Cell function experiments show that exo_circ_0006602 can significantly improve the proliferation and invasion ability of liver cancer cell lines and also promoted the expression of tumor proliferation-related protein Snail. In conclusion, our results suggested that exo_circ_0006602 can be used as a potential non-invasive biomarker for the early diagnosis and screening of liver cancer, the sensitivity and specificity of diagnosis are higher than traditional tumor markers.
Collapse
Affiliation(s)
- Sen Guo
- Department of General Surgery, Qilu Hospital of Shandong University Jinan, China
| | - Chunxiao Hu
- Department of General Surgery, Qilu Hospital of Shandong University Jinan, China
| | - Xiangyu Zhai
- Department of General Surgery, Qilu Hospital of Shandong University Jinan, China
| | - Dong Sun
- Department of General Surgery, Qilu Hospital of Shandong University Jinan, China
| |
Collapse
|
|
19
|
Sorop A, Constantinescu D, Cojocaru F, Dinischiotu A, Cucu D, Dima SO. Exosomal microRNAs as Biomarkers and Therapeutic Targets for Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:ijms22094997. [PMID: 34066780 PMCID: PMC8125948 DOI: 10.3390/ijms22094997] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/28/2021] [Accepted: 05/04/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second most common cause of cancer-related death globally. This type of liver cancer is frequently detected at a late stage by current biomarkers because of the high clinical and biological heterogeneity of HCC tumours. From a plethora of molecules and cellular compounds, small nanoparticles with an endosomal origin are valuable cancer biomarkers or cargos for novel treatments. Despite their small sizes, in the range of 40–150 nm, these particles are delimited by a lipid bilayer membrane with a specific lipid composition and carry functional information—RNA, proteins, miRNAs, long non-coding RNAs (lncRNAs), or DNA fragments. This review summarizes the role of exosomal microRNA (miRNA) species as biomarkers in HCC therapy. After we briefly introduce the exosome biogenesis and the methods of isolation and characterization, we discuss miRNA’s correlation with the diagnosis and prognosis of HCC, either as single miRNA species, or as specific panels with greater clinical impact. We also review the role of exosomal miRNAs in the tumourigenic process and in the cell communication pathways through the delivery of cargos, including proteins or specific drugs.
Collapse
Affiliation(s)
- Andrei Sorop
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania; (A.S.); (D.C.); (S.O.D.)
- Department DAFAB, Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania; (F.C.); (A.D.)
| | - Diana Constantinescu
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania; (A.S.); (D.C.); (S.O.D.)
| | - Florentina Cojocaru
- Department DAFAB, Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania; (F.C.); (A.D.)
| | - Anca Dinischiotu
- Department DAFAB, Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania; (F.C.); (A.D.)
| | - Dana Cucu
- Department DAFAB, Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania; (F.C.); (A.D.)
- Correspondence: ; Tel.: +40-728-257-607
| | - Simona Olimpia Dima
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania; (A.S.); (D.C.); (S.O.D.)
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, 022238 Bucharest, Romania
| |
Collapse
|
|
20
|
Zhang W, Hu Z, Tian J, Fang C. A narrative review of near-infrared fluorescence imaging in hepatectomy for hepatocellular carcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:171. [PMID: 33569473 PMCID: PMC7867918 DOI: 10.21037/atm-20-5341] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Hepatectomy is a main therapeutic strategy for hepatocellular carcinoma (HCC), which requires removal of primary and disseminated tumors and maximum preservation of normal liver tissue. However, in a clinical operation, it is difficult to recognize the tumor tissue and its boundary with the naked eye and palpation, which often leads to insufficient or excessive resection. Near-infrared fluorescence (NIRF) imaging, a non-invasive, real-time, low-cost, and highly sensitive imaging technique has been extensively studied in surgical navigation. With the development of fluorescence imaging system and fluorescent probe, intraoperative tumor detection and margin definition can be achieved, making the operation more accurate. Advances in fluorescence imaging of HCC in the NIR region have focused on the traditional first NIR window (NIR-I, 700–900 nm), and have recently been extended to the second NIR window (NIR-II, 1,000–1,700 nm). Compared with NIR-I imaging, fluorescence imaging in the NIR-II exhibits great advantages, including higher spatial resolution, deeper penetration depth, and lower optical absorption and scattering from biological substrates with minimal tissue autofluorescence. There is no doubt that developing novel NIRF probes for in vivo imaging of HCC has high significance and direct impact on the field of liver surgery. In this article, the development of various NIRF probes for fluorescence image guided HCC hepatectomy is reviewed, and current challenges and potential opportunities of these imaging probes are discussed.
