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Wang W, Zhou Y, Li W, Quan C, Li Y. Claudins and hepatocellular carcinoma. Biomed Pharmacother 2024; 171:116109. [PMID: 38185042 DOI: 10.1016/j.biopha.2023.116109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/23/2023] [Accepted: 12/28/2023] [Indexed: 01/09/2024] Open
Abstract
Hepatocellular carcinoma (HCC) has a high incidence and dismal prognosis, making it a significant global health burden. To change this, the development of new therapeutic strategies is imminent. The claudin (CLDN) family, as key components of tight junctions (TJs), plays an important role in the initiation and development of cancer. Dysregulated expression of CLDNs leads to loss of intercellular adhesion and aberrant cell signaling, which are closely related to cancer cell invasion, migration, and epithelial-mesenchymal transition (EMT). CLDN1, CLDN3, CLDN4, CLDN5, CLDN6, CLDN7, CLDN9, CLDN10, CLDN11, CLDN14, and CLDN17 are aberrantly expressed in HCC, which drives the progression of the disease. Consequently, they have tremendous potential as prognostic indicators and therapeutic targets. This article summarizes the aberrant expression, molecular mechanisms, and clinical application studies of different subtypes of CLDNs in HCC, with a particular emphasis on CLDN1.
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Affiliation(s)
- Wentao Wang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, Jilin 130021, China; The Second Norman Bethune College of Clinical Medicine, Jilin University, Changchun 130021, China
| | - Yi Zhou
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, Jilin 130021, China; The First Norman Bethune College of Clinical Medicine, Jilin University, Changchun 130021, China
| | - Wei Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, Jilin 130021, China
| | - Chengshi Quan
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, Jilin 130021, China
| | - Yanru Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, Jilin 130021, China.
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Liu H, Chen L, Wang C, Zhou H. The expression and significance of vascular endothelial growth factor A in adenoid cystic carcinoma of palatal salivary gland. Eur Arch Otorhinolaryngol 2022; 279:5869-5875. [PMID: 35781742 DOI: 10.1007/s00405-022-07502-8] [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: 04/19/2022] [Accepted: 06/09/2022] [Indexed: 01/04/2023]
Abstract
OBJECTIVE To explore the VEGF-A expression in salivary gland adenoid cystic carcinoma tissues and detect the relationship between the mechanism of occurrence, development and metastasis of jaws with salivary gland adenoid cystic carcinoma and VEGF-A expression. METHODS Paraffin samples from 58 cases of SACC of the palate and ten cases of normal salivary gland tissues were collected. The expression levels of VEGF-A protein were detected using the immunohistochemistry EnVision system. RESULTS Among the 58 cases, there were 20 cases of the cribriform type, 17 cases of the tubular type, and 21 cases of the solid type. There were 9 cases with lymph node metastasis and 21 cases without lymph node metastasis. And there were 8 cases of T1, 15 cases of T2, and 7 cases of T3/T4. The positive expression rate of VEGF-A in SACC of the palate was 74.1%, which was higher than that found in normal salivary gland tissues (10%). The VEGF-A was localized in the cytoplasm/cell membrane. CONCLUSION VEGF-A is highly expressed in SACC of the palate. The level of expression is closely related to the pathological grade, lymph node metastasis, and clinical stage of the tumor, and it can thus be used as an important indicator for judging the biological behavior of SACC of the palate.
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Affiliation(s)
- Haitao Liu
- Department of Oral and Maxillofacial Surgery, First People's Hospital of Jiujiang City, Jiujiang, 332000, Jiangxi, China
| | - Linlin Chen
- Department of Oral and Maxillofacial Surgery, Stomatological Hospital of Nanchang University, No. 49 Fuzhou Road, Nanchang, 320049, Jiangxi, China.
| | - Chenliang Wang
- Department of Pathology, First People's Hospital of Jiujiang City, Jiujiang, 332000, Jiangxi, China
| | - Haibo Zhou
- Department of Oral and Maxillofacial Surgery, First People's Hospital of Jiujiang City, Jiujiang, 332000, Jiangxi, China
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TED: Two-stage expert-guided interpretable diagnosis framework for microvascular invasion in hepatocellular carcinoma. Med Image Anal 2022; 82:102575. [DOI: 10.1016/j.media.2022.102575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 07/08/2022] [Accepted: 08/11/2022] [Indexed: 12/16/2022]
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Lee SW, Yen CL, Cheng YC, Shun Yang S, Lee TY. The radiological prognostic factors of transcatheter arterial chemoembolization to hepatocellular carcinoma. Medicine (Baltimore) 2022; 101:e30875. [PMID: 36254047 PMCID: PMC9575733 DOI: 10.1097/md.0000000000030875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Transcatheter arterial chemoembolization (TACE) is the recommended treatment modality for intermediate stage hepatocellular carcinoma (HCC). The aim of this study was to determine the HCC radiological characteristics associated with prognosis of patients with intermediate stage HCC receiving TACE. Patients with HCC BCLC stage B from January 2005 to December 2009 were collected. According to mRECIST criteria, patients with complete response and partial response were assigned to the objective response (OR) group, while those with stable disease and progressive disease were assigned to the nonobjective response (non-OR) group. Among a total of 128 enrolled patients, there were 66 (51.6%) and 62 (48.4%) patients in the OR group and non-OR group, respectively. The clinical parameters in the two groups were similar, although HCC size was smaller in the OR group. Logistic analysis found combined radiological characteristics including complete lipiodol retention, tumor feeding artery blockage, and no residual tumor blush were significant correlated with achievement of OR (odds ratio 2.46, 95% CI 1.08-5.61, P = .032). However, no radiological characteristics had significant strength to predict overall survival. Patients with OR after TACE had significantly longer survival time than those with non-OR. Combined characteristics of complete lipiodol retention, tumor feeding artery blockage, and no residual tumor blush had a positive impact on OR in TACE. In patients receiving TACE, those who achieved OR had a better overall survival.
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Affiliation(s)
- Shou-Wu Lee
- Division of Hepatology and Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Internal Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Internal Medicine, Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, Chung Hsing University, Taiwan
| | - Chieh-Ling Yen
- Division of Hepatology and Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yu-Chi Cheng
- Koo Foundation Sun Yat-Sen Cncer Center Department of Radiology, Taipei, Taiwan
- Department of Internal Medicine, Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Sheng Shun Yang
- Division of Hepatology and Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Internal Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Internal Medicine, Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Biomedical Sciences, Chung Hsing University, Taichung, Taiwan
| | - Teng-Yu Lee
- Division of Hepatology and Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Internal Medicine, Chung Shan Medical University, Taichung, Taiwan
- *Correspondence: Teng-Yu Lee, Division of Hepatology and Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, 1650 Taiwan Boulevard, Sec. 4, Taichung 40705, Taiwan (e-mail: )
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Tang Z, Wu S, Zhao P, Wang H, Ni D, Li H, Jiang X, Wu Y, Meng Y, Yao Z, Cai W, Bu W. Chemical Factory-Guaranteed Enhanced Chemodynamic Therapy for Orthotopic Liver Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2201232. [PMID: 35712774 PMCID: PMC9376848 DOI: 10.1002/advs.202201232] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/09/2022] [Indexed: 05/05/2023]
Abstract
In the field of nanomedicine, there is a tendency of matching designed nanomaterials with a suitable type of orthotopic cancer model, not just a casual subcutaneous one. Under this condition, knowing the specific features of the chosen cancer model is the priority, then introducing a proper therapy strategy using designed nanomaterials. Here, the Fenton chemistry is combined with zinc peroxide nanoparticles in the treatment of orthotopic liver cancer which has a "chemical factory" including that liver is the main place for iron storage, metabolism, and also the main metabolic sites for the majority of ingested substances, guaranteeing customized and enhanced chemodynamic therapy and normal liver cells protection as well. The good results in vitro and in vivo can set an inspiring example for exploring and utilizing suitable nanomaterials in corresponding cancer models, ensuring well-fitness of nanomaterials for disease and satisfactory therapeutic effect.
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Affiliation(s)
- Zhongmin Tang
- Tongji University Cancer CenterShanghai Tenth People's HospitalTongji University School of MedicineShanghai200072P. R. China
- Departments of Radiology, Medical Physics, Materials Science & EngineeringPharmaceutical SciencesUniversity of Wisconsin − MadisonMadisonWI53705USA
| | - Shiman Wu
- Department of RadiologyHuashan HospitalFudan UniversityShanghai200040P. R. China
| | - Peiran Zhao
- Department of Materials Science and State Key Laboratory of Molecular Engineering of PolymersFudan University220 Handan RoadShanghai200438P. R. China
| | - Han Wang
- Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghai200240P. R. China
| | - Dalong Ni
- Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghai200240P. R. China
| | - Huiyan Li
- Department of Materials Science and State Key Laboratory of Molecular Engineering of PolymersFudan University220 Handan RoadShanghai200438P. R. China
| | - Xingwu Jiang
- Department of Materials Science and State Key Laboratory of Molecular Engineering of PolymersFudan University220 Handan RoadShanghai200438P. R. China
| | - Yelin Wu
- Tongji University Cancer CenterShanghai Tenth People's HospitalTongji University School of MedicineShanghai200072P. R. China
| | - Yun Meng
- Tongji University Cancer CenterShanghai Tenth People's HospitalTongji University School of MedicineShanghai200072P. R. China
| | - Zhenwei Yao
- Department of RadiologyHuashan HospitalFudan UniversityShanghai200040P. R. China
| | - Weibo Cai
- Departments of Radiology, Medical Physics, Materials Science & EngineeringPharmaceutical SciencesUniversity of Wisconsin − MadisonMadisonWI53705USA
| | - Wenbo Bu
- Tongji University Cancer CenterShanghai Tenth People's HospitalTongji University School of MedicineShanghai200072P. R. China
- Department of Materials Science and State Key Laboratory of Molecular Engineering of PolymersFudan University220 Handan RoadShanghai200438P. R. China
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Characterization of the Impacts of Living at High Altitude in Taif: Oxidative Stress Biomarker Alterations and Immunohistochemical Changes. Curr Issues Mol Biol 2022; 44:1610-1625. [PMID: 35723368 PMCID: PMC9164078 DOI: 10.3390/cimb44040110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 04/05/2022] [Accepted: 04/06/2022] [Indexed: 11/17/2022] Open
Abstract
At high elevations, the human body experiences a number of pathological, physiological, and biochemical changes, all of which have adverse impacts on human health and organ vitality. This study aimed to investigate the alterations in the liver and kidney biomarkers, oxidative stress markers, gene expression, and cellular histology of rats maintained at high altitudes and normal sea level. A total of twenty male Wistar rats at 2 months of age were randomly assigned to two groups. The rats in group A were maintained at normal sea level in Jeddah, whereas rats in group B were maintained in an area in Taif 2600 m above sea level. After 2 months of housing, orbital blood samples were collected for the analysis of significant biochemical indicators of oxidative stress biomarkers of the liver and kidneys. Liver and kidney tissues from both groups were taken to examine the hepatorenal changes occurring at the biochemical, histological, immunohistochemical, and genetic levels. The results revealed substantial increases in the serum levels of liver and kidney biomarkers (GPT, GOT, urea, and creatinine) and decreases in the serum levels of antioxidant biomarkers (SOD, catalase, GSH, and NO). In parallel, the levels of the malondialdehyde (MDA) tissue damage marker and inflammatory cytokines (IL-1β, TNF-α, and IFN-γ) were increased in the high-altitude group compared to the normal sea level group. In addition, there were significant alterations in the oxidative and inflammatory status of rats that lived at high altitude, with considerable upregulation in the expression of hepatic VEGF, type 1 collagen, Cox-2, TNF-α, and iNOS as well as renal EPASI, CMYC, HIF-α, and EGLN-2 genes in the high-altitude group compared with controls housed at normal sea level. In conclusion, living at high altitude induces hepatorenal damage and biochemical and molecular alterations, all of which may serve as critical factors that must be taken into account for organisms living at high altitudes.