Collapse
Affiliation(s)
- Weiqi Zhang
- The First Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangdong Provincial Clinical and Engineering Center of Digital Medicine, Guangzhou, China.,CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, The State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, Beijing, China
| | - Zhenhua Hu
- CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, The State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Jie Tian
- CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, The State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Engineering Research Center of Molecular and Neuro Imaging of Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, China.,Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Medicine, Beihang University, Beijing, China
| | - Chihua Fang
- The First Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangdong Provincial Clinical and Engineering Center of Digital Medicine, Guangzhou, China
| |
Collapse
|
|
21
|
Attallah AM, Albannan MS, El-Deen MS, Farid K, Khedr FM, Attallah KA, Abdallah SO. Diagnostic role of collagen-III and matrix metalloproteinase-1 for early detection of hepatocellular carcinoma. Br J Biomed Sci 2020; 77:58-63. [PMID: 31903873 DOI: 10.1080/09674845.2019.1708534] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 12/16/2019] [Indexed: 12/13/2022]
Abstract
Background: As the poor prognosis of hepatocellular carcinoma (HCC) is mostly due to late detection at an advanced stage there is a strong need for establishing more effective strategies for early identification. We hypothesized that collagen-III and matrix metalloproteinase-1 (MMP-1) and their ratio (CMR) are effective markers for identifying early-HCC when used alongside serum AFP, alkaline phosphatase and bilirubin.Methods: We recruited 148 patients with HCC, 133 with cirrhosis and 121 with fibrosis. Liver fibrosis was staged according to METAVIR, HCC was diagnosed by on histological findings or typical imaging characteristics by ultrasound and computed tomography. Collagen-III and MMP-1 were identified based on Western blotting and quantified in sera using ELISA, liver function tests (LFTs) by routine methods.Results: Patients with HCC showed a significantly (P < 0.05) higher collagen-III and collagen-III/MMP-1 ratio (CMR) than fibrotic and cirrhotic patients. Patients with HCC showed significantly (P < 0.05) lower concentration of MMP-1 than those without. As expected, numerous LFTs were also abnormal. A score of AFP, alkaline phosphatase and bilirubin together with CMR (the HCC-ABC test) was then constructed, This yielded ROC area under curves of 0.85 (95% CI 0.79-0.98) for identifying small tumour size (<3 cm), 0.87 (0.79-0.98) for identifying CLIP (0-1) [Cancer of the Liver Italian Program] disease severity, and 0.87 (0.74-0.93) for identifying BCLC disease severity (all p < 0.001), which is each case exceeded the predictive value of AFP.Conclusion: HCC-ABC diagnostic Test is a promising index for HCC early detection with a high degree of accuracy that may facilitate therapy.
Collapse
Affiliation(s)
- A M Attallah
- Research & Development Department, Biotechnology Research Center, New Damietta, Egypt
| | - M S Albannan
- Research & Development Department, Biotechnology Research Center, New Damietta, Egypt
| | - M S El-Deen
- Research & Development Department, Biotechnology Research Center, New Damietta, Egypt
| | - K Farid
- Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - F M Khedr
- Research & Development Department, Biotechnology Research Center, New Damietta, Egypt
| | - K A Attallah
- Research & Development Department, Biotechnology Research Center, New Damietta, Egypt
| | - S O Abdallah
- Faculty of Science, Cairo University, Giza, Egypt
| |
Collapse
|
|
22
|
Wang H, Lu Z, Zhao X. Tumorigenesis, diagnosis, and therapeutic potential of exosomes in liver cancer. J Hematol Oncol 2019; 12:133. [PMID: 31815633 PMCID: PMC6902437 DOI: 10.1186/s13045-019-0806-6] [Citation(s) in RCA: 189] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 10/17/2019] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC, also called primary liver cancer) is one of the most fatal cancers in the world. Due to the insidiousness of the onset of HCC and the lack of effective treatment methods, the prognosis of HCC is extremely poor, and the 5-year average survival rate is less than 10%. Exosomes are nano-sized microvesicle and contain various components such as nucleic acids, proteins, and lipids. Exosomes are important carriers for signal transmission or transportation of material from cell to cell or between cells and tissues. In recent years, exosomes have been considered as potential therapeutic targets of HCC. A large number of reports indicate that exosomes play a key role in the establishment of an HCC microenvironment, as well as the development, progression, invasion, metastasis, and even the diagnosis, treatment, and prognosis of HCC. However, the exact molecular mechanisms and roles of exosomes in these processes remain unclear. We believe that elucidation of the regulatory mechanism of HCC-related exosomes and its signaling pathway and analysis of its clinical applications in the diagnosis and treatment of HCC can provide useful clues for future treatment regimens for HCC. This article discusses and summarizes the research progress of HCC-related exosomes and their potential clinical applications.