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Lei P, Chen H, Feng C, Yuan X, Xiong Z, Liu Y, Liao W. Noninvasive Visualization of Sub-5 mm Orthotopic Hepatic Tumors by a Nanoprobe-Mediated Positive and Reverse Contrast-Balanced Imaging Strategy. ACS NANO 2022; 16:897-909. [PMID: 35005889 DOI: 10.1021/acsnano.1c08477] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Delineation of small malignant lesions and their vasculature enables early and accurate diagnosis of hepatocellular carcinoma (HCC). However, it remains challenging to identify these features simultaneously by noninvasive imaging technology. Reverse contrast imaging emerges as a powerful means to detect early-stage HCC by taking inspiration from the intrinsic liver phagocytosis toward exogenous agents to generate negative tumor-to-normal tissue signals. However, this mechanism conflicts with the signal-enhancing requirements for vasculature visualization. Here, we solve this conundrum by designing a positive and reverse contrast-balanced imaging strategy based on a multifunctional PEG-Ta2O5@CuS nanoprobe that combines advanced gemstone spectral computer tomography (GSCT) with photoacoustic (PA) imaging. The nanoprobe exhibits preferential accumulation in Kupffer cells and hepatocytes over tumor cells, and its spectral properties are well matched with GSCT, leading to the enhancement of reverse contrast signals that enable clear delineation of 2-4 mm orthotopic HCC lesions. Meanwhile, its strong PA imaging capability at the second near-infrared (NIR-II) window makes vascular evaluation accessible by monitoring the positive signal enhancement derived from the limited tumor accumulation of the nanoprobe. In addition, the nanoprobe enables NIR-II photohyperthermia for timely tumor ablation. Overall, this proposed strategy shows potential in early detection and theranostics of HCC for improved clinical outcomes.
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Affiliation(s)
- Peng Lei
- Department of Radiology, Xiangya Hospital, Central South University, Changsha 410008, China
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha 410082, China
| | - Hong Chen
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha 410082, China
| | - Cai Feng
- Department of Radiology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xi Yuan
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha 410082, China
| | - Zongling Xiong
- Department of Radiology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yanlan Liu
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha 410082, China
| | - Weihua Liao
- Department of Radiology, Xiangya Hospital, Central South University, Changsha 410008, China
- Molecular Imaging Research Center of Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
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Dong RJ, Yang HS, Li J, Wang RR, Wang L, Li YY. Giant Spider Angioma Following Cirrhosis in HIV-Infected Individuals. Am J Med Sci 2022; 364:347-352. [PMID: 34990592 DOI: 10.1016/j.amjms.2021.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 11/10/2021] [Accepted: 12/20/2021] [Indexed: 11/01/2022]
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9
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Deng L, He K, Pan Y, Wang H, Luo Y, Xia Q. The role of tumor-associated macrophages in primary hepatocellular carcinoma and its related targeting therapy. Int J Med Sci 2021; 18:2109-2116. [PMID: 33859517 PMCID: PMC8040428 DOI: 10.7150/ijms.56003] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 03/03/2021] [Indexed: 12/12/2022] Open
Abstract
Liver macrophages consist of ontogenically distinct populations termed Kupffer cells and monocyte-derived macrophages. Tumor-associated macrophages (TAMs) inhepatocellularcarcinoma (HCC) play a prominent role in tumormicroenvironment by presenting M1(induced by IFN γ along with LPS) and M2(induced by IL-4 and IL13) polarization. Although TAMs are involved in tumor immune surveillance during the course of HCC, they contribute to tumour progression at different levels by inhibiting the anti-tumor immune response, promoting the generation of blood vessels and lymphatic vessels, and supporting the proliferation and survival of tumor cells. In this paper, the multiple functions of TAMs in HCC were reviewed to provide assistance for future researches about therapeutic approaches.
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Affiliation(s)
- Lu Deng
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kang He
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yixiao Pan
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hai Wang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yi Luo
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Zhang Q, Wu J, Bai X, Liang T. Evaluation of Intra-Tumoral Vascularization in Hepatocellular Carcinomas. Front Med (Lausanne) 2020; 7:584250. [PMID: 33195338 PMCID: PMC7652932 DOI: 10.3389/fmed.2020.584250] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 09/07/2020] [Indexed: 12/13/2022] Open
Abstract
Intratumoral neovascularization has intricate effects on tumor growth, metastasis, and treatment. Over the last 30 years, Microvessel density (MVD) has been the standard method for laboratory and clinical evaluation of angiogenesis. Hepatocellular carcinoma (HCC) is a typical hypervascularized tumor, and the predictive value of MVD for prognosis is still controversial. According to previous viewpoints, this has been attributed to the determination of hotspot, counting methods, vascular endothelial markers, and different definitions of high and low vascular density; however, the heterogeneity of tumor angiogenesis patterns should be factored. The breakthroughs in artificial intelligence and algorithm can improve the objectivity and repeatability of MVD measurement, thus saving a lot of manpower. Presently, anti-angiogenesis therapy is the only effective systematic treatment for liver cancer, and the use of imaging technology-assisted MVD measurement is expected to be a reliable index for evaluating the curative effect. MVD in multinodular hepatocellular carcinoma represents a subject area with huge understudied potential, and exploring it might advance our understanding of tumor heterogeneity.
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Affiliation(s)
- Qi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China.,Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China
| | - Jiajun Wu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China.,Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China.,Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China
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Luo N, Li W, Xie J, Fu D, Liu L, Huang X, Su D, Jin G. Preoperative normalized iodine concentration derived from spectral CT is correlated with early recurrence of hepatocellular carcinoma after curative resection. Eur Radiol 2020; 31:1872-1882. [PMID: 33037444 DOI: 10.1007/s00330-020-07330-6] [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: 05/05/2020] [Revised: 08/10/2020] [Accepted: 09/21/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVES To investigate whether normalized iodine concentration (NIC) correlates with tumor microvessel density and early recurrence in patients with HCC. MATERIALS AND METHODS We included 71 patients with surgically resected single HCC in this prospective study who underwent preoperative spectral CT between November 2014 and June 2016. Two observers independently measured the NIC in the arterial phase (AP) and portal venous phase (PVP). The relationship between NIC and microvessel density was evaluated. Univariate and multivariate logistic regression was performed to evaluate independent predictors of early recurrence. RESULTS Early recurrence occurred in 28 of 71 patients (39.4%) during the 2-year follow-up. NIC-AP positively correlated with microvessel density for the two observers (r = 0.593 and 0.527). Based on multivariate analysis, independent risk factors for early HCC recurrence were tumor size (odds ratio, 1.200; p = 0.043) and NIC-AP (odds ratio, 2.522; p = 0.005). For the two observers, areas under the receiver operating characteristic curve for predicting early HCC recurrence were 0.719 and 0.677. Early recurrence rates were significantly higher among patients with NIC-AP values higher than the optimal cutoff than among those with values below the cutoff. CONCLUSION Normalized iodine concentration in the arterial phase from spectral CT reflects tumor-derived angiogenesis and is a potential predictive biomarker for early recurrence of hepatocellular carcinoma. KEY POINTS • Normalized iodine concentration in the arterial phase positively correlated with microvessel density of hepatocellular carcinoma. • In the patients with hepatocellular carcinoma, tumor size and normalized iodine concentration in the arterial phase were independent risk factors for early hepatocellular carcinoma recurrence. • Early hepatocellular carcinoma recurrence rates were significantly higher when normalized iodine concentration in the arterial phase values was above the optimal cutoff.
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Affiliation(s)
- Ningbin Luo
- Department of Radiology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
- Department of Radiology, Guangxi Clinical Medical Research Center of Imaging Medicine, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
- Department of Radiology, Guangxi Key Clinical Specialties, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
- Department of Radiology, Guangxi Medical University Cancer Hospital Superiority Cultivation Discipline, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
| | - Wenzhu Li
- Department of Radiology, Hainan People's Hospital, Haikou, Hainan, People's Republic of China
| | - Jisheng Xie
- Department of Radiology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
- Department of Radiology, Guangxi Clinical Medical Research Center of Imaging Medicine, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
- Department of Radiology, Guangxi Key Clinical Specialties, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
- Department of Radiology, Guangxi Medical University Cancer Hospital Superiority Cultivation Discipline, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
| | - Danhui Fu
- Department of Radiology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
- Department of Radiology, Guangxi Clinical Medical Research Center of Imaging Medicine, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
- Department of Radiology, Guangxi Key Clinical Specialties, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
- Department of Radiology, Guangxi Medical University Cancer Hospital Superiority Cultivation Discipline, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
| | - Lidong Liu
- Department of Radiology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
- Department of Radiology, Guangxi Clinical Medical Research Center of Imaging Medicine, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
- Department of Radiology, Guangxi Key Clinical Specialties, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
- Department of Radiology, Guangxi Medical University Cancer Hospital Superiority Cultivation Discipline, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
| | - Xiangyang Huang
- Department of Radiology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
- Department of Radiology, Guangxi Clinical Medical Research Center of Imaging Medicine, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
- Department of Radiology, Guangxi Key Clinical Specialties, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
- Department of Radiology, Guangxi Medical University Cancer Hospital Superiority Cultivation Discipline, 71 Hedi Road, Nanning, Guangxi, People's Republic of China
| | - Danke Su
- Department of Radiology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, Guangxi, People's Republic of China.
- Department of Radiology, Guangxi Clinical Medical Research Center of Imaging Medicine, 71 Hedi Road, Nanning, Guangxi, People's Republic of China.
- Department of Radiology, Guangxi Key Clinical Specialties, 71 Hedi Road, Nanning, Guangxi, People's Republic of China.
- Department of Radiology, Guangxi Medical University Cancer Hospital Superiority Cultivation Discipline, 71 Hedi Road, Nanning, Guangxi, People's Republic of China.
| | - Guanqiao Jin
- Department of Radiology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, Guangxi, People's Republic of China.
- Department of Radiology, Guangxi Clinical Medical Research Center of Imaging Medicine, 71 Hedi Road, Nanning, Guangxi, People's Republic of China.
- Department of Radiology, Guangxi Key Clinical Specialties, 71 Hedi Road, Nanning, Guangxi, People's Republic of China.
- Department of Radiology, Guangxi Medical University Cancer Hospital Superiority Cultivation Discipline, 71 Hedi Road, Nanning, Guangxi, People's Republic of China.
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Zhang L, Xia W, Yan ZP, Sun JH, Zhong BY, Hou ZH, Yang MJ, Zhou GH, Wang WS, Zhao XY, Jian JM, Huang P, Zhang R, Zhang S, Zhang JY, Li Z, Zhu XL, Gao X, Ni CF. Deep Learning Predicts Overall Survival of Patients With Unresectable Hepatocellular Carcinoma Treated by Transarterial Chemoembolization Plus Sorafenib. Front Oncol 2020; 10:593292. [PMID: 33102242 PMCID: PMC7556271 DOI: 10.3389/fonc.2020.593292] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 09/14/2020] [Indexed: 12/12/2022] Open
Abstract
Objectives To develop and validate a deep learning-based overall survival (OS) prediction model in patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) plus sorafenib. Methods This retrospective multicenter study consisted of 201 patients with treatment-naïve, unresectable HCC who were treated with TACE plus sorafenib. Data from 120 patients were used as the training set for model development. A deep learning signature was constructed using the deep image features from preoperative contrast-enhanced computed tomography images. An integrated nomogram was built using Cox regression by combining the deep learning signature and clinical features. The deep learning signature and nomograms were also externally validated in an independent validation set of 81 patients. C-index was used to evaluate the performance of OS prediction. Results The median OS of the entire set was 19.2 months and no significant difference was found between the training and validation cohort (18.6 months vs. 19.5 months, P = 0.45). The deep learning signature achieved good prediction performance with a C-index of 0.717 in the training set and 0.714 in the validation set. The integrated nomogram showed significantly better prediction performance than the clinical nomogram in the training set (0.739 vs. 0.664, P = 0.002) and validation set (0.730 vs. 0.679, P = 0.023). Conclusion The deep learning signature provided significant added value to clinical features in the development of an integrated nomogram which may act as a potential tool for individual prognosis prediction and identifying HCC patients who may benefit from the combination therapy of TACE plus sorafenib.