Collapse
Affiliation(s)
- Hongbo Wang
- Department of Radiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Zaiming Lu
- Department of Radiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Xiangxuan Zhao
- Department of Radiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China.
| |
Collapse
|
|
23
|
Wang H, Lu Z, Zhao X. Tumorigenesis, diagnosis, and therapeutic potential of exosomes in liver cancer. J Hematol Oncol 2019; 12:133. [DOI: doi10.1186/s13045-019-0806-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 10/17/2019] [Indexed: 09/01/2023] Open
Abstract
AbstractHepatocellular carcinoma (HCC, also called primary liver cancer) is one of the most fatal cancers in the world. Due to the insidiousness of the onset of HCC and the lack of effective treatment methods, the prognosis of HCC is extremely poor, and the 5-year average survival rate is less than 10%. Exosomes are nano-sized microvesicle and contain various components such as nucleic acids, proteins, and lipids. Exosomes are important carriers for signal transmission or transportation of material from cell to cell or between cells and tissues. In recent years, exosomes have been considered as potential therapeutic targets of HCC. A large number of reports indicate that exosomes play a key role in the establishment of an HCC microenvironment, as well as the development, progression, invasion, metastasis, and even the diagnosis, treatment, and prognosis of HCC. However, the exact molecular mechanisms and roles of exosomes in these processes remain unclear. We believe that elucidation of the regulatory mechanism of HCC-related exosomes and its signaling pathway and analysis of its clinical applications in the diagnosis and treatment of HCC can provide useful clues for future treatment regimens for HCC. This article discusses and summarizes the research progress of HCC-related exosomes and their potential clinical applications.
Collapse
|
|
24
|
Zhang Q, Han Z, Tao J, Zhao M, Zhang W, Li P, Tang L, Gu Y. An innovative peptide with high affinity to GPC3 for hepatocellular carcinoma diagnosis. Biomater Sci 2019; 7:159-167. [PMID: 30417190 DOI: 10.1039/c8bm01016a] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Glypican-3 (GPC3) is a key biomarker for early diagnosis of human hepatocellular carcinoma (HCC) due to its overexpression in most HCC tumor tissues. Recently, peptides with high affinity to GPC3 have attracted more attention because of their high biocompatibility, non-immunogenicity, fast clearing and easy modification. Herein, we have designed an innovative GPC3 targeting peptide (sequence: DYEMHLWWGTEL, denoted as IPA) by using structure-based virtual simulation. The higher binding abilities of IPA over the reported peptide (YP) were displayed on different cell lines, showing a positive correlation with GPC3 expressions, which were further verified by the GPC3 protein binding assay. The GPC3 targeting specificity of IPA was proved by peptide blocking and siRNA experiment. The localized anchor of peptide IPA on the cell membranes of HepG2 and Huh-7 with GPC3 overexpression confirmed the GPC3 binding capacity. By connecting a near-infrared dye MPA, the in vivo identification ability of IPA to GPC3 was also demonstrated on GPC3-positive (HepG2) and GPC3-negative (U87) xenograft-bearing mice. These results indicated that the designed IPA presented desirable GPC3 targeting ability, showing promising prospects in detecting the expression of GPC3 for HCC targeting imaging.