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Affiliation(s)
- Lei Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Wei Xia
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Zhi-Ping Yan
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Institution of Medical Imaging, Shanghai, China
| | - Jun-Hui Sun
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bin-Yan Zhong
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhong-Heng Hou
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Min-Jie Yang
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Institution of Medical Imaging, Shanghai, China
| | - Guan-Hui Zhou
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wan-Sheng Wang
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xing-Yu Zhao
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Jun-Ming Jian
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Peng Huang
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Rui Zhang
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Shen Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jia-Yi Zhang
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Zhi Li
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiao-Li Zhu
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xin Gao
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Cai-Fang Ni
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
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13
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Kim JH, Yoon JH, Joo I, Lee JM. Evaluation of Primary Liver Cancers Using Hepatocyte-Specific Contrast-Enhanced MRI: Pitfalls and Potential Tips. J Magn Reson Imaging 2020; 53:655-675. [PMID: 32700807 DOI: 10.1002/jmri.27213] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 04/24/2020] [Accepted: 04/24/2020] [Indexed: 12/11/2022] Open
Abstract
When radiologists interpret hepatic focal lesions seen on dynamic magnetic resonance imaging (MRI) scans, it is important not only to distinguish malignant lesions from benign ones but also to distinguish nonhepatocellular carcinoma (HCC) malignancies from HCCs. In addition, most major guidelines, including those of the American Association for the Study of Liver Disease, European Association for the Study of the Liver, and Korean Liver Cancer Association and National Cancer Center, allow for the noninvasive imaging diagnosis of HCC in at-risk patients. However, ~40% of HCC cases show atypical imaging features mimicking non-HCC malignancies. Furthermore, several benign and malignant lesions, such as flash-filling hemangioma and intrahepatic mass-forming cholangiocarcinoma, frequently look like HCC. In contrast, although multiparametric MRI options, including hepatobiliary phase and diffusion-weighted imaging, provide useful information that could help address these challenges, there remain several unresolved issues with regard to the noninvasive diagnostic criteria characterizing HCC. In this article, we discuss the typical imaging features and challenging situations related to primary liver cancers in MRI, while considering how to make a correct diagnosis. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY STAGE: 3.
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Affiliation(s)
- Jae Hyun Kim
- Department of Radiology, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Radiology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong Hee Yoon
- Department of Radiology, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Radiology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ijin Joo
- Department of Radiology, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Radiology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong Min Lee
- Department of Radiology, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Radiology, Seoul National University College of Medicine, Seoul, Republic of Korea.,Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Republic of Korea
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14
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de Oliveira ARCP, Castanhole-Nunes MMU, Biselli-Chicote PM, Pavarino ÉC, da Silva RDCMA, da Silva RF, Goloni-Bertollo EM. Differential expression of angiogenesis-related miRNAs and VEGFA in cirrhosis and hepatocellular carcinoma. Arch Med Sci 2020; 16:1150-1157. [PMID: 32864004 PMCID: PMC7444729 DOI: 10.5114/aoms.2020.97967] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 01/24/2018] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Liver cirrhosis (LC) is a heterogeneous liver disease, the last stage of liver fibrosis, and the major risk factor for hepatocellular carcinoma (HCC). Our study aimed to evaluate the expression of microRNAs and the endothelial vascular growth factor (VEGFA) gene in LC and HCC. MATERIAL AND METHODS The sample group consisted of 46 tissue samples: 21 of LC, 15 of HCC, and 10 of non-tumoural and non-cirrhotic liver tissue (control group). MiRNAs were chosen based on a mirDIP prediction database as regulators of the VEGFA gene. Gene expression of VEGF and miRNAs was quantified by real-time quantitative polymerase chain reaction. VEGFA protein expression was evaluated by ELISA. RESULTS VEGFA gene expression was significantly overexpressed in LC compared to the control group (p < 0.0001). Hsa-miR-206 (p = 0.0313) and hsa-miR-637 (p = 0.0156) were down-expressed in LC. In HCC, hsa-miR-15b (p = 0.0010), hsa-miR-125b (p = 0.0010), hsa-miR-423-3p (p = 0.0010), hsa-miR-424 (p = 0.0313), hsa-miR-494 (p < 0.0001), hsa-miR-497 (p < 0.0001), hsa-miR-612 (p = 0.0078), hsa-miR-637 (p < 0.0001), and hsa-miR-1255b (p = 0.0156) presented down-expression. CONCLUSIONS Overexpression of VEGFA in LC suggests impairment of angiogenesis in this tissue. The differential expression of microRNAs in LC and HCC observed in our study can lead to the evaluation of possible biomarkers for these diseases.
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Affiliation(s)
- André R C P de Oliveira
- Departament of Molecular Biology, UPGEM - Genetics and Molecular Biology Research Unit, São José do Rio Preto Medical School - FAMERP, São José do Rio Preto, Brazil
- Study Group of Liver Tumors - GETF, Hospital de Base - São José do Rio Preto (SP) and Medical School Foundation - FUNFARME - São José do Rio Preto, Brazil
| | - Márcia M U Castanhole-Nunes
- Departament of Molecular Biology, UPGEM - Genetics and Molecular Biology Research Unit, São José do Rio Preto Medical School - FAMERP, São José do Rio Preto, Brazil
- Study Group of Liver Tumors - GETF, Hospital de Base - São José do Rio Preto (SP) and Medical School Foundation - FUNFARME - São José do Rio Preto, Brazil
| | - Patrícia M Biselli-Chicote
- Departament of Molecular Biology, UPGEM - Genetics and Molecular Biology Research Unit, São José do Rio Preto Medical School - FAMERP, São José do Rio Preto, Brazil
| | - Érika C Pavarino
- Departament of Molecular Biology, UPGEM - Genetics and Molecular Biology Research Unit, São José do Rio Preto Medical School - FAMERP, São José do Rio Preto, Brazil
| | - Rita de C M A da Silva
- Study Group of Liver Tumors - GETF, Hospital de Base - São José do Rio Preto (SP) and Medical School Foundation - FUNFARME - São José do Rio Preto, Brazil
| | - Renato F da Silva
- Study Group of Liver Tumors - GETF, Hospital de Base - São José do Rio Preto (SP) and Medical School Foundation - FUNFARME - São José do Rio Preto, Brazil
| | - Eny M Goloni-Bertollo
- Departament of Molecular Biology, UPGEM - Genetics and Molecular Biology Research Unit, São José do Rio Preto Medical School - FAMERP, São José do Rio Preto, Brazil
- Study Group of Liver Tumors - GETF, Hospital de Base - São José do Rio Preto (SP) and Medical School Foundation - FUNFARME - São José do Rio Preto, Brazil
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15
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Sadik NA, Ahmed NR, Mohamed MF, Ashoush OA. Serum Vascular Endothelial Growth Factor in Patients with Hepatocellular Carcinoma and its Validity as a Tumor Biomarker. ACTA ACUST UNITED AC 2019. [DOI: 10.2174/1875318301909010084] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Background:
Hepatocellular Carcinoma (HCC) is one of the most common cancers associated with deaths worldwide and the presence of valid biomarkers for early diagnosis in high-risk patients can ameliorate the outcome of HCC. Vascular Endothelial Growth Factor (VEGF) has been found to play an essential role in the process of HCC growth and progression.
Objectives:
Therefore, we evaluated the serum VEGF levels in patients with HCC and liver cirrhosis and estimated its significant value for differentiating HCC patients from liver cirrhosis patients.
Material and methods:
Eighty-one subjects were enrolled in the study, 30 patients had HCC, 31 patients had liver cirrhosis and 20 were healthy control subjects. VEGF and AFP were measured using ELIZA. Abdominal ultrasound and triphasic abdominal computed tomography were performed in all subjects. Receiver Operating Characteristics curve analysis was performed for serum VEGF to determine its validity as a tumor biomarker.
Results:
The median levels of the serum VEGF were highly expressed in the HCC group (418 pg/ml) and the liver cirrhosis group (308 pg/ml) with no significant difference (P = 0.767); however both groups showed a significant increase compared to the control group (0.8 pg/ml, P <0.000). Serum VEGF showed high sensitivity (100%) and high specificity (100%) in differentiating HCC patients from controls with a cut-off value of ≥ 64.2 pg/ml, although it showed low sensitivity (29.2%) and specificity (85.7%) for differentiating HCC patients from liver cirrhosis patients.
Conclusion:
VEGF can be used as a reliable biomarker for differentiating HCC patients from healthy subjects but it can't be used as a reliable biomarker for differentiating HCC patients from high-risk patients as liver cirrhosis. The elevated serum VEGF levels in HCC and liver cirrhosis patients can elucidate the crucial role of angiogenesis in HCC and liver cirrhosis.
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16
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Chang KH, Hwang ZA, Chang PY, Lin HH, Shih YL, Chang WC, Huang GS, Hsu HH. Predictive imaging for tumor response to drug-eluting microsphere transarterial chemoembolization in patients with BCLC-C advanced hepatocellular carcinoma. Sci Rep 2019; 9:20032. [PMID: 31882969 PMCID: PMC6934464 DOI: 10.1038/s41598-019-56545-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 12/13/2019] [Indexed: 01/01/2023] Open
Abstract
Drug-eluting microsphere transarterial chemoembolization (DEM-TACE) has been introduced to ensure more sustained and tumor-selective drug delivery for permanent embolization of HCC. The aim of this study was to determine the imaging characteristics that related to favourable treatment response in BCLC-C HCC patients treated with DEM-TACE. In total, 64 patients with BCLC-C HCC that treated with DEM-TACE using doxorubicin-eluted microspheres were retrospectively included. The images were assessed at baseline and at 4-12 weeks follow-up after receiving DEM-TACE. Pre- and post-procedural imaging characteristics were analysed by two independent radiologists and treatment response was evaluated using the modified Response Evaluation Criteria in Solid Tumors criteria. Multivariate analysis showed that vascular lake phenomenon (OR = 5.94, p = 0.03*), and homogeneous tumor enhancement (HTE) on cone-beam computed tomography (CBCT) during angiography (OR = 11.66, p < 0.001*) are associated with better radiological response. In contrast, residual tumor blush (OR = 0.11, p < 0.001*) is associated with worse radiological response. In conclusion, the initial tumor burden <50% (p = 0.012*) and HTE on CBCT (p = 0.040*) are good predictors for locoregional tumor control in patients with advanced HCCs, which can potentially improve patients' outcome.
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Affiliation(s)
- Kai-Hsiang Chang
- Department of Radiology, Tri-Service General Hospital, Taipei, Taiwan, Republic of China.,School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Zhen-An Hwang
- Department of Radiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, Republic of China
| | - Ping-Ying Chang
- School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan, Republic of China
| | - Hsuan-Hwai Lin
- School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan, Republic of China
| | - Yu-Lueng Shih
- School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan, Republic of China
| | - Wei-Chou Chang
- Department of Radiology, Tri-Service General Hospital, Taipei, Taiwan, Republic of China. .,School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China.
| | - Guo-Shu Huang
- Department of Radiology, Tri-Service General Hospital, Taipei, Taiwan, Republic of China.,School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Hsian-He Hsu
- Department of Radiology, Tri-Service General Hospital, Taipei, Taiwan, Republic of China.,School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
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17
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Zhang Y, Qu S, Yi W, Zhai J, Zhang X, Wei L, Lau WY, Wu M, Shen F, Fan H, Wu D. A Pretreatment CT Model Predicts Survival Following Chemolipiodolization in Patients With Hepatocellular Carcinoma. Technol Cancer Res Treat 2019; 18:1533033819844488. [PMID: 31204599 PMCID: PMC6582374 DOI: 10.1177/1533033819844488] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Purpose: To establish a computed tomography–based prognostic model for patients with hepatocellular carcinoma treated with transarterial chemoembolization. Materials and Methods: Using prospectively collected data from 195 consecutive patients with hepatocellular carcinoma who underwent chemolipiodolization at the Eastern Hepatobiliary Surgery Hospital between 2013 and 2016, we established a prognostic model based on hepatocellular carcinoma enhancement patterns on computed tomography scans to predict the outcome of transarterial chemoembolization. Furthermore, a histopathology analysis was performed on 108 different patients undergoing resection between 2014 and 2016 to identify whether there was a correlation between enhancement pattern and microvessel density. Results: The prognostic model classified hepatocellular carcinoma into 3 types: type I, which reached peak enhancement during the arterial phase and had a high mean microvessel density (101.5 vessels/0.74 mm2); type II, which reached peak enhancement during the portal venous or delayed phase and had an intermediate microvessel density (53.6 vessels/0.74 mm2); and type III, in which the tumor was insignificantly enhanced and had a low microvessel density (21.1 vessels/0.74 mm2). For type I, II, and III hepatocellular carcinoma, the post-transarterial chemoembolization 1-year tumor complete necrosis rates were 13.7%, 36.5%, and 0%, respectively (P < .001), and the 3-year overall survival rates were 14.1%, 38.6%, and 0%, respectively (P < .001). Conclusion: Our results indicate that hepatocellular carcinoma type is an independent predictor of complete necrosis and overall survival
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Affiliation(s)
- Yijun Zhang
- 1 Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,2 Department of Radiological Intervention treatment, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Shuping Qu
- 1 Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wanwan Yi
- 3 Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Jian Zhai
- 2 Department of Radiological Intervention treatment, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xiaobing Zhang
- 2 Department of Radiological Intervention treatment, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Lixin Wei
- 4 Tumor Immunology and Gene Therapy Center, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wan Yee Lau
- 1 Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,5 Faculty of Medicine, the Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Mengchao Wu
- 1 Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Feng Shen
- 1 Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Hengwei Fan
- 1 Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Dong Wu
- 1 Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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18
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Peng S, Ding H, Fu T, Wang B, Wang W, Zhou J. Savitzky-Golay filter based contrast-enhanced ultrasound quantification in hepatic tumors: Methodology and its correlation with tumor angiogenesis. Clin Hemorheol Microcirc 2019; 73:271-282. [PMID: 30103307 DOI: 10.3233/ch-180432] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Shiyun Peng
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai, China
- Present address: Department of Diagnostic Ultrasound, Second University Hospital of Sichuan University, Cheng Du, Sichuan, China
| | - Hong Ding
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tiantian Fu
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Medical Imaging, Shanghai, China
| | - Bengang Wang
- Shanghai Institute of Medical Imaging, Shanghai, China
| | - Wenping Wang
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jinzhu Zhou
- Medical Imaging College, Shanghai University of Medicine and Health Sciences, Shanghai, China
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19
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Roviello G, Sohbani N, Petrioli R, Rodriquenz MG. Ramucirumab as a second line therapy for advanced HCC: a significant achievement or a wasted opportunity for personalised therapy? Invest New Drugs 2019; 37:1274-1288. [PMID: 30879152 DOI: 10.1007/s10637-019-00760-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 03/08/2019] [Indexed: 02/08/2023]
Abstract
The second line treatment of hepatocellular carcinoma (HCC) has recently become an exciting area of interest since new emerging options have demonstrated survival benefits versus placebo. Unfortunately, predictive biomarkers are unavailable for these treatments. Ramucirumab, a monoclonal antibody against VEGFR-2, has demonstrated overall survival superiority against placebo as a second line therapy for patients with AFP > 400 ng/ml in the recent REACH-2 trial. This review will provide the current updated knowledge regarding the HCC cancerogenesis and angiogenic VEGF/VEGFR-2 pathways and the clinical development of ramucirumab in advanced HCC. This study will also critically assess the gaps in a previous negative phase III trial that tested other potentially useful treatments and suggest ways to modernise clinical trials and personalise therapy for advanced HCC.