Collapse
Affiliation(s)
- Qi Zhang
- State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, Gulou District 210009, China.
| | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Chikhaliwala P, Rai R, Chandra S. Simultaneous voltammetric immunodetection of alpha-fetoprotein and glypican-3 using a glassy carbon electrode modified with magnetite-conjugated dendrimers. Mikrochim Acta 2019; 186:255. [DOI: 10.1007/s00604-019-3354-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 03/05/2019] [Indexed: 12/26/2022]
|
|
26
|
The association between vitamin D receptor gene polymorphisms and hepato-cellular carcinoma in Egyptian patients with chronic liver disease. GENE REPORTS 2018. [DOI: 10.1016/j.genrep.2018.07.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
|
|
27
|
Abstract
The differential diagnosis of hepatic mass lesions is broad and arriving at the right diagnosis can be challenging, especially on needle biopsies. The differential diagnosis of liver tumors in children is different from adults and is beyond the scope of this review. In adults, the approach varies depending on the age, gender, and presence of background liver disease. The lesions can be divided broadly into primary and metastatic (secondary), and the primary lesions can be further divided into those of hepatocellular origin and nonhepatocellular origin. The first category consists of benign and malignant lesions arising from hepatocytes, while the second category includes biliary, mesenchymal, hematopoietic, and vascular tumors. Discussion of nonepithelial neoplasms is beyond the scope of this review. The hepatocytic lesions comprise dysplastic nodules, focal nodular hyperplasia, hepatic adenoma, and hepatocellular carcinoma, and the differential diagnosis can be challenging requiring clinicopathological correlation and application of immunohistochemical (IHC) markers. Liver is a common site for metastasis, sometimes presenting with an unknown primary site, and proper workup is the key to arriving at the correct diagnosis. The correct diagnosis in this setting requires a systematic approach with attention to histologic features, imaging findings, clinical presentation, and judicious use of IHC markers. The list of antibodies that can be used for this purpose keeps on growing continually. It is important for pathologists to be up to date with the sensitivity and specificity of these markers and their diagnostic role and clinical implications. The purpose of this review is to outline the differential diagnosis of hepatic masses in adults and discuss an algorithmic approach to make a right diagnosis.
Collapse
Affiliation(s)
- Monika Vyas
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| | - Dhanpat Jain
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| |
Collapse
|
|
28
|
Islam MK, Kim S, Kim HK, Kim YH, Lee YM, Choi G, Baek AR, Sung BK, Kim M, Cho AE, Kang H, Lee GH, Choi SH, Lee T, Park JA, Chang Y. Synthesis and Evaluation of Manganese(II)-Based Ethylenediaminetetraacetic Acid-Ethoxybenzyl Conjugate as a Highly Stable Hepatobiliary Magnetic Resonance Imaging Contrast Agent. Bioconjug Chem 2018; 29:3614-3625. [PMID: 30383368 DOI: 10.1021/acs.bioconjchem.8b00560] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In this study, we designed and synthesized a highly stable manganese (Mn2+)-based hepatobiliary complex by tethering an ethoxybenzyl (EOB) moiety with an ethylenediaminetetraacetic acid (EDTA) coordination cage as an alternative to the well-established hepatobiliary gadolinium (Gd3+) chelates and evaluated its usage as a T1 hepatobiliary magnetic resonance imaging (MRI) contrast agent (CA). This new complex exhibits higher r1 relaxivity (2.3 mM-1 s-1) than clinically approved Mn2+-based hepatobiliary complex Mn-DPDP (1.6 mM-1 s-1) at 1.5 T. Mn-EDTA-EOB shows much higher kinetic inertness than that of clinically approved Gd3+-based hepatobiliary MRI CAs, such as Gd-DTPA-EOB and Gd-BOPTA. In addition, in vivo biodistribution and MRI enhancement patterns of this new Mn2+ chelate are comparable to those of Gd3+-based hepatobiliary MRI CAs. The diagnostic efficacy of the new complex was demonstrated by its enhanced tumor detection sensitivity in a liver cancer model using in vivo MRI.