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Affiliation(s)
- Giandomenico Roviello
- Department of Health Sciences, University of Florence, viale Pieraccini, 6, 50139, Florence, Italy.
| | - Navid Sohbani
- Department of Medical, Surgery and Health Sciences, University of Trieste, Piazza Ospitale 1, 34129, Trieste, Italy
| | - Roberto Petrioli
- Medical Oncology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Maria Grazia Rodriquenz
- Division of Medical Oncology, Department of Onco-Hematology, IRCCS-CROB, Referral Cancer Center of Basilicata, via Padre Pio 1, 85028, Rionero, Vulture, PZ, Italy
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20
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Wang J, Meng J, Ran W, Lee RJ, Teng L, Zhang P, Li Y. Hepatocellular Carcinoma Growth Retardation and PD-1 Blockade Therapy Potentiation with Synthetic High-density Lipoprotein. NANO LETTERS 2019; 19:5266-5276. [PMID: 31361965 DOI: 10.1021/acs.nanolett.9b01717] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The long progression-free survival (PFS) of patients with inoperable hepatocellular carcinoma (HCC) tumors is an unmet clinical need. Imaging-guided in situ ablation and vaccination with nanoplatforms could be a promising way to achieve durable disease control and long PFS. In the present work, we show that a biomimetic nanoplatform, namely, synthetic high-density lipoprotein (sHDL), can transport photothermal agent DiR and other drugs preferentially into the cytosol of HCC cells, enabling imaging-guided combination therapy for HCC in vivo. With a single injection, the sHDLs reduced the tumor burden, triggered immunogenic cell death (ICD), promoted dendritic cell (DC) maturation, and induced CD8+ T cell responses, which together sensitized the tumors to PD-1 blockade. Tumor remission and immune protection were achieved using sHDL loaded with DiR and a stimulator of interferon genes agonist vadimezan, in conjunction with a PD-1 blockade. The replacement of vadimezan with the chemotherapeutic mertansine potentiated ICD of HCC cells, but the drug interfered with DC maturation and subsequent CD8+ T cell priming, resulting in unsatisfactory disease control. Our work provides a generalizable nanoplatform for the combined photothermal ablation and immunotherapy of HCC and highlights the importance of cancer-cell-specific ICD induction and simultaneous DC activation during in situ vaccination.
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Affiliation(s)
- Junyang Wang
- State Key Laboratory of Drug Research & Center of Pharmaceutics , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China
- School of Life Sciences , Jilin University , Changchun 130012 , China
| | - Jia Meng
- State Key Laboratory of Drug Research & Center of Pharmaceutics , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China
- University of Chinese Academy of Sciences , Beijing 100049 , China
| | - Wei Ran
- State Key Laboratory of Drug Research & Center of Pharmaceutics , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China
- University of Chinese Academy of Sciences , Beijing 100049 , China
| | - Robert J Lee
- School of Life Sciences , Jilin University , Changchun 130012 , China
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy , The Ohio State University , Columbus , Ohio 43210 , United States
| | - Lesheng Teng
- School of Life Sciences , Jilin University , Changchun 130012 , China
| | - Pengcheng Zhang
- State Key Laboratory of Drug Research & Center of Pharmaceutics , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China
- University of Chinese Academy of Sciences , Beijing 100049 , China
| | - Yaping Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China
- University of Chinese Academy of Sciences , Beijing 100049 , China
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21
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Elsanousi OM, Mohamed MA, Salim FH, Adam EA. Selective devascularization treatment for large hepatocellular carcinoma: Stage 2A IDEAL prospective case series. Int J Surg 2019; 68:134-141. [PMID: 31265917 DOI: 10.1016/j.ijsu.2019.06.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Accepted: 06/25/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Rapid growth and invasiveness of hepatocellular carcinoma (HCC) largely depends on its vascularity and active angiogenic capacity. That feature was used to control the tumor in the past with some limitations. These deficiencies were addressed in our new procedure by hepatic artery ligation and extrahepatic collaterals division (HALED) of the liver lobe containing large HCC. This study tried to assess the feasibility, safety and the short term effects of HALED. MATERIALS AND METHODS This is a prospective stage 2a development IDEAL (Idea, Development, Exploration, Assessment and Long-term monitoring) case series. It included adult patients with large-sized HCC (diameter > 5 cm) subjected to HALED carried out in our center during five years' trial evaluating one-month postoperative outcomes. Patients will be reported prospectively in a sequential order with explanation of reasons for rejected cases and description of changes to technique or indication as the procedure evolved. This study registry number is NCT03129685 at the ClinicalTrials.gov. RESULTS The first HALED operation was carried out safely on 2013, followed by nineteen patients by 2018. Patients' mean age (±standard deviation) was 62·45 (±9·27), range 38-76 years. Eleven (55%) patients had tumors diameter > 10 cm 13 (65%) patients were advanced BCLC stage. Seven modifications were made on the technique and indications of the procedure towards stability. According to the modified response evaluation criteria in solid tumors, 13 patients (65%) attained complete response. Operative mortality was 5% (one patient) and major morbidity was 10% (two patients). Liver infarction and abscess formation were not noticed in this study. CONCLUSION Our forerunner study showed that HALED for large HCC is safe and induces tumor necrosis. Further long-term studies are suggested before starting the 2b stage.
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Affiliation(s)
- Osama M Elsanousi
- Department of Surgery, Ribat University Hospital, The National Ribat University, Sudan.
| | - Murtada A Mohamed
- Department of Interventional Radiology, Ribat University Hospital, Sudan.
| | - Fatima H Salim
- Department of Medicine, Ribat University Hospital, The National Ribat University, Sudan.
| | - Elsadig A Adam
- Department of Pathology, Ribat University Hospital, The National Ribat University, Sudan.
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Hidaka H, Izumi N, Aramaki T, Ikeda M, Inaba Y, Imanaka K, Okusaka T, Kanazawa S, Kaneko S, Kora S, Saito H, Furuse J, Matsui O, Yamashita T, Yokosuka O, Morita S, Arioka H, Kudo M, Arai Y. Subgroup analysis of efficacy and safety of orantinib in combination with TACE in Japanese HCC patients in a randomized phase III trial (ORIENTAL). Med Oncol 2019; 36:52. [DOI: 10.1007/s12032-019-1272-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 04/17/2019] [Indexed: 11/25/2022]
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Harding JJ, Khalil DN, Abou-Alfa GK. Biomarkers: What Role Do They Play (If Any) for Diagnosis, Prognosis and Tumor Response Prediction for Hepatocellular Carcinoma? Dig Dis Sci 2019; 64:918-927. [PMID: 30838478 DOI: 10.1007/s10620-019-05517-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common illness that affects patients worldwide. The disease remains poorly understood though several recent advances have increased the understanding of HCC biology and treatment. METHODS A literature review was conducted to understand the role of biomarkers in HCC clinical practice and highlight areas of critical investigation. RESULTS Candidate biomarkers may include differential alterations in HCC genomics, epigenomics, gene expression and transcriptomic profiles, protein expression, cellular composition of the microenvironment, and vasculature. To date no circulating or tumor diagnostic markers have been established in this disease. Likewise, prognostication is currently adjudicated by clinicopathologic features and it remains unclear if the incorporation of any biomarkers may help enhance the prognostic understanding following curative intents like surgery, transplant, and select regional therapy or palliative treatment including embolization or systemic therapy. Predictive biomarkers are investigational and are under evaluation for molecular pathways like TOR, MET, VEGFA, and FGF19. Tumoral genomics, HLA allele diversity and tumoral immune activation as predictive markers for immune checkpoint inhibitors are key focuses of ongoing research. CONCLUSIONS Diagnostic, prognostic, and predictive tumor and circulating biomarkers for HCC have not been defined though several markers have been proposed to guide patient care.
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Affiliation(s)
- James J Harding
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA. .,Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
| | - Danny N Khalil
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA.,Department of Medicine, Weill Cornell Medical College, New York, NY, USA.,Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Ghassan K Abou-Alfa
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA.,Department of Medicine, Weill Cornell Medical College, New York, NY, USA
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24
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Hui T, Chuah T, Low H, Tan C. Predicting early recurrence of hepatocellular carcinoma with texture analysis of preoperative MRI: a radiomics study. Clin Radiol 2018; 73:1056.e11-1056.e16. [PMID: 30213434 DOI: 10.1016/j.crad.2018.07.109] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Accepted: 07/30/2018] [Indexed: 12/11/2022]
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25
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915-MHz microwave-assisted laparoscopic hepatectomy: a new technique for liver resection. Surg Endosc 2018; 33:395-400. [PMID: 30374791 DOI: 10.1007/s00464-017-5945-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 10/17/2017] [Indexed: 01/23/2023]
Abstract
BACKGROUND Hemorrhage during the liver transection is the major hazard for laparoscopic hepatectomy (LH). We aimed to evaluate the feasibility and safety of a 915-MHz microwave device used in LH. METHODS Data were retrospectively analyzed regarding 60 patients who underwent LH with or without 915-MHz microwave coagulation at our center from January 2016 to June 2016. 30 patients underwent the 915-MHz microwave-assisted LH (MW group), and 30 patients otherwise were considered as control group. RESULTS No perioperative mortality was observed. Intraoperative blood loss amounts in microwave group and control group were 26.83 ml and 186.33 ml, respectively (P < 0.001). The durations of parenchyma transaction (55.17 vs. 70.83 min, P < 0.001), blood occlusion (2.17 vs. 25.33 min, P < 0.001), and operation (120.67 vs. 148.00 min, P < 0.001) were much shorter in microwave group compared with control group. Lower incidence of postoperative complications (0.0 vs. 14.3%, P = 0.038) and shorter length of postoperative hospital stay (6.00 vs. 7.23 days, P = 0.027) were also noted in the microwave group, compared with the control group. CONCLUSION 915-MHz microwave-assisted LH was found to be safe and efficient.
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26
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Yao F, Zhang L, Jiang G, Liu M, Liang G, Yuan Q. Osthole attenuates angiogenesis in an orthotopic mouse model of hepatocellular carcinoma via the downregulation of nuclear factor-κB and vascular endothelial growth factor. Oncol Lett 2018; 16:4471-4479. [PMID: 30214582 PMCID: PMC6126190 DOI: 10.3892/ol.2018.9213] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 06/27/2018] [Indexed: 12/21/2022] Open
Abstract
Osthole has been demonstrated to have antitumor activity. Previous studies by our group indicated that osthole effectively inhibited tumor growth in hepatocellular carcinoma (HCC) through the induction of apoptosis and enhancement of antitumor immune responses in mice. The importance of angiogenesis in the proliferation, invasion and metastasis of tumor cells in HCC is well established. The present study aimed to investigate the effects of osthole on angiogenesis in an orthotopic mouse model of HCC. Orthotopic HCC in mice was established, and osthole at 61, 122 and 244 mg/kg was administered intraperitoneally once daily to the tumor-bearing mice for 14 consecutive days. Immunohistochemistry was performed to analyze the microvessel density (MVD) of tissues, and the level of vascular endothelial growth factor (VEGF) was measured by ELISA. The protein levels of nuclear factor-κB (NF-κB) p65 and IκB-α were also detected by western blotting. MVD was positively correlated with tumor weight in the orthotopic mouse model of HCC. Osthole administration significantly decreased MVD in tumor and adjacent tissues, and inhibited tumor growth. Furthermore, osthole downregulated the expression of VEGF and NF-κB p65, and upregulated IκB-α expression in tumor and adjacent tissues. To the best of our knowledge, the results of the present study demonstrated for the first time that osthole inhibits angiogenesis in an orthotopic mouse model of HCC, which may be one of the mechanisms underlying the anti-HCC activity of osthole, which in turn may be mediated by the NF-κB/VEGF signaling pathway. Therefore, osthole, a potential angiogenesis inhibitor and immune system enhancer, may be a promising lead compound for the treatment of HCC.
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Affiliation(s)
- Fei Yao
- Laboratory of Clinical Pharmacy of Chinese Herb, Suzhou Hospital of Traditional Chinese Medicine, Suzhou, Jiangsu 215000, P.R. China
| | - Lurong Zhang
- Laboratory of Clinical Pharmacy of Chinese Herb, Suzhou Hospital of Traditional Chinese Medicine, Suzhou, Jiangsu 215000, P.R. China.,Laboratory of Clinical Pharmacy of Chinese Herb, Suzhou Academy of Wumen Chinese Medicine, Suzhou, Jiangsu 215003, P.R. China
| | - Guorong Jiang
- Laboratory of Clinical Pharmacy of Chinese Herb, Suzhou Hospital of Traditional Chinese Medicine, Suzhou, Jiangsu 215000, P.R. China.,Laboratory of Clinical Pharmacy of Chinese Herb, Suzhou Academy of Wumen Chinese Medicine, Suzhou, Jiangsu 215003, P.R. China
| | - Min Liu
- Laboratory of Clinical Pharmacy of Chinese Herb, Suzhou Hospital of Traditional Chinese Medicine, Suzhou, Jiangsu 215000, P.R. China
| | - Guoqiang Liang
- Laboratory of Clinical Pharmacy of Chinese Herb, Suzhou Hospital of Traditional Chinese Medicine, Suzhou, Jiangsu 215000, P.R. China
| | - Qin Yuan
- Laboratory of Clinical Pharmacy of Chinese Herb, Suzhou Hospital of Traditional Chinese Medicine, Suzhou, Jiangsu 215000, P.R. China
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Liver regeneration microenvironment of hepatocellular carcinoma for prevention and therapy. Oncotarget 2018; 8:1805-1813. [PMID: 27655683 PMCID: PMC5352100 DOI: 10.18632/oncotarget.12101] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 09/12/2016] [Indexed: 02/06/2023] Open
Abstract
Research on liver cancer prevention and treatment has mainly focused on the liver cancer cells themselves. Currently, liver cancers are no longer viewed as only collections of genetically altered cells but as aberrant organs with a plastic stroma, matrix, and vasculature. Improving the microenvironment of the liver to promote liver regeneration and repair by affecting immune function, inflammation and vasculature can regulate the dynamic imbalance between normal liver regeneration and repair and abnormal liver regeneration, thus improving the microenvironment of liver regeneration for the prevention and treatment of liver cancer. This review addresses the basic theory of the liver regeneration microenvironment, including the latest findings on immunity, inflammation and vasculature. Attention is given to the potential design of molecular targets in the microenvironment of hepatocellular carcinoma (HCC). In an effort to improve the liver regeneration microenvironment of HCC, researchers have extensively utilized the enhancement of immunity, anti-inflammation and the vasculature niche, which are discussed in detail in this review. In addition, the authors summarize the latest pro-fibrotic transition characteristics of the vascular niche and review potential cell therapies for liver disease.
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He C, Zhang Y, Lin X. Increased Overall Survival and Decreased Cancer-Specific Mortality in Patients with Hepatocellular Carcinoma Treated by Transarterial Chemoembolization and Human Adenovirus Type-5 Combination Therapy: a Competing Risk Analysis. J Gastrointest Surg 2018; 22:989-997. [PMID: 29435900 PMCID: PMC5978816 DOI: 10.1007/s11605-018-3703-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 01/25/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND In analyzing cancer patient survival data, the problem of competing risks is often ignored. This study used a competing risk approach to evaluate the efficacy of recombinant human type-5 adenovirus (H101) in patients with hepatocellular carcinoma (HCC) treated by transarterial chemoembolization (TACE). METHODS In this retrospective study, 476 patients were included. The cumulative probabilities of cancer-specific mortalities were analyzed by the Kaplan-Meier (KM) method and a competing risk model. Competing risk regression was used to assess the predictive factors for cumulative cancer-specific mortalities. RESULTS Two hundred thirty-eight HCC patients received combination TACE and H101 therapy, and another 238 HCC patients received TACE therapy alone. For patients in the TACE with H101 group, estimated 1-, 2-, and 3-year overall survival (OS) rates were 61.0, 40.0, and 31.5%, respectively, while for patients in the TACE group, the estimated 1-, 2-, and 3-year OS rates were 55.0, 33.4, and 22.3%, respectively. The 1-, 2-, and 3-year cancer-specific mortality rates for patients in the TACE with H101 group vs. the TACE group were 37.3 vs. 42.0%, 55.7 vs. 63.5%, and 61.9 vs. 74.7%, respectively. Multivariate competing risk analysis established that a combination of TACE and H101 therapy was an independent factor in decreasing cancer-specific mortality. CONCLUSIONS Compared with TACE therapy, patients who were diagnosed with unresectable HCC treated with combined TACE and H101 therapy had increased OS and decreased cancer-specific mortality. The survival benefit was more obvious in patients with elevated AFP, absence of metastasis, single tumor, enlarged tumor, and HBsAg-positivity.
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Affiliation(s)
- Chaobin He
- Department of Hepatobiliary and Pancreatic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Yu Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yet-sen University, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Xiaojun Lin
- Department of Hepatobiliary and Pancreatic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People's Republic of China.
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29
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Chebib I, Shabani-Rad MT, Chow MS, Zhang J, Gao ZH. Microvessel Density and Clinicopathologic Characteristics in Hepatocellular Carcinoma with and without Cirrhosis. Biomark Insights 2017. [DOI: 10.1177/117727190700200013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Angiogenesis is essential to the survival, growth, invasion, and metastasis of various human solid tumors. We compared the microvessel density (MVD) and clinicopathologic features of two different groups of hepatocellular carcinoma (HCC), namely HCC with cirrhosis (HCC-C) and without cirrhosis (HCC-NC). A tissue microarray composed of 20 normal livers, 20 cirrhotic livers, tumor and adjacent background non-neoplastic liver tissues from 20 HCC-C and 20 HCC-NC were constructed and stained immunohistochemically with antibodies against the antigen CD34. The MVD was determined by the measurement of the area and density of CD34 positive sinusoidal endothelial cells using the Image Pro Plus software. There was a trend of increased MVD in cirrhotic liver compared to normal liver and in cirrhotic background non-neoplastic liver adjacent to the tumor compared to the non-cirrhotic background non-neoplastic liver. Tumor tissue of HCC-C and HCC-NC both showed significantly higher MVD than their adjacent background non-neoplastic liver tissue. There was no statistical difference in MVD between HCC-C and HCC-NC. A higher value of MVD was seen in tumors of intermediate size (5–10 cm), high histologic grade, the presence of lymphvascular space invasion, and the underlying etiology of hepatitis C and alcoholic steatohepatitis. This data indicates that MVD may play an important role in liver carcinogenesis and neoplastic progression. The difference in clinical behavior between HCC-C and HCC-NC does not seem to be associated with differences in tumor MVD. Objective measurement of MVD using standardized computer software could potentially be used as a clinical marker to predict patients’ prognosis.
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Affiliation(s)
- Ivan Chebib
- Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, Alberta, Canada
| | - Meer Taher Shabani-Rad
- Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, Alberta, Canada
| | - Michelle S. Chow
- Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, Alberta, Canada
| | - James Zhang
- Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, Alberta, Canada
| | - Zu-hua Gao
- Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, Alberta, Canada
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30
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BRG1 promotes VEGF-A expression and angiogenesis in human colorectal cancer cells. Exp Cell Res 2017; 360:236-242. [DOI: 10.1016/j.yexcr.2017.09.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 08/30/2017] [Accepted: 09/08/2017] [Indexed: 11/18/2022]
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31
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Kudo M, Cheng AL, Park JW, Park JH, Liang PC, Hidaka H, Izumi N, Heo J, Lee YJ, Sheen IS, Chiu CF, Arioka H, Morita S, Arai Y. Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Lancet Gastroenterol Hepatol 2017; 3:37-46. [PMID: 28988687 DOI: 10.1016/s2468-1253(17)30290-x] [Citation(s) in RCA: 144] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 08/22/2017] [Accepted: 08/29/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Orantinib is an oral multi-kinase inhibitor. This study was done to evaluate the efficacy of orantinib combined with conventional transcatheter arterial chemoembolisation (cTACE) in patients with unresectable hepatocellular carcinoma. METHODS This randomised, double-blind, placebo-controlled, phase 3 study was done at 75 sites in Japan, South Korea, and Taiwan. Patients with unresectable hepatocellular carcinoma, no extra-hepatic tumour spread, and Child-Pugh score of 6 or less were randomly assigned (1:1) by interactive web response system using a computer-generated sequence to receive orantinib or placebo, within 28 days of cTACE. Randomisation was stratified by region, Child-Pugh score (5 vs 6), alpha fetoprotein concentrations (<400 ng/mL vs ≥400 ng/mL), and size of the largest lesion (≤50 mm vs >50 mm). Orantinib at 200 mg, twice per day, or placebo was given orally until TACE failure or unacceptable toxicity. The patients, investigators, and study personnel were masked to treatment assignment. The primary endpoint was overall survival, analysed in the full analysis set (patients who had received at least one dose of study drug). This study is registered at ClinicalTrials.gov, number NCT01465464, and has been terminated. FINDINGS Between Dec 10, 2010, and Nov 21, 2013, 889 patients were randomly assigned to receive either orantinib (445 patients; 444 treated) or placebo (444 patients; all treated). The study was ended at interim analysis for futility evaluation. Median follow-up was 17·3 months (IQR 11·3-26·4). There was no improvement in overall survival with orantinib compared with placebo (median 31·1 months [95% CI 26·5-34·5] vs 32·3 months [28·4-not reached]; hazard ratio 1·090, 95% CI 0·878-1·352; p=0·435). The main adverse events in the orantinib group were oedema, ascites, and elevation of aspartate and alanine aminotransferases. The most frequent adverse events of grade 3 or worse in the orantinib group included elevated aspartate aminotransferase (189 [43%] patients in the oratinib group, 161 [36%] patients in the placebo group), elevated alanine aminotransferase (150 [34%] patients in the oratinib group, 132 (30%) patients in the placebo group), and hypertension (47 [11%] patients in the oratinib group, 39 [9%] patients in the placebo group). Serious adverse events were reported in 200 (45%) patients in the orantinib group and 134 (30%) patients in the placebo group. INTERPRETATION Orantinib combined with cTACE did not improve overall survival in patients with unresectable hepatocellular carcinoma. FUNDING Taiho Pharmaceutical.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.