Collapse
Affiliation(s)
| | | | | | - Yeoun-Hee Kim
- Institute of New Drug Research , Myungmoon Bio , 180, Yuram-ro , Dong-gu, Daegu 41059 , Korea
| | | | | | | | | | - Minsup Kim
- Department of Bioinformatics , Korea University Sejong Campus , 2511, Sejong-ro , Sejong City 30019 , Korea
| | - Art E Cho
- Department of Bioinformatics , Korea University Sejong Campus , 2511, Sejong-ro , Sejong City 30019 , Korea
| | | | | | - Seon Hee Choi
- Laboratory Animal Center , Daegu-Gyeongbuk Medical Innovation Foundation , 80, Chumbok-ro , Dong-gu, Daegu 41061 , Korea
| | - Taekwan Lee
- Laboratory Animal Center , Daegu-Gyeongbuk Medical Innovation Foundation , 80, Chumbok-ro , Dong-gu, Daegu 41061 , Korea
| | - Ji-Ae Park
- Molecular Imaging Research Center , Korea Institute of Radiological and Medical Sciences , Seoul 139-706 , Korea
| | - Yongmin Chang
- Department of Radiology , Kyungpook National University Hospital , 130 Dongdeok-ro , Jung-gu, Daegu 41944 , Korea
| |
Collapse
|
|
29
|
Hwang HM, Heo CK, Lee HJ, Kwak SS, Lim WH, Yoo JS, Yu DY, Lim KJ, Kim JY, Cho EW. Identification of anti-SF3B1 autoantibody as a diagnostic marker in patients with hepatocellular carcinoma. J Transl Med 2018; 16:177. [PMID: 29954402 PMCID: PMC6025833 DOI: 10.1186/s12967-018-1546-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 06/12/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Tumor-associated (TA) autoantibodies, which are generated by the immune system upon the recognition of abnormal TA antigens, are promising biomarkers for the early detection of tumors. In order to detect autoantibody biomarkers effectively, antibody-specific epitopes in the diagnostic test should maintain the specific conformations that are as close as possible to those presenting in the body. However, when using patients' serum as a source of TA autoantibodies the characterization of the autoantibody-specific epitope is not easy due to the limited amount of patient-derived serum. METHODS To overcome these limits, we constructed a B cell hybridoma pool derived from a hepatocellular carcinoma (HCC) model HBx-transgenic mouse and characterized autoantibodies derived from them as tumor biomarkers. Their target antigens were identified by mass spectrometry and the correlations with HCC were examined. With the assumption that TA autoantibodies generated in the tumor mouse model are induced in human cancer patients, the enzyme-linked immunosorbent assays (ELISA) based on the characteristics of mouse TA autoantibodies were developed for the detection of autoantibody biomarkers in human serum. To mimic natural antigenic structures, the specific epitopes against autoantibodies were screened from the phage display cyclic random heptapeptide library, and the streptavidin antigens fused with the specific epitopes were used as coating antigens. RESULTS In this study, one of HCC-associated autoantibodies derived from HBx-transgenic mouse, XC24, was characterized. Its target antigen was identified as splicing factor 3b subunit 1 (SF3B1) and the high expression of SF3B1 was confirmed in HCC tissues. The specific peptide epitopes against XC24 were selected and, among them, XC24p11 cyclic peptide (-CDATPPRLC-) was used as an epitope of anti-SF3B1 autoantibody ELISA. With this epitope, we could effectively distinguish between serum samples from HCC patients (n = 102) and healthy subjects (n = 85) with 73.53% sensitivity and 91.76% specificity (AUC = 0.8731). Moreover, the simultaneous detection of anti-XC24p11 epitope autoantibody and AFP enhanced the efficiency of HCC diagnosis with 87.25% sensitivity and 90.59% specificity (AUC = 0.9081). CONCLUSIONS ELISA using XC24p11 peptide epitope that reacts against anti-SF3B1 autoantibody can be used as a novel test to enhance the diagnostic efficiency of HCC.
Collapse
Affiliation(s)
- Hai-Min Hwang
- Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141 South Korea
- Department of Microbiology and Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134 South Korea
| | - Chang-Kyu Heo
- Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141 South Korea
- Department of Microbiology and Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134 South Korea
| | - Hye Jung Lee
- Proteometech Inc., 1101 Wooree Venture Town, 466 Gangseo-ro, Gangseo-gu, Seoul, 07573 South Korea
- Graduate Program for Nanomedical Science, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722 South Korea
| | - Sang-Seob Kwak
- Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141 South Korea
- Department of Functional Genomics, University of Science and Technology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141 South Korea
| | - Won-Hee Lim
- Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141 South Korea
- Department of Functional Genomics, University of Science and Technology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141 South Korea
| | - Jong-Shin Yoo
- Biomedical Omics Group, Korea Basic Science Institute, 162 YeonGuDanji-ro, Ochang-eup, Cheongju, Chungbuk 28119 South Korea
| | - Dae-Yuel Yu
- Disease Model Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141 South Korea
| | - Kook Jin Lim
- Proteometech Inc., 1101 Wooree Venture Town, 466 Gangseo-ro, Gangseo-gu, Seoul, 07573 South Korea
- Graduate Program for Nanomedical Science, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722 South Korea
| | - Jeong-Yoon Kim
- Department of Microbiology and Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134 South Korea
| | - Eun-Wie Cho
- Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141 South Korea
- Department of Functional Genomics, University of Science and Technology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141 South Korea
| |
Collapse
|
|
30
|
Long noncoding RNAs in the initiation, progression, and metastasis of hepatocellular carcinoma. Noncoding RNA Res 2017; 2:129-136. [PMID: 30159431 PMCID: PMC6084840 DOI: 10.1016/j.ncrna.2017.11.001] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 11/27/2017] [Accepted: 11/27/2017] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Despite awareness of risk factors for the development of HCC and advances in the diagnosis and clinical management of the disease, the molecular mechanisms underlying hepatocarcinogenesis remain poorly understood. Recent experimental studies provide strong evidence that long noncoding RNAs (lncRNAs), non-protein-coding transcripts with lengths >200 basepairs, contribute to the pathogenesis of numerous human diseases. Over the past decade, a role for lncRNAs in the initiation, progression, and metastasis of HCC has likewise emerged and developed into a highly active area of research. Although many lncRNAs appear to be dysregulated in HCC, extensive functional characterization has been performed on only a small proportion of these candidates to date. This review summarizes select lncRNAs that have been shown to wield functional relevance in the initiation, progression, or metastasis of HCC, focusing on the specific mechanisms by which lncRNA effects might be linked to clinical manifestations of the disease. In addition, an overview of circulating lncRNAs that have been identified as potential biomarkers for the diagnosis and prognosis of HCC is provided.
Collapse
|
|
31
|
Jacobson IM, Lim JK, Fried MW. American Gastroenterological Association Institute Clinical Practice Update-Expert Review: Care of Patients Who Have Achieved a Sustained Virologic Response After Antiviral Therapy for Chronic Hepatitis C Infection. Gastroenterology 2017; 152:1578-1587. [PMID: 28344022 DOI: 10.1053/j.gastro.2017.03.018] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Chronic hepatitis C virus infection is well-recognized as a common blood-borne infection with global public health impact affecting 3 to 5 million persons in the United States and more than 170 million persons worldwide. Chronic hepatitis C virus infection is associated with significant morbidity and mortality due to complications of liver cirrhosis and hepatocellular carcinoma. Current therapies with all-oral direct-acting antiviral agents are associated with high rates of sustained virologic response (SVR), generally exceeding 90%. SVR is associated with a reduced risk of liver cirrhosis, hepatic decompensation, need for liver transplantation, and both liver-related and all-cause mortality. However, a subset of patients who achieve SVR will remain at long-term risk for progression to cirrhosis, liver failure, hepatocellular carcinoma, and liver-related mortality. Limited evidence is available to guide clinicians on which post-SVR patients should be monitored vs discharged, how to monitor and with which tests, how frequently should monitoring occur, and for how long. In this clinical practice update, available evidence and expert opinion are used to generate best practice recommendations on the care of patients with chronic hepatitis C virus who have achieved SVR.
Collapse
Affiliation(s)
- Ira M Jacobson
- Department of Medicine, Mount Sinai Beth Israel Medical Center, Icahn School of Medicine at Mount Sinai, New York, New York.
| | - Joseph K Lim
- Section of Digestive Diseases and Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut
| | - Michael W Fried
- Division of Gastroenterology and Hepatology, UNC Liver Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| |
Collapse
|
|
32
|
Bevilacqua V, Brunetti A, Trotta GF, Carnimeo L, Marino F, Alberotanza V, Scardapane A. A Deep Learning Approach for Hepatocellular Carcinoma Grading. ACTA ACUST UNITED AC 2017. [DOI: 10.4018/ijcvip.2017040101] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction and objective: Computer Aided Decision (CAD) systems based on Medical Imaging could support radiologists in grading Hepatocellular carcinoma (HCC) by means of Computed Tomography (CT) images, thus avoiding medical invasive procedures such as biopsies. The identification and characterization of Regions of Interest (ROIs) containing lesions is an important phase allowing an easier classification in two classes of HCCs. Two steps are needed for the detection of lesioned ROIs: a liver isolation in each CT slice and a lesion segmentation. Materials and methods: Materials consist in abdominal CT hepatic lesion from 18 patients subjected to liver transplant, partial hepatectomy, or US-guided needle biopsy. Several approaches are implemented to segment the region of liver and, then, detect the lesion ROI. Results: A Deep Learning approach using Convolutional Neural Network is followed for HCC grading. The obtained good results confirm the robustness of the segmentation algorithms leading to a more accurate classification.