| | - Ann-Lii Cheng
- Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
| | - Joong-Won Park
- Center for Liver Cancer, National Cancer Center Korea, Gyeonggi-do, South Korea
| | - Jae Hyung Park
- Department of Radiology, Seoul National University Hospital, Seoul, South Korea; Department of Radiology, Myongji Hospital, Gyeonggi-do, South Korea
| | - Po-Chin Liang
- Division of Abdomen Radiology, National Taiwan University Hospital, Taipei City, Taiwan
| | - Hisashi Hidaka
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Kanagawa, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Jeong Heo
- Department of Internal Medicine, College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Busan, South Korea
| | - Youn Jae Lee
- Division of Gastroenterology, Inje University Busan Paik Hospital, Busan, South Korea
| | - I-Shyan Sheen
- Department of Hepato-gastroenterology, Chang Gung Memorial Hospital-Linkou, Taoyuan County, Taiwan
| | - Chang-Fang Chiu
- Division of Hematology/Oncology, China Medical University Hospital, Taichung City, Taiwan
| | - Hitoshi Arioka
- Department of Medical Oncology, Yokohama Rosai Hospital, Kanagawa, Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yasuaki Arai
- Department of Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan
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Park HJ, Kim JH, Choi SY, Lee ES, Park SJ, Byun JY, Choi BI. Prediction of Therapeutic Response of Hepatocellular Carcinoma to Transcatheter Arterial Chemoembolization Based on Pretherapeutic Dynamic CT and Textural Findings. AJR Am J Roentgenol 2017; 209:W211-W220. [PMID: 28813195 DOI: 10.2214/ajr.16.17398] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE The objective of our study was to assess the value of CT texture analysis for prediction of therapeutic response of hepatocellular carcinoma (HCC) to transcatheter arterial chemoembolization (TACE) with pretherapeutic dynamic CT. MATERIALS AND METHODS We retrospectively analyzed 132 HCCs in 96 patients treated with TACE who underwent dynamic CT before initial TACE. Imaging findings and arterial enhancement ratios were analyzed. All HCCs were manually segmented, and their texture features were quantitatively extracted using in-house software. CT texture was quantified with 2D and 3D analysis. HCCs were classified as with and without complete response (CR) according to modified Response Evaluation Criteria in Solid Tumors. Predictive factors for CR were assessed with multivariate analysis. Radiologic responses were correlated with time to progression (TTP). RESULTS Of the 132 HCCs, CR was achieved in 75 (56.8%). Tumor size, subjective arterial tumor attenuation, and arterial enhancement ratios were significantly associated with CR. On 2D and 3D analysis, tumors with CR showed significantly lower homogeneity and higher mean attenuation, gray-level co-occurrence matrix (GLCM) moments, and CT number percentiles (p < 0.05). On multivariate analysis, higher subjective tumor attenuation (adjusted odds ratio [OR] = 23.35), arterial enhancement ratio (OR = 14.07), GLCM moments (OR = 6.57), smaller tumor size (OR = 17.26), and lower homogeneity (OR = 0.69) were significant predictors of CR compared with incomplete response (p < 0.05). Median survival value for TTP was significantly longer in tumors with CR (p < 0.001). CONCLUSION Pretherapeutic dynamic CT texture analysis can be valuable to predict CR of HCC to TACE. Higher arterial enhancement and GLCM moments, lower homogeneity, and smaller tumor size are significant predictors of CR after TACE.
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Affiliation(s)
- Hyun Jeong Park
- 1 Department of Radiology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Jung Hoon Kim
- 2 Department of Radiology and Institute of Radiation Medicine, Seoul National University College of Medicine, 101 Daehang-no, Chongno-gu, Seoul 110-744, Republic of Korea
| | - Seo-Youn Choi
- 3 Department of Radiology, Soonchunhyang Bucheon University Hospital, Bucheon, Republic of Korea
| | - Eun Sun Lee
- 1 Department of Radiology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Sang Joon Park
- 4 Department of Radiology and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jae Young Byun
- 5 Department of Radiology, Seoul St. Mary's Hospital, Catholic University of Korea, Seoul, Republic of Korea
| | - Byung Ihn Choi
- 1 Department of Radiology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea
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Modulation of HIF-1α and STAT3 signaling contributes to anti-angiogenic effect of YC-1 in mice with liver fibrosis. Oncotarget 2017; 8:86206-86216. [PMID: 29156788 PMCID: PMC5689678 DOI: 10.18632/oncotarget.21039] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 08/16/2017] [Indexed: 12/25/2022] Open
Abstract
Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The aim of the study was to evaluate the mechanisms of HIF-1α inhibitor, YC-1, during bile duct ligation (BDL)-induced liver fibrosis in mice. Liver fibrosis was induced in mice, and YC-1 was then given intraperitoneally (50 mg/kg) once daily following 5 days. Liver injuries mice that were treated with YC-1 showed improved inflammatory response and diminished angiogenesis and hepatic fibrosis. YC-1 treatment inhibited liver neutrophil infiltration, while a decreased in TNF-α signaling as well as macrophage aggregation. In addition, YC-1 downregulates iNOS and COX-2 levels by inhibiting the activation of NF-κB and STAT3 phosphorylation by negative regulation the expression of SOCS1 and SOCS3 signaling. On the other hand, YC-1 decreased angiogenesis, as shown by the downregulation of hypoxia-inducible cascade genes, i.e. VEGF. YC-1 treatment resulted in a significant decrease in hepatic fibrogenesis, α-SMA abundance, and TGF-βR1 expression as well as hypoxia were assessed using VEGFR1, vWF and HIF-1α immunostaining. These results suggest that multi-targeted therapies directed against angiogenesis, hypoxia, and fibrosis. Therefore, it may be suggested that YC-1 treatment may be a novel therapeutic agent for the treatment of liver disease.
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Elsonbaty SM, Zahran WE, Moawed FS. Gamma-irradiated β-glucan modulates signaling molecular targets of hepatocellular carcinoma in rats. Tumour Biol 2017; 39:1010428317708703. [PMID: 28810822 DOI: 10.1177/1010428317708703] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
β-glucans are one of the most abundant forms of polysaccharides known as biological response modifiers which influence host's biological response and stimulate immune system. Accordingly, this study was initiated to evaluate irradiated β-glucan as a modulator for cellular signaling growth factors involved in the pathogenesis of hepatocellular carcinoma in rats. Hepatocellular carcinoma was induced with 20 mg diethylnitrosamine/kg BW. Rats received daily by gastric gavage 65 mg irradiated β-glucan/kg BW. It was found that treatment of rats with diethylnitrosamine induced hepatic injury and caused significant increase in liver injury markers with a concomitant significant increase in both hepatic oxidative and inflammatory indices: alpha-fetoprotein, interferon gamma, and interleukin 6 in comparison with normal and irradiated β-glucan-treated groups. Western immunoblotting showed a significant increase in the signaling growth factors: extracellular signal-regulated kinase 1 and phosphoinositide 3-kinase proteins in a diethylnitrosamine-treated group while both preventive and therapeutic irradiated β-glucan treatments recorded significant improvement versus diethylnitrosamine group via the modulation of growth factors that encounters hepatic toxicity. The transcript levels of vascular endothelial growth factor A and inducible nitric oxide synthase genes were significantly higher in the diethylnitrosamine-treated group in comparison with controls. Preventive and therapeutic treatments with irradiated β-glucan demonstrated that the transcript level of these genes was significantly decreased which demonstrates the protective effect of β-glucan. Histological investigations revealed that diethylnitrosamine treatment affects the hepatic architecture throughout the significant severe appearance of inflammatory cell infiltration in the portal area and congestion in the portal vein in association with severe degeneration and dysplasia in hepatocytes all over hepatic parenchyma. The severity of hepatic architecture changes was significantly decreased with both β-glucan therapeutic and preventive treatments. In conclusion, irradiated β-glucan modulated signal growth factors, vascular endothelial growth factor A, extracellular signal-regulated kinase 1, and phosphatidylinositol-3-kinase, which contributed to experimental hepatocarcinogenesis.
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Affiliation(s)
- Sawsan M Elsonbaty
- 1 National Center for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt
| | - Walid E Zahran
- 2 Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Fatma Sm Moawed
- 1 National Center for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt
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Della Corte CM, Viscardi G, Papaccio F, Esposito G, Martini G, Ciardiello D, Martinelli E, Ciardiello F, Morgillo F. Implication of the Hedgehog pathway in hepatocellular carcinoma. World J Gastroenterol 2017; 23:4330-4340. [PMID: 28706416 PMCID: PMC5487497 DOI: 10.3748/wjg.v23.i24.4330] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Revised: 04/13/2017] [Accepted: 05/19/2017] [Indexed: 02/06/2023] Open
Abstract
The prognosis for patients who are diagnosed with advanced stage hepatocellular carcinoma (HCC) is poor because there are few treatment options. Recent research has focused on the identification of novel molecular entities that can be targeted to inhibit oncogenic signals that are involved in the carcinogenesis, proliferation and progression of HCC. Among all of the pathways that are involved in the development of HCC, Hedgehog (HH) signalling has demonstrated a substantial role in hepatocarcinogenesis and HCC progression. HH plays a physiological role in embryogenesis, through the induction of the differentiation of hepatocytes from endodermal progenitors. The re-activation of the HH pathway in chronic damaged liver is a mechanism of fibrotic degeneration and is implicated in various stages of HCC development. HH activation sustains the sub-population of immature liver epithelial cells that are involved in the pathogenesis of cirrhosis and HCC, and HH itself is a mediator of the alcohol-derived malignant transformation of liver cells. High levels of expression of HH protein markers in liver tumour tissues are correlated with aggressive histological and biological features and a poor clinical outcome. In vitro and in vivo inhibition models of the HH pathway confirm that HH is essential in maintaining tumour growth, metastasis and a mesenchymal phenotype.
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Salum GM, Bader El Din NG, Ibrahim MK, Anany MA, Dawood RM, Khairy A, El Awady MK. Vascular Endothelial Growth Factor Expression in Hepatitis C Virus-Induced Liver Fibrosis: A Potential Biomarker. J Interferon Cytokine Res 2017; 37:310-316. [PMID: 28472595 DOI: 10.1089/jir.2016.0127] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The major complication of hepatitis C virus (HCV) infection is the induction of hepatic fibrosis. In this study, we investigated the correlation between the expression level of vascular endothelial growth factor (VEGFA) at mRNA and protein levels and the progression of HCV-related liver fibrosis. One hundred twenty subjects were selected for this study: 15 controls and 105 chronic HCV patients with different fibrosis grades (44 F0-F1 and 61 F2-F4). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure VEGFA mRNA in peripheral blood mononuclear cells, while enzyme-linked immunosorbent assay (ELISA) was used to measure the secreted VEGFA protein in serum. Both qRT-PCR and ELISA results showed that HCV patients have significantly higher VEGFA expression than that of controls (P = 0.036 and 0.043, respectively). Moreover, patients with late fibrotic stages (F2-F4) exhibited the highest levels of VEGFA mRNA and protein (P = 0.008 and 0.041, respectively) when compared with controls. An area under the receiver operating characteristic curve (AUC of the ROC) for the circulatory VEGFA protein between HCV patients with fibrosis and healthy controls was 0.92 (P = 0.043). Our data suggest that VEGFA protein is a promising noninvasively diagnostic biomarker for HCV-induced liver fibrosis.
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Affiliation(s)
- Ghada M Salum
- 1 Department of Microbial Biotechnology, Genetic Engineering Division, National Research Center, Giza, Egypt
| | - Noha G Bader El Din
- 1 Department of Microbial Biotechnology, Genetic Engineering Division, National Research Center, Giza, Egypt
| | - Marwa K Ibrahim
- 1 Department of Microbial Biotechnology, Genetic Engineering Division, National Research Center, Giza, Egypt
| | - Mohamed A Anany
- 1 Department of Microbial Biotechnology, Genetic Engineering Division, National Research Center, Giza, Egypt
| | - Reham M Dawood
- 1 Department of Microbial Biotechnology, Genetic Engineering Division, National Research Center, Giza, Egypt
| | - Ahmed Khairy
- 2 Department of Endemic Medicine, Faculty of Medicine, Cairo University , Cairo, Egypt
| | - Mostafa K El Awady
- 1 Department of Microbial Biotechnology, Genetic Engineering Division, National Research Center, Giza, Egypt
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El-Shal AS, Zidan HE, Rashad NM, Wadea FM. Angiopoietin-like protein 3 and 4 expression 4 and their serum levels in hepatocellular carcinoma. Cytokine 2017; 96:75-86. [PMID: 28371666 DOI: 10.1016/j.cyto.2017.03.006] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Revised: 03/09/2017] [Accepted: 03/11/2017] [Indexed: 01/30/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the 6th most common cancer and the 3rd leading cause of cancer causing death allover the world. The aim of this research to explore the clinical relevance of blood angiopoietin-like protein-3 (ANGPTL3) and ANGPTL4 expression and their proteins levels as non invasive biomarkers in cirrhotic and HCC patients and their influence on the clinicopathological features of HCC. MATERIAL AND METHODS This work comprised 200 patients with chronic hepatitis (120 cases complicated with cirrhosis, 80 patients with primary HCC) and 100 controls. circulating ANGPTL3 and ANGPTL4 expression was estimated by real-time polymerase chain reaction (RT-PCR). ANGPTL3 and ANGPTL4 protein levels were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS The circulating ANGPTL3 and ANGPTL 4 expression was significantly elevated in HCC cases compared to chronic hepatitis patients and controls. There were much more serum ANGPTL3 and ANGPTL4 values in HCC and chronic hepatitis patients as compared to controls, but we couldn't detect this significance between chronic hepatitis and HCC cases as regards ANGPTL4. By Multiple stepwise linear regression analysis, an increased ANGPTL3 expression, alpha-fetoprotein (AFP), serum ANGPTL 3 levels, Child-Pugh grade were significantly assosciatedassociated with increased risk of HCC. Logistic regression analysis revealed that ANGPTL 3 expression and AFP levels were the only pridectorspredictors of HCC (odd's ratio (OR)=8.9; 8.6 respectively, P=0.003). Receiver operator characteristic (ROC) demonsterated that serum ANGPTL3 and ANGPTL4 levels were usufuluseful biomarkers discriminating chronic hepatitis cases from controls (AUC=0.820,0.887, respectively P<0.001). However, they fail to discriminate HCC patients from chronic hepatitis patients (P=0.27,0.12 respectively). Moreover, ANGPTL3 and ANGPTL 4 expression were promising biomarkers discriminating chronic hepatitis cases from controls and those HCC cases from chronic hepatitis patients (P<0.001). Combined ANGPTL3 expression and serum level wasn't useful in discriminating HCC patient from chronic hepatitis (P=0.09). In contrast, combined ANGPTL4 expression and serum level was an useful biomarker discriminating HCC cases from chronic hepatitis. CONCLUSION ANGPTL3 and ANGPTL 4 expression and serum levels can be promising non invasive biomarkers in diagnosis of chronic hepatitis and HCC especially their expression could be useful in discriminating HCC from chronic hepatitis patients.