Collapse
Affiliation(s)
- Vitoantonio Bevilacqua
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Bari, Italy
| | - Antonio Brunetti
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Bari, Italy
| | | | - Leonarda Carnimeo
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Bari, Italy & Apulia Intelligent Systems Ltd, Bari, Italy
| | - Francescomaria Marino
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Bari, Italy
| | - Vito Alberotanza
- Interdisciplinary Department of Medicine - Section of Diagnostic Imaging, University of Bari, Bari, Italy
| | - Arnaldo Scardapane
- Interdisciplinary Department of Medicine - Section of Diagnostic Imaging, University of Bari, Bari, Italy
| |
Collapse
|
|
33
|
Hernandez R, Sun H, England CG, Valdovinos HF, Ehlerding EB, Barnhart TE, Yang Y, Cai W. CD146-targeted immunoPET and NIRF Imaging of Hepatocellular Carcinoma with a Dual-Labeled Monoclonal Antibody. Am J Cancer Res 2016; 6:1918-33. [PMID: 27570560 PMCID: PMC4997246 DOI: 10.7150/thno.15568] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 06/27/2016] [Indexed: 12/16/2022] Open
Abstract
Overexpression of CD146 has been correlated with aggressiveness, recurrence rate, and poor overall survival in hepatocellular carcinoma (HCC) patients. In this study, we set out to develop a CD146-targeting probe for high-contrast noninvasive in vivo positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging of HCCs. YY146, an anti-CD146 monoclonal antibody, was employed as a targeting molecule to which we conjugated the zwitterionic near-infrared fluorescence (NIRF) dye ZW800-1 and the chelator deferoxamine (Df). This enabled labeling of Df-YY146-ZW800 with (89)Zr and its subsequent detection using PET and NIRF imaging, all without compromising antibody binding properties. Two HCC cell lines expressing high (HepG2) and low (Huh7) levels of CD146 were employed to generate subcutaneous (s.c.) and orthotopic xenografts in athymic nude mice. Sequential PET and NIRF imaging performed after intravenous injection of (89)Zr-Df-YY146-ZW800 into tumor-bearing mice unveiled prominent and persistent uptake of the tracer in HepG2 tumors that peaked at 31.65 ± 7.15 percentage of injected dose per gram (%ID/g; n=4) 72 h post-injection. Owing to such marked accumulation, tumor delineation was successful by both PET and NIRF, which facilitated the fluorescence image-guided resection of orthotopic HepG2 tumors, despite the relatively high liver background. CD146-negative Huh7 and CD146-blocked HepG2 tumors exhibited significantly lower (89)Zr-Df-YY146-ZW800 accretion (6.1 ± 0.5 and 8.1 ± 1.0 %ID/g at 72 h p.i., respectively; n=4), demonstrating the CD146-specificity of the tracer in vivo. Ex vivo biodistribution and immunofluorescent staining corroborated the accuracy of the imaging data and correlated tracer uptake with in situ CD146 expression. Overall, (89)Zr-Df-YY146-ZW800 showed excellent properties as a PET/NIRF imaging agent, including high in vivo affinity and specificity for CD146-expressing HCC. CD146-targeted molecular imaging using dual-labeled YY146 has great potential for early detection, prognostication, and image-guided surgical resection of liver malignancies.
Collapse
|
|
34
|
Grözinger G, Bitzer M, Syha R, Ketelsen D, Nikolaou K, Lauer U, Horger M. Correlation of magnetic resonance signal characteristics and perfusion parameters assessed by volume perfusion computed tomography in hepatocellular carcinoma: Impact on lesion characterization. World J Radiol 2016; 8:683-692. [PMID: 27551338 PMCID: PMC4965352 DOI: 10.4329/wjr.v8.i7.683] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 03/14/2016] [Accepted: 05/11/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To find out if magnetic resonance (MR)-signal characteristics of hepatocellular carcinomas (HCC) correlate with perfusion parameters assessed by volume perfusion computed tomography (VPCT).