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Affiliation(s)
- Amal S El-Shal
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
| | - Haidy E Zidan
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Nearmeen M Rashad
- Internal Medicine Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Fady M Wadea
- Internal Medicine Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Chen D, Zhang F, Ren H, Luo J, Wang S. Role of cytokines and chemokines in alcohol-induced tumor promotion. Onco Targets Ther 2017; 10:1665-1671. [PMID: 28360527 PMCID: PMC5364014 DOI: 10.2147/ott.s129781] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Excessive chronic alcohol consumption has become a worldwide health problem. The oncogenic effect of chronic alcohol consumption is one of the leading concerns. The mechanisms of alcohol-induced tumorigenesis and tumor progression are largely unknown, although many factors have been implicated in the process. This review discusses the recent progress in this research area with concentration on alcohol-induced dysregulation of cytokines and chemokines. Based on the available evidence, we propose that alcohol promotes tumor progression by the dysregulation of the cytokine/chemokine system. In addition, we discuss specific transcription factors and signaling pathways that are involved in the action of these cytokines/chemokines and the oncogenic effect of alcohol. This review provides novel insight into the mechanisms of alcohol-induced tumor promotion.
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Affiliation(s)
- Danlei Chen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, People's Republic of China
| | - Fengyun Zhang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, People's Republic of China
| | - Haifeng Ren
- School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, People's Republic of China
| | - Jia Luo
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, College of Medicine, Lexington, KY, USA
| | - Siying Wang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, People's Republic of China
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PSG9 promotes angiogenesis by stimulating VEGFA production and is associated with poor prognosis in hepatocellular carcinoma. SCIENCE CHINA-LIFE SCIENCES 2017; 60:528-535. [PMID: 28078509 DOI: 10.1007/s11427-016-0226-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 11/04/2016] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is a common malignant solid tumor characterized by rich vascularization. Pregnancy-specific glycoprotein 9 (PSG9) is a member of the carcinoembryonic antigen (CEA)/PSG family and is produced at high levels during pregnancy. We previously identified PSG9 as an HCC-related protein. However, the expression of PSG9 and its regulation during HCC carcinogenesis remain poorly explored. In the present study, we first found that the levels of PSG9 protein were significantly increased in the plasma of HCC patients. PSG9 overexpression also increased the proliferation ability of an HCC cell line. High expression of PSG9 was associated with angiogenesis by accelerating VEGFA expression. In addition, Cox's proportional hazards model analysis revealed that the plasma level of PSG9 was an independent prognostic factor for overall survival. We propose that PSG9 is a novel indicator of prognosis in patients with HCC and could serve as a novel therapeutic target for HCC. Furthermore, our results indicate that PSG9 protein may facilitate the development of HCC by fostering angiogenesis via promoting VEGFA production in cancer cells.
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Morita K, Shirabe K, Taketomi A, Soejima Y, Yoshizumi T, Uchiyama H, Ikegami T, Yamashita YI, Sugimachi K, Harimoto N, Itoh S, Ikeda T, Maehara Y. Relevance of microRNA-18a and microRNA-199a-5p to hepatocellular carcinoma recurrence after living donor liver transplantation. Liver Transpl 2016; 22:665-76. [PMID: 26783726 DOI: 10.1002/lt.24400] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 11/20/2015] [Accepted: 12/09/2015] [Indexed: 02/07/2023]
Abstract
There are few reports about recurrence-related microRNAs (miRNAs) after liver transplantation (LT) for hepatocellular carcinoma (HCC). The purpose of this study was to identify novel recurrence-related miRNAs after living donor liver transplantation (LDLT) for HCC. First, we performed microarray analyses of samples from a liver with primary HCC, a liver that was noncancerous, and a liver that had recurrence-metastasis from 3 patients with posttransplant recurrence. Then we selected miRNAs with consistently altered expression in both primary HCC and recurrence as potential candidates of recurrence-related miRNAs. Expression of the miRNAs in HCC and noncancerous livers was assessed in 70 HCC patients who underwent LDLT. The target genes regulated by the recurrence-related miRNAs were identified. MicroRNA-18a (miR-18a) expression was increased, and microRNA-199a-5p (miR-199a-5p) expression was decreased in both primary HCC and recurrence. Increased miR-18a expression correlated with high levels of tumor markers, large tumor size, and a high recurrence rate. Decreased miR-199a-5p expression correlated with high levels of tumor markers, portal venous invasion, and a high recurrence rate. In HCC cells, miR-18a regulated the expression of tumor necrosis factor alpha-induced protein 3 (TNFAIP3), and miR-199a-5p regulated the expression of hypoxia-inducible factor 1 alpha (HIF1A), vascular endothelial growth factor A (VEGFA), insulin-like growth factor 1 receptor, and insulin-like growth factor 2. In conclusion, increased miR-18a levels and decreased miR-199a-5p levels are relevant to HCC recurrence after LDLT. MiR-18a and miR-199a-5p could be novel therapeutic targets of recurrent HCC after LDLT. Liver Transplantation 22 665-676 2016 AASLD.
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Affiliation(s)
- Kazutoyo Morita
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University Hospital, Fukuoka, Japan
| | - Ken Shirabe
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University Hospital, Fukuoka, Japan
| | - Akinobu Taketomi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University Hospital, Fukuoka, Japan
| | - Yuji Soejima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University Hospital, Fukuoka, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University Hospital, Fukuoka, Japan
| | - Hideaki Uchiyama
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University Hospital, Fukuoka, Japan
| | - Toru Ikegami
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University Hospital, Fukuoka, Japan
| | - Yo-Ichi Yamashita
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University Hospital, Fukuoka, Japan
| | - Keishi Sugimachi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University Hospital, Fukuoka, Japan
| | - Norifumi Harimoto
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University Hospital, Fukuoka, Japan
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University Hospital, Fukuoka, Japan
| | - Tetsuo Ikeda
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University Hospital, Fukuoka, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University Hospital, Fukuoka, Japan
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Microvessel density analysis in patients with viral hepatitis-related hepatocellular carcinoma. J Gastrointest Cancer 2016; 46:104-8. [PMID: 25645584 DOI: 10.1007/s12029-015-9684-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
AIM The aim of this study is to compare tumoral microvessel density (MVD) and overall survival in two different groups of hepatocellular carcinoma (HCC), namely, viral hepatitis-related HCC (VHr-HCC) versus non-hepatitis-related HCC (NHr-HCC). METHODS Seventy-eight consecutive cases of HCC (47 hepatitis and 31 non-hepatitis cases) were studied. Microvessel numbers were assessed by staining for the antigens CD31, CD34, and CD240. The highest number of microvessel density and number of vessels were counted in the tumor, and the mean value represented the final MVD. Overall survival (OS) was analyzed between the two groups. RESULTS VHr-HCC and NHr-HCC were observed in 47 and 31 cases, respectively. No significant differences were seen between the VHr-HCC and NHr-HCC groups with respect to age, gender, or Child-Pugh class distribution. Mean number of vessels was significantly higher in Hr-HCC using CD31 (97.7 vs 83.7) and CD34 (82.4 vs 71.9) (p value 0.025 and 0.039, respectively). Higher MVD was detected in Hr-HCC compared to NHr-HCC using CD31 (4.9 vs 4.4) and CD34 (4.7 vs 4.3) (p value 0.0095 and 0.0190, respectively). No significant difference was observed between VHr-HCC and NHr-HCC using CD240 immunostaining for MVD (p value 0.0945 and 0.906, respectively). Overall survival was not statistically significantly different between VHr-HCC and NHr-HCC groups (p value 0.104). CONCLUSIONS HCC due to viral hepatitis has higher tumor microvessel formation and higher MVD values. This observation may explain the higher response of agents that target vascular endothelial growth factor (such as sorafenib) in patients with VHr-HCC.
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Drug delivery system targeting advanced hepatocellular carcinoma: Current and future. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2016; 12:853-869. [PMID: 26772424 DOI: 10.1016/j.nano.2015.12.381] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Revised: 12/16/2015] [Accepted: 12/22/2015] [Indexed: 12/21/2022]
Abstract
UNLABELLED Hepatocellular carcinoma (HCC) has a fairly high morbidity and is notoriously difficult to treat due to long latent period before detection, multidrug resistance and severe drug-related adverse effects from chemotherapy. Targeted drug delivery systems (DDS) that can selectively deliver therapeutic drugs into tumor sites have demonstrated a great potential in cancer treatment, which could be utilized to resolve the limitations of conventional chemotherapy. Numerous preclinical studies of DDS have been published, but targeted DDS for HCC has yet to be made for practical clinical use. Since rational targeted DDS design should take cancer-specific properties into consideration, we have reviewed the biological and physicochemical properties of HCC extensively to provide a comprehensive understanding on HCC, and recent DDS studies on HCC, aiming to find some potential targeted DDSs for HCC treatment and a meaningful platform for further development of HCC treatments. FROM THE CLINICAL EDITOR Hepatocellular carcinoma has a high incidence worldwide and is known to be multidrug resistant. Thus, intensive research is being carried out to find better chemotherapeutic agents as well as new drug delivery systems. In this article, the authors reviewed in depth the current challenges facing new drug designs and also outlined novel targeted drug delivery systems (DDS) in the fight against HCC.
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Different expression of VEGF and EGFL7 in human hepatocellular carcinoma. Dig Liver Dis 2016; 48:76-80. [PMID: 26542361 DOI: 10.1016/j.dld.2015.09.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 09/18/2015] [Accepted: 09/30/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF) is one of several angiogenic factors expressed in cirrhosis and during progression to malignancy, that seem to play a major role in hepatocellular carcinoma development. Lately, another angiogenic factor, epidermal growth factor-like domain multiple 7 (EGFL7), has attracted interest due to its possible relationship with hepatocellular carcinoma metastasis. AIMS To evaluate expression of VEGF and EGFL7 in human hepatocellular carcinoma, compared to corresponding cirrhotic surrounding tissue. METHODS Tumoural and cirrhotic tissue was harvested from 12 consecutive patients undergoing surgical resection. VEGF and EGFL7 were assessed by immunofluorescence and quantitative reverse transcriptase-polymerase chain reaction, compared with normal controls. RESULTS Both angiogenic factors were over-expressed in cirrhotic livers compared to normal controls. VEGF and EGFL7 expressions did not differ according to disease aetiology, nodule size or other clinical variables. While VEGF expression was constant, regardless of tumour differentiation stage and unchanged compared to surrounding cirrhotic tissue, EGFL7 expression increased in less differentiated hepatocellular carcinoma. CONCLUSIONS The preferential expression of EGFL7 in less differentiated hepatocellular carcinoma compared to VEGF, suggests a possible important role of this angiogenic factor in a later oncogenic and infiltrative/metastatic phase.