METHODS: From October 2009 to January 2014, 26 (mean age, 69.3 years) patients with 36 HCC lesions who underwent both VPCT and MR liver imaging were analysed. We compared signal intensity in the T1w- and T2w-images and wash-in/wash-out kinetics on post-contrast MR images with mean values of blood flow (BF, mL/100 mL per minute), blood volume (BV, mL/100 mL), k-trans (mL/100 mL per minute), arterial liver perfusion (mL/100 mL per minute), portal venous perfusion and hepatic perfusion index (HPI, %) obtained by VPCT. Signal intensity on magnetic resonance imaging (MRI) was classified hyper/iso/hypointense compared with surrounding liver parenchyma.
RESULTS: Signal intensity on native T1w- and T2w-images was hyper/iso/hypo in 4/16/16 and 21/14/1 lesions, respectively. Wash-in and wash-out contrast kinetics were found on MRI in 33 of 36 lesions (91.7%) and 25 of 36 lesions (69.4%), respectively. The latter was observed significantly more often in higher graded lesions (P < 0.005). HPI was 94.7% ± 6.5%. There was no significant relationship between lesion’s MR-signal intensity, MR signal combinations, size and any of the VPCT-perfusion parameters. However HPI was constantly high in all HCC lesions.
CONCLUSION: VPCT parameters add limited value to MR-lesion characterization. However in HCC lesions with atypical MR signal characteristics HPI can add a parameter to ensure HCC diagnosis.
Collapse
|
|
35
|
Yang SH, Lin J, Lu F, Han ZH, Fu CX, Lv P, Liu H, Gao DM. Evaluation of antiangiogenic and antiproliferative effects of sorafenib by sequential histology and intravoxel incoherent motion diffusion-weighted imaging in an orthotopic hepatocellular carcinoma xenograft model. J Magn Reson Imaging 2016; 45:270-280. [PMID: 27299302 DOI: 10.1002/jmri.25344] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 05/27/2016] [Indexed: 12/11/2022] Open
Abstract
PURPOSE To investigate the effectiveness of intravoxel incoherent motion (IVIM) in the assessment of the therapeutic efficacy of sorafenib in an orthotopic hepatocellular carcinoma (HCC) xenograft model. MATERIALS AND METHODS Thirty-five HCC nude mouse models were established. IVIM was performed on a 1.5T MR scanner at baseline (n = 5) and serially at 7, 14, and 21 days after sorafenib treatment. The apparent diffusion coefficient (ADCtotal ), true diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) at these timepoints were measured and compared between the treated (n = 15) and control group (n = 15). Differences in measurements among different timepoints were evaluated. Correlations between IVIM parameters and histologic features including necrotic fraction (NF) and microvessel density (MVD) were analyzed. RESULTS Compared to the control group, ADCtotal and D were significantly higher at each timepoint (P = 0.009), while f significantly decreased at 7 days (P = 0.009) and increased at 21 days (P = 0.028) in the treated group. Serial measurements in the treated group showed that both ADCtotal and D increased significantly at 7, 14, and 21 days compared to baseline (P < 0.05), while f significantly declined at 7 days (P = 0.016) and increased at 21 days (P = 0.009). Significant correlations were found between ADCtotal and NF (r = 0.811, P < 0.001), D and NF (r = 0.838, P < 0.001), and between f and NF (r = 0.528, P = 0.017) in the treated group. CONCLUSION IVIM may provide useful biomarkers for evaluating the therapeutic effects of sorafenib on HCC. LEVEL OF EVIDENCE 1 J. Magn. Reson. Imaging 2017;45:270-280.
Collapse
Affiliation(s)
- Shuo-Hui Yang
- Department of Radiology, Zhongshan Hospital, Shanghai Medical College, Fudan University, and Shanghai Institute of Medical Imaging, Shanghai, China
| | - Jiang Lin
- Department of Radiology, Zhongshan Hospital, Shanghai Medical College, Fudan University, and Shanghai Institute of Medical Imaging, Shanghai, China
| | - Fang Lu
- Department of Radiology, Shuguang Hosipital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhi-Hong Han
- Department of Pathology, Shuguang Hosipital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Cai-Xia Fu
- Siemens Shenzhen Magnetic Resonance Ltd., Shenzhen, China
| | - Peng Lv
- Department of Radiology, Zhongshan Hospital, Shanghai Medical College, Fudan University, and Shanghai Institute of Medical Imaging, Shanghai, China
| | - Hao Liu
- Department of Radiology, Zhongshan Hospital, Shanghai Medical College, Fudan University, and Shanghai Institute of Medical Imaging, Shanghai, China
| | - Dong-Mei Gao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| |
Collapse
|