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DCE-MRI of hepatocellular carcinoma: perfusion quantification with Tofts model versus shutter-speed model--initial experience. MAGNETIC RESONANCE MATERIALS IN PHYSICS BIOLOGY AND MEDICINE 2015; 29:49-58. [PMID: 26646522 DOI: 10.1007/s10334-015-0513-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 11/02/2015] [Accepted: 11/17/2015] [Indexed: 01/07/2023]
Abstract
OBJECTIVE To quantify hepatocellular carcinoma (HCC) perfusion and flow with the fast exchange regime-allowed Shutter-Speed model (SSM) compared to the Tofts model (TM). MATERIALS AND METHODS In this prospective study, 25 patients with HCC underwent DCE-MRI. ROIs were placed in liver parenchyma, portal vein, aorta and HCC lesions. Signal intensities were analyzed employing dual-input TM and SSM models. ART (arterial fraction), K (trans) (contrast agent transfer rate constant from plasma to extravascular extracellular space), ve (extravascular extracellular volume fraction), kep (contrast agent intravasation rate constant), and τi (mean intracellular water molecule lifetime) were compared between liver parenchyma and HCC, and ART, K (trans), v e and k ep were compared between models using Wilcoxon tests and limits of agreement. Test-retest reproducibility was assessed in 10 patients. RESULTS ART and v e obtained with TM; ART, ve, ke and τi obtained with SSM were significantly different between liver parenchyma and HCC (p < 0.04). Parameters showed variable reproducibility (CV range 14.7-66.5% for both models). Liver K (trans) and ve; HCC ve and kep were significantly different when estimated with the two models (p < 0.03). CONCLUSION Our results show differences when computed between the TM and the SSM. However, these differences are smaller than parameter reproducibilities and may be of limited clinical significance.
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Murakami K, Kasajima A, Kawagishi N, Ohuchi N, Sasano H. Microvessel density in hepatocellular carcinoma: Prognostic significance and review of the previous published work. Hepatol Res 2015; 45:1185-94. [PMID: 25594920 DOI: 10.1111/hepr.12487] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2014] [Revised: 12/13/2014] [Accepted: 01/11/2015] [Indexed: 12/13/2022]
Abstract
AIM Assessment of the microvessel density (MVD) may yield important information leading to an effective antiangiogenic treatment for hepatocellular carcinoma (HCC). METHODS The intratumoral MVD of 136 HCC patients was retrospectively evaluated using CD34. The correlation between the MVD and clinicopathological findings was assessed. In addition, the prognostic factors influencing the 2-year disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS The MVD of each tumor size group (<2, 2-5 and >5 cm) was 196 ± 51, 181 ± 63 and 147 ± 69. The MVD of each histological grade (well-, moderately and poorly differentiated) was 200 ± 56, 184 ± 61 and 114 ± 55. The optimum cut-off values of the MVD for the 2-year DFS and OS were 118.3 and 112.7, respectively. For the 2-year DFS, high tumor marker levels (α-fetoprotein >100 ng/mL and protein induced by vitamin K absence/antagonist-II >100 mAU/mL), poorly differentiated hepatocellular carcinoma (HCC), a high Ki-67 index (>20%), a large tumor size (>5 cm), vascular invasion, high tumor-node-metastasis (TNM) stage (III/IV) and a low MVD were the significant unfavorable prognostic factors. For the OS, a high Ki-67 index, a large tumor size, vascular invasion, high TNM stage and a low MVD were the significant risk factors for death. By the multivariate analysis, a low MVD was identified as an independent predictor of the 2-year DFS as well as the OS. CONCLUSION A low MVD can be used to predict an unfavorable prognosis in HCC patients.
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Affiliation(s)
| | | | - Naoki Kawagishi
- Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University School of Medicine, Sendai, Japan
| | - Noriaki Ohuchi
- Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University School of Medicine, Sendai, Japan
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Shen A, Liu S, Yu W, Deng H, Li Q. p53 gene therapy-based transarterial chemoembolization for unresectable hepatocellular carcinoma: A prospective cohort study. J Gastroenterol Hepatol 2015; 30:1651-6. [PMID: 25968838 DOI: 10.1111/jgh.13009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/20/2015] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND AIM Transarterial chemoembolization (TACE) is used for treating unresectable hepatocellular carcinoma (HCC), but its efficacy still needs to be improved. Recombinant adenovirus p53 (rAd-p53) injection is a gene therapeutic agent that could improve the prognosis of HCC patients. This study aimed to evaluate the efficacy and safety of rAd-p53-based TACE for treating unresectable HCC. METHODS Prospective analysis of patients who received rAd-p53-based TACE or TACE alone in Chongqing Cancer Institute from January 1, 2011 to December 31, 2012. The primary endpoint is overall survival. The secondary endpoints were progression-free survival, response rate, and safety. RESULTS One hundred two patients were enrolled in this study. Forty-nine patients received the rAd-p53-based TACE, and 53 patients received TACE alone. The rAd-p53-based TACE treatment strategy improved the overall survival (hazard ratio: 0.58, 95% confidence interval: 0.35-0.96, P = 0.035), progression-free survival (hazard ratio: 0.60, 95% confidence interval: 0.37-0.97, P = 0.037), response rate (P = 0.047) compared with TACE monotherapy. The rAd-p53-based TACE treatment group caused more occurrences of fever than with TACE alone (P = 0.01). However, symptomatic treatment may solve this problem. CONCLUSIONS rAd-p53-based TACE treatment strategy is effective and safe for treating unresectable HCC. Large-scale randomized clinical trials are needed to verify these results.
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Affiliation(s)
- Ai Shen
- Department of Hepatobiliary Surgery, Chongqing Cancer Institute, Chongqing, China
| | - Shihong Liu
- Department of Medical Oncology, Chongqing Cancer Institute, Chongqing, China
| | - Weiqian Yu
- Department of Medical Oncology, Chongqing Cancer Institute, Chongqing, China
| | - Hejun Deng
- Department of Hepatobiliary Surgery, Chongqing Cancer Institute, Chongqing, China
| | - Qingdong Li
- Department of Hepatobiliary Surgery, Chongqing Cancer Institute, Chongqing, China
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AGK enhances angiogenesis and inhibits apoptosis via activation of the NF-κB signaling pathway in hepatocellular carcinoma. Oncotarget 2015; 5:12057-69. [PMID: 25474138 PMCID: PMC4323001 DOI: 10.18632/oncotarget.2666] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2014] [Accepted: 10/28/2014] [Indexed: 01/14/2023] Open
Abstract
High levels of angiogenesis and resistance to apoptosis are major clinical features of hepatocellular carcinoma (HCC), a lethal disease with a high incidence worldwide. However, the precise mechanisms underlying these malignant properties remain unclear. Here, we demonstrated that acylglycerol kinase (AGK) is markedly overexpressed in HCC cell lines and clinical tissues. Immunohistochemical analysis of 245 clinical HCC specimens revealed patients with high levels of AGK expression had poorer overall survival compared to patients with low AGK expression. Furthermore, overexpressing AGK significantly enhanced angiogenesis and inhibited apoptosis in vitro and promoted the tumorigenicity of HCC cells in vivo; silencing endogenous AGK had the opposite effects. Importantly, AGK enhanced angiogenesis and inhibited apoptosis in HCC in part via activation of NF-κB signaling. Our findings provide new evidence that AGK plays an important role in promoting angiogenesis and providing resistance to apoptosis, thus AGK may represent a novel therapeutic target for HCC.
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Watanabe R, Munemasa T, Matsumura M. Contrast-enhanced ultrasound with perflubutane in the assessment of anti-angiogenic effects: early prediction of the anticancer activity of bevacizumab in a mouse xenografted model. ULTRASOUND IN MEDICINE & BIOLOGY 2015; 41:2497-2505. [PMID: 26022792 DOI: 10.1016/j.ultrasmedbio.2015.04.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Revised: 04/23/2015] [Accepted: 04/26/2015] [Indexed: 06/04/2023]
Abstract
To investigate the feasibility of contrast-enhanced ultrasound (CEUS) with perflubutane for evaluating anti-angiogenic effects, we assessed the contrast enhancement of mice xenograft treated with bevacizumab. SJSA-1 implanted mice were imaged before and 2, 6, 9 and 13 d after initiation of bevacizumab or saline treatment. Intra-tumoral perfusion areas were quantified by binarizing the ultrasound images and the micro-vessel density was observed by CD31 immunohistochemistry. As a result, the perfusion area and its ratio in the tumor were smaller in the bevacizumab group than the control group at 9 and 13 d, although tumor size was not significantly different. CD31-positive areas were smaller in the bevacizumab group than the control group and correlated well with the ratio of intra-tumoral perfusion areas. CEUS with perflubutane was found to have potential for early prediction of the anti-cancer activity of bevacizumab, and the perfusion area measured by binarized ultrasound images could be used as an indicator.
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Affiliation(s)
- Rira Watanabe
- Translational Medicine & Clinical Pharmacology Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
| | - Toshiko Munemasa
- Translational Medicine & Clinical Pharmacology Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan
| | - Manabu Matsumura
- Translational Medicine & Clinical Pharmacology Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan
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Zhuang PY, Wang JD, Tang ZH, Zhou XP, Yang Y, Quan ZW, Liu YB, Shen J. Peritumoral Neuropilin-1 and VEGF receptor-2 expression increases time to recurrence in hepatocellular carcinoma patients undergoing curative hepatectomy. Oncotarget 2015; 5:11121-32. [PMID: 25333267 PMCID: PMC4294350 DOI: 10.18632/oncotarget.2553] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 09/30/2014] [Indexed: 12/29/2022] Open
Abstract
PURPOSE To determined Neuropilin-1 (NRP-1) and vascular endothelial growth factor receptor 2 (VEGFR-2) expression in the tumoral and peritumoral tissues of 214 treatment-naïve HCC patients and its correlation with overall survival (OS) and time to recurrence (TTR). EXPERIMENTAL DESIGN NRP-1 and VEGFR-2 expression were examined by tissue microarray and peritumoral hypoxia by pimonidazole staining and angiogenesis by microvessel density (MVD). OS and TTR were evaluated by Kaplan-Meier analysis and log-rank test. RESULTS Peritumoral NRP-1 and VEGFR-2 expression were significantly higher than that of the tumoral tissue (p < 0.001 for both), and high peritumoral expression of both factors was negatively associated with tumor size (p < 0.001 for both). Patients with high peritumoral expression of both proteins had the longest median OS (>94.0 months) and TTR (>84.0 months). The multivariate Cox proportional hazards analysis revealed that patients with high peritumoral expression of both NRP-1 and VEGFR-2 were more than 4 times less likely to have recurrence (p = 0.004) and more than 10 times likely to survive (p < 0.001). CONCLUSIONS Peritumoral NRP-1 and VEGFR-2 expression is associated with prolonged TTR and extended OS of HCC patients and both may be useful as predictors of surgical outcome of HCC patients and explored as potential therapeutic targets.
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Affiliation(s)
- Peng-Yuan Zhuang
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200082, China
| | - Jian-Dong Wang
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200082, China
| | - Zhao-Hui Tang
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200082, China
| | - Xue-Ping Zhou
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200082, China
| | - Yong Yang
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200082, China
| | - Zhi-Wei Quan
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200082, China
| | - Ying-Bin Liu
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200082, China
| | - Jun Shen
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200082, China
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50
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Jeng KS, Chang CF, Jeng WJ, Sheen IS, Jeng CJ. Heterogeneity of hepatocellular carcinoma contributes to cancer progression. Crit Rev Oncol Hematol 2015; 94:337-47. [PMID: 25680939 DOI: 10.1016/j.critrevonc.2015.01.009] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Revised: 10/24/2014] [Accepted: 01/21/2015] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous disease displaying differences in angiogenesis, extracellular matrix proteins, the immune microenvironment and tumor cell populations. Additionally, genetic variations and epigenetic changes of HCC cells could lead to aberrant signaling pathways, induce cancer stem cells and enhance tumor progression. Thus, the heterogeneity in HCC contributes to disease progression and a better understanding of its heterogeneity will greatly aid in the development of strategies for the HCC treatment.
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Affiliation(s)
- Kuo-Shyang Jeng
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
| | - Chiung-Fang Chang
- Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Wen-Juei Jeng
- Department of Hepato-Gastroenterology, Chang-Gung Memorial Hospital, LinKou Medical Center, Chang Gung University, Taiwan
| | - I-Shyan Sheen
- Department of Hepato-Gastroenterology, Chang-Gung Memorial Hospital, LinKou Medical Center, Chang Gung University, Taiwan
| | - Chi-Juei Jeng
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
